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Phase I and pharmacokinetic study of the new taxane analog BMS-184476 given weekly in patients with advanced malignancies

Lookup NU author(s): Professor Ruth Plummer, Dr Paula Calvert, Professor Alan Calvert


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Purpose: The study was designed to establish the maximum administered dose and maximum tolerated dose (MTD) of BMS-184476, an analogue of paclitaxel, given weekly for 3 consecutive weeks every 28 days, later amended to a regimen of weekly administration for 2 consecutive weeks every 21 days. Experimental Design: Adult patients with solid tumors received BMS-184476 i.v. on days 1, 8, and 15 without premedication. The trial followed a modified accelerated titration design. Doses of 7, 14, 28, 40, 50, and 60 mg/m(2)/wk were investigated. Pharmacokinetics of BMS-184476 in plasma and urine were investigated by high-performance liquid chromatography assay. Results: Fifty-three patients were treated; the maximum administered dose was 60 Mg/m(2)/wk, and the MTD was 50 mg/m(2)/wk. Dose-limiting neutropenia was the main toxicity. Neutropenia at the higher dose levels frequently prevented administration of the day 15 dose, and a modified schedule at MTD dosing on days 1 and 8 every 21 days was evaluated and found more feasible for Phase II studies. Diarrhea was the main nonhematological toxicity; other toxicities were vomiting, cumulative fatigue, and loss of appetite. Two patients died of neutropenia-related complications. Antitumor activity was observed in patients with breast and non-small cell lung cancer, with confirmed partial responses in 22% of patients. BMS-184476 was the main species found in the plasma with <5% present as paclitaxel or sulfoxide metabolites. The PKs of BMS-184476 appeared to be linear in the dose range of 7-60 mg/m(2). Conclusion: The recommended dose and schedule of weekly BMS-184476 is 50 mg/m(2) on days 1 and 8 every 21 days.

Publication metadata

Author(s): Plummer ER, Ghielmini M, Calvert PM, Voi M, Renard J, Gallant G, Gupta E, Calvert AH, Sessa C

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2002

Volume: 8

Issue: 9

Pages: 2788-2797

ISSN (print): 1078-0432

ISSN (electronic):