Inclusion Criteria:

- Metastatic or locally advanced (unresectable) colorectal cancer with histological
confirmation of adenocarcinoma.

- Age 18 years of age. Note: Because no dosing or adverse event data are currently
available on the use of cetuximab or bevacizumab in subjects <18 years of age,
children are excluded from this study.

- Measurable disease as defined in Section 11.0.

- KRAS wild-type tumor (codons 12 and 13).

Note: Evidence of EGFR expression in the tumor is not required.

Note: Although testing for other RAS mutations is not required, a known mutation in other
regions of KRAS, NRAS, or HRAS is exclusionary.

- 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.

Note: Childbearing potential is defined as a female who has experienced menarche and who
has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or who is not postmenopausal (defined as amenorrhea 12
consecutive months; or women on hormone replacement therapy with documented serum follicle
stimulating hormone level >35 mIU/mL). Women who are using oral, implanted, or injectable
contraceptive hormones or mechanical products such as intrauterine device or barrier
methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing
abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of
childbearing potential.

- ECOG Performance Status (PS): 0 or 1 (form available on the ACCRU member website at
https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html).

- Adequate organ and bone marrow function as defined below (see Section 3.19b)

- The following laboratory values obtained 14 days prior to randomization.

- Total serum bilirubin institutional upper limit of normal (ULN)

- Absolute neutrophil count (ANC) 1500/mm3

- Platelet count >100,000/mm3

- Hemoglobin 9.0 g/dL (hemoglobin may be supported by transfusion)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 x ULN
( 5 x ULN for subjects with liver involvement of their cancer)

- Creatinine within institutional limits of normal OR

- creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal.

- Urinary protein 1+

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

- Partial thromboplastin time (PTT) 1x institutional ULN and international normalized
ratio (INR) 1.5, unless participant is on full dose anticoagulation therapy.
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 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.

- Willing to provide tissue and blood samples for mandatory correlative and research
purposes (see Sections 6.0, 14.0 and 17.0).

- 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 any RAS mutation

- 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.

Note: Participants with brain or CNS metastases are excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- 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, because this study involves agents whose genotoxic, mutagenic
and teratogenic effects on the developing fetus and newborn are unknown:

- 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 HIV positive

Note: HIV-positive individuals on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with irinotecan, cetuximab, and
bevacizumab. In addition, these individuals are at increased risk of lethal infections
when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in
participants receiving combination antiretroviral therapy when indicated.

- 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.

3.29l 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).

Minimum Eligible Age: 18 Years

Maximum Eligible Age: N/A

Eligible Gender: Both