• Ruth Plummer, Michele Ghielmini, Paula Calvert, Maurizio Voi, Josette Renard, Gilles Gallant, Elora Gupta, Hilary Calvert, and Cristiana Sessa.
• Northern Centre for Cancer Treatment, Newcastle Upon Tyne, United Kingdom NE4 6BE.
• Clin Cancer Res. 2002 Sep 1; 8 (9): 2788-97.

PurposeThe 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 DesignAdult 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.ResultsFifty-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).ConclusionThe recommended dose and schedule of weekly BMS-184476 is 50 mg/m(2) on days 1 and 8 every 21 days.

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