Multinational phase 1-2 trial of olaparib and irinotecan for recurrent/refractory malignancies in children and young adults

Arm D of the AcSé-ESMART proof-of-concept phase 1-2 trial evaluated the combination of olaparib and irinotecan for recurrent or refractory malignancies in pediatric patients. Olaparib was adminstered orally twice daily on days 1-10 and irinotecan intravenously on days 4-8 of 21-day cycles. Cohorts were enriched for alterations in homologous recombination repair (HRR) pathways. 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 recommended phase 2 dose was olaparib 90 mg/m² twice daily and irinotecan 20 mg/m² per day. Olaparib exposure in children was equivalent to exposure in adults. Overall response rate was 9.1%; 11.8% in the cohort with diverse tumor types and 6.3% in the Ewing sarcoma cohort. Four patients with osteosarcoma, pineoblastoma, choroid plexus carcinoma, and neuroblastoma experienced a partial response and were treated for 9 to 51 cycles, whereas two patients with Ewing sarcoma experenced 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. The authors conclude that the combination of olaparib and irinotecan demonstrated activity in pediatric tumors which was enhanced among tumors that exhibited aneuploidy.