1095 Background: SHR6390 is a novel inhibitor of cyclin-dependent kinase 4/6 (CDK 4/6). This study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of SHR6390 in patients (pts) with advanced breast cancer (ABC). Methods: In this open-label, single-arm phase I study, pts who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible pts 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 cycle. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8−10 pts. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. Results: Between Apr 15, 2016 and Dec 21, 2018, 40 pts were enrolled. All pts were diagnosed of hormone receptor positive and HER2-negative ABC. 45.0% of pts had at least three prior chemotherapies and 55.0% had at least two prior endocrine therapies. SHR6390 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 pts, respectively. No dose limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade ≥3 were observed in 22 (55.0%) of 40 pts, 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, median time to peak concentration was 2.5−4.0 h, and mean terminal half-life was 40.3−51.4 h with single-dose SHR6390. Following multiple dosing, steady state SHR6390 was observed on day 8. The steady state areas under the concentration and peak concentration increased slightly greater than the increase rate of dose, with steady state Cmax at day 21 of 41.1, 53.4, 87.0, 115.0, 126.0, and 155.0 ng/mL in 50, 75, 100, 125, 150, and 175 mg cohorts, respectively. The disease control rate was 62.5% (25/40, 95% CI 45.8% to 77.3%). Two pts (5%, one in 125 mg, one in 150 mg cohort) achieved partial response, with responses lasting 169 and 356+ days, respectively. Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in pts with ABC. The recommended phase II dose was 150 mg. Preliminary evidence of clinical activity was observed, warranted further study. Clinical trial information: NCT02684266 .
A Phase I, Dose Escalation, Single Dose Trial of Oral Attenuated Salmonella typhimurium Containing Human IL-2 in Patients With Metastatic Gastrointestinal Cancers
