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

OBJECTIVES:

Primary

• Determine the efficacy of bevacizumab, irinotecan hydrochloride, leucovorin calcium, and fluorouracil, in terms of partial or complete response, in patients with unresectable metastatic colorectal cancer.

Secondary

• Determine the duration of response in patients treated with this regimen.
• Determine the overall survival and progression-free survival of patients treated with this regimen.
• Determine the tolerability of this regimen in these patients.
• Assess the pharmacogenetics and change in genetic polymorphisms susceptible to modification by this regimen.

OUTLINE: This is a nonrandomized, multicenter study.

Patients receive irinotecan hydrochloride IV over 90 minutes, leucovorin calcium IV over 2 hours, and bevacizumab IV on day 1. Patients also receive fluorouracil IV over 46 hours beginning on day 1. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Blood and tissue samples are collected periodically for pharmacogenetic and genetic polymorphism analysis.

PROJECTED ACCRUAL: A total of 61 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum

• No other histological types
• Metastatic, unresectable disease

• No bone metastases only
• Unidimensionally measurable metastatic disease
• No CNS metastases

PATIENT CHARACTERISTICS:

• WHO performance status (PS) 0-2 OR Karnofsky PS 70-100%
• Life expectancy ≥ 12 weeks
• ANC > 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL
• Bilirubin ≤ 1.25 times normal (1.5 times normal in presence of hepatic metastases)
• AST and ALT < 3 times normal (5 times normal in presence of hepatic metastases)
• Creatinine < 1.25 times normal
• No proteinuria
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other cancer in the past 5 years except for carcinoma in situ of the uterine cervix or basal cell skin cancer
• No hypersensitivity to fluorouracil
• No hypersensitivity to leucovorin calcium, bevacizumab, or their excipients
• No hypersensitivity to Chinese hamster ovarian cell products or other recombinant humanized or nonhumanized monoclonal antibodies
• No allergy to irinotecan hydrochloride
• No prior reaction to attenuated vaccines (fever, jaundice)
• No poor nutritional status
• No Biermer anemia or other anemia due to vitamin B12 deficiency
• No uncontrolled symptomatic occlusion or subocclusion
• No medullary hypoplasia or severe insufficiency
• No prior chronic intestinal disease
• No Gilbert's syndrome
• No intra-abdominal inflammatory reaction (e.g., gastroduodenal ulcer, diverticulitis, or colitis)
• No chronic intestinal inflammatory disease
• No thromboembolic arterial condition in the past 6 months, including any of the following:

• Cardiovascular accident
• Transient ischemic attack
• Myocardial infarction
• No infection or serious noncancerous disease
• No condition that is unstable or would increase risk to the patient, including any of the following:

• Unstable angina
• Poorly controlled hypertension
• Severe cardiac insufficiency
• Serious arrhythmia
• Bleeding diathesis
• Pulmonary disease at risk of decompensation
• No familial, geographical, social, or psychological condition that would preclude study participation
• No prisoners or patients without guardians

PRIOR CONCURRENT THERAPY:

• At least 8 weeks since prior surgery
• At least 6 months since prior adjuvant chemotherapy
• At least 1 month since prior palliative chemotherapy
• No prior abdominal or pelvic radiotherapy
• At least 30 days since prior participation in another investigational study
• No prior bevacizumab
• No extensive intestinal resection (e.g., partial colectomy or extensive thin resection)
• No concurrent warfarin, Hypericum perforatum (St. John's wort), or prophylactic phenytoin