Phase IB trial of ixabepilone and vorinostat in metastatic breast cancer.

PURPOSE: To translate promising preclinical data on the combination of vorinostat and ixabepilone for metastatic breast cancer (MBC) into clinical trials.

METHODS: We conducted a randomized two-arm Phase IB clinical trial of ascending doses of vorinostat and ixabepilone in prior -treated MBC patients. To determine the maximum tolerated dose (MTD), 37 patients were randomized to schedule A: every-3-week ixabepilone + vorinostat (days 1-14), or schedule B: weekly ixabepilone + vorinostat (days 1-7; 15-21) Pharmacokinetics were assessed. Nineteen additional patients were randomized to schedule A or B and objective response rate (ORR), clinical benefit rate (CBR), toxicity, progression-free survival (PFS), and overall survival (OS) were assessed.

RESULTS: The schedule A MTD was vorinostat 300 mg daily (days 1-14), ixabepilone 32 mg/m2 (day 2); 21-day cycle 27% dose-limiting toxicities (DLTs). The schedule B MTD was vorinostat 300 mg daily (days 1-7; 15-21), ixabepilone 16 mg/m2 (days 2, 9, 16); 28-day cycle; no DLTs. Vorinostat and ixabepilone clearances were 194 L/h and 21.3 L/h/m2 , respectively. Grade 3 peripheral sensory neuropathy was reported in 8% (A) and 21% (B) of patients. The ORR and CBR were 22 and 22% (A); 30 and 35% (B). Median PFS was 3.9 (A) and 3.7 (B) months. OS was 14.8 (A) and 17.1 (B) months.

CONCLUSIONS: We established the MTD of vorinostat and ixabepilone. This drug combination offers a novel therapy for previously treated MBC patients. The potential for lower toxicity and comparable efficacy compared to current therapies warrants further study.