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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01236560
• Collaborator: (none)
• Enrollment: 101
• Locations: 137
• Arms: 6
• Patients Per Site: 0.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Brain Stem Glioma; Cerebral Astrocytoma; Childhood Cerebellar Anaplastic Astrocytoma; Childhood Cerebral Anaplastic Astrocytoma; Childhood Spinal Cord Neoplasm	Biological: Bevacizumab; Drug: Temozolomide; Drug: Vorinostat	Phase 2/Phase 3

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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.

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

3. 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.

4. 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.

5. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 101 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II/III Study of Vorinostat and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas
• Actual Study Start Date: Nov 15, 2010
• Actual Primary Completion Date: Sep 27, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (vorinostat, Phase II Arm A) Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ ; Drug: Vorinostat; Given PO; Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza
Experimental: Arm II (temozolomide, Phase II Arm B) Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ
Experimental: Arm III (Bevacizumab, Phase II Arm) Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ
Experimental: Arm IV (temozolomide, Phase 3 Arm B) Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ
Experimental: Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy) Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ ; Drug: Vorinostat; Given PO; Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza
Experimental: Feasibility (vorinostat) Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.	Biological: Bevacizumab; Given IV; Other Names: ABP 215 Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF Monoclonal Antibody SIBP04 Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar ABP 215 Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar GB-222 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar Mvasi Bevacizumab Biosimilar MYL-1402O Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 Bevacizumab Biosimilar Zirabev Bevacizumab-awwb Bevacizumab-bvzr BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Mvasi MYL-1402O Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 SIBP 04 SIBP-04 SIBP04 Zirabev ; Drug: Temozolomide; Given PO; Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac TMZ ; Drug: Vorinostat; Given PO; Other Names: L-001079038 MSK-390 SAHA Suberanilohydroxamic Acid Suberoylanilide Hydroxamic Acid Zolinza

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) of Vorinostat [10 weeks]

   The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy.

2. Event-free Survival [1 year after enrollment]

   Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a ≥ 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).

Secondary Outcome Measures

1. Overall Survival [1 year after enrollment]

   Time from enrollment to death or last follow-up, whichever occurs first.

2. Cumulative Incidence of Disease Progression in Each Treatment Arm [1 year after enrollment]

   Cumulative incidence of progression where death from any cause prior to progression and diagnosis of a second malignant neoplasm prior to progression are considered competing events. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a ≥ 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35233
2	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
3	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Kaiser Permanente Downey Medical Center	Downey	California	United States	90242
5	Loma Linda University Medical Center	Loma Linda	California	United States	92354
6	Miller Children's and Women's Hospital Long Beach	Long Beach	California	United States	90806
7	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
8	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
9	Mattel Children's Hospital UCLA	Los Angeles	California	United States	90095
10	Valley Children's Hospital	Madera	California	United States	93636
11	UCSF Benioff Children's Hospital Oakland	Oakland	California	United States	94609
12	Kaiser Permanente-Oakland	Oakland	California	United States	94611
13	Children's Hospital of Orange County	Orange	California	United States	92868
14	Lucile Packard Children's Hospital Stanford University	Palo Alto	California	United States	94304
15	Rady Children's Hospital - San Diego	San Diego	California	United States	92123
16	UCSF Medical Center-Parnassus	San Francisco	California	United States	94143
17	UCSF Medical Center-Mission Bay	San Francisco	California	United States	94158
18	Children's Hospital Colorado	Aurora	Colorado	United States	80045
19	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
20	Yale University	New Haven	Connecticut	United States	06520
21	Alfred I duPont Hospital for Children	Wilmington	Delaware	United States	19803
22	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
23	Children's National Medical Center	Washington	District of Columbia	United States	20010
24	Lee Memorial Health System	Fort Myers	Florida	United States	33901
25	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida	United States	33908
26	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida	United States	32207
27	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
28	Nicklaus Children's Hospital	Miami	Florida	United States	33155
29	AdventHealth Orlando	Orlando	Florida	United States	32803
30	Arnold Palmer Hospital for Children	Orlando	Florida	United States	32806
31	Nemours Children's Clinic - Orlando	Orlando	Florida	United States	32806
32	Orlando Health Cancer Institute	Orlando	Florida	United States	32806
33	Nemours Children's Clinic - Pensacola	Pensacola	Florida	United States	32504
34	Johns Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
35	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida	United States	33607
36	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia	United States	30322
37	Memorial Health University Medical Center	Savannah	Georgia	United States	31404
38	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
39	Lurie Children's Hospital-Chicago	Chicago	Illinois	United States	60611
40	University of Illinois	Chicago	Illinois	United States	60612
41	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
42	Saint Jude Midwest Affiliate	Peoria	Illinois	United States	61637
43	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
44	Riley Hospital for Children	Indianapolis	Indiana	United States	46202
45	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana	United States	46260
46	Blank Children's Hospital	Des Moines	Iowa	United States	50309
47	University of Kentucky/Markey Cancer Center	Lexington	Kentucky	United States	40536
48	Norton Children's Hospital	Louisville	Kentucky	United States	40202
49	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
50	Tufts Children's Hospital	Boston	Massachusetts	United States	02111
51	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
52	C S Mott Children's Hospital	Ann Arbor	Michigan	United States	48109
53	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
54	Michigan State University Clinical Center	East Lansing	Michigan	United States	48824-7016
55	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
56	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
57	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota	United States	55404
58	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
59	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
60	Children's Mercy Hospitals and Clinics	Kansas City	Missouri	United States	64108
61	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri	United States	63104
62	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
63	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
64	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska	United States	68114
65	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
66	Alliance for Childhood Diseases/Cure 4 the Kids Foundation	Las Vegas	Nevada	United States	89135
67	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada	United States	89169
68	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
69	Morristown Medical Center	Morristown	New Jersey	United States	07960
70	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey	United States	08903
71	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
72	Overlook Hospital	Summit	New Jersey	United States	07902
73	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
74	Albany Medical Center	Albany	New York	United States	12208
75	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
76	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
77	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York	United States	11040
78	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
79	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
80	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
81	University of Rochester	Rochester	New York	United States	14642
82	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
83	New York Medical College	Valhalla	New York	United States	10595
84	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
85	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
86	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
87	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
88	Children's Hospital Medical Center of Akron	Akron	Ohio	United States	44308
89	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
90	Rainbow Babies and Childrens Hospital	Cleveland	Ohio	United States	44106
91	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
92	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
93	Dayton Children's Hospital	Dayton	Ohio	United States	45404
94	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio	United States	43606
95	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
96	Oregon Health and Science University	Portland	Oregon	United States	97239
97	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania	United States	18017
98	Penn State Children's Hospital	Hershey	Pennsylvania	United States	17033
99	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
100	Children's Oncology Group	Philadelphia	Pennsylvania	United States	19104
101	Saint Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134
102	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
103	Rhode Island Hospital	Providence	Rhode Island	United States	02903
104	Medical University of South Carolina	Charleston	South Carolina	United States	29425
105	Prisma Health Richland Hospital	Columbia	South Carolina	United States	29203
106	BI-LO Charities Children's Cancer Center	Greenville	South Carolina	United States	29605
107	Greenville Cancer Treatment Center	Greenville	South Carolina	United States	29605
108	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
109	East Tennessee Childrens Hospital	Knoxville	Tennessee	United States	37916
110	Saint Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
111	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
112	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
113	Driscoll Children's Hospital	Corpus Christi	Texas	United States	78411
114	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
115	Cook Children's Medical Center	Fort Worth	Texas	United States	76104
116	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas	United States	77030
117	Methodist Children's Hospital of South Texas	San Antonio	Texas	United States	78229
118	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
119	Scott and White Memorial Hospital	Temple	Texas	United States	76508
120	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
121	Naval Medical Center - Portsmouth	Portsmouth	Virginia	United States	23708-2197
122	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
123	Seattle Children's Hospital	Seattle	Washington	United States	98105
124	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington	United States	99204
125	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington	United States	98405
126	West Virginia University Charleston Division	Charleston	West Virginia	United States	25304
127	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
128	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
129	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226
130	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
131	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
132	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
133	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
134	The Montreal Children's Hospital of the MUHC	Montreal	Quebec	Canada	H3H 1P3
135	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
136	Saskatoon Cancer Centre	Saskatoon	Saskatchewan	Canada	S7N 4H4
137	Centre Hospitalier Universitaire de Quebec	Quebec		Canada	G1V 4G2

