Activation Date: February 15, 2010 Includes Update #5 CANCER

For NCI Use Only Version Date: 11/04/11

1

12/15/11

Activation Date: February 15, 2010 Includes Update #5

CANCER AND LEUKEMIA GROUP B

CALGB 30801

A RANDOMIZED PHASE III DOUBLE BLIND TRIAL EVALUATING SELECTIVE COX-2 INHIBITION IN COX-2 EXPRESSING ADVANCED NON-SMALL CELL LUNG CANCER

Celecoxib/Placebo (NSC #719627, CALGB IND #107051) will be supplied by the NCI PMB

Study Chair Martin J. Edelman, M.D.

University of Maryland Greenebaum Cancer Center 22 South Greene Street

Baltimore, Maryland 21201 Tel: 410-328-2703 Fax: 410-328-1975

[email protected]

Respiratory Committee Chair Respiratory Pathology Cadre Leader Everett Vokes, MD Richard Cheney Tel: 773-702-9306 Tel: 716-845-7700 Fax: 773-702-3002 Fax: 716-845-3427

[email protected] [email protected] Respiratory Correlative Sciences Chair Respiratory Correlative Sciences Co-chair

Robert Kratzke, MD Ginger Milne Tel: 612-626-3794 Tel: 615-936-5611 Fax: 612-625-6919 Fax: 615-322-3669 [email protected] [email protected]

PET Committee Chair PET Committee Co-chair

Mark Ratain, MD Michael Maitland, M.D., Ph.D. Tel: 773-702-4400 Tel: 773-834-8981 Fax: 773-702-3969 Fax: 773-834-0188

[email protected] [email protected]

Respiratory Faculty Statistician PET Faculty Statistician Xiaofei Wang, Ph.D. Kouros Owzar, Ph.D. Tel: 919-681-5406 Tel: 919-681-1829 Fax: 919-681-8028 Fax: 919-668-8028


Staff Statistician Lydia Hodgson, M.S. Tel: 919-681-1632 Fax: 919-681-8028

[email protected]

Data Coordinator Protocol Coordinator Edythe Parker Colleen RB Watt

Tel: 919-668-9365 Tel: 773-702-4670 Fax: 919-668-9348 Fax: 312-345-0117


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CALGB Central Office 230 West Monroe Street, Suite 2050

Chicago, IL 60606 Tel: 773-702-9171 Fax: 312-345-0117

www.calgb.org

Adverse Event Reporting http://ctep.cancer.gov/reporting/adeers.html

CALGB Pathology Coordinating Office The Ohio State University

Innovation Centre 2001 Polaris Parkway Columbus, OH 43240

Tel: 614-293-7073 Fax: 614-293-7967 [email protected]

CALGB Statistical Center Hock Plaza

2424 Erwin Road, Suite 802 Durham, NC 27705 Tel: 919-668-9350

Data Operations Fax: 919-668-9348 Biostatistics Fax: 919-681-8028

CALGB Patient Registration Tel: 919-668-9396 Fax: 919-668-9397

CALGB 30801 Pharmacy Contact Carol Hubbard, RPh Tel: 315-342-6215

[email protected]

CALGB 30801 Nursing Contact Michelle Bedor-Turner

Tel: 410-328-3929 [email protected]

This study is supported by the NCI Cancer Trials Support Unit (CTSU). Institutions not aligned with CALGB will participate through the CTSU mechanism as outlined

below and detailed in the CTSU logistical appendix. This trial is open only to US and Canadian sites for both CALGB and the CTSU.

• The study protocol and all related forms and documents must be downloaded from the protocol-specific Web page of the CTSU Web site located at http://www.ctsu.org

• Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU logistical appendix for specific instructions and documents to be submitted.

• Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for specific instructions and forms to be submitted.

• Data management will be performed by the CALGB. Case report forms (with the exception of patient enrollment forms), clinical reports, and transmittals must be sent to CALGB unless otherwise directed by the protocol. Do not send study data or case report forms to the CTSU Data Operations.

• Data query and delinquency reports will be sent directly to the enrolling site by CALGB (generally via e-mail but may be sent via fax or postal mail). Please send query responses and delinquent data to CALGB and do not copy the CTSU Data Operations. Query responses should be sent to CALGB via postal mail (no transmittal form needs to accompany response). Each site should have a designated CTSU Administrator and Data Administrator and must keep their CTEP IAM account contact information current. This will ensure timely communication between the clinical site and the CALGB Statistical Center.

Lead Group – Investigators from this Group should enroll patients through CALGB. CALGB Ordering Group(s) – Investigators must have a current affiliation with one of these Groups to receive investigational agent and / or an Investigator’s Brochure for this protocol.

CALGB and CTSU Endorsing Groups–Investigators from these Groups must enroll patients via the CTSU.

SWOG Karen L. Reckamp, M.D.

626-256-4673 [email protected]

The pharmacogenomic component of this study is conducted as part of the NIH Pharmacogenomics Research Network, which is funded through a separate U01 mechanism (see http://www.nigms.nih.gov/pharmacogenomics/research_net.html) for details

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Patient Pre-registration Eligibility Criteria Required Initial Laboratory Values (Pre-reg and Reg)

Histologically or cytologically documented NSCLC Granulocytes ≥1,500/µl Stage IV and selected stage IIIB (Section 4.1.2) Platelets ≥100,000/µl Tissue specimen required No untreated CNS metastases (Section 4.1.2)

Calculated Creatinine Clear.

≥ 45 ml/min

Measurable or non-measurable disease (Section.4.1.3). Bilirubin ≤1.5 mg/dl No prior chemotherapy, immunotherapy or systemic AST and ALT ≤2.0 x ULN (up to treatments for NSCLC including adjuvant therapy. ≥2 weeks since prior surgery and recovered

Reg only:

5 x ULN if liver mets)

ECOG PS 0-2 Serum albumin ≥ 2.5 g/dl Age ≥18 years. No concurrent malignancy (Section 4.1.6). No known hypersensitivity to aspirin, NSAIDs or sulfonamides No active ulcer disease. No treatment with other investigational therapy. No chronic therapy w/ non-steroidal anti-inflammatory drugs (Section 4.1.10). No cardiac disease (Section 4.1.11) Patients must be able to swallow capsules. Non-pregnant and non-nursing Patient Registration Eligibility Criteria COX-2 index ≥ 2 Prior radiotherapy must be completed 2 weeks before protocol therapy begins.

Schema: 1 cycle = 21 days

* Patients treated with prior chest radiotherapy should receive carboplatin at an AUC=5.0 when combined with gemcitabine.

Treat patients for a maximum of 6 cycles. For responding or stable disease after 6 cycles, continue treatment with celecoxib/placebo beyond 6 cycles until tumor progression or unacceptable toxicity. Discontinue all protocol therapy for disease progression or unacceptable toxicity.

ARM A For Squamous Carcinoma: Gemcitabine 1000 mg/m2 IV d 1,8 Carboplatin AUC = 5.5* IV d 1 Celecoxib 400 mg (1 capsule) po bid OR For Non-squamous Carcinoma: Pemetrexed 500 mg/m2 IV d 1 w/ pre-meds Carboplatin AUC = 6 IV d 1 Celecoxib 400 mg (1 capsule) po bid

ARM B For Squamous Carcinoma: Gemcitabine 1000 mg/m2 d 1,8 Carboplatin AUC = 5.5* IV d 1 Placebo (1 capsule) po bid OR For Non-squamous Carcinoma: Pemetrexed 500 mg/m2 IV d 1 w/ pre-meds Carboplatin AUC = 6 IV d 1 Placebo (1 capsule) po bid

PRE-REG I STER

COX-2 ≥2

COX-2 <2

Not registered; treat at physician’s discretion

Tissue submission for COX-2 testing by IHC

REG I STER/RANDOMI ZE

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TABLE OF CONTENTS SECTION PAGE

1.0 INTRODUCTION ...........................................................................................................5

2.0 OBJECTIVES..............................................................................................................11

3.0 ON-STUDY GUIDELINES ............................................................................................12

4.0 ELIGIBILITY CRITERIA ...............................................................................................12

5.0 PRE-REGISTRATION, REGISTRATION/RANDOMIZATION AND STRATIFICATION .......14

6.0 DATA AND SAMPLE SUBMISSION ..............................................................................17

7.0 REQUIRED DATA .......................................................................................................21

8.0 TREATMENT PLAN .....................................................................................................22

9.0 DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES ....................................24

10.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION.........................................27

11.0 ANCILLARY THERAPY.................................................................................................34

12.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE ......................................35

13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY...............................................40

14.0 STATISTICAL CONSIDERATIONS................................................................................40

15.0 CORRELATIVE SCIENCES METHODOLOGY...............................................................45

16.0 ADVERSE EVENT (AER) REPORTING .........................................................................50

17.0 REFERENCES ............................................................................................................52

18.0 MODEL CONSENT FORM ...........................................................................................56

APPENDIX I CTSU LOGISTICS ...............................................................................................69

APPENDIX II CRADA LANGUAGE...........................................................................................73

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1.0 INTRODUCTION

Of 150,000 patients who will develop non-small cell lung cancer (NSCLC) in the United States in the next year, at least 40% will present with metastatic disease, and the vast majority of the remainder will eventually develop metastases. Recent advances in chemotherapy have improved the outlook for patients with Stage IV disease. Studies employing “best supportive care” result in a 4-6 month median survival with only 10% of patients alive at one year. By comparison, median survival of about 6-8 months and one year survival of 20% are achieved with “older” platinum (cisplatin or carboplatin) based regimens (e.g., single-agent platinum, cisplatin/etoposide, cisplatin/vindesine). Most recent studies evaluating combinations of platinums with “newer agents” (carboplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/vinorelbine) have reported improved median survivals to 8-10 months with one year survival of 30-35%, and/or reduced toxicity relative to older combinations (1-3)

The recently reported results of the Eastern Cooperative Oncology Group trial (ECOG 1594) compared four platinum-based “new drug regimens”: cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel and carboplatin/paclitaxel and found all to be roughly equivalent in terms of response and survival. The regimen of cisplatin/gemcitabine was significantly superior in terms of time-to-progression while the regimen of carboplatin/paclitaxel was superior in terms of toxicity (4). Supporting the conclusion of the equivalence of these regimens were the results of SWOG 9509 which demonstrated similar response and survival for cisplatin/vinorelbine and carboplatin/paclitaxel (5). Though these results represent a therapeutic advance, only 10-15% of patients will survive two years, and there are few long-term survivors.

Recently ECOG presented data (ECOG 4599) demonstrating that bevacizumab (Avastin) was beneficial in selected patients with advanced NSCLC. This study compared carboplatin/paclitaxel (AUC =6 and 200 mg/m2, respectively) vs. the same doses of chemotherapy with bevacizumab (15 mg/kg), all drugs administered q21 days. A significant advantage was found for patients on the experimental arm in terms of response, median and one-year survival. However, this study involved a highly selected population, excluding individuals with squamous cell carcinoma, CNS metastases, bleeding or thrombotic disorder or a history of hemoptysis.

1.1 COX-2 inhibition (Celecoxib)

Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to prostaglandins is overexpressed in a variety of malignancies. Khuri and colleagues demonstrated that overexpression of COX-2 is common in non-small cell lung cancer and associated with poor prognosis (5). Nearly 80% of NSCLC express the COX-2 enzyme (6,7). COX-2 has been shown to be expressed not only in the tumor cells but also in the tumor vasculature (8,9). Inhibition of COX-2 has resulted in reduced proliferation of cancer cells in vitro (10). Celecoxib, a selective inhibitor of COX-2, inhibits tumor growth of Lewis lung carcinoma implanted in mice in a dose-dependent manner. The extent of inhibition ranges from 48% to 85% with increasing doses of celecoxib (9). A selective COX-2 inhibitor, ns-398, enhanced the effects of radiation in COX-2 overexpressing cells (11). In addition, it has recently been shown that expression of COX-2 could be associated with overexpression of p-glycoprotein (12). Inhibition of COX -2 could potentially reverse drug resistance. Several selective COX-2 inhibitors are now commercially available. Selective COX -2 inhibitors, such as celecoxib, have the potential to inhibit tumor angiogenesis and metasases and might serve as ideal agents for long term maintenance therapy. Celecoxib is generally well tolerated and has no overlapping toxicities with standard chemotherapy agents (carboplatin, gemcitabine, paclitaxel and docetaxel). Celecoxib is a proven and approved agent for the reduction of adenomatous polyps (a premalignant lesion) in patients with familial adencomatous polyposis (13).

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Several trials have evaluated cyclooxygenase inhibition in general, and COX-2 inhibition specifically, in lung cancer. Of note, there is considerable epidemiological evidence that inhibition of cyclooxygenase is effective for the prevention of lung cancer (14). Csiki et al evaluated the combination of celecoxib and docetaxel for second-line treatment of metastatic NSCLC (15). There was no overall survival benefit; however, patients who had evidence of inhibition of urinary PGE-M levels (a metabolite of PGE-2, the product of COX-2) had prolonged survival compared to other patients. Part of this benefit may come from inhibition of COX-2 expression induced by chemotherapy. Altorki et al evaluated COX-2 expression after neoadjuvant chemotherapy (carboplatin/paclitaxel) in localized lung cancer and found that intratumoral levels were 3-fold higher than patients who did not receive chemotherapy. However, this effect was abrogated when celecoxib was administered concurrently with chemotherapy (16).

1.2 CALGB 30203

CALGB 30203 tested the concept of eicosanoid inhibition in advanced lung cancer (17). The hypothesis was that eicosanoid inhibition in addition to standard chemotherapy would potentially increase progression free survival. Furthermore, the concept of single vs. double pathway inhibition was tested with inhibitors of COX-2 and 5-LOX as both single agents and in combination. A pilot trial at the University of Maryland demonstrated that the combination of celecoxib and zileuton was well tolerated when combined with either carboplatin/gemcitabine or carboplatin/paclitaxel. CALGB 30203 enrolled 140 patients in under one year. Neither the population as a whole nor any of the three arms achieved the predetermined criterion for a successful outcome. However, the study required the submission of tissue specimens. We had also hypothesized that immunohistochemistry (IHC) for COX-2 and/or 5-LOX might identify a population of patients who would be particularly benefited by this strategy. Of 107 specimens submitted, 80 were of adequate quality for analysis. This analysis demonstrated the following:

1. Analysis of arm A (chemotherapy + zileuton, the 5-LOX inhibitor) demonstrated that patients with overexpression of COX-2 had a worse overall survival than those who did not have overexpression (HR for moderate overexpression = 2.68 , p = 0.018 ). For those with high levels of overexpression the result was even more dramatic, with a HR of 4.16, p=0.009. This is the first prospective confirmation that COX-2 overexpression is a negative prognostic factor.

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4.3 (3.1,6.7)

4.7 (3.2,6.7)

3.9(3.1,5.2)

14.7 (7.3,22.3)

14.7 (9.4,22.3)

13.3 (7.3, )

MST (low expression) (mo)

3.8 (3.3,4.2)

.2921.680 (.641,4.403)

>9 (6)FFS

3.4 (0.8,6.4)

.0972.00(.883,4.530)

>4 (11)FFS

4.2 (2.9,7.7)

.2020.600 (.237,1.315)

>1 (17)FFS

4.0 (3.4,6.5)

.0094.155 (1.437,12.014)

>9 (6)Survival

3.8(0.9,10.5)

.0182.683 (1.195,6.856)

>4 (11)Survival

7.1 (3.4,16.7)

.4031.459 (0.602,3.540)

>1 (17)Survival

MST (high expression)(mo)

P-value

HR (95% CI)Cut point of COX-2 index (n)

Endpoint

2. Patients receiving celecoxib (with or without zileuton) who had overexpression of COX-2 had a superior outcome compared with patients with overexpression who did not receive celecoxib.

6.5(5.5,10.5)

3.8 (3.3,4.2)

.009.218 (0.070,.681)>9 (6,14)FFS

6.5(4.8,8.4)

3.4(0.8,6.4)

.006.312(0.135,0.718)

>4 (11,21)FFS

3.9(2.8,4.6)

3.9 (3.1,5.2)

.707.866 (.408,1.835)<1 (12,18)FFS

11.3 (8.0, )

4.0 (3.4,6.5)

.006.194 (.060..629)

>9 (6,14)Survival

10.6 (8.3,17.6)

3.8 (0.9,10.5)

.039.420 (0.184,.9555)

>4 (11,21)Survival

8.1 (4.9,14.9)

13.3 (7.3, )

.1781.843 (.757,4.485)

<1 (12,18)Survival

Did receive celecoxib(mo)

Did notreceive celecoxib(mo)

P-valueHR (95% CI)Cut point of COX-2 index (n for A vsB/C)

Endpoint

3. The higher the degree of COX-2 overexpression the greater the degree of benefit

from celecoxib. Those with moderate to high expression (i.e. >4) had a HR of 0.420, p=0.039, while those with high levels of expression (i.e. >9) had a HR of

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0.194, p=0.006. There appeared to be a steadily increasing level of benefit with increased COX-2 expression. The overall population for COX-2 ≥ 2 had a HR of 0.879 (p = ns). However, the number of patients with COX-2 index of 2-3 was very small.

4. Patients who did not demonstrate overexpression of COX-2 (i.e., COX-2 index = 0) and received celecoxib appeared to have an inferior outcome, HR = 1.84, p=0.178. For patients with COX-2 index <2, the HR was 1.455.

5. Multivariate analysis considering potentially confounding factors of stage (IIIb vs. IV), sex and performance status, confirmed the independent predictive value of COX-2 expression and response to celecoxib (with a HR = 0.17 (0.06, 0.49), P=0.0011).

6. 5-LOX expression was neither prognostic nor predictive.

These findings lead to the current hypothesis: inhibition of COX-2 with celecoxib can improve outcome in patients with a moderate or higher degree of tumor COX-2 expression, defined as a COX-2 index of ≥ 4. Given the small numbers of patients, it is possible that those with lower levels of COX-2 expression, i.e., ≥2, may also benefit. The finding that a negative prognostic marker is a positive predictive marker for a therapy targeting that marker is reminiscent of HER-2-neu and trastuzumab. Interestingly, a similar finding for COX-2 has been reported in renal cell carcinoma in which a small study of interferon alpha + celecoxib demonstrated the best results for the COX-2 overexpressing patients despite the fact that these patients demonstrated several other negative prognostic variables in addition to COX-2 overexpression (18). This small (n=25) study evaluated interferon alpha + celecoxib. Only patients who overexpressed COX-2 demonstrated measurable response and increased time to progression. Importantly, there are supporting data from other lung cancer studies. A multicenter trial of gefitinib + celecoxib in second-line NSCLC has recently been reported with negative overall results. However, tissue was obtained from 21 patients, evenly divided between COX-2 non-expressing and overexpressing patients. COX-2 overexpressing patients had substantially superior survival (p=0.03) (19). A study in metastatic breast cancer combining capecitabine with celecoxib also noted significantly improved progression-free and overall survival for patients with moderate-to-high levels of COX-2 expression (20). Further supporting the concept of a selective effect of COX-2 inhibition on COX-2 expressing malignancy is a recent report from a large retrospective study (n=130,274) that demonstrated that aspirin, a nonselective COX inhibitor, only suppressed COX-2 expressing colorectal cancers (21). An industry sponsored phase III study adding celecoxib to chemotherapy in advanced NSCLC has been completed and did not demonstrate a survival advantage. However, as this study was done in an unselected population of patients, it is not relevant to the current study.

1.3 Justification for a Phase III trial

A phase III trial represents an enormous expenditure of time and resources. The many recent negative Phase III trials with a diverse group of promising agents (e.g. erlotinib, gefitinib, bexarotene, etc) indicate that a phase III trial should be undertaken only after considerable thought. There should be clear pre-clinical and clinical evidence to justify a phase III study. The current evidence for COX-2 inhibition meets these criteria.

