Phase Ib study of ixabepilone (I) in combination with epirubicin (E) in women with metastatic breast cancer

Abstract

1058 Background: Ixabepilone and anthracyclines are effective in the treatment of breast cancer. The primary objective of this phase I trial was to determine the maximum tolerated doses of the combination of epirubicin and ixabepilone. Methods: The safety, tolerability, pharmacokinetic and antitumor activity of epirubicin and ixabepilone in combination administered every 3 weeks was assessed in women with advanced breast cancer. Eligible pts with a cumulative dose of ≤ 300 mg/m2 for doxorubicin, ≤ 450 mg/m2 for epirubicin and ≥ 3 months of progression free interval after adjuvant anthracycline were enrolled. Three dose levels were explored in a 3 + 3 dose escalation design: epirubicin/ixabepilone at 75/25, 75/30 and 75/35 mg/m2. PK blood samples were collected during cycle 1 and estimated by non-compartment analysis. Results: Twenty-six pts have been enrolled to date, median age was 54 yrs (33–68). Eight pts received prior chemotherapy in adjuvant setting. Safety data are preliminary and available on 23 pts across the 3 dose levels for a total of 130 cycles (median 6 cycles, range 2–8). Neutropenia was the dose limiting toxicity, occurring in 1/6 pts at 75/25, 1/11 at 75/30 and 2/6 at 75/35 mg/m2. This included 1 pt with febrile neutropenia and 3 pts with grade 4 neutropenia of ≥ 5 days duration. Enrollment at 75/30 mg/m2 dose level is continuing. The most frequent grade 3 or 4 AE was neutropenia (4/23 and 15/23 respectively). Nonhematologic grade 3 and 4 toxicities were infrequent and included 2 pts with grade 3 neuropathy and 3 pts with grade 3 vomiting. No deaths were reported. No pharmacokinetic interaction was observed. Responses were seen at all dose levels tested. Of twelve women with measurable disease 10 achieved a partial response, one stable disease and one progressed. Six pts with non measurable disease had clinical benefit and/or no disease progression. Conclusions: Based on these preliminary data the recommended dose level of epirubicin 75 mg/m2 and ixabepilone 30 mg/m2 has a favourable toxicity and efficacy profile and warrants further investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb