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
Phase: PHASE2
Conditions: Brain Stem Glioma, Cerebral Astrocytoma, Childhood Cerebellar Anaplastic Astrocytoma, Childhood Cerebral Anaplastic Astrocytoma, Childhood Spinal Cord Neoplasm
Sponsor: National Cancer Institute (NCI)

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ACNS0822 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
5 
ABSTRACT 
7 
EXPERIMENTAL DESIGN SCHEMA: FEASIBILITY STUDY - VORINOSTAT WITH RADIATION 
THERAPY 
8 
EXPERIMENTAL DESIGN SCHEMA: PHASE II 
9 
EXPERIMENTAL DESIGN SCHEMA: PHASE III 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Objectives 
11 
1.2 
Secondary Objectives 
11 
2.0 
BACKGROUND 
12 
2.1 
High Grade Gliomas 
12 
2.2 
Rationale for Bevacizumab and Temozolomide post RT in all arms 
13 
2.3 
Rationale for Randomization during Initial Chemoradiotherapy 
18 
2.4 
Rationale for Biology Studies 
24 
2.5 
Rationale for MR Perfusion and Diffusion Imaging Studies 
26 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
28 
3.1 
Study Enrollment 
28 
3.2 
Patient Criteria 
29 
4.0 
TREATMENT PROGRAM 
34 
4.1 
Overview of Treatment Plan 
34 
4.2 
Concomitant Therapy Restrictions 
35 
4.3 
Definitions of Dose Limiting Toxicities, Maximum Tolerated Dose, and Dose De-
Escalation Criteria for Feasibility Study 
36 
4.4 
Description of Treatment Arms 
37 
4.5 
Arm A Chemoradiotherapy with Vorinostat (Feasibility Study Only) 
38 
4.6 
Arm A Chemoradiotherapy with Vorinostat (Phases II and III) 
41 
4.7 
Arm B Chemoradiotherapy with Temozolomide 
44 
4.8 
Arm C Chemoradiotherapy with Bevacizumab 
48 
4.9 
Maintenance Therapy 
50 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
53 
5.1 
Dose Modifications During Chemoradiotherapy 
53 
5.2 
Dose Modifications during Maintenance Therapy 
54 
5.3 
Bevacizumab Dose Modifications 
55 
6.0 
DRUG INFORMATION 
59 
6.1 
Bevacizumab 
59 
6.2 
TEMOZOLOMIDE 
65 
6.3 
VORINOSTAT 
67 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
73 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
73 
7.2 
Optional Biology and Imaging Studies 
74 
7.3 
Follow-up 
75 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA75 
8.1 
Criteria for Removal From Protocol Therapy 
75 
8.2 
Off Study Criteria 
75 
9.0 
STATISTICAL CONSIDERATIONS 
76 
9.1 
Statistical Design 
76 
9.2 
Patient Accrual and Expected Duration of Trial 
76 
9.3 
Statistical Analysis Methods 
77 
9.4 
Interim Monitoring 
79 
9.5 
Analysis Plans 
81 
9.6 
Gender and Ethnicity Considerations 
82 
9.7 
Gender and Minority Accrual Estimates 
82 
10.0 
EVALUATION CRITERIA 
83 
10.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
83 
10.2 
Methodology to Determine Tumor Measurement 
83 
10.3 
Selection of Target and Non-Target Lesions 
85 
10.4 
Response Criteria for Target Lesions 
85 
10.5 
Response Criteria for Non-target Lesions 
86 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
86 
11.1 
Purpose 
86 
11.2 
Determination of reporting requirements 
86 
11.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
87 
11.4 
Reporting method 
88 
11.5 
When to report an event in an expedited manner 
88 
11.6 
Other recipients of adverse event reports 
88 
11.7 
Reporting of Adverse Events for investigational agents – AdEERS 24-hour notifications, 
and complete report requirements 
88 
11.8 
Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 90 
11.9 
Routine Adverse Event Reporting 
91 
12.0 
STUDY REPORTING AND MONITORING 
91 
12.1 
CDUS 
91 
12.2 
Data and Safety Monitoring Committee 
91 
12.3 
CRADA/CTA 
92 
13.0 
NEUROSURGICAL GUIDELINES 
93 
13.1 
Neurosurgical Procedures 
93 
13.2 
Definitions of Extent of Resection 
94 
13.3 
Imaging Confirmation of Extent of Resection 
94 
13.4 
Peri-operative Corticosteroids 
94 
13.5 
Special Precautions for Bevacizumab 
94 
14.0 
RADIATION THERAPY GUIDELINES 
95 
14.1 
Indications for Radiation Therapy 
95 
14.2 
Emergency Irradiation 
96 
14.3 
Equipment 
96 
14.4 
Target Volumes 
96 
14.5 
Target Dose 
98 
14.6 
Treatment Technique 
98 
14.7 
Organs at Risk 
99 
14.8 
Dose Calculations and Reporting 
100 
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14.9 
Quality Assurance Documentation 
102 
14.10 
Definitions of Deviations in Protocol Performance 
103 
15.0 
NEUROPATHOLOGY GUIDELINES AND CENTRAL PATHOLOGY REVIEW SPECIMEN 
REQUIREMENTS 
103 
15.1 
Central Review 
103 
15.2 
Specimen Handling 
104 
15.3 
Required Pathology Review Material 
104 
15.4 
Specimen Shipping 
104 
16.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
105 
16.1 
Overview of Biology Specimen Requirements 
105 
16.2 
Snap Frozen Tumor Specimens 
105 
16.3 
Telomerase activity, hTert expression, and telomere length studies 
107 
16.4 
Gene expression and miRNA profiling 
107 
16.5 
Genome Allelotype and SNP Array Analyses 
107 
16.6 
MGMT status and immmunohistochemical marker studies 
108 
16.7 
Description of Biology Studies 
108 
16.8 
Optional Imaging Studies (MR Perfusion and MR Diffusion Tensor Imaging) 
109 
17.0 
NEUROIMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
111 
17.1 
Timing of MRIs 
111 
17.2 
Whole Brain MRI With and Without Contrast 
111 
17.3 
Spinal MRI With and Without Contrast 
112 
17.4 
Tumor Response Assessment 
112 
17.5 
Central Review for Phase II and III 
113 
17.6 
Address Information 
113 
APPENDIX I: 90TH AND 95TH PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT IN 
GIRLS AGE 1-17 YEARS 
114 
APPENDIX II: 90TH AND 95TH PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT IN 
BOYS AGE 1-17 YEARS 
115 
APPENDIX III:  DOSING GUIDELINES FOR VORINOSTAT CAPSULE FORMULATION 
116 
APPENDIX IV:  TEMOZOLOMIDE DOSING DURING CHEMORADIOTHERAPY 
117 
APPENDIX V:  TEMOZOLOMIDE DOSING DURING MAINTENANCE 
119 
APPENDIX VI: INSTRUCTIONS FOR ADMINISTRATION OF TEMOZOLOMIDE (PATIENTS 
UNABLE TO SWALLOW CAPSULES AND CANNOT OBTAIN A SUSPENSION) 
123 
APPENDIX VII:  ENZYME INDUCING AND NON-ENZYME INDUCING ANTICONVULSANTS124 
APPENDIX VIII: YOUTH INFORMATION SHEETS 
125 
REFERENCES 
135 
SAMPLE 
INFORMED 
CONSENT/PARENTAL 
PERMISSION 
FOR 
PARTICIPATION 
IN 
RESEARCH – FEASIBILITY STUDY 
143 
SAMPLE 
INFORMED 
CONSENT/PARENTAL 
PERMISSION 
FOR 
PARTICIPATION 
IN 
RESEARCH – PHASE II STUDY 
165 
SAMPLE 
INFORMED 
CONSENT/PARENTAL 
PERMISSION 
FOR 
PARTICIPATION 
IN 
RESEARCH – PHASE III STUDY 
188 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate protects 
against the involuntary release of information about your subjects collected during the course of our 
covered studies.  The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances.  For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm 
to self or others 
 
ABSTRACT  
 
The outcome for children with high grade gliomas (HGG) remains poor despite the use of multi-modal 
therapy with surgery, radiation therapy (RT) and chemotherapy. Although RT does prolong survival slightly, 
adjuvant chemotherapy has had little impact on survival in children with high grade gliomas. CCG 945 
showed no improvement in survival for patients treated with the 8-in-1drug regimen compared to the 
CCNU/vincristine/prednisone regimen. Five year progression-free survival (PFS) was 19% ± 3%, while those 
who did not have a GTR had a 5 year PFS of 11% ± 4%.1  Novel therapies are required to improve the 
outcome for children with newly diagnosed HGG. Synergistic effects of bevacizumab with other 
chemotherapeutic agents including camptothecins have been seen in preclinical studies, and the combination 
of bevacizumab and temozolomide has shown promising results in adult studies of recurrent HGG. 
Deregulation of histone acetylation has been implicated in the development of several types of cancer, and 
findings from preclinical studies suggest a potential role for HDAC inhibitors in the treatment of children 
with hematological and solid tumor malignancies. The use of temozolomide in preclinical models also 
suggest that temozolomide has at least additive activity with radiation in human glioblastoma cells.2-6 Hence, 
the current proposal will study these three agents’ roles as radiosensitizers.  This study will be done in three 
parts: an initial feasibility study within the phase II part which will determine the dose of vorinostat that is 
safe and tolerable in combination with radiation therapy for patients less than 22 years of age; a phase II part 
that will employ a randomized “pick the winner” approach to determine if either of 2 experimental treatment 
arms (bevacizumab or vorinostat during chemoradiotherapy), have a higher nominal 1-year event-free 
survival (EFS) than the de facto standard treatment arm (temozolomide during chemoradiotherapy); and a 
randomized phase III part  where patients will be randomized to either the chosen experimental arm or the 
temozolomide arm for a formal efficacy (EFS) comparison. EFS, PFS, and overall survival (OS) on each 
treatment arm will be estimated using Kaplan-Meier curves. All phases of this study, including the feasibility 
phase, will be available to all COG institutions. Vorinostat will be administered at a starting dose of 230 
mg/m2/dose and, if proved to be safe, will be the dose used in subsequent phases of the study. Descriptive 
statistics will be used to investigate molecular and biologic markers and their associations with treatment 
outcome. 
 
 
 
 
 
 
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EXPERIMENTAL DESIGN SCHEMA: FEASIBILITY STUDY - VORINOSTAT WITH 
RADIATION THERAPY 
 
As of Amendment #1, the Feasibility Study was completed. 
 
 
 
 
 
  
 
 
Study Entry
*Dose assigned at entry is either 230 mg/m2/dose or 180 mg/m2/dose
PD = Progressive Disease 
Surgery
Maintenance Chemotherapy
Bevacizumab 10 mg/kg/dose every 2 weeks
and
Temozolomide 200
 
mg/m2/dose
Days 1-5
(for up to 12 cycles in the absence of
PD and unacceptable toxicities)
Chemoradiotherapy
Vorinostat ( dose assigned at study entry*)
5 days/ week for 6 weeks
and
Radiation Therapy for 6 weeks
and 4 week rest
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EXPERIMENTAL DESIGN SCHEMA: PHASE III 
 
 
 
 
 
 
Study Entry and
Randomization
Superior
 Chemoradiotherapy Arm
from Phase II 
Maintenance Chemotherapy
Bevacizumab 10 mg/ kg/dose every 2 weeks
and 
Temozolomide 200 mg/ m2/Dose Days 1-5 
( for up to 12 cycles in the absence of 
Progressive Disease and unacceptable toxicities)
Surgery
Arm B
Chemoradiotherapy
Temozolomide 90 mg/m
2/dose
Daily for 42 days
And
Radiation Therapy for 6 weeks
and 4 week rest
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objectives 
 
1.1.1 
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).  
 
1.1.2 
Phase II: To evaluate if either vorinostat (using MTD from feasibility phase) or bevacizumab gives a more 
promising outcome compared to temozolomide, as measured by one-year event-free survival (EFS), when 
given in combination with radiotherapy (RT) followed by maintenance chemotherapy with bevacizumab and 
temozolomide in patients with newly diagnosed high-grade gliomas (HGG). 
 
1.1.3 
Phase III: To determine if the agent that has a more promising outcome than temozolomide in the Phase II 
portion, or the agent with the higher outcome between vorinostat and bevacizumab if both are more 
promising than temozolomide in the Phase II portion, results in superior event-free survival (EFS) compared 
to temozolomide, when given in combination with radiotherapy (RT) followed by maintenance 
chemotherapy with bevacizumab and temozolomide in patients with newly diagnosed high-grade gliomas 
(HGG). 
 
1.2 
Secondary Objectives 
 
1.2.1 
Phase II/III: To evaluate the anti-tumor activity as measured by event-free survival (EFS), progression-
free survival (PFS), and overall survival (OS) of treatment with either vorinostat, bevacizumab, or 
temozolomide, when given in combination with radiotherapy followed by maintenance chemotherapy 
with bevacizumab and temozolomide in patients with newly diagnosed HGG. 
 
1.2.2 
To define and evaluate the toxicities of each of the treatment arms of the study. 
 
1.2.3 
To conduct gene expression profiling and SNP arrays in patients with newly diagnosed HGG. 
 
1.2.4 
To assess telomerase activity, hTert expression, and telomere length in patients with newly diagnosed 
HGG. 
 
1.2.5 
To document changes in MR perfusion and diffusion using MR imaging obtained at baseline, prior to 
initiation of maintenance therapy with bevacizumab and temozolomide, prior to cycle 3 of maintenance 
therapy, and subsequent to completion of maintenance therapy. 
 
1.2.6 
To correlate functional changes in tumor with responses to bevacizumab treatment using MR 
diffusion/perfusion imaging. 
 
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1.2.7 
To correlate the results of the bevacizumab biology studies in serum or tumor with EFS. 
 
1.2.8 
To explore the prognostic significance of MGMT status for patients newly diagnosed with HGG treated 
with combined surgery, radiation, chemotherapy, and anti-angiogenic therapy.  
 
 
2.0 
BACKGROUND 
 
2.1 
High Grade Gliomas 
The outcome for children with high grade gliomas remains poor despite the use of multi-modal therapy with 
surgery, radiation therapy (RT) and chemotherapy. Although RT does prolong time to progression slightly, 
adjuvant chemotherapy has had little impact on survival in children with high grade gliomas.  
 
The first prospective, randomized study in pediatrics was conducted by the Children’s Cancer Group (CCG) 
in 58 patients with high-grade astrocytoma who were randomized to study the effectiveness of chemotherapy 
as an adjuvant to standard surgical treatment and radiotherapy. Following surgical therapy, patients were 
assigned randomly to radiotherapy with or without chemotherapy consisting of chloroethyl-cyclohexyl 
nitrosourea (CCNU), vincristine (VCR), and prednisone. In this initial study (CCG 943), 5-year event-free 
survival (EFS) was 46% for patients in the radiotherapy and chemotherapy group, and 18% for patients in the 
radiotherapy only group. Five-year survival was similarly improved. In patients with glioblastoma 
multiforme (GBM) and at least a partial resection, the benefit from chemotherapy was clear with a 5-year 
progression free survival (PFS) of 42% for patients in the radiotherapy and chemotherapy group and 6% for 
patients in the radiotherapy only group (P=0.001). Five-year overall survival (OS) in this same subgroup was 
36% for patients in the radiotherapy and chemotherapy group vs 5% for patients in the radiotherapy only 
group. Patients whose initial surgery was limited to biopsy and patients with basal ganglia lesions also had 
significantly worse outcome.7  
 
Based on the CCG 943 trial, CCG 945 randomized patients to receive an 8-in-1 drug regimen or the 
CCNU/vincristine/prednisone regimen (control arm). Between 1985 and 1990, 85 patients were randomly 
assigned to the control arm and 87 patients were assigned to the experimental (8-in-1 drug) regimen. CCG 
945 showed no improvement in survival for patients treated with the 8-in-1 drug regimen compared to the 
CCNU/vincristine/prednisone regimen. Five year PFS was 33% and 5-year OS was 39% in the experimental 
group (8-in-1) compared to a PFS of 26% and OS of 29% in the control group. Those who did not have a 
GTR had a 5-year PFS of 11% (± 4%)1.  
 
Five-year PFS for patients with anaplastic astrocytomas (AA) was 28% (SE=7%) and for patients with GBM 
was 16% (SE=17%). A stepwise Cox life-table regression analysis identified independent predictors of 
improved PFS as a 90% or greater resection of tumor (P<0.02), AA histology (P<0.01) and female sex 
(P<0.01).  
 
Patients with centrally reviewed AA and a 90% or greater resection had a median time to progression of 31 
months, compared with a median time to progression of 12 months in those with less than a 90% resection. 
For the GBM group, the extent of resection only conferred a modest advantage in terms of survival with a 
median time to progression of 12 months vs 8 months.  
 
Interestingly, the patients in the control arm in CCG 945, who were treated with prednisone, lomustine, and 
vincristine (PCV), did not demonstrate the same PFS advantage as those treated with adjuvant PCV 
chemotherapy in the CCG 943 study. Five-year PFS in CCG 943 for the chemotherapy arm was 46% vs 
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26 (±8%) for the CCG 945 control arm. An updated centralized review of the pathology based on the WHO 
criteria conducted retrospectively confirmed the benefit of the addition of chemotherapy in patients with 
confirmed GBM treated on CCG 943.  
 
CCG 9933 (1993-1998) evaluated the efficacy of 3 different chemotherapy regimens prior to radiotherapy. 
Seventy six evaluable patients were randomized to receive 4 courses of high-dose chemotherapy (HDCT) 
prior to RT. The chemotherapy regimens included etoposide with carboplatin OR ifosfamide OR 
cyclophosphamide. Patients then went onto receive RT followed by CCNU and VCR. Objective responses to 
the chemotherapy regimens ranged from 8%-27%. Five-year EFS was 8% (±3%) with an OS of 24% (±5%). 
There was no difference among the response rates of the HDCT regimens; the relapse rate during HDCT was 
30%. Twenty nine percent experienced severe non-hematological toxicities.8 
 
POG 9135 was a phase III study that randomized patients between pre-irradiation cisplatin and BCNU or 
vincristine and cyclophosphamide. The 5-year survival of 20% for the cisplatin/BCNU arm was better than 
the 5% 5-year survival rate for those treated with vincristine and cyclophosphamide (P<0.05).9 
 
Based on the adult study by Stupp et al,10 ACNS0126 treated newly diagnosed children with involved field 
irradiation with concurrent temozolomide followed by temozolomide 200 mg/m2 daily for 5 days every 28 
days for 10 cycles. 11  (Please see full results in section 2.2.2 ) 
 
2.2 
Rationale for Bevacizumab and Temozolomide post RT in all arms 
Malignant gliomas are highly vascularized and infiltrative tumors. They are dependent on endothelial cell 
proliferation regulated by proangiogenic cytokines, such as vascular endothelial growth factor (VEGF), 
which is the dominant angiogenic mediator in high grade gliomas.12,13  In fact, VEGF expression has been 
shown to correlate with worse prognosis in patients with high grade gliomas14,15 and antibodies to VEGF 
have inhibited the growth of GBM in a xenograft model.16 
 
2.2.1 
Bevacizumab 
Bevacizumab (Avastin; Genentech, San Francisco, CA) is a vascular endothelial growth factor 
(VEGF)-specific recombinant, humanized monoclonal antibody.  The antibody was generated by 
engineering the VEGF binding residues of a murine neutralizing antibody (A4.6.1) into the framework of 
normal human immunoglobulin G (IgG1). Bevacizumab binds directly to all four VEGF isoforms 
(VEGF121, VEGF165, VEGF 189, and VEGF206) with high affinity and specificity and inhibits VEGF from 
binding to its receptors. 
 
In preclinical studies and clinical studies in adults, bevacizumab has induced stabilization and in some 
cases regression of tumors including glioblastoma multiforme (GBM).17-20 Bevacizumab has also been 
shown to potentiate the cytotoxic effects of chemotherapy and radiation in a number of different adult 
tumor types, including colorectal cancer and non-small cell lung cancer.21 Bevacizumab has been 
approved by Food and Drug Administration (FDA) for usage for first- or second-line treatment in 
combination with chemotherapy in adults with colorectal carcinoma. 
 
The safety of bevacizumab has been evaluated in a number of adult clinical trials. The most significant 
adverse events include hypertension, proteinuria, thrombosis and bleeding. Hypertension is the most 
common Grade 3/4 toxicity reported. Grade 3 hypertension (requiring more than one drug or more 
intensive therapy than previously) occurs in approximately 10%-20% of study subjects.  Reports of Grade 
4 hypertension (hypertensive crisis) have been uncommon. Asymptomatic proteinuria, across all grades, 
is frequently reported with a rare incidence of Grade 4 proteinuria (nephrotic syndrome). Venous 
thrombotic events have been described in association with bevacizumab therapy; however, in large 
randomized studies with and without bevacizumab there does not appear to be a statistically significant 
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increase in venous thrombotic events. A small but significant increase in arterial thrombotic events has 
also been observed in patients receiving bevacizumab. At-risk groups include those with a history of 
atherosclerosis and those over the age of 65.19,22,23 
 
Manageable Grade 1/2 bleeding events are commonly observed with bevacizumab therapy. The incidence 
of more significant bleeding (Grade 3/4) was not significantly increased in a large randomized trial for 
patients with metastatic colorectal cancer treated with bevacizumab.22 However, in a phase II trial in 
patients with non-small-cell lung cancer, life-threatening hemoptysis or pulmonary hemorrhage was 
observed in 6 of 67 patients who received bevacizumab in combination with paclitaxel and carboplatin.24 
The bleeding in these patients seemed to be linked to the central location, proximity to major blood 
vessels and tumor cavitation, features common in squamous cell carcinoma. In the follow-up phase III 
trial, patients with this histology as well as patients with a significant history of gross hemoptysis were 
excluded and the preliminary results suggest a decreased incidence of fatal bleeding in patients receiving 
bevacizumab.25  
 
Neovascularization is an important process in surgical wound healing. Inhibition of angiogenesis 
theoretically may impair or delay wound healing. Preclinical models to assess the impact of anti-
angiogenic agents in wound repair have been inconsistent, and clinical studies in humans have been 
limited. Recently, the effect of bevacizumab on postoperative wound healing was assessed in patients 
with colorectal cancer enrolled in 2 randomized trials. No increased risk of wound healing was noted in 
patients who began bevacizumab therapy 28-60 days after primary cancer surgery compared to 
chemotherapy alone. Patients who required major surgery during bevacizumab therapy tended to have 
more wound healing complications (13% versus 3%), but the difference was not statistically significant.26 
 
Schedule and dose of bevacizumab in adult trials has varied between 5 to 15 mg/kg every 2 to 3 weeks.  
Recent analysis of pharmacokinetic data from 2 phase II adults trials (AVF0780 in colorectal carcinoma 
and AVF0757 in non-small cell lung cancer) using 2 dosing schedules, 5 mg/kg every 2 weeks and 7.5 
mg/kg every 3 weeks, respectively, determined that the overall exposure to bevacizumab was similar. 
 
Recently, the Children’s Oncology Group (COG) completed a pediatric phase I study of bevacizumab in 
patients with refractory solid tumors. Three dose levels (5 mg/kg, 10 mg/kg and 15 mg/kg every 2 weeks 
intravenously) were studied in a total of 18 evaluable patients. No dose-limiting toxicities were observed 
at the highest dose level. Only one Grade 3 toxicity, lymphopenia, was observed. In a limited number of 
patients, pharmacokinetic studies revealed increased serum exposure with dose. The median clearance of 
bevacizumab was 4.1 ml/day/kg (range 3.5-15.9), and the median half-life was 11.8 days. No objective 
responses were observed. Five patients had disease stabilization for greater than 3 months.27 
 
Bevacizumab has demonstrated synergy with several chemotherapeutic agents including cisplatin, 
camptothecins and cyclophosphamide in preclinical xenograft models, and has decreased vascular 
permeability and increased cellular apoptosis in glioblastoma xenograft models.28  
 
2.2.2 
Temozolomide 
Temozolomide is an orally administered alkylating agent, a second generation imadazotetrazine.  A prodrug 
of MTIC, temozolomide spontaneously decomposes to MTIC at physiologic pH. It exerts its effect by cross-
linking DNA. This is likely a site specific alkylation at the O6-position of guanine with some effect at the N7 
position. Temozolomide reaches its peak concentration in 1 hour.  Food reduces the rate and extent of 
absorption.  It has an elimination half-life of 1.13hr (intraperitoneally) and 1.29hr (orally) with an oral 
bioavailability of 0.98.  
 