1. COX-2 inhibition (celecoxib) has unequivocal effect in the prevention of colorectal cancer. There is no question that celecoxib is an effective chemopreventive agent.

2. The population most likely to benefit can be clearly identified.

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3. Strong preliminary evidence from a multicenter, cooperative group trial, i.e., CALGB 30203 exists. Obtaining tissue was feasible and accrual rapid despite the 3-arm design.

4. The results of CALGB 30203 are biologically plausible and supported by other studies.

5. Celecoxib is well tolerated. The side-effect profile of this agent is superior to that of virtually any other anticancer drug. Adverse cardiovascular effects are relatively uncommon and, while not acceptable in the management of minor ailments, would be acceptable for life-prolonging therapy in advanced NSCLC.

1.4 Toxicity Issues

There has been significant concern regarding the safety of selective COX-2 inhibitors. Significant cardiovascular complications (stroke, myocardial infarction) led to withdrawal of rofecoxib from the market. In December 2004, the Adenoma Prevention with Celecoxib trial was halted prematurely due to increased risk of cardiovascular death from the drug (22). As noted above, though this trial was halted due to toxicity concerns, it was unequivocally positive in demonstrating a marked decrease in colorectal adenomas and carcinoma, confirming the chemopreventive benefit of celecoxib. While it appears that this benefit is not obtained at an acceptable degree of risk in the prevention of cancer, the treatment of established disease is a completely different matter and must be viewed in the context of other active anticancer agents. The cardiotoxicity of celecoxib is relatively infrequent and far less than that of accepted cancer treatments, including anthracyclines and trastuzumab. Several recent trials, including CALGB 30203, did not demonstrate any significant number of cardiovascular deaths. Therefore, in this scenario, the potential benefits outweigh the small risk involved.

1.5 Current Trial Design

The primary endpoint for this trial will be progression free survival for those patients with COX-2 index ≥ 4. This is based upon the findings that this group demonstrated significantly improved PFS and OS on CALGB 30203. However, as there were too few patients with COX-2 index of 2-3 to exclude a potential benefit, those patients will also be eligible for this trial, but will be analyzed separately.

In CALGB 30203 the “core regimen” employed was carboplatin/gemcitabine. Since that study there have been several developments in the chemotherapy of advanced NSCLC. Specifically, the approvals of bevacizumab and pemetrexed for first line use in non-squamous carcinoma. Bevacizumab was approved in combination with carboplatin/paclitaxel based upon ECOG 4599 (42) This trial randomized patients between carboplatin/paclitaxel with or without bevacizumab 15 mg/kg and demonstrated an improved overall and median survival favoring the bevacizumab containing regimen. There was a significantly greater degree of neutropenic fever in the bevacizumab arm. A similar trial (AVAIL) has been reported with a randomization between cisplatin/gemcitabine and two bevacizumab containing arms (7.5 mg/kg and 15 mg/kg). This study demonstrated improved median but not overall survival. In general, studies utilizing bevacizumab have demonstrated a greater degree of both arterial and venous thromboembolic disease. Given the potential overlapping toxicity with celecoxib, the use of bevacizumab will not be permitted on this trial.

An industry sponsored trial compared pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on Day 1 of a 21-day cycle (PC) versus gemcitabine 1250 mg/m2 on Day 1 and Day 8 plus cisplatin 75 mg/m2 on Day 1 of a 21-day cycle (GC), met its primary endpoint and demonstrated that OS with PC was noninferior to GC, with significantly fewer side effects (43). In the intent-to-treat (ITT) population (all histologies), the 2 arms of the study were equivalent in terms of OS (unadjusted HR 0.93; 95% CI: 0.83

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to 1.04; median 10.3 months for both arms), PFS (unadjusted HR 1.04; 95% CI: (0.95 to 1.15); median PFS 4.8 and 5.1 months for the pemetrexed and gemcitabine arms, respectively), and RR (30.6% versus 28.2% for the pemetrexed versus the gemcitabine arm).

Preplanned analyses evaluating the differences in OS with respect to baseline patient and disease characteristics identified a differential effect on survival according to NSCLC histologic subgroups. Overall survival time with PC was statistically superior to GC in patients with nonsquamous histology (adjusted HR 0.844; 95% CI: 0.74 to 0.96; p = 0.01 ). For patients with squamous histology, overall survival time with PC was shorter than with GC (adjusted HR 1.229; 95% CI: 1.00 to 1.51; p = 0.050).

As a result of the above data both the U.S. Food and Drug Administration and the European Medicines Agency issued an approval for use of pemetrexed with cisplatin in the initial treatment of NSCLC other than predominantly squamous histology. Retrospectively, two other controlled trials comparing pemetrexed to other treatments in non-small cell lung cancer were evaluated for the influence of histology on outcomes. In the second line treatment of NSCLC after progression from first line platinum based chemotherapy comparing pemetrexed to docetaxel (44). It is hypothesized that the selective benefit of pemetrexed in non-squamous lung cancer relates to the relatively low levels of thymidylate synthase present in those histologies.

The combination of pemetrexed and carboplatin has been extensively evaluated. A Phase 1 mesothelioma study verified the safety of the combination (45). A 32% RR was noted, with acceptable toxicity. The industry sponsored Phase 2 studies examined pemetrexed with carboplatin and vitamin supplementation to determine whether the combination would maintain the efficacy achieved with pemetrexed plus cisplatin in advanced NSCLC. Scagliotti et al reported a study of 83 chemonaive patients with Stage IIIB or IV NSCLC who were randomized to receive pemetrexed 500 mg/m2 plus either carboplatin area under the curve (AUC) 6 (41 patients) or oxaliplatin 120 mg/m2 (42 patients) on Day 1 of a 21-day cycle, for up to 6 cycles of therapy (46). In the pemetrexed-carboplatin arm, 12 of the 38 evaluable patients (31.6%) had best overall response of PR and 17 (44.7%) had best overall response of SD. Median TTP was 5.7 months, the 1-year survival rate was 43.9%, and median OS was 10.5 months. Grade 3/4 neutropenia was observed in 10 (25.6%) of 39 patients evaluable for safety. Grade 3/4 thrombocytopenia was reported in 7 (17.9%) patients. Grade 3 events also included anemia and fatigue, each reported in 3 (7.7%) patients, and stomatitis and febrile neutropenia, each reported in 1 (2.6%) patient. One (2.6%) patient experienced Grade 4 infection without neutropenia. Zinner reported a trial of 50 chemonaive patients with Stage IIIB (with effusion) or IV NSCLC who received pemetrexed 500 mg/m2 and carboplatin AUC 6 on Day 1 every 3 weeks for 6 cycles (47). Twelve patients (24%) had PRs, and 25 (50%) had SD. Median TTP was 5.4 months, the 1-year survival rate was 56%, and median OS was 13.5 months. Grade 3/4 neutropenia was observed in 13 (26%) patients. One (2%) patient had Grade 3 thrombocytopenia, and 1 (2%) patient had Grade 4 anemia. Three (6%) patients experienced Grade 3 nonhematologic side effects (nausea, fatigue, diarrhea, and vomiting). These Phase 2 trials demonstrated that the combination of pemetrexed with carboplatin is tolerable and that its activity in first-line treatment of advanced-stage NSCLC is comparable to other standard platinum doublets. The toxicity with the pemetrexed and carboplatin combination appears to be less than that seen with other standard regimens in first-line NSCLC.

Given the emerging data regarding the selective efficacy of pemetrexed regimens for nonsquamous carcinoma, this study will utilize the regimen of carboplatin/pemetrexed for those histologies. Patients with NSCLC with histologies of adenocarcinoma, large cell carcinoma, undifferentiated or not otherwise specified will be treated with carboplatin/pemetrexed. Patients with mixed histologies will be treated based upon the predominant histology.

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The approval for pemetrexed specifies that the agent should not be utilized concurrently with NSAIDs (48). This restriction was based upon prior experience with altered clearance with methotrexate, most likely due to competition for renal tubular secretion resulting in increased systemic exposure. However, more recent data demonstrates that patients with preserved renal function can receive pemetrexed simultaneously with NSAIDs with only mild increases in exposure (49). Therefore, in CALGB 30801, patients will receive celecoxib/placebo concurrently with the carboplatin/pemetrexed regimen.

1.6 Inclusion of Women and Minorities

Both men and women of all races and ethnic groups are eligible for this study without alteration in eligibility criteria. There is currently no evidence to suggest that differences in response to treatment exist between groups on the basis of gender or race. Exploratory analyses will be conducted using Cox's proportional hazards model to determine whether treatment differences in survival are consistent across men and women, and are also consistent among races.

2.0 OBJECTIVES

2.1 Primary Objective

To confirm the beneficial effect of COX-2 inhibition in patients who have NSCLC that expresses COX-2. The primary endpoint is to demonstrate improvement in progression-free survival in patients with a COX-2 index ≥4 with an estimated hazard ratio of 0.6.

2.2 Secondary Objectives

2.2.1 To describe the response rate, as well as the distribution of progression free survival and overall survival.

2.2.2 To compare progression free survival between treatment arms for patients with COX-2 ≥2. The comparison will also be made adjusting for CYP2C9 genotype and celecoxib trough concentrations as covariates.

2.2.3 To correlate urinary PGE-M level with COX-2 expression, COX-2 inhibition and outcome.

2.2.4 To evaluate the association between the -765G/C polymorphism in PTGS2 and COX-2 expression in non-small cell lung cancer specimens.

2.2.5 To characterize a trough plasma celecoxib concentration which will be used as a measure of patient adherence to protocol treatment and which may be used in the future in correlations with genotype and pharmacodynamic outcomes of the study.

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3.0 ON-STUDY GUIDELINES

The following guidelines are to assist physicians in selecting patients for whom protocol therapy is safe and appropriate. Physicians should recognize that the following may seriously increase the risk to the patient entering this protocol:

• Psychiatric illness, which could prevent the patient from giving informed consent or compliance with treatment.

• Medical conditions such as uncontrolled infection (including HIV), interstitial pneumonia, fibroid lung, uncontrolled diabetes mellitus, inability to take oral medications, malabsorption or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient.

• Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the chemotherapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives (Norplant), or double-barrier method (diaphragm plus condom).

• Life expectancy ≥3 months.

4.0 ELIGIBILITY CRITERIA

4.1 Pre-registration Eligibility Criteria

4.1.1 Histologic documentation: All patients must have histologically- or cytologically- documented, non-small cell carcinoma of the lung (adenocarcinoma, large cell, squamous, or mixtures of these types). A tissue block must be available at the time of registration.

4.1.2 Extent of Disease (AJCC v. 6)

• Patients with Stage IIIB because of a malignant pleural effusion are eligible. Patients with supraclavicular node involvement or contralateral hilar nodes are eligible providing they are not candidates for potentially curative chemoradiotherapy.

• Patients with Stage IV disease are eligible. Patients with recurrent disease, not amenable to (or refusing) a potentially “curative therapy,” are eligible.

• Patients with CNS metastases that are symptomatic must have received therapy (surgery, XRT, gamma knife) and be neurologically stable and off of steroids. The patient should be off steroids at least 14 days before registration. Asymptomatic CNS metastatic disease without associated edema, shift, requirement for steroids or antiseizure medications are eligible after discussion with the Study Chair. Patients with leptomeningeal disease or carcinomatous meningitis are NOT eligible.

4.1.3 Patients must have Measurable or Non-measurable Disease

Measurable Disease Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral CT scan.

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Non-measurable Disease All other lesions, including small lesions (longest diameter < 20 mm with conventional techniques or < 10 mm with spiral CT scan) and truly non-measurable lesions.

Lesions that are considered non-measurable include the following:

• Bone lesions

• Leptomeningeal disease

• Ascites

• Pleural/pericardial effusion

• Inflammatory breast disease

• Lymphangitis cutis/pulmonis

• Abdominal masses that are not confirmed and followed by imaging techniques

• Cystic lesions

4.1.4 Prior Treatment:

No prior chemotherapy, immunotherapy or systemic treatments for NSCLC, including adjuvant therapy;

≥ 2 weeks since prior surgery and completely recovered

4.1.5 ECOG Performance Status: 0-2

Age ≥18 years

4.1.6 No “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse.

4.1.7 No known hypersensitivity to aspirin, non-steroidal anti-inflammatory agents, or sulfonamides.

4.1.8 No active ulcer disease. No history of GI bleeding within the past three years.

4.1.9 No treatment with other investigational therapy.

4.1.10 Patients who are chronically (i.e., > 4 weeks of daily use) utilizing a regimen of another NSAID are not eligible. Such medications include: aspirin (≤325 mg daily is allowed), celecoxib, choline Mg, trisalicylate (Trilisate), or other non-steroidal anti-inflammatory drugs such as ibuprofen (Advil or Motrin), naproxen (Aleve, Naprosyn or Anaprox), etodolac (Lodine), oxaprozin (Daypro), diflunisal (Dolobid), nabumetone (Relafen), tolmetin (Tolectin), or valdecoxib (Bextra). Patients currently receiving NSAIDs must be off all NSAIDs (except low dose aspirin) for at least 14 days prior to treatment.

4.1.11 No myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, cerebrovascular accident or transient ischemic attack, pulmonary embolism, symptomatic carotid artery or peripheral vascular disease, deep vein thrombosis, or other significant thromboembolic event in the past 6 months.

4.1.12 Non-pregnant and non-nursing because of significant risk to the fetus/infant.

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4.1.13 Required Initial Laboratory Data:

Granulocytes ≥1,500/µl Platelets ≥100,000/µl Calculated Creatinine Clearance ≥ 45 ml/min Bilirubin ≤1.5 mg/dl AST and ALT ≤2.0 x ULN (≤ 5.0 x ULN if liver mets)

4.2 Registration Eligibility Criteria

4.2.1 COX-2 index ≥2

4.2.2 Prior radiotherapy: Prior radiation therapy must be completed two weeks before protocol therapy begins.

4.2.3 Registration Laboratory Requirements

Granulocytes ≥1,500/µl Platelets ≥100,000/µl Calculated Creatinine Clearance ≥ 45 ml/min Bilirubin ≤1.5 mg/dl AST and ALT ≤2.0 x ULN (≤ 5.0 x ULN if liver mets) Serum albumin ≥ 2.5 g/dl

5.0 PRE-REGISTRATION, REGISTRATION/RANDOMIZATION AND STRATIFICATION

Patients with a tissue specimen available will be eligible for pre-registration. The tissue will be submitted for COX-2 testing, and those patients with COX-2 index ≥2 will be registered/randomized.

The CT/MRI scan is required within 30 days prior to registration. The scan may be obtained after pre-registration, but must be obtained prior to registration.

5.1 Pre-registration Requirement

Informed Consent: The patient must be aware of the neoplastic nature of his/her disease and willingly consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts. Human protection committee approval of this protocol and consent form is required.

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5.2 Patient Pre-registration Procedures

This study uses the CALGB Web-based Patient Registration system. Pre-registration will be accepted only through CALGB Main Member Institutions, selected affiliate institutions and CCOPs using the Web-based Patient Registration system. Confirm pre-eligibility criteria (Section 4.1). Complete the Pre-registration Worksheet. Access the Web-based Patient Registration system via the Patient Registration tab on the CALGB Member Website at www.calgb.org. If the study does not appear on the list of studies in the Patient Registration system, the registration must be performed by the CALGB Registrar via phone or fax. If the registering CRA requires assistance, he/she may consult the on-line help file at the bottom of the screen or call the IS Help Desk at 1-888-44CALGB. If further assistance is required, the registering CRA may call the CALGB Registrar (919)-668-9396, Monday-Friday, 9 AM – 5 PM, Eastern Time. Enter the following information:

CALGB patient ID #, if applicable Study Name of group (CALGB) Name of institution where patient is being treated Name of treating physician NCI investigator number Name of person in contact with the patient record (responsible contact) CRA’s name, telephone number and e-mail address Protocol IRB approval date Date of signed consent Treatment Start Date Date [of] HIPAA authorization signed by the patient Patient’s initials Patient’s gender Patient’s race Patient’s ethnicity ECOG performance status Patient’s height (cm) and weight (kg) Type of insurance (Method of Payment) Patient’s postal code Disease, type and stage, if applicable Eligibility criteria met (no, yes) Companion studies patient has consented

When the patient is pre-registered, a CALGB patient identification number will be generated. Please write the number in your records, as it will be needed for the registration/randomization.

The Main Member Institution and registering institution will receive a Confirmation of pre-registration. Please check the confirmation for errors. Submit corrections in writing to the data coordinator at the CALGB Statistical Center, Data Operations, 2424 Erwin Rd, Ste 802 Hock Plaza, Durham, NC 27705, or fax to 919-668-9397.

5.3 Patient Registration/Randomization Procedures

Tumor specimens must be submitted for COX-2 analysis at pre-registration. Upon completion of COX-2 analysis at the CALGB Pathology Coordinating Office (PCO), the results will be sent (within 72 hours of specimen receipt) to the CALGB Statistical Center; the PCO will also notify the institution of eligibility status within 72 hours. Those patients that have a COX-2 score <2 will not be registered/randomized. Those patients with a COX-2 score ≥2 should be registered/randomized. To register/randomize the patient access the Web-based Patient Registration system via

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the Patient Registration tab on the CALGB Member Website at www.calgb.org. Enter the CALGB ID number obtained at pre-registration and the stratification factors into the online registration system.

NOTE: No blinded starter supplies will be available for this study. Initial blinded, patient-specific clinical supplies of celecoxib / placebo will be shipped from the Pharmaceutical Management Branch (PMB) to the registering investigator at the time of patient randomization and should arrive within 10 to 14 days of randomization (see Section 10.7).

Registration to the optional PET and correlative science substudies will be done at the same time as registration to the treatment study. Registration to both the treatment trial and the substudies will not be completed if eligibility requirements are not met.

5.4 Registration to Companion Studies

There are two substudies within CALGB 30801. These correlative science studies must be offered to all patients enrolled on CALGB 30801 (although patients may opt to not participate). These substudies does not require separate IRB approval. The substudies included within CALGB 30801 are:

• CALGB 150908: Urinary PGE-M (see Section 15.2)

• CALGB 60904: PG and PK studies (Sections 15.3 and 15.4)

If a patient answers “yes” to “I agree that my blood may be used for the research study described above” question #1 in the model consent, they have consented to participate in CALGB 60904. If a patient answers “yes” to “I agree that my specimens may be used for the research described above” question #2 in the model consent, they have consented to participate in CALGB 150908.

The patient should be registered to CALGB 150908 and CALGB 60904 at the same time they are randomized to the treatment trial (CALGB 30801). Samples should be submitted per Section 6.1.2, 6.1.3, and 6.1.4.

5.5 Stratification Factors

Sex: Male vs. female

Stage: IIIB vs. IV

Histology: Squamous vs. non-squamous

Smoking status: Never/former light smoker (defined as ≤10 pack years AND quit ≥ 1 year ago) vs smoker

COX-2 expression status: COX-2 index ≥4 vs COX-2 index ≥2 but <4 (to be entered by the Statistical Center; both patient and institution are blinded to this)

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6.0 DATA AND SAMPLE SUBMISSION

Forms should be submitted to the CALGB Statistical Center, Data Operations, in compliance with the Data Submission schedule below. There are three options for submitting forms that use the Teleform barcode and cornerstones:

• The forms may be faxed to 919-416-4990. Please note that the four cornerstones and the form id (“bitmap”) must appear on the form. Copies must be 100% of the original form size.

• The forms may be mailed to the CALGB Statistical Center, Hock Plaza, 2424 Erwin Road, Suite 802, Durham, NC 27705. Please note that the four cornerstones and the form id (“bitmap”) must appear on the form. Copies must be 100% of the original form size.

• Data may be entered electronically by logging onto the CALGB web site and locating the specific web-ready form.

Form* Submission Schedule Pre-Registration1

C-1872 C-1873

30801 COX-2 Sample Submission Form 30801 Sample Submission Form (for those patients that consent to 60904))

Submit to PCO with pre-registration sample. Submit copy to CALGB Statistical Center.

