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

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 1-10 and irinotecan intravenously on Days 4-8 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 those in adults. 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 9 to 51 cycles. Two patients with Ewing sarcoma experienced a complete and a partial response for 10 and 42 cycles, respectively. Genetic analyses suggest high aneuploidy score possibly being 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.