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Transcript of FDA Advisory Panel Miltenyi Biotec CliniMACS ® CD34 Reagent System September 23, 2011 With Sincere...
FDA Advisory PanelMiltenyi Biotec
CliniMACS® CD34 Reagent SystemSeptember 23, 2011
With Sincere Thanks and Appreciation To:
2
The CliniMACS® CD34 Reagent System
FDA Advisory PanelSeptember 23, 2011
Nancy Johansen
Director, Regulatory Affairs
Miltenyi Biotec Incorporated
3
Company Overview, Product Introduction and Registration of the CliniMACS® CD34 Reagent System as a Humanitarian Use Device
Overview of the Clinical Indication and Unmet Medical Need and Summary of the BMT CTN 0303 Clinical Trial
Summary of the CliniMACS® CD34 Reagent System Performance
Summary of the BMT CTN 0303 versus BMT CTN 0101 Data Analysis Protocol Findings
Summary of Safety and Probable Benefit of the CliniMACS® CD34 Reagent System
Agenda and Presenters Nancy JohansenDirector, Regulatory Affairs Miltenyi Biotec Incorporated
Steven Devine, M.D.Ohio State UniversityArthur G. James Cancer Center
Carolyn Keever-Taylor, PhDMedical College of Wisconsin
Marcelo Pasquini, M.D., M.S.Center for International Blood and Marrow Transplant Research (CIBMTR)Medical College of Wisconsin
Kai Pinkernell, M.D.Head of Clinical DevelopmentMiltenyi Biotec GmbH
4
• Founded in 1989 in Bergisch Gladbach, Germany
• Roughly 1100 employees worldwide
• Subsidiaries in 10 countries; N.A. Headquarters in Auburn, CA
Miltenyi Biotec Corporate Overview
5
The overall function of the CliniMACS® CD34 Reagent System
is to select CD34+ cells from heterogeneous hematologic cell populations
CliniMACS® CD34 Reagent System
6
CliniMACS®plus Instrument
CliniMACS® CD34 Reagent
CliniMACS® PBS/EDTA Buffer
CliniMACS® Tubing Sets (Standard and Large Scale)
Standard: 0.6 x 109 CD34+ Cells
from 60 x 109 Cells
Large Scale: 0.6-1.2 x 109 CD34+ Cells from 60-120 x 109 Cells
CliniMACS® CD34 Reagent System
7
Magnetic labeling
Magnetic Separation (elution of the non-labeled
cell fraction)
Elution of the labeled cell
fraction
The Principle of the CliniMACS® CD34 Reagent System
8
Location of CliniMACS®plus
Instruments in the USA
162 instruments within 97 institutions in the U.S.
9
84 IDE protocols utilize the CliniMACS® CD34 Reagent System Strict distribution procedures are in place to
ensure that investigational products are provided only for FDA/IRB approved protocols
CliniMACS® CD34 Reagent System Protocols (as of July 2011)
10
CliniMACS® plus Instruments are installed by qualified Miltenyi personnel Installation and Operational Qualification (IQ/OQ) is
performed at time of installation All subsequent servicing and Preventative Maintenance are
performed by qualified Miltenyi personnel Customer Training
Performed by qualified Miltenyi personnel Training validated by written test
Emergency Hotline Support Monday through Friday (9 a.m. – 9 p.m. EST) If pre-arranged, outside of normal business hours
Installation, Training and Customer Support
11
1997 CE marked
1998 US MF Submitted
2004 Pre-IDE Meeting
2004-2008 BMT CTN
Study Conducted
2005-HUD Designation
2011 HDE Submitted
Dec 2009FDA pre-HDE meeting
2010 DAP Finalized
12
Humanitarian Use Device The device is designed to treat or diagnose a
disease or condition that affects fewer than 4,000 individuals per year in the U.S.
The device is not available otherwise, and there is no comparable device available to treat or diagnose the disease or condition; and
The device will not expose patients to unreasonable or significant risk, and the benefits to health from the use outweigh the risks
Clinical data must support “safety” and “probable benefit” argument
Exempt from “effectiveness requirement” consistent with the HDE requirements
13
Miltenyi supported a Phase II multi-center clinical trial sponsored by the BMT CTN (BB-IDE 11965) which enrolled 47 AML patients from October 2005-December 2008 Evaluated the use of the CliniMACS® CD34 Reagent
System for selecting CD34+ cells from HLA-matched related donors for allogeneic stem cell transplantation after myeloablative therapy in patients with Acute Myeloid Leukemia (AML) in 1st or 2nd CR, without additional GVHD prophylaxis
Clinical Trial Supporting the HUD Registration of the
CliniMACS® CD34 Reagent System*
* Miltenyi provided material goods only in the support of this study.
