RATIONALE: Monoclonal antibodies can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether monoclonal antibody therapy is more effective with or without irinotecan in treating metastatic colorectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without irinotecan plus monoclonal antibody therapy in treating patients who have metastatic colorectal cancer.

OBJECTIVES: I. Evaluate the efficacy, in terms of duration of survival, time to disease progression, objective response rate, and duration of objective response of bevacizumab (rhuMAb VEGF) with fluorouracil, leucovorin calcium, and irinotecan as opposed to placebo with fluorouracil, leucovorin calcium, and irinotecan in patients with metastatic colorectal cancer. II. Evaluate the safety of these regimens in these patients. III. Determine the plasma pharmacokinetics of irinotecan with fluorouracil, leucovorin calcium, and bevacizumab (rhuMAb VEGF) versus irinotecan with fluorouracil and leucovorin calcium in these patients. IV. Determine the pharmacokinetics of bevacizumab (rhuMAb VEGF) in these patients. V. Evaluate and compare the quality of life in patients treated with these regimens.

OUTLINE: This is a randomized, active-controlled, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), site of primary disease (colon vs rectum), and number of metastatic sites (1 vs more than 1). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive irinotecan IV over 90 minutes followed by leucovorin calcium IV over 1-2 minutes and fluorouracil IV over 1-2 minutes weekly for 4 weeks. Patients also receive placebo IV over 30-90 minutes every other week. Courses repeat every 6 weeks. Arm II: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in arm I. Patients also receive bevacizumab (rhuMAb VEGF) IV over 30-90 minutes every other week. Courses repeat every 6 weeks. Treatment continues for a maximum of 16 courses in the absence of disease progression or unacceptable toxicity. All patients with progressive disease may continue to receive treatment on this study with another chemotherapy agent with or without bevacizumab (rhuMAb VEGF). Patients in arm I with progressive disease may continue to receive another chemotherapy agent and are not allowed to receive bevacizumab (rhuMAb VEGF). Patients in arm II with progressive disease may continue to receive bevacizumab (rhuMAb VEGF) alone or in combination with another chemotherapy agent. Patients are followed every 4 months for survival.

PROJECTED ACCRUAL: Approximately 900 patients will be accrued for this study.

• Biological: bevacizumab
• Drug: FOLFIRI regimen
• Drug: fluorouracil
• Drug: irinotecan hydrochloride
• Drug: leucovorin calcium

• Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42.
• Kabbinavar FF, Hurwitz HI, Yi J, Sarkar S, Rosen O. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol. 2009 Jan 10;27(2):199-205. Epub 2008 Dec 8.
• Grothey A, Hedrick EE, Mass RD, Sarkar S, Suzuki S, Ramanathan RK, Hurwitz HI, Goldberg RM, Sargent DJ. Response-independent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol. 2008 Jan 10;26(2):183-9.

DISEASE CHARACTERISTICS: Histologically confirmed metastatic colorectal cancer At least 2 bidimensionally measurable lesions No CNS disease (e.g., primary brain tumor, seizures not controlled with standard therapy, or any brain metastases) No clinically detectable ascites

PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-1 Life expectancy: More than 3 months Hematopoietic: Absolute neutrophil count at least 1,500/mm3 Platelet count at least 75,000/mm3 Hemoglobin at least 9 g/dL (may be transfused) No bleeding diathesis or coagulopathy Hepatic: AST or ALT no greater than 2.5 times upper limit of normal (ULN) (less than 5 times ULN if liver metastasis present) Bilirubin no greater than 1.6 mg/dL International normalized ratio less than 1.5 Renal: Creatinine no greater than 2.0 mg/dL No proteinuria or clinically significant impairment of renal function Cardiovascular: No clinically significant cardiovascular disease including uncontrolled hypertension, myocardial infarction, or unstable angina within past year No New York Heart Association class II-IV congestive heart failure within past year No serious cardiac arrhythmia requiring medication or grade II or greater peripheral vascular disease within past year Other: Must be able to tolerate CT scan contrast dye No other invasive malignancy within past 5 years except basal cell skin cancer No CNS disease including uncontrolled seizures or stroke No active infection requiring parenteral antibiotics No serious nonhealing wound, ulcer, or bone fracture No other disease or medical condition that would preclude study Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy: No prior biologic therapy for colorectal cancer Chemotherapy: At least 12 months since prior fluoropyrimidines with leucovorin and/or levamisole No other prior chemotherapy Endocrine therapy: Not specified Radiotherapy: At least 14 days since prior radiotherapy No prior radiotherapy to any indicator lesion Surgery: At least 28 days since prior surgical procedure At least 7 days since prior fine needle aspiration No concurrent major surgical procedure Other: At least 10 days since prior full-dose oral or parenteral anticoagulants except to maintain patency of pre-existing, permanent indwelling IV catheters At least 10 days since prior full-dose oral or parenteral thrombolytic agent At least 28 days since participation in other experimental drug study No chronic, daily aspirin or nonsteroidal anti-inflammatory medications No concurrent full-dose oral or parenteral anticoagulants (except for indwelling IV catheter maintenance) or thrombolytic agent