Genotype-guided Dosing of mFOLFIRINOX Chemotherapy in Patients With Previously Untreated Advanced Gastrointestinal Malignancies

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity (DLT) rate in cycle #1 in each of two UGT1A1
genotype groups (*1*1, *1*28) using genotype-guided dosing of irinotecan as part of the
modified (m) FOLFIRINOX regimen.

SECONDARY OBJECTIVES:

I. To determine the cumulative dose intensity of irinotecan achieved in each genotype group.

II. To determine the response rates by Response Evaluation Criteria in Solid Tumors (RECIST)
(version 1.1) for each different disease (pancreatic cancer, biliary cancers, gastric cancer,
colorectal cancer, adenocarcinoma of unknown primary) treated in the study.

OUTLINE:

Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan hydrochloride IV
over 1.5 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV continuously over 46
hours on days 1 and 15. Treatment repeats every 4 weeks for up to 6 courses in the absence of
disease progression or unacceptable toxicity.

Inclusion Criteria:

- Histologically or cytologically confirmed locally advanced or metastatic pancreatic
adenocarcinoma, colorectal adenocarcinoma, gastric adenocarcinoma, cholangiocarcinoma,
gall bladder adenocarcinoma, ampullary carcinoma, adenocarcinoma of unclear primary
(with a gastrointestinal primary suspected), or other primary gastrointestinal
malignancy for which the treating physician feels that mFOLFIRINOX is a reasonable
therapeutic option.

- Amendment (January 2014): only subjects with the following histologies will be
eligible

Cohort # 1 (pancreatic cohort): locally advanced or metastatic pancreatic adenocarcinoma
(19 subjects evaluable for the primary endpoint after the amendment)

Cohort #2 (biliary tract cohort): locally advanced or metastatic cholangiocarcinoma, gall
bladder adenocarcinoma, or ampullary carcinoma (19 subjects evaluable for the primary
endpoint after the amendment). Patients with adenocarcinoma of unclear primary that are
most likely of biliary tract origin (in the opinion of the treating physician) will also be
allowed on this cohort.

- Patients with a history of obstructive jaundice due to the primary tumor must have a
metal biliary stent in place,

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1,

- Life expectancy > 3 months,

- Absolute neutrophil count (ANC) >= l500/ul,

- Hemoglobin >= 9g/dL,

- Platelets >= 100,000/ ul,

- Total bilirubin < 1.5 x upper limit of normal,

- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate
transaminase (SGPT) < 2.5 x upper limit of normal for patients without liver
metastases OR SGOT and SGPT < 5 x upper limit of normal for patients with liver
metastases,

- Creatinine =< 1.5 x upper limit of normal,

- Measurable or non-measurable disease will be allowed,

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation, up until 30 days after final study treatment;
should a woman become pregnant or suspect that she is pregnant while participating in
this study, she should inform her treating physician immediately,

- Patients taking substrates, inhibitors, or inducers of Cytochrome P450 3A4 (CYP3A4)
should be encouraged to switch to alternative drugs whenever possible, given the
potential for drug-drug interactions with irinotecan

- Signed informed consent.

Exclusion Criteria:

- Prior chemotherapy or radiation therapy for any cancer,

- Inflammatory bowel disease (Crohn's disease, ulcerative colitis),

- Diarrhea, grade 1 or greater by the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE, v. 4.0); pancreatic cancer patients with
clinical evidence of pancreatic insufficiency must be taking pancreatic enzyme
replacement,

- Neuropathy, grade 2 or greater by NCI-CTCAE, v. 4.0,

- Documented brain metastases,

- Serious underlying medical or psychiatric illnesses that would, in the opinion of the
treating physician, substantially increase the risk for complications related to
treatment,

- Active uncontrolled bleeding,

- Pregnancy or breastfeeding,

- Major surgery within 4 weeks,

- Previous or concurrent malignancy, except for adequately treated basal cell or
squamous cell skin cancer, in situ cervical cancer, or any other cancer for which the
patient has been previously treated and the lifetime recurrence risk is less than 30%,

- Patients with any polymorphism in UGT1A1 other than *1 or *28.