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Stupp et al reported the results of a study in which adults with newly-diagnosed, histologically confirmed 
glioblastoma were randomly assigned to receive radiotherapy alone or radiotherapy plus continuous daily 
temozolomide, followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 
days during each 28-day cycle), The primary end point was overall survival. A total of 573 patients 
underwent randomization. The median age was 56 years, and 84 percent of patients had undergone 
debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with 
radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The two-year survival rate was 
26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant 
treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 
percent of patients. Thus, the authors concluded that the addition of temozolomide to radiotherapy for 
adults with newly diagnosed glioblastoma resulted in a statistically significant survival benefit with 
minimal additional toxicity. This regimen has become the standard of care for adults with this disease.10  
 
The results of RTOG 0625: A Randomized Phase II Trial of Bevacizumab with either Irinotecan (CPT) or 
Dose-Dense Temozolomide (TMZ) in Recurrent Glioblastoma (GBM) TMZ 75-100 mg/m2 d 1-21 of 28 d 
cycle have recently been analyzed.  Sixty patients were enrolled on TMZ arm and 57 pts on CPT arm. All  
had prior radiation and temozolomide.  For the TMZ arm, 6m-PFS rate was 40% (95% CI: 27-53%); for 
the CPT arm, the 6m-PFS rate was 39% (95% CI: 26-52%).  Objective responses: TMZ arm with 1 (2%) 
CR, 11 (19%) PR; CPT arm with 2 (4%) CR, 13(24%) PR.   Moderate toxicity was noted: TMZ arm with 
30 (50%) grade 3, 10 (17%) grade 4, and 3 (5%) grade 5 (fatal) toxicities; CPT arm had 22(39%) grade 3, 
7 (12%) grade 4, and 3 (5%) grade 5 (fatal) toxicities.  The 6m-PFS surpassed the predetermined efficacy 
threshold for both arms, corroborating the efficacy of bevacizumab and CPT and confirming activity for 
bevacizumab and protracted TMZ for recurrent/progressive GBM, even after prior temozolomide 
exposure.  Toxicities were within anticipated frequencies with a moderately high rate of venous 
thrombosis, moderate hypertension and one intracranial hemorrhage. Studies to determine the efficacy of 
bevacizumab in newly diagnosed GBM are underway. (Gilbert et al, Personal Communication) 
 
The combination of TMZ and bevacizumab with or without the addition of irinotecan is currently being 
tested nationally in several studies for adults with newly diagnosed HGG. Recently, Vrendenburg et al 
reported the preliminary results of a study using bevacizumab in combination with temozolomide (TMZ) 
and radiation therapy (XRT) followed by BEV, TMZ, and irinotecan for newly diagnosed glioblastoma 
multiforme (GBM).  125 patients received radiation therapy and TMZ at 75 mg/m2/d beginning between 
2-6 weeks post-craniotomy. Bevacizumab at 10 mg/kg every 14 days was added a minimum of 4 weeks 
post- op. Following radiation therapy, patients received 6-12 monthly cycles of TMZ at 200 mg/m2/d days 
1-5, bevacizumab at 10 mg/kg and irinotecan on days 1 and 15. The dose of irinotecan was 340 mg/m2 for 
patients on enzyme inducing anti-epileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAED. 
Efficacy analysis is based on the first 75 patients and the toxicity analysis includes all 125 patients. The 
median PFS doubled on this current protocol, 14 months vs. 6.9 months historically. The median overall 
survival has not been reached, but 56% of the patients are alive at a minimum follow-up of 18 months. In 
addition, 28% remain progression-free at a median follow- up of 23 months. The regimen was tolerable; 
122 of 125 patients completed radiation therapy and 78 completed 6 cycles of post-radiation 
bevacizumab, TMZ, and irinotecan.  There were 4 toxic deaths, MI, PE, PCP, and sepsis.  The authors 
concluded that the addition of bevacizumab to TMZ and radiation followed by TMZ, bevacizumab, and 
irinotecan is tolerable. The median progression-free survival is improved and the overall survival is 
prolonged. 29  
 
Lai, Cloughesy et al recently presented the updated results of a phase II trial of bevacizumab in 
combination with temozolomide and regional radiation therapy for upfront treatment of adults with newly 
diagnosed GBM. This was an open label multicenter phase II trial with 70 patients in which bevacizumab 
was combined with the standard backbone of RT/TMZ. Bavacizumab was also given concurrently with 
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radiation. The primary objective was overall survival and progression-free survival. Treatment was 
tolerated well among the 70 patients. Treatment delivery characteristics were similar to the historical 
control group.30 PFS was increased from 6.9 to 14.1 months, while OS increased from 14.6 to 20.3 
months.  The authors concluded that this bevacizumab-based regimen had promising activity for PFS 
compared to the historical control data. The treatment appeared tolerable with a toxicity profile consistent 
with prior bevacizumab studies.31   
 
The current RTOG study 0825 is a Phase III double-blind placebo-controlled trial of conventional 
concurrent chemoradiation and adjuvant temozolomide plus bevacizumab versus conventional concurrent 
chemoradiation and adjuvant temozolomide in patients with newly diagnosed glioblastoma, Preliminary 
results demonstrate that the combination is well-tolerated, (
, personal communication). 
 
Temozolomide is well-tolerated in children. Nicholson et al reported the results of a phase II trial of 
temozolomide in children with recurrent CNS malignancies. When temozolomide was administered orally 
every day for 5-day of each 28-day cycle at doses of 200 mg/m2/d (patients with no prior craniospinal 
irradiation [CSI]) or 180 mg/m2/d (prior CSI), 5 PRs and 1 CR were observed among 104 evaluable 
patients. PRs occurred in 1 of 23 evaluable patients with high-grade astrocytoma, 1 of 21 with low-grade 
astrocytoma, and 3 of 25 with medulloblastoma/primitive neuroectodermal tumor (PNET). The CR 
occurred in an additional patient with medulloblastoma/PNET. The most frequent toxicities were grade 3 
or 4 neutropenia (19%) and thrombocytopenia (25%); nonhematologic toxicity was infrequent.32  
 
Similar to Stupp et al’s study, ACNS0126 study used TMZ as a radiosensitizer followed by 10 cycles of 
temozolomide 200 mg/m2/day x 5 days of every 28 day cycle. 107 patients with a diagnosis of anaplastic 
astrocytoma (AA), glioblastoma multiforme (GBM) or gliosarcoma were enrolled.  Outcome was 
compared to the results for children treated on Children’s Cancer Group (CCG) study CCG-945. Ninety  
patients were eligible (31 AA, 55 GBM and 4 other).  The three-year EFS and OS were 11 ± 3% and 22 ± 
5%, respectively. The results with temozolomide given during radiation therapy and as adjuvant therapy 
were similar to CCG 945 (p=0.98). The three-year EFS for AA was 13 ± 6% for ACNS0126 compared to 
22 ± 5.5% for CCG-945 (p= 0.95).  The three-year EFS for GBM was 7 ± 4% for ACNS0126 compared 
to 15 ± 5% for CCG-945 (p=0.77).  The two-year EFS rate was 17±5% among patients without 
overexpression of MGMT and 5±4% among those with overexpression of MGMT (p=0.045).  
Interestingly, 1-year PFS for adults receiving TMZ chemoradiotherapy on the Stupp trial was 26.9% as 
compared to 38% for children on this study, suggesting that the initial response and outcome for children 
with HGG treated with TMZ chemoradiotherapy is not inferior to that in adults. (Ken Cohen, PI, personal 
communication). Although ACNS0126 did not demonstrate an improved survival for children with newly 
diagnosed HGG who were treated with temozolomide, the study did demonstrate comparable survival 
with less toxicity than in studies utilizing prior nitrosourea-based regimens.  TMZ was well-tolerated. 
Hematologic toxicity was the most common adverse event and was self-limited.  No life-threatening acute 
toxic events occurred. (Ken Cohen, PI, personal communication) 
 
Although ACNS0126 did not demonstrate an improved survival for children with newly diagnosed HGG 
who were treated with temozolomide, the study did demonstrate comparable survival with less toxicity 
than in studies utilizing prior nitrosourea-based regimens.  TMZ was well-tolerated. Hematologic toxicity 
was the most common adverse event and was self-limited.  No life-threatening acute toxic events 
occurred, based on its better tolerability and similar efficacy to prior nitrosurea regimens, temozolomide 
is reasonable backbone to build on for the current proposed study. 
 
Finally, preliminary results are available in 6 children and young adults with newly diagnosed HGG < 30 
years of age who have been treated with bevacizumab and TMZ during RT, followed by bevacizumab, 
temozolomide and irinotecan in a study at Cincinnati Children’s Hospital Medical Center. Only one 
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patient experienced a dose-modifying toxicity (grade 4 thrombocytopenia/neutropenia) attributable to 
temozolomide during chemoradiotherapy; prolonged thrombocytopenia prompted discontinuation of 
therapy.  Grade 3 toxicities at least possibly attributable to therapy included neutropenia (1) and 
hypertension (1).  The regimen was well-tolerated both during the chemo-RT and maintenance in children 
and young adults with newly diagnosed HGG. (
, personal communication) 
 
Thus, based on temozolomide’s better tolerability and similar efficacy to prior nitrosurea regimens in 
children with newly diagnosed HGG, its tolerability and efficacy in combination with bevacizumab in 
both recurrent and newly diagnosed adults with HGG, and preliminary data about the combination’s 
feasibility in children with newly diagnosed HGG, we believe that the combination of temozolomide and 
bevacizumab is a reasonable backbone for the currently proposed study.  
 
2.2.3 
Adult Studies of the Use of Bevacizumab Combinations in HGG 
Vredenburgh et al evaluated the combination of bevacizumab and irinotecan in patients with recurrent 
advanced malignant gliomas in a phase II trial. Bevacizumab was administered at 10 mg/kg IV every 14 
days. The irinotecan dose for patients on EIACD was 340 mg/m2, compared to 125 mg/m2 for those not 
on EIACD. OR were noted in 63%, with a median progression free survival (PFS) of 23 weeks. The 6 
month PFS was 38% (34% if including only patients who had received RT more than 12 weeks prior to 
study entry. Three patients developed a DVT or pulmonary emboli and one patient had an arterial 
ischemic stroke.33 
 
Kang et al reported that, among 27 patients with recurrent HGG treated with irinotecan and bevacizumab, 
6 month PFS was 46%, with a median PFS of 5.1 months. Median overall survival (OS) was 12.6 
months.34  
 
Raval et al reported that 22 patients with recurrent gliomas were treated with bevacizumab 5 mg/kg IV 
and irinotecan 125 mg/m2 IV every 2 weeks. All but two patients had a radiographic response (2 CR +, 14 
PR +, 4 MR), with a median time to progression (TTP) of 3 months and a median OS of 4.6 months.35  
 
Goli et al reported a phase II trial of irinotecan 125 mg/m2 (for patients not on EIACD) or 350 mg/m2 (for 
patients on EIACD) and bevacizumab 10 mg/kg in 68 patients with recurrent high grade glioma. The last 
36 patients were treated with irinotecan weekly and bevacizumab 15 mg/kg on Days 1 and 22. The 6 
month PFS for GBM was 43% with a median PFS of 23 weeks. For Grade 3 astrocytomas, the 6 month 
PFS was 61% with a median PFS of 42 weeks. Toxicities included Grade 2 proteinuria, thromboembolic 
events (n=8) and CNS hemorrhage (n=1).36  
  
Cloughesy et al reported the interim results of a randomized phase II trial using bevacizumab versus 
bevacizumab/irinotecan in patients with recurrent high grade glioma, in which 167 patients were 
randomized to receive bevacizumab 10 mg/kg (n=85) or bevacizumab 10 mg/kg + irinotecan 125 mg/m2 
over 90 minutes (n=82), (or irinotecan 340 mg/m2 in patients receiving EIACD) every 2 weeks. The 
median number of months of therapy was 16.1 months for bevacizumab alone versus 22.2 months for the 
bevacizumab/irinotecan combination. Six month PFS was 35.6% for bevacizumab (ORR=21.2%) and 
51% for bevacizumab/irinotecan (ORR=34.1%), based on independent radiological review.37  
 
Friedman et al 29reported the results of a study that evaluated the efficacy of bevacizumab, alone and in 
combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, 
noncomparative trial. One hundred sixty-seven patients were randomly assigned to receive bevacizumab 
10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant 
enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month 
progression-free survival and objective response rate, as determined by independent radiology review. 
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Secondary end points included safety and overall survival. In the bevacizumab-alone and the 
bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 
50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall 
survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were 
taking corticosteroids at baseline to take stable or decreasing doses over time. Of the patients treated with 
bevacizumab alone or bevacizumab plus irinotecan, 46.4% and 65.8%, respectively, experienced ≥ 3 
adverse events, the most common of which were hypertension (8.3%) and convulsion (6.0%) in the 
bevacizumab-alone group and convulsion (13.9%), neutropenia (8.9%), and fatigue (8.9%) in the 
bevacizumab-plus-irinotecan group. Intracranial hemorrhage was noted in two patients (2.4%) in the 
bevacizumab-alone group (Grade 1) and in three patients (3.8%) patients in the bevacizumab-plus-
irinotecan group (Grades 1, 2, and 4, respectively). The authors concluded that bevacizumab, alone or in 
combination with irinotecan, was well tolerated and active in recurrent glioblastoma.  
 
Based on data from adults with recurrent high-grade gliomas, summarized above, the Food and Drug 
Administration recently approved the use of bevacizumab in patients with recurrent GBM. 
 
 
2.2.4 
Pediatric Studies of the Use of Bevacizumab Combinations in HGG 
Recently Gururangan et al completed a phase II study of bevacizumab and irinotecan in patients with 
recurrent high grade glioma and diffuse intrinsic pontine gliomas (DIPG) through the Pediatric Brain 
Tumor Consortium. Thirty four eligible patients were enrolled on study; 31 were evaluable. These 31 
patients received a median of two courses of bevacizumab plus irinotecan (range, 1 to 19). There were no 
sustained responses in either stratum. Median time to progression for all 34 eligible patients enrolled was 
127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% 
for MG and BSG, respectively. Toxicities related to bevacizumab included grade 1 to 3 fatigue in seven 
patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 
4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of bevacizumab in 
patients with MG only. Vascular permeability parameters did not change significantly after therapy in 
either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients 
after bevacizumab exposure. The authors concluded that although the regimen was well-tolerated, the 
combination of bevacizumab and irinotecan lacked efficacy in patients with recurrent HGG or DIPG.. 149 
 
Preliminary results are available in 6 children and young adults < 30 years of age with newly diagnosed 
HGG treated with bevacizumab and TMZ during RT, followed by bevacizumab, temozolomide and 
irinotecan in a study at Cincinnati Children’s Hospital Medical Center. Results are summarized in Section 
2.2.2. 
 
2.3 
Rationale for Randomization during Initial Chemoradiotherapy 
 
2.3.1 
Rationale for Arm A: Vorinostat (SAHA) During Radiation Therapy 
Chinnaiyan et al39 showed that pre-treating U373, a malignant glioma cell line, with 0.75-1 μM of 
vorinostat for 48-72 hours, and continuing vorinostat with radiation significantly increased its 
radiosensitivity. This report and another related study of vorinostat in a melanoma cell line7 identified that 
vorinostat treatment and radiation significantly reduced DNA repair proteins in the non-homologous end-
joining (NHEJ; Ku70, Ku80, DNA-PK) and homologous recombination repair (HRR; Rad51) pathways. 
Since radiation is thought to exert its anti-tumor effect by inducing double-stranded DNA (dsDNA) 
breaks, and dsDNA breaks are repaired by the NHEJ and HRR pathways, it has been hypothesized that 
radiation-enhancement by vorinostat and other HDAC inhibitors is partly mediated by decreased DNA 
repair proteins. In all the pre-clinical studies, optimal radiation enhancement was observed when HDAC 
inhibition preceded radiation by 24-72 hours and was continued concurrently with radiation.39-44  
 
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Rationale for HDAC Inhibitors as Radiosensitizers 
The basal unit of chromatin is the nucleosome. Nucleosomes are composed of 146 BP of DNA wrapped 
around a protein core formed with histones (H2A, H2B, H3, and H4), which have a lysine-rich 
amino-terminal tail.45 The amino terminal tail contains half of the positively charged residues and most of the 
post translational modification sites of the core histones. The positive charge helps histones bind tightly to the 
negatively charged DNA. The acetylation status of histones alters the net charge and chromatin structure, thus 
affecting gene expression.46  
 
Two classes of enzymes are involved in determining the acetylation of histones: histone acetyltransferases 
(HATs) and histone deacetylases (HDACs).47 Acetylation of histones is associated with transcriptional 
activation, whereas histone deacetylation is associated with transcriptional repression.48  
 
Deregulated Acetylation in Cancer 
Deregulation of histone acetylation has been implicated in the development of several types of cancer. Genes 
that encode HAT enzymes are translocated, amplified, overexpressed and/or mutated in various cancers.46  
The breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to histone acetylation.49 The 
carboxy-terminal domain (BCRT) of BRCA1 is associated with histone deacetylases HDAC1 and HDAC2. 
Thus, mutated BCRA1 may compromise HDAC recruitment and lead to hereditary breast cancer.50 Several 
leukemogenic transcription factors repress the expression of specific genes because of aberrant recruitment of 
HDACs.45 This repression of gene expression is an important step in the leukemogenic action of these 
transcription factors.51-54 Acute myeloid leukemia (AML) M2 disease is associated with an (8,21) 
translocation that leads to the formation of a potent dominant transcription repressor, AML1-Eto fusion 
protein, via HDAC recruitment leading to lymphoid oncogenic transformation.55,56 
 
These findings indicate that deregulated acetylation of histones plays a role in the pathogenesis of 
hematological as well as solid tumors by changing the chromatin structure and transcription of genes 
involved in cell cycle control, differentiation or apoptosis. Thus, there is considerable interest in histone 
deacetylase inhibition as a potential therapeutic modality in the treatment of hematological and solid tumor 
malignancies. 
 
HDAC inhibitors have been shown to inhibit proliferation of a variety of pediatric transformed cell lines, 
including neuroblastoma, rhabdomyosarcoma, osteosarcoma and malignant rhabdoid tumors.57,58 HDAC 
inhibitors have also been shown to markedly suppress the growth of a range of pediatric solid tumor 
xenograft models including neuroblastoma,59 Ewing’s and undifferentiated sarcoma.58  These agents lead to 
histone acetylation in vivo and induce tumor cell differentiation or apoptosis, depending on the cell type. 
These preclinical data have generated significant interest in the clinical evaluation of HDAC inhibitors, such 
as vorinostat, for the treatment of children with cancer. 
 
HDAC Inhibitors and High Grade Gliomas 
Ugur et al examined the antiproliferative effect of vorinostat in six glioblastoma and one endothelial cell lines 
in vitro. In addition, one glioblastoma cell line (U87MG) was used in in vivo short term (14 days) and 
survival studies in an orthotopic human glioma athymic mice model. Tumor volume, apoptosis rate, 
microvessel density, and proliferation index were determined by immunohistochemistry. Vorinostat treatment 
inhibited the growth of all cell lines in concentrations ranging from 1 μM to 30 μM. For short-term studies, 
histological analysis showed an 80% reduction of tumor volume in the treatment group (P < 0.001). This 
reduction in tumor volume was associated with a significant increase in the apoptosis rate (31.9%, P < 0.001), 
a significant decrease in both the proliferation rate (36.8%, P < 0.001) and angiogenesis rate (30%, P < 0.05). 
For survival studies, the mean survival time was 22 days in the control group compared to 42 days in the 
treatment group.60 
 
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Yin et al measured the effect of vorinostat on growth of GBM cell lines and explants by 
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Changes of the cell cycle and relative gene 
expression were detected by fluorescence-activated cell sorting, real-time reverse transcription-PCR, and 
Western blotting. After glioma cells were implanted in the brains of mice, the ability of vorinostat to decrease 
tumor growth was studied. Proliferation of GBM cell lines and explants were inhibited in vitro by vorinostat 
(ED50, 2 to 20 μM, with 5-day exposure). Vorinostat exposure of human U87 and T98G glioma cell lines, 
DA66 and JM94 GBM explants, as well as a murine GL26 GBM cell line resulted in an increased 
accumulation of cells in G2-M of the cell cycle. Many proapoptotic, antiproliferative genes increased in their 
expression (DR5, TNFalpha, p21WAF1, p27KIP1), and many antiapoptotic, progrowth genes decreased in 
their levels (CDK2, CDK4, cyclin D1, cyclin D2) as measured by real-time reverse transcription-PCR and/or 
Western blot after these GBM cells were cultured with vorinostat (2.5 μM, 1 day). Chromatin 
immunoprecipitation assay found that acetylation of histone 3 on the p21(WAF1) promoter was markedly 
increased by vorinostat. In vivo murine experiments suggested that vorinostat (10 mg/kg IV, or 100 mg/kg 
IP) could cross the blood-brain barrier as shown by prominent increased levels of acetyl-H3 and acetyl-H4 in 
the brain tissue. Furthermore, the drug significantly (P < 0.05) inhibited the proliferation of the GL26 glioma 
cells growing in the brains of mice and increased their survival. Studies of the activity of the HDAC inhibitor, 
vorinostat, in combination with other therapies have shown additive (imatynib mesylate, all-trans retinoic 
acid) or synergistic (radiation therapy, flavopiridol) activity in transformed cell lines.61 
 
Eyupoglu et al demonstrated that treatment of four glioma cell lines (U87MG, C6, F98, and SMA-560) with 
MS-275 significantly reduced cell growth in a concentration-dependent manner (IC(90), 3.75 μM). Its 
antiproliferative effect was corroborated using a bromodeoxyuridine proliferation assay and was mediated by 
G(0)-G(1) cell cycle arrest (i.e., up-regulation of p21/WAF) and apoptotic cell death. Implantation of 
enhanced green fluorescent protein-transfected F98 glioma cells into slice cultures of rat brain confirmed the 
cytostatic effect of MS-275 in a dose escalation up to 20 μM.62 
 
Finally, Hockly et al showed that vorinostat can cross the blood brain barrier in an R6/2Hd mouse model of 
Huntingdon’s chorea and increases histone acetylation in the brain.63 
 
HDAC Inhibitors as Radiosensitizers  
Histone modification has emerged as a promising approach to cancer therapy.64 Numerous preclinical and 
clinical studies have been evaluating several HDAC inhibitors including a prodrug of butyric acid 
[pivaloylomethyl butyrate, AN-965,66, hydroxamic acids [suberoylanilide hydroxamic acid (SAHA) 
(vorinostat), TSA],67 benzamide derivatives [MS-275 and CI-994],68,69 cyclic peptides [trapoxin, apicidin, and 
depsipeptide],70 valproic acid,71 and phenylbutyrate derivatives.72 Recent studies have revealed 
radiosensitizing capacities of various HDAC inhibitors, including MS-27573, vorinostat,70,74,75; valproic acid,76 
TSA 77, and butyric acid (BA)41,72, the parental form of AN-978. These data, as well as data derived from other 
combination studies,79,80 highlight the potential for incorporating HDAC inhibitors into the multimodality 
treatment of gliomas. Vorinostat, in particular, has shown promising clinical results,10,81,82 and has the added 
key benefit of enhancing radiation-induced cytotoxicity in human malignancies.39,75 
 
Several studies have explored the mechanisms of radiosensitization by HDAC inhibitors and indicate that 
HDAC inhibitors interfere with DNA damage repair.83,84 Recent publications report that HDAC inhibitors 
suppress repair of DNA double-strand breaks 39,44,69,73,75,76,85 primarily by affecting non-homologous-end 
joining (NHEJ) pathways39,44,75,85 in some reports homologous recombination (HR) is effected as well.39,44  
For example, vorinostat and butyric acid reduce expression of both NHEJ (Ku70, Ku80 and DNA-PKcs) and 
HR (Rad 50, Rad 51) repair-related genes in several human tumor cell lines.39,44 The ability of HDAC 
inhibitors to impede DNA repair following radiation is reflected in several studies that explore the expression 
of phospho--H2AX, a hallmark of DNA damage. Vorinostat, MS-275, valproic acid, and 
depsipeptide44,73,75,76 all prolong expression of phospho--H2AX reflecting enhanced DNA damage following 
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HDAC inhibition. Entin-Meer et al specifically examined the effects of combined radiation and HDAC 
inhibitor treatment on gliomas in vitro and in vivo. They found that AN-9-mediated radiosensitization is 
associated with increased expression of phospho--H2AX within glioma xenografts, further supporting the 
conclusion that enhanced radiation-induced DNA damage plays a role in the combined effects of AN-9 and 
radiation.  
 
In all the pre-clinical studies examining the radiosensitizing properties of HDAC inhibitors, optimal radiation 
enhancement was observed when HDAC inhibition preceded radiation by 24-72 hours and was continued 
concurrently with radiation.  
 
Vorinostat: Adult Studies 
In two phase II trials, vorinostat 400 mg/day was safe and effective with an overall response rate of 24-30% 
in refractory advanced patients with CTCL including large cell transformation and Sézary syndrome, leading 
to FDA approval recently for use in patients with CTCL.86,87 
 
The recommended phase II dose, based on multiple phase I studies using several different doses and 
schedules, is 400 mg PO daily. Observed Cmax in the 400 mg daily regimen averaged 658 +/- 439 μg/ml 
(2.67 +/- 1.78 μM), and these values exceeded the IC50 (0.5 to 2 μM) required in pre-clinical studies against 
malignant gliomas. Dose limiting toxicities have included anorexia, fatigue, dehydration, diarrhea and 
thrombocytopenia.  
 
Galanis et al 88 reported the preliminary results of a phase II trial of 68 patients with recurrent GBM who 
received vorinostat 200 mg bid x 14 days every 3 weeks. Grade 3+ non-hematologic toxicity consisting 
mainly of fatigue, diarrhea and dehydration occurred in 23% of patients; Grade 3+ hematologic toxicity 
consisting mainly of thrombocytopenia occurred in 25% of patients. Patients receiving EIACD had 
significantly less Grade 3+ non-hematologic toxicity (P=0.01) and Grade 3/4 thrombocytopenia (P=0.04). 
Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0-24h) values and higher vorinostat-
glucuronide C-max and AUC (0-24h) values in patients receiving EIACD. The trial met the prospectively 
defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being 
progression-free at 6 months. RNA array analysis, performed in paired baseline and post-vorinostat treatment 
samples in a subgroup of 5 surgical recurrent GBM patients who received vorinostat for 6 doses prior to 
surgery, showed upregulation of E-cadherin (P=0.02), thus indicating a biologic effect of the HDAC inhibitor 
on the glioblastoma tumors. Thus, vorinostat was well tolerated in patients with recurrent GBM. Patients on 
EIACD have less toxicity, which is likely due to increased vorinostat metabolism via glucuronidation. 
Interim efficacy analysis is indicative of antitumor activity.  
 
