Abstract
Background: 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 SHR6390 in patients with advanced breast cancer (ABC).Methods: In this open-label, phase 1 study, patients who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible patients were given a single-dose of SHR6390 in week 1, followed by once daily continuous doses for three weeks, and one 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. Results: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. SHR6390 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).Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.Trial registration: ClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016. https://clinicaltrials.gov/ct2/show/NCT02684266.
A Phase 1 Open-Label Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Enzalutamide Alone or Combined with an Aromatase Inhibitor in Women with Advanced Breast Cancer