Baseline C-1868 30801 On-Study Report Pathology/Cytology Report Report Baseline CT Scan or MRI Reports C-2000 Solid Tumor Evaluation Form (RECIST 1.1)

Within one month of registration

C-1959 Non-small cell lung cancer staging form

Sample Submission

C-1873 30801 Specimen Submission Form Submit copy to PCO with samples to PCO and original to Statistical Center.

C-1917 30801 PK Sample Submission Form Submit copy to Dr. Egorin’s lab

with samples and original to Statistical Center

During Treatment2 C-1869 30801 Treatment Form C-1870 30801 Adverse Event Form3

Each cycle during protocol therapy.

C-1871 30801 Follow-up and Response Form C-2000 Solid Tumor Evaluation Form (RECIST 1.1) Report CT Scan or MRI Reports

Every 2 cycles during protocol therapy.

Follow-up (Post-treatment)4 C-1871 Follow-up and Response Form C-2000 Solid Tumor Evaluation Form (RECIST 1.1) Report CT Scan or MRI Reports

Every 2 months for 2 yrs, then every 6 months for 3 yrs. (After progression submit only C-1871.)

This study will use NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for routine toxicity reporting on study forms.

* Use CALGB Remarks Addenda (C-260) if additional comments are necessary or additional writing space is needed.

1 If patient is determined to be ineligible during COX-2 analysis, no additional data is required. Only submit C-1873 and PG samples for consenting patients.

2 S-060 30801 Medication Calendar has been provided for patient and institutional use. This form does not need to be submitted to the Statistical Center.

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3 Submit AE form until all protocol treatment related events have resolved or until non-protocol treatment begins.

4 If patient never starts treatment, submit the following: all baseline data, Form C-1869 to report the reason for not starting protocol therapy, C-1871, C-2000 and CT/MRI reports as specified in the follow-up (post-treatment) section.

6.1 Correlative Studies: The following sections will provide details about how specimens will be collected, when they will be collected, and where they will be submitted. Briefly, the samples which will be submitted as part of CALGB 30801 are as follows:

Timepoint Tissue to PCO for COX-2

testing (Section 6.1.1)

Blood to PCO for DNA

(Section 6.1.2)

Blood to Univ. of Pitt. for PK (Section 6.1.3)

Urine to PCO (Section 6.1.4)

Pre-registration X X

Prior to treatment X

8 days after start of celecoxib/placebo, Cycle 1*

X X

* Samples are to be collected eight days after the start of celecoxib/placebo therapy. Blood and urine should be obtained PRIOR to therapy on that day.

Tissue for COX-2 testing is required for all patients. Blood for DNA, blood for PK and urine studies must be offered to all patients, although patients may choose not to participate.

6.1.1 Tissue Sample Submission for Analysis of COX-2

COX-2 expression will be assessed in all patients prior to registration. Patients should not be pre-registered unless a paraffin block is available. The results of the COX-2 test will not be given to the physician or patient at any time. Submit an adequate sized paraffin block with tumor tissue/cells taken at the time of initial diagnosis (or subsequently), patient’s pathology report, and Form C-1872 to the CALGB PCO:

CALGB Pathology Coordinating Office The Ohio State University Innovation Centre 2001 Polaris Parkway Columbus, OH 43240 Tel: 614-293-7073

Please consider using a secure and temperature-safe method of packaging your specimens. [Extreme heat precautions should be taken when packaging blocks.] Use of a shipping method that is traceable is recommended.

The CALGB has instituted special considerations for the small percentage of hospitals whose policy prohibits long-term storage of blocks or the release of any block. If, due to institutional policy, a block cannot be sent, please call the CALGB PCO at 614-293-7073 to obtain a protocol for other options.

The goal of the PCO is to provide investigators with quality histology sections for their research while maintaining the integrity of the tissue. All paraffin blocks that are to be stored at the PCO will be vacuum-packed to prevent oxidation and will be stored at 4ºC to minimize degradations of cellular antigens. For these reasons, it is preferred that the PCO bank the block until the study investigator requests thin sections. Please contact the PCO if additional assurances with your hospital pathology department are required.

6.1.2 Blood Collection for Pharmacogenomics (CALGB 60904)

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1. For those patients who consent, collect 10 ml of whole blood in EDTA (purple-top) tube at pre-registration. Either peripheral or central venous access is acceptable. Immediately after collection, gently invert at least five times to mix completely.

2. Store (without centrifugation) at 4oC until shipping.

3. Label the sample permanently and indelibly labeled with patient’s initials, (last, first, middle), CALGB number, study number, and date drawn.

4. On the same day the sample is obtained, ship it on a cold pack (not dry ice) in an insulated container by overnight express courier. DO NOT FREEZE. Send the completed form C-1686 with the samples to the CALGB PCO:

CALGB Pathology Coordinating Office (PCO) Innovation Centre 2001 Polaris Parkway Columbus, OH 43240 Tel: 614-293-7073 Fax: 614-293-7967

Send a copy of Form C-1873 to the CALGB Statistical Center, Data Operations.

The sample should be logged and shipped via the LabTrak application. Use a method of shipping that is secure and traceable. Extreme heat precautions should be taken when necessary. Samples should be shipped Monday-Friday by overnight service to arrive Tuesday-Saturday. IF SHIPPING ON FRIDAY, FEDEX OR UPS MUST BE USED AND THE AIR BILL MUST BE MARKED “FOR SATURDAY DELIVERY.” DO NOT SHIP SPECIMENS ON SATURDAYS.

6.1.3 Blood Collection for Pharmacokinetics (CALGB 60904)

1. Collect one pediatric (5 ml) green-top vacutainer (containing heparin anti-coagulant) of venous blood from a peripheral vein 8 days after the start of celecoxib/placebo. Samples should be collected before treatment is given on the 8th day.

2. Immediately after sample collection, the blood sample should be gently inverted several times to mix the anti-coagulant completely. The tube should then be placed into an ice bath.

3. Within 2-3 hours after collection, each blood sample should be centrifuged at approximately 1,000xg to separate the cellular elements from the plasma. Plasma should be transferred to a screw-cap polypropylene tube and the tube clearly and indelibly labeled.

4. Plasma samples should be stored at -20°C or colder. Frozen samples should be shipped to the analytical laboratory on dry ice.

5. Record the date, planned time and actual time of collection for the specimen on the pharmacokinetic form: the study number and the patient’s unique patient identifier should be included on this form. In addition, the date and exact time when the celecoxib/placebo dose was ingested should be recorded on the appropriate pharmacokinetic form.

6. The shipment of human blood samples must comply with appropriate regulations as specified by the carrier. At a minimum, all samples must be packaged within two containers with absorbent material between containers to control any spill or leakage. The outer container must be puncture-resistant (e.g. cardboard mailing tube, corrugated cardboard box). A biohazard sticker must be affixed to both the inner and outer containers.

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7. All samples should be shipped via overnight express courier in insulated containers with enough dry ice to maintain the samples in a frozen state. A copy of the C-1917 should be included with each shipment.

8. All specimens are to be shipped to:

University of Pittsburgh Cancer Institute Room G.28 Hillman Research Laboratories 5117 Centre Avenue Pittsburgh, PA 15213.

Please notify the lab at 412-623-3216 or 412-623-1213 at least 24 hours prior to shipment. Samples should be shipped only Monday-Wednesday for Tuesday-Thursday delivery. A name, phone number, fax number, or email address should be included with samples so that receipt can be acknowledged.

6.1.4 Urine Collection for PGE-M Analysis (CALGB 150908)

1. Collect urine in a urine cup before any protocol treatment and then 8 days after the start of celecoxib/placebo, prior to treatment on the 8th day.

2. After collection, transfer 10 mL of urine to five 2ml cyrovials and keep at 4oC until frozen. Samples should be frozen within several hours of collection, at -80oC. Frozen samples should be shipped to the repository on dry ice.

The CALGB strongly recommends the usage of 2 ml cryovials for storage of urine specimens. Acceptable cryovials include:

Company name Catalog number

Nalgene 03-337-7Y (through Fisher) NNI No.: 5012-0020

Fisher brand 05-669-57 (through Fisher)

Corning 03-374-21 (through Fisher) CLS430659 (through Sigma) Corning: 430488

VWR 16001-102

All samples should be permanently or indelibly labeled with patient’s last, first and middle initials, CALGB patient ID number, CALGB study number, sample type (i.e., urine) and date drawn.

The aliquoted, frozen urine samples should be shipped within 30 days on dry ice by overnight express courier. Send the completed form C-1873 with the samples to the CALGB PCO, with a copy to the CALGB Statistical Center, Data Operations at the time of shipment.

CALGB Pathology Coordinating Office (PCO) Innovation Centre 2001 Polaris Parkway Columbus, OH 43240 Tel: 614-293-7073 Fax: 614-293-7967

Samples should be logged and shipped via the LabTrak application. Please be sure to use a method of shipping that is secure and traceable. Extreme heat cautions should be taken when necessary. Samples should be shipped Monday-Friday by overnight service to arrive Tuesday-Saturday. IF SHIPPING ON FRIDAY, FEDEX OR UPS MUST BE USED AND THE AIR BILL MUST BE MARKED “FOR SATURDAY DELIVERY.” DO NOT SHIP SPECIMENS ON SATURDAYS.

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7.0 REQUIRED DATA

To be completed within 16 days before pre-registration: - All blood work

To be completed within 30 days before registration: - Any X-ray, scan of any type or ultrasound which is utilized for tumor measurement

per protocol.

To be completed within 42 days before pre-registration: - Any x-ray, scan of any type or ultrasound of uninvolved organs which is not utilized

for tumor measurement. Test & Observation

Prior to Pre-reg

Day 1 of Each Cycle*

Post-Treatment Follow-up**

History & Physical exam X X X Performance Status X X X WeightΨ/BSA X X Pulse/Blood pressure X X Tumor Measurements X q 2 cycles X Tumor specimen for COX-2 X Toxicity Assessments X

Laboratory Studies

CBC, Diff, Platelets X Day 1 and 8*** Serum CreatinineΨ (Calc. CrCl), BUN

X X

Serum Electrolytes, LDH X X Alk.Phos., Bilirubin, Ca X X ALT, AST X X Tot. Prot. Albumin X X Pregnancy test in women of child-bearing potential

X

Radiologic Studies

CT Chest & Upper Abd. (w/ adrenals and liver) or MRIA

XA q 2 cycles X

Brain MRI PRN

Substudies Urine for PGEM analysis B B Blood for PK/PG C C

* Pre-registration labs may be used for day 1 of cycle 1 tests if obtained within 7 days prior to day 1 of Cycle 1. For subsequent cycles labs may be obtained within 48 hours prior to day of treatment.

** Every 2 months for 2 years, then q 6 months for 3 years until disease progression.

*** Day 1 for all patients; day 8 for those patients receiving gemcitabine.

Ψ It is not necessary to change the dose of chemotherapy unless the calculated dose changes by ≥ 10%.

A. CT/MRI scan is required within 30 days prior to registration. The scan may be obtained after pre-registration, but must be obtained prior to registration. CT Scan requirements for this protocol: Optimal Technique: The requirements listed below are to be used for the chest CT scan whenever possible.

• Scanning mode: Helical • Patient position: Supine, arms up • Scan extent: Thoracic inlet through adrenal glands

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• Scan time: Single breath-holding period, in full inspiration • Section thickness: 1.5mm or less • Enhancement: Intravenous contrast unless contraindicated by allergy • Reconstruction: Contiguous or overlapping sections; no gaps

Minimum CT requirements are listed below. Note that a chest CT scan made as part of a PET-CT is acceptable if it meets these requirements. Any CT scan that does not meet these minimal requirements must be repeated. • Scanning mode: Helical

• Patient position: Supine

• Scan extent: Thoracic inlet through adrenal glands

• Scan time: Single breath-holding period, in full inspiration

• Section thickness: 5mm or less

• Enhancement: Preferred but not required

• Reconstruction: Contiguous or overlapping sections; no gaps

B. For patients who consent to CALGB 150908, urine should be collected prior to starting any treatment and then 8 days after the start of celecoxib/placebo, before treatment on the 8th day.

C. For patients who consent to CALGB 60904, blood should be collected at pre-registration for DNA and then 8 days following the start of celecoxib/placebo, before therapy on the 8th day.

8.0 TREATMENT PLAN

NOTE: No blinded starter supplies will be available for this study. Initial blinded, patient-specific clinical supplies of celecoxib / placebo will be shipped from the Pharmaceutical Management Branch (PMB) to the registering investigator at the time of patient randomization and should arrive within 10 to 14 days of randomization (see Section 10.7).

Treatment will begin within 14 days of randomization. Treatment with celecoxib/placebo may be delayed up to 14 days after the start of chemotherapy. Patients that are COX-2 ≥ 2 will be randomized to receive one of the following treatments:

8.1 Arm A

For Squamous Carcinoma: Gemcitabine 1000 mg/m2 IV days 1 and 8. Repeat every 21 days for up to 6 cycles.

Carboplatin AUC=5.5 IV day 1 every 21 days for up to 6 cycles (following the administration of gemcitabine on day 1). Patients with prior chest radiotherapy should receive carboplatin at an AUC = 5.0

Celecoxib 400 mg (1 capsule) orally twice daily until progression, starting on day 1 (or up to 14 days following the start of chemotherapy)

OR For Non-squamous Carcinoma Pemetrexed* 500 mg/m2 IV day 1. Repeat every 21 days for up to 6 cycles.

Carboplatin AUC=6.0 IV on day 1 every 21 days for up to 6 cycles (following the administration of pemetrexed).

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Celecoxib 400 mg (1 capsule) orally twice daily until progression, starting on day 1 (or up to 14 days following the start of chemotherapy)

* Pemetrexed Premedications: Folic Acid: Start a low-dose oral folic acid preparation or multivitamin with folic acid at least 1 week before the first pemetrexed dose and continue for 21 days after the last dose of pemetrexed. Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must be administered at least 1 week before the initial pemetrexed dose and repeated every 3 cycles while on pemetrexed. Dexamethasone: Dexamethasone (or equivalent) 4 mg orally should be administered BID daily the day before, the day of, and the day after each dose of pemetrexed, for a total of 6 doses per cycle.

8.2 Arm B

For Squamous Carcinoma Gemcitabine 1000 mg/m2 IV days 1 and 8, every 21 days for up to 6 cycles

Carboplatin AUC= 5.5 IV day 1 every 21 days for up to 6 cycles (following the administration of gemcitabine on day 1). Patients with prior chest radiotherapy should receive carboplatin at an AUC = 5.0

Placebo (1 capsule) orally twice daily until progression, starting on day 1 (or up to 14 days following the start of chemotherapy)

OR

For Non-squamous Carcinoma Pemetrexed* 500 mg/m2 IV day 1. Repeat every 21 days for up to 6 cycles

Carboplatin AUC=6.0 IV on day 1 every 21 days for up to 6 cycles (following the administration of pemetrexed)

Placebo (1 capsule) orally twice daily until progression, starting on day 1 (or up to 14 days following the start of chemotherapy)

* Pemetrexed Premedications: Folic Acid: Start a low-dose oral folic acid preparation or multivitamin with folic acid at least 1 week before the first pemetrexed dose and continue for 21 days after the last dose of pemetrexed. Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must be administered at least 1 week before the initial pemetrexed dose and repeated every 3 cycles while on pemetrexed. Dexamethasone: Dexamethasone (4 mg orally or equivalent) should be administered BID daily the day before, the day of, and the day after each dose of pemetrexed, for a total of 6 doses per cycle.

8.3 Patients may receive a maximum of 6 cycles of therapy (1 cycle = 21 days). Following six cycles of therapy, those patients with responding or stable disease will continue on the celecoxib/placebo until disease progression or unacceptable toxicity.

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8.4 Calculation of Carboplatin Dose

* Creatinine clearance (CrCl) will be calculated using the Cockroft-Gault equation as follows:

CrCI (ml/min) = (140-age) x actual wt (in kg) 72 x serum creatinine (mg/dl)

FOR FEMALES, USE 85% OF CALCULATED CrCI VALUE

Dose of carboplatin (mg) for squamous patients= 5.5 x [CrCI (ml/min) + 25] OR in patients with prior chest radiation therapy, dose of carboplatin = 5 x [CrCI (ml/min) + 25]

Dose of carboplatin (mg) for non-squamous patients= 6 x [CrCI (ml/min) + 25]

Use the serum Cr value reported by the laboratory; do not apply any correction factors to the reported value.

The maximum CrCl that can be used in this calculation, for both women and men, is 125 mL/min. For squamous carcinoma patients the maximum carboplatin dose is 825 mg for patients who have not had prior chest radiotherapy. For patients with prior chest radiotherapy the maximum carboplatin dose is 750 mg. For non-squamous carcinoma patients the maximum carboplatin dose is 900 mg.

In the case of low creatinine values resulting in high CrCl values that seem to overestimate renal function, a 24-hour urine collection for determination of CrCl is recommended.

9.0 DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES

9.1 General Guidelines

• If more than one of the dose modifications apply, use the most stringent (i.e., the greatest dose reduction).

• Celecoxib/placebo will be continued when chemotherapy is held for toxicities.

• Chemotherapy will be continued when celecoxib/placebo is held for toxicities.

• The following dose levels are used for dose modifications. If dose reduction below level -2 is required, discontinue the drug causing the toxicity, and continue the other drug. Continue the celecoxib/placebo.

Dose Level Pemetrexed Carboplatin Gemcitabine

0 500 mg/m2 100% 1000 mg/m2

-1 375 mg/m2 75% 750 mg/m2

-2 250 mg/m2 50% 500 mg/m2

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9.2 Hematologic Toxicity

• For ANC <1,500 or platelets <100,000 on day 1, delay treatment with carboplatin and pemetrexed or gemcitabine until ANC ≥1,500 and platelets ≥100,000, then resume at the previous doses. If treatment is delayed for ≥ 3 weeks, discontinue all protocol treatment.

• For platelets <25,000, decrease carboplatin and pemetrexed or gemcitabine by one dose level for all subsequent doses. Hold celecoxib/placebo until platelets >25,000.

• For febrile neutropenia occurring at any time during a cycle, decrease carboplatin and pemetrexed or gemcitabine by one dose level for all subsequent doses.

• For ANC 500-999 or platelets 50,000 – 74,999 on day 8, decrease gemcitabine by one dose level for the current and all subsequent doses.

• For ANC <500 or platelets <50,000 on day 8, skip gemcitabine and decrease gemcitabine by one dose level for all subsequent doses.

• For a second episode of thrombocytopenia <25,000 or febrile neutropenia, decrease carboplatin and pemetrexed or gemcitabine by one dose level for all subsequent doses.

9.3 Gastrointestinal Toxicity

9.3.1 Diarrhea

For grade 3 or 4 diarrhea despite antidiarrheal medication and prophylactic vitamin supplementation, delay carboplatin and pemetrexed and interrupt celecoxib/placebo in non-squamous carcinoma. Once diarrhea resolves to ≤ grade 2, resume therapy with carboplatin and celecoxib/placebo at the previous dose, and one dose level reduction of pemetrexed for all subsequent cycles. If treatment is delayed for ≥ 3 weeks, discontinue all protocol therapy.

There are no dose modifications for diarrhea for carboplatin and gemcitabine in squamous carcinoma.

9.3.2 Mucositis

For grade 3 or 4 mucositis despite prophylactic vitamin supplementation, delay carboplatin and pemetrexed and interrupt celecoxib/placebo in non-squamous carcinoma until toxicity resolves to ≤ grade 2. When mucositis resolves to ≤ grade 2, resume carboplatin at the previous dose and pemetrexed with a one level dose reduction for all subsequent cycles and resume celecoxib/placebo. If treatment is delayed for > 3 weeks, discontinue all protocol therapy.

There are no dose modifications for mucositis for carboplatin and gemcitabine in squamous carcinoma.

