Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Celecoxib in Treating Patients With Stage III Colon Cancer Previously Treated With Surgery

• Recurrence-free survival [ Designated as safety issue: No ]
• Overall survival at 3 years [ Designated as safety issue: No ]
• Toxicity of celecoxib [ Designated as safety issue: Yes ]
• Cardiovascular-specific events [ Designated as safety issue: Yes ]
• Differences in toxicity, particularly cumulative peripheral neuropathy, of 6 vs 12 courses of FOLFOX [ Designated as safety issue: Yes ]

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving oxaliplatin, leucovorin calcium, and fluorouracil is more effective with or without celecoxib in treating colon cancer.

PURPOSE: This randomized phase III trial is studying giving oxaliplatin, leucovorin calcium, and fluorouracil together to compare how well they work when given together with or without celecoxib in treating patients with stage III colon cancer previously treated with surgery.

OBJECTIVES:

Primary

• To compare disease-free survival of patients with resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin calcium with versus without celecoxib.

Secondary

• To contribute to an international prospective pooled analysis comparing disease-free survival of patients treated with these regimens.
• To compare overall survival at 3 years of patients treated with these regimens.
• To contribute to an international prospective pooled analysis comparing disease-free survival of patients treated with 6 versus 12 courses of FOLFOX chemotherapy.
• To assess toxicities of celecoxib as maintenance adjuvant therapy in these patients.
• To assess differences in cardiovascular-specific events in patients treated with versus without celecoxib.
• To evaluate differences in toxicities, particularly cumulative peripheral neuropathy, in patients treated with 6 versus 12 courses of FOLFOX chemotherapy.

OUTLINE: This is a multicenter study. Patients are stratified according to number of positive lymph nodes* (1-3 vs 4 or more) and concurrent regular low-dose of aspirin (yes vs no). Patients are randomized to 1 of 4 treatment arms.

NOTE: *Patients with N1c-only disease (i.e., no positive nodes but N1c disease by AJCC 7) should be stratified to 1-3 nodes.

• Arm I: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours (FOLFOX) on day 1. Patients also receive oral celecoxib once daily on days 1-14 beginning on day 1 of course 2 of FOLFOX. Courses repeat every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive FOLFOX as in arm I and oral placebo once daily on days 1-14 beginning on day 1 of course 2. Courses repeat every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.
• Arm III: Patients receive FOLFOX and celecoxib as in arm I. Courses repeat every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm IV: Patients receive FOLFOX and placebo as in arm II. Courses repeat every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

In all arms, treatment with celecoxib or placebo continues for 3 years in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples maybe collected for biomarker analysis and pharmacogenomic studies.

After completion of study therapy, patients are followed up every 3 months for 1 year, every 6 months for years 2-3, and then annually for 3 years.

• Drug: celecoxib
  Given orally
• Drug: fluorouracil
  Given IV
• Drug: leucovorin calcium
  Given IV
• Drug: oxaliplatin
  Given IV
• Other: placebo
  Given orally

• Experimental: Arm I
  Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46-48 hours (FOLFOX) on day 1. Patients also receive oral celecoxib once daily on days 1-14 beginning on day 1 of course 2. Courses repeat every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: celecoxib
  • Drug: fluorouracil
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
• Placebo Comparator: Arm II
  Patients receive FOLFOX as in arm I and oral placebo once daily on days 1-14 beginning on day 1 of course 2. Courses repeat every 14 days for 12 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: fluorouracil
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
  • Other: placebo
• Experimental: Arm III
  Patients receive FOLFOX and celecoxib as in arm I. Courses repeat every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: celecoxib
  • Drug: fluorouracil
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
• Placebo Comparator: Arm IV
  Patients receive FOLFOX and placebo as in arm II. Courses repeat every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: fluorouracil
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
  • Other: placebo

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon

  • Stage III disease

  • The gross inferior (caudal) margin of the primary tumor must lie above the peritoneal reflection

    • No rectal cancer

  • Synchronous colon cancers allowed

    • No synchronous colon and rectal primary tumors

• Completely resected tumor

  • Patients with adherent to adjacent structures, en bloc R_o resected tumor, must have it documented in the operative report

    • Near or positive radial margin are not exclusions as long as en bloc resection was performed
    • Positive proximal margin or distal margin is an exclusion
  • Patients with resected stage IV disease are not eligible

• Node-positive disease (N1 or N2) as designated in AJCC version 7

  • Either at least one pathologically confirmed positive lymph node or N1c (defined as tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional lymph node metastases)
• No evidence of residual involved lymph node disease or metastatic disease

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Granulocyte count ≥ 1,500/μL
• Platelet count ≥ 100,000/μL
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Bilirubin ≤ 1.5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 8 weeks after completion of chemotherapy
• No prior or concurrent malignancy except treated basal cell or squamous cell cancer of the skin, treated in situ cervical cancer, treated lobular or ductal carcinoma in situ in 1 breast, or any other cancer for which the patient has been disease-free for ≥ 5 years
• 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 the past 3 years

  • Patients with ulceration, bleeding, or perforation in the lower bowel are not excluded
• No symptomatic pulmonary fibrosis or interstitial pneumonitis ≥ grade 2

• No cardiac risk factors including, but not limited to, any of the following:

  • Uncontrolled high BP (systolic BP > 150 mm Hg)
  • Unstable angina
  • History of documented myocardial infarction or cerebrovascular accident
  • NYHA class III-IV heart failure
• :

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No concurrent NSAIDs ≥ 2 times per week on average or aspirin at > 325 mg ≥ 3 times per week on average

  • Low-dose aspirin not exceeding 100 mg/day allowed
  • Patients who agree to stop regular NSAIDs or higher-dose aspirin are eligble and no wash-out period is required