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Progress Report

April 2015 – March 2016

www.bmtctn.net

Center for International Blood and Marrow Transplant Research 9200 W. Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226 USA Phone: (414) 805-0700 Fax: (414) 805-0714

The Emmes Corporation 401 N. Washington Street, Suite 700, Rockville, MD 20850 USA Phone: (301) 251-1161 Fax: (301) 251-1355

National Marrow Donor Program/Be The Match 500 N. 5th Street, Minneapolis, MN 55401 USA Phone: (763) 406-5800 Fax: (763) 406-4370

This is a publication of the Blood and Marrow Transplant Clinical Trials Network Data and Coordinating Center © 2016 All Rights Reserved

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Table of Contents

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Table of Contents

1.0 Value the BMT CTN Brings to the HCT Community ................................................................................................. 1 1.1 Areas of Study ................................................................................................................................................................... 2 1.2 Accrual Success ................................................................................................................................................................. 2 1.3 Dissemination of Results ................................................................................................................................................. 4

1.3.1 Publications ................................................................................................................................................................ 4 1.3.2 Presentations .............................................................................................................................................................. 5

1.4 Significant Findings and Impact .................................................................................................................................... 5 1.5 Biorepository and Clinical Trial Data Resources ...................................................................................................... 18 1.6 Network Efficiency ......................................................................................................................................................... 18 1.7 Funding Leverage ........................................................................................................................................................... 19 1.8 Key Collaborations ......................................................................................................................................................... 20

2.0 Organizational Overview ................................................................................................................................................. 21 2.1 Data and Coordinating Center ..................................................................................................................................... 21 2.2 Clinical Centers ............................................................................................................................................................... 22

2.2.1 Core Centers ............................................................................................................................................................. 22 2.2.2 Affiliate Centers ....................................................................................................................................................... 25

2.3 Committee Structure ...................................................................................................................................................... 27 2.3.1 Steering Committee ................................................................................................................................................. 27 2.3.2 Protocol Teams ......................................................................................................................................................... 28 2.3.3 Technical Committees ............................................................................................................................................. 28 2.3.4 Administrative Committees .................................................................................................................................. 31 2.3.5 Ad Hoc Committees ................................................................................................................................................ 31 2.3.6 Review Committees ................................................................................................................................................ 32

3.0 Administrative Functions of the DCC ........................................................................................................................... 33 3.1 DCC Partner Organizations .......................................................................................................................................... 33 3.2 Policies and Procedures ................................................................................................................................................. 38 3.3 Administrative Support ................................................................................................................................................. 38 3.4 Fiscal Planning and Contracting Support .................................................................................................................. 38

3.4.1 Cost-Saving Mechanisms ....................................................................................................................................... 39 3.5 Communication ............................................................................................................................................................... 39

3.5.1 Maintaining BMT CTN Websites ......................................................................................................................... 39 3.5.2 Developing Patient Support and Marketing Materials .................................................................................... 40 3.5.3 Communicating Trial Results ................................................................................................................................ 41 3.5.4 Social Media Engagement ...................................................................................................................................... 41

3.6 Training… ........................................................................................................................................................................ 43 3.7 Transplant Center Monitoring ...................................................................................................................................... 43 3.8 Specimen Repository Support ...................................................................................................................................... 44

3.8.1 Specimen Collection ................................................................................................................................................ 44


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3.8.2 Research Sample Repository and Central Processing Lab ............................................................................... 47 3.8.3 Maximizing Sample Collection, Quality, and Availability .............................................................................. 48

4.0 Concept to Publication: The Protocol Process.............................................................................................................. 50 4.1 Concept Evaluation and Approval .............................................................................................................................. 50

4.1.1 DCC Review ............................................................................................................................................................. 50 4.1.2 Executive Committee Review ............................................................................................................................... 51 4.1.3 Steering Committee Review .................................................................................................................................. 51

4.2 Protocol Development ................................................................................................................................................... 51 4.2.1 Establishment of a Protocol Team ........................................................................................................................ 51 4.2.2 Statistical Design ...................................................................................................................................................... 51 4.2.3 Accrual Planning ..................................................................................................................................................... 52 4.2.4 Budget Preparation ................................................................................................................................................. 53 4.2.5 Federal Regulations ................................................................................................................................................. 54 4.2.6 Final Draft Protocol ................................................................................................................................................. 54

4.3 Protocol Approval........................................................................................................................................................... 54 4.3.1 Steering Committee Review .................................................................................................................................. 54 4.3.2 Protocol Review Committee .................................................................................................................................. 55 4.3.3 Data and Safety Monitoring Board Review ........................................................................................................ 55 4.3.4 Final Review Prior to Release to Centers ............................................................................................................ 56

4.4 Protocol Pre-Activation .................................................................................................................................................. 56 4.4.1 Designing Case Report Forms ............................................................................................................................... 56 4.4.2 Educational Materials and Other Study Documents ........................................................................................ 56 4.4.3 Release to Center IRBs ............................................................................................................................................ 57 4.4.4 Site Initiation Training ............................................................................................................................................ 57 4.4.5 Medical Monitor Assignment ............................................................................................................................... 58

4.5 Protocol Activation ......................................................................................................................................................... 58 4.6 Protocol Maintenance ..................................................................................................................................................... 58

4.6.1 Accrual Monitoring and Intervention.................................................................................................................. 58 4.6.2 High-Quality Clinical and Laboratory Data Collection ................................................................................... 61 4.6.3 Data Audits ............................................................................................................................................................... 62 4.6.4 Amendments ............................................................................................................................................................ 63

4.7 Study Completion ........................................................................................................................................................... 63 4.7.1 Notice to Cease Enrollment ................................................................................................................................... 63 4.7.2 Follow-up Data Collection after Closure............................................................................................................. 63 4.7.3 Data Review and Analysis ..................................................................................................................................... 63

4.8 Dissemination of Results ............................................................................................................................................... 64 4.8.1 Authorship ................................................................................................................................................................ 64

4.9 Ancillary and Correlative Studies ................................................................................................................................ 64

5.0 Collaborations with other NIH-funded Research Networks ................................................................................... 75


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6.0 Future Directions ................................................................................................................................................................ 76 6.1 Continued Planning for the Current Grant Cycle ..................................................................................................... 76 6.2 State of the Science Symposia ....................................................................................................................................... 76

6.2.1 2007 State of the Science Symposium .................................................................................................................. 76 6.2.2 2014 State of the Science Symposium .................................................................................................................. 78

6.3 Projected Study Activities during the Next Reporting Period ............................................................................... 81 6.3.1 Anticipated Results ................................................................................................................................................. 81 6.3.2 Studies Nearing Completion of Accrual ............................................................................................................. 82 6.3.3 Studies Activated ..................................................................................................................................................... 82 6.3.4 Studies to be Activated ........................................................................................................................................... 83 6.3.5 Future Study Concepts ........................................................................................................................................... 84

6.4 Conclusions ...................................................................................................................................................................... 84

7.0 Protocol Descriptions......................................................................................................................................................... 87 7.1 Protocols Open to Accrual ............................................................................................................................................. 87

BMT CTN 07LT ................................................................................................................................................................. 88 BMT CTN 1101 .................................................................................................................................................................. 90 BMT CTN 1102 .................................................................................................................................................................. 92 BMT CTN 1202 .................................................................................................................................................................. 94 BMT CTN 1203 .................................................................................................................................................................. 96 BMT CTN 1205 .................................................................................................................................................................. 98 BMT CTN 1301 ................................................................................................................................................................ 100 BMT CTN 1302 ................................................................................................................................................................ 102 BMT CTN 1304 / DFCI 10-106 / IFM/DFCI 2009 (The DETERMINATION Study) ............................................ 104 BMT CTN 1505 ................................................................................................................................................................ 106

7.2 Protocols that Completed Accrual during this Reporting Period ........................................................................ 107 BMT CTN 0903 ................................................................................................................................................................ 108 BMT CTN 1204 ................................................................................................................................................................ 110

7.3 Protocols that Completed Accrual during a Previous Reporting Period ........................................................... 113 BMT CTN 0101 ................................................................................................................................................................ 115 BMT CTN 0102 ................................................................................................................................................................ 116 BMT CTN 0201 ................................................................................................................................................................ 118 BMT CTN 0202 ................................................................................................................................................................ 120 BMT CTN 0301 ................................................................................................................................................................ 121 BMT CTN 0302 ................................................................................................................................................................ 123 BMT CTN 0303 ................................................................................................................................................................ 125 BMT CTN 0401 ................................................................................................................................................................ 127 BMT CTN 0402 ................................................................................................................................................................ 128 BMT CTN 0403 ................................................................................................................................................................ 130 BMT CTN 0501 ................................................................................................................................................................ 131 BMT CTN 0502 / CALGB 100103 ................................................................................................................................. 132


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BMT CTN 0601 ................................................................................................................................................................ 133 BMT CTN 0603 / 0604 .................................................................................................................................................... 135 BMT CTN 0701 ................................................................................................................................................................ 136 BMT CTN 0702 ................................................................................................................................................................ 137 BMT CTN 0703 / SWOG 0410 ....................................................................................................................................... 138 BMT CTN 0704 / CALGB 100104 / ECOG 100104 ..................................................................................................... 139 BMT CTN 0801 ................................................................................................................................................................ 141 BMT CTN 0802 ................................................................................................................................................................ 142 BMT CTN 0803 ................................................................................................................................................................ 144 BMT CTN 0804 / CALGB 100701 ................................................................................................................................. 145 BMT CTN 0805 / SWOG 0805 ....................................................................................................................................... 146 BMT CTN 0901 ................................................................................................................................................................ 147 BMT CTN 0902 ................................................................................................................................................................ 148

7.4 Protocols Released to Centers ..................................................................................................................................... 151 BMT CTN 1401 ................................................................................................................................................................ 152

Attachment A: Committee Rosters ..................................................................................................................................... 155 Attachment A1: Steering Committee Roster .................................................................................................................. 155 Attachment A2: Biomarkers Committee Roster ............................................................................................................ 157 Attachment A3: Clinical Research Associates Committee Roster .............................................................................. 158 Attachment A4: Pharmacy Committee Roster............................................................................................................... 159 Attachment A5: Special Populations (Pediatrics / Human Subjects) Committee Roster ....................................... 160 Attachment A6: Toxicity and Supportive Care Committee Roster............................................................................ 161 Attachment A7: Publications, Abstracts, and Presentations Committee Roster ..................................................... 162

Attachment B: Publications, Abstracts, and Presentations ........................................................................................... 163 Attachment B1: Publications by Year .............................................................................................................................. 163 Attachment B2: Presentations by Year ............................................................................................................................ 174

Attachment C: Center Performance Report ...................................................................................................................... 185 Attachment C1: Center Performance Report Template ............................................................................................... 185 Attachment C2: Center Performance Report Rating Metric ........................................................................................ 191

Attachment D: Terms and Abbreviations ......................................................................................................................... 193

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 1.0 Value the BMT CTN Brings to the HCT Community

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1.0 Value the BMT CTN Brings to the HCT Community

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN or the “Network”) was established in October 2001 to conduct large, multi-institutional clinical trials to improve the outcomes of hematopoietic cell transplantation (HCT) for patients facing life-threatening disorders. The BMT CTN allows the HCT community to conduct prospective, collaborative, clinical research within an infrastructure expressly designed to:

• Facilitate effective communication and cooperation among transplant centers and collaborators at the National Institutes of Health (NIH), particularly the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI);

• Implement and complete well-designed, multicenter trials of high scientific merit; • Offer participation in HCT clinical trials to patients in all regions of the United States (US).

About 21,000 HCTs are performed in the US annually, and the number increases by approximately 2% per year. This increase reflects the utility of HCT in treating both malignant and non-malignant diseases, higher donor availability, and treatment advances that allow HCT to be performed in older and sicker patients. While HCT is a rapidly evolving field, HCT clinical trials face unique challenges, including the relatively small number of transplantations performed at any single center, the diverse indications for HCT, the complexities of the procedure, and multiple competing risks in the post-transplant period. The BMT CTN was established to address these challenges and execute multicenter HCT trials with broad national participation. The Network:

• Effectively fosters development of innovative and important concepts into well-designed trials that answer questions in the most efficient manner;

• Supports timely implementation and completion of those trials; • Ensures protection of subjects (both donors and recipients); • Provides high-quality data and adherence to regulatory requirements in an increasingly complex

environment; • Promotes timely publication of study results, which advances the field of HCT and impacts patient care.

The BMT CTN and its network of Core and Affiliate Centers (Section 2.2) play a critical role in improving patient outcomes and advancing the science of HCT. The BMT CTN’s many scientific achievements include:

• Launching 39 trials, including one this reporting period; • Completing accrual to 28 trials, including 2 this reporting period; • Accruing almost 8,900 patients to its trials from more than 100 centers, including almost 1,000 patients

this reporting period; • Achieving an overall accrual rate that is 129% of projections among trials that are currently open for

enrollment; • Establishing a Research Sample Repository that currently includes more than 366,475 biospecimens; • Engaging in 38 ancillary and correlative studies; 25 of these studies used cryopreserved biospecimens

from the BMT CTN Research Sample Repository or samples shipped directly to a project laboratory, and 4 were completed and published this reporting period;

• Publishing 58 manuscripts, including 8 this reporting period; • Presenting 65 abstracts, including 15 this reporting period.


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This Progress Report highlights the following: 1. Accomplishments of the BMT CTN, including a detailed report of the Network’s progress for the period

of April 1, 2015, through March 31, 2016, (highlights bolded throughout the report) as well as plans for the upcoming year;

2. Organizational structure of the Network; 3. Structure, responsibilities, and focus of the Network’s Data and Coordinating Center (DCC); 4. Network collaborations; 5. Protocol selection, development, and management processes; 6. Past, current, and future protocol status updates.

1.1 Areas of Study

The BMT CTN studies diverse transplant and cellular therapy treatment options, including both allogeneic and autologous transplantation, with a focus on more complex allografting issues. During this reporting period, 100% of the transplants performed on BMT CTN studies were allogeneic. Comparatively, 54% of the US transplants reported to the CIBMTR® (Center for International Blood and Marrow Transplant Research®) were allogeneic transplants. The BMT CTN has answered relevant research questions in both common and rare diseases. Its research portfolio includes studies in leukemia, myelodysplasia, lymphoma, and multiple myeloma as well as rare transplant indications, such as aplastic anemia, sickle cell disease, human immunodeficiency virus (HIV)-associated cancers, and hemophagocytic syndromes / primary immune deficiencies. Issues addressed and being addressed include:

• Comparison of HCT to non-transplant standard therapies for myelodysplastic syndromes (MDS) and sickle cell disease;

• Optimal timing of HCT; • Pre-transplant conditioning regimens; • Graft source [autologous, human leukocyte antigen (HLA)-identical and haploidentical related donors,

unrelated donors, and umbilical cord blood]; • Anticancer vaccine therapy; • Acute and chronic graft-versus-host disease (GVHD); • Graft manipulation to decrease GVHD; • Maintenance therapy; • Post-transplant infection; • Post-transplant organ toxicity; • Disease control; • Biomarkers for transplant complications; • Outcomes of transplant in patient populations of all ages, including children and older adults; • Quality of life; • Better ways of obtaining consent.

1.2 Accrual Success

During this reporting period, BMT CTN trials accrued more than 1,000 patients, bringing the Network total to almost 8,900. Among the eight Network-led protocols currently open, the overall accrual rate is at 129% of target projections. Figure 1.1 displays a graph of BMT CTN total annual accrual by progress report time frame (April 1 – March 31).


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Figure 1.1. BMT CTN annual and cumulative accrual


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To fully leverage accrual efforts, several BMT CTN studies are designed for co-enrollment, including studies on quality of life (0902), consent form evaluation (1205), and a biomarker repository protocol (1202). Approximately 400 patients co-enrolled on more than one Network study. The BMT CTN also leverages the outcomes registry of the CIBMTR, which is funded by the NHLBI, NCI, National Institute of Allergy and Infectious Diseases (NIAID), and Health Services and Research Administration. This registry captures data on almost all transplants performed in the US, and the Network utilizes it to design studies to maximize accrual, recruit centers likely to accrue to specific protocols, and monitor accrual so that issues can be addressed early in the course of protocols. Accrual to BMT CTN studies closely mirrors the CIBMTR database in gender and racial composition. Males are over-represented because several of the common indications for transplantation (e.g. multiple myeloma, acute lymphoblastic leukemia, etc.) are either more common in males or have a worse prognosis with standard chemotherapy in males, leading to increased use of transplantation. During the current reporting period, the BMT CTN continued several initiatives to increase participation of underrepresented populations in BMT CTN trials (Section 4.6.1.1). Eleven centers in the Network are participating in the RECRUIT trial, a national study exploring the effectiveness of novel recruitment approaches to increase minority participation on clinical trials. Also, to increase the number of research specimens from both children and minorities, the biomarkers repository protocol, 1202, was kept open to pediatric and minority enrollment after rapidly meeting its original overall accrual goal. The aim was to accrue specimens from at least 200 African American and 200 pediatric patients. The pediatric cohort accrual target was met, and accrual was closed; the African American target is anticipated to be met in April 2016.

1.3 Dissemination of Results

1.3.1 Publications

BMT CTN investigators have published 58 manuscripts, including 16 primary study results papers, from 20 trials and the DCC / Network in the peer-reviewed journals listed below. Eight manuscripts were published during this reporting period in the journals listed in bold below. Two of these manuscripts were primary results papers. An additional six manuscripts were submitted for publication, including two primary results manuscripts.

• American Journal of Health-System Pharmacy; • Biology of Blood and Marrow Transplantation; • Blood; • Cancer; • Clinical Infectious Diseases; • Clinical Trials; • Current Malignancy Hematology Reports; • Journal of Antimicrobial Chemotherapy; • Journal of Clinical Oncology; • Journal of Comparative Effectiveness Research; • Journal of Immunology; • Journal of the National Cancer Institute; • Journal of the Society for Clinical Trials; • Lancet Haematology; • Lancet Oncology; • Molecular Therapy; • New England Journal of Medicine;


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• Statistics in Medicine. All trials with primary results available for publication were published or submitted with the exception of 0601, 0801, and 0901, for which data only became available during the current reporting period. Manuscripts for all three studies are drafted and will be submitted early in the next reporting period. A full list of the Network’s publications is provided in Appendix B1.

1.3.2 Presentations

BMT CTN investigators have presented 65 abstracts from 25 trials and the DCC / Network at the national and international meetings listed below. Fifteen abstracts were presented during this reporting period at the meetings listed in bold below. A full list of the Network’s presentations is provided in Appendix B2.

• American Society of Clinical Oncology (ASCO); • American Society of Hematology (ASH), including the 2011 Plenary Session; • BMT Tandem Meetings; • European Group for Blood and Marrow Transplantation (EBMT); • European Hematology Association; • International Myeloma Workshop; • International Society for Cellular Therapy; • Interscience Conference on Antimicrobial Agents and Chemotherapy; • Institute for Healthcare Advancement’s Annual Health Literacy Conference; • IPOS/APOS World Congress on Psycho-Oncology; • NCI-ASCO Cancer Trial Accrual Symposium; • Public Responsibility in Medicine and Research; • Society for Clinical Trials.

1.4 Significant Findings and Impact

The research findings of the BMT CTN provide information with effects on clinical practice. To date, BMT CTN trials have provided important insights into several areas of HCT (Table 1.1). Full citations for the publications listed in the table, as well as all others from the BMT CTN, are provided in Appendix B1.


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Table 1.1. Significant findings and impact of BMT CTN studies

Significant Findings and Impact of BMT CTN Studies

BMT CTN Study Results Relevant Publications Impact / Future Outlook

CONDITIONING REGIMENS / INTENSITY

0401: Phase III Rituxan / BEAM versus Bexxar / BEAM with autologous hematopoietic stem cell transplantation for persistent or relapsed chemotherapy sensitive diffuse large B cell non-Hodgkin’s lymphoma (DLBCL)

Determined the addition of radioimmunotherapy to the standard conditioning regimen of BEAM provides no clinical benefit for patients undergoing autologous HCT for DLBCL

Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with Iodine-131 tositumomab / BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 Trial. Journal of Clinical Oncology. 2013 May 1; 31(13): 1662-1668. Epub 2013 Mar 11.

Although several small Phase II studies suggested that dose-intensification might decrease relapse, the primary cause of treatment failure after autologous HCT for DLBCL, this study failed to show an impact on relapse but did show increased toxicity. Future trials will focus on maintenance strategies and/or immune therapies after HCT to improve disease control, marking a significant change in direction for the field.

BMT CTN collaborated with Alliance to design a randomized double blind Phase III study of ibrutinib during and following autologous HCT vs. placebo in patients with relapsed or refractory DLBCL (Alliance A051301 / BMT CTN 1201). This protocol will be released during the next reporting period.

0502: A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia (AML) in first morphologic complete remission using a nonmyeloablative preparative regimen

Demonstrated the feasibility and effectiveness of allogeneic transplant using reduced-intensity conditioning in this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in first remission

Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: Results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology) / Blood and Marrow Transplant Clinical Trial Network 0502. Journal of Clinical Oncology. 2015 Dec 10; 33(35): 4167-4175. Epub 2015 Nov 2.

This protocol was a collaborative effort between the BMT CTN and Cancer and Leukemia Group B (CALGB). CALGB accrual began in 2006, but enrollment was low; BMT CTN activated the study, and the trial rapidly met its original accrual goal. The study demonstrates that, with reduced-intensity conditioning, patients older than 60 can benefit from the graft-versus-leukemia effects of allogeneic HCT with outcomes similar to younger patients. These data should increase the use of HCT in older AML patients.


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CONDITIONING REGIMENS / INTENSITY (continued)

0701: Phase II trial of non-myeloablative allogeneic hematopoietic cell transplantation for patients with relapsed follicular non-Hodgkin’s lymphoma beyond first complete response

Determined that a rituximab-containing reduced intensity conditioning regimen is safe and efficacious for patients with relapsed follicular non-Hodgkin lymphoma

Primary results presented at 2014 ASH Annual Meeting; the manuscript was submitted and is being revised per reviewer request to include an additional analysis.

This study demonstrated that allogeneic HCT using a rituximab-containing reduced intensity conditioning regimen confers high complete response rates, a low incidence of relapse / progression, and prolonged survival with acceptable toxicity in heavily pretreated follicular lymphoma patients. This study provides justification for future trials comparing nontransplant with transplant salvage strategies in this disease.

0901: A randomized, multi-center Phase III study of allogeneic stem cell transplantation comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia

Found that reduced-intensity conditioning results in higher relapse rates and lower treatment-related mortality compared to myeloablative conditioning

Primary results presented at 2015 ASH Annual Meeting; manuscript is drafted and will be submitted in May 2016.

The data from this trial support myeloablative conditioning as the standard of care for patients who are able to receive it. For patients who are not candidates for myeloablative conditioning, novel regimens, which incorporate enhanced anti-leukemia activity without increasing toxicity, are needed. One such regimen of maintenance therapy post-HCT for FLT3-positive acute myeloid leukemia (AML) patients will be evaluated in an upcoming study (BMT CTN 1506).


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GRAFT SOURCES

0201: A Phase III randomized, multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors

Found no difference in survival for recipients of unrelated donor peripheral blood versus bone marrow grafts, but an increased risk of chronic GVHD requiring prolonged immune suppression with peripheral blood grafts

Five year quality of life follow-up results showed that recipients of bone marrow grafts have better psychological well-being and less burdensome chronic GVHD symptoms than recipients of peripheral blood grafts

Peripheral-blood stem cells versus bone marrow from unrelated donors. New England Journal of Medicine. 2012 Oct 18; 367(16): 1487-1496.

Comparison of characteristics and outcomes of trial participants and nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 Trial. Biology of Blood and Marrow Transplantation. 2015 Oct 1; 21(10): 1815-1822. Epub 2015 Jun 11.

Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors. Biology of Blood and Marrow Transplantation. 2016 Feb 1; 22(2): 359-370. Epub 2015 Sep 25.

Recovery of unrelated donors of peripheral blood stem cells versus bone marrow: A prespecified analysis from the Phase III BMT CTN Protocol 0201. Biology of Blood and Marrow Transplantation. 2016 Mar 21. [Epub ahead of print].

Peripheral blood has largely replaced bone marrow as a graft source for unrelated donor transplantation. This study suggests this may not be appropriate in the myeloablative conditioning setting since it offers no survival advantage but produces higher rates of chronic GVHD requiring prolonged immune suppression.

Five year results of patient-reported outcomes showed a quality of life advantage for recipients of bone marrow grafts although the impact on unrelated donor requests is yet to be determined. These results were presented, and the manuscript was submitted for publication.

Ancillary studies of immune reconstitution, infection, and donor clinical outcomes and quality of life were published. An analysis performed in collaboration with the CIBMTR demonstrated that the patients and outcomes in this study were representative of the larger BMT population was also published.

This is the largest study of unrelated donor transplantation ever performed and would not have been possible without the infrastructure provided by the BMT CTN.


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GRAFT SOURCES (continued)

0501: Multi-center, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia

Demonstrated no survival benefit and more acute GVHD for children receiving infusion of two umbilical cord blood units versus one umbilical cord blood unit after transplantation for hematologic malignancies

One- versus two-unit cord blood transplant for leukemia. New England Journal of Medicine. 2014 Oct 30; 371(18): 1685-1694.

This study indicates, unexpectedly, that increasing cell dose beyond the accepted minimum by adding another cord blood unit does not improve survival after cord blood transplantation in children and increases the risk of acute GVHD. This has important implications for future strategies to improve hematopoietic recovery and decrease transplant-related mortality after cord blood HCT.

0603 / 0604: Multicenter, Phase II trials of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow / umbilical cord blood from unrelated donors in patients with hematologic malignancies

Confirmed single-center results in a multicenter setting using reduced-intensity conditioning and haploidentical bone marrow transplantation or double cord blood transplantation in adults with hematologic malignancies, with data supporting a subsequent Phase III trial

Alternative donor transplantation: results of parallel Phase II trials using HLA-mismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul 14; 118(2): 282-288. Epub 2011 Apr 28.

Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1485-1492. Epub 2014 May 23.

Acceptable outcomes of double cord and haploidentical bone marrow transplantation suggest that many more adults should be offered HCT, even when an HLA-matched adult donor is not available. Publication of these studies led to substantial increase in use of haploidentical donors for transplantation in the US. These approaches are now being compared in a randomized Phase III trial (BMT CTN 1101).

A subsequent three year follow-up analysis was conducted and showed continued evidence of equipoise between HLA haploidentical related donor and double umbilical cord blood transplantation.


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GVHD PREVENTION AND TREATMENT

0302: Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin in combination with corticosteroids

Identified MMF plus corticosteroids as the most promising regimen to compare against corticosteroids alone in a Phase III trial

Determined that GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment non-responsiveness or death and that biomarker panels may provide opportunities for early intervention and improved survival following HCT

Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute graft-versus-host disease, a randomized Phase II trial from the BMT CTN. Blood. 2009 Jul 1; 114(3): 511-517. Epub 2009 May 14.

Graft-versus-host disease treatment: predictors of survival. Biology of Blood and Marrow Transplantation. 2010 Dec; 16(12): 1693-1699. Epub 2010 Jun 10.

Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a BMT CTN study. Blood. 2012 Apr 19; 119(16): 3854-3860. Epub 2012 Mar 1.

A prognostic score for acute graft-versus-host disease based on biomarkers: A multicentre study. Lancet Haematology.2015 Jan 1; 2(1): 21-29. Epub 2014 Dec 22.

A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biology of Blood and Marrow Transplantation. 2015 Apr 1; 21(4): 761-767. Epub 2015 Jan 10.

Additional secondary analyses published in previous reporting periods are listed in the BMT CTN 0302 Protocol Table in Section 7.3.

The results from the 0302 study were used to create and conduct BMT CTN 0802, a Phase III randomized study of MMF / corticosteroids vs. corticosteroids alone.

The wider use of biomarkers to identify patients at high risk of GVHD will allow us to tailor our therapies to better control this complication in these patients and to reduce toxicity in patients who are unlikely to benefit from intensive immune suppression. The BMT CTN is now incorporating biomarker-defined risk stratification into the design of GVHD treatment trials, currently with the BMT CTN 1501 protocol (treatment of low risk GVHD as identified by biomarkers), which will be released during the next reporting period.


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GVHD PREVENTION AND TREATMENT (continued)

0303: A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission

Confirmed in a multicenter setting the feasibility and consistency of T cell depletion by CD34 selection, with results in AML that warranted consideration of a Phase III trial versus non-T cell depleted transplantation

Low risk of chronic graft-versus-host disease and relapse associated with T cell depleted peripheral blood stem cell transplantation for acute myeloid leukemia in first remission: results of the Blood and Marrow Transplant Clinical Trials Network Protocol 0303. Biology of Blood and Marrow Transplantation. 2011 Sep; 17(9): 1343-1351. Epub 2011 Feb 12.

Characteristics of CliniMACS(®) System CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303. Biology of Blood and Marrow Transplantation. 2012 May; 18(5): 690-697. Epub 2011 Aug 26.

Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-vs-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology. 2012 Sep 10; 30(26): 3194-3201. Epub 2012 Aug 6.

These data were used by the US Food and Drug Administration (FDA) in its determination to approve a CD34 selection column for clinical use in the US. A comparative analysis of outcomes for patients enrolled on this study and patients enrolled on another BMT CTN study who received T-replete grafts was also undertaken. The results suggested that T cell depletion via CD34 selection may lower long term morbidity as a result of less chronic GVHD. A Phase III three arm trial comparing outcomes of CD34-selected transplants using this approach vs. another calcineurin inhibitor-free strategy (post-transplant cyclophosphamide) vs. standard calcineurin-inhibitor based GVHD prophylaxis (tacrolimus / methotrexate) was activated during this reporting period (BMT CTN 1301).


12



GVHD PREVENTION AND TREATMENT (continued)

0402: A Phase III randomized, multicenter trial comparing sirolimus / tacrolimus with tacrolimus / methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell transplantation

Identified a high risk of toxicity when sirolimus is substituted for standard methotrexate for GVHD prophylaxis when the conditioning regimen includes busulfan and no advantage in acute GVHD-free survival

Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008 Dec 1; 112(12)4425-4431. Epub 2008 Sep 5.

Tacrolimus / sirolimus versus tacrolimus / methotrexate as GVHD prophylaxis after matched, related donor allogeneic hematopoietic cell transplantation. Blood. 2014 Aug 21; 124(8): 1372-1377. Epub 2014 Jun 30.

Although the study showed a modest improvement in grade III-IV acute GVHD, the findings do not support substituting sirolimus for methotrexate since it may increase toxicity in patients who receive busulfan for conditioning, it was associated with higher risks of chronic GVHD, and it did not improve survival. Novel approaches to preventing GVHD are needed and are being explored in the soon to be completed BMT CTN 1203 PROGRESS I study and the recently opened BMT CTN 1301 PROGRESS II study.

0802: A multi-center, randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil (MMF) versus corticosteroids with placebo as initial systemic treatment of acute GVHD

Found no GVHD-free survival benefit with the addition of MMF

See page 10 for 0302 / 0802 ancillary study results

Phase III clinical trial steroids / mycophenolate mofetil vs steroids / placebo as therapy for acute graft-versus-host disease: BMT CTN 0802. Blood. 2014 Nov 20; 124(22): 3221-3227. Epub 2014 Aug 26.

Although the 0802 results were discouraging, the BMT CTN has used these studies to focus on a newer therapeutic agent, sirolimus, in the upcoming BMT CTN 1501 study using a biomarker risk stratification developed in BMT CTN 0302 and 0802. The Network’s ability to conduct GVHD studies in timely manner allows for definitive Phase III results to be quickly disseminated and promising agents to be efficiently tested in new studies.


13



MULTIPLE MYELOMA TREATMENT

0102: A trial of tandem autologous stem cell transplants with or without post-second autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma

Determined, in the second largest study of HCT for multiple myeloma ever conducted (superseded only by BMT CTN 0702), that tandem autologous HCT and autologous HCT followed by allogeneic HCT offer similar progression-free survival rates in patients with standard risk disease

Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment trial. Lancet Oncology. 2011 Dec 1; 12(13): 1195-1203. Epub 2011 Sep 29.

This study highlights the need to reduce transplant-related toxicity in the allogeneic HCT setting to allow the graft-versus-tumor effect of allografts to translate into survival benefits. It also indicated that the graft-versus-tumor effect in standard risk myeloma may not be as important as previously thought. The use of tandem autologous-allogeneic HCTs has decreased substantially over the past few years, in part, because of the data from this trial. Evaluation of the high-risk cohort informed the Network's next allogeneic transplant trial in this disease (BMT CTN 1302), which was recently activated.

0704: A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma

Determined lenalidomide maintenance therapy dramatically improves progression-free survival and overall survival after autologous HCT for multiple myeloma

Phase III study of lenalidomide versus placebo after HCT for multiple myeloma. New England Journal of Medicine. 2012 May 10; 366(19): 1770-1781.

Anatomy of a successful practice-changing study: A Blood and Marrow Transplant Clinical Trials Network-National Cancer Institute Cooperative Group Collaboration. Biology of Blood and Marrow Transplantation. 2013 Jun 1; 19(6): 858-859. Epub 2013 Mar 29.

The data have led to a major change in clinical practice, with most myeloma patients now receiving lenalidomide maintenance after transplantation.

The BMT CTN was an important contributor to this study, which was led by CALGB, and used its Network and the CIBMTR Research Database to devise an accrual plan that allowed the trial to successfully meet its enrollment target after initial accrual difficulties. Details of this collaboration were published in a commentary article. Its success provides a paradigm for ensuring timely accrual to future national BMT studies.


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QUALITY OF LIFE

0902: A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic recipients

Demonstrated no improvement in physical or mental quality of life with exercise training, stress management training, or combined stress management and exercise training compared to usual care

Exercise and stress management training prior to hematopoietic cell transplantation: Blood and Marrow Transplant Clinical Trial Network (BMT CTN) 0902. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10): 1530-1536. Epub 2014 Jun 6.

Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). Cancer. 2016 Jan 1; 122(1): 91-98. Epub 2015 Oct 6.

This trial tested modest, easily applied interventions in the early transplant period. While lack of an effect was disappointing, the trial enrolled more than 700 patients in 19 months, demonstrating that the BMT CTN has an effective infrastructure to conduct studies addressing quality of life issues. An ancillary analysis was published during this reporting period showing that a patient-reported outcome (pre-HCT Medical Outcomes Study Short Form-36 Health Survey physical component summary scale) independently predicted overall mortality in allogeneic HCT recipients, adding to the prognostic information of currently used performance and co-morbidity scores. This easily applied measure could aid in patient selection and counseling. Additional ancillary studies are in progress.


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RARE DISEASES

0301: Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated donors in severe aplastic anemia

Identified the optimal dose of cyclophosphamide for unrelated donor HCT in severe aplastic anemia is less than 150 mg/kg

Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose de-escalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biology of Blood and Marrow Transplantation. 2012 July 1; 18(7): 1007-1011. Epub 2012 Apr 30.

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: A Phase 1-2 dose de-escalation study. Lancet Haematology. 2015 Sept 1; 2(9): 367-375. Epub 2015 Sep 8.

Optimizing transplantation regimens for rare diseases is difficult and requires a multicenter effort. This study determined that fludarabine is not sufficiently immune suppressive to replace cyclophosphamide in conditioning regimens for unrelated donor transplantation for aplastic anemia. Additionally, it found excess toxicity with a commonly used dose of cyclophosphamide when combined with fludarabine. This unexpected finding is anticipated to change practice in many centers. A follow-up study for aplastic anemia patients is in development (BMT CTN 1502) using the optimal cyclophosphamide dose found in this study. Additionally, the upcoming study will incorporate cord blood and haploidentical donors to reach patients who are not able to find an unrelated donor.


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RARE DISEASES (continued)

0601: Unrelated donor reduced intensity bone marrow transplant for children with severe sickle cell disease

Determined that a reduced-intensity conditioning regimen of alemtuzumab, fludarabine, and melphalan, followed by bone marrow HCT resulted in low rates of regimen-related organ toxicity and a one year event-free survival of 76% but unacceptably high rates of GVHD

Initially found that this regimen, although effective for engraftment of bone marrow, was associated with unacceptably high levels of graft failure after cord blood transplantation; this led to the closure of the cord blood cohort

Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the Phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of Blood and Marrow Transplantation. 2012 Aug 1; 18(8): 1265-1272. Epub 2012 Feb 16.

Primary results presented at 2015 ASH Annual Meeting; manuscript is drafted and will be submitted in Spring 2016.

This finding confirmed that using a reduced-intensity regimen followed by bone marrow HCT results in acceptable rates of engraftment and survival but high risks of chronic GVHD, underscoring the need for future trials on effective GVHD prophylaxis. Additionally, early on in the study, there was a disappointing finding that using cord blood as a stem cell source resulted in unacceptably high levels of graft failure, which indicates the need for novel transplant strategies for the large number of sickle cell disease patients who cannot find an HLA-matched adult donor. Two additional BMT CTN sickle cell transplant trials are currently in development. One compares HLA-matched bone marrow HCT to standard of care (BMT CTN 1503), and the other uses haploidentical donors (BMT CTN 1507).

0803: High dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients

Determined that patients with HIV-associated lymphoma may successfully undergo autologous transplant with favorable outcomes

Primary results presented at 2014 ASH Annual Meeting; manuscript was submitted for publication.

The BMT CTN conducted this study in collaboration with the AIDS Malignancy Consortium in an effort to assess whether autologous HCT is a viable therapeutic option for a patient population frequently excluded from HCT clinical trials. Based on the study findings, autologous transplant should be considered the standard of care for patients with relapsed / refractory HIV-associated lymphoma who meet standard eligibility criteria. The BMT CTN and AIDS Malignancy Consortium are also evaluating the use of allogeneic HCT for HIV-infected patients with hematological cancers and MDS in the newly completed BMT CTN 0903 trial.


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SUPPORTIVE CARE

0101: A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients

Demonstrated that fluconazole, a low-cost antifungal agent, generally has similar efficacy as and is generally more cost-effective than the newer and more expensive drug, voriconazole, in preventing serious fungal infections in the first six months after HCT but that voriconazole may be cost-effective for those undergoing an allogeneic HCT for AML

Randomized double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9; 116(24): 5111-5118. Epub 2010 Sep 8.

Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. American Journal of Health-System Pharmacy. 2013 Sept 1; 70(17): 1518-1527.

This study of a Phase III comparison of fluconazole and voriconazole indicates that newer is not always better and that, for most patients, standard fluconazole is effective fungal prophylaxis. However, an ancillary study suggested there is a subset of patients for whom primary antifungal prophylaxis with voriconazole may be cost-effective, allowing more informed treatment planning by transplant centers.

0403: A Phase III, randomized double-blind, placebo controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of acute non-infectious pulmonary dysfunction (idiopathic pneumonia syndrome) following allogeneic stem cell transplantation

Showed no increase in response with the addition of etanercept to corticosteroids in the treatment of idiopathic pneumonia syndrome; however, the reduced sample size (34 instead of 120 patients) precluded a definitive conclusion

A randomized double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome following allogeneic stem cell transplantation: Blood and Marrow Transplant Clinical Trials Network protocol. Biology of Blood and Marrow Transplantation. 2014 Jun 1; 20(6):858-864. Epub 2014 Mar 7.

This study failed to show an advantage for etanercept and also highlighted the decreasing incidence of idiopathic pneumonia syndrome in an era of reduced conditioning regimen intensity and better diagnostic tests for infectious pathogens.


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1.5 Biorepository and Clinical Trial Data Resources

The Network’s Research Sample Repository is a valuable resource. To date, protocols have yielded a biological research sample collection of more than 366,470 stored specimens provided by more than 5,680 subjects. An inventory of BMT CTN research samples collections is available on the Network’s public website as a resource for investigators planning correlative and ancillary studies. This website section summarizes the planned sample collection schedules and sample processing, and it lists biological samples available for all BMT CTN studies by time point and sample type. Clinical trial outcome data associated with completed trials represent another resource for investigators who want to examine research objectives other than those addressed in the original trials. During this reporting period, new sections were added to the Network’s public website to provide investigators with general patient and clinical characteristics summaries and case report forms for completed trials to assist in the development of secondary data analyses. Analyses and published results using data derived from the analysis of biorepository samples and associated trial outcome data are listed, along with other ancillary studies, in Tables 4.2a and 4.2b.

1.6 Network Efficiency

Over the past several years, initiatives were undertaken to improve Network efficiency. These included creating an Activation Task Force to evaluate performance and make recommendations to improve processes, reevaluating the protocol development process, and implementing a shorter study development timeline. New practices were implemented because of these initiatives. During this reporting period, the DCC evaluated time point data to assess Network performance as part of its continuous process improvement process. Figure 1.2. Increasing efficiency by decreasing timeframes: BMT CTN median milestone timeframes in previous vs. current grant cycles

Acronyms: PRC = Protocol Review Committee, DSMB = Data and Safety Monitoring Board

0.0 3.0 6.0 9.0 12.0 15.0 18.0 21.0 24.0

Evaluable Data to Manuscript Submission

Protocol Team Formation to PRC Submission

Protocol Release to Centers to Study Activation

DSMB Approval to Protocol Release to Centers

PRC Submission to DSMB Approval

PRC Approval to DSMB Submission

PRC Submission to PRC Approval

Protocol Team Formation to Study Activation

Months

2001-2009

2011-2015


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Data in Figure 1.2 represent the median Network milestone times for BMT CTN-led studies. Two comparative timeframes are shown: 2001-2009 (previous BMT CTN grant cycles) and 2011-2015 (current BMT CTN grant cycle). The data show a decrease in times for every category except one – Data and Safety Monitoring Board approval to protocol release, with an increase from 1.5 to 3.6 months due to 4 studies that were not released until more than 7 months after approval because of difficulty in contracting with the companies providing drug and support, additional FDA-mandated training requirements for vaccine manufacture, and/or a protocol amendment prior to release. Notably, the median timeframe during this current grant cycle from protocol team formation to protocol activation decreased from 23.0 months to 18.6 months, a decrease of 4.4 months. The DCC also reviewed center performance data for the current and previous grant cycles and found there has been continued improvement in overall assessment scores over the course of eight years. In 2015, the most successful year yet, no centers received a “Needs Improvement” score (Section 3.7). The DCC also evaluates publication timelines. The time from evaluable data to manuscript submission decreased significantly from 12.6 to 8.7 months from the previous to current grant cycle. Of note, of the 20 BMT CTN-led studies that have reached primary endpoint, only three are not submitted or published, and data only became available for these studies during the current reporting period. Manuscripts for all three studies are drafted and will be submitted early in the next reporting period. While the improvements in milestone times and center performance data are impressive, the DCC continues efforts to improve upon them further. Two initiatives undertaken during this reporting period include hosting one day in-person protocol development meetings for the 1501 and 1507 protocols to shorten protocol development timeline and using an Institutional Review Board (IRB) of Record for the 1501 and 1503 studies to shorten protocol release to activation timeframe. It is too early to evaluate the impact, if any, of these initiatives.

1.7 Funding Leverage

BMT CTN leadership understands that optimizing external funding is critical at any time but particularly in the current economic environment. The Network works hard to leverage NIH support with public-private partnerships that provide both direct and in-kind contributions. The DCC develops relationships and contracts with pharmaceutical companies and laboratory vendors for additional budgetary support and for drugs used in studies, always with proper attention paid to avoid potential conflicts of interest. This year, the following supplemental support activities took place:

• BMT CTN 1302: Multicenter Phase II, placebo controlled trial of maintenance ixazomib after allogeneic hematopoietic stem cell transplantation for high risk multiple myeloma.

o An agreement was fully executed with Millennium Pharmaceuticals, Inc. to provide funding in the amount of $1.15 million as well as in kind contributions of ixazomib, bortezomib, and placebo.

o Millennium Pharmaceuticals, Inc. agreed to provide additional funding in the amount of $290,000 for minimal residual disease (MRD) testing. The revised funded amount will total $1.44 million.

• BMT CTN 1401: Phase II multicenter trial of single autologous hematopoietic cell transplant followed by lenalidomide maintenance for multiple myeloma with or without vaccination with dendritic cell / myeloma fusions.

o An agreement was fully executed with Celgene Corporation to provide $5.1 million as well as in kind contributions of lenalidomide.

• BMT CTN 1506: A multi-center, randomized, double-blind, placebo-controlled Phase III trial of the FLT3 inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients


20

with FLT3/ITD AML. o Negotiations are in process with Astellas Pharma Global Development, Inc. to fully fund 1506,

including providing gilteritinib and placebo. All non-government third party contributions are made through an NHLBI-approved Memoranda of Agreement. The total of all non-BMT CTN core funding additions has increased the effective investment from NIH by an estimated $376 million. The BMT CTN DCC also encourages investigators to apply for supplemental funding to support ancillary or correlative studies. During this reporting period, investigators were awarded the following grants:

• STRIDE: Unrelated donor transplantation for adults with sickle cell disease study (R01; $6.98 million) • BMT CTN 1101 Ancillary cost-effectiveness analysis (R01; $1.72 million)

1.8 Key Collaborations

As highlighted throughout this report, the BMT CTN fosters successful collaborations with other NIH Institutes, Networks / Consortia, and organizations:

• AIDS Malignancy Consortium; • The Alliance for Clinical Trials in Oncology (formerly CALGB); • Canadian Blood and Marrow Transplant Group; • Centers for Disease Control and Prevention Office of Minority Health & Health Disparities; • Children’s Oncology Group (COG); • Dana-Farber Cancer Institute (DFCI) / Intergroupe Francophone du Myelome (IFM); • Deutsche Knochenmarkspenderdatei (DKMS) – German Bone Marrow Donor Center; • Eastern Cooperative Oncology Group (ECOG) – American College of Radiology Imaging Network

(ACRIN) Cancer Research Group; • National Institute on Minority Health and Health Disparities; • NCI National Clinical Trials Network; • NCI-sponsored Cancer Trials Support Unit; • NIAID; • Office of Rare Diseases Research • Pediatric Blood and Marrow Transplant Consortium (PBMTC); • Sickle Cell Disease Clinical Research Network; • SWOG.

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 2.0 Organizational Overview

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2.0 Organizational Overview

The BMT CTN is comprised of a network of organizations that work together to achieve common goals. It includes the following elements, each of which is described in this section:

• Data and Coordinating Center; • Twenty Core Centers / Consortia; • Affiliate Centers; • Steering Committee; • Protocol Teams; • Technical Committees; • Administrative Committees; • Ad Hoc Committees; • Review Committees.

2.1 Data and Coordinating Center

The DCC is managed by three organizations with extensive HCT research expertise: the CIBMTR, the National Marrow Donor Program® (NMDP)/Be The Match®, and The Emmes Corporation (a contract research organization). Together they are responsible for maintaining continuity of operations and effective communications, data management, and statistical support for the Network. Figure 2.1 illustrates the DCC’s relationship to the organization as a whole, which is explained more fully in Section 3.

Figure 2.1. BMT CTN organizational structure

NHLBI & NCIProtocol Review

CommitteeProtocol Review

Committee

Data and Safety Monitoring

Board

Data and Safety Monitoring

Board

BMT CTN Steering

Committee

20 Core Clinical Centers / Consortia

20 Core Clinical Centers / Consortia

Executive Committee

Protocol Teams

Administrative Committees

Technical Committees

Scientific Advisory

Committees

DCC

Affiliate Clinical Centers

Affiliate Clinical Centers


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2.2 Clinical Centers

2.2.1 Core Centers

The BMT CTN has 20 Core Clinical Centers (Table 2.1), some of which are consortia of two or more centers. Each Core Center holds a cooperative agreement with the NHLBI to participate in the BMT CTN. These centers were chosen by virtue of the scientific merit of their grant applications to the NIH as well as evidence of their ability to collaborate in carrying out the Network mission of developing and completing high-quality trials as efficiently as possible.