MBI has negotiated rights through the National Marrow Donor Program (NMDP) to cross reference the BMT CTN 0303 IDE submission for purposes of product registration
14
“Humanitarian Use Device: Authorized by U.S. Federal law for processing allogeneic HLA-matched hematopoietic progenitor cells-apheresis (HPC-A) from a related donor to obtain a CD34+ cell enriched population intended for hematopoietic reconstitution following a myeloablative preparative regimen without the need for additional graft-vs-host disease (GVHD) prophylaxis in patients with acute myeloid leukemia (AML) in first or second morphologic complete remission”
CliniMACS® CD34 Reagent SystemProposed Humanitarian Use Indication
15
Steven Devine, M.D.Professor of Internal Medicine
Director, Blood and Marrow Transplant ProgramThe Ohio State University
Arthur G. James Cancer Center
BMT CTN 0303
Co-Study Chair
16
1 http://www.Cancer.org; 8/26/102 Koreth, J et al. JAMA 2009
Acute Myeloid Leukemia (AML)
Most common leukemia diagnosis in adults1
U.S. incidence: ~ 12,330 new cases diagnosed annually Mortality is roughly 8,950 cases per year However, less than 2,500 patients progress to transplant
Allogeneic stem cell transplantation (SCT) is the single most effective therapy currently available for the prevention of relapse and shows significant survival benefit in AML patients with intermediate and poor risk cytogenetics in first complete remission (CR1)2
17
Reduced incidence of leukemic relapse and overall survival often not realized due to complications caused by GVHD
Acute GVHD (aGVHD) risk is 35-45%
33-81% of these patients will develop chronic GVHD (cGVHD), resulting in post-transplant morbidity, mortality and reduced quality of life
Immunosuppressive agents used to prevent and treat aGVHD do not affect incidence of cGVHD
Previous studies demonstrate that T cell depletion reduces the risk of severe acute and chronic GVHD
Graft Versus Host Disease (GVHD) Complicates Allogeneic
Transplantation From Matched Related Donors (MRD)1-6
1 Ferrara J, et al. Lancet 2009 2 Chao N, et al. NEJM 1993 3 Devine S, et al. J Lab Clin Med 20034 Clift R, et al. Blood 1991 5 Nash R, et al. Blood,2000 6 Ratanatharathorn V, et al. Blood 1998
18
Chronic GVHD of the Skin
Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org
19
Chronic GVHD of the Oral Mucosa
Walker, I; 2011 BMT Tandem Meetings CBMTG Section; Clinical Trials Network Meeting. www.cbmt.org
20
Chronic GVHD and Quality of Life
Quality of life (QoL) at 6 or 12 months is significantly worse in patients with acute or cGVHD after transplant1
QoL at 12 months improves unless cGVHD develops1
Significantly less patients return to work if they develop cGVHD after allogeneic transplantation2
Only 41% of patients with cGVHD return to work at 3 years, compared to 95% of patients without cGVHD2
1 Lee et al. BMT 2006; (38) 305-102 Wong et al. Blood. 2010; 115(12)2508-19
21
Chronic GVHD Treatment
The treatment of cGVHD with long-term corticosteroids increases the risk of cataract formation, avascular necrosis, and osteoporosis1
The 10-year survival is less than 5% for patients affected by severe cGVHD
There are no effective options for the prevention or treatment of chronic GVHD
1 Horowitz, ME., and Sullivan, KM. Blood Reviews (2006); 20: 15–27
22
The incidence and severity of GVHD are most effectively reduced by ex vivo T cell depletion (TCD) of the allograft
There is currently no approved method for ex vivo TCD for allogeneic SCT in the United States
If approved, the CliniMACS® CD34 Reagent System will be the only FDA approved method of CD34+ enrichment and passive TCD available
Unmet Medical Need Served by The CliniMACS® CD34 Reagent System
23
Use of ex vivo T cell depletion (TCD) has been limited by logistical difficulties and variability in TCD
methods lack of an FDA-approved method concerns regarding potential risk of graft
rejection and leukemic relapse
A multi-center trial of TCD in AML patients in complete remission (CR1/CR2) using standard eligibility criteria and a uniform method of TCD was warranted
Clinical Study Rationale
24
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*
S Devine, S Carter, R Soiffer, M Pasquini, P Hari, A Stein, H Lazarus, C Linker, E Stadtmauer, E Alyea, C Keever-Taylor, and R O'Reilly
(BMT CTN) Protocol 0303
* Devine, S et al; BBMT, 2011
Blood and Marrow Transplant Clinical Trials Network (BMT CTN)
• Established: Sept. 2001; renewed July 2011• Funded by NHLBI/NCI• 20 Core Center cooperative agreements• 1 DCC cooperative agreement• >80 affiliate centers access trials through
DCC
• Goal of the Program:
• Provide the infrastructure needed to allow promising HCT therapies to be developed/ evaluated in high quality multicenter studies.
