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    Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer

    Access Status
    Open access via publisher
    Authors
    Dent, R.
    Lindeman, G.
    Clemons, M.
    Wildiers, H.
    Chan, Arlene
    McCarthy, N.
    Singer, C.
    Lowe, E.
    Watkins, C.
    Carmichael, J.
    Date
    2013
    Type
    Journal Article
    
    Metadata
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    Citation
    Dent, R. and Lindeman, G. and Clemons, M. and Wildiers, H. and Chan, A. and McCarthy, N. and Singer, C. et al. 2013. Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancer. Breast Cancer Research. 15 (5).
    Source Title
    Breast Cancer Research
    DOI
    10.1186/bcr3484
    ISSN
    1465-5411
    School
    Centre for Population Health Research
    URI
    http://hdl.handle.net/20.500.11937/14874
    Collection
    • Curtin Research Publications
    Abstract

    Introduction: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC). Methods: Eligible patients who had received =1 prior cytotoxic regimen for mTNBC were treated with olaparib 200 mg bid continuously plus weekly paclitaxel 90 mg/m2 for three weeks per four-week cycle. Dose modifications in a large proportion of patients due to neutropenia resulted in enrollment of a second cohort of patients who, if they experienced grade =2 neutropenia in cycle 1, received granulocyte-colony stimulating factor, which was continued prophylactically in subsequent cycles. All patients had measurable disease; tumor responses were evaluated according to RECIST (version 1.0). Results:Nineteen patients (cohort 1, n = 9; cohort 2, n = 10) received treatment; 15 had received prior taxane chemotherapy. The most frequent adverse events were diarrhea (n = 12, 63%), nausea (n = 11, 58%) and neutropenia (n = 11, 58%). Seven neutropenia events were reported in cohort 1 (four grade =3) and four in cohort 2 (two grade =3, including one event of febrile neutropenia). The median (range) dose intensity of paclitaxel was 57% (26 to 100%) in cohort 1 and 73% (29 to 100%) in cohort 2. Seven patients (37%) had a confirmed partial response; one patient remains on olaparib monotherapy without progression. Conclusions: The combination of olaparib and weekly paclitaxel was complicated by a significant clinical interaction, with higher-than-expected rates of neutropenia despite secondary prophylaxis. Given the encouraging response rate, alternative scheduling and dosing strategies should be considered (funded by AstraZeneca; ClinicalTrials.gov, NCT00707707). © 2013 Dent et al.; licensee BioMed Central Ltd.

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