4835 - Phase-I dose-escalation and expansion study of the PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors

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 BRCA^Mut. In patients with BRCA^Mut, 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 BRCA^Mut 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 BRCA^Mut 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.