Zhang Pin, Xu Binghe, Gui Lin, Wang Wenna, Xiu Meng, Zhang Xiao, Sun Guilan, Zhu Xiaoyu, Zou Jianjun
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Jiangsu Hengrui Medicine Co. Ltd, Shanghai, China.
Biomark Res. 2021 Apr 12;9(1):24. doi: 10.1186/s40364-021-00271-2.
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).
In 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.
Between 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).
Dalpiciclib 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.
ClinicalTrials.gov identifier: NCT02684266 . Registered Feb 17, 2016.
达尔西利（SHR6390）是一种新型细胞周期蛋白依赖性激酶4/6抑制剂，在临床前模型中显示出有前景的抗肿瘤效力。这项首次人体研究旨在评估达尔西利在晚期乳腺癌（ABC）患者中的耐受性、药代动力学、安全性和初步抗肿瘤活性。
在这项开放标签的1期研究中，入组了标准治疗失败的中国患者，以25 - 175毫克的剂量按3 + 3剂量递增模式口服达尔西利。符合条件的患者在第1周接受单剂量达尔西利，随后连续每日给药3周，每28天为一个周期，休息1周。根据剂量递增阶段揭示的耐受性、药代动力学和活性数据，选择三个剂量组扩展至8 - 10名患者。主要终点是最大耐受剂量（MTD）和药代动力学。
2016年4月15日至2018年12月21日期间，入组了40名患者；所有患者均被诊断为激素受体阳性且人表皮生长因子受体2阴性的ABC。达尔西利100毫克、125毫克和150毫克组扩展至10名患者。未观察到剂量限制性毒性，未达到MTD。40名患者中有22名（55.0%）发生3级或4级不良事件，分别为中性粒细胞减少（52.5%）、白细胞减少（35.0%）、血小板减少（5.0%）和高血压（2.5%）。未报告严重不良事件。在50 - 175毫克剂量下，浓度 - 时间曲线下的稳态面积和峰浓度几乎与剂量成比例增加。疾病控制率（DCR）为62.5%（25/40，95%CI：45.8 - 77.3）。两名患者（5%；125毫克和150毫克组）达到部分缓解，缓解分别持续169天和356 +天。在三个扩展组中，150毫克组的DCR在数值上最高，为80.0%（95%CI：44.4 - 97.5），中位无进展生存期最长，为8.4个月（95%CI：2.1 - 未达到）。
达尔西利在ABC中国患者中显示出可接受的安全性和剂量依赖性血浆暴露。推荐的2期剂量为150毫克。观察到了临床活性的初步证据，值得进一步验证。
ClinicalTrials.gov标识符：NCT02684266。于2016年2月17日注册。
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