Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2018 Jul 15;24(14):3253-3262. doi: 10.1158/1078-0432.CCR-17-3421. Epub 2018 Apr 10.
The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Forty-seven patients with solid tumors received LY3023414 at once-daily (20-450 mg) or twice-daily dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. .
PI3K/mTOR 通路在癌症中经常发生异常。LY3023414 是一种有效的、选择性的 ATP 竞争性抑制剂，可抑制 I 类 PI3K 同工型、mTOR 和 DNA-PK。在此，我们报告了 LY3023414 首次人体 I 期研究的剂量递增结果。在每日一次和每日两次口服 LY3023414 的 3+3 剂量递增后，进行了 CYP3A4 药物相互作用 (DDI) 评估的扩展队列。主要目的是确定 II 期推荐剂量 (RP2D)。其他目标包括安全性、药代动力学/药效学和抗肿瘤活性。47 名实体瘤患者接受了 LY3023414 治疗，剂量为每日一次（20-450mg）或每日两次（150-250mg）。在 3 名患者中观察到每日一次 450mg 剂量限制毒性（血小板减少症、低血压、高钾血症），4 名患者中每日两次 250mg 剂量限制毒性（低磷血症、疲劳、粘膜炎），在 15 名患者中 1 名患者（恶心）每日两次 200mg 剂量限制毒性。常见的相关不良反应包括恶心（38%）、疲劳（34%）和呕吐（32%），多为轻度或中度。LY3023414 的药代动力学显示，暴露量与剂量呈依赖性增加，在 ≥150mg 剂量下，≥90%的目标抑制率。DDI 分析表明，LY3023414 是 CYP3A4 的弱抑制剂。在一名患有子宫内膜癌的患者中观察到持久的部分缓解，该患者携带 PIK3R1 和 PTEN 截断突变，另外 13 名患者（28%）的靶病变减少了多达 30%。LY3023414 在晚期癌症患者中具有可耐受的安全性和单药活性。基于安全性、耐受性和药代动力学/药效学数据，LY3023414 单药治疗的 II 期推荐剂量为 200mg，每日两次。
