A Phase I Study of Eribulin Mesylate (E7389), a Mechanistically Novel Inhibitor of Microtubule Dynamics, in Patients with Advanced Solid Malignancies

Abstract

Purpose: Eribulin mesylate (E7389), a non-taxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This phase I study determined the maximum tolerated dose (MTD) and pharmacokinetics of eribulin administered on a 3 of 4 week schedule in patients with advanced solid malignancies. Experimental Design: Patients received eribulin mesylate (1-hour i.v. infusion) on days1, 8, and 15 of a 28-day cycle. Dosing began at 0.25 mg/m 2 with escalation guided by dose-limiting toxicities (DLT). MTD, DLTs, safety, pharmacokinetics, and antitumor activity were characterized. Results:Thirty-two patients received eribulin mesylate (0.25, 0.5, 0.7, 1.0, or 1.4 mg/m 2 ). Neutropenia was the principal DLT: At 1.4 mg/m 2 , two patients experienced grade 4 neutropenia, one of whom also developed grade 3 fatigue; three additional patients experienced grade 3 neutropenia and were not treated during cycle 1on day 15. Therefore, the MTD was 1.0 mg/m 2 . Fatigue (53% overall, 13% grade 3, no grade 4), nausea (41%, all grade 1/2), and anorexia (38% overall, 3% grade 3, no grade 4) were the most common eribulin-related adverse events. Eight patients reported grade 1/2 neuropathy (no grade 3/4). Eribulin pharmacokinetics were dose-proportional over the dose range studied. One patient (cervical cancer) achieved an unconfirmed partial response lasting 79 days. Ten patients reported stable disease. Conclusions: Eribulin mesylate, given on days 1, 8, and 15 of a 28-day cycle, exhibits manageable tolerability at 1.0 mg/m 2 with further dose escalation limited by neutropenia and fatigue.

Comparison of Neuropathy-Inducing Effects of Eribulin Mesylate, Paclitaxel, and Ixabepilone in Mice

“…All 3 chemotherapeutic drugs have antineoplastic activity in various animal models (6,7,17) and human cancer conditions (2,37,38). Importantly, all 3 compounds have shown efficacy in multiple in vivo cancer efficacy models at doses often less than the MTD described in this study in the case of eribulin mesylate (17), or generally comparable with the MTD, in the case of paclitaxel (17) and ixabepilone (6,7).…”

Eribulin monotherapy in a patient with heavily pretreated metastatic breast cancer: Case study and review of the literature

“…Several phase 1 studies of eribulin in patients with advanced solid tumors have demonstrated that eribulin has a manageable safety profile, with neutropenia and febrile neutropenia being the only dose-limiting toxicities observed [29] . (13079} [30] Two single-arm phase 2 studies evaluated eribulin monotherapy.…”

Eribulin Mesylate

“…At the maximum tolerated dose (MTD), plasma levels of eribulin are above concentrations required for in vitro cytotoxicity for >1 week. Eribulin demonstrates a triphasic elimination with a halflife ranging from 36 to 48 hours (10)(11)(12), and it is eliminated primarily by biliary excretion. In a dedicated hepatic impairment trial, eribulin was generally safe and well tolerated.…”

“…Hepatic dysfunction decreased clearance and prolonged elimination half-life, resulting in increased exposure to eribulin, when compared with patients with normal liver function (13). Renal excretion is minimal with 5% to 11% of the administered dose eliminated in the urine (10)(11)(12). CYP3A4 is the major enzyme responsible for eribulin metabolism; however, metabolism represents a minor component in drug clearance as no major human metabolites are formed.…”