A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours
Middleton MR., Wilson RH., Jeffry Evans TR., Molife LR., Spicer J., Dieras V., Roxburgh P., Giordano H., Jaw-Tsai S., Goble S., Plummer R.
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. Doselimiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles. Results: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, 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 hours) 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)