Recently, Ree at al reported the results of a study in which patients with gastrointestinal carcinoma scheduled 
to receive pelvis irradiation (30 Gy in 3 Gy daily fractions) received escalating doses of vorinostat 3 hours 
before each daily fraction. Among 16 evaluable patients, grade 3 adverse events included grade 3 adverse 
events included fatigue (n=5), anorexia (n=3), diarrhoea (n=2), hyponatraemia (n=1), hypokalaemia (n=1), 
and acneiform rash (n=1). Of these, treatment-related grade 3 events (ie, dose-limiting toxicities) were 
observed in one of six patients at vorinostat 300 mg once daily (fatigue and anorexia), and in two of six 
patients at vorinostat 400 mg once daily (two events of diarrhea and one each of fatigue, anorexia, 
hyponatraemia, and hypokalaemia). The maximum-tolerated dose of vorinostat in combination with palliative 
radiotherapy was thus determined to be 300 mg once daily. Histone hyperacetylation was detected, indicating 
biological activity of vorinostat.150  
 
 
 
 
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Vorinostat: Pediatric Phase 1 Studies 
The pediatric single agent MTD has been established as 230 mg/m2 daily. Dose limiting toxicities have 
included thrombocytopenia, and fatigue.  
 
2.3.2 
Rationale for Arm B: Temozolomide as a Radiosensitizer 
Temozolomide is an imidazotetrazine prodrug that undergoes spontaneous hydrolysis to the active metabolite 
MTIC, which methylates DNA at O6-guanine and other sites. This drug has excellent oral bioavailability and 
crosses the blood-brain barrier.89 Temozolomide can be given concurrent with cranial radiotherapy, with 
adults tolerating 75 mg/m2/day for up to 42 consecutive days,10,81 and children tolerating 90 mg/m2/day.82 
Advantages of protracted temozolomide include exposure to a greater cumulative amount of drug, depletion 
of the resistance protein methylguainine-DNA methyltransferase, and anti-angiogenic effects.90 A large phase 
III trial showed that protracted temozolomide given concurrently with radiotherapy, followed by maintenance 
temozolomide (5 days every 4 weeks), was superior to radiotherapy alone  (2 year OS: 26% versus 10%).10 
This new standard of care for adults with GBM has been investigated in the COG trial ACNS0126. 
Preliminary results of ACNS0126 are comparable to those of the historical control group (CCG 945) that has 
had the best survival outcome to date among children with malignant gliomas. Despite that, the results are 
still suboptimal, which highlights the need to build upon the temozolomide regimen in an effort to improve 
outcome. 
 
Preclinical data also suggest that temozolomide has at least additive activity with radiation in human 
glioblastoma cells.2-6 Van Nifterik et al recently reported that, in temozolomide-sensitive GBM cell lines, 
temozolomide can act as a radiosensitizer and is at least additive to gamma-irradiation. Enhancement of the 
radiation response by temozolomide seemed to be independent of the epigenetically silenced MGMT. They 
exposed 3 genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) to various 
single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of gamma-irradiation. Repeated 
temozolomide doses were given before and concurrent with irradiation treatment. Immediately plated 
clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation 
experiments. To establish the net effect on clonogenic cell survival and cell proliferation, growth curves were 
determined, expressed as the number of surviving cells. All 3 cell lines showed MGMT promoter 
methylation, lacked MGMT protein expression, and were sensitive to temozolomide. The isotoxic 
temozolomide concentrations used were in a clinically feasible range. Temozolomide was able to 
radiosensitize 2 cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number 
of surviving cells after treatment with the combination of temozolomide and fractionated irradiation was seen 
in all 3 cell lines.91  
 
2.3.3 
Rationale for Arm C: Bevacizumab as a Radiosensitizer 
 
Gorski et al demonstrated that irradiation of tumor cells induced increased VEGF expression.  Pre-treatment 
of various tumor xenografts in vivo with anti-VEGF therapy, including U87 glioblastoma, had a greater than 
additive effect when combined with subsequent radiation.92 Using the same model, Lee et al demonstrated 
that anti-VEGF mAB exposure induced reduction of tumor vascular density and a reduction of tumor 
interstitial fluid pressure by 74%. Simultaneously, pO2 significantly increased. Combined treatment with 
radiation yielded greater than additive tumor growth delay, independent of experimentally induced normoxic 
or hypoxic conditions, suggesting that anti-VEGF therapy mitigated the impact of hypoxic conditions in this 
glioblastoma model in vivo.93 More recently, the kinetics of vascular changes and ‘window of normoxia’ was 
investigated in orthotopically placed U87 glioblastoma in mouse brain following DC101 anti-VEGR2 
therapy.  Maximum tumor oxygenation occurred by Day 5 following DC101 exposure, and decreased again 
by Day 8.  Radiation exposure Days 4-6 following DC101 exposure yielded synergistic effects, whereas 
alternative schedules had no more than additive effects.94 Such findings have been confirmed by independent 
investigators in melanoma and various carcinoma xenograft models.92,95 
 
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Batchelor et al reported that anti-VEGF therapy normalized the tumor vasculature and alleviates edema in 
glioblastoma patients.  In their report of 16 glioblastoma patients treated with the anti-VEGF agent 
AZD2171, the onset of vascular normalization was rapid and sustainable, but reversible by 28 days following 
cessation of drug therapy.96 Gonzalez et al similarly reported the MD Anderson experience with 15 patients 
with malignant glioma, 8 of who were diagnosed with radiation necrosis.  Bevacizumab anti-VEGF therapy, 
either alone or in combination with chemotherapy, reduced radiation necrosis by decreasing capillary leak 
and associated brain edema in all 8 patients demonstrated by MRI performed 8 weeks following therapy 
initiation.97 
 
Such attenuation of the effects of radiation necrosis and brain edema may improve quality of life for patients, 
and may decrease the diagnosis of pseudo progression (radiation-induced tumor inflammation) frequently 
noted in the first months following chemoradiotherapy in approximately 15% of patients.98,99 
 
Mohile et al conducted a study in patients with recurrent high-grade glioma, who received bevacizumab 10 
mg/kg IV q 2 weeks and stereotactic intensity modulated IMRT: 30 Gy in 5 fractions over 15 days. Twelve 
patients with HGG received a median of 5.5 cycles of therapy. Grade 3 events occurred in 10 patients, 
including hypertension, headache, neutropenia, seizures, hyponatermia and hypophosphatemia. There were 
no Grade 4 or 5 events, no DLTs and no intracranial hemorrhage. Seven out of twelve patients had objective 
responses (3 CR, 4 PR). Estimated 6 month PFS was 76%. MR perfusion imaging demonstrated a decrease in 
mean perfusion values after 1 cycle of bevacizumab.100 
 
Narayana et al reported the results of a feasibility study in which 15 patients with high-grade glioma were 
treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 
mg/kg on Days 14 and 28 and temozolomide 75 mg/m2.101 Subsequently, bevacizumab 10 mg/kg was 
continued every 2 weeks with temozolomide 150 mg/m2 for 12 months. Changes in relative cerebral blood 
volume, perfusion-permeability index, and tumor volume measurement were measured to assess the 
therapeutic response. Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation 
therapy. Four Grade III/IV non-hematologic toxicities were seen. Radiographic responses were noted in 13 of 
14 assessable patients (92.8%). Six patients have experienced relapse, 3 at the primary site and 3 as diffuse 
disease. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively. 
The authors concluded that the use of bevacizumab with radiation and temozolomide in the management of 
newly-diagnosed high-grade glioma patients is feasible.  
 
Desjardins et al presented preliminary results of the Duke study in which adults with newly diagnosed GBM 
or gliosarcoma received radiation therapy with bevacizumab 10 mg/kg weeks 3 and 5 of RT as well as 
temozolomide 75 mg/m2 days 1-42 of RT, followed by a post RT maintenance regimen consisting of 
irinotecan, avastin q 2 weeks with temozolomide given days 1-5 of each 28 day course.102 One hundred and 
twenty five were enrolled, 119 completed RT and 6 did not.  Toxicities during radiotherapy included: 3 grade 
4 thrombocytopenias (attributable to temozolomide), 1 grade 4 neutropenia. Non hematological toxicities ≥ 
grade 3 during RT included 2 DVT/PE, 1 stitch abscess,1 wound dehiscence, 2 seizures and 1 CNS 
hemorrhage (grade 2), sudden death secondary to MI (n=1). Hematological toxicities during the maintenance 
phase included 3 grade 3 thrombocytopenias, 10 grade 4 thrombocytopenia, 14 grade 3 neutropenia, 6 grade 
4 neutropenia. (Please note that the myelosuppression was most likely due to temozolomide given during 
maintenance therapy, which will not be given in ACNS0822). Grade 3 or 4 non-hematological toxicities 
during maintenance therapy included: 3 DVT/PE, 3 GI toxicities, 1 rectal abscess, 1 sepsis, 1 wound 
dehiscence, 1 optic neuritis, 2 PCP, 7 patients were taken off study for decreased Karnofsky score or because 
of patient choice. Thus, the treatment regimen is feasible and tolerable in adults.  One-year progression-free 
survival was reported to be 60%, with a one-year overall survival of 79%. The updated survival data for this 
trial will be presented at ASCO 2010. Preliminarily, this regimen has doubled the median progression-free 
survival to 14 months from 6.9 months historically. (
, personal communication).  
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Vredenburgh et al reported the preliminary results of the study of Bevacizumab in combination with 
temozolomide and radiation therapy followed by BEV, TMZ, and irinotecan for newly diagnosed 
glioblastoma multiforme (GBM). 125 newly diagnosed GBM patients were enrolled between 8/07 and 
3/09. Patients received radiation therapy and TMZ at 75 mg/m2/d beginning between 2-6 weeks post-
craniotomy. BEV at 10 mg/kg every 14 days was added a minimum of 4 weeks post- op. Following 
radiation therapy, patients received 6-12 monthly cycles of TMZ at 200 mg/m2/d days 1-5, BEV at 10 
mg/kg and irinotecan on days 1 and 15. The dose of irinotecan was 340 mg/m2 for patients on enzyme 
inducing anti-epileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAED. The addition of BEV 
and irinotecan to standard therapy doubled the median PFS, 14 months vs. 6.9 months. The median 
overall survival has not been reached, but 56% of the patients are alive at a minimum follow-up of 18 
months. In addition, 28% remain progression-free at a median follow- up of 23 months. The regimen was 
tolerable, 122 of 125 patients completed radiation therapy and 78 completed 6 cycles of post-radiation 
BEV, TMZ, and irinotecan. There were 4 toxic deaths, from a myocardial infaction, pulmonary embolus, 
PCP and sepsis. The addition of BEV to TMZ and radiation followed by TMZ, BEV, and irinotecan is 
tolerable. The median progression-free survival is improved and the overall survival is prolonged.29 
 
In addition, preliminary data are available from a study in 7 patients with newly diagnosed high-grade 
gliomas or diffuse intrinsic pontine gliomas < 30 years of age (4 of whom are less than 21 years of age) in 
a study at Cincinnati Children’s Hospital Medical Center. (
, personal communication). In this 
protocol, patients with HGG receive bevacizumab and temozolomide during RT followed by 12 courses 
of bevacizumab, temozolomide and irinotecan post RT, and patients with DIPG receive the same therapy 
without temozolomide. Among the 4 patients less than 21 years of age treated on this protocol, the 
following non-hematological toxicities attributable to therapy have been observed during the RT-
chemotherapy period: grade 1 PTT (n=1), grade 3 infection with normal ANC (n=1), grade 1 anorexia 
(n=1), grade 1 dermatitis associated with radiation, (n=1). In addition, the following hematological 
toxicities attributable to therapy have been observed: grade 1 thrombocytopenia (n=1), grade 2 
lymphopenia (n=1), grade 1 low WBC (n=1). 
 
2.3.4 Summary of Feasibility Study in ACNS0822 with Vorinostat and Radiation Therapy 
Six patients with high grade gliomas were enrolled on the feasibility study. All patients were evaluable 
for toxicity and received vorinostat 230 mg/m2/day 5 days per week for 6 weeks during RT.  No dose 
limiting toxicities were reported at this dose level of vorinostat and patients tolerated the combination of 
RT and vorinostat well.  There were no grade 3 or higher non-hematologic toxicities reported during the 
DLT observation period.  All patients’ pathology specimens were centrally reviewed. There were three 
patients with GBM and three with AA. 
 
As part of Amendment #1, the study will re-open to the Phase II portion of the study and all future 
patients on Arm A will receive vorinostat 230 mg/m2/day, Monday through Friday, during the chemo-
radiation phase. 
 
 
2.4 
Rationale for Biology Studies 
 
2.4.1 
Gene expression profiling, miRNA analysis, and SNP arrays 
Faury et al recently published data on 32 pediatric GBM (pGBM) and 7 adult GBM (aGBM) samples which 
they investigated using biochemical and transcriptional profiling. Ras and Akt pathway activation was 
assessed through the phosphorylation of downstream effectors, and gene expression profiles were generated 
using the University Health Network Human 19K cDNA arrays. Results were validated using real-time 
polymerase chain reaction and immunohistochemistry and compared with existing data sets on aGBM. There 
are at least two subsets of pGBM. One subset, associated with Ras and Akt pathway activation, has very poor 
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prognosis and exhibits increased expression of genes related to proliferation and to a neural stem-cell 
phenotype, similar to findings in aggressive aGBM. This subset was still molecularly distinguishable from 
aGBM after unsupervised and supervised analysis of expression profiles. A second subset, with better 
prognosis, is not associated with activation of Akt and Ras pathways, may originate from astroglial 
progenitors, and does not express gene signatures and markers shown to be associated with 
long-term survival in aGBM. This small study of gene expression profiles in pGBM, provides valuable 
insight into active pathways and targets in a cancer with minimal survival,suggests that pediatric malignant 
gliomas cannot be understood exclusively through studies of adult GBM, and provides a strong rationale for 
examination of Akt signaling pathway activation, and its relationship to prognosis in the planned cohort, as 
well as a broad-based assessment of gene expression and genomic alternations as defined by whole genome 
SNP array profiling in these tumors.103   
 
 
The Cancer Genome Atlas (TCGA) pilot project recently reported the interim integrative analysis of DNA 
copy number, gene expression and DNA methylation aberrations in 206 glioblastomas and nucleotide 
sequence104 aberrations in 91 of the 206 glioblastomas. This analysis provided insights into the roles of 
ERBB2, NF1 and TP53, demonstrated frequent mutations of the phosphatidylinositol-3-OH kinase regulatory 
subunit gene PIK3R1, and provided a network view of the pathways altered in the development of 
glioblastoma. Integration of mutation, DNA methylation and clinical treatment data revealed a link between 
MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in 
treated glioblastomas.  
 
Since their initial identification in lower organisms around 15 years ago, several hundred105-108 
microRNAs (miRNAs) are now known to exist within the human genome.109 These small, non-protein-
encoding RNAs play a fundamental role in regulating gene expression which in turn influences many 
biological processes. Not surprisingly, their role in many types of cancer is now beginning to be 
appreciated.110 No comprehensive analysis of miRNA expression changes has been published in pediatric 
gliomas and only two small studies have been published in adult GBMs to date.111,112 Ciafrè and 
colleagues reported that miR-221 expression was frequently upregulated in a small group of nine primary 
glioblastoma samples while miR-128, miR-181a, miR-181b and miR-181c were downregulated. 111 In 
contrast, Malzkorn and colleagues investigated the expression changes occurring in miRNAs in a cohort 
of four secondary glioblastoma patients. They found that increased expression of miR-9, miR-15a, miR-
16, miR-17, miR-9a, miR-20a, miR-21, miR-25, miR-28, miR-130b, miR-140 and miR-210 and reduced 
expression of miR184 and miR 328 were associated with malignant progression in these patients’ 
tumors.112 
 
2.4.2 
Telomerase activity, hTert expression, hTERC, and telomere length  
Telomerase is a ribonucleoprotein complex that elongates telomeric DNA and appears to play an 
important role in cellular immortalization and cancers. Because telomerase is expressed in the vast 
majority of malignant gliomas but not in normal brain tissues, it is a logical target for glioma-specific 
therapy. Telomerase adds hexameric repeats of 5'-TTAGGG-3' to the ends of telomeres to compensate for 
the progressive loss with each cell division.109,110,111  Telomerase activity, which is generally undetectable 
in normal somatic cells, is expressed in approximately 90% of tumors.112-114 In malignant gliomas, 
telomerase activity is very often detected.115-128 In Grade I and II gliomas, telomerase activity is detected 
in 0% and 0% to 33%, respectively. In malignant gliomas, telomerase is positive in 10% to 100% of 
anaplastic astrocytomas and in 26% to 100% of GBM. Although the ratio of telomerase-positive cells in 
gliomas varies, most of the reports show that the incidence of telomerase expression is closely correlated 
with the malignancy, and telomerase is detected in the vast majority of malignant gliomas. By contrast, 
normal brain tissues do not express telomerase activity,116,122,126,128 while telomerase is detectable only in 
human embryonic neural precursor cells at low levels.129   
 
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Boldrini et al examined telomerase activity by the telomeric repeat amplification protocol (TRAP) assay 
in 42 gliomas, (32 glioblastomas, 4 anaplastic astrocytomas, 4 differentiated astrocytomas, 
1 oligoastrocytoma and 1 oligosarcoma). Telomerase messenger expression (hTERT mRNA) was 
evaluated by reverse transcription-PCR analysis in the same group of tumors. High telomerase activity 
was detected in 21 of 42 gliomas (50%). The levels of telomerase in terms of its messenger level 
expression overlapped the activity; in fact, a significant association between telomerase activity and 
hTERT mRNA expression was found (P<0.0001). At univariate analysis, advanced age as well as high 
telomerase activity and hTERT mRNA levels were significant predictors of worse prognosis regarding 
both overall survival (P=0.007, P=0.007, and P=0.04, respectively) and disease-free interval (P=0.008, 
P=0.008, and P=0.04, respectively). All these variables maintained a significant independent prognostic 
role in multivariate analyses. Therefore, telomerase is expected to represent a good candidate not only for 
a useful prognostic and diagnostic marker of malignant gliomas, but in the future may constitute a target 
for malignant gliomas.130    However, the generalizability of expression and prognostic relevance of this 
target in pediatric malignant gliomas remains to be established, and the current study will address this 
issue.  
 
2.4.3 
Assessment of MGMT Promoter Methylation Status in Plasma and Tumor and MGMT Protein 
Expression in Tumor  
O6-methyl-guanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that promotes resistance of 
tumor cells to the cytolytic effects of alkylating agents such as temozolomide20,103,109,110 and possibly 
incompletely to TMZ/IRI synergy.32  This enzyme removes methyl adducts at the O6 position of guanine, 
an important biologically active target of TMZ and nitrosureas. Expression of MGMT protein and activity 
is under epigenetic control via MGMT promoter CpG island methylation. Methylation of the MGMT 
promoter leads to gene silencing, diminished MGMT protein expression, and increased susceptibility to 
TMZ-based therapy.103 
 
Variability in MGMT activity has been correlated with the methylation status of CpG islands within the 
MGMT promoter.131 MGMT promoter hypermethylation is associated with a loss of transcription and 
decreased expression of MGMT.132 Tumor MGMT promoter hypermethylation is quite variable among 
pediatric malignancies; although the frequency of MGMT promotor hypermethylation in pediatric 
patients with primary brain tumors is unknown, there is clear evidence from the CCG-945 study and the 
ACNS0126 cohort that patients whose tumors had MGMT overexpression has a significantly worse 
response to alkylator-based therapies with lomustine and temozolomide, respectively.133,134  
 
In this study, we plan to compare EFS between patients with MGMT overexpression and those without, 
and those with MGMT promoter methylation and those without.  Given that some of treatment arms will 
involve use of nonalkylator-based therapy, this would allow a determination of whether patients with 
MGMT overexpression have an adverse prognosis specifically in the context of alkylator-based therapy, 
or whether such children have an adverse outcome independent of therapeutic approach. 
 
Because MGMT status has been analyzed by several techniques in previous studies, the tumor MGMT 
protein status will be assessed directly via protein expression analyses performed via 
immunohistochemical techniques as well as indirectly by assessing the methylation status of the MGMT 
promoter via methylation-specific polymerase chain reaction (PCR) assays performed on tumor DNA.103  
 
2.5 
Rationale for MR Perfusion and Diffusion Imaging Studies 
Using magnetic resonance imaging (MRI) techniques, Batchelor et al showed that normalization of tumor 
vessels in recurrent glioblastoma patients by daily administration of AZD2171 (an oral tyrosine kinase 
inhibitor of VEGF receptors) has rapid onset, is prolonged but reversible, and has the significant clinical 
benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for 
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as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased 
when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed 
after drug interruption. This study suggests that the timing of combination therapy may be critical for 
optimizing activity against this tumor.96 
 
T2*-weighted perfusion MRI, a method based on the rapid intravenous administration of Gd-DTPA, has 
been used for the assessment of treatment response to antiangiogenic agents in adults with recurrent 
high-grade gliomas.135,136 
 
In the referenced studies, the variations observed during therapy using this sequence seemed to correlate 
with the clinical response experienced by the patients. A third study used this sequence in adults with 
newly diagnosed high-grade glioma and demonstrated its usefulness to assess angiogenesis and 
microvascular leakage, two characteristics associated with the malignant potential of these tumors.137 The 
latter study also demonstrated considerable heterogeneity of the measured parameters within regions of 
WHO grade III and IV gliomas. 
 
Hamstra et al assessed the role of diffusion magnetic resonance imaging (MRI) using a functional diffusion 
map (fDM) in providing an earlier measure to predict patient survival. Sixty patients with high-grade glioma 
were enrolled onto a study of intratreatment MRI at 1, 3, and 10 weeks. Receiver operating characteristic 
curve analysis was used to evaluate imaging parameters as a function of patient survival at 1 year. Both 
log-rank and Cox proportional hazards models were utilized to assess overall survival. Greater increases in 
diffusion in response to therapy over time were observed in those patients alive at 1 year compared with 
those who died as a result of disease. The volume of tumor with increased diffusion by fDM at 3 weeks was 
the strongest predictor of patient survival at 1 year, with larger fDM predicting longer median survival 
(52.6 vs 10.9 months, P < .003); hazard ratio [HR] = 2.7; (95% CI, 1.5 to 5.9). Radiologic response (RR) at 
10 weeks had similar prognostic value (median survival, 31.6 v 10.9 months; log-rank 
P<.001; HR = 2.9; (95% CI, 1.7 to 7.2). Radiologic response and fDM differed in 25% of cases. A 
composite index of response including fDM and RR provided a robust predictor of patient survival and may 
identify patients in whom RR does not correlate with clinical outcome. The authors concluded that with 
conventional neuroimaging, fDM provided an earlier assessment of equal predictive value, and the 
combination of fDM and RR provided a more accurate prediction of patient survival than either metric 
alone.138 
 
For imaging assessment, conventional MR imaging techniques will be utilized as well as more advanced 
MRI techniques for characterization of the tumor at baseline and to assess treatment response in a 
multiparametric fashion. Advanced techniques will include optional MR perfusion imaging using 
dynamic susceptibility weighted contrast enhanced –MRI (DSC-MRI) and diffusion tensor imaging 
(DTI).  These techniques will allow assessment of tumor size (Anatomic MRI) and estimate cellularity 
(DTI) and vascularity (perfusion).139 Imaging techniques will be performed at a level common to many 
different scanners likely to be encountered in clinical practice. 
 
MR perfusion: 
T2*-weighted perfusion MRI using the rapid intravenous administration of Gd-DTPA (dynamic 
susceptibility weighted contrast enhanced –MRI  or DSC-MRI) is an imaging method that can assess 
tumor microvascularity and has been shown to correlate with tumor grade in astrocytomas140,141 and 
treatment response to antiangiogenic agents in adults with high-grade gliomas.136 In addition, a recent 
study has demonstrated that cerebral blood volume (CBV) measurements by DSC-MRI can predict time 
to progression and survival in patients with gliomas, independent of pathologic findings.140  Sadeghi et 
al,141 found significant correlations between CBV measurements and microvessel density in 
stereotactically obtained biopsies in patients with brain gliomas.   
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The perfusion protocol will be performed using a dynamic, contrast enhanced T2* weighted perfusion 
technique. Evaluation of cerebral perfusion dynamics will include cerebral blood volume (rCBV), 
cerebral blood flow (CBF), and mean transit time (MTT) of contrast through the vasculature of the tumor 
and brain parenchyma.   
 
Diffusion Tensor Imaging: 
Imaging of water diffusion (DTI) is an elegant technique to probe brain and tumor microstructure. To 
completely define the tensor at least six non co-linear diffusion directions are needed. Typical metrics 
defined are mean diffusivity (MD), apparent diffusion coefficient (ADC), and fractional anisotropy (FA). 
Although diffusion imaging has been investigated and shown to be effective as a tool to differentiate 
some intracranial tumor types, results in this regard have been mixed and overlap exists.142  Changes in 
water diffusion have been documented occurring in the first few weeks after initiation of treatment and 
may be useful to predict response to therapy. In a study of patients with glioma treated with radiation and 
chemotherapy, those with stable disease showed higher ADC in tumor relative to normal appearing white 
matter at 1 month than in those with tumor progression.142  Similar findings have been noted in metastatic 
brain lesions.143 A more advanced metric involves the calculation of a functional diffusion map.138,144  
This metric utilizes fusion of pre- and post treatment MR imaging and analyzes the change in ADC values 
in common voxels between the two studies, resulting in a metric that relates to the volume of tumor 
exhibiting a change in ADC. Volume of tumor exhibiting an increase in ADC correlates well with initial 
response rate and patient survival.138 
 
 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration  
Prior to enrollment on this study, patients must be assigned a COG patient ID number. This number is 
obtained via the eRDE system once authorization for the release of protected health information (PHI) has 
been obtained. The COG patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help.   
 
