This phase I/II trial studies the side effects of genetic analysis-guided dosing of paclitaxel albumin-stabilized nanoparticle formulation, fluorouracil, leucovorin calcium, and irinotecan hydrochloride (FOLFIRABRAX) in treating patients with gastrointestinal cancer that has spread to other parts of the body and usually cannot be cured or controlled with treatment. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, fluorouracil, leucovorin calcium, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Genetic analysis may help doctors determine what dose of irinotecan hydrochloride patients can tolerate.

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity (DLT) rate in cycle #1 in each of three uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotype groups (*1/*1, *1/*28, *28/*28) using genotype-guided dosing of irinotecan (irinotecan hydrochloride) as part of the FOLFIRABRAX regimen.

SECONDARY OBJECTIVES:

I. To determine the cumulative dose of each chemotherapy drug (nab-paclitaxel [paclitaxel albumin-stabilized nanoparticle formulation], irinotecan, 5-FU [fluorouracil]) administered in each genotype group.

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

OUTLINE:

Patients receive FOLFIRABRAX comprising paclitaxel albumin-stabilized nanoparticle formulation intravenously (IV) over 0.5 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 1.5 hours, and fluorouracil IV over 46 hours on days 1 and 15. Courses repeat every 4 weeks for up to 6 months in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• Histologically or cytologically confirmed locally advanced or metastatic pancreatic 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 FOLFIRABRAX is a reasonable therapeutic option
• 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) >= 1500/ul
• Hemoglobin > 9 g/dL
• Platelets > 100,000/ul
• Total bilirubin =< 1.25 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
• Measurable or non-measurable disease will be allowed, but only those with measurable disease will be evaluable for the response rate endpoint
• Women of childbearing potential and sexually active males must use an effective contraception method during treatment and for three months after completing treatment
• Negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test at screening for patients of childbearing potential
• 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, version [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 taking substrates, inhibitors and inducers of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) should be encouraged to switch to alternative drugs whenever possible
• Patients with any polymorphism in UGT1A1 other than *1 or *28 (e.g., *6)
• History of interstitial lung disease, idiopathic pulmonary fibrosis, silicosis or connective tissue disorders
• Subjects known to be human immunodeficiency virus (HIV)-positive, including those on combination antiretroviral therapy, are ineligible