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Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.

Fludeoxyglucose F-18

Irinotecan Hydrochloride

Sridharan Gururangan

This phase II trial is studying how well giving bevacizumab together with irinotecan works in treating young patients with recurrent, progressive, or refractory glioma, medulloblastoma, ependymoma, or low grade glioma. 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. Bevacizumab may also stop the growth of glioma by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan may kill more tumor cells.

PRIMARY OBJECTIVES:

I. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric patients with recurrent, progressive, or refractory malignant glioma (Stratum A \[closed to accrual as of 4/21/2009\]) or recurrent/progressive/refractory intrinsic brain stem glioma (Stratum B \[closed to accrual as of 4/21/2009\]).

II. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients with recurrent or progressive medulloblastoma (Stratum C \[closed to accrual as of 10/27/2009\]) or recurrent or progressive ependymoma (Stratum D \[closed to accrual as of 7/29/2010\]).

III. Estimate the sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low grade glioma (Stratum E \[closed to accrual as of 7/29/2010\]).

SECONDARY OBJECTIVES:

I. Estimate the rate of treatment-related toxicity of this regimen in these patients.

II. Estimate the cumulative incidence of sustained objective responses as a function of this regimen in these patients.

III. Estimate the distributions of survival and event-free survival of these patients.

IV. Correlate functional changes in tumor with progression-free survival and response using MR perfusion/diffusion imaging and fludeoxyglucose F 18 positron emission tomography.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade glioma \[closed to accrual as of 4/21/2009\] vs intrinsic brain stem tumor \[closed to accrual as of 4/21/2009\] vs medulloblastoma \[closed to accrual as of 10/27/2010\] vs ependymoma \[closed to accrual as of 7/29/2010\] vs low grade glioma \[closed to accrual as of 7/29/2010\]).

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.

After completion of study treatment, patients are followed for 30 days and then every 3 months for up to 2 years.

Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

Phase II Study of Bevacizumab Plus Irinotecan (Camptosar™) in Children With Recurrent, Progressive, or Refractory Malignant Gliomas, Diffuse/Intrinsic Brain Stem Gliomas, Medulloblastomas, Ependymomas and Low Grade Gliomas

Objective response is either a complete response or a partial response observed during the first four courses of treatment and sustained for 8 weeks. The objective response rate will be reported separately for patients with recurrent/progressive malignant glioma(Stratum A), recurrent/progressive instrinsic brain stem tumors(Stratum B), recurrent/progressive medulloblastoma(Stratum C), and recurrent/progressive ependymoma(Stratum D). CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. This outcome measures is not defined for the Stratum E in the protocol.

Disease stabilization is defined as a complete response(CR) or partial response(PR) observed during the first four courses and sustained for 8 weeks; or stable disease (SD) sustained for 6 courses characterized by SD at the end of course 2, at the end of course 4 and at the end of course 6. CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. SD is at least stable and maintenance corticosteroid dose not increased in neurologic examination.

Adverse events are monitored and graded according to the Common Terminology Criteria for Adverse Events. The grade 1 = mild, grade 2=moderate, grade 3 =severe, grade 4=life threatening/disabling, grade 5=death.

Cumulative incidence of sustained objective response provides a percentage of participants experiencing the event of interest at a given follow-up time point (for example, 6-months, 1-year, etc.) in the presence of competing events such as progressive disease or death, and it is estimated using the event data for both the event of interest and the competing events experienced by the study participants. In this sense, it is different than the incidence rates estimated in epidemiological studies in terms of 'incidences per 1000 person years. 6-month Cumulative incidence of sustained objective responses will be reported separately for each stratum.

Progression-Free survival is the interval of time between of protocol treatment and minimum date of documentation of progressive Disease,second malignancy,death due to any cause, or date of last follow-up. Progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression,OR the appearance of new tumor OR a \> 25% increase in the sum of the products of two longest perpendicular diameters of all measurable tumors. K-M method was used to estimate progression-free survival.

Perfusion ratio obtained from magnetic resonance(MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the perfusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from perfusion ratio at Baseline to perfusion ratio at Day 15(values of perfusion ratio at Day 15 - values of perfusion ratio at baseline). The higher of perfusion ratio is worse.

MR perfusion ratio is perfusion solid part of tumor from CBV divided by perfusion frontal while matter. There is no a unit available.

Diffusion ratio obtained from magnetic resonance (MR) diffusion imaging may explain changes in the tumor after therapy. Changes in the diffusion ratio will be reported for those strata that have a sufficient number of participants with MR diffusion imaging. The change was calculated from diffusion ratio at Baseline to diffusion ratio at Day 15 (values of diffusion ratio at Day 15 -values of diffusion ration at baseline). The higher of diffusion ratio is better. MR diffusion ratio is the diffusion solid part of tumor divided by the diffusion frontal white matter. There is no a unit available.

Using Cox proportional hazards models, the association of tumor volume based on FLAIR images with PFS will be investigated for those strata that have a sufficient number of participants with volume FLAIR measurements. Volumetric magnetic resonance imaging is performed to investigate surrogate markers of tumor growth. Volume FLAIR measurements were longitudinal. As we are not comparing the strata, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on FLAIR. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.

Using Cox Proportional hazards Models, the association of Log-transformed tumor enhancing volume with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Tumor enhancing volumes were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor enhancing volume. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.

Using Cox Proportional Hazards Models, the association of cystic necrosis with progression-free survival will be investigated. Volumetric magnetic resonance (MR) imaging is performed to investigate surrogate markers of tumor growth. Volumes of cystic necrosis were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section and we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume based on cystic necrosis. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.

Using Cox Proportional Hazards Models, the association of tumor diffusion ratios with progression-free survival will be investigated. Magnetic resonance (MR) diffusion imaging is performed to investigate surrogate markers of tumor growth. Tumor diffusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. And we consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor diffusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.

Using Cox Proportional Hazards Models, the association of tumor perfusion ratio with progression-free survival will be investigated. Magnetic resonance (MR) perfusion imaging is performed to investigate surrogate markers of tumor growth. Tumor perfusion ratios were longitudinal. As we are not comparing the strata or study arms, analyses will be done in each stratum separately, and thus we cannot report the Cox model results in the Statistical Analysis section. We consider these estimates 'descriptive' within each stratum. In this analysis, the hazard ratio is a relative measure of likelihood that a study participant experiences the event of interest compared to another participant who has a one-unit lower Log-transformed tumor volume perfusion ratio. The Cox survival model provides the mean hazard ratio along with its 95% confidence interval, which we report below.

Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the volume of distribution. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper "Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation" published by British Journal of Clinical Pharmacology ,2016 volume 81(1):148-160. The estimates of the volume of distribution were calculated by the model described in the paper.

Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the systemic clearance. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper "Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation" published by British Journal of Clinical Pharmacology, 2016 volume 81(1):148-160. The estimates of the systemic clearance were calculated by the model described in the paper.

Blood specimens were collected on the days listed for pharmacokinetic studies for Bevacizumab. These specimens were analyzed to produce steady-state plasma Bevacizumab concentration-time data in study participants. The concentration-time data were analyzed to provide an estimate of the PK parameters. The data were collected but the analyses of the PK data were conducted by Genentech using a broader cohort of pediatric patients from multiple trials in the paper "Bevacizumab dosing strategy in paediatric cancer patients based on population pharmacokinetic analysis with external validation" published by British Journal of Clinical Pharmacology,2016 volume 81(1):148-160. The estimates of the terminal half-life were calculated by the method described in the paper.

The change in VEGF-R2 was calculated from baseline to the time of the 2nd dose (values of 24-48 hours after the 2nd dose at Day 15 - values of pre-dose 1 Day1, i.e., baseline). VEGF-R2 is measured in the relative phosphorylation score which is generated as a ratio of normalized phosphorylated VEGF-R2 versus normalized total VEGF-R2 protein.

The changes in VEGF-R2 are calculated by values at Day 15 minus values at baseline for the patients who had the changes in perfusion from magnetic resonance perfusion imaging. The purpose of reporting descriptive statistics of changes of VEGF-R2 is to provide the information for the correlation coefficients in Section 19.

The change of perfusion in magnetic resonance imaging is calculated by taking the difference between the Day-15 measurements and the Baseline measurements for patients who had the changes of VEGF-R2. The purpose of reporting the descriptive statistics is to provide the information for the correlation coefficients reported in the next section, Section 19. MR perfusion ratio is the ratio of the perfusion measurements in the tumor and the perfusion measurerement in comparative frontal while matter, which is the comparative healthy part of the brain.

