Bevacizumab Plus Fluorouracil and Leucovorin in Treating Patients With Locally Advanced or Metastatic Stage IV Colorectal Cancer That Has Progressed After Standard Chemotherapy

OBJECTIVES:

• Determine the response rate of patients treated with bevacizumab, fluorouracil, and leucovorin calcium for stage IV colorectal cancer that has progressed after standard chemotherapy.
• Determine the time to progression and overall survival of patients treated with this regimen.
• Determine the safety of administering "bolus" and continuous infusion fluorouracil and leucovorin calcium in patients treated with this regimen.

OUTLINE: This is an open-label, multicenter study. Patients receive 1 of 2 treatment regimens.

• Regimen I: Patients receive bevacizumab IV on days 1, 15, 29, and 42 (every 2 weeks) and leucovorin calcium (CF) IV over 2 hours and fluorouracil (5-FU) IV bolus on days 1, 8, 15, 22, 29, and 36.
• Regimen II: Patients receive bevacizumab as in regimen I and CF IV over 2 hours and 5-FU IV bolus followed by a continuous infusion over 22 hours on days 1, 2, 15, 16, 29, 30, 43, and 44.

For both regimens, courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed for tumor response and survival.

PROJECTED ACCRUAL: Various NCI-designated Clinical Cancer Centers and other medical institutions across the United States will participate in this study. A total of 35-125 patients will be accrued for this study within 3 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed colorectal adenocarcinoma

• Stage IV (metastatic) disease
• Not curable by surgery or radiotherapy
• Must have received prior standard chemotherapy regimens, including oxaliplatin and irinotecan, and meet both of the following criteria:

• Disease progression during or after irinotecan-based chemotherapy for metastatic disease OR relapsed disease within 6 months after adjuvant irinotecan-based therapy
• Disease progression during or after oxaliplatin-based chemotherapy for metastatic disease OR relapsed disease within 6 months after adjuvant oxaliplatin-based therapy
• No brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9 g/dL (transfusion allowed)
• No evidence of bleeding diathesis or coagulopathy

Hepatic

• Bilirubin no greater than 1.5 mg/dL
• AST less than 5 times upper limit of normal (ULN)
• Alkaline phosphatase less than 5 times ULN
• PT and INR no greater than 1.5 times ULN
• PTT no greater than ULN

Renal

• Creatinine no greater than 1.5 times ULN
• Proteinuria less than grade 1 OR
• Proteinuria less than 500 mg/24 hours

Cardiovascular

• No prior stroke
• No uncontrolled high blood pressure
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No myocardial infarction within the past 6 months
• No New York Heart Association class III or IV heart disease
• No thromboembolism within the past 6 months

Other

• Chemonaive
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3 months after study participation
• No significant traumatic injury within the past 6 weeks
• No prior allergic reaction attributed to compounds of similar chemical or biological composition to bevacizumab or other study agents
• No active infection
• No psychiatric illness or social situation that would preclude study compliance
• No serious nonhealing wound (including wounds healing by secondary intention), ulcer, or bone fracture
• No CNS disease, including either of the following:

• Primary brain tumor
• Seizures not controlled with standard medical therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 8 weeks since prior monoclonal antibody therapy
• No prior bevacizumab

Chemotherapy

• See Disease Characteristics

Endocrine therapy

• Not specified

Radiotherapy

• At least 4 weeks since prior major radiotherapy (e.g., chest or bone palliative radiotherapy)

Surgery

• More than 6 weeks since prior major surgical procedure or open biopsy
• More than 7 days since prior fine needle aspiration or core biopsy
• No concurrent surgery

Other

• Recovered from prior therapy
• At least 3 weeks since prior cytotoxic agents
• No concurrent therapeutic anticoagulation

• Prophylactic anticoagulation of venous access devices allowed provided PT/INR or PTT criteria are met
• No concurrent chronic aspirin (greater than 325 mg/day) or nonsteroidal anti-inflammatory drugs
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational or commercial agents for the malignancy