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The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors

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Abstract

Purpose

To evaluate the effect of lapatinib on the QTc interval and ECG parameters in patients with advanced solid tumors.

Methods

This was a multicenter, placebo-controlled study in subjects with advanced solid tumors. Subjects were administered two doses of matching placebo on day 1, 12 h apart and one dose in the morning on day 2. Two doses of lapatinib 2000 mg were administered orally on day 3, 12 h apart and one dose in the morning on day 4. Twelve-lead digital ECGs were extracted from continuous Holter recordings at pre-specified time points over the 24-h period on days 2 and 4. Venous blood samples for lapatinib concentrations were obtained immediately following the ECGs.

Results

A maximum mean baseline-adjusted, placebo time-matched increase in QTcF, (ddQTcF) in the evaluable, (EV) population (n = 37) of 8.8 ms (90% CI 4.1, 13.4) occurred approximately 10 h after the third lapatinib dose. These results were consistent with those in the pharmacodynamic, PD population, (n = 52) (ddQTcF = 7.9 ms; 90% CI 4.1, 11.7). No subject experienced QTcF increases from baseline of > 60 ms on lapatinib or placebo. The geometric mean lapatinib Cmax of 3902 ng/mL was observed at 3.6 h post-dose.

Conclusions

These data show a relevant, treatment-related increase in QTcF after treatment with three doses of lapatinib 2000 mg. This study confirms the need for caution in patients with solid tumors treated with lapatinib, and who are concomitantly receiving drugs that are strong CYP3A inhibitors and/or prolong the QTc.

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Acknowledgements

We thank our patients and their families without whom this study would not have been possible. We also wish to thank our colleague oncologists, research nurses and study coordinators at each study site.

Funding

Original funding for this study (NCT01328054) was provided by GlaxoSmithKline. As of March 2015 lapatinib is an asset of Novartis Pharmaceutical Corporation, the current sponsor of this study.

Author information

Author notes

  1. Shodeinde A. Coker

    Present address: Bristol-Myers Squibb, 3401, Princeton Pike, Lawrenceville, NJ, 08648, USA

  2. Herbert I. Hurwitz

    Present address: Genentech, 1 DNA Way MS 45-4B, South San Francisco, CA, 94080, USA

Authors and Affiliations

  1. Section of Clinical Pharmacology, Department of Medicine, The Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA

    Shodeinde A. Coker & Lionel D. Lewis

  2. Section of Hematology/Oncology, Department of Medicine, The Geisel School of Medicine at Dartmouth and The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA

    Shodeinde A. Coker & Lionel D. Lewis

  3. Division of Medical Oncology, Duke University Medical Center, 10 Bryan Searle Drive, Durham, NC, 27710, USA

    Herbert I. Hurwitz

  4. The Huntsman Cancer Center, University of Utah, 2000 Circle of Hope, Suite 2125, Salt Lake City, UT, 84112, USA

    Sunil Sharma

  5. Henry Ford Hospital, Pallister Place, 2799 West Grand Boulevard, Detroit, MI, 48202, USA

    Ding Wang

  6. Novartis Pharma AG, 4002, Basel, Switzerland

    Pierre Jordaan & Juan Pablo Zarate

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  1. Shodeinde A. Coker
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Corresponding author

Correspondence to Lionel D. Lewis.

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Conflict of interest

SAC: Has declared no conflicts of interest regarding the conduct of this clinical trial or drafting the manuscript. HIH: Received research funding from GlaxoSmithKline, paid through Duke University Medical Center at the time of this work and drafting the manuscript. He is currently employed by Genentech/Roche and owns Roche stock. SS: Received research funding from GlaxoSmithKline/Novartis at the time of this work and has served on GlaxoSmithKline and Novartis Advisory Boards. DW: Has declared no conflicts of interest regarding the conduct of this clinical trial or drafting the manuscript. JPZ: Is employed by Novartis. LDL: Received research funding from GlaxoSmithKline/Novartis, paid through Dartmouth College to support the costs of this study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the participating institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Coker, S.A., Hurwitz, H.I., Sharma, S. et al. The effects of lapatinib on cardiac repolarization: results from a placebo controlled, single sequence, crossover study in patients with advanced solid tumors. Cancer Chemother Pharmacol 84, 383–392 (2019). https://doi.org/10.1007/s00280-019-03880-9

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