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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Brain Stem Glioma, Cerebral Astrocytoma, Childhood Cerebellar Anaplastic Astrocytoma, Childhood Cerebral Anaplastic Astrocytoma, Childhood Spinal Cord Neoplasm

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Temozolomide
* Drug: Vorinostat


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (vorinostat, Phase II Arm A)<br>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<br>* Given IV<br>* Other names: Zirabev;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Drug: Vorinostat<br>* Given PO<br>* Other names: Zolinza;|
| Experimental: Arm II (temozolomide, Phase II Arm B)<br>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<br>* Given IV<br>* Other names: Zirabev;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Experimental: Arm III (Bevacizumab, Phase II Arm)<br>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<br>* Given IV<br>* Other names: Zirabev;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Experimental: Arm IV (temozolomide, Phase 3 Arm B)<br>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<br>* Given IV<br>* Other names: Zirabev;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Experimental: Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)<br>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<br>* Given IV<br>* Other names: Zirabev;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Drug: Vorinostat<br>* Given PO<br>* Other names: Zolinza;|
| Experimental: Feasibility (vorinostat)<br>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<br>* Given IV<br>* Other names: Zirabev;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;Drug: Vorinostat<br>* Given PO<br>* Other names: Zolinza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Vorinostat | The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy. | 10 weeks | 
| Event-free Survival | 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). | 1 year after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from enrollment to death or last follow-up, whichever occurs first. | 1 year after enrollment | 
| Cumulative Incidence of Disease Progression in Each Treatment Arm | 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). | 1 year after enrollment |