背景:本研究旨在评估安全性,药代动力学(PKs),以及细胞周期蛋白依赖性激酶7(CDK7)的共价抑制剂LY3405105的初步活性,晚期实体瘤患者。
方法:LY3405105单药治疗每天一次(QD;A1部分)或每周三次(TIW;A2部分),从1和2mg口服开始,分别,并根据成年患者的贝叶斯设计进行升级。主要终点是安全性,次要终点包括PKs和抗肿瘤活性。
结果:纳入54例患者:A1部分43例,A2部分11例。七名患者有剂量限制性毒性,部分A1(45mg:n=3;35mg:n=3;25mg:n=1)。35例患者(64.8%)报告至少1例治疗相关不良事件(TRAE)。TRAEs(≥10%)为腹泻,恶心,疲劳,呕吐,腹痛,贫血,虚弱,血小板计数减少。与TIW给药相比,QD给药显示持续暴露,峰谷波动较小。达到最大浓度的中位时间为1-2小时,半衰期为15-19小时。第15天时皮肤和外周血中CDK7目标的占有率是剂量依赖性的,在≥15mgQD时达到接近75%的最大占有率。最大耐受剂量(MTD)为20mgQD。A1部分的12名患者(27.9%)和A2部分的5名患者(45.5%)对稳定疾病的总体反应最好。没有观察到完全反应或部分反应。
结论:LY3405105单药治疗的MTD为20mgQD。最常见的毒性是胃肠道不良事件,骨髓抑制,疲劳,和虚弱。在此I期试验中观察到有限的临床活动,也没有进一步发展的计划。
背景:NCT03770494。
BACKGROUND: This study aimed to evaluate the safety, pharmacokinetics (PKs), and preliminary activity of LY3405105, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), in patients with advanced solid tumors.
METHODS: LY3405105 monotherapy was given once daily (QD; part A1) or thrice weekly (TIW; part A2) starting at 1 and 2 mg orally, respectively, and escalated per a Bayesian design in adult patients. The primary endpoint was safety, and secondary endpoints included PKs and antitumor activity.
RESULTS: Fifty-four patients were enrolled: 43 in part A1 and 11 in part A2. Seven patients had dose-limiting toxicities, all in part A1 (45 mg: n = 3; 35 mg: n = 3; 25 mg: n = 1). Thirty-five patients (64.8%) reported at least one treatment-related adverse event (TRAE). TRAEs (≥10%) were diarrhea, nausea, fatigue, vomiting, abdominal pain, anemia, asthenia, and decreased platelet count. QD dosing showed sustained exposure with less peak-trough fluctuation compared to TIW dosing. Median time to maximum concentration was 1-2 hours and half-life was 15-19 hours. CDK7-target occupancy in skin and peripheral blood on day 15 was dose-dependent and reached near maximal occupancy of 75% at ≥15 mg QD. The maximum tolerated dose (MTD) was 20 mg QD. Twelve patients in part A1 (27.9%) and 5 patients in part A2 (45.5%) had a best overall response of stable disease. No complete response or partial response was observed.
CONCLUSIONS: The MTD of LY3405105 monotherapy was 20 mg QD. The most common toxicities were gastrointestinal adverse events, myelosuppression, fatigue, and asthenia. Limited clinical activity was observed in this phase I trial, and there are no plans for further development.
BACKGROUND: NCT03770494.