Irinotecan and Cetuximab With or Without Bevacizumab in Treating Patients With Metastatic Colorectal Cancer That Progressed During First-Line Therapy

Inclusion Criteria:

* Patients must have metastatic colorectal cancer that has been histologically or cytologically confirmed; confirmation may be from either the primary tumor or a metastasis; patients must have wild type KRAS
* Patients must be registered within 28 days of documented disease progression on first line chemotherapy with bevacizumab plus either FOLFOX, OPTIMOX, or XELOX; this progression must have occurred within 90 days after the last dose of bevacizumab; patients who discontinued oxaliplatin, continued with 5-FU/LV or capecitabine and bevacizumab and then had subsequent progression while on fluoropyrimidine and bevacizumab are eligible; patients who discontinued bevacizumab due to adverse events in the first-line setting are not eligible
* Measurable or nonmeasurable disease
* At least 14 days must have elapsed since the last dose of first line chemotherapy and bevacizumab
* Patients must not have received prior treatment with irinotecan (either as adjuvant or metastatic treatment)
* Patients must have no history of prior treatment with cetuximab or other agents targeting VEGF or EGFR (except for bevacizumab)
* Prior radiotherapy is allowed, provided at least 28 days have elapsed since the last treatment; all adverse events related to radiation therapy must be resolved
* Prior surgery is allowed, provided at least 28 days have elapsed since any major surgery and patient has recovered from all effects
* Zubrod performance status 0-2
* Absolute neutrophil count (ANC) \>= 1,500/mm\^3
* Platelet count \>= 100,000/mm\^3
* Hemoglobin \>= 9 g/dL
* Total bilirubin =\< 1.5 times upper limit of normal (ULN)
* Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvate transaminase (SGPT) =\< 2.5 x IULN; if there are known liver metastases, SGOT or SGPT must be =\< 5 x IULN; these results must be obtained within 28 days prior to registration
* Serum creatinine =\< IULN or measured or estimated creatinine clearance \>= 60 mL/min
* Patients must not have a history or known presence of brain metastasis
* Patients may be on full dose anticoagulation with warfarin provided that the patient has an acceptable International Normalized Ratio (INR) (between 2 and 3), obtained within 28 days prior to registration
* No clinically relevant bleeding diathesis or coagulopathy
* Patients must not have experienced nephrotic range proteinuria from prior bevacizumab therapy; urine protein must be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio \> 0.5, 24-hour urine protein must be obtained and the level must be \< 1,000 mg for patient enrollment; urine protein and creatinine used in calculating the UPC ratio must be obtained within 28 days prior to registration
* No uncontrolled high blood pressure (BP) (i.e., systolic BP \> 150 mm Hg and diastolic BP \> 90 mm Hg)
* No cardiovascular event within the past 6 months, including any of the following:

  * Arterial thrombosis
  * Unstable angina
  * Myocardial infarction
  * Cerebrovascular accident
* Patients must not have New York Heart Association (NYHA) \>= Grade 2 congestive heart failure
* Patients must not have unstable symptomatic arrhythmia requiring medication; (patients with chronic, controlled arrhythmias such as atrial fibrillation or paroxysmal supraventricular tachycardia \[PSVT\] are eligible)
* No clinically significant peripheral vascular disease
* No serious or nonhealing active wound, ulcer, or bone fracture
* No history of gastrointestinal (GI) perforation while on prior bevacizumab
* No significant bleeding episodes (e.g., hemoptysis or upper or lower GI bleeding) within the past 6 months unless the source of bleeding has been resected
* No known hypersensitivity to bevacizumab or known potential hypersensitivity to cetuximab
* No other concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any other type of anticancer treatment
* Due to the possibility of harm to a fetus or nursing infant from this treatment regimen, patients must not be pregnant or nursing; women and men of reproductive potential must have agreed to use an effective contraceptive method
* No other malignancy within the past 5 years except for adequately treated basal or squamous cell skin cancer or cervical cancer in situ
* All patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines
* At the time of patient registration, the treating institution's name and identification (ID) number must be provided to the Data Operations Center in Seattle in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered into the data base