A Randomized Phase II/III Study of Vorinostat (IND# 71976) and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab (IND# 7921) and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas

Inclusion Criteria:

- Newly diagnosed high-grade glioma

- Anaplastic astrocytoma

- Glioblastomamultiforme

- Gliosarcoma

- Primary spinal cord malignant glioma allowed

- No oligodendroglioma oroligoastrocytoma

- Patient must have histological verification of diagnosis

- No M+ disease (defined as evidence of neuraxis dissemination)

- No positive CSF cytology

- ECOG performance status (PS) 0-2

- Karnofsky PS 50-100% (patients > 16 years of age)

- Lansky PS 50-100% (patients ≤ 16 years of age)

- ANC ≥ 1,000/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 8.0 mg/dL (transfusion independent)

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

- 0.4 mg/dL (1 month to < 6 months of age)

- 0.5 mg/dL (6 months to < 1 year of age)

- 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 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)

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

- Proteinuria < 2+ OR urine; protein ratio (UPC) ≤ 0.5

- If UPC > 0.5, a 24-hour urine protein should be obtained and level should be <
1,000 mg of protein

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT < 2.5 times ULN

- Serum albumin ≥ 2 g/dL

- PT INR ≤ 1.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during all study therapy and for ≥
6 months after completion of bevacizumab

- Hypertension well controlled (≤ 95^th percentile for age and height if patient is ≤
17years) by stable doses of medication allowed

- For patients > 17 years, systolic blood pressure (BP) ≤ 150 mm Hg or diastolic
BP ≤ 100 mm Hg)

- Seizure disorder allowed provided patient is well-controlled and on
nonenzyme-inducing anticonvulsants

- No history of myocardial infarction, severe or unstable angina, clinically
significant peripheral vascular disease, ≥ grade 2 heart failure, or serious and
inadequately controlled cardiac arrhythmia

- No known bleeding diathesis or coagulopathy

- No prior arterial thromboembolic events, including transient ischemic attacks
orcerebrovascular accidents

- No prior diagnosis of a deep venous thrombosis, including pulmonary embolism, and no
known thrombophilic condition (e.g., protein S, protein C, antithrombin III
deficiency, Factor V Leiden or Factor II G202`0A mutation, homocysteinemia, or
antiphospholipid antibody syndrome)

- No history of an abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within the past 6 months

- No serious or non-healing wound, ulcer, or bone fracture

- No evidence of significant postoperative intracranial hemorrhage, defined as > 1 cm
of blood on postoperative MRI scan (potentially in addition to the postoperative
scan) obtained within the past 14days

- No history of allergic reaction to Chinese hamster ovary cell products or other
recombinanthuman antibodies

- No more than 31 days since definitive surgery

- Must not have received any prior chemotherapy, radiotherapy, immunotherapy, or bone
marrow transplant

- More than 7 days since major surgical procedure and recovered

- For patients scheduled to receive bevacizumab:

- More than 28 days since major procedure

- More than 14 days since intermediate procedure

- More than 7 days since minor procedure (lumbar picture or placement of PICC
lines are not considered minor procedures)

- No other current anti-cancer agents

- No concurrent nonsteroidal anti-inflammatory medications known to inhibit platelet
function or known to selectively inhibit cyclooxygenase activity

- No concurrent enzyme inducing anticonvulsants

- No concurrent HDAC inhibitors (e.g., valproic acid)

- No concurrent anticoagulants including systemic thrombolytic agents, heparin, low
molecular weight heparins, or warfarin except as required to maintain patency of
pre-existing permanent vascular catheters or for prevention of thrombosis in the
post-operative period