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Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1)

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Summary

Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and preliminary efficacy of olaparib combined with carboplatin and/or paclitaxel. Methods Patients with advanced solid tumors received olaparib (capsule bid) plus carboplatin (Part A), carboplatin and paclitaxel (Part B), or paclitaxel (Part C). In each part of the study, different drug doses were given to define the most appropriate dose/drug combination to use in further studies. Safety assessments included evaluation of dose-limiting toxicities (DLTs; cycle 1 only), adverse events (AEs) and physical examinations. PK assessments of olaparib, carboplatin and paclitaxel were performed. Tumor responses (RECIST) were assessed every two cycles. Results Fifty-seven patients received treatment. DLTs were reported in two patients (both receiving olaparib 100 mg bid and carboplatin AUC 4; Part A, cohort 2): grade 1 thrombocytopenia with grade 2 neutropenia lasting for 16 days, and grade 2 neutropenia lasting for 7 days. Non-hematologic AEs were predominantly grade 1–2 and included fatigue (70%) and nausea (40%). Bone marrow suppression, mainly neutropenia (51%) and thrombocytopenia (25%), frequently led to dose modifications. Conclusions Olaparib in combination with carboplatin and/or paclitaxel resulted in increased hematologic toxicities, making it challenging to establish a dosing regimen that could be tolerated for multiple cycles without dose modifications.

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Acknowledgements

This study was sponsored by AstraZeneca. Editorial assistance was provided by Claire Routley PhD from 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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  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, Martijn P. Lolkema, Andre T. Brunetto, Hendrik-Tobias Arkenau & Johann S. de Bono

  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 Science s (UIPS), Utrecht University, Domplein 29, 3512, JE, Utrecht, The Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

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Ilian Tchakov was an employee of AstraZeneca at the time of this study.

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van der Noll, R., Jager, A., Ang, J.E. et al. Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1). Invest New Drugs 38, 1117–1128 (2020). https://doi.org/10.1007/s10637-019-00856-7

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