Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Division of Leukemia, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res. 2022 Mar 1;28(5):870-881. doi: 10.1158/1078-0432.CCR-21-1295.
This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers.
Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1.
Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2-27.4] in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), and 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively.
A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies.
这项 I 期、剂量递增研究旨在确定 siremadlin（一种 p53-MDM2 抑制剂）在野生型 TP53 晚期实体瘤或血液系统恶性肿瘤患者中的扩展推荐剂量（RDE）。
初始剂量方案为：1A（第 1 天；21 天周期；剂量 12.5-350mg）和 2A（第 1-14 天；28 天周期；剂量 1-20mg）。替代方案包括 1B（第 1 天和第 8 天；28 天周期）和 2C（第 1-7 天；28 天周期）。主要终点是第 1 周期中剂量限制性毒性（DLT）的发生率。
共有 115 例实体瘤患者和 93 例血液系统恶性肿瘤患者接受了治疗。在 92 例实体瘤患者中有 8 例和 53 例血液系统恶性肿瘤患者中有 10 例发生 DLT。在实体瘤中，1B 方案确定了 siremadlin 的 RDE 为 120mg。在血液系统肿瘤中，1A 方案确定了 siremadlin 的 RDE 为 250mg，1B 方案为 120mg，2C 方案为 45mg。与实体瘤相比，更多的血液系统恶性肿瘤患者出现 3/4 级治疗相关不良事件（71% vs. 45%），最常见的原因是骨髓抑制。血液系统恶性肿瘤患者的不良事件更为频繁和严重，22 例患者发生肿瘤溶解综合征。在 RDE 下，实体瘤的总体缓解率为 10.3%（95%CI，2.2-27.4%），1B、1A 和 2C 方案下的急性髓系白血病（AML）分别为 4.2%（95%CI，0.1-21.1%）、20%（95%CI，4.3-48.1%）和 22.2%（95%CI，8.6-42.3%）。
确定了一个共同的安全性特征，并观察到初步疗效，特别是在 AML 中。对剂量方案的综合研究得出了 siremadlin 用于未来联合研究的推荐剂量/方案。
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