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Phase I and Pharmacokinetic Study of a New Taxoid, RPR 109881A, Given as a 1-Hour Intravenous Infusion in Patients With Advanced Solid Tumors

From the Division of Internal Medicine, National Cancer Center Hospital, Tokyo; Department of Internal Medicine and Department of Surgery, National Shikoku Cancer Center Hospital, Matsuyama City; Department of Obstetrics and Gynecology, Kawasaki Medical School, Kurashiki City; Department of Internal Medicine, National Kyushu Cancer Center, Fukuoka City; and Rhône-Poulenc Rorer Japan, Inc, Ibaraki Laboratory, Research and Development Division, Chiyoda-Machi, Ibaraki Prefecture, Ibaraki, Japan.

Address reprint requests to Takayasu Kurata, MD, or Yashuhiro Shimada, MD, Division of Internal Medicine, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045; email welnet{at}urban.ne.jp

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/m². 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/m² 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/m², and the recommended dose for phase II study was 60 mg/m² as a 1-hour infusion every 3 weeks.

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