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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 ⩾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 publication

DOI

10.1038/bjc.2017.36

Type

Journal article

Journal

Br J Cancer

Publication Date

28/03/2017

Volume

116

Pages

884 - 892

Keywords

Administration, Intravenous, Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Cisplatin, Cyclophosphamide, Dose-Response Relationship, Drug, Epirubicin, Female, Follow-Up Studies, Humans, Indoles, Male, Middle Aged, Neoplasm Staging, Neoplasms, Paclitaxel, Prognosis, Survival Rate, Tissue Distribution