Spearman correlation coefficient is used to measure the correlation of the changes in VEGF-R2 with the changes in perfusion ratios. The changes are calculated by values at Day 15 minus values at baseline for VEGF-2 in Section 17 above and perfusion in Section 18 above, respectively. The correlation coefficients are reported in each stratum separately.

The expression of Hypoxia inducible factor-2α, carbonic anhydrase IX (CA9), VEGF-A, and VEGF-R2 will be estimated by immunohistochemistry of paraffin sections in the medulloblastoma,ependymoma and low grade glioma strata. Reported separately for each stratum.

The association of hypoxia inducible factor-2alpha expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with hypoxia inducible factor-2alpha measurements. The hazard ratio was reported for patients who had hypoxia inducible factor-2alpha expression.

The association of CA9 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with CA9 measurements.

The association of VEGF-A expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-A measurements.

The association of VEGF-R2 expression with progression-free survival will be investigated for those strata that have a sufficient number of participants with VEGF-R2 measurements.

National Cancer Institute (NCI)

Children with recurrent,progressive,or refractory malignant gliomas, diffuse/intrinsic brain stem gliomas, medulloblastomas and low grade gliomas

PBTC-022

Recurrent, progressive or refractory high-grade gliomas (Stratum A): The only patients with Recurrent, progressive or refractory high-grade gliomas were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

High-grade Gliomas

Recurrent,progressive or refractory intrinsic brain stem tumors (Stratum B): The only patients with Recurrent,progressive or refractory intrinsic brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Brain Stem Tumors

Recurrent or progressive medulloblastoma(Stratum C): The only patients with recurrent or progressive medulloblastoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive ependymoma (Stratum D):The only patients with recurrent or progressive ependymoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent low grade glioma (Stratum E): The only patients with recurrent low grade glioma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Low Grade Glioma

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Neuroimaging data capturing Volume Enhancing and Perfusion Ratio was so limited to run any statistical model. Similarly, due to limited data, some PK and Biology objectives were not able to be addressed.

Shengjie Wu

Recurrent, progressive or refractory high-grade gliomas (Stratum A): The only patients with recurrent, progressive or refractory high-grade gliomas were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent, progressive or refractory intrinsic brain stem tumors (Stratum B):The only patients with recurrent, progressive or refractory brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive medulloblastoma(Stratum C):The only patients with recurrent or progressive medulloblastoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Two patients in the Stratum A,one patient in the Stratum C, and one patient in the Stratum D were inevaluable for this outcome measure.

Objective Response Rate Sustained for ≥ 8 Weeks

Patients with recurrent or progressive low grade glioma were treated with any courses.

Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E)

Recurrent, progressive or refractory high-grade gliomas(Stratum A): The only patients with recurrent, progressive or refractory high-grade gliomas were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent, progressive or refractory intrinsic brain stem tumors(Stratum B):The only patients with recurrent, progressive or refractory brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive ependymoma(Stratum D): The only patients with recurrent or progressive ependymoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive low grade glioma(Stratum E):The only patients with recurrent or progressive low grade glioma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

The patients were treated with any dose treatment.

Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity

Recurrent, progressive or refractory high-grade gliomas(Stratum A):The only patients with Recurrent, progressive or refractory high-grade gliomas were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent, progressive or refractory intrinsic brain stem tumors(Stratum B):The only patients with Recurrent, progressive or refractory brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive medulloblastoma(Stratum C):The only patients with Recurrent or progressive medulloblastoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive ependymoma(Stratum D): The only patients with Recurrent or progressive ependymoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive low grade glioma(Stratum E): The only patients with Recurrent or progressive low grade glioma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Cumulative Incidence of Sustained Objective Responses

Recurrent or progressive medulloblastoma(Stratum C): The only patients with Recurrent or progressive Medulloblastoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive ependymoma(Stratum D): The only patients with Recurrent, progressive ependymoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Progression-free Survival

Recurrent, progressive or refractory intrinsic brain stem tumors(Stratum B):The only patients with Recurrent, progressive or refractory Brain Stem Tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive low grade glioma(Stratum E):The only patients with Recurrent or progressive low grade glioma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

There are no sufficient data for the analyses in the Medulloblastoma arm and Ependymoma arm.

Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging

Recurrent or progressive ependymoma(Stratum D):The only patients with Recurrent or progressive ependymoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent low grade glioma(Stratum E):The only patients with recurrent low grade glioma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

There are no sufficient data for the analyses in the Medulloblastoma arm.

Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image

Recurrent, progressive or refractory high-grade gliomas(Stratum A):The only patients with recurrent, progressive or refractory high-grade gliomas were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Patients had Flair volume at Pre-treatment and at least one on treatment.

Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates

Recurrent,progressive or refractory instrinsic brain stem tumors(Stratum B):The only patients with recurrent, progressive or refractory brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Patients had tumor enhancing volume at Pre-treatment and at least one on treatment.

Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates

Patients had volume of cystic necrosis at Pre-treatment and at least one on treatment.

Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates

Patients had diffusion ratio at pre-treatment scans and at least one on treatment scans.

Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates

The analyses cannot be performed with the Cox proportional hazard model since there are no sufficient measurements of perfusion ratio and events.

Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates

High-grade Gliomas(stratum A), Medulloblastoma (stratum B), Brain Stem Tumors (stratum C), Ependymoma (stratum D), and Low Grade Glioma (stratum E) were combined for this secondary objective.

Combined All Strata

The study participants across the strata (stratum A, stratum B, stratum C, stratum D, and stratum E) were combined for this secondary objective. The number of participants with available data.

Volume of Distribution

Systemic Clearance

Terminal Half-life

Recurrent, progressive or refractory intrinsic brain stem tumors(Stratum B): The only patients with Recurrent, progressive or refractory brain stem tumors were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Recurrent or progressive medulloblastoma(Stratum C):The only patients with recurrent, progressive medulloblastoma were treated in this arm. Therapy will begin with single-agent bevacizumab 10 mg/kg given intravenously (i.v) on day 1 and day 15 (+/- 24 hours) followed by MR-perfusion/diffusion imaging within 24-48 hours following the 2nd dose of bevacizumab. The first dose of irinotecan will be given i.v following this MR-perfusion scan. Subsequently, bevacizumab and irinotecan will be given every two weeks. The irinotecan dose will depend on whether the patient is on an enzyme-inducing anticonvulsant drug (EIACD). The irinotecan dose will be 250 mg/m2 (\~ 80 % of dose tolerated by adults in the Duke Phase II study of bevacizumab plus irinotecan) every two weeks for those on EIACDs. If the patient is not on an EIACD, the starting dose will be 125 mg/m2.

Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15

The analyses are performed for the patients who had the changes in both VEGF-R2 and perfusion.

Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging

Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC)

Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging

Only strata were reported, in which the patients had tissue samples available.

Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline

Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline

Number of Patients With High VEGF-A Expression at Baseline

Number of Patients With High VEGF-R2 Expression at Baseline

The number of patients in strata C and D was not sufficient to perform the analysis exploring the association of hypoxia inducible factor-2alpha expression with progression-free survival. Thus the association analysis was performed for the patients in Stratum E only.

Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression

Only the number of patients in strata E was sufficient to perform the analysis exploring the association of carbonic anhydrase 9 (CA9) expression with progression-free survival.

Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression

Only the number of patients in strata E was sufficient to perform the analysis exploring the association of VEGF-A expression with progression-free survival.

Progression-free Survival Hazard Ratio by VEGF-A Expression

Only the number of patients in strata E was sufficient to perform the analysis exploring the association of VEGF-R2 expression with progression-free survival.

Progression-free Survival Hazard Ratio by VEGF-R2 Expression

Overall Study

Temozolomide

Vorinostat

Antineoplastic Agents, Alkylating

Alkylating Agents

Histone Deacetylase Inhibitors

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.

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.

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.

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.

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.

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.

Maryam Fouladi

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.

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

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

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

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

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).

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.

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

Feasibility (Vorinostat)

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

Arm I (Vorinostat, Phase II Arm A)

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

Arm II (Temozolomide, Phase II Arm B)

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma	NCT00381797	Childhood Cereb... Childhood Oligo... Childhood Spina... Recurrent Child... Recurrent Child... Recurrent Child...	Bevacizumab Fludeoxyglucose... Irinotecan Hydr...	- 21 Years	National Cancer Institute (NCI)
Vorinostat, Temozolomide, or Bevacizumab in Combination With Radiation Therapy Followed by Bevacizumab and Temozolomide in Young Patients With Newly Diagnosed High-Grade Glioma	NCT01236560	Brain Stem Glio... Cerebral Astroc... Childhood Cereb... Childhood Cereb... Childhood Spina...	Bevacizumab Temozolomide Vorinostat	3 Years - 21 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for childhood cerebral anaplastic astrocytoma