Table 2.1. Core Centers and Principal Investigators

BMT CTN Core Centers and Principal Investigators

Center Principal Investigator

Baylor College of Medicine / Methodist Hospital (Consortium) 1. Baylor College of Medicine / Methodist Hospital 2. Children’s National Medical Center

1. Helen Heslop, MD, DSc (Hon) 2. Catherine Bollard, MBChB, MD

Case Western Reserve University Ireland Cancer Center (Consortium) 1. Case Medical Center 2. Oregon Health Sciences (Adults) 3. Cleveland Clinic 4. West Virginia University

1. Hillard Lazarus, MD 2. Richard Maziarz, MD 3. Ronald Sobecks, MD 4. Michael Craig, MD

City of Hope National Medical Center Ryo Nakamura, MD

Dana Farber / Partners in Cancer Care (Consortium) 1. Brigham & Women’s Hospital 2. Massachusetts General Hospital 3. Boston Children’s Hospital

Joseph Antin, MD

Duke University Medical Center Joanne Kurtzberg, MD

Fred Hutchinson Cancer Research Center Frederick Appelbaum, MD

H. Lee Moffitt Cancer Center Claudio Anasetti, MD

Johns Hopkins University Oncology Center Richard Jones, MD

Memorial Sloan-Kettering Cancer Center Sergio Giralt, MD

Northside Hospital Atlanta Asad Bashey, MD, PhD

Ohio State University Comprehensive Cancer Center (Consortium) 1. Ohio State University 2. Roswell Park Cancer Institute 3. University of North Carolina 4. University of California-San Francisco 5. Virginia Commonwealth University

1. Steven Devine, MD 2. Philip McCarthy, MD

Theresa Hahn, PhD 3. Thomas Shea, MD 4. Lloyd Damon, MD 5. John McCarty, MD

PBMTC (Pediatric Blood & Marrow Transplant Consortium) 47 pediatric centers in the US and Canada (see Table 2.2)

Michael Pulsipher, MD


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BMT CTN Core Centers and Principal Investigators

Center Principal Investigator

Stanford Hospital and Clinics Robert Lowsky, MD

University of Florida College of Medicine (Consortium) 1. University of Florida 2. Emory University

1. John Wingard, MD 2. Edmund Waller, MD, PhD

University of Michigan Medical Center Consortium 1. University of Michigan 2. Mayo Clinic 3. Mount Sinai Hospital 4. Vanderbilt University

1. Gregory Yanik, MD, MS 2. William Hogan, MBBCh

Mark Litzow, MD 3. John Levine, MD 4. Madan Jagasia, MBBS, MS

University of Minnesota Daniel Weisdorf, MD

University of Nebraska Medical Center (Consortium) 1. University of Nebraska 2. University of Kansas

1. Julie Vose, MD, MBA 2. Joseph McGuirk, DO

University of Pennsylvania Hospital Edward Stadtmauer, MD

University of Texas MD Anderson Cancer Center Amin Alousi, MD

Washington University Peter Westervelt, MD, PhD

Table 2.2. PBMTC Centers that have participated in BMT CTN studies

PBMTC Centers that have Participated in BMT CTN Studies

Center Location

All Children's Hospital St Petersburg, FL

Ann and Robert H. Lurie Children's Hospital of Chicago Chicago, IL

British Columbia Children’s Hospital Vancouver, Canada

Cardinal Glennon Children's Medical Center – Saint Louis University St. Louis, MO

CancerCare Manitoba Winnipeg, Canada

Carolinas Medical Center / Levine Children's Hospital Charlotte, NC

Children's Healthcare of Atlanta Atlanta, GA

Children’s Hospital at Oakland Oakland, CA

Children's Hospital Los Angeles Los Angeles, CA

Children's Hospital of Denver Denver, CO

Children's Hospital of New Orleans New Orleans, LA

Children's Hospital of Philadelphia Philadelphia, PA

Children's Medical Center of Dallas

Dallas, TX

Children's Mercy Hospital and Clinics Kansas City, MO


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PBMTC Centers that have Participated in BMT CTN Studies

Center Location

Children's National Medical Center Washington, DC

Cincinnati Children's Hospital Medical Center Cincinnati, OH

Columbia University Medical Center New York, NY

Cook Children's Medical Center Fort Worth, TX

Hackensack University Medical Center Hackensack, NJ

Hopital Sainte-Justine Montreal, Canada

Karmanos Cancer Institute / Children’s Hospital of Michigan Detroit, MI

Mattel Children’s Hospital at UCLA Los Angeles, CA

Medical University of South Carolina Charleston, SC

McGill University Montreal, Canada

Midwest Children's Cancer Center Milwaukee, WI

Nationwide Children's Hospital Columbus, OH

Nemours / Alfred I. DuPont Hospital for Children Wilmington, DE

Nemours Children’s Clinic

Jacksonville, FL

New York Medical College Valhalla, NY

Oregon Health and Science University Portland, OR

Penn State College of Medicine Hershey, PA

Phoenix Children's Hospital

Phoenix, AZ

Primary Children's Medical Center Salt Lake City, UT

Riley Hospital for Children-Indiana University Indianapolis, IN

Texas Transplant Institute San Antonio, TX

The Steven and Alexandra Cohen Children's Hospital of New York New Hyde Park, NY

University of California Los Angeles Los Angeles, CA

University of California San Francisco School of Medicine San Francisco, CA

University of Alabama at Birmingham Birmingham, AL

University of Iowa Hospital and Clinics Iowa City, IA

University of Louisville / Kosair Children's Hospital Louisville, KY

University of Miami Miller School of Medicine – Sylvester Cancer Center Miami, FL

University of Mississippi Medical Center Jackson, MS

University of Rochester Medical Center Rochester, NY

University of Texas Southwestern Medical Center Dallas, TX

Vanderbilt University Nashville, TN

Washington University / St. Louis Children’s Hospital

St. Louis, MO


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2.2.2 Affiliate Centers

The BMT CTN has almost 70 Affiliate Centers (Table 2.3) that accrue patients to Network trials. About 17% of the BMT CTN’s overall accrual comes from Affiliate Centers; for this reporting period, the figure is 12%. However, excluding BMT CTN 1202, which is a large, fast accruing biospecimen study that was only opened to a select few Affiliate Centers, the figure is 21%. Accrual from Affiliate Centers decreased throughout the years as more Affiliate Centers have become Core Centers, either individually or as part of a Consortium. In 2001, 20 non-PBMTC centers were Core Centers or part of Core Consortia; as of March 31, 2016, there are 35. The Network encourages and facilitates broad participation of the HCT community through its Affiliate Center system. Affiliate Centers participate in one or more BMT CTN trials through individual contracts with the DCC. Applications for participation in Network trials are available online at bmtctn.net. Table 2.3. Affiliate Centers

BMT CTN Affiliate Centers

Center Location

Advocate Lutheran General Hospital Park Ridge, IL

Arizona Cancer Center / University of Arizona Tucson, AZ

Aurora St. Luke’s Medical Center Milwaukee, WI Avera Hematology & Transplant Center Sioux Falls, SD

Banner Research Institute Phoenix, AZ

Baylor University Medical Center

Dallas, TX

Beth Israel Deaconess Medical Center Boston, MA

British Columbia Children's Hospital Vancouver, Canada

Cancer Centers of the Carolinas Greenville, SC

Cancer Institute of New Jersey / Robert Wood Johnson University New Brunswick, NJ

Christiana Care Health System Newark, DE

Colorado Blood Cancer Institute Denver, CO

DeKalb Medical Center Decatur, GA

Florida Hospital Cancer Institute Orlando, FL

Fox Chase - Temple University BMT Program Philadelphia, PA

Georgia Health Sciences University Augusta, GA

Hackensack University Medical Center Hackensack, NJ

Henry Ford Health System Detroit, MI

Indiana BMT Clinics Beech Grove, IN

Indiana University Medical Center / Riley Hospital Indianapolis, IN

Intermountain BMT Program

Salt Lake City, UT

Jewish Hospital BMT Program Cincinnati, OH

Kansas City Cancer Centers Kansas City, MO

Kapi'olani Medical Center for Women and Children – University of

Honolulu, HI

Karmanos Cancer Institute Detroit, MI


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Center Location

Louisiana State University Health Sciences Center Baton Rouge, LA

Loyola University Medical Center Maywood, IL

Mayo Clinic Arizona Phoenix, AZ

Mayo Clinic Florida Jacksonville, FL

Medical College of Wisconsin Milwaukee, WI

Medical University of South Carolina Charleston, SC

Montefiore Medical Center Bronx, NY

Nashville VA Medical Center Healthcare Nashville, TN

National Cancer Institute - NIH Bethesda, MD

North Shore University Hospital Manhasset, NY

Northwestern University Chicago, IL

Penn State College of Medicine - The Milton S. Hershey Medical Center Hershey, PA

Providence Portland Medical Center Portland, OR

Roger Williams Medical Center Providence, RI

Rush University Medical Center Chicago, IL

Sarah Cannon BMT Program Nashville, TN

Spectrum Health Grand Rapids, MI

St. Louis University

St. Louis, MO

St. Lukes Mountain States Tumor Institute Boise, ID

Stony Brook University Medical Center Stony Brook, NY

SUNY Upstate Medical University Syracuse, NY

Texas Transplant Institute San Antonio, TX

Thompson Cancer Survival Center

Knoxville, TN

Tufts Medical Center Boston, MA


University of California Davis Medical Center Sacramento, CA

University of California Los Angeles Los Angeles, CA

University of California San Diego Medical Center La Jolla, CA

University of Chicago

Chicago, IL

University of Illinois Chicago, IL

University of Iowa Hospitals and Clinics Iowa City, IA

University of Kentucky Lexington, KY

University of Maryland Medical Systems - Greenebaum Cancer Center Baltimore, MD

University of Massachusetts / Memorial Medical Center Worcester, MA


27


Center Location

University of Miami Miami, FL

University of Mississippi Medical Center Jackson, MI

University of Oklahoma Medical Center Oklahoma City, OK

University of Pittsburgh Cancer Institute

Pittsburgh, PA

University of Rochester Medical Center (Adults and Pediatric) Rochester, NY

University of Texas Southwestern Medical Center Dallas, TX

University of Virginia Charlottesville, VA

University of Wisconsin Hospital & Clinics Madison, WI

Utah BMT / University of Utah Medical School

Salt Lake City, UT

Vanderbilt University Medical Center Nashville, TN

Wake Forest University Health Sciences Winston-Salem, NC

Weill Cornell Medical College / New York Presbyterian Hospital New York, NY

Western Pennsylvania Cancer Institute Pittsburgh, PA

Wichita Community Clinical Oncology Program Wichita, KS

Yale University School of Medicine / Yale-New Haven Hospital New Haven, CT

2.3 Committee Structure

The BMT CTN committee structure ensures the Network works toward common goals. Each committee is described in this section.

2.3.1 Steering Committee

The Steering Committee consists of the Principal Investigator of each Core Center or Consortium, the DCC Principal Investigator and Co-Principal Investigators, the NHLBI Project Officer, the NCI Project Officer, a representative of each of the NCI-funded Cancer Cooperative Groups, and representatives of Affiliate Centers that meet standards for exemplary accrual and participation in BMT CTN trials. Other members of the DCC, Core Centers, and NIH regularly participate in Steering Committee meetings. The Steering Committee roster is listed in Attachment A1. The Steering Committee sets the scientific agenda and oversees the selection, design, execution, and analysis of all BMT CTN studies. The Committee ensures the most relevant studies are chosen, they are appropriately designed and executed, and data analyses are properly conducted. Additionally, the Steering Committee works in collaboration with the DCC to ensure participating transplant centers adhere to BMT CTN policies and procedures. The Committee also resolves any operational issues raised by investigators, Clinical Research Associates, laboratory and repository staff, DCC members, or others. The Steering Committee selects a Committee Chair who first serves a two-year term as Vice Chair, then a one year term as Chair Elect, followed by a two-year term as Chair, and finally a one-year term as Immediate Past Chair. Steven Devine, MD, Ohio State University Medical Center, began a two-year term as Chair on January 1, 2016. Richard Jones, Johns Hopkins University, is the Vice Chair, and Frederick Appelbaum, MD, Fred Hutchinson Cancer Research Center, is the Immediate Past Chair.


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2.3.2 Protocol Teams

Each Protocol Team consists of one to four Chairs; at least three co-investigators from Core and Affiliate Centers; an NHLBI and/or NCI representative; an NHLBI Statistician; and a DCC Protocol Officer, Coordinator, Statistician, and Contracts Representative. A Protocol Team is formed when a proposal is accepted by the Network. This team develops the study concept into a working study design and provides scientific oversight for the trial throughout its life cycle. The Protocol Team also:

• Reviews applications for participation from Affiliate Centers; • Develops patient and physician educational materials; • Monitors accrual and compliance with protocol requirements; • Prepares amendments as necessary; • Reviews endpoint data for accuracy and consistency; • Analyzes and interprets study data; • Prepares manuscripts.

2.3.3 Technical Committees

Standing and ad hoc Technical Committees generally consist of a maximum of nine members who are not associated with the DCC or NIH. Each Technical committee is also assigned one or more NHLBI and NCI representatives and one or more DCC staff members. These committees conduct specified functions of Network activity, advise the Steering Committee on certain Network policies and procedures, and provide technical expertise to protocol design. All standing Technical Committees must review each protocol before they are distributed to centers for implementation. Most Technical Committee meetings are conducted by conference call. During this reporting period, the Technical Committees reviewed five new protocols (1501, 1502, 1503, 1506, and 1507). Committee members are appointed by the Executive Committee to three-year terms. Nominations are open to participating Core and Affiliate centers. A Nominating Committee reviews the nominations and proposes a slate of candidates. These candidates are approved by the Executive and Steering Committees.

2.3.3.1 Biomarkers Committee The Biomarkers Committee, which is made up of Core and Affiliate Center transplant physicians, was formed to:

• Inform the Network’s scientific agenda with a focus on questions involving analysis of biologic specimens for genomic and proteomic markers;

• Review new and existing studies for opportunities to collect blood and tissue samples for analysis of potential prognostic markers;

• Advise the Network protocol teams in their review of ancillary study proposals that request the use of BMT CTN research samples.

The current Biomarkers Committee roster is listed in Attachment A2. During this reporting period, the Biomarkers Committee participated in the review of a new protocol (BMT CTN 1506), focusing on the associated correlative study concepts and proposed biospecimen collection schedules written into the protocol. Recommendations and comments regarding the potential impact of the proposed study concepts and the use of calendar-driven research biospecimen collections were submitted to the protocol teams for consideration as they made final decisions regarding study approvals. The proposed research sample collection strategy, correlative study objectives, and clinical outcome data collection incorporated into the BMT CTN 1506 study was reviewed by the committee, and guidance was provided to the protocol team for consideration as they finalized the study and obtained necessary NHLBI approvals.


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During this reporting period, the BMT CTN Executive Committee, together with the 1202 Protocol Team and 1202 End Point Review Committee members, developed procedures associated with:

• The management of the 1202 biospecimen/clinical data collection; • Submission of ancillary laboratory study proposals; • The adjudication and final approval of meritorious studies.

The Biomarkers Committee will play a lead role in the review, prioritization, and approval of ancillary studies submitted to the BMT CTN. Final review of proposals, together with Biomarkers Committee comments and recommendations, will be conducted by the BMT CTN Executive Committee.

2.3.3.2 Clinical Research Associates Committee The Clinical Research Associate Committee consists of Clinical Research Associates and Data Managers from Core and Affiliate Centers. This committee:

• Reviews each BMT CTN protocol before it is distributed to centers, focusing on reviewing and resolving logistical issues (e.g., shipping and receipt of specimens or drugs);

• Assists in developing and reviewing Case Report Forms; • Reviews educational materials for use at participating clinical centers; • Provides input for the BMT CTN Coordinators’ meeting held during the BMT Tandem Meetings.

In addition to reviewing three new protocols this reporting period, the Clinical Research Associate Committee reviewed Case Report Forms for five protocols (07LT, 1301, 1302, 1401, and 1501). The Committee also provided feedback regarding the workflow for the collection of the blood sample for biomarker analysis as well as the communication of results to treating physicians for BMT CTN 1501. The current Clinical Research Associates Committee roster is listed in Attachment A3.

2.3.3.3 Pharmacy Committee The Pharmacy Committee consists of pharmacists from Core and Affiliate Centers. It reviews BMT CTN protocols for appropriate use and administration of pharmaceuticals. It also advises Protocol Teams about possible pharmacokinetic or other ancillary studies. The current Pharmacy Committee roster is listed in Attachment A4. During this reporting period, the Pharmacy Committee continued to participate in the BMT CTN Chemotherapy Dosing Task Force that was formed last year. The Task Force, which includes Pharmacy Committee members and select Steering Committee members, was charged by the Steering Committee with reviewing the American Society for Blood and Marrow Transplantation (ASBMT) position statement on conditioning chemotherapy dose adjustment in obese patients (published January 2014) and provide recommendations for BMT CTN protocols. The Task Force presented their recommendations to the Steering Committee in September 2015, and the Steering Committee approved the recommendations with a few minor stipulations. The final recommendations were approved by the Executive Committee in December 2015. The recommendations included chemotherapy dosing adjustments in obese patients with template dose adjustment language for upcoming BMT CTN protocols, including recommendations on dosing adjustments for renal and hepatic insufficiency. The Task Force recommendations also included proposals for four amended / future research studies:

• Add a question that addresses obesity to a planned ancillary study (STaMINA myeloma study), which will use BMT CTN 0702 hip to waist ratio data (pre and post HCT) and conduct cytokine analyses using 0702 samples;

• Add an obesity analysis to a planned toxicity analysis of 2,000 BMT CTN patients;


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• Conduct a new retrospective analysis of CIBMTR data regarding the effect of BEAM dose adjustments on the outcomes of patients with lymphoma (approved at the 2016 BMT Tandem Meetings by the Regimen Related Toxicity Working Committee);

• Consider a retrospective study of cyclophosphamide dosing in obese patients (applied for R01 funding in February 2016).

Work on all of these projects will commence during the next reporting period. Additionally, the Task Force drafted a position manuscript and will submit for publication this year.

2.3.3.4 Special Populations Committee The Special Populations Committee consists of pediatric and adult transplant physicians from Core and Affiliate Centers as well as an ethicist. It ensures that children, women, and minority study participants are considered for inclusion in all appropriate investigational protocols developed by the Network. It also ensures that, for studies involving pediatric participants, appropriate modifications are addressed in informed consent, patient care, and monitoring documents. The current Special Populations Committee roster is listed in Attachment A5. Evaluation of HCT in the pediatric population presents some unique challenges. The Network is committed to developing strategies to address these challenges and increase the participation of children in HCT clinical trials. Sixteen Network trials have enrolled or are enrolling children (BMT CTN 0101, 0201, 0301, 0302, 0402, 0501, 0601, 0603, 0604, 0801, 0802, 0803, 0903, 1202, 1204, and 1301); three of them focused specifically on pediatric issues (BMT CTN 0501, 0601, and 1204). Four upcoming protocols also include children / adolescents (1501, 1502, 1503, and 1507), including one study for aplastic anemia patients and two others for patients with sickle cell disease. The proportion of BMT CTN trial participants under age 16 is only slightly lower than the overall proportion in the US transplant population. Since many US pediatric HCT recipients also have access to HCT trials through the COG, Network leadership feels these enrollment figures are appropriate. Last year, the Steering Committee charged the Special Populations Committee with a special project to evaluate the current special population participation on BMT CTN trials, identify underserved populations, and provide recommendations to increase special population participation. The Committee conducted their evaluation and presented recommendations to the Steering Committee in June 2015. The recommendations included:

• Develop a training module for centers regarding the accurate capture of race and ethnicity data; • Offer double BMT CTN accrual credit for enrollment of underserved minorities, when feasible; • Offer more pediatric trials, and lower the age requirement of adult trials to 15 to include adolescent

and young adult populations; • Remind Special Populations Committee members of their charge to carefully review eligibility criteria

of new protocols to ensure the studies are inclusive of pediatric and other special population patients. The DCC is working with the Committee to implement the prioritized recommendations.

2.3.3.5 Toxicity and Supportive Care Committee The Toxicity and Supportive Care Committee consists of Core and Affiliate Center transplant physicians. This committee:

• Works with the DCC to define methods for evaluating adverse events and toxicities after transplantation; • Reviews the evaluation and monitoring requirements for toxicities on BMT CTN protocols; • Designs and approves forms and procedures for collecting toxicity data, including standards for

expedited reporting of certain adverse events. The current Toxicity and Supportive Care Committee roster is listed in Attachment A6.


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2.3.4 Administrative Committees

2.3.4.1 Executive Committee The Executive Committee consists of the Steering Committee Chair, Chair-Elect or Immediate Past Chair, Vice Chair, NHLBI and NCI Project Officers, and DCC Principal Investigator and Co-Principal Investigators. The Executive Committee is a subcommittee of the Steering Committee and works in collaboration with the DCC. Executive Committee members are indicated by an asterisk (*) in Attachment A1. The Executive Committee ensures participating transplant centers adhere to BMT CTN policies and procedures, and it works together with the Steering Committee to resolve operational issues raised by investigators, Clinical Research Associates, laboratory and repository staff, members of the DCC, and others. It appoints Technical and Administrative Committee members. The Executive Committee also:

• Addresses policy making issues; • Reviews contractual arrangements and financial matters affecting the Network as a whole; • Makes recommendations to the Steering Committee; • Reviews and approves Transplant Center Performance Reports, audits, and corrective action plans; • Provides initial review of research proposals submitted to the BMT CTN for new trials and ancillary

studies; • Assists in developing Steering Committee meeting agendas.

2.3.4.2 Publications, Abstracts, and Presentations Committee The Publications, Abstracts, and Presentations Committee consists of Core and Affiliate Center transplant physicians. This committee develops publication and presentation policies. It also reviews publications and presentations to ensure confidentiality of study participants and proprietary information as well as to ensure appropriate acknowledgements of contributions, sponsorship, and authorship. During this reporting period, the Committee reviewed 9 abstracts and 14 manuscripts. Publications Committee members are appointed by the Executive using the same nomination process as described above. The current Publications, Abstracts, and Presentations Committee roster is listed in Attachment A7.

2.3.5 Ad Hoc Committees

Additional administrative and technical committees are convened as needed. For example, a Nominating Committee is formed to propose candidates for open committee positions.

• Scientific Advisory Committees. As a result of the Network’s 2007 State of the Science Symposium (Section 6.2.1), 12 Scientific Advisory Committees were formed to address specific areas pertinent to HCT trials. After the conclusion of the State of the Science Symposium, these Scientific Advisory Committees continued to operate and meet on an ad hoc basis to review and prioritize the Network’s scientific agenda. In the summer of 2011, the committees reviewed and summarized protocol concepts submitted by Core Center applicants for discussion at the July Steering Committee Meeting, the first meeting with new Core Center representatives. The Committees were redesigned and reconvened to plan for the 2014 State of the Science Symposium (Section 6.2.2).

• GVHD Committee. During this reporting period, the GVHD Committee continued to work with BMT CTN investigators to evaluate and propose new GVHD study concepts. In particular the Committee assessed potential follow-on studies to BMT CTN 1203, which is slated to complete accrual in April, almost a year ahead of projections. Three acute GVHD study proposals were presented to the Steering Committee in February, and the Steering Committee approved further development of the concepts as well as exploration into external funding options. The Committee will continue their efforts this year


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and will report back to the Steering Committee when concepts are refined and funding secured. • Returning Genetics Results Task Force. Also during this reporting period, a task force comprised of

Network physicians and DCC staff was assembled to review and evaluate issues related to genetic testing and return of incidental findings to patients enrolled in BMT CTN protocols. The Returning Genetics Results Task Force evaluated current informed consent language regarding banked samples and potential future research using these samples for genetic tests. The Task Force also reviewed current recommendations from the NHLBI working group, actionable findings generated from genetic tests, and options for study participants in receiving these results. After this careful review, the Task Force determined that additional work was needed to draft language to be included in consent forms, review incidental genetic findings, confirm their validity, and outline a course of action and provide guidance for physicians in returning genetic results to subjects (patients and donors) involved in BMT CTN studies. The Task Force presented these recommendations to the Steering Committee in February 2016. The Steering Committee asked the Task Force to formally document these recommendations and work with the BMT CTN Biomarkers Committee (Section 2.3.3.1) to draft necessary language and standard operating procedures.

2.3.6 Review Committees

Three independent Review Committees provide additional oversight for BMT CTN trials: • Protocol Review Committee. The Protocol Review Committee is appointed by the NHLBI and consists of

a Chairperson and Members whose experience reflect areas of expertise necessary to evaluate the scientific merit and design of BMT CTN protocols. Consultants may be added on an ad hoc basis if needed. The Protocol Chair (or designee), Protocol Officer, Statistician, and senior members of the DCC represent the Protocol Team at Protocol Review Committee meetings.

• Data and Safety Monitoring Boards. The two Data and Safety Monitoring Boards are independent boards appointed by the NHLBI and/or NCI. Each is composed of a Chair and Members with expertise in biostatistics, clinical trials, bioethics, and the specific research area(s) of the Network studies. Consultants may be added on an ad hoc basis if needed. Each Board handles about half of the Network portfolio of trials.

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 3.0 Administrative Functions of the DCC

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3.0 Administrative Functions of the DCC

The DCC is a collaborative partnership of three organizations with extensive experience in multicenter, HCT-related clinical research. The DCC is led by Mary Horowitz, MD, MS (CIBMTR); Adam Mendizabal, PhD (The Emmes Corporation); and Dennis Confer, MD (NMDP/Be The Match). The DCC supports and manages the efficient development, implementation, and completion of high-quality Phase II and III clinical trials for the Network, including:

• Evaluating and prioritizing study concepts; • Developing protocols with appropriate statistical designs; • Activating studies and developing plans to accrue patients in a timely manner; • Monitoring for safety, regulatory, and protocol compliance as well as data accuracy; • Collecting complete clinical and laboratory data; • Analyzing and sharing research results.

The DCC also coordinates and supports overall BMT CTN activities to enhance Network effectiveness, including:

• Maintaining the Administrative and Technical Manuals of Procedures; • Facilitating communication and maintaining public and private websites; • Maintaining a state-of-the-art research database; • Maintaining systems for acquisition and storage of biologic specimens; • Facilitating study completion, and publishing results in a timely manner ; • Managing contractual arrangements and fiscal activities; • Monitoring and improving overall center performance; • Supporting all Network committees and activities with meeting planning and other logistical support; • Collaborating with government organizations to avoid competing studies and foster intra-group

participation.

3.1 DCC Partner Organizations

The DCC consists of three partners: • CIBMTR (Milwaukee, Wisconsin, and Minneapolis, Minnesota) is a research organization formed in 2004

from the affiliation of the International Bone Marrow Transplant Registry at the Medical College of Wisconsin (MCW) and the Research Department of NMDP/Be The Match. The CIBMTR has a proven history of clinical research and publication in both HCT and statistical methodology. It has fostered effective collaborations with a large network of transplant centers. It also maintains an extensive observational research database of virtually all allogeneic transplantations and most autologous transplantations performed in the US.

• The Emmes Corporation (Rockville, Maryland) is a contract research organization established in 1978 that has managed more than 1,000 Phase I-IV trials and registries in 60 countries on 6 continents. Emmes provides experience in planning, implementing, and managing multicenter clinical trials in a variety of areas, including HCT, statistical design and analysis, clinical trial design and management, complex data collection system design and implementation, site monitoring, and regulatory support.

• NMDP/Be The Match (Minneapolis, Minnesota) was established in 1987. It is the world leader in HCT donor registry and graft procurement management, and it operates the world’s largest HCT-related Research Sample Repository. NMDP/Be The Match has a large network of donor, collection and transplant centers as well as cord blood banks; a skilled Contracts and Procurement Department that manages contracts with 178 US and international transplant centers and maintains contractual


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relationships with specimen repositories and contract laboratories; an experienced Patient and Health Professional Services department that provides educational and counseling services to patients in need of a transplant; and a Case Management department that facilitates most of the unrelated donor transplantations performed in the US.

Figure 3.1 illustrates the relationship among DCC organizations and its distribution of responsibilities, and Table 3.1 describes the specific responsibilities of each DCC member. Figure 3.2 displays the organizational structure of the DCC.

Figure 3.1. DCC organization


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Table 3.1. Responsibilities of DCC members

DCC Member Responsibilities CIBMTR NMDP/Be The Match Emmes

Administrative Functions

Provide overall scientific /administrative leadership Lead Support Support

Develop Manuals of Procedures / Standard Operating Procedures Support Support Lead

Facilitate meeting logisticsa Support Lead Support

Coordinate meeting materialsb Support Support Lead

Manage electronic communications (general and study-specific) Support Support Lead

Maintain roster of participants Support Support Lead

Prepare budget and track financials Support Lead Support

Trials Development & Management

Develop / review concepts Lead Support Support

Develop protocols Shared Shared Shared

Protocol Team

Serve as Protocol Officer Shared Shared -----

Serve as Protocol Statistician Shared ----- Shared

Serve as Patient Services Representative ----- Lead -----

Serve as Protocol Coordinator ----- ----- Lead

Manage Protocol Document Support Support Lead

Provide Protocol Review Committee supportc Shared Shared Shared

Protocol Implementation

Identify centers Lead Support Support

Certify centersd Support Support Lead

Contract with centers Support Lead Support

Identify laboratories / repositories Support Lead Support

Contract with laboratories Support Lead Support

Maintain roster of study participants Support ----- Lead

Manage data management systeme Support Support Lead

Develop Case Report Forms Support Support Lead

Coordinate laboratory & repository functions Support Lead Support

Ensure quality of therapeutic & diagnostic modalities Support Support Lead


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DCC Member Responsibilities CIBMTR NMDP/Be The Match Emmes

Manage site activation process, including monitoring regulatory compliance ----- ----- Lead

Train site personnel Support Support Lead

Develop patient materials Support Lead Support

Monitor Adverse Events Support Support Lead

Develop and implement accrual plan Shared Shared Shared

Provide Data and Safety Monitoring Board support Support Support Lead

Review performance of centers Shared Shared Shared

Monitor accrual Shared Support Shared

Monitor data accuracy and conduct data review sessions Support ----- Lead

Prepare reports / manuscripts Shared Shared Shared

Coordinate dissemination of results Shared Shared Shared

Develop Statistical Methodology Shared ----- Shared

a Schedule site location, travel arrangements, conference calling, travel reimbursements

b Develop agendas, supporting materials, reports, and minutes

c Support Steering and Protocol Review Committees during review process

d Certify ability of centers to execute special requirements of protocol

e Including systems for registration, Web-based data entry, database design, study archive backup, contingency plans


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Figure 3.2. DCC organizational structure as of March 31, 2016

The Emmes CorporationAdam Mendizabal, PhD

DCC Co-Principal Investigator

The Emmes CorporationAdam Mendizabal, PhD

DCC Co-Principal Investigator

Beth Blackwell, ScDPeter Dawson, PhDJill El-Khorazaty, MSGeorgia Koliou, MSMat Makowski, PhD

Cindy Wu, MS~ Maggie Wu, MSJessica Zhu, MS

Statisticians

Beth Blackwell, ScDPeter Dawson, PhDJill El-Khorazaty, MSGeorgia Koliou, MSMat Makowski, PhD

Cindy Wu, MS~ Maggie Wu, MSJessica Zhu, MS

Statisticians

Brianne Allison~ Kate BickettAchintya Jaitly

Cathryn Mudrick, MPH~ Courtney Nelson

Brady NesbittKelly O’Brien, PhD

Theresa Pritchard, MSAlyssa Ramirez

Laura RawlsWhitney Sheffer

Samantha Wilkins, MAHeather Wittsack

Protocol Coordinators

Brianne Allison~ Kate BickettAchintya Jaitly

Cathryn Mudrick, MPH~ Courtney Nelson

Brady NesbittKelly O’Brien, PhD

Theresa Pritchard, MSAlyssa Ramirez

Laura RawlsWhitney Sheffer

Samantha Wilkins, MAHeather Wittsack

Protocol Coordinators

~ Ellen Parker, MBAJensen PodbielskiThomas Tamura

Admin Coordinators

~ Ellen Parker, MBAJensen PodbielskiThomas Tamura

Admin Coordinators

Veronica GarciaKate Ketkaew

~ Mary MaglioccoIris Yu

Clinical Systems Analysts

Veronica GarciaKate Ketkaew

~ Mary MaglioccoIris Yu

Clinical Systems Analysts

Iris Gersten, MSProject Director

Iris Gersten, MSProject Director

~ Gillian Armstrong, PhDAlan Ramnath

Regulatory

~ Gillian Armstrong, PhDAlan Ramnath

Regulatory

~ Jennifer Romeril, RNAudra Thompson, RN

Lauren ZahraSafety Monitors

~ Jennifer Romeril, RNAudra Thompson, RN

Lauren ZahraSafety Monitors

Alex BorbelySue Isman

Brianna Johnson~ Kristin Knust, MS

Roe WrightData Managers

Alex BorbelySue Isman

Brianna Johnson~ Kristin Knust, MS

Roe WrightData Managers

Michelle LaMotteoBill Karabelas

Programmer / Analysts

Michelle LaMotteoBill Karabelas

Programmer / Analysts

~ Cynthia Couture, RNProtocol Monitor

~ Cynthia Couture, RNProtocol Monitor

CIBMTR MilwaukeeMary Horowitz, MD, MS

^ DCC Principal Investigator

CIBMTR MilwaukeeMary Horowitz, MD, MS

^ DCC Principal Investigator

NMDP / CIBMTR MinneapolisDennis Confer, MD

^ DCC Co-Principal Investigator

NMDP / CIBMTR MinneapolisDennis Confer, MD

^ DCC Co-Principal Investigator

Stephen Spellman, MBSDirector, Immunobiology &

Observational Research

Stephen Spellman, MBSDirector, Immunobiology &

Observational Research

Alan Howard, PhDPrincipal Immunobiology

Research Scientist

Alan Howard, PhDPrincipal Immunobiology

Research Scientist

Stephanie WaldvogelImmunobiology

Research Scientist

Stephanie WaldvogelImmunobiology

Research Scientist

NMDP/Be The MatchSupport Services

NMDP/Be The MatchSupport Services

Rebecca DrexlerSenior Manager,

Prospective Research

Rebecca DrexlerSenior Manager,

Prospective Research

Jana DworskiProject Coordinator

Jana DworskiProject Coordinator

Elizabeth Murphy,EdD, RN

VP, Patient Services

Elizabeth Murphy,EdD, RN

VP, Patient Services

Mary FreyDirector, Contracts

& Procurement

Mary FreyDirector, Contracts

& Procurement

Ellen Denzen, MSSr Manager, Health Services Research

Ellen Denzen, MSSr Manager, Health Services Research

Gina GravesDirector, Finance

and Controller

Gina GravesDirector, Finance

and Controller

Nancy Poland, MASr Mgr, Contracts& Procurement

Nancy Poland, MASr Mgr, Contracts& Procurement

Kevin WeberSr Accountant,

Contracts & Awards

Kevin WeberSr Accountant,

Contracts & Awards

Jenna DahlbergSupervisor,

Contract & Award Accounting

Jenna DahlbergSupervisor,

Contract & Award Accounting

Heather Moore, MPH, CHES

Program Specialist

Heather Moore, MPH, CHES

Program Specialist

Lensa IdossaProgram Analyst

Lensa IdossaProgram Analyst

Pam BudnickRenee Carby, MS

Kiila LeeContract

Representatives

Pam BudnickRenee Carby, MS

Kiila LeeContract

Representatives

Susan LahtiSr ParalegalSusan LahtiSr Paralegal

Peggy SchmidtCost Accountant, Gov’t Accounting

Peggy SchmidtCost Accountant, Gov’t Accounting

Jeanette Carreras, MPHRaphael Fraser, PhD

Brent Logan, PhDWaleska Perez, MPH

Biostatisticians

Jeanette Carreras, MPHRaphael Fraser, PhD

Brent Logan, PhDWaleska Perez, MPH

BiostatisticiansCristina Gonzalez

Grants Financial ManagerCristina Gonzalez

Grants Financial Manager

Kim JacksonAdministrative Asst

Kim JacksonAdministrative Asst

Kavita BhavsarBMT CTN Data

Coordinator

Kavita BhavsarBMT CTN Data

Coordinator

Mita DesaiData Entry

Coordinator

Mita DesaiData Entry

Coordinator

* Weiyun Ai, PhD, MD* Christopher Bredeson, MD

* Steven Deeks, MD* Dianna Howard, MD

* Tammy Kindwall-Keller, MD* Gabrielle Meyers, MD^ * Willis Navarro, MD* Eneida Nemecek, MD^ * Marcie Riches, MD

* Bipin Savani, MD* Shannon Smiley, MD

* Angie Smith, MD* Trisha Wong, MD, MS

KEY Emmes Corporation, Rockville, MD ^ Protocol Officer CIBMTR, Milwaukee, WI * Medical Monitor NMDP/CIBMTR, Minneapolis, MN ~ Group Manager Various Locations

Amy Foley, MABMT CTN Project

Manager

Amy Foley, MABMT CTN Project

Manager

Ashley SpahnImmunobiology

Research Scientist

Ashley SpahnImmunobiology

Research Scientist

Patricia Steinert, PhDAdministrator

Patricia Steinert, PhDAdministrator

Jessica Gillis-Smith, MPHPublishing Coordinator

Jessica Gillis-Smith, MPHPublishing Coordinator

Tucker GraczkowskiProgrammer AnalystTucker GraczkowskiProgrammer Analyst

^ Anita D’Souza, MD^ * Mary Eapen, MD

^ Mehdi Hamadani, MD^ * Marcelo Pasquini, MD

^ * Wael Saber, MD* Liza Thiel, MD

^ Anita D’Souza, MD^ * Mary Eapen, MD

^ Mehdi Hamadani, MD^ * Marcelo Pasquini, MD

^ * Wael Saber, MD* Liza Thiel, MD

Denise King, MSProject Director

Denise King, MSProject Director


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3.2 Policies and Procedures

The BMT CTN has two Manuals of Procedures: Administrative and Technical. The Administrative Manual includes policies and procedures related to:

• Participation in Network protocols, including detailed steps for proposing, drafting, and executing studies;

• Roles and duties of Core and Affiliate Centers and Network committees; • Roles of the CIBMTR, NMDP/Be The Match, and Emmes within the DCC; • Transplant center site monitoring; • Adverse event reporting; • Human subject protection and regulatory procedures; • Publications, abstracts, and presentations; • Ancillary and secondary analysis studies.

The Technical Manual of Procedures is a composite of policies and procedures pertinent to practice guidelines and laboratory evaluations unique to HCT. The Technical Manual includes detailed policies and procedures regarding:

• Acute and chronic GVHD; • Characterization and processing for hematopoietic cellular products; • Diagnosing and grading infectious diseases; • Technical Committees’ policies.

An updated version of the Administrative Manual of Procedures was released in August 2015. The Technical Manual will be updated during the next reporting period. These manuals and other procedural documents are available on the BMT CTN public website (bmtctn.net) and a password-protected, secure website for Network members (bmtctnsp.net).

3.3 Administrative Support

The DCC coordinates and schedules meetings and conference calls for the Steering, Executive, Scientific Advisory, Administrative, and Technical Committees as well as for Protocol Teams. From April 1, 2015, through March 31, 2016, the DCC managed 436 conference calls. DCC representatives attend and participate in all Network meetings, providing logistical support to ensure the meetings are conducted efficiently and effectively. Two or more DCC staff members participate on all Technical Committee and Protocol Team calls, preparing and circulating agendas and minutes for these committees. The DCC also maintains version control of protocols during development and after their approval, including all amendments.

3.4 Fiscal Planning and Contracting Support

NMDP/Be The Match manages fiscal planning and contract support for the BMT CTN. Personnel from the NMDP/Be The Match Contracts and Procurement Department participate in DCC conference calls, protocol development calls, Executive and Steering Committee calls, and in-person Steering Committee meetings. NMDP/Be The Match develops and executes Requests for Proposals, service agreements, and agreements for laboratory and pharmacy services to support specific protocols. Throughout the history of the BMT CTN, and in collaboration with both NHLBI and NCI, NMDP/Be The Match has negotiated a number of Memoranda of Agreement to sponsor contributions that offset the cost of individual protocols or provide pharmaceutical products. NMDP/Be The Match has also executed agreements with each of the NCI Cooperative Groups, fostering collaboration with groups outside the Network. On an ongoing basis, the NMDP/Be The Match Contracts and Procurement Department:


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• Executes Master Agreements and corresponding Clinical Study Protocol Riders for each protocol, facilitating participation of Affiliate and Core Centers in BMT CTN protocols;

• Coordinates and manages the protocol budget development process, including reimbursements for protocol-specific patient costs; generates financial reports on protocol spending; and provides forecasts of future spending based on observed patterns, when requested;

• Assists the protocol teams in selecting the best-performing Affiliate Centers by developing performance “snapshots” for each Affiliate Center applying to participate on a study. The snapshot shows the amount of time it takes a center to sign each rider as well as the average number of months for all BMT CTN riders; the amount of time it takes from approval to activation and the average for all BMT CTN studies; enrollment history on BMT CTN studies; and other relevant facts.

3.4.1 Cost-Saving Mechanisms

The DCC carefully manages the resources of the Network. It established a uniform budgeting model to project trial costs accurately and uses a competitive bid process to procure laboratory, pharmacy, and other services, ensuring that NIH funds are used wisely. To minimize delays associated with contracting with private companies, the DCC established a policy of face-to-face meetings with potential contributors early in the protocol development process. These meetings familiarize potential contributors with the Network, its membership, and its research activities, and they allow the DCC to identify specific corporate contract liaisons. Additionally, the Steering Committee encourages Protocol Teams to consider cost-saving mechanisms such as:

• Restricting study requirements, such as research repository samples, to those that are essential to answering the primary and secondary questions;

• Limiting the number of secondary questions to the most scientifically important; • Reducing the length of follow-up periods and using the established CIBMTR Research Database for long

term follow-up of enrolled patients beyond the primary endpoint.

3.5 Communication

Managing the large Network and its protocol activity requires excellent communication. Information must flow among DCC members, Network committees, transplant centers, laboratory and repository facilities, the medical community, and the lay public. Weekly teleconferences for leadership and DCC members and monthly teleconferences for the Executive Committee are conducted. Steering Committee meetings are scheduled either in-person or by teleconference each month. Additional communication efforts are described in this section.

3.5.1 Maintaining BMT CTN Websites

The DCC maintains a public website (bmtctn.net) and a secure, password-protected website (bmtctnsp.net). The Network’s public website features:

• A BMT CTN organizational overview and contact information; • The current BMT CTN Progress Report; • The current State of the Science Symposium Report; • Current versions of open protocols; • Educational materials for all open protocols; • Applications to participate in BMT CTN protocols as an Affiliate Center; • Administrative and Technical Manuals of Operations; • A list of BMT CTN publications; • A summary of the BMT CTN’s research sample collection listing biological samples available for all

studies, by time point and sample type, and two summary tables: GVHD treatment trial samples and


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allogeneic transplant trial samples; • Links to related DCC and government partner websites; • A password-protected page for BMT CTN Principal Investigators and Coordinators that includes links to:

o Data reports on site activation, accrual by site, projected accrual, demographics, missing forms summary, lab compliance (overall), monthly accrual by center, and data quality by center;

o Private BMT CTN, AdvantageEDC data collection, and GlobalTrace specimen tracking websites; o AdvantageEDC and GlobalTrace training modules.

The Network’s secure, password-protected website uses Microsoft SharePoint Server™ software to allow Network participants to share confidential information. It features:

• Meeting materials, including agendas, minutes, and conference call materials; • Protocol Team materials, including the current version of protocols in development; • Rosters of personnel at participating centers; • Rosters for the Steering, Administrative, and Technical Committees as well as Protocol Teams; • Study accrual reports; • Monthly recruitment reports.

The DCC uses a separate password-protected area of the secure site to post Data and Safety Monitoring Board meeting materials, share confidential information, and distribute monthly safety monitoring reports. All necessary meeting materials are posted two weeks before scheduled meetings. Adverse events reports and stopping guideline (safety) tables and graphs are posted monthly. Data and Safety Monitoring Board members can access the accrual, monthly recruitment, data quality, and site activation status reports, which are updated nightly or monthly depending on the report. The CIBMTR’s public website (cibmtr.org) has a page dedicated to the Network, including an overview of its functions, a list of all BMT CTN protocols, and a link to the BMT CTN public website. Additionally, the CIBMTR displays information about the Network and its protocols at national and international meetings. NMDP/Be The Match’s public website (bethematch.org) also has a page dedicated to the BMT CTN, including an overview of the Network and links to the BMT CTN and government partner websites.

3.5.2 Developing Patient Support and Marketing Materials

NMDP/Be The Match’s Patient and Health Professional Services Department assists the Network in developing patient-friendly study materials. This department managed an extensive project to reformat the Network’s patient consent and assent forms for easier readability and comprehension. This resulted in a 2011 manuscript that summarized recommendations of the review team for the development and formatting of accessible consent forms for multicenter clinical trials (Denzen et al., Biology of Blood and Marrow Transplantation, full citation listed in Appendix B1.) The intent of these recommendations is to guide the informed consent form writing process, simplify local IRB review of consent forms, enhance patient comprehension, and improve patient satisfaction. The recommendations are being tested in a randomized study of the updated consent versus the standard format in the Easy-to-Read Informed Consent study (BMT CTN 1205). Several members of the original Patient and Health Professional Services team who revised the consent form format are on the BMT CTN 1205 protocol team. The Patient and Health Professional Services Department and NMDP/Be The Match Marketing and Communications Department also support communications for accrual enhancement, help develop patient education materials, and assist in the design of Network publicity materials, such as protocol flyers and posters used for national meetings and emailed accrual updates.


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3.5.3 Communicating Trial Results

Communicating trial results rapidly and accurately is a fundamental activity of the DCC. Efficient and accurate data collection, processing, and analysis — each stage of which is supported by the DCC — ensures the integrity of Network trials and provides the foundation for publication and dissemination of study results. For all BMT CTN primary results publications since inception, the median number of days from the DCC statistician’s dissemination of the final analysis report to manuscript submission is 232 days. The median number of days from submission to publication is 134 days. The DCC helps Protocol Teams disseminate study results and publish as quickly as possible, assisting investigators in developing study slide sets and poster presentations for national and international meetings. The DCC also provides administrative support to the Publications Committee in its oversight of the publication process and assures proper acknowledgement of trial contributors. DCC staff members coordinate, compile, and distribute the annual BMT CTN Progress Report to the research community and the public to provide them with updated information on protocol activity, including published findings. These reports are available in print and digital format, and they are posted on the Network’s public website (https://web.emmes.com/study/bmt2/ Progress%20Reports.html).

3.5.4 Social Media Engagement

During the previous reporting period, the Steering Committee approved the Social Media Task Force’s recommendations to target communications to healthcare providers via social media. The targeted audience includes those at BMT CTN Core, Consortia, and Affiliate Centers: physicians, physician assistants, nurse practitioners, pharmacists, nurses, study coordinators, data managers, statisticians, and laboratory and regulatory staff; NHLBI and NCI Project Officers; referring physicians and research staff outside the Network; related organizations (e.g. ASBMT, NMDP/Be The Match, ASH, American Association of Blood Banks); and medical students. The primary goals of the BMT CTN’s adoption of social media forums are:

• Visibility of the Network – increasing awareness of the BMT CTN, participating centers, and Network clinical trial portfolio and publications;

• Inclusiveness – communicating with individuals at BMT CTN centers who are not included on BMT CTN distribution lists and do not attend meetings (e.g. junior investigators) as well as reaching referring hematology / oncology and community physicians;

• Collaboration – engaging new, and therefore a wider variety of, voices within and outside the Network; • Education – sharing BMT CTN resources as well as linked content from other affiliated groups (e.g.

ASBMT, NMDP/Be The Match, NIH). Based on the Task Force’s background research, including interviews with other similar organizations and cooperative groups, it was determined the optimal platforms to reach the targeted audiences were Twitter and Facebook. After Steering Committee approval in June 2014, the DCC formed an internal Social Media Team to develop the Network’s social media policy, develop content, and launch the accounts. The Network’s Twitter (@BMTCTN) (Figure 3.3) and Facebook (facebook.com/bmtctn) (Figure 3.4) accounts were launched in October 2014. As of March 31, 2016, the BMT CTN has 607 Twitter followers and 142 Facebook “likes”, which is an increase of 332 and 30, respectively. The greatest activity continues to be during the annual ASH and BMT Tandem Meetings. A number of new Twitter followers and Facebook likes were gained during these meetings, and it proved to be an effective way of promoting BMT CTN activities and presentations during the meetings.


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Figure 3.3. Screen shot of BMT CTN Twitter account

Figure 3.4. Screen shot of BMT CTN Facebook account

The DCC Social Media Team continues to meet weekly to develop content. During this reporting period, the team created a monthly dashboard, capturing key metrics to evaluate the Network’s overall social media performance and, in particular, which content is most successful in reaching the target audience. In evaluating the annual metrics this year, the team discovered that the Twitter metrics were being met consistently while the Facebook metrics lagged. The DCC Social Media Team developed a comprehensive survey to assess usage by other similar organizations (e.g. NCI cooperative groups, other research networks). The survey will be sent this spring and will evaluate which accounts these groups are using, their activity level, the successfulness and usefulness of their accounts, the benefits and disadvantages of each, the amount of time spent on social media efforts, and their target metrics. Based on the survey results and re-evaluation of the metrics, the DCC Social Media Team will make recommendations to the DCC leadership regarding future strategies for the accounts.


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3.6 Training

Ongoing education is imperative for ensuring protocol compliance and data quality. DCC staff members conduct site visits and calls to transplant centers to initiate protocols and educate center personnel on Network policies and procedures. Research staff members at the center receive an initiation report. Clinical Research Associate training sessions are held annually in conjunction with the BMT Tandem Meetings. These sessions cover data entry, quality control issues, and reviews of procedures and protocol requirements. They also provide the DCC with useful feedback from centers. General Clinical Research Associate calls and protocol-specific calls are held as necessary, with minutes distributed to research staff. Additionally, the Network provides online training in its AdvantageEDC and GlobalTrace software packages that includes training modules with a training practicum (AdvantageEDC) and competency assessments (GlobalTrace). The Network also prepares an electronic newsletter for research staff and provides a variety of materials to assist centers in understanding and implementing protocol requirements.

3.7 Transplant Center Monitoring

The DCC regularly monitors the performance of BMT CTN Core Centers and their contributions to the Network. Daily or monthly accrual reports, form delinquency, number of data queries, and major and minor protocol violations are tracked. The Data and Safety Monitoring Board routinely reviews these data. Center Performance Reports (Attachment C1) are prepared annually (most recently in January 2016). Overall scores on Center Performance Rating (Attachment C2) are based on five categories:

• Scientific / administrative contributions (10 points); • Patient accrual (60 points); • Activation and enrollment (10 points); • Data quality (10 points); • Laboratory compliance (10 points).

Final scoring is a composite of category-specific metrics associated with each of these measures of commitment and involvement. Centers that receive a “needs improvement” score in any area must submit an action plan for resolving problems within six weeks of receiving the report. Additionally, Center Performance “snapshots” of actual-versus-projected accrual and laboratory compliance reports are distributed to Core Centers quarterly. During this reporting period, the DCC reviewed center performance data for the current grant cycle (2012-2015; reports were not issued for 2011 as the grant cycle started mid-year). As shown in Figure 3.5, there has been continued improvement in overall assessment scores over the course of seven years. In 2015, the most successful year yet, no centers received an overall “Needs Improvement” score. Data by Core Center / Consortium are provided in Table 3.2.


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Figure 3.5. Overall assessment of Core Center performance by year

3.8 Specimen Repository Support

3.8.1 Specimen Collection

Each BMT CTN protocol creates an important new opportunity for the scientific community to collect baseline and post-transplant / post-treatment biologic specimens for clinical research. For most protocols, biologic samples are collected for use in protocol-defined research aimed at answering specific questions for that patient population and its transplantation outcomes. Collection of supplementary samples is incorporated into most protocols for use in future research. These samples and the associated clinical data are made available as a valuable resource for investigators at large. BMT CTN research sample inventories continue to be regularly updated on the Network’s public website to help investigators better utilize this resource. This section provides important information regarding the procedures associated with biospecimen requests, the study proposal approval process, and biospecimen summaries listing available samples for all studies by time point and sample type. The DCC receives requests for the use of its research samples for transplantation or post-transplantation treatment-related ancillary studies. The procedures for judging the scientific merit of such studies, including evaluations by the parent study Protocol Team, Biomarkers Committee, DCC, and Steering Committee, are defined in the Administrative Manual of Procedures.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2008 2009 2010 2012 2013 2014 2015

Outstanding

Acceptable

Needs Improvement


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Table 3.2. Core Center / Consortium-specific assessment of center performance Center Performance by Core Center / Consortium

Center Name

2012 2013 2014 2015

Overall Score Overall Assessment



Overall Score

Overall Assessment

Baylor College of Medicine Consortium1 25.0 Needs Improvement 40.0 Needs Improvement 85.9 Acceptable 100

Outstanding

Case Western Reserve Univ Consortium 77.4 Acceptable 79.2 Acceptable 79.4 Acceptable 86.1 Acceptable

City of Hope National Medical Center 88.8 Acceptable 60.3 Acceptable 84.6 Acceptable 67.7 Acceptable

Dana Farber Consortium 86.0 Acceptable 68.8 Acceptable 89.2 Acceptable 89.4 Acceptable

Duke University Medical Center 33.8 Needs Improvement 81.9 Acceptable 79.3 Acceptable 70.8 Acceptable

Fred Hutchinson Cancer Research

91.3 Outstanding 86.8 Acceptable 88.5 Acceptable 86.4 Acceptable

H. Lee Moffitt Cancer Center 86.3 Acceptable 77.5 Acceptable 92.0 Outstanding 81.6 Acceptable

Johns Hopkins University 36.9 Needs Improvement 81.0 Acceptable 72.1 Acceptable 90.0 Outstanding

Memorial Sloan-Kettering Cancer Center 85.6 Acceptable 78.2 Acceptable 85.9 Acceptable 85.0 Acceptable

Northside Hospital Atlanta 76.9 Acceptable 91.1 Outstanding 93.5 Outstanding 87.9 Acceptable

Ohio State University Consortium 70.1 Acceptable 85.0 Acceptable 89.6 Acceptable 94.5 Outstanding

PBMTC 31.5 Needs Improvement 38.3 Needs Improvement 83.6 Acceptable 89.3 Acceptable

Stanford Hospital and Clinics 42.0 Needs Improvement 93.2 Outstanding 94.5 Outstanding 89.3 Acceptable

University of Florida Consortium 89.7 Acceptable 83.0 Acceptable 86.0 Acceptable 85.3 Acceptable

University of Michigan Consortium2 73.7 Acceptable 91.9 Outstanding 87.5 Acceptable 94.4 Outstanding

University of Minnesota 91.8 Outstanding 60.8 Acceptable 34.1 Needs Improvement 89.3 Acceptable

University of Nebraska Consortium 77.0 Acceptable 83.6 Acceptable 78.0 Acceptable 80.2 Acceptable

University of Pennsylvania Hospital 34.0 Needs Improvement 25.7 Needs Improvement 84.5 Acceptable 79.3 Acceptable

University of Texas MD Anderson 53.5 Needs Improvement 50.6 Needs Improvement 94.4 Outstanding 90.6 Outstanding

Washington University 83.0 Acceptable 27.0 Needs Improvement 84.5 Acceptable 79.9 Acceptable Notes: 1 Children’s National Medical Center joined the Baylor College of Medicine Consortium in January 2014, so the 2012 and 2013 assessments of the consortium only

measured the Baylor College of Medicine. 2 Mayo Clinic joined the University of Michigan Consortium in January 2013, so the 2012 assessment of the consortium only measured the University of Michigan.


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As of March 31, 2016, a total of 366,475 available research specimens, provide by 5,687 subjects, were being stored by the BMT CTN Repository Network: NHLBI Repository, BMT CTN Sample Repository operated by NMDP/Be The Match, and the AIDS and Cancer Specimen Resource Repository. A summary of currently available research samples at the NHLBI Repository, BMT CTN Sample Repository, and AIDS and Cancer Specimen Resource Repository is displayed in Tables 3.3a, 3.3b, and 3.3c, respectively.

