Phase I and pharmacokinetic study of a new taxoid, RPR 109881A, given as a 1-hour intravenous infusion in patients with advanced solid tumors.

PURPOSE: RPR 109881A is a new semisynthetic taxoid compound that has a similar mechanism of action to docetaxel. The purpose of this phase I study was to characterize the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetic profile, and antitumor effects of this agent. PATIENTS AND METHODS: Nineteen eligible patients with advanced solid tumors were enrolled. RPR 109881A was administered as a 1-hour intravenous infusion every 3 weeks at doses ranging from 15 to 75 mg/m(2). Pharmacokinetic evaluation was performed at the first cycle. RESULTS: Neutropenia (febrile neutropenia) and fatigue were dose-limiting toxicities at doses of 60 and 75 mg/m(2) and seemed to be dose-related. Both thrombocytopenia and anemia were infrequent. Nonhematologic toxicities were generally mild. Pharmacokinetic studies indicated that RPR 109881A plasma disposition was bi- or triphasic, with a high total plasma clearance, a large volume of distribution, and a long terminal half-life. The area under the concentration-time curve (AUC) and the peak concentration of RPR 109881A seemed to increase with increasing dose proportionally, suggesting linear pharmacokinetics. Urinary excretion over 48 hours was low, with a mean of 0.8 +/- 0.36% of the administered dose. A significant relationship existed between the percentage decrease of neutrophil counts and the AUC of RPR 109881A. Among 18 assessable patients, two partial and two minor responses were documented. CONCLUSION: RPR 109881A was found to be a well-tolerated and promising taxoid agent. The MTD was 75 mg/m(2), and the recommended dose for phase II study was 60 mg/m(2) as a 1-hour infusion every 3 weeks.