25
= PBMTC Centers= Affiliate Centers= Core Centers
Mmh06_16.ppt
BMT CTN Centers, 2011>100 centers have enrolled >3900
patients since 2003
26
Single center studies show reduced GVHD without increased relapse rates in AML patients receiving T cell depleted (TCD) allografts in CR1-3
One randomized, prospective, multi-center TCD trial showed no increase in relapse in AML patients receiving TCD allografts4
BMT CTN 0303 Historical References
1 Aversa et al. Blood Cells Mol and Disease 20082 Pappadopoulos et al, Blood, 19983 Soiffer et al; Blood 19974 Wagner, J. et al. Lancet 2005 27
28
Randomized, Prospective, Multi-center T Cell Depletion (TCD) Vs. Methotrexate and
Cyoclosporine (M/C) Trial
Wagner et al., Lancet 366:733, 2005
29
The sample size was 45 patients, wherein 47 patients were enrolled and 44 completed treatment
There were no blinding or randomization aspects to this trial
The median follow up of the patients was 34 months (Range: 11.5- 51.5 months)
BMT CTN 0303 Statistical Sampling and
Time Points
BMT CTN 0303 Study Eligibility
AML in CR1 or CR2 Age 18-65 HLA-identical sibling available No more than 2 induction cycles of chemotherapy
required to induce remission No more than six months from CR to transplant
(three months for CR2) Other standard organ function criteria No uncontrolled bacterial/fungal/viral infections Karnofsky performance status > 70%
30
31
Primary Endpoint: Disease-Free Survival (DFS) at 6 months >75%
Secondary Endpoints: Acute and chronic GVHD Overall Survival (OS) Disease-Free Survival at 2 years Transplant-Related Mortality (TRM) Relapse Engraftment/graft failure Infusional Toxicities Incidence of EBV reactivation and PTLD Proportion of grafts containing > 5 x 106 CD34+ cells/kg and < 1 x 105
CD3+ cells /kg
BMT CTN 0303 Study Endpoints
Site Patients Accrued
Dana Farber/Partners Cancer Center 18
Ohio State University 8
Memorial Sloan Kettering Cancer Center 7
Medical College of Wisconsin 7
City of Hope National Medical Center 3
University Hospitals of Cleveland 2
University of CA, San Francisco 1
University of Pennsylvania 1
TOTAL 47
Eight Centers Enrolled Patients onto BMT CTN 0303
44 patients were evaluable on study32
BMT CTN 0303Patient
CharacteristicsPatient Age Mean (range) 46.3 (21-59 )
Donor age Mean (range) 46.2 (16-63)
GenderMale 16 (36%)
Female 28 (64%)
Leukemia stageCR1 37 (84%)
CR2 7 (16%)
Cytogenetic Risk (CR1/CR2)
Favorable 0 / 2
Intermediate 25 / 3
Unfavorable 10 / 1
Unknown* 2 / 1
* Unknown cytogenetic risk due to lack of metaphase during testing33
34
BMT CTN 0303 Patient Conditioning Regimen
Day of Tx -9 -8 -7 -6 -5 -4 -3 -2 -1 0
TBI 1375 cGy*
11 total doses; administered on days -9 through -6
Thiotepa @ 5mg/kg
Thymoglobulin @ 2.5 mg/kg
Cyclophosphamide @ 60mg/kg
CliniMACS® CD34-enriched cells
35
BMT CTN 0303 Donor Mobilization &
Leukapheresis Received daily G-CSF for mobilization
following screening and enrollment
Leukapheresis performed according to institutional standards
Daily leukapheresis with subsequent CD34+ cell selection using the CliniMACS® CD34 Reagent System continued until a post-selection target dose of > 5.0 x 106 CD34+
cells/kg and < 1 x 105 CD3+ cells/kg was met
36
Carolyn Keever-Taylor, PhDProfessor of Medicine
Director BMT Laboratories Division of Hematology and Oncology
Medical College of Wisconsin
BMT CTN 0303
Steering Committee Laboratory Representative
37
The Manuscript Entitled:
“Characteristics of CliniMACS® System CD34-Enriched T Cell-Depleted Grafts in a Multi-Center Trial for Acute Myeloid Leukemia-Blood and Marrow
Transplant Clinical Trials Network (BMT CTN) Protocol 0303”
has been submitted and accepted for publication by the peer reviewed journal,
“Biology of Blood and Marrow Transplantation”
38
Leukapheresis collections from a Matched Related Donor were performed in order to obtain a minimum of ≥ 2.0 x 106 CD34+ cells/kg Target of > 5.0 x 106 CD34+ cells/kg and
< 1 x 105 CD3+ cells/kg
Up to three collections were allowed to achieve the minimum CD34+ cell dose
The CliniMACS® Tubing Sets (Standard or Large Scale) were used based on starting nucleated cell counts
Secondary Endpoint: CliniMACS® CD34 Reagent System
Performance
39
Cellular Testing Requirements
Cell Viability (7-AAD), TNC and CD34+ cell content At product receipt After platelet and antibody wash On CliniMACS® CD34-enriched fraction
