Abstract
BackgroundThis phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours.MethodsEligible patients with ECOG PS 0–1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF.ResultsTotally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses.ConclusionsEribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed.
Highlights
This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulinliposomal formulation in patients with advanced solid tumours
Eribulin has a novel mode of action that distinguishes it from other tubulin-targeted drugs, including vinca alkaloids: it leads to irreversible mitotic blockade by binding to a small number of high-affinity sites on growing ends of microtubules to inhibit their growth, without having a measurable effect on microtubule shortening.[1,2,4]
Patient disposition and demographics The study was conducted between 11 December 2012 and 16 May 2016 at four sites in the United Kingdom
Summary
This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulinliposomal formulation (eribulin-LF) in patients with advanced solid tumours. Primary objectives: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF. The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses. Eribulin is approved as a monotherapy for patients with metastatic breast cancer (MBC) who have previously been treated with at least 2 (in the United States) or 1 (in Europe) prior chemotherapeutic regimens, including an anthracycline and a taxane, in either adjuvant or metastatic settings.[6,7,8] in a phase 3 clinical trial of patients with advanced liposarcoma or leiomyosarcoma, eribulin significantly prolonged overall survival compared with dacarbazine, and eribulin is approved for unresectable or metastatic liposarcoma in patients who have already received an anthracycline-containing regimen.[7,8,9]
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