Genotype-guided Dosing of mFOLFIRINOX Chemotherapy in Patients With Previously Untreated Advanced Gastrointestinal Malignancies
Genotype-guided Dosing of mFOLFIRINOX Chemotherapy in Patients With Previously Untreated Advanced Gastrointestinal Malignancies
This study is being done to determine the dose of a chemotherapy drug (irinotecan [irinotecan
 hydrochloride]) that can be tolerated as part of a combination of drugs. There is a
 combination of chemotherapy drugs often used to treat gastrointestinal cancer, which consists
 of 5-FU (fluorouracil), leucovorin (leucovorin calcium), irinotecan and oxaliplatin and is
 known as "FOLFIRINOX". FOLFIRINOX is a current drug therapy combination (or regimen) used for
 people with advanced pancreatic cancer, although this combination is not Food and Drug
 Administration (FDA) approved for this indication. FOLFIRINOX was recently shown in a
 separate clinical trial to increase survival compared to another commonly used drug in
 pancreatic cancer called gemcitabine. FOLFIRINOX is also a reasonable regimen for those with
 other advanced cancers of the gastrointestinal tract, including colon cancer, rectal cancer,
 esophagus cancer, stomach cancer, gall bladder cancer, bile duct cancer, ampullary cancer,
 and cancers with an unknown primary location. The best dose of irinotecan to use in
 FOLFIRINOX is not known. This study will analyze one gene (uridine 5'-diphospho [UDP]
 glucuronosyltransferase 1 family, polypeptide A1 [UGT1A1] gene) of subjects for the presence
 of an alteration in that gene, which may affect how the body handles irinotecan. Genes help
 determine some of the investigators individual characteristics, such as eye color, height and
 skin tone. Genes may also determine why people get certain diseases and how medicines may
 affect them. The result of the genetic analysis will divide subjects into one of three
 groups: A, B, or C. Group A (approximately 45% of subjects) will receive the standard dose of
 irinotecan. Group B (approximately 45% of subjects) will receive a lower dose of irinotecan.
 Group C (approximately 10% of subjects) will receive an even lower dose of irinotecan
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.