A phase Ib study of the safety and pharmacology of nilotinib to prevent paclitaxel-induced peripheral neuropathy in patients with breast cancer.

Abstract

TPS12128 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of paclitaxel, but convincing evidence for a preventative technique founded on mechanistic rationale is lacking. We previously report that paclitaxel accumulation is mediated by the murine organic anion transporting polypeptide, OATP1B2 in mice (OATP1B1 and OATP1B3 in humans) (Leblanc, J Clin Invest, 2018). We found that paclitaxel induces acute and chronic neurotoxicity in mice in an OATP1B2-dependent manner, which is reversed by pre-treatment with FDA-approved tyrosine kinase inhibitor, nilotinib. Methods: This phase Ib dose finding study of nilotinib in combination with weekly paclitaxel is investigating the hypothesis that intermittent dosing of nilotinib 24 hours before paclitaxel infusion (excluding C1D1) and again 30 minutes before paclitaxel infusion will inhibit OATP1B1 and prevent CIPN. This hypothesis will be assessed using an adaptive Bayesian method for dose finding based on efficacy-toxicity trade-offs in patients with breast cancer stages I-III who qualify for paclitaxel therapy. Patients with previous ≥ grade 2 neuropathy on breast cancer therapies will be excluded. The primary objectives are to find the recommended phase II dose of nilotinib in combination with paclitaxel for early stage breast cancer, defined as the lowest intermittent dose of nilotinib that temporarily inhibits OATP1B1 function without affecting paclitaxel plasma pharmacokinetics (PK), and to determine the toxicity profile of nilotinib in combination with paclitaxel. OATP1B1 inhibition by nilotinib will be assessed via validated surrogate endogenous substrates, glycochenodeoxycholate sulfate (GCDGA-S) and chenodeoxycholate-24-glucuronide (CDCA-24G). Effective OATP1B1 inhibition will be ≥5-fold increase in AUC of GCDCA-S from pre- to post- treatment or detectable CDCA-24G levels post-treatment. The 4 nilotinib dose levels are 50 mg (dose level -1), 100 mg (dose level 1), 200 mg (dose level 2), 300 mg (dose level 3). IV paclitaxel dose of 80 mg/m2 on D1,8,15 for 12 total weekly doses will be used. Oral nilotinib will be administered 24 hours before paclitaxel infusion on C1D7,D14 and again 30 minutes before infusion on C1D8,D15. Secondary objectives are to determine paclitaxel’s effect on PK of nilotinib and vice versa. Quality of life via CIPN-20 survey, disease free survival, event free survival, overall survival are exploratory objectives. NCT04205903 enrollment opened February 2020 and is accepting patients. Clinical trial information: NCT04205903 .