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Phase I and Pharmacokinetic Trial of the Novel Taxane BMS-184476 Administered as a 1-Hour Intravenous Infusion in Combination with Cisplatin Every 21 Days

Abrahmson Family Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania [W. S., J. P. S., M. L. G., D. V., S. M. H., D. G. H., P. J. O.]; Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey [M. C.]; Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut [G. G.]

BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel that displays potency superior to paclitaxel against tumor cells in culture and human tumor xenografts. It also inhibits the growth of paclitaxel-resistant human tumor cell lines with multidrug resistance mediated by either P-glycoprotein or mutated tubulin. Given the known synergy between taxanes and cisplatin in vitro and their clinical activity in combination, we performed a Phase I trial of BMS-184476 as a 1-h i.v. infusion followed by cisplatin every 21 days. Twenty-seven patients with a variety of solid tumors and good performance status received 116 cycles of therapy at BMS-184476 doses of 40–60 mg/m² together with cisplatin at 75 mg/m². The early observation of hypersensitivity reactions required prophylactic premedication in all patients. At the planned highest dose of BMS-184476 (60 mg/m²) and cisplatin (75 mg/m²), we observed dose-limiting toxicity in the form of neutropenia and diarrhea. Also at this level, five patients experienced grade 3 or worse nausea and vomiting. Aggressive prophylactic treatment eliminated the gastrointestinal toxicity. Mild to moderate peripheral neuropathy was infrequent, as was alopecia. Patient benefits included three partial responses in patients with mesothelioma, esophageal cancer, and head and neck cancer, and two additional minor responses. Plasma pharmacokinetic data are available for 23 patients treated at 40–60 mg/m². The mean maximum plasma concentrations and areas under the curves increased in a dose-related manner. The pharmacokinetics of BMS-184476 appeared independent of dose. The mean (± SE) values for clearance, volume of distribution at steady state, and the apparent terminal half-lives of the three dose groups during cycle 1 were 243 ± 5 ml/min/m², 423 ± 58 l/m², and 32.2 ± 4.5 h, respectively. BMS-184476 60 at mg/m² with cisplatin at 75 mg/m² with appropriate supportive therapy is the dose recommended for further evaluation.

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