APG-1387 是一种新型的第二种线粒体衍生的半胱天冬酶模拟激活剂、靶向凋亡蛋白抑制剂的小分子抑制剂。我们报告了两项 I 期试验的结果，这些试验评估了 APG-1387 单药疗法和 APG-1387 加特瑞普利单抗（一种程序性细胞死亡 1 (PD-1) 抑制剂）治疗晚期实体瘤的耐受性、安全性和抗肿瘤活性。受试者年龄≥18 岁组织学证实患有晚期实体瘤且没有适当标准护理（或标准护理难治性）的年份符合资格。患者接受递增静脉注射剂量的 APG-1387 单独治疗或与固定剂量特瑞普利单抗（每 3 周 240 毫克）联合治疗，采用“3 3”设计。主要终点是单药治疗试验中的剂量限制毒性 (DLT) 和最大耐受剂量 (MTD)，以及联合治疗试验中的推荐 II 期剂量 (RP2D)。次要终点包括两项试验的药代动力学和药效学特征以及初步疗效。在单药治疗试验中，招募了 28 名受试者并接受≥1 个治疗周期。 28 名受试者中没有报告 DLT，并且未达到 MTD。一名参与者 (3.6%) 发生≥3 级丙氨酸转氨酶升高的治疗相关不良事件 (TRAE)。在23名参与者的疗效分析中，没有人达到客观缓解，疾病控制率为21.7%。在联合试验中，22 名受试者被纳入并纳入所有分析。有 1 例 DLT 脂肪酶升高为 3 级。未达到 MTD。三名参与者 (13.6%) 发生了 4 次 ≥3 级 TRAE，其中最常见的是脂肪酶升高 (n = 2)。 RP2D 为每周 45 毫克。客观缓解率为13.6%，其中一名受试者达到完全缓解，疾病控制率为54.5%。APG-1387 45 mg每周加特瑞普利单抗耐受性良好，建议进一步研究，研究中观察到初步临床活性患有晚期实体瘤的参与者。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

APG-1387 is a novel second mitochondrial-derived activator of caspases mimetic, small-molecule inhibitor targeting inhibitor of apoptosis proteins. We report results from two phase I trials evaluating the tolerability, safety, and antitumor activity of APG-1387 monotherapy and APG-1387 plus toripalimab [a programmed cell death 1 (PD-1) inhibitor] for advanced solid tumors.Participants aged ≥18 years who had histologically confirmed advanced solid tumors with no appropriate standard of care (or refractory to standard care) were eligible. Patients received escalating intravenous doses of APG-1387 alone or combined with fixed-dose toripalimab (240 mg every 3 weeks) in a '3 + 3' design. Primary endpoints were dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) in the monotherapy trial, and recommended phase II dose (RP2D) in the combination therapy trial. Secondary endpoints included the pharmacokinetic and pharmacodynamic profiles and preliminary efficacy in both trials.In the monotherapy trial, 28 subjects were enrolled and received ≥1 treatment cycle. No DLT was reported among the 28 subjects, and the MTD was not reached. One participant (3.6%) had a grade ≥3 treatment-related adverse event (TRAE) of alanine aminotransferase elevation. In efficacy analysis of 23 participants, none achieved an objective response, and the disease control rate was 21.7%. In the combination trial, 22 subjects were enrolled and included in all analyses. There was one DLT of grade 3 lipase elevation. The MTD was not reached. Four grade ≥3 TRAEs occurred in three participants (13.6%), with the most common being lipase elevation (n = 2). The RP2D was 45 mg weekly. The objective response rate was 13.6%, with complete response achieved in one subject, and the disease control rate was 54.5%.APG-1387 45 mg weekly plus toripalimab was well tolerated and is recommended for further study, with preliminary clinical activity observed in study participants with advanced solid tumors.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.