Eribulin mesylate in patients with refractory cancers: a Phase I study

Toru Mukohara, Shunji Nagai, Hirofumi Mukai, Masayuki Namiki, Hironobu Minami, Toru Mukohara, Shunji Nagai, Hirofumi Mukai, Masayuki Namiki, Hironobu Minami

Abstract

Eribulin mesylate (Halaven™, E7389) is a synthetic analog of the marine natural product halichondrin B that acts via a mechanism distinct from conventional tubulin-targeted agents. This Phase I study (clinicaltrials.gov identifier: NCT00326950) was the first to investigate eribulin mesylate in Japanese patients. The study determined the recommended dose, MTD, DLTs, safety, pharmacokinetics, and antitumor activity of eribulin administered on Days 1 and 8 of a 21-day cycle in Japanese patients with advanced solid tumors. Fifteen patients received eribulin mesylate 0.7-2.0 mg/m(2) as a 2- to 10-min intravenous injection. Neutropenia was the principal DLT. DLTs were observed in two of six patients treated at 1.4 mg/m(2), and in all three patients at 2.0 mg/m(2). The recommended dose was 1.4 mg/m(2) and the MTD was 2.0 mg/m(2). Neutropenia (67%), lymphocytopenia (20%), febrile neutropenia (33%), and fatigue (13%) were the most common grade 3 or 4 toxicities. Eribulin exhibited triphasic pharmacokinetics with a long terminal half-life, high volume of distribution, and low urinary clearance. Three patients achieved partial responses (two with NSCLC, one with head and neck cancer) at 1.4 mg/m(2) dose level. Eribulin mesylate, administered on Days 1 and 8 of a 21-day cycle, exhibits manageable tolerability at 1.4 mg/m(2). DLT was neutropenia.

Figures

Fig. 1
Fig. 1
PK analysis of enrolled patient population: a relationship between plasma concentration versus time profiles for each eribulin dose group; b relationship between Cmax versus dose following a 2- to 10-min injection of eribulin on Day 1; and c relationship between AUC0-t versus dose following a 2- to 10-min injection of eribulin on Day 1
Fig. 2
Fig. 2
AUC0-t on Day 1 and decrease in neutrophil count from baseline fitted according to Emax

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