科研之友
微信
新浪微博
Facebook
分享链接
摘要
Objective: Fluzoparib(SHR3162) is a novel, potent poly(ADP-ribose) polymerases(PARP)1, 2 inhibitor that showed anti-tumor activity in xenograft models.We conducted a phase Ⅰ, first-in-human, dose-escalation and expansion(D-Esc and D-Ex) trial in patients with advanced solid cancer.Methods: This was a 3+3 phase Ⅰ D-Esc trial with a 3-level D-Ex at 5 hospitals in China.Eligible patients for DEsc had advanced solid tumors refractory to standard therapies, and D-Ex enrolled patients with ovarian cancer(OC).Fluzoparib was administered orally once or twice daily(bid) at 11 dose levels from 10 to 400 mg/d.Endpoints included dose-finding, safety, pharmacokinetics, and antitumor activity.Results: Seventy-nine patients were enrolled from March, 2015 to January, 2018 [OC(47, 59.5%); breast cancer(BC)(16, 20.3%); colorectal cancer(8, 10.1%), other tumors(8, 10.1%)]; 48 patients 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 9.14 h.Grade 3/4 adverse events included anemia(7.6%) and neutropenia(5.1%).The objective response rate(ORR) was 30%(3/10)in patients with platinum-sensitive OC and 7.7%(1/13) in patients with BC.Among patients treated with fluzoparib ≥120 mg/d, median progression-free survival(m PFS) was 7.2 [95% confidence interval(95% CI),1.8-9.3] months in OC, 9.3(95% CI, 7.2-9.3) months in platinum-sensitive OC, and 3.5(range, 2.0-28.0) months in BC.In patients with germline BC susceptibility gene mutation(g BRCAMut)(11/43 OC; 2/16 BC), m PFS was 8.9 months for OC(range, 1.0-23.2; 95% CI, 1.0-16.8) and 14 and 28 months for BC(those two patients both also had somatic BRCAMut).Conclusions: The MTD of fluzoparib was 150 mg bid in advanced solid malignancies.Fluzoparib demonstrated single-agent antitumor activity in BC and OC, particularly in BRCAMut and platinum-sensitive OC.
- 单位
