A phase 1b/2, open-label, dose-escalation, and dose-confirmation study of eribulin mesilate in combination with capecitabine

Chris Twelves, Alan Anthoney, Claudio I Savulsky, Matthew Guo, Larisa Reyderman, Nicola Cresti, Vladimir Semiglazov, Constanta Timcheva, Ishtiaq Zubairi, Rosemary Morrison, Ruth Plummer, T R Jeffry Evans, Chris Twelves, Alan Anthoney, Claudio I Savulsky, Matthew Guo, Larisa Reyderman, Nicola Cresti, Vladimir Semiglazov, Constanta Timcheva, Ishtiaq Zubairi, Rosemary Morrison, Ruth Plummer, T R Jeffry Evans

Abstract

Background: Capecitabine and eribulin are widely used as single agents in metastatic breast cancer (MBC) and have nonoverlapping toxicities.

Methods: In phase 1b (dose escalation), patients with advanced, treatment-refractory, solid tumours received eribulin mesilate intravenously in 21-day cycles according to schedule 1 (day 1) or schedule 2 (days 1, 8) with twice-daily oral capecitabine (1000 mg/m2 days 1-14). In phase 2 (dose confirmation), women with advanced/MBC and ≤3 prior chemotherapies received eribulin mesilate at the maximum tolerated dose (MTD) per the preferred schedule plus capecitabine. Primary objectives were MTD and dose-limiting toxicities (DLTs; phase 1b) and objective response rate (ORR; phase 2). Secondary objectives included progression-free survival (PFS), safety, and pharmacokinetics.

Results: DLTs occurred in 4/19 patients (schedule 1) and 2/15 patients (schedule 2). Eribulin pharmacokinetics were dose proportional, irrespective of schedule or capecitabine coadministration. The MTD of eribulin was 1.6 mg/m2 day 1 for schedule 1 and 1.4 mg/m2 days 1 and 8 for schedule 2. ORR in phase 2 (eribulin 1.4 mg/m2 days 1, 8 plus capecitabine) was 43% and median PFS 7.2 months. The most common treatment-related adverse events were neutropenia, leukopenia, alopecia, nausea, and lethargy.

Conclusions: The combination of capecitabine and eribulin showed promising efficacy with manageable tolerability in patients with MBC.

Trial registration: ClinicalTrials.gov NCT01323530.

Conflict of interest statement

C. Twelves has received honoraria from Roche, Eisai, AstraZeneca, Nektar, Pierre Fabre, and Pfizer. C.I.S., M.G., and L.R. are employees of Eisai Inc. R.P. has received honoraria from Roche, Bristol-Myers Squibb, AstraZeneca, Bayer, Clovis, Vertex, Astex, Novartis, Karus Therapeutics, Mission Therapeutics, and MSD. T.R.J.E. has received research funding from AstraZeneca, Celgene, Eisai, GSK, Roche, Basilea, e-Therapeutics, Immunocore, Vertex, Merck, Daiichi Sankyo, and Bristol-Myers Squibb; has received honoraria from Bristol-Myers Squibb; worked in a consulting or advisory role for Bristol-Myers Squibb, Baxter, Karus Therapeutics, and Eisai; and has received travel and accommodation expenses from, and participated in speakers’ bureaus for, Bristol-Myers Squibb and Celgene. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Patient disposition and primary reason for discontinuation from study treatment (combining treatment phase and extension phase)
Fig. 2
Fig. 2
Mean eribulin plasma concentration–time profiles (phase 1b, schedule 1, day 1; schedule 2, day 1)
Fig. 3
Fig. 3
Kaplan–Meier estimates of progression-free survival in the dose-confirmation cohort (phase 2) for all patients

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