Capecitabine, Cetuximab, Oxaliplatin, and Bevacizumab 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