This randomized phase II trial studies how well irinotecan and cetuximab with or without bevacizumab work in treating patients with RAS wild-type colorectal cancer that has spread to other places in the body (locally advanced/metastatic) and cannot be removed by surgery. Irinotecan may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as cetuximab and bevacizumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving irinotecan and cetuximab with or without bevacizumab may work betting in treating patients with colorectal cancer.

PRIMARY OBJECTIVES:

I. To assess and compare the progression-free survival (PFS) of patients receiving irinotecan, cetuximab, and bevacizumab with patients receiving irinotecan, cetuximab and placebo, in the population of patients with RAS wild-type, irinotecan-refractory metastatic colorectal cancer (mCRC) who also previously received bevacizumab in at least one prior line therapy.

SECONDARY OBJECTIVES:

I. To assess the adverse event (AE) profile and safety of the proposed treatment in this population.

II. To assess and compare the overall survival (OS) between treatment arms in this population.

III. To assess and compare the disease control rate (DCR) between treatment arms in this population.

IV. To assess and compare the overall response rate (ORR) between treatment arms in this population.

V. To assess and compare the duration of response between treatment arms in this population.

VI. To assess and compare time to treatment failure between treatment arms in this population.

VII. To assess relative dose intensity of treatment agents between treatment arms in this population.

CORRELATIVE OBJECTIVES:

I. Determine the change in genotype concentrations of prespecified gene mutations in circulating cell-free deoxyribonucleic acid (DNA) (cfDNA) collected serially during protocol treatment.

II. Explore the predictive value of pretreatment mutation status, germline single nucleotide polymorphisms (SNPs), and gene expression signatures for cetuximab sensitivity and resistance.

III. Explore the predictive value of dynamic changes in mutation status and gene expression signatures for cetuximab sensitivity and resistance.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cetuximab intravenously (IV) over 90-120 minutes, bevacizumab IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive cetuximab IV over 90-120 minutes, placebo IV over 30-90 minutes, and irinotecan IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for up to 2 years.

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 =< 7 days prior to registration, for women of childbearing potential only

• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0 or 1

• Total serum bilirubin =< institutional upper limit of normal (ULN) obtained =<14 days prior to randomization

• Absolute neutrophil count (ANC) >= 1500/mm^3 obtained =<14 days prior to randomization

• Platelet count >= 100,000/mm^3 obtained =<14 days prior to randomization

• Hemoglobin >= 9.0 g/dL (hemoglobin may be supported by transfusion) obtained =<14 days prior to randomization

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for subjects with liver involvement of their cancer) obtained =<14 days prior to randomization

• Creatinine within institutional limits of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal obtained =<14 days prior to randomization

• Urinary protein =< 1+ obtained =<14 days prior to randomization

  • Patients discovered to have >= 2+ proteinuria must have a spot urine protein:creatinine ratio (UPCR) < 1.0

• Partial thromboplastin time (PTT) =< 1 x institutional ULN and international normalized ratio (INR) =< 1.5 , unless participant is on full dose anticoagulation therapy obtained =<14 days prior to randomization; patients on full-dose anticoagulation are eligible if the following criteria are met:

  • Patient has an in-range INR (usually 2-3) on a stable dose of warfarin or other anticoagulant =< 14 days or is on a stable dose of low molecular weight heparin
  • Patient has no active bleeding or pathological condition that carries a high risk of bleeding (i.e., tumor involving major vessels or known varices)
  • Patients receiving anti-platelet agents are eligible; in addition, patients who are on daily prophylactic aspirin or anticoagulation for atrial fibrillation are eligible

• Life expectancy > 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 =< 14 days prior to randomization

• Prior radiotherapy to > 25% of bone marrow; Note: standard rectal cancer chemoradiation will not exclude subject from study protocol

• Radiation therapy =< 2 weeks prior to randomization

• Any of the following:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception

• Co-morbid systemic illnesses or other severe concurrent disease, history of any psychiatric or addictive disorder, or laboratory abnormality, which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Patients known to be human immunodeficiency virus (HIV) positive

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, symptomatic pulmonary fibrosis or interstitial pneumonitis, or psychiatric illness/social situations that, in the opinion of the investigator, may increase the risks associated with study participation or study treatment, or may interfere with the conduct of the study or the interpretation of the study results

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanoma skin cancer, prostatic intraepithelial neoplasia without evidence of prostate cancer, lobular carcinoma in situ in one breast, or carcinoma-in-situ of the cervix that has been treated

• History of prior malignancy for which patient is receiving other specific treatment for their cancer

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to irinotecan, cetuximab, and/or bevacizumab that led to discontinuation of those agents

• Significant history of bleeding events or pre-existing bleeding diathesis =< 6 months of randomization (unless the source of bleeding has been resected)

• History of gastrointestinal perforation =< 12 months prior to randomization

• Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of > 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 =< 6 months prior to randomization; Note: this includes transient ischemic attack (TIA), cerebrovascular accident (CVA), unstable angina or angina requiring surgical or medical intervention in the past 6 months, or myocardial infarction (MI)

• Clinically significant peripheral artery disease (e.g., claudication with < 1 block) or any other arterial thrombotic event

• Serious or non-healing wound, ulcer, or bone fracture

• History of hypertension not well-controlled (>= 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)