1. Academic Validation
  2. Phase I dose-escalation and expansion study of PARP inhibitor, fluzoparib (SHR3162), in patients with advanced solid tumors

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

  • Chin J Cancer Res. 2020 Jun;32(3):370-382. doi: 10.21147/j.issn.1000-9604.2020.03.08.
Huiping Li 1 Rongrui Liu 2 Bin Shao 1 Ran Ran 1 Guohong Song 1 Ke Wang 3 Yehui Shi 3 Jihong Liu 4 Wenjing Hu 5 Fu Chen 1 Xiaoran Liu 1 Gairong Zhang 2 Chuanhua Zhao 2 Ru Jia 2 Quanren Wang 6 Hope S Rugo 7 Yifan Zhang 8 Guangze Li 6 Jianming Xu 2
Affiliations

Affiliations

  • 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 2 Department of Gastrointestinal Oncology, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China.
  • 3 Department of Gynecological Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300060, China.
  • 4 Department of Gynecologic Oncology, Sun Yat-sen University Cancer Centre, Guangzhou 510060, China.
  • 5 The Comprehensive Cancer Center of Drum Tower Hospital, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, China.
  • 6 Department of Clinical Medicine-Oncology, Jiangsu Hengrui Medicine Co., Ltd., Shanghai 201203, China.
  • 7 Department of Medicine, University of California San Francisco Comprehensive Cancer Center, San Francisco 94127, USA.
  • 8 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract

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 D-Esc 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 (mPFS) 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 (gBRCA Mut) (11/43 OC; 2/16 BC), mPFS 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 somaticBRCA Mut).

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 BRCA Mut and platinum-sensitive OC.

Keywords

PARP inhibitor (fluzoparib); Phase I; antitumor activity; pharmacokinetics; safety; solid tumor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114778
    99.85%, PARP1抑制剂