9.3.3 For GI bleeding not associated with thrombocytopenia (platelets <75,000), or for GI ulceration, discontinue celecoxib/placebo. Continue carboplatin/pemetrexed or carboplatin/gemcitabine.

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9.4 Nephrotoxicity

If creatinine clearance is < 45ml/min, delay carboplatin and pemetrexed in non-squamous carcinoma, carboplatin and gemcitabine in squamous carcinoma and interrupt celecoxib/placebo until CrCl ≥ 45 ml/min. When CrCl improves to ≥ 45 ml/min, resume carboplatin and pemetrexed (or gemcitabine) at the previous doses and resume celecoxib/placebo at 400 mg BID. If treatment is delayed/interrupted for ≥ 3 weeks, discontinue all protocol therapy.

9.5 Clinically Significant Effusions

For patients who develop clinically significant pleural or pericardial effusions (on the basis of symptoms or physical examination) during therapy, consideration should be given to draining the effusion prior to the next dose of pemetrexed. However, in the opinion of the treating physician, if the effusion represents progression of disease, the patient should discontinue protocol therapy.

9.6 Pulmonary Toxicity

Gemcitabine may rarely cause pulmonary toxicity characterized by dyspnea and interstitial pneumonitis. The pneumonitis will usually respond to steroids. Other causes of dyspnea should be excluded (i.e., anemia, cardiac, COPD exacerbation, etc.) before concluding that pulmonary toxicity is drug associated.

• For grade 2 pulmonary toxicity due to gemcitabine, hold protocol treatment. Patients may be retreated with a two level dose reduction in gemcitabine dose on the next and all subsequent cycles at the physician’s discretion if pulmonary symptoms improve to grade 0-1 within 3 weeks.

• For grade 3 and 4 pulmonary toxicity, discontinue protocol therapy.

9.7 Skin Toxicity

Gemcitabine • Grade 2: Decrease gemcitabine by one dose level.

• Grade 3 or 4: Discontinue gemcitabine.

Pemetrexed • Grade 3: Hold pemetrexed until toxicity improves to ≤ grade 1, then resume

pemetrexed at the previous dose level. For recurrent grade 3 skin toxicity, hold pemetrexed until toxicity improves to ≤ grade 1, then resume pemetrexed with one dose level reduction. If pemetrexed is held for skin toxicity for 3 weeks, discontinue pemetrexed.

9.8 Cardiovascular Toxicity

For grade 3 or 4 thrombosis or cardiac ischemia, or ≥ grade 2 stroke, discontinue celecoxib/placebo. Continue carboplatin/pemetrexed or carboplatin/ gemcitabine.

9.9 Hypersensitivity Reactions

For grade 3 allergic or anaphylaxis reactions thought to be due to carboplatin, gemcitabine or pemetrexed discontinue all protocol therapy.

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9.10 Other Non-Hematologic

Grade 3 Toxicity (not described above): Delay all drugs until toxicity improves to ≤ grade 2, then resume treatment with one dose level reduction for each agent except celecoxib/placebo. If treatment is delayed for > 3 weeks, discontinue all protocol therapy.

For recurrent other non-hematologic grade 3 toxicity: Discontinue all protocol therapy.

Grade 4 Toxicity (not described above): Discontinue all protocol therapy.

10.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION

10.1 Qualified personnel who are familiar with procedures that minimize undue exposure to themselves and to the environment should undertake the preparation, handling, and safe disposal of chemotherapeutic agents in a self-contained, protective environment.

10.2 Discard unused portions of injectable chemotherapeutic agents that do not contain a bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial entry to minimize the risk of bacterial contamination.

10.3 The total administered dose of chemotherapy may be rounded up or down within a range of 5% of the actual calculated dose.

10.4 Carboplatin

Please refer to the FDA approved package insert for additional information.

Availability

Carboplatin is commercially available and supplied as a sterile lyophilized powder available in single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin. Each vial contains equal parts by weight of carboplatin and mannitol.

Preparation

Immediately before use the content of each vial must be reconstituted with either Sterile Water for Injection, USP, 5% dextrose in water, or 0.9% Sodium Chloride for Injection, USP according to the following schedule:

Vial Strength Diluent Volume 50 mg 5 ml

150 mg 15 ml

450 mg 45 ml

These dilutions all produce a carboplatin concentration of 10 mg/ml. When prepared as directed, carboplatin solutions are stable for eight hours at room temperature. There is no antibacterial preservative in the formulation, therefore, it is recommended that carboplatin solutions be discarded eight hours after dilution.

Note: Aluminum reacts with carboplatin causing precipitate formation and loss of potency: therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of carboplatin.

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Storage and Stability

Unopened vials of carboplatin are stable for the life indicated on the package when stored at controlled room temperature and protected from light.

Administration

See Sections 8.1 and 8.2.

AUC dosing will be used to determine carboplatin dosing. The protocol permits use of the Cockcroft-Gault formula to estimate creatinine clearance. However, in markedly obese patients, the Cockcroft-Gault formula will tend to overestimate the creatinine clearance. The actual body weight (in kilograms) will be utilized in the Cockcroft-Gault formula. However, if the calculated creatinine clearance exceeds an upper limit for creatinine clearance, as specified below, then this ceiling value for creatinine clearance, rather than the calculated creatinine clearance, will be used in the Calvert formula to calculate the dose of carboplatin.

The maximum allowable creatinine clearance for males and females is 125 ml/min.

Alternatively, at the treating physician's discretion, a measured 24 hour creatinine clearance can be obtained. In this case, the measured creatinine clearance can be used to calculate the carboplatin dose in the Calvert formula.

Toxicities

Myelosuppression, nausea and vomiting, peripheral neuropathy, nephrotoxicity, hepatotoxicity, electrolyte imbalance, hypomagnesemia, hypocalcemia, and allergic reactions.

10.5 Gemcitabine


Availability

Gemcitabine HCl (2’2’-difluorodeoxicytidine) is a nucleoside analogue that exhibits antitumor activity. It is commercially available and supplied as a lyophilized powder in sterile glass vials containing 200 mg or 1000 mg of active drug as the hydrochloride salt (expressed as the free base), mannitol, and sodium acetate.

Preparation

The appropriate dose of gemcitabine should be diluted in 250 mL of normal saline (maximum concentration of 40 mg/mL) and administered intravenously as a constant infusion over 30 minutes. Normal saline is the only diluent approved; do not use other diluents. Nothing else should be added to the bag. Since gemcitabine is NOT a vesicant, extravasation should be handled according to local hospital policy concerning extravasation of drugs.


The intact vials should be stored at controlled room temperature between 59°-86°F (15°-30°C). The intact vials are stable for 3 years at controlled room temperature. Reconstituted solutions should be used within 24 hours; unused portions should be discarded.

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Administration

See Sections 8.1 and 8.2.

Toxicity

The DLT is myelosuppression. Other possible clinical toxicities include fever, chills, nausea, vomiting, diarrhea, constipation, skin rash or confluent erythema, edema, paresthesia, fatigue, anorexia, headache, muscle aches, cough, rhinitis, insomnia, sweating, drowsiness, hypotension, and mucositis.

Dyspnea on exertion or at rest has occasionally been reported after gemcitabine therapy. Nonprogressive liver function abnormalities and dip-stick-positive proteinuria, or hematuria may occur. Episodes of hemolytic uremic syndrome have been reported in patients treated with gemcitabine. There were no reports of injection site necrosis with gemcitabine in US trials. There may be some local irritation and injection site pain due to the low pH of the solution (pH≈3).

10.6 Pemetrexed


Availability

Pemetrexed is available commercially as a lyophilized powder for reconstitution in single-use vials containing 500 mg pemetrexed.


Intact vials of pemetrexed should be stored at room temperature. The reconstituted and further diluted solutions for infusions are stable for up to 24 hours when refrigerated or stored at room temperature.

Preparation

Each 500 mg of pemetrexed is reconstituted with 20 mL of 0.9% sodium chloride for injection, resulting in a concentration of 25 mg/mL. The desired dose should be withdrawn and further diluted in 100 mL of 0.9% sodium chloride for injection, for IV infusion.

Administration

Pemetrexed will be administered as an IV infusion every 21 days. Pemetrexed premedications include:

Folic Acid: Start a low-dose oral folic acid preparation or multivitamin with folic acid at least 1 week before the first pemetrexed dose and continue for 21 days after the last dose of pemetrexed. Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must be administered at least 1 week before the initial pemetrexed dose and repeated every 3 cycles while on pemetrexed. Dexamethasone: Dexamethasone (4 mg orally or equivalent) should be administered BID daily the day before, the day of, and the day after each dose of pemetrexed, for a total of 6 doses per cycle.

Toxicities

The most common toxicities reported with pemetrexed to date include myelosuppression, GI toxicities, rash and fatigue. Neutropenia is more common than thrombocytopenia, and it is minimized with vitamin supplementation. Specifically, folic acid and Vitamin B12 starting before pemetrexed and continuing throughout pemetrexed therapy are recommended. It is thought that severe pemetrexed toxicity

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is due to a subclinical folate deficiency, as may be documented by an elevated plasma homocysteine. Similarly, diarrhea and mucositis are also minimized with the use of folic acid and B12. Single agent pemetrexed was associated with nausea and vomiting in approximately 30% of patients. In the majority of patients, nausea and vomiting were ≤ grade 2 severity. The incidence and severity of pemetrexed-induced rash appears to be decreased with the administration of dexamethasone, beginning the day before pemetrexed. Fatigue, grade 1-3 severity, is also common.

Drug Interactions

As is the case with methotrexate, the potential exists for various drugs (e.g., NSAIDs, probenecid, salicylates, sulfonamides) to delay pemetrexed renal clearance and increase toxicity (see Section 11.4).

10.7 Celecoxib (NSC #719627, CALGB IND #107051) / Placebo

Availability

Celecoxib (NSC 719627) and matching Placebo will be provided free of charge by Pfizer and distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).

Celecoxib and matching Placebo will be supplied in bottles containing 100 – 400mg capsules (Celecoxib) or 100 – 0mg capsules (Placebo) with a child-resistant cap and a tamper-evident seal. Each blinded, patient-specific bottle will be labeled with:

´• the protocol number (i.e., “CALGB-30801”)

´• the bottle number (i.e., “Bottle 1 of 3”, “Bottle 2 of 3”, “Bottle 3 of 3”)

´• the number of capsules (i.e., “100 capsules”)

´• the patient ID number (e.g., “999999", where “999999” represents a unique patient identifier assigned by CALGB at pre-registration)

´• the patient initials (i.e., last initial, first initial, middle initial [e.g., "L,FM"])

´• the agent identification (i.e., “Celecoxib 400 mg or Placebo”)

´• a blank line for the pharmacist to enter the patient’s name

´• administration instructions (i.e., “Take one capsule twice daily with food.”)

´• storage instructions (i.e., “Store at room temperature (15ºC to 25ºC, 59ºF to 77ºF).”)

´• emergency contact instructions

´• a Julian date

The Julian date indicates the day the bottle was labeled and shipped and is composed of the last two digits of the calendar year (e.g., 2009 = 09, 2010 = 10) and a day count (e.g., January 1 = 001, December 31 = 365). For example, a bottle labeled and shipped on January 1, 2009 would have a Julian date of ‘09001’ and a bottle labeled and shipped on December 31, 2010 would have a Julian date of ‘10365’. The Julian date will be used by PMB for recalls. When a lot expires, PMB will determine the last date the expired lot was shipped and will recall all bottles (i.e., both Celecoxib and Placebo) shipped on or before that date thus eliminating any chance of breaking the blind.

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Questions about drug orders, transfers, returns, or accountability should be addressed to the PMB by calling 301-496-5725 Monday through Friday between 8:30AM and 4:30PM Eastern Time or by emailing <[email protected]> anytime. Drug Ordering

No blinded starter supplies will be available for this study. Blinded, patient specific clinical supplies will be sent to the registering investigator at the time of randomization and should arrive within approximately 10 to 14 days. Shipments to United States sites can be expedited (i.e., receipt on Thursday in example above) by the provision of an express courier account name and number to the CALGB Statistical Center at the time the patient is randomized. The randomization will be performed by the CALGB Statistical Center in Durham, NC. The assigned CALGB patient ID number must be recorded by the registering institution for proper bottle dispersion. Once a patient has been registered with the CALGB Statistical Center, the CALGB Statistical Center will electronically transmit a clinical drug request for that patient to the PMB. This request will be entered and transmitted by the CALGB Statistical Center the day the patient is registered and will be processed by the PMB the next business day and shipped the following business day. Shipments within the United States will be sent by US Priority Mail (generally two to three day delivery) and shipments to Canada will be sent by FedEx (generally one to two day delivery). Thus, if a patient is registered on Monday, CALGB would enter a clinical drug request for that patient on Monday and PMB would process that request on Tuesday and ship the drug on Wednesday. United States sites could expect to receive their order approximately Friday or Monday (see table) and Canadian sites could expect to receive their order either Thursday or Friday. Shipments to United States sites can be expedited (i.e., receipt on Thursday in example above) by the provision of an express courier account name and number to the CALGB Statistical Center at the time the patient is randomized. The initial request will be for 3 – 100 capsule bottles (a 6-cycle / 18 week supply at a dose of one capsule twice daily) of Celecoxib or matching Placebo. At the start of the sixth (6th) cycle (3 weeks before needed), sites may reorder an additional 3 – 100 capsule bottles (a 6-cycle / 18 week supply at a dose of one capsule twice daily) by completing an NCI Clinical Drug Request form and faxing it to the PMB at 301-480-4612. The NCI Clinical Drug Request form is available on the CTEP home page (http://ctep.cancer.gov). The protocol number (i.e., CALGB-30801), the assigned patient ID number (e.g., "999999"), the patient initials (e.g., "L,FM"), and the number of bottles remaining from the previous shipment should be entered on each order.

All drug orders will be shipped directly to the registering physician at the shipping address listed on their most recent Supplemental Investigator Data Form (IDF) on file with CTEP. The registering investigator must maintain an active investigator status with CTEP, DCTD through the annual submission of an FDA Form 1572 (Statement of Investigator), a Curriculum Vitae, a Supplemental Investigator Data Form (IDF), and a Financial Disclosure Form (FDF) (http://ctep.cancer.gov/InvestigatorResources/investigator_registration.htm).

CALGB-30801 Shipment Schedule Patient Randomized

with CALGB Initial e-Order Sent by CALGB

Initial e-Order Received and Approved by PMB

Initial Order Shipped By PMB

Initial Order Received at Site **

Monday Monday Tuesday Wednesday Monday Tuesday Tuesday Wednesday Thursday Tuesday

Wednesday Wednesday Thursday Friday Wednesday Thursday Thursday Friday Monday Thursday

Friday Friday Monday Tuesday Friday ** arrival time approximate / shipments sent by US Priority Mail

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How Supplied

"Celecoxib" and matching "Placebo" are supplied as a size 0 white to off-white opaque hard gelatin capsule for oral administration. Each tamper-evident, child-resistant, 180ml, square, white, opaque, high-density polyethylene (HDPE) bottle contains 100 capsules. For “Celecoxib”, each capsule contains 400mg of celecoxib with croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate. For “Placebo”, each capsule contains croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate.


"Celecoxib" and matching "Placebo" are shipped at room temperature by US Priority Mail and by FedEx to Canada. The capsules should be stored at controlled room temperature (15ºC to 25ºC, 59ºF to 77ºF). The intact bottles of 100 capsules are stable for five years when stored at controlled room temperature.

Route of Administration

Oral. Celecoxib/placebo at doses of 400mg orally twice daily should be administered with food to improve absorption.

Drug Transfers

Bottles may NOT be transferred from one patient to another patient or from one protocol to another protocol. All other transfers (e.g., a patient moves from one participating clinical site to another participating clinical site, the investigator at a given clinical site changes) must be approved in advance by the PMB. To obtain an approval for transfer, investigators should complete and submit to the PMB (fax number 301-402-0429) a Transfer Investigational Agent Form available on the CTEP home page (http://ctep.cancer.gov). The patient ID number (e.g., "999999"') and the patient initials (e.g., "L,FM") must be entered in the "Received on NCI Protocol No." and the "Transferred to NCI Protocol No." fields in addition to the protocol number (i.e., "CALGB-30801").

Drug Returns

Only undispensed clinical supplies should be returned to the PMB. When it is necessary to return study drug (e.g., sealed bottles remaining when a patient permanently discontinues protocol treatment, expired bottles recalled by the PMB), investigators should return the study drug to the PMB using the NCI Return Drug List available on the CTEP home page (http://ctep.cancer.gov). The patient ID number (e.g., "999999") and the patient initials (e.g., "L,FM") should be entered in the "Lot Number" field. A separate line item is required for each patient ID number (e.g., "999999") being returned. Dispensed bottles with remaining tablets should be documented in the patient-specific NCI Investigational Agent Accountability Record (i.e., logged is as “returned by patient” and logged out as “destroyed on site”) and destroyed on site in accordance with institutional policy. Drug Accountability

The investigator, or a responsible party designated by the investigator, must maintain a careful record of the receipt, disposition, and return of all drugs received from the PMB using the NCI Investigational Agent Accountability Record available on the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 301-496-5725. A separate NCI Investigational Agent Accountability Record must be maintained for each patient ID number (e.g., "999999") on this protocol. It is recommended that the combination julian date / order number in the upper right hand corner of the patient-specific bottle label be recorded as the lot number.

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Unblinding Procedures

Unblinding can be done only in the case of an emergency. Follow the directions below to unblind patient treatment. Please note that, if treatment is unblinded due to an emergency, the patient must permanently discontinue all protocol therapy.

Emergency Unblinding Procedures

Examples of emergencies include …

1) a life threatening unexpected adverse event that is at least possibly related to the investigational agent and for which unblinding would influence treatment decisions

OR

2) a medication error, such as an accidental overdose.

Expected adverse events are listed in the “Toxicities” section below.

Contact a CALGB Approving Physician (i.e., Executive Officer) by calling the pager number, 773-652-0098. If an Executive Officer cannot be reached, contact the CALGB Statistical Center at 1-877-442-2542 and the Statistical Center will contact an Approving Physician. Note: The Statistical Center cannot give permission for unblinding; only a CALGB Approving Physician can authorize emergency unblinding.

The following information will be required when contacting the CALGB Approving Physician:

• CALGB study number (i.e., “CALGB-30801”)

• CALGB patient ID number (e.g., “999999”)

• Patient initials (e.g., “L,FM”)

• Institution name

• Name and telephone number of treating physician

• Name and telephone number of person requesting the unblinding procedure

• Name and telephone number of contact person to inform of treatment assignment

• Reason for emergency unblinding

After authorization by a designated CALGB Approving Physician, the treatment assignment will be provided to the contact person by the CALGB Statistical Center.

Toxicities

Celecoxib/placebo is generally well tolerated and has no overlapping toxicities with gemcitabine or carboplatin. The most common toxicity reported in arthritis trials is headache. Other possible toxicities include peripheral edema, insomnia, dizziness, skin rash, dyspepsia, diarrhea, abdominal pain, nausea, flatulence, back pain, upper respiratory tract infection, sinusitis, pharyngitis, and rhinitis.

The incidence of GI ulcers documented by endoscopy in arthritis trials is 7%. GI bleeding is more likely to occur in patients with a history of peptic ulcer disease and/or GI bleeding. The risk of GI ulceration, bleeding or perforation with celecoxib is increased with concomitant use of aspirin. Chronic use of aspirin (>325 mg/day) or other NSAIDs is not allowed on this trial (see also Section 4.1.10).

As is the case with non-selective NSAIDS, celecoxib may be associated with nephrotoxicity in patients in whom renal prostaglandins are important in

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maintenance of renal blood flow. Specifically, patients with pre-existing renal dysfunction, heart failure, liver dysfunction or dehydration, elderly patients, or patients taking diuretics or ACE inhibitors are at the greatest risk for significant inhibition of renal blood flow and nephrotoxicity. In addition, long-term use of NSAIDs has been associated with renal injury, including renal papillary necrosis. Unlike other non-selective NSAIDS, celecoxib does not appear to inhibit platelet aggregation.

