Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors

M. Koczywas, P. H. Frankel, T. W. Synold, H. J. Lenz, J. E. Mortimer, A. B. El-Khoueiry, David R Gandara, M. C. Cristea, V. M. Chung, D. Lim, K. L. Reckamp, Derick H Lau, L. A. Doyle, C. Ruel, M. I. Carroll, E. M. Newman

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background:Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.Methods:Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m<sup>-2</sup> and CP 60-75 mg m<sup>-2</sup>. Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m<sup>-2</sup>, CP 60 mg m<sup>-2</sup>) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.Results:On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); G 3 anorexia/fatigue/hypokalemia (1.2 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); G 4 mucositis (1.4 mg m<sup>-2</sup>, 60 mg m<sup>-2</sup>); and G 3 hypokalemia (1.2 mg m<sup>-2</sup>, 75 mg m<sup>-2</sup>). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m<sup>-2</sup> (days 1, 8) and CP 75 mg m<sup>-2</sup> (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).Conclusions:On the 21-day cycle, eribulin mesylate 1.2 mg m<sup>-2</sup>, administered on days 1 and 8, in combination with CP 75 mg m<sup>-2</sup>, administered on day 1 is well tolerated and showed preliminary anticancer activity.

Original languageEnglish (US)
Pages (from-to)2268-2274
Number of pages7
JournalBritish Journal of Cancer
Volume111
Issue number12
DOIs
StatePublished - Dec 9 2014

Keywords

  • advanced solid tumours
  • cisplatin
  • eribulin mesylate (E7389)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Koczywas, M., Frankel, P. H., Synold, T. W., Lenz, H. J., Mortimer, J. E., El-Khoueiry, A. B., Gandara, D. R., Cristea, M. C., Chung, V. M., Lim, D., Reckamp, K. L., Lau, D. H., Doyle, L. A., Ruel, C., Carroll, M. I., & Newman, E. M. (2014). Phase i study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors. British Journal of Cancer, 111(12), 2268-2274. https://doi.org/10.1038/bjc.2014.554