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

TY - JOUR

T1 - A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

AU - Wilson, Richard H

AU - Evans, Tr Jeffry

AU - Middleton, Mark R

AU - Molife, L Rhoda

AU - Spicer, James

AU - Dieras, Veronique

AU - Roxburgh, Patricia

AU - Giordano, Heidi

AU - Jaw-Tsai, Sarah

AU - Goble, Sandra

AU - Plummer, Ruth

PY - 2017/3/28

Y1 - 2017/3/28

N2 - 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).British Journal of Cancer advance online publication 21 February 2017; doi:10.1038/bjc.2017.36 www.bjcancer.com.

AB - 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).British Journal of Cancer advance online publication 21 February 2017; doi:10.1038/bjc.2017.36 www.bjcancer.com.

U2 - 10.1038/bjc.2017.36

DO - 10.1038/bjc.2017.36

M3 - Article

C2 - 28222073

SN - 0007-0920

SP - 884

EP - 892

JO - BJC: British Journal of Cancer

JF - BJC: British Journal of Cancer

ER -