A safety analysis performed in December, 2004, of several long term celecoxib trials was conducted following the removal of rofecoxib from the market because of an increased risk of adverse cardiovascular events. The celecoxib analysis resulted in the suspension of drug use for patients enrolled in the Adenoma Prevention with Celecoxib (APC) trial. In this trial, the risk of cardiovascular death, myocardial infection or stroke in the celecoxib groups was 2-3 times higher than the risk in the placebo group. This increased hazard with celecoxib was not observed in another long term trial.

Drug Interactions

Celecoxib is metabolized in the liver by cytochrome P450 2C9. Drugs that inhibit (e.g., fluconazole) or induce (e.g., rifampin) the 2C9 isoenzyme might be expected to result in increased toxicity or decreased effect of celecoxib, respectively. In addition, celecoxib is reported to inhibit the 2D6 isoenzyme, potentially enhancing the effects of drugs metabolized by this isoenzyme.

The following describes possible drug interactions:

ACE-inhibitors: NSAIDs may diminish the antihypertensive effect of ACE-inhibitors.

Coumadin: Celecoxib does not alter PT/INR; there have been reports of prolonged prothrombin time and bleeding in elderly patients taking both coumadin and celecoxib.

Fluconazole: Concomitant administration of celecoxib and fluconazole results in a two-fold increase in celecoxib levels.

Lithium: Concomitant administration of celecoxib and lithium results in an increase in steady-state lithium levels.

11.0 ANCILLARY THERAPY

11.1 Patients should receive full supportive care, including transfusions of blood and blood products, antibiotics, antiemetics, etc., when appropriate. Steroids may be used as antiemetics in this study. The reason(s) for treatment, dosage, and the dates of treatment should be recorded on the remarks addendum.

11.2 Treatment with other chemotherapeutic agents or hormones (except for Megace, if used for appetite stimulation) will result in the patient's removal from protocol therapy,

11.3 CALGB Policy Concerning the Use of Growth Factors

11.3.1 Epoietin (EPO)

The use of EPO is permitted at the discretion of the treating physician.

11.3.2 Filgrastim (G-CSF), pegfilgrastim and sargramostim (GM-CSF)

1. Filgrastim (G-CSF) or pegfilgrastim and sargramostim (GM-CSF) may be used in accordance with ASCO guidelines.

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2. For the treatment of febrile neutropenia, the use of CSFs should not be

routinely instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs may be indicated in patients who have prognostic factors that are predictive of clinical deterioration such as pneumonia, hypotension, multi- organ dysfunction (sepsis syndrome) or fungal infection, as per the ASCO guidelines. Investigators should therefore use their own discretion in using the CSFs in this setting. The use of CSF (filgrastim or sargramostim) must be documented and reported on flow sheets.

3. If growth factors are used, they must be obtained from commercial sources.

11.4 Concomitant Medications

Patients should be instructed to avoid NSAIDs, such as rofecoxib (Vioxx), aspirin (≤325 mg daily is allowed), choline Mg, trisalicylate (Trilisate), or other non-steroidal anti-inflammatory drugs such as ibuprofen (Advil or Motrin), naproxen (Aleve, Naprosyn or Anaprox), etodolac (Lodine), oxaprozin (Daypro), diflunisal (Dolobid), nabumetone (Relafen), or tolmetin (Tolectin).

11.5 Palliative Radiotherapy

Palliative radiation for the treatment of painful bone lesions that were previously known (i.e., do not represent new and therefore progressive lesions) and are less than 5% of marrow is permitted.

12.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE

For the purposes of this study, patients should be reevaluated every 6-8 weeks. In addition to a baseline scan, confirmatory scans should also be obtained ≥ 4 weeks following initial documentation of objective response.

12.1 Target Lesions

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as target lesions and will be recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, and should be chosen based on their suitability for accurate repetitive measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible repeated measurements in which case the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum LD will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.

12.1.1 Complete Response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.

12.1.2 Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

12.1.3 Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least

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5 mm. (Note: the appearance of one or more new lesions is also considered progression).

12.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum diameters while on study.

12.2 Non-target Lesions

All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.

12.2.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response.

12.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.

12.2.3 Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.

Although a clear progression of non-target lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed later on by the review panel (or Study Chair).

12.2.4 FDG-PET While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:

a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.

b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.

c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be

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acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.

Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.

12.3 Cytology and Histology

If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.

These techniques can be used to differentiate between PR and CR in rare cases (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain).

The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease.

12.4 Evaluation of Best Overall Response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient’s best response assignment will depend on the achievement of both measurement and confirmation criteria (see Section 12.6.1).

For Patients with Measurable Disease (i.e., Target Disease)

Target Lesions Non-target Lesions

New Lesions Overall Response

Best Overall Response when Confirmation is

Required

CR CR No CR ≥ 4 wks confirmation*

CR Non-CR/Non-PD No PR

CR Not evaluated No PR

PR Non-CR/Non-PD/not evaluated

No PR

≥ 4 wks

confirmation*

SD Non-CR/Non-PD/not evaluated

No SD Documented at least once ≥ 4

wks from baseline*

PD Any Yes or No PD

Any PD** Yes or No PD

Any Any Yes PD

No prior SD, PR

or CR

* Only for non-randomized trials with response as the primary endpoint.

** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression.

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Note:

• Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as “symptomatic deterioration” on the Off-treatment Form (C-300) under “other.” Every effort should be made to document the objective progression even after discontinuation of treatment.

For Patients with Non-measurable Disease (i.e., Non-target Disease)

Non-Target Lesions New Lesions Overall Response CR No CR

Non-CR/non-PD No Non-CR/non-PD*

Not all evaluated No not evaluated

Unequivocal PD Yes or No PD

Any Yes PD

* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised

12.5 Guidelines for Evaluation of Measurable Disease

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment.

The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.

12.5.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin nodules, palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended.

12.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable.

12.5.3 Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases.

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Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible.

12.5.4 PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed.

12.5.5 Ultrasound (US): Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances.

12.5.6 Endoscopy and Laporascopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint.

12.5.7 Tumor Markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response.

12.6 Confirmation Measurement/Duration of Response

12.6.1 Confirmation

To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat studies that should be performed no less than 4 weeks after the criteria for response are first met. In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.

12.6.2 Duration of Overall Response

The duration of overall response is measured from the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

The duration of overall complete response is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.

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12.6.3 Duration of Stable Disease

Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.

13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY

13.1 Duration of Treatment

Patients will receive six cycles of chemotherapy with carboplatin/gemcitabine or carboplatin/pemetrexed as well as celecoxib/placebo. After completion of the six cycles of cytotoxic chemotherapy patients will continue to receive the celecoxib/placebo until unacceptable toxicity or disease progression. Patients with disease progression or unacceptable toxicities at any time during protocol therapy will discontinue treatment.

13.2 Extraordinary Medical Circumstances or withdrawal of consent by the patient: If, at any time, the constraints of this protocol are detrimental to the patient’s health and/or the patient no longer wishes to continue protocol therapy, the patient shall be withdrawn from protocol therapy. In this event:

• Notify the Study Chair. • Document the reason(s) for withdrawal on the C-1869 and Remarks Addenda. • Follow the patient for disease progression and survival.

14.0 STATISTICAL CONSIDERATIONS

14.1 Study Design and Objectives

The primary endpoint of this trial is progression-free survival. Current regimens in an unselected population produce a median survival of approximately 8 to 10 months and 30-40% one year survival. In ECOG 4599, the selected population median survival was 12 months and the control was 10 months. Hence, the selection criteria of E4599 biased the study towards a favorable group. Based upon CALGB 30203, COX-2 overexpression will select for an unfavorable group of patients. We conservatively estimate that patients with COX-2 expression index of ≥ 4 will have a median progression-free survival of 4.0 months and overall survival of 6.0 months. Our hypothesis is that if these patients receive celecoxib + chemotherapy, this median progression free survival will increase to 6.2 months and the median overall survival will increase to 9.2 months.

14.2 Efficacy Endpoint

The primary objective of this phase III trial is to evaluate the benefit of COX-2 inhibition combined with chemotherapy (arm A) as compared to chemotherapy only (arm B) in advanced NSCLC patients who have “over-expressed” COX-2 (COX-2 index ≥ 4). The primary endpoint used for sample size calculation is progression free survival (PFS), but overall survival (OS) will be used in the interim analyses to decide if the trial can be stopped early for superiority and futility. The secondary objectives are: (i) to determine response rate and toxicity; (ii) to evaluate the survival benefit of arm A over arm B in patients with COX-2 index ≥ 2; (iii) to verify the adverse prognostic value of COX-2 expression.

Eligible patients will be approached for pre-registration. After the expression level of COX-2 is determined, the CALGB Statistical Center will be notified by email. Based on the result, pre-registered patients will be classified as “over-expressed” (COX-2 index ≥ 4), “moderately expressed” (2 ≤ COX-2 index <4), and “negative” (COX-2 index

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<2). In order to address the secondary objective ii, all COX-2 “expressed” patients (COX-2 index ≥ 2) will be randomized with equal allocation to arm A and arm B. To ensure balance, randomization will be implemented using a permuted-block scheme (24) stratified by sex (female vs. male), Stage (IIIb vs. IV), histology (squamous vs non-squamous), smoking status (never/light smoker defined as ≤ 10 pack years AND quit > 1 year ago vs. smoker) and the COX-2 expression status (COX-2 index ≥4, ≥2 but <4).

Approximately 792 eligible patients will be pre-registered. With an allowance of 25% registered patients who fail to yield high quality specimens for COX-2 analysis, we expect that 594 patients will have COX-2 measured. Of them, 297 patients (50%) are COX-2 expressers (COX-2 index ≥2) and are randomized to arm A and arm B. Of these patients, 208 patients have COX-2 index ≥4, At a monthly rate of 19 patients, the study is expected to accrue 792 patients over a period of approximately 42 months. All patients are required to be followed for 4 years or to death, whichever comes first.

Power Analysis for COX-2 Over-expression (COX-2 index ≥4)

CALGB 30203 enrolled 140 patients within one year. A total of 107 specimens were submitted. Of them, 82 (77%) were of adequate quality for COX-2 analysis and 53 (35%) had COX-2 index ≥ 4 (COX-2 “overexpressed”). The study found that patients receiving celecoxib (with or without zileuton) who had over-expressed COX-2 demonstrated superior survival compared with over-expressed patients who did not receive celecoxib: the median survival (OS) is 11.3 months (95%CI: 9.2-17.6) for over-expressed patients receiving celecoxib and 3.8 months (95%CI: 0.9-10.5) for over-expressed patients not receiving celecoxib - HR=0.34 (95%CI: 0.16-0.75). Similarly, the median progression free survival (PFS) is 6.5 months (95%CI: 4.8-8.46) for over-expressed patients receiving celecoxib and 3.4 months (95%CI: 0.8-6.4) for over-expressed patients not receiving celecoxib - HR=0.29 (95%CI: 0.13-0.68).

For the current study the sample size is determined to have adequate power to detect the benefit of over-expressed patients (COX-2 ≥ 4) on arm A against those on arm B in terms of progression-free survival. The following assumptions are made: (1) 75% of specimens submitted by registered patients yield evaluable specimens for COX-2 assays; (2) 35% of evaluable patients are COX-2 over-expressed (COX-2 index ≥4); (3) the median PFS is 6.2 months for arm A and is 4.0 months for arm B, corresponding to a hazard ratio λA/λB of 0.645 (1/1.55) under constant hazards; (4) an accrual period of 42 months at a monthly rate of 19 registered patients; (5) a minimum follow-up of 6 months after enrollment. Under these assumptions, we expect that a total of 792 patients will be pre-registered to the study; 594 will be COX-2 evaluable patients; 208 will be COX-2 over-expressed (COX-2 ≥ 4) and will be randomized with equal allocation to arm A and arm B. At the time of final analysis, or approximately 48 months after the first enrollment, a total of 192 events are expected on the celecoxib arm (93 events) and on the placebo arm (99 events) under alternative hypotheses. Under fixed sample size design, the power in detecting the expected PFS benefit for arm A over arm B is at least 85% using a log-rank test at a two-sided significance level of 0.05. With the same study size and the same assumptions, the study has about 81% power to detect a median OS of 9.2 months for arm A and 6 months for arm B (a hazard ratio λA/λB of 0.652). At the final analysis, a total of 177 deaths are expected, with 84 deaths on arm A and 93 on arm B under alternative hypotheses.

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14.3 Correlative Science Endpoints

14.3.1 PGE-M analysis

One primary objective of the correlative study is to correlate the change of urinary PGE-M (from baseline to one week of treatment) with overall survival for patients on arm A. Csiki et al. have shown that the greater the drop of PGE-M at one week of treatment relative to baseline, the longer the survival (15). Assuming at least 77 deaths are observed over a 3.25 year period on arm A, we are able to detect a covariate effect of PGE-M change with 80% power at 5% Type I error (2-sided test), when the increase in log(hazard) per unit s.d. shift in the covariate is 0.32, which corresponds to a hazard ratio of Δ=1.38 per unit s.d. shift in the covariate of PGE-M change. Patients in arm A will be classified as High, Moderate and Low of PGE-M change according to the 67% and 33% percentiles. Univariate analysis will be performed using a log rank test to correlate overall survival and the group of PGE-M change. A Cox proportional hazard regression will be used to correlate the change of PGE-M as a continuous predictor with overall survival with and without adjusting for other prognostic factors. Similar univariate and multivariate analyses will be conducted for progression-free survival. Correlation between PGE-M and COX2 at baseline will be evaluated using Spearmen’s rank correlation.

In addition to the methodology described above, aliquots of urine will be stored at the PCO for potential evaluation of alternative methodologies for determining urinary PGE-M.

14.3.2 Statistical Considerations for the Pharmacogenetic Companion Study

The primary statistical objective for the pharmacogenetic companion of this study is to investigate the potential association between COX-2 protein expression and a PTGS2 polymorphism (rs20417). COX-2 expression will be determined using the described method of intensity scoring (<4 vs ≥ 4) as a binary outcome (under- versus moderate/over-expressed). It is hypothesized that the presence of the C allele is associated with lower COX-2 expression.

Assumptions: The assumed putative allelic relative frequency for rs20417 is 0.30 (C allele). Furthermore, it will be assumed that the genotypic distribution for this single nucleotide polymorphism (SNP) is not dependent on African ancestry. The assumed putative probability for being under-expressed in this population is 0.61. The assumed yield of evaluable specimens for COX-2 staining is a target sample size for the main study of 594 patients. It will be assumed that the typical rate of consent to a companion genetic study and yield of usable germline DNA samples will be a rate similar to previous CALGB studies (0.8), therefore, the expected sample size is at least 475.

The analysis will be formulated within the framework of a 2x2 contingency table. Let pA denote the probability of being COX-2 under-expressed for patients with at least one copy of the C allele and pB denote the probability of being COX-2 under-expressed for patients with no copies of the C allele. The power of Fisher’s test, at the one-sided level of 0.05, is illustrated in Table 1. For a given pA, p is chosen so as to satisfy 0.61=pA*0.3+pB*0.7. The corresponding effect size (odds-ratio) is denoted by OR.

pA pB OR Power 0.50 0.657 1.92 0.93 0.52 0.649 1.70 0.81 0.54 0.640 1.51 0.63

Table 1: Power Illustration

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The SNP will be tested for Hardy-Weinberg Equilibrium (HWE). The degree of association between COX-2 expression and rs20417 will be estimated using the conditional Maximum-Likelihood Estimator (MLE) point and interval estimator for the OR. The association between rs20417 and clinical endpoints of the study will be explored. A one-sided level will be used for the primary hypotheses while a two-sided unadjusted level of 0.05 will be used for all secondary tests and estimators.

Polymorphisms of CYP2C9 have been implicated in altered metabolism (25). This may relate to both toxicity and potentially efficacy (26, 27) As a secondary analyses, we seek to investigate if the relative harm (or benefit) attributed to celoxib depends on the genotype. To this end, we will consider potential SNP by celoxib interactions with respect to toxicity and survival among the randomized patients. These analyses will be carried out within the framework of multiplicative logistic (for toxicity) and Cox (for censored time-to-event outcomes) ANOVA models. Additionally, we will seek to explore a potential association between trough plasma celecoxib concentration and CYP2C9. The Kruskal-Wallis test will be used for this purpose.

An unadjusted two-sided level of 0.05 will be used for all secondary analyses.

14.4 Analytic Methods

Overall survival is defined as the time between randomization and death from all causes. Progression-free survival is defined as the time between randomization and disease relapse or death from any cause, whichever comes first. Overall survival and progression-free survival (PFS) will be characterized by the Kaplan-Meier method (28). The primary analysis is to test the survival benefit of arm A over arm B using log rank test in the intent-to-treat population (29). As secondary analysis, the treatment difference will be evaluated using a Cox’s proportional hazard model (30) with the significant prognostic factors as initial model covariates, such as sex, stage, presence of CNS metastatses, age, smoking status, and histological type. A step-down procedure that consists of dropping the least significant covariates, one at a time, will be used to obtain a more parsimonious model. The multivariate analyses will be done for both the intent-to-treat population and the as-treated population. Similar analyses will be conducted for progression-free survival (PFS).

Response rate and its 95% confidence interval will be estimated by treatment arm. The association of response rate will be tested by Fisher’s exact test and will be modeled using the logistic regression (31) with other prognostic factor eligible to enter the model.

The survival benefit of a COX-2 inhibitor in patients with COX-2 ≥ 2 will also be evaluated using a similar procedure. The differential survival benefit for patients with COX-2 index ≥ 4 and patients with COX-2 index ≥2 but <4 will be tested.

The prognostic value of the COX-2 index will be evaluated for the correlation with OS and PFS in patients on placebo.

Contingency tables will be used to summarize the frequency of toxicity by severity and treatment. For comparison of the frequency of toxic events, the Cochran-Mantel-Haenszel test will be used to take advantage of the trend effect among toxicity grades.

14.5 Logistics of Study Conduct

14.5.1 Accrual

Once 792 patients have been pre-registered to this trial or 208 patients with COX-2 index ≥ 4 have been randomized, whichever comes later, a notice to close the study will be issued to the Group via an e-mail broadcast effective within 14

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days. According to CALGB 30203, more than 50% of COX-2 evaluable patients have index ≥2. We expect that approximately 297 patients with COX-2 ≥2 of which 89 patients have COX-2 index ≥2 but <4 and 208 have COX-2 index ≥4 will be randomized at study closure. Based on the result of interim analysis, a recommendation for early stopping of the trial is also possible. Based on the experience of CALGB 30203 and with the participation of other cooperative groups, a registration rate of 19 patients per month is expected. At this rate, a period of approximately 42 months is needed to reach accrual target. In order to observe the full overall survival curve, a follow-up period of 5 years is required for all patients after enrollment.

14.5.2 Plan for Interim Analysis

The CALGB DSMB will review the study data at each of its semiannual meetings after study activation (32). This will include toxicity, progression-free survival and overall survival. Early stopping of this trial could occur for superiority (arm A is superior to arm B) and for futility (arm A is equivalent or inferior to arm B). Since there is interest in both the PFS and OS results, to be conservative, we will base the decision of early stopping of the trial on the result of the interim analyses on overall survival and we will start the futility monitoring 6 months after the superiority monitoring starts. The first formal interim analysis on superiority will occur after 46 deaths have been observed or approximately 1.5 years after study activation. The rest of the formal interim analyses on superiority and futility will be conducted at years 2, 2.5, 3, 3.5 and the final analysis at year 4, corresponding to approximately 71, 98, 127, 155 and 177 deaths. The stratified log rank test will be used to generate the one-sided p-values for these interim tests. Using S+SeqTrial (33) we will construct the superiority in the spirit of O’Brien and Fleming (34) with a use of the Lan-DeMets alpha spending function (50), and nominal p-value will be truncated at 0.001 in the spirit of Freidlin and Korn (35). The futility boundary is based on testing the alternative hypothesis at a one-sided 0.005 alpha level. Specifically, Z-score futility boundary is calculated as -2.576 – log (0.652)*sqrt (n/4), where n is the total number of observed deaths.

