Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors
Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors
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DOI：
10.1007/s10637-020-01049-3
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发表时间：
2021-01-22
影响因子：
3.4
通讯作者：
Batist, Gerald
中科院分区：
文献类型：
--
作者：
Chu, Quincy Siu-chung;Bouganim, Nathaniel;Batist, Gerald
背景极光 A 激酶 (AurA) 过度表达可能有助于肿瘤发生，因此是癌症治疗的一个有吸引力的靶点。这项 1 期研究旨在确定 LY3295668 erbumine（一种 AurA 抑制剂）在局部晚期或转移性实体瘤患者中的安全性、药代动力学和抗肿瘤活性。方法 纳入患有局部晚期或转移性实体瘤、东部肿瘤合作组表现状态为 0-1 级、且在 1 至 4 种既往治疗方案后出现疾病进展的患者。主要目的是确定最大耐受剂量（MTD）；次要目标包括评估 LY3295668 的耐受性和安全性以及药代动力学。所有患者均接受每日两次 (BID) 口服 LY3295668，以 21 天为一个周期，剂量递增。结果 12 名患者入组第 1 期（25 mg，n = 8；50 mg，n = 2；75 mg，n = 2），1 名患者随后入组。总体而言，4 名患者在第一个周期内经历了剂量限制性毒性 (DLT)（75 mg：3 级腹泻[一名患者]、4 级粘膜炎和 3 级角膜沉积物[一名患者]；50 mg：粘膜炎和腹泻[均为 3 级，一名患者]；25 mg：3 级粘膜炎[一名患者]）。表现出 DLT 的患者在稳定状态下的模型预测暴露量最高。粘膜炎是最常见的不良事件（67%），其次是腹泻、疲劳、脱发、厌食、便秘和恶心。 9名患者病情稳定反应最佳；疾病控制率为69%。结论 LY3295668 的 MTD 为 25 mg BID。 LY3295668 具有可控的毒性特征，并在一些局部晚期或转移性实体瘤患者中表现出活性。
Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors.