Department of Clinical Research, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou.
Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou.
ESMO Open. 2024 Aug;9(8):103651. doi: 10.1016/j.esmoop.2024.103651. Epub 2024 Jul 25.
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.
APG-1387 是一种新型的第二线粒体衍生的胱天蛋白酶激活剂模拟物，是一种针对凋亡抑制蛋白的小分子抑制剂。我们报告了两项 I 期临床试验的结果，这些试验评估了 APG-1387 单药治疗和 APG-1387 联合 toripalimab（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。
年龄≥18 岁、组织学证实患有晚期实体瘤且无合适标准治疗（或对标准治疗耐药）的患者有资格参加。患者接受递增剂量的静脉注射 APG-1387 单药治疗或联合固定剂量 toripalimab（每 3 周 240mg）治疗，采用“3+3”设计。单药治疗试验的主要终点为剂量限制性毒性（DLT）和最大耐受剂量（MTD），联合治疗试验的推荐 II 期剂量（RP2D）。次要终点包括两项试验中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，28 名患者入组并接受了至少 1 个治疗周期。28 名患者中未报告 DLT，且未达到 MTD。1 名患者（3.6%）发生 1 例 3 级治疗相关不良事件（TRAE）的丙氨酸氨基转移酶升高。在 23 名可评估疗效的患者中，无客观缓解，疾病控制率为 21.7%。在联合治疗试验中，22 名患者入组并纳入所有分析。1 例患者发生 3 级脂肪酶升高的 DLT。未达到 MTD。3 名患者（13.6%）发生 4 例 3 级 TRAE，最常见的是脂肪酶升高（n=2）。RP2D 为每周 45mg。客观缓解率为 13.6%，1 例患者完全缓解，疾病控制率为 54.5%。
APG-1387 每周 45mg 联合 toripalimab 耐受性良好，推荐进一步研究，在晚期实体瘤患者中观察到初步临床活性。
