Ibudilast for prevention of oxaliplatin-induced acute neurotoxicity: a pilot study assessing preliminary efficacy, tolerability and pharmacokinetic interactions in patients with metastatic gastrointestinal cancer.

Abstract

This prospective, open-label, sequential 'before vs. after' pilot study was conducted to provide preliminary efficacy and tolerability data for ibudilast in the prevention of oxaliplatin-induced neurotoxicity in patients with metastatic upper gastrointestinal or colorectal cancer. Any potential impact of ibudilast on oxaliplatin and 5-fluorouracil pharmacokinetics was also explored. Participants were administered a chemotherapy cycle (FOLFOX or CapeOx), followed by a chemotherapy cycle with co-administration of ibudilast 30mg b.i.d. p.o. Efficacy was assessed on Day 3 and end of cycle using the Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and additional clinical/patient-reported neurotoxicity measures. A population pharmacokinetic approach was used to determine oxaliplatin and 5-fluorouracil pharmacokinetics with and without ibudilast. Sixteen participants consented; 14 completed both chemotherapy cycles. Across all measures, the majority of participants experienced either an improvement or no worsening of neurotoxicity with ibudilast treatment. Based on OSNS assessments, acute neurotoxicity was unchanged in 12/14 participants and improved in 2/14 participants. The 90% confidence interval (CI) of the dose-normalised ratio of oxaliplatin AUC (90% CI 95.0-109%) and 5-fluorouracil AUC (90% CI 66.5-173%) indicated no significant impact of ibudilast on systemic exposure. This pilot study indicated ibudilast co-administration may improve or stabilise oxaliplatin-induced neurotoxicity. Given the expected worsening of symptoms in patients with continued chemotherapy, this represents a signal of effect that warrants further investigation. Pharmacokinetic analysis indicates ibudilast has no significant effect on oxaliplatin pharmacokinetics, and is unlikely to influence pharmacokinetics of 5-fluorouracil. Trial registration number: UTN U1111-1209-0075 and ANZCTRN12618000232235 (registered 13/02/2018).