Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Department of Hematology-Oncology, Memorial Regional Hospital/Joe Dimaggio Children's Hospital, Hollywood, FL, United States.
Oncologist. 2024 Jul 5;29(7):638-e952. doi: 10.1093/oncolo/oyae096.
The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib.
Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response.
Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed.
Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual.
CLINICALTRIALS.GOV IDENTIFIER: NCT03233204. IRB approved: initial July 24, 2017.
国家癌症研究所-儿童肿瘤组儿科分子分析治疗选择（MATCH）精准肿瘤学平台试验招募了 1-21 岁患有难治性实体肿瘤和预先确定的可操作遗传改变的儿童。肿瘤中存在 DNA 损伤修复（DDR）基因突变的患者被分配接受奥拉帕利治疗。
肿瘤和血液样本被提交进行集中分子检测。肿瘤和种系测序同时进行。奥拉帕利以每天两次的剂量开始给药，起始剂量比成人推荐的 2 期剂量（RP2D）低 30%，持续 28 天一个周期。主要终点是客观缓解。
18 名患者根据肿瘤测序中检测到的 BRCA1/2、RAD51C/D 或 ATM 有害基因突变，在没有种系减法或杂合性丢失（LOH）分析的情况下进行匹配（筛查患者的 1.5%）。11 名患者（61%）携带种系突变，只有 1 名患者存在 LOH。6 名患者入组并接受奥拉帕利起始剂量为 135mg/m2/剂量。2 名参与者完全可评估；4 名参与者不可评估，因为在第 1 周期中仅给予了<85%的规定剂量。没有剂量限制毒性或反应。观察到轻微的血液学毒性。
在 Pediatric MATCH 中检测到的大多数 DDR 基因突变是种系的、单等位基因的，不太可能导致同源重组缺陷，预测对奥拉帕利单药治疗敏感。由于入组人数少，该研究关闭。
临床试验.gov 标识符：NCT03233204。IRB 批准：2017 年 7 月 24 日首次批准。
