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Phase I and Pharmacokinetic Study of the New Taxane Analog BMS-184476 Given Weekly in Patients with Advanced Malignancies¹

Northern Centre for Cancer Treatment, Newcastle Upon Tyne, United Kingdom NE4 6BE [R. P., P. C., H. C.]; Oncology Institute of Southern Switzerland, Bellinzona, CH 6504, Switzerland [M. G., C. S.]; Bristol-Myers Squibb, Waterloo, B-1410 Belgium [M. V., J. R., G. G.]; and Bristol-Myers Squibb, Princeton, New Jersey 08543 [E. G.]

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/m²/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/m²/wk, and the MTD was 50 mg/m²/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/m².

Conclusion: The recommended dose and schedule of weekly BMS-184476 is 50 mg/m² on days 1 and 8 every 21 days.

Commentary

Taxane Analogues: Distinguishing Royal Robes from the "Emperor’s New Clothes"

Eric K. Rowinsky
Clin. Cancer Res. 2002 8: 2759-2763. [Full Text] [PDF]

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