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Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours

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Abstract

Purpose

Trametinib is a reversible, selective inhibitor of the mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and 2 (MEK2). Cardiotoxicity (congestive heart failure, decreased heart rate, left ventricular dysfunction, and hypertension) related to trametinib is an infrequent, but serious, adverse event (AE). Prolongation of the QT interval increases the risk of life-threatening cardiac arrhythmia. Thus, the risk of trametinib inducing QT prolongation at putative supratherapeutic exposure was evaluated.

Methods

Eligible patients with solid tumours received placebo on day 1, once-daily trametinib 2-mg doses on days 2–14, and a single trametinib 3-mg dose on day 15 to achieve supratherapeutic dosing for QTc measurement. Electrocardiogram was assessed by 12-lead ambulatory 24-h Holter monitoring pre-dose, and on day 1 and day 15. Pharmacokinetic (PK) and pharmacodynamics (PD) parameters were measured.

Results

Thirty-two of 35 patients completed the study. There was no effect of trametinib when compared with time-matched placebo on the change from baseline in QTcF, QTcB, or QTcI interval. Mean AUC0–24 and C max following trametinib 2-mg repeat doses were 364 ng.h/mL and 22.9 ng/mL, respectively; the corresponding values for the 3-mg dose were 454 ng.h/mL and 29.2 ng/mL. Median T max was approximately 2 h for both doses. Statistical analysis and PK/PD modelling showed no significant relationship between QTcF interval and trametinib plasma concentrations. AEs were consistent with those reported previously. No electrocardiogram abnormalities were reported as AEs.

Conclusions

The results of this study suggest trametinib has no significant effect on QT prolongation at supratherapeutic exposure.

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Acknowledgments

We thank the patients who participated in this study and all of the personnel involved in patient care and data collection. The authors wish to acknowledge the following individuals for their contribution and critical review during development of this manuscript: Bijoyesh Mookerjee, Anny Chen, and Stanley Carson. Financial support for medical editorial assistance was provided by Novartis Oncology. We also thank Heather Edens, Ph.D. (ArticulateScience, LLC, Hamilton, NJ), for her medical editorial assistance with this manuscript.

Funding

This study was sponsored by GlaxoSmithKline; however, as of 2 March 2015, trametinib became an asset of Novartis AG.

Author information

Author notes

  1. John W. Bauman

    Present address: Quinitles, 4820 Emperor Boulevard, Durham, NC, 27703, USA

  2. Donna S. Cox

    Present address: Teva Pharmaceuticals Industries, Ltd., 1090 Horsham Road, North Wales, PA, 19454, USA

Authors and Affiliations

  1. South Texas Accelerated Research Therapeutics (START), 4383 Medical Drive, San Antonio, TX, 78229, USA

    Amita Patnaik, Anthony Tolcher, Kyriakos P. Papadopoulos, Murali Beeram & Drew Rasco

  2. Huntsman Cancer Institute, 2000 Circle of Hope Drive, Salt Lake City, UT, 84112, USA

    Theresa L. Werner & Sunil Sharma

  3. GlaxoSmithKline, Research Triangle Park, NC, 27709, USA

    John W. Bauman

  4. MedImmune, 1 Medimmune Way, Gaithersburg, MD, 20878, USA

    Anita Scheuber

  5. GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA, 19426, USA

    Donna S. Cox, YanYan Zhou, Mohammed Hamid & Daniel Schramek

  6. GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA, USA

    Bela R. Patel

Authors
  1. Amita Patnaik
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  2. Anthony Tolcher
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  7. John W. Bauman
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  10. Bela R. Patel
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  12. Mohammed Hamid
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Corresponding author

Correspondence to Amita Patnaik.

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Conflict of interest

TLW reports no competing interests; KPP, MB, and SS received research funding from GlaxoSmithKline for the submitted work; AP received research funding to their institution from GlaxoSmithKline; AT and DR received research funding to their institution from Merck. JWB, AS, DSC, BRP, YZ, MH, and DS were employees of GlaxoSmithKline in the previous 3 years (at the time this study was conducted); DSC owned stock in GlaxoSmithKline in the previous 3 years; SS participated in an advisory board for GlaxoSmithKline. There are no other relationships or activities that could appear to have influenced the submitted work.

Research involving human participants

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

Informed consent

Written informed consent was obtained from each patient prior to performance of any study-specific procedures.

Electronic supplementary material

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280_2016_3090_MOESM1_ESM.pdf

Supplementary material 1 Supplement Fig. 1 Visual predictive check goodness-of-fit plots by dose group. A total of 500 simulations were performed with the final pharmacokinetic/pharmacokinetic parameters for (A) placebo, (B) trametinib 2 mg, and (C) trametinib 3 mg to compare the distribution of simulated QTcF intervals with that of the observed data. The majority of observed data fell within the range between the 5th and 95th percentiles of the simulated values (grey zones), indicating that the final model sufficiently describes the observed QTcF data. QTcF, QT interval corrected for heart rate by the Fridericia formula (PDF 918 kb)

Supplementary material 2 (DOCX 13 kb)

Supplementary material 3 (DOCX 11 kb)

Supplementary material 4 (DOCX 12 kb)

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Patnaik, A., Tolcher, A., Papadopoulos, K.P. et al. Phase 1 study to evaluate the effect of the MEK inhibitor trametinib on cardiac repolarization in patients with solid tumours. Cancer Chemother Pharmacol 78, 491–500 (2016). https://doi.org/10.1007/s00280-016-3090-y

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  • DOI: https://doi.org/10.1007/s00280-016-3090-y

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