Background: AcSé-ESMART is a proof-of-concept, phase I/II, multicenter, prospective basket trial designed to explore targeting agents in a molecularly enriched cancer population; treatment arms with targeted agents as single agent or in combination regimens are explored independently. Arm D explores the PARP inhibitor olaparib (ola) in combination with irinotecan (iri). The design is based on the hypothesis that in pediatric cancer pathogenic BRCA alterations are extremely rare and proliferative capacity is high requiring a chemotherapy sensitisation approach. Preclinical data in pediatric cancer suggest PARP inhibitor activity in other genomic alterations impairing homologous recombination (HR) and demonstrate synergy with iri. We here report the results of the Phase I part of the trial. Methods: Children and adolescents with relapsed/refractory cancer and comprehensive molecular profiling (whole exome and RNA sequencing) at relapse were eligible. Dose-escalation followed a continuous reassessment method design of pre-specified dose combinations of oral ola and iv iri. Plasma for pharmacokinetics (PK) was collected. Results: From Oct 2016 to April 2018, 27 pts (19 sarcomas, 3 brain tumors, 5 other) with a median age of 15 y (range 4;22) were enrolled over 4 dose levels. Dose limiting toxicities occurred in 7 of 24 evaluable pts (gastrointestinal (n = 4), febrile neutropenia (n = 1), thrombocytopenia (n = 2)). The RP2D was defined as ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Twenty-three pts evaluable for response received a median of 2 cycles (range 1-27+). Confirmed PRs were seen in one osteosarcoma, one pinealoblastoma and one neuroblastoma; time to progression was 22.4, 50 and 89+ weeks, respectively. Eight pts experienced disease stabilization (median 14.8 weeks, range 9;42.3). PK and biomarker analysis (ie. HR alterations, DNA and gene expression signatures) is ongoing to identify factors associated with clinical benefit and data will be presented. Conclusions: The RP2D of the combination is ola 90 mg/m2 BID day 1-10 and iri 20 mg/m2 day 4-8. Preliminary activity led to the ongoing Phase II part of the arm. Clinical trial information: NCT02813135