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Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study

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Summary

Background The aim of this phase I study was to determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of orally administered olaparib (AZD2281) in combination with topotecan in patients with advanced solid tumors. Patients and methods Patients aged ≥18 years with histologically or cytologically diagnosed advanced solid tumors for whom no suitable effective therapy exists were included. Patients in four cohorts received topotecan (0.5 mg/m2/day × 3 days or 1.0 mg/m2/day × 3 days) intravenously in combination with oral olaparib 50, 100 or 200 mg bid for six cycles. The primary objectives were to determine the safety and tolerability and to establish the MTD of olaparib in combination with topotecan. Results Twenty-one patients were enrolled and 19 received treatment. Dose-limiting toxicities were neutropenia and thrombocytopenia. The MTD was established as topotecan 1.0 mg/m2/day × 3 days plus olaparib 100 mg bid. The most common adverse events (AEs) included fatigue and gastrointestinal events. There was an olaparib and topotecan dose-related increase in neutropenia which was dose limiting. Conclusions Further development of olaparib and topotecan in combination was not explored due to dose-limiting hematological AEs and the resulting sub-therapeutic MTD.

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Acknowledgements

We thank Dr Juliet Fawcett from Mudskipper who provided editorial assistance funded by AstraZeneca. This study was funded by AstraZeneca.

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Authors and Affiliations

  1. St George’s Hospital, Blackshaw Rd, London, UK

    Jens Samol

  2. Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK

    Malcolm Ranson

  3. Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK

    Edwina Scott & Anne Thomas

  4. AstraZeneca, Alderley Park, Macclesfield, UK

    Euan Macpherson & James Carmichael

  5. The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN, UK

    James Cassidy

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  1. Jens Samol
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  2. Malcolm Ranson
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  3. Edwina Scott
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  4. Euan Macpherson
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  5. James Carmichael
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  6. Anne Thomas
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  7. James Cassidy
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Correspondence to James Cassidy.

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Anne Thomas and James Cassidy are joint senior authors.

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Samol, J., Ranson, M., Scott, E. et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs 30, 1493–1500 (2012). https://doi.org/10.1007/s10637-011-9682-9

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  • DOI: https://doi.org/10.1007/s10637-011-9682-9

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