Table 3.3a. BMT CTN center processed samples available at the NHLBI Repository

BMT CTN Protocol

Currently Available Biospecimens

Subjects with Available Biospecimens

0101

NHLBI Managed Open Collection (only clinical data)

NHLBI Managed Open Collection (only clinical data)

The biospecimens initially stored have been shipped to protocol-defined and ancillary project laboratories.

0102 10,482 613 patients

85 donors

0201 NHLBI Managed Open Collection (biospecimens and clinical data)

6,940

NHLBI Managed Open Collection (biospecimens and clinical data)

436 patients

0402 16,244 280 patients 184 donors

Table 3.3b. Samples processed and available at the BMT CTN Sample Repository

BMT CTN Protocol



0302 437 134 patients

0401 219 116 patients

0701 89 53 patients

0702 39,409 656 patients

07LT 1,101 90 patients

0801 4,136 143 patients

0802 3,538 201 patients

0901 1,356 276 patients

1101 10,461 188 patients

75 donors

1102 2,738 122 patients

1202 256,760 1,694 patients

1203 7,913 222 patients

1204 3,264 33 patients


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BMT CTN Protocol



1301 224 27 patients


Table 3.3c. Samples processed and available at the AIDS and Cancer Specimen Resource Repository BMT CTN Protocol




0903 126 7 patients

During this reporting period, 4,933 frozen sample aliquots were shipped from the BMT CTN / NHLBI repositories to project laboratories for the following protocol-defined and ancillary correlative studies:

• BMT CTN 0402: 1,163 samples – GVHD biomarker analyses of plasma samples from the BMT CTN 0402 Phase III clinical trial of tacrolimus-sirolimus vs tacrolimus-methotrexate

• BMT CTN 0402: 1,231 samples – Biomarkers of inflammation, endothelial damage, and angiogenesis after hematopoietic cell transplantation

• BMT CTN 0802: 195 samples - Assessment of T cell receptor (TCR) diversity in HCT recipients at the time of diagnosis of GVHD and the assessment of the relatedness of TCR sequences between subsets of patients based upon shared characteristics such as female donors into male recipients, HLA, or specific HLA mismatches

• BMT CTN 0201 and 0402: 169 samples - Allogeneic HY antibodies detected 3 months following sex-mismatched HCT predict chronic GVHD and non-relapse mortality: A BMT-CTN validation study

• BMT CTN 0302, 0402, and 0802: 1,988 samples - Validation of a microRNA signature for the prediction, diagnosis, and prognosis of acute graft-versus-host disease

• BMT CTN 0302 and 0802: 187 samples – Re-validation of Ann Arbor GVHD risk score algorithm

3.8.2 Research Sample Repository and Central Processing Lab

The central processing laboratory at the BMT CTN Research Sample Repository plays an important role in standardizing complex specimen processing procedures and expanding the collection of quality sample types for correlative studies. The availability of these services, which will be applicable to many future studies, helps reduce the research sample processing burden for clinical sites. The BMT CTN processing laboratory has received and processed samples from more than 3,100 Network shipments during this reporting period, with recent monthly averages of more than 165 shipments. The laboratory is currently processing peripheral blood samples into serum, plasma, PAXgene RNA lysates, viable peripheral blood mononuclear cell (PBMC), granulocyte, and buffy coat sample types. Bone marrow aspirates, buccal swabs, and viable marrow product mononuclear cell sample types are also being processed and stored at the BMT CTN Research Sample Repository. Over the past three reporting periods, there was a significant need throughout the Network to provide clinical sites with a way to collect research biospecimens on a Friday when their patients are seen by transplant center care providers. Previously, if samples were collected on Fridays, they would have been:

• Missed; • Collected outside of the target collection window (if study permitted);


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• Collected, held over the weekend and shipped on Monday, thereby decreasing the quality of sample and often becoming unusable for many purposes;

• Processed and frozen by the clinical site, if they were willing to do so and sample type would allow. In response to this need and requests from several BMT CTN clinical sites, the NMDP/Be The Match and BMT CTN responded in the previous reporting period by extending the hours of staffing and sample processing and biospecimen storage to now include Saturdays. This solution, implemented in February 2015, is demonstrating a positive impact on compliance and increased partnership in this BMT CTN network-wide research-related initiative. In this reporting period, the BMT CTN Biorepository received and processed samples from 380 shipments, which were associated with 7 different BMT CTN clinical trials.

3.8.3 Maximizing Sample Collection, Quality, and Availability

The DCC continues to invest substantial efforts to improve Network procedures for research sample collection, associated data accuracy, sample storage, and research sample testing. Highlights of these efforts and benefits include:

• Promoting the use of stored biospecimens and associated clinical trial data for ancillary laboratory research studies. The DCC obtained BMT CTN Steering Committee support and released a request for applications (RFA) for laboratory study proposals from investigators who wished to address supplemental questions that develop from the Network’s portfolio of prospective clinical trials and available research biospecimens. Five proposals were received and evaluated for scientific merit, perceived impact, feasibility of completion within the desired project time frame, and scope of the requested budget. Four of the five laboratory studies were approved and awarded, resulting in an investment of approximately $355,000. During this reporting period, DCC staff members worked with investigators to qualify, select, and ship biospecimens as well as to provide clinical trial data needed for the analysis of biomarker testing results in the context of the various transplant outcomes being studied. One investigator completed her analysis and presented results at the 2016 BMT Tandem Meetings. All other studies are underway and anticipated to be completed during the next reporting period.

• Continued integration of standardized sample acquisition forms and sample tracking (AdvantageEDC and GlobalTrace). Systematic sample data collection and specimen tracking provides additional real-time center assessment opportunities to increase the accuracy and compliance of sample collection information at each critical time point. The availability of sample acquisition forms in the AdvantageEDC forms grid provides centers an additional reminder of future sample collection target dates, facilitating patient appointment scheduling.

• Continued development of a network of research and clinical laboratories that support current and future studies. There are currently 19 active laboratory agreements, some of which were established through competitive Requests for Proposals. Announcements of future laboratory support opportunities are communicated on the BMT CTN public website and via email to current and past Core and Affiliate Center Principal Investigators at pre-screened clinical and research laboratories. Additionally, the ASBMT and the American Society for Clinical Pharmacology and Therapeutics send notification emails to their members regarding Request for Proposal opportunities for laboratory support of BMT CTN ancillary studies.

• Continued review of all pending sample shipments to the NHLBI Repository for older protocols. This process continues to provide an opportunity to review key procedures with center staff and to discuss effective sample management strategies, build relationships with research staff, and receive feedback on transplant center needs. The DCC continues to work with Network Centers and NHLBI BioLINCC staff


49

to proactively review sample manifest inventory data to ensure accurate linkage of clinical data associated with research samples being submitted for inclusion in BMT CTN biospecimen collections.

• Review of comprehensive center-specific sample collection and required laboratory testing compliance reports. Clinical centers receive the information they need to assess their achievements and areas of deficiencies and to facilitate discussions with DCC staff. These reports are periodically reviewed by DCC staff members who contact centers to discuss opportunities for improvement and process optimization. DCC staff members are receiving on average of 80 inquiries per week from clinical sites regarding guidance concerning upcoming research sample collection requirements, related procedures, and patient scheduling alternatives. The productive center relationships that have been built over the years have resulted in a high level of trust and confidence in the DCC, both in terms of their leadership and their abilities to manage and provide guidance on difficult situations encountered at centers.

• Focus on more complete instructional materials, training, and educational opportunities for research staff. Education efforts have improved understanding of the purpose and importance of the research sample collections by transplant center staff. Staff members are encouraged to discuss and develop best practices for tracking upcoming research sample collections and improving accuracy of patient information associated with biologic research samples. Dedicated DCC personnel and Research Sample Repository staff are always available to answer questions and support transplant center staff.

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 4.0 Concept to Publication: The Protocol Process

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4.0 Concept to Publication: The Protocol Process

Since its establishment in 2001, the Network has refined its processes for supporting selection, development, and implementation of studies. Current procedures reflect the Network’s commitment to efficient use of its resources to implement well-designed studies that accrue sufficient numbers of patients as rapidly as possible. This section describes the typical sequence of events. There is substantial overlap in the timeframes of these steps, as the Network seeks to implement tasks in parallel rather than sequentially whenever possible. Transplant center investigators, Protocol Team members, DCC staff members, external oversight bodies (Protocol Review Committee and Data and Safety Monitoring Board), NCI Cooperative Group collaborators, and funding partners (NHLBI and NCI) are all involved in developing, implementing, and completing studies. The Steering Committee is responsible for:

• Reviewing and prioritizing all concepts proposed for Network consideration; • Approving final draft protocols prior to Protocol Review Committee and Data and Safety Monitoring

Board review; • Overseeing execution and analysis of approved Network trials.

Figure 4.1 displays the protocol development and implementation processes described in this section.

Figure 4.1. Schema for protocol development and implementation

Protocol Development

ProposalConcept

Evaluation / Approval

Protocol Development

Protocol Approval

Steering PRC DSMB IRBs Committee

Technical Committees

Protocol Implementation / Completion

ActivationCase Report Forms* / Study

documents and procedures* / Data systems* / Contracts / Accrual plan* / Educational materials* / Site training

MaintenanceAccrual / Compliance / Data quality / Safety /

Amendments / Continued site training

ClosureData review / Data

files / Analysis / Abstracts /

Publications

* Work on these documents / tasks begins during the protocol development phase and is generally close

to completed by the time the first IRB approvals are available.

4.1 Concept Evaluation and Approval

Any investigator may submit study concepts for consideration. Study proposal requirements are posted on the Network’s public website (https://web.emmes.com/study/bmt2/Newstudyform.html).

4.1.1 DCC Review

Study concepts are submitted first to the DCC, which performs a preliminary review to ensure the proposed study does not conflict with an active study and the proposal is complete. The DCC then distributes the study concept to the Executive Committee for discussion at a regularly scheduled monthly meeting.


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4.1.2 Executive Committee Review

The Executive Committee reviews the study concept to ensure that it is consistent with the Network’s mission, does not compete with active BMT CTN protocols or BMT CTN protocols in development, and poses no major conflicts of interest. Eligible proposals are scheduled for review by the Steering Committee.

4.1.3 Steering Committee Review

Study concepts are scheduled for discussion at the monthly Steering Committee conference calls or in person meetings, which are held three times per year. The Steering Committee evaluates concepts for scientific merit, feasibility, and Network members’ willingness to participate. The Steering Committee may accept, reject, or recommend changes to the study concept. The DCC assists in the review process, using CIBMTR data to assess feasibility based on study population and eligibility requirements. The DCC supports the Steering Committee in its deliberations by providing the following information whenever possible:

• Numbers of patients currently undergoing transplantation at Core and Affiliate Centers who might meet eligibility criteria;

• Outcomes of interest in the specified population; • Evaluation of sample size requirements; • Suggestions for alternate study designs; • Special requirements for research samples and/or necessary agents; • Potential competing protocols.

4.2 Protocol Development

4.2.1 Establishment of a Protocol Team

When the Steering Committee approves a study concept, the DCC assigns it a protocol number, and a Protocol Team is formed. The Protocol Team meets weekly by teleconference during the development process and may hold in-person meetings to expedite the development of the protocol. The Steering Committee reviews team progress as needed. The Protocol Team includes:

• Protocol Chairs (Study Principal Investigators). The Protocol Chairs, generally the investigators who submitted the original concept, have primary responsibility for the protocol’s development and progress. Most Network protocols have two Chairs.

• Core and Affiliate Centers Representatives. Most Protocol Teams have four to six representatives (co-investigators) from Core and Affiliate centers.

• Protocol Officer. The Protocol Officer is a physician DCC member who helps address scientific and medical issues.

• Protocol Coordinator. A DCC Protocol Coordinator manages logistical and practical issues, such as coordinating meetings, preparing minutes, and maintaining protocol version control.

• Protocol Statisticians. DCC and NHLBI statisticians create and coordinate the Statistical Analysis Plan (Section 4.2.2).

• Contracts Representative. A DCC Contracts Representative manages Core and Affiliate Clinical Trials Agreements as well as laboratory, central pharmacy, supply procurement, and contributor agreements.

4.2.2 Statistical Design

Statistical analyses of study data are prepared and documented either in a Statistical Analysis Plan within the protocol document or as a standalone plan. This plan includes a synopsis of the study design; endpoints;


52

hypotheses; randomization and stratification procedures; sample size and power calculations; stopping rules for efficacy, futility, and/or toxicity; planned analyses of primary and secondary endpoints; adjustment for multiple testing; and control of type I error and subgroup analyses. Since the potential pool of patients for HCT trials is limited, statistical designs must make optimal use of available patients. Additionally, HCT trials face some unique challenges:

• When donors and recipients are consented and randomized separately, delays in this process can lead to dropout, as seen in BMT CTN 0201.

• There is the potential for multiple complications (infection, organ toxicity, GVHD, relapse, etc.) during the early post-transplantation period. Therefore, competing risks must be considered with all study endpoints. Competing risks are commonly addressed using composite endpoints as the primary outcome measure, as in BMT CTN 0101, 0402, 1203, and 1301. The CIBMTR Research Database helps identify patient candidates for study exclusion due to high risks of competing events. Cumulative incidence estimators are used to approximate probabilities of individual events occurring in the presence of competing risks.

• Non-proportional hazards and crossing survival curves occur when treatments under investigation have different timing of events, as with allogeneic versus autologous HCT (BMT CTN 0102), different regimen intensities (BMT CTN 0901), or different graft sources / donor types (BMT CTN 1101). If this occurs, the usual log-rank test is inappropriate, and a pointwise comparison of survival probabilities is often performed instead. CIBMTR data are again useful in identifying an appropriate follow-up time point, a time when most events of interest have occurred. More efficient methods for comparing groups with non-proportional hazards were recently implemented for the analysis of BMT CTN 0901.

• Analysis of quality-of-life data must consider non-ignorable missing data due to early mortality, particularly when quality of life is the primary endpoint, as in BMT CTN 0902.

• Primary and key secondary endpoints may be closely related, and explicit control of the familywise Type I Error rate is required, as seen with the gatekeeping procedures implemented in BMT CTN 1301.

• Selection of a clinically meaningful primary endpoint is extremely important in determining the size and interpretability of a clinical trial. This selection must carefully balance the time required to observe clinically meaningful differences (e.g. overall survival may require years of follow-up) versus the need to complete trials and report results to the scientific community in a reasonable timeframe. BMT CTN statisticians have extensive experience in navigating this balance while maintaining interpretability as shown in the upcoming BMT CTN 1506 study, which included extensive consultations with the FDA regarding the benefits and risks of relapse-free survival as the primary endpoint for a Phase III trial.

Emmes and CIBMTR statisticians are experts in analysis of HCT data, with many methodological publications to their credit. This expertise is an invaluable resource for addressing statistical challenges. DCC statisticians hold regular conference calls as well as ad hoc calls with PhD and Master’s-level statisticians to discuss current analyses and approaches to statistical issues. These discussions help ensure consistent, high quality, and appropriate statistical analyses for BMT CTN studies.

4.2.3 Accrual Planning

Accrual planning is an important step in the protocol development process. The BMT CTN Project Manager works with Protocol Team members to develop a customized accrual plan for each study. The accrual plan for each study considers projected accrual rates from Core and Affiliate Centers, data on potentially eligible patients from the CIBMTR Research Database, potential accrual barriers and competing studies, a list of advocacy and


53

other groups that should receive information about the trial, materials to be developed for referring physicians and study participants, and target meetings and audiences for presentations and educational sessions. When eligibility criteria are established, the Protocol Coordinator invites Core Centers to participate. The invitation survey also asks investigators to provide projected accrual, input into the study design (e.g. potential accrual barriers), and primary study contacts. Using the CIBMTR Research Database, accrual projections are compared to each center’s reported activity, and discrepancies are resolved. Often there are not enough potentially eligible patients from participating Core Centers, so the DCC reaches out to Affiliate Centers that have both the potential for contributing substantively to accrual and the necessary expertise to execute the study. During review of the accrual plan, the protocol team assesses anticipated accrual barriers and considers ways to minimize the barriers. The team also determines if any additional study materials need to be developed, e.g. for patients or referring physicians. Informational and educational materials are particularly important for studies involving patient populations that are not usual HCT candidates or that involve complex research activities. For example, during this reporting period, study synopses and letters for the two upcoming sickle cell disease protocols (1503 and 1507) were sent from the Protocol Chairs to hematologists responsible for treating sickle cell disease patients. These materials informed the hematologists of the studies and requested their participation in referring potential patients to their local transplant center. Previously, the 0801 team developed a video to demonstrate the chronic GVHD assessments required by the protocol. The 1101 team published an article to promote the study, which included follow-up data from the Phase II 0603/0604 precursor studies and a donor selection algorithm flow chart. Protocol teams also assess whether informational or educational sessions should be held to promote the study and the target audiences for these sessions. During this reporting period, informational meetings about the upcoming 1506 study were held at the BMT Tandem Meetings in Hawaii and at the Annual EBMT Congress in Spain since the plan is for an international trial. During the next reporting period, investigator meetings for the two upcoming sickle cell disease studies will be held at the Foundation for Sickle Cell Disease Research annual meeting, which is well-attended by non-transplant hematologists treating these patients. Educational sessions are also planned during the annual BMT Tandem Meetings, at the BMT CTN Coordinators or Investigators Meetings, as a component of the scientific sessions, or as standalone investigator meetings. Other educational sessions have included grand round presentations at participating centers by Protocol Chairs and webinars for transplant center investigators and coordinators. The accrual plan is approved by the protocol team prior to release of the protocol. It is re-evaluated throughout the course of the study, as needed, e.g. if unanticipated accrual barriers occur, accrual is slower than anticipated, or opportunities for additional educational opportunities are identified. See Section 4.6.1 for more information about accrual monitoring and intervention.

4.2.4 Budget Preparation

When a draft protocol is available, the NMDP/Be The Match-based Financial Analyst arranges a teleconference with the Protocol Chair(s), Officer, and Coordinator as well as other key parties to initiate budget preparation. The Financial Analyst drafts a budget based on the final draft protocol as well as laboratory and services requirements. Costs of labor for center and DCC personnel, medications, other therapies, shipping, and supplies are also considered. The Protocol Chair(s) and Protocol Officer review the draft budget, which is included in the materials that are distributed to the Protocol Review Committee. Before submission to NHLBI and NCI for approval, the NMDP/Be The Match Chief Financial Officer (or appropriate designee), Steering Committee Chair, and DCC Principal Investigator review and sign the final draft budget.


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4.2.5 Federal Regulations

The DCC maintains protocol-specific regulatory files for the Network, including FDA 1572 forms, investigator curriculum vitae, IRB approvals and approved consent forms, financial disclosures, medical licenses, pharmacy licenses (if applicable), and evidence of Human Subjects Research Training staff certification for each Core and Affiliate Center. The DCC prepared and submitted four Investigational Device Exemption applications, which were required for BMT CTN protocols 0101, 0303, 0801, and 1301. The DCC also submitted 12 Investigational New Drug applications to the FDA for BMT CTN protocols 0102, 0201, 0302 / 0403, 0401, 0701, 0702 / 07LT, 0801, 1101, 1203, 1302, 1401, and 1501. The FDA subsequently deemed Investigational New Drug / Investigational Device Exemption applications unnecessary for BMT CTN protocols 0101, 0701, 0801, 1101, and 1501.

4.2.6 Final Draft Protocol

The development process results in a final draft protocol document that provides the necessary details to perform a clinical trial. This document includes:

• An outline of the study design; • Study background, scientific rationale, and objectives; • Detailed description of treatments; • Detailed description of experimental design, including the Statistical Analysis Plan; • Definition of primary and secondary endpoints; • Eligibility requirements; • Follow-up schedules and requirements for patient exams; • Specimen submission schedules; • Safety measurements and adverse event reporting procedures; • Registration and randomization procedures; • Procedures for blinding study treatments; • Protocol-specific technical guidelines (e.g., donor selection criteria and graft processing techniques); • Informed consent template; • References; • Appendices.

The final draft protocol then undergoes a multi-step review process, as follows.

4.3 Protocol Approval

The final draft protocol requires approval by the Steering Committee, BMT CTN Technical Committees, the Protocol Review Committee, the Data and Safety Monitoring Board, and, finally, local IRBs.

4.3.1 Steering Committee Review

Two weeks in advance of Steering Committee review of a final draft protocol, the Steering Committee Chair assigns two or three members as primary reviewers. These reviewers study the final draft protocol in detail. They complete a BMT CTN Reviewer Checklist and evaluate the study’s background and rationale, design, endpoints, clinical and laboratory tests, statistical considerations, informed consent, and ancillary studies. They also provide an overall assessment of the protocol. The final draft of the protocol is then presented at a Steering Committee meeting.


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If approved by the Steering Committee, a Protocol Review Committee presentation is scheduled. Simultaneously, the final draft protocol is distributed to the five Technical Committees responsible for final draft protocol review.

4.3.2 Protocol Review Committee

The Protocol Review Committee assessment is scheduled through NHLBI. This group performs scientific review of each study. Several weeks in advance of each scheduled meeting, the DCC submits review materials, listed below, to the Protocol Review Committee:

• Final draft protocol and informed consent(s); • Frequently Asked Questions document; • Accrual plan; • Budget; • Reviewer Checklist.

The Protocol Review Committee conducts a preliminary evaluation of the documents and returns the checklist to the Protocol Team with comments regarding the study objectives, design, feasibility, statistical approach, study operations, and human subjects protection. The Protocol Team sends its written responses back to the Protocol Review Committee prior to the scheduled presentation. This approach makes deliberations more efficient and usually avoids the need for follow-up meetings and potential delays in implementation of the protocol. Once it receives Protocol Review Committee approval, the protocol is scheduled for Data and Safety Monitoring Board review.

4.3.3 Data and Safety Monitoring Board Review

Each BMT CTN trial is approved and monitored by one of two NHLBI-appointed Data and Safety Monitoring Boards. Boards have scheduled Webcasts in March, May, October, and December as well as in-person meetings in April and November to review the safety and efficacy endpoints outlined in the statistical sections of each protocol being presented. The DCC is responsible for providing the Boards with the information necessary for them to make their determinations. The Data and Safety Monitoring Boards must approve all new protocols or protocol amendments before implementation. When protocols or amendments are scheduled for review, the Data and Safety Monitoring Board provides written comments to the Protocol Team for response prior to the Data and Safety Monitoring Board meeting, similar to the Protocol Review Committee process. The BMT CTN’s Data Safety Monitoring Plan was reviewed by the Data and Safety Monitoring Boards and approved by NHLBI. All clinical sites enrolling patients on BMT CTN trials must adhere to the reporting requirements in the approved Data Safety Monitoring Plan. The DCC prepares all materials for Data and Safety Monitoring Board meetings and posts them for the Board on a password-protected website (bmtctnsp.net). The DCC also posts monthly safety monitoring reports, including adverse event reports and stopping guideline safety tables and graphs. These reports, in addition to accrual, monthly recruitment data quality, and site activation status reports, are available to the Data and Safety Monitoring Board members and to NIH program staff. After all Data and Safety Monitoring Board reviews, the DCC disseminates the Board’s recommendations (after approval by NHLBI) to the Protocol Chairs; Protocol Officer; additional protocol team members; and Investigators, Coordinators, and other key personnel at the participating centers. These memos are also posted on the appropriate protocol-specific pages of the Network password-protected website (bmtctnsp.net). The DCC ensures center compliance with the recommendations, including center IRB review and approval, training,


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accrual closure, and additional data review, as needed.

4.3.4 Final Review Prior to Release to Centers

After the Data and Safety Monitoring Board approves the protocol, the two Protocol Chairs and the Protocol Officer review the protocol a final time, using a review checklist. Starting in 2011, a final sign-off process was implemented. After the review is complete, at least two of the three reviewers must sign the first page of the protocol before it is distributed to centers.

4.4 Protocol Pre-Activation

To expedite study implementation and facilitate timely activation and successful accrual, the following activities occur concomitantly with protocol development:

• Creating Case Report Forms; • Preparing and distributing other protocol-specific materials, including a Laboratory Research Sample

Information Guide, Data Management Manual and Forms Guide, and guides for pharmacy procedures; • Modifying data systems to receive and monitor protocol-specific data; • Developing systems to acquire, store, distribute, and analyze protocol-specific biospecimens; • Contracting with centers, laboratories, pharmacies, and contributors.

The Protocol Team also forms an Endpoint Review Committee, with a charter, before the study opens to accrual. The Protocol Coordinator and Statistician are responsible for preparing review materials for the Endpoint Review Committee. These materials:

• Outline the primary and secondary endpoints to be evaluated; • Identify the endpoints to be adjudicated and the process for adjudication; • Define procedures for resolving discrepancies and recording results; • Outline the mechanisms for assessing subject eligibility and protocol compliance; • Conduct final reviews of the study data in a blinded manner whenever possible.

4.4.1 Designing Case Report Forms

Designing data collection forms is a collaborative venture involving each study’s scientific and clinical leadership, statisticians, laboratory collaborators, and the DCC. Standard processes ensure the study will have clear, easy-to-use forms that provide data to support its objectives without overwhelming study resources. The DCC is responsible for developing Case Report Forms and, to date, has developed 16 core Case Report Forms for use in all protocols. Another 380 protocol-specific forms were developed and are in use. Protocol-specific forms capture data on particular endpoints, important covariates, protocol-specified treatments, severe adverse events, and protocol compliance. Draft forms are distributed to the Protocol Team for review and input, and the revised forms are then reviewed by the Clinical Research Associate Committee, which evaluates them from a practical use perspective. Each data element is explicitly defined in a User’s Guide to minimize variability in responses. DCC staff members test each form prior to release.

4.4.2 Educational Materials and Other Study Documents

The NMDP/Be The Match’s Patient and Health Professional Services Department works with the Network to develop patient education materials to support new clinical trials. These materials help educate potential patients about the basics of clinical trials and provide a patient-friendly summary of the specific clinical trial. Educational materials are created for each new study and are available with the protocol when it is released for initial IRB submission. Patient and Health Professional Services staff members also help design informed consent documents so that they are patient-friendly and written at an eighth-grade reading level. The Network is


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evaluating a new two-column template for Informed Consent documents via the randomized Easy-to-Read Informed Consent study (BMT CTN 1205).

4.4.3 Release to Center IRBs

Once the protocol is approved by the Data and Safety Monitoring Board, the DCC releases the protocol materials to centers that agreed to participate so that they can submit the materials to their local IRBs. Each protocol includes a template for documenting Informed Consent that can be modified by participating centers to meet their local IRB requirements. In 2016, the DCC instituted an optional single IRB approach for the upcoming BMT CTN 1501 and 1503 studies. The NMDP IRB agreed to serve as the IRB of Record for this pilot project. NHLBI leadership approved this plan and encourages centers to participate. The NMDP IRB is accredited by the Association for the Accreditation of Human Research Protection Programs and was audited by the FDA in 2006 and 2015, both times with no findings. This IRB will assume responsibility for the studies on behalf of institutions that agree. Institutions must complete an IRB Authorization Agreement and a local context questionnaire in order to delegate responsibility to the NMDP IRB.

4.4.4 Site Initiation Training

Prior to protocol implementation, the Protocol Coordinator arranges either an initiation site visit or activation calls with key center personnel to review materials and processes. A Protocol Chair or Officer also participates in the call. The purpose of the training is to make certain the responsibilities and communication lines within the center are clear. Study procedures are discussed, including procedures for data and sample collection. If local pharmacies or laboratories are involved in a study, representatives from those departments participate in the site initiation meetings as well. A site initiation visit report is issued to all site personnel involved in the protocol within 60 days. The Network’s Sample Repository Research Administrator plays an important role in preparing centers for their biospecimen submissions by:

• Creating a protocol-specific Research Sample Information Guide; • Providing telephone and email support for site-specific questions regarding the IRB, project laboratories,

repositories, or information in the Research Sample Information Guide; • Providing training and ongoing technical and contractual support for all project laboratory staff on the

protocol. Customized initiation training is provided when needed, as in BMT CTN 1101, 1202, 1301, and 1401. BMT CTN 1101 has cord blood training requirements that differ from other trials, requiring additional training calls for clinical centers activating this trial. BMT CTN 1202 has complex sample collection / processing requirements that differ from previous studies. In a new initiative related to this trial, the Sample Repository Research Administrator holds additional research sample-specific training calls for the clinical centers that activate this trial. The Research Administrator also reviews sample submission for compliance for the first few patients enrolled by each center. BMT CTN 1301 is under an investigational device exemption (IDE) involving the CliniMACS® CD34 Reagent System to perform a cell selection procedure, which is not commonly performed on other trials. Training in the operation of the device is provided to center’s stem cell laboratory personnel by Miltenyi Biotec. The CliniMACS® CD34+ Cell Selection Procedure Standard Operating Procedure (BMT-1301-01.01 v2.0) was created specifically for this study to ensure centers follow a similar approach across multiple centers. The standard operating procedure requires sign off by the Stem Cell Laboratory Director at each center to acknowledge that


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they have reviewed and understand the procedure. To help ensure quality and consistency of processed products across multiple centers, stem cell laboratory personnel of each center are required to attend a Laboratory Coordinator training, via web conference. BMT CTN 1401 is a unique study that involves not only a clinical component but also a cell therapy component. Sites are manufacturing patient specific vaccine in their own good manufacturing practice-compliant cell processing facilities. This process involves cell collection, sterile culture, and storage of myeloma tumor cells. These selected sites have undergone hands-on training at the 1401 central laboratory at Beth Israel Deaconess Medical Center in Boston, MA. Furthermore, these sites are also required to generate successful mock runs of vaccine generation at their own facility and send aliquots to Beth Israel Deaconess Medical Center to test whether the vaccine meets the specified release criteria prior to site activation. Because of the complexity of the training and regulatory oversight, there are a limited number of sites allowed to participate in the 1401 trial.

4.4.5 Medical Monitor Assignment

The DCC assigns a Medical Monitor to each study when it is activated. Medical Monitors are transplant physicians familiar with the conduct of clinical research and regulatory requirements for safety monitoring and reporting. When applicable, Medical Monitors with disease-specific expertise are also recruited to monitor the study (e.g. sickle cell disease, HIV). The Network’s Medical Monitors hold teleconferences quarterly to ensure uniformity in assessing adverse events and to share updates on regulatory requirements. As a matter of policy and to avoid bias, these physicians may not enroll patients or care for patients enrolled in a study on which they serve as Medical Monitor.

4.5 Protocol Activation

A protocol is activated when a sufficient number of committed centers receive IRB approval and provide all necessary documents to the DCC. Each center must provide proof of approval from its IRB and submit required regulatory documents. Centers must also demonstrate proficiency in data submission by reviewing an online training module and completing a post-module practicum.

4.6 Protocol Maintenance

4.6.1 Accrual Monitoring and Intervention

The success of a clinical trial depends on timely accrual, which is influenced by many factors. To ensure that problems relating to accrual are minimized, and promptly identified and addressed if they occur, the Protocol Team develops an accrual plan that includes monitoring accrual milestones, planning and holding trial promotion events, and assessing off-protocol transplantation activity through data obtained from the CIBMTR Research Database. Centers receive a quarterly report that compares their actual versus projected accrual to each protocol. The CIBMTR Research Database provides the denominator of total transplantations performed in patients potentially fulfilling clinical trial eligibility, and these data are used to interpret accrual by transplant centers. When accrual to a study lags, the Protocol Team intervenes quickly to identify and resolve delays. These actions may include:

• Holding calls or meetings with investigators to discuss accrual challenges and strategies; • Resending accrual surveys to participating centers to obtain new or revised accrual projections; • Amending the protocol to address unanticipated accrual barriers; • Submitting regular study update emails to participating center investigators and coordinators to

highlight current and target accrual;


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• Contacting investigators from participating centers that have not enrolled patients to encourage them to enroll;

• Preparing protocol-specific educational materials to facilitate accrual; • Recruiting additional centers.

Among the eight Network-led protocols currently open, the overall accrual rate is at 129% of target projections.

4.6.1.1 Recruitment of Underrepresented Populations The BMT CTN is committed to the ethical conduct of research involving all eligible patients, including women, minorities, and children. No patients are excluded on the basis of race or sex. Accrual to BMT CTN studies closely mirrors the CIBMTR Research Database in gender and racial composition and is only slightly disparate in pediatric composition (Table 4.1). Notably, the percentage of males enrolled on BMT CTN protocols from 2008 through 2013 was 57.8%; during this same period, the percentage of male CIBMTR subjects was 59.0%. Males are over represented in the transplant population because several of the common indications for transplant (e.g. multiple myeloma, acute lymphoblastic leukemia, etc.) are either more common in males or have a worse prognosis with standard chemotherapy in males, leading to increased use of transplant, but the number of females reported is more than sufficient to study sex-specific differences in response to therapy. Table 4.1. Characteristics of subjects enrolled in BMT CTN protocols, 2008-2013, compared to CIBMTR subjects

Characteristic BMT CTN CIBMTR

Number of Patients 3,429 80,804

Age

Median 53 years 54 years

≤ 16 years 7.7% 10.5%

> 16 years 92.3% 89.5%

Sex

Female 42.2% 41.0%

Male 57.8% 59.0%

Race

American Indian / Alaskan Native 0.4% 0.5%

Asian 2.8% 3.0%

Hawaiian / Pacific Islander 0.3% 0.3%

Black or African American 9.8% 10.8%

White 84.1% 83.4%

Other / Unknown Race 2.6% 2.0%


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Regarding race, minority patients made up 15.9% of BMT CTN subjects versus 16.6% of CIBMTR subjects, including 2.6% and 2.0% of patients with other / unknown race reported, respectively. The BMT CTN and CIBMTR percentages of minority patients are both lower than the U.S. minority population rate of 22% (US Census 2013 Population Estimates Data) and reflect the overall barriers to transplantation for minority patients. The rates of BMT CTN and CIBMTR pediatric patients differ slightly at 7.7% and 10.5%, respectively. The slightly lower rate of BMT CTN pediatric patient subjects is due in part to large studies involving disease indications more prevalent in adults, studies of treatments that have not been sufficiently tested in children for inclusion in multicenter studies, and studies involving quality of life or comprehension primary endpoints for which there are not pediatric evaluation materials available. Additionally, pediatric patients have access to large transplant trials through the COG, and the BMT CTN is careful not to compete with these. As noted below, the BMT CTN has made and continues to make concerted efforts to increase pediatric participation on its studies and offers pediatric-specific studies in its portfolio. During this reporting period, the Network continued several initiatives to increase recruitment of underrepresented populations:

• Double Accrual Credit for Non-Caucasian and Pediatric Patients Enrolled on BMT CTN 1202 and Accrual Closure of Adult Caucasians. The DCC observed that the average monthly Caucasian enrollment rate on the BMT CTN 1202 Biomarkers trial was approximately 87%, which is higher than anticipated and higher than the NIH standard of 75%. In an attempt to boost accrual of non-Caucasian adults and children, the DCC elected to provide double accrual credit for non-Caucasian patients enrolled on the BMT CTN 1202 study beginning in February 2015. Comparison of the accrual data from January to February 2015 suggested the accrual credit incentive was effective; however, before it could be fully evaluated, the accrual target of 1,500 patients was met. The protocol team decided that additional pediatric and minority patients would be beneficial for the analyses, so they proposed closure of enrollment to Caucasian adults and the study remain open until at least 200 pediatric and 200 African American patients were enrolled. The Data and Safety Monitoring Board approved the proposal, and in April, the study was closed to Caucasian adults. Double accrual credit continued to be offered and in September the pediatric patient target accrual was met and enrollment closed to this group; the accrual target for African American patients is anticipated to be met in April 2016. The DCC plans to further explore these approaches for boosting enrollment of underrepresented populations in other protocols.

• Participation in RECRUIT Trial. The Network also decided to participate in the Randomized Recruitment Intervention Trial (RECRUIT) trial, being conducted by Barbara Tilley, PhD, a statistician at the University of Texas Health Science Center at Houston. The study is funded by a National Institute on Minority Health and Health Disparities grant, which allows for collaboration among other NIH-funded Networks / Groups. The study’s primary objective is to test an intervention targeting clinical trial site investigators and coordinators to increase subject diversity in multi-site treatment trials for diseases that require physician referral. Eleven of the 16 eligible BMT CTN Core Centers agreed to participate. This study, BMT CTN 1505, was activated in the spring of 2015 and will continue until the spring of 2017.

• Special Populations Committee Evaluation of Enrollment. In December 2014, the Steering Committee charged the Special Populations Committee with a project to evaluate participation on BMT CTN trials, identify underrepresented populations, and provide recommendations to increase special population participation. The Committee conducted their evaluation and presented recommendations to the Steering Committee during this reporting period. The DCC will work with the Committee during the next reporting period to determine how to implement their recommendations. In preparation for these efforts, the Steering Committee recommended that additional members with expertise in health


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disparities be solicited to serve on the Special Populations Committee. Nominations were re-opened, and two additional members were selected by the Nominating Committee with terms starting in January 2016.

• Continued Prioritization of Studies Targeting Underrepresented Populations. The Steering Committee carefully considers inclusion of underrepresented patient populations in the Network’s portfolio of studies. Three of the five BMT CTN-led protocols in development (sickle cell disease studies 1503 and 1507 and aplastic anemia study 1502) include patients with diseases predominant in minority patients (1503, 1507), pediatric and adolescent patients (all), and patients with rare diseases (all). Four of the seven open BMT CTN-led studies enrolling new patients (1101, 1202, 1301, and 1302) include diseases, graft sources, and/or enrollment restrictions that target a higher proportion of minority patients (1101, 1202, and 1302) and pediatric and adolescent patients (1202 and 1301).

4.6.2 High-Quality Clinical and Laboratory Data Collection

One measure of the Network’s success is its efficient and accurate collection, processing, and retrieval of clinical and laboratory data. The Network uses several tools, described in this section, to ensure the integrity of each trial. In doing so, the Network provides the foundation for study results that can be analyzed properly and disseminated for use by physicians caring for patients.

4.6.2.1 AdvantageEDC The Emmes AdvantageEDC system is a Web-based, interactive data entry system, which serves as the Network’s primary data collection tool. To ensure high-quality data collection, the system performs field-level checks during data entry to ensure accuracy, consistency, and completeness of data. If an entry does not pass the validation check or the data do not meet the specified requirements, the system requires the user to resolve the inconsistency. As data are entered, they are maintained in data entry transaction master files, which are periodically processed into master files for analysis. Data entry transaction files are stored separately from the master analysis databases. This procedure provides the statisticians with a stable, fixed dataset for a predetermined period that can be used for multiple or frequently repeated analyses without needing to make private copies. It also pre-processes data for anomalies. Master files are updated nightly and typically stored in SAS® format. These files are the basis for all project reports and analyses. A dynamic forms grid provides an online list of currently submitted, due, and delinquent forms. During the past year, almost 60,000 forms were submitted in the AdvantageEDC system for BMT CTN. Accrual reports stratified by center, gender, and ethnicity are updated nightly. Reports summarizing each trial’s progress are updated either weekly or monthly, depending on the report. The DCC developed an integrated, Web-based Severe Adverse Events module. Notification of severe adverse events is provided to Medical Monitors and other key personnel through an automated email system, allowing rapid dissemination of critical information. Source data regarding severe adverse events is available to the Medical Monitors, and review of severe adverse events is incorporated into the data system. Integration of Medical Monitoring functionality in the data entry system has facilitated rapid review and reporting of events to study sponsors and regulatory bodies.

4.6.2.2 Specimen Tracking with GlobalTrace and Staff GlobalTrace is a proprietary Emmes product that the Network uses for all studies. This product is a unique, Web-based application for specimen tracking, inventory, and shipping. It uses bar-coded specimen labels to improve the reliability of specimen inventories by tracking individual samples shipped to either project


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laboratories or a repository. Individual centers and the NMDP/Be The Match Repository can use GlobalTrace to generate electronic manifests and trace / track each individual specimen. The application allows the study management team to know in real-time which specimens were collected, where they are, and when they were received by the NMDP/Be The Match Repository. This system has been used by the BMT CTN for more than 10 years for several clinical trials. An online training and competency assessment module for the GlobalTrace application is available on the secured BMT CTN website for all new clinical site staff. A GlobalTrace user guide can be easily accessed from the AdvantageEDC website to review functionality of specific elements of procedures related to this system. In addition to GlobalTrace, the DCC also has a unique asset in the HCT-knowledgeable staff at the CIBMTR and NMDP/Be The Match Research Sample Repository / Central Processing Laboratory. The Repository staff maintains a local database of processed and stored Network inventory that supports DCC queries.

4.6.2.3 CIBMTR Data Reporting All transplant centers in the US, including Network centers, are required by law to report pre-and post-transplantation clinical data on allogeneic HCT recipients to the Stem Cell Transplant Outcomes Database, which is a component of the C.W. Bill Young Cell Transplantation Program and is managed by the CIBMTR. The Network stipulates that Core and Affiliate Centers must also report similar data for autologous transplant recipients. Some pre-and post-HCT information collected by the CIBMTR is deliberately not captured by AdvantageEDC but rather is transferred from the CIBMTR Research Database to the Emmes database for incorporation into study files. All long term follow-up for Network studies (beyond the primary and secondary endpoints) is captured through CIBMTR report forms to avoid a duplicative long term follow-up program. The Network is committed to maximizing bidirectional data sharing between the databases, AdvantageEDC (Emmes) and FormsNet™ (CIBMTR), as a means of minimizing transplant center reporting burden. The CIBMTR collects data at two levels: a Transplant Essential Data level and a Comprehensive Report Form level. The Transplant Essential Data set contains a limited number of key variables for all consecutive transplant recipients. The Comprehensive Report Form data set captures additional patient, disease, and treatment-related data. Comprehensive Report Form level data is collected for the majority of BMT CTN studies. The CIBMTR reimburses centers for all completed Comprehensive Report Forms utilizing a variety of funding sources, including the CIBMTR’s U24 grant. During this reporting period, more than 7,000 CIBMTR forms were submitted for patients enrolled on BMT CTN studies. A detailed description of CIBMTR data collection procedures is available at cibmtr.org/DataManagement.

4.6.3 Data Audits

Data quality is critical to the BMT CTN’s success and is an important element for assessing transplant center performance. Data audits are performed at each center at least every three years and as often as biannually for centers with high enrollment. These visits provide an opportunity for information exchange between the centers and the DCC as well as an opportunity to provide continuing education on protocol adherence and case report forms completion to help maximize data and overall study quality. During the past year, the DCC conducted data audit site visits at 35 BMT CTN centers. The Auditors / Protocol Monitors evaluated data submission compliance (missing forms / missing values completion), laboratory sample compliance (collection and shipment of protocol-defined research samples), regulatory compliance, protocol compliance, and data quality.


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Reports are issued to the participating transplant centers after each visit, detailing what was reviewed during the visit, such as regulatory files, pharmacy procedures, laboratory compliance, forms completion, and data accuracy. Findings from the visit, as well as an action items list, are included in the report, and center staff members are expected to successfully address all action items before the site visit is considered complete. Reports are reviewed by the NHLBI and DCC and referred to the Executive Committee if results are below expectations or other issues of concern are identified.

4.6.4 Amendments

Protocol amendments are necessary for a variety of reasons, including clarifying study procedures, addressing unexpected toxicities, and improving accrual. The Protocol Coordinator, in consultation with the Protocol Team, drafts amendments and coordinates the Data and Safety Monitoring Board approval process. Like the initial protocol, the two Protocol Chairs and the Protocol Officer review the protocol amendment a final time, using a review checklist. The DCC ensures that centers have the most current amendments and provides training, if necessary, for changes in study procedures.

4.7 Study Completion

4.7.1 Notice to Cease Enrollment

As a trial nears its accrual goal, a memo is sent to each participating center notifying them of the closing date, after which no patient may be enrolled. Centers are required to maintain IRB approval for each study that has completed accrual until follow-up is finished, endpoint data review is complete, the first manuscript is published, and the BMT CTN DCC protocol coordinator has notified the site that it is appropriate to permanently close the study with their IRB.

4.7.2 Follow-up Data Collection after Closure

Once the protocol has closed to accrual, centers may be queried by the Endpoint Review Committee to submit outstanding report forms, follow-up data, or source documentation.

4.7.3 Data Review and Analysis

The Endpoint Review Committee provides an independent review of submitted data. The Committee consists of an independent panel of physicians, usually including the Protocol Chair and Protocol Officer; a DCC Statistician; and a DCC Coordinator. To conduct an Endpoint Review, the Committee:

• Establishes an Endpoint Review Committee Charter to define the review scope and procedure; • Determines the rules for endpoints adjudications; • Conducts central review of Case Report Forms and source documents; • Clarifies discrepant information; • Reviews complex grading or staging of clinical conditions, such as GVHD and disease status; • Adjudicates complex endpoints, such as primary cause of death.

Endpoint Review Committees examine the study data in a blinded manner and meet regularly via phone or in-person to reach consensus; the DCC coordinator records adjudicated data in the data system. Source documents and clinical notes are provided by the participating sites, as needed, to facilitate the Endpoint Review. All data discrepancies identified during the review are resolved prior to the data lock for final analyses and primary publication. As of March 31, 2016, Endpoint Reviews were completed for 18 protocols (0101, 0102, 0201, 0301, 0302, 0303, 0401, 0402, 0403, 0501, 0601, 0603, 0604, 0701, 0801, 0802, 0803, and 0901). Each protocol-specific Endpoint


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Review Committee retrospectively reviewed all study data related to the primary endpoint, and most important secondary endpoints, for each study participant. The primary manuscripts were published for 13 of these studies. Abstracts for the other five (0601, 0701, 0801, 0803, and 0901) were accepted during this reporting period, with the primary results manuscripts expected during the next reporting period. Endpoint Review Committees were also established to prospectively conduct data review for protocols 0702 and 1202 to ensure the study data regarding myeloma disease (0702) and acute GVHD (1202) are submitted accurately. For protocol 0702, the Endpoint Review Committee completed the review of baseline disease status on 682 of the 758 enrolled participants and adjudicated the primary endpoint for 136 participants. For protocol 1202, the Endpoint Review Committee reviewed 1,312 of the 1,736 transplanted participants at least once and completed the review of acute GVHD onset through Day 100 for 716 participants. When centers have provided all required data and data review is complete, the dataset is locked for analysis. The DCC completes data analysis and prepares reports in accordance with the Statistical Analysis Plan (Section 4.2.2). Upon completion of the statistical analysis, the DCC issues an analysis report (technical data report) for the study. In general, the analysis report is available within two months of locking the trial dataset. Study results are available for presentation after final analyses are reviewed by the Protocol Team, Endpoint Review Committee, and Steering Committee.

4.8 Dissemination of Results

Substantial effort is made by Protocol Teams to move forward quickly with manuscript preparation. When completed, the Publications Committee reviews proposed publications and presentations to ensure scientific validity and appropriate authorship and acknowledgements.

4.8.1 Authorship

Network authorship guidelines are outlined in the Administrative Manual of Procedures, which is available on the public website (https://web.emmes.com/study/bmt2/MOP.html). Authorship status is based on intellectual input and effort throughout the lifecycle of the trial. The Publications Committee maintains authorship policy guidelines, which are ratified by the Steering Committee and consistent with American Medical Association guidelines. Authorship credit on BMT CTN publications is a privilege commensurate with both personal and center contribution to the research, including:

• Membership and active participation on the Protocol Team; • Active accrual to the protocol; • Timely and accurate reporting of data; • Active participation in data review and analysis.

These activities may involve participation in hypothesis generation, concept development, protocol development, study implementation, subject enrollment, data collection, data analysis, and manuscript preparation.

4.9 Ancillary and Correlative Studies

BMT CTN ancillary studies use data, biospecimens, and/or analyses that are outside the main objectives of the primary study. Within the BMT CTN, many ancillary studies are protocol-defined, but some are independent (not included in the primary protocol). Independent ancillary studies must be reviewed and endorsed by the Protocol Team and Biomarkers Committee, if applicable, and approved by the Executive or Steering Committee before the Network can endorse them. Figure 4.2 illustrates this process. A one-page summary document, which


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outlines these BMT CTN procedures, associated requesting clinical data or biospecimens for ancillary laboratory studies, and the review of study proposal concepts by the Biomarkers and Executive / Steering Committees can also be found on the Network’s public website (https://web.emmes.com/study/bmt2/ResearchSample.html). Prioritization depends on scientific merit, complexity of the request, and available resources. The goal of the Network is to make its data and specimens as available as possible to investigators to allow important questions to be addressed and, thereby, enhance the worth of NIH’s investment in the BMT CTN.

Figure 4.2. Ancillary study proposal approval process

A description of available BMT CTN trial data and summaries of available research biospecimen collections is available on the Network’s public website as a resource for investigators planning correlative and ancillary studies. This website section summarizes the planned data and sample collection schedules and sample processing, and it lists biological samples available for all BMT CTN studies by time point and sample type. Many patients enrolled in BMT CTN trials also contributed pre-transplant biospecimens to the CIBMTR Biorepository. These linked biospecimen collections represent a unique opportunity for investigators to propose a wide range of correlative laboratory study investigations associated with HCT. During this reporting period, a new resource was created on the CIBMTR public website (cibmtr.org) to provide research investigators with linked BMT CTN / CIBMTR biospecimen inventory summaries associated with BMT transplant study patients who have submitted biospecimens to both collections. In an effort to promote the use of BMT CTN biospecimen and clinical data resources, direct links on the CIBMTR website to the BMT CTN resources were added to provide investigators access to comprehensive biospecimen and clinical trial data summaries for future study planning. Procedures were developed for investigators to submit study proposals requesting linked biospecimens and associated clinical data from both the BMT CTN and CIBMTR collections. Proposals will be reviewed and approved primarily through established BMT CTN procedures; however, this process will also involve working closely with the CIBMTR to assess sample availability and obtain all necessary approvals for the linked biospecimens and associated clinical data for approved studies.

Ancillary Proposal

Protocol Team

BMT CTN Steering/Exec Committees

Biomarkers Committee External

ReviewersDCC

Proposals utilizing samples or data from a specific protocol

Primary Review

Secondary Review

Proposals utilizing samples or data from multiple trials

Expert review of methodologiesOversight of all biospecimen-related ancillary studies


66

Correlative studies are defined in the protocol, and ancillary laboratory or secondary data analyses performed after the primary analysis is complete. Funding for ancillary and correlative studies may come from Network resources or non-Network public or private funding agencies.

During this reporting period, there were 38 BMT CTN protocol-defined correlative or ancillary studies proposed or ongoing. The Network’s protocol-defined correlative and ancillary studies in progress are described in Table 4.2a. Reporting period updates are listed in bold font.

Table 4.2a. Correlative and ancillary studies in progress

Correlative and Ancillary Studies in Progress

Protocol Project Status Laboratory / Location

BMT CTN 0101

Investigational fungal diagnostic assays to diagnose Aspergillus and other infections

• Protocol-defined correlative study • Research samples shipped • Clinical data file received from NHLBI /

BioLINCC; data conversion and migration to another database, with associated query / reporting tool set, completed

• Design and initiation of various studies in progress

University of Florida College of Medicine

BMT CTN 0101

Assessment of microRNA expression in acute graft-versus-host disease

• Study completed • Two manuscripts in preparation:

o Letter describing the miR-155 biomarker and acute GVHD

o Manuscript describing the miR-29a biomarker and relationship with acute GVHD

The Ohio State University

BMT CTN 0102

Free light chain analysis in patients undergoing autologous or allogeneic hematopoietic stem cell transplantation for multiple myeloma

• Ancillary study • Study completed • Initial results presented at ASH in 2011 by

P Hari, et al. • Long term follow-up results presented at

2015 European Hematology Association meeting by A D’Souza, et al.

• Manuscript submitted to British Journal of Haematology by A D’Souza, et al.