In order for an institution to maintain COG membership requirements, every newly diagnosed patient needs 
to be offered participation in ACCRN07, Protocol for the Enrollment on the Official COG Registry, The 
Childhood Cancer Research Network (CCRN).  
 
A Biopathology Center (BPC) number will be assigned as part of the registration process. Each patient will 
be assigned only one BPC number per COG Patient ID. For additional information about the labeling of 
specimens please refer to the Pathology and/or Biology Guidelines in this protocol.  
 
3.1.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to enrolling patients. Sites must 
submit IRB/REB approvals to the NCI’s Cancer Trials Support Unit (CTSU) Regulatory Office and allow 
3 business days for processing. The submission must include a fax coversheet (or optional CTSU IRB 
Transmittal Sheet) and the IRB approval document(s).  The CTSU IRB Certification Form may be 
submitted in lieu of the signed IRB approval letter.  All CTSU forms can be located on the CTSU web 
page (https://www.ctsu.org). Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the RSS Tab. 
 
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IRB/REB 
approval 
documents 
may 
be 
faxed 
(1-215-569-0206), 
emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office. 
 
When a site has a pending patient enrollment within the next 24 hours, this is considered a “Time of 
Need” registration.  For Time of Need registrations, in addition to marking your submissions 
as ‘URGENT’ and faxing the regulatory documents, call the CTSU Regulatory Helpdesk at: 1-866-651-
CTSU. For general (non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been met. Study 
enrollment is accomplished by going to the Enrollment application in the RDE system. If you have 
problems with enrollment, refer to online help in the Applications area of the COG website.  
 
3.1.4 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must be 
no later than 31 days after definitive surgery and no later than 14 calendar days after the date of study 
enrollment. Patients who are started on protocol therapy on a Phase II study prior to study 
enrollment will not be entered on study.  
 
All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to 
enrollment unless otherwise indicated in the eligibility section below. 
 
3.1.5 
Bilingual Services  
To allow non-English speaking patients to participate in the study, bilingual health care services will be 
provided in the appropriate language. 
 
3.1.6 
Mandatory Submission of Tissue for Central Pathology Review (see Section 15.0) 
All patients must have tissue submitted for central pathology review, prior to the start of maintenance.  
 
3.1.7 
Randomization 
The first 6 to 12 patients (depending on toxicities experienced) will be enrolled onto the feasibility part of 
the study and will not be randomized to treatment. These patients will be assigned to the vorinostat with 
RT treatment arm, with the dose of vorinostat assigned at time of study entry (either 230 mg/m2/day or 
180/mg/m2/day). The vorinostat MTD determined upon completion of the feasibility part will be the 
vorinostat dose used during the remainder of the study. 
 
Following the feasibility study, randomization will take place at the time a patient is enrolled on Study via 
RDE. In Phase II, patients will be randomized to one of the following arms of chemoradiotherapy: Arm A 
(vorinostat with RT), Arm B (temozolomide with RT), or Arm C (bevacizumab with RT). In Phase III, 
patients will be randomized to one of two arms: the superior chemoradiotherapy arm from Phase II (either 
Arm A or Arm C) or Arm B (temozolomide with RT). Randomization will be stratified by extent of resection 
(near total resection or gross total resection vs. other) and histology (glioblastoma multiforme vs. other). 
 
3.2 
Patient Criteria 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived 
(per COG policy posted 5/11/01). All clinical and laboratory data required for determining 
eligibility of a patient enrolled on this trial must be available in the patient's medical/research 
record which will serve as the source document for verification at the time of audit.  
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INCLUSION CRITERIA 
 
3.2.1 
Age 
Patients must be greater than or equal to 3 years and less than 22 years at the time of enrollment. 
 
3.2.2 
Diagnosis  
 
3.2.2.1 
Patients must have a newly diagnosed high-grade glioma such as: anaplastic astrocytoma, glioblastoma 
multiforme, or gliosarcoma. Patients with primary spinal cord malignant gliomas are eligible. Patients 
with primary brainstem tumors are not eligible. Patients with a diagnosis of oligodendroglioma or 
oligoastrocytoma are NOT eligible. 
 
 
3.2.2.2 
Patients must have histologic verification of diagnosis. Patients with M+ disease (defined as evidence 
of neuraxis dissemination) are not eligible. CSF cytology must be done if clinically indicated prior to 
study enrollment. If cytology proves positive, the patient would be considered to have metastatic 
disease and would, therefore, be ineligible. 
 
Note: False positive cytology can occur within 10 days of surgery.   
 
3.2.2.3 
For patients with intracranial tumors, a pre-operative and post-operative brain MRI with and without 
gadolinium and a spine MRI if clinically indicated must be obtained.  For patients with spinal cord primaries, 
only a pre and post-operative spine MRI with gadolinium must be obtained. The post-operative MRIs must 
be obtained within 4 weeks prior to enrollment onto study. The requirement for a post-operative MRI is 
waived for patients who undergo biopsy only (see Section 7.1). 
 
3.2.3 
Performance Level (See https://members.childrensoncologygroup.org/prot/reference_materials.asp) 
Patients must have a Lansky or Karnofsky performance status score of ≥ 50%, corresponding to ECOG 
categories of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients  16 years of 
age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be 
considered ambulatory for the purpose of assessing the performance score. 
 
3.2.4 
Prior Therapy 
 
3.2.4.1 
Patients must not have received any prior chemotherapy, radiation therapy, immunotherapy, or bone 
marrow transplant. 
 
3.2.5 
Cardiac Disease or Hypertension 
- 
Hypertension must be well controlled (≤ 95th percentile for age and height if patient is ≤ 17 
years) on stable doses of medication. (See Appendices I and II for tables of blood pressure 
based on age and gender. If a patient falls between percentiles for height and age, then the 
average value should be considered the appropriate one.) If patient is > 17 years, adult normal 
values should be used (ie, patients must have a SBP ≤ 150 mmHg and/or DBP ≤100 mmHg.) 
 
Please see additional exclusion criteria in 3.2.8 – 3.2.11. 
 
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3.2.6 
Concomitant Medications Restrictions (Please see Section 4.2 for the concomitant therapy 
 
restrictions for patients during the study). 
 
a. 
Study Specific:   
1) Patients must not be currently receiving other anti-cancer agents. 
2) Patients must not be receiving nonsteroidal anti-inflammatory medications known to inhibit platelet 
function or known to selectively inhibit cyclooxygenase activity. Medicines in this class are 
excluded. 
3) Patients must not be currently receiving enzyme inducing anticonvulsants. (Please see Appendix VII 
for a list of enzyme inducing and non-enzyme inducing anticonvulsants) 
4) Patients must not be receiving other HDAC inhibitors (e.g., valproic acid), as severe 
thrombocytopenia and gastrointestinal bleeding have been reported with concurrent administration 
with vorinostat. 
5) Patients must not be receiving anticoagulants including systemic thrombolytic agents, heparin, low 
molecular weight heparins, or warfarin except as required to maintain patency of preexisting 
permanent vascular catheters or for prevention of thrombosis in the post-operative period.  
 
3.2.7 
Surgical Procedures 
Patients with a major surgical procedure within 7 days prior to planned start of therapy should be 
excluded. Patients must have recovered from any surgical procedure before enrolling on this study (see 
Table below for examples of major, intermediate, and minor surgical procedures).   
Please note: For patients receiving bevacizumab, those who have had surgical procedures should not 
receive bevacizumab within 28 days of a major procedure, 14 days of an intermediate procedure and 7 
days of a minor procedure. (Please see below for definitions of types of procedure).  
Examples of Major, Intermediate, or Minor Surgical Procedures 
Major Procedures 
Intermediate Procedures 
Minor Procedures 
Major craniotomy for tumor 
resection 
VP-shunt placement 
Incision and drainage of superficial 
skin abscesses 
Organ resection 
Stereotactic brain biopsy 
Punch biopsy of skin lesions 
Bowel wall anastomosis 
 
Superficial skin wound suturing 
Arteriovenous grafts 
 
Bone marrow aspirate and/or 
biopsy 
Exploratory Laparotomy 
 
Fine needle aspirations 
Thoracotomy 
 
Broviac line or infusaport 
placement 
 
 
Paracentesis or thoracocentesis 
 
Please note: Lumbar punctures or placement of PICC lines are not considered minor procedures and may 
occur at any time prior to or during therapy. 
 
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3.2.8 
Organ Function Requirements 
All patients must have:  
 
3.2.8.1 Adequate Bone Marrow Function Defined As 
- 
Peripheral absolute neutrophil count (ANC)  1000/L 
- 
Platelet count  100,000/L (transfusion independent) 
- 
Hemoglobin  8.0 gm/dL (transfusion independent) 
 
3.2.8.2 Adequate Renal Function Defined As 
 
- 
Creatinine clearance or radioisotope GFR  70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 
3.2.8.3 Urine protein should be screened by urine analysis. If protein ≥ 2+ on urinalysis, then Urine 
Protein Creatinine (UPC) ratio should be calculated.  If UPC ratio > 0.5, 24-hour urine protein 
should be obtained and the level should be < 1000 mg for patient enrollment. 
 
Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion – a UPC ratio of 1 
is roughly equivalent to a 24-hour urine protein of 1000 mg.  UPC ratio is calculated using one of 
the following formulae: 
- [urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL 
- [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 
 
3.2.8.4 Adequate Liver Function Defined As  
- 
Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- 
SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age, and 
- 
Serum albumin ≥ 2 g/dL. 
 
3.2.8.5 Central Nervous System Function Defined As 
- 
Patients with a seizure disorder may be enrolled if well-controlled and on nonenzyme- 
inducing anticonvulsants. If on nonenzyme-inducing anticonvulsants, patient must not be 
taking valproic acid.  
 
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3.2.8.6 Adequate Coagulation Defined As 
- 
PT INR ≤ 1.5 x upper limit of normal 
 
  
EXCLUSION CRITERIA 
 
3.2.9 
Patients must not have a history of myocardial infarction, severe or unstable angina, clinically significant 
peripheral vascular disease, Grade 2 or greater heart failure, or serious and inadequately controlled 
cardiac arrythmia.  
 
3.2.10 
Patients must not have a known bleeding diathesis or coagulopathy 
 
3.2.11 
Patients who have experienced arterial thromboembolic events, including transient ischemic attacks or 
cerebrovascular accidents are excluded from participation. 
 
3.2.12 
Patients must not have been previously diagnosed with a deep venous thrombosis (including pulmonary 
embolism), and must not have a 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). 
 
3.2.13 
Patients must not have a history of an abdominal fistula, gastrointestinal perforation, or intra-abdominal 
abscess within the last 6 months prior to study entry. 
 
3.2.14 
Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible for this study. 
 
3.2.15 
Patients must not have 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 14 
days prior to study entry.  
 
3.2.16 
Patients with a history of allergic reaction to Chinese hamster ovary cell products, or other recombinant 
human antibodies are ineligible. 
 
3.2.17  
Pregnant female patients are not eligible for this study. Pregnancy tests with a negative result must be 
obtained in all post-menarchal females.  
 
3.2.18 
Lactating females must agree they will not breastfeed a child while on this study. 
 
3.2.19 
Males and females of reproductive potential may not participate unless they agree to use an effective 
contraceptive method and continue to do so for at least 6 months after the completion of bevacizumab 
therapy. 
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REGULATORY 
 
3.2.20 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.21 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
4.0 
TREATMENT PROGRAM 
 
4.1 
Overview of Treatment Plan 
This is a 2 phase study. The first phase of the study will include a feasibility study component to assess 
for dose-limiting toxicities (DLTs) and define the maximum tolerable dose (MTD) of vorinostat when 
given concurrently with radiation therapy (see Experimental Schema). The feasibility study is open to all 
COG institutions. The MTD found in the feasibility study component will be used in all subsequent 
phases of the study. The phase II component of the study will compare 2 experimental treatments to a 
commonly used chemoradiotherapy arm (Arm B with temozolomide). Upon completion of the phase II 
part of the study, a comparison of 1 year EFS will be made between the experimental arms and the 
temozolomide chemoradiotherapy arm. If one or both of the experimental arms has a superior 1 year EFS 
to that of the temozolomide chemoradiotherapy arm, the study will enter the phase III part of the study.  If 
none of the experimental arms is superior to the temozolomide chemoradiotherapy arm, the study will not 
proceed to Phase III. In Phase III of this study, patients will continue to be accrued and randomly assigned 
to either the superior experimental arm identified in Phase II or to the temozolomide chemoradiotherapy 
arm.  
 
All patients must begin therapy within 31 days after definitive surgery. Radiation will be given in 
standard fractions (total dose 59.4 Gy) over 6 weeks (see Section 14.0 for details). During radiation, 
patients will receive chemotherapy per one of the three arms described in Section 4.4. All patients will 
begin Maintenance therapy with bevacizumab and temozolomide commencing 4 weeks after completion 
of RT for up to a total of 12 cycles. 
 
Growth plate evaluation: Patients who have not yet obtained full adult height will have a plain AP 
radiograph of a single tibial growth plate obtained prior to initial treatment. If a patient is found to have a 
closed tibial growth plate, no further radiographs will be required for that patient. If the patient is found to 
have an open tibial growth plate, then repeat plain AP radiographs of the same tibial growth plate will be 
obtained every 12 weeks during Maintenance therapy. 
 
Patients with evidence of growth plate thickening or other changes or abnormalities should have MRI 
scans of both knees performed to further assess the degree of physeal pathology and a consultation with 
an orthopedic surgeon is recommended.  However, no dose modifications will be made for bevacizumab. 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care.  Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  
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4.2 
Concomitant Therapy Restrictions 
 
4.2.1 
General Restrictions for All Patients on Therapy 
 
4.2.1.1 
Patients must not be receiving nonsteroidal anti-inflammatory medications known to inhibit platelet 
function or known to selectively inhibit cyclooxygenase activity. 
 
4.2.1.2 
Patients should not receive coumarin-derivative anticoagulants (eg, warfarin), as prolongation of 
prothrombin time (PT) and International Normalized Ratio (INR) were observed in patients receiving 
vorinostat with coumarin-derivative anticoagulants (eg, warfarin). In general, since all patients will 
receive bevacizumab during maintenance therapy, patients must not be treated with anticoagulants 
including systemic thrombolytic agents, heparin, low molecular weight heparins, or warfarin while on 
protocol therapy, except as required to maintain patency of preexisting permanent vascular catheters.  
 
4.2.1.3 
Filgrastim (G-CSF) may be used at the treating physician’s discretion to enhance neutrophil recovery 
when clinically indicated (eg, for culture proven bacteremia or invasive fungal infection). Routine use of 
filgrastim in clinically well patients awaiting count recovery is not recommended.  
 
4.2.1.4 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to be 
used as necessary. 
 
4.2.1.5 
Corticosteroid therapy is permissible only for treatment of increased intracranial pressure. The lowest 
dose consistent with good medical management should be used. Corticosteroids should NOT be used as 
an antiemetic due to their effect on the blood brain barrier. Use of corticosteroids must be documented on 
the appropriate case report form. 
 
4.2.2 
Concomitant Therapy Restrictions for Patients Receiving Temozolomide 
There have been multiple episodes of pneumocystis carinii pneumonia (also called Pneumocystis jiroveci 
pneumonia) (PCP) reported in patients receiving temozolomide, particularly when taking corticosteroids. 
For this reason, patients should receive PCP prophylaxis during treatment. However, there have been 
three reports of prolonged myelosuppression and death in older adults receiving chemoradiotherapy with 
temozolomide at low-dose along with trimethoprim/sulfamethoxazole (also called TMP/SMX, 
cotrimoxazole, Bactrim, Septra) prophylaxis. For this reason, trimethoprim/sulfamethoxazole may not be 
utilized as PCP prophylaxis during chemoradiotherapy in patients receiving temozolomide as a 
radiosensitizer. Monthly inhaled or IV pentamidine or an appropriate alternative must be 
administered during chemoradiotherapy if patients are receiving temozolomide as a radiosensitizer.  
TMP/SMX may be used during adjuvant 5-day temozolomide. PCP prophylaxis should be discontinued 3 
months after chemotherapy has discontinued. 
 
For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference materials.asp under Standard 
Sections for Protocols. 
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4.3 
Definitions of Dose Limiting Toxicities, Maximum Tolerated Dose, and Dose De-Escalation 
Criteria for Feasibility Study 
 
This information applies to the feasibility study only. For dose modifications based on toxicities during 
Phase II and Phase III of the study, refer to Section 5.0.  
 
4.3.1 
Definition of Dose Limiting Toxicities 
Dose-limiting toxicity is assessed during chemoradiotherapy with vorinostat (ie, starting with the first 
dose of vorinostat and concluding at 2 weeks after the completion of chemoradiotherapy) for each patient 
treated in the feasibility portion of this study. Dose-limiting toxicities are based on Version 4.0 of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE). A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Dose-limiting toxicities are 
defined as: 
 
4.3.1.1 Hematological DLT:  
a) Grade 3 decreased platelet count that requires transfusion therapy on greater 
than 2 occasions during radiation therapy 
b) Grade 4 decreased neutrophil count or decreased platelet count 
 
4.3.1.2 Non Hematological DLT 
a) Any grade 4 non-hematological toxicity 
b) Any grade 3 non-hematological toxicity with the specific exception of 
i. Grade 3 nausea and vomiting of less < 5 days duration responsive to 
antiemetic therapy; 
ii. Grade 3 increased alanine aminotransferase (ALT or SGPT) that 
return to levels that meet initial eligibility criteria within 7 days of study 
drug interruption and that do not recur upon study re-challenge with 
study drug 
iii. Grade 3 fever or infection < 5 days duration. 
iv. Grade 3 hypokalemia, hypophosphatemia, hypocalcemia and/or 
hypomagnesemia responsive to oral supplementation 
c) Any grade 2 non-hematological toxicity that persists for ≥ 7 days and is 
considered sufficiently medically significant or sufficiently intolerable 
by patients that it requires treatment interruption 
d) Grade 2 allergic reactions that necessitate discontinuation of study drug will 
not be considered dose-limiting. 
e) Any Grade 2 or higher adverse event requiring interruption of study drug for > 
7 days or which recurs upon drug rechallenge. 
 
4.3.1.3 Any Grade 2 or higher toxicity requiring interruption of radiation therapy for > 5 consecutive days 
or 10 days total. 
 
4.3.2 
Definition of Maximum Tolerated Dose 
The dose level that has 0 or 1 DLT among the 6 patients will be chosen as the MTD. 
 
4.3.3 
Rules for Dose De-Escalation During Feasibility Portion of the Study 
The following rules will be applied during the feasibility portion of the study. Six patients will be enrolled 
at vorinostat 230 mg/m2/dose with daily RT. If there are fewer than 2 patients with DLTs, this dose will 
be declared the recommended phase II dose. If there are 2 or more DLTs in this cohort of 6 patients, the 
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dose will be de-escalated to 180 mg/m2/dose, at which level 3 additional patients will be enrolled. If 0 or 
1 of the 3 patients has a DLT, an additional 3 patients will be enrolled onto this cohort. If fewer than 2 of 
the 6 patients have a DLT, the 180 mg/m2/dose will be declared the recommended phase II dose. If 2 or 
more of the 6 patients at 180 mg/m2/dose have a DLT, the study will be amended. 
 
Upon completion of the feasibility study, the study will be amended for the MTD to be used in the 
remainder of the study. Patients currently on study will continue with maintenance therapy after 
completion of chemoradiotherapy (see Section 4.9). 
 
4.4 
Description of Treatment Arms 
 
4.4.1 
Treatment Arm During Feasibility Study  
As of Amendment #1, the Feasibility Study was completed. 
There will be one treatment arm during this part of the study. Patients will receive chemoradiotherapy 
with vorinostat at the dose assigned at study enrollment (see Section 3.1.7). 
 
4.4.2 
Treatment Arms During Phase II of the Study 
Patients will be randomized at study enrollment to one of the three following arms for 
chemoradiotherapy:  
 
Arm A: Vorinostat at 230 mg/m2/day, orally, Monday through Friday starting on the first day of 
radiotherapy as determined in the feasibility study. Vorinostat should be administered 1 to 2 hours prior to 
each radiation dose. If the first day of RT is not on a Monday, then the patient should receive the first 
week doses starting on the weekday that radiation therapy starts until Friday of that week. 
 
Arm B: Temozolomide at 90 mg/m2/dose orally, started in the first week of initiation of RT on a daily 
basis continuously throughout RT (ie, 7 days a week). The 42 days of temozolomide should be given 
regardless of the end date of RT. 
 
Arm C: Bevacizumab at 10 mg/kg/dose IV over 90 minutes, Day 22 (± 2 day) and Day 36 (± 2 day) of 
RT. Bevacizumab should be given at least 2 hours prior to RT. There must be at least 14 days between 
bevacizumab doses.  
 
4.4.3 
Treatment Arms During Phase III of the Study 
If the one-year EFS of either treatment Arm A or treatment Arm C is superior to that of the treatment arm 
B with temozolomide, the study will continue to the phase III portion. In the phase III portion, patients 
will be randomized at study enrollment to one of the two following arms for chemoradiotherapy: 
 
Arm B: Temozolomide at 90 mg/m2/dose orally, started in the first week of initiation of RT on a daily 
basis continuously throughout RT and should continue until the last dose of RT. The 42 days of 
temozolomide should be given regardless of the end date of RT. 
 
Superior Arm from Phase II of the Study: The treatment arm from Phase II that has a one-year EFS that is 
superior to temozolomide (either Arm A or Arm C). If neither Arm A nor Arm C is superior to 
temozolomide, the study will not continue to the phase III portion. 
 
See Section 7.1 for baseline studies to be obtained prior to starting chemoradiotherapy.  See Section 
7.2 for optional biology studies and optional imaging studies for patients who have provided 
consent. See Section 16.0 for details of specimen collection, handling, and shipping for optional 
biology studies, and Section 16.8 for details of optional imaging studies to be obtained.  
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See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special precautions and suggestions for patient monitoring during the infusion. As applicable, also see the 
CAG for suggestions on hydration, or hydrate according to institutional guidelines. 
 
4.5 
Arm A Chemoradiotherapy with Vorinostat (Feasibility Study Only) 
As of Amendment #1, the Feasibility Study was completed. 
 
For the feasibility study only, the dose of vorinostat will be assigned at time of study entry, and will be 
one of two doses (either 230 mg/m2/day or 180 mg/m2/day). The Arm A chemoradiotherapy course lasts 
70 days, and is comprised of 6 weeks of concurrent chemotherapy and radiation therapy and a 4 week rest 
period. 
 
Radiation Therapy 
Radiation therapy will be given over 6 weeks during this course. The goal of treatment planning and dose 
prescription is that the dose to the ICRU reference point shall be 54 Gy given over 6 weeks. The boost 
volume, when present, will receive an additional 5.4 Gy for a total dose of 59.4 Gy. Radiation will be given 
in standard fractions. Radiation treatments should not be interrupted or delayed, except for any life 
threatening infection or severe hematological toxicity defined as ANC < 300/L or platelets less than 
40,000/L during the course of treatment. See Section 14.0 for Radiation Therapy Guidelines.  
 
Dosing should be based on actual BSA. The maximum daily dose of vorinostat is 400 mg. 
 
The therapy map described below assumes Day 1 of RT occurs on a Monday; thus Days 1-5, 8-12, etc. 
are Monday through Friday. 
 
Vorinostat: PO 
Dose: Assigned dose at enrollment (maximum dose 400 mg). 
Days: 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, daily (Monday through Friday) concomitantly with radiation 
therapy. 
NOTE: Give 1 to 2 hours prior to daily RT dose. Please see Appendix III for dosing guidelines based 
on BSA. For patients who cannot swallow capsules, see Section 6.3 for guidelines for preparing 
vorinostat suspension. Patients with BSA < 1 m2 or patients who cannot swallow capsules will receive the 
vorinostat suspension rounded to the nearest 5 mg (See section 6.3 for preparation guidelines.)   If a dose 
of vorinostat is given and radiation therapy is NOT administered due to sedation or technical issues, the 
vorinostat dose should not be made up (ie, no more than 30 doses of vorinostat should be given).   
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for Arm A chemoradiotherapy during the feasibility study is on the next 2 
pages.  
 
Following completion of Arm A chemoradiotherapy, Maintenance chemotherapy (see Section 4.9) starts 
on Day 71 (29 days after the end of chemoradiotherapy) or when criteria to begin Maintenance are met 
(whichever occurs later).  
 
See Section 15.3 for required pathology materials that must be received by the COG Biopathology 
Center prior to the start of Maintenance therapy. 
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4.5.1a   Chemoradiotherapy for Arm A (Feasibility Study ONLY) 
 
Arm A chemoradiotherapy is for patients receiving vorinostat. 
This course lasts 70 days (10 weeks). 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course lasts 70 
days and this Therapy Delivery Map is on 2 pages. Details are in Section 4.0 (Treatment Overview). Radiation therapy 
is to be given for six (6) weeks and vorinostat should be given daily (Monday through Friday) throughout RT. (See 
Section 14.0 for details of radiation therapy). 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Vorinostat (VORIN) 
 
PO 
Assigned dose at 
enrollment 
 
1-5, 
8-12, 
15-19, 
22-26, 
29-33, 
36-40 
Give 1 to 2 hours prior 
to daily RT dose. 
 
