Phase I clinical and pharmacokinetic study of 3-weekly, 3-h infusion of ixabepilone (BMS-247550), an epothilone B analog, in Japanese patients with refractory solid tumors

Background Ixabepilone (BMS-247550) is the first in a new class of anti-neoplastic agents, the epothilone analogs, and is a highly active non-taxane anti-microtubule agent. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety profile, pharmacokinetics, and antitumor activity of ixabepilone in Japanese patients. Patients and methods Patients with solid tumors previously treated with up to four chemotherapy regimens received a 3-h intravenous infusion of ixabepilone every 3 weeks. Results Fourteen patients received 43 cycles (median 3, range 1-8). The most common adverse events were neutropenia, mild-to-moderate fatigue, anemia, and peripheral neuropathy. DLTs occurred in one patient receiving 40 mg/m(2) (grade 4 neutropenia for 9 days) and in two patients receiving 50 mg/m(2) (grade 3 mucositis, ileus and febrile neutropenia; grade 4 neutropenia for 10 days). One paclitaxel- and docetaxel-pretreated patient with non-small cell lung cancer achieved a partial response lasting for 3 months; six additional patients (43%) achieved disease stabilization with tumor shrinkage of 3-35%. The plasma concentration-time profiles of ixabepilone during cycle 1 were similar across all doses evaluated. Conclusions The MTD of ixabepilone is 50 mg/m(2) given over 3 h every 3 weeks. The recommended phase II dose is 40 mg/m(2), which is well tolerated and active. Data from Japanese patients are consistent with published phase I data from non-Japanese patients.