Because of the negligible impact of interim analyses under these boundaries on the type I error, the final analysis will be conducted using a 2-sided significance level of 0.05. The following table displays the operating characteristics on survival comparison between treatment arms, including power, average number of deaths, stopping probabilities under true hazard ratios λA/ λB of 1.25, 1.0, 0.85, 0.652 and 0.45.

Hazard Ratio (λA/ λB)

Averge Number of Deaths

Prob. for Crossing Superiority Boundary

Prob. For Crossing Futility Boundary

1.25 94 0.0004 0.9433 1.0 133 0.0189 0.5916 0.85 155 0.1380 0.2311 0.652 133 0.7055 0.0124 0.45 76 0.9977 0.0000

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14.5.3 Long-term Follow-up

Patients will be followed for 5 years or until death, whichever comes earlier.

15.0 CORRELATIVE SCIENCES METHODOLOGY

15.1 COX-2 Determination by Immunohistochemistry The COX-2 immunohistochemistry assay will be performed to determine if patients are eligible for the clinical trial. The same method for COX-2 determination will be employed as was performed in CALGB 30203. If the patient’s COX-2 index is equal to 2 or greater then they are eligible for the study and will be randomized to the trial therapies. The CALGB Molecular Pathology Reference Laboratory will be performing the COX-2 immunohistochemistry assay for the CALGB 30801 trial. The laboratory is located in the Department of Pathology at The Ohio State University Comprehensive Cancer Center Innovation Centre. The laboratory is CLIA approved and CAP accredited. The laboratory participates in proficiency testing for all assays to ensure that methology and test results achieve national clinical laboratory standards. Each new assay is validated against sets of clinical cases and verified by other national laboratories performing the same clinical tests. The CALGB Molecular Pathology Reference laboratory is located in the suite of laboratories including the laboratories that comprise the CALGB Pathology Coordinating Office (CALGB PCO). Thus a seamless interaction exists between the CALGB PCO and the IHC laboratory and thus the operations are set up such that receipt, management and analysis of biospecimens can occur rapidly and this will allow for rapid turnaround time of molecular results needed for this trial. The CALGB Pathology Coordinating Office and Molecular Pathology Reference Laboratory operations are managed by Dr. Scott Jewell. COX-2 expression will be assessed in all patients at the time of pre-registration. An adequate sized paraffin block with tumor tissue/cells taken at the time of initial diagnosis (or subsequently) will be submitted to the CALGB PCO. A secure and temperature-safe method of packaging will be used and the shipment will be traceable via courier. Once the samples arrive at the PCO they will be processed immediately to obtain the COX-2 results within 72 hours of receipt of the sample. Residual material will be stored appropriately as to ensure integrity of the antigen by vacuum sealing and refrigerating the material in a Rees monitored biorepository. Paraffin embedded tissue is cut at 4um and placed on positively charged slides. Slides with specimens will then be placed in a 60 degree oven for 1 hour, cooled, and deparaffinized and rehydrated through xylene and graded alcohol solutions to water. All slides are quenched for 5 minutes in 3% hydrogen peroxide in water to block for endogenous peroxidase. Antigen retrieval is performed using Dako's TRS, pH 6.1, in a vegetable steamer. Slides are then placed on a Dako Autostainer for automated staining. An antibody to Cox-2, clone SP21 (Labvision Corp), is diluted 1:50 and incubated for 1 hour at room temperature. The detection system used is a Labeled Streptavidin-Biotin Complex. This method is based on the consecutive application of 1.) A primary antibody against the antigen to be localized, 2.) biotinylated linking antibody, 3.) enzyme conjugated streptavidin, and 4.) substrate chromogen (DAB). Tissues are avidin and biotin blocked prior to the application of the biotinylated secondary reagent. Slides are then counterstained in Richard Allen Hematoxylin, dehydrated through graded ethanol solutions and coverslipped. After the Cox-2 immunohistochemistry assay is performed, images of the slides along with the pathology reports will be electronically transferred for reading by the study pathologist(s). The CALGB-PCO has implemented a virtual microscopy system, which allows CALGB pathologists to view the tissues via the internet. The slide scanning system (Aperio Scanscope XT) and the server are located and maintained at the CALGB PCO. The process has been developed to improve or

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minimize a number of operating issues such as packaging, shipping, and return shipment of original glass H&E slides. The slides will be annotated electronically by Drs. Jon Ritter, Kisha Mitchell and Richard Cheney, members of the CALGB Respiratory Pathology Cadre and certified anatomical pathologists. All slides are reviewed by a certified anatomical pathologist without knowledge of the patient history.

The scoring procedure for COX-2 expression is semi-quantitative/ordered categorical. The neoplastic cells for any given case represented by one stained slide are scored for intensity (range of scores 0-3) and percentage of cells 0 (0%), 1 (1-9%), 2 (10-49%), 3 (50-100%) staining. An immunohistochemistry (IHC) index (range of scores 0-9) is defined as the product of the intensity and percentage of cells staining.

Accuracy is determined by comparing the measurement against the true or accepted value. An accuracy measurement of COX-2 by immunohistochemistry (IHC) as defined against a true or accepted value was not performed in developing the present IHC test simply because there is currently no gold standard for measuring COX-2 protein product in tissue. The accuracy of the COX-2 IHC assay is determined to be acceptable based on the monoclonal rabbit anti-human COX-2 antibody that will be used for the assay has been shown to be specific to the antigen as it was used to isolate COX-2 in both western blotting and precipitation of COX-2 as determined by HPLC.

Precision is the degree of refinement with which an operation is performed or a measurement stated. We have performed two forms of precision testing for the COX-2 assay. First, we have stained a set of samples with a range of IHC indices on consecutive days and had them analyzed by the study pathologist. This experiment measures the day-to-day variability of the assay and the consistency with which the assay performs. The results were extremely reproducible. The two readings of COX-2 did not have any significant differences on any of the samples. All the 95% CI for the estimates of Alpha contain 0, and all the 95% CI for the estimate for Beta contain 1. The intraclass correlation and Kappa coefficient were all above 0.8636, suggesting a strong correlation between the readings.

The second assay precision experiment involved a set of 26 specimens and these specimens were stained and analyzed by two pathologists in order to evaluate the consistency of values in two separate sets of observations. The results of this analysis show that the two readings are strongly correlated with one another and do not have any significant differences. A linear model was fitted with the measure from one pathologist as the outcome variable and that of the other pathologist as the explanatory variable. The 95% confidence interval for the intercept estimate contains 0, and that of the slope estimate contains 1. The joint test for the intercept=0 and the slope=1 is not statistically significant (p-value=0.5156). Similar findings held for COX-2 intensity and COX-2 percents. The intraclass correlation is 0.81260 for COX-2 index, 0.81308 for intensity, and 0.67726 for percentage. After dichotomizing COX-2 index at 2, the agreement between RC and CM as measured by Kappa coefficient (0.7797; 95%CI: 0.3666, 1.000) is also good. All these findings suggest the reading of COX-2 expression can be reproduced by different pathologists

Proficiency standards for IHC assays are often provided by CAP. When CAP does not offer proficiency standards it is up to individual laboratories to exchange tissue specimens. We are in the process of setting up proficiency testing using a small set of cases that can be tested by both the CALGB Molecular Pathology Reference Laboratory and the OSU clinical immunohistochemistry laboratory. Both laboratories are CLIA licensed and CAP certified. Other CALGB pathology labs that are CLIA certified may also participate in the proficiency testing.

A training set demonstrating the degrees of percent positive cells and intensity of COX-2 staining in tumor tissues will be established as a reference to assist pathologist in maintaining a consistency in reading cases.

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The turn around time for the assay is 72 hours from receipt of the tissue sample at the testing laboratory. The failure rate of the assay is <5%. Controls for the assay will include both negative and positive controls as well as an isotype negative control. Human lung tissue that has been typed as negative and positive will be assayed with each study specimen run and an isotype negative control reagent (substitution of non-specific matched isotype antibody in place of the primary antibody) will be assayed for each study specimen.

15.2 Correlation of Urinary PGE-M Determination with COX-2 Expression, COX-2 Inhibition and Outcome

Changes in urinary PGE-M have been demonstrated to correlate with response to COX-2 inhibition in studies at Vanderbilt and UCLA (15). Similar results have been reported from the UCLA group (36). While intriguing, both studies were small, lacked adequate controls and were inadequately powered to establish whether urinary PGEM could be utilized as a surrogate for the determination of COX-2 dependency in advanced NSCLC. Determination of urinary PGE-M may provide a method of determining possible COX-2 dependence of NSCLC without the requirement for initial tissue for IHC and may also be an early marker for response to therapy.

The urinary PGE-M assay that will be used in the CALGB 30801 trial will be performed in the Eicosanoid Core Laboratory at Vanderbilt University Medical Center under the direction of the laboratory director, Dr. Ginger Milne. The Vanderbilt group first identified the metabolite of PGE2 in the 1970’s and developed the current methodology to quantify it in 2004. Since then they have been extremely active in the field, analyzing 12,000-15,000 eicosanoid samples per year. Specifically for the metabolite of PGE2, they analyze between 100-200 samples per month.

The urinary PGE-M assay to be used in the CALGB 30801 trial is described in detail in a publication by the Vanderbilt group entitled “Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and those with lung cancer. (Analytical Biochemistry 334 (2004) 266–275).

In brief, urine (1 ml) is acidified to pH 3 with 1M HCl, and endogenous PGE-M is then converted to the O-methyloxime derivative by treatment with 0.5ml of 16% (w/v) methyloxime HCl in 1.5M sodium acetate buffer (pH 5). Following a 1-h incubation, the methoximated PGE-M is extracted with 10ml water adjusted to pH 3, and the aqueous sample is applied to a C-18 Sep-Pak (Waters, Milford, MA, USA) that has been preconditioned with 5ml methanol and 5ml water (pH 3). The Sep-Pak is washed with 20 ml water (pH 3) and 10ml heptane. PGE-M is then eluted from the Sep-Pak with 5ml ethyl acetate, and any residual aqueous material is removed from the eluate by aspiration. The [2H6]Omethyloxime PGE-M internal standard (6.2 ng in 10 ul ethanol) is then added, and the eluate is evaporated under a continuous stream of nitrogen at 37 °C. The dried residue is resuspended in 50 ul mobile phase A (95:4.9:0.1 (v/v/v) 5mM ammonium acetate:acetonitrile: acetic acid) and is filtered through a 0.2-micron Spin-X Filter (Corning, Corning, NY, USA). Sample analysis is performed by LC/MS/MS.

LC is performed on a 2.1 x 50-mm, 5 um particle Zorbax Eclipse XDB-C18 column (Aligent, Palo Alto, CA, USA) attached to a Surveyor MS Pump (Thermo- Finnigan, San Jose, CA, USA). Samples are separated by a gradient of 98–40% of mobile phase A over 15min at a flow rate of 75 ul/min prior to delivery to a ThermoFinnigan TSQ Quantum triple quadrupole mass spectrometer operating in the selected reaction monitoring (SRM) mode. The mass spectrometer is operated in the negative ion mode with a capillary temperature of 210 °C, a spray voltage of 3.0kV, and a tube lens voltage of 118V. The source collision-induced dissociation (CID) is set at 10eV. Precursor ions (m/z 385 and 391 for unlabeled PGE-M and the [2H6]PGE-M internal standard, respectively) are collisionally activated at 22 eV under 1.5mT argon gas.

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For endogenous PGE-M, the predominant product ion m/z 336 representing [M-(OCH3+H2O)]- and the analogous ion, m/z 339 [M-(OC[2H3]+H2O)]-, for the deuterated internal standard are monitored in SRM mode. Quantification of endogenous PGE-M uses the ratio of the mass chromatogram peak areas of the m/z 336 and 339 ions. Data are expressed after correction for urinary creatinine (Cr) concentrations and are reported as nanograms per milligram Cr. Urine Cr is measured by an Autoanalyzer technique (Technicon, Buffalo Grove, IL, USA).

Though the original studies were performed utilizing aliquots from 24-hour urine collections, more recent data indicate that spot urine samples are adequate (Johnson, personal communication). Therefore, the additional burden on the investigator is minimal as only two collection timepoints are required on this study.

Several procedures were performed to establish the accuracy of this assay. Initially, to assess the linearity of response of the assay, varying amounts of unlabeled PGE-M were added to a fixed amount of the [2H6]PGE-M internal standard and were analyzed. The ratio of the measured signal of the product ions, m/z 336 and 339, was plotted as a function of expected ratio. The results of this analysis showed that the response is linear over a 1000- fold range. In another experiment to esatblish the accuracy of the assay, a known amount (8.4 ng) of chemically synthesized PGE-M was added to five additional 1-ml aliquots of the urine sample from the precision determination and was analyzed. The concentration of endogenous PGE-M was subtracted from the total measured concentration, and the accuracy of measurement of the added 8.4 ng of PGE-M was calculated. The accuracy of the assay was established to be 93% (n=4, separate experiments). As the response of PGE-M over a wide concentration range is linear, we expect that PGE-M can be accurately quantified at both very high and very low levels. To this end, we recently had the opportunity to measure levels of PGE-M in samples containing known amounts of newly synthesized PGE-M. We measured samples containing 70 ng and 5.5 ng in duplicate and obtained the following results: 71.09/76.05 and 5.16/5.11, respectively.

To establish assay precision, five 1-ml aliquots of urine from the same larger sample were individually prepared and analyzed. The coefficient of variation of PGE-M concentrations as determined from the mass chromatograms was determined to be only 7.2% (n=4, separate experiments).

In addition to establishing the accuracy and precision of the assay, the investigators assessed the recovery of PGE-M through the assay. Recovery through the extraction process was determined using [3H7]PGE2. When added to a urine sample, methoximated, and extracted, 97% of radioactivity was recovered in the purified sample.

It has been reported previously that storage of urine at -20 °C results can result in a progressive decomposition of PGE-M over a few months. Therefore, in this trial we have decided to store the urine at -70 °C or colder. To assess the stability of PGE-M in urine samples stored at -70 °C and under various other conditions, several experiments were performed. Multiple aliquots of the same sample were frozen at -70 °C and analyzed over the course of 12 months and were compared with the value for PGE-M obtained when an aliquot was analyzed at the time of collection. There was no effect of storage on urinary PGE-M concentrations. The concentration of PGE-M at the time of collection was 10.9 +/- 1.0 ng/mg Cr, and after 12 months it was 12.0 +/- 3.1 ng/mg Cr (P=ns).

Reference samples have been collected from a 24-hour urine sample donated by a volunteer and will be used as controls for the assay. The 24-hour urine sample has been divided into 1mL aliquots that have been frozen and stored. Levels of PGE-M were measured in 12 of the aliquots and the average PGE-M value and standard deviation were calculated. A range of acceptable PGE-M values for this sample was then determined to be +/- two standard deviations (< 20% variability) from the

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average PGE-M value of the aliquots. To control for quality each day, reference samples are analyzed side-by-side with study samples. If the PGE-M value of the reference sample is outside of the accepted range, the analysis is repeated. On the mass spectrometer each day, a standard (consisting of synthesized PGE-M) is also analyzed to determine sensitivity and performance of the instrument. If an LC/MS chromatogram of a sample is determined to be uninterpretable, the sample analysis will be performed a second time. If, after two analyses, an acceptable result is not obtained the sample will be reported as “no result”. Additionally, for this study, calibration curves. will be repeated once per month to maintain that the response is still linear.

15.3 Association Between the -765G/C Polymorphism in PTGS2 and COX-2 Expression in Non-small Cell Lung Cancer Specimens

The effects of celecoxib on survival for NSCLC patients with tumors that stain intensely for COX-2 in CALGB 30203 suggests better understanding the biology of COX-2 expression in NSCLC could improve treatment outcomes for a subset of NSCLC patients. Based on these data, tumor expression of COX-2 by IHC is the best available assay, but additional phenotyping assays are proposed in this study.

Evidence from other fields of medicine suggests a germline genetic test might be useful, with a specific role for rs20417, the common promoter single nucleotide polymorphism -765G>C of PTGS2 (the gene encoding COX-2), in cell and tissue expression of COX-2. There are no data available on the relationship between PTGS2 -765 genotype and lung tumor expression of COX-2. However, Cipollone, et al. demonstrated reproducible associations between the G allele and expression of COX- 2 detected by IHC in atheromatous plaques and by immunoblot in peripheral blood mononuclear cells. Homozygosity for the G allele was associated with the highest level of COX-2 expression, while CC homozygosity the lowest. The lower expressing allele was associated with lower circulating concentrations of serum CRP and lower risk for myocardial infarction or stroke in a >1700 patient case/control study. Brosens, et al. demonstrated the same trend in association between rs20417 allele and COX-2 expression in duodenal mucosa of patients with familial adenomatous polyposis. In tumor tissue, somatic mutation and epigenetic regulation might or might not dramatically alter these relationships. If in NSCLC they do not, then

rs20417 genotyping might be a useful method to screen for NSCLC patients that will have intense COX-2 staining and be appropriate for further testing for COX-2 tumor expression. The primary objective of the correlative study therefore is to determine the association between rs20417 genotype and the rate of NSCLC tumors with > 4 intensity score for COX-2 protein expression on IHC.

Celecoxib metabolism may be affected by cytochrome P450 polymorphisms. Specifically, polymorphisms of CYP2C9 have been implicated in altered metabolism (38). This may relate to both toxicity and potentially efficacy (39, 40). Drug related GI bleeding was found to be related to CYP2C9 polymorphisms with CYP2C9*1/*3 and * 1/*2 associated with significantly greater risk of GI bleeding (OR 12,9 and 3.8, respectively). There is a possible association between the COX-2 polymorphism -765G>C and the efficacy of NSAID use as a preventative agent for colorectal polyps (p=.07).

The randomized design of this investigation and the number of NSCLC patients enrolled provides an opportunity to collect sufficient genomic DNA samples to consider genome-wide association approaches to identifying heritable factors associated with good and poor prognosis, good and poor response to the addition of celecoxib, toxicities from celecoxib, changes in proximal phenotypes such as PGE-M, and more exploratory investigations.

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15.4 Pharmacokinetics of Celecoxib

Celecoxib concentrations will be determined with an HPLC assay that has been validated to FDA guidelines in the CALGB Pharmacology Reference Laboratory (41). The assay is a rapid and sensitive HPLC method using a monolithic column with UV detection, which enables the determination of celecoxib with good accuracy at low drug concentrations in plasma using single-step extraction procedure. Separation will be performed on a reversed-phase monolithic column, which has lower separation impedance compared with the particulate packings, and therefore, it allows easy optimizing chromatographic conditions to obtain desirable resolution in a short time. The sample preparation only involves a simple one-step protein precipitation and no evaporation step is required. 450 ul of plasma in a glass-stoppered 15-ml centrifuge tube is added to 50 ul of mefenamic acid, 500 ul of acetonitrile and 100-mg NaCl. After mixing for 30 seconds, the mixture is centrifuged for 15 min at 8000 rpm. 20ul of the supernatant is injected into liquid chromatograph. The separation is performed on Chromolith Performance column from Merck (Darmstadt, Germany). The wavelength is set at 254 nm.

16.0 ADVERSE EVENT (AER) REPORTING

Investigators are required by Federal Regulations to report serious adverse events as defined in the table below. CALGB investigators are required to notify the CALGB Central Office, the Study Chair, and their Institutional Review Board if a patient has a reportable serious adverse event. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting beginning October 1, 2010. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). All reactions determined to be “reportable” in an expedited manner must be reported using the NCI Adverse Event Expedited Reporting System (AdEERS).