The Binding Site

BMT CTN 0102

Long term patient follow-up analysis

• Data analysis nearing completion • Manuscript draft in progress

0102 Protocol Team

BMT CTN 0102 Patient quality of life analysis

• Data analysis nearing completion • Manuscript design planning in progress

0102 Protocol Team


67



BMT CTN 0201

Immune reconstitution studies • Immunophenotype assays of

lymphoid subsets and dendritic cells

• Assays for antigen-specific T cells

• TREC assay for de novo T cell generation

• Protocol-defined correlative study • Data analysis in progress by EK Waller, B

Logan, et al.

Emory University Winship Cancer Institute

BMT CTN 0201

Immune reconstitution studies • Antibody and cytokine levels

• Protocol-defined correlative studies led by EK Waller

• Testing completed, and dataset provided to Protocol Team

• Data analysis in progress by EK Waller, B Logan, et al.

Esoterix Clinical Trials Services (Division of LabCorp)

BMT CTN 0201

Impact on donor selection / failure to change practice

• Ancillary study analysis led by M Horowitz and N Khera in progress

• Manuscript draft in progress 0201 Protocol Team

BMT CTN 0201

Patient quality of life – 5-year follow-up

• Ancillary study analysis led by S Lee • Results presented at 2015 ASH meeting by S

Lee, et al. • Manuscript submitted to JAMA Oncology in

2016 by S Lee, et al.

0201 Protocol Team

BMT CTN 0201 Late donor symptoms

• Ancillary study analysis led by G Switzer • Data analysis in progress

0201 Protocol Team

BMT CTN 0302

Pharmacogenetics of steroid responsive acute graft-versus-host disease

• Revised protocol-defined correlative study • Sample testing and data analysis completed • Manuscript by M Arora, et al. in progress

University of Minnesota

BMT CTN 0302, 0402

& 0802 RFA

Funded Study

Validation of a microRNA signature for the prediction, diagnosis, and prognosis of acute graft-versus-host disease

• RFA award ancillary study led by Y He • In progress

Duke University

BMT CTN 0402

Immune reconstitution studies - immunophenotyping

• Protocol-defined correlative study • Testing completed, and final dataset provided

to Protocol Team for analysis • Data analysis led by C Cutler in progress

Esoterix Clinical Trials Services (Division of LabCorp)


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BMT CTN 0402 RFA Funded Study

Inflammation, endothelial damage, and angiogenesis after HCT: A biomarker study of BMT CTN 0402

• RFA award ancillary study led by S Holtan • Sample testing and data analysis associated

with three study aims in progress o Aim 1: Completed and two manuscripts in

preparation o Aim 2: Completed with manuscript in

preparation; results reported in oral abstract at 2016 BMT Tandem Meetings by L Newell


BMT CTN 0402

Validation of a six-biomarker panel for the prediction of acute or chronic GVHD and correlations with day 365 non-relapse mortality

• Ancillary study led by S Paczesny • Sample testing completed and data analysis

on-going • Manuscript planning in progress

Indiana University

BMT CTN 0402 &

0201 RFA Funded Study

Allogeneic HY antibodies detected 3 months following sex-mismatched HCT predict chronic GVHD and non-relapse mortality: A BMT CTN validation study

• RFA award ancillary study led by D Miklos • In progress

Stanford University

BMT CTN 0403

Proteomic and genomic analysis of plasma and genomic cytokine and inflammatory markers

• Protocol-defined correlative study led by K Cooke

• In progress Johns Hopkins University

BMT CTN 0501 Immune reconstitution studies

• Protocol-defined correlative studies • Testing and result dataset verification

completed • Study team assembled and data analysis in

progress

Duke University

BMT CTN 0702

Obesity and multiple myeloma ancillary study

• Ancillary study led by L Metheny • Data maturing • In progress - final study plan approved,

biospecimens being shipped, and testing and data analysis to follow

Case Western Reserve University School of Medicine

BMT CTN 0702

PRIMeR study: minimal residual disease in multiple myeloma by flow cytometry

• Ancillary study • Patient sample testing completed • Data analysis in progress

Roswell Park Cancer Institute

Participating Centers

BMT CTN 0801

Regulatory T cell / B cell immunophenotyping and B cell activating factor biomarker levels by ELISA

• Protocol-defined correlative study • Testing completed • Protocol Team to begin data analysis soon

Dana-Farber Cancer Institute


69



BMT CTN 0802 RFA Funded Study

Assessments of TCR diversity in HCT recipients at the time of diagnosis of GVHD and relatedness of TCR sequences between subsets of patients based upon shared characteristics, such as female donors into male recipients, HLA, or specific HLA mismatches

• RFA award ancillary study led by E Meyer • In progress

Stanford University

BMT CTN 0803

Microbial translocation marker measurements

• Protocol-defined correlative study • Testing completed • Protocol Team-led data analysis plan in

progress

University of North Carolina

BMT CTN 0803

Characterization of HIV infection in AIDS-related malignancies: • HIV single-copy HIV viral

titer measurements • Plasma DNA tumor

monitoring

• Protocol-defined correlative study • Sample testing completed • Protocol Team-led data analysis plan in

progress

Johns Hopkins University

BMT CTN 0803

Immunophenotypic and functional characterization of immune reconstitution

• Protocol-defined correlative study • Testing completed • Protocol Team-led data analysis plan in

progress

Ohio State University

BMT CTN 0901

Busulfan pharmacokinetics study

• Protocol-defined correlative study • Testing completed and final dataset provided • Study analysis near completion • Manuscript planning underway

Seattle Cancer Care Alliance

Pharmacokinetics Laboratory

BMT CTN 0902

Sleep disturbance among autologous HCT patients

• Ancillary study led by H Jim • Trial dataset provided • Secondary data analysis in progress

H. Lee Moffitt Cancer Center


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BMT CTN 0902

Pre-transplant health-related quality of life factors as predictors of outcomes following HCT

• Ancillary study led by J Knight • Trial dataset provided and secondary data

analysis completed • Abstract presented at the 2015 IPOS/APOS

World Congress on Psycho-Oncology by J Knight, et al.

• Manuscript undergoing final study team review for submission to the journal Cancer

Medical College of Wisconsin

BMT CTN 0902

Patterns of quality of life after transplant

• Ancillary study led by H Jim • Trial dataset provided • Manuscript undergoing final BMT CTN review

prior to submission to the British Journal of Haematology

H. Lee Moffitt Cancer Center

BMT CTN 0902 Pre-transplant exercise

• Ancillary study led by J Wingard • Dataset and study plan elements in final stages • Data analysis to begin soon

University of Florida College of Medicine

BMT CTN 0902

Psychometrics of cancer and treatment-related distress data

• Ancillary study led by K Syrjala • Trial dataset provided and secondary data

analysis completed • Abstract presented at the 2015 IPOS / APOS

World Congress on Psycho-Oncology by K Syrjala, et al.

• Manuscript undergoing final study team review

Fred Hutchinson Cancer Research Center

BMT CTN 0902

Sociodemographic factors of quality of life and distress

• Ancillary study led by N Majhail • Dataset and study plan elements in final stages • Final study plan approved by the BMT CTN;

data analysis to begin soon

Cleveland Clinic

BMT CTN 0903

Immunophenotypic and functional characterization of immune reconstitution

• Protocol-defined correlative study • In progress

Ohio State University

BMT CTN 0903

Microbial translocation marker measurements



BMT CTN 0903

Characterization of HIV infection and latent HIV reservoirs


Johns Hopkins University


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BMT CTN 0903

Characterization of HIV infection in AIDS-related malignancies: HIV single-copy HIV viral titer measurements (PBMC & plasma)


University of Pittsburgh

BMT CTN 1101 & 1102

Determine cost-effectiveness expressed as cost per quality adjusted life year

• Companion sub-study to BMT CTN 1101 and 1102

• Currently accruing patients enrolled on BMT CTN 1101 and 1102


BMT CTN 1202

Perspective: Real-time acute GVHD clinical data adjudication

• Analysis and manuscript preparation led by J Levine, R Reshef, and J Hansen 1202 Protocol Team

Four ancillary studies were completed this reporting period, bringing the total number of completed protocol-defined correlative or ancillary studies to 17. These studies are described in Table 4.2b. Reporting period updates are listed in bold font. Table 4.2b. Correlative and ancillary studies completed

Correlative and Ancillary Studies Completed

Protocol Project Status Laboratory/Location

BMT CTN 0101

Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

• Ancillary study • Study completed • Cost-effectiveness analysis of voriconazole

compared with fluconazole for prevention of invasive fungal infection in patients receiving allogeneic HCT. American Journal of Health-System Pharmacy. 2013 Sept 1; 70(17):1518-1527

RTI Health Solutions

BMT CTN 0101

Pharmacokinetic studies of voriconazole and fluconazole administered for prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients

• Protocol-defined correlative study • Study completed • Results presented at 2014 ICAAC meeting

by W Hope, et al. • Manuscript in press: Voriconazole

pharmacokinetics following HCT: Results from the BMT CTN 0101 trial. Journal of Antimicrobial Chemotherapy

Antimicrobial Pharmacodynamics and Therapeutics Laboratory

Department of Molecular and Clinical Pharmacology

University of Liverpool


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BMT CTN 0201

Immune reconstitution studies • Donor HCT graft

characterization

• Protocol-defined correlative study • Results presented at ASH in 2011 by

EK Waller, et al. • Improved survival after transplantation of

more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMT CTN 0201. Journal of Clinical Oncology. 2014 Aug 1; 32(22):2365-2372. Epub 2014 Jun 30

Emory University Winship Cancer Institute

BMT CTN 0201

Health-related quality of life of bone marrow versus peripheral blood stem cell donors: a pre-specified subgroup analysis from a Phase III RCT – BMT CTN Protocol 0201

• Protocol-defined correlative study • Health-related QoL of bone marrow vs.

PBSC donors: a pre-specified subgroup analysis from a Phase III RCT-BMT CTN protocol 0201. Biology of Blood and Marrow Transplantation. 2014 Jan 1; 20(1):118-127

University of Pittsburgh

BMT CTN 0201

Donor Clinical Manuscript / Donor as a Research Subject

• Protocol-defined correlative study • Results presented at 2016 EBMT Congress

by L Burns, et al. • Recovery of unrelated donors of PBSC vs.

recovery of unrelated donors of bone marrow: A pre-specified analysis from the Phase III BMT CTN protocol 0201. Biology of Blood and Marrow Transplantation. 2016 Jun 1; 22(6):1108-1116. Epub 2016 Mar 21

0201 Protocol Team

BMT CTN 0201

Analysis of infectious complications related to patients’ clinical risk, comparing two treatment cohorts (peripheral blood stem cell versus marrow) and adjusting for other relevant clinical risk factors

• Protocol-defined correlative study • Results presented at 2015 BMT Tandem

Meetings by J Young, et al. • Infections following transplantation of

bone marrow or PBSC from unrelated donors. Biology of Blood and Marrow Transplantation. 2016 Feb 1; 22(2):359-370. Epub 2015 Sep 25



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BMT CTN 0302

Analysis of serum biomarkers during treatment of acute GVHD

• Protocol-defined correlative study • Study completed • Results presented at EBMT Congress in

2011 by JE Levine, et al. • Acute GVHD biomarkers measured during

therapy can predict treatment outcomes: A BMT CTN study. Blood. 2012 Apr 19; 119(16):3854-3860. Epub 2012 Mar 1

University of Michigan

BMT CTN 0302

Mycophenolate pharmacokinetics and association with response to acute GVHD treatment from the BMT CTN

• Protocol-defined correlative study • Study completed • Mycophenolate pharmacokinetics and

association with response to acute GVHD treatment from the BMT CTN. Biology of Blood and Marrow Transplantation. 2010 Mar 1; 16(3):421-429


BMT CTN 0302

Graft-versus-host disease treatment: predictors of survival

• Correlative study • Study completed • GVHD treatment: predictors of survival.

Biology of Blood and Marrow Transplantation. 2010 Dec 1; 16(12):1693-1699. Epub 2010 Jun 10

N/A

BMT CTN 0302

Lymphocyte phenotype during therapy for acute graft versus host disease: a brief report from BMT CTN 0302

• Correlative study • Study completed • Lymphocyte phenotype during therapy for

acute GVHD: a brief report from BMT-CTN 0302. Biology of Blood and Marrow Transplantation. 2013 Mar 1; 19(3):481-485. Epub 2012 Dec 12

N/A

BMT CTN 0303

Characteristics of CliniMACS(®) system CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia-BMT CTN protocol 0303

• Correlative study • Study completed • Characteristics of CliniMACS(®) System

CD34-enriched T cell-depleted grafts in a multicenter trial for AML – BMT CTN protocol 0303. Biology of Blood and Marrow Transplantation. 2012 May 1; 18(5):690-697. Epub 2011 Aug 26

N/A


74



BMT CTN 0303

Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation

• Correlative study • Study completed • Comparative outcomes of donor graft

CD34+ selection and immune suppressive therapy as GVHD prophylaxis for patients with AML in complete remission undergoing HLA-matched sibling allogeneic HCT. Journal of Clinical Oncology. 2012 Sep 10; 30(26):3194-3201

N/A

BMT CTN 0802 / 0302

Angiogenic biomarkers of acute GVHD (utilizing 0302/0802 samples)

• Ancillary study • Circulating angiogenic factors associated

with response and survival in patients with acute GVHD: Results from BMT CTN 0302 and 0802. Biology of Blood and Marrow Transplantation. 2015 Jun 1; 21(6):1029-1036. Epub 2015 Mar 7


BMT CTN 0802 / 0302

Extended acute GVHD biomarker testing and Ann Arbor GVHD scoring validation (utilizing 0802 / 0302 samples)

• Ancillary study • A prognostic score for acute GVHD based

on biomarkers: A multicentre study. Lancet Haematology. 2015 Jan 1; 2(1):e21-29. Epub 2014 Dec 23

University of Michigan

BMT CTN 0802 / 0302

Acute GVHD risk score (utilizing 0802 / 0302 samples)

• Ancillary study • A refined risk score for acute GVHD that

predicts response to initial therapy, survival, and transplant-related mortality. Biology of Blood and Marrow Transplantation. 2015 Apr 1; 21(4):761-767. Epub 2015 Jan 10


BMT CTN 0902

Baseline SF36 independent prognostic factors for overall survival

• Ancillary study led by W Wood • Patient-reported physical functioning

predicts the success of HCT (BMT CTN 0902). Cancer. 2016 Jan 1; 122(1):91-98. Epub 2015 Oct 6


BMT CTN 1101

Cost-effective analysis methods paper

• Design of a cost -effectiveness analysis alongside a randomized trial of transplantation using UCB vs. HLA-haploidentical related bone marrow in advanced hematologic cancer. Journal of Comparative Effectiveness Research. 2014 Mar 1; 3(2):135-144


Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 5.0 Collaborations with other NIH-funded Research Networks

75

5.0 Collaborations with other NIH-funded Research Networks

The mission of the BMT CTN overlaps with the mission of NCI-sponsored National Clinical Trials Network and Cancer Clinical Trials Cooperative Groups as well as other NIH-sponsored networks and investigators. A major responsibility of DCC leadership is to enhance communication among these groups to minimize the number of competing trials and to foster collaboration to decrease the time required to complete studies. To that end, the Network has:

• Collaborated and shared accrual on 16 protocols: o BMT CTN-led studies:

BMT CTN 0102 – SWOG BMT CTN 0401 – SWOG BMT CTN 0501 – COG BMT CTN 0601 – Sickle Cell Disease Clinical Research Network and NIH’s National

Center for Minority Health and Health Disparities BMT CTN 0701 – Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research

Group, SWOG BMT CTN 0702 – Alliance for Clinical Trials in Oncology, ECOG-ACRIN Cancer Research

Group, SWOG BMT CTN 0803 and 0903 – AIDS Malignancy Consortium

o Cooperative group-led studies: Alliance for Clinical Trials in Oncology / CALGB 100103 – BMT CTN 0502 SWOG 0410 – BMT CTN 0703 Alliance for Clinical Trials in Oncology / CALGB 100104 – BMT CTN 0704 Alliance for Clinical Trials in Oncology / CALGB 100701 – BMT CTN 0804 SWOG 0805 – BMT CTN 0805 Alliance for Clinical Trials in Oncology / A051301 – BMT CTN 1201 DFCI / IFM 10-106 – BMT CTN 1304 University of Texas RECRUIT – BMT CTN 1505

• Implemented a shared national agenda for myeloma transplantation trials that is represented by CALGB 100104 / BMT CTN 0704, BMT CTN 0702, BMT CTN 1302, DFCI 10-106 / BMT CTN 1304, and BMT CTN 1401; this agenda was led by the BMT CTN-initiated Multiple Myeloma Intergroup, including representatives from The Alliance for Clinical Trials in Oncology, ECOG-ACRIN, and SWOG;

• Participated in the NCI Lymphoma, Myeloma, and Leukemia Steering Committees; • Included cooperative group representation on the Network Steering Committee to promote

communication and collaborative partnerships with these groups; • Partnered with the AIDS Malignancy Consortium to support innovative trials for AIDS-associated

malignancies (BMT CTN 0803 and 0903).

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 6.0 Future Directions

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6.0 Future Directions

6.1 Continued Planning for the Current Grant Cycle

Prior to the start of the current grant cycle, a group of BMT CTN leaders met to lay out goals for the DCC and the Network. This group has continued to meet to evaluate ways to enhance the BMT CTN’s proficiency and efficiency, identify optimal uses of funds, and refine processes to promote success and scientific productivity of the Network. It was these leaders, along with the Steering Committee, that determined another State of the Science Symposium should be conducted to survey the HCT landscape and identify greatest areas of need. The 2014 State of the Science Symposium was held in February 2014 during the BMT Tandem Meetings and detailed in the 2014 Progress Report. Updates from the 2007 and 2014 State of the Science Symposiums, including status of prioritized concepts are provided below. These priority concepts will serve as a road map for future studies recommended for implementation by the US transplant community using the resources of the BMT CTN, NCI Cooperative Groups, and other programs.

6.2 State of the Science Symposia

6.2.1 2007 State of the Science Symposium

The publication from the Network’s 2007 State of the Science Symposium, listed below, provided prior guidance for high-priority studies to be developed by the Network and/or NCI Cooperative Groups.

• Ferrara J, Anasetti C, Stadtmauer E, Antin J, Wingard J, Lee SJ, Levine J, Schultz K, Appelbaum F, Negrin R, Giralt S, Bredeson C, Heslop H and Horowitz M. BMT CTN State of the Science Symposium 2007. Biology of Blood and Marrow Transplantation. 2007; 13:1268-128.

During this reporting period, primary results from three studies (BMT CTN 0801 and 0901 and SWOG S0805 / BMT CTN 0805) were presented and will be submitted for publication during the next reporting period. Two studies completed enrollment but have not yet reached the date of evaluable analysis (BMT CTN 0702 and 1204), and another just reached evaluable analysis (CALGB 100701 / BMT CTN 0804), which will be completed during the next reporting period. Table 6.1 displays the status of studies prioritized at the 2007 State of the Science Symposium. Table 6.1. Status of studies prioritized at the 2007 State of the Science Symposium

Studies Prioritized at the 2007 State of the Science Symposium

Proposal Comments / Status BMT CTN Protocol Number

Phase III trial of tandem autologous transplant versus consolidation with bortezomib, lenalidomide, and dexamethasone after a single autologous transplant versus maintenance therapy with lenalidomide after a single autologous transplant for myeloma

Accrual was completed in November 2013. Prospective data review is ongoing by the Endpoint Review Committee. The primary analysis is anticipated to be conducted in early 2017, as the primary endpoint is progression-free survival as a time to event endpoint censored after 38 months of follow-up.

BMT CTN 0702


77



Phase III trial of chemotherapy versus unrelated donor transplantation in patients with high-risk AML in first complete remission

Development deferred. N/A

Phase II trial of chemotherapy and dasatinib versus allogeneic HCT in patients with Philadelphia chromosome positive ALL

This collaborative study is led by SWOG, with active involvement of BMT CTN representatives; accrual was completed in October 2013. The primary endpoint is relapse-free survival at one year. Data analysis was completed and the primary results manuscript is drafted.

BMT CTN 0805 / SWOG S0805

Phase III trial of peri-transplant stress management versus standard of care

The primary manuscript was published in Biology of Blood and Marrow Transplantation in June 2014 by PB Jacobsen et al. An ancillary analysis was submitted, and several others are underway.

BMT CTN 0902

Phase II trial of allogeneic HCT with reduced-intensity conditioning in patients with very high-risk CLL

This collaborative study is being led by Alliance, with active involvement of BMT CTN representatives; accrual was completed in January 2014. The primary endpoint is two year progression-free survival. Data analysis is expected to start in early 2016.

BMT CTN 0804 / CALGB 100701

Phase II trial of HLA-matched, viral-specific cytotoxic T lymphocytes to treat adenoviral infections

Presented at July 2011 Steering Committee meeting and voted as lower priority as available pilot data not considered adequate. Concept re-presented at the February 2013 Steering Committee meeting and voted as higher priority. Design reconfigured and presented at 2014 State of the Science Symposium. Selected as priority study, but not selected to be developed during this reporting period.

Not yet applicable

Phase III trial of full-intensity conditioning versus reduced-intensity conditioning for allogeneic HCT in recipients with AML ages 30–60 years

Accrual to this trial was halted permanently in April 2014 after preliminary data appeared to show benefit for more intensive conditioning for allogeneic HCTs in patients eligible for the study. The primary endpoint of overall survival at 18 months was completed, and a late-breaking abstract was presented at the annual 2015 ASH Annual Meeting as well as at the 2016 BMT Tandem Meetings as a special invite abstract. The primary results manuscript is drafted and will be submitted for publication in Spring 2016.

BMT CTN 0901


78



Phase II trial of allogeneic HCT with reduced-intensity conditioning in children with hemophagocytic syndromes

Accrual was completed in March 2015, much sooner than expected; consequently, an amendment was requested to expand the sample size from 35 patients total to 35 hemophagocytic lymphohistiocytosis (HLH) patients. Accrual remained open to all patients during the extension. The protocol was closed to enrollment in December 2015, one year ahead of projections despite the increase in sample size. A total of 36 HLH patients and 11 patients with other hemophagocytic disorders enrolled. The primary endpoint is one year overall survival.

BMT CTN 1204

Phase II trial of allogeneic HCT with reduced-intensity conditioning as primary therapy for T-cell lymphoma

Protocol concept no longer high priority. N/A

Phase II trial of autologous HCT for refractory Crohn’s disease No protocol concept presented to date. N/A

Phase II trial of calcineurin-free treatment regimens in patients with high-risk chronic GVHD

The primary results were presented at the 2016 BMT Tandem Meetings, and a manuscript is drafted. BMT CTN 0801

6.2.2 2014 State of the Science Symposium

The publication from the BMT CTN’s 2014 State of the Science Symposium, listed below, outlines the high-priority studies to be developed by the Network and/or NCI Cooperative Groups.

• Appelbaum F, Anasetti C, Antin J, Atkins H, Davies S, Devine S, Giralt S, Heslop H, Laport G, Lee S, Logan B, Pasquini M, Pulsipher M, Stadtmauer E, Wingard J, Horowitz M. Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2014. Biology of Blood and Marrow Transplantation. 2015 Feb 1; 21(2): 202-224. Epub 2014 Oct 14.

Following the State of the Science Symposium, the symposium review committee prioritized twelve studies. During this reporting period, the Network developed five of the prioritized concepts and continued collaborations on two others to be led by other NIH Networks. Tables 6.2 and 6.3 display the status of each of the prioritized studies.


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Table 6.2. Status of studies prioritized at the 2014 State of the Science Symposium



Leukemia #1: AML: FLT3 inhibition compared to placebo as maintenance therapy after allotransplant for FLT3+ AML

The protocol team was formed in July 2015. In March 2016, the protocol was approved by the Protocol Review Committee and also underwent Data and Safety Monitoring Board review. It is anticipated the protocol will be released to centers in May 2016.

BMT CTN 1506

Leukemia #2: AML / MDS: low dose azacytidine maintenance compared to no maintenance

Development deferred; additional funding sources being sought. N/A

Lymphoma #1: Relapsed and refractory diffuse large B cell lymphoma: ibrutinib vs. placebo during and after autologous HCT

Although initially planned as a BMT CTN-led study, it was determined the study was a better fit for the NCI National Clinical Trials Network since the drug was available through NCI’s cooperative research and development agreement (CRADA). Alliance is the lead cooperative group. It was already in development before the symposium, but its identification as a priority showcased the need for its timely development. BMT CTN has provided input on the study design throughout the development process. The protocol is anticipated to be released to centers in June 2016.

BMT CTN 1201 /

Alliance A051301

Non-Malignant Diseases #1: Multiple Sclerosis: autologous HCT vs. best standard of care

The NIAID committed to the development of this study, which will be conducted by the Immune Tolerance Network (ITN). The BMT CTN will endorse the study and collaborate with the NIAID / ITN on protocol development. The NIAID / ITN is holding a protocol development meeting during this summer.

N/A

Pediatric Transplant – Indications #1: ALL post-HCT with either moxetumomab or inotuzumab

A phase II trial of posttransplant moxetumomab was launched by the PBMTC, with help from the DCC, but was recently closed for toxicity; other agents are being considered.

N/A

Pediatric Transplant – Outcomes #1: Daily vs. alternating day dosing of steroids in chronic GVHD

Development deferred to next funding cycle. N/A

Optimal Donor and Graft Source #1: Post-HCT cyclophosphamide

The Network has committed to evaluating the post-transplant cyclophosphamide / haploidentical donor transplantation approach in the reduced intensity conditioning setting (1101, and upcoming 1502 and 1507 protocols). Development of a protocol using myeloablative conditioning with haploidentical donors is still under consideration.

N/A


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GVHD #2a: Acute GVHD treatment for high risk patients: rand Phase II of 1-2 agents vs. control

The GVHD Committee presented several initial study concepts to the Steering Committee in February 2016, and it is anticipated that a concept will be approved and protocol development will begin during the next reporting period.

N/A

GVHD #2b: Acute GVHD treatment for low risk patients: rand Phase II of 1 agent vs. control

The protocol was approved by the Protocol Review Committee in December and Data and Safety Monitoring Board in February. It is anticipated the protocol will be released to centers in April.

BMT CTN 1501

Gene and Cell Therapy #2: Haploidentical donor natural killer cells for AML patients

This protocol will be developed once data from pilot studies are available, anticipated to be the end of 2016. Potential contributions from industry partners are being explored.

BMT CTN 1601

Comorbidity / Regimen-Related Toxicity #1: Improving health assessment and prediction of toxicity / mortality in older patients undergoing allogeneic HCT


Infection / Immune Reconstitution #1: Cytomegalovirus-specific T cell adoptive therapy (joint proposal with Gene and Cell Therapy Committee)

Development deferred although potential collaborations with biotech companies are being explored. N/A

Infection / Immune Reconstitution #2: Novel parainfluenza entry inhibitor in HCT recipients with parainfluenza virus upper respiratory tract infection


Late Effect / Quality of Life / Economics #1: Zoledronic acid vs. placebo for prevention of bone loss after allogeneic HCT


At its February 2015 meeting, the Steering Committee additionally prioritized two studies of transplantation for non-malignant disease for development in 2015, one for aplastic anemia patients and the other for sickle cell disease patients. Each was recommended by the State of the Science Symposium Non-Malignant Disease Subcommittee though not included in the high priority list above. Additionally, the Steering Committee approved a second sickle cell disease study be developed using a different transplant approach. Table 6.3 displays the status of each of the prioritized studies.


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Table 6.3. Status of studies prioritized after the 2014 State of the Science Symposium

Studies Prioritized after the 2014 State of the Science Symposium


Non-Malignant Diseases: Haploidentical bone marrow and/or unrelated cord blood transplantation for aplastic anemia

The protocol team was formed in January 2015. The protocol was approved by the Protocol Review Committee in December 2015. It will be submitted to the Data and Safety Monitoring Board in April 2016. It is anticipated the protocol will be released to centers in May 2016.

BMT CTN 1502

Non-Malignant Diseases: Unrelated donor transplantation vs. standard of care (biologic assignment) in young adults with sickle cell anemia

The protocol team was formed in July 2015. The protocol was approved by the Protocol Review Committee in December 2015 and was reviewed by the Data and Safety Monitoring Board in March 2016; approval is pending. It is anticipated the protocol will be released to centers in May 2016.

BMT CTN 1503

Non-Malignant Diseases: Haploidentical bone marrow transplantation for children and adults with severe sickle cell disease

The protocol team was formed in July 2015 and was submitted to the Protocol Review Committee in February 2015. It is anticipated the protocol will be submitted to Data and Safety Monitoring Board in early May 2016 and released to centers in June 2016.

BMT CTN 1507

6.3 Projected Study Activities during the Next Reporting Period

6.3.1 Anticipated Results

In the coming year, four trials will reach primary endpoints. The results will be analyzed to address important questions:

• BMT CTN 0702. Does a second autologous transplant or consolidation therapy post first transplant improve progression-free survival for multiple myeloma patients compared to maintenance therapy alone? Does the presence of minimal residual disease after first auto transplant influence the need for additional dose-intensive therapy?

• BMT CTN 0903. What is the feasibility and safety of allogeneic HCT in this patient population? Can the previously reported experience of HIV cure after transplantation with a CCR5delta2+ donor be replicated?

• BMT CTN 1204. Does allogeneic HCT with reduced-intensity conditioning in patients with hemophagocytic syndromes result in an acceptable survival rate?

• BMT CTN 1205. Will patients’ comprehension of and their satisfaction and anxiety related to the consent process improve with the use of an “easy-to-read” consent form? What are the barriers to implementing an “easy-to-read” consent form at BMT CTN centers?

Additionally, 26 ancillary and correlative studies will be complete (Section 4.9).


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6.3.2 Studies Nearing Completion of Accrual

Four studies are likely to complete accrual during the next reporting period: • BMT CTN 1202: Prospective multicenter cohort for the evaluation of biomarkers predicting risk of

complications and mortality following allogeneic HCT o The study was activated in June 2013 with planned enrollment of 1,500 patients. This was

amended to ensure enrollment of at least 200 African American and 200 pediatric patients. Accrual to Caucasian adults closed in March 2015. Accrual to pediatric patients closed in September 2015 when the target accrual was met. It is anticipated accrual to the African American cohort will be complete, and the study closed to accrual, in April 2016.

• BMT CTN 1203: A multicenter Phase II trial randomizing novel approaches for graft-versus-host disease prevention compared to contemporary controls

o The protocol was approved by the Protocol Review Committee and Data and Safety Monitoring Board in May 2013. Target accrual is 270 patients, which is expected to be complete in April 2016.

• BMT CTN 1205: Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical trials

o The protocol was approved by the Data and Safety Monitoring Board in March 2013. The study was activated in November 2013. Target accrual was 160 patients but increased to 198 patients as the completion rate for the patient assessments was <80%. It is anticipated the revised target will be met in Summer 2016. The protocol includes an evaluation study component focused on institutional barriers to consent form simplification. Site interviews for the evaluation study are complete and analyses underway.

• BMT CTN 1304 / DFCI 10-106 / IFM/DFCI 2009 (The DETERMINATION Study): A randomized Phase III study comparing conventional dose treatment using a combination of lenalidomide, bortezomib, and dexamethasone to high-dose treatment with peripheral stem cell transplant in the initial management of myeloma in patients up to 65 years of age

o This study is a collaboration between the DFCI and IFM with DFCI coordinating the study in the US and IFM in France. DFCI activated the study in October 2010. Slow accrual led the DFCI group to request BMT CTN endorsement. The BMT CTN endorsed the study in November 2013 when accrual to the competing BMT CTN 0702 completed. Participating BMT CTN centers have received accrual credit since then, and the monthly accrual more than doubled. Target accrual is 660 patients, which is anticipated to be met this year.

6.3.3 Studies Activated

Three studies were activated during this reporting period: • BMT CTN 1301: A randomized, multicenter, Phase III trial of calcineurin inhibitor-free interventions for

prevention of graft-versus-host disease o The protocol was approved by the Protocol Review Committee in December 2013 and Data and

Safety Monitoring Board in February 2014. The IDE was approved by the FDA in July 2014. Version 1.0 of the protocol was released to centers in September 2014. It was determined a significant protocol amendment was needed prior to activating the study, including a change to chemotherapy dose calculations; language clarifying that donors of patients randomized to the CD34 selection arm are considered research subjects and new informed consent / assent forms for these donors; and additional language regarding data submission, adverse event reporting, ethics, and regulatory requirements. Version 2 of the protocol was approved by the Data and Safety


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Monitoring Board in April 2015 and released to centers in May 2015. The study was activated in August 2015. Target accrual is 345 patients over 42 months; as of March 31, 2016, 33 patients were enrolled.

• BMT CTN 1302: Multicenter Phase II, double-blind placebo controlled trial of maintenance ixazomib after allogeneic hematopoietic stem cell transplantation for high risk multiple myeloma

o The protocol was approved by the Protocol Review Committee in February 2014 and Data and Safety Monitoring Board in July 2014. The investigational new drug (IND) application was approved by the FDA in November 2014. The protocol was released to centers in March 2015 and activated in August 2015. Target accrual is 138 patients over 36 months; as of March 31, 2016, 17 patients were enrolled.

• BMT CTN 1505: A randomized recruitment intervention trial (RECRUIT) o This study is an intervention targeting site investigators and coordinators (the research subjects)

to increase subject diversity in clinical trials. Core Centers were invited to participate in January 2015, and centers that agreed were randomized in February. The kick off meetings for intervention centers were held in April 2015, and the study was activated that month. The study will complete in Spring 2017.

6.3.4 Studies to be Activated

Seven protocols will be activated during the next reporting period: • BMT CTN 1201 / Alliance A051301: Phase III Study of ibrutinib during and following autologous HCT

vs. placebo in patients with relapsed / refractory DLBCL of the activated-B-cell subtype o Initially approved by BMT CTN in January 2012, this protocol was transferred to the NCTN to

take advantage of NCI’s CRADA for ibrutinib, with Alliance serving as the lead group. The protocol was reviewed by NCI’s Cancer Therapy Evaluation Program and the FDA this year. It is anticipated the protocol will be released to centers in June 2016.

• BMT CTN 1401: Phase II multicenter trial of single autologous hematopoietic cell transplant followed by lenalidomide maintenance for multiple myeloma with or without vaccination with dendritic cell / myeloma fusions

o The protocol team was formed in April 2014. The protocol was approved by the Protocol Review Committee in December 2014 and Data and Safety Monitoring Board in February 2015. The IND was approved by the FDA in October 2015. The protocol was released to centers in January 2016. The study will be activated in April 2016.

• BMT CTN 1501: Randomized, Phase II, multi-center, open label study comparing sirolimus to prednisone in patients with refined Minnesota standard risk, Ann Arbor 1/2 confirmed acute GVHD

o The protocol team held its first meeting in February 2015. The protocol was approved by the Protocol Review Committee in December 2015 and Data and Safety Monitoring Board in February 2016. It will be released to centers in April 2016.

• BMT CTN 1502: Optimizing cord blood and haploidentical aplastic anemia transplantation (CHAMP) o The protocol team held its first meeting in January 2015. The protocol was approved by the

Protocol Review Committee in December 2015 and will be submitted to the Data and Safety Monitoring Board in April 2016. It is anticipated the protocol will be released to centers in June 2016.

• BMT CTN 1503: STRIDE2: A study to compare bone marrow transplantation to standard care in adolescents and young adults with severe sickle cell disease

o The protocol team held its first meeting in July 2015. The protocol was approved by the Protocol


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Review Committee in December 2015. Data and Safety Monitoring Board approval is pending, and it is anticipated the protocol will be released to centers in May 2016.

• BMT CTN 1506: Multi-center, randomized, double-blind, placebo-controlled Phase III trial of the FLT3 inhibitor gilteritinib administered as maintenance therapy following allogeneic HCT for patients with FLT3 / ITD AML

o The protocol team held its first meeting in July 2015. The protocol was approved by the Protocol Review Committee and submitted to the Data and Safety Monitoring Board in March 2016. It is anticipated the protocol will be released to centers in May 2016.

• BMT CTN 1507: Reduced intensity conditioning for haploidentical bone marrow transplantation in patients with symptomatic sickle cell disease

o The protocol team held its first meeting in July 2015. The protocol was submitted to the Protocol Review Committee in February 2016. Submission to the Data and Safety Monitoring Board is slated for May 2016. It is anticipated the protocol will be released to centers in June 2016.

6.3.5 Future Study Concepts

Two additional study concepts are expected to be submitted for Protocol Review Committee review during the next reporting period:

• BMT CTN 1504: Low dose interleukin-2 for chronic GVHD • BMT CTN 1601: Bridging trial of haploidentical donor natural killer cells for AML patients with active

disease prior to transplant

6.4 Conclusions

The BMT CTN has created a successful and efficient infrastructure for conducting important HCT trials. Network trials address critical issues in optimal graft sources, conditioning intensity, regimen-related toxicity, engraftment, GVHD, infection, disease control, and quality of life. Because of its comprehensive portfolio and successful accrual, the Network is recognized as the leading group to facilitate and complete clinical studies addressing HCT issues. This is clearly evidenced by successful collaborations with affiliate transplant centers, NIH cooperative groups and the National Clinical Trials Network, the Cancer Trials Support Unit, other consortia and research networks, and the increasing number of investigators and groups seeking partnerships with the Network. The availability of an effective network for transplant trials has also led to greater interest on the part of pharmaceutical and device companies to invest in transplant indications and to consider public-private partnerships that advance the field’s scientific agenda. While multicenter trials pose logistical and scientific challenges beyond those of a single-center study, they also address questions unanswerable in single institutions. Both large Phase II and Phase III approaches bring the strength of broader multi-institutional enrollment to confirm, amplify, or clarify conclusions from prior, more limited pilot studies. The HCT community understands that innovative and multi-institutional trials are needed to address the hardest questions facing patients with life-threatening hematopoietic diseases and are enthusiastic about the opportunities to conduct these trials through the Network. The BMT CTN plays a crucial role in advancing the field of HCT in a variety of ways. The most important is by providing the infrastructure to conduct trials successfully and efficiently. However, the Network also makes its data and specimens available for ancillary and correlative studies, disseminates research results, and brings the community together to determine future research needs. Through involvement of more than 100 transplant centers, BMT CTN trials have accrued almost 8,900 patients in a timely manner. Of the 38 studies opened, 28 are complete.


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The Network is committed to sharing the results of these trials in HCT, hematology, oncology, and medical peer-reviewed journals as well as at scientific meetings. To date, the BMT CTN has published and shared more than 120 manuscripts and presentations, including 8 manuscripts (2 of primary study results) and 15 presentations during this reporting period. The Network works together with the CIBMTR and ASBMT to publicize results and activities at the annual BMT Tandem Meetings where it has a prominent place in the meeting agenda organizing sessions for investigators and for clinical research staff. Additionally, the BMT CTN collaborates with leaders throughout the fields of hematology and oncology to survey the HCT landscape to determine future research directions through periodic State of the Science Symposia, which lay out an agenda for multicenter trials to have the maximal impact on improving health of patients facing life-threatening and/or debilitating blood diseases. The DCC and the Network’s Core and Affiliate Centers represent the highest level of commitment and participation by patients, researchers, transplant center staff, and support personnel – all working together in this valuable endeavor to achieve the BMT CTN’s original mission: to improve the outcomes of HCT for patients with life-threatening disorders.


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Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 7.1 Protocols Open to Accrual

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7.0 Protocol Descriptions

The following section describes each BMT CTN research study. Accrual graphs, included as appropriate, are based on the period from study inception through March 31, 2016. Reporting period updates are highlighted in bold font. Protocols are grouped by study development stage:

• Open to accrual and actively accruing patients (10) • Completed accrual during this reporting period (2) • Completed accrual during a previous reporting period (26) • Released to centers (1)

7.1 Protocols Open to Accrual

BMT CTN Protocols Open to Accrual (as of March 31, 2016)

BMT CTN Protocol # Protocol Title

07LT Continued, long-term follow-up and lenalidomide maintenance therapy for patients who have enrolled on BMT CTN 0702

1101 A multi-center Phase III randomized trial of reduced intensity conditioning and transplantation of double unrelated umbilical cord blood versus HLA-haploidentical related bone marrow for patients with hematologic malignancies

1102 A multi-center biologic assignment trial comparing reduced intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50-75 with intermediate-2 and high risk myelodysplastic syndrome

1202 Prospective multi-center cohort for the evaluation of biomarkers predicting risk of complications and mortality following allogeneic HCT

1203 A multi-center Phase II trial randomizing novel approaches for graft-versus-host disease prevention compared to contemporary controls

1205 Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical trials

1301 A randomized, multi-center, Phase III trial of calcineurin inhibitor-free interventions for prevention of graft-versus-host disease

1302 Multicenter Phase II, double-blind placebo controlled trial of maintenance ixazomib after allogeneic hematopoietic stem cell transplantation for high risk multiple myeloma

1304 / DFCI 10-106 /

IFM/DFCI 2009

A randomized Phase III study comparing conventional dose treatment using a combination of lenalidomide, bortezomib, and dexamethasone (RVD) to high-dose treatment with peripheral stem cell transplant in the initial management of myeloma in patients up to 65 years of age

1505 A randomized recruitment intervention trial (RECRUIT)


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BMT CTN 07LT

Protocol Number: BMT CTN 07LT

Title: Continued, long-term follow-up and lenalidomide maintenance therapy for patients who have enrolled on BMT CTN 0702

Rationale:

Therapeutic advances in multiple myeloma have resulted in substantially improved survival. In a large population-based study of 45,595 multiple myeloma patients, myeloma-specific 5-year median overall survival improved from 36% to 68% under age 50, and from 34% to 58% among patients of ages 51-65 in the years between 1973 and 2009. Post-transplant consolidation and maintenance strategies have also yielded improved progression-free survival (PFS) and overall survival. The BMT CTN 0702 study randomized patients to receive two autologous HCTs, one autologous HCT and post-transplant consolidation, or one autologous HCT with maintenance. Of note, all patients receive a total of 3 years of maintenance therapy using lenalidomide. Since the implementation of BMT CTN 0702, the experience with maintenance has broadened, and at least two large Phase III clinical trials that continued lenalidomide maintenance for longer periods were associated with longer survival compared to placebo. This long-term follow-up protocol focuses on extending the follow-up period for all patients on BMT CTN 0702 to assess long-term outcomes, such as PFS and incidence of second primary malignancies. A secondary objective is to provide patients with lenalidomide maintenance therapy free of charge until there is evidence of disease progression.

Primary Objective: To compare PFS as a time to event analysis between the three randomized treatment arms from the BMT CTN 0702 protocol as a pairwise comparison. The analysis will be conducted once all surviving patients have been followed for at least 5 years post randomization on the BMT CTN 0702 protocol.

Secondary Objectives: To examine the cumulative incidence of second primary malignancies, probability of overall survival, probability of event-free survival, and health quality of life on all patients, including those not receiving long-term lenalidomide maintenance therapy.

Team Principals: Name Email

Chairs: Amrita Krishnan [email protected] George Somlo [email protected] Edward Stadtmauer [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Brianne Allison [email protected] Medical Monitor: Shannon Smiley [email protected] Statistician: Nancy Geller [email protected] Contract Rep: Nancy Poland [email protected] Additional Members: Email PRC Approval Date: 06/10/2014 Angela Dispenzieri [email protected] DSMB Approval Date: 07/30/2014 Sergio Giralt [email protected] Opened to Accrual: 03/04/2015 John Koreth [email protected] Closed to Accrual: N/A Adam Mendizabal [email protected] Target Accrual: 450 patients Philip McCarthy [email protected] Total Accrual as of 3/31/2016: 130 patients Courtney Nelson [email protected] Reporting Period Accrual: 128 patients Hari Parameswaran [email protected] IND Number: 104912 Muzaffar Qazilbash [email protected] Recent Version Released: 09/30/2014 David Vesole [email protected] Key Highlights: In November 2013, a proposal was submitted to the Steering Committee to amend the BMT CTN 0702


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Protocol Number: BMT CTN 07LT protocol to continue lenalidomide maintenance therapy until progression based on recent data from two major clinical trials, including BMT CTN 0704 / CALGB 100104. The Steering Committee elected to implement BMT CTN 07LT as a separate protocol instead of an amendment to 0702 in order to reduce the impact on the 0702 primary endpoint and to provide patients with the option to withdraw from long-term maintenance or follow up. From a regulatory standpoint, a separate protocol also provides the opportunity to finish, close, and conduct analyses on 0702 before all patients progress. The protocol v1 was released on September 30, 2014, and the study opened to accrual on March 4, 2015.

Reporting Period Update:

There are a total of 39 sites activated on the protocol. Accrual is behind projections primarily because of slower-than-anticipated center activation and consent timing logistics due to time between and location of 0702 patient follow-up visits. Investigator calls were held to promote accrual and review study logistics. Version 2.0 of the protocol was approved by the DSMB in December 2015 and will be released to centers in Spring 2016. This amendment included modifications and clarifications to adverse event reporting requirements.

BMT CTN 07LT

Target accrual = 450 patients


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BMT CTN 1101

Protocol Number: BMT CTN 1101

Title: A multi-center Phase III randomized trial of reduced intensity conditioning and transplantation of double unrelated umbilical cord blood versus HLA-haploidentical related bone marrow for patients with hematologic malignancies

Rationale:

Reduced intensity conditioning (RIC) HCT has allowed older and less clinically fit patients to receive potentially curative treatment with allogeneic HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated donor. Even when a suitably matched unrelated donor is identified, data from NMDP/Be The Match indicate that a median of four months is required to complete searches that result in transplantation; thus some number of patients succumb to their disease while awaiting identification and evaluation of a suitably matched adult unrelated donor. Single or dual center studies showed partially HLA-mismatched related bone marrow and unrelated double umbilical cord blood are valuable sources of donor cells for RIC HCT, extending this treatment modality to patients who lack other donors. In order to study the reproducibility, BMT CTN conducted two parallel prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of related haplo-bone marrow (BMT CTN 0603) and double umbilical cord blood (BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced early results similar to that reported with unrelated donor, and even HLA-matched sibling, BMT. These data demonstrate not only the efficacy of both of these approaches but also that both can be safely exported from the single center setting. Both haplo-bone marrow and double umbilical cord blood grafts can be obtained rapidly for >90% of patients lacking an HLA-matched donor. In addition to the primary protocol, the 1101 study includes a companion Cost-Effectiveness protocol, which evaluates the cost differences between the two 1101 study arms.

Primary Objective:

To compare progression-free-survival at two years between patients who receive unrelated double cord blood unit versus HLA haploidentical related bone marrow transplantation. Cost-Effectiveness: To determine the cost-effectiveness between these two transplantation methodologies expressed as the cost per quality adjusted life year.

Secondary Objectives:

To evaluate neutrophil recovery, graft failure, platelet recovery, donor cell engraftment, acute and chronic GVHD, overall survival, treatment-related mortality, infections, hospital admission and length of stay, health related quality of life, and relapse / progression. Cost-Effectiveness: To examine out-of-pocket costs, the cost of informal caregiving, and the impact on workplace productivity, for both patients and caregivers.

Team Principals: Name Email PRC Approval Date: 10/22/2011

Chairs: Claudio Brunstein [email protected] DSMB Approval Date: 01/09/2012 Ephraim Fuchs [email protected] Opened to Accrual: 6/19/2012 Paul O’Donnell [email protected] Closed to Accrual: N/A

Officer: Mary Eapen [email protected] Target Accrual: 410 patients Coordinator: Kate Bickett [email protected] Total Accrual as of 03/31/16: 236 patients Medical Monitor: Gabrielle Meyers [email protected] Reporting Period Accrual: 76 patients Statistician: Brent Logan [email protected] IND Number: N/A Contract Rep: Pam Budnick [email protected] Recent Version Released: 01/16/2015 Additional Members: Email Additional Members: Email Omar Aljitawi [email protected] Nancy DiFronzo [email protected] Joe Antin [email protected] Mary Horowitz [email protected] Karen Ballen [email protected] Chatchada Karanes [email protected] Javier Bolaños-Meade [email protected] Elizabeth Rich [email protected]


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Luciano Costa [email protected] Liz Wagner [email protected] Corey Cutler [email protected] John Wingard [email protected] Steve Devine [email protected]

Key Highlights:

BMT CTN 1101 is a Phase III randomized follow-on study to the Phase II 0603 (haplo bone marrow) and the 0604 (double umbilical cord blood) studies. The protocol was approved by the PRC in October 2011 and DSMB in January 2012. Version 1 of the protocol was released to centers in February 2012. The study was opened to accrual in June 2012. The Cost-Effectiveness Companion study protocol was released in November 2012. The study has continually struggled to meet accrual targets. In addition to revising the restrictive eligibility criteria through several amendments, the protocol team identified challenging issues hampering accrual, including referring and transplant physician bias and competing protocols. Accrual initiatives to address these barriers included the development of educational material explaining the trial and donor choices, site visits from the study chairs to interested centers, and routine email communication to 1101 site PIs and coordinators.


Accrual continues to be a challenge for the study; however, with the addition of new sites and promotion from the protocol team, the study achieved 79% of the target enrollment for the reporting period. The study team continues to work with sites to identify barriers and address institutional biases. The team’s collaboration with DKMS and German transplant centers continues, with activation of German sites expected in 2016. Version 4.0 of the companion Cost Effectiveness Ancillary study, which includes a HIPAA authorization form, was released in January 2016.

Publications:

1. Design of a cost-effectiveness analysis alongside a randomized trial of transplantation using UCB versus HLA-haploidentical related bone marrow in advanced hematologic cancer. Journal of Comparative Effectiveness Research. 2014 Mar 1; 3(2):135-144.

2. Donor selection recommendations (including 0603 / 0604 long term follow-up data): Mismatched related and unrelated donors for allogeneic HCT for adults with hematologic malignancies. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1485-1492. Epub 2014 May 23.

BMT CTN 1101



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BMT CTN 1102


Title: A multi-center biologic assignment trial comparing reduced intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50-75 with intermediate-2 and high risk myelodysplastic syndrome

Rationale:

Advances in both the understanding of MDS and in the development of alternatives to standard leukemia induction therapy in the treatment of MDS, including hypomethylating therapy and RIC allogeneic HCT for older patients, lead to questions about the appropriate role and timing of these therapies. This trial will compare RIC allogeneic HCT with hypomethylating / best supportive care in patients with higher risk MDS who are referred for transplantation evaluation. The study is consistent with the National Comprehensive Cancer Center Treatment Guidelines for MDS

and with suggestions from a recent review article by Giralt et al. regarding clinical trials to provide evidence for Medicare coverage of allogeneic transplant for MDS. The design will use assignment to transplantation when a donor is available or best supportive care (usually hypomethylating therapy) when a suitable matched related or unrelated donor is not available. Patients with an HLA-matched sibling or unrelated donor will proceed to allogeneic transplantation utilizing an institutionally-approved RIC regimen. Patients without a suitable donor will be offered hypomethylating therapy (or other best supportive care). The primary objective is to determine whether there is a meaningful benefit (overall survival advantage) among those who undergo RIC allogeneic HCT when compared to those who continue on hypomethylating therapy / best supportive care.

Primary Objective: To compare the three-year overall survival probabilities between RIC allogeneic HCT and non-transplant therapy / best supportive care using an intent-to-treat analysis.

Secondary Objectives: To compare leukemia-free survival at 3 years from enrollment and quality of life measures between treatment arms.

