Phase I Study of Eribulin Mesylate Administered Once Every 21 Days in Patients with Advanced Solid Tumors

Abstract

Purpose: To evaluate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of eribulin mesylate (E7389), a halichondrin B analogue, administered every 21days in patients with advanced solid tumors. Experimental Design: Eribulin mesylate was given as a 1-hour infusion every 21days at doses of 0.25, 0.5, 1, 2, 2.8, and 4 mg/m 2 .The MTD was identified using an accelerated titration design. The pharmacokinetics of eribulin were evaluated in the plasma and urine with the first dose. Results: Twenty-one patients were enrolled. At 4 mg/m 2 , three patients experienced a DLT of febrile neutropenia on day 7. The dose level was reduced to 2.8 mg/m 2 where two of three patients experienced dose-limiting febrile neutropenia. Six additional patients were enrolled at 2 mg/m 2 (seven patients in total received this dose) and one of these patients experienced a neutropenic DLT. The MTD of eribulin mesylate was therefore 2 mg/m 2 . Nonhematologic toxicities included alopecia, fatigue, anorexia, and nausea. Pharmacokinetic analysis showed linear kinetics for eribulin over the dose range studied and a terminal half-life of 2 days. The plasmaconcentration-time profile exhibited a rapid distribution phase followed by a slow elimination phase. Drug clearance was nonrenal. One patient with non^small cell lung cancer achieved an unconfirmed partial response and 12 patients had stable disease. Conclusions: Eribulin mesylate administered as a 1-hour infusion every 21 days has a manageable toxicity profile at 2 mg/m 2 , with further dose escalation limited by neutropenia.

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.…”

“…Four dose-finding studies were conducted with eribulin (10)(11)(12)17). The initial phase I trial by the California Cancer Consortium included a rapid titration design with real-time pharmacokinetics to guide dose escalation.…”

“…All 3 patients in the 4 mg/m 2 cohort and 2 of 3 patients treated at the 2.8 mg/m 2 dose developed febrile neutropenia. The MTD was determined to be 2.0 mg/m 2 (12). A phase I trial in Japanese patients with refractory solid tumors similarly reported an MTD of 2.0 mg/m 2 when eribulin was administered over 5 minutes on days 1 and 8 every 21 days (17).…”

Potential clinical applications of halichondrins in breast cancer and other neoplasms

“…The MTD was 2 mg/m 2 due to neutropenia as the dose limiting toxicity at higher doses. 21 a similar recommended dose of eribulin as 1.4 mg/m 2 administered for 5 minutes on days 1 and 8 of a 21-day cycle. 22 In a Phase I study conducted on patients with liver impairment (Child A and B), eribulin was generally safe and well tolerated.…”