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Maryam Fouladi, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01236560
• Other Study ID Numbers: NCI-2011-02616; NCI-2011-02616; CDR0000688443; ACNS0822; 11-00910; ACNS0822; ACNS0822; U10CA180886; U10CA098543
• First Posted: Nov 7, 2010
• Last Update Posted: Jul 28, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Glioma; Astrocytoma; Spinal Cord Neoplasms; Bevacizumab; Antineoplastic Agents, Immunological; Temozolomide; Vorinostat; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Pre-assignment Detail	After one-year EFS, neither Vorinostat nor Bevacizumab were found superior to temozolomide, therefore Phase III portion of the study did not occur.

Arm/Group Title	Feasibility (Vorinostat)	Arm I (Vorinostat, Phase II Arm A)	Arm II (Temozolomide, Phase II Arm B)	Arm III (Bevacizumab, Phase II Arm C)	Arm IV (Temozolomide, Phase III Arm B)	Arm V (Vorinostat/Bevacizumab, Phase III, Chemoradiotherapy
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO
Period Title: Overall Study
STARTED	6	32	31	32	0	0
COMPLETED	1	8	11	10	0	0
NOT COMPLETED	5	24	20	22	0	0

Baseline Characteristics

Arm/Group Title	Feasibility (Vorinostat)	Arm I (Vorinostat, Phase II Arm A)	Arm II (Temozolomide, Phase II Arm B)	Arm III (Bevacizumab, Phase II Arm C)	Arm IV (Temozolomide, Phase III Arm B)	Arm V (Vorinostat/Bevacizumab, Phase III, Chemoradiotherapy	Total
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Total of all reporting groups
Overall Participants	6	32	31	32	0	0	101
Age (Count of Participants)
<=18 years	6 100%	29 90.6%	29 93.5%	29 90.6%	0 NaN	0 NaN	93 92.1%
Between 18 and 65 years	0 0%	3 9.4%	2 6.5%	3 9.4%	0 NaN	0 NaN	8 7.9%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	12.6	12.2	11.3	11.8	11.8
Sex: Female, Male (Count of Participants)
Female	3 50%	16 50%	15 48.4%	12 37.5%	0 NaN	0 NaN	46 45.5%
Male	3 50%	16 50%	16 51.6%	20 62.5%	0 NaN	0 NaN	55 54.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	4 12.5%	6 19.4%	3 9.4%	0 NaN	0 NaN	13 12.9%
Not Hispanic or Latino	6 100%	26 81.3%	24 77.4%	27 84.4%	0 NaN	0 NaN	83 82.2%
Unknown or Not Reported	0 0%	2 6.3%	1 3.2%	2 6.3%	0 NaN	0 NaN	5 5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Asian	0 0%	3 9.4%	1 3.2%	1 3.1%	0 NaN	0 NaN	5 5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 3.2%	0 0%	0 NaN	0 NaN	1 1%
Black or African American	0 0%	0 0%	6 19.4%	3 9.4%	0 NaN	0 NaN	9 8.9%
White	6 100%	25 78.1%	21 67.7%	27 84.4%	0 NaN	0 NaN	79 78.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 NaN	0 NaN	0 0%
Unknown or Not Reported	0 0%	4 12.5%	2 6.5%	1 3.1%	0 NaN	0 NaN	7 6.9%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Vorinostat
Description	The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy.
Time Frame	10 weeks

Outcome Measure Data

Analysis Population Description

MTD is determined using only patients treated with vorinostat

Arm/Group Title	Feasibility (Vorinostat)
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO
Measure Participants	6
Number [mg/sq m]	230

2. Primary Outcome

Title	Event-free Survival
Description	Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a ≥ 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).
Time Frame	1 year after enrollment

Outcome Measure Data

Analysis Population Description

Only eligible patients included in analysis

Arm/Group Title	Feasibility (Vorinostat)	Arm I (Vorinostat, Phase II Arm A)	Arm II (Temozolomide, Phase II Arm B)	Arm III (Bevacizumab, Phase II Arm C)
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO
Measure Participants	6	31	27	32
Number (95% Confidence Interval) [percent probability]	33.3	41.3	59.3	43.8

