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Study Protocol and Statistical Analysis Plan ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY CALGB/SWOG C80702 A PHASE III TRIAL OF 6 VERSUS 12 TREATMENTS OF ADJUVANT FOLFOX PLUS CELECOXIB OR PLACEBO FOR PATIENTS WITH RESECTED STAGE III COLON CANCER Investigational agent: Celecoxib/placebo, NSC #719627 (Alliance IND #107051), will be supplied by Pfizer, Inc., and distributed by CTEP, DCTD, NCI Participation limited to U.S. and Canadian sites. ClinicalTrials.gov Identifier: NCT01150045 Alliance Study Chair, Alliance GI Committee Co-Chair SWOG Study Co-Chair Jeffrey A. Meyerhardt, MD, MPH Anthony F. Shields, MD, PhD Alliance GI Committee Co-Chair SWOG GI Committee Chair Alliance Corr. Sci. Co-Chair SWOG Corr. Sci. Co-Chair PPP Co-Chair Alliance Primary Statistician SWOG Primary Statistician Secondary Statistician Data Manager Protocol Coordinator CCTG Champion NRG Oncology Champion Participating Organizations ALLIANCE / Alliance for Clinical Trials in Oncology, SWOG / SWOG, ECOG-ACRIN / ECOG-ACRIN Cancer Research Group, NRG / NRG Oncology, CCTG / Canadian Cancer Trials Group 1 Version Date: 02/24/2021 Update #13 CALGB/SWOG C80702 Study Resources Alliance Protocol Operations Program Office Alliance Statistics and Data Center Medidata RAVE® iMedidata Portal Adverse Event Reporting Alliance Patient Registration Alliance Biorepository at Ohio State University CALGB/SWOG C80702 Pharmacy Contact CALGB/SWOG C80702 Nursing Contact Drug Distribution Contact Protocol-related questions may be directed as follows: Questions Contact (via email) Questions regarding patient eligibility, treatment, Study Chair, Nursing Contact, Protocol and dose modification: Coordinator, and (where applicable) Data Manager Questions related to data submission, RAVE or Data Manager patient follow-up: Questions regarding the protocol document and Protocol Coordinator model informed consent: Alliance Regulatory Inbox Questions related to IRB review: Questions regarding CTEP-AERS reporting: Alliance Pharmacovigilance Inbox Questions related to drug supply: Pharmaceutical Management Branch (PMB) Questions regarding specimens/specimen Alliance Biorepository at Ohio State University submissions: 2 Version Date: 02/24/2021 Update #13 CALGB/SWOG C80702 CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION For regulatory For patient enrollments: For data submission: requirements: Regulatory documentation Refer to the patient enrollment Data collection for this study will be must be submitted to the section of the protocol for done exclusively through Medidata CTSU via the Regulatory instructions on using the Rave. Refer to the data submission Submission Portal. Oncology Patient Enrollment section of the protocol for further Network (OPEN). OPEN is instructions. (Sign in at accessed at and select the Regulatory > Regulatory Submission.) Institutions with patients waiting that are unable to use Contact the CTSU Help Desk the Portal should alert the with any OPEN related CTSU Regulatory Office questions by phone or email : immediately at to receive further instruction and support. Contact the CTSU Regulatory Help Desk at for regulatory assistance. The most current version of the study protocol and all supporting documents must be downloaded from the protocol-specific page located on the CTSU members’ website . Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and requires log on with CTEP- IAM username and password. Permission to view and download this protocol and its supporting documents is restricted and is based on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). Supplies can be ordered by downloading and completing the CTSU Supply Request Form (available on the protocol-specific page on the CTSU website) and submitting it as instructed on the form. For clinical questions (i.e. patient eligibility or treatment-related) see Protocol Contacts, Page 2. For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) contact the CTSU Help Desk by phone or e-mail: CTSU General Information Line – . All calls and correspondence will be triaged to the appropriate CTSU representative. 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). 