Journal Article

Olaparib for childhood tumors harboring defects in DNA damage repair genes: arm H of the NCI-COG Pediatric MATCH trial

Parsons, Donald W, Alonzo, Todd A, Williams, Paul M, Berg, Stacey L, Janeway, Katherine A, Roy-Chowdhuri, Sinchita, Saguilig, Lauren, Takebe, Naoko, Ramirez, Nilsa C, Tricoli, James V, Reid, Joel M, Pinkney, Kerice, Piao, Jin, Seibel, Nita L, Patton, David R, Fox, Elizabeth, Glade Bender, Julia L, Mooney, Margaret M, Weigel, Brenda J, Hawkins, Douglas S, Coffey, Brent D

2024

Overview

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. This article reports clinical trial results of the National Cancer Institute-Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice precision oncology platform trial, which enrolled patients aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Those with tumors harboring alterations in DNA damage repair genes were assigned to receive olaparib.

• Publisher: Oxford University Press
• Subject: Adolescent / Adult / Ataxia Telangiectasia Mutated Proteins - genetics / BRCA1 Protein - genetics / BRCA2 Protein - genetics / Cancer / Care and treatment / Child / Child, Preschool / Clinical Trial Results / DNA / DNA damage / DNA Damage - drug effects / DNA Repair - drug effects / DNA Repair - genetics / DNA-Binding Proteins - genetics / Drug therapy / Female / Gene mutations / Genes / Genetic aspects / Genetic research / Germ-Line Mutation / Health aspects / Humans / Infant / Male / Neoplasms - drug therapy / Neoplasms - genetics / Oncology / Pediatric research / Pediatrics / Pharmacology, Experimental / Phthalazines - administration & dosage / Phthalazines - adverse effects / Phthalazines - therapeutic use / Physiological aspects / Piperazines - administration & dosage / Piperazines - adverse effects / Piperazines - therapeutic use / Poly(ADP-ribose) Polymerase Inhibitors - adverse effects / Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use / Tumors / Tumors in children / Young Adult