A phase 1 study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumors.

Richard Wilson, Jeffery Evans, Mark Middleton, L Rhoda Molife, J. Spicer, V. Dieras, Patricia Roxburgh, H. Giordano, S. Jaw-Tsai , S. Goble, Ruth Plummer

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Abstract

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 3 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).
Original languageEnglish
Pages (from-to)884-892
Number of pages8
JournalBritish Journal of Cancer
Volume116
Issue number7
DOIs
Publication statusPublished - 01 Mar 2017

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    Wilson, R., Evans, J., Middleton, M., Molife, L. R., Spicer, J., Dieras, V., Roxburgh, P., Giordano, H., Jaw-Tsai , S., Goble, S., & Plummer, R. (2017). A phase 1 study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumors. British Journal of Cancer, 116(7), 884-892. https://doi.org/10.1038/bjc.2017.36