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

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.

TERTIARY 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. Courses 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. Courses 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 3 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)