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Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial

  • PHASE III STUDIES
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Summary

Purpose Trabectedin is metabolized by the liver and has been associated with transient, noncumulative transaminase elevation. Two recent studies further characterize hepatic tolerability with trabectedin therapy: a phase 1 pharmacokinetic study (Study #1004; NCT01273493) in patients with advanced malignancies and hepatic impairment (HI), and a phase 3 study (Study #3007; NCT01343277) of trabectedin vs. dacarbazine in patients with advanced sarcomas and normal hepatic function. Methods In Study #1004, patients received a single 3-h intravenous (IV) infusion of trabectedin: control group, trabectedin 1.3 mg/m2; HI group (baseline total bilirubin >1.5 and ≤3× upper limit of normal [ULN]; AST and ALT ≤2.5× ULN), trabectedin 0.58 or 0.9 mg/m2. In Study #3007, the trabectedin group received 1.5 mg/m2 by 24-h IV infusion every 3 weeks until disease progression or unacceptable toxicity. Results In Study #1004, dose-normalized trabectedin exposure was higher in HI patients (n = 6) versus controls (n = 9) (geometric mean ratios [90% CI] AUClast: 1.97 [1.20; 3.22]). In Study #3007, following trabectedin administration, 90% of patients had elevated ALT (32% grade 3–4) and 84% had elevated AST (17% grade 3–4). Transaminase elevations were transient and noncumulative. Progression-free survival was similar in patients with grade 3–4 hepatotoxicity (n = 109) versus grade 0–2 hepatotoxicity (n = 231) (median [95% CI]: 4.63 [4.01, 5.85] months versus 3.55 [2.73, 4.63] months; P = 0.545, HR = 0.91 [0.68–1.23]). Conclusion Trabectedin treatment of patients with HI results in higher plasma exposures. Hepatotoxicity in patients with normal liver function can be effectively addressed through dose reductions and delays.

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Acknowledgments

The authors thank the patients for their participation in this study and acknowledge the collaboration and commitment of all investigators and clinical site staff for their participation in this study. The authors also thank Peter Zannikos, PhD, of Janssen Research & Development LLC (Raritan, NJ, USA) for supporting the development of the PK study design and Chi Fung Keung for involvement in the pharmacokinetic data analysis. This study was funded by Janssen Research & Development, LLC (Raritan, NJ, USA). Medical writing support for this manuscript was provided by Yvonne E. Yarker, PhD, ISMPP CMPP™ of InSeption (Lansdale, PA, USA), supported by Janssen Research & Development, LLC (Raritan, NJ, USA).

Funding

This study was funded by Janssen Research & Development, LLC, Raritan, NJ, USA.

Author information

Author notes

  1. Patricia LoRusso

    Present address: Yale Cancer Center, Yale University of Medicine, New Haven, CT, USA

  2. Lorrin Yee

    Present address: Vista Oncology, Olympia, WA, USA

Authors and Affiliations

  1. START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain

    Emiliano Calvo

  2. Molecular Therapeutics Research Unit, Department of Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

    Analia Azaro & Jordi Rodon

  3. Pharmacology Department, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Analia Azaro & Jordi Rodon

  4. Oncology Center GZA Hospitals Sint Augustinus, Translational Cancer Research Unit, Department of Medical Oncology, Antwerp, Belgium

    Luc Dirix

  5. Antwerp University Hospital, Antwerp, Belgium

    Manon Huizing

  6. Hem Onc Northwest PC, Tacoma, WA, USA

    Francis Mark Senecal

  7. Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Patricia LoRusso

  8. Northwest Medical Specialties PLLC, Tacoma, WA, USA

    Lorrin Yee

  9. Janssen-Cilag SpA, Cologno Monzese, Milan, Italy

    Italo Poggesi

  10. Janssen Research & Development, San Diego, CA, USA

    Jan de Jong

  11. Janssen Research & Development, Raritan, NJ, USA

    Spyros Triantos, Youn C. Park, Roland E. Knoblauch & Trilok V. Parekh

  12. Sarcoma Center and Ludwig Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    George D. Demetri

  13. Fox Chase Cancer Center, Philadelphia, PA, USA

    Margaret von Mehren

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  1. Emiliano Calvo
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Corresponding author

Correspondence to Emiliano Calvo.

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Conflict of interest

The following authors declare that they have no conflict of interest: Emiliano Calvo, Analia Azaro, Luc Dirix, Manon Huizing, Patricia LoRusso, Francis Mark Senecal, and Lorrin Yee.

Jordi Rodon: Member of Advisory Boards of Orion, Peptomyc, Novartis, Lilly, and Servier.

George D. Demetri: Research support from Bayer, Novartis, Pfizer, and Janssen Oncology; Consulting fees from Novartis, EMD-Serono, Sanofi Oncology, Janssen Oncology, PharmaMar, Daiichi-Sankyo, Adaptimmune, and Eisai; Patent licensed to Novartis from Dana-Farber Cancer Institute with royalty paid to Dana-Farber Cancer Institute; Blueprint Medicines Member, Board of Directors, Member, Scientific Advisory Board, consulting fees, and equity (minor stake, public).

Margaret von Mehren: Member of Janssen Advisory Board, and Scientific Steering Committee for the study in this report.

The following authors are Janssen/Johnson & Johnson employees: Italo Poggesi (and shareholder), Jan de Jong (and stock owner), Spyros Triantos (and shareholder), Youn C. Park, Roland E. Knoblauch (and stock owner), and Trilok V. Parekh (and shareholder).

Research involving human participants and/or animals

Ethical approval: 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.

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

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Calvo, E., Azaro, A., Rodon, J. et al. Hepatic safety analysis of trabectedin: results of a pharmacokinetic study with trabectedin in patients with hepatic impairment and experience from a phase 3 clinical trial. Invest New Drugs 36, 476–486 (2018). https://doi.org/10.1007/s10637-017-0546-9

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