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

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.