Abstract
BackgroundDalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC).MethodsIn this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25–175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8–10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics.ResultsBetween Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50–175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8–77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4–97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1–not reached).ConclusionsDalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.Trial registrationClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016.
Highlights
Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models
Estrogen-mediated hyperactivity of the cyclin D (CCND)–cyclindependent kinase 4/6 axis (CDK4/6) axis is a central feature of hormone receptor (HR)-positive breast cancer, and the tumors usually retain a functional retinoblastoma protein (Rb) [6], which can be targeted by CDK4/6 inhibitors
Three CDK4/6 inhibitors including palbociclib, ribociclib, and abemaciclib have been approved by the US Food and Drug Administration and the European Medicines Agency in combination with endocrine therapy as the first- and second-line treatment for HRpositive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC)
Summary
Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC). Endocrine therapy is the cornerstone in the treatment of hormone receptor (HR)-positive advanced breast cancer (ABC). Three CDK4/6 inhibitors including palbociclib, ribociclib, and abemaciclib have been approved by the US Food and Drug Administration and the European Medicines Agency in combination with endocrine therapy as the first- and second-line treatment for HRpositive and human epidermal growth factor receptor 2 (HER2)-negative ABC. Abemaciclib has been approved as a monotherapy for HR-positive and HER2negative breast cancer progressing on prior endocrine therapy or chemotherapy in the metastatic setting [16]
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