Abstract
Summary 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)
Highlights
Breast cancer (BC) has become the most common lifethreatening malignancy in women worldwide
Cyclin D1 is a transcriptional target of the estrogen receptor (ER) and forms complexes with Cyclin-dependent kinases 4 and 6 (CDK4/6) [4]
Plasma concentration and PK parameters of FCN-437c were assessed through descriptive analysis
Summary
Breast cancer (BC) has become the most common lifethreatening malignancy in women worldwide. Cyclin-dependent kinases 4 and 6 (CDK4/6) play an important role in cell proliferation and are often dysregulated in BC, in hormone-receptor (HR)-positive disease [2, 3]. Cyclin D1 is a transcriptional target of the estrogen receptor (ER) and forms complexes with CDK4/6 [4]. Activation of the CDK4/6–cyclin D1 complex contributes to the hyperphosphorylation of the retinoblastoma (Rb) protein, which causes inactivation of the cell growth-inhibitory effects by releasing E2F transcription factors and the cell-cycle progression from G1 to S phase [5, 6]. Because of the essential role of this pathway in cell cycle regulation, inhibition of CDK4/6 has been regarded as a promising target for antitumor therapies. Small molecule CDK4/6 inhibitors may block tumor cell growth by
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