Maximum dose: 400 mg. 
a) 
History, PE (Ht, Wt, BSA, VS), 
Performance Status 
b) 
CBC (differential, platelets) 
c) 
BUN, Creatinine, AST, ALT, 
bilirubin 
d) 
Electrolytes (Ca++, PO4, Mg++) 
e) 
Optional Imaging studies (see section 
16.8) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
VORIN 
____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
The day numbering below is provided for your 
convenience, and assumes Day 1 of RT is on a Monday. 
The timing (days) of chemoradiotherapy will vary, 
depending on which day of the week is Day 1 of RT 
therapy. 
 
 
 
 
 
Enter calculated dose above and actual dose 
administered dose below.
 
 
 
 
1 
____mg 
a,  b, c, d, e 
 
 
 
2 
____mg 
 
 
 
 
3 
____mg 
 
 
 
 
4 
____mg 
 
 
 
 
5 
____mg 
 
 
 
 
8 
____mg 
b, c, d 
 
 
 
9 
____mg 
 
 
 
 
10 
mg 
 
 
 
 
11 
____mg 
 
 
 
 
12 
____mg 
 
 
 
 
15 
____mg 
b, c, d 
 
 
 
16 
____mg 
 
 
 
 
17 
____mg 
 
 
 
 
18 
____mg 
 
 
 
 
19 
____mg 
 
 
 
 
22 
____mg 
b, c, d 
 
 
 
23 
____mg 
 
 
 
 
24 
mg 
 
 
 
 
25 
____mg 
 
 
 
 
26 
____mg 
 
 
 
 
Course continues on overleaf (Days 29-70). 
 
Page 1 of 2 
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4.5.1b   Chemoradiotherapy for Arm A (Feasibility Study ONLY) - 
Continued 
 
Arm A chemoradiotherapy is for patients receiving vorinostat. 
This course lasts 70 days (10 weeks). 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course 
lasts 70 days and this Therapy Delivery Map is on 2 pages. Details are in Section 4.0 (Treatment Overview). 
Radiation therapy is to be given for six (6) weeks and vorinostat should be given daily (Monday through Friday) 
throughout RT. (See Section 14.0 for details of radiation therapy). 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Vorinostat (VORIN) 
 
PO 
Assigned dose at 
enrollment 
1-5, 
8-12, 
15-19, 
22-26, 
29-33, 
36-40 
Give 1 to 2 hours prior to 
daily RT dose. 
 
Maximum dose: 400 mg. 
a) 
History & PE (Ht, Wt, BSA, VS), 
Performance status 
b) 
CBC (differential, platelets) 
c) 
BUN, Creatinine, AST, ALT, 
bilirubin 
d) 
Electrolytes (Ca++, PO4, Mg++) 
e) 
Optional Imaging studies (see 
section 16.8) 
 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
VORIN 
____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
The day numbering below is provided for your 
convenience, and assumes Day 1 of RT is on a 
Monday. The timing (days) of chemoradiotherapy will 
vary, depending on which day of the week is Day 1 of 
RT therapy. 
 
 
 
 
 
Enter calculated dose above and actual dose 
administered dose below.
 
 
 
 
29 
____mg 
b, c, d 
 
 
 
30 
____mg 
 
 
 
 
31 
____mg 
 
 
 
 
32 
____mg 
 
 
 
 
33 
____mg 
 
 
 
 
36 
mg 
b, c, d 
 
 
 
37 
____mg 
 
 
 
 
38 
____mg 
 
 
 
 
39 
____mg 
 
 
 
 
40 
____mg 
 
 
 
 
43 
 
(a, b, c, d) # 
 
 
 
71 
Start Maintenance chemotherapy (see Section 
4.9) on Day 71 or when Maintenance starting 
criteria are met (whichever occurs later). 
 
 
 
Observation Note: 
# Obtain during Week 7. 
 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference materials.asp under Standard Sections 
for Protocols. 
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4.6 
Arm A Chemoradiotherapy with Vorinostat (Phases II and III) 
 
For Phases II and III of this study, the dose of vorinostat used in Arm A will be 230 mg/m2/day Monday 
through Friday, the MTD determined in the feasibility study. The Arm A chemoradiotherapy course lasts 
70 days, and is comprised of 6 weeks of concurrent chemotherapy and radiation therapy and a 4 week rest 
period. 
 
Radiation Therapy 
Radiation therapy will be given over 6 weeks during this course. The goal of treatment planning and dose 
prescription is that the dose to the ICRU reference point shall be 54 Gy given over 6 weeks. The boost 
volume, when present, will receive an additional 5.4 Gy for a total dose of 59.4 Gy. Radiation will be given 
in standard fractions. Radiation treatments should not be interrupted or delayed, except for any life 
threatening infection or severe hematological toxicity defined as ANC < 300/L or platelets less than 
40,000/L during the course of treatment. See Section 14.0 for Radiation Therapy Guidelines.  
 
The therapy map described below assumes Day 1 of RT occurs on a Monday; thus Days 1-5, 8-12, etc. 
are Monday through Friday. 
 
Dosing should be based on actual BSA. The maximum daily dose of vorinostat is 400 mg. 
 
Vorinostat: PO 
Dose: 230 mg/m2/day (maximum dose 400 mg). 
Days: 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, daily (Monday through Friday) concomitantly with radiation 
therapy. 
NOTE: Give 1 to 2 hours prior to daily RT dose. Please see Appendix III for dosing guidelines based 
on BSA. For patients who cannot swallow capsules, see Section 6.4 for guidelines for preparing 
vorinostat suspension. Patients with BSA < 1 m2 or patients who cannot swallow capsules will receive the 
vorinostat suspension rounded to the nearest 5 mg (See Section 6.4 for preparation guidelines.) If a dose 
of vorinostat is given and radiation therapy is NOT administered due to sedation or technical issues, the 
vorinostat dose should not be made up (ie, no more than 30 doses of vorinostat should be given).  
 
If a patient vomits within 30 minutes after the dose of vorinostat is administered and the pill is visible that 
dose should be repeated. If a patient vomits after 30 minutes, the dose will not be repeated. Patients 
receiving liquid preparation should not be redosed.  
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for Arm A chemoradiotherapy during phases II and III is on the next 2 
pages.  
 
Following completion of Arm A chemoradiotherapy, Maintenance chemotherapy (see Section 4.9) starts 
on Day 71 (29 days after the end of chemoradiotherapy) or when criteria to begin Maintenance are met 
(whichever occurs later).  
 
See Section 15.3 for required pathology materials that must be received by the COG Biopathology 
Center prior to the start of Maintenance therapy. 
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4.6.1a   Chemoradiotherapy for Arm A (Phases II and III) 
 
Arm A chemoradiotherapy is for patients receiving vorinostat. 
This course lasts 70 days (10 weeks). 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course lasts 70 
days and this Therapy Delivery Map is on 2 pages. Details are in Section 4.0 (Treatment Overview). Radiation therapy 
is to be given for six (6) weeks and vorinostat should be given daily (Monday through Friday) throughout RT. (See 
Section 14.0 for details of radiation therapy.) 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Vorinostat (VORIN) 
 
PO 
230 mg/m2/day  
1-5, 
8-12, 
15-19, 
22-26, 
29-33, 
36-40 
Give 1 to 2 hours prior 
to daily RT dose. 
 
Maximum dose: 400 mg. 
a) 
History, PE (Ht, Wt, BSA, VS), 
Performance Status 
b) 
CBC (differential, platelets) 
c) 
BUN, Creatinine, AST, ALT, 
bilirubin 
d) 
Electrolytes (Ca++, PO4, Mg++) 
e) 
Optional Imaging studies (see section 
16.8) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
VORIN 
____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
The day numbering below is provided for your 
convenience, and assumes Day 1 of RT is on a 
Monday. The timing (days) of chemoradiotherapy 
will vary, depending on which day of the week is 
Day 1 of RT therapy. 
 
 
 
 
 
Enter calculated dose above and actual 
dose administered dose below.
 
 
 
 
1 
____mg 
a,  b, c, d, e,  
 
 
 
2 
____mg 
 
 
 
 
3 
____mg 
 
 
 
 
4 
____mg 
 
 
 
 
5 
____mg 
 
 
 
 
8 
____mg 
b, c, d 
 
 
 
9 
____mg 
 
 
 
 
10 
mg 
 
 
 
 
11 
____mg 
 
 
 
 
12 
____mg 
 
 
 
 
15 
____mg 
b, c, d 
 
 
 
16 
____mg 
 
 
 
 
17 
____mg 
 
 
 
 
18 
____mg 
 
 
 
 
19 
____mg 
 
 
 
 
22 
____mg 
b, c, d 
 
 
 
23 
____mg 
 
 
 
 
24 
mg 
 
 
 
 
25 
____mg 
 
 
 
 
26 
____mg 
 
 
 
 
Course continues on overleaf (Days 29-70). 
 
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4.6.1b   Chemoradiotherapy for Arm A (Phases II and III)  
Continued 
 
Arm A chemoradiotherapy is for patients receiving vorinostat. 
This course lasts 70 days (10 weeks). 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course lasts 70 
days and this Therapy Delivery Map is on 2 pages. Details are in Section 4.0 (Treatment Overview). Radiation therapy 
is to be given for six (6) weeks and vorinostat should be given daily (Monday through Friday) throughout RT. (See 
Section 14.0 for details of radiation therapy.) 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Vorinostat (VORIN) 
 
PO 
230 mg/m2/day 
1-5, 
8-12, 
15-19, 
22-26, 
29-33, 
36-40 
Give 1 to 2 hours prior to 
daily RT dose. 
 
Maximum dose: 400 mg. 
a) 
History & PE (Ht, Wt, BSA, VS), 
Performance status 
b) 
CBC (differential, platelets) 
c) 
BUN, Creatinine, AST, ALT, 
bilirubin 
d) 
Electrolytes (Ca++, PO4, Mg++) 
e) 
Optional Imaging Studies (see 
section 16.8) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
 
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
VORIN 
____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
The day numbering below is provided for your 
convenience, and assumes Day 1 of RT is on a 
Monday. The timing (days) of chemoradiotherapy will 
vary, depending on which day of the week is Day 1 of 
RT therapy. 
 
 
 
 
 
Enter calculated dose above and actual dose 
administered dose below.
 
 
 
 
29 
____mg 
b, c, d 
 
 
 
30 
____mg 
 
 
 
 
31 
____mg 
 
 
 
 
32 
____mg 
 
 
 
 
33 
____mg 
 
 
 
 
36 
____mg 
b, c, d 
 
 
 
37 
____mg 
 
 
 
 
38 
____mg 
 
 
 
 
39 
mg 
 
 
 
 
40 
____mg 
 
 
 
 
43 
 
(a, b, c, d) # 
 
 
 
71 
Start Maintenance chemotherapy (see Section 
4.9) on Day 71 or when Maintenance starting 
criteria are met (whichever occurs later). 
 
 
 
Observation Note: 
# Obtain during Week 7. 
 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference materials.asp under Standard Sections for 
Protocols. 
 
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4.7 
Arm B Chemoradiotherapy with Temozolomide  
 
Phases II and III of this study will include treatment Arm B chemoradiotherapy with temozolomide. The Arm 
B chemoradiotherapy course lasts 70 days, and is comprised of concurrent chemotherapy and radiation therapy 
for 42 days and a 4 week rest period. 
 
Radiation Therapy 
Radiation therapy will be given over 6 weeks during this course. The goal of treatment planning and dose 
prescription is that the dose to the ICRU reference point shall be 54 Gy given over 6 weeks. The boost volume, 
when present, will receive an additional 5.4 Gy for a total dose of 59.4 Gy. Radiation will be given in standard 
fractions. Radiation treatments should not be interrupted or delayed, except for any life threatening infection or 
severe hematological toxicity defined as ANC < 300/L or platelets less than 40,000/L during the course of 
treatment. See Section 14.0 for Radiation Therapy Guidelines.  
 
Dosing should be based on actual BSA. There is no maximum dosing. 
 
Temozolomide: PO 
Dose: 90 mg/m2/dose. 
Days:  1 - 42. Must be given by Day 5 of radiation therapy, and continue throughout radiation therapy.  
 
NOTE: Absorption is affected by food and therefore, consistency of administration with respect to food is 
suggested. Preferably, administer at bedtime on an empty stomach (at least 1 hour before or 2 hours after food) 
to decrease nausea and vomiting and improve absorption.  The whole dose, even if comprised of several 
capsule sizes, should be taken at one time at approximately the same time each day.  
 
The temozolomide dose should be rounded off to the nearest 5 mg (round 2.5 mg down [see Appendix IV]). It 
is recommended that antiemetics be given 30 minutes prior to each temozolomide dose. If emesis occurs 
within 20 minutes of taking a given dose, then the dose may be repeated once. If emesis occurs after 20 
minutes, the dose should not be repeated. Guidelines for administration of temozolomide capsules to patients 
who are unable to swallow capsules are provided in Appendix VI or an oral suspension may be compounded 
(see drug monograph in Section 6.2). 
 
The 42 days of temozolomide should be given regardless of the end date of RT. If a dose of temozolomide is 
given and radiation therapy is NOT administered due to sedation or technical issues, the temozolomide dose 
should not be made up (ie, no more than 42 doses of temozolomide should be given).  
 
Trimethoprim/sulfamethoxazole (also called TMP/SMX, cotrimoxazole, Bactrim, Septra) should not be 
utilized as PCP prophylaxis during chemoradiotherapy. Monthly inhaled or IV pentamidine or an 
appropriate alternative should be administered during chemoradiotherapy (see Section 4.2.2 above).  
 
Pharmacy note: Temozolomide capsules are available in 6 different strengths. Daily doses are usually 
comprised of multiple capsules of different strengths. To prevent errors, each strength of temozolomide 
capsules must be dispensed in a separate bottle and the total number of each strength of capsules needed for the 
full course must be dispensed at one time. See drug monograph for additional details and examples. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 
 
 
 
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The therapy delivery map (TDM) for Arm B Chemoradiotherapy is on the next page.  
 
Following completion of Arm B chemoradiotherapy, Maintenance chemotherapy (see Section 4.9) starts on 
Day 71 (29 days after the end of chemoradiotherapy) or when criteria to begin Maintenance are met 
(whichever occurs later).  
 
See Section 15.3 for required pathology materials that must be received by the COG Biopathology 
Center prior to the start of Maintenance therapy. 
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4.7.1a   Chemoradiotherapy for Arm B 
 
Arm B chemoradiotherapy is for patients receiving temozolomide. 
This course lasts 70 days (10 weeks). 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course lasts 70 
days and this Therapy Delivery Map is on 2 pages. Details are in Section 4.0. Radiation therapy is to be given for 6 weeks 
and temozolomide should be given continuously throughout RT. (See Section 14.0 for details of radiation therapy.) 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Temozolomide 
(TEMO) 
PO 
90 mg/m2/dose 
 
1* through 42 
*Must begin by Day 5 of RT, 
and 
continue 
for 
42 
consecutive days. 
 
Round dose to nearest 5 mg. 
 
See 
admin. 
guidelines 
in 
Section 4.7. 
a) 
History & PE (Ht, Wt, BSA, VS), 
Performance Status 
b) 
CBC (differential, platelets) 
c) 
BUN, Creatinine, AST, ALT, bilirubin 
d) 
Electrolytes (Ca++, PO4, Mg++) 
e) 
Optional Imaging Studies (see section 
16.8) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
 
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
TEMO 
____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
The day numbering below is provided for your convenience, and assumes 
Day 1 of RT is on a Monday. The timing (days) of chemoradiotherapy will 
vary, depending on which day of the week is Day 1 of RT therapy. 
 
 
 
 
 
Enter calculated dose above and actual dose 
administered dose below. 
 
 
 
 
1 
____mg 
a, b, c, d, e 
 
 
 
2 
____mg 
 
 
 
 
3 
____mg 
 
 
 
 
4 
____mg 
 
 
 
 
5 
____mg 
 
 
 
 
6 
____mg 
 
 
 
 
7 
____mg 
 
 
 
 
8 
____mg 
b, c, d 
 
 
 
9 
____mg 
 
 
 
 
10 
____mg 
 
 
 
 
11 
mg 
 
 
 
 
12 
____mg 
 
 
 
 
13 
____mg 
 
 
 
 
14 
____mg 
 
 
 
 
15 
____mg 
b, c, d 
 
 
 
16 
____mg 
 
 
 
 
17 
____mg 
 
 
 
 
18 
____mg 
 
 
 
 
19 
____mg 
 
 
 
 
20 
____mg 
 
 
 
 
21 
mg 
 
 
 
 
22 
____mg 
b, c, d 
 
 
 
23 
____mg 
 
 
 
 
24 
____mg 
 
 
 
 
25 
____mg 
 
 
 
 
26 
____mg 
 
 
 
 
27 
____mg 
 
 
 
 
28 
mg 
 
 
Course continues on overleaf (Days 29-70). 
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4.7.1b  Chemoradiotherapy for Arm B - Continued  
 
Arm B chemoradiotherapy is for patients receiving temozolomide. 
This course lasts 70 days (10 weeks). 
                    
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course lasts 
70 days and this Therapy Delivery Map is on 2 pages. Radiation therapy is to be given for 6 weeks and temozolomide 
should be given continuously throughout RT. (See Section 14.0 for details of radiation therapy.) 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Temozolomide 
(TEMO) 
PO 
90 mg/m2/dose 
 
 
 
1* through 42 
*Must begin by Day 5 of RT, and 
continue for 42 consecutive days. 
 
Round dose to nearest 5 mg. 
 
See admin. guidelines in Section 
4.7. 
a) 
History & PE (Ht, Wt, 
BSA, VS), Performance 
Status 
b) 
CBC (differential, 
platelets) 
c) 
BUN, Creatinine, AST, 
ALT, bilirubin 
d) 
Electrolytes (Ca++, PO4, 
Mg++) 
e) 
Optional Imaging Studies 
(see section 16.8) 
 
OBTAIN OTHER STUDIES 
AS REQUIRED FOR GOOD 
PATIENT CARE 
 
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
TEMO 
____mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
The day numbering below is provided for your convenience, 
and assumes Day 1 of RT is on a Monday. The timing (days) 
of chemoradiotherapy will vary, depending on which day of 
the week is Day 1 of RT therapy. 
 
 
 
 
 
Enter calculated dose above and actual dose 
administered dose below. 
 
 
 
 
29 
____mg 
b, c, d 
 
 
 
30 
____mg 
 
 
 
 
31 
____mg 
 
 
 
 
32 
____mg 
 
 
 
 
33 
____mg 
 
 
 
 
34 
____mg 
 
 
 
 
35 
____mg 
 
 
 
 
36 
____mg 
b, c, d 
 
 
 
37 
____mg 
 
 
 
 
38 
____mg 
 
 
 
 
39 
mg 
 
 
 
 
40 
____mg 
 
 
 
 
41 
____mg 
 
 
 
 
42 
____mg 
 
 
 
 
43 
 
(a, b, c, d) #  
 
 
 
71 
Start Maintenance chemotherapy (see Section 4.9) 
on Day 71 or when Maintenance starting criteria are 
met (whichever occurs later). 
 
 
Observation Note: 
# Obtain during Week 7. 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference materials.asp under Standard Sections for 
Protocols. 
 
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4.8 
Arm C Chemoradiotherapy with Bevacizumab 
Phase II of this study will include treatment Arm C chemoradiotherapy with bevacizumab. Pending the results 
from Phase II, Phase III of the study may also include treatment arm C. The Arm C chemoradiotherapy course 
lasts 70 days, and is comprised of 6 weeks of concurrent chemotherapy and radiation therapy and a 4 week rest 
period. 
 
Radiation Therapy 
Radiation therapy will be given over six (6) weeks during this course. The goal of treatment planning and dose 
prescription is that the dose to the ICRU reference point shall be 54 Gy given over 6 weeks. The boost volume, 
when present, will receive an additional 5.4 Gy for a total dose of 59.4 Gy. Radiation will be given in standard 
fractions. Radiation treatments should not be interrupted or delayed, except for any life threatening infection or 
severe hematological toxicity defined as ANC < 300/L or platelets less than 40,000/L during the course of 
treatment. See Section 14.0 for Radiation Therapy Guidelines.  
 
Dosing should be based on weight. There is no maximum dosing. 
 
The therapy map described below assumes Day 1 of RT occurs on a Monday; thus Days 1-5, 8-12, etc. are 
Monday through Friday. 
 
Bevacizumab: IV Over 90 Minutes 
Dose: 10 mg/kg/dose  
Days: Day 22 (± 2 days) and Day 36 (± 2 days) of RT. Bevacizumab should be given at least 2 hours prior to 
RT. There must be at least 14 days between Bevacizumab doses. A platelet count of 75,000/µL, with or 
without platelet transfusion, is required to administer bevacizumab. 
 
Note: Infuse first dose over 90 minutes. If tolerated without infusion-related side effects, the second dose may 
be given over 60 minutes. Check vital signs prior to infusion and monitor for infusion-related reactions every 
30 minutes and at the end of the infusion. Monitor every 15 minutes while the infusion rate is being adjusted. 
Routine premedication is not required for the first dose of bevacizumab. If infusional reactions occur, 
acetaminophen [10-15 mg/kg (max 650 mg)], diphenhydramine [1 mg/kg (max 50 mg)], or other medications 
may be given for symptom control and for premedication as needed. (See Section 4.2 for concomitant therapy 
restrictions.) Anaphylactic precautions should be observed during bevacizumab administration. If an infusion 
reaction occurs, subsequent doses of bevacizumab should be administered over the shortest period that was 
well-tolerated. Bevacizumab is incompatible with D5W (the drug is inactivated). 
 
Special precautions: Black box warning includes risk of gastrointestinal perforation and wound healing 
complications (fatal results have occurred). Suspend dosing at least 28 days prior to elective surgery. Do not 
initiate bevacizumab for at least 28 days after a major surgery (eg, organ resection, exploratory laparotomy, 
thoractomy) or 14 days after intermediate surgical procedure (eg, paracentesis or thoracocentesis) and until the 
surgical wound is fully healed. Minor surgical procedures (eg, biopsies, infusaport, or Broviac line placement) 
need to have fully healed and occurred > 7 days prior to initiation of bevacizumab.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for Arm C chemoradiotherapy is on the next page.  
 
Following completion of Arm C chemoradiotherapy, Maintenance chemotherapy (see Section 4.9) starts on 
Day 71 (29 days after the end of chemoradiotherapy) or when criteria to begin Maintenance are met 
(whichever occurs later).  
See Section 15.3 for required pathology materials that must be received by the COG Biopathology 
Center prior to the start of Maintenance therapy. 
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4.8.1a  Chemoradiotherapy for Arm C 
 
Arm C chemoradiotherapy is for patients receiving bevacizumab.  
This course lasts 70 days (10 weeks). 
 
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
 
Criteria to start this course: ANC  1000/L and platelets  100,000/L (transfusion independent). This course lasts 
70 days and this Therapy Delivery Map is on 1 page. Radiation therapy is to be given for six (6) weeks and 
bevacizumab should be given prior to RT on Days 22 and 36. (See Section 14.0 for details of radiation therapy.) 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Bevacizumab 
(BEVA) 
 
IV over 90 
minutes* 
10 mg/kg/dose 
Days 22 and 
36 (± 2 days) 
Bevacizumab should be given at 
least 2 hours prior to RT. There 
must be at least 14 days between 
Bevacizumab doses. A platelet 
count of 75,000/µL, with or 
without platelet transfusion, is 
required 
to 
administer 
bevacizumab. 
 
*Second infusion may be given 
over shorter duration if well-
tolerated. See admin. guidelines 
in Section 4.8. 
a) 
History, Ht, Wt, BSA 
Performance Status 
b) 
PE (VS, inc BP), CBC 
(differential, platelets) 
Electrolytes (Ca++, PO4, Mg++)  
c) 
BUN, Creatinine, AST, ALT, 
bilirubin,  
d) 
Urinalysis for Protein (urine 
dipstick or UPC ratio) 
e) 
Optional Imaging Studies (see 
section 16.8) 
 
OBTAIN OTHER STUDIES AS 
REQUIRED 
FOR 
GOOD 
PATIENT CARE 
 
Ht_____cm 
        Wt____kg  
          
 
Date 
Due 
Date 
Given 
Day 
BEVA____mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
The day numbering below is provided for your convenience, and 
assumes Day 1 of RT is on a Monday. The timing (days) of 
chemoradiotherapy will vary, depending on which day of the 
week is Day 1 of RT therapy. 
 
 
 
 
 
Enter calculated dose above and actual dose 
administered dose below.
 
 
 
 
1 
 
a, b, c, d, e 
 
 
 
8 
 
b, c, d 
 
 
 
15 
 
b, c, d 
 
 
 
22 
mg 
b$, c, d, 
 
 
 
29 
 
b, c, d 
 
 
 
36 
____mg 
b$, c, d,  
 
 
 
43 
 
(a, b, c, d) # 
 
 
 
71 
Start Maintenance chemotherapy (see Section 4.9) on 
Day 71 or when Maintenance starting criteria are met 
(whichever occurs later). 
 
 
Observation Note: 
# Obtain during Week 7. 
$ Obtain BP only. 
 
 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference materials.asp under Standard Sections for 
Protocols. 
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4.9 
Maintenance Therapy 
 
All patients will receive maintenance therapy upon completion of chemoradiotherapy and tumor evaluation, in 
the absence of disease progression and unacceptable toxicities (See Section 5.0).  
 
