Phase I T rial a nd P harmacokinetic S tudy o f B MS-247550, a n Epothilone B A nalog, A dministered I ntravenously o n a D aily Schedule f or F ive D ays

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/m 2 /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/m 2 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/m 2 /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 BMS247550 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 BMS247550 on the daily schedule for 5 days is 6 mg/m 2 /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. J Clin Oncol 21:1866-1873. © 2003 by American Society of Clinical Oncology.