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

Ruud van der Noll*, Agnes Jager, Joo Ern Ang, Serena Marchetti, Marja W.J. Mergui-Roelvink, Martijn P. Lolkema, Maja J.A. de Jonge, Diane A. van der Biessen, Andre T. Brunetto, Hendrik Tobias Arkenau, Ilian Tchakov, Jos H. Beijnen, Johann S. de Bono, Jan H.M. Schellens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)1117-1128
Number of pages12
JournalInvestigational New Drugs
Volume38
Issue number4
DOIs
Publication statusPublished - 1 Aug 2020

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.

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