RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as cetuximab and bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab and bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving capecitabine together with cetuximab, oxaliplatin, and bevacizumab may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving capecitabine together with cetuximab, oxaliplatin, and bevacizumab works in treating patients with metastatic or recurrent colorectal cancer that cannot be removed by surgery.

OBJECTIVES:

Primary

• Determine the response rate in patients with unresectable metastatic or recurrent colorectal adenocarcinoma treated with capecitabine, cetuximab, oxaliplatin, and bevacizumab.

Secondary

• Determine the safety and tolerability of this regimen in these patients.
• Determine the progression-free and overall survival of patients treated with this regimen.

Exploratory

• Determine the effect of this regimen on the angiogenesis biomarkers in these patients.
• Determine the effect of this regimen on wound angiogenesis in these patients.

OUTLINE: This is a multicenter study.

Patients receive oral capecitabine twice daily on days 1-14. Patients will also receive cetuximab IV over 1-2 hours, oxaliplatin IV over 2 hours, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for 1 month.

PROJECTED ACCRUAL: Approximately 45 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the colon or rectum

  • Unresectable disease
  • Metastatic or recurrent disease

• Not amenable to potentially curative treatment

• No untreated leptomeningeal or brain metastases

PATIENT CHARACTERISTICS:

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 2,000/mm^3
• Platelet count ≥ 100,000/mm^3
• No known uncontrolled coagulopathy

Hepatic

• AST and ALT < 2.5 times upper limits of normal (ULN) (5 times ULN if liver metastases are present)
• Bilirubin < 2.0 times ULN

Renal

• Creatinine clearance > 40 mL/min
• Urine protein negative
• Urine protein:creatinine ratio > 1

Cardiovascular

• No unstable or uncontrolled hypertension (i.e., blood pressure [BP] > 150/100 mm Hg despite antihypertensive therapy)

  • Patients who recently started or have adjusted antihypertensive medications are eligible provided BP is < 140/90 mm Hg for ≥ 3 different measurements over 14 days

• No arterial thromboembolic events within the past 6 months, including any of the following:

  • Transient ischemic attack
  • Cerebrovascular accident
  • Unstable angina
  • Myocardial infarction
  • Clinically significant peripheral vascular disease

• No New York Heart Association class III-IV congestive heart failure

• No uncontrolled symptomatic coronary artery disease or cardiac arrhythmia

• No other significant uncontrolled cardiac disease

Gastrointestinal

• No lack of physical integrity of the upper gastrointestinal tract
• No malabsorption syndrome
• No inability to tolerate oral medication

Immunologic

• No prior severe infusion reaction to a monoclonal antibody
• No history of an allergic reaction attributed to compounds of similar chemical or biologic composition to oxaliplatin, cetuximab, capecitabine, or bevacizumab
• No prior unanticipated, severe reaction to fluoropyrimidine therapy or known hypersensitivity to fluoroucacil

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during the study and for 3-4 months after completion of study treatment
• No peripheral neuropathy ≥ grade 2
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix
• No known dihydropyrimidine dehydrogenase deficiency

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior adjuvant bevacizumab or cetuximab
• No other concurrent anticancer immunotherapy or biologic therapy

Chemotherapy

• At least 6 months since a prior adjuvant fluorouracil-, leucovorin calcium-, or capecitabine-based regimen
• At least 12 months since prior adjuvant oxaliplatin
• No prior chemotherapy for metastatic or recurrent disease

Endocrine therapy

• No concurrent hormonal therapy

Radiotherapy

• No concurrent radiotherapy

Surgery

• More than 4 weeks since prior major surgery and recovered
• More than 6 months since vascular surgery, stenting, or angioplasty

Other

• At least 4 weeks since prior and no concurrent sorivudine or brivudine

• More than 4 weeks since prior participation in any investigational drug study

• No prior therapy that affects or targets the epidermal growth factor pathway

• No concurrent cimetidine

  • Concurrent ranitidine, famotidine, or proton-pump inhibitors allowed

• Concurrent anticoagulation therapy with full-dose anticoagulant allowed provided dose is stable for at least 2 weeks