CD3+ T cell content At product receipt On CliniMACS® CD34-enriched fraction
Other cellular testing on CliniMACS® CD34-enriched fraction only CD14+ monocytes CD19+ or CD20+ B cells CD56+ NK Cells
40
Donors and Products
47 patients enrolled, 44 proceeded to transplant
86 products collected Total lots (cells from one tubing set)
assessed=84– Collections pooled for 2 patients
4 sites processed from 9 to 34 lots
4 sites processed ≤ 4 lots
41
CliniMACS® CD34 Reagent System Post-Processing Performance
N = 84
% CD34+ Recovery
% CD34+ Purity Log10 TCD % Viability
Mean 66.06 93.0 4.78 96.57
SD±20.25 ±8.3 ±0.55 ±3.84
Min 29.9 61.5 3.2 74.0
Max 125.6 99.8 5.9 100.0
42
Center to CenterStatistical Analysis
Sites processing ≥ 9 lots compared individually (N=4)
Sites processing ≤ 4 lots pooled (N=4)
Multivariate analysis used a linear mixed effect model to account for repeated measures (≥ 2 lots for most patients)
Pairwise center comparisons were performed with Tukey-Kramer adjustment for multiple comparisons
43
Pre-Processing Cell Counts
44
Post Processing Outcomes
All centers were able to process grafts that met the study criteria
45
CD34+ Cells x 106/kg of Patient Weight Infused
CD34+ Target Dose
All patients received the minimum CD34+ dose (> 2.0x106 cells/kg)
84.1% of patients received > 5 x 106 CD34+ cells/kg
CD34+ Minimum
Dose
CD
34+
/kg
46
CD3+ Cells x 105/kg of Patient Weight Infused
Upper limit of CD3+
dose
No patients received more than 1.0x105 CD3+ cells/kg
CD
3+/k
g
47
All gram stains/14 day cultures were negative All endotoxin < 5.0 EU/kg No significant infusion related toxicities observed
Parameter Result
Median CD34+ dose 7.92 x 106/kg
Range 2.4 - 30.3 x 106/kg
Median CD3+ dose 0.7 x 104/kg
Range 0.1 – 8.3 x 104/kg
Median Log10 TCD 4.9 logs
Range 3.2 – 5.9 logs
Final Cellular Product Summary
48
All sites, and all products met and most exceeded study goals for: CD34+ cell infusion dose > 2 x 106/kg
– 84% met the goal of > 5 x 106/kg CD3+ cell infusion dose < 1 x 105/kg
The performance of the CliniMACS® CD34 Reagent System was stable and reproducible, resulting in a consistently high degree of CD34+ cell enrichment,
T cell depletion and sterility in a multi-center setting
Conclusions - Secondary EndpointCliniMACS® CD34 Reagent System
Performance
49
Steven Devine, M.D.Professor of Internal Medicine
Director, Blood and Marrow Transplant ProgramThe Ohio State University
Arthur G. James Cancer Center
BMT CTN 0303
Co-Study Chair
50
Primary Endpoint6 Month Disease-Free Survival of >75%
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Disease Free Survival for All Transplanted Patients
N=44
81.8% @ 6 months (95% CI 66.9-90.5)
Secondary EndpointsNeutrophil/Platelet Engraftment
Analysis NMedian Days
to EngraftmentDay 30
EstimateDay 100 Estimate
Platelet Engraftment
>20K/µL 44 16 days
93.2% (95% CI: 85.2-100)
97.7 %(95% CI: 92-100)
Cumulative Incidence of Neutrophil
Engraftment
>500/µL44 12 days
100%
(95% CI:
85.5-100)
• No primary graft failures • One secondary graft failure at Day +54 after initially engrafting on Day +12
51
52
Secondary Endpoint Cumulative Incidence of Transplant-Related
Mortality (1yr)
Stopping guideline of <30% TRM at 1 year was not exceeded
TRM at 2 years was 19.9% (95% CI: 7.1-32.7)
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of TRM for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of TRM by Remission Stage
First CR (N=37) Second CR (N=7)
All Patients By CR1/CR2
13.6% @ 1yr(95% CI: 3.4-23.8)
53
Secondary Endpoint Cumulative Incidence of EBV Reactivation
All Patients By CR1/CR2
13.6% (95% CI: 3.4-23.8)
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of EBV for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of EBV by Remission Stage
First CR (N=37) Second CR (N=7)
18.2% @ 2 yrs 18.9% @ 2 yrs
14.3% @ 2 yrs
• 8 patients treated for EBV DNA levels >1000 copies/mL• One case of PTLD with subsequent death • EBV monitoring performed weekly
54
Secondary EndpointCumulative Rate of Relapse
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of Relapse for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of Relapse by Remission Stage
First CR (N=37) Second CR (N=7)
20.6% @ 1 yr
23.7% @ 2 yrs
57.1% @ 2 yrs
17.4%* @ 2 yrs
