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A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors

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Summary

Background Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. Methods In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m2; Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. Results Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. Conclusion Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

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Acknowledgments

We would like to thank all of the patients, and the investigators and their teams, who participated in these studies. We also thank Biotrial (Rennes, France), which provided logistical support for this study, and Varinia Munoz, PhD, from Complete Medical Communications, who provided medical writing support funded by Eisai Inc.

Disclosures

L. Reyderman and A. Kristensen are employees of Eisai Inc. and K. Law is an employee of Eisai Ltd. At the time of study, J. Wanders and G. Edwards were employees of Eisai Ltd. T. Lesimple has received research funding from Roche and Bristol-Myers Squibb, and has acted as a consultant for Roche. B. Darpo has acted as a consultant for Mangan AB. J. Edeline, T.J. Carrothers, F. Cvitkovic, J. P. Delord, H. Léna and N. Penel have no potential conflicts of interest to disclose.

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Authors and Affiliations

  1. Clinical Research Unit, Medical Oncology Department, Comprehensive Cancer Center Eugène Marquis, CS 44229, 35042, Rennes Cedex, France

    Thierry Lesimple & Julien Edeline

  2. Biotrial, Rennes, France

    Thierry Lesimple

  3. Pharsight, Sunnyvale, CA, USA

    Timothy J. Carrothers

  4. Hôpital René Huguenin, Institut Curie, Saint-Cloud, France

    Frédérique Cvitkovic

  5. Department of Clinical Science and Education, Section of Cardiology, Karolinska Institute, South Hospital, Stockholm, Sweden

    Borje Darpo

  6. Institut Claudius Regaud, Toulouse, France

    Jean-Pierre Delord

  7. Service de Pneumologie, Centre Hospitalier Universitaire, Rennes, France

    Hervé Léna

  8. Centre Oscar Lambret, Lille, France

    Nicolas Penel

  9. Eisai Ltd, Hatfield, UK

    Geoff J. Edwards, Kenneth Law & Jantien Wanders

  10. Eisai Inc, Woodcliff Lake, NJ, USA

    Allan Kristensen & Larisa Reyderman

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  1. Thierry Lesimple
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  2. Julien Edeline
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  13. Larisa Reyderman
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Correspondence to Thierry Lesimple.

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Financial support

This study was funded by Eisai Inc.

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Lesimple, T., Edeline, J., Carrothers, T.J. et al. A phase I, open-label, single-arm study for QT assessment of eribulin mesylate in patients with advanced solid tumors. Invest New Drugs 31, 900–909 (2013). https://doi.org/10.1007/s10637-012-9893-8

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  • DOI: https://doi.org/10.1007/s10637-012-9893-8

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