Phase 1 multicenter, open-label study to establish the maximum tolerated dose (MTD) of two administration schedules of E7389 (eribulin) liposomal formulation in patients (pts) with solid tumors.

Background: Eribulin, a microtubule dynamics inhibitor, is approved in the US for the treatment of pts with metastatic breast cancer who have previously received ≥ 2 chemotherapeutic regimens for metastatic disease including an anthracycline and a taxane in the adjuvant/metastatic setting. Preclinical evidence suggested improved efficacy and lower toxicity with a liposomal formulation of eribulin (eribulin-LF). The primary objective of this study was to determine the MTD and dosing schedule for eribulin-LF. Secondary objectives included determining safety, pharmacokinetics (PK), and efficacy. Methods: Using a conventional 3 + 3 study design, eligible pts received escalating doses (1.0 to 3.5 mg/m2) of eribulin-LF (60-min, i.v. infusion) on day (D) 1 of a 21-day cycle (schedule [S] 1) or on D1 and D15 of a 28-day cycle (S2). An expansion phase confirmed the safety of eribulin-LF in pts with endometrial, ovarian, or HER2-negative breast cancer. Results: Of 58 pts (S1: n = 20; S2: n = 38): 65% were female, median age was 62 yrs (range 33–75), 65% had an ECOG PS of 1, and 10 pts had metastatic breast cancer. Dose-limiting toxicities were: S1, grade (G) 4 hypophosphatemia (n = 1), G4 increased ALT/AST (n = 1), both at eribulin-LF 1.5 mg/m2; S2, G4 febrile neutropenia (n = 1; 1.5 mg/m2); G3 increased ALT/AST (n = 1), and G4 neutropenia (n = 1), both at 2 mg/m2. MTD was 1.4 mg/m2 in S1 and 1.5 mg/m2in S2; the latter dose and schedule were used in the expansion phase (n = 23). Treatment-emergent adverse events (TEAEs) included peripheral neuropathy (S1: 35%, S2: 8%) and neutropenia (S1: 20%, S2: 34%). TEAEs of G3 or higher occurred in 55% (S1) and 39% (S2). Eribulin-LF exhibited single-phase PK, and was quantifiable ~18 days postdose. Exposure was dose-dependent and t1/2 was ~35 hrs. Promising clinical activity was observed in pts with breast cancer (5/10 partial responses, 3/10 stable disease). Conclusions: In this phase 1 study, eribulin-LF was well tolerated, with promising activity in patients with breast cancer. Eisai Inc. Clinical trial information: NCT01945710