Irinotecan and Cetuximab With or Without Bevacizumab in Treating Patients With RAS Wild-Type Locally Advanced or Metastatic Colorectal Cancer That Cannot Be Removed by Surgery

Inclusion Criteria

• Metastatic or locally advanced (unresectable) colorectal cancer with histological confirmation of adenocarcinoma
• Measurable disease
• RAS wild-type tumor; Note: evidence of EGFR expression in the tumor is not required
• Previous failure of at least one fluoropyrimidine- and irinotecan-containing chemotherapy regimen for metastatic disease; Note: previous failure is defined as disease progression while receiving treatment or within 6 weeks after the last dose of irinotecan; failure for this assessment is defined as any enlargement of measurable or assessable lesion(s) or the development of any new lesion; a rising tumor marker alone is not sufficient to define failure; patients can have received irinotecan in any previous line of therapy
• Treatment with bevacizumab in at least one prior line of therapy for metastatic disease
• Negative serum or urine pregnancy test done = = 1500/mm^3 obtained = = 100,000/mm^3 obtained = = 9.0 g/dL (hemoglobin may be supported by transfusion) obtained = = 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal obtained = = 2+ proteinuria must have a spot urine protein:creatinine ratio (UPCR) 3 months
• Provide informed written consent
• Willing to provide blood samples for mandatory correlative and research purposes
• Willing to provide tissue and blood samples for mandatory banking purposes
• Any major surgery or open biopsy completed >= 4 weeks prior to randomization
• Any minor surgery or core biopsy completed >= 1 week prior to randomization and patient must have fully recovered from the procedure; Note: insertion of a vascular access device is not considered major or minor surgery

Exclusion Criteria

• Presence of a RAS mutation in exons 2, 3, or 4 of KRAS or NRAS (patients with mutations in exons 2, 3, or 4 of KRAS and/or NRAS are excluded)
• Prior treatment with cetuximab or panitumumab
• Prior intolerance to irinotecan and/or bevacizumab despite dose reduction
• Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis
• Active, uncontrolled infection, including hepatitis B, hepatitis C
• Concurrent anti-cancer therapy, including chemotherapy agents, targeted agents, or biological agents not otherwise specified in this protocol
• Anti-cancer therapy = 25% of bone marrow; Note: standard rectal cancer chemoradiation will not exclude subject from study protocol
• Radiation therapy = 3 loose stools daily in subjects without a colostomy or ileostomy; subjects with a colostomy or ileostomy may be entered at investigator discretion
• Arterial thrombotic events = = 160/90) even though on a regimen of anti-hypertensive therapy
• Evidence of Gilbert?s syndrome or known homozygosity for the UGT1A1*28 allele (special screening not required)