Phase I trial of SPH4336, a novel cyclin-dependent kinase 4/6 inhibitor, in patients with advanced solid tumors

Abstract Background Preclinical models demonstrated promising anti-tumor activity of SPH4336, a novel oral, highly selective cyclin-dependent kinase (CDK) 4/6 inhibitor. Methods This phase I study enrolled patients who received SPH4336 orally in 6 dose-escalation cohorts (50-600 mg) in a 3 + 3 design. Based on tolerability, pharmacokinetics (PK) and activity data from the dose-escalation phase, 2-3 dose cohorts were expanded. Dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase II dose (RP2D), efficacy, safety, tolerability, and pharmacokinetics (PK) were investigated. Results A total of 29 patients with breast cancer (BC) (n = 14), sarcoma (n = 8), non-small cell lung cancer (n = 2) and others (n = 5) were enrolled. Neither DLT nor MTD were reached. All patients had at least one treatment-related adverse events (TRAEs), most of which were grade 1/2. Grade ≥ 3 TRAEs occurred in 51.7% of patients. One patient died from disease progression and five reported serious adverse events. Plasma concentrations increased dose-dependently, except at 600 mg, and steady state was reached at 2 weeks for 400 mg. One BC patient in the 600-mg cohort had a confirmed partial response. The disease control rate was 59.3% (95% CI, 38.8-77.6). Conclusion SPH4336 demonstrated an acceptable safety profile and dose-dependent plasma exposure in patients with various advanced solid tumors. (ClinicalTrials.gov Identifier: NCT05905614; IRB Approved.)