RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and ramucirumab, 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 ramucirumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet know whether giving cetuximab and irinotecan hydrochloride together is more effective with or without ramucirumab in treating colorectal cancer.

PURPOSE: This randomized phase II trial is studying the side effects and how well giving cetuximab and irinotecan hydrochloride with or without ramucirumab work in treating patients with advanced colorectal cancer with progressive disease after treatment with bevacizumab-containing chemotherapy.

OBJECTIVES:

• To evaluate the progression-free survival of patients with advanced K-ras wild-type colorectal cancer, following progression on bevacizumab-contained chemotherapy, treated with irinotecan hydrochloride and cetuximab with versus without ramucirumab as second-line therapy.
• To evaluate the response rate in patients treated with these regimens.
• To evaluate the grade 3-4 toxicity rates of these regimens in these patients.
• To evaluate the overall survival of patients treated with these regimens.

OUTLINE: This is a multicenter, randomized study. Patients are stratified according to performance status (0 vs 1), discontinuation of oxaliplatin before disease progression (yes vs no), and time to disease progression since last treatment (≤ 6 months vs > 6 months). Patients are randomized to 1 of 2 treatment arms.

• Arm A: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride over 60-90 minutes on day 1.
• Arm B: Patients receive ramucirumab IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Arm B was closed early due to excessive toxicities and Arm C was then added to the study with reduced dose of protocol drugs.
• Arm C: Patients receive reduced dose of ramucirumab, cetuximab and irinotecan hydrochloride as in arm B.

In all arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed up periodically for 5 years.

Inclusion Criteria:

• Measurable disease
• Histologically confirmed adenocarcinoma of the colon or rectum
• K-ras wild type based on either primary or metastatic tumor
• Must have received prior first-line therapy comprising oxaliplatin-based fluoropyrimidine-containing chemotherapy and bevacizumab for metastatic colorectal cancer
• Registration within 42 days since confirmed disease progression
• Performance status 0-1
• ANC ≥ 1,500/μL
• Platelet count ≥ 75,000/μL
• Hemoglobin ≥ 9 g/dL
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 40 mL/min
• Urine protein ≤ 1+ on dipstick or routine urinalysis (if ≥ 2+, a 24-hour urine collection must demonstrate < 1,000 mg of protein)
• Total bilirubin ≤ 2.0 mg/dL
• AST and ALT ≤ 3.0 times ULN (5.0 times ULN for patients with liver metastases)
• INR ≤ 1.6 (≤ 3.0 for patients on warfarin and no active bleeding [i.e., no bleeding within the past 14 days])
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after completion of study therapy
• At least 28 days and no more than 90 days since prior bevacizumab
• Concurrent stable dose of oral anticoagulant or low-molecular weight heparin allowed

Exclusion Criteria:

• Brain or CNS metastases
• Pregnant or nursing
• Prior therapy with drugs other than oxaliplatin and a fluoropyrimidine plus bevacizumab for colorectal cancer
• Clinically significant (equivalent to NCI CTCAE grade 3-4) bleeding episodes within the past 3 months
• Active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Symptomatic or poorly controlled cardiac arrhythmia
• Uncontrolled thrombotic or hemorrhagic disorder
• Uncontrolled or poorly controlled hypertension despite standard medical management (e.g., consistently systolic BP > 160 mm Hg and diastolic BP > 90 mm Hg)
• Acute arterial thrombotic events within the past 6 months, including cerebrovascular accident, transient ischemic attack, myocardial infarction, or unstable angina
• Other cancer requiring therapy within the past 3 years except in situ carcinoma or nonmelanoma skin cancer
• Acute or subacute intestinal obstruction
• History of inflammatory bowel disease requiring pharmacological and/or surgical intervention within the past 12 months
• Known allergy to any of the treatment components
• Major surgery within the past 28 days
• Subcutaneous venous access device placement within the past 7 days

Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.