Team Principals: Name Email PRC Approval Date: 01/24/2013

Chairs: Corey Cutler [email protected] DSMB Approval Date: 05/02/2013 Ryo Nakamura [email protected] Opened to Accrual: 12/16/2013

Officer: Wael Saber [email protected] Closed to Accrual: N/A Coordinator: Alyssa Ramirez [email protected] Target Accrual: 338-400 pts Medical Monitor: Bipin Savani [email protected] Total Accrual as of 03/31/16: 165 patients Statistician: Raphael Fraser [email protected] Reporting Period Accrual: 96 patients Contract Rep: Renee Carby [email protected] IND Number: N/A Additional Members: Email Recent Version Released: 07/02/2015 Fred Appelbaum [email protected] Additional Members: Email Joseph Alvarnas [email protected] Adam Mendizabal [email protected] Richard Champlin [email protected] Betul Oran [email protected] Dennis Confer [email protected] Joycelynne Palmer [email protected] Steve Forman [email protected] Marcelo Pasquini [email protected] Steven D. Gore [email protected] Scott Ramsey [email protected] Mary Horowitz [email protected] Bart Scott [email protected] Eric Leifer [email protected] Mikkael Sekeres [email protected] Moira Lewis [email protected] Richard Stone [email protected] Brent Logan [email protected] Roni Tamarir [email protected]

Key Highlights: The protocol was approved by the PRC in January 2013 and DSMB in May 2013. Version 1.0 was released to centers for local IRB submission in August 2013. The study was activated for enrollment on December 16, 2013, after several centers received IRB approval. Twenty-eight Core Centers and 8

mailto:[email protected]



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Protocol Number: BMT CTN 1102 Affiliate Centers are activated for enrollment. Version 2.0 of the protocol was released to centers in July 2014. This amendment updated the eligibility requirements to state the unrelated donor search may begin once a patient consents, and the bone marrow aspirate may be within 30 days prior to consent instead of 30 days prior to enrollment. There was also a list of acceptable MDS subtypes added to the eligibility criteria. A Segment 0 enrollment staging area was added to capture patients who have consented but do not have a recent bone marrow biopsy. Lastly, the informed consent was updated to include more information about the different treatment options for MDS and to include more information about the risks associated with hypomethylating therapy, reduced-intensity conditioning, and transplant. Version 3.0 of the protocol was released to centers in December 2014.The brief amendment updated the eligibility requirements to state the bone marrow aspirate could be performed within 60 days prior to consent instead of 30 days. This timeframe had been identified as one of the most common accrual barriers, and after the amendment was implemented, accrual increased. The start of the unrelated donor search was also clarified to be at the time samples are requested from potential NMDP/Be The Match donors.


Accrual has increased to upwards of 97% of projections during this reporting period. Version 4.0 of the protocol was released to centers on July 2, 2015. This amendment incorporated the Ancillary Cost-Effectiveness Analysis Protocol as an appendix to the study and added information regarding objectives, endpoints, and data for this ancillary study.

Publications:

1. Treatment of older patients with high-risk MDS: The emerging role of allogeneic HCT. Current Hematologic Malignancy Reports. 2014 Mar 1; 9(1):57-65.

2. Multicenter biologic assignment trial comparing reduced-intensity allogeneic HCT to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk MDS: BMT CTN #1102 study rationale, design, and methods. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1566-1572. Epub 2014 Jun 24.

BMT CTN 1102



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BMT CTN 1202


Title: Prospective multi-center cohort for the evaluation of biomarkers predicting risk of complications and mortality following allogeneic HCT

Rationale:

While HCT offers the only cure for many patients with malignant and non-malignant hematologic diseases, this treatment is associated with significant risks, leading to high rates of morbidity and mortality. There is a critical need for more effective prevention and treatment strategies for HCT-associated complications. The most serious of the latter include GVHD, cancer recurrence, organ toxicity, and opportunistic infection. Although some clinical variables (e.g., recipient age, donor-recipient HLA mismatch) predict higher risk of some events (e.g., GVHD, infection), no diagnostic tests exist that reliably predict occurrence, severity, or response to therapy of any of these complications. Recent compelling results from single center studies suggest that biomarkers can be identified that stratify patients into discrete risk groups for some outcomes and for overall mortality. However, these relatively small studies generally lack the statistical power or validation necessary to allow their results to be incorporated into practice. One key factor in the success of biomarker studies is the quality of clinical outcomes data that is linked to the specimens being analyzed. An adequate resource for these studies requires longitudinal sample collection integrated with longitudinal collection of comprehensive, standardized, high quality clinical data regarding complications, from onset to resolution, and regarding other clinical variables affecting risk of post-HCT outcomes. The 1202 resource is designed to allow genomic, proteomic and transcriptional data to be integrated with high quality clinical phenotype and outcomes data to identify risk factors for development and severity of acute GVHD, chronic GVHD, organ toxicity, relapse, mortality, infection and other clinically significant complications occurring after allogeneic HCT.

Primary Objective: To establish a cohort of biologic samples collected prospectively from patients treated in BMT CTN centers that will be a shared biospecimen resource for conducting future allogeneic HCT correlative studies.

Team Principals: Name: Email:

Chairs: John Hansen [email protected] John Levine [email protected]

Officer: Wael Saber [email protected]

Coordinators: Brianna Johnson [email protected] Cathryn Mudrick [email protected]

Medical Monitor: Wael Saber [email protected] Statistician: Mat Makowski [email protected] Contract Rep: Renee Carby [email protected] Additional Members: Email: PRC Approval Date: 11/19/2012 Amin Alousi [email protected] DSMB Approval Date: 12/17/2012 Asad Bashey [email protected] Opened to Accrual: 06/11/2013 Dennis Confer [email protected] Closed to Accrual: N/A James Ferrara [email protected] Target Accrual: 1,500 patients Theresa Hahn [email protected] Total Accrual as of 3/31/16: 1,736 patients Vincent Ho [email protected] Reporting Period Accrual: 159 patients Mary Horowitz [email protected] IND Number: N/A Alan Howard [email protected] Recent Version Released: 03/18/2015 Leslie Kean [email protected] Additional Members: Email: Phillip McCarthy [email protected] Stefanie Sarantopoulos [email protected]


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Adam Mendizabal [email protected] Steve Spellman [email protected] Bill Merritt [email protected] Elizabeth Wagner [email protected] Miguel-Angel Perales [email protected]

Key Highlights:

The BMT CTN 1202 Protocol Team was formed in March 2012. The protocol received PRC approval in November 2012 and DSMB approval in December 2012. The protocol opened to enrollment on June 11, 2013. Forty-four centers have been activated. Version 2.0 of the protocol was released in August 2013 to modify the specimen collection. Version 3.0 of the protocol was released in March 2015 to continue enrollment of non-Caucasian adult and pediatric participants until 200 African American and 200 pediatric participants are enrolled and transplanted. Due to rapid accrual, >1,500 transplanted patients were enrolled by March 2015 (originally projected for February 2018). However, an evaluation of enrolled patients showed fewer minority and pediatric patients than originally anticipated. In an attempt to boost accrual of non-Caucasian adults and children, the DCC elected to provide double accrual credit for non-Caucasian patients enrolled on the BMT CTN 1202 study beginning in February 2015. To increase the sample size of these patient populations even though the study accrual target was almost met, the Steering Committee also approved a protocol amendment in February 2015 to extend accrual until at least 200 African American and 200 pediatric participants are enrolled and transplanted. The DSMB approved the amendment.


The target accrual of 200 pediatric patients was met during this reporting period, and in September 2015, accrual was restricted to African American patients only. Double accrual credit continues to be offered. It is anticipated the target accrual of 200 African American patients will be met in April 2016.

BMT CTN 1202

Target accrual = 1,500 patients



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BMT CTN 1203


Title: A multi-center Phase II trial randomizing novel approaches for graft-versus-host disease prevention compared to contemporary controls

Rationale:

Acute GVHD is an important cause of morbidity and mortality after allogeneic HCT. Clinically significant grade II-IV acute GVHD occurs in 34-40% of patients undergoing HLA-matched related donor HCT, 47-52% of HLA-matched unrelated donor HCT, and is further increased in those lacking HLA-matched donors. The goal of this multi-center Phase II clinical trial is to evaluate three novel GVHD prophylaxis approaches for their efficacy in improving the proportion of patients who do not develop severe acute GVHD, chronic GVHD that requires systemic therapy, and disease progression or relapse by one year post-transplant. All treatment arms will be compared to a contemporary control group from the CIBMTR Research Database in which all patients received the most commonly used GVHD prophylaxis regimen, tacrolimus and methotrexate. The results of this study will identify the most promising approach(es) to be tested in a Phase III trial. Selection of the most promising therapy(ies) will be made based on the magnitudes of difference in the primary endpoint between each intervention group and the control.

Primary Objective:

To compare one year GVHD / relapse or progression-free survival after HCT between each of three novel GVHD prophylaxis approaches and a contemporary control from the CIBMTR Research Database. An event for this time to event outcome is defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse or progression, or death by any cause.


To describe for each treatment arm: rates of grade II-IV and III-IV acute GVHD, visceral acute GVHD, chronic GVHD, immunosuppression-free survival at one year, hematologic recovery (neutrophil and platelet), donor cell engraftment, disease relapse or progression, TRM, rates of Grade ≥ 3 toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, incidence of infections, immune reconstitution, and overall survival.


Chairs: Javier Bolaños-Meade [email protected] John Koreth [email protected] Ran Reshef [email protected]

Officer: Marcelo Pasquini [email protected]

Coordinators: Iris Gersten [email protected] Terry Pritchard [email protected]

Medical Monitors: Shannon Smiley (primary) [email protected] Dianna Howard (alternate) [email protected]

Statistician: Brent Logan [email protected] Contract Rep: Nancy Poland [email protected] Additional Members: Email: PRC Approval Date: 03/25/2013 Amin Alousi [email protected] DSMB Approval Date: 05/02/2013 Joseph Antin [email protected] Opened to Accrual: 09/17/2014 Nancy DiFronzo [email protected] Closed to Accrual: N/A Nancy Geller [email protected] Target Accrual: 270 patients David Jacobsohn [email protected] Total Accrual as of 3/31/16: 259 patients Richard Jones [email protected] Reporting Period Accrual: 205 patients Margaret MacMillan [email protected] IND Number: 119524 Mat Makowski [email protected] Recent Version Released: 07/20/2015


97


Adam Mendizabal [email protected] Additional Members: Email: Marco Mielcarek [email protected] David Porter [email protected] Joseph Pidala [email protected] Daniel Weisdorf [email protected]

Key Highlights: The protocol was approved by the PRC in March 2013 and DSMB in May 2013; it was released to centers in December 2013 and opened to enrollment in September 2014.


Protocol version 3.0 was released to sites on July 20, 2015. Changes include tightening of pre-transplant required assessment timeframes as well as minor additions to eligibility criteria and clarifications concerning adverse event reporting. Twenty-nine of 31 activated centers have enrolled patients on the trial. Fifty-four patients were enrolled during the last reporting period (September 2014 – March 2015) and 205 patients this reporting period. Accrual has been significantly ahead of projections and is at 95% completion. The study is projected to complete accrual approximately a year ahead of schedule. A request for endpoint review will be submitted to the DSMB at the end of April 2016, proposing to convene the ERC process in the Fall of 2016.

BMT CTN 1203



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BMT CTN 1205


Title: Easy-to-read informed consent (ETRIC) for hematopoietic cell transplantation clinical trials

Rationale:

This study hypothesizes that use of a novel evidence-based ETRIC form template with enhanced readability and processability components will be associated with higher levels of patient comprehension of BMT CTN treatment protocols than use of the existing standard institution-specific consent forms. Furthermore, the ETRIC form may be associated with lower anxiety and greater satisfaction with the consent process. Also, institutional barriers exist to the implementation of the ETRIC form, and it is important to understand what these are so that they can be addressed effectively if this form is proved to be superior to standard forms. The study has two components: 1. Randomized Study: Randomized, multicenter, prospective comparative study of ETRIC or standard

consent form to improve patient comprehension of BMT CTN parent clinical trials. Patients who are being considered for one of the clinical trials will be approached, and on providing verbal consent to 1205, will be randomized to and will undergo the consent process for the parent trial using either ETRIC or standard consent form. Assessments will be conducted for patient comprehension of the clinical trial and satisfaction and anxiety related to the consent process.

2. Evaluation Study: To understand barriers to implementation of ETRIC, site visits to 10-12 transplant centers participating in the BMT CTN parent studies will be conducted with semi-structured interviews of IRB administrators, site protocol investigators, and study coordinators. Sites will include centers that are participating and are not participating in the ETRIC study.

Primary Objective:

To determine whether the ETRIC form increases patient comprehension of informed consent compared to the standard consent form for the BMT CTN 1101, 1203, and 1301 studies (considered the “parent” clinical trials for the 1205 protocol). This will be achieved by comparing patient comprehension scores on the Quality of Informed Consent Part A instrument between patients randomized to the two arms.


To compare additional measures of comprehension and measures of patient anxiety, satisfaction, and information location between the two arms. Specifically, these will include subjective comprehension scores on the Quality of Informed Consent (Part B) instrument, comprehension scores on the modified Deaconess Informed Consent Comprehension Test, state anxiety scores on the State Trait Anxiety Inventory, satisfaction scores, and time taken for information location. The study will also explore patient consent rates on parent clinical trials for the two arms.


Chairs: Navneet Majhail [email protected] Ryan Spellecy [email protected]

Officer: Mary Horowitz [email protected] Coordinator: Cathryn Mudrick [email protected] Statistician: Sergey Tarima [email protected] Contract Rep: Kiila Lee [email protected] Additional Members: Email: PRC Approval Date: N/A Ellen Denzen [email protected] DSMB Approval Date: 03/04/2013 Amy Foley [email protected] Opened to Accrual: 11/26/2013 Iris Gersten [email protected] Closed to Accrual: N/A Mitchell Horwitz [email protected] Target Accrual: 198 patients Lensa Idossa [email protected] Total Accrual as of 3/31/16: 171 patients Steven Joffe [email protected] Reporting Period Accrual: 113 patients Naynesh Kamani [email protected] IND Number: N/A


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Roberta King [email protected] Recent Version Released: 11/19/2014 Heather Moore [email protected]

Elizabeth Wagner [email protected]

Key Highlights:

The protocol was approved by the DSMB on March 4, 2013. Version 1.0 of the protocol and the study assessments were released to 12 centers in July 2013 and seven centers in September 2013. The study was activated for enrollment in November 2013 after several centers received IRB approval. Twenty centers have been activated on the randomized study. Accrual decreased significantly when the 0901 parent study closed unexpectedly, so it was determined that the 1203 study should be added as a new parent study. Version 2.0 of the 1205 protocol was released in June 2014 to remove the parent protocol 0901 and add the parent protocol 1203. Accrual continued to lag, so Version 3.0 was released in November 2014, adding BMT CTN 1301 as another parent study.


Due to an estimated 25% incompletion rate of the Quality of Informed Consent assessments (the primary endpoint), the DSMB approved an amendment to increase accrual from 160 to 198 participants. The amended protocol (v4) was released in January 2016. The protocol team addressed the incompletion rate with participating centers, and compliance has since increased. It is anticipated the accrual target of 198 patients will be met in Summer 2016. Site interviews for the Evaluation Study are complete, and the analysis is underway with anticipated manuscript submission for publication during this reporting period.

Presentation: 1. ETRIC forms for multi-center HCT clinical trials (BMT CTN 1205). Presented: Institute for Healthcare Advancement’s 14th Annual Health Literacy Conference, Irvine, CA, May 2015

BMT CTN 1205

Target accrual = 198* patients

* Target accrual was expanded from original sample size of 160 to 198, approved by DSMB in December 2015 and implemented in January 2016.


100

BMT CTN 1301


Title: A randomized, multi-center, Phase III trial of calcineurin inhibitor-free interventions for prevention of graft-versus-host disease

Rationale:

Chronic GVHD is a devastating complication that affects HCT survivors and may offset the associated benefits of reducing rates of post-transplant disease relapse. The combination of calcineurin inhibitors (tacrolimus and cyclosporine A) with methotrexate is the most common GVHD prophylaxis used worldwide in the context of myeloablative conditioning transplants. This regimen, implemented more than three decades ago, demonstrated better control of acute GVHD. However, this strategy is ineffective against chronic GVHD. Management of chronic GVHD remains a challenge and it has become a significant health problem in transplant survivors with more frequent use of mobilized peripheral blood stem cells. Additionally, several issues arise with this treatment approach: 1) methotrexate-accentuated risk of conditioning regimen-related oral mucositis and renal toxicity; 2) increased risk of thrombotic microangiopathy due to calcineurin inhibitors; 3) requirement for chronic monitoring of calcineurin inhibitor serum levels; and 4) chronic immunosuppression is not a conducive platform for post HCT cellular therapies for treatment or prevention of infections or disease relapse. In vivo graft manipulation with anti thymocyte globulin or alemtuzumab, ex vivo graft manipulation with CD34 selection and T-cell depletion, and, most recently, use of high doses of cyclophosphamide after transplant are strategies that are associated with lower rates of chronic GVHD. In addition, a benchmark analysis of novel approaches to prevent GVHD using data from the CIBMTR identified two strategies for T-cell depletion, using either CD34-selection or administration of post-transplantation cyclophosphamide, as the most effective in preventing both acute and chronic GVHD after HCT. This clinical trial further explores these approaches to prevent chronic GVHD which have the additional benefit of not requiring prolonged immunosuppression.

Primary Objective: To compare chronic GVHD / relapse-free survival as a time to event endpoint after hematopoietic stem cell transplant between each of the calcineurin inhibitor-free interventions and a tacrolimus / methotrexate control.


To compare rates of grade II-IV and III-IV acute GVHD, chronic GVHD, chronic GVHD-free survival, immunosuppression-free survival at one year, neutrophil and platelet engraftment, disease relapse, transplant-related mortality, rates of Grade ≥3 toxicity; incidence of cytomegalovirus and Epstein-Barr virus reactivation, incidence of infections; immune reconstitution, quality of life, and overall survival.


Chairs: Leo Luznik [email protected] Miguel Perales [email protected]

Chair / Officer: Marcelo Pasquini [email protected] Coordinator: Brady Nesbitt [email protected]

Medical Monitors: Tamila Kindwall-Keller [email protected] Dianna Howard [email protected]

Statistician: Brent Logan [email protected] Contract Rep: Pam Budnick [email protected] Additional Members: Email: PRC Approval Date: 12/17/2013 Steve Devine [email protected] DSMB Approval Date: 02/06/2014 Nancy DiFronzo [email protected] Opened to Accrual: 08/17/2015 Nancy Geller [email protected] Closed to Accrual: N/A Sergio Giralt [email protected] Target Accrual: 345 patients Helen Heslop [email protected] Total Accrual as of 3/31/16: 33 Vincent Ho [email protected] Reporting Period Accrual: 33


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Carolyn Keever-Taylor [email protected] IDE Number: 16059 Lauren Kunz [email protected] Last Version Released: 05/29/2015 Adam Mendizabal [email protected] Additional Member: Email: Eneida Nemecek [email protected] Scott Solomon [email protected] Robert Soiffer [email protected]

Key Highlights:

The study was approved by the PRC in December 2013 and DSMB in February 2014.Version 1.0 of the protocol was released to centers for IRB submission in September 2014. Twenty Core Centers and 6 Affiliate Centers had committed to participate on the study. A protocol version 2.0 amendment to the protocol was reviewed and approved by the DSMB in April 2015. This amendment included a change to chemotherapy dose calculations; language clarifying that donors of patients randomized to the CD34 selection arm will be considered research subjects because their specimens will be processed through an investigational device; additional language regarding data submission, adverse event reporting, ethics, and regulatory requirements; and new donor informed consent and assent forms for donors of patients randomized to the CD34 selection arm.


The study was activated August 2015 and is currently open to enrollment at 21 of 31 possible participating centers. Accrual has been higher than anticipated with 33 patients enrolled when only 10 were projected. A protocol version 3.0 amendment was submitted to the DSMB in November 2015, reviewed in December 2015, and subsequently approved. The amendment is currently awaiting release to centers. This amendment will update the inclusion criteria to allow for patients with planned post-transplant maintenance therapies using FLT3 inhibitors and other tyrosine kinase inhibitors. The window from randomization to transplant will be expanded from 21 days to 28 days. Weekly toxoplasmosis monitoring via NAAT for patients on the CD34 cell selection arm was replaced with a required prophylaxis for patients at high risk.

BMT CTN 1301



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BMT CTN 1302


Title: Multicenter Phase II, double-blind placebo controlled trial of maintenance ixazomib after allogeneic hematopoietic stem cell transplantation for high risk multiple myeloma

Rationale:

The treatment outcomes of high risk multiple myeloma patients remain suboptimal even in the era of novel agents and abundance of available regimens. There is considerable unmet need to improve their therapeutic outlook, and the role of allogeneic HCT in this population remains to be defined. The introduction of reduced intensity regimen has resulted in reduced TRM in allogeneic HCT for patients with myeloma. Emerging single center experience supports the feasibility of RIC regimen of fludarabine, melphalan plus bortezomib in patients with multiple myeloma. However, myeloma relapse still needs to be reduced in order to maximize the efficiency of this therapeutic approach in high risk patients. This clinical trial addresses these two challenges with allogeneic HCT. First, addition of bortezomib to the conditioning regimen can optimize the anti-myeloma effect of melphalan against malignant plasma cells and bortezomib after the stem cell infusion is associated with lower rates of severe acute GVHD. Second, the addition of a novel maintenance drug may further reduce the risk of disease relapse long enough for the graft versus myeloma to take effect. Given the small number of myeloma patients treated with an allogeneic HCT at individual institutions, we will perform a multicenter study evaluating the conditioning regimen of fludarabine, melphalan plus bortezomib followed by allogeneic HCT from a HLA-matched related or unrelated donor in patients with high risk multiple myeloma. Patients will be randomized to placebo-controlled maintenance therapy of ixazomib (MLN9708) after allografting, and the maintenance therapy will be prescribed for one year. The study will assess the novel conditioning regimen in high risk population as well as the efficacy of ixazomib in preventing disease relapse/progression following allogeneic HCT. The results of this trial will assist in understanding the role of this novel agent in post-allogeneic HCT maintenance and will assist in designing a definitive trial for this population with high risk multiple myeloma.

Primary Objective: To compare progression-free survival as a time to event endpoint from the time of randomization between patients randomized to ixazomib versus placebo maintenance in patients with high risk multiple myeloma.


To describe for each treatment arm: rates of grade II-IV and III-IV GVHD, chronic GVHD, best disease response rates, disease progression, transplant related mortality, overall survival, rates of Grade ≥ 3 toxicity according to CTCAE Version 4.0, incidence of infections, and health-related quality of life.


Chairs: Qaiser Bashir [email protected] Parameswaran Hari [email protected] Taiga Nishihori [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Samantha Wilkins [email protected] Medical Monitor: Dianna Howard [email protected] Statistician: Peter Dawson [email protected] Contract Rep: Kiila Lee [email protected] Additional Members: Email: PRC Approval Date: 02/04/2014 Melissa Alsina [email protected] DSMB Approval Date: 07/30/2014 Claudio Anasetti [email protected] Opened to Accrual: 08/17/2015 Yvonne Efebera [email protected] Closed to Accrual: N/A Cristina Gasparetto [email protected] Target Accrual: 138 Nancy Geller [email protected] Total Accrual as of 3/31/16: 17 Sergio Giralt [email protected] Reporting Period Accrual: 17


103


John Koreth [email protected] IDE Number: 124415 Phil McCarthy [email protected] Last Version Released: 03/11/2015 Emma Scott [email protected] Additional Member: Email: Edward Stadtmauer [email protected] David Vesole [email protected]

Key Highlights: The accrual period is 36 months, and patients will be followed for two years after transplant. The protocol was approved by the PRC in February 2014 and DSMB in July 2014. Version 1.0 of the protocol was released to centers in March 2015. Thirty-two centers plan to participate in the trial.


The protocol was opened to enrollment in August 2015. Nineteen Core and six Affiliate centers have been activated, and 17 patients have been enrolled. In March 2016, accrual was halted due to a higher than expected occurrence of toxicities within 100 days post transplant. The DSMB and NHLBI are reviewing the data and will provide their recommendations to the protocol team in April 2016.

BMT CTN 1302



104

BMT CTN 1304 / DFCI 10-106 / IFM/DFCI 2009 (The DETERMINATION Study)

Protocol Number: BMT CTN 1304 / DFCI 10-106 / IFM/DFCI 2009 (The DETERMINATION Study)

Title: A randomized Phase III study comparing conventional dose treatment using a combination of lenalidomide, bortezomib, and dexamethasone (RVD) to high-dose treatment with peripheral stem cell transplant in the initial management of myeloma in patients up to 65 years of age

Rationale:

For 15 years, high-dose therapy followed by autologous peripheral blood stem cell transplant has been the standard treatment for multiple myeloma in younger patients. For the last four or five years, the arrival of novel therapies (thalidomide, bortezomib, and lenalidomide) has revolutionized conventional therapeutic regimens. The use of these new therapies has improved complete response and very good partial response rates of high-dose therapy, as well as those of conventional-dose therapy, to such a point that these rates have now become similar in both groups of treatment. Thus, the arrival of novel therapies has brought into question the necessity of high-dose therapy as first-line therapy in young patients.

Primary Objective: To compare progression-free survival between conventional-dose treatment and high-dose therapy plus autologous peripheral blood stem cell transplant when both treatment arms receive novel drugs as part of induction, consolidation, and maintenance.


To compare the response rates, time to progression, overall survival, toxicity, and quality of life between the two arms; define genetic prognostic groups evaluated by gene expression profiling; examine the best treatment in each Gene Expression Profile-defined prognostic group; and collect medical resource utilization information which may be used in economic evaluation models.

Team Principals: Name: Email: PRC Approval Date: DFCI

Chairs: Marcelo Pasquini (BMT CTN) [email protected] DSMB Approval Date: DFCI

Paul Richardson (DFCI) paul_richardson@ dfci.harvard.edu Opened to Accrual: DFCI: 10/2010

BMT CTN: 11/16/13 Officer: DFCI Closed to Accrual: N/A

Coordinators: Amy Foley (BMT CTN) [email protected] Target Accrual: 660 patients

Andrea Zeytoonjian andreaa_zeytoonjian@ dfci.harvard.edu

Total Accrual as of 3/31/16: 598 patients

Medical Monitor: DFCI Reporting Period Accrual: 175 patients Statistician: DFCI IND Number: Held by DFCI Contract Rep: DFCI

Key Highlights:

This study is a collaboration between the DFCI and IFM with DFCI serving as the coordinating center for the US and the IFM coordinating the study in France. The French accrual (700 patients) is complete. The DFCI opened the study in October of 2010. Slower-than-anticipated accrual led the DFCI group to request BMT CTN endorsement of the study. The study was presented to the BMT CTN Steering Committee in February 2013, and the Committee agreed the BMT CTN would endorse the study and provide accrual credit for participating centers when the BMT CTN 0702 myeloma study completed accrual. The BMT CTN Myeloma Intergroup agreed with this plan and indicated 1304 would be the Network’s top priority myeloma study after BMT CTN 0702 closed. BMT CTN 0702 participating centers were invited to participate on the 1304 study in June 2013 and complete activation requirements during the final months of 0702 accrual. The 0702 study closed to accrual on November 15, 2013, and centers were informed 1304 accrual credit would be provided as of the following day. To ease confusion about the multiple collaborators and study numbers, the study acronym of DETERMINATION (Delayed versus Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy) was also created and is used on all study communications.


There are 48 BMT CTN Core, Consortia, and Affiliate Centers activated on the study, which is an increase of 20 centers since the previous reporting period. BMT CTN centers have enrolled 354 patients since BMT CTN endorsement of the study in November 2013, including 159 this reporting period. Monthly accrual


105

Protocol Number: BMT CTN 1304 / DFCI 10-106 / IFM/DFCI 2009 (The DETERMINATION Study)

more than doubled since BMT CTN endorsement. The IFM study results were presented during the 2015 ASH Annual Meeting, showing a progression-free survival benefit at 3 years post-randomization. There was no statistically significant difference in overall survival. A key difference of the DETERMINATION study is that lenalidomide maintenance therapy is given until disease progression whereas in the French study it was limited to one year post-transplant. Accrual onto the DETERMINATION study has remained steady since the French results were presented, and it is anticipated that accrual will be complete by the end of the year.

This is a DFCI-led study, so a different type of accrual graph is provided. DFCI opened the trial to accrual in October 2010, and the BMT CTN endorsed it in November 2013.

BMT CTN 1304 / DFCI10-106 / IFM/DFCI 2009 (The DETERMINATION Study)

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BMT CTN Endorsement


106

BMT CTN 1505


Title: A randomized recruitment intervention trial (RECRUIT)

Rationale:

The lack of minority participation in clinical trials is a long-standing problem. This lack of diversity in clinical trial participation is a barrier to the development of new therapies because of potential racial / ethnic differences in response to treatment. Very little rigorous research has been conducted regarding approaches to increasing subject diversity in clinical trials. This trial tests an enhanced training program based on what was learned from a previous recruitment trial, the literature, and on an intervention mapping strategy to improve and enhance implementation of a recruitment program to increase subject diversity in clinical trials that require physician referrals.

Primary Objective: To test an intervention targeting clinical trial site investigators and coordinators to increase subject diversity in multi-site treatment trials for diseases that require physician referral.


To compare intervention and control sites on the number of referrals from community physicians, mean potential and enrolled participant satisfaction scores, and numbers and types of recruitment activities.

TEAM PRINCIPALS Name Email ACCRUAL

Chairs: Barbara Tilley (RECRUIT) [email protected] Opened: TBD Adam Mendizabal (BMT CTN) [email protected] Closed: N/A

Officer: N/A Target: TBD Coordinator: RECRUIT Total as of 3/31/16: N/A Medical Monitor: N/A Reporting Period: N/A Statistician: RECRUIT

Key Highlights:

The RECRUIT study is conducted by Dr. Barbara Tilley, a PhD statistician at the University of Texas Health Science Center at Houston. The study is funded by a National Institute on Minority Health and Health Disparities grant, and the grant allows for collaboration among other NIH-funded networks / groups. Participating centers are randomized into one of two arms: intervention or control. The intervention centers receive an educational recruitment program and will work with the RECRUIT team to enhance and individualize their recruitment methods. Training includes an all-day kickoff meeting, 4-5 one hour training webinars, and follow-up calls with RECRUIT team members. The control centers follow their institution’s standard recruitment practices. All participating centers send a monthly screening logs and recruitment activities checklist to the RECRUIT coordinating center. Centers are also required to distribute anonymous satisfaction surveys screened for and/or enrolled on the selected BMT CTN “parent” studies. The RECRUIT team will collect recruitment data until the sites have completed recruitment to the parent studies or for approximately two years. Dr. Tilley presented the study to the BMT CTN Steering Committee in December 2014, and the Steering Committee approved the Network’s participation. Three BMT CTN “parent” studies were selected to be included in the RECRUIT study: 1203, 1301, and 1302. The RECRUIT team screened BMT CTN Core and Consortia Centers for eligibility, including minimum of 25% minority population within 30 mile radius of the center and minimum of six patients projected to be enrolled on the three parent studies annually. BMT CTN Core and Consortia Centers were invited to participate in the study in January 2015, and 13 of the 16 eligible centers agreed to participate. For this study, the investigators and coordinators at participating centers are the research subjects. Consents were obtained from participants and centers were randomized in February 2015.


The training kickoff meetings for intervention centers were held in April 2015, and centers were activated starting that month. Two of the randomized centers were ultimately unable to participate and withdrew from the study. Eleven randomized centers are participating. The study is slated to remain open until the Spring of 2017 at the end of the two year study period.

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 7.2 Protocols that Completed Accrual during this Reporting Period

107

7.2 Protocols that Completed Accrual during this Reporting Period

BMT CTN Protocols that Completed Accrual during this Reporting Period (April 1, 2015 – March 31, 2016)


0903 Allogeneic hematopoietic cell transplant for hematological cancers and myelodysplastic syndromes in HIV-infected individuals

1204 Reduced-intensity conditioning for children and adults with hemophagocytic syndromes or selected primary immune deficiencies

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BMT CTN 0903


Title: Allogeneic hematopoietic cell transplant for hematological cancers and myelodysplastic syndromes in HIV-infected individuals

Rationale:

Survival in patients with HIV has improved dramatically with the advent of highly active antiretroviral therapy (HAART). Despite improvements in HIV infection-related survival, the risk of malignancies remains significant in patients with HIV infection. While non-Hodgkin lymphoma is an AIDS-defining diagnosis, a comparison of a large cohort of HIV-infected patients to Surveillance, Epidemiology and End Results data demonstrates a significantly higher incidence of vaginal, liver, lung, oropharyngeal, colorectal, and renal cancers as well as Hodgkin lymphoma, melanoma, and leukemia in patients with HIV infection. Prior to the advent of HAART, the treatment of patients with malignancy in the setting of HIV infection was hamstrung by limited chemotherapy tolerance and complications due to opportunistic infection. Since the widespread availability of HAART, there have been significant improvements in the capacity to treat these patients in a fashion comparable to that of patients without HIV infection. This, in turn, has led to marked improvements in the outcomes of patients with malignancies in the setting of HIV infection. The prognosis for patients with AIDS-related lymphoma is dramatically different in the era of HAART therapy. In a comparison of treatment outcomes for patients treated before and after the advent of HAART, there is a statistically significant improvement in the overall survival of patients treated with HAART (p=0.002). While the International Prognostic Index remains a useful tool for estimating the prognosis of patients with AIDS-related non-Hodgkin lymphoma, the CD4 count of less than 100 per microliter has independent prognostic value for this group of patients. The impact of HAART therapy upon the immunological and functional status of patients with HIV infection has permitted the extension of aggressive therapeutic regimens to this patient population. HAART allows a significant portion of patients to reduce their viral load to undetectable levels and, therefore, tolerate far more aggressive therapeutic interventions than would have been possible previously.

Primary Objective: To assess non-relapse morality at 100 days after allogeneic HCT.


To analyze disease status at day 100 post HCT; time to hematopoietic recovery; chimerism at 30, 100, and 180 days; hematologic function at 100 and 180 days; infections; 6-month overall survival; acute and chronic GVHD; immunologic reconstitution at 8 weeks as well as 180 and 365 days; and the impact of HCT on the HIV reservoir at day 100, 6 months, 1 year, and 2 years post HCT for all patients and for those who have been maintained on optimized antiretroviral therapy throughout.


Chairs: Joseph Alvarnas [email protected] Richard Ambinder [email protected]

Officer: Willis Navarro [email protected] Coordinator: Cathryn Mudrick [email protected] Medical Monitor: Tammy Kindwall-Keller [email protected] Statistician: Maggie Wu [email protected] Contract Rep: Pamela Budnick [email protected] Additional Members: Email: PRC Approval Date: 09/15/2010 Robert Baiocchi [email protected] DSMB Approval Date: 03/29/2011 Steven Devine [email protected] Opened to Accrual: 05/11/2012 Christine Durand [email protected] Closed to Accrual: 12/03/2015 Charles Flexner [email protected] Target Accrual: 15 patients Stephen Forman [email protected] Total Accrual: 18 patients


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Mary Horowitz [email protected] Reporting Period Accrual: 2 patients Rick Jones [email protected] IND Number: N/A Amrita Krishnan [email protected] Recent Version Released: 03/12/2014 Richard Little [email protected] Additional Members: Email: Alexandra Levine [email protected] Ariela Noy [email protected] Brent Logan [email protected] Uday Popat [email protected] John Mellors [email protected] Ryan Shields [email protected] Adam Mendizabal [email protected] Aruna Subramanian [email protected] Deb McMahon [email protected] John Zaia [email protected]

Key Highlights:

The protocol was approved by the PRC in September 2010 and DSMB in March 2011. Protocol Version 1 was released to centers in April 2011; however, due to the need for immediate protocol amendments, study activation was delayed. Protocol Version 2 was released in January 2012, and the protocol opened to accrual in May 2012. Protocol Version 3 was released March 2014 to modify guidance for antiretroviral therapy and add risks of Enfuvirtide. Like its sister study, BMT CTN 0803, this trial is a partnership with the NCI-supported AIDS Malignancy Consortium. Additional funding is provided by the NCI Cancer Therapy Evaluation Program for Non-AIDS-Defining Cancers.


On December 3, 2015, the study closed to screening new patients. There are currently 18 total patients now enrolled. Sixteen of these patients have received a transplant, and two did not make it to transplant. It is anticipated another 1-2 patients still in screening from Fall 2015 will be enrolled onto the transplant segment.

BMT CTN 0903



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BMT CTN 1204


Title: Reduced-intensity conditioning for children and adults with hemophagocytic syndromes or selected primary immune deficiencies

Rationale:

HLH, HLH-related disorders, chronic granulomatous disease, hyper-IgM syndrome, immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance and severe leukocyte adhesion deficiency represent primary immune disorders that are typically fatal without HCT. However, transplant is often complicated by inflammation, infection, and other co-morbidities. In addition, these disorders have been shown to be cured with partial chimerism, making them an ideal target for the use of reduced intensity approaches, where a portion of patients may not achieve full donor chimerism but instead achieve stable mixed chimerism. Reduced-intensity conditioning strategies have demonstrated improved survival with decreased TRM in institutional series for patients with HLH. However, graft loss and unstable chimerism remain challenges. An institutional case series from Cincinnati Children’s Hospital demonstrated full or high-level chimerism and improved durable engraftment using intermediate (Day -14) timing alemtuzumab.

Primary Objective: To prospectively determine the 1-year overall survival in subjects treated for hemophagocytic syndromes or primary immune deficiencies using a standardized, reduced-intensity conditioning protocol consisting of fludarabine, melphalan, and intermediate timing of alemtuzumab.


To measure sustained engraftment; incidence of HLH reactivation and death from disease; immune reconstitution and functional immune recovery at 1-year; cumulative incidence of grade II-IV and III-IV acute and chronic GVHD; transplant-related complications (veno-occlusive disease, central nervous system toxicity); infectious complications, including reactivation of cytomegalovirus, adenovirus, Epstein-Barr virus, invasive fungal infection, or bacterial sepsis; and overall survival and rate of sustained engraftment of specific disease subsets.


Chairs: Carl Allen [email protected] Michael Pulsipher [email protected]

Officer: Mary Eapen [email protected] Coordinator: Alyssa Ramirez [email protected] Medical Monitor: Liza Thiel [email protected] Statistician: Peter Dawson [email protected] Contract Rep: Pam Budnick [email protected] Additional Members: Email: PRC Approval Date: 07/12/2013 K. Scott Baker [email protected] DSMB Approval Date: 08/05/2013 Catherine Bollard [email protected] Opened to Accrual: 11/14/2013 Lauri Burroughs [email protected] Closed to Accrual: 12/04/2015 Nancy DiFronzo [email protected] Target Accrual: 35 HLH patients Lisa Filipovich [email protected] Total Accrual: 47 patients Stephen Grupp [email protected] Reporting Period Accrual: 12 patients Rabi Hanna [email protected] IND Number: N/A Leslie Kean [email protected] Recent Version Released: 06/16/2015 Eric Leifer [email protected] Additional Member: Email: Sung-Yun Pai [email protected] Shalini Shenoy [email protected] Philip Roehrs [email protected] Julie-An Talano [email protected] Kirk Schultz [email protected]


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Key Highlights:

The protocol was approved by the PRC in July 2013 and DSMB in August 2013. It was released to centers for IRB submission in September 2013. The study was activated for enrollment in November 2013, after one center had received IRB approval and was ready to enroll a patient. The time from release to activation, and first patient enrollment, was 71 days – the shortest activation timeframe for any Network protocol. This may be due in part to the protocol team’s proactive outreach approach and target goal setting at time of protocol release, activities that were adopted for future studies. Twenty-seven centers were activated, including 17 PBMTC centers. A protocol Version 2 amendment was released to centers for IRB submission in December 2013. It changed the fludarabine dosing; distinguished HLA-matching requirements for sibling donors versus related non-sibling donors; clarified that future research blood samples are optional and noted maximum volumes; added a list of standard of care health observations to the informed consent; and added statements in the informed consent to further address and clarify genome-wide association study concerns. A protocol Version 3 amendment was released to centers for IRB submission in July 2014. It updated the inclusion criteria to allow patients as young as three months to be enrolled (previously four months) and to specify that donors must be willing and able to donate bone marrow stem cells. A criterion was added to exclude patients with certain prior malignancies. The donor selection criteria were updated to clarify that related donors of HLH patients with known HLH-associated gene mutations should not have the same HLH-causing gene mutations, while related donors of HLH patients with unknown genetic cause of HLH should not have a medical history concerning for HLH and should not have lab values suggestive of the presence of HLH. It was clarified in several places in the protocol that if an infection occurs between enrollment and the start of conditioning, that infection must be controlled before the patient can start conditioning. Lastly, chronically active Epstein-Barr virus reactivation and B cell reconstitution were added as secondary endpoints.


During the DSMB’s routine review of safety and efficacy data in April 2015, the Board expressed concern over the incidence of reversible posterior leukoencephalopathy syndrome (RPLS) or posterior reversible encephalopathy syndrome (PRES) in study patients, as three cases of PRES had been reported. The three patients had hypertension at the time of the related incidents. All physicians and BMT staff members treating 1204 patients were notified that blood pressure should be strictly controlled to prevent central nervous system toxicity, and a memo was prepared for transplant centers to distribute to their enrolled 1204 patients. On June 16, the protocol Version 4 amendment was released, adding language to the protocol and consent form regarding the risk of RPLS / PRES as well as the directive to report all occurrences of RPLS / PRES via the expedited adverse event reporting system. A new appendix was also added with tables of blood pressure levels according to age and weight percentiles for assistance with monitoring and control of blood pressure to prevent RPLS / PRES. This amendment also expanded the sample size from 35 patients with HLH and other hemophagocytic syndromes to 35 HLH patients with allowance for as many patients with other hemophagocytic syndromes to also be enrolled before 35 HLH patients were enrolled. The protocol was closed to enrollment on December 4, 2015, one year ahead of projections despite the increase in sample size. A total of 36 HLH patients and a total of 11 patients with other hemophagocytic disorders were enrolled. The primary endpoint is one year overall survival.


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BMT CTN 1204


Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 7.3 Protocols that Completed Accrual during a Previous Reporting Period

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7.3 Protocols that Completed Accrual during a Previous Reporting Period

BMT CTN Protocols that Completed Accrual during a Previous Reporting Period


0101 A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients

0102 A trial of tandem autologous stem cell transplants with or without post second autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma

0201 A Phase III randomized multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors

0202 Autologous vs. non-myeloablative allogeneic hematopoietic stem cell transplantation for patients with chemosensitive follicular non-Hodgkin’s lymphoma beyond first complete response or first partial response

0301 Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated donors in severe aplastic anemia

0302 Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin in combination with corticosteroids

0303 A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission

0401 Phase III Rituxan / BEAM versus Bexxar / BEAM with autologous hematopoietic stem cell transplantation for persistent or relapsed chemotherapy sensitive diffuse large B-cell non-Hodgkin’s lymphoma

0402 A Phase III randomized, multicenter trial comparing sirolimus / tacrolimus with tacrolimus / methotrexate as GVHD prophylaxis after HLA-matched, related peripheral blood stem cell transplantation

0403 A Phase III, randomized double-blind, placebo controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of acute non-infectious pulmonary dysfunction (idiopathic pneumonia syndrome) following allogeneic cell transplantation

0501 Multi-center, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia

0502 / CALGB 100103

A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia in first morphologic complete remission using a non-myeloablative preparative regimen

0601 Unrelated donor reduced intensity bone marrow transplant for children with severe sickle cell disease (SCURT)

0603 / 0604 A multi-center, Phase II trial of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow (0603) or umbilical cord blood from unrelated donors (0604) for patients with hematologic malignancies

0701 Phase II trial of non-myeloablative allogeneic hematopoietic cell transplantation for patients with relapsed follicular non-Hodgkin’s lymphoma beyond first complete response


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0702 A trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance for patients with multiple myeloma

0703 / SWOG 0410

Tandem autologous stem cell transplantation for patients with primary progressive or recurrent Hodgkin disease (a BMT study), Phase II

0704 / CALGB 100104 / ECOG 100104

A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 or placebo following autologous stem cell transplantation for multiple myeloma

0801 A Phase II / III randomized, multicenter trial comparing sirolimus plus prednisone, and sirolimus / calcineurin inhibitor plus prednisone for the treatment of chronic graft-versus-host disease

0802 A multi-center, randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute GVHD

0803 High dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients

0804 / CALGB 100701

Phase II study of reduced-intensity allogeneic stem cell transplant for high-risk chronic lymphocytic leukemia

0805 / SWOG 0805

A Phase II study of combination of hyper-CVAD and dasatinib with or without allogeneic stem cell transplant in patients with Philadelphia chromosome positive and / or BCR-ABL positive acute lymphoblastic leukemia (a BMT study)

0901 A randomized, multi-center Phase III study of allogeneic stem cell transplantation comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia

0902 A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic recipients


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BMT CTN 0101


Title: A randomized double-blind trial of fluconazole versus voriconazole for the prevention of invasive fungal infections in allogeneic blood and marrow transplant recipients

Primary Objective: To compare the fungal-free survival rates between the two study arms through day 180.


To compare the frequencies of invasive fungal infection, time to invasive fungal infection, survival rate, duration of amphotericin B or caspofungin therapy for possible invasive fungal infection, time to neutrophil and platelet engraftment, time to and severity of acute and chronic GVHD, and adverse events and routine laboratory tests; also, to explore the quantitative aspects of the galactomannan assay.

TEAM PRINCIPALS Name Email

Chairs: Thomas Walsh [email protected] John Wingard [email protected]

Officer: Dennis Confer [email protected] Coordinator: Iris Gersten [email protected] Statistician: Adam Mendizabal [email protected]

ACCRUAL DATES Opened: 12/01/2003 PRC Approval: 11/15/2002 Closed: 09/21/2006 DSMB Approval: 01/22/2003 Target: 600 patients Last Version Released: 03/29/2006 Total: 600 patients Evaluable for Primary Analysis: 09/2007

IDE Number: G020306 (closed prior to enrollment)

Key Highlights:

The study experienced a delay from DSMB approval to study activation due to prolonged negotiations for drug acquisition and funding. Ultimately, an over-encapsulated blinded drug was secured, and the trial opened to accrual in December 2003. The study closed to accrual in September 2006 when 600 patients, as planned, were enrolled. The Endpoint Review Committee, which included five transplant physicians from the protocol team, spent considerable time checking and reconciling data, including a review of primary data documents to confirm diagnoses.


The voriconazole pharmacokinetic analysis was completed, and the manuscript was accepted by the Journal of Antimicrobial Chemotherapy.

Publications:

1. Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole vs. voriconazole after allogeneic HCT. Clinical Infectious Disease. 2004 Oct 15; 39 Suppl 4:S176-180.

2. Primary results: Randomized double-blind trial of fluconazole vs. voriconazole for prevention of invasive fungal infection after allogeneic HCT. Blood. 2010 Dec 9; 116(24):5111-5118. Epub 2010 Sep 8.

3. Cost-effectiveness analysis of voriconazole compared with fluconazole for prevention of invasive fungal infection in patients receiving allogeneic HCT. American Journal of Health-System Pharmacy. 2013 Sept 1; 70(17):1518-1527.

4. Voriconazole pharmacokinetics following HCT: Results from the BMT CTN 0101 trial. Journal of Antimicrobial Chemotherapy. [In press].

Presentations:

1. Results of a randomized, double-blind trial of fluconazole vs. voriconazole for the prevention of invasive fungal infections in 600 allogeneic BMT patients. Presented: 49th ASH Annual Meeting, Atlanta, GA, December 2007.

2. Relationship between voriconazole concentrations and the probability of breakthrough fungal infection. Presented: Interscience Conference of Antimicrobial Agents and Chemotherapy Meeting, Washington DC, June 2014.


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BMT CTN 0102


Title: A trial of tandem autologous stem cell transplants with or without post second autologous transplant maintenance therapy versus single autologous stem cell transplant followed by matched sibling nonmyeloablative allogeneic stem cell transplant for patients with multiple myeloma

Primary Objective: To compare three-year progression-free survival between the two arms.

Secondary Objectives: To compare current myeloma-stable survival, three-year overall survival, and incidence of progression. TEAM PRINCIPALS Name Email

Chairs: Amrita Krishnan [email protected] David Maloney [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Kristin Knust [email protected] Statistician: Brent Logan [email protected]


IND Number: 67956

Key Highlights:

Accrual and analysis for this study were based on the anticipated number of standard-risk multiple myeloma patients with an available HLA-matched sibling donor. Statistical power required that 150 standard-risk patients be assigned to the autologous-allogeneic transplant arm. Enrollment would remain open until this goal was achieved, with concurrent enrollment of both standard-risk and high-risk patients, with and without HLA-matched sibling donors. When the protocol was developed, it was estimated that 500–750 total subjects would be required, as it was assumed that 20% to 30% of subjects would have available HLA-matched sibling donors. The study closed to enrollment on March 30, 2007, after 150 patients declared their intent to receive an allogeneic transplant. A total of 710 subjects were required to obtain 189 subjects with standard-risk disease biologically assigned to the autologous-allogeneic transplant arm. Patients were followed for three years after their second transplant. The Endpoint Review Committee formed in July 2008 after all patients completed maintenance therapy; the Committee conducted an independent assessment of the study’s primary and secondary endpoints. This preliminary review demonstrated many inconsistencies between the reported data and interpretation of disease response by transplant centers. Adjudication of such discrepancies was required, with source document review and consultation with the institutional PIs. The Endpoint Review Committee acknowledged the inherent difficulties in interpreting disease response in multiple myeloma, which suggests ongoing review of incoming data is preferred during active accrual for future myeloma clinical trials conducted by the BMT CTN. The Endpoint Review Committee completed review of all patients in June 2010. A review of long term follow-up data for a secondary analysis was completed in February 2014.


An abstract on heavy light chain ratio normalization was presented at the 20th Congress of the European Hematology Association in June 2015. The corresponding manuscript was submitted for publication during this reporting period. An abstract and manuscript on long term follow-up and QOL data are expected to be submitted in the next reporting period.

Publications: 1. Use of biological assignment in HCT clinical trials. Clinical Trials. 2008; 5(6):607-616. 2. Tandem vs. single autologous HCT for the treatment of multiple myeloma: a systematic review and

meta-analysis. Journal of the National Cancer Institute. 2009 Jul 1; 101(13):964; author reply 966-


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Protocol Number: BMT CTN 0102 967. Epub 2009 Jun 17. [Comment on: Journal of the National Cancer Institute 101(2):100-106, 2009].

3. Primary results: Autologous HCT followed by allogeneic or autologous HCT in patients with multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment trial. Lancet Oncology. 2011 Dec; 12(13):1195-1203. Epub 2011 Sep 29.

Presentations:

1. Biologic assignment clinical trials in HCT for multiple myeloma: baseline characteristics by treatment allocation from BMT CTN 0102 according to availability of an HLA-matched sibling donor. Presented: 49th ASH Annual Meeting, Atlanta, GA, December 2007.

2. Tandem autologous HCT with or without maintenance therapy vs. single autologous HCT followed by HLA matched sibling non-myeloablative allogeneic HCT for patients with standard risk multiple myeloma: results from the BMT CTN 0102 trial. Presented: 52nd ASH Annual Meeting, Orlando, FL, December 2010.

3. Tandem autologous HCT with or without maintenance therapy vs. single autologous HCT followed by HLA-matched sibling non-myeloablative allogeneic HCT for patients with high risk multiple myeloma: results from the BMT CTN 0102 trial. Presented: 52nd ASH Annual Meeting, Orlando, FL, December 2010.

4. Tandem autologous HCT vs. single autologous HCT followed by HLA matched sibling non-myeloablative allogeneic HCT for patients with standard risk multiple myeloma: results from the BMT CTN 0102 trial. Presented: 13th International Myeloma Workshop, Paris, France, May 2011.

5. Immunoglobulin free light chain and heavy chain / light chain assays – comparison with electrophoretic responses in multiple myeloma. Presented: 53rd ASH Annual Meeting, San Diego, CA, December 2011.

6. Heavy light chain ratio normalization allows identification of electrophoretic non-complete response patients with improved outcomes: A long term follow up update for BMT CTN 0102 correlative study. Presented: 20th Congress of the European Hematology Association, Vienna, Austria, June 2015.


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BMT CTN 0201


Title: A Phase III randomized multicenter trial comparing G-CSF mobilized peripheral blood stem cell with marrow transplantation from HLA compatible unrelated donors

Primary Objective: To compare two-year survival probabilities between patients receiving peripheral blood stem cell (PBSC) versus marrow transplants from unrelated donors using an intent-to-treat analysis.


