Phase I trial of olaparib (PARP inhibitor) and vistusertib (mTORC1/2 inhibitor) in recurrent endometrial, ovarian and triple negative breast cancer.

Abstract

5504 Background: We sought to determine the recommended phase II dose (RP2D) of olaparib (O) and vistusertib (V) and evaluate molecular markers of response. Methods:Two oral schedules for V were explored with O tablet BID. Arm 1: BID continuous (5 dose levels (DL)) and Arm 2: BID 2 days on/5 days off (4 DL). Clinical benefit rate (CBR) was defined as objective response or stable disease ≥ 6 cycles by RECIST 1.1. Patients (pts) were evaluable for response if they received at least 1 cycle (28 days). An expansion phase (n = 30) was performed at RP2D of Arm 2 with biopsies at baseline and 28 days. Results: 74 pts were enrolled, 8 with BRCA mutation (11%). Median prior therapies was 4 (1-8). There were 2 DLTs on Arm 1 at DL 5 (O 300mg/V 50mg; G4 thrombocytopenia, G3 allergic reaction). There were 3 DLTs on Arm 2. 2 DLTs at DL 1 (O 100mg/V 125mg; G3 neutropenia > 7 days (n = 1); G3 hyperglycemia (n = 1)) and 1 DLT at DL1b (O 200mg/V 100mg; G3 fatigue). RP2D of Arm 1 was O 200mg/V 50mg. RP2D of Arm 2 was O 300mg/V 100mg. Most common adverse events (≥20%) were nausea (84%, G3/4 4%), anemia (83%, G3/4 15%), hyperglycemia (76%, G3/4 3%), fatigue (73%, G3/4 11%), leukopenia (55%, G3/4 9%), increased creatinine (50%, G3/4 0%), headache (42%, G3/4 0%), vomiting (41%, G3/4 5%), hypercholesterolemia (41%, G3/4 0%), diarrhea (39%, G3/4 0%), hypertriglyceridemia (38%, G3/4 1%), thrombocytopenia (38%, G3/4 14%), mucositis (28%, G3/4 4%), transaminitis (28%, G3/4 1%), constipation (28%, G3/4 1%), and pain (28%, G3/4 1%). Of 64 evaluable pts, response rate (RR) across all DL was 19% with median duration 14 mo (4-34). CBR was 34%. RR was 27%, 20%, and 6% for endometrial, ovarian, and breast cancer, respectively. Among 49 evaluable pts treated on Arm 2, RR was 19% and CBR 37%. In Arm 2, RR was 31%, 15%, and 8% for endometrial, ovarian and breast cancer, respectively. Among 6 endometrial cancer responders (3 endometrioid, 3 serous), PI3K pathway, ARID1A, or FBXW7 mutations were common (67%). Conclusions: The combination of olaparib and vistusertib is well tolerated with durable anti-tumor activity. Promising response was seen in both histologies of endometrial cancer. Assessment of molecular correlatives of response will be presented. Clinical trial information: NCT02208375.