Abstract 4835
Background
Fluzoparib (FLU; SHR3162) is a selective PARP1 inhibitor that showed antitumour activity in xenograft models. We conducted a two-arm phase I, first-in-human, dose-escalation and expansion (D-Esc and D-Ex) trial of FLU in patients (pts) with advanced cancer. (ClinicalTrials.gov NCT03509636).
Methods
This was a 3 + 3 phase I D-Esc trial with a 3-level dose expansion (D-Ex) at 5 centers in China. Eligible pts were diagnosed with advanced solid tumors refractory to standard therapies or with no standard therapy. FLU was administered orally (daily or 2x/day (BID)) at 11 dose levels from 10–400 mg/day. The D-Ex arm evaluated FLU at 80, 100 or 150 mg BID in pts with ovarian cancer (OC). Endpoints included dose-finding, safety, tolerability, pharmacokinetics, and estimation of preliminary antitumor activity.
Results
79 pts with advanced solid tumors: (OC) [47; 59.5%]; breast cancer (BC) [16; 20.3%]; colorectal cancer [8; 10.1%], other tumors: [8; 10·1%]) were enrolled from 3/2015 to 3/2019. 48 pts were treated in the D-Esc arm and 31 in the D-Ex arm. The maximum tolerated dose (MTD) was 150 mg BID, with a half-life of 9 hours. Hematologic adverse events (AEs; all grades) included anemia (53.2%), thrombocytopenia (17.7%) and neutropenia (24.1%); main non-hematologic AEs (all grades) were fatigue (48.1%), vomiting (17.7%), nausea (34.2%) and decreased appetite (29.1%). Grade 3/4 AEs included anemia (7.6%) and neutropenia (5.1%). Objective responses were observed in 3 of 10 (30%) patients with platinum-sensitive OC and 1 of 13 (7·7%) with BC. Among patients treated with FLU ≥120 mg/day, median progression free survival (mPFS, range) was 4.4 mo (1–24) in OC; 10.2 mo (2–24) in platinum-sensitive OC; 3.5 mo (2–28) in BC. 11/43 OC and 2/16 BC had BRCAMut. In patients with BRCAMut, mPFS was 14 mo (one pt with BC at 160 mg/d) and 8.5 mo (range 1-24; 95%CI 0-17.1; 11 pts with OC). As of 3/1/2019, one pt with BC (BRCA wild type, 60 mg BID,28+mo) and 3 pts with BRCAMut OC (one at 80 mg BID, +21 mo; two at 150 mg BID, +15 and +14mo) continue on FLU.
Conclusions
The MTD of FLU was 150mg BID in advanced solid malignancies. FLU demonstrated single-agent antitumour activity in BC and OC, particularly in platinum-sensitive and BRCAMut OC.
Clinical trial identification
NCT03509636.
Editorial acknowledgement
Legal entity responsible for the study
Huiping Li.
Funding
Jiangsu Hengrui Medicine Co.
Disclosure
All authors have declared no conflicts of interest.
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