Maintenance consists of 12 cycles of chemotherapy. Maintenance will commence 4 weeks after the completion 
of radiation therapy. Criteria to start the first cycle of maintenance chemotherapy include: 
 
 
Peripheral absolute neutrophil count (ANC)  1000/l  
 
Platelet Count > 100,000/l (without transfusion within the last 7 days) 
 
Serum creatinine  1.5 x normal for age (see Section 3.2.8.2) 
 
Total bilirubin  1.5 x normal for age, and SGPT (ALT) < 2.5 x normal for age 
 
The patient has no evidence of progressive disease (see Section 10.4) as assessed clinically and/or 
by imaging studies 
 
Cycles will be repeated every 28 days. Criteria to start the second and subsequent cycles of maintenance 
chemotherapy include:  
 
 
Peripheral absolute neutrophil count (ANC)  750/l  
 
Platelet Count > 75,000/l (without transfusion within the last 7 days) 
 
Serum creatinine  1.5 x normal for age (see Section 3.2.8.2) 
 
Total bilirubin  1.5 x normal for age, and SGPT (ALT) < 2.5 x normal for age 
 
The patient has no evidence of progressive disease (see Section 10.4) as assessed clinically and/or 
by imaging studies 
 
The patient did not experience a bevacizumab-related targeted toxicity that requires 
discontinuation or withholding of bevacizumab as listed in Section 5.3. 
 
Prior to beginning Maintenance therapy, obtain optional biology samples and imaging studies for patients who 
have provided consent. See Section 16.0 for details of biology specimen collection, handling, and shipping and 
Section 16.8 for details of optional imaging studies to be obtained. 
 
Disease evaluations should occur prior to every odd number maintenance cycle and growth plate evaluations 
should occur every 12 weeks during maintenance therapy (see Section 7.1 for details).  
 
See Section 15.3 for required pathology materials that must be received by the COG Biopathology 
Center prior to the start of Maintenance therapy. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for 
special 
precautions and suggestions for patient monitoring during the infusion. As applicable, also see the CAG for 
suggestions on hydration, or hydrate according to institutional guidelines. 
 
The administration schedule below describes one 4-week cycle of Maintenance therapy. 
 
Dosing for bevacizumab is to be calculated by weight.  
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Bevacizumab: IV over 90 minutes* 
Dose: 10 mg/kg/dose. 
Days: 1 and 15. A platelet count of  >75,000/µL, with or without platelet transfusion, is required to administer 
bevacizumab. 
Note: *Infuse first dose over 90 minutes. If tolerated without infusion-related side effects, the second dose may 
be given over 60 minutes. Again, if tolerated, the third dose and all subsequent doses may be given over 30 
minutes. Check vital signs prior to infusion and monitor for infusion-related reactions every 30 minutes 
(during 60 and 90 minute infusions) and at the end of the infusion. Monitor every 15 minutes while the 
infusion rate is being adjusted. Routine premedication is not required for the first dose of bevacizumab. If 
infusional reactions occur, acetaminophen [10-15 mg/kg (max 650 mg)], diphenhydramine [1 mg/kg (max 50 
mg)], or other medications may be given for symptom control and for premedication as needed. (See Section 
4.2 for concomitant therapy restrictions.) Anaphylactic precautions should be observed during bevacizumab 
administration. If an infusion reaction occurs, subsequent doses of bevacizumab should be administered over 
the shortest period that was well-tolerated. Bevacizumab is incompatible with D5W (the drug is inactivated). 
 
Special precautions: Black box warning includes risk of gastrointestinal perforation and wound healing 
complications (fatal results have occurred). Suspend dosing at least 28 days prior to elective surgery. Do not 
initiate bevacizumab for at least 28 days after a major surgery (eg, organ resection, exploratory laparotomy, 
thoractomy) or 14 days after intermediate surgical procedure (eg, paracentesis or thoracocentesis) and until the 
surgical wound is fully healed. Minor surgical procedures (eg, biopsies, infusaport, or Broviac line placement) 
need to have fully healed and occurred > 7 days prior to initiation of bevacizumab.  
 
Temozolomide: PO 
Dose: 200 mg/m2/dose. 
Days:  1 – 5 of each cycle.  
 
NOTE: Absorption is affected by food and therefore, consistency of administration with respect to food is 
suggested. Preferably, administer at bedtime on an empty stomach (at least 1 hour before or 2 hours after food) 
to decrease nausea and vomiting and improve absorption.  The whole dose, even if comprised of several 
capsule sizes, should be taken at one time at approximately the same time each day.  
 
The temozolomide dose should be rounded off to the nearest 5 mg (round 2.5 mg down).  See Appendix V.  It 
is recommended that antiemetics be given 30 minutes prior to each temozolomide dose. If emesis occurs 
within 20 minutes of taking a given dose, then the dose may be repeated once. If emesis occurs after 20 
minutes, the dose should not be repeated. Guidelines for administration of temozolomide capsules to patients 
who are unable to swallow capsules are provided in Appendix VI or an oral suspension may be compounded 
(see drug monograph in Section 6.2). 
 
Pharmacy note: Temozolomide capsules are available in 6 different strengths. Daily doses are usually 
comprised of multiple capsules of different strengths. To prevent errors, each strength of temozolomide 
capsules must be dispensed in a separate bottle and the total number of each strength of capsules needed for the 
full course must be dispensed at one time. See drug monograph for additional details and examples. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for Maintenance is on the next page.  
 
Following completion of the first Maintenance cycle, the Maintenance cycle is repeated for up to 12 cycles, as 
tolerated and in the absence of disease progression (see Section 10.4 for Response Evaluation). Subsequent 
Maintenance cycles should begin on Day 29 or when starting criteria (see above) are met (whichever occurs 
later). 
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4.9.1  Maintenance – All Patients 
Maintenance is given in 12 cycles. Each cycle lasts 28 days. 
This course lasts 336 days. 
Use a copy of this page once for each cycle. (Please note cycle number below.) 
 
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
Criteria to start cycle 1: ANC  1000/l,  platelets > 100,000/l (transfusion independent), serum creatinine  1.5 x normal for 
age (see Section 3.2.8.2) , total bilirubin  1.5 x normal for age, and SGPT (ALT) < 2.5 x normal for age. Criteria to start 
cycles 2 through 12: ANC  750/l, platelets > 75,000/l (transfusion independent), serum creatinine  1.5 x normal for age, 
total bilirubin  1.5 x normal for age, SGPT (ALT) < 2.5 x normal for age, bevacizumab-related targeted toxicity that requires 
discontinuation or withholding of bevacizumab as listed in Section 5.3, and no progressive disease. This Therapy Delivery 
Map relates to one cycle, and this Therapy Delivery Map is on 1 page. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Bevacizumab 
(BEVA) 
 
IV 
over 
90 
minutes* 
10 mg/kg/dose 
1 and 15 
 
*May 
be 
given 
over 
shorter duration if well-
tolerated. 
See 
admin. 
guidelines in Section 4.9. 
a) 
History & Performance Status 
b) 
PE (Ht, Wt, BSA, VS, inc BP), 
c) 
CBC (differential, platelets) 
d) 
BUN, creatinine, AST, ALT, bilirubin, 
Electrolytes (Ca++, PO4, Mg++) 
e) 
MRI of the Head with and without gadolinium 
(with echo) 
f) 
MRI of the Spine with gadolinium 
g) 
X-ray of right knee 
h) 
Urinalysis for protein (urine dipstick or UPC 
ratio) 
i) 
Optional imaging studies (see Sections 16.8  for 
details) 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Temozolomide 
(TEMO) 
PO 
200 mg/m2/dose 
1 through 5 
Round dose to nearest 5 
mg. 
 
See admin. guidelines in 
Section 4.9. 
Please enter Cycle # _______  
Ht_____cm 
        Wt____kg  
         BSA____m2 
 
Date 
Due 
Date 
Given 
Day 
BEVA 
____mg 
TEMO 
____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered dose below. 
 
 
 
1 
____mg 
____mg 
a, b, c, d, e*, f^ , h+, i# 
 
 
 
2 
 
____mg 
 
 
 
 
3 
 
____mg 
 
 
 
 
4 
 
____mg 
 
 
 
 
5 
 
mg 
 
 
 
 
15 
____mg 
 
b$, c 
 
 
 
28 
 
 
c@, g& , i# 
 
 
 
29 
Begin next cycle on Day 29 or when criteria to begin cycle are met 
(whichever occurs later). Repeat for a total of 12 cycles. See Section 7.1 
for end of therapy evaluations. 
 
Observation Notes: 
* Obtain prior to every odd number maintenance cycle. 
^ Obtain prior to every odd number maintenance cycle only if patient has spinal primary or if clinically indicated.   
& Obtain tibial x-ray (AP and lateral views) of the right knee in patients who have not yet obtained full adult height at the 
completion of cycles 3, 6, 9, and 12. If abnormalities are detected on routine X-rays following treatment, MRI scan of both 
knees should be performed 
+ If urine dipstick is 2+ or greater from protein, hold bevacizumab and obtain UPC ratio within 3 days of Day 1 dose of bevacizumab. 
See bevacizumab dose modifications for proteinuria (Section 5.3). If UPC ratio is > 1, collection of 24 hour urine for 
measurement of urine protein level is recommended but not required. 
# Obtain prior to starting Maintenance, prior to Cycle 3 and at the end of Maintenance. 
$ Obtain BP only. 
@  Obtain on Day 28 of maintenance cycle 12. Repeat weekly until results are normal. 
 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference materials.asp under Standard Sections 
for Protocols. 
 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
The following dose modifications for toxicities are for use during phase II and phase III of the study. 
Notify the Study Chair at the time of removing a patient from protocol therapy for toxicity. 
 
5.1 
Dose Modifications During Chemoradiotherapy  
Doses reduced due to vorinostat, temozolomide, related-toxicity will not be re-escalated, even if there is 
minimal or no toxicity with the subsequent reduction in dose. For patients receiving vorinostat or 
temozolomide during RT, one dose reduction is allowed. Patients who again experience dose modifying 
toxicity after a single dose reduction will no longer receive vorinostat or temozolomide, but will continue 
protocol-defined therapy as planned (continue with radiation therapy and maintenance therapy).  
 
Thus, if, in the feasibility component of the study, the dose of 230 mg/m2 of vorinostat is deemed to be 
intolerable, and a cohort of patients are enrolled at the 180 mg/m2 dose level, patients receiving 180 
mg/m2/dose will be allowed one dose reduction (to 130 mg/m2/dose) if they experience dose limiting 
hematological or non-hematological toxicities.  
 
There will be no dose reductions made for toxicity related to bevacizumab. Treatment should be 
interrupted or discontinued for certain adverse events, as described in section 5.3.For patients receiving 
bevacizumab during RT, see Section 5.3 for dose modifications. If bevacizumab is stopped, patients 
should contine protocol-defined therapy as planned. 
 
5.1.1 
Hematological Toxicities  
 
5.1.1.1 
If Grade 3 decreased platelet count that requires transfusion therapy on greater than 2 occasions during 
radiation therapy occurs, reduce the dose of the respective study arm-specific agent as follows: 
 
Reduce the temozolomide dose to 60 mg/m2/dose (see Dosing Table in Appendix IV) 
 
Reduce the vorinostat dose to 180 mg/m2/dose (or 130 mg/m2/dose if starting at the 
dose of 180 mg/m2/dose [see section 5.1, above]) 
 
Hold the dose of bevacizumab 
 
5.1.1.2 
If Grade 4 decreased neutrophil count or Grade 4 decreased platelet count occurs, discontinue vorinostat, 
temozolomide, or bevacizumab. CBCs should be checked twice weekly until: 
 
ANC > 750/μL 
 
Platelet count > 75,000/μL (transfusion independent) 
If the counts recover to above criteria within 14 days of drug discontinuation, resume vorinostat, 
temozolomide at the reduced doses discussed in section 5.1.1.1. Resume Bevacizumab at the same dose  
of 10 mg/kg. 
 
Please notify the Study Chair if counts have not recovered to the above criteria within 14 days of 
discontinuing vorinostat, temozolomide, or bevacizumab. If Grade 4 toxicity recurs, despite these dose 
reductions, vorinostat, temozolomide, or bevacizumab should be discontinued and not restarted, the 
patient should complete remaining radiation therapy and should receive temozolomide and bevacizumab 
as maintenance therapy. 
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5.1.2 
Non-Hematological Toxicities 
 
5.1.2.1 
 
If platelets do not recover to > 75,000/μL or ANC does not recover to ≥ 750/μL by 14 days after the 
planned start of the next treatment cycle, temozolomide and bevacizumab should be held.  Bevacizumab 
and temozolomide may be given if platelets have recovered to > 75,000/μL and ANC has recovered to ≥ 
750/μL.  Temozolomide doses should be reduced by 25% to150 mg/m2/day x 5 days for the next course, 
at the time of recovery.  Bevacizumab should be resumed at the same dose. 
 
5.1.2.2   
If, despite the dose reduction for subsequent courses, the ANC does not recover to ≥ 750/μL and the 
platelets to >75,000/μL by 14 days after the planned start of the next treatment course, no further 
temozolomide should be given and the patient may continue to receive bevacizumab in subsequent 
courses as soon as the criteria required for subsequent courses of therapy (see Section 4.9) are met.  
 
5.1.2.3  
Chemotherapy will be held for the remainder of the cycle if Grade 4 decreased neutrophil count (<500/ 
μL) or Grade 4 decreased platelet count (<25,000/ μL) is observed. CBCs should be checked twice 
weekly until count recovery has occurred. Chemotherapy with bevacizumab and temozolomide may be 
restarted if platelets have recovered to >75,000/μL and if ANC has recovered to ≥ 750/μL. Temozolomide 
doses should be reduced by 25% to150 mg/m2/day x 5 days for the next course when the criteria required 
for subsequent courses of therapy are met. Bevacizumab should be resumed at the same dose. 
 
5.2 
Dose Modifications during Maintenance Therapy  
 
5.2.1 
Hematological Toxicities 
 
5.2.1.1 
 
If platelets do not recover to > 75,000/μL or ANC does not recover to ≥ 750/μL by 14 days after the 
planned start of the next treatment cycle, temozolomide and bevacizumab should be held.  Bevacizumab 
and temozolomide may be given if platelets have recovered to ≥ 75,000/μL.  
 
5.2.1.2  
Chemotherapy will be held for the remainder of the cycle if Grade 4 decreased neutrophil count for 
greater than 7 days or Grade 4 decreased platelet count on 2 separate days in a 7 day period is observed. 
CBCs should be checked twice weekly until count recovery has occurred. Bevacizumab and 
temozolomide may be given if platelets have recovered to ≥ 75,000/μL.  
 
5.2.2 
Non-Hematological Toxicities 
 
5.2.2.1 
Patients who experience bevacizumab-related toxicities listed in Section 5.3 should follow guidelines 
delineated in this section.  
 
5.2.2.2 
Patients with toxicity attributed to bevacizumab but not listed in Section 5.3 may continue on study 
provided the toxicity is reversible to eligibility requirements within 14 days after the planned start of the 
next treatment course.  
 
5.2.2.3 
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6.0 
DRUG INFORMATION  
Drugs are listed in alphabetical order. 
 
6.1 
Bevacizumab  
(rhuMAb VEGF, Avastin®) NSC#  704865  
  (11/08/11) 
 
Source and Pharmacology:  
Bevacizumab is a recombinant humanized anti-vascular endothelial growth factor (anti-VEGF) 
monoclonal antibody, consisting of 93% human and 7% murine amino acid sequences. The agent is 
composed of human IgG framework and murine antigen-binding complementarity-determining regions. 
Bevacizumab approximate molecular weight is 149,000 daltons. Bevacizumab blocks the binding of 
VEGF to its receptors resulting in inhibition of angiogenesis. 
 
The estimated half-life of bevacizumab is approximately 20 days (range 11-50 days). The predicted time 
to reach steady state was 100 days in 491 patients who received 1 to 20 mg/kg weekly, every 2 weeks, or 
every 3 weeks. The clearance and the central volume of distribution are higher in males than females. 
Clearance was higher in those patients with a higher tumor volume. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via AdEERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguidelines.pdf 
for 
further 
clarification.  
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
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11Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX 
compared to mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of 
menses and an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term 
effects of bevacizumab exposure on fertility are unknown. 
12Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack, and stroke. 
 
Also reported on Bevacizumab (rhuMAb VEGF) trials but with the relationship to Bevacizumab 
(rhuMAb VEGF) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(idiopathic thrombocytopenia purpura); Disseminated intravascular coagulation 
CARDIAC DISORDERS - Pericardial effusion 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Gait disturbance; Sudden death 
NOS 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INVESTIGATIONS - Platelet count decreased 
METABOLISM AND NUTRITION DISORDERS - Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Musculoskeletal and connective 
tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and connective tissue disorder - Other 
(myasthenia gravis) 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Peripheral motor neuropathy; Seizure 
PSYCHIATRIC DISORDERS - Confusion 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Pneumonitis; Pneumothorax; Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Palmar-plantar erythrodysesthesia syndrome; 
Skin ulceration 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
PLEASE NOTE:  The potential risks listed in the CAEPR whose relationship to bevacizumab is still 
undetermined are not required by CTEP to be described in the ICD; however, they may be communicated to 
patients according to local IRB requirements. 
 
Effect in Pregnancy and Lactation: 
Bevacizumab has been shown to be teratogenic in rabbits when administered in doses that are two-fold 
greater than the recommended human dose on a mg/kg basis. Observed effects included decreases in 
maternal and fetal body weights, an increased number of fetal resorption, and an increased incidence of 
specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. 
Angiogenesis is critical to fetal development and the inhibition of angiogenesis following administration of 
Bevacizumab is likely to result in adverse effects on pregnancy. It is not known whether Bevacizumab is 
secreted in human milk. Because human IgG1 is secreted into human milk, the potential for absorption and 
harm to the infant after ingestion is unknown. 
 
Effect on Growth and Development: 
Studies of bevacizumab in animals showed a decrease in ovarian function and abnormal bone growth. 
These and other effects of bevacizumab may potentially impair growth and development.  Abnormal 
changes in the bones after treatment with bevacizumab have been observed in young children with 
growing bones.  This side effect appeared to be reversible after the treatment was stopped, but has not 
been assessed with long-term use of the drug. 
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Formulation and Stability: Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready 
for parenteral administration. Each 400 mg (25mg/mL, 16 mL fill) glass vial contains bevacizumab with 
phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP. Upon receipt, refrigerate the 
intact bevacizumab vials at 2-8°C (36-46°F). Store in the outer carton to protect bevacizumab vials from 
light. Do not freeze. Do not shake. 
 
Bevacizumab vials contain no antibacterial preservatives and are labeled for single use.  Discard any 
unused portion left in the vial immediately after use.  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the protocol. 
Do not administer as an intravenous (IV) push or bolus. Prior to administration, dilute the dose in 0.9% 
sodium chloride for injection to a final concentration of 1.4-16.5 mg/mL. Inspecte visually for particulate 
matter and discoloration prior to administration.   
 
The chemical and physical stability of the diluted solution in 0.9% sodium chloride is 48 hours at 2°C-
30°C. From a microbiological point of view, the product should be used immediately. If not used 
immediately, in-use storage times and conditions are the responsibility of the user and would normally 
not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated 
aseptic conditions. Bevacizumab is incompatible with D5W. 
 
To ensure complete delivery of bevacizumab IV infusion line must be flushed with 0.9% sodium chloride. 
The following are two recommended methods for flushing the line: 
 
1. 
When the bevacizumab infusion is complete, while maintaining a closed system, add an additional 
50mL of 0.9% sodium chloride for injection to the bevacizumab infusion bag. Continue the infusion 
until a volume equal to that of the volume contained in the tubing has been administered. 
2. Replace the empty bevacizumab infusion bag with a 50mL bag of 0.9% sodium chloride for injection 
and infuse a volume equal to the volume contained in the tubing.  
 
Please note: the flush is not included in the total recommended infusion times. 
 
Supplier: Supplied by Genentech and distributed by the NCI DTCD. Do not use commercially available 
drug. 
 
Agent Ordering 
NCI supplied agent   may be requested by the Principal Investigator (or their authorized designee) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be 
shipped directly to the institution where the patient is to be treated.  PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained.)  The CTEP assigned protocol 
number must be used for ordering all CTEP supplied investigational agents. The responsible investigator 
at each participating institution must be registered with CTEP, DCTD through an annual submission of 
FDA form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one 
institution, CTEP supplied investigational agents for the study should be ordered under the name of one 
lead investigator at that institution. 
 
Agent may be requested by completing a Clinical Drug Request (NIH-986) and faxing it to the 
Pharmaceutical 
Management 
Branch 
at 
(301) 
480-4612. 
The 
form 
can 
be 
obtained 
at 
http://ctep.cancer.gov/forms/default.htm. For questions about drug orders, transfers, returns, or 
accountability call (301) 496-5725 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
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Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received from DCTD using the 
NCI Drug Accountability Record Form (DARF).  (See the CTEP home page at http://ctep.cancer.gov for 
the Procedures for Drug Accountability and Storage and http://ctep.cancer.gov/forms/default.htm to 
obtain a copy of the DARF and Clinical Drug Request form.) 
 
Agent Returns 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI clinical 
repository as soon as possible when: the agent is no longer required because the study is completed or 
discontinued and the agent cannot be transferred to another DCTD sponsored protocol; the agent is 
outdated or the agent is damaged or unfit for use. Regulations require that all agents received from the 
DCTD, NCI be returned to the DCTD, NCI for accountability and disposition. Return only unused 
vials/bottles. Do NOT return opened or partially used vials/bottles unless specifically requested otherwise 
in the protocol. See the CTEP web site for Policy and Guidelines for Investigational agent Returns at: 
http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. The appropriate forms may be 
obtained at:  http://ctep.cancer.gov/forms/default.htm. 
 
 
6.2 
TEMOZOLOMIDE    
(Temodar®, Temodal®) NSC# 362856   
 
 
 
 
 
(05/10/11) 
 
Source and Pharmacology:  
An orally administered alkylating agent, a second generation imidazotetrazine. A prodrug of MTIC, 
temozolomide spontaneously decomposes to MTIC at physiologic pH. Exerts its effect by cross-linking 
DNA. This is likely a site specific alkylation at the O6-position of guanine with some effect at the 
N7 position. Temozolomide reaches its peak concentration in 1 hour. Food reduces the rate and extent of 
absorption. It has an elimination half-life of 1.13 hr (intraperitoneally) and 1.29 hr (orally) with an oral 
bioavailability of 0.98. Total apparent body clearance is 100 mL/min/m2 and plasma elimination half-life is 
~ 100 minutes.  
 
Toxicity: 
 
Common 
Happens to 21-100 subjects 
out of every 100 
Occasional
Happens to 5-20 subjects out 
of every 100 
Rare
Happens to < 5 subjects out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Anorexia, 
constipation, 
nausea, vomiting, 
Abdominal 
pain, 
diarrhea, 
headache, 
rash, 
itching, 
urinary 
frequency 
and/or 
infection 
Convulsions, 
anaphylaxis, 
hemiparesis, 
dizziness, 
ataxia, 
confusion, 
dysphagia, 
anxiety, thrombo-embolism (L)  
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression 
Mucositis, 
lethargy, 
peripheral edema 
Prolonged lymphopenia with increased risk of 
infection 
or 
death, 
amnesia, 
insomnia, 
depression, myalgia, diplopia, visual changes 
Delayed: 
Anytime 
later 
during therapy 
 
Alopecia, hepatotoxicity
 
Late: 
Anytime 
after 
completion 
of 
therapy 
 
 
Secondary tumors or cancer
 
Formulation and Stability: Temozolomide capsules are available in six different strengths (5, 20, 100, 
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140, 180, 250 mg). The capsules vary in size, color, and imprint according to strength. In the US, capsules 
are packaged in 5-count and 14-count bottles. In other countries temozolomide may be packaged in 5- 
count, 14-count or 20-count bottles. Temozolomide capsules are stored at controlled room temperature. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the protocol. 
 
There is a potential for medication errors involving temozolomide capsules resulting in drug overdosages, 
which may have been caused by dispensing/taking the wrong number of capsules per day and/or product 
usage exceeding the prescribed dosing schedule. 
 
When dispensing, it is extremely important that prescribing and dispensing include clear instructions on 
which capsules, and how many of each capsule(s) are to be taken per day. Only dispense what is needed 
for the course, and clearly indicate how many days of dosing the patient will have and how many days are 
without temozolomide dosing. When counseling patients, it is important for each patient/parent to 
understand the number of capsules per day and the number of days that they take temozolomide. It is also 
important for the patient/parent to understand the number of days that they will be off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original glass bottle. Based 
on the dose prescribed, determine the number of each strength of temozolomide capsules needed for the 
full course as prescribed by the physician. For example, 275 mg/day for 5 days would be dispensed as 
five 250-mg capsules, five 20-mg capsules, and five 5-mg capsules. Label each container with the 
appropriate number of capsules to be taken each day. Dispense to the patient/parent, making sure each 
container lists the strength (mg) per capsule and that he or she understands to take the appropriate number 
of capsules of temozolomide from each bottle or vial to equal the total daily dose prescribed by the 
physician. Institutions that have the capability to dispense temozolomide as daily doses in a blister pack 
may do so, taking specific precautions to ensure that the appropriate dose is provided and that the patient 
is educated to understand the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be formulated into a suspension. 
To prepare a 10mg/mL suspension triturate the contents of ten 100mg capsules (1000mg), 500mg povidone 
K-30 and 25mg anhydrous citric acid dissolved in 1.5mL purified water in a glass mortar to form a uniform 
paste. To the paste add 50 mL of Ora-Plus® by adding a small amount, mixing, and then adding the balance. 
Transfer to a glass graduated cylinder.  Add Ora-Sweet® or Ora-Sweet® SF to a total volume of 100mL by 
rinsing the mortar with small amounts of the syrup (Ora-Sweet® or Ora-Sweet® SF).  Rinse at least four 
times. Package in an amber plastic prescription bottle. The packaged suspension is stable for 7 days at room 
temperature or 60 days in the refrigerator. The suspension should be shaken well before each use. 
Procedures for proper handling and disposal of cytotoxic drugs should be used when preparing the 
suspension. (Trissel LA, Yanping Z, Koontz SE.  Temozolomide stability in extemporaneously 
compounded oral suspensions. Int J Pharm Compounding 10:396-9, 2006). 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice (see Appendix VI in the 
protocol). 
 
