Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma
Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma
This randomized phase II/III trial is studying vorinostat, temozolomide, or bevacizumab to
 see how well they work compared with each other when given together with radiation therapy
 followed by bevacizumab and temozolomide in treating young patients with newly diagnosed
 high-grade glioma. Vorinostat may stop the growth of tumor cells by blocking some of the
 enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in
 different ways to stop the growth of tumor cells, either by killing the cells or by stopping
 them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in
 different ways. Some block the ability of tumor cells to grow and spread. Others find tumor
 cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses
 high-energy x-rays to kill tumor cells. It is not yet known whether giving vorinostat is more
 effective then temozolomide or bevacizumab when given together with radiation therapy in
 treating glioma.
PRIMARY OBJECTIVES:

 I. To identify the dose of vorinostat that is feasible when given in combination with
 radiotherapy (RT) in patients with newly diagnosed high-grade gliomas (HGG). II. To compare
 1-year event-free survival of patients with newly diagnosed HGG treated with vorinostat
 (using MTD) versus bevacizumab versus temozolomide when given in combination with RT followed
 by maintenance therapy with bevacizumab and temozolomide. (Phase II) III. To compare the
 event-free survival of patients with newly diagnosed HGG treated with the superior
 chemoradiotherapy (from phase II portion) versus temozolomide given in combination with RT
 followed by maintenance chemotherapy with bevacizumab and temozolomide. (Phase III)

 SECONDARY OBJECTIVES:

 I. To evaluate the anti-tumor activity, as measured by event-free survival (EFS),
 progression-free survival (PFS), and overall survival (OS), of patients with newly diagnosed
 HGG treated with vorinostat, bevacizumab, or temozolomide when given in combination with RT
 followed by maintenance chemotherapy with bevacizumab and temozolomide. II. To define and
 evaluate the toxicities of each of the treatment arms of the study.

 III. To conduct gene expression profiling and SNP arrays in patients with newly diagnosed
 HGG.

 IV. To assess telomerase activity, hTert expression, and telomere length in patients with
 newly diagnosed HGG. V. To document changes in perfusion and diffusion using MR imaging at
 baseline, prior to, during (prior to course 3), and after maintenance therapy with
 bevacizumab and temozolomide.

 VI. To correlate functional changes in tumor with responses to bevacizumab treatment using MR
 diffusion/perfusion imaging. VII. To correlate the results of the bevacizumab biology studies
 in serum or tumor with EFS.

 VIII. To explore the prognostic significance of MGMT status for patients newly diagnosed with
 HGG treated with combined surgery, radiation, chemotherapy, and anti-angiogenic therapy.

 OUTLINE: This is a multicenter, feasibility, dose-escalation study of vorinostat, followed by
 a phase II study, followed by a phase III study.

 FEASIBILITY STUDY: Patients undergo 3-D conformal radiotherapy (RT) or intensity-modulated RT
 5 days a week for 6 weeks. Patients also receive vorinostat orally (PO) once daily on days
 1-5. Courses repeat every week for 6 weeks in the absence of disease progression or
 unacceptable toxicity.

 MAINTENANCE THERAPY: Beginning 4 weeks after completion of chemoradiotherapy, patients
 receive bevacizumab IV over 30-90 minutes on days 1 and 15 and temozolomide PO on days 1-5.
 Treatment repeats every 28 days for 12 courses in the absence of disease progression or
 unacceptable toxicity.

 PHASE II STUDY: Patients are stratified according to extent of resection (near total
 resection or gross total resection vs other) and histology (glioblastoma multiforme vs
 other). Patients are randomized to 1 of 3 treatment arms.

 ARM I: Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the
 maximum-tolerated dose determined in the feasibility study.

 ARM II: Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily
 for 42 days by day 5 of RT.

 ARM III: Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90
 minutes on days 22 and 36.

 Maintenance therapy in arms I, II, III: Patients in all arms receive maintenance therapy as
 in the feasibility study.

 PHASE III study: Patients are randomized to 1 of 2 treatment arms.

 ARM IV: Patients receive RT and temozolomide as in phase II, arm II.

 ARM V: Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was
 established as the superior chemoradiotherapy arm in phase II.

 Maintenance Therapy: Beginning 4 weeks after completion of chemoradiotherapy, patients
 receive bevacizumab IV over 30-90 minutes on days 1 and 15 and temozolomide PO on days 1-5.
 Treatment repeats every 28 days for 12 courses in the absence of disease progression or
 unacceptable toxicity. Some patients undergo blood and tumor tissue sample (from surgery)
 collection for telomerase activity, hTert expression, telomere length, and gene expression
 profiling and SNP arrays analysis.

 After completion of study therapy, patients are followed up every 3 months for 1 year, every
 6 months for 4 years, and then annually for 5 years.
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