Background: Sorafenib, an orally bioavailable, multi-target tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated single agent activity in various malignancies. This study was designed to determine the maximum tolerated dose of sorafenib in combination with irinotecan and assess the feasibility of incorporating patient reported outcome (PRO) measures into a phase I trial in children with relapsed or refractory solid tumors. Methods: Sorafenib was administered orally twice daily, continuously, beginning at 150 mg/m²/dose with irinotecan, 70 mg/m²/dose orally, once daily for 5 days to complete a 21-day cycle (dose level 1). Sorafenib was escalated to 200 mg/m²/dose (dose level 2) followed by escalation of irinotecan to 90 mg/m²/dose (dose level 3). Three patients enrolled initially at each dose level. Secondary aims included evaluating PRO measures as an adjunct to traditional phase 1 endpoints and determining the pharmacokinetic profile of sorafenib and irinotecan in children. Results: Twelve evaluable patients [6 male, 6 female; median age 13 years (range 4.6-19.8)] with Wilms tumor (n= 4), osteosarcoma (n=3), neuroblastoma (n=1), CNS tumor (n=1), desmoplastic small round cell tumor (n=1), soft tissue sarcoma (n=1) and germ cell tumor (n=1) have enrolled to date. No dose limiting toxicities (DLT) were seen at dose level 1 (n=3). Two of 3 patients at dose level 2 experienced DLT (grade 3 diarrhea with dehydration, grade 3 hyponatremia). Dose level 1 was expanded to evaluate up to 12 patients. Of 9 patients who have completed therapy at this dose level, one patient had DLT, grade 4 thrombocytopenia. Three patients received ≥6 cycles with stable disease prior to disease progression. Two additional patients were removed from protocol therapy after experiencing responses that rendered them eligible for surgical resection. All eligible patients (n=4) completed PRO measures. Conclusions: The recommended dose for children is anticipated to be sorafenib 150 mg/m²/dose, twice daily, continuously with irinotecan 70 mg/m²/dose, once daily for 5 days, repeated every 21 days. This convenient, oral outpatient regimen is well tolerated in pediatric patients. Clinical trial information: NCT01518413.