To compare survival, incidences of neutrophil and platelet engraftment, graft failure, acute GVHD, chronic GVHD, time off immunosuppressive therapy, relapse, infections, adverse events, immune reconstitution, and quality of life. Donors in each arm of the study were compared for time to return to baseline toxicity score, complete blood count and white blood count differential values after donation, and quality of life.

TEAM PRINCIPALS Name Email Chair: Claudio Anasetti [email protected] Officer: Dennis Confer [email protected] Coordinator: Kristin Knust [email protected] Statistician: Brent Logan [email protected]


IND Number: 6821

Key Highlights:

A coordinated effort involving transplant and donor centers and the NMDP Search Coordinating Unit made this study possible. It is the only study of its kind, and the BMT CTN is the only mechanism through which it could be accomplished. A total of 551 patients and unrelated donors were enrolled on this study, which successfully closed to accrual on October 16, 2009. The Endpoint Review Committee was formed in January 2010 to review outcomes data and was completed in November 2011. The trial, through its ancillary laboratory studies, will also provide important information on multiple parameters of immune reconstitution and their correlation with clinical outcomes.


Two secondary analyses were conducted and published this reporting period – one of infection data and one of donor clinical symptoms. The 5 year patient QOL analysis was also undertaken and presented at the 2015 ASH Annual Meeting. The manuscript was submitted for publication. Additionally, a comparitive analysis of 0201 participants to CIBMTR registered patients was also completed and published.

Publications:

1. Human CMV-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen. Journal of Immunology. 2012 Nov 15; 189(10):5082-5088. Epub 2012 Oct 17.

2. Primary results: PBSC vs. bone marrow from unrelated donors. New England Journal of Medicine. 2012 Oct 18; 367(16):1487-96.

3. Health-related QoL of bone marrow vs. PBSC donors: a pre-specified subgroup analysis from a Phase III RCT-BMT CTN protocol 0201. Biology of Blood and Marrow Transplantation. 2014 Jan 1; 20(1):118-127.

4. Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMT CTN 0201. Journal of Clinical Oncology. 2014 Aug 1; 32(22):2365-2372. Epub 2014 Jun 30.

5. Comparison of characteristics and outcomes of trial participants and nonparticipants: Example of BMT CTN 0201 trial. Biology of Blood and Marrow Transplantation. 2015 Oct 1; 21(10):1815-1822. Epub 2015 Jun 11.

6. Infections following transplantation of bone marrow or PBSC from unrelated donors. Biology of Blood and Marrow Transplantation. 2016 Feb 1; 22(2):359-370. Epub 2015 Sep 25.

7. Recovery of unrelated donors of PBSC vs. recovery of unrelated donors of bone marrow: A prespecified


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analysis from the Phase III BMT CTN Protocol 0201. Biology of Blood and Marrow Transplantation. 2016 Jun 1; 22(6):1108-1116. Epub 2016 Mar 21.

Presentations:

1. Health-related quality-of-life among adult unrelated stem cell donors: a BMT CTN randomized trial of marrow versus PBSC donation. Presented: 52nd ASH Annual Meeting, Orlando, FL, December 2010.

2. Increased incidence of chronic GVHD and no survival advantage with filgrastim-mobilized PBSC compared to bone marrow transplants from unrelated donors: results of BMT CTN Protocol 0201, a Phase III, prospective, randomized trial. Presented: 53rd ASH Annual Meeting, San Diego, CA, December 2011.

3. Larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from unrelated donors are associated with improved survival: results from BMT CTN 0201. Presented: 53rd ASH Annual Meeting, San Diego, CA, December 2011.

4. Grade III - IV acute GVHD and treatment-related mortality are reduced among recipients of larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from unrelated donors: results from BMT CTN 0201. Presented: 38th Annual EBMT Congress, Geneva, Switzerland, April 2012.

5. Increased incidence of chronic GVHD and no survival advantage with filgrastim-mobilized PBSC compared to bone marrow transplants from unrelated donors: results of BMT CTN Protocol #0201, a Phase III, prospective, randomized trial. Presented: ASCO Annual Meeting, Chicago, IL, June 2012.

6. More infections with transplantation of bone marrow vs. PBSC from unrelated donors. Presented: BMT Tandem Meetings, San Diego, CA, February 2015.

7. 5 year results of BMT CTN 0201: Unrelated donor bone marrow is associated with better psychological well-being and less burdensome chronic GVHD symptoms than peripheral blood. Presented: 57th ASH Annual Meeting, Orlando, FL, December 2015.


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BMT CTN 0202


Title: Autologous vs. non-myeloablative allogeneic hematopoietic stem cell transplantation for patients with chemosensitive follicular non-Hodgkin’s lymphoma beyond first complete response or first partial response

Primary Objective: To compare three-year progression-free survival between the two treatment arms.


To compare three-year overall survival, time to progression, time to complete and partial response, time to off-study therapy, and incidence of infections and NCI CTCAE Version 3.0 Grade ≥ 3 toxicities. Secondary objectives for the nonmyeloablative allogeneic HCT recipients include the incidence and severity of acute and chronic GVHD and incidence of primary and secondary graft failure. Additional objectives are the efficacy of cyclophosphamide plus rituximab in vivo purging, the prediction of disease relapse by measurement of t(14;18) by quantitative polymerase chain reaction, and quality of life as measured by the SF-36 and the FACT-BMT.


Chairs: Ginna Laport [email protected] Robert Negrin [email protected]

Officer: Marcie Riches [email protected] Coordinator: Kristin Knust [email protected] Statistician: Marian Ewell [email protected]


Key Highlights:

When the study closed to accrual in March 2006, 22 patients were enrolled on the autologous HCT + rituximab arm and eight on the allogeneic HCT + rituximab arm. Discussions with BMT CTN and Cooperative Group investigators and analysis of the CIBMTR Research Database led the Protocol Team to conclude that poor accrual on this trial came from low referrals of eligible patients by primary care oncologists. The Network continued to follow the enrolled patients for three-year survival and adverse events as recommended by the DSMB. The last patient three-year survival follow-up finished on April 13, 2009. Important questions regarding the role of HCT for patients with follicular lymphoma must still be addressed. The NCI-funded Cooperative Group Transplant and Lymphoma Committee Chairs collaborated with the Network to design and implement a new trial with better feasibility (BMT CTN 0701, which opened on April 27, 2009, and completed accrual on October 22, 2012).

Reporting Period Update: N/A

Publication: 1. Primary results: Autologous vs. reduced intensity allogeneic HCT for patients with chemosensitive

follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biology of Blood and Marrow Transplantation. 2011 Jul; 17(7):1051-1057. Epub 2010 Nov 10.

Presentation: 1. Autologous vs. reduced-intensity allogeneic HCT for patients with follicular non-Hodgkins lymphoma

beyond first complete response or first partial response. Presented: ASCO Annual Meeting, Chicago, IL, May 2008.


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BMT CTN 0301


Title: Fludarabine-based conditioning for allogeneic marrow transplantation from HLA-compatible unrelated donors in severe aplastic anemia

Primary Objective: To select the optimal cyclophosphamide dose in a regimen of fludarabine, cyclophosphamide, total body irradiation and antithymocyte globulin, based on day 100 assessments of graft failure (primary and secondary), regimen-related toxicity, and early death.

Secondary Objectives: To evaluate post-transplant survival, graft failure, treatment-related mortality, and acute and chronic GVHD.


Chairs: Paolo Anderlini [email protected] Joachim Deeg [email protected]

Officer: Mary Eapen [email protected] Coordinator: Iris Gersten [email protected] Medical Monitor: Christopher Bredeson [email protected] Statistician: Maggie Wu [email protected] Contract Rep: Pamela Budnick [email protected]

ACCRUAL DATES Opened: 01/24/2006 PRC Approval: 03/31/2005 Closed: 12/02/2013 DSMB Approval: 07/15/2005 Target: 94 patients Last Version Released: 06/06/2013 Total: 97 patients Evaluable for Primary Analysis: 06/25/2014

Key Highlights:

This study was activated in January 2006. Thirty-one centers were activated, and 23 centers enrolled patients. Patient accrual was initially slower than projected. The most significant factor affecting accrual was study design, which required review of day 100 outcomes data from a sufficient number of patients to ensure that stopping boundaries were not crossed. Another factor was the lack of severe aplastic anemia patients referred for unrelated donor transplantation (85 per year average in the US). Accrual on the trial was temporarily suspended in May 2008 for DSMB review of toxicities. An amendment was released to centers in August 2008 after the consent form was revised to address the findings of the 150 mg/kg (excess toxicity) and 0 mg/kg cyclophosphamide (excess graft failure) cohorts. In addition, the stopping rules were revised to reflect a combined day 100 endpoint of graft failure and treatment-related mortality. Accrual resumed in December 2008. An amendment was released in February 2010, allowing accrual on parallel tracks using cyclophosphamide at 100 mg/kg and 50 mg/kg levels, with the proviso that if a stopping threshold was reached on 100 mg/kg, the DCC would notify the DSMB before enrolling to the 50 mg/kg dose. As a result, the protocol temporarily closed less often while patients were followed to the day 100 safety point. This amendment enhanced accrual, and the DSMB recommendation in Fall 2011 to preferentially enroll on the 50mg/kg dose level until at least 20 patients with 8/8 HLA match were accrued was met. In June 2013, the protocol was amended to extend study accrual beyond the original goal of 78-81 patients to 94 patients with completion anticipated in Spring 2014. The objective was to rebalance HLA matched (8/8) and HLA-mismatched (7/8) transplants and gain more data on engraftment in the 50 mg/kg cyclophosphamide dose level. The study completed accrual with 97 patients in December 2013. In November 2013, the DSMB approved a request for an endpoint review committee to conduct a blinded data review of participants with 24 month follow-up once the 97th enrolled participant reached their Day 100. The Endpoint Review Committee formed in May 2014 and completed their review of the primary endpoint in July 2014.


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Reporting Period Update: The primary results manuscript was published in Lancet Haematology in September 2015.

Publications:

1. Optimization of therapy for severe aplastic anemia based on clinical, biological and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the BMT CTN, March 2010. Biology of Blood and Marrow Transplantation. 2011 Mar; 17(3)291-299. Epub 2010 Oct 27.

2. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biology of Blood and Marrow Transplantation. 2012 July; 18(7):1007-1011. Epub 2012 Apr 27.

3. Primary results: Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Lancet Haematology. 2015 Sep 1; 2(9):e367-375. Epub 2015 Sep 2.

Presentations:

1. Fludarabine-based conditioning for allogeneic marrow transplantations from unrelated donors in severe aplastic anemia: serious and unexpected adverse events in pre-defined cyclophosphamide dose levels. Presented: 53rd ASH Annual Meeting, San Diego, CA, December 2011.

2. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in severe aplastic anemia: serious and unexpected adverse events in pre-defined cyclophosphamide dose levels. Presented: 38th Annual EBMT Congress, Geneva, Switzerland, April 2012.

3. Optimized cyclophosphamide dosing in combination with fludarabine, TBI and ATG as conditioning for unrelated donor bone marrow transplantation in severe aplastic anemia: A Phase I / II study from the BMT CTN. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.


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BMT CTN 0302


Title: Initial systemic treatment of acute GVHD: a Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox (Ontak), and pentostatin in combination with corticosteroids

Primary Objective: To estimate the proportion of day 28 complete remissions for newly-diagnosed acute GVHD for each of these agents given in combination with corticosteroids.


To determine the proportion of patients achieving a partial response, mixed response, and progression at day 28; proportion of patients with treatment failure (no response, progression, administration of additional therapy for GVHD, or mortality) by day 14; incidence of GVHD flares requiring increasing therapy before day 90; incidences of discontinuation of immune suppression without flare by days 90, 180, and 270 after initiation of therapy; incidence of chronic GVHD by 9 months; overall survival at 6 and 9 months after initiation of therapy; incidences of systemic infections within 3 months of initiation of therapy; and incidence of Epstein-Barr virus-associated lymphoma.

TEAM PRINCIPALS Name Email Chair: Daniel Weisdorf [email protected] Officer: Marcelo Pasquini [email protected] Coordinator: Kristin Knust [email protected] Statistician: Maggie Wu [email protected]


IND Number: 11726

Key Highlights:

Despite early concerns about slow accrual, the May 2006 amendment had a positive impact on the accrual rate, and the study was completed on March 24, 2008, with 180 patients enrolled as planned. That amendment involved four changes: (1) development of a second stratum (3-arm, balanced randomization with etanercept, pentostatin, and Ontak) for patients previously exposed to mycophenolate mofetil for GVHD prophylaxis; (2) enrollment of all patients with acute GVHD in whom the clinical decision to treat with corticosteroids was made at the participating center rather than to exclude those patients with upper gastrointestinal GVHD or limited skin diseases as the sole manifestations; (3) consent, enrollment, and randomization within 48 hours (previously 24) of initiating corticosteroid therapy; and (4) allowing enrollment of patients administered low-dose steroids for less than 7 days prior to enrollment. The DSMB approved formation of an Endpoint Review Committee comprised of six transplant physicians from BMT CTN 0302 centers. All patients completed follow-up per protocol except two who were lost to follow up before nine months. The Endpoint Review Committee reviewed the study data for each patient, and results are published in a primary manuscript and secondary manuscripts. The results of the study suggested that mycophenolate mofetil was the most promising candidate for evaluation in a Phase III study. BMT CTN protocol 0802 was developed as a Phase III, randomized double blind, placebo controlled trial to evaluate the addition of mycophenolate mofetil versus placebo to systemic corticosteroids as initial therapy for acute GVHD. Protocol 0802 was closed due to futility in November 2011, and study results were published in a primary manuscript.


A pharmacogenetics secondary analysis was conducted. The manuscript will be submitted during the next reporting period. Additionally, a validation analysis of microRNA signature for the prediction, diagnosis, and prognosis of acute GVHD was undertaken using the lab samples and data obtained on this and other studies (BMT CTN 0402 and 0802). A manuscript will be drafted and submitted in the next reporting period.


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Publications:

1. Optimal two-stage randomized Phase II clinical trials. Clinical Trials. 2005 Feb 1; 2(1):5-12. 2. Primary results: Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute

GVHD, a randomized Phase 2 trial from the BMT CTN. Blood. 2009 Jul 16; 114(3)511-517. Epub 2009 May 14.

3. Mycophenolate pharmacokinetics and association with response to acute GVHD treatment from the BMT CTN. Biology of Blood and Marrow Transplantation. 2010 Mar 1; 16(3):421-429.

4. GVHD treatment: predictors of survival. Biology of Blood and Marrow Transplantation. 2010 Dec 1; 16(12):1693-1699. Epub 2010 Jun 10.

5. Acute GVHD biomarkers measured during therapy can predict treatment outcomes: A BMT CTN study. Blood. 2012 Apr 19; 119(16):3854-3860. Epub 2012 Mar 1.

6. Lymphocyte phenotype during therapy for acute GVHD: A brief report from BMT CTN 0302. Biology of Blood and Marrow Transplantation. 2013 Mar 1; 19(3)481-485. Epub 2012 Dec 12.

7. A prognostic score for acute GVHD based on biomarkers: A multicentre study. Lancet Haematology. 2015 Jan 1; 2(1):e21-29. Epub 2014 Dec 23.

8. A refined risk score for acute GVHD that predicts response to initial therapy, survival, and transplant-related mortality. Biology of Blood and Marrow Transplantation. 2015 Apr 1; 21(4):761-767. Epub 2015 Jan 10.

9. Circulating angiogenic factors associated with response and survival in patients with acute GVHD: Results from BMT CTN 0302 and 0802. Biology of Blood and Marrow Transplantation. 2015 Jun 1; 21(6):1029-1036. Epub 2015 Mar 7.

Presentations:

1. BMT CTN 0302: A Phase II randomized trial evaluating etanercept, mycophenolate mofetil, denileukin diftitox and pentostatin in combination with corticosteroids in 180 patients with newly diagnosed acute GVHD. Presented: 50th ASH Annual Meeting, San Francisco, CA, December 2008.

2. GVHD biomarkers measured during treatment independently predict response to therapy and survival: a Blood and Marrow Transplant Clinical Trials Network study. Presented: 37th EBMT Congress, Paris, France, April 2011.

3. A new Ann Arbor grading system uses biomarkers to risk stratify patients for non-relapse mortality at the onset of acute GVHD. Presented: 40th EBMT Congress, Milan, Italy, March-April 2014.

4. Circulating angiogenic factors as biomarkers of acute GVHD onset and response to therapy: repair and regeneration vs. endothelial damage and inflammation. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.

5. A biomarker algorithm defines onset grades of acute GVHD with distinct non-relapse mortality. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.

6. Prognostic impact of follistatin in acute GVHD: Results from BMT CTN 0302 and 0802. Presented: BMT Tandem Meetings, San Diego, CA, February 2015.


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BMT CTN 0303


Title: A single-arm, multicenter Phase II trial of transplants of HLA-matched, CD34+ enriched, T cell depleted peripheral blood stem cells isolated by the CliniMACS system in the treatment of patients with AML in first or second morphologic complete remission

Primary Objective: To assess disease-free survival six months after transplant. Outcome measures to assess this endpoint were death or relapse.


To assess infusional toxicity, time to neutrophil and platelet engraftment, incidence and severity of acute and chronic GVHD, incidence of TRM, incidence of Epstein-Barr virus after transplant, lymphoproliferative disorder, time to leukemia relapse, probability of survival and disease-free survival at 2 years, and the proportion of grafts with both > 5 x 106/kg CD34+ cells and < 1 x 105/kg CD3 cells.


Chairs: Steve Devine [email protected] Richard O’Reilly [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Kristin Knust [email protected] Statistician: Shelly Carter [email protected]


IDE Number: 11965

Key Highlights:

There was a delay between PRC and DSMB approvals, due to a determination by the DSMB in April 2004 that safety data were required for donors and recipients. This required protocol resubmission to the DSMB. The long interval between DSMB approval and study activation was due to lengthy processing of the IDE. The protocol was submitted on September 30, 2004, to the FDA; it was approved by the FDA on December 28, 2004, and released to centers in January 2005. The study was opened to accrual on June 30, 2005, after centers had received training by Miltenyi Biotech, Inc. and provided laboratory standard operating procedures for review. The study completed accrual in December 2008 with 47 patients enrolled. The Endpoint Review Committee completed an independent assessment of the primary and secondary endpoints of the study. In January 2014, the FDA approved the CliniMACS CD34 Reagent System as a Humanitarian Use Device for the prevention of graft-versus-host disease in patients with AML in first complete remission undergoing allogeneic HCT from a matched related donor. The BMT CTN 0303 data were used by the FDA in their determination.


The follow-up study to BMT CTN 0303, a Phase III calcineurin inhibitor-free GVHD prophylaxis protocol utilizing the CliniMACS CD34 Reagent System (BMT CTN 1301), is ongoing.

Publications:

1. Primary results: Low risk of chronic GVHD and relapse associated with T cell depleted PBSC transplantation for AML in first remission: results of the BMT CTN Protocol 0303. Biology of Blood and Marrow Transplantation. 2011 Sep 1; 17(9):1343-1351. Epub 2011 Feb 12.

2. Characteristics of CliniMACS(®) System CD34-enriched T cell-depleted grafts in a multicenter trial for AML – BMT CTN Protocol 0303. Biology of Blood and Marrow Transplantation. 2012 May 1; 18(5):690-697. Epub 2011 Aug 26.

3. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as GVHD prophylaxis for patients with AML in complete remission undergoing HLA-matched sibling allogeneic HCT. Journal of Clinical Oncology. 2012 Sep 10; 30(26):3194-3201.


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Presentations:

1. HLA-identical sibling-matched, CD34+ selected, T cell depleted PBSC following myeloablative conditioning for first or second remission AML, results of BMT CTN Protocol 0303. Presented: 51st ASH Annual Meeting, New Orleans, LA, December 2009.

2. Comparative effectiveness analysis of CD34+ selected, T cell depleted HLA-matched sibling grafts on allogeneic HCT for patients with AML in complete remission. Presented: BMT Tandem Meetings, Orlando, FL, February 2010.

3. Characteristics of CD34-enriched products processed at multiple centers using the CliniMACS System - BMT CTN 0303. Presented: 16th Annual International Society for Cellular Therapy meeting, Philadelphia, PA, May 2010.


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BMT CTN 0401


Title: Phase III Rituxan / BEAM versus Bexxar / BEAM with autologous hematopoietic stem cell transplantation for persistent or relapsed chemotherapy sensitive diffuse large B-cell non-Hodgkin’s lymphoma

Primary Objective: To compare progression-free survival after autologous HCT for chemotherapy-sensitive DLBCL using Rituxan / BEAM versus Bexxar / BEAM as a pre-transplant conditioning regimen.


To compare overall survival; time to progression; proportion of complete response and partial response at day 100; time to hematopoietic recovery; hematologic function; incidence of infection; maximum mucositis score by day 21; immune reconstitution; treatment-related mortality; and development of myelodysplasia, secondary acute myelogenous leukemia, or abnormal cytogenetics.

TEAM PRINCIPALS Name Email Chair: Julie Vose [email protected] Officer: Marcie Riches [email protected] Coordinator: Kristin Knust [email protected] Statistician: Maggie Wu [email protected]


IND Number: 12520

Key Highlights:

This study was activated on December 7, 2005. Although diffuse large B cell non-Hodgkin lymphoma is a common indication for autologous HCT, an increasing percentage of these procedures are performed in diverse community hospitals without academic programs, so only a few transplant centers have access to large numbers of eligible patients. To increase patient accrual, additional centers were recruited, and a collaboration with SWOG was developed. The study closed on July 17, 2009, after reaching its accrual goal of 224 patients. Thirty-seven centers enrolled patients on the study. An Endpoint Review Committee was formed in April 2011, completing data review in June 2011 and presenting at ASH in December 2011. The primary manuscript was published in the Journal of Clinical Oncology in Mary 2013.


Publication: 1. Primary results: Phase III randomized study of BEAM compared with Iodine-131 tositumomab /

BEAM with autologous HCT for relapsed DLBCL: results from the BMT CTN 0401 trial. Journal of Clinical Oncology. 2013 May 1; 31(13):1662-1668. Epub 2013 Mar 11.

Presentation: 1. Randomized Phase III trial of 131Iodine-tositumomab (bexxar) / BEAM vs. rituximab / BEAM and

autologous HCT for relapsed DLBCL: no difference in progression-free or overall survival. Presented: 53rd ASH Annual Meeting, San Diego, CA, December 2011.


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BMT CTN 0402


Title: A Phase III randomized, multicenter trial comparing sirolimus / tacrolimus with tacrolimus / methotrexate as GVHD prophylaxis after HLA-matched, related PBSC transplantation

Primary Objective: To compare day 114 grades II through IV acute GVHD-free survival rates between patients receiving sirolimus and tacrolimus with those receiving methotrexate and tacrolimus from the time of patient randomization, using an intent-to-treat analysis.


To compare time to neutrophil and platelet engraftment, incidence of grades III-IV acute GVHD, mucositis severity, time to first hospital discharge after transplantation, all infections, cytomegalovirus reactivation, thrombotic microangiopathy incidence, veno-occlusive disease during the first 100 days after transplantation, malignant disease relapse, and one-year relapse-free and overall survival rates.


Chairs: Joseph Antin [email protected]

Corey Cutler [email protected] Officer: Marcelo Pasquini [email protected] Coordinator: Kristin Knust [email protected] Statistician: Brent Logan [email protected]


Key Highlights:

Although this protocol was approved by the DSMB in a timely fashion, the Network delayed activating the study until closure of BMT CTN 0101 to reduce competition for a similar patient population. Initial accrual to this study was slower than projected. Protocol version 2.0, released in June 2007, increased the allowed cholesterol / triglyceride level at study entry, removed the requirement for donor toxicity assessments, and modified the required mucositis assessment periods. In September 2007, the veno-occlusive stopping guideline was crossed, and enrollment was suspended. The DSMB approved re-opening the study in October 2007, with exclusion of the busulfan and cyclophosphamide conditioning regimen. The revised protocol was released to centers in November 2007. Some centers were unable to transition to a total body irradiation-based conditioning regimen in lieu of the busulfan regimen, so additional center participation was solicited. Version 4.0 of the protocol was released in December 2010 to allow patients whose primary disease was acute biphenotypic leukemia in first or subsequent remission. Twenty-six centers (13 Core and 13 Affiliate) participated on this trial. The study completed accrual in October 2011. The protocol team began the Endpoint Data Review in December 2011. The primary manuscript was published in Blood in June 2014.


A secondary analysis of immune reconstitution data is ongoing. A biomarker ancillary analysis of angiogenic factors was conducted and presented at the 2016 BMT Tandem Meetings. The manuscript will be submitted during the next reporting period.

Publications:

1. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic HCT. Blood. 2008 Dec 1; 112(12)4425-4431. Epub 2008 Sep 5.

2. Primary results: Tacrolimus / sirolimus vs. tacrolimus / methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014 Aug 21; 124(8): 1372-1377. Epub 2014 Jun 30.


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Presentations:

1. Tacrolimus / sirolimus vs. tacrolimus / methotrexate for GVHD prophylaxis after HLA-matched, related donor HCT: Results of BMT CTN trial 0402. Presented: 54th ASH Annual Annual Meeting, Atlanta, GA, December 2012.

2. Angiogenic factors, inflammation, and outcomes in myeloablative allogeneic HCT: A biomarker analysis of GVHD prophylaxis in BMT CTN Protocol 0402. Presented: BMT Tandem Meetings, Honolulu, HI, February 2016.


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BMT CTN 0403


Title: A Phase III, randomized double-blind, placebo controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of acute non-infectious pulmonary dysfunction (idiopathic pneumonia syndrome, IPS) following allogeneic cell transplantation

Primary Objective: To determine the day 28 response rate following treatment with etanercept plus corticosteroids compared with placebo plus corticosteroids for patients with IPS after allogeneic HCT. (Response is defined as (1) survival at day 28; and (2) discontinuation of all supplemental oxygen support for more than 72 consecutive hours by day 28.)


To evaluate response to therapy at day 56; overall mortality in patients with IPS; time to discontinuation of supplemental oxygen; and pro-inflammatory markers of pulmonary disease in both bronchoalveolar lavage fluid and plasma of patients with IPS.


Chairs: Kenneth Cooke [email protected] Gregory Yanik [email protected]

Officer: Mary Horowitz [email protected] Coordinator: Roe Wright [email protected] Statistician: Maggie Wu [email protected]


IND Number: 11726 (Part of 0302 IND)

Key Highlights:

The study was activated August 27, 2007. A protocol amendment was released in January 2008 that adjusted the eligibility criteria to include patients who developed IPS within 120 days after a donor leukocyte infusion, revised definitions of cytomegalovirus infection, and revised study drug blinding logistics. An additional protocol amendment in January 2009 extended eligibility to patients who develop IPS within 180 days post transplantation or post donor leukocyte infusion. Protocol Version 4 was released in October 2009, relaxing the bronchoscopy requirements for patients less than 30 days post transplantation who were too medically unstable to undergo the procedure. Protocol Version 5 was released to centers in June 2010, reducing the sample size from 120 patients (60 per arm) to 60 patients (30 per arm). Accrual continued to lag behind projections, despite the amendments. In April 2011, the DSMB approved the Protocol Team’s accrual plan for two interval assessments of enrollment; however, these accrual targets were not met, and the Protocol Team received DSMB approval to close the study on September 14, 2011. The Endpoint Review Committee was formed and reviewed the study data from March to August 2012. After completion of data review, the study results were presented at the 2013 BMT Tandem Meetings. The primary manuscript was published in Biology of Blood and Marrow Transplantation in March 2014.The final study data was submitted to the NHLBI BioLINCC data repository in December 2014.


The lab samples for the bioassay studies are being finalized for the proteomic and genomic analysis of plasma and genomic cytokine and inflammatory markers.

Publication: 1. Primary results: Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor:

Enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome following allogeneic HCT: BMT CTN protocol. Biology of Blood and Marrow Transplantation. 2014 Jun 1; 20(6):858-864. Epub 2014 Mar 7.

Presentation: 1. Randomized, double blind, placebo-controlled trial of a TNF inhibitor (etanercept) for the treatment of

idiopathic pneumonia syndrome after allogeneic HCT, a BMT CTN study. Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013.


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BMT CTN 0501


Title: Multi-center, open label, randomized trial comparing single versus double umbilical cord blood transplantation in pediatric patients with leukemia and myelodysplasia

Primary Objective: To determine the efficacy of using two cord blood units versus one; the primary endpoint is one-year survival rate.

Secondary Objectives: To compare disease-free survival, incidences of neutrophil and platelet engraftment, chimerism, acute GVHD, chronic GVHD, TRM, infections, immune reconstitution, and relapse in patients randomized to the two study arms.


Chairs: Joanne Kurtzberg [email protected] John Wagner [email protected]

Officer: Mary Eapen [email protected] Coordinator: Roe Wright [email protected] Statistician: Maggie Wu [email protected]


Key Highlights:

This trial received PRC approval in January 2006 and DSMB approval in April 2006. In September 2006, the protocol was amended to include patient registration procedures for COG. The study was activated October 16, 2006. Ten BMT CTN Core Centers and 38 COG Centers were activated for enrollment. Accrual on this study was completed in February 2012 with 224 patients enrolled. In April 2011, the DSMB approved the Protocol Team’s request to review blinded data on patients that have met the primary endpoint; this review process began in January 2012. The Endpoint Review Committee completed an independent assessment of the primary and secondary endpoints of the study. The primary study results were presented at ASH in December 2012, and the results compared to an earlier cord blood transplantation study (COBLT) were presented at the BMT Tandem Meetings in February 2013. The primary manuscript was published in the New England Journal of Medicine in October 2014.


Secondary analyses including comparison to the COBLT results and an immune reconstitution analysis are on-going.

Publication: 1. One-unit vs. two-unit cord-blood transplantation for hematologic cancers. New England Journal of Medicine. 2014 Oct 30; 371(18):1685-1694.

Presentations:

1. No survival advantage after double UCB compared to single UCB transplant in children with hematological malignancy: Results of the BMT CTN 0501 randomized trial. Presented: 54th ASH Annual Meeting, Atlanta, GA, December 2012.

2. Superior survival after single unit UCB transplantation in children with hematological malignancies treated on BMT CTN 0501 relative to the cord blood transplantation (COBLT). Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013.


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Protocol Number: BMT CTN 0502 / CALGB 100103

Title: A Phase II study of allogeneic transplant for older patients with acute myeloid leukemia in first morphologic complete remission using a non-myeloablative preparative regimen

Primary Objective:

To determine if allogeneic transplantation from an HLA-matched sibling or unrelated donor using a reduced-intensity preparative regimen results in two-year disease-free survival that is better than that reported in published trials evaluating standard chemotherapy among patients with AML in first complete remission who are older than 60 years of age.


To evaluate two-year actuarial risk of TRM; acute and chronic GVHD and relapse rates; rate and extent of recovery of T and B cell number and function; time course of T cell, B cell, and myeloid progenitor chimerism following this preparative regimen; and pharmacokinetics of intravenous busulfan when used in a reduced-intensity preparative regimen in patients older than 60.


Chairs: Steven Devine [email protected] Sergio Giralt [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Kate Bickett [email protected] Statistician: CALGB

ACCRUAL DATES

Opened: 08/29/2006 CALGB PRC Approval: CALGB 01/29/2007 BMT CTN DSMB Approval: CALGB

Closed: 12/29/2011 Last Version Released: 12/01/2014 Target: 136 patients

Total: 132 (41 through BMT CTN)

Key Highlights:

This protocol is a collaborative effort between CALGB and BMT CTN. CALGB patient accrual began August 29, 2006; the BMT CTN activated the study January 29, 2007. The study met its original accrual goal December 29, 2008. After DSMB review, the study was re-activated in November 2009 after NCI approved a CALGB amendment to increase the accrual goal to 136 to allow adequate numbers for separate analysis of related and unrelated donor transplantations. The study closed to enrollment at both CALGB and BMT CTN centers on December 29, 2011, after enrolling 132 patients. Of the 132 patients, 41 enrolled directly through the BMT CTN and were accrued by five Core Centers and three Affiliate Centers. An additional 71 of the 132 patients were accrued by six BMT CTN Core Centers that enrolled patients directly through CALGB. An abstract for the study was presented at the December 2012 ASH meeting.

Reporting Period Update: The primary manuscript was published in the Journal of Clinical Oncology in December 2015.

Publication:

1. Phase II study of allogeneic transplantation for older patients with AML in first complete remission using a reduced-intensity conditioning regimen: Results from CALGB 100103 (Alliance for Clinical Trials in Oncology) / BMT CTN 0502. Journal of Clinical Oncology. 2015 Dec 10; 33(35):4167-4175. Epub 2015 Nov 2.

Presentation: 1. A Phase II study of allogeneic transplant for older patients with AML in first morphologic

complete remission using a reduced intensity preparative regimen: results from CALGB 100103 / BMT CTN 0502. Presented: 54th ASH Annual Meeting, Atlanta, GA, December 2012.


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BMT CTN 0601


Title: Unrelated donor reduced intensity bone marrow transplant for children with severe sickle cell disease (SCURT)

Primary Objective: To determine one-year event-free survival after unrelated donor bone marrow transplantation in patients with sickle cell disease (death, disease recurrence, or graft rejection rates at one year will be used to measure this endpoint).


To determine the effect of HCT on clinical and laboratory manifestations of sickle cell disease, inc. stroke; the incidence of other transplant-related outcomes, inc. overall survival, neutrophil and platelet recovery, grades II-IV and III-IV acute GVHD, chronic GVHD, hepatic veno-occlusive disease, idiopathic pneumonia syndrome, central nervous system toxicity (reversible posterior leukoencephalopathy syndrome, hemorrhage, and seizures), neurocognitive dysfunction, cytomegalovirus infection, adenovirus infection, Epstein-Barr virus after transplant, lymphoproliferative disease, invasive fungal infection, donor chimerism, immune reconstitution, and health-related quality of life.

TEAM PRINCIPALS Name: Email:

Chairs: Naynesh Kamani [email protected] Shalini Shenoy [email protected]

Officer: Mary Eapen [email protected] Coordinator: Iris Gersten [email protected] Statistician: Brent Logan [email protected]

ACCRUAL DATES Opened: 06/27/2008 PRC Approval: 08/13/2007 Closed: 04/24/2014 DSMB Approval: 11/19/2007 Target: 30 BM recipients / 8 CB Last Version Released: 06/04/2014 Total: 30 BM recipients / 8 CB Evaluable for Primary Analysis: 06/04/2015

Key Highlights:

This study, known as the “SCURT” study (sickle cell unrelated transplantation), was activated in June 2008. The trial was delayed because centers were not activated until enrollment of a first patient, to minimize activating too many centers for a study that targets only 45 patients. Two Core and 16 PBMTC Centers were activated. In June 2010, the DSMB recommended an amendment to exclude cord blood grafts, due to an observed high graft failure rate after cord blood transplantation. Cord blood as a graft source was removed from Protocol Version 6. In addition, eligibility criteria were modified to increase the age limit to 19.75 years and include increased transcranial Doppler findings as a clinically significant neurological event. The amendment excluding cord blood grafts required centers to submit a revised protocol to their IRBs before continuing enrollment. Before this revision, 8 of 15 transplants used cord blood as the graft source. Not unexpectedly, accrual significantly slowed. The original accrual projections and completion were revised in April 2011 to address both the pause in enrollment required by these events and the anticipated decrease in the rate of future accrual since fewer patients would have an available graft source. In May 2011, the glomerular filtration rate requirement in the protocol was adjusted to include patients 16 years of age and older. In October 2011, the protocol was modified to ensure consistent HLA-matching criteria language. The protocol was further amended in June 2012 to reduce the targeted sample size to 30 bone marrow recipients and again in December 2012 (version 10.0) to change the liver biopsy requirements from 30 days prior to initiation of alemtuzumab to 90 days prior. In December 2013, as recommended by the DSMB, study investigators were notified of the increased incidence of RPLS / PRES, and the need to maintain strict blood pressure control, as outlined in the protocol. In addition, patients and family members were informed and instructed, via a “RPLS and PRES Letter for Participants”, to report any symptoms of RPLS / PRES that may be evident to the transplant


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physician. In April 2014, the BMT CTN DCC submitted information to the Office for Human Research Protections regarding the increased incidence of PRES in BMT CTN 0601 patients. The Office for Human Research Protections responded that the report and the corrective actions were appropriate under HHS regulations and did not request any additional information. The study closed to accrual in April 2014. In June 2014, the protocol team released a “physician advisory document” for distribution to BMT CTN 0601 patients’ health care providers. The purpose of this document is to raise awareness for maintaining and controlling (via parenteral intervention if necessary) blood pressures within 10% above the baseline age-related blood pressures for sickle cell patients pre-transplant and through day 180 post transplant. This information was also added to version 11.0 of the protocol. In November 2014, the DSMB recommended the data be released at one year for analysis, preliminary publication, and an ASH abstract submission.


The Endpoint Review Committee was formed in March 2015. Data review began in April 2015 after the last patient transplanted on the trial completed one year of follow-up and was completed in August 2015. Results were presented as an oral abstract at the ASH Annual Meeting in December 2015 and at the 2016 BMT Tandem Meetings. The primary manuscript is drafted and undergoing the submission process.

Publication: 1. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one

cohort from the Phase II study from the BMT CTN. Biology of Blood and Marrow Transplantation. Epub 2012 Feb 16.

Presentations:

1. A multicenter Phase II trial of unrelated donor reduced intensity bone marrow transplantation for children with severe sickle cell disease (SCURT): results of the BMT CTN 0601 study. Presented: 57th ASH Annual Meeting, Orlando, FL, December 2015. Received a Best Abstract Award.

2. Results of the BMT CTN 0601 study: SCURT – A multicenter Phase II trial of unrelated donor reduced intensity bone marrow transplantation for children with severe sickle cell disease. Presented: BMT Tandem Meetings, Honolulu, HI, February 2016.


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BMT CTN 0603 / 0604

Protocol Number: BMT CTN 0603 / 0604

Title: A multi-center, Phase II trial of non-myeloablative conditioning and transplantation of partially HLA-mismatched bone marrow (0603) or umbilical cord blood from unrelated donors (0604) for patients with hematologic malignancies

Primary Objective: To determine overall survival 180 days after HLA-haploidentical bone marrow transplantation or double cord blood transplantation using a non-myeloablative preparative regimen.

Secondary Objectives: To assess neutrophil and platelet recovery, graft failure, acute GVHD, chronic GVHD, incidence of infection, treatment-related mortality, time to relapse / progression, overall survival time, and progression-free survival time.


Chairs: Claudio Brunstein (0604) [email protected] Ephraim Fuchs (0603) [email protected]

Officer: Mary Eapen [email protected] Coordinator: Kristin Knust [email protected] Statistician: Brent Logan [email protected]

ACCRUAL 0603 0604 DATES Opened: 10/17/2008 12/23/2008 PRC Approval: 12/21/2007 Closed: 05/17/2010 03/31/2010 DSMB Approval: 06/06/2008 Target: 50 patients 50 patients Last Version Released: 01/28/2009 Total: 55 patients 54 patients Evaluable for Primary Analysis: 12/2010

Key Highlights:

A single Protocol Team was formed in December 2006 to develop both BMT CTN 0603 and 0604. Presentation to the DSMB for both protocols was delayed to allow competing protocols to near completion. The protocols were released to centers for IRB approval in Summer 2008. Institutions participating in both protocols were required to submit allocation schemes or prioritization plans to avoid bias. These required approval by the Protocol Team before site activation. The 0603 protocol was activated in October 2008. Eight Core Centers and 9 Affiliate Centers enrolled a total of 55 patients on the trial. The study closed to enrollment in May 2010, well ahead of projections. The 0604 protocol was activated in December 2008. Eight Core Centers and 8 Affiliate Centers enrolled a total of 54 patients on the trial. The study closed to enrollment in March 2010, well ahead of projections. The Endpoint Review Committee formed in summer 2010 and conducted data review for all the primary and secondary endpoints of the study. A secondary data review with all patients followed for two years was completed in 2014. The manuscript summarizing the two year follow-up results was published in Biology of Blood and Marrow Transplantation in May 2014.

Publications:

1. Primary results: Alternative donor transplantation after reduced intensity conditioning: results of parallel Phase II trials using HLA-mismatched related bone marrow or unrelated UCB grafts. Blood. 2011 Jul 14; 118(2):282-288. Epub 2011 Apr 28.

2. Long term follow-up (including donor selection recommendations for 1101 investigators): Mismatched related and unrelated donors for allogeneic HCT for adults with hematologic malignancies. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1485-1492. Epub 2014 May 23.

Presentations:

1. Phase II trial of nonmyeloablative conditioning and partially HLA-mismatched BMT for patients with hematologic malignancies: results of BMT CTN Protocol 0603. Presented: BMT Tandem Meetings, Honolulu, HI, February 2011. Received a Best Abstract Award.

2. Phase II trial of non-myeloablative conditioning double UCB transplantation from unrelated donors in patients with hematologic malignancies: results of BMT CTN Protocol 0604. Presented: BMT Tandem Meetings, Honolulu, HI, February 2011.


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BMT CTN 0701


Title: Phase II trial of non-myeloablative allogeneic hematopoietic cell transplantation for patients with relapsed follicular non-Hodgkin’s lymphoma beyond first complete response

Primary Objective: To measure two-year progression-free survival after allogeneic HCT with a reduced-intensity pre-transplant conditioning regimen of fludarabine, cyclophosphamide, and rituximab.


To examine two-year overall survival; time to complete and partial responses; time to off-study therapy; incidences and severity of acute and chronic GVHD; treatment-related mortality; and incidences of primary and secondary graft failure; quality of life, as measured by the SF-36 and the FACT-BMT; and the ability to predict disease relapse by measuring t(14;18) using a quantitative polymerase chain reaction.

TEAM PRINCIPALS Name Email Chair: Ginna Laport [email protected] Officer: Marcie Riches [email protected] Coordinator: Iris Gersten [email protected] Statistician: Brent Logan [email protected]

ACCRUAL DATES Opened: 04/27/2009 PRC Approval: 04/01/2008 Closed: 10/22/2012 DSMB Approval: 05/20/2008 Target: 65 patients Last Version Released: 05/12/2011 Total: 65 patients IND Application Number: Exempt

Key Highlights:

The study was placed on the Cancer Trials Support Unit (CTSU) roster in February 2009 and endorsed by SWOG, CALGB, and ECOG. The study was activated on April 27, 2009, after several centers received IRB approval. Twelve Core Centers and 25 Affiliate Centers were activated for enrollment, 13 of which participated through the CTSU. Several initiatives were implemented to address slower-than-anticipated enrollment, including periodic study updates to transplant center PIs and Coordinators; template referral and insurance appeal letters to centers; a campaign to encourage all non-enrolling centers to enroll; and advertisements in the CTSU, American Society of Blood and Marrow Transplant, Leukemia / Lymphoma Society, and Leukemia Research Foundation newsletters. The Protocol Version 5 amendment was approved May 12, 2011. This amendment clarified the inclusion criteria to allow patients with stable follicular lymphoma to enroll if all lymph node masses are ≤ 3 cm and are smaller or unchanged in size to the most recent salvage regimen. The study closed to accrual in October 2012 when 65 patients, as planned, were enrolled. The Endpoint Review Committee formed in September 2013, once the majority of patients had completed two year follow-up. The endpoint data review was completed in June 2014, and an oral abstract was presented at the ASH Annual Meeting in December 2014.

Reporting Period Update: The primary results manuscript is drafted and pending submission.

Presentation: 1. Reduced intensity conditioning with rituximab yields excellent outcomes after allogeneic HCT for

relapsed follicular lymphoma: A Phase II multicenter trial from the BMT CTN (0701). Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.


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BMT CTN 0702


Title: A trial of single autologous transplant with or without consolidation therapy versus tandem autologous transplant with lenalidomide maintenance for patients with multiple myeloma

Primary Objective: To compare three-year progression-free survival among the three treatment arms.


To compare response rates of very good partial remission or better; rates of complete remission conversion for patients not in complete remission at initiation of maintenance; overall survival; rates of Grade ≥ 3 toxicity according to CTCAE; incidences of infections; treatment-related mortality rates; and rates of discontinuation of therapy. The study will also describe and compare quality-of-life in the three arms.


Chairs: Amrita Krishnan [email protected] George Somlo [email protected] Edward Stadtmauer [email protected]


Coordinators: Courtney Nelson [email protected] Sam Wilkins [email protected]

Statistician: Beth Blackwell [email protected] ACCRUAL DATES

Opened: 06/01/2010 PRC Approval: 10/31/2008 Closed: 11/15/2013 DSMB Approval: 03/18/2009 Target: 750 patients Last Version Released: 01/26/2016 Total: 758 patients Evaluable for Primary Analysis: 02/2017

IND Number: 104912

Key Highlights:

This trial is the follow-on study to BMT CTN 0102 and BMT CTN 0704 / CALGB 100104 and is known as the STaMINA (Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents) study. It was developed by the BMT CTN Multiple Myeloma Intergroup that included representatives from SWOG, CALGB, ECOG, and BMT CTN. The protocol was placed on the CTSU roster in March 2010. This was one of the high-priority trials recommended during the 2007 State of the Science Symposium. It was identified as important to assess the role of post-transplantation treatment for myeloma in the era of novel agents. The study closed to accrual ahead of projections in November 2013 with 758 patients enrolled.


Currently, most patients remain in follow up, which is expected to be completed in 2017. An amended version of the protocol was released in January 2016 with updated adverse event reporting requirements. The Endpoint Review Committee is reviewing patients as they reach the primary endpoint. A long term follow-up study (BMT CTN 07LT) was released in September 2014 to allow eligible patients on 0702 to be followed and receive lenalidomide maintenance until progression.


138

BMT CTN 0703 / SWOG 0410

Protocol Number: BMT CTN 0703 / SWOG 0410

Title: Tandem autologous stem cell transplantation for patients with primary progressive or recurrent Hodgkin disease (a BMT study), Phase II

Primary Objective: To assess the two-year progression-free survival for patients with primary progressive or recurrent Hodgkin lymphoma treated with a tandem transplant program (two cycles of high-dose therapy with autologous stem cell rescue).

Secondary Objectives: To evaluate the response rate and toxicity in patients with primary progressive or recurrent Hodgkin lymphoma treated with this regimen.


Chairs: Ginna Laport (BMT CTN) [email protected] Patrick Stiff (SWOG) [email protected]

Officers: Eileen Smith (SWOG) [email protected] Marcie Riches (BMT CTN) [email protected]

Coordinator: Laura Devillier [email protected] Statistician: SWOG

ACCRUAL DATES

Opened: 10/15/2005 SWOG PRC Approval: N/A 03/18/2008 BMT CTN DSMB Approval: N/A

Closed: 02/01/2009 Last Version Released: 11/07/2007 SWOG Target: 85 patients

Total: 9 BMT CTN, 89 SWOG

Key Highlights:

This protocol was a collaborative effort between SWOG and BMT CTN. Six BMT CTN Core Centers enrolled patients. SWOG closed the study upon accrual completion on February 1, 2009. An analysis is being performed by SWOG, and the BMT CTN provided data as requested. The primary results were presented at the ASH Annual Meeting in December 2014.

Reporting Period Update: The primary results manuscript was submitted for review.

Presentation: 1. SWOG S0410 / BMT CTN 0703: A Phase II trial of tandem autologous HCT for patients with

primary progressive or recurrent Hodgkin lymphoma. Presented: 56th ASH Annual Meeting, San Francisco, December 2014.


139

BMT CTN 0704 / CALGB 100104 / ECOG 100104

Protocol Number: BMT CTN 0704 / CALGB 100104 / ECOG 100104

Title: A Phase III, randomized, double-blind study of maintenance therapy with CC-5013 (NSC #703813, IND #70116) or placebo following autologous stem cell transplantation for multiple myeloma

Primary Objective: To compare the efficacy of lenalidomide and placebo as maintenance therapy after autologous HCT in terms of time to disease progression in patients with multiple myeloma.


To compare complete response rates as well as progression-free and overall survival times and to determine the feasibility of long-term treatment with lenalidomide in these patients.


Chairs:

Kenneth Anderson (CALGB) [email protected] Sergio Giralt (BMT CTN) [email protected] Philip Greipp (ECOG) [email protected] Philip McCarthy (CALGB) [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: CALGB Statistician: CALGB

ACCRUAL DATES

Opened: 12/15/2004 (CALGB) 05/15/2007 (BMT CTN) PRC Approval: CALGB

Closed: 07/02/2009 DSMB Approval: CALGB Target: 533 patients total (40 BMT CTN) Last Version Released: 06/15/2008 Total: 529 patients total (172 BMT CTN) Evaluable for Primary Analysis: 12/2009

Key Highlights:

This CALGB-led, ECOG-endorsed trial opened in December 2004. It was designed to determine the importance of maintenance therapy with lenalidomide for prolonging disease response and survival in patients who have undergone HCT for treatment of multiple myeloma. Its target patient population overlapped with that of BMT CTN 0102, which opened in November 2003. The Multiple Myeloma Intergroup considered a follow-on trial to BMT CTN 0102 at that time, and the accrual difficulties of CALGB 100104 were discussed. Rather than open another competing trial, BMT CTN endorsed the CALGB trial and urged its centers to open the trial through local CALGB and ECOG mechanisms as soon as 0102 reached its enrollment target, which it did in May 2007. To allow BMT CTN centers that were not part of CALGB or ECOG to participate, the DCC worked with NCI to have the trial posted to the CTSU roster. The BMT CTN Accrual Coordinator and other DCC staff worked with the CALGB Protocol Team to develop an accrual enhancement plan that included identifying and contacting centers with potentially large numbers of eligible patients using the CIBMTR’s database of transplant activity. Webinars were also conducted to increase awareness of the trial. Network centers began accruing patients to this trial in summer 2007, and all of these strategies resulted in significant improvement (at least a doubling) in accrual. In December 2009, the CALGB DSMB decided to release the trial results early, due to the significantly longer time to disease progression in patients who received lenalidomide maintenance than those receiving placebo. Timely completion of this trial answered an important question in post-transplant treatment in multiple myeloma and led well into the STaMINA trial (BMT CTN 0702), which incorporates maintenance therapy in all treatment arms. This effort is a good example of how the BMT CTN has played a leadership role in developing and completing transplant trials by fostering collaboration on a national level. The primary manuscript was published in the New England Journal of Medicine and was highlighted as a contributor to one of ASCO’s 17 Major Advances in Clinical Cancer Research in 2012.


Additional secondary analyses of longer term follow-up, including an analysis of second primary malignancies, were conducted. Two analyses were presented during this reporting period (ASCO and International Myeloma Workshop); an additional analysis will be presented this year (ASCO). A subsequent


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Protocol Number: BMT CTN 0704 / CALGB 100104 / ECOG 100104

publication is anticipated during the next reporting period.

Publications:

1. Primary results: Lenalidomide after HCT for multiple myeloma. New England Journal of Medicine. 2012 May 10; 366(19):1770-1781.

2. Anatomy of a successful practice-changing study: a BMT CTN – NCI Cooperative Group Collaboration. Biology of Blood and Marrow Transplantation. 2013 Jun 01; 19(6)858-859.

Presentations:

1. Maximizing accrual to transplant trials in multiple myeloma, lessons from the BMT CTN, ECOG and CALGB collaboration. Presented: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010.

2. Phase III intergroup study of lenalidomide vs. placebo maintenance therapy following single autologous HCT for multiple myeloma: CALGB 100104. Presented: ASCO Annual Meeting, Chicago, IL, June 2010.

3. Phase III intergroup study of lenalidomide vs. placebo maintenance therapy following single autologous HCT for multiple myeloma: CALGB 100104. Presented: 52nd ASH Annual Meeting, Orlando, FL, December 2010.

4. Phase III intergroup study of lenalidomide vs. placebo maintenance therapy following single autologous HCT for multiple myeloma: CALGB ECOG BMT-CTN 100104. Presented: International Myeloma Workshop, Paris, France, May 2011.

