Phase I Clinical Trial of the Wee1 inhibitor Adavosertib (AZD1775) with Irinotecan in Children with Relapsed Solid Tumors. A COG Phase 1 Consortium Report (ADVL1312).
Wee1 抑制剂 Adavosertib (AZD1775) 联合伊立替康治疗儿童复发实体瘤的 I 期临床试验。一份 COG 第一阶段联合报告 (ADVL1312)。

摘要

PURPOSE:Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Anti-tumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D) and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.
METHODS:Using a 3+3 escalation design, 5 dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day), delivered on days 1-5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood gH2AX was performed.
RESULTS:Thirty-seven patients were enrolled; twenty-seven were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, 3 regimens) and 21 (78%) received prior radiation therapy. Eleven patients had a primary CNS malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose limiting grade 3 dehydration. A patient with Ewing Sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.
CONCLUSION:Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the maximum tolerated dose in children and adolescents with solid and CNS tumors.

译文

目的: Adavosertib (AZD1775),WEE1 激酶的抑制剂,增强由致癌基因或化疗引起的复制应激。Adavosertib 的抗肿瘤活性已经在儿童癌症的临床前模型中得到证明。进行这个第一阶段试验是为了定义剂量限制毒性 (DLT),推荐的第二阶段剂量 (RP2D) 和 adavosertib 联合伊立替康治疗儿童和青少年复发或难治性实体瘤或原发性中枢神经系统肿瘤的药代动力学。
方法: 使用 3 3 升级设计,adavosertib 和伊立替康组合的 5 个剂量组 (50/70; 65/70; 65/90; 85/90; 110/90; mg/m2/天), 研究了 21 天周期的第 1-5 天交付。进行外周血 gH2AX 的药代动力学和分析。
结果: 37 例患者被纳入; 27 例可评估。中位 (范围) 年龄为 14 (2-20) 岁。25 例 (93%) 接受过化疗 (中位数,3 种方案),21 例 (78%) 接受过放疗。11 名患者患有原发性中枢神经系统恶性肿瘤。常见毒性为血液学和胃肠道。两名接受 adavosertib (110 mg/m2) 联合伊立替康 (90 mg/m2) 的患者经历了 3 级剂量限制脱水。一名尤因肉瘤患者有确诊的部分反应,2 名患者 (室管膜瘤和神经母细胞瘤) 病情稳定时间延长 (≥ 6 个周期)。Adavosertib 的药代动力学是可变的,但通常在年轻患者中剂量比例和清除率较低。
结论: Adavosertib (85 mg/m2) 与伊立替康 (90 mg/m2) 联合口服 5 天是儿童和青少年实体和中枢神经系统肿瘤的最大耐受剂量。

adavosertib

肿瘤 AZD1775 药物
概述  :  

Wee1 激酶是参与细胞周期 G /M 检查点和DNA损伤修复过程的关键激酶。超过50%的肿瘤存p53基因缺失或突变,导致细胞周期 G1/S 检查点的缺陷,使得肿瘤细胞DNA的复制及损伤修复过程更依赖于G2/M检查点。抑制Wee1激酶活性后,肿瘤细胞的DNA损伤不能及时修复便进入M期,造成基因组不稳定性和染色体缺失,引发有丝分裂灾难,导致肿瘤细胞凋亡。adavosertib是阿斯利康公司研发的小分子选择性Wee1激酶抑制剂,通过选择性抑制Wee1激酶,阻滞p53基因缺陷型肿瘤在G2/M期检查

Adavosertib 

释    义   n. 酪氨酸激酶WEE1的小分子抑制剂,一种药物

例    句   Adavosertib in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue.

Adavosertib联合吉西他滨和放射治疗的耐受性良好,其剂量可使替代组织产生靶向作用。

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