A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

Wilson, R. H. et al. (2017) A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. British Journal of Cancer, 116(884), (doi: 10.1038/bjc.2017.36) (PMID:28222073)

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Background: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours. Methods: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1–14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles. Results: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1–7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade greater than or equal to3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml−1 min−1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers. Conclusions: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).

Item Type:Articles
Glasgow Author(s) Enlighten ID:Evans, Professor Jeff and Roxburgh, Dr Patricia
Authors: Wilson, R. H., Evans, T.R. J., Middleton, M. R., Molife, L. R., Spicer, J., Dieras, V., Roxburgh, P., Giordano, H., Jaw-Tsai, S., Goble, S., and Plummer, R.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:British Journal of Cancer
Publisher:Nature Publishing Group
ISSN (Online):1532-1827
Published Online:21 February 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in British Journal of Cancer 116:884-892
Publisher Policy:Reproduced under a Creative Commons License

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