Phase 1 Trial of CUDC-907 in Children and Young Adults With Relapsed or Refractory Solid Tumors, CNS Tumors, or Lymphoma

• Age \> 1 years and ≤ 21 years at time of enrollment.

• Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 50% for patients \<16 years of age (see Appendix A)

• Diagnosis requirement

• For Parts A and B, participants must have evaluable or measurable disease (see Section 11).

• For Part A, participants must have histologically confirmed solid tumors, CNS tumors, or lymphoma based upon biopsy or surgery at initial diagnosis and/or relapse/progression. The only exception to histologic confirmation is for pediatric tumors that are routinely diagnosed exclusively by standard clinical imaging criteria: diffuse intrinsic pontine glioma and optic pathway glioma.

• For Part B, participants must have one of the following diagnoses histologically confirmed:

‣ Neuroblastoma with evidence of Mycn/Myc positivity based on any of the following:

• MYCN amplification (\> 4 copy amplification) from COG reference laboratory or other CLIA-certified laboratory; or

∙ Mycn protein expression \> 1+ according to validated assay in Children's Hospital Los Angeles (CHLA) Clinical Pathology Laboratory; or

∙ Myc expression \> 1+ according to validated assay in CHLA Clinical Pathology Laboratory.

⁃ One of the following mature B cell lymphoma diagnoses:

• Diffuse large B cell lymphoma

∙ Burkitt lymphoma

• Participants must have disease that is relapsed or refractory and for which standard curative or palliative measures do not exist or are no longer effective.

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy except organ function as noted in Section 3.1.6). Patients must meet the following minimum washout periods prior to enrollment:

• Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive chemotherapy (42 days for nitrosourea or mitomycin C).

• Radiotherapy:

‣ At least 14 days after local palliative XRT (small port);

⁃ At least 90 days must have elapsed after prior TBI, craniospinal XRT or if \>50% radiation of pelvis;

⁃ At least 42 must have elapsed if other substantial BM radiation;

⁃ At least 42 days must have passed since last MIBG or other radionuclide therapy.

• Small molecule biologic therapy: At least 7 days following the last dose of a biologic agent. For agents with known adverse events occurring beyond 7 days, this duration must be extended beyond the time in which adverse events are known to occur. If extended duration is required, this should be discussed and approved by the study chair.

• Monoclonal antibody: At least 21 days after the last dose of anitbody

• Myeloid growth factors: At least 14 days following the last dose of long-acting growth factor (e.g. Neulasta) or 7 days following short-acting growth factor.

• Stem Cell Infusion or Cellular Therapies: The patient must have no evidence of graft versus host disease and at least 42 days must have elapsed after transplant, stem cell infusion, or cellular therapy.

• Major Surgery: At least 3 weeks from prior major surgical procedure. Note: Biopsy and central line placement/removal are not considered major.

• PI3K and HDAC inhibitors: The patient must not have received prior CUDC-907 therapy. Prior treatment with individual PI3K or HDAC inhibitors is allowed. Patients must not have received therapy with the combination of PI3K and HDAC inhibitors.

• Participants must have normal organ function as defined below.

• Bone Marrow Function:

‣ Absolute neutrophil count ≥1,000/uL

⁃ Platelets ≥75,000/uL and transfusion independent, defined as not receiving a platelet transfusion for at least 5 days prior to CBC documenting eligibility.

• Hepatic Function:

‣ Total bilirubin ≤ 1.5 x upper limit of normal for age

⁃ ALT (SGPT) ≤ 135 U/L For the purpose of this study, the ULN for ALT is 45 U/L

⁃ Serum albumin \> 2 g/dL

• Renal Function:

⁃ -A serum creatinine based on age/gender as follows: Age Maximum Serum Creatinine (mg/dL) Male Female

‣ to \< 2 years 0.6 0.6

• 6 to \< 10 years 1 1 10 to \< 13 years 1.2 1.2 13 to \< 16 years 1.5 1.4

• ≥ 16 years 1.7 1.4 OR

⁃ -Creatinine clearance ≥ 70 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.

• Adequate Cardiac Function: QTc \< 480 msec

• Adequate GI Function: Diarrhea \< grade 2 by CTCAE version 4

• Adequate Metabolic Function: Fasting glucose \< grade 2 (\< 160 mg/dL or \< 8.9 mmol/L) without the use of antihyperglycemic agents.

• Additional Agent-Specific Requirements

• Patients must be able to swallow either intact capsules or mini-tabs without chewing.

• In order to limit dose deviations due to rounding, patients must have a body surface area of at least 0.5 m2

• For patients with CNS tumors (primary or metastatic), any baseline neurologic deficits (including seizure) must be stable for at least one week prior to study enrollment.

• Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, using an institutionally approved informed consent procedure.