This phase Ib trial studies side effects and best dose of dasatinib in preventing oxaliplatin-induced peripheral neuropathy in patients with gastrointestinal cancers who are receiving FOLFOX regimen with or without bevacizumab. Drugs used in chemotherapy, such as leucovorin, fluorouracil, and oxaliplatin (FOLFOX regimen), 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. However, the buildup of oxaliplatin in the cranial nerves can result in damage or the nerves. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Blocking these enzymes may reduce oxaliplatin-induced peripheral neuropathy.

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of dasatinib in combination with oxaliplatin and fluorouracil (5FU) (modified version 6 regimen of leucovorin, fluorouracil and oxaliplatin [mFOLFOX6]) with or without bevacizumab in patients with colon, rectal or other GI cancer, defined as the lowest intermittent dose of dasatinib that affects serum biomarkers of OCT2 without influencing the pharmacokinetic properties of oxaliplatin.

II. To determine the toxicity profile (based on Chemotherapy-Induced Peripheral Neuropathy [CIPN]20 and Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0) of dasatinib in combination with oxaliplatin/5-FU/bevacizumab in patients with colorectal cancer or other GI cancer.

SECONDARY OBJECTIVES:

I. To evaluate the influence of dasatinib on the pharmacokinetics of oxaliplatin and vice versa in these patients.

OUTLINE: This is a dose-escalation study of dasatinib.

Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin IV over 2 hours, fluorouracil slow IV push over 2-4 minutes followed by continuous infusion over 46 hours on days 1 and 15. Patients also receive dasatinib orally (PO) once daily (QD) on days 14, 15, and 28 of cycle 1 and day 1 of cycle 2. Patients may receive bevacizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to cycle 3 day 1 in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

• Confirmed confirmed stage II, III or IV colon or rectal cancer and other gastrointestinal (GI) cancers (e.g. pancreas, esophagogastric, bile duct, small bowel cancers etc) who are candidates for mFOLFOX6, with or without bevacizumab therapy. Pathological confirmation of colon,rectal or other GI cancer is required. Patients may have had prior therapy for GI cancer.
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x upper limit of normal (ULN) unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• Serum creatinine: =< 1.5 x upper limit of normal (ULN), or measured or calculated creatinine clearance (estimated by Cockcroft-Gault formula or measured ) >= 50 mL/min urine protein:creatinine (UPC) < 2
• Total bilirubin =< 2 x ULN
• Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN, unless evidence of liver metastases, then AST/alanine aminotransferase (ALT) =< 5 x ULN
• Blood pressure (if receiving bevacizumab): systolic blood pressure (SBP) > 150 or diastolic blood pressure (DBP) > 100
• Serum potassium and magnesium within the institution normal range.
• Corrected QT (QTc) interval =< 450 mSec
• Women of child-bearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation and for 3 months after completion of study treatment administration
• Prior chemotherapy in the adjuvant or metastatic setting is allowed including prior exposure to oxaliplatin in the adjuvant setting for colorectal cancer or other GI cancer as long as neuropathy is grade 1 or less.
• Pre-existing neuropathy is allowed as long as it is grade 1 or less.

Exclusion Criteria:

• Treatment with any other investigational agents within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of dasatinib
• Gastrointestinal (GI) disease or impairment of GI function that is likely to significantly alter the absorption of dasatinib
• Use of potent OCT2 and/or CYP3A4 inhibitors if treatment cannot be either safely discontinued or switched to a different medication prior to starting dasatinib
• Concurrent cetuximab panitumumab or any other biological/targeted agent.
• Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, known human immunodeficiency virus (HIV) diagnosis if receiving combination antiretroviral therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations, including psychotic disorders, dementia and substance use disorders, that would limit compliance with study requirements
• Because there is an unknown potential risk for adverse events in nursing infants secondary to treatment of the mother with dasatinib and/or oxaliplatin, breastfeeding should be discontinued
• Inability to understand and sign informed consent
• Any other condition that in the opinion of the investigators would make the study therapy unsafe