| Abstract: |
Background: 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. Methods: 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. Results: 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. Conclusion: 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. © The Author(s) 2024. Published by Oxford University Press. |
| Keywords: |
adolescent; adult; child; clinical article; preschool child; school child; child, preschool; young adult; dna binding protein; gene mutation; genetics; dna-binding proteins; drug efficacy; dna replication; neoplasm; neoplasms; phenotype; dna damage; gene; homologous recombination; dna repair; phase 2 clinical trial; breast cancer; prevalence; gene frequency; drug effect; brca1 protein; brca2 protein; histology; childhood cancer; irinotecan; infant; heterozygosity; mismatch repair; atm protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; radiosensitivity; maximum plasma concentration; heterozygosity loss; piperazines; drug therapy; piperazine derivative; comparative genomic hybridization; brca1 protein, human; germ-line mutation; olaparib; personalized medicine; phthalazine derivative; phthalazines; germline mutation; high throughput sequencing; brca2 protein, human; dna damage repair; humans; human; male; female; article; ataxia telangiectasia mutated proteins; whole exome sequencing; poly(adp-ribose) polymerase inhibitors; parp inhibition; atm protein, human; rad51c protein, human; pediatric match; rad51d protein, human
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