Phase 2 and 3 Trials: AdEERS Expedited Reporting Requirements for Adverse Events That Occur Within 30 Days1 of the Last Dose of Treatment

Grade 1

Grade 2

Grade 2

Grade 3

Grade 3

Grades 4 & 5

Grades 4 & 5

Unexpected Expected

Unexpected and

Expected

Unexpected

Expected with Hospitali-

zation

without Hospitali-

zation

with Hospitali-

zation

without Hospitali-

zation

Unexpected Expected

Unrelated Unlikely

Not Required

Not Required

Not Required

Not Required

Not Required

Not Required

Not Required

10 Calendar Days

10 Calendar

Days

Possible Probable Definite

Not Required

Not Required

Not Required

Not Required

Not Required

Not Required

Not Required

10 Calendar

Days

10 Calendar

Days 1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last

dose of treatment require reporting as follows: AdEERS 10 calendar day report:

• Grade 4 unexpected events • Grade 5 expected or unexpected events

March 2005

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Note: All deaths on study require both routine and expedited reporting regardless of causality. Attribution to treatment or other cause should be provided. • Expedited AE reporting timelines defined:

"10 calendar days" - A complete AdEERS report on the AE must be submitted within 10 calendar days of the investigator learning of the event.

• Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be reported via AdEERS.

• Use the NCI protocol number and the protocol-specific patient ID provided during trial registration on all reports.

Additional Instructions or Exclusions from AdEERS Expedited Reporting Requirements:

• Deaths occurring greater than 30 days after the last dose of treatment that are due to disease progression do not require AdEERS expedited reporting.

• All grade 4 events that are unexpected and that are at least possibly related to treatment must be reported via AdEERS within 10 calendar days.

• Grade 4 events that are expected do not require AdEERS expedited reporting, even if they result in hospitalization.

• Adverse events include those listed in Section 10.0 and in the package inserts.

• AdEERS reports should be submitted electronically to the CALGB Central Office ([email protected]).

• All adverse events reported via AdEERS (i.e., serious adverse events) should also be forwarded to your local IRB.

• The reporting of adverse events described in the table above is in addition to and does not supplant the reporting of adverse events as part of the report of the results of the clinical trial, e.g., study summary forms or cooperative group data reporting forms (see Section 6.1 for required CALGB forms).

• Cases of secondary AML/MDS are to be reported using AdEERS. The event(s) may be reported as either: 1) Leukemia secondary to oncology chemotherapy; 2) Myelodysplastic syndrome; or 3) Treatment related secondary malignancy.

• New primary malignancies should be reported using study form C-1001.

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17.0 REFERENCES

1. Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18:623-31.

2. Wozniak AJ, Crowley JJ, Balcerzak S, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: A cooperative group study. J Clin Oncol 10:1066-1073, 1992.

3. Sandler A, Nemunatis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced and metastatic non-small cell lung cancer. J Clin Oncol 18:122-130, 2000.

4. Schiller, J.H., Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 2002. 346(2): p. 92-8.

5 Kelly K, Crowley J, Bunn PA et al. Randomized phase three trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 19:3210-8, 2001.

6 Khuri FR, Hong W, Lee JJ et al. Cyclooxygenase 2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 7: 861-7, 2001.

7 Wolff, K. Saukkonen, et al. (1998). “Expression of cyclooxygenase-2 in human lung carcinoma.” Cancer Research 58(22): 4997-5001

8 Ochiai, M., T. Oguri, et al. (1999). “Cyclooxygenase-2 (COX-2) mRNA expression levels in normal lung tissues and non-small cell lung cancers.” Japanese Journal of Cancer Research 90(12): 1338-43

9 Masferrer, J. L., K. M. Leahy, et al. (2000). “Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors.” Cancer Research 60(5): 1306-11.

10 Asktorab H, Larbi D, Tackey R, et al. Cyclooxygenase-2 inhibitor celecoxib alone and in combination with folic acid inhibits proliferation of colon cancer cell lines. Proc AACR 42: abstr 3305, 2001.

11 Pyo H, Choy H, Amorino GP et al. A selective cyclooxygenase-2 inhibitor, ns-398, enhances the effect of radiation in vitro and in vivo preferentially on the cells that express cycloxygenase-2. Clin Cancer Res 2998-3005, 2001.

12. Ratnasinghe, D., P. J. Daschner, et al. (2001). “Cyclooxygenase-2, P-glycoprotein-170 and drug resistance; is chemoprevention against multidrug resistance possible?” Anticancer Research 21(3C): 2141-7.

13. Steinbach G, Lynch PM, Phillips RKThe effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000 Jun 29;342(26):1946-52

14. Moysich KB, Menezes RJ, Ronsani A et al. Regular aspirin use and lung cancer risk. BMC Cancer. 2002 Nov 26;2:31

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15. Csiki I, Morrow JD, Sandler A. et al. Targeting cyclooygenase-2 in recurrent non-small cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Ca Res 2005:11; 6634-6640.

16. Altorki NK, Port JL, Zhang F et al. Chemotherapy induces the expression of cyclooxygenase-2 in non-small cell lung cancer. Clin Ca Res 2005; 11, 4191-4197.

17. Edelman MJ, Watson D, Xiaofei W, Morrison C, Kratzke RA, Jewell S, Hodgson L, Mauer AM, Gajra A, Masters GA, Bedor M, Green MJ, Vokes EE. Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial 30203. J Clin Oncol, . 2008;26:848-55.

18. Rini BL, Weinberg V,Dunlap S et al. Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma. Cancer 2006;106:566-75.

19. Fidler M, Argiris A, Patel JD, Johnson DH, Sandler A, Villaflor V, Coon J, Buckingham L, Bonomi P. The potential predictive value of cyclooxygenase -2 expression and increased risk of gastrointestinal hemorrhage in advanced non-small cell lung cancer patients treated with celecoxib and erlotinib. IASLC Novel Agents Symposium (Santa Monica, CA), 2007.

20. Fabi A, Metro G, Papaldo P Impact of celecoxib on capecitabine tolerability and activity in pretreated metastatic breast cancer: results of a phase II study with biomarker evaluation. Cancer Chemother Pharmacol. 2008 Sep;62(4):717-25

21. Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007 May 24;356:2131-42

22. Solimon SD, McMurray JJV, Pheffer MA, et al. Cardiovascular risk associated with celecoxib in aclinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-80.

23. Johnson DH, Zhu J, Schiller J et al. E-1594- A randomized phase III trial in metastatic non-small cell lung cancer (NSCLC)- outcome of PS 2 patients (pts): An Eastern Cooperative Group Trial (ECOG). Proc Am Soc Clin Oncol 18:461a (#1779), 1999

24. Zelen M. The randomization and stratification of patients to clinical trials. J Chronic Dis 1974;27:365-75

25. Kirchheiner J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics. 2003 Aug;13(8):473-80

26. Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, Niro V, Andriulli A, Leandro G, Di Mario F, Dallapiccola B. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007 Aug;133(2):465-71. Epub 2007 May 21.

27. Cross JT, Poole EM, Ulrich CM. A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia. Pharmacogenomics J. 2008 Jan 15 [Epub ahead of print]

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28. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.

29. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163-70.

30. Cox DR. Regression models and life-tables. J R Stat Soc [B] 1972;34: 187-220.

31. Cox DR, Snell EJ. Analysis of binary data. 2nd ed. London: Chapman & Hall, 1989.

32. Freidlin B, Korn EL, George SL. Data monitoring committees and interim monitoring guidelines. Control Clinical Trials. 1999; 20(5):395-407.

33. Emerson, S. (2000). S+SEQTRIAL: Technical Overview. Research Report No. 98, Data Analysis Products Division, MathSoft, Inc.

34. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979; 35(3):549-556.

35. Freidlin B, Korn EL, George SL. Data monitoring committees and interim monitoring guidelines. Control Clinical Trials. 1999; 20(5):395-407.

36. Reckamp KL, Krysan K, Morrow JD et al. A phase I trial to determine the optimal biological dose of celecoxib when combined with erlotinib in advanced non-small cell lung cancer. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3381-8

37. Murphey LJ, Williams MK, Sanchez SC et al. Quantification of the major urinary metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay: determination of cyclooxygease-specific PGE2 synthesis in healthy humans and those with lung cancer. Analytical Biochem 2004 334:266-275.

38. Kirchheiner J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites. Pharmacogenetics. 2003 Aug;13(8):473-80

39. Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, Niro V, Andriulli A, Leandro G, Di Mario F, Dallapiccola B. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007 Aug;133(2):465-71. Epub 2007 May 21.

40. Cross JT, Poole EM, Ulrich CM. A review of gene-drug interactions for nonsteroidal anti-inflammatory drug use in preventing colorectal neoplasia. Pharmacogenomics J. 2008 Jan 15 [Epub ahead of print]

41. Zarghi A, Shafaati A, Foroutan SM, Khoddam A. Simple and rapid high-performance liquid chromatographic method for determination of celecoxib in plasma using UV detection: application in pharmacokinetic studies.J Chromatogr B Analyt Technol Biomed Life Sci. 2006 May 1;835:100-104

42. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. . N Engl J Med. 2006 Dec 14;355(24):2542-50.

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43 Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.J Clin Oncol. 2008 Jul 20;26(21):3543-51

44. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. 2004. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9):1589-1597.

45. Hughes A, Calvert P, Azzabi A, Plummer R, Johnson R, Rusthoven J, Griffin M, Fishwick K, Boddy AV, Verrill M, Calvert H. 2002. Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma. J Clin Oncol 20(16):3533-3544.

46. Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, O’Brien M, Peterson PM, Castellano D, Selvaggi G, Novello S, Blatter J, Kayitalire L, Crino L, Paz-Ares L. 2005. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer Res 11(2 Pt 1):690-696.

47. Zinner RG, Fossella FV, Gladish GW, Glisson BS, Blumenschein GR Jr, Papadimitrakopoulou VA, Pisters KM, Kim ES, Oh YW, Peeples BO, Ye Z, Curiel RE, Obasaju CK, Hong WK, Herbst RS. 2005. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer. Cancer 104(11):2449-2456.

48. Alimta (package insert). Indianapolis (IN): Eli Lilly and Co.; 2008.

49. Sweeney CJ, Takimoto CH, Latz JE, Baker SD, Murry DJ, Krull JH, Fife K, Battiato L, Cleverly A, Chaudhary AK, Chaudhuri T, Sandler A, Mita AC, Rowinsky EK. Two drug interaction studies evaluating the pharmacokinetics and toxicity of pemetrexed when coadministered with aspirin or Ibuprofen in patients with advanced cancer. Clin Cancer Res. 2006 Jan 15;12(2):536-42.

50. Lan K, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika. 1983; 70:659-653.

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18.0 MODEL CONSENT FORM


This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to you. Clinical trials include only people who choose to take part. Please take your time to make your decision about taking part. You may discuss your decision with your friends and family. You can also discuss it with your health care team. If you have any questions, you can ask your study doctor for more explanation. You are being asked to take part in this study because you have non-small cell lung cancer.

Why is this study being done?

The purpose of this study is to compare the effects, good and/or bad, of adding an experimental drug, celecoxib, to chemotherapy. This research is being done because current standard treatments for your type of lung cancer are usually not effective in preventing the cancer from growing. In this study we will test a sample of your cancer to see if it has an enzyme called COX-2. It is thought that cancers that have high levels of this enzyme may benefit from the addition of celecoxib to standard chemotherapy. You will receive standard chemotherapy of either gemcitabine and carboplatin or pemetrexed and carboplatin, depending on the type of non-small cell lung cancer you have. Along with standard chemotherapy, you will get either celecoxib or a placebo (a substance that looks like celecoxib, but contains no medication). We do not know whether or not adding celecoxib to the chemotherapy is beneficial. Celecoxib is not approved by the Food and Drug Administration (FDA) for the treatment of lung cancer.

How many people will take part in the study?

About 300 people will take part in this study.

What will happen if I take part in this research study?

Before you begin the study…. Required Test Recent studies have shown that people who have high levels of COX-2 in tumor tissue appear to benefit from treatment with celecoxib or other similar drugs. For

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this reason, your tumor sample will be tested to find out if it has high levels of COX-2 since this study is evaluating treatments that contain celecoxib. This test can be done on tumor tissue that was removed at any time. If the test shows that your tumor does not have a high level of COX-2 you will not continue with treatment on this trial. You and your doctor will then decide on the appropriate treatment strategy outside of this clinical trial. The results of the COX-2 test will not ever be given to you or your doctor. Optional Test We are also interested in studying the DNA in your blood to determine: a) whether or not it has certain characteristics that can predict if you will have high or low levels of COX-2 and b) how the activity of certain genes influence the effectiveness and side effects of the drugs used in this study. Before it is determined whether you are eligible for the study, we would like to collect about 2 teaspoons of blood for research purposes only, to study the DNA in your blood. This research blood test will not be used to determine your eligibility. The blood sample will be processed to collect your DNA. DNA is the substance that makes up your genes. Genes are the units of inheritance that are passed down from generation to generation. They are responsible for eye color, hair color, blood type, and hundreds of other traits. Genetic studies use DNA to study your genes. There are specific risks associated with genetic studies. To help you make your decision, additional information is included at the end of this consent form. This information describes how your personal information will be protected by the CALGB and its researchers. New scientific tools will now allow researchers to look at your whole DNA, not just one part or gene. This kind of research can provide information to researchers about the development of cancer and response to treatment. It can also provide information about a variety of other conditions and diseases, including heart disease, diabetes and Alzheimer’s disease. Because the information gained in these DNA wide studies can be very valuable, especially when they are shared with the research community, the National Institutes of Health (NIH) has requested that this data be placed in a central location housed at the NIH. The idea behind this is to speed up the process for discovery of new treatments, prevention and diagnosis of disease. Researchers must get approval from the NIH, before they can access the research results and clinical information from your specimen. All information will be coded with a unique number. Researchers will not have access to your identity; they will only see coded information. While we believe that the risks to you and your family are very low, we cannot tell you exactly what all of the risks are from taking part in genetic research studies. Your privacy and confidentiality will be protected to the fullest extent possible.

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The choice to provide this blood sample is up to you. The test is optional and no matter what your decide to do, it will not affect your care. 1) I agree that my blood may be used for the research study described above.

_________ Yes __________ No ________ Initials Medical Tests If you take part in this study, you will have the following tests and procedures: • Blood tests • CT scan or MRI of chest and abdomen Several of these tests will be repeated during the study. If you participate in this study, some of these tests may be done more frequently than if you were not taking part in this research study. Treatment Plan

You will be "randomized" into one of the study groups described below. Randomization means that you are put into a group by chance. A computer program will place you in one of the study groups. Neither you nor your doctor can choose the group you will be in. You will have an equal chance of being placed in either group. You and your doctor will not know which group you are assigned to. However, your treatment information will be available to your doctor in case of emergency. Within each group there are 2 treatments, and the treatment you will receive will depend on the type of lung cancer you have. There are 3 different types of non-small cell lung cancer: adenocarcinoma, squamous cell carcinoma and large cell carcinoma. Past studies have shown that patients with squamous cell lung cancer have many more side-effects when treated with pemetrexed. Therefore, patients with squamous cell carcinoma will be treated with gemcitabine. All other patients will be treated with pemetrexed. The possible treatments are listed below: Group A: Treatment with one of the below combinations, depending on which type of non-small cell lung cancer you have: Gemcitabine by IV (by vein) on days 1 and 8 of each treatment cycle Carboplatin (immediately after the gemcitabine) by IV on day 1 Celecoxib, one capsule, taken by mouth 2 times daily Or Pemetrexed by IV (by vein) on day 1 Carboplatin (immediately after the pemetrexed) by IV on day 1 Celecoxib, one capsule, taken by mouth 2 times daily

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OR Group B: Treatment with one of the below combinations, depending on which type of non-small cell lung cancer you have: Gemcitabine by IV on days 1 and 8 of each treatment cycle Carboplatin (immediately after the gemcitabine) by IV on day 1 Placebo, one capsule, taken by mouth 2 times daily every day Or Pemetrexed by IV on day 1 Carboplatin (immediately after the pemetrexed) by IV on day 1 Placebo, one capsule, taken by mouth 2 times daily every day

The treatment will be repeated every 21 days (1 cycle = 21 days). You will receive up to 6 cycles of treatment. When the 6 cycles (18 weeks) are over you may continue to take the celecoxib/placebo, as long as your tumor does not grow. While on this study you will be asked to avoid taking aspirin or other non-steroidal anti-inflammatory drugs such as rofecoxib (Vioxx), aspirin (≤325 mg per day is allowed), choline Mg, trisalicylate (Trilisate), or other non-steroidal anti-inflammatory drugs such as ibuprofen (Advil or Motrin), naproxen (Aleve, Naprosyn or Anaprox), etodolac (Lodine), oxaprozin (Daypro), diflunisal (Dolobid), nabumetone (Relafen), or tolmetin (Tolectin).

How long will I be in the study?

We think your treatment will last about 5 months, but could last longer, depending upon how your disease responds and what kind of side-effects you experience. You and your doctor may decide to continue on the celecoxib/placebo if, after 6 cycles of chemotherapy, your tumor is shrinking or staying the same. Following treatment, you will receive follow-up examinations at least every 2 months for 2 years and then at least 6 months for 3 years. Your doctor will discuss these tests with you.

The researcher or your doctor may decide to take you off study treatment if: • The treatment does not work in your cancer. • Your health gets worse. • Your cancer begins to grow.

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You can stop participating at any time. However, if you decide to stop participating in the study, we encourage you to talk to the researcher and your doctor first.

Can I stop being in the study?

Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. It is important to tell the study doctor if you are thinking about stopping so any risks from the drugs can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what followup care and testing could be most helpful for you. The doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; if you do not follow the study rules; or if the study is stopped.

What side effects or risks can I expect from being in the study?

You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don’t know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking the therapy. In some cases, side effects can be serious, long lasting, or may never go away. There also is a risk of death. You should talk to your study doctor about any side effects that you have while taking part in the study. The risks and side effects of gemcitabine, carboplatin and celecoxib are listed below. If you are randomized to the gemcitabine, carboplatin and placebo you will not be receiving the active drug celecoxib. Sometimes, even while taking placebo, people experience side effects. These side-effects may or may not be due to the placebo. Some side-effects for patients on placebo may or may not be similar to the side effects of celecoxib.

Celecoxib Less Likely • Headache. • Heartburn. • Diarrhea • Belly pain. • Bleeding in some organ(s) of the digestive tract, for example, blood in your stool. • Nausea and vomiting

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• Hypertension • Swelling in the arms and legs Rare but Serious • Kidney damage. • Heart attack • Stroke • Chest pain (angina) • Blood clots Patients who continue to take the celecoxib/placebo after 1 year may be more likely to have a heart attack, stroke, or other cardiovascular problems.

Carboplatin

Likely • Lowered white blood cell count* that may lead to infection. • Lowered platelets* that may lead to an increase in bruising or bleeding. • Lowered red blood cells* that may cause anemia, tiredness, or shortness of breath. • Nausea, vomiting. • Abnormal liver function blood tests. • Time away from work.

* Should this occur it can be treated with blood products (transfusions for low platelets

and red blood cells), antibiotics for low white blood cells, and a reduction in the amount of drug given to you for low white blood cells and platelets.

Less Likely • Tingling, like pins and needles, in your hands and feet. • Hearing loss (rare). • Allergic reactions. • Constipation or diarrhea. • Hair loss. • Stomach pain. • Abnormal kidney function blood tests.

