Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma

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