3. Secondary Outcome

Title	Overall Survival
Description	Time from enrollment to death or last follow-up, whichever occurs first.
Time Frame	1 year after enrollment

Outcome Measure Data

Analysis Population Description

Only eligible patients included in analysis

Arm/Group Title	Feasibility (Vorinostat)	Arm I (Vorinostat, Phase II Arm A)	Arm II (Temozolomide, Phase II Arm B)	Arm III (Bevacizumab, Phase II Arm C)
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO
Measure Participants	6	31	27	32
Number (95% Confidence Interval) [percent probability]	33.3	82.2	85.2	67.3

4. Secondary Outcome

Title	Cumulative Incidence of Disease Progression in Each Treatment Arm
Description	Cumulative incidence of progression where death from any cause prior to progression and diagnosis of a second malignant neoplasm prior to progression are considered competing events. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a ≥ 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).
Time Frame	1 year after enrollment

Outcome Measure Data

Analysis Population Description

Only eligible patients included in analysis.

Arm/Group Title	Feasibility (Vorinostat)	Arm I (Vorinostat, Phase II Arm A)	Arm II (Temozolomide, Phase II Arm B)	Arm III (Bevacizumab, Phase II Arm C)
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO	Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO	Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO
Measure Participants	6	31	27	32
Number (95% Confidence Interval) [percent probability]	67	59	53	37

