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Clinical Trial
. 2019 Feb;120(4):379-386.
doi: 10.1038/s41416-019-0377-x. Epub 2019 Jan 25.

Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours

T R Jeffry Evans  1   2 , Emma Dean  3 , L Rhoda Molife  4 , Juanita Lopez  4 , Malcolm Ranson  3 , Fatima El-Khouly  5 , Ishtiaq Zubairi  6 , Claudio Savulsky  7 , Larisa Reyderman  8 , Yan Jia  8 , Lorna Sweeting  6 , Alastair Greystoke  9 , Jorge Barriuso  3 , Rebecca Kristeleit  5
Affiliations
Clinical Trial

Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours

T R Jeffry Evans et al. Br J Cancer. 2019 Feb.

Abstract

Background: This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours.

Methods: Eligible 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.

Results: Totally, 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.

Conclusions: Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed.

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Conflict of interest statement

T.R.J.E.: honoraria from Bristol-Myers Squibb and Eisai; participated in speaker’s bureau for Bristol-Myers Squibb, Eisai and Celgene; paid consultancy from Bristol-Myers Squibb, Eisai, Celgene and Karus Therapeutics; received research funding from Astra Zeneca, Celgene, Eisai, GlaxoSmithKline, Roche, Ono, Bristol-Myers Squibb, Eli Lily, Basilea, Vertex, Merck, Daiichi Sankyo, Nutide, Sierra, Immunocore Verastem; expenses paid by Bristol-Myers Squibb; Subject Editor of the British Journal of Cancer. E.D.: research fees from The Christie NHS Foundation; employee of AstraZeneca with stock options; Independent Safety Physician for Theradex CRO; participated in advisory board for Aptus Clinical Limited. J.L.: paid consultancy for Merck and Eisai. M.R.: financial support from Eisai. C.S.: employee of Eisai. L.R.: employee of Eisai. Y.J.: employee of Eisai. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Pharmacokinetic profile of eribulin-LF. Mean plasma concentration–time curves of eribulin by dose of eribulin-LF on a linear scale and log-linear scale (a) and individual AUC versus eribulin-LF dose in Schedule 1 and Schedule 2 (b)—patients with DLTs are highlighted in red. AUC(I) area under the curve (infinity), DLT dose-limiting toxicity, LF liposomal formulation
Fig. 2
Fig. 2
Waterfall plot displaying maximum percentage change from baseline in sums of lesion diameters in patients with breast, ovarian or endometrial cancers from the dose-expansion phase (Schedule 2). *Patients who achieved a partial response (PR)
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