A phase I study of ixabepilone in combination with epirubicin in patients with metastatic breast cancer

PurposeThe objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLT), pharmacokinetics, and the recommended phase II dose for ixabepilone in combination with epirubicin in women with metastatic breast cancer.Patients and MethodsPatients ≥18 years old with an histologically or cytologically confirmed diagnosis of invasive breast cancer and clinical evidence of locally recurrent or metastatic disease were enrolled and treated with a fixed dose of epirubicin (75 mg/m²) and escalating doses of ixabepilone (25, 30, and 35 mg/m²).ResultsForty-two women were treated at 3 different dose levels of ixabepilone: 25 (n = 6), 30 (n = 30), and 35 mg/m² (n = 6) in combination with 75 mg/m² epirubicin. The MTD of ixabepilone in combination with epirubicin 75 mg/m² was 30 mg/m², and the DLT dose was 35 mg/m² with grade 4 neutropenia. Grade 3/4 neutropenia was the most frequent moderate-to-severe adverse event and was manageable and reversible. No deaths were reported. Objective responses were achieved in 18 of 32 patients with measurable disease (56% [90% CI, 40%-71%]) and in 9 of 22 evaluable patients treated at the MTD (41% [90% CI, 23%-61%]). Ixabepilone clearance and the epirubicin pharmacokinetic profile were similar across ixabepilone dose levels.ConclusionsThe combination of ixabepilone and epirubicin was clinically active. The recommended dose for evaluation in phase II is epirubicin 75 mg/m², followed by ixabepilone 30 mg/m² every 3 weeks.