All Patients By CR1/CR2
* N=7 patients treated in CR2; 4 patients relapsed (95% CI: 14.6-99.6%)
Secondary Endpoint - Cumulative Incidence ofAcute GVHD Grades II-IV
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Days Post Transplant
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
Cumulative Incidence of Acute GVHD Grades II-IV for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Days Post Transplant
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
Cumulative Incidence of Acute GVHD Grades II-IV by Remission Stage
First CR (N=37) Second CR (N=7)
22.7% @ 100 days(95% CI: 10.2-35.2)
• No Grade IV acute GVHD observed• Published acute GVHD risk 35-45%
All Patients By CR1/CR2
55
56
Secondary Endpoint - Cumulative Incidence of Acute GVHD Grades III-IV
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Days Post Transplant
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
Cumulative Incidence of Acute GVHD Grades III-IV for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Days Post Transplant
0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
Cumulative Incidence of Acute GVHD Grades III-IV by Remission Stage
First CR (N=37) Second CR (N=7)
• No Grade IV acute GVHD observed
4.5% @ 100 days(95% CI: 0 – 10.8%)
All Patients By CR1/CR2
57
Secondary Endpoint Cumulative Incidence of Chronic GVHD (2 yrs)
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of Chronic GVHD for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of Chronic GVHD by Remission Stage
First CR (N=37) Second CR (N=7)
19% @ 2 years (95% CI: 6.8-31.1)
Includes Limited and Extensive
All Patients By CR1/CR2
• Published chronic GVHD risk 33-81%
Secondary Endpoint Cumulative Incidence of Extensive
Chronic GVHD (2 Years)
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of Extensive Chronic GVHD for All Transplanted Patients
N=44
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Cumulative Incidence of Extensive Chronic GVHD by Remission Stage
First CR (N=37) Second CR (N=7)
6.8% @ 2 years
(95% CI: 0-14.4)
All Patients By CR1/CR2
58
59
Secondary EndpointDisease-Free Survival at 2 Years
All Patients By CR1/CR2
By Stage
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Disease Free Survival for All Transplanted Patients
N=44 P
roba
bilit
y0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Disease Free Survival for All Transplanted Patients by Remission Stage
First CR (N=37) Second CR (N=7)
65.7% @ 1 yr 56.4%
@ 2 yrs
61.9% @ 2 yrs
28.6% @ 2 yrs
• Historical data estimates 2 year DFS < 60% in CR11-3
• 2º endpoints were > 70% for CR1 and > 60% for CR21 Suciu Blood 2003 2 Brunet et al, Hematologica 2004 3 Cornelissen et al, Blood 2007
Secondary EndpointOverall Survival at 2 Years
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post Transplant0 2 4 6 8 10 12 14 16 18 20 22 24
Overall Survival for All Transplanted Patients
N=44
77.3% @ 1 yr
59.4% @ 2 yrs
60
61
Adverse Events (AEs)
Toxicities were reported as AEs No Unexpected Grade 3-5 AEs were reported AEs were due to regimen related events and
toxicities common to allo HCT and could not be attributed to the CliniMACS® CD34 Reagent System
The most common toxicities within 1 year post-transplant: Regimen related Grade 3 or 4 GI toxicity (40.9%) Abnormal liver function (36.4%)
• Graded using the NCI’s CTCAE version 3.0
Causes of Death by2 Years Post-Transplant
Cause N
Recurrence 6
Infection 4
Idiopathic Pneumonia
Organ failure
Other*
2
2
1
PTLD 1
Total 16
* Possibly cardiac related 62
63
HCT following myeloablative preparative regimen for patients with AML in CR1 or CR2 can be performed in a multicenter setting using the CliniMACS® CD34 Reagent System without additional post-transplant pharmacologic GVHD prophylaxis
All 1º and most 2º endpoints were met, demonstrating: 81.8% Disease-Free Survival 6 months post TX No primary graft failure; consistent neutrophil and platelet
engraftment Acute GVHD grades II-III <23%. No Grade IV aGVHD Chronic GVHD at 2 years 19%; extensive 6.8% TRM <20% at 2 years Overall risk of relapse was low at 23.7% at 2 years
The CliniMACS® CD34 Reagent System consistently produced a graft with > 2 x 106 CD34+ cells/kg and < 1 x 105 CD3+ cells/kg with no reported device related toxicities
BMT CTN 0303 Conclusions
64
Marcelo Pasquini, M.D., M.S.
Assistant Professor of Medicine Medical College of Wisconsin
Assistant Scientific Director Center for International Blood and Marrow
Transplant Research (CIBMTR)
Principal InvestigatorBMT CTN 0101 versus BMT CTN 0303
Data Analysis Protocol
65
A Single Arm, Multi-center 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 (BMT CTN) Protocol 0303
A Randomized Double-blind Trial of Fluconazole versus Voriconazole for the Prevention of Invasive Fungal Infections in Allogeneic Blood
and Marrow Transplant Patients(BMT CTN) Protocol 0101
66
Performed according to FDA approved Data Analysis Protocol #1001-34 which was a prospective statistical comparison of retrospective data
This comparison of the 0101 and 0303 data has been submitted for publication. The manuscript is currently under review.
The Data Analysis Protocol (DAP)
67
Enrollment Period BMT CTN 0101 versus BMT CTN 0303
15 53
23% of 0101 47.5% of 0303
0101
0303
2003 2006
2005 2008
Enrolling Centers by Protocol, and Their Contribution to Each Study
68
Test the hypothesis that T cell depletion using the CliniMACS® CD34 Reagent System as the sole form of immune suppression (BMT CTN 0303) demonstrates a comparable safety profile as compared to conventional GVHD prophylaxis post-transplant (BMT CTN 0101) in AML patients in CR1/CR2 receiving a Peripheral Blood Stem Cell (PBSC) allograft from a matched related donor
Data Analysis Protocol (DAP) Objective
69
Disease-Free Survival (DFS) Overall Survival (OS) Engraftment Graft Failure Transplant-Related Mortality (TRM) Relapse Incidence and Severity of Acute GVHD (aGVHD) Incidence and Severity of Chronic GVHD (cGVHD)
The Following One Year* Endpoints Were Statistically Compared
* BMT CTN 0101 follow-up was limited to 1 year
70
Patient Age 18-65 Unmodified PBSC Allograft HLA identical sibling donor AML in CR1 or CR2 All cytogenetic risk patients included in
0101 Only CR2 patients in 0303 enrolled favorable
cytogenetic risk patients
Eligibility Criteria for 0303 was Matched in 0101 Patient Subsets
71
DAP Patient Selection
Patients Randomized
N=600
No TransplantN=1
Received Transplant
N=599
Patients meeting eligibility
N=84
Eligibility CriteriaAge 18-65
HLA Match-SiblingPBSC
AML in CR1 or CR2
Patients Enrolled
N=47
AML CR2N=19
AML CR1N=65
No TransplantN=3
Received Transplant
N=44
AML CR2N=7
AML CR1N=37
Patients meeting eligibility
N=44
BMT CTN 0101 BMT CTN 0303
72
Baseline Characteristics
Karnofsky Performance Status Similar in Both Protocols 100% 22 (26.2%) 17 (38.6%)
0.36> 90% 46 (54.8%) 17 (38.6%)
> 80% 13 (15.5%) 8 (18.2%)
> 70% 3 (3.6%) 2 (4.5%)
Median Age 45.1 48.5 0.14
% > 50 yrs of Age 32.1% 43.2% 0.22
Patient Ages Similar in Both Protocols
0101 (N=84) % of patients
0303 (N=44) % of patients p-Value
Significantly More Females in 0303Female 44% 63.6%
0.04Male 56% 36.4%
73
Cytogenetic Risk Profile By Protocol
Cytogenetic Risk Profile*
Control (0101) (N=84) N (%)
CD34+ Enriched (0303) (N=44) N (%)
p Value
Favorable9
(10.7%) 2 (4.5%)
0.34Intermediate 55 (65.5%)
28(63.6%)
Unfavorable 12 (14.3%)
11 (25.0%)
Unknown 8 (9.5%)
3 (6.8%)
Slightly more unfavorable cytogenetics in 0303 than in 0101;overall, statistically similar
* Slovak M et al. Blood 2001. SWOG/ECOG classification used for profile determination.
