Patients with advanced solid tumours treated with combined oral paclitaxel plus novel HM30181 demonstrated bioavailability that was equivalent to i.v. paclitaxel and an encouraging safety profile, according to preliminary findings from abioavailability study presented at the ESMO Asia 2017 in Singapore, an Annual Congress organised by the European Society for Medical Oncology.
The combination also removed the need for steroid pre-treatment and the possibility of allergic reactions to the i.v. vehicle, since it is administered orally.
Dr. Christopher Jackson of the Department of Medicine at the University of Otago in Dunedin, New Zealand explained that Oraxol is a formulation of oral paclitaxel plus HM30181, a novel oral non-absorbed specific inhibitor of intestinal p-glycoprotein (Pgp). HM30181 was designed to resolve the poor oral bioavailability seen with paclitaxel that is due to active excretion by Pgp, which is expressed on intestinal epithelial cells.
Furthermore, oral administration is preferable to i.v. administration to minimize i.v. site specific adverse events, and also avoids allergic reactions to cremaphor, the vehicle used for i.v. delivery of paclitaxel and other drugs having poor water-solubility.
Dr. Jackson reported preliminary bio-equivalence data from a scheduled interim analysis of the first 6 patients in this randomised crossover study (ACTRN 12615000894594) comparing the combination of oral paclitaxel plus HM30181 compared to i.v. paclitaxel in patients with advanced solid tumours.
The patients received HM30181 at 15 mg plus oral paclitaxel at 205 mg/m2 once daily for 3 consecutive days and also crossed over to receive a single dose of i.v. paclitaxel at 80 mg/m2. Blood samples for pharmacokinetics analysis were taken up to day 9 for the combination and to day 5 for i.v. paclitaxel.
Similar bioavailability seen with HM30181 plus oral paclitaxel and i.v. paclitaxel
Comparison of HM30181/paclitaxel versus i.v. paclitaxel by area under the curve measurements (AUC0-∞) revealed that the geometric mean ratio (GMR) was 87.09% (90% confidence interval [CI] 74.61-101.66%) and the intra-subject coefficients of variation (CV) were 12.62%.
The time over minimum effective concentration was increased five-fold with the oral combination to 30 hours, compared to 6 hours for i.v. paclitaxel.
No grade 3/4 toxicities were seen with combined HM30181 and oral paclitaxel.
Based on these findings the combination has been taken further to a phase III trial.
HM30181 plus oral paclitaxel administered to patients with solid tumours achieved AUC levels of paclitaxel that were comparable to paclitaxel delivered by i.v.
The investigators noted that a sample size of 30 subjects is required to formally demonstrate bioequivalence between the combination and i.v. paclitaxel and additional patients are being enrolled to achieve this. A phase III study is underway to demonstrate efficacy compared to three weekly i.v. paclitaxel in advanced breast cancer.
They pointed out that the oral combination of HM30181 and paclitaxel has many advantages for patients as it does not require steroid pre-medication, reduces the time needed to administer treatment, thus offering improved convenience for both patients and clinicians and may provide cost-savings.
This study was sponsored by Athenex.
133O – Jackson CGCA, et al. 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.