Phase IB study of eribulin mesylate in combination with carboplatin in patients with advanced solid tumors.

Abstract

2589 Background: Eribulin mesylate (E7389), a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, has clinical activity as monotherapy in breast cancer and other solid tumors. This phase I, open-label, dose-finding study determined the maximum tolerated dose (MTD) for eribulin in combination with carboplatin. Methods: Patients with advanced solid tumors whose prior standard therapy failed were enrolled. Carboplatin was administered by 30-min IV infusion and eribulin by 2- to 5-min IV bolus, separated by 1 h. In stage 1, eribulin mesylate (0.7, 0.9, 1.1, and 1.4 mg/m2) was dose escalated with carboplatin AUC5 in a 3+3 design in two schedules differing by the order of administration. In stage 2, eribulin mesylate (1.1 and 1.4 mg/m2) was dose escalated with carboplatin AUC6 using the preferred schedule from stage 1. In both stages, the MTD was defined as the highest dose where <2/6 patients had dose-limiting toxicities (DLTs). The safety, efficacy, and pharmacokinetics (PK) of eribulin were also assessed. Results: 52 patients (27 females, 25 males) with a median age of 60 years (range: 38-80 years) were treated. In stage 1, a DLT (diarrhea) was experienced in 1/5 patients at 1.4 mg/m2 in the carboplatin-first schedule and in 0/3 patients in the eribulin-first schedule, defining the MTD as 1.4 mg/m2 (same as the monotherapy dose) with eribulin given first. In stage 2, eribulin was given first and DLTs occurred in 1/6 patients (febrile neutropenia) at 1.1 mg/m2 and in 2/3 patients (febrile neutropenia, neutropenia) at 1.4 mg/m2, defining the MTD as 1.1 mg/m2. PK analyses for both agents suggest the absence of any PK interaction. Most frequent AEs (%) across doses/cycles were neutropenia (52; 40 grade 3/4), thrombocytopenia (29; 13 grade 3/4), fatigue (58; 4 grade 3/4), and nausea (40; 0 grade 3/4). Two partial responses by RECIST were observed in prostate cancer and one complete response in tonsillar cancer. Conclusions: Combination of eribulin with carboplatin was tolerated and showed preliminary activity. An extension arm with the combination at recommended phase II doses (eribulin mesylate 1.1 mg/m2, carboplatin AUC6) is enrolling patients with chemo-naive, advanced non-small cell lung cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai, K and L Consulting Services Eisai Eisai