Background: Histone modification plays a key role in oncogenesis and progression of malignancy. Histone deacetylase (HDAC) inhibition has shown promise as anti-cancer therapy. Entinostat is an oral small molecule inhibitor of class I and IV HDACs that has not previously been evaluated in pediatric patients. We report the results of a phase 1 study of entinostat in children and adolescents with solid tumors. Methods: Children and adolescents (age £ 21 years) with relapsed or refractory solid tumors, including CNS tumors were eligible. Body-surface area ³ 1.17 m² was required. Entinostat (1 or 5 mg tablets) was administered orally, once weekly, in 4-week cycles. A rolling 6 design was used to evaluate two dose levels of 3 or 4 mg/m². A pharmacokinetic (PK) cohort was enrolled at the recommended dose. Results: Twenty eligible patients (10 male, 10 female), median (range) age 14.4 (8 -20) years were enrolled. Diagnoses included patients with CNS tumors (n = 11), sarcomas (n = 6) or other solid tumors (n = 3). Twelve patients were evaluable for DLT. Eight patients were not evaluable due to progression of disease prior to receiving the required percent of protocol prescribed therapy. No DLTs were observed at 3 mg/m² (n = 3) or among 9 patients (6 in dose escalation and 3 in the PK cohort) at the 4 mg/m² dose level. Grade 3 toxicities included neutropenia (n = 4), lymphopenia (n = 1), and leukopenia (n = 1). Most common non-hematologic toxicities (all grade £ 2) were elevated AST, fatigue, and hypophosphatemia (n = 4 each) and elevated ALT, hypoalbuminemia, and vomiting (n = 3 each). Pharmacokinetics of entinostat were evaluated and will be reported. Conclusions: Entinostat was well-tolerated with no DLTs observed. The recommended phase 2 dose in pediatric patients with solid tumors is 4 mg/m². Evaluation of entinostat in combination with other agents is planned. Clinical trial information: NCT02780804