Background: CUDC-907 is a first-in-class small molecule inhibitor of histone deacetylases and phosphatidylinositol-3-kinases. Data from pediatric preclinical models, and adult clinical studies suggest that CUDC-907 can downregulate Myc/Mycn, providing a potential therapeutic strategy for Myc/Mycn-driven pediatric tumors. Methods: Using a 3+3 dose escalation design, CUDC-907 was administered at 3 dose levels to patients 1-21 years of age with relapsed/refractory solid tumors, brain tumors and lymphomas (NCT02909777). Primary objectives were to determine the pediatric recommended phase II dose (RP2D), describe toxicities, and describe PK parameters. Other endpoints included antitumor activity and pharmacodynamic effects. Patients received CUDC-907 orally on a 5 days on / 2 days off (“5/2”) schedule in 28-day cycles, with a pediatric mini-tab formulation for children who could not swallow pills. Results: As of 11/16/2017, 15 patients enrolled, with a median age of 15 (4.6-20.9) years. Diagnoses included: osteosarcoma (n = 4); alveolar rhabdomyosarcoma (n = 3); DIPG (n = 2); ependymoma (n = 2); Ewing sarcoma (n = 2); CNS germ cell tumor (n = 1); and alveolar soft part sarcoma (n = 1). Patients received a median of 2 (1-7+) cycles. No DLTs were observed in 3 evaluable patients each at dose levels 1 and 2. A single first cycle DLT (grade 3 metabolic acidosis) was observed in 1 of 6 evaluable patients at dose level 3 (45 mg/m2; 128% of the adult RP2D). The most common treatment-related AEs were: thrombocytopenia (87%), nausea (80%), lymphopenia (80%), diarrhea (73%), leukopenia (73%), anemia (67%), tachycardia (67%), vomiting (67%), fatigue (67%), and anorexia (67%). The mean T_max was 2.5 hrs and T_1/2 was 1.4 hrs. No objective responses were seen. One patient with Ewing sarcoma and one patient with ependymoma had stable disease for 6 and 7+ cycles, respectively. Pharmacodynamic studies are pending. Conclusions: CUDC-907 was well tolerated with a pediatric RP2D of 45 mg/m2 administered orally on a 5/2 schedule. An expansion stage will evaluate this dose in groups of interest: mature B-cell lymphoma; MYCN amplified neuroblastoma; and solid tumors with MYC/MYCN amplification/high-copy gain. Clinical trial information: NCT02909777