358P - Pharmacokinetics of eribulin mesilate in combination with capecitabine in patients with advanced/metastatic cancer: results from a phase IB dose-esc...

Date 29 September 2012
Event ESMO Congress 2012
Session Poster presentation I
Topics Pharmacology
Breast Cancer, Metastatic
Presenter Christopher Twelves
Authors C. Twelves1, M. Nasim2, A. Anthoney1, N. Cresti3, C. Savulsky4, C. Johnston4, L. Reyderman5, J. Wanders4, R. Plummer3, T.R..J. Evans6
  • 1Clinical Cancer Research Groups, Leeds Institute of Molecular Medicine and St James’s Institute of Oncology, Leeds/UK
  • 2Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow/UK
  • 3Medical Oncology, Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle/UK
  • 4Medical Oncology, Eisai Ltd, Hatfield/UK
  • 5Medical Oncology, Eisai Inc., Woodcliff Lake, New Jersey/US
  • 6Beatson West of Scotland Cancer Centre, Glasgow/UK

Abstract

Background

Eribulin is a microtubule dynamics inhibitor EMA approved for certain patients (pts) with locally advanced (LA)/metastatic breast cancer (MBC) who have received ≥2 prior chemotherapeutic regimens for advanced disease. Prior therapy should have included an anthracycline and taxane. This Phase Ib, open-label dose-escalation study assessed maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of eribulin in combination with capecitabine in pts with advanced/metastatic cancer.

Methods

Pts received eribulin mesilate (2–5-min IV) by Schedule 1 (1.2, 1.6 or 2.0 mg/m2 on Day [D] 1) or Schedule 2 (0.7, 1.1 or 1.4 mg/m2 on D1 and D8) in combination with twice-daily oral capecitabine 1000 mg/m2 on D1–14 every 21 days. To assess PK and drug-drug interaction of eribulin, capecitabine and capecitabine metabolites in Cycle 1 and 2, samples were taken on D1 (pre-, 0, 0.25, 0.5, 1–4, 6 and 8 h post-dose), any time on D2–3 and D4–6, and D8 (Schedule 1: pre-, 0.5, 1–4 and 6 h post-capecitabine; Schedule 2: pre-dose). PK was examined by non-compartmental analysis, and cardiac repolarization by 12-lead ECGs at screening, D1 (pre- and 4 h post-dose), D2–3, D8 and D15. Correlation of eribulin and capecitabine plasma concentrations with change from baseline (Δ) QTc was explored.

Results

Schedule 1 (n = 19) and Schedule 2 (n = 15) MTDs were 1.6 and 1.4 mg/m2 eribulin mesilate, respectively. Dose-limiting toxicities (all n = 1) were: Grade (G) 4 neutropenia, G3 febrile neutropenia, G3 fatigue, G3 lethargy (Schedule 1); G4 neutropenic sepsis, G3 neutropenia (Schedule 2). There were no unexpected toxicities. Eribulin PK was independent of schedule and had dose-related increases in exposure. No accumulation occurred upon multiple dosing; at each dose, eribulin PK was comparable in Cycles 1 and 2. Exposure to capecitabine and metabolites was variable and independent of schedule. Co-administration had no effect on ΔQTc.

Conclusions

No drug-drug interaction of eribulin and capecitabine was observed. From these results, the combination appears to be tolerated without effect on cardiac repolarization. A Phase II LA/MBC study evaluating Schedule 2 MTD is ongoing.

Disclosure

C.J. Twelves: The author declares the following conflicts of interest: consultant/advisory role (Eisai) and honoraria/speakers bureau (Eisai).

C. Savulsky: The author declares the following conflicts of interest: employee (Eisai Ltd).

C. Johnston: The author declares the following conflicts of interest: employee (Eisai Ltd).

L. Reyderman: The author declares the following conflicts of interest: employee (Eisai Inc.).

J. Wanders: The author declares the following conflicts of interest: employee at the time of study (Eisai Ltd).

R. Plummer: The author declares the following conflicts of interest: research funding (Eisai Ltd).

T.R..J. Evans: The author declares the following conflicts of interest: research funding (Eisai Ltd).

All other authors have declared no conflicts of interest.