Supplier: Commercially available. See package insert for further information.  
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6.3 
VORINOSTAT   
(Zolinza®, suberoylanilide hydroxamic acid, SAHA)    NSC# 701852, 
   
(11/02/11)  
 
Source and Pharmacology: Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA), is a 
histone deacetylase (HDAC) inhibitor.  Its chemical name is N-hydroxy-N’-phenyl-octane-1, 8-diotic acid 
diamide, N-hydroxy-N’-phenyl (9CI) octanediamide.  The HDAC enzymes catalyze the removal of acetyl 
groups from the lysine residues of proteins, such as histones and transcription factors.  In some cancer 
cells, there is an overexpression of HDACs or an abnormal recruitment of HDACs to oncogenic 
transcription factors causing hypoacetylation of core nucleosomal histones.  Hypoacetylation of histones 
is associated with a condensed chromatin structure and repression of gene transcription.  
 
Vorinostat inhibits HDAC by binding directly to the catalytic pocket of HDAC1, HDAC2, and HDAC3 
(Class I) and HDAC6 (Class II) enzymes.  Inhibition of HDAC activity allows for the accumulation of 
acetylated histones.  This accumulation influences the regulation of gene expression.  In vitro, exposure of 
cultured transformed cell to vorinostat led to G1 or G2 phase cell-cycle arrest, apoptosis, or 
differentiation and demonstrated synergistic and additive activity in combination with other cancer 
therapies (including radiation, kinase inhibitors, cytotoxic agents, and differentiating agents). The 
mechanism of the antineoplastic effect of vorinostat has not been fully characterized. 
 
After oral administration, vorinostat is rapidly absorbed, however, administration with a high-fat meal 
resulted in a 33% increase in the extent of absorption and a 2.5-hour delay in the rate of absorption 
compared to the fasted state.  Vorinostat is approximately 71% bound to human plasma protein. It is 
extensively metabolized to inactive metabolites, primarily by glucuronidation and hydrolysis followed by 
beta-oxidation. The two metabolites, O-glucuronide of vorinostat and 4-anilino-4-oxobutanoic acid are 
pharmacologically inactive. In vitro studies indicate that vorinostat is not metabolized by and does not 
inhibit the activity of cytochrome P-450 enzymes. Less than 1% of an administered dose is excreted 
unchanged in the urine. Approximately 35-52% of an oral dose of vorinostat is excreted in the urine as the 
two major metabolites. The mean terminal half-life of vorinostat and the O-glucuronide metabolite is 
approximately 2 hours, while that of the 4-anilino-4-oxobutanoic acid metabolite it is 11 hours.  
 
Prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed in 
patients receiving vorinostat with coumarin-derivative anticoagulants (eg, warfarin). Therefore PT and 
INR should be monitored when coumarin-dervative anticoagulants are started or discontinued. When 
vorinostat was administered with other HDAC inhibitors (eg, valproic acid), severe thrombocytopenia and 
gastrointestinal bleeding have been reported.  
 
 
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Gingival pain; Lower gastrointestinal hemorrhage; Mucositis oral; Oral hemorrhage; Small intestinal 
obstruction; Stomach pain; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema 
limbs; Gait disturbance; General disorders and administration site conditions - Other (angioedema); 
General disorders and administration site conditions - Other (failure to thrive); Malaise; Multi-organ 
failure; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (Herpes zoster) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Vascular access 
complication; Wound dehiscence 
INVESTIGATIONS - Activated partial thromboplastin time prolonged4; Cardiac troponin I increased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; INR increased4; Investigations - 
Other (elevated LDH); Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hypoglycemia; Hypomagnesemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Chest 
wall pain; Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Depressed level of 
consciousness; Dysphasia; Encephalopathy; Facial muscle weakness; Facial nerve disorder; 
Headache; Intracranial hemorrhage; Ischemia cerebrovascular; Lethargy; Memory impairment; 
Nervous system disorders - Other (Guillain-Barre syndrome); Nervous system disorders - Other 
(head injury); Nervous system disorders - Other (polyneuropathy); Paresthesia; Peripheral motor 
neuropathy; Peripheral sensory neuropathy; Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Personality 
change; Psychosis 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria; Proteinuria; Urinary 
frequency; Urinary incontinence; Urinary retention; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Uterine hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Epistaxis; Hypoxia; Nasal congestion; Pharyngeal mucositis; Pharyngolaryngeal pain; Pleural 
effusion; Pleuritic pain; Pneumonitis 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Palmar-
plantar erythrodysesthesia syndrome; Pruritus; Purpura; Rash maculo-papular 
VASCULAR DISORDERS - Flushing; Hematoma; Hot flashes; Hypertension; Hypotension; 
Thromboembolic event; Vascular disorders - Other (arterial thrombosis); Vasculitis 
 
Note: Vorinostat (SAHA) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
PLEASE NOTE:  The potential risks listed in the CAEPR whose relationship to vorinostat is still 
undetermined are not required by CTEP to be described in the ICD; however, they may be 
communicated to patients according to local IRB requirements. 
 
Effect in pregnancy: Vorinostat is Pregnancy Category D. It may cause fetal harm when administered 
to a pregnant woman. Adequate contraception must be used by all patients (both male and female) and 
their partners during therapy with vorinostat and for 30 days after the completion of study drug 
administration. 
 
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Formulation and Stability: Vorinostat is supplied as a white, opaque gelatin, size 3 capsule, containing 100 
mg of vorinostat.  The inactive ingredients in each capsule include microcrystalline cellulose, sodium 
croscarmellose, and magnesium stearate.  Vorinostat 100 mg capsules are supplied in bottles containing 120 
capsules. 
 
Store vorinostat capsules at room temperature, 15 to 30ºC (59 to 86ºF). Do not store above 30ºC and avoid 
exposure to excessive moisture.  
 
A formulation for compounding vorinostat suspension by the pharmacy is provided below: 
 
Ingredients: 
Vorinostat 100 mg capsules 
20 capsules 
OraPlus or Suspensol S  
20 mL 
OraSweet 
 
 
20 mL 
 
Instructions:  
Add 20 mL of Suspensol S or OraPlus into an amber or clear glass 4 ounce bottle.  Place the contents of 20 
capsules of vorinostat 100 mg into the same bottle and shake to disperse.  Shaking may take up to 3 minutes.  
Once dispersed, add 20 mL of OraSweet to achieve a total volume of 40 mL.  Shake again to disperse.  The 
final concentration is 50 mg/mL.  Store at room temperature.  The suspension is stable for 2 weeks. 
 
Guidelines for Administration:  See Treatment and Dose Modification sections of the protocol. 
Vorinostat should be taken with food.  The capsules should not be opened or crushed.  A suspension can be 
prepared by the pharmacy for patients that cannot swallow (see Formulation and Stability section above). 
 
If a patient needs less than 120 capsules for a treatment cycle, the exact number of capsules needed for 
treatment can be counted into a prescription bottle.   
 
Direct contact of the powder in vorinostat capsules with the skin or mucous membranes should be 
avoided. If such contact occurs, wash thoroughly. Clean powder spills from broken or damaged vorinostat 
capsules carefully minimizing inhalation. Wash spill area at least 3 times with ethyl alcohol, followed by 
water. 
 
Supplier:  Supplied by Merck Research Laboratories and distributed by the NCI DTCD. Do not use 
commercially available drug. 
 
Agent Ordering 
NCI supplied agent may be requested by the Principal Investigator (or their authorized designee) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that agent be 
shipped directly to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained). The CTEP assigned protocol 
number must be used for ordering all CTEP supplied investigational agents. The responsible investigator 
at each participating institution must be registered with CTEP, DCTD through an annual submission of 
FDA form 1572 (Statement of Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF). If there are several participating investigators at one 
institution, CTEP supplied investigational agents for the study should be ordered under the name of one 
lead investigator at that institution. 
 
Agent may be requested by completing a Clinical Drug Request (NIH-986) and faxing it to the 
Pharmaceutical 
Management 
Branch 
at 
(301) 
480-4612. 
The 
form 
can 
be 
obtained 
at 
http://ctep.cancer.gov/forms/default.htm. For questions about drug orders, transfers, returns, or 
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accountability call (301) 496-5725 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received from DCTD using the 
NCI Drug Accountability Record Form (DARF).  (See the CTEP home page at http://ctep.cancer.gov for 
the Procedures for Drug Accountability and Storage and to obtain a copy of the DARF and Clinical Drug 
Request form.) 
 
Agent Returns 
Investigators/Designees must return unused DCTD supplied investigational agent to the NCI clinical 
repository as soon as possible when: the agent is no longer required because the study is completed or 
discontinued and the agent cannot be transferred to another DCTD sponsored protocol; the agent is 
outdated or the agent is damaged or unfit for use. Regulations require that all agents received from the 
DCTD, NCI be returned to the DCTD, NCI for accountability and disposition. Return only unused 
vials/bottles. Do NOT return opened or partially used vials/bottles unless specifically requested otherwise 
in the protocol. See the CTEP web site for Policy and Guidelines for Investigational agent Returns at: 
http://ctep.cancer.gov/forms/returns-03.pdf. 
The 
appropriate 
forms 
may 
be 
obtained 
at: 
http://ctep.cancer.org 
 
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below.  
 
7.1 
Required Clinical, Laboratory and Disease Evaluations  
 
 
Obtain prior to start of phase unless otherwise indicated.   
Observation 
Baseline 
During  
ChemoRT 
During Maintenance 
Therapy 
At Time of 
Progression 
At Completion 
of Therapy 
History 
X 
Weeks 1 and 
7 
Prior to each cycle 
X 
 
Physical Exam (Ht, Wt, BSA, 
VS[including BP]) 
X 
Weeks 1 and 
7 
BP prior to 
each dose of 
bevacizumab 
Prior to each cycle; 
BP prior to each dose 
of bevacizumab 
X 
 
Performance Status 
X 
Weeks 1 and 
7 
Prior to each cycle 
 
 
CBC (differential, platelets) 
X 
Weekly 
Prior to each 
bevacizumab dose 
 
X1 
PT INR 
X 
 
 
 
 
Electrolytes 
(including 
Ca++, 
PO4, Mg++)  
X 
Weekly 
Prior to each cycle 
 
 
BUN, Creatinine 
X 
Weekly 
Prior to each cycle 
 
X1 
AST, ALT, bilirubin 
X 
Weekly 
Prior to each cycle 
 
X1 
Urinalysis for dipstick or protein 
and urine protein creatinine (UPC) 
ratio 
X10 
Weekly 
Arm C 
Prior to each cycle7 
 
 
Total protein/albumin 
X 
 
 
 
 
MRI of brain with and without 
gadolinium8  
X5 
 
Prior to each odd 
number cycle 
X4 
X2 
MRI of spine with gadolinium8 
X3 
 
Prior to each odd 
number cycle3 
X3 
 
Pregnancy Test (for females of 
childbearing potential) 
X 
      
 
 
 
Required Specimens for Pathology 
Central Review (see Section 15.0)  
 
 
Prior to first cycle 
 
 
Growth Plate Evaluation 
X-ray of right knee6 
X 
 
End of Cycles 3, 6, 9, 
12 
 
 
Optional Biology and Imaging 
(See Section 16.0) 
X 
 
X9 
 
X 
1. Obtain on Day 28 of maintenance cycle 12. Repeat weekly until results are normal. 
2. Obtain 3-4 weeks following the final bevacizumab+temozolomide administration on Cycle 12. 
3. Obtain if patient has spinal primary or if clinically indicated. If positive for neuraxis dissemination (development of metastatic 
disease), then patient is ineligible. 
4. Because of the high incidence of disseminated disease at the time of relapse, spinal MRIs are encouraged. 
5. Obtain brain pre-op MRI and baseline post-op MRI both with and without gadolinium. Post-op MRI must be done within 4 weeks 
prior to starting treatment. Post-op MRI is not required if the patient underwent biopsy only. 
6. Obtain pre-treatment tibial x-ray (AP and lateral views) of the right knee in patients who have not yet obtained full adult height 
and to be repeated every 12 weeks during Maintenance. If abnormalities are detected on routine X-rays following treatment, MRI 
scan of both knees should be performed and a consultation with an orthopedic surgeon is recommended.  However, no dose 
modifications will be made for bevacizumab. 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are based on 
schedules derived from the experimental design or on established standards of care.  Minor unavoidable departures 
(up to 72 hours) from protocol directed therapy and/or disease evaluations (and up to 1 week for surgery) for valid 
clinical, patient and family logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per 
COG Administrative Policy 5.14 (except where explicitly prohibited within the protocol).  
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7.3 
Follow-up  
See COG Late Effects Guidelines for  recommended post treatment follow-up at  
http://www.childrensoncologygroup.org/disc/LE/default.htm. 
 
The following studies are recommended until the patient is off study as defined in Section 8.2.  
 
7.3.1 
Recommended Observations Following Completion of Protocol Therapy 
 
Observation 
3 
Months 
6 
Months 
9
Months 
1
Year 
1.5
Years 
2
Years 
2.5
Years 
3
Years 
3.5 
Years 
 
4 Years 
Annually 
5  to 10 
Years 
At
Relapse 
History, Physical 
Exam incl. Ht, Wt, 
BSA, VS (inc. BP) 
X 
X 
X
X
X
X
X
X
X 
X
X
X
MRI of Brain with 
and without  
gadolinium 
X 
X 
X
X
X
X
X
X
X 
X
X
X
MRI of the Spine 
with gadolinium 
X1 
X1 
X1
X1
X1
X1
X1
X1
X1 
X1
X1
X*
 1  Obtain if patient has spinal primary or if clinically indicated. 
* Spinal MRIs with gadolinium performed due to the high incidence of disseminated disease at the time of relapse. 
 
This table only includes evaluations necessary to answer the primary and secondary aims.  Obtain 
other studies as indicated for good clinical care.  
 
See 
COG 
Late 
Effects 
Guidelines 
for 
recommended 
post 
treatment 
follow-up 
http://www.childrensoncologygroup.org/disc/LE/default.htm 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
8.1 
Criteria for Removal From Protocol Therapy 
a) 
Progressive disease (see Section 10.4). 
b) 
Development of unacceptable toxicity as outlined in Section 4.3 for the feasibility phase of study and 
as outlined in Section 5.0 for phases II and III of study. 
c) 
Refusal of further protocol therapy by patient/parent/guardian. 
d) 
Completion of planned therapy. 
e) 
Physician determines it is in patient’s best interest. 
g)  
Development of a second malignancy. 
h) 
Patient becomes pregnant/breatfeeding while on study. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below).  
Follow-up data will be required unless consent was withdrawn. 
 
8.2 
Off Study Criteria 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Patient enrollment onto another COG study with tumor therapeutic intent (eg, at recurrence). 
d) 
Withdrawal of consent for any further data submission. 
e) 
The tenth anniversary the date the patient was enrolled on this study. 
 
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9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
Statistical Design 
This is a study for patients with newly diagnosed high-grade gliomas. Patients will be treated with local 
irradiation with a particular radiosensitizer, followed by maintenance chemotherapy with bevacizumab and 
temozolomide. The study has a feasibility part to obtain the MTD of vorinostat when given concurrently with 
RT. Upon its successful completion, the study will open to the Phase II part where patients will be 
randomized to receive concurrent radiation with 1 of the 3 radiosensitizers: vorinostat, bevacizumab, or 
temozolomide, and maintenance chemotherapy with bevacizumab and temozolomide. In the Phase II part, 
temozolomide is considered the control treatment; vorinostat and bevacizumab are considered 
experimental treatments. If at least one of the experimental treatments has a higher 1-year EFS than 
temozolomide in the Phase II part, the Phase III part of the study will open and the experimental treatment 
with a higher 1-year EFS between the 2 experimental treatments will be chosen for Phase III. Phase III of the 
study will formally compare the experimental treatment identified in Phase II to treatment with 
temozolomide. For the Phase II/III parts, randomization will be stratified by extent of resection (near total 
resection or gross total resection vs. other) and histology (glioblastoma multiforme vs. other). More details 
on each part of the study are discussed below. 
 
The feasibility part will enroll 6 patients at 230 mg/m2/dose with daily RT. If there are fewer than 2 
patients with DLTs, we will declare this dose of vorinostat as the recommended Phase II dose to be used 
with RT. If we have 2 or more DLT in this cohort of 6 patients, we would then dose de-escalate to 180 
mg/m2 and open the cohort to 3 patients at this dose level. If 0 or 1 of the 3 patients has a DLT, we will 
expand this cohort by adding 3 additional patients. If fewer than 2 of the 6 patients have a DLT, this dose 
level (180 mg/m2) will be declared as the recommended Phase II dose. If 2 or more of the 6 patients at 
180 mg/m2 have a DLT, the study will be amended. The probability that a dose level will be considered 
tolerable (ie, 0 or 1 DLT among 6 patients) is 0.89, 0.66, 0.42, or 0.23 if the true rate of DLT at that dose 
level is 10%, 20%, 30%, or 40%, respectively.   
 
Upon successful completion of the feasibility part, the study will open for the Phase II part, with 108 patients 
randomized to one of the three treatments (36 patients per arm): vorinostat, bevacizumab, or temozolomide. 
At the end of the Phase II part, if neither of the 2 experimental arms has a 1-year EFS rate that is higher 
than that of the temozolomide arm, the study will be closed. If 1 of the 2 experimental arms has a 1-year 
EFS rate that is higher than that of the temozolomide arm, the study will continue to the Phase III part and 
this experimental arm will be chosen for comparison with temozolomide in the Phase III part of the study. 
If both experimental arms have a higher 1-year EFS rate than that of the temozolomide arm, the 
experimental treatment with the higher 1-year EFS rate will be chosen for further comparison with 
temozolomide. If the study continues to the Phase III part, patients will be randomized between 2 arms: 
one control arm (temozolomide) and one experimental arm. In the Phase III part, accrual will continue 
until 64 additional patients are randomized to each of the 2 arms.  The final Phase III comparison will 
include patients randomized to the 2 arms in both the Phase II part and Phase III part of the study. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
Recent COG studies of patients with newly diagnosed high-grade gliomas (HGG) include ACNS0126 and 
ACNS0423. ACNS0126 accrued 99 eligible HGG patients between December 2002 and October 2004, with 
an average accrual rate of 54 patients per year. ACNS0423 accrued 107 eligible HGG patients between 
March 2005 and August 2007; the average accrual rate after the first 6 months was also about 54 patients per 
year. Therefore, the estimated annual accrual for the current study is 54 patients.  
 
The feasibility part of the study will accrue 6-12 eligible patients. Given the overall annual accrual rate 
estimate of 54 patients, accruing 6-12 patients should take less than 6 months. Consider the 8 weeks 
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evaluation period after the first 6 patients, or also after the first 9 and 12 patients, the complete duration for 
the feasibility part is expected to be about 12 months. The Phase II part of the study will accrue 108 eligible 
patients which is expected to take about 2 years. One year of additional follow-up will be needed to evaluate 
the Phase II outcome. If the study opens to the Phase III part, we will accrue an additional 128 eligible 
patients, which is expected to take about 2.4 years. Therefore, the total accrual duration (only the time when 
the study is open to accrual), if the study continues to the Phase III part, will be about 5 years. The total study 
duration from study activation until the end of accrual (including evaluation periods for the feasibility/II 
parts), is expected to be about 6.5 years. A minimal 1-year of additional follow-up is planned before the final 
Phase III analysis can be performed.  
 
Of the 118 patients enrolled on the previous HGG study ACNS0423, 12 (10%) were deemed ineligible.  
As of Amendment #1, the accrual for the feasibility part of the study was 6 patients and all were eligible. 
Considering a 10% rate of ineligible enrollment on this study, the total accrual for Phase II may be up to 
120 patients and the total accrual for Phase III may be up to 142 patients.  
 
9.3 
Statistical Analysis Methods 
 
9.3.1 
Endpoints 
Safety and feasibility endpoints: 
 
Feasibility part: DLT for vorinostat, when given concurrently with RT.   
 
Phase II: toxic death, individual toxicities especially Grade 3 or 4 hemorrhage, significant delay 
(> 2 weeks) in the completion of RT, and significant delay (> 2 weeks) in the start of any course 
of maintenance therapy. 
 
Phase III: toxic death, individual toxicities especially Grade 3 or 4 hemorrhage 
 
Efficacy endpoints for Phase II/III: 
 
Event-free survival (EFS), defined as time to the first occurrence of any of the following events: 
disease progression, relapse, second malignant neoplasm, or death from any cause. 
 
Overall survival (OS), defined as time to death from any cause. 
 
Progression-free survival (PFS), defined as time to the occurrence of disease progression or 
recurrence.  
 
9.3.2 
Power Considerations for Phase II/III 
In the Phase II part of the study, patients are randomized to 1 of the 3 arms: 1 control arm (temozolomide) 
and 2 experimental arms (vorinostat, bevacizumab). At the end of the Phase II part, the experimental 
treatment with a  higher 1-year EFS rate among the 2 experimental arms, if its 1-year EFS is also higher 
than that of the temozolomide arm, will be chosen for further comparison with temozolomide in the Phase 
III part. If temozolomide arm has the highest 1-year EFS among the 3 arms, the study will be closed. We 
use 1-year EFS as the main endpoint for the Phase II part because, in this study, tumor response and 
shorter-term EFS are not considered good indicators of treatment effect.  
 
ACNS0126 and ACNS0423 both used temozolomide and concurrent radiation therapy to treat patients 
with newly diagnosed high-grade gliomas. The maintenance therapies used in these 2 studies and in the 
current study are all different. Based on November 2008 data, the observed 1-year EFS (±SE) on 
ACNS0126 is 39% ± 5%; the observed 1-year EFS (±SE) on ACNS0423 is 49% ± 5%. Given these data, 
for power considerations we assume a 1-year EFS rate of 45% for the temozolomide arm (control arm) on 
this study. For the Phase III part of the study which will compare the overall EFS curves for the 2 arms, 
we assume a long-term EFS rate of 15% for the temozolomide arm, based on limited long-term data on 
ACNS0126 and long-term outcome data on an earlier high-grade glioma protocol CCG 945. 
  
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Between the 2 experimental arms, we use arm 1 to denote the arm with the better EFS in truth and arm 2 
to denote the other. Below we discuss the probability of selecting arm 1 after the Phase II part and the 
probability of establishing its superiority in EFS over temozolomide at the end of the Phase III part. 
Obviously such probabilities depend on the true EFS of arm 1 and that of temozolomide arm. However, 
since the design only picks the better performer of the 2 experimental arms from the Phase II part, 1-year 
EFS for arm 2 will also influence the probability of selecting arm 1 after the Phase II part, and in term 
affect the probability of establishing the superiority of arm 1 over temozolomide at the end of the Phase 
III part.  
 
In the table below, the selection probabilities for arm 1 and arm 2 after the Phase II part are presented in 
columns 2 and 3. For example, if the 1-year EFS rates for arm 1 and arm 2 are 60% and 40% respectively, 
the probability that the study will continue to the Phase III part with arm 1 is 0.85. On the other hand, if 
the 1-year EFS rate for arm 1 is 60% but the 1-year EFS rate for arm 2 is 55%, the probability of selecting 
arm 1 is reduced to 0.63, because under this scenario the chance of selecting arm 2 increases even though 
arm 1 is still better than arm 2 in truth. The probability of the study not continuing on to the Phase III 
part, meaning that neither of the 2 experimental arms has a 1-year EFS rate that is higher than that of the 
temozolomide arm, is one minus the probabilities in column 2 and column 3. In these scenarios, the 1-
year EFS of arm 1 needs to be at least 60% compared to 45% in temozolomide arm for arm 1 to have a 
decent probability of being selected for the Phase III part. The probability of selecting arm 1 decreases 
with increasing 1-year EFS in arm 2.  
 
Table 1: Probability of selection (after Phase II) and that of establishing superiority to 
temozolomide (after Phase III) for each experimental arm 
 
Scenarios 
Phase II** Selection 
Probability 
Overall Phase III*** 
Success Probability 
 
arm 1 
arm 2 
arm 1 
arm 2 
arm 1 = 65%* 
 
 
 
 
   arm 2 = 60% 
0.66 
0.32 
0.65 
0.30 
   arm 2 = 55% 
0.78 
0.18 
0.77 
0.13 
   arm 2 = 50% 
0.88 
0.09 
0.86 
0.03 
   arm 2 = 45% 
0.91 
0.04 
0.90 
0.01 
   arm 2 = 40% 
0.94 
0.01 
0.92 
<0.01 
 
 
 
 
 
arm 1 = 60%* 
 
 
 
 
    arm 2 = 55% 
0.63 
0.31 
0.57 
0.21 
    arm 2 = 50% 
0.74 
0.17 
0.66 
0.07 
    arm 2 = 45% 
0.81 
0.08 
0.73 
0.01 
    arm 2 = 40% 
0.85 
0.03 
0.76 
<0.01 
 
 
 
 
 
arm 1 = 45%* 
 
 
 
 
    arm 2 = 45% 
0.31 
0.31 
0.03 
0.03 
    arm 2 = 40% 
0.38 
0.17 
0.04 
<0.01 
    *Temozolomide arm is the control arm, with 45% 1-year EFS. 
    **36 patients in each of the 3 arms. 
    ***100 patients in each of the 2 arms including the 36 patients from the Phase II part. 
 
