Center for Medical Ethics and Health Policy Staff Publications
Publication Date
7-5-2024
Journal
The Oncologist
DOI
10.1093/oncolo/oyae096
PMID
38815151
PMCID
PMC11224971
PubMedCentral® Posted Date
5-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Infant, Male, Young Adult, Ataxia Telangiectasia Mutated Proteins, BRCA1 Protein, BRCA2 Protein, DNA Damage, DNA Repair, DNA-Binding Proteins, Germ-Line Mutation, Neoplasms, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors, olaparib, PARP inhibition, DNA damage repair, pediatric MATCH
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.
Clinicaltrials.gov identifier: NCT03233204. IRB approved: initial July 24, 2017.