Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia.
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Pediatr Blood Cancer. 2021 Sep;68(9):e29065. doi: 10.1002/pbc.29065. Epub 2021 Apr 21.
Prexasertib (LY2606368) is a novel, second-generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors.
Prexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28-day cycle. Four dose levels, 80, 100, 125, and 150 mg/m , were evaluated using a rolling-six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity.
Thirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2-20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose-limiting toxicities. Common cycle 1, drug-related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80-150 mg/m dose range.
Although the MTD of prexasertib was not defined by this study, 150 mg/m administered i.v. on days 1 and 15 of a 28-day cycle was determined to be the RP2D.
普雷沙替尼（LY2606368）是一种新型第二代双重细胞周期蛋白依赖性激酶 1（CHK1）和 2（CHK2）抑制剂。我们进行了一项普雷沙替尼的 I 期试验，以估计最大耐受剂量（MTD）和/或推荐的 II 期剂量（RP2D），确定和描述毒性，并描述儿科患者中普雷沙替尼的药代动力学（PK）复发或难治性实体瘤和中枢神经系统（CNS）肿瘤。
普雷沙替尼于 28 天周期的第 1 天和第 15 天静脉输注（i.v.）。使用滚动六设计评估 80、100、125 和 150mg/m 四个剂量水平。在第 1 周期进行 PK 分析。肿瘤组织检查普雷沙替尼活性的生物标志物（CHK1 和 TP53）。
共纳入 30 例患者，25 例可评估。中位年龄为 9.5 岁（范围：2-20），21 例（70%）为男性。12 例患者（40%）患有实体瘤，18 例患者（60%）患有 CNS 肿瘤。无第 1 周期或更晚的剂量限制毒性。常见的第 1 周期药物相关 3/4 级毒性（>10%的患者）包括中性粒细胞减少症（100%）、白细胞减少症（68%）、血小板减少症（24%）、淋巴细胞减少症（24%）和贫血症（12%）。无客观反应；3 例患者的最佳总体反应为 5 个周期的疾病稳定（肝细胞癌）、3 个周期的疾病稳定（室管膜瘤）和 5 个周期的疾病稳定（未分化肉瘤）。PK 表现出在 80-150mg/m 剂量范围内与剂量成正比。
尽管本研究未确定普雷沙替尼的 MTD，但确定静脉输注 150mg/m，第 1 天和第 15 天，28 天周期为 RP2D。