5. Analysis of overall survival in the context of cross-over from placebo to lenalidomide and the incidence of second primary malignancies in the Phase III study of lenalidomide vs. placebo maintenance therapy following autologous HCT for multiple myeloma CALGB (Alliance) ECOG BMT CTN 100104. Presented: 14th International Myeloma Workshop, Kyoto, Japan April 2013.

6. Updated analysis of CALGB / ECOG / BMT CTN 100104: Lenalidomide vs. placebo maintenance therapy after single autologous HCT for multiple myeloma. Presented: ASCO Annual Meeting, Chicago, IL, May-June 2015.

7. Analysis of second primary malignancies in CALGB (Alliance) / ECOG / BMT CTN 100104. Presented: 15th International Myeloma Workshop, Rome, Italy, September 2015.


141

BMT CTN 0801


Title: A Phase II / III randomized, multicenter trial comparing sirolimus plus prednisone, and sirolimus / calcineurin inhibitor plus prednisone for the treatment of chronic graft-versus-host disease

Primary Objective:

Phase II study: To compare a treatment regimen that contains sirolimus without a calcineurin inhibitor, to a comparator regimen of sirolimus with a calcineurin inhibitor, with the goal of determining if sirolimus plus prednisone is a sufficiently promising treatment regimen for further comparison in the Phase III trial.


Phase II study: To compare percent reductions in average daily dose of prednisone by 6 and 12 months; cumulative incidences of treatment failure at 1 year; prevalence of active symptomatic chronic GVHD at 1 and 2 years; cumulative incidences of discontinuation of all systemic immunosuppressive therapy at 1 and 2 years; overall and cancer progression-free survival at 1 and 2 years; candidate serum biomarkers of chronic GVHD at baseline, 2 months, and 6 months. Phase III study: To compare percent reduction in average daily dose of prednisone at 6, 12, and 24 months; cumulative incidences of treatment failure at 1 and 2 years; prevalence of active symptomatic chronic GVHD at 1 and 2 years; cumulative incidence of discontinuation of all systemic immunosuppressive therapy at 1 and 2 years; overall and cancer progression-free survival at 1 and 2 years; candidate serum and urine biomarkers of chronic GVHD at baseline, 2 months, and 6 months.


Chairs: Mukta Arora [email protected] Paul Carpenter [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Kelly O’Brien [email protected] Statistician: Brent Logan [email protected]

ACCRUAL DATES Opened: 04/15/2010 PRC Approval: 05/18/2009 Closed: 12/09/2013 DSMB Approval: 09/17/2009 Target: 110 patients (Phase II) + 200 patients (Phase III) Last Version Released: 07/09/2012 Total: 161 patients Evaluable for Primary Analysis: N/A

Key Highlights:

This study was rated as “high priority” at the 2007 State of the Science Symposium. The protocol was approved by the PRC in May 2009 and DSMB in September 2009; it was activated in April 2010. The trial was designed as two parallel studies of sirolimus + prednisone, sirolimus / extracorporeal photopheresis (ECP) + prednisone, and sirolimus / calcineurin inhibitor. The Protocol Team met in June 2011 to address slow accrual (n=31), particularly on the ECP study (n=6). Accrual initiatives were undertaken, but the team closed the ECP study in September 2011 after the DSMB determined it would not compromise the scientific integrity of the trial. More than 100 patients were enrolled on the Phase II portion of the study, and the principles on whether to proceed to the Phase III study of the trial were applied. Overall response rates (CR+PR) at 6 months for the experimental arm (sirolimus + prednisone) were plotted relative to the respective comparator arm (sirolimus + calcineurin inhibitor + prednisone). The results indicated accrual should not proceed to Phase III but all patients should be followed for the Phase III endpoints. After the results were reviewed by the DSMB, the study was closed to enrollment in December 2013. The Endpoint Review Committee reviewed the 6 month data of all patients and completed the adjudication of the chronic GVHD response endpoint.


The primary results of the study were presented at the BMT Tandem Meetings in February 2016. The 2-year follow-up analysis is ongoing.

Presentation: 1. Prednisone / sirolimus compared to PDN / SRL / calcineurin inhibitor as treatment for chronic GVHD: A

randomized Phase II study from the BMT CTN. Presented: BMT Tandem Meetings, Honolulu, HI, February 2016.


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BMT CTN 0802


Title: A multi-center, randomized, double blind, Phase III trial evaluating corticosteroids with mycophenolate mofetil versus corticosteroids with placebo as initial systemic treatment of acute GVHD

Primary Objective: To estimate GVHD-free survival (acute or chronic) at day 56 after randomization without additional therapy.


To evaluate proportions of complete, partial, mixed response, no response, and progression among surviving patients at day 14, 28, and 56; treatment failure (defined as no response, progression, administration of additional therapy for GVHD, or mortality) at day 14, 28, and 56; incidence of acute GVHD flare prior to day 90; and incidence of discontinuation of immune suppression without acute GVHD flare and without disease progression/ recurrence by days 56, 180, and 360 post therapy. Additional secondary endpoints include steroid dose at day 28 and 56 post randomization, incidence of topical / non-absorbable therapy given by day 56, incidence of chronic GVHD by 6 and 12 months post randomization, overall and GVHD-free survival at 6 and 12 months post randomization, incidences of systemic infections within 6 months of initiation of therapy, incidence of Epstein-Barr virus-associated lymphoproliferative disorder or reactivation requiring therapy, malignancy-free survival at 6 and 12 months post randomization, non-relapse mortality at 6 and 12 months, and change in patient-reported outcomes from enrollment to day 56.


Chairs: Javier Bolaños-Meade [email protected] Vincent Ho [email protected]

Officer: Mary Horowitz [email protected] Coordinator: Kate Bickett [email protected] Statistician: Brent Logan [email protected]


Key Highlights:

BMT CTN 0802 is a follow-on study to the randomized Phase II 0302 study, which completed accrual and follow-up in May 2008. The protocol was approved by the PRC in May 2009 and DSMB in June 2009. The study was activated on February 1, 2010, and closed to enrollment on November 14, 2011, due to crossing a futility boundary. A total of 236 patients were enrolled from 36 centers. An endpoint review was completed in March 2012, and an abstract was presented at the February 2013 Tandem meetings. The primary manuscript was published in Blood in November 2014.


Publications:

1. Phase 3 clinical trial steroids / mycophenolate mofetil vs steroids / placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014 Nov 20; 124(22):3221-3227. Epub 2014 Aug 28.

2. A refined risk score for acute GVHD that predicts response to initial therapy, survival, and transplant-related mortality. Biology of Blood and Marrow Transplantation. 2015 Apr 1; 21(4):761-767. Epub 2015 Jan 10.

3. Circulating angiogenic factors associated with response and survival in patients with acute GVHD: Results BMT CTN 0302 and 0802. Biology of Blood and Marrow Transplantation. 2015 Jun 1; 21(6):1029-1036. Epub 2015 Mar 7.


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Presentations:

1. A multi-center, randomized, double blind, Phase III clinical trial comparing steroids / placebo vs. steroids / mycophenolate mofetil as initial therapy for acute GVHD. BMT CTN Study 0802. Presented: BMT Tandem Meetings, Salt Lake City, UT, February 2013.

2. A new Ann Arbor grading system uses biomarkers to risk stratify patients for non relapse mortality at the onset of acute GVHD. Presented: 40th EBMT Congress, Milan, Italy, March-April 2014.

3. Circulating angiogenic factors as biomarkers of acute GVHD onset and response to therapy: repair and regeneration vs. endothelial damage and inflammation. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.

4. A biomarker algorithm defines onset grades of acute GVHD with distinct non-relapse mortality. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.

5. Prognostic impact of follistatin in acute GVHD: Results from BMT CTN 0302 and 0802. Presented: BMT Tandem Meetings, San Diego, CA, February 2015.


144

BMT CTN 0803


Title: High dose chemotherapy with autologous stem cell rescue for aggressive B cell lymphoma and Hodgkin lymphoma in HIV-infected patients

Primary Objective: To assess overall survival after autologous HCT for chemotherapy-sensitive aggressive B cell lymphoma or Hodgkin lymphoma in patients with HIV, using BEAM for pre-transplant conditioning.


To evaluate time-to-progression, progression-free survival, complete remission (CR), and CR+PR (partial remission) proportion at day 100, time to progression after CR, lymphoma disease-free survival, time to hematopoietic recovery, hematologic function at day 100, toxicities, incidence of infections, treatment-related mortality, immunologic reconstitution, assessment of microbial gut translocation and assessment of DNA in blood (clonal Ig DNA in plasma, Epstein-Barr virus DNA in plasma and peripheral blood mononuclear cells) as tumor markers.


Chairs: Joseph Alvarnas [email protected] Richard Ambinder [email protected]

Officer: Willis Navarro [email protected] Coordinator: Cathryn Mudrick [email protected] Medical Monitor: Bipin Savani [email protected] Statistician Brent Logan [email protected] Contract Rep: Pamela Budnick [email protected]


Key Highlights:

The BMT CTN 0803 Protocol Team was formed in November 2008. In November 2009, the protocol received PRC approval, followed by DSMB approval in January 2010. It was released to centers for IRB submission in January 2010. On April 30, 2010, Protocol Version 2 was released to centers for IRB submission. The amendment removed the HIV reservoir ancillary study from the protocol. Eleven Core, 4 Affiliate, and 4 AIDS Malignancy Consortium Centers participated in the study, which opened to accrual in July 2010. The study closed to accrual on May 15, 2013, after 43 patients were enrolled. The study is conducted in partnership with the AIDS Malignancy Consortium, an NCI-supported clinical trials group. Additional funding is provided by the NCI program for Non-AIDS-Defining Cancers. The Endpoint Review Committee completed its data review in June 2014. The primary results were presented at the ASH Annual Meeting in December 2014 and selected to be included in the ASH press release.


The primary results manuscript was submitted for publication in August 2015. The editors requested an additional follow-up analysis be completed, and the manuscript was revised and resubmitted in January 2016.

Presentation: 1. Autologous HCT in patients with chemotherapy-sensitive, relapsed / refractory HIV-associated

lymphoma: Results from the BMT CTN 0803 / AIDS Malignancy Consortium (AMC-071) trial. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.


145


Protocol Number: BMT CTN 0804 / CALGB 100701

Title: Phase II study of reduced-intensity allogeneic stem cell transplant for high-risk chronic lymphocytic leukemia

Primary Objective: To determine if this treatment improves the current two-year rate of PFS in the early-disease cohort compared to historical controls, specifically assessing whether 2-year PFS ≥ 70% is achievable and whether two-year PFS ≤ 50% can be excluded.


To evaluate whether two-year current PFS ≥ 50% is achievable and two-year PFS ≤ 30% can be excluded in the advanced disease cohort; objective response rate; incidences of grades 2-4 and 3-4 acute GVHD; incidence of extensive chronic GVHD; incidences of TRM at 100 days and one year; overall survival; donor chimerism for CD3+ cells at one and two years after transplantation; presence of donor antigen-specific T cell clones before and after withdrawal of immune suppression; relapse profiles of patients with T cell responses against CLL to those whose CLL cells that are not reactive; and to prospectively examine the impact of high-risk genomic features and immune-based single nucleotide polymorphisms on response, toxicity, and two-year PFS to reduced-intensity allogeneic HCT.

TEAM PRINCIPALS Name Email Chair: Richard Maziarz [email protected] Officer: Mary Horowitz [email protected] Coordinator: Amy Foley [email protected] Statistician: CALGB

ACCRUAL DATES Opened: 03/16/2011 PRC Approval: CALGB

Closed: 12/02/2013 (early disease cohort) DSMB Approval: CALGB 01/27/2014 (adv disease cohort) Last Version Released: 01/15/2012

Target: 86 patients Evaluable for Primary Analysis: 02/2016 Total: 69 total, 27 BMT CTN

Key Highlights:

This study was rated as a “very high priority” at the 2007 State of the Science Symposium. The protocol is a collaborative effort between Alliance for Clinical Trials in Oncology and BMT CTN. Alliance patient accrual began in February 2010. BMT CTN opened the trial to enrollment in March 2011. Accrual to the early disease cohort remained slower than anticipated. The Alliance Data Safety and Monitoring Board determined this cohort should be closed to new patient accrual in December 2013. The advanced disease cohort remained open, and the accrual target was met. This cohort closed to accrual in January 2014.

Reporting Period Update: The primary endpoint is two year progression-free survival. Data analysis is anticipated to start early in the next reporting period.


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BMT CTN 0805 / SWOG 0805

Protocol Number: BMT CTN 0805 / SWOG 0805

Title: A Phase II study of combination of hyper-CVAD and dasatinib with or without allogeneic stem cell transplant in patients with Philadelphia chromosome positive and/or BCR-ABL positive acute lymphoblastic leukemia (a BMT study)

Primary Objective:

To test whether the relapse-free survival after allogeneic HCT among Philadelphia+ and / or BCR-ABL gene+ ALL patients given an intensive short-term chemotherapy regimen of hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, and dexamethasone) in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant further investigation, and to test whether the continuous complete remission rate for previously untreated Philadelphia+ and / or BCR-ABL+ ALL patients given an intensive short-term chemotherapy regimen of hyper-CVAD in combination with the tyrosine kinase inhibitor dasatinib is sufficiently high to warrant Phase III investigation.


To investigate, in a preliminary manner, the relative effectiveness of minimum residual disease detection using real-time quantitative polymerase chain reaction for BCR/ABL versus flow cytometry to predict the outcome of patients treated by the hyper-CVAD + dasatinib regimen and/or allogeneic stem cell transplant; estimate the frequency and severity of toxicities of the intensive short-term chemotherapy regimen in these patients; and estimate the overall survival of all patients on the study.


Chairs: David Porter (BMT CTN) [email protected] Farhad Ravandi (SWOG) [email protected]

Officer: SWOG

Coordinators: Amy Foley (BMT CTN) [email protected] Sandi Jo McMillan (SWOG) [email protected]

Statistician: SWOG ACCRUAL DATES

Opened: SWOG: 09/01/2009 PRC Approval: SWOG CTSU: 08/09/2010 DSMB Approval: SWOG

Closed: 10/01/2013 Last Version Released: 04/26/2014 Target: 85 patients Evaluable for Primary Analysis: 04/2015 Total: 91 patients IND Application Number: Held by SWOG

Key Highlights:

This study was rated as a “very high priority” trial during the 2007 State of the Science Symposium; the collaborative study is led by SWOG with active involvement of BMT CTN and ECOG representatives on the Protocol Team. This protocol opened to accrual to SWOG centers in September 2009 and through the CTSU in August 2010, where the study could be accessed by all BMT CTN centers. Several centers affiliated with both SWOG and the BMT CTN participated in the study. The BMT CTN continues to contribute to patient reimbursement for all patients on the transplant arm. One BMT CTN Core center was activated to participate on the study through the BMT CTN and enrolled one patient. Thirteen other BMT CTN Core / Consortia centers were activated through SWOG or the CTSU and enrolled 46 total patients. Accrual was completed in October 2013.


The primary endpoint of relapse-free survival at one year was met this year, and data analysis was completed. The primary results were presented at the 2015 ASH Annual Meeting. The drafted primary results manuscript will be submitted for publication during the next reporting period.

Presentation: 1. Multi-center US intergroup study of intensive chemotherapy plus dasatinib followed by allogeneic

HCT in patients with Philadelphia chromosome positive acute lymphoblastic leukemia younger than 60. Presented: 57th ASH Annual Meeting, Orlando, FL, December 2015.


147

BMT CTN 0901


Title: A randomized, multi-center Phase III study of allogeneic stem cell transplantation comparing regimen intensity in patients with myelodysplastic syndrome or acute myeloid leukemia

Primary Objective: To compare 18-month overall survival between the two groups. The hypothesis to be tested is that reducing the intensity of the conditioning regimen will decrease treatment-related mortality without increasing relapse so that overall survival will be improved.


To compare disease-free survival rate after transplantation, rate of TRM, hematologic recovery, kinetics of donor cell engraftment, incidence of graft failure, incidence and severity of acute and chronic GVHD, immune reconstitution, quality of life, rates of infectious complications, rates of ≥ grade 3 toxicities according to CTCAE, and quality of life.


Chairs: Mitchell Horwitz [email protected] Bart Scott [email protected]

Officer: Marcelo Pasquini [email protected] Coordinator: Brianne Allison [email protected] Statistician: Brent Logan [email protected]

ACCRUAL DATES Opened: 06/02/2011 PRC Approval: 07/23/2010 Closed: 04/18/2014 DSMB Approval: 09/15/2010 Target: 356 Last Version Released: 03/03/2014 Total: 272 Evaluable for Primary Analysis: 10/2015

Key Highlights:

The concept for this protocol was approved by the Steering Committee in October 2008 after being rated as a “high priority” at the 2007 State of the Science Symposium. The Protocol Team was formed in December 2008 and held its first meeting in March 2009. The protocol was approved by the PRC in June 2010 and DSMB in September 2010. It was activated in June 2011 after several centers received IRB approval and identified potential patients. Twenty-one Core and 16 Affiliate Centers were activated, 32 of which enrolled patients. Accrual to this trial was halted permanently in April 2014 after preliminary data appeared to show benefit for one approach to the intensity of conditioning for allogeneic HCT in patients eligible for the study. All patients enrolled on the protocol continued to be followed as specified in the study.


All patients completed the primary endpoint of overall survival at 18 months in October 2015. The Endpoint Review Committee completed their review of all 272 patients. The abstract was accepted as a Late Breaking Abstract and presented at the ASH Annual Meeting in December 2015. The abstract was also selected as a Special Invite Abstract and presented at the 2016 BMT Tandem Meetings. The primary results manuscript has been drafted and will be submitted for publication in Spring 2016.

Presentations:

1. Results of a Phase III randomized, multi-center study of allogeneic HCT after high vs. reduced intensity conditioning in patients with MDS or AML: BMT CTN 0901. Presented: 57th ASH Annual Meeting, Orlando, FL, December 2015. Late Breaking Abstract.

2. Results of a Phase III randomized, multi-center study of allogeneic HCT after high vs. reduced intensity conditioning in patients with MDS or AML: BMT CTN 0901. Presented: BMT Tandem Meetings, Honolulu, HI, February 2016.


148

BMT CTN 0902


Title: A Phase III randomized, multicenter trial testing whether exercise or stress management improves functional status and symptoms of autologous and allogeneic recipients

Primary Objective: To determine whether exercise or stress management improves self-reported physical and mental functioning compared to standard care at 100 days post-transplant, using an intent-to-treat analysis


To evaluate whether exercise or stress management improves physical and mental functioning compared to standard care at 100 days; physical and mental functioning among the four groups; symptoms (fatigue, pain, sleep, nausea, cancer and treatment distress) at 100 days; the number of hospital days within the first 100 days; durability of effects by comparing functional status and symptoms at 6 months; and overall survival at 6 months.


Chairs: Paul Jacobsen [email protected] Stephanie Lee [email protected]

Officer: Mary Horowitz [email protected] Coordinator: Laura Devillier [email protected] Statistician: Brent Logan [email protected]


Key Highlights:

This study is the Network’s first trial examining quality of life as its primary endpoint, and it was identified as one of 11 high-priority trials during the 2007 State of the Science Symposium. The protocol was approved by the PRC in December 2009 and DSMB in March 2010. Patient materials, including exercise and stress management videos and brochures, were finalized in September 2010 and released to centers for IRB approval. The trial opened for enrollment in January 2011 when the first center received IRB approval. Protocol Version 2 was released to centers in March 2011; the amendment specified three new exclusion criteria. Accrual was completed in June 2012, 17 months earlier than projected. Twenty-one centers enrolled a total of 711 patients on the trial. An Endpoint Review Committee completed their review, and an oral abstract was presented at the ASH Annual Meeting in December 2013. The primary manuscript was published in October 2014. An abstract on patient-reported quality of life was presented at the ASH Annual Meeting in December 2014.


Two additional analyses and presentations were completed in 2015. Manuscripts for both of these analyses are in development.

Publications:

1. Exercise and stress management training prior to HCT: BMT CTN 0902. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1530-1536. Epub 2014 Jun 6.

2. Patient-reported physical functioning predicts the success of HCT (BMT CTN 0902). Cancer. 2016 Jan 1; 122(1):91-98. Epub 2015 Oct 6.

Presentations:

1. Exercise and stress management training for patients undergoing autologous or allogeneic HCT. Results from BMT CTN 0902. Presented: 55th ASH Annual Meeting, New Orleans, LA, December 2013.

2. Patient-reported quality of life is an independent predictor of survival after allogeneic HCT: A secondary analysis from the BMT CTN 0902. Presented: 56th ASH Annual Meeting, San Francisco, CA, December 2014.


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3. Pre-transplant health-related quality of life factors as predictors of outcomes following HCT – a study from the BMT CTN 0902 trial. Presented: IPOS / APOS World Congress of Psycho-Oncology IPOS/APOS Meeting, Washington, DC, July 2015.

4. Cancer and treatment distress measurements in a multicenter cohort of HCT recipients. Presented: IPOS / APOS World Congress of Psycho-Oncology IPOS/APOS Meeting, Washington, DC, July 2015.


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Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 7.4 Protocols Released to Centers

151

7.4 Protocols Released to Centers

BMT CTN Protocols Released to Centers (as of March 31, 2016)


1401 Phase II multicenter trial of single autologous hematopoietic cell transplant followed by lenalidomide maintenance for multiple myeloma with or without vaccination with dendritic cell / myeloma fusions

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BMT CTN 1401


Title: Phase II multicenter trial of single autologous hematopoietic cell transplant followed by lenalidomide maintenance for multiple myeloma with or without vaccination with dendritic cell / myeloma fusions

Rationale:

Multiple myeloma (MM) is associated with immune suppression, including defects in antigen presentation and effector cell function that are thought to play a role in disease progression. Although the outcomes for myeloma patients have improved greatly over the past decade, the majority of patients relapse even after autologous stem cell transplant and post-transplant maintenance therapy with lenalidomide. This study assesses a tumor vaccine in which patient-derived myeloma cells are fused with autologous dendritic cells (DCs), such that a broad array of myeloma antigens are presented in the context of DC-mediated costimulation. Early phase clinical data demonstrate that post-transplant vaccination with a DC-MM fusion product with GM-CSF adjuvant increases the number of MM-specific T cells. Furthermore, it appears that lenalidomide can specifically augment vaccine-stimulated induction of MM-specific T cells. The study is therefore interested in combining standard immunomodulatory therapy (lenalidomide) with a potential immune stimulant (DC-MM vaccination) to increase post-transplant clinical response. Finally, pre-clinical data has suggested that immunomodulatory agents augment natural killer (NK) cell activity and that NK cells interact with and can be activated by DCs. Thus this study will also assess the NK immunophenotype in the setting of post-transplant maintenance lenalidomide and the changes to this phenotype in the setting of DC-MM fusion vaccination. The study postulates that post-transplant lenalidomide maintenance will augment post-transplant anti-myeloma immunity, thus providing an ideal platform for DC/MM fusion vaccination. Additionally, to understand the effect of vaccine versus the adjuvant in the post-transplant setting, the non-vaccine arms are split into lenalidomide alone and lenalidomide plus GM-CSF, with GM-CSF administered in the exact same schedule and dosing as in the vaccine arm. The results of this trial will provide information on whether this patient-specific vaccine administered after transplant is promising for further comparison with current standard of care treatment. Furthermore, this trial will address several important aspects of anti-myeloma immunity, including how lenalidomide maintenance influences post-transplant recovery and myeloma control. Lastly, isolating the effect of the GM-CSF adjuvant will address whether any effect observed is related solely to the vaccine.

Primary Objective:

To compare the proportion of patients alive and in complete response at one year post-transplant between patients receiving DC/MM vaccine / GM-CSF with lenalidomide maintenance therapy to those receiving lenalidomide maintenance therapy with or without GM-CSF. Immunologically: To compare the effect of DC/MM vaccine / GM-CSF with lenalidomide maintenance therapy to lenalidomide maintenance therapy alone or with GM-CSF on treatment-induced expansion of myeloma-specific T cells, defined as a 2.4-fold increase from pre-therapy to peak post-treatment levels.


Clinically: To compare DC/MM vaccine / GM-CSF with lenalidomide maintenance therapy to lenalidomide maintenance therapy with or without GM-CSF with respect to: myeloma response, conversion of partial to complete response, disease progression, treatment-related mortality, progression-free survival, overall survival, toxicities according to the CTCAE v4.0, incidence of infections, and measures of minimal residual disease at one year post transplant (or approximately 10 months from randomization). Secondary exploratory analyses will also be conducted to compare in a pairwise fashion the vaccine arm, lenalidomide / GM-CSF arm, and lenalidomide alone arm to describe the proportion of patients with collection of tumor cells who reach randomization, compliance with vaccine, and reproducibility of the vaccine manufacturing based on the release criteria. Immunologically: To compare each of the treatment arms for the percent of patients achieving at least a 10-fold expansion of myeloma-specific T cells, expansion of myeloma antigen-specific T cells by tetramer analysis, quantification of T cell subsets and PD-1 expressing lymphocytes, quantification of NK


153


cells and identification of activation and inhibitory ligands, assessment of NK-mediated killing of myeloma targets, and assessment of humoral response against whole myeloma cells and myeloma-associated antigens by SEREX.


Chairs: David Avigan [email protected] David Chung [email protected] Nina Shah [email protected]


Coordinators: Courtney Nelson [email protected] Kelly O’Brien [email protected]

Medical Monitor: Marcie Riches [email protected] Statistician: Brent Logan [email protected] Contract Rep: Nancy Poland [email protected] Additional Members: Email: PRC Approval Date: 12/19/2014 Natalie Callander [email protected] DSMB Approval Date: 02/04/2015 Adam Cohen [email protected] Opened to Accrual: N/A Steven Devine [email protected] Closed to Accrual: N/A Yvonne Efebera [email protected] Target Accrual: 188 patients Joseph Fay [email protected] Total Accrual as of 3/31/16: N/A Sarah Holstein [email protected] Reporting Period Accrual: N/A Carolyn Keever-Taylor [email protected] IND Number: 16655 Hillard Lazarus [email protected] Last Version Released: 01/15/2016 Adam Mendizabal [email protected] Additional Member: Email: Aaron Rapoport [email protected] Robert Soiffer [email protected] Jacalyn Rosenblatt [email protected] Edmund Waller [email protected] David Siegel [email protected]

Key Highlights:

The study was approved by the PRC in December 2014 and DSMB in February 2015. The FDA provided notice that the study may proceed in October 2015. Version 1.0 of the protocol was released to centers for IRB submission in January 2016. Ten Core Centers and five Affiliate Centers have committed to participate on the study.


The study was released to sites in January 2016 and is pending activation. It is anticipated that the first patient will be enrolled in May 2016.


154


Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A1: Steering Committee Roster

155

Attachment A: Committee Rosters

Attachment A1: Steering Committee Roster

The Executive Committee is a subcommittee of the Steering Committee. Individuals who also serve on the Executive Committee are identified by an asterisk (*).

Core Center Principal Investigators Center

Amin Alousi, MD MD Anderson Cancer Center, Houston, TX

Claudio Anasetti, MD H. Lee Moffitt Cancer Center, Tampa, FL

Joseph Antin, MD Dana-Farber Cancer Institute, Boston, MA

*Frederick Appelbaum, MD (Immediate Past Chair)

Fred Hutchinson Cancer Research Center, Seattle, WA

Asad Bashey, MD Northside Hospital, Atlanta, GA

*Steven Devine, MD (Chair) Ohio State University, Columbus, OH

Sergio Giralt, MD Memorial Sloan-Kettering Cancer Center, New York, NY

Helen Heslop, MD Baylor College of Medicine, Houston, TX

*Richard Jones, MD (Vice Chair) Johns Hopkins University, Baltimore, MD

Joanne Kurtzberg, MD Duke University, Durham, NC

Robert Lowsky, MD Stanford University, Stanford, CA

Hillard Lazarus, MD Case Western Reserve University, Cleveland, OH

Gregory Yanik, MD University of Michigan, Ann Arbor, MI

Ryo Nakamura, MD City of Hope National Medical Center, Duarte, CA

Michael Pulsipher, MD University of Utah, Salt Lake City, UT

Edward Stadtmauer, MD University of Pennsylvania, Philadelphia, PA

Julie Vose, MD University of Nebraska, Omaha, NE

Daniel Weisdorf, MD University of Minnesota, Fairfield, MN

Peter Westervelt, MD, PhD Washington University, St. Louis, MO

John Wingard, MD University of Florida, Gainesville, FL

Cooperative Group Representatives Center

Alliance: Steven Devine, MD Ohio State University, Columbus, OH

SWOG: Patrick Stiff, MD Loyola University, Chicago, IL

COG: Stephan Grupp, MD, PhD Children’s Hospital of Philadelphia, PA

ECOG: Hillard Lazarus, MD Case Western Reserve University, Cleveland, OH

Affiliate Center Representatives Center

Parameswaran Hari, MD, MS Medical College of Wisconsin, Milwaukee, WI

DCC Principal Investigators Organization

*Dennis Confer, MD (Co-PI) NMDP/Be The Match, Minneapolis, MN

*Mary Horowitz, MD, MS (PI) CIBMTR, Milwaukee, WI

*Adam Mendizabal, PhD (Co-PI) The Emmes Corporation, Rockville, MD

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A1: Steering Committee Roster

156

Core Center Principal Investigators Center

NHLBI and NCI Project Officers Organization

*Nancy DiFronzo, PhD National Heart, Lung, and Blood Institute, NIH, Bethesda, MD

*William Merritt, PhD National Cancer Institute, NIH, Bethesda, MD

*Elizabeth Wagner, MPH National Heart, Lung, and Blood Institute, NIH, Bethesda, MD

*Roy Wu, PhD National Cancer Institute, NIH, Bethesda, MD

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A2: Biomarkers Committee Roster

157

Attachment A2: Biomarkers Committee Roster

Name Organization Term Expiration

Ami Bhatt ([email protected])

Stanford University Palo Alto, CA

2018

Shernan Holtan ([email protected])

University of Minnesota Minneapolis, MN

2018

Ryo Nakamura ([email protected])

City of Hope Duarte, CA

2018

Effie Petersdorf ([email protected])

Fred Hutchinson Cancer Research C enter Seattle, WA

2018

Leslie Kean (Chair) ([email protected])

Seattle Children’s Seattle, WA

2017

Ramiro Garzon ([email protected])

Ohio State University Medical Center Columbus, OH

2016

Andrew Harris ([email protected])

University of Utah Salt Lake City, UT

2016

Dennis Confer (ex-officio) ([email protected])

NMDP/Be The Match Minneapolis, MN

-

Nancy DiFronzo (ex-officio) ([email protected])

National Heart, Lung, and Blood Institute, NIH Bethesda, MD

-

John Hansen (ex-officio) ([email protected])

Fred Hutchinson Cancer Research Center Seattle, WA

-

Alan Howard (ex-officio) ([email protected])

CIBMTR Minneapolis, MN

-

John Levine (ex-officio) ([email protected])

Mount Sinai Medical Center New York, NY

-

Adam Mendizabal (ex-officio) ([email protected])

The Emmes Corporation Rockville, MD

-

William Merritt (ex-officio) ([email protected])

National Cancer Institute, NIH Bethesda, MD

-

Marcelo Pasquini (ex-officio) ([email protected])

CIBMTR Milwaukee, WI

-

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A3: Clinical Research Associates Committee Roster

158

Attachment A3: Clinical Research Associates Committee Roster


Adam Fiebelkorn ([email protected])

Children’s Hospital of Wisconsin Milwaukee, WI

2018

Michelle Leveque ([email protected])

Children’s Hospital of Wisconsin Milwaukee, WI

2018

Robert Thompson ([email protected])


2018

Noah Tucker ([email protected])

Johns Hopkins University Baltimore, MD

2018

Terry Furlong [email protected])


2017

Mildred Pasek ([email protected])

Dana-Farber Cancer Institute Boston, MA

2017

Anjela Tsirunyan ([email protected])

City of Hope Duarte, CA

2017

Meghan Vazquez ([email protected])

University of Florida Gainesville, FL

2016

Cynthia Couture (ex-officio) ([email protected])


-



-

Mary Magliocco (Chair) (ex-officio) ([email protected])


-



-





Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A4: Pharmacy Committee Roster

159

Attachment A4: Pharmacy Committee Roster


Valkal Bhatt ([email protected])

Memorial Sloan Kettering Cancer Center New York City, NY

2018

Janel Boyle ([email protected])

University of California, San Francisco San Francisco, CA

2018

Joseph Bubalo (Chair) ([email protected])

Oregon Health Sciences University Portland, OR

2017

Philip Lubanski ([email protected])

Kansas University Medical Center Kansas City, KS

2017

Melissa Sanacore ([email protected])

Northside Hospital Atlanta, GA

2017

Amy Carver ([email protected])

University of Colorado Aurora, CO

2016



-

Iris Gersten (ex-officio) ([email protected])


-



Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A5: Special Populations Committee Roster

160

Attachment A5: Special Populations (Pediatrics / Human Subjects) Committee Roster


Staci Arnold ([email protected])

Emory University Atlanta, GA

2018

Jim Connelly ([email protected])

University of Michigan Ann Arbor, MI

2018

Rabi Hanna ([email protected])

Cleveland Clinic Cleveland, OH

2018

Adetola Kassim ([email protected])

Vanderbilt University Medical Center Nashville, TN

2018

Andrew Artz ([email protected])

University of Chicago Chicago, IL

2017

Javier Bolanos-Meade ([email protected])

Johns Hopkins Baltimore, MD

2017

Shalini Shenoy ([email protected])

St. Louis Children’s St. Louis, MO

2017

Sonali Chaudhury ([email protected])

Ann & Robert H. Lurie Children’s Hospital Chicago, IL

2016

David Jacobsohn ([email protected])

Children’s National Medical Center Washington, DC

2016

Eneida Nemecek ([email protected])

Oregon Health Sciences University Portland, OR

2016

Michael Nieder (Chair) ([email protected])

H. Lee Moffitt Cancer Center Tampa, FL

2016



-

Mary Horowitz (ex-officio) ([email protected])


-

Brent Logan (ex-officio) ([email protected])


-



-

Marlene Peters-Lawrence (ex-officio) ([email protected])





Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A6: Toxicity and Supportive Care Committee Roster

161

Attachment A6: Toxicity and Supportive Care Committee Roster


Anita D'Souza ([email protected])


2018

Chris Dvorak ([email protected])

University of California, San Francisco San Francisco, CA

2018

Shin Mineishi ([email protected])


2018

Celalettin Ustun ([email protected])

University of Minnesota Minneapolis, MN

2018

Leona Holmberg ([email protected])


2017

Hillard Lazarus ([email protected])

Case Western Reserve University Cleveland, OH

2017

Andrew Rezvani ([email protected])

Stanford University Palo Alto, CA

2017

Greg Yanik ([email protected])

University of Michigan Ann Arbor, MI

2017

Muzaffar Qazilbash ([email protected])

MD Anderson Cancer Center Houston, TX

2016



-



-


Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment A7: Publications, Abstracts, and Presentations Committee Roster

162

Attachment A7: Publications, Abstracts, and Presentations Committee Roster


Parameswaran Hari ([email protected])


2018

Paul O'Donnell ([email protected])

Massachusetts General Hospital Boston, MA

2018

Asad Bashey (Co-Chair) ([email protected])

Northside Hospital Atlanta, GA

2017

Stella Davies ([email protected])

Cincinnati Children’s Cincinnati, OH

2017

Claudio Anasetti ([email protected])

H. Lee Moffitt Cancer Center Tampa, FL

2016

Kirk Schultz (Co-Chair) ([email protected])

University of British Columbia Vancouver, BC

2016



-

Nancy Geller (ex-officio) ([email protected])


-



-



-

Nancy Poland (ex-officio) ([email protected])

CIBMTR Minneapolis, MN

-

William Merritt (ex-officio) ([email protected])

National Cancer Institute, NIH Bethesda, MD

-





Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment B1: Publications

163

Attachment B: Publications, Abstracts, and Presentations

Attachment B1: Publications by Year

Number Publication Protocol Number PMCID

2004

1

Wingard JR. Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation. Clinical Infectious Disease. 2004 Oct 15; 39 Suppl 4:S176-180.

BMT CTN 0101 N/A (pre-dates

PMCID requirements)

2005

2

Logan BR. Optimal two-stage randomized Phase II clinical trials. Clinical Trials. 2005 Feb 1; 2(1):5-12.

BMT CTN 0302 N/A (pre-dates

PMCID requirements)

3

Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. BMT CTN Toxicity Committee consensus summary, thrombotic microangiopathy after hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation. 2005 Aug 1; 11(8):571-575.

Network publication

N/A (pre-dates

PMCID requirements)

2007

4

Keating K. Editorial: Prospective clinical trials in BMT come of age in the US: The Blood and Marrow Transplant Clinical Trials Network. Biology of Blood and Marrow Transplantation. 2007 Mar 1, 13(3):255-256.

Network publication

N/A (pre-dates

PMCID requirements)

5

Weisdorf D, Carter S, Confer D, Ferrara J, Horowitz M. Blood and Marrow Transplant Clinical Trials Network (BMT CTN): Addressing unanswered questions. Biology of Blood and Marrow Transplantation. 2007 Mar 1; 13(3):257-262.

Network publication

N/A (pre-dates

PMCID requirements)

6

Ferrara J, Anasetti C, Stadtmauer E, Antin J, Wingard J, Lee SJ, Levine J, Schultz K, Appelbaum F, Negrin R, Giralt S, Bredeson C, Heslop H, Horowitz M. BMT CTN State of the Science Symposium 2007. Biology of Blood and Marrow Transplantation. 2007 Nov 1; 13:1268-1285.

Network publication

N/A (pre-dates

PMCID requirements)


164


2008

7

Logan B, Leifer E, Bredeson C, Horowitz M, Ewell M, Carter S, Geller N. Use of biological assignment in hematopoietic stem cell transplantation clinical trials. Clinical Trials. 2008 Jan 1; 5(6):607-616.

BMT CTN 0102 PMC2671015

8

Cutler C, Stevenson K, Kim HT, Richardson P, Ho VT, Linden E, Revta C, Ebert R, Warren D, Choi S, Koreth J, Armand P, Alyea E, Carter S, Horowitz M, Antin JH, Soiffer R. Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation. Blood. 2008 Dec 1; 112(12):4425-4431. Epub 2008 Sep 5.

BMT CTN 0402 PMC2597119

2009

9

Alousi A, Weisdorf D, Logan B, Bolaños-Meade J, Carter S, DiFronzo N, Pasquini M, Goldstein S, Ho V, Hayes-Lattin B, Wingard J, Horowitz M, Levine J. Etanercept, mycophenolate, denileukin or pentostatin plus corticosteroids for acute graft-versus-host disease: A randomized Phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009 Jul 16; 114(3):511-517. Epub 2009 May 14.

BMT CTN 0302 PRIMARY

MANUSCRIPT

PMC2713466

10

Giralt S, Vesole DH, Somlo G, Krishnan A, Stadtmauer E, McCarthy P, Pasquini MC, BMT CTN Multiple Myeloma Working Group. Re: Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: A systematic review and meta-analysis. Journal of the National Cancer Institute. 2009 Jul 01; 101(13):964; author reply 966-967. Epub 2009 Jun 17. [Comment on: Journal of the National Cancer Institute 101(2):100-106, 2009].

BMT CTN 0102 N/A Correspondence

2010

11

Jacobson PA, Huang J, Wu J, Kim M, Logan B, Alousi A, Grimley M, Bolaños-Meade J, Ho V, Levine JE, Weisdorf D. Mycophenolate pharmacokinetics and association with response to acute graft-versus-host disease treatment from the Blood and Marrow Transplant Clinical Trials Network. Biology of Blood and Marrow Transplantation. 2010 Mar 1; 16(3):421-429.

BMT CTN 0302 PMC3104501

12

Levine JE, Logan B, Wu J, Alousi AM, Ho V, Bolaños-Meade J, Weisdorf D, On behalf of the BMT CTN. Graft-versus-host disease treatment: predictors of survival. Biology of Blood and Marrow Transplantation. 2010 Dec 1; 16(12):1693-1699. Epub 2010 Jun 9.

BMT CTN 0302 PMC2955996


165


13

Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, Gersten ID, Mendizabal AM, Leather HL, Confer DL, Maziarz RT, Stadtmauer EA, Bolaños-Meade J, Brown J, DiPersio JF, Boeckh M, Marr KA; BMT CTN. Randomized double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010 Dec 9; 116(24):5111-5118. Epub 2010 Sep 8.


MANUSCRIPT

PMC3012532

14

Pulsipher MA, Young NS, Tolar J, Risitano AM, Deeg HJ, Anderlini P, Calado R, Kojima S, Eapen M, Harris R, Scheinberg P, Savage S, Maciejewski JP, Tiu RV, DiFronzo N, Horowitz MM, Antin JH. Optimization of therapy for severe aplastic anemia based on clinical, biological and treatment response parameters: conclusions of an international working group on severe aplastic anemia convened by the BMT CTN, March 2010. Biology of Blood and Marrow Transplantation. 2011 Mar 1; 17(3):291-299. Epub 2010 Oct 27.

BMT CTN 0301 PMC3053041

15

Tomblyn MR, Ewell M, Bredeson C, Kahl BS, Goodman SA, Horowitz MM, Vose JM, Negrin RS, Laport GG. Autologous versus reduced intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non-Hodgkin lymphoma beyond first complete response or first partial response. Biology of Blood and Marrow Transplantation. 2011 Jul 1; 17(7):1051-1057. Epub 2010 Nov 10.


MANUSCRIPT

PMC3114272

16

Horwitz EM, Horowitz MM, DiFronzo NL, Kohn DB, Heslop HE, BMT CTN State of the Science Cell and Gene Therapy Committee. Guidance for developing Phase II cell therapy trial proposals for consideration by the BMT CTN. Biology of Blood and Marrow Transplantation. 2011 Feb 1; 17(2):192-196. Epub 2010 Dec 21.

Network publication

PMC3387575

2011

17

Devine SM, Carter S, Soiffer RJ, Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Stadtmauer EA, Alyea EP 3rd, Keever-Taylor CA, O'Reilly RJ. Low risk of chronic graft-versus-host disease and relapse associated with T cell depleted peripheral blood stem cell transplantation for acute myeloid leukemia in first remission: results of the Blood and Marrow Transplant Clinical Trials Network protocol 0303. Biology of Blood and Marrow Transplantation. 2011 Sep 1; 17(9):1343-1351. Epub 2011 Feb 12.


MANUSCRIPT

PMC3150599


166


18

Kohn DB, Dotti G, Brentjens R, Savoldo B, Jensen M, Cooper LJ, June C, Rosenberg S, Sadelain M, Heslop HE. CARs on track in the clinic: Workshop of the Blood and Marrow Transplant Clinical Trials Network sub-committee on cell and gene therapy. Molecular Therapy. 2011 Mar 1; 19(3):432-438. Epub 2011 Mar 1.

Network publication

PMC3048197

19

Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O'Donnell PV. Alternative donor transplantation after reduced intensity conditioning: results of parallel Phase 2 trials using HLA-mismatched related bone marrow or unrelated umbilical cord blood grafts. Blood. 2011 Jul 14; 118(2):282-288. Epub 2011 Apr 28.

BMT CTN 0603 / BMT CTN 0604

PRIMARY MANUSCRIPT

PMC3138683

20

Denzen EM, Burton Santibáñez ME, Moore H, Foley A, Gersten I, Gurgol G, Majhail NS, Spellecy R, Horowitz MM, Murphy EA. Easy-to-read informed consent forms for hematopoietic cell transplantation clinical trials. Biology of Blood and Marrow Transplantation. 2012 Feb 1; 18(2):183–189. Epub 2011 Jul 30.

Network publication

PMC3242929

21

Keever-Taylor CA, Devine SM, Soiffer RJ, Mendizabal A, Carter S, Pasquini MC, Hari PN, Stein A, Lazarus HM, Linker C, Goldstein SC, Stadtmauer EA, O'Reilly RJ. Characteristics of CliniMACS(®) System CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia- Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0303. Biology of Blood and Marrow Transplantation. 2012 May 1; 18(5):690-697. Epub 2011 Aug 26.

BMT CTN 0303 PMC3762249

22

Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a Phase 3 biological assignment trial. Lancet Oncology. 2011 Dec 1; 12(13):1195-1203. Epub 2011 Sep 29.


MANUSCRIPT

PMC3611089


167


2012

23

Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, Logan B, Moore T, Panepinto J, Parikh S, Pulsipher MA, Sande J, Schultz KR, Spellman S, Shenoy S. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the Phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of Blood and Marrow Transplantation. 2012 Aug 1; 18(8):1265-1272. Epub 2012 Feb 16.

BMT CTN 0601 PMC3618440

24

Levine J, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ferrara JLM, Ho VT, Weisdorf DJ, Paczesny S. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood. 2012 Apr 19; 119(16):3854-3860. Epub 2012 Mar 1.

BMT CTN 0302 PMC3335389

25

Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty J, Adams R, Ewell M, Leifer E, Gersten I, Carter S, Horowitz MM, Nakamura R, Pulsipher MA, DiFronzo NL, Confer DL, Eapen M, Anderlini P. Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels. Biology of Blood and Marrow Transplantation. 2012 July 1; 18(7):1007-1011. Epub 2012 Apr 27.

BMT CTN 0301 PMC3677744

26

McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Sexton M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. New England Journal of Medicine. 2012 May 10; 366(19):1770-1781.

BMT CTN 0704 / CALGB 100104 /

ECOG 100104 PRIMARY

MANUSCRIPT

PMC3744390

27

Pasquini M, Devine S, Mendizabal A, Baden L, Wingard J, Lazarus H, Appelbaum F, Keever-Taylor C, Horowitz M, Carter S, O’Reilly R, Soiffer R. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graft-versus-host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. Journal of Clinical Oncology. 2012 Sep 10; 30(26):3194-3201. Epub 2012 Aug 6.

BMT CTN 0303 PMC3434978


168


28 Logan BR, Zhang MJ. The use of group sequential designs with common competing risks tests. Statistics in Medicine. 2013 Mar 15; 32(6):899-913. Epub 2012 Sep 4.

Network publication

PMC3574186

29

Foley B, Cooley S, Verneris MR, Curtsinger J, Luo X, Waller EK, Anasetti C, Weisdorf D, Miller JS. Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen. Journal of Immunology. 2012 Nov 15; 189(10):5082-5088. Epub 2012 Oct 17.

BMT CTN 0201 PMC3490031

30

Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Peripheral blood stem cells versus bone marrow from unrelated donors. New England Journal of Medicine. 2012 Oct 18; 367(16):1487-1496.


MANUSCRIPT

PMC3816375

31

Bolaños-Meade J, Wu J, Logan BR, Levine JE, Ho VT, Alousi AM, Weisdorf DJ, Luznik L. Lymphocyte phenotype during therapy for acute graft-versus-host disease: a brief report from BMT-CTN 0302. Biology of Blood and Marrow Transplantation. 2013 Mar 1; 19(3):481-485. Epub 2012 Dec 12.

BMT CTN 0302 PMC3653300

2013

32

Vose JM, Carter S, Burns LJ, Ayala E, Press O, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder RF, Fenske TS, Horowitz MM, Fisher RI, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, melphalan (BEAM) compared with Iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN trial. Journal of Clinical Oncology. 2013 May 1; 31(13):1662-1668. Epub 2013 Mar 11.


MANUSCRIPT

PMC3635682

33

Giralt S, McCarthy PL, Anderson KC, Carter SL, Richardson PG, Rajkumar SV, Laport GG, Stadtmauer EA, Pasquini MC, Horowitz MM. Anatomy of a successful practice-changing study: a Blood and Marrow Transplant Clinical Trials Network-National Cancer Institute Cooperative Group Collaboration. Biology of Blood and Marrow Transplantation. 2013 Jun 01; 19(6)858-859. Epub 2013 Mar 29.

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

N/A


169


34

Mauskopf J, Chirila C, Graham J, Gersten I, Mullins D, Maziarz R, Baden L, Bolaños-Meade J, Brown J, Walsh T, Horowitz M, Kurtzberg J, Marr K and Wingard J. Cost-effectiveness analysis of voriconazole compared With fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants. American Journal Health-System Pharmacy. 2013 Sep 1; 70(17):1518-1527.

BMT CTN 0101 PMC4019750

35

Switzer GE, Bruce JG, Harrington D, Haagenson M, Drexler R, Foley A, Confer D, Bishop M, Anderlini P, Rowley S, Leitman SF, Anasetti C, Wingard JR. Health-related QoL of bone marrow versus PBSC donors: a pre-specified subgroup analysis from a phase III RCT BMT CTN protocol 0201. Biology of Blood and Marrow Transplantation. 2014 Jan 1; 20(1):118-127. Epub 2013 Nov 1.

BMT CTN 0201 PMC3978600

36

Ferrara J. Blood and Marrow Transplant Clinical Trials Network: Progress since the State of the Science Symposium 2007. Biology of Blood and Marrow Transplantation. 2014 Feb 1; 20(2):149-153. Epub 2013 Nov 12.

Network publication

PMC24239651

2014

37

Roth JA, Bensink ME, O’Donnell PV, Fuchs EJ, Eapen M, Ramsey SD. Design of a cost -effectiveness analysis alongside a randomized trial of transplantation using umbilical cord blood versus HLA-haploidentical related bone marrow in advanced hematologic cancer. Journal of Comparative Effectiveness Research. 2014 Mar 1; 3(2):135-144.

BMT CTN 1101 PMC4036637

38

Atallah E, Bylow K, Troy J, Saber W. Treatment of older patients with high-risk myelodysplastic syndromes (MDS): The emerging role of allogeneic hematopoietic stem cell transplantation (Allo HSCT). Current Hematologic Malignancy Reports. 2014 Mar 1; 9(1):57-65.

BMT CTN 1102

PMC4031643

39

Yanik GA, Horowitz MM, Weisdorf DJ, Logan BR, Ho VT, Soiffer RJ, Carter SL, Wu J, Wingard JR, DiFronzo NL, Ferrara JL, Giralt S, Madtes DK, Drexler R, White ES, Cooke KR. Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: Enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome following allogeneic stem cell transplantation: Blood and Marrow Transplant Clinical Trials Network protocol. Biology of Blood and Marrow Transplantation. 2014 Jun 1; 20(6):858-864. Epub 2014 Mar 7.


MANUSCRIPT

PMC4128626


170


40

Eapen M, O’Donnell P, Brunstein C, Wu J, Barowski K, Mendizabal A, Fuchs E. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1485-1492. Epub 2014 May 23.

BMT CTN 0603 / 0604 and

1101

PMC4163123

41

Jacobsen PB, Le-Rademacher J, Jim H, Syrjala K, Wingard JR, Logan B, Wu J, Majhail NS, Wood W, Rizzo JD, Geller NL, Kitko C, Faber E, Abidi MH, Slater S, Horowitz MM, Lee SJ. Exercise and stress management training prior to hematopoietic cell transplantation: Blood and Marrow Transplant Clinical Trial Network (BMT CTN) 0902. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1530-1536. Epub 2014 Jun 6.


MANUSCRIPT

PMC4163109

42

Saber W, Le-Rademacher J, Sekeres M, Logan B, Lewis M, Mendizabal A, Leifer E, Appelbaum F, Horowitz M, Nakamura R, Cutler C. Multicenter biologic assignment trial comparing reduced-intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 study rationale, design, and methods. Biology of Blood and Marrow Transplantation. 2014 Oct 1; 20(10):1566-1572. Epub 2014 Jun 24.

BMT CTN 1102 PMC4169902

43

Waller EK, Logan BR, Harris WA, Devine SM, Porter DL, Mineishi M, McCarty JM, Gonzalez CE, Spitzer TR, Krijanovski OI, Linenberger ML, Woolfrey A, Howard A, Wu J, Confer DL, Anasetti A. Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMT CTN 0201. Journal of Clinical Oncology. 2014 Aug 1; 32(22):2365-2372. Epub 2014 Jun 30.

BMT CTN 0201 PMC4180368

44

Cutler C, Logan B, Nakamura R, Johnston L, Choi S, Porter D, Hogan W, Pasquini M, MacMillan M, Hsu J, Waller E, Grupp S, McCarthy P, Wu J, Hu Z, Carter S, Horowitz M, Antin J. Tacrolimus / sirolimus versus tacrolimus / methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT. Blood. 2014 Aug 21; 124(8):1372-1377. Epub 2014 Jun 30.


