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Phase I and Pharmacokinetic Study of BMS-184476, a Taxane With Greater Potency and Solubility Than Paclitaxel

From the Institute for Drug Development, Cancer Therapy and Research Center and University of Texas Health Science Center at San Antonio; Brooke Army Medical Center, San Antonio, TX; and Bristol-Myers Squibb, Wallingford, CT.

Some patients were treated at the Frederic C. Barter General Clinical Research Center of the Audie Murphy Veterans Administration Hospital, supported in part by National Institutes of Health grant no. MO1 RR01346. M.H. is a recipient of grant no. PF 97 52273279 from the Ministerio de Educacion y Cultura, Spain, and a National Cancer Institute–European Organization for Research and Treatment of Cancer Fellowship Award.Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.Address reprint requests to Manuel Hidalgo, MD, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, Mail Code 7884, San Antonio, TX 78229; email manuelh{at}oncology .uthscsa.edu.

PURPOSE: To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks.

PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474.

RESULTS: Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m². Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m² dose level. In contrast, of 15 assessable patients treated at the 60 mg/m² dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m² dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean ± SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 ± 89 mL/min/m², 402 ± 231 L/m², and 40.8 ± 21.8 hours, respectively.

CONCLUSION: The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m² as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

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