Phase I and pharmacokinetic study of BMS-184476, a taxane with greater potency and solubility than paclitaxel

Purpose: To assess the feasibility, toxicity, pharmacokinetics, and prelimi nary activity of BMS-184476 administered as a 1-hour intravenous (IV) infus ion every 3 weeks. Patients and Methods: Patients with advanced solid malignancies were treate d 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 pharmacok inetics and pharmacodynamics of BMS-184474. Results: Thirty-four patients were treated with 78 courses of EMS-184476 at five dose levels ranging from 20 to 80 mg/m(2). Dose-limiting toxicity (DL T), consisting of severe neutropenia with fever, severe diarrhea, and/or se vere mucositis, was experienced during course 1 by six of nine minimally pr etreated patients treated at the 70 and 80 mg/m(2) dose level. In contrast, of 15 assessable patients treated at the 60 mg/m(2) dose level, which is t he maximum-tolerated dose (MTD) of EMS-184476 on this administration schedu le, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR durin g a second course of BMS-184476 at the 40 mg/m(2) dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophagea l junction herd a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. mean a SD values for clearance, volume o f distribution at steady-state, and terminal half-life were 220 a 89 ml/min /m(2), 402 +/- 231 L/m(2), and 40.8 +/- 21.8 hours, respectively. Conclusion: The MTD and recommended dose for phase II evaluations of BMS-18 4476 is 60 mg/m(2) as a 1-hour IV infusion every 3 weeks. The results of th is study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and admin istration and warrants further clinical development. J Clin Oncol 19:2493-2 503. (C) 2001 by American Society of Clinical Oncology.