Abstract
ObjectiveFluzoparib (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.MethodsThis 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.ResultsSeventy-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 (gBRCAMut) (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 somaticBRCAMut). ConclusionsThe 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.
Highlights
The incidence of breast cancer (BC) is the highest in women
Olaparib was the first poly(ADP-ribose) polymerases (PARP) inhibitor receiving USA Food and Drug Administration approval in 2014 to treat women with ovarian cancer (OC) associated with a deleterious gBRCAMut [3,7]
Olaparib and rucaparib are approved for maintenance treatment of recurrent, platinum-sensitive OC, regardless of BRCAMut status [5,9,10], and olaparib and talazoparib are approved for the treatment of patients with HER2-negative metastatic BC with a gBRCAMut [11]
Summary
The incidence of breast cancer (BC) is the highest in women. At present, the treatment of BC has tended to be standardized. PARP inhibitors (PARPis) have shown promising efficacy in treatment and maintenance therapy of ovarian cancer (OC) [1,2]. PARPis, including olaparib, rucaparib, niraparib and talazoparib, have been approved to treat OC and BC with germline breast cancer susceptibility gene mutation (gBRCAMut) [36]. Olaparib was the first PARP inhibitor receiving USA Food and Drug Administration approval in 2014 to treat women with OC associated with a deleterious gBRCAMut [3,7]. Rucaparib is approved to treat women with germline or somatic BRCAMut or homologous recombination deficiencies [4,8]. Olaparib and rucaparib are approved for maintenance treatment of recurrent, platinum-sensitive OC, regardless of BRCAMut status [5,9,10], and olaparib and talazoparib are approved for the treatment of patients with HER2-negative metastatic BC with a gBRCAMut [11]
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