Background: CUDC-907 is an oral first-in-class small molecule inhibitor of histone deacetylases (HDACs) and phosphatidylinositol-3-kinases (PI3Ks), two enzyme classes commonly implicated in pediatric malignancies. Preclinical data demonstrate that inhibition of these enzymes decreases tumor growth across a range of histologies. Data from preclinical and clinical studies suggest that down-regulation of Myc or Mycn signaling may be important in the antineoplastic effects of CUDC-907. Myc or Mycn signaling appears to drive a number of pediatric cancers, heralds a poor prognosis in many of these diseases and has proven difficult to target. CUDC-907 has completed adult phase I testing in patients with hematologic malignancies. The drug was tolerable using a 5 days on/2 days off (5/2) dosing strategy, with a recommended phase II dose of 60 mg. Diarrhea, fatigue, nausea and thrombocytopenia were the most commonly reported side effects. Partial and complete responses were observed in patients with Myc-altered diffuse large B cell lymphoma. Methods: This study is a phase I, open-label, multicenter trial of CUDC-907 in patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). The primary objectives are to determine the recommended phase II dose, describe toxicities, and describe pharmacokinetic parameters of CUDC-907 in this population. Other objectives include evaluation of disease response and exploration of the pharmacodynamic effects of CUDC-907. Patients receive CUDC-907 orally on a 5/2 schedule in 28-day cycles, with a pediatric mini-tab formulation available for younger children. Part A consists of a standard 3+3 design evaluating up to three dose levels. Following dose escalation, Part B consists of two expansion cohorts for patients with Mycn/Myc-driven neuroblastoma or mature B-cell lymphoma. Up to 44 patients may be enrolled across Parts A and B. Detailed pharmacokinetic testing is required in the first two cycles. Optional pharmacodynamic testing will quantify histone acetylation, Myc protein, and phospho-S6 in serial blood samples. Enrollment began in October 2016 and is ongoing. Clinical trial information: NCT02909777