Phase 1a study of the CDK4/6 inhibitor, FCN-437c, in Chinese patients with HR + /HER2- advanced breast cancer

Abstract

Purpose This phase 1a, first-in-human study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), and antitumor activity of FCN-437c, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Methods The study enrolled female patients with HR + /HER2- advanced breast cancer (BC) who failed standard of care therapy. A 3 + 3 dose-escalation design was utilized with a starting dose of 50 mg daily for 3 weeks on and 1 week off treatment in 28-day cycles. Patients received escalating doses of FCN-437c monotherapy (50, 100, 200, 300, and 450 mg). Results Seventeen patients received FCN-437c 50 mg (n = 3), 100 mg (n = 3), 200 mg (n = 3), 300 mg (n = 6), and 450 mg (n = 2). Two patients who received the 450-mg dose experienced dose-limiting toxicities (DLTs; grade 4 thrombocytopenia and neutropenia); no DLT was observed at any other dose level. Frequently reported treatment-emergent adverse events (TEAEs) of any grade were hematological: leukopenia (94.1%), neutropenia (88.2%), anemia (64.7%), and thrombocytopenia (47.1%). Grade 3-4 TEAEs included neutropenia (64.7%) and leukopenia (47.1%). Exposure of FCN-437c increased almost proportionally to doses ranging from 50 to 200 mg. At doses from 200 to 450 mg, there appeared to be a trend of saturation. The MTD was determined to be 300 mg. Of 15 patients with measurable disease, nine (60.0%) patients experienced stable disease; no complete or partial responses were observed. Conclusions These results established an acceptable safety profile for FCN-437c in patients with advanced BC, and there were no unexpected signals relative to other CDK4/6 inhibitors. (NCT04488107; July 13, 2020).

Keywords: Antitumor activity; CDK4/6 inhibitor; FCN-437c; Pharmacokinetics; Safety.

Conflict of interest statement

The study was initiated, funded, and sponsored by Avanc Pharmaceutical Co., Ltd. Jian Zhang, Xiaojia Wang, Xian Wang, and Xichun Hu declare no potential conflicts of interest. Aimin Hui is a full-time employee of Fosun Pharma USA Inc. Zhuli Wu, Changjiang Xu, Yuchen Yang, and Wenjing Zhang are full-time employees of Beijing Fosun Pharmaceutical Research and Development Co., Ltd. Ling Tian is a full-time employee of Avanc Pharmaceutical Co., Ltd.

© 2021. The Author(s).

Figures

Fig. 1

Mean plasma concentrations of FCN-437c versus time by dose level following a single dose (linear scale); b single dose (semi-log scale); c multiple doses (linear scale); d multiple doses (semi-log scale)

Fig. 2

a Waterfall plot and b spider plot of best percentage change from baseline in sum of diameters by dose level