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

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)

What this study is about