Clinical and Pharmacokinetic Study of Ixabepilone (IXA) Plus Epirubicin (EPI) as Therapy for Women with Advanced Breast Cancer (BC).
Authors: Gianni L. , Dalenc F. , De Benedictis E. , Gladieffe L. , Zambetti M. , Mudenda B. , Iacono L. , Parker S. , Roche H. 
Published: December 2010

Abstract
Background: IXA and EPI have established single agent activity in early and late stage BC, however, safety and pharmacokinetics (PK) of the combination are unknown. This study aimed to determine the dose-limiting toxicities (DLT), define the maximum tolerated dose (MTD), investigate PK, and evaluate safety and activity of the combination of IXA and EPI in women with advanced BC.Patients and Methods: Women with locally advanced, recurrent or metastatic BC with ≤ 1 prior chemotherapy regimen as 1st line therapy, a maximum cumulative dose of ≤ 450 mg/m2 for EPI, or ≤300 mg/m2 for doxorubicin were eligible. A short IV infusion of EPI was followed by a 3-hour IV infusion of IXA given every 3 weeks. Three cohorts (3 to 6 patients (pts) per cohort) received IXA/EPI at 25/75, 30/75 and 35/75 mg/m2 respectively. An additional 24 pts were enrolled at the MTD. Blood samples for PK analysis of IXA, EPI and epirubicinol (EOL, major metabolite of EPI) were collected from all pts during cycle 1 and analyzed using LC/MS/MS. PK samples were collected out to 120 h for ixabepilone and 24 h for EPI/EOL. PK parameters were generated by non-compartmental methods.Results: Forty-two pts, median age of 57 (33-69) yrs were treated, 6 at 25/75 mg/m2, 6 at 35/75 mg/m2 and 30 at 30/75 mg/m2, receiving a total of 249 cycles (median 6, range 1-10). All pts were evaluable for safety and efficacy and 38 were evaluable for PK. Two DLTs, febrile neutropenia and grade 3 vomiting, occurred at the 35/75 mg/m2 dose level; therefore 30/75 mg/m2 (IXA/EPI) was defined as the MTD. No deaths or grade 4 non-hematological toxicities were reported. Neutropenia was the most frequent treatment related severe toxicity.Objective responses were seen at all dose levels in 18/32 pts (56%) with measurable disease. In addition, 2/10 pts (17%) with non-measurable disease had complete response. PFS was ≥6 mo in 27 (64%) pts and ≥ 9 mo in 18 (43%). IXA plasma concentrations declined rapidly in the first 24 hrs, followed by a slower elimination phase. Observed means of both elimination half-life (34-52 h) and clearance (25-27 L/h) within each cohort indicate a slow elimination of IXA from plasma. The IXA Cmax and AUC were linear across the 3 dose levels evaluated. With the EPI dose remaining at 75mg/m2, no alteration in EPI AUC was observed across dose levels. Exposure to EOL decreased with increasing IXA dose (Geo Mean AUC: 575.48, 314.46 and 204.46 in each dose group respectively). This may be due to altered metabolism of EPI in the presence of IXA or Cremophor in the IXA formulation. No relationship was observed between PK parameters of IXA, EPI or EOL and nausea, vomiting, and neutropenia.Conclusions: The combination of IXA/EPI is feasible, efficacious and has an acceptable safety profile at the studied dose levels. No clinically relevant PK interactions were observed. The observed effect on EOL exposure deserves further investigation.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2097.