First-in-human phase 1 study of SPH4336, a novel cyclin-dependent kinase 4/6 inhibitor, in patients with advanced solid tumors.

e15107 Background: The inhibition of cyclin-dependent kinases (CDKs) is a highly promising and attractive strategy for the development of anticancer drugs. SPH4336, a novel oral inhibitor with high selectivity and improved inhibition for CDK4/6, has demonstrated promising anti-tumor activity in preclinical studies. This was a first-in-human, multicenter, phase 1 dose-escalation and -expansion study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of SPH4336 in patients with advanced solid tumors. Methods: Patients aged 18-70 years with histologically or cytologically confirmed advanced solid tumors that were refractory or intolerant to standard treatment or for which no standard treatment exists were included. Dose escalation of SPH4336 was conducted at doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg and 600 mg once a day. Primary endpoint was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of SPH4336. Secondary endpoints included assessment of adverse events (AEs) and efficacy. Descriptive statistics summarized safety, efficacy and PK parameters. Kaplan-Meier method was used to analyze time-to-event variables. Results: A total of 29 patients were enrolled with a median age of 55.0 years (23–66) and 72% being females. The most common tumor types were breast cancer (n=14, 48.3%) and sarcoma (n=8, 27.6%). No DLT was observed within 50 to 600 mg and MTD was not determined. Treatment-related adverse events (TRAEs) were reported in 29 (100%) patients, the most common TRAEs were white blood cell count decreased (n=21, 72.4%), diarrhea (n=20, 69.0%), neutrophil count decreased (n=19, 65.5%) and anemia (n=18, 62.1%). No grade 4 TRAEs were observed and death occurred in 1 patient (200 mg cohort) due to disease progression. Of the 27 evaluable patients, 1 patient achieved partial response lasting 169 days, and disease control rate was 59.3% (95% CI: 38.8%-77.6%). Regression of target lesion was observed in 100, 400 and 600 mg cohorts from baseline. PK assessments showed that the exposure of SPH4336 increased in a dose-dependent manner except with 600 mg dose. SPH4336 reached a steady state at 2 weeks of continuous dosing administration at 400 mg. Conclusions: This study demonstrated that SPH4336 was well tolerated at doses ranging from 50 to 600 mg dose levels. A dose of 400 mg could be considered for further clinical trials. Clinical trial information: NCT05905614 .