小鼠双分钟 2 同源物 (MDM2) 癌基因在许多癌症中发挥致癌活性，是潜在的治疗靶点。该试验评估了新型MDM2/p53抑制剂alrizomadlin (APG-115)在晚期实体瘤患者中的安全性、药代动力学、药效学和初步疗效。 经组织学证实已进展至标准治疗或缺乏标准治疗的晚期实体瘤患者招募了有效的疗法。 Alrizomadlin 每天给药一次，每隔一天给药一次，持续 28 天周期中的 21 天，直至疾病进展或出现无法耐受的毒性。 共有 21 名患者入组并接受 alrizomadlin 治疗； 57.1% 为男性，中位年龄为 47 (25-60) 岁。 alrizomadlin 的最大耐受剂量为 150 mg，推荐的 II 期剂量为 100 mg。 200 mg 队列中的一名患者出现了血小板减少症和发热性中性粒细胞减少症的剂量限制性毒性。最常见的 3/4 级治疗相关不良事件是血小板减少症 (33.3%)、淋巴细胞减少症 (33.3%)、中性粒细胞减少症 (23.8%) 和贫血 (23.8%)。 Alrizomadlin 表现出近似线性的药代动力学（剂量范围 100-200 mg），并且与血浆巨噬细胞抑制性细胞因子-1 增加相关，表明 p53 途径激活。在 20 名可评估的患者中，2 名（10%，95% 置信区间 (CI) 1.2% 至 31.7%）患者实现部分缓解，10 名（50%，95% CI 27.2% 至 72.8%）患者病情稳定。中位无进展生存期为 6.1 (95% CI 1.7-10.4) 个月，野生型 TP53 患者与突变型 TP53 患者相比显着更长（分别为 7.9 个月与 2.2 个月；P < 0.001）。在 MDM2 扩增和野生型 TP53 的患者中，总体缓解率为 25% (2/8)，疾病控制率为 100% (8/8)。Alrizomadlin 具有可接受的安全性，并在 MDM2 中表现出有前景的抗肿瘤活性-扩增的和TP53野生型肿瘤。这项研究支持进一步探索阿利佐马德林的推荐剂量为 100 mg q.o.d。连续 21 天，休息 7 天。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

The mouse double minute 2 homolog (MDM2) oncogene exerts oncogenic activities in many cancers and represents a potential therapeutic target. This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, in patients with advanced solid tumors.Patients with histologically confirmed advanced solid tumors who had progressed to standard treatment or lacked effective therapies were recruited. Alrizomadlin was administered once daily every other day for 21 days of a 28-day cycle until disease progression or intolerable toxicity.A total of 21 patients were enrolled and treated with alrizomadlin; 57.1% were male and the median age was 47 (25-60) years. The maximum tolerated dose of alrizomadlin was 150 mg and the recommended phase II dose was 100 mg. One patient in the 200-mg cohort experienced dose-limiting toxicity of thrombocytopenia and febrile neutropenia. The most common grade 3/4 treatment-related adverse events were thrombocytopenia (33.3%), lymphocytopenia (33.3%), neutropenia (23.8%), and anemia (23.8%). Alrizomadlin demonstrated approximately linear pharmacokinetics (dose range 100-200 mg) and was associated with increased plasma macrophage inhibitory cytokine-1, indicative of p53 pathway activation. Of the 20 assessable patients, 2 [10%, 95% confidence interval (CI) 1.2% to 31.7%] patients achieved partial response and 10 (50%, 95% CI 27.2% to 72.8%) showed stable disease. The median progression-free survival was 6.1 (95% CI 1.7-10.4) months, which was significantly longer in patients with wild-type versus mutant TP53 (7.9 versus 2.2 months, respectively; P < 0.001). Among patients with MDM2 amplification and wild-type TP53, the overall response rate was 25% (2/8) and the disease control rate was 100% (8/8).Alrizomadlin had an acceptable safety profile and demonstrated promising antitumor activity in MDM2-amplified and TP53 wild-type tumors. This study supports further exploration of alrizomadlin with recommended doses of 100 mg q.o.d. in 21 days on and 7 days off regimen.Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.