3 Version Date: 02/24/2021 Update #13 CALGB/SWOG C80702 A PHASE III TRIAL OF 6 VERSUS 12 TREATMENTS OF ADJUVANT FOLFOX PLUS CELECOXIB OR PLACEBO FOR PATIENTS WITH RESECTED STAGE III COLON CANCER Patient Eligibility Required Initial Laboratory Values Histologically documented adenocarcinoma of the colon (see §4.1.1) Granulocytes ≥ 1500/µL Completely resected tumors w/ Ro en bloc resection for tumors Platelet Count ≥ 100,000/µL adherent to adjacent structures (see §4.1.2) Creatinine ≤ 1.5 x ULN At least one pathologically confirmed positive lymph node or N1c disease as *Total Bilirubin ≤ 1.5 x ULN defined in AJCC version 7 (see §4.1.3) * In the absence of Gilbert’s syndrome. No evidence of residual involved lymph node disease or metastatic disease at If patient has Gilbert’s syndrome: time of registration (see §4.1.4) Direct Bilirubin ≤ 1.5 x ULN Patients with synchronous colon cancers are eligible but patients with synchronous colon and rectal primary tumors are not eligible (see §4.1.5) Patients are ineligible if they use NSAIDs at any dose more than 2 times a week on average or aspirin at more than 325 mg at least three times per week on average. Low-dose aspirin not exceeding 100 mg/day is permitted (see §4.2) No previous or concurrent malignancy, except treated basal cell or squamous cell cancer of skin, treated in situ cervical cancer, treated lobular or ductal carcinoma in situ in one breast, or other cancer for which patient has been disease-free for ≥5 years (see §4.3.1) No neurosensory or neuromotor toxicity ≥ grade 2 No known allergy to platinum compounds No prior allergic reaction or hypersensitivity to sulfonamides, celecoxib or NSAIDs No history of upper gastrointestinal ulceration, upper gastrointestinal bleeding, or upper gastrointestinal perforation within past 3 years (see §4.3.5) No symptomatic pulmonary fibrosis or interstitial pneumonitis No cardiac risk factors including uncontrolled high BP (systolic > 150), unstable angina, history of documented MI or cerebrovascular accident, or NYHA Class III or IV heart failure Non-pregnant and not nursing (see §4.4) ECOG Performance Status: 0-2 Age ≥ 18 years Schema 2 x 2 Factorial Randomization All patients will be randomized to receive: Placebo or Celecoxib (Double-Blind) Arm A Arm B 12 cycles of 12 cycles of 6 or 12 FOLFOX FOLFOX plus plus cycles of Placebo Celecoxib FOLFOX daily 400 mg daily (1 cycle = 14 days) Arm C Arm D 6 cycles of 6 cycles of FOLFOX FOLFOX plus plus Placebo Celecoxib daily 400 mg daily Celecoxib/placebo will be continued for a total of 3 years from the day that study drug was initiated. Stratification for the duration of adjuvant chemotherapy randomization: • Number of positive lymph nodes (1-3 vs. 4 or more) Stratification for the celecoxib randomization: • Number of positive lymph nodes (1-3 vs. 4 or more) • Current regular low dose aspirin usage (Yes vs. No) 4 Version Date: 02/24/2021 Update #13 CALGB/SWOG C80702 TABLE OF CONTENTS 1.0 INTRODUCTION .............................................................................................................................. 7 1.1 Colorectal cancer ............................................................................................................................ 7 1.2 Adjuvant therapy for colon cancer ................................................................................................. 7 1.3 Oxaliplatin ...................................................................................................................................... 7 1.4 FOLFOX for colon cancer .............................................................................................................. 7 1.5 Duration of adjuvant therapy .......................................................................................................... 8 1.6 Cyclooxygenase and colon cancer .................................................................................................. 9 1.7 Aspirin and NSAIDs in early stage colon cancer ......................................................................... 10 1.8 Celecoxib and cardiovascular risks .............................................................................................. 11 1.9 Rationale for the current trial ....................................................................................................... 11 1.10 Inclusion of women and minorities........................................................................................... 12 2.0 OBJECTIVES .................................................................................................................................. 12 2.1 Primary objective.......................................................................................................................... 12 2.2 Secondary objectives .................................................................................................................... 12 3.0 ON-STUDY GUIDELINES ............................................................................................................. 13 4.0 ELIGIBILITY
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