Gemcitabine

Likely

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• Lowered white blood cell count that may lead to an increased risk of infection • Lowered platelet count that may lead to increased bruising or bleeding • Lowered red blood cell count that may cause anemia, tiredness, or shortness of

breath. • Nausea, vomiting, diarrhea. • Flu-like symptoms that may include: muscle aches, fatigue, fever and/or chills,

sweating, joint or chest pain, headache or cough. • Swelling in arms and/or legs. • Rash, usually mild, sometimes with itching. Less likely • Hair loss. • Abnormal liver function blood tests. • Constipation. • Numbness in fingers and toes. • Mouth or throat sores. • Shortness of breath or difficulty breathing. • Mild allergic reaction (rash, hives, watery or itchy eyes). Rare, but serious • Kidney damage that could lead to renal failure. • Breathing difficulties resulting from damage to the lungs which could be permanent.

Pemetrexed

Likely • Nausea and/or vomiting • Feeling tired Less Likely • Lowered platelet count that may lead to increased bruising or bleeding • Lowered white blood cell count that may lead to an increased risk of infection • Lowered red blood cell count that may cause anemia, tiredness, or shortness of

breath. • Abnormal liver function blood tests. • Abnormal kidney function blood tests.

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• Burning, itchy, watery eyes • Numbness, tingling in the hands and feet • Muscle weakness • Rash, mouth sores and diarrhea Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. Women should not breastfeed a baby while on this study. It is important you understand that you need to use birth control while on this study. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. For more information about risks and side effects, ask your study doctor.

Are there benefits to taking part in the study?

Taking part in this study may or may not make your health better. While doctors hope that using celecoxib with chemotherapy will be more useful against cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about celecoxib as a treatment for cancer. This information could help future cancer patients.

What other choices do I have if I do not take part in this study?

Your other choices may include: • Getting treatment or care for your cancer without being in a study • Taking part in another study • Getting no treatment • Getting comfort care, also called palliative care. This type of care helps reduce pain,

tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.

Talk to your doctor about your choices before you decide if you will take part in this study.

Will my medical information be kept private?

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is

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published or presented at scientific meetings, your name and other personal information will not be used.

Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include: • Cancer and Leukemia Group B (CALGB) • The National Cancer Institute (NCI) and other government agencies, like the Food

and Drug Administration (FDA), involved in keeping research safe for people • Pfizer, Inc, the maker of the celecoxib and placebo • Lilly, a company that is helping pay for the distribution of the celecoxib and placebo

If your doctor is participating in this study through the Cancer Trials Support Unit (the CTSU is a clinical trials mechanism sponsored by the NCI to provide greater access to phase III trials), a record of your progress will also be kept by the CTSU. If your record is used or disseminated for such purposes, it will be done under conditions that will protect your privacy to the fullest extent possible consistent with laws relating to public disclosure of information and the law-enforcement responsibilities of the agency.

The CALGB has received a Certificate of Confidentiality from the federal government, which will help us to protect your privacy. The Certificate protects against the involuntary release of information about you collected during the course of the study. The researchers involved in this project may not be forced to identify you in any legal proceedings (criminal, civil, administrative, or legislative) at the federal, state, or local level. However, some information may be required by the Federal Food, Drug, and Cosmetic Act, the U.S. Department of Health and Human Services, or for purposes of program review or audit. Also, you may choose to voluntarily disclose the protected information under certain circumstances. For example, if you or your guardian requests the release of information about you in writing (through, for example, a written request to release medical records to an insurance company), the Certificate does not protect against that voluntary disclosure.

What are the costs of taking part in this study?

You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating your cancer in this study. Some health plans will not pay these costs for people taking part in studies. Check with your health plan or insurance company to find out what they will pay for. Taking part in this study may or may not cost your insurance company more than the cost of getting regular cancer treatment. The gemcitabine, or pemetrexed, and carboplatin will be charged to you/your insurance company. Pfizer, Inc. will supply the celecoxib/placebo at no charge while you take part in this study, the National Cancer Institute will distribute it, and Lilly, Inc. will pay for the distribution. Pfizer, Lilly, and the National Cancer Institute will not cover the cost of getting the celecoxib/placebo ready and giving it to you, so you or your insurance company may have to pay for this.

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Even though it probably won’t happen, it is possible that the Pfizer may not continue to provide the celecoxib/placebo to the National Cancer Institute for some reason. If this would occur, other possible options are: • You might be able to get the celecoxib from the manufacturer or your pharmacy but

you or your insurance company may have to pay for it. • If there is no celecoxib available at all, no one will be able to get more and the study

would close. If a problem with getting celecoxib occurs, your study doctor will talk to you about these options.

You will not be paid for taking part in this study.

For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site.

Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.

What happens if I am injured because I took part in this study?

It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ [telephone number]. You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment.

What are my rights if I take part in this study?

Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. We will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study. A Data Safety Monitoring Board will be regularly meeting to monitor safety and other data related to this study. The Board members may receive confidential patient

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information, but they will not receive your name or other information that would allow them to identify you by name. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.

Who can answer my questions about the study?

You can talk to your study doctor about any questions or concerns you have about this study. Contact your study doctor __________________ [name(s)] at __________________ [telephone number]. For questions about your rights while taking part in this study, call the ________________________ [name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ (telephone number). [Note to Local Investigator: Contact information for patient representatives or other individuals in a local institution who are not on the IRB or research team but take calls regarding clinical trial questions can be listed here.]

*You may also call the Operations Office of the NCI Central Institutional Review Board (CIRB) at 888-657-3711 (from the continental US only). [*Only applies to sites using the CIRB.]

Where can I get more information?

You may call the National Cancer Institute's Cancer Information Service at:

1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615

You may also visit the NCI Web site at http://cancer.gov/

• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/

• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/

You will get a copy of this form. If you want more information about this study, ask your study doctor.

Related research studies

Please note: The following section of the informed consent document is about additional research studies that are being done with people who are taking part in the main study. You may take part in these additional studies if you

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want to. You can still be part of the main study even if you say “no” to taking part in any of these additional studies. The results of these research studies will not be provided to you or your doctor, nor will the results have any affect on your treatment. It is unlikely that what we learn from these studies will have a direct benefit to you. However, the information learned from these studies may benefit other patients in the future. The results of these studies may be published, but individual patients will not be identified in these publications. There will be no charge to you for participating in these research studies. Your samples will only be used for research and will not be sold. The research done with your sample may help to develop new products in the future. The greatest risk to you is the release of information from your health records. We will do our best to make sure that your personal information will be kept private. The chance that this information will be given to someone is very small. If you decide now to participate and then change your mind at any time about participating in these studies for any reason, you should contact your institution and let them know that you do not want the researchers to use your sample. The sample then will no longer be used for research. It will either be destroyed or returned to your institution for storage. The sample will also be returned to your institution upon request if needed for any other medical or legal reasons.

Please mark your choice by saying “yes” or “no” to each of the following: Research Studies on Blood and Urine An additional objective of this clinical trial is for investigators to study your blood and urine to determine whether or not it has certain characteristics that may make you more likely to respond to drugs like celecoxib. A sample of blood (about 1 teaspoon each time) will be collected before you receive treatment, and then if you are registered to the study, another one will be collected 1 week after you start treatment. The urine will be collected before you start treatment, and then one week after you begin treatment. Analysis of your blood and urine specimens will be done at a CALGB approved laboratory. 2) I agree that my specimen(s) may be used for the research described above. _________ Yes __________ No ________ Initials

Storage of Your Specimens:

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We would like to keep some of the tissue, blood and urine that are left over for future research. If you agree, these specimens will be kept and may be used in research to learn more about cancer and other diseases. The research that may be done with your specimens is not designed specifically to help you. It might help people who have cancer and other diseases in the future. Reports about research done with your specimens will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an affect on your care. The choice to let us keep left over specimens for future research is up to you. You have the right to receive the planned therapy on this study without allowing your specimens to be stored for future research. Please read the sentences below and think about your choice. After reading the sentence, please mark your choice. No matter what you decide to do, it will not affect your care. 3) My specimen(s) may be kept for future use in research to learn about, prevent,

or treat cancer. _________ Yes __________ No ________ Initials 4) My specimen(s) may be kept for future use in research to learn about, prevent,

or treat other health problems (for example: diabetes, Alzheimer disease, and heart disease).

_________ Yes __________ No ________ Initials 5) My doctor or someone from CALGB may contact me in the future to ask me

to take part in more research. _________ Yes __________ No ________ Initials

Signature I have been given a copy of all _____ [insert total of number of pages] pages of this form. I have read it or it has been read to me. I understand the information and have had my questions answered. I agree to take part in this study.

Participant ________________________________ Date _____________________________________

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APPENDIX I

CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES

To submit site registration documents: For patient enrollments:

CTSU Regulatory Office 1818 Market Street, Suite 1100 Philadelphia, PA 19103 Phone: 1-888-823-5923 Fax: 215-569-0206

CTSU Patient Registration Phone: 1-888-462-3009 Fax: 1-888-691-8039 Hours: 9:00 AM – 5:30 PM Eastern Time, Monday – Friday (excluding holidays)

(Registrations received after 5:00 PM ET will be handled the next business day. For CTSU patient enrollments that must be completed within approximately one hour, or other extenuating circumstances, call 301-704-2376 between 9:00 AM and 5:30 PM.)

Submit study data directly to the Lead Cooperative Group unless otherwise specified in the protocol:

CALGB Statistical Center Hock Plaza 2424 Erwin Road, Suite 802 Durham, NC 27705 Tel: 919-668-9350 Data Operations Fax: 919-668-9348 Teleform Fax: 919-416-4990

Sites should submit Teleforms via Fax or Mail. See Section 6.0 Data Submission Section for details on forms submission. Do not submit study data or forms to CTSU Data Operations. Do not copy the CTSU on data submissions.

For patient eligibility or treatment related questions: Contact the CALGB Study Chair. For questions unrelated to patient eligibility, treatment, or data submission contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line – 1-888-823-5923, or [email protected]. All calls and correspondence will be triaged to the appropriate CTSU representative.

The CTSU Web site is located at: www.ctsu.org

REGISTRATION/RANDOMIZATION

Prior to the recruitment of a patient for this study, investigators must be registered members of the CTSU. Each investigator must have an NCI investigator number and must maintain an “active” investigator registration status through the annual submission of a complete investigator registration packet (FDA Form 1572 with original signature, current CV, Supplemental Investigator Data Form with signature, and Financial Disclosure Form with original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms are available on the CTSU registered member Web site (www.ctsu.org) or by calling the PMB at 301-496-5725 Monday through Friday between 8:30 AM and 4:30 PM Eastern time. Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll patients. Study centers can check the status of their registration packets by querying the Regulatory Support System (RSS) site registration status page of the CTSU member web site at http://www.ctsu.org.

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All forms and documents associated with this study can be downloaded from the CALGB-30801 Web page on the CTSU registered member Web site (http://www.ctsu.org). Patients can be registered only after pre-treatment evaluation is complete, all eligibility criteria have been met, and the study site is listed as ‘approved’ in the CTSU RSS. Requirements for CALGB 30801 site registration: • CTSU IRB Certification • CTSU IRB/Regulatory Approval Transmittal Sheet Prestudy requirements for patient enrollment on CALGB 30801: • Patient must meet all inclusion criteria, and no exclusion criteria should apply • Patient has signed and dated all applicable consents and authorization forms • All baseline laboratory tests and prestudy evaluations performed within the time period

specified in the protocol. CTSU Procedures for Patient Enrollment 1. Contact the CTSU Patient Registration Office by calling 1-888-462-3009 between 9:00 AM

and 5:30 PM Eastern Time. Leave a voicemail to alert the CTSU Patient Registrar that an enrollment is forthcoming. For immediate registration needs (e.g., within one hour), call the registrar cell phone at 1-301-704-2376.

2. Complete the following forms:

• CTSU Patient Enrollment Transmittal Form • CALGB Registration Worksheet (indicate participation on companion studies CALGB

150908 and CALGB 60904) Note: The patient should be registered to CALGB 150908 and/or CALGB 60904 at the same time they are registered to the treatment trial (CALGB 30801).

3. Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of

9:00 AM and 5:30 PM, Mon-Fri, Eastern Time (excluding holidays); however, please be aware that registrations received after 5:00 PM will be processed the next day. Registration is limited to operating hours of the CALGB Registration office (9AM-5PM ET). The CTSU registrar will check the investigator and site information to ensure that all regulatory requirements have been met. The registrar will also check that forms are complete and will follow-up with the site to resolve any discrepancies.

4. Once investigator eligibility is confirmed and enrollment documents are reviewed for

compliance, the CTSU registrar will contact the CALGB, within the confines of CALGB’s registration hours, to obtain assignment of a unique patient ID (to be used on all future forms and correspondence). Since this is a double-blind study, a specific treatment arm will not be assigned. The CTSU registrar will confirm registration by fax.

Protocol therapy will begin within 14 days of registration/randomization to allow time for the blinded, patient-specific clinical supplies of celecoxib/placebo to arrive at the study sites. DATA SUBMISSION AND RECONCILIATION

1. All case report forms (CRFs) and transmittals associated with this study must be downloaded from the CALGB-30801 Web page located on the CTSU registered member Web site (http://www.ctsu.org). Sites must use the current form versions and adhere to the instructions and submission schedule outlined in the protocol.

2. Submit all completed CRFs (with the exception of patient enrollment forms), clinical

reports, and transmittals directly to the CALGB (see contact table or section 6.0) unless an

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alternate location is specified in the protocol. Do not send study data to the CTSU. A completed CTSU-CALGB coversheet should accompany all data submissions.

3. The CALGB Statistical Center will send (general via e-mail but may be sent via postal mail

or fax) query notices and delinquency reports directly to the site for reconciliation. Please send query responses and delinquent data to the CALGB Statistical Center (via postal mail or fax) and do not copy the CTSU Data Operations. Each site should have a designated CTSU Administrator and Data Administrator and must keep their CTEP AMS account contact information current. This will ensure timely communication between the clinical site and the CALGB Statistical Center.

SPECIAL MATERIALS OR SUBSTUDIES

There are two sub-studies in CALGB 30801. The sub-studies must be offered to all patients, although patients may opt not to participate. The patient should be registered to CALGB 60904 and/or CALGB 150908 at the same time they are registered to the treatment trial (CALGB 30801).

1. Specimen collection for pharmacogenetic correlatives – CALGB 60904 (protocol Section 6.1.2 and 6.1.3)

• Collect, prepare, and submit specimens as outlined in the protocol

• Do not send specimens, supporting clinical reports, or transmittals to the CTSU

2. Urine collection for PGE-M Analysis – CALGB 150908 (protocol section 6.1.4)

• Submit completed forms as outlined in the protocol

• Do not send forms to the CTSU

SERIOUS ADVERSE EVENT (AE) REPORTING (SECTION 16.0)

1. CTSU sites must comply with the expectations of their local Institutional Review Board (IRB) regarding documentation and submission of adverse events. Local IRBs must be informed of all reportable serious adverse reactions.

2. CTSU sites will assess and report adverse events according to the guidelines and timelines specified in the protocol. You may navigate to the CTEP Adverse Event Expedited Report System (AdEERS) from either the Adverse Events tab of the CTSU member home page (http://www.ctsu.org) or by selecting Adverse Event Reporting Forms from the document center drop down list on the protocol number Web page.

3. Do not send adverse event reports to the CTSU. 4. Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, or ALL

via the NCI/CTEP AML-MDS Report Form in lieu of AdEERS. Submit the completed form and supporting documentation as outlined in the protocol.

DRUG PROCUREMENT (SECTION 10.0)

Investigational agents: Celecoxib and matching placebo Celecoxib and matching placebo will be provided free of charge by Pfizer and distributed by the Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). No blinded starter supplies will be available for this study. 1. Information on drug formulation, procurement, storage and accountability, administration,

and potential toxicities are outlined in section 10.0 of the protocol. 2. You may navigate to the drug forms by selecting Pharmacy Forms from the document

center drop down list on the CALGB-30801 Web page. REGULATORY AND MONITORING

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Study Audit To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314 and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program (CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the conduct of clinical trials and study data validity, all protocols approved by NCI/CTEP that have patient enrollment through the CTSU are subject to audit. Responsibility for assignment of the audit will be determined by the site’s primary affiliation with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered through CTSU will become the responsibility of the Group receiving credit for the enrollment. For CTSU Independent Clinical Research Sites (CICRS), the CTSU will coordinate the entire audit process. For patients enrolled through the CTSU, you may request the accrual be credited to any Group for which you have an affiliation provided that Group has an active clinical trials program for the primary disease type being addressed by the protocol. Per capita reimbursement will be issued by the credited Group provided they have endorsed the trial, or by the CTSU if the Group has not endorsed the trial. Details on audit evaluation components, site selection, patient case selection, materials to be reviewed, site preparation, on-site procedures for review and assessment, and results reporting and follow-up are available for download from the CTSU Operations Manual located on the CTSU Member Web site. Health Insurance Portability and Accountability Act of 1996 (HIPAA) The HIPAA Privacy Rule establishes the conditions under which protected health information may be used or disclosed by covered entities for research purposes. Research is defined in the Privacy Rule referenced in HHS 45 CFR 164.501. Templated language addressing NCI-U.S. HIPAA guidelines are provided in the HIPAA Authorization Form located on the CTSU Web site. The HIPAA Privacy Rule does not affect participants from outside the United States. Authorization to release Protected Health Information is NOT required from patients enrolled in clinical trials at non-US sites. Clinical Data System–Web (CDS-Web) Monitoring This study will be monitored by the Clinical Data System (CDS-Web). The sponsoring Group fulfills this reporting obligation by transmitting the CDS data collected from the study-specific case report forms, via the Web to the NCI Center for Biometrics (NCICB). Cumulative CDS data are submitted quarterly.

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APPENDIX II NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by a Clinical Trials Agreement (CTA) a Cooperative Research and Development Agreement (CRADA)or a Clinical Supply Agreement, hereinafter referred to as Collaborative Agreement: The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) (hereinafter referred to as ”Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to Collaborator” (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the terms of award, apply to the use of the Agent(s) in this study: 1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can

Agent(s) be transferred or licensed to any party not participating in the clinical study. Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by the investigators. The protocol documents for studies utilizing investigational Agents contain confidential information and should not be shared or distributed without the permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family member participating on the study, the individual should sign a confidentiality agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov.

2. For a clinical protocol where there is an investigational Agent used in combination with

(an)other investigational Agent(s), each the subject of different collaborative agreements, the access to and use of data by each Collaborator shall be as follows (data pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data”.):

a. NCI will provide all Collaborators with prior written notice regarding the

existence and nature of any agreements governing their collaboration with NIH, the design of the proposed combination protocol, and the existence of any obligations that would tend to restrict NCI's participation in the proposed combination protocol.

b. Each Collaborator shall agree to permit use of the Multi-Party Data from the

clinical trial by any other Collaborator solely to the extent necessary to allow said other Collaborator to develop, obtain regulatory approval or commercialize its own investigational Agent.

c. Any Collaborator having the right to use the Multi-Party Data from these trials

must agree in writing prior to the commencement of the trials that it will use the Multi-Party Data solely for development, regulatory approval, and commercialization of its own investigational Agent.

3. Clinical Trial Data and Results and Raw Data developed under a Collaborative

Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless additional disclosure is required by law or court order.. Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed consistent with all applicable federal statutes and regulations for the protection of human subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.

4. When a Collaborator wishes to initiate a data request, the request should first be sent

to the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact them.

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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the

guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC for this clinical trial.

6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by

the Group office for Cooperative Group studies or by the principal investigator for non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and comment prior to submission for publication. Collaborator(s) will have 30 days from the date of receipt for review. Collaborator shall have the right to request that publication be delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) days prior to submission, but in any case, prior to presentation at the meeting or publication in the proceedings. Press releases and other media presentations must also be forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press release/ media presentation should be sent to:

Regulatory Affairs Branch, CTEP, DCTD, NCI Executive Plaza North, Suite 7111 Bethesda, Maryland 20892 FAX 301-402-1584 Email: [email protected]

The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ proprietary information.

Activation Date: February 15, 2010 Includes Update #5 CANCER

Documents

Transcript of Activation Date: February 15, 2010 Includes Update #5 CANCER