MANUSCRIPT

PMC4141519

45

Bolaños-Meade J, Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, Goldstein SC, Hexner EO, Horowitz MM, Lee SJ, Levine JE, MacMillan ML, Martin PJ, Mendizabal AM, Nakamura R, Pasquini MC, Weisdorf DJ, Westervelt P, Ho VT. Phase 3 clinical trial of steroids / mycophenolate mofetil vs steroids / placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014 Nov 20; 124(22):3221-3227. Epub 2014 Aug 28.


MANUSCRIPT

PMC4239331


171


46

Howard A, Fernandez-Vina MA, Appelbaum FR, Confer DL, Devine SM, Horowitz MM, Mendizabal A, Laport GG, Pasquini MC, Spellman SR. Recommendations for donor human leukocyte antigen assessment and matching for allogeneic stem cell transplantation: consensus opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biology of Blood and Marrow Transplantation. 2015 Jan 1; 21(1):4-7. Epub 2014 Sep 30.

Network publication

PMC4272893

47

Appelbaum F, Anasetti C, Antin J, Atkins H, Davies S, Devine S, Giralt S, Heslop H, Laport G, Lee S, Logan B, Pasquini M, Pulsipher M, Stadtmauer E, Wingard J, Horowitz M. Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2014. Biology of Blood and Marrow Transplantation. 2015 Feb 1; 21(2):202-224. Epub 2014 Oct 15.

Network publication

PMC4426907

48

Wagner JE Jr, Eapen M, Carter S, Wang Y, Schultz KR, Wall DA, Bunin N, Delaney C, Haut P, Margolis D, Peres E, Verneris MR, Walters M, Horowitz MM, Kurtzberg J. One-unit versus two-unit cord-blood transplant for hematologic cancers. New England Journal of Medicine. 2014 Oct 30; 371(18):1685-1694.


MANUSCRIPT

PMC4257059

49

Levine JE , Braun TM, Harris AC, Holler E, Taylor A, Miller H, Magenau J, Weisdorf DJ, Ho VT, Bolaños-Meade J, Alousi AM, Ferrara JL, Blood and Marrow Transplant Clinical Trials Network. A prognostic score for acute graft-versus-host disease based on biomarkers: A multicentre study. Lancet Haematology. 2015 Jan 1; 2(1):e21-29. Epub 2014 Dec 23.

BMT CTN 0302 PMC4340092

2015

50

MacMillan ML, Robin M, Harris AC, DeFor TE, Martin PJ, Alousi A, Ho VT, Bolaños-Meade J, Ferrara JLM, Jones R, Arora M, Blazar, BR, Holtan SG, Jacobsohn D, Pasquini M, Socie G, Antin JH, Levine JE, Weisdorf DJ. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biology of Blood and Marrow Transplantation. 2015 Apr 1; 21(4):761-767. Epub 2015 Jan 10.

BMT CTN 0302 and 0802

PMC4359643

51

Holtan SG, Verneris MR, Schultz KR, Newell LF, Meyers G, He F, DeFor TE, Vercellotti GM, Slungaard A, MacMillan ML, Cooley SA, Blazar BR, Panoskaltsis-Mortari A, Weisdorf DJ. Circulating angiogenic factors associated with response and survival in patients with acute graft-versus-host disease: Results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802. Biology of Blood and Marrow Transplantation. 2015 Jun 1; 21(6):1029-1036. Epub 2015 Mar 7.


PMC4426052


172


52

Khera N, Majhail NS, Brazauskas R, Wang Z, He N, Aljurf MD, Akpek G, Atsuta Y, Beattie S, Bredeson CN, Burns LJ, Dalal JD, Freytes CO, Gupta V, Inamoto Y, Lazarus HM, LeMaistre CF, Steinberg A, Szwajcer D, Wingard JR, Wirk B, Wood WA, Joffe S, Hahn TE, Loberiza FR, Anasetti C, Horowitz MM, Lee SJ. Comparison of characteristics and outcomes of trial participants and nonparticipants: Example of Blood and Marrow Transplant Clinical Trials Network 0201 trial. Biology of Blood and Marrow Transplantation. 2015 Oct 1; 21(10):1815-1822. Epub 2015 Jun 11.

BMT CTN 0201 PMC4568172 (Available

October 1, 2016)

53

Anderlini P, Wu J, Gersten I, Ewell M, Tolar J, Antin JH, Adams R, Arai S, Eames G, Horwitz ME, McCarty J, Nakamura R, Pulsipher MA, Rowley S, Leifer E, Carter SL, DiFronzo NL, Horowitz MM, Confer D, Deeg HJ, Eapen M. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Lancet Haematology. 2015 Sep 1; 2(9):e367-375. Epub 2015 Sep 2.


MANUSCRIPT

PMID 26685770 (PubMed – In

Process)

54

Young JH, Logan BR, Wu J, Wingard JR, Weisdorf DJ, Mudrick C, Knust K, Horowitz MM, Confer DL, Dubberke ER, Pergam SA, Marty FM, Strasfeld LM, Brown JWM, Langston AA , Schuster MG, Kaul DR, Martin SI, Anasetti C, Blood and Marrow Transplant Clinical Trials Network Trial 0201. Infections after transplantation of bone marrow or peripheral-blood stem cells from unrelated donors. Biology of Blood and Marrow Transplantation. 2016 Feb 1; 22(2):359-370. Epub 2015 Sep 25.


February 1, 2017)

55

Giralt S, Garderet L, Durie B, Cook G, Gahrton G, Bruno B, Hari P, Lokhorst H, McCarthy P, Krishnan A, Sonneveld P, Goldschmidt H, Jagannath S, Barlogie B, Mateos M, Gimsing P, Sezer O, Mikhael J, Lu J, Dimopoulos M, Mazumder A, Palumbo A, Abonour R, Anderson K, Attal M, Blade J, Bird J, Cavo M, Comenzo R, de la Rubia J, Einsele H, Garcia-Sanz R, Hillengass J, Holstein S, Johnsen HE, Joshua D, Koehne G, Kumar S, Kyle R, Leleu X, Lonial S, Ludwig H, Nahi H, Nooka A, Orlowski R, Rajkumar V, Reiman A, Richardson P, Riva E, San Miguel J, Turreson I, Usmani S, Vesole D, Bensinger W, Qazilbash M, Efebera Y, Mohty M, Gasparreto C, Gajewski J, LeMaistre CF, Bredeson C, Moreau P, Pasquini M, Kroeger N, Stadtmauer E. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biology of Blood and Marrow Transplantation. 2015 Dec 1; 21(12):2039-2051. Epub 2015 Sep 30.

Network publication

PMC4757494


173


56

Wood WA, Le-Rademacher J, Syrjala KL, Jim H, Jacobsen PB, Knight JM, Abidi MH, Wingard JR, Majhail NS, Geller NL, Rizzo JD, Fei M, Wu J, Horowitz MM, Lee SJ. Patient-reported physical functioning predicts the success of hematopoietic cell transplantation (BMT CTN 0902). Cancer. 2016 Jan 1; 122(1):91-98. Epub 2015 Oct 6.


January 1, 2017)

57

Devine SM, Owzar K, Blum W, Mulkey F, Stone RM, Hsu JW, Champlin RE, Chen YB, Vij R, Slack J, Soiffer RJ, Larson RA, Shea TC, Hars V, Sibley AB, Giralt S, Carter S, Horowitz MM, Linker C, Alyea EP. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: Results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology) / Blood and Marrow Transplant Clinical Trial Network 0502. Journal of Clinical Oncology. 2015 Dec 10; 33(35):4167-4175. Epub 2015 Nov 2.

CALGB 100103 / BMT CTN 0502

PMC4658453

2016

58

Burns LJ, Logan BR, Chitphakdithai P, Miller JP, Drexler R, Spellman S, Switzer GE, Wingard JR, Anasetti C, Confer DL, Blood and Marrow Transplant Clinical Trials Network. Recovery of unrelated donors of peripheral blood stem cells versus recovery of unrelated donors of bone marrow: A prespecified analysis from the Phase III Blood and Marrow Transplant Clinical Trials Network protocol 0201. Biology of Blood and Marrow Transplantation. 2016 Jun 1; 22(6):1108-1116. Epub 2016 Mar 21.

BMT CTN 0201 PMID 27013014 (PubMed – In

Process)

59

Hope W, Walsh T, Goodwin J, Peloquin C, Howard A, Kurtzberg J, Mendizabal A, Confer D, Bulitta J, Baden L, Neely M, Wingard J. Voriconazole pharmacokinetics following hematopoietic stem cell transplantation: Results from the BMT CTN 0101 trial. Journal of Antimicrobial Chemotherapy. [In Press].

BMT CTN 0101 Not yet available

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment B2: Presentations

174

Attachment B2: Presentations by Year

Number Presentation Protocol Number

2007

1 Pasquini M, Ewell M, Stadtmauer E, Bredeson C, Alyea E, Stockerl-Goldstein K, Krishnan A, Sahebi F, Rowley S, Maloney D, Vesole D, Horowitz M, Carter S, Geller N, Giralt S. Biologic assignment clinical trials in hematopoietic stem cell transplantation (HSCT) for multiple myeloma: baseline characteristics by treatment allocation from BMT CTN 0102 according to availability of an HLA-matched sibling donor. Poster presentation: 49th ASH Annual Meeting, Atlanta, GA, December 2007

BMT CTN 0102

2 Wingard J, Carter S, Walsh T, Kurtzberg J, Small T, Gersten I, Mendizabal A, Leather H, Confer D, Baden L, Maziarz R, Stadtmauer E, Bolaños-Meade J, Brown J, DiPersio J, Boeckh M, Marr K. Results of a randomized, double-blind trial of fluconazole (FLU) vs. voriconazole (VORI) for the prevention of invasive fungal infections (IFI) in 600 allogeneic blood and marrow transplant (BMT) patients. Oral presentation: 49th ASH Annual Meeting, Atlanta, GA, December 2007

BMT CTN 0101

2008

3 Laport G, Bredeson C, Tomblyn MR, Kahl BS, Goodman SA, Ewell M, Klein J, Horowitz MM, Vose JM, Negrin RS. Autologous versus reduced-intensity allogeneic hematopoietic cell transplantation for patients with follicular non-Hodgkin lymphoma (FL) beyond first complete response or first partial response. Oral presentation: ASCO Annual Meeting, Chicago, IL, May-June, 2008

BMT CTN 0202

4 Alousi A, Weisdorf D, Logan B, Bolaños-Meade J, Goldstein S, Ho V, Hayes-Lattin B, Wingard J, Horowitz M, Levine J. BMT CTN 0302: A Phase II randomized trial evaluating etanercept, mycophenolate mofetil (MMF), denileukin diftitox, and pentostatin in combination with corticosteroids in 180 patients (pts) with newly diagnosed acute graft vs. host disease (aGVHD). Oral presentation: 50th ASH Annual Meeting, San Francisco, CA, December 2008

BMT CTN 0302

2009

5 Devine S, Soiffer R, Pasquini M, Carter S, Hari P, Devore S, Stein A, Lazarus H, Linker C, Stadtmauer E, Keever-Taylor C, O’Reilly R. HLA-identical sibling-matched, CD34+ selected, T cell depleted peripheral blood stem cells following myeloablative conditioning for first or second remission acute myeloid leukemia (AML): Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303. Oral presentation: 51st ASH Annual Meeting, New Orleans, LA, December 2009

BMT CTN 0303


175


2010

6 Pasquini M, Devine S, Mendizabal A, Baden L, Wingard J, Lazarus H, Appelbaum F, Keever-Taylor C, O'Reilly R and Soiffer R. Comparative effectiveness analysis of CD34+ selected, T cell depleted (TCD) HLA-matched sibling grafts on allogeneic hematopoietic cell transplantation for patients with acute myeloid leukemia (AML) in complete remission. Poster presentation: BMT Tandem Meetings, Orlando, FL, February 2010

BMT CTN 0303

7 Gurgol C, Foley A, Belt P, Denzen E, Duffy S, Gallagher C, Grodman C, Horowitz M, Confer D, Carter S, on behalf of the BMT CTN Sponsored by NHLBI and NCI. Developing materials for transplant centers to share BMT CTN clinical trial results with their patients, a pilot study. Poster presentation: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010

Network abstract

8 Foley A, Horowitz M, Confer D, Carter S on behalf of the BMT CTN, sponsored by NHLBI and NCI. Development of an accrual assessment tool for BMT CTN transplant trials, a proactive approach. Poster presentation: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010

Network abstract

9 Pasquini M, Foley A, Carter S, Confer D, Horowitz M, Gurgol C, Giralt S, Schilsky R, McCarthy P on behalf of the Cancer and Leukemia Group B and the Blood and Marrow Transplant Clinical Trial Network. Maximizing accrual to transplant trials in multiple myeloma (MM), lessons from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), Eastern Cooperative Oncology Group (ECOG), and Cancer and Leukemia Group B (CALGB) collaboration. Poster presentation: NCI ASCO Cancer Trials Accrual Symposium, Bethesda, MD, April 2010

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

10 Keever-Taylor C, Devine SM, Soiffer RJ, Carter SL, Pasquini MC, Hari P, Stein A, Lazarus HM, Linker C, Goldstein S, O’Reilly RJ on behalf of the BMT CTN. Characteristics of CD34-enriched products processed at multiple centers using the CliniMacs System - BMT CTN 0303. Oral presentation: 16th Annual International Society for Cellular Therapy Meeting, Philadelphia, PA, May 2010

BMT CTN 0303

11 McCarthy PL, Owzar K, Anderson KC, Hofmeister CC, Hassoun H, Hurd DD, Stadtmauer EA, Giralt S, Hars V, Linker CA. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104. Oral presentation: ASCO Annual Meeting, Chicago, IL, June 2010

BMT CTN 0704 / CALGB 100104 /

ECOG 100104


176


12 McCarthy PL, Owzar K, Anderson K, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Richardson PG, Weisdorf DJ, Vij R, Moreb JS, Callander N, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Hars V, Postiglione J, Jiang C, Bennett E, Barry SS, Bressler L, Kelly M, Sexton M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous hematopoietic stem cell transplantation (AHSCT) for multiple myeloma: CALGB 100104. Oral presentation: 52nd ASH Annual Meeting, Orlando, FL, December 2010

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

13 Krishnan A, Pasquini MC, Ewell M, Stadtmauer EA, Alyea EP, Antin JA, Comenzo RL, Goodman S, Hari P, Negrin R, Qazilbash MH, Rowley SD, Sahebi F, Somlo G, Vesole DH, Vogl DT, Weisdorf DJ, Geller N, Horowitz MM, Giralt S and Maloney DG. Tandem autologous hematopoietic stem cell transplants (AuHCT) with or without maintenance therapy (auto-auto) versus single AuHCT followed by HLA matched sibling non-myeloablative allogeneic HCT (auto-allo) for patients with standard risk (SR) multiple myeloma (MM): results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 trial. Oral presentation: 52nd ASH Annual Meeting, Orlando, FL, December 2010

BMT CTN 0102

14 Stadtmauer EA, Krishnan A, Pasquini MC, Ewell M, Alyea EP, Antin JH, Castro-Malaspina H, Kassim AA, Negrin R, Qazilbash MH, Rizzo JD, Rowley SD, Sahebi F, Somlo G, Vesole DH, Vogl DT, Weisdorf DJ, Geller N, Horowitz MM, Maloney DG, Giralt S. Tandem autologous stem cell transplants (auto-auto) with or without maintenance therapy versus single autologous transplant followed by HLA-matched sibling non-myeloablative allogeneic stem cell transplant (auto-allo) for patients (pts) with high risk (HR) multiple myeloma: Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial. Oral presentation: 52nd ASH Annual Meeting, Orlando, FL, December 2010

BMT CTN 0102

15 Switzer GE, Harrington D, Haagenson MD, Drexler R, Foley A, Confer DL, Bishop M, Anderlini P, Rowley SD, Leitman S, Anasetti C, Wingard Jr. Health-related quality-of-life among adult unrelated stem cell donors: a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) randomized trial of marrow versus PBSC donation. Oral presentation: 52nd ASH Annual Meeting, Orlando, FL, December 2010

BMT CTN 0201

2011

16 Fuchs EJ, Wu J, Carter S, Brunstein C, Costa L, Wingard J, Jagasia M, D’Elia J, Eapen M, O’Donnell PV. Phase II trial of non-myeloablative conditioning and partially HLA-mismatched (HLA-haploidentical) bone marrow transplantation (BMT) for patients with hematologic malignancies: results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0603. Oral presentation: BMT Tandem Meetings, Honolulu, HI, February 2011 *Received a Best Abstract Award

BMT CTN 0603


177


17 Brunstein CG, Carter S, Fuchs EJ, Karanes C, Devine S, Cutler C, Ballen KK, Thompson J, O'Donnell PV, Eapen M. Phase II trial of non-myeloablative conditioning (NST) double umbilical cord blood transplantation (DUCBT) from unrelated donors in patients with hematologic malignancies: results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0604. Oral presentation: BMT Tandem Meetings, Honolulu, HI, February 2011 *Received a Best Abstract Award

BMT CTN 0604

18 Levine JE, Logan BR, Wu J, Alousi AM, Bolaños-Meade J, Ho VT, Weisdorf DJ, Paczesny S. GVHD biomarkers measured during treatment independently predict response to therapy and survival: a Blood and Marrow Transplant Clinical Trials Network study. Oral presentation: 37th Annual EBMT Congress, Paris, France, April 2011

BMT CTN 0302

19 McCarthy P, Owzar K, Anderson K, Hofmeister C, Richardson P, Hassoun H, Stadtmauer E, Giralt S, Hurd D, Hars V, Jiang C, Postiglione J, Bressler L, Devine S, Linker C. Phase III intergroup study of lenalidomide versus placebo maintenance therapy following single autologous stem cell transplant (ASCT) for multiple myeloma (MM): CALGB 100104 / ECOG 100104. Oral presentation: 13th International Myeloma Workshop, Paris, France, May 2011

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

20 Krishnan A, Pasquini M, Logan B, Stadtmauer EA, Alyea III E, Antin J, Comenzo R, Goodman S, Hari P, Negrin R, Qazilbash M, Rowley S, Sahebi F, Somlo G, Vesole D, Vogl D, Weisdorf D, Wu J, Geller N, Horowitz MM, Giralt S, and Maloney D. Tandem autologous HCT (auto-auto) versus single autologous HCT followed by HLA matched sibling non-myeloablative allogeneic HCT (auto-allo) for patients with standard risk multiple myeloma: results from the BMT-CTN 0102 trial. Poster presentation: 13th International Myeloma Workshop, Paris, France, May 2011

BMT CTN 0102

21 Hari P, Pasquini M, Logan B, Stadtmauer E, Krishnan A, Howard A, Alvi S, Harding S, Carter S, Rajkumar V, Alyea E, Qazilbash M, Laport G, Maloney D, Giralt S, Vesole D. Immunoglobulin free light chain (FLC) and heavy chain/light chain (HLC) assays – comparison with electrophoretic responses in multiple myeloma (MM). Poster presentation: 53rd ASH Annual Meeting, San Diego, CA, December 2011

BMT CTN 0102

22 Anasetti C, Logan B, Lee SJ, Waller EK, Weisdorf D, Wingard JR, Cutler C, Westervelt P, Woolfrey A, Couban S, Johnston L, Maziarz R, Pulsipher M, Anderlini P, Bensinger W, Leitman S, Rowley SD, Carter SL, Horowitz MM, Confer DL. Increased incidence of chronic graft-versus-host disease (GVHD) and no survival advantage with filgrastim-mobilized peripheral blood stem cells (PBSC) compared to bone marrow (BM) transplants from unrelated donors: Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0201, a Phase III, prospective, randomized trial. Oral presentation (plenary session): 53rd ASH Annual Meeting, San Diego, CA, December 2011

BMT CTN 0201


178


23 Waller EK, Harris WAC, Devine S, Porter DL, Mineishi S, McCarty JM, Gonzalez CE, Spitzer TR, Krijanovski OI, Linenberger ML, Woolfrey A, Howard A, Gurgol C, Logan BR, Confer DL, Anasetti C. Larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from unrelated donors are associated with improved survival: results from BMT CTN 0201. Oral presentation: 53rd ASH Annual Meeting, San Diego, CA, December 2011

BMT CTN 0201

24 Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty J, Adams R, Eapen M, Ewell M, Leifer E, Gersten I, Carter SL, Horowitz MM, Confer D, Nakamura R, Pulsipher MA, DiFronzo N, Anderlini P. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in severe aplastic anemia (SAA): serious and unexpected adverse events in pre-defined cyclophosphamide (CY) dose levels. Poster presentation: 53rd ASH Annual Meeting, San Diego, CA, December 2011

BMT CTN 0301

25 Vose JM, Carter SL, Burns L , Ayala E, Press O, Moskowitz C, Stadtmauer E, Mineshi S, Ambinder R, Fenske T, Horowitz M, Tomblyn M. Randomized Phase III trial of 131Iodine-Tositumomab (Bexxar)/Carmustine, Etoposide, Cytarabine, Melphalan (BEAM) versus Rituximab/BEAM and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma (DLBCL): no difference in progression-free (PFS) or overall survival (OS). Oral presentation: 53rd ASH Annual Meeting, San Diego, CA, December 2011

BMT CTN 0401

26 Spellecy R, Denzen E, Burton Santibáñez M, Moore H, Foley A, Gersten I, Gurgol C, Horowitz M, Majhail N, Murphy E. Informed consent: improving the form and the process. Oral presentation: Public Responsibility in Medicine and Research, National Harbor, MD, November-December 2011

Network abstract

2012

27 Waller EK, Harris WA, Devine S, Porter DL, Ferrara J, McCarty JM, Gonzalez CE, Spitzer TR, Krijanovski OI, Howard A, Gurgol C, Logan BR, Confer DL, Anasetti C. Grade III-IV acute GVHD and treatment-related mortality are reduced among recipients of larger numbers of donor naïve CD8+ T-cells and plasmacytoid dendritic cell precursors in allogeneic BM grafts from unrelated donors: results from BMT CTN 0201. Oral presentation: 38th Annual EBMT Congress, Geneva, Switzerland, April 2012

BMT CTN 0201

28 Anderlini P, Tolar J, Deeg HJ, Arai S, Horwitz M, Antin JH, McCarty JM, Adams RH, Ewell M, Leifer E, Gersten I, Carter SL, Horowitz MM, Confer DL, Nakamura R, Pulsipher M, DiFronzo NL, Eapen M. Fludarabine-based conditioning for allogeneic marrow transplantation from unrelated donors in severe aplastic anaemia: serious and unexpected adverse events in pre-defined cyclophosphamide dose levels. Poster presentation: 38th Annual EBMT Congress, Geneva, Switzerland, April 2012

BMT CTN 0301

29 Crann ME, Mendizabal AM, Gersten ID, and Carter SL. Adverse event reporting for hematopoietic cell transplantation. Poster presentation: Society for Clinical Trials Annual Meeting, Miami, FL, May 2012

Network abstract


179


30 Anasetti C, Logan B, Lee SJ, Waller EK, Weisdorf D, Wingard JR, Cutler C, Westervelt P, Woolfrey A, Couban S, Johnston L, Maziarz R, Pulsipher M, Anderlini P, Bensinger W, Leitman S, Rowley SD, Carter SL, Horowitz MM, Confer DL. Increased incidence of chronic graft-versus-host disease (GVHD) and no survival advantage with filgrastim-mobilized peripheral blood stem cells (PBSC) compared to bone marrow transplants from unrelated donors: results of Blood and Marrow Transplant Clinical Trials Network protocol #0201, a Phase III, prospective, randomized trial. Oral presentation: ASCO Annual Meeting (ASCO/ASH Joint Session), Chicago, IL, June 2012

BMT CTN 0201

31 Cutler C, Logan BR, Nakamura R, Johnston L, Choi SW, Porter DL, Hogan WJ, Pasquini MC, MacMillan ML, Wingard JR, Waller EK, Grupp SA, McCarthy PL, Wu J, Hu Z, Carter SL, Horowitz MM, Antin JH. Tacrolimus/sirolimus vs. tacrolimus/methotrexate for graft-vs.-host disease prophylaxis after HLA-matched, related donor hematopoietic stem cell transplantation: results of Bone Marrow Transplant Clinical Trials Network 0402. Oral presentation: 54th ASH Annual Meeting, Atlanta, GA, December 2012

BMT CTN 0402

32 Wagner JE, Eapen M, Carter SL, Haut P, Peres E, Schultz K, Thompson J, Wall D, Kurtzberg J. No survival advantage after double umbilical cord blood (UCB) compared to single UCB transplant in children with hematological malignancy: results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501) randomized trial. Oral presentation: 54th ASH Annual Meeting, Atlanta, GA, December 2012

BMT CTN 0501

33 Devine SM, Owzar K, Blum W, DeAngelo DJ, Stone RM, Hsu JW, Champlin R, Chen YA, Vij R, Slack JL, Soiffer RJ, Larson RA, Shea TC, Hars V, Bennett E, Spangle S, Giralt SA, Carter SL, Horowitz MM, Linker C, Alyea EP. A Phase II study of allogeneic transplantation for older patients with AML in first complete remission using a reduced intensity conditioning regimen: results from CALGB 100103/BMT CTN 0502. Oral presentation: 54th ASH Annual Meeting, Atlanta, GA, December 2012


2013

34 Yanik D, Ho VT, Horowitz MM, Weisdorf DJ, Logan BR, Wu J, Soiffer RJ, Wingard JR, Levine JE, Ferrara JL, Giralt SA, White E, Carter SL, DiFronzo N, Cooke KR. Randomized, double blind, placebo-controlled trial of a TNF inhibitor (etanercept) for the treatment of idiopathic pneumonia syndrome (IPS) after allogeneic stem cell transplant (SCT), a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) study. Oral presentation: BMT Tandem Meetings, Salt Lake City, UT, February 2013

BMT CTN 0403

35 Kurtzberg J, Carter SL, Mendizabal A, Wall DA, Schultz KR, Kernan NA, Eapen M, Wagner JE. Superior survival after single unit umbilical cord blood transplantation (UCBT) in children with hematological malignancies treated on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0501 relative to the cord blood transplantation (COBLT). Oral presentation: BMT Tandem Meetings, Salt Lake City, UT, February 2013

BMT CTN 0501


180


36 Bolaños-Meade J , Logan BR, Alousi AM, Antin JH, Barowski K, Carter SL, Hexner EO, Horowitz MM, Levine JE, MacMillan ML, Martin PJ, Nakamura R, Pasquini MC, Weisdorf DJ, Westervelt P, Ho VT. A multi-center, randomized, double blind, Phase III clinical trial comparing steroids/placebo vs. steroids/mycophenolate mofetil as initial therapy for acute graft-versus-host disease, Blood and Marrow Transplant Clinical Trials Network Study 0802. Oral presentation: BMT Tandem Meetings, Salt Lake City, UT, February 2013

BMT CTN 0802

37 McCarthy P, Owzar K, Hofmeister C, Richardson P, Hassoun H, Stadtmauer E, Giralt S, Hurd D, Qazilbash M, McClune B, Pasquini M, Hars V, Jiang C, Postiglione J, Kelly M, Bressler L, Devine S, Anderson K, Linker C. Analysis of overall survival (OS) in the context of cross-over from placebo to lenalidomide and the incidence of second primary malignancies (SPM) in the Phase III study of lenalidomide versus placebo maintenance therapy following autologous stem cell transplant (ASCT) for multiple myeloma (MM), CALGB (Alliance) ECOG, BMT CTN 100104. Oral presentation: 14th International Myeloma Workshop, Kyoto, Japan, April 2013

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

38 Lee SJ, Le-Rademacher JL, Jim H, Syrjala KL, Wingard JL, Logan BR, Wu J, Majhail NS, Wood WA, Rizzo JD, Geller NL, Kitko CL, Faber Jr. EA, Abidi MH, Slater SE, Horowitz MM, Jacobsen P. Exercise and stress management training for patients undergoing autologous or allogeneic hematopoietic cell transplantation. Results from Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902. Oral presentation: 55th ASH Annual Meeting, New Orleans, LA, December 2013

BMT CTN 0902

2014

39 Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller H, Magenau J, Weisdorf DJ, Ho VT, Bolaños-Meade J, Alousi AM, Ferrara JL. A new Ann Arbor grading system uses biomarkers to risk stratify patients for non relapse mortality at the onset of acute graft versus host disease. Oral presentation: 40th EBMT Congress, Milan, Italy, March-April 2014


40 Mendizabal AM, Pasquini MC, Logan BR, Gersten ID, DiFronzo NL, Wagner EL, Merritt WD, Wu RS, Confer DL, Horowitz MM. Leveraging resources to design, conduct, and analyze hematopoietic stem cell transplant clinical trials: the ongoing collaboration between the Center for International Blood and Marrow Transplant Research and the Blood and Marrow Transplant Clinical Trials Network. Oral presentation: Society for Clinical Trials 35th Annual Meeting, Philadelphia, PA, May 2014

Network abstract

41 Hope WW, Walsh TJ, Goodwin J, Neely M, Peloquin C, Howard A, Kurtzberg J, Mendizabal A, Confer D, Bulitta J, Neely M, Baden L, Wingard J. Relationship between voriconazole concentrations and the probability of breakthrough fungal infections. Poster presentation: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, September 2014

BMT CTN 0101


181


42 Anderlini P, Wu J, Deeg J, Gersten I, Ewell M, Tolar J, Antin JH, Arai S, Horwitz ME, McCarty JM, Nakamura R, Pulsipher MA, Adams RH, Leifer E, Carter SL, DiFronzo NL, Horowitz MM, Confer DL, Eapen M. Optimized cyclophosphamide (CY) dosing in combination with fludarabine, TBI and ATG as conditioning for unrelated donor bone marrow transplantation (BMT) in severe aplastic anemia (SAA): A Phase I/II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Oral presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014

BMT CTN 0301

43 Holtan SG, Verneris MR, Schultz KR, Newell L, Meyers G, He FC, DeFor TE, MacMillan ML, Cooley SA, Panoskaltsis-Mortari A, Weisdorf DJ. Circulating angiogenic factors as biomarkers of acute GVHD onset and response to therapy: repair and regeneration versus endothelial damage and inflammation. Poster presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014


44 Levine JE, Braun TM, Harris AC, Holler E, Taylor A, Miller HK, Magenau JM, Weisdorf DJ, Ho VT, Bolaños-Meade J, Alousi AM, Ferrara JL. A biomarker algorithm defines onset grades of acute graft-vs-host disease with distinct non-relapse mortality. Oral presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014


45 Laport GG, Wu J, Logan BR, Bachanova V, Hosing CM, Fenske TS, Longo WL, Devine SM, Nademanee AP, Gersten I, Horowitz MM, Lazarus HM, Riches ML. Reduced intensity conditioning (RIC) with rituximab yields excellent outcomes after allogeneic hematopoietic cell transplantation (alloHCT) for relapsed follicular lymphoma (FL): A Phase II multicenter trial from the Blood and Marrow Transplant Network (BMT CTN 0701). Oral presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014

BMT CTN 0701

46 Smith EP, Li H, Friedberg JW, Constine L, Rimsza LM, Laport GG, Popplewell LL, Maloney DG, Leblanc M, Forman SJ, Fisher RI, Stiff PJ. SWOG S0410 / BMT CTN 0703: A Phase II trial of tandem autologous stem cell transplantation (AHCT) for patients with primary progressive or recurrent Hodgkin lymphoma (HL). Oral presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014

BMT CTN 0703

47 Alvarnas J, Le-Rademacher J, Wang Y, Little RF, Akpek G, Ayala E, Devine S, Kaplan L, Noy A, Popat U, Thompson J, Horowitz MM, Mendizabal A, Navarro WH, Ambinder R.

Autologous hematopoietic stem cell transplantation (AHCT) in patients with chemotherapy-sensitive, relapsed / refractory (CSRR) human immunodeficiency virus (HIV)-associated lymphoma (HAL): Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803) / AIDS Malignancy Consortium (AMC-071) trial. Oral presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014

BMT CTN 0803

48 Wood WA, Le-Rademacher J, Fei M, Logan BR, Syrjala KL, Majhail NS, Wingard JR, Abidi MH, Geller NL, Wu J, Rizzo JD, Faber Jr EA., Jim H, Jacobsen P, Horowitz MM, Lee SJ.

Patient-reported quality of life is an independent predictor of survival after allogeneic hematopoietic cell transplantation: A secondary analysis from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902. Oral presentation: 56th ASH Annual Meeting, San Francisco, CA, December 2014

BMT CTN 0902


182


2015

49 Holtan S, Verneris MR, Schultz KR, Newell LF, Meyers G, He F, DeFor TE, MacMillan ML, Cooley S, Blazar BR, Panoskaltsis-Mortari A, Weisdorf DJ. Prognostic impact of follistatin in acute graft-versus-host disease: Results from BMT CTN 0302 and 0802. Oral presentation: BMT Tandem Meetings, San Diego, CA, February 2015


50 Young JH, Logan BR, Wu J, Wingard JR, Weisdorf DJ, Mudrick C, Knust K, Horowitz MM, Confer DL, Anasetti C. More infections with transplantation of bone marrow, versus peripheral-blood stem cells, from unrelated donors. Oral presentation: BMT Tandem Meetings, San Diego, CA, February 2015

BMT CTN 0201

51 Moore HK, Denzen EM, Idossa L, Murphy EA, Foley A, Gersten ID, Majhail NS, Spellecy R, Horowitz MM. Easy-to-read informed consent (ETRIC) forms for multi-center hematopoietic cell transplant clinical trials (BMT CTN 1205). Poster presentation: Institute for Healthcare Advancement’s 14th Annual Health Literacy Conference, Irvine, California, May 2015

BMT CTN 1205

52 Holstein SA, Owzar K, Richardson PG, Jiang C, Hofmeister CC, Hassoun H, Hurd DD, Stadtmauer EA, Giralt S, Devine SM, Hars V, Postiglione JR, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Martin TG, Shea TC, Anderson KC, McCarthy PL. Updated analysis of CALGB / ECOG / BMT CTN 100104: Lenalidomide (Len) vs. placebo (PBO) maintenance therapy after single autologous stem cell transplant (ASCT) for multiple myeloma (MM). Poster presentation: ASCO Annual Meeting, Chicago, IL, May-June 2015

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

53 D'Souza A, Pasquini MC, Logan BR, Giralt SA, Krishnan A, Antin J, Howard A, Horowitz MM, Goodman S, Laport GG, Qazilbash M, Mendizabal AM, Sahebi F, Weisdorf D, Vesole D, Stadtmauer EA, Maloney D, Hari P. Heavy light chain ratio normalization allows identification of electrophoretic non-complete response patients with improved outcomes: A long term follow up update for BMT CTN 0102 correlative study. Poster presentation: 20th Congress of European Hematology Association, Vienna, Austria, June 2015

BMT CTN 0102

54 Knight JM, Martens M, Syrjala KL, Le-Rademacher J, Logan BR, Lee SJ, Jacobsen PB, Wood WA, Jim H, Wingard JR, Horowitz MM, Majhail NS, Abidi MH, Geller NL, Fei M, Wu J, Rizzo JD. Pre-transplant health-related quality of life factors as predictors of outcomes following hematopoietic cell transplantation: A study from the BMT CTN 0902 trial. Oral presentation: IPOS / APOS World Congress on Psycho-Oncology, Washington DC, July-August 2015

BMT CTN 0902

55 Syrjala KL, Sutton SK, Yi JC, Jim H, Knight JM, Wood WA, Jacobsen PB, Majhail NS, Abidi MH, Wingard JR, Horowitz MM, Rizzo JD, Le-Rademacher J, Wu J, Lee SJ. Cancer and treatment distress measurement over time in a multicenter cohort of hematopoietic cell transplantation (HCT) recipients. Oral presentation: IPOS / APOS World Congress on Psycho-Oncology, Washington DC, July-August 2015

BMT CTN 0902


183


56 Holstein SA., Owzar K, Richardson PG, Jiang C, Hofmeister CC, Hassoun H, Hurd DD, Stadtmauer EA, Giralt S, Devine SM, Hars V, Postiglione JR, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Pasquini MC, Martin TG, Shea TC, Anderson KC, McCarthy PL. Analysis of second primary malignancies (SPMs) in CALGB (Alliance) / ECOG / BMT CTN 100104. Poster presentation: 15th International Myeloma Workshop, Rome, Italy, September 2015

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

57 Scott BL, Pasquini MC, Logan BR, Wu J, Devine S, Porter DL, Maziarz RT, Warlick E, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt SA, Leifer E, Geller N, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Results of a Phase III randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Oral presentation: 57th ASH Annual Meeting, Orlando, FL, December 2015 * Late Breaking Abstract

BMT CTN 0901

58 Ravandi F, Othus M, O'Brien S, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. Multi-center US intergroup study of intensive chemotherapy plus dasatinib followed by allogeneic stem cell transplant in patients with Philadelphia chromosome positive acute lymphoblastic leukemia younger than 60. Oral presentation: 57th ASH Annual Meeting, Orlando, FL, December 2015

BMT CTN 0805

59 Shenoy S, Eapen M, Wu J, Walters MC, Levine JE, Logan BR, Gersten ID, Kamani NR. A multicenter Phase II trial of unrelated donor reduced intensity bone marrow transplantation for children with severe sickle cell disease (SCURT): Results of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0601) study. Oral presentation: 57th ASH Annual Meeting, Orlando, FL, December 2015

BMT CTN 0601

60 Lee SJ, Logan BR, Westervelt P, Cutler CS, Woolfrey AE, Khan S, Waller EK, Maziarz RT, Wu J, Shaw BE, Confer DL, Horowitz MM, Anasetti C. 5 year results of BMT CTN 0201: Unrelated donor bone marrow is associated with better psychological well-being and less burdensome chronic GVHD symptoms than peripheral blood. Oral presentation: 57th ASH Annual Meeting, Orlando, FL, December 2015

BMT CTN 0201

2016

61 Carpenter PA, Logan BR, Lee SJ, Weisdorf DJ, Johnston L, Costa LJ, Kitko CL, Bolanos-Meade J, Alousi AM, Horowitz MM, Abhyankar S, Waller EK, Mendizabal A, Wang Y, Lazaryan A, Carter SL, Nemecek ER, Pavletic SZ, Cutler CS, Arora M. Prednisone (PDN) / sirolimus (SRL) compared to PDN / SRL / calcineurin inhibitor (CNI) as treatment for chronic graft-versus-host-disease (cGVHD): A randomized Phase II study from the Blood and Marrow Transplant Clinical Trials Network. Oral presentation: BMT Tandem Meetings, Honolulu, HI, February 2016

BMT CTN 0801


184


62 Scott BL, Pasquini MC, Logan BR, Wu J, Devine S, Porter DL, Maziarz RT, Warlick E, Fernandez HF, Alyea EP, Hamadani M, Bashey A, Giralt SA, Leifer E, Geller N, Le-Rademacher J, Mendizabal AM, Horowitz MM, Deeg HJ, Horwitz ME. Results of a Phase III randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Oral presentation: BMT Tandem Meetings, Honolulu, HI, February 2016 * Special Invited Abstract: BMT CTN 0901 Randomized Trial

BMT CTN 0901

63 Newell LF, Verneris MR, Panoskaltsis-Mortari A, Defor TE, Blazar BR, Cutler CS, Antin JH, MacMillan ML, Weisdorf DJ, Holtan S. Angiogenic factors, inflammation, and outcomes in myeloablative allogeneic hematopoietic cell transplantation: A biomarker analysis of GVHD prophylaxis in Blood and Marrow Transplant Clinical Trials Network protocol (BMT CTN) 0402. Oral presentation: BMT Tandem Meetings, Honolulu, HI, February 2016

BMT CTN 0402

64 Shenoy S, Eapen M, Wu J, Walters MC, Levine JE, Logan BR, Gersten ID, Kamani NR. Results of the Blood and Marrow Transplant Clinical Trials Network study BMT CTN 0601: SCURT - a multicenter Phase II trial of unrelated donor reduced intensity bone marrow transplantation (BMT) for children with severe sickle cell disease. Oral presentation: BMT Tandem Meetings, Honolulu, HI, February 2016

BMT CTN 0601

65 Maziarz RT, Lazarus HM, Riches ML, Mudrick C, Mendizabal A. BMT CTN trials: A rich source for regimen related toxicity assessments in the modern era. Poster presentation: BMT Tandem Meetings, Honolulu, HI, February 2016

Network abstract

66 Anderlini P, Wu J, Deeg HJ, Gersten ID, Ewell M, Tolar J, Antin J, Arai S, Horwitz M, McCarty J, Nakamura R, Pulsipher M, Adams R, Leifer E, DiFronzo N, Horowitz MM, Confer DL, Eapen M. Cyclophosphamide (CY) conditioning in patients with severe aplastic anaemia (SAA) given unrelated marrow transplantation: Final results of a Phase 1-2 dose de-escalation study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0301). Poster to be presented: 42nd EBMT Congress, Valencia, Spain, April 2016

BMT CTN 0301

67 Burns LJ, Logan BR, Chitphakdithai P, Miller J, Drexler R, Spellman S, Switzer G, Wingard J, Anasetti C, Confer DL. Faster recovery of unrelated donors of peripheral blood stem cells (PBSC) vs bone marrow (BM): A prespecified analysis from BMT CTN 0201. Poster to be presented: 42nd EBMT Congress, Valencia, Spain, April 2016

BMT CTN 0201

68 Attal M, Palumbo A, Holstein SA, Lauwers-Cances V, Petrucci MT, Richardson PG, Hulin C, Tosi P, Anderson KC, Caillot D, Magarotto V, Moreau P, Marit G, Yu Z, McCarthy PL. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS). Oral abstract to be presented: ASCO Annual Meeting, Chicago, IL, June 2016

BMT CTN 0704 / CALGB 100104 /

ECOG 100104

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment C1: Center Performance Report Template

185

Attachment C: Center Performance Report

Attachment C1: Center Performance Report Template

CENTER PERFORMANCE REPORT

Center Name:

Date of Evaluation:

SCIENTIFIC AND ADMINISTRATIVE ACTIVITY Items # Protocol5 N % Total N1

Protocol Chairs or Co-chairs 4 Protocol Team members Protocol Team conference call participation2 in 2015 /=% Protocol Endpoint Review Call participation3 in 2015 Steering Committee Chair / Chair-Elect / Past Chair in 2015 % Steering Committee meeting / call participation in 2015 %

Notes: 1 Total N for all centers and all protocols, which were active in 2015. 2 Percentages for call are calculated based on the protocols that the center is one of the chairs / members. 3 Percentages for call are calculated based on the protocols that the center is one of Endpoint Review Committee. 4 ― means not applicable or not calculated. 5 Only protocols that were active in 2015 are included.

PROTOCOL TEAM CONFERENCE CALL PARTICIPATION IN 2015

Protocol Protocol Team Calls

Not Attending Team Calls

Endpoint Review Committee Calls

Not Attending Endpoint Review Calls

Overall Call Participation (%)1

0701 0702 0801 0901 1101 1102 1202 Total

Note: 1 Based on the protocol team call participation and endpoint review call participation, weighted by the total number of team calls and endpoint review calls.


186

ACTIVATION AND ENROLLMENT

PROTOCOL Protocol Activated

# Accrual in 2015

# Projected Accrual in 20151

(%2)

# Days to Consent Preview1

# Days to Activation

# Days from Activation to 1st

Patient

0301

0601

0701

0702

07LT

0803

0804

0901

0902

0903

1101

1102

1202

1203

1204

1205

1301


187

PROTOCOL Protocol Activated

# Accrual in 2015

# Projected Accrual in 20151

(%2)

# Days to Consent Preview1

# Days to Activation

# Days from Activation to 1st

Patient

1302

1304

1505

Total/Overall N_Total=

N_Recent= [4]

N_Total= N_Total= (/=%) [85%]

Median_Overall= Median_Recent=

[56]


[180]


[56]

Notes: 1 Date of consent preview is available only for BMT CTN-led protocols after 0702. 2 % is the actual accrual total over projected accrual total (including only protocols “activated”). If projected accrual number was not available, the actual accrual

number was used as projected number. 3 N_Recent means N only counts the protocols opened within the preceding 4 years (starting with 1101, highlighted in gray).

Median_Recent means median only counts the protocols opened within the preceding 4 years. 4 for row “Protocol activated” means site is not participating the study. for other rows means not activated yet, not applicable, or information not available. 5 Accrual to protocols 07LT, 1203 CIBMTR Control Cohort, and 1505 receive get 50% accrual credit. Non-Caucasian adult and all pediatric patients enrolled on 1202

since 1/26/15 get double accrual credit. 6 Targets are in “[ ]”.


188

DATA QUALITY

PROTOCOL # # Accrual in Total

Data Audit Error Rate (%)

# Protocol Deviations in 2015 (% of Enrolled Patients)

# Required Forms

# Forms > 30 Days Overdue

Forms > 30 days Overdue / Patient

0301

0701

0702

07LT

0801

0803

0901

0903

1101

1102

1202

1203

1204

1205

1302

Total/Overall [2%] (%) [2%] [5]

Notes: 1 Protocols that have finished following up patients before Jan 1, 2015, are not included in this table. Protocols that Emmes does not monitor data quality are not

included. 2 for row “# Accrual” means site is not participating in the study or not activated yet. for row “Data audit error rate” means there were no data audit performed

within the preceding 3 years. for other rows means not applicable due to no patients. 3 Targets are in “[ ]”.


189

CIBMTR REPORT FORM COMPLIANCE

# BMT CTN Patients # Patients Registered with CIBMTR (%) # CIBMTR Report Forms Due # CIBMTR Report Forms Received (%)

(%) (%)

LABORATORY COMPLIANCE EVALUATION

2015 Quarterly

Protocol # 2014 Overall 2015 Overall Q1 Q2 Q3 Q4

0601

0702

07LT

0803

0903

1101

1102

1202

1203

1204

Annual Rating Notes:

OS – Outstanding (93-100%) AA – Above Average (85-92%) AC – Acceptable (65-84%) MA – Marginally Acceptable (50-64%) IN – Improvement Needed (0-49%) -- indicates not participating or no activity in the time period


190

PERFORMANCE RATING

Score Rating

Scientific and Administrative

Accrual

Activation and Enrollment

Data Quality

Laboratory Compliance

Overall Assessment

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment C2: Center Performance Report Rating Metric

191

Attachment C2: Center Performance Report Rating Metric

Administrative Activity max=10 points

Outstanding (10 points)

Holds Steering Committee Chair, Past-Chair or Chair- Elect position OR Protocol Team Chair + > 70% of team calls participation

Acceptable (5.1-9 points) % Call Participation × 10

Needs Improvement (0-5 points) Attends < 33% of Protocol Team calls

Accrual max=60 points

Outstanding (60 points)

Accrues > 24 patients and meets ≥ 100% of projected accrual OR Enrolls > 48 patients

Acceptable (40-59 points)

Score = (Actual/Projected) x 60 then adjust for maximum For centers enrolling 20 or more patients, can get a maximum score of 60; for centers enrolling < 20 patients, can only get a maximum of 45 points even if meeting or exceeding projections

Needs Improvement (<40 points)

Score < 40 points For centers enrolling < 18 patients, can only get a maximum of 10 points even if meeting or exceeding projections

Activation and Enrollment max=10 points • # protocols activated within preceding 4 years [4] • # days to consent preview [56] • # days to activation [180] • # days activation to 1st patient [56]

Outstanding (10 points) Meets 4 of 4 metrics

Acceptable (5 points) Meets 2-3 of 4 metrics

Needs Improvement (0 points) Meets < 2 of 4 metrics

Data Quality max=10 points • Data audit error rate [2%] • % protocol deviations [2%] • Forms >30 days past due per patient [5] • CIBMTR form compliance [90%]

Outstanding (10 points) Meets 4 of 4 metrics

Acceptable (5 points) Meets 2-3 of 4 metrics

Needs Improvement (0 points) Meets < 2 of 4 metrics

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment C2: Center Performance Report Rating Metric

192

Laboratory Compliance max=10 points • Average compliance percentage for all

participating protocols • Evaluated by Alan Howard

Outstanding (8.1-10 points) OS - Outstanding

Acceptable (5.1-8.0 points) AA - Above Average 7.5; AC - Acceptable 5.0

Needs Improvement (0-5 points) UN - Unacceptable; MA - Marginally Acceptable 2.5

Overall Assessment max=100 points

Outstanding > 90 points

Acceptable 60 – 90 points

Needs Improvement < 60 points; center required to submit action plan

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment D: Terms and Abbreviations

193

Attachment D: Terms and Abbreviations

Term/ Abbreviation Definition

AIDS acquired immunodeficiency syndrome ALL acute lymphoblastic leukemia AML acute myelogenous leukemia ASBMT American Society for Blood and Marrow Transplantation ASCO American Society of Clinical Oncology ASH American Society of Hematology BEAM carmustine (BCNU), etoposide, cytarabine, and melphalan BMT blood and marrow transplant / transplantation BMT CTN Blood and Marrow Transplant Clinical Trials Network (also “the Network”) CALGB Cancer and Leukemia Group B (member Alliance for Clinical Trials in Oncology) CIBMTR Center for International Blood and Marrow Transplant Research CLL chronic lymphocytic leukemia COG Children’s Oncology Group CR complete remission CTCAE common terminology criteria for adverse events CTSU Cancer Trials Support Unit CVAD cyclophosphamide, vincristine, adriamycin and dexamethasone DCC Data and Coordinating Center

DETERMINATION Delayed versus Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy; BMT CTN Protocol 1304

DFCI Dana-Farber Cancer Institute DLBCL diffuse large B cell lymphoma DNA deoxyribonucleic acid DSMB Data and Safety Monitoring Board EBMT European Group for Blood and Marrow Transplantation ECOG Eastern Cooperative Oncology Group ECP extracorporeal photopheresis ETRIC Easy-To-Read Informed Consent; BMT CTN Protocol 1205 FACT Foundation for the Accreditation of Cellular Therapy FDA Food and Drug Administration G-CSF granulocyte-colony stimulating factor GVHD graft-versus-host disease HAART highly-active antiretroviral therapy HCT hematopoietic stem cell transplantation HIV human immunodeficiency virus HLA human leukocyte antigen HLH hemophagocytic lymphohistiocytosis IDE investigational device exemption IFM Intergroupe Francophone du Myelome IND investigational new drug

Blood and Marrow Transplant Clinical Trials Network Progress Report 2016 Attachment D: Terms and Abbreviations

194

Term/ Abbreviation Definition

IPS idiopathic pneumonia syndrome IRB Institutional Review Board MDS myelodysplastic syndrome MM multiple myeloma MMF mycophenolate mofetil NCI National Cancer Institute NHLBI National Heart, Lung, and Blood Institute NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NK natural killer NMDP National Marrow Donor Program PBMC peripheral blood mononuclear cell PBMTC Pediatric Blood and Marrow Transplant Consortium PBSC peripheral blood stem cell PFS progression-free survival PI Principal Investigator PR partial remission PRC protocol review committee PRES posterior reversible encephalopathy syndrome

PROGRESS Prevention and Reduction of GVHD and Relapse Enhancing Survival after Stem Cell Transplantation; BMT CTN Protocol 1203

PROGRESS II BMT CTN Protocol 1301 RFA Request for Applications RIC reduced-intensity conditioning

RICHI Reduced-Intensity Conditioning for Children and Adults with Hemophagocytic Syndromes or Selected Primary Immune Deficiencies; BMT CTN Protocol 1204

RPLS reversible posterior leukoencephalopathy syndrome RVD lenalidomide, bortezomib, and dexamethasone SCURT Sickle Cell Unrelated Transplantation; BMT CTN Protocol 0601

STaMINA Stem Cell Transplantation for Multiple Myeloma Incorporating Novel Agents; BMT CTN Protocol 0702

TCR T cell receptor TNF tumor necrosis factor TRM transplant-related mortality / treatment-related mortality vs. versus

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