Phase Ib adaptive study of dasatinib for the prevention of oxaliplatin-induced neuropathy in patients with gastrointestinal (GI) cancers receiving FOLFOX chemotherapy with or without bevacizumab.

Abstract

745 Background: Neurotoxicity is one of the most significant and disabling side effects of oxaliplatin (OX) and frequently limits the amount of OX that can be used. OX uptake by organic cation transporter 2 (OCT2) into mouse and rat dorsal root ganglia is a prerequisite for OX-induced peripheral neuropathy (OIPN). Preclinical data in rat and mouse models from our group showed that by inhibiting YES1, pre-treatment with dasatinib (D) inactivated OCT2 and prevented acute and chronic OIPN. A phase I trial is ongoing investigating addition of D prior to OX to prevent OIPN. Methods: This was a Bayesian Phase 1b dose-finding study with adaptive dose selection using efficacy-toxicity trade-offs in patients (pts) with GI cancers who are candidates for mFOLFOX6 ± bevacizumab [NCT04164069]. Pts received chemotherapy on day 1 and 15 schedule, every 28 days. D was administered at one of 2 dose levels – 100mg or 140mg PO, given 24 hours and 30 mins prior to OX on C1D14, C1D15 respectively and repeated on C1D28 and C2D1. During cycle 1, pharmacokinetic and pharmacodynamic data was obtained at baseline, during, and up to 24 hours after D or OX administration. Recommended Phase 2 dose (RP2D) was defined as the lowest intermittent dose of D that affects serum biomarkers of OCT2, including methylnicotinamide (NMN) and creatinine, by ≥2-fold without influencing the clearance of oxaliplatin by ≥20%. CIPN20 questionnaire was completed prior to each dose of FOLFOX on screening through to C3D1. Weakly informative Jeffreys priors were used for response and toxicity probabilities, with the latter constrained to be increasing with dose. Results: 13 pts were screened. 5 pts enrolled in cohort 1 (D 100 mg), 2 in cohort 2 (D 140 mg) and 2 in cohort 3 (D 140mg). 6 pts were not evaluable for the efficacy and toxicity endpoints due to screen failure or early study discontinuation. 7 patients were evaluated for efficacy biomarkers and 6 pts were evaluated for both efficacy biomarkers and toxicity. There were no DLTs observed in any cohort. 4/7 pts had ≥2-fold increase in AUC of NMN, and 3/7 pts had ≥2-fold increase in AUC of creatinine. 6/7 pts had ≤20% change in the clearance of OX. Conclusions: Addition of D 100mg or 140mg to traditional FOLFOX regimen was safe and in the majority of pts appeared to alter serum biomarkers of OCT2 in a manner suggesting inhibition of OX uptake in the DRG. 140mg was the chosen RP2D. A randomized phase II study is planned using D to prevent OPIN. Clinical trial information: NCT04164069 . [Table: see text]