Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors.

Abstract

1009 Background: Olaparib (AZD2281) is an oral PARP inhibitor active in advanced ovarian and breast cancers. We conducted a multicenter, dose-finding study assessing safety/ tolerability of olaparib capsules plus cisplatin in patients (pts) with advanced solid tumors (NCT00782574), for potential use in the neoadjuvant setting. Methods: Pts received 21-day(d) cycles of olaparib, continuously (Cont) or intermittently (Int), plus cisplatin on d1 of each cycle.Each cohort recruited ≥3 evaluable pts with expansion to ≥6 pts if ≥1 had a dose-limiting toxicity. The last cohort was expanded to ensure ≥6 pts completed 4 treatment cycles. Pts who completed 6 combined therapy cycles or who stopped cisplatin due to cisplatin-related toxicity could enter the monotherapy phase (up to 400 mg BID olaparib). Primary objective: safety/ tolerability of ≥4 combined cycles; secondary objectives: pharmacokinetics, antitumor activity. Results: 54 pts received treatment; pts had breast (n=42), ovarian (n=10), pancreatic (n=1) or peritoneal (n=1) cancer. Median number of prior regimens = 4 (1–13). C2, C4 and C6 enrolled >6 pts. Most common grade (G) 3/4 AEs: neutropenia (n=9; 16.7%), leukopenia (n=4; 7.4%), anemia (n=3; 5.6%), vomiting (n=3; 5.6%). In C1–C5, 3 pts had AEs leading to discontinuation: 1 in C2 (thrombocytopenia); 2 in C3 (fatigue; complex migraine, dyspnea). In C6, all pts have ended combination phase and no G3/4 hematologic AEs were seen. Overall, 46% of pts had a dose reduction; 32% due to hematologic AEs. There were no drug-related deaths. 35 pts (65%) completed ≥4 combined cycles (C6, n=8). 18/54 evaluable pts (33%) had an objective response (complete, n=1; partial, n=17); 23 (43%) achieved stable disease. 7 pts (13%) had durable responses on monotherapy for ≥1 year. PK and BRCA1/2 data will be presented. Conclusions: Hematologic AEs led to dose reductions + schedule changes of olaparib with cisplatin 75 mg/m2. Tolerability improved with cisplatin 60 mg/m2. Antitumor activity was seen during combination and olaparib monotherapy phases, with some long responders. [Table: see text]