Abstract C104: A phase I clinical pharmacokinetic study of sagopilone (ZK-EPO), a novel first fully synthetic epothilone, in Japanese patients with refractory solid tumors

Background: Epothilones are a new class of cytotoxic agents that induce tubulin polymerization. Sagopilone (ZK-EPO), the fully synthetic, third-generation epothilone, is a highly potent tubulin stabilizer that has shown substantial antitumor activity against a broad range of tumor models. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of sagopilone in Japanese patients (pts) with refractory solid tumors. Methods: Pts with histologically or cytologically confirmed advanced solid tumors that were refractory to conventional antineoplastic treatment, or for whom no standard therapy was available were enrolled on the trial. sagopilone was given as a 30-minute intravenous infusion once every 3 weeks up to a maximum of 6 courses; the starting dose was 12.4 mg/m2. Treatment was continued until disease progression or unacceptable toxicity occurred. Results: Seventeen Japanese pts (8 male and 9 female, median age 52 years; range 27–66) have received the study drug. Six patients were treated at dose of 12.4 mg/m2, 6 at 16.5 mg/m2, and 5 at 22.0 mg/m2. The most common adverse events (AEs) were peripheral neuropathy in 14 pts (82.4%), nausea and lymphocytopenia in 13 each (76.5%), leukopenia and arthralgia in 12 each (70.6%), and neutropenia in 11 (64.7%). Nine pts (52.9%) experienced at least 1 Grade (Gr) 3 treatment-related AEs including peripheral neuropathy in 5 pts (29.4%); in the 3rd and 6th course at 12.4 mg/m2, and in the 1st (2 pts) and 2nd course at 22.0 mg/m2. All of them improved after discontinuation of the study treatment. No pts experienced Gr 4 or 5 AEs. Seven pts (41.2%) had at least 1 DLT during the study. At 12.4 mg/m2 dose, 4 pts experienced DLTs: Gr 3 peripheral neuropathy in 2 pts as well as Gr 2 liver enzyme increase and Gr 2 weight decrease that persisted for 5 weeks in 1 pt each. No DLT was observed at 16.5 mg/m2, but 3 of 5 pts treated at 22.0 mg/m2 had Gr 3 dose-limiting peripheral neuropathy. The PK data demonstrated that Cmax and AUC of sagopilone increased in a dose-dependent manner. Mean systemic clearance was between 616 and 765 mL/min (CV, 20.7% to 32.4%), and mean distribution volume at the steady state ranged from 3075 to 3688 L (CV, 19.6% to 50.1%). Mean terminal half-life was between 74.4 and 93.1 h (CV, 16.4% to 32.5%). Although incidence of neuropathy seemed to depend on the dose, no clear relationships between the toxicity and PK parameters were observed. No pts had a CR or PR. Nine pts had SD. Prolonged SD over 12 weeks was observed in 2 pts with breast cancer. Conclusions: Sagopilone demonstrated clinically favorable safety and tolerability with indications of antitumor activity in heavily pretreated Japanese pts with solid tumors. MTD was 16.5 mg/m2, and the main and dose-limiting toxicity was peripheral neuropathy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C104.