OBJECTIVES:

• Compare the progression-free survival of patients with metastatic colorectal cancer treated with capecitabine and irinotecan vs fluorouracil, leucovorin calcium, and irinotecan with vs without celecoxib.
• Compare the safety of these regimens in these patients.
• Compare the response rate in patients treated with these regimens.
• Compare the time to treatment failure and overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, double-blind*, multicenter study. Patients are stratified according to participating center, prior adjuvant therapy (yes vs no), and risk group (poor vs intermediate vs good). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive irinotecan IV over 30-90 minutes on days 1 and 22; oral capecitabine twice daily on days 1-15 and 22-36; and oral celecoxib twice daily on days 1-42.
• Arm II: Patients receive irinotecan and capecitabine as in arm I and oral placebo twice daily on days 1-42.
• Arm III: Patients receive irinotecan IV over 30-90 minutes on days 1, 15, and 29; leucovorin calcium (CF) IV over 2 hours and fluorouracil (5-FU) IV over 22 hours on days 1, 2, 15, 16, 29, and 30; and oral celecoxib twice daily on days 1-42.
• Arm IV: Patients receive irinotecan, CF, and 5-FU as in arm III and oral placebo twice daily on days 1-42.

In all arms, treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. If all chemotherapy is discontinued due to toxicity, patients may continue celecoxib or placebo until disease progression, unacceptable toxicity, or starting a new cytotoxic regimen.

NOTE: *The double-blind treatment only applies to the celecoxib and placebo randomization

Patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 692 patients (173 per treatment arm) will be accrued for this study within 3.5 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum
• Metastatic disease

• Measurable disease

  • Patients who received prior radiotherapy must have measurable or evaluable disease outside the radiotherapy field
• No CNS metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 2 times upper limit of normal (ULN)
• AST and ALT no greater than 2.5 times ULN (5 times ULN in the presence of liver metastases)

Renal

• Creatinine clearance at least 51 mL/min
• No severe renal impairment

Cardiovascular

• No severe cardiac disease
• No uncontrolled angina pectoris
• No myocardial infarction within the past 6 months

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 6 months after study participation
• No active Crohn's disease
• No other malignancy except adequately treated carcinoma in situ of the cervix or nonmelanoma skin cancer
• No other uncontrolled severe medical condition
• No psychological, familial, sociological, or geographical condition that would preclude study compliance and follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No concurrent active or passive immunotherapy for colon cancer

Chemotherapy

• No prior chemotherapy for metastatic disease

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy
• No concurrent radiotherapy

Surgery

• Not specified

Other

• At least 6 months since prior adjuvant therapy
• More than 4 weeks since prior investigational drugs
• No concurrent sorivudine or chemically related analogues (e.g., brivudine)
• No other concurrent investigational drugs
• No other concurrent cytotoxic agents
• No concurrent prophylactic fluconazole
• No concurrent or planned cyclo-oxygenase-2 (COX-2) inhibitors or nonsteroidal anti-inflammatory drugs

• No concurrent chronic use of full-dose aspirin (325 mg/day or greater)

  • Concurrent low-dose (cardioprotective) aspirin prophylaxis (no more than 325 mg every other day OR no more than 162.5 mg per day) allowed