74
0101 (N=84)# (%)
0303(N=44) # (%)
Conditioning Regimen
TBI based 43 (51) 44 (100)
Busulfan based 41 (49) 0
ATG 7 (8) 44 (100)
GVHD Prophylaxis
T cell depletion 0 44 (100)
Tacrolimus based 48 (57) 0
Cyclosporine A based 37 (43) 0
Conditioning RegimenBMT CTN 0101 versus BMT CTN 0303
75
Day +30 Neutrophil Engraftment (> 500/µL)*
Prob
abilit
y
0.0
0.2
0.4
0.6
0.8
1.0
Days Post Transplant0 7 14 21 28 35 42
0101 (N=84)0303 (N=44)
96.4% in Control (0101)
100% in CD34+ (0303)
*Cumulative Incidence
3 primary graft failures in the Control (0101) 0 primary graft failures in the CD34+ Enriched (0303) 1 secondary graft failure in each trial
p=0.002
76
Day +100 Platelet Engraftment (≥ 20,000/µL)*
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6
0101 (N=84)0303 (N=44)
88.1% in Control (0101)
97.7% in CD34+ (0303)
p=0.228
*Cumulative Incidence
77
Transplant-Related Mortality*P
roba
bilit
y
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
0101 (N=84)0303 (N=44)
Prob
abilit
y
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
0101 and CR1 (N=65)0101 and CR2 (N=19)0303 and CR1 (N=37)0303 and CR2 (N=7)
All Patients by Protocol CR1/CR2 and Protocol
16.7% in Control (0101)
13.6% in CD34+ (0303)
p=0.62
*Cumulative Incidence
78
p=0.91
20.3% in Control (0101)
20.6% in CD34+ (0303)
Incidence of 12 Month Relapse*
*Cumulative Incidence
79
12 Month Relapse* CR1/CR2 By Protocol
Prob
abilit
y
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
0101 and CR1 (N=65)0101 and CR2 (N=19)0303 and CR1 (N=37)0303 and CR2 (N=7)
CR2p=N/A**
**Statistical calculations not performed due to low patient numbers 4/7 in 0303 and 6/19 in 0101 relapsed
CR1 p=0.57
57.1%
31.6%
17%
13.7%
*Cumulative Incidence
p=
0.02
80
12 Month Disease-Free Survival
Pro
bability
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
Pro
babili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Disease-Free SurvivalBy Protocol: CR1 and CR2
0101 (N=84)0303 (N=44)
I I III IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIII
65.7% in CD34+ (0303)
63% in Control (0101)
p=0.59
81
12 Month DFS in CR1/CR2 By Protocol
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Disease-Free SurvivalBy Protocol and Remission Status: CR1 and CR2
0101 and CR1 (N=65)0101 and CR2 (N=19)0303 and CR1 (N=37)0303 and CR2 (N=7)
IIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
I I IIIIIIII
I IIIIIIIIIIIIIIIIIIIIIIII
II
p=N/A*CR2
p=0.39CR1
72.8%
66.1%
52.6%
28.6%
p=0.7
* Statistical comparisons were not performed on CR2 patients due to low patient numbers
82
DFS Stratification by Age > 50CR1 and CR2
p=0.88
68.3% 0101 < 50
51.9% 0101 > 50
59.7% 0303 < 50
73.7% 0303 > 50
83
12 Month Overall SurvivalP
roba
bilit
y
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
Prob
abili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Overall SurvivalBy Protocol: CR1 and CR2
0101 (N=84)0303 (N=44)
I I III IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Overall SurvivalBy Protocol and Remission Status: CR1 and CR2
0101 and CR1 (N=65)0101 and CR2 (N=19)0303 and CR1 (N=37)0303 and CR2 (N=7)
I III IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
I I IIIIIIIII
I IIIIIIIIIIIIIIIIIIIIIIIIIII
IIII
p=0.87
All Patients by Protocol CR1/CR2 and Protocol
p=0.61
77.3% in CD34+ (0303)
73.8% in Control (0101)
84
Acute GVHD Grades II-IV*
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Days Post-Transplant0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
0101 (N=84)0303 (N=44)
39.3% in Control (0101)
22.7% in CD34+ (0303)
*Cumulative Incidence
p=0.068
85
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Days Post-Transplant0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
0101 and <=50 years (N=57)0101 and >50 years (N=27)0303 and <=50 years (N=25)0303 and >50 years (N=19)
Acute GVHD Grades II-IV in Patients < 50 Years of Age*
47.4% in Control < 50 (0101)
24% in CD34+ < 50 (0303)p=0.028
*Cumulative Incidence
86
Acute GVHD Grades III-IV *
Pro
babili
ty
0.0
0.2
0.4
0.6
0.8
1.0
Days Post-Transplant0 7 14 21 28 35 42 49 56 63 70 77 84 91 98
0101 (N=84)0303 (N=44)
p=0.31
9.5% in Control (0101)4.5% in CD34+ (0303)
*Cumulative Incidence
87
Limited/Extensive Chronic GVHD*
Pro
babi
lity
0.0
0.2
0.4
0.6
0.8
1.0
Months Post-Transplant0 1 2 3 4 5 6 7 8 9 10 11 12
0101 (N=84)0303 (N=44)
p=0.000449.9% in Control (0101)
15.9% in CD34+ (0303)
