Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
摘要：
背景：小鼠双分2同源物（MDM2）癌基因在许多癌症中发挥致癌活性，并代表潜在的治疗靶标。这项试验评估了安全性，药代动力学，药效学,和阿利佐马地林（APG-115）的初步疗效，一种新型MDM2/p53抑制剂，晚期实体瘤患者。
方法：招募组织学证实的晚期实体瘤患者，这些患者已进展至标准治疗或缺乏有效治疗。Alrizomadlin每隔一天每天一次，持续28天周期的21天，直到疾病进展或无法耐受的毒性。
结果：共有21例患者入组并接受alrizomadlin治疗；57.1%为男性，中位年龄为47(25-60)岁。阿利佐马地林的最大耐受剂量为150mg，推荐的II期剂量为100mg。200mg队列中的一名患者经历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为血小板减少症（33.3%），淋巴细胞减少症（33.3％），中性粒细胞减少症（23.8%），贫血（23.8%）。Alrizomadlin显示出近似线性的药代动力学（剂量范围100-200mg），并且与血浆巨噬细胞抑制性细胞因子1增加有关，表明p53途径激活。在20名可评估的患者中，2[10%，95％置信区间（CI）1.2％至31.7％]患者获得部分缓解，10（50％，95%CI27.2%至72.8%)显示疾病稳定。中位无进展生存期为6.1(95%CI1.7-10.4)个月,野生型与突变型TP53患者的时间明显更长（7.9个月对2.2个月，分别；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）。
结论：Alrizomadlin具有可接受的安全性，并在MDM2扩增和TP53野生型肿瘤中显示出有希望的抗肿瘤活性。这项研究支持进一步探索alrizomadlin，推荐剂量为100mgq.o.d。在21天和7天的治疗方案中。
方法：招募组织学证实的晚期实体瘤患者，这些患者已进展至标准治疗或缺乏有效治疗。Alrizomadlin每隔一天每天一次，持续28天周期的21天，直到疾病进展或无法耐受的毒性。
结果：共有21例患者入组并接受alrizomadlin治疗；57.1%为男性，中位年龄为47(25-60)岁。阿利佐马地林的最大耐受剂量为150mg，推荐的II期剂量为100mg。200mg队列中的一名患者经历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为血小板减少症（33.3%），淋巴细胞减少症（33.3％），中性粒细胞减少症（23.8%），贫血（23.8%）。Alrizomadlin显示出近似线性的药代动力学（剂量范围100-200mg），并且与血浆巨噬细胞抑制性细胞因子1增加有关，表明p53途径激活。在20名可评估的患者中，2[10%，95％置信区间（CI）1.2％至31.7％]患者获得部分缓解，10（50％，95%CI27.2%至72.8%)显示疾病稳定。中位无进展生存期为6.1(95%CI1.7-10.4)个月,野生型与突变型TP53患者的时间明显更长（7.9个月对2.2个月，分别；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）。
结论：Alrizomadlin具有可接受的安全性，并在MDM2扩增和TP53野生型肿瘤中显示出有希望的抗肿瘤活性。这项研究支持进一步探索alrizomadlin，推荐剂量为100mgq.o.d。在21天和7天的治疗方案中。
