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

van der Noll, R; Jager, A; Ang, JE; Marchetti, S; Mergui-Roelvink, MWJ; de Bono, JS; Lolkema, MP; ... Schellens, JHM; + view all (2020) Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2). Investigational New Drugs , 38 pp. 1096-1107. 10.1007/s10637-019-00857-6. Green open access

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Abstract

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).

Type: Article
Title: Phase I study of intermittent olaparib capsule or tablet dosing in combination with carboplatin and paclitaxel (part 2)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s10637-019-00857-6
Publisher version: https://doi.org/10.1007/s10637-019-00857-6
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Olaparib, Carboplatin, Paclitaxel, PARP inhibitor, Pharmacokinetics, Phase I
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10092958
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