1 year post-hoc power for the comparison between 0101 and 0303 was 98%
*Cumulative Incidence
88
Infectious ComplicationsControl (0101)N=84
CD34+ Enriched (0303)N=44
# of Infectious Reports # of Patients
1-3 44 20
4-5 7 7
6-10 6 3
>10 0 2
Total # of Patients with Infections (% of Patients)
57
(67.9%)
32
(72.7%)
Patients with Infections
89
Control(0101)N=84
CD34+ Enriched (0303)N=44
# of Infections and (# of Patients)
Bacterial 103 (48) 62 (25)
Viral 46 (30) 41 (24)**
Fungal 9 (9)* 8 (5)
Protozoal 0 (0) 1 (1)
Other 4 (3) 0 (0)
Total Infection Events 162 112
Types of Infections Seen By Protocol
* Represents confirmed infections only; 10 possible and 3 presumptive infections not included
** 8 of 24 viral infections in CD34+ enriched cohort (0303) were due to EBV reactivation
90
Control (0101)N=84
CD34+ Enriched(0303)N=44
Maximum Severity by Patient# of Patients
(% of Patients)
None 28 (33.3%) 12 (27.3%)
Moderate 30 (35.7%) 15 (34.1%)
Severe 23 (27.4%) 13 (29.5%)
Life Threatening/Fatal 3 (3.6%) 4 (9.1%)
Infection Events
Percentage of all deaths due to infection were
18.2% in 0101 and 20% in 0303
91
Causes of Death atOne Year Post-Transplant
Control (0101)
N and % of Deaths
CD34+ Enriched (0303)
N and % of Deaths
Recurrence 9 (40.9%) 3 (30%)
Acute GVHD 1 (4.5%) 0
Chronic GVHD 1 (4.5%) 0
Infection 4 (18.2%) 2 (20%)
Interstitial Pneumonia 0 2 (20%)
Veno-occlusive Disease 1 (4.5%) 0
ARDS 1 (4.5%) 0
Organ Failure 5 (22.7%) 2 (20%)
PTLD 0 1 (10%)
Total 22 (23.1%) 10 (18.9%)
92
The incidence of chronic GVHD at one year post-transplant was significantly lower for recipients of CD34+ enriched allografts (p= 0.0004)
Between patients receiving CD34+ enriched versus unmanipulated grafts, there was no significant difference in: Platelet and Neutrophil Engraftment, Acute GVHD, DFS, OS,
TRM, and Relapse Low numbers of CR2 patients in both cohorts make statistical
comparisons of relapse inconclusive
DAP Statistical Comparison Summary
93
DAP Conclusion
The DAP results support a comparable safety profile for CD34+ enriched
transplants as compared to patients receiving unmanipulated grafts and conventional GVHD prophylaxis but
with a significant reduction in cGVHD
94
Kai Pinkernell, M.D.Head of Clinical Development
Miltenyi Biotec GmbH
Overall Conclusions of Safety and Probable Benefit of the CliniMACS® CD34 Reagent
System
95
The CliniMACS® CD34 Reagent System consistently produced a graft with > 2 x 106 CD34+ cells/kg and < 1 x 105 CD3+
cells/kg 84% of the grafts contained > 5 x 106 CD34+ cells/kg
There was no significant difference between CD34+ enriched and unmanipulated allografts for: Platelet and Neutrophil Engraftment, Acute GVHD, DFS, OS,
TRM, and Relapse
While 0303 patients experienced more infectious episodes/patient (112/44 patients in 0303 versus 162/84 patients in 0101), these did not translate to higher infectious death rates (18.2% of deaths in 0101 vs. 20% in 0303) Increased incidence of EBV reactivation reports most likely
due to stringent protocol specified monitoring of EBV in 0303
Performance and Safety ConclusionsCliniMACS® CD34 Reagent System
96
The CliniMACS® CD34 Reagent System was shown to consistently yield CD34+ enriched, T cell depleted, sterile cellular grafts in a multi-center setting
Low rates of both acute and chronic GVHD without the risks associated with traditional pharmacologic GVHD prophylaxis while maintaining consistent engraftment, excellent DFS and OS, low TRM, and a low incidence of relapse
Significantly reduced incidence of chronic GVHD without compromising survival
Probable Benefit Conclusions CliniMACS® CD34 Reagent System
97
Safety and Probable Benefit Objectives Met
The CliniMACS® CD34 Reagent System is safe, and has a probable benefit in
significantly reducing the incidence of chronic GVHD while eliminating the need for pharmacologic GVHD prophylaxis for
AML patients in complete remission, undergoing PBSC transplantation from a
matched related donor
98
Acknowledgements
BMT CTN NHLBI/NCI CIBMTR/EMMES/NMDP Investigators and Contributors
Steven Devine Marcelo Pasquini Carolyn Keever-Taylor Richard O’Reilly Robert Soiffer John Wingard Adam Mendizabal, EMMES Shelly Carter, EMMES Nancy DiFronzo, NHLBI Mary Horowitz, CIBMTR Nancy Poland, NMDP Many, Many others
The patients and their families who have made these trials possible
99
Thank You