Bevacizumab and Cetuximab With or Without Irinotecan in Treating Patients With Irinotecan-Refractory Metastatic Colorectal Cancer

Inclusion Criteria:

Histologically or cytologically confirmed colorectal cancer

Metastatic disease by diagnostic imaging studies

Measurable disease

At least 1 unidimensionally measurable lesion with minimum lesion size at least twice the slice thickness of the imaging study used

Refractory to irinotecan, evidenced by clinical documentation

Received at least 1 prior irinotecan-containing chemotherapy regimen for metastatic disease and progressed during or within 6 weeks after completion of therapy

Must have received prior irinotecan according to 1 of the following schedules:

Weekly administration with a starting dose of 100-125 mg/m^2
Biweekly administration (every other week) with a starting dose of approximately 180 mg/m^2
Once every three weekly administration with a starting dose of 300-350 mg/m^2
No known brain metastases
No prior primary CNS tumors
Performance status - ECOG 0-1
Performance status - Karnofsky 80-100%
More than 3 months
WBC >= 3,000/mm^3
Absolute neutrophil count >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 9 g/dL
No bleeding diathesis or coagulopathy
Bilirubin normal
AST and ALT =< 2.5 times upper limit of normal (ULN) (5 times ULN in the presence of known liver metastases)
INR < 1.5 (for patients receiving warfarin)
Creatinine =< ULN
Creatinine clearance ≥ 60 mL/min
No proteinuria
No prior stroke
No symptomatic congestive heart failure
No unstable angina pectoris
No uncontrolled hypertension
No clinically significant cardiac arrhythmia

None of the following arterial thromboembolic events within the past 6 months:

Myocardial infarction
Cerebrovascular accident
Transient ischemic attack
Unstable angina
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 28 days
No grade 3 or greater neurotoxicity
No uncontrolled seizures
No prior allergic reactions attributed to compounds of similar chemical or biological composition to study agents
No prior irinotecan intolerance
No ongoing or active infection requiring parenteral antibiotics
No serious nonhealing active wound, ulcer, or bone fracture
No psychiatric illness or social situation that would preclude study compliance
No other concurrent uncontrolled illness that would preclude study participation
No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
No prior cetuximab
No other prior epidermal growth factor receptor-directed therapy

No prior anticancer murine or chimeric monoclonal antibody therapy

Prior humanized monoclonal antibody therapy allowed
No prior bevacizumab
No other prior vascular endothelial growth factor-targeted therapy
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
More than 4 weeks since prior radiotherapy
More than 28 days since prior major surgical procedure or open biopsy
Recovered from all prior therapy
Any number of prior standard or investigational regimens allowed
No other concurrent investigational agents
No other concurrent anticancer therapy
No recent or concurrent thrombolytic agents
No recent or concurrent full-dose warfarin except as required to maintain patency of preexisting, permanent indwelling IV catheters

No concurrent therapeutic heparin

Concurrent prophylactic low-molecular weight heparin allowed
No concurrent chronic daily aspirin (> 325 mg/day)
No concurrent nonsteroidal anti-inflammatory medications known to inhibit platelet function
No concurrent combination antiretroviral therapy for HIV-positive patients