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

van der Noll, R; Jager, A; Ang, JE; Marchetti, S; Mergui-Roelvink, MWJ; Lolkema, MP; de Jonge, MJA; ... Schellens, JHM; + view all (2020) Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1). Investigational New Drugs , 38 pp. 1117-1128. 10.1007/s10637-019-00856-7. Green open access

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Abstract

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. 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.

Type: Article
Title: Phase I study of continuous olaparib capsule dosing in combination with carboplatin and/or paclitaxel (Part 1)
Open access status: An open access version is available from UCL Discovery
DOI: 10.1007/s10637-019-00856-7
Publisher version: https://doi.org/10.1007/s10637-019-00856-7
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/10092957
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