An open-label, randomized cross-over bioavailability study of oral paclitaxel and HM30181 compared with weekly intravenous (IV) paclitaxel in patients with advanced solid tumours

Abstract

Background: Paclitaxel has poor oral bioavailability due to active excretion by p-glyco-protein (Pgp) on intestinal epithelial cells. Oral administration is preferable to IV administration to minimize IV access, avoid allergic reactions to cremaphor, obviate steroid pre-medication, reduce day stay, provide cost-savings, and improve patient convenience. Oraxol (Athenex, USA) is a combination of oral paclitaxel and HM30181, a novel oral non-absorbed specific inhibitor of intestinal Pgp. Following a previously reported phase 1 dose-escalation study, we report the preliminary bio-equivalence results of a three-day schedule of Oraxol compared to IV paclitaxel. Methods: We conducted a randomized crossover study recruiting patients from 2 sites 2 V in New Zealand. HM30181 15mg plus oral paclitaxel 205mg/m ( R Oraxol) were administered orally once daily for 3 consecutive days and compared to a single dose of IV paclitaxel (80 mg/m 2) in patients with advanced solid tumours. PK blood samples were taken up to day 9 for Oraxol and day 5 for IV paclitaxel. Results: A scheduled interim analysis of the first 6 patents' Oraxol PK (AUC0-1) compared to IV paclitaxel showed:-Geometric mean ratios (GMR) = 87.09%, (90% CI 74.61-101.66%)-Intra-subject coefficients of variation (CV) = 12.62%-Time over minimum effective concentration was approximately 6 hours for IV paclitaxel, and 30 hours for Oraxol. Further results will be presented. The safety profile of Oraxol was acceptable without grade 3-4 toxicities. A total sample size of 30 subjects is required to demonstrate bioequivalence between Oraxol and IV paclitaxel (90% CI of the GMR is within the limits of 80%-125%), with 80% power. Conclusions: Oraxol 615mg/m 2 orally over three days achieved paclitaxel AUC comparable to IV paclitaxel 80mg/m 2. A three-day schedule of Oraxol is within predicted range needed to demonstrate bioequivalence, and further patients are being enrolled to achieve adequate power. A phase 3 study is now underway.