Phase I/II Study of the PARP Inhibitor Olaparib and Irinotecan in Children and Young Adults with Recurrent/Refractory Malignancies: Arm D of the AcSé-ESMART Trial
Mené sur 70 enfants et jeunes adultes atteints d'une tumeur réfractaire ou récidivante (âge médian : 14,9 ans), cet essai de phase I/II détermine la dose maximale tolérée de l'olaparib en combinaison avec l'irinotécan, puis évalue l'efficacité de cette combinaison du point de vue du taux de réponse
Purpose: Arm D of the AcSé-ESMART proof-of-concept phase I/II platform trial aimed to define the recommended phase II dose (RP2D), pharmacokinetics, activity, and biomarkers of the PARP inhibitor olaparib with irinotecan in pediatric patients with recurrent/refractory malignancies.
Patients and Methods: Olaparib was administered orally twice daily on days 1 to 10 and irinotecan intravenously on days 4 to 8 of a 21-day cycle. Dose escalation followed the continuous reassessment method; activity was assessed in diverse tumor types (cohort 1) and Ewing sarcoma (cohort 2) according to a minimax Simon 2-stage design. Cohorts were enriched for alterations in homologous recombination repair (HRR) pathways.
Results: Seventy patients (median age, 14.9 years; range, 5.0–23.8) were included, 34 with diverse tumor types (25 with HRR gene alterations) and 36 with Ewing sarcoma. Sixty-six patients received 348 treatment cycles (median, 2; range, 1–51) over four dose levels. Main toxicities were gastrointestinal and myelosuppression; the RP2D was olaparib 90 mg/m2 twice daily and irinotecan 20 mg/m2/day. Olaparib exposure in children was equivalent to that in adults. The overall response rate was 9.1% (cohort 1, 11.8%; cohort 2, 6.3%). Four patients with osteosarcoma, pineoblastoma, choroid plexus carcinoma, and neuroblastoma experienced a partial response and were treated for nine to 51 cycles. Two patients with Ewing sarcoma experienced a complete and a partial response for 10 and 42 cycles, respectively. Genetic analyses suggest a high aneuploidy score possibly associated with objective response and prolonged stable disease.
Conclusions: Olaparib combined with irinotecan demonstrated activity in pediatric tumors, which was enriched among tumors that exhibited aneuploidy.
Clinical Cancer Research , résumé, 2026