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Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2)

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Summary

Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients with advanced solid tumors (part D) and enriched for ovarian and breast cancer (part E) received olaparib (capsule and tablet formulations) using intermittent schedules (2 to 10 days of a 21-day cycle) combined with carboplatin/paclitaxel. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs), and physical examinations. Pharmacokinetic assessments of olaparib capsule and tablet combined with carboplatin/paclitaxel were performed. Tumor responses (RECIST) were assessed every 2 cycles. Results In total, 132 heavily pre-treated patients were included. One DLT of grade 3 elevated alanine aminotransferase lasting for 8 days was reported (olaparib tablet 100 mg bid days 3–12, carboplatin area under the curve 4 and paclitaxel 175 mg/m2). The most common hematological AEs were neutropenia (47%) and thrombocytopenia (39%), which frequently led to dose modifications. Non-hematological AEs were predominantly grade 1–2, including alopecia (89%) and fatigue (84%). Overall objective response rate was 46%. Conclusions Discontinuous dosing of olaparib resulted in significant myelosuppression leading to dose interruptions and/or delays. Anti-tumor activity was encouraging in patients enriched with BRCA-mutated breast and ovarian cancer. The most appropriate olaparib tablet dose for use in further studies evaluating olaparib in combination with carboplatin and paclitaxel is 50 mg bid (days 1–5).

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Acknowledgements

Nigel Baker of AstraZeneca is acknowledged for his support with the statistical analysis of this study. Editorial assistance was provided by Claire Routley, PhD, of Mudskipper Business Ltd., funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD).

Funding

This study was funded by AstraZeneca.

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Author notes

  1. Ilian Tchakov

    Present address: Eisai, Mosquito Way, Hatfield, AL10 9SN, UK

Authors and Affiliations

  1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Ruud van der Noll, Serena Marchetti, Marja W. J. Mergui-Roelvink & Jan H. M. Schellens

  2. Department of Medical Oncology, Erasmus University MC Cancer Institute, PO Box 5201, 3008 AE, Rotterdam, The Netherlands

    Agnes Jager, Martijn P. Lolkema, Maja J. A. de Jonge & Diane A. van der Biessen

  3. The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Downs Road, Sutton, Surrey, SM2 5PT, UK

    Joo Ern Ang, Johann S. de Bono, Martijn P. Lolkema, Andre T. Brunetto & Hendrik-Tobias Arkenau

  4. AstraZeneca, Alderley Park, Park Estate, Macclesfield, SK10 4TF, UK

    Ilian Tchakov

  5. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Jos H. Beijnen

  6. Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Domplein 29, 3512 JE, Utrecht, The Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

  7. Department of Medical Oncology, Oncologisch Centrum UZ Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090, Jette, Belgium

    Jacques De Grève

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  1. Ruud van der Noll
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Corresponding author

Correspondence to Ruud van der Noll.

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Conflict of interest

Ilian Tchakov was an employee of AstraZeneca at the time of this study. The other authors have no conflicts of interest.

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. The study was performed in accordance with the Good Clinical Practice and the AstraZeneca policy on Bioethics.

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All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and all applicable laws and regulations.

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

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van der Noll, R., Jager, A., Ang, J.E. et al. Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2). Invest New Drugs 38, 1096–1107 (2020). https://doi.org/10.1007/s10637-019-00857-6

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