Background: Neurotoxicity is one of the most significant and disabling side effects of oxaliplatin and frequently limits the cumulative amount that can be used. The mechanism of oxaliplatin-induced neurotoxicity remains uncertain, although our preliminary studies suggest that oxaliplatin uptake by organic cation transporter 2 (OCT2) into mouse and rat dorsal root ganglion is a prerequisite for oxaliplatin-induced peripheral neuropathy. The activity of OCT2 is dependent on tyrosine phosphorylation by the SRC-kinase family member Yes1, which is highly sensitive to inhibition by several FDA-approved, small molecule kinase inhibitors such as dasatinib. We have previously shown that pre-treatment with oral dasatinib prevented acute and chronic oxaliplatin-induced peripheral neuropathy in mouse and rat models. Methods: This is a phase Ib dose-finding study of dasatinib given in combination with mFOLFOX6 with or without bevacizumab. The study explores the hypothesis that the addition of dasatinib prior to oxaliplatin will inhibit OCT2 activity and reduce oxaliplatin-induced neuropathy. This hypothesis will be tested in a Bayesian Phase 1b trial with adaptive dose selection using efficacy-toxicity trade-offs (modified toxicity-efficacy probability interval dose-finding design) in patients with confirmed stage IV colorectal cancer who are candidates for mFOLFOX6 with bevacizumab therapy. Patients who have documented peripheral neuropathy or prior exposure to oxaliplatin will be excluded. The primary objective is to determine the recommended Phase 2 dose which is defined as the lowest intermittent dose of dasatinib that affects serum biomarkers of OCT2, including methylnicotinamide and creatinine, by ≥2-fold without influencing the clearance of oxaliplatin by > 20%. The following doses will be used: oxaliplatin 85mg/m² IV, 5FU bolus 400mg/m² IV bolus with Leucovorin 400mg/m², bevacizumab 5mg/kg, followed by infusional 5FU 2400mg/m² IV over 46 hours given on a day 1 and 15 schedule every 28 days. Dasatinib will be administered at one of 2 dose levels – 100mg or 140mg po. Dasatinib will be given 24 hours and 30 mins prior to oxaliplatin on C1D14, C1D15 respectively and repeated on C1D28 and C2D1. Secondary objectives include evaluation of the influence of dasatinib on the pharmacokinetics of oxaliplatin and vice versa. Quality of life will be explored using the CIPN20 questionnaire. The trial opened to enrollment in Dec 2019 (NCT04164069) and is accepting patients. Clinical trial information: NCT04164069.