A phase I study of oral rucaparib in combination with carboplatin.

2586 Background: Targeting poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA damage repair, may increase efficacy of DNA-damaging agents. This study evaluated the tolerability of oral rucaparib, a potent and selective PARP1/2 inhibitor, in combination with carboplatin (CP). Methods: Patients (pts) aged ≥18 with advanced solid tumors were included. Pts received lead-in doses of IV and oral rucaparib on Days -10 and -5, respectively, followed by CP on Day 1 and oral rucaparib on Days 1-14 q21 days. Treatment continued until disease progression. Pts with benefit could continue on rucaparib monotherapy once CP dosing was completed. Dose escalation was based on toxicities observed in Cycle 1 in cohorts of n=3-6. PK was assessed during Cycle 1. Results: 23 pts (median age 62 yrs [range 20 – 76]; 16 female; 9 ECOG PS=0; 6 ovarian/peritoneal cancer (OC), 5 breast cancer (BC), 2 NSCLC, 10 other tumor) were enrolled. Rucaparib doses of 80, 120, 180, 240, and 360 mg were administered with AUC3 CP, followed by 360 mg rucaparib with AUC4 CP, and currently with AUC5 CP. No DLTs have been reported. Median treatment cycles is 3 (range 1 – 15+). Treatment-related adverse events in ≥4 pts, all grades, include anemia (n=10), fatigue (n=9), nausea (n=7), thrombocytopenia (n=6), constipation (n=5), lethargy (n=5), neutropenia (n=5), and anorexia (n=4). One pt (OC, BRCAwt, AUC3 CP/180 mg rucaparib) had a PR of 5.1 mo duration. Two patients (both with OC; 1 BRCAunk, 1BRCAwt) discontinued CP (after 4 & 8 cycles) and continued on rucaparib monotherapy (additional 5 and 7+ cycles, respectively). An additional 4 pts (all BRCAunk) had stable disease (SD) >12 wks. Overall disease control rate (CR+PR+SD>12 wks) in OC pts across all dose levels was 50% (3/6). Dose-proportional increase in rucaparib exposure was observed with steady state achieved by Day 14 and mean t1/2of 15 h. Oral bioavailability was 38% and dose-independent. Rucaparib exposure was not changed by CP co-administration. Conclusions: The combination of oral rucaparib and CP is well tolerated and exhibits activity at clinically relevant doses of each agent. Further studies in platinum-sensitive and homologous recombination repair deficient populations are warranted. Clinical trial information: NCT01009190.