Oral paclitaxel with encequidar tested for cancer in dogs

Abstract

Paclitaxel is an antimitotic agent that targets elements of the cancer phenotype, including cell proliferation, DNA repair, and apoptosis, predicting its broad activity in a spectrum of cancers. An oral paclitaxel formulation has been developed to overcome challenges associated with parenteral administration of this drug, notably the development of Cremophor-induced acute hypersensitivity reactions, which are particularly problematic in dogs. The aim of this open-label, dose-escalating study was to evaluate the tolerability and determine the maximum tolerated dosage (MTD) and dose-limiting toxicity (DLT) of oral paclitaxel when co-administered with the P-glycoprotein pump inhibitor, encequidar, in dogs with cancer. Paclitaxel was administered as a 3-consecutive-day course starting at 90 mg/mwith encequidar weekly for 3 weeks, using escalation of 30 mg/mincrements. MTD was established using a rolling-six dose escalation study design, based on the number of dogs experiencing any DLT assessed after each dosing cycle and during a 28-day post-treatment monitoring period. Nineteen client-owned dogs were enrolled. MTD was established at 90 mg/mand the most frequent adverse events (AEs) were gastrointestinal, followed by hematologic, with the majority being self-resolving and low grade. VCOG Grades 3 and 4 gastrointestinal toxicity, Grade 4 neutropenia, and acute kidney injury were defined as DLTs at 120 mg/m. Conclusions of this study define oral paclitaxel MTD in cancer-bearing dogs at 90 mg/mwhen given with encequidar for 3 consecutive days weekly for 3 weeks. Future Phase 2 trials evaluating the therapeutic activity of oral paclitaxel at its MTD co-administered with encequidar in defined tumour histologies are warranted.