Background: Poly (ADP-ribose) Polymerase inhibitors (PARPi) target tumors with deficiencies in DNA repair mechanisms. Talazoparib (TAL), a potent PARP inhibitor, demonstrated significant efficacy in a Ewing sarcoma model when combined with DNA-damaging irinotecan (IRN). We performed a phase I trial to determine the maximum tolerated doses (MTDs) of TAL and IRN in pediatric patients with solid tumors. Methods: Cohorts of 3-6 eligible patients (pts) with recurrent/refractory solid tumors received escalating doses of oral (PO) TAL and intravenous (IV) IRN in a 3+3 design (Table 1). Each course was 21 days. Serum for TAL and IRN pharmacokinetics (PK) were obtained. Toxicities were assessed using CTCAE v.4 and responses were evaluated by RECIST v.1.1. Results: Twenty-four pts (9 male; median age, 11 years; 18 recurrent) received a median of 2 courses (range, 1-18). Fifteen pts had prior exposure to IRN. Table 1 summarizes the dose-limiting toxicities (DLTs) in course 1. The most common grade 3 or higher non-hematologic and hematologic toxicities in 82 evaluable courses were febrile neutropenia (5), elevated gamma-glutamyltransferase (GGT, 4), neutropenia (22) and lymphopenia (17). Two of 22 evaluable patients had a response (CR Ewing sarcoma, 18 courses; PR synovial sarcoma, 10 courses) and 9 had disease stabilization, median 4 courses (range, 4-10). Results of PK tests will be presented. Conclusions: The recommended phase II doses are TAL 600mcg/m² (max 1000mcg/dose) days 1-6 and IRN 40mg/m²/day days 2-6. This regimen is feasible with evidence of anti-tumor activity and warrants further investigation. Clinical trial information: NCT02392793