Background: CDK4/6 have been proved to play an essential role in cell proliferation and are often dysregulated particularly in HR-positive breast cancer. To date, three orally bioavailable CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib, have been approved for the treatment of ER+HER2- ABC in combination with AI/Fulvestrant or as monotherapy. FCN-437c is an oral, second generation CDK4/6 inhibitor, with antitumor activities of the combination with AI/Fulvestrant in in-vivo models with high potency, as well as good pharmacokinetic (PK) characteristics with brain penetration, and tolerable toxicities observed. Methods: This is a phase I, open label, first-in-human trial aiming to evaluate the safety, maximum tolerated dose (MTD), PK profile and anti-tumor activity of FCN-437c as monotherapy in patients with ABC failure to standard of care (phase 1a) and in combination with Letrozole in patients with 1L ABC (phase 1b). Here we report the phase 1a study result. Regular 3+3 dose escalation design was utilized with starting dose of 50 mg for 3 weeks on-1 week off in a 28-day cycle. 17 patients were enrolled from Feb.13th 2019 to Apr. 15th 2020 in different dose level: 50(n = 3), 100(n = 3), 200(n = 3), 300(n = 6) and 450(n = 2) mg. Results: As of the cut-off date on Aug. 10th 2020, a total of 17 patients participated in phase 1a. Sixteen patients (94.1%) and 13 patients (76.5%) had been treated with endocrine therapy and chemotherapy for ABC, respectively. Two patients in the 450 mg dose group experienced DLT of grade 4 thrombocytopenia and G4 neutropenia respectively, and no DLT was observed in other dose level. The most frequently reported was hematological TEAEs as of leukopenia (16/17 pts, 94.1%), neutropenia (15/17 pts, 88.2%), anemia (11/17 pts, 64.7%) and thrombocytopenia (8/17 pts, 47.1%). Major grade 3-4 TEAEs were neutropenia and leukopenia, occurred in 11 (64.7%) and 8 (47.1%) patients, respectively. The exposure (Cmax,AUC0-∞ ,AUC0-24,Cav-ss 24h) increased almost in proportion with dose following a multi-dose from 50 to 200mg. In multiple dose at 200 - 450 mg dose level, there appeared to be a trend of saturation. MTD of FCN-437c monotherapy was determined to be 300 mg and RP2D was 200 mg based on safety and PK data. Of 15 response evaluable patients, 9 (60.0%) had stable disease and no response was observed. PFS and OS were immature for report due to short follow-up duration.Conclusions: FCN-437c has established an acceptable safety profile and the toxicities were generally tolerable and manageable. A phase II trial of FCN-437c is now ongoing in combination with Letrozole or Fulvestrant in patients with ER+HER2- ABC, both in treatment naïve and relapse/refractory settings at 200 mg dose level.

Citation Format: Jian Zhang, Xiaojia Wang, Xian Wang, Aimin Hui, Zhuli Wu, Ling Tian, Changjiang Xu, Yuchen Yang, Wenjing Zhang, Xichun Hu. Phase I dose-escalation and dose-expansion trial of CDK4/6 inhibitor FCN-437c in Chinese female patients with ER+HER2- advanced breast cancer (ABC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT117.