Bevacizumab and Combination Chemotherapy as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed By Surgery

OBJECTIVES:

Primary

• Compare the progression-free survival at 6 months in patients with unresectable metastatic colorectal cancer treated with first-line therapy comprising bevacizumab and irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) vs bevacizumab and irinotecan hydrochloride and capecitabine (XELIRI).

Secondary

• Compare the toxicities of these regimens in these patients.
• Compare the objective response rate and duration of response in patients treated with these regimens.
• Compare the tumor control in patients treated with these regimens.
• Compare the progression-free and overall survival of patients treated with these regimens.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is an open-label, randomized, multicenter study. Patients are stratified according to participating center, WHO performance status (0 or 1 vs 2), age (< 65 years vs ≥ 65 years), and number of metastatic sites (1 vs ≥ 2). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive bevacizumab IV over 30-90 minutes, irinotecan hydrochloride IV over 90 minutes, and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for 12 courses in the absence of disease progression or unacceptable toxicity. Patients may then continue to receive bevacizumab alone every 2 weeks in the absence of disease progression.
• Arm II: Patients receive bevacizumab IV over 30-90 minutes and irinotecan hydrochloride IV over 90 minutes on day 1 and oral capecitabine on days 1-14. Treatment repeats every 3 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. Patients may then continue to receive bevacizumab alone every 3 weeks in the absence of disease progression.

Quality of life is assessed periodically.

After completion of study therapy, patients are followed periodically.

PROJECTED ACCRUAL: A total of 144 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

• Unresectable metastatic disease
• Measurable disease
• No CNS metastases

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Life expectancy > 3 months
• Absolute neutrophil count > 1,500/mm³
• Platelet count > 100,000/mm³
• Hemoglobin > 9 g/dL (transfusion allowed)
• INR < 1.5
• Alkaline phosphatase < 1.5 times upper limit of normal (ULN)
• Bilirubin < 1.5 times ULN
• AST and ALT < 2.5 times ULN (5 times ULN if liver metastases are present)
• Creatinine clearance > 30 mL/min
• Urine protein < 2+ OR ≤ 1 g/L by 24-hour urine collection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No contraindications to study therapy
• No gastrointestinal or duodenal ulcers
• No AIDS
• No serious illness, active infection, or other serious condition that would preclude study therapy
• No coagulation problem
• No bleeding diathesis
• No sensitivity to Chinese hamster ovarian cells or other recombinant human antibodies
• No severe renal insufficiency
• No uncontrolled hypertension
• No active or severe cardiovascular conditions, including the following:

• Cerebrovascular accident
• Myocardial infarction within the past 6 months
• New York Heart Association class II-IV cardiac insufficiency
• Severe cardiac arrhythmia (even if treated)
• No primitive stenosis or symptomatic peritoneal carcinosis causing a risk of intestinal subocclusion or occlusion
• No nonhealing wound or fracture
• No prior thromboembolic disease
• No other cancer within the past 2 years except for basal cell skin cancer or carcinoma in situ of the uterine cervix
• No geographical, social, or psychological condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy for metastatic disease
• At least 6 months since prior adjuvant chemotherapy (fluorouracil with or without oxaliplatin)

• No prior adjuvant chemotherapy comprising irinotecan hydrochloride with or without bevacizumab
• At least 28 days since prior major surgery
• Prior radiotherapy allowed except to target lesions
• At least 10 days since prior anticoagulants
• No concurrent chronic acetylsalicylic acid (at doses > 325 mg/day)
• No other concurrent investigational therapy
• No other concurrent anticancer therapy