Irinotecan Hydrochloride With FOLFIRI and Cetuximab as First-Line Therapy in Treating Patients With RAS Wild-Type Colorectal Cancer

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD), the dose limiting toxicity (DLT) and the
phase II recommended dosage of irinotecan (irinotecan hydrochloride) administered in the
FOLFIRI regimen plus cetuximab in metastatic colorectal cancer (mCRC) patients with *1/*1
and *1/*28 uridine diphosphate glucuronosyltransferase (UGT1A1) genotype treated as first
line chemotherapy.

SECONDARY OBJECTIVE:

To estimate the response rate, progression-free survival (PFS) and metastasectomy (with
curative intent) rate in the overall patient population (both genotype cohorts).

OTHER OBJECTIVES:

I. To evaluate the variability of irinotecan pharmacokinetics, in combination with
cetuximab, in patients with *1/*1 and *1/*28 genotype and the effect of the pharmacokinetic
profile on toxicity and response rate.

II. To evaluate the pharmacokinetic profile of irinotecan and its major metabolites in the
absence and the presence of cetuximab administration, in order to define the effect of the
chimeric monoclonal antibody on irinotecan pharmacokinetics.

OUTLINE: This is a dose-escalation study of irinotecan hydrochloride in patients with
UGT1A1.

Patients receive irinotecan hydrochloride intravenously (IV) over 1-2 hours, fluorouracil IV
continuously over 46 hours, and leucovorin calcium IV on days 1 and 15. Patients also
receive cetuximab IV over 2 hours on days 3 and 15 of course 1 and days 1 and 15 of all
subsequent courses. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

Inclusion Criteria:

- Histologically or cytologically confirmed diagnosis of mCRC

- RAS wild-type status (by a Clinical Laboratory Improvement Amendments [CLIA]
certified assay that includes all known mutations in Kirsten rat sarcoma viral
oncogene homolog [KRAS], Harvey rat sarcoma viral oncogene homolog [HRAS], and
neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS])

- No prior chemotherapy for metastatic disease

- Able to understand and provide written informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Life expectancy > 3 months

- Measurable or evaluable disease defined by Response Evaluation Criteria in Solid
Tumors (RECIST, version 1.1) criteria, i.e. lesions that can be accurately measured
in at least one dimension with the longest diameter >= 20 mm using conventional
techniques or >= 10 mm using spiral computed tomography (CT) scan

- Absolute neutrophil count (ANC) > l500/ul

- Hemoglobin > 9g/dL

- Platelets > 100,000/ul

- Total bilirubin =< 1.5 times upper limit of normal

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times upper
limit of normal

- Alkaline phosphatase < 2.5 times the upper limit of normal, unless bone metastasis is
present in the absence of liver metastasis

- Creatinine < 1.5 mg/dL

- Patients genotyped for UGT1A1*28 polymorphism with *1/*1 or *1/*28 genotype

- Men and women of childbearing potential must agree to use adequate contraception
(double barrier birth control) for the duration of study therapy

- Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at
screening for patients of childbearing potential

Exclusion Criteria:

- Patients with both variant alleles (*28/*28)

- Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g, *6)

- Uncontrolled or severe cardiovascular disease, including myocardial infarct or
unstable angina within 6 months prior to study treatment, New York Heart Association
(NYHA) class II or greater congestive heart failure, serious arrhythmias requiring
medication for treatment, clinically significant pericardial disease or cardiac
amyloidosis

- Patients with specific contraindications to the use of anti-EGFR therapy such as
pulmonary fibrosis, interstitial pneumonia history

- Unresolved diarrhea and bowel obstruction

- Active bleeding

- Documented cerebral metastasis

- Serious active infectious disease

- Pregnancy

- Radiotherapy or major surgery within 4 weeks

- Psychiatric illness or social situations that would limit compliance with study
requirements

- Presence of previous or concomitant neoplasm with exclusion of in situ cervical
cancer

- Patients taking substrates, inhibitors and inducers of CYP3A4 should be encouraged to
switch to alternative drugs whenever possible, given the potential for drug-drug
interactions with irinotecan