Adverse Events

Time Frame	Up to 5 years
Adverse Event Reporting Description	Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution, via expedited reporting (NCI AdEERs / CAeRs). The "AE Other" table reflects all CTCAEs collected excluding those that were reported as SAEs. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
Arm/Group Title	Feasibility (Vorinostat)		Arm I (Vorinostat, Phase II Arm A)		Arm II (Temozolomide, Phase II Arm B)		Arm III (Bevacizumab, Phase II Arm C)
Arm/Group Description	Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO		Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO Vorinostat: Given PO		Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO		Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities. Bevacizumab: Given IV Temozolomide: Given PO
All Cause Mortality
	Feasibility (Vorinostat)		Arm I (Vorinostat, Phase II Arm A)		Arm II (Temozolomide, Phase II Arm B)		Arm III (Bevacizumab, Phase II Arm C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		24/29 (82.8%)		22/27 (81.5%)		23/32 (71.9%)
Serious Adverse Events
	Feasibility (Vorinostat)		Arm I (Vorinostat, Phase II Arm A)		Arm II (Temozolomide, Phase II Arm B)		Arm III (Bevacizumab, Phase II Arm C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		9/29 (31%)		10/27 (37%)		12/32 (37.5%)
Endocrine disorders
Adrenal insufficiency	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Eye disorders
Optic nerve disorder	0/6 (0%)	0	1/29 (3.4%)	1	1/27 (3.7%)	1	0/32 (0%)	0
Gastrointestinal disorders
Nausea	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Vomiting	2/6 (33.3%)	2	0/29 (0%)	0	0/27 (0%)	0	0/32 (0%)	0
General disorders
Death NOS	0/6 (0%)	0	3/29 (10.3%)	3	5/27 (18.5%)	5	1/32 (3.1%)	1
Fever	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Infections and infestations
Infections and infestations - Other, specify	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	1/32 (3.1%)	1
Injury, poisoning and procedural complications
Wound dehiscence	1/6 (16.7%)	1	0/29 (0%)	0	0/27 (0%)	0	2/32 (6.3%)	2
Investigations
Neutrophil count decreased	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Platelet count decreased	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	2/32 (6.3%)	2
Weight loss	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
White blood cell decreased	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Dehydration	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Hyperuricemia	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Hyponatremia	1/6 (16.7%)	1	0/29 (0%)	0	0/27 (0%)	0	0/32 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	1/6 (16.7%)	1	0/29 (0%)	0	0/27 (0%)	0	0/32 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/6 (33.3%)	2	1/29 (3.4%)	1	1/27 (3.7%)	1	3/32 (9.4%)	3
Nervous system disorders
Hydrocephalus	0/6 (0%)	0	2/29 (6.9%)	2	0/27 (0%)	0	0/32 (0%)	0
Intracranial hemorrhage	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	2/32 (6.3%)	2
Nystagmus	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Peripheral motor neuropathy	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Seizure	1/6 (16.7%)	1	1/29 (3.4%)	1	1/27 (3.7%)	1	3/32 (9.4%)	3
Syncope	0/6 (0%)	0	1/29 (3.4%)	1	1/27 (3.7%)	1	0/32 (0%)	0
Renal and urinary disorders
Proteinuria	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Respiratory failure	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Surgical and medical procedures
Surgical and medical procedures - Other, specify	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Vascular disorders
Thromboembolic event	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Vascular disorders - Other, specify	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Other (Not Including Serious) Adverse Events
	Feasibility (Vorinostat)		Arm I (Vorinostat, Phase II Arm A)		Arm II (Temozolomide, Phase II Arm B)		Arm III (Bevacizumab, Phase II Arm C)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		13/29 (44.8%)		14/27 (51.9%)		16/32 (50%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	2/29 (6.9%)	2	1/27 (3.7%)	1	2/32 (6.3%)	2
Febrile neutropenia	0/6 (0%)	0	2/29 (6.9%)	2	2/27 (7.4%)	2	1/32 (3.1%)	1
Eye disorders
Eye disorders - Other, specify	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Gastrointestinal disorders
Dysphagia	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Mucositis oral	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Nausea	1/6 (16.7%)	1	2/29 (6.9%)	2	0/27 (0%)	0	2/32 (6.3%)	2
Vomiting	1/6 (16.7%)	1	4/29 (13.8%)	4	0/27 (0%)	0	1/32 (3.1%)	1
General disorders
Fatigue	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	1/32 (3.1%)	1
Fever	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Gait disturbance	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Immune system disorders
Anaphylaxis	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Infections and infestations
Appendicitis	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Infections and infestations - Other, specify	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Tooth infection	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Investigations
Alanine aminotransferase increased	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	1/32 (3.1%)	1
Creatinine increased	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Lymphocyte count decreased	1/6 (16.7%)	1	3/29 (10.3%)	3	3/27 (11.1%)	3	2/32 (6.3%)	2
Neutrophil count decreased	0/6 (0%)	0	3/29 (10.3%)	3	5/27 (18.5%)	5	8/32 (25%)	8
Platelet count decreased	0/6 (0%)	0	5/29 (17.2%)	5	8/27 (29.6%)	8	6/32 (18.8%)	6
Weight gain	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
White blood cell decreased	0/6 (0%)	0	2/29 (6.9%)	2	5/27 (18.5%)	5	4/32 (12.5%)	4
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	1/29 (3.4%)	1	1/27 (3.7%)	1	0/32 (0%)	0
Dehydration	0/6 (0%)	0	1/29 (3.4%)	1	1/27 (3.7%)	1	1/32 (3.1%)	1
Hypoglycemia	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Hypokalemia	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Muscle weakness lower limb	0/6 (0%)	0	0/29 (0%)	0	2/27 (7.4%)	2	0/32 (0%)	0
Scoliosis	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	1/6 (16.7%)	1	0/29 (0%)	0	0/27 (0%)	0	2/32 (6.3%)	2
Nervous system disorders
Ataxia	1/6 (16.7%)	1	0/29 (0%)	0	1/27 (3.7%)	1	1/32 (3.1%)	1
Cognitive disturbance	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Concentration impairment	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Headache	0/6 (0%)	0	1/29 (3.4%)	1	3/27 (11.1%)	3	3/32 (9.4%)	3
Hydrocephalus	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	1/32 (3.1%)	1
Memory impairment	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Seizure	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Syncope	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Tremor	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Respiratory, thoracic and mediastinal disorders
Apnea	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Epistaxis	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Respiratory failure	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Skin and subcutaneous tissue disorders
Skin ulceration	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0
Urticaria	0/6 (0%)	0	0/29 (0%)	0	0/27 (0%)	0	1/32 (3.1%)	1
Vascular disorders
Hypertension	0/6 (0%)	0	1/29 (3.4%)	1	1/27 (3.7%)	1	1/32 (3.1%)	1
Hypotension	0/6 (0%)	0	1/29 (3.4%)	1	0/27 (0%)	0	0/32 (0%)	0
Vascular disorders - Other, specify	0/6 (0%)	0	0/29 (0%)	0	1/27 (3.7%)	1	0/32 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.