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

Abstract

SummaryEribulin 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/m2 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/m2, and in all three patients at 2.0 mg/m2. The recommended dose was 1.4 mg/m2 and the MTD was 2.0 mg/m2. 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/m2 dose level. Eribulin mesylate, administered on Days 1 and 8 of a 21-day cycle, exhibits manageable tolerability at 1.4 mg/m2. DLT was neutropenia.

Evolving Approaches to Metastatic Breast Cancer Patients Pre-treated with Anthracycline and Taxane

“…This study was conducted to investigate higher doses of eribulin and to determine the dose-limiting toxicities (DLT), the recommended dose and the maximum tolerated dose in Japanese patients. As expected, the pharmacokinetic parameters of C max and area under the drug concentration–time curve (AUC) of eribulin increased with each dose level (Table 2), and an increase in dose correlated with the incidence of adverse events [26]. This phase I study established the recommended dose of 1.4 mg/m 2 .…”

“…In a phase I study of eribulin in patients with advanced solid tumours, the mean half-life was 46.5 h [25]. A similarly prolonged half-life was seen in a dose-ranging study of eribulin in Japanese patients with refractory solid tumours (36.4–59.9 h with doses of 0.7–2.0 mg/m 2 (Table 2) [26]. Eribulin exhibited triphasic pharmacokinetics with a long terminal half-life, high volume of distribution and low urinary clearance.…”

“…Phase I studies have suggested that eribulin doses of 1.0–2.0 mg/m 2 result in a manageable toxicity profile, and as a result the approved dosage of eribulin is a 2–5 min infusion of 1.4 mg/m 2 on days 1 and 8 of a cycle lasting 21 days [12, 25, 26, 33]. Eribulin continued to exhibit an acceptable toxicity profile in both phase II [27–29] and phase III [30, 31] studies.…”

Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

“…To characterize the PK of eribulin, data from seven phase 1 studies, one phase 2, and one phase 3 study, were combined. Eribulin PK was described well by a three‐compartment model with linear elimination from the central compartment.…”

Predicting success in regulatory approval from Phase I results

“…[8–10] However, confirmed partial responses were observed in the subsequent Phase I trials of these agents using similar or different schedules. [11–13] Previously Von Hoff et al in an analysis of 113 chemotherapeutic agents from 1970–1983 reported that the FDA approved agents were associated with a median of six responses in the Phase I trials. [14].…”