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Trabectedin has a low cardiac risk profile: a comprehensive cardiac safety analysis

Cancer Chemotherapy and Pharmacology volume 68, pages 1223–1231 (2011)Cite this article

Abstract

Purpose

This analysis provides a cross-study evaluation of the cardiac safety of trabectedin.

Methods

Drug-related cardiac adverse events (CAEs) were retrieved from phase I–III clinical trials, pharmacovigilance databases, and spontaneously reported cases. Left ventricular ejection fraction (LVEF) was monitored in combination phase I studies with doxorubicin or pegylated liposomal doxorubicin (PLD) and in a phase III trial (with PLD).

Results

CAEs [grade 4 cardiac arrest with severe pancytopenia and sepsis (n = 1 patient), grade 4 atrial fibrillation (n = 2), and grade 1 tachycardia (n = 1)] occurred in 4/283 patients (1.4%) in 6 single-agent phase I trials. CAEs (grade 1 sinus tachycardia in a hypertensive patient and grade 1 ventricular dysfunction) occurred in 2/155 patients (1.3%) in 4 phase I combination trials. Results from 19 single-agent phase II trials showed CAEs in 20/1,132 patients (1.8%): arrhythmias (tachycardia/palpitations; n = 13; 1.1%) were the most common. A rather similar rate of symptomatic CAEs was observed in both arms of a phase III trial in recurrent ovarian cancer: 6/330 patients (1.8%; PLD) and 11/333 patients (3.3%; trabectedin/PLD). No clinically relevant LVEF changes occurred in phase I combination trials. In the phase III trial, LVEF decreases from baseline were similar: 9% of patients (PLD) and 7% (trabectedin/PLD), with no relevant symptoms. During postmarketing experience in soft tissue sarcoma (2,046 patients treated), 4 CAEs (2 cardiac arrest, 2 cardiac failure; ~0.2%) occurred in patients with preexisting conditions.

Conclusions

Trabectedin has a low incidence of CAEs, consisting mainly of arrhythmias. This extensive data review indicates a low cardiac risk profile for trabectedin.

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Fig. 1

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Acknowledgments

The authors would like to acknowledge the patients and their families for their participation in the clinical trials, and the investigators, nurses, and clinical staff that participated in clinical trials for their contribution in trabectedin development.

Conflict of interest

C. Lebedinsky, J. Gómez, A. Nieto, A. Soto-Matos, V. Alfaro, E.Roy, P.Lardelli and C. Kahatt are employees of PharmaMar and stock ownership. Youn. C. Park and Trilok Parekh are employees of Johnson and Johnson Pharmaceutical Research and Development and stock ownership.

Author information

Affiliations

  1. PharmaMar, Colmenar Viejo, Madrid, Spain

    Claudia Lebedinsky, Javier Gómez, Antonio Nieto, Arturo Soto-Matos, Vicente Alfaro, Elena Roy, Pilar Lardelli & Carmen Kahatt

  2. Johnson and Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ, USA

    Youn C. Park & Trilok Parekh

  3. Pharma Mar S.A.U., Parc Científic de Barcelona, Torre D, c/Baldiri i Reixac, 4-6, 08028, Barcelona, Spain

    Vicente Alfaro

Authors
  1. Claudia Lebedinsky
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  2. Javier Gómez
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  3. Youn C. Park
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  4. Antonio Nieto
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  5. Arturo Soto-Matos
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  7. Vicente Alfaro
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  8. Elena Roy
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  9. Pilar Lardelli
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  10. Carmen Kahatt
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Corresponding author

Correspondence to Vicente Alfaro.

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Lebedinsky, C., Gómez, J., Park, Y.C. et al. Trabectedin has a low cardiac risk profile: a comprehensive cardiac safety analysis. Cancer Chemother Pharmacol 68, 1223–1231 (2011). https://doi.org/10.1007/s00280-011-1614-z

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  • DOI: https://doi.org/10.1007/s00280-011-1614-z

Keywords

  • Trabectedin
  • Cardiac events
  • Safety
  • Pharmacovigilance