A Phase I Study of Vorinostat and Bortezomib in Children With Refractory or Recurrent Solid Tumors, Including CNS Tumors and Lymphomas

Inclusion Criteria:

- Histologically confirmed solid tumors, including CNS tumors or lymphoma

- Histological confirmation not required for the following diagnoses

- Intrinsic brain stem tumors

- Optic pathway gliomas

- Pineal tumors and elevations of cerebral spinal fluid or serum tumor
markers, including alpha-fetoprotein or beta-human chorionic gonadotropin,
allowed

- Relapsed or refractory disease

- Must have measurable or evaluable tumor

- No known curative therapy or therapy proven to prolong survival with an acceptable
quality of life

- Karnofsky performance status (PS) 60-100% for patients > 16 years of age OR Lansky
PS60-100% for patients ≤ 16 years of age

- Neurologic deficits inpatients with CNS tumors must have been relatively stable
for a minimum of 1week

- Patients who are unable to walk because ofparalysis, but who are up in a
wheelchair, will be considered ambulatory for thepurpose of assessing the
performance score

- ANC ≥ 1,000/μL

- Platelet count ≥ 100,000/μL (transfusion independent, defined as not receiving
platelet transfusions within the past 7 days)

- Patients with known bone marrow metastatic disease allowed provided they meet
the blood count criteria and are not known to be refractory to platelet
transfusion

- Hemoglobin ≥ 8.0 g/dL (may receive RBC transfusions)

- Patients with known bone marrow metastatic disease allowed provided they meet
the blood count criteria and are not know to be refractory to RBC or platelet
transfusion

- Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age
and/or gender as follows:

- 0.6 mg/dL (1 to < 2 years of age)

- 0.8 mg/dL (2 to < 6 years of age)

- 1.0 mg/dL (6 to < 10 years of age)

- 1.2 mg/dL (10 to < 13 years of age)

- 1.5 (male) or 1.4 (female) (13 to < 16 years of age)

- 1.7 (male) or 1.4 (female) ( ≥ 16 years of age)

- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 times upper limit ofnormal

- ALT ≤ 110 U/L

- Serum albumin ≥ 2 g/dL

- QTc interval ≤ 450 milliseconds

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Must be able to swallow capsules or liquids

- Able to comply withthe safety-monitoring requirements of the study, in the opinion of
the investigator

- No peripheral neuropathy ≥ grade 2 within the past 14 days

- No known hypersensitivity to vorinostat or bortezomib

- No uncontrolled infection

- No concurrent enzyme-inducing anticonvulsants

- Must be recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy

- More than 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosourea)

- At least 7 days since prior therapy with any of the following:

- Hematopoietic growth factors

- Biologic (anti-neoplastic) agent

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which
adverse events are known to occur

- Corticosteroids unless on a stable or decreasing dose

- At least 7 days or 3 half-lives, whichever is longer, since prior monoclonal
antibodies

- At least 2 weeks since prior local palliative radiotherapy (small port)

- At least 6 months since prior total-body irradiation therapy, craniospinal
radiotherapy, or ≥ 50% of pelvis irradiated

- At least 6 weeks since prior substantial bone marrow radiotherapy

- At least 3 months since prior stem cell transplantation or rescue and no evidence of
active graft-vs-host disease

- At least 2 weeks since prior and no concurrent valproic acid

- At least 6 weeks since priorimmunotherapy (e.g., tumor vaccines)

- No prior vorinostat

- No other concurrent investigational drugs or other anticancer agents, including
chemotherapy, radiotherapy, immunotherapy, or biologic therapy