Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
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.

PubMed Disclaimer

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)
See this image and copyright information in PMC

References

    1. Jordan MA, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol. Cancer Ther. 2005;4:1086–1095. doi: 10.1158/1535-7163.MCT-04-0345. - DOI - PubMed
    1. Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol. Cancer Ther. 2008;7:2003–2011. doi: 10.1158/1535-7163.MCT-08-0095. - DOI - PMC - PubMed
    1. Smith JA, et al. Eribulin binds at microtubule ends to a single site on tubulin to suppress dynamic instability. Biochemistry. 2010;49:1331–1337. doi: 10.1021/bi901810u. - DOI - PMC - PubMed
    1. Dybdal-Hargreaves NF, Risinger AL, Mooberry SL. Eribulin mesylate: mechanism of action of a unique microtubule-targeting agent. Clin. Cancer Res. 2015;21:2445–2452. doi: 10.1158/1078-0432.CCR-14-3252. - DOI - PMC - PubMed
    1. Kawano S, Asano M, Adachi Y, Matsui J. Antimitotic and non-mitotic effects of eribulin mesilate in soft tissue sarcoma. Anticancer Res. 2016;36:1553–1561. - PubMed

Publication types