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Phase I Trial and Pharmacokinetic Study of BMS-247550, an Epothilone B Analog, Administered Intravenously on a Daily Schedule for Five Days

Jame Abraham, Manish Agrawal, Susan Bakke, Ann Rutt, Maureen Edgerly, Frank M. Balis, Brigitte Widemann, Louis Davis, Bharat Damle, Daryl Sonnichsen, David Lebwohl, Susan Bates, Herb Kotz, Tito Fojo

From the Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV; National Cancer Institute Center for Cancer Research, Bethesda, MD; and Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Address reprint requests to Tito Fojo, MD, PhD, Center for Cancer Research, National Cancer Institute, Bldg 10, Rm 12N226, 9000 Rockville Pike, Bethesda, MD 20892; email: tfojo{at}helix.nih.gov.

Purpose: The epothilones are a novel class of nontaxane microtubule-stabilizing agents. BMS-247550 is a semisynthetic analog of the natural product epothilone B. We conducted a phase I study administering BMS-247550 as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days.

Patients and Methods: Twenty-one patients received BMS-247550 without filgrastim in the first cycle. An additional six patients were enrolled at a starting dose of 8 mg/m²/d with filgrastim support. Twenty-one of the 27 patients had received prior paclitaxel, docetaxel, or both.

Results: One hundred seven cycles were administered to 27 patients. The maximum-tolerated dose was 6 mg/m² of BMS-247550 administered as a 1-hour intravenous infusion daily for 5 consecutive days every 21 days. Dose-limiting toxicity at a dose of 8 mg/m²/d was neutropenia with or without filgrastim support. Nonhematologic grade 3 toxicities included fatigue (seven cycles), stomatitis (two cycles), and anorexia (one cycle). The mean terminal half-life of BMS-247550 was 16.8 ± 6.0 hours, the volume of distribution at steady-state was 798 ± 375 L, and the clearance was 712 ± 247 mL/min. Objective responses were observed in patients with breast, cervical, and basal cell cancer. Reductions in CA-125 levels were noted in patients with ovarian cancer.

Conclusion: The recommended phase II dose of BMS-247550 on the daily schedule for 5 days is 6 mg/m²/d. Neutropenia was dose limiting, but higher doses were tolerated by a large fraction of patients with filgrastim support. Peripheral neuropathy was mild, even after multiple cycles of therapy, and was not dose limiting.

The order of the first two authors is arbitrary.

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