Note that an experimental arm is only chosen for further study in the Phase III part if its 1-year EFS rate 
is higher than that of the temozolomide arm; if its outcome equals that of the temozolomide arm, it will 
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not be chosen. In these calculations, for the rare situation where the 1-year EFS is the same for the 2 
experimental arms and better than that of the temozolomide arm, half of that probability is added to the 
selection probability of arm 1 and half to that of arm 2.  This simple approach means that, in the event of 
such a “tie”, we will randomly pick one experimental arm for further study. However, we will most likely 
consider other factors, such as toxicity profiles, for tie-breaking if such a tie occurs. The probabilities of 
such a tie are so rare that they have little impact on the results presented above.  
 
For the Phase III part, a log rank test will be performed to compare the EFS between the 2 arms (100 
patients each) after a minimal of 1 year of additional follow-up at a 1-sided alpha level of 0.05. However, 
for this study, the traditional power and size for this test between the chosen experimental arm and the 
temozolomide arm cannot be easily defined. This is because the occurrence of the Phase III part depends 
on the outcomes in the Phase II part which also involves the non-chosen experimental arm. In addition, 
the Phase II patients are included in the Phase III comparison; their early outcomes (1-year EFS) are 
already observed and have to occur in a particular direction (experimental arm higher than temozolomide) 
for the Phase III part to happen. 
 
In column 4 and 5 of Table 1, we illustrate the overall probability of establishing a significantly better 
outcome for arm 1 (or arm 2) at the end of the Phase III with the specified log rank test in the current 
study design. For example, the success rate for arm 1 (with 60% 1-year EFS) ranges from 0.57- 0.76 if 
arm 2 has a 1-year EFS that is between 55% and 40%. The probability presented is the overall probability 
for a particular arm before the inception of the Phase II/III part, so is not conditional on the arm being 
chosen for Phase III. Note that if this is a standard Phase III comparison with the same sample size and 
other parameters, the power for the comparison between arm 1 and the temozolomide arm will be about 
0.84. Here, the reduction in “power” is because arm 1, though the best of the 3 in truth, is not always 
chosen after the Phase II part, which reduces its overall success probability. Comparing column 2 and 
column 4, one can see that if arm 1 is truly the best of the 3 and “wins” in the Phase II part, the 
conditional probability of its overall success given the Phase II success and Phase II outcome will be quite 
high. In Table 1, selection probabilities for the Phase II part are computed by exact binomial probabilities. 
The overall success rates for the final Phase III comparison are estimated from simulation studies because 
the log rank test compares the entire EFS curve rather than just 1-year EFS. To carry out the simulations, 
additional assumptions need to be made on the failure patterns of the patients. Event-free survival curves 
are approximated by cure models where a proportion of the patients become long-term survivors and 
failures for the remaining patients follow an exponential pattern. The temozolomide arm is assumed to 
have 45% 1-year EFS and 15% long-term EFS. The whole EFS curve under the cure model with 
exponential failure is fully specified by EFS rates at these 2 time points. The differences in event free 
survival between the temozolomide arm and the experimental arm are assumed to be the same at 1 year 
and at long term, which then specify the whole EFS curves for the experimental arms.  
 
9.4 
Interim Monitoring 
 
9.4.1 
Monitoring for Toxic Death and Grade 3 or 4 Hemorrhage 
During the Phase II part of the study, we will monitor the rate of toxic death and that of Grade 3 or 4 
hemorrhage separately for each arm during RT. In ACNS0126, among 99 patients there were 2 deaths 
within 1 month on study, which are considered slightly attributable to the treatment. In ACNS0423, all 7 
deaths which occurred during treatment or within 31 days after treatment are considered due to disease 
progression. Two incidences of Grade 3 or 4 hemorrhage were reported among 105 patients during 
chemoradiotherapy on ACNS0423. Based on these data, for the current study we consider 2% the 
maximum tolerable rate for both toxic death and for Grade 3 or 4 hemorrhage. For each arm, we will 
accept at most 2 toxic deaths or 2 incidences of Grade 3 or 4 hemorrhage among the 36 patients. The 
monitoring rule will be triggered 3.5%, 37%, 56%, or 82% of the time if the true incidence is 2%, 6%, 
8%, or 12%, respectively. We will also monitor toxic death rate and Grade 3 or higher hemorrhage rate 
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separately during maintenance therapy for patients from all 3 arms combined, since they all receive the 
same maintenance therapy. The rule for maintenance therapy will be triggered if at least 4/54, 6/108 
patients experience toxic death/hemorrhage; it is satisfied 4% of the time if the true incidence is 2%, and 
80% of the time when the true incidence is 7%.  
 
If the study opens to the Phase III part, the rate for toxic death and that for Grade 3 or 4 hemorrhage 
during chemoradiotherapy will be also examined for each arm. Among the 100 patients on each arm 
(temozolomide arm and the chosen experimental arm), we can accept at most 4 incidences for toxic 
deaths or for Grade 3 or 4 hemorrhage. The chance that the combined rule for Phase II/III (≥3/36, ≥5/100) 
will be satisfied is 7% if the true incidence is 2%, and is 85% if the true incidence is 7%. The rate of toxic 
death and that for Grade 3 or 4 hemorrhage during the common maintenance will also be examined by 
including all patients treated on Phase II or Phase III parts. We will consider the rate for toxic death or 
that for Grade 3 or 4 hemorrhage unacceptable if we observe 9 or more incidences among the 236 Phase 
II/III patients. The combined rule (≥4/54, ≥ 6/108, ≥ 9/236) will be satisfied 7% of the time if the true 
incidence is 2%; it will be met 85% of the time when the true incidence is 5%.  
 
When a safety monitoring rule is met, the study accrual will be temporarily suspended. The study 
committee will perform a careful review of the toxicity incidences, and report the results and study 
committee recommendation such as accrual suspension or therapy modification for the involved arm to 
the DSMC. DSMC also may make other recommendations based on their review of the toxicity and 
safety data at any time.  
 
9.4.2 
Monitoring for Feasibility of Each Radiosensitizer and Common Maintenance Chemotherapy 
During the Phase II part of the study, the feasibility of each radiosensitizer and the common maintenance 
therapy will be examined via the incidence of significant delay (> 2 weeks) in the completion of RT and 
the incidence of significant delay (> 2 weeks) in the start of any course of maintenance (among total 
courses combining all 3 arms). A review of treatment feasibility and patient safety will be undertaken 
when we observe > 10% significant delays in the completion of RT specifically if we observe at least 
5/18 or 8/36 significant delays. The rule will be met about 4% of the time if the true incidence of delay is 
10%, and 90% of the time if the true incidence is 30%. Because the number of total maintenance courses 
cannot be easily estimated (as patients may not all complete 12 courses), it is not feasible to specify the 
set of statistics-based boundaries for monitoring delays in maintenance therapy. The monitoring will be 
based on the marginal incidence of significant delay in the start of any course of maintenance observed at 
each interim report.  Similar review will be undertaken if the rate of delays during maintenance exceeds 
10%. 
 
9.4.3 
Efficacy monitoring 
At the end of the Phase II part, interim comparisons of EFS by log rank test will be performed to evaluate 
whether there is early compelling evidence of improvement in EFS in either experimental arm compared 
to the control arm. The monitoring boundary will be based on Lan-Demet’s method with spending 
function αt2. If there is significant evidence of efficacy for either experimental arm compared to the 
control arm, the study will be referred to DSMC for consideration of early closure after the Phase II part 
due to efficacy. If the study continues to the Phase III part, an interim comparison of EFS by log rank test 
between the chosen experimental arm and the control arm will be performed approximately halfway 
through the Phase III enrollments and will be based on Lan-Demet’s method with spending function αt2. 
In addition, during Phase II/III, for each interim Data and Safety Monitoring Committee (DSMC) report, 
outcome of the current study participants will be compared to historical data on ACNS0126 and 
ACNS0423. This informal monitoring aims to compare outcome of patients who received maintenance 
therapy with bevacizumab to patients who did not receive maintenance therapy with bevacizumab. Since 
such comparison is not an aim of the study, we will not employ any formal monitoring rules; if, in an 
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interim analysis, the outcome of the current study is significantly worse than those of the prior studies 
(with a p value of < 0.05), the issue will be brought to the DSMC for their attention and evaluation.   
 
 
9.5 
Analysis Plans 
 
9.5.1 
Analysis plans for the primary aims of Phase II/III 
We will estimate event-free survival (EFS) for patients on each arm by Kaplan-Meier product-limit 
method. After the Phase II part, the experimental arm with a higher nominal 1-year EFS will be chosen 
for further study in the phase III part if its 1-year EFS rate is also higher than that of the temozolomide 
arm. If the study opens to the Phase III part, Kaplan-Meier curves will be used to estimate EFS of the 2 
arms combining all patients randomized to the regimen during the Phase II and the Phase III parts. The 
primary analysis will be based on a log rank test that compares the EFS between the chosen experimental 
arm and the temozolomide arm; the cutoff value for the Z-statistics will be 1.64.  
 
9.5.2 
Analysis plans for Phase II/III secondary aim 
Event-free survival (EFS), overall survival (OS), and progression-free survival (PFS) will be calculated 
for patients treated with each radiosensitizer by Kaplan-Meier estimates. Log rank tests will be used to 
compare these survival outcomes between different treatment groups on the current study.  Similar log 
rank analyses will be performed to compare outcomes for patients treated on the current study to those for 
HGG patients treated on previous COG protocols (ACNS0126 and ACNS0423); in particular, outcomes 
for patients on Arm B (temozolomide) will be compared to that for HGG patients on ACNS0126 and 
ACNS0423 to isolate contribution of bevacizumab plus temozolomide maintenance therapy versus single 
agent temozolomide maintenance therapy and temozolomide plus lomustine maintenance therapy, 
respectively.  Incidence of individual toxicities will be estimated for each chemoradiotherapy arm and for 
maintenance chemotherapy.  
 
9.5.3 
Analysis plans for laboratory and imaging aims 
Descriptive statistics will be used to summarize the biological/laboratory/imaging measures for the study, 
including telomerase activity, hTert expression, telomere length, MGMT promoter methylation status, 
MGMT protein expression, and various measures in MR perfusion and diffusion from MR imaging. 
Changes in these measures across time-points (baseline, prior to maintenance therapy, prior to cycle 3 and 
after maintenance therapy) will be summarized similarly, using descriptive statistics on the measures that 
are collected at multiple time points. Mean and standard deviation will be used to summarize continuous 
measures; log transformation of a continuous measure may be considered when appropriate. Categorical 
measures will be described by percentage distribution of the categories; in the case of binary measures a 
95% CI will be estimated. SNP analysis and gene expression and microRNA analysis will be carried out 
using Affymetrix software, and dChip or GCOS software respectively. Exploratory analyses to correlate a 
particular biological/laboratory/imaging characteristic with survival outcomes might be performed. Log 
rank tests will be used to explore the prognostic significance of a categorical factor on EFS, OS or PFS. 
Cox proportional hazards models will be used to explore the effect of a continuous marker on survival 
outcomes, and will be used for exploratory multivariate analysis examining the effect of the characteristic 
of interest with adjustments for other patient or treatment characteristics. The power of such exploratory 
analyses examining the association of a laboratory or imaging characteristics with survival outcomes 
depend on many factors: 1) total sample size of the study (whether the study goes to Phase III); 2) the 
portion of patients that participate in the particular optional study; 3) the proportion of patients possessing 
the high risk characteristics (assuming a simple comparison based on a binary risk factor); 4) the survival 
outcomes in the high-risk group and in the low-risk group. Therefore, it is difficult to prospectively 
estimate the power characteristics for individual biology analysis and these analyses are exploratory in 
nature.  
 
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9.6 
Gender and Ethnicity Considerations 
Review of outcome data from previous COG studies for high-grade glioma indicates that treatment effects 
are consistent within gender and ethnicity. That is, no one treatment examined has proven superior for one 
gender or ethnic group. Because of this, the study size will not be adjusted to ensure high power to detect 
differences in outcome in groups defined by ethnicity or gender.  
 
 
9.7 
Gender and Minority Accrual Estimates 
The target for the feasibility part of the study was 6-12 eligible patients. As of Amendment #1, the accrual for 
the feasibility part of the study has been completed and was 6 patients and all were eligible. The expected 
accrual for the Phase II and Phase III parts of the study are 108 eligible patients and 128 eligible patients, 
respectively. The accrual target on the study, therefore, is 242 eligible patients. Considering a 10% 
ineligibility rate for Phase II and Phase III, the maximum enrollment for this study may be up to 268 patients 
in order to assure that the required number of eligible patients are enrolled.   
   
The gender and minority distribution of the study population is expected to be: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender
Females
Males
Total
Hispanic or Latino 
11 
9 
20 
Not Hispanic or Latino 
111 
137 
248 
Ethnic Category: Total of all subjects 
122 
146 
268 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
6 
5 
11 
Black or African American 
16 
9 
25 
Native Hawaiian or other Pacific Islander
2 
0 
2 
White 
98 
132 
230 
Racial Category: Total of all subjects 
122 
146 
268 
 
This distribution was derived from the recent COG study ACNS0423 for patients with newly diagnosed high-
grade gliomas. 
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The sections that follow discuss the selection and evaluation of each of these types of lesions. 
 
 
10.3 
Selection of Target and Non-Target Lesions 
1. For most CNS tumors, only one lesion/mass is present and therefore is considered a “target” 
for measurement/follow up to assess for tumor progression/response. Note that patients with 
M+ disease are not eligible for enrollment on this study. 
2. If multiple measurable lesions are present, up to 3 should be selected as “target” lesions. 
Target lesions should be selected on the basis of size and suitability for accurate repeated 
measurements.  All other lesions will be followed as non-target lesions (including CSF 
positive for tumor cells).   
3. The lower size limit of the target lesion(s) should be at least twice the thickness of the slices 
showing the tumor to decrease the partial volume effect (e.g. 8 mm lesion for a 4 mm slice). 
4. Any change in size of non-target lesions should be noted, though does not need to be 
measured. 
 
10.4 
Response Criteria for Target Lesions 
1. Response criteria are assessed in 2 dimensions – the product of W x T.  
2. To assess response/progression, the ratio is calculated: 
W x T (current scan)  
W x T (reference scan) 
 
3. Development of new disease or progression in any established lesions is considered 
progressive disease, regardless of response in other lesions – e.g. when multiple lesions show 
opposite responses, the progressive disease takes precedence. 
 
4. Response Criteria for target lesions: 
 
Complete Response (CR): Disappearance of all target lesions.  
Partial response (PR): ≥ 50% decrease in the sum of the products of the two perpendicular diameters of 
target lesions, compared to baseline measurement. 
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the two perpendicular 
diameters of all target lesions to qualify for PR (taking as reference the initial baseline measurements), 
nor sufficient increase in a single target lesion to qualify for PD, (taking as reference the smallest disease 
measurement since the treatment started). 
 
Progressive Disease (PD): ≥ 25% increase in the product of perpendicular diameters of ANY target 
lesion, taking as reference the smallest product observed since the start of treatment (see exception 
below); 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).  
 
However, because radiotherapy may be associated with transient, reversible swelling during or within the 
first 3 months after completion of RT, there may be a lag time between the initiation of therapy and 
maximal anti-tumor effect. Removing a patient from protocol therapy as soon as tumor area increases by 
25% may result in the treatment being terminated prematurely. It is quite possible that if these patients 
were maintained on protocol therapy, their disease might eventually stabilize and even regress.  
 
Therefore, patients will not be considered to have progressive disease and will not be removed from 
protocol therapy for radiographic worsening secondary to local tumor enlargement (LTE), defined 
as increase in maximal bi-dimensional tumor area of 25% or more but less than 50%, and with no 
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new lesions on any MRI performed within 3 months from completion of RT (i.e. on the required 
MRI 4 weeks after completing RT, or the scan performed prior to cycle 3 of the maintenance). 
Thus, during and for 3 months after completion of RT, patients should only be removed from protocol 
therapy for progressive disease if there is 50% or more increase in tumor area (with or without 
neurological worsening), OR if there is the appearance of one or more new lesions on the MRI outside 
the radiation port. 
 
The criteria for progressive disease as defined above will commence with the required brain MRI scans 
done more than 3 months after completion of RT (i.e. prior to cycle 5 of therapy, or scans done for 
suspected progression more that 3 months after completion of RT).  Patients whose tumors meet these 
criteria will be removed from protocol therapy.  
 
Local progression is defined as progression of known residual tumor or the appearance of tumor at known 
prior sites of disease that were at some point without evidence of disease. Distant progression is defined 
as the appearance of tumor at sites other than known prior sites of disease. Distant progression most often 
occurs in the subarachnoid space and may occur at any point within the neuraxis. Although rare, extra-
CNS metastasis represents distant failure. Combined local and distant progression is defined when 
evaluation of the entire neuraxis reveals local and distant progression. 
 
10.5 
Response Criteria for Non-target Lesions 
Complete Response (CR): Disappearance of all non-target lesions.  
Incomplete Response/Stable Disease (IR/SD):  The persistence of one or more non-target lesions.  
Progressive Disease (PD): The appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Certain adverse events must be reported in an expedited manner to allow for timelier 
monitoring of patient safety and care. The following sections provide information about expedited 
reporting. 
 
11.2 
Determination of reporting requirements 
 
Reporting requirements may include the following considerations: 1) whether the patient has received an 
investigational or commercial agent; 2) the characteristics of the adverse event including the grade 
(severity), the relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization or 
prolongation of hospitalization was associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New Drug Application 
(IND).  In some instances, the investigational agent may be available commercially, but is actually being 
tested for indications not included in the approved package label.  
 
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Commercial agents are those agents not provided under an IND but obtained instead from a commercial 
source. The NCI, rather than a commercial distributor, may on some occasions distribute commercial 
agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply. 
 
Concurrent administration: When an investigational agent is used in combination with a 
commercial agent, the combination is considered to be investigational and expedited 
reporting of adverse events would follow the guidelines for investigational agents. 
 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a period of 
time prior to starting the investigational agent, expedited reporting of adverse events which 
occur prior to starting the investigational agent would follow the guidelines for commercial 
agents.  Once therapy with the investigational agent is initiated, all expedited reporting of 
adverse events follow the investigational agent reporting guidelines. 
 
 
11.3 
Steps to determine if an adverse event is to be reported in an expedited manner 
 
Step 1: Identify the type of event using the CTEP Version 4.0 of the NCI Common Terminology Criteria 
(CTCAE). The CTEP version of the CTCAE v4.0 provides descriptive terminology and a grading scale 
for each adverse event listed. The CTEP version of the CTCAE version 4.0 is identified and located on 
the CTEP website at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). All 
appropriate treatment locations should have access to a copy of the CTEP CTCAE v4.0. 
 
Step 2: Grade the event using the NCI CTCAE. 
 
Step 3: Determine the attribution of adverse event in relation to the protocol therapy.   Attribution categories 
are: Unrelated, Unlikely, Possible, Probable, and Definite. 
 
Step 4: Determine the prior experience of the adverse event.   
Expected events for a CTEP IND agent are defined as those listed in the ASAEL (Agent 
Specific Adverse Event List), a subset of the CAEPR (Comprehensive Adverse Event and 
Potential Risks). For investigational agents that are not commercially available and are being 
studied under a company’s IND, expected AEs are usually based on the Investigator’s Brochure.   
 
Unexpected events for a CTEP IND agent are defined as those NOT listed in the ASAEL. 
 
Guidance on expectedness of the agent is provided in the Drug Information Section of this protocol. 
 
Step 5: Review Tables A and/or B in this section to determine if: 
 
 
there are any protocol-specific requirements for expedited reporting of specific adverse 
events that require special monitoring; and/or 
 
there are any protocol-specific exceptions to the reporting requirements. 
 
Step 6: Determine if the protocol treatment given prior to the adverse event included an investigational 
agent, a commercial agent, or a combination of investigational and commercial agents.  
 
Note: If the patient received at least one dose of investigational agent, follow the guidelines in Table A.  
If no investigational agent was administered, follow the guidelines in Table B. 
 
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11.4 
Reporting method 
 
 
Use the NCI’s Adverse Event Expedited Reporting System (AdEERS). The NCI’s 
guidelines for AdEERS can be found at http://ctep.cancer.gov. 
 
 
An AdEERS report must be submitted by the following methods: 
 
- 
Electronically submit the report via the AdEERS Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adeers.htm,  
 
 
Fax supporting documentation for AEs related to investigational agents to: 
o  The NCI for agents supplied under a CTEP IND only (fax # 301-230-0159).  
o and to COG for all IND studies (fax # 626-241-1795; attention: COG AE Coordinator).  
 
 
DO NOT send the supporting documentation for AEs related to commercial agents to 
the NCI. Fax this material to COG (fax # 626-241-1795; attention: COG AE Coordinator).  
 
 
ALWAYS include the ticket number on all faxed documents. 
 
Use the NCI protocol number and the protocol-specific patient ID provided during 
trial registration on all reports. 
 
11.5 
When to report an event in an expedited manner 
 
 
Some adverse events require notification within 24 hours (refer to Table A) to NCI via the 
web based application and/or by telephone call to the Study Chair. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be 
made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-7497. 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned in 
must be entered into the electronic AdEERS system by the original submitter of the report at 
the site.   
 
 
Submit the report within 5 calendar days of learning of the event. 
 
11.6 
Other recipients of adverse event reports 
 
COG will forward reports and supporting documentation to the Study Chair, to the FDA (when COG 
holds the IND) and to the pharmaceutical company (for industry sponsored trials).  
 
Adverse events determined to be reportable must also be reported according to the local policy and 
procedures to the Institutional Review Board responsible for oversight of the patient. 
 
11.7 
Reporting of Adverse Events for investigational agents – AdEERS 24-hour notifications, 
and complete report requirements. 
 
Reporting requirements are provided in Table A.  The investigational agents used in this study are 
bevacizumab 
 and vorinostat 
 
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Table A     
Phase 2 and 3 Trials and COG Group-wide Pilot Studies utilizing an Agent under a CTEP IND or a 
Non-CTEP IND:  AdEERS Expedited Reporting Requirements for Adverse Events That Occur 
Within 30 Days1 of the Last Dose of the Investigational Agent 
 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
Grade 3 
Grade 33 
Grades 
4 & 52 
Grades
43 & 52 
Unexpected 
and 
Expected 
 
Unex-
pected 
 
 
Expected 
Unexpected
Expected
Unex- 
pected  
Expected 
with 
Hospitali-
zation 
without 
Hospitali- 
zation 
with 
Hospitali- 
zation 
without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
5 
Calendar 
Days 
Not 
Required 
5 
Calendar 
Days 
5 
Calendar 
Days 
5 
Calendar 
Days 
Not 
Required 
24-Hour; 
5 Calendar
Days 
5 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after 
the last dose of treatment with an agent under a CTEP IND or non-CTEP IND require reporting as 
follows: 
AdEERS 24-hour notification (via AdEERS for CTEP IND agents; via e-mail to COG AE Coordinator for 
agents in Non-CTEP IND studies) followed by complete report within 5 calendar days for: 
 Grade 4 and Grade 5 unexpected events  
 
AdEERS 5 calendar day report: 
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization (see exceptions 
below 
 Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a 
full report is required as outlined in the table. 
3 Please see exceptions below under section entitled “Additional Instructions or Exceptions.” 
March 2005 
 
Note: All deaths on study require timely reporting to COG via RDE regardless of causality.  
Attribution to treatment or other cause must be provided.   
 
 
Expedited AE reporting timelines defined: 
 
“24 hours; 5 calendar days” – The investigator must initially report the AE (via 
AdEERS for CTEP IND agents; via e-mail to COG AE Coordinator for agents in  
non-CTEP IND studies) within 24 hours of learning of the event followed by a 
complete AdEERS report within 5 calendar days of the initial 24-hour report. 
 
“5 calendar days” - A complete AdEERS report on the AE must be submitted 
within 5 calendar days of the investigator learning of the event.  
 
 
Any medical event equivalent to CTCAE Grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as 
protocol-specific expedited adverse event reporting exclusions. 
 
 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported via AdEERS if the event occurs following 
treatment with an agent under a CTEP IND. 
 
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 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
 
Protocol specific reporting of AEs, in addition to the AdEERS requirements, are to be 
entered in the COG remote data entry system.   
 
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Phase 2 
and 3 Trials Utilizing an Agent under a CTEP IND or Non-CTEP IND: 
 
 Any death that occurs more than 30 days after the last dose of treatment with an 
investigational agent which can be attributed (possibly, probably, or definitely) to the agent 
and is not due to cancer recurrence/progression must be reported via AdEERS for an agent 
under a CTEP IND [and via AdEERS for non-CTEP IND agent] per the timelines outlined 
in the table above. 
 
 Grades 1- 4 myelosuppression do not require expedited reporting unless unexpected. 
 
 
As of August 25, 2010 all secondary malignancies should be reported via AdEERS 
 
 The following SAEs will be exempted from expedited reporting through AdEERS 
 
G3-4 Decreased neutrophil count/febrile neutropenia, regardless of 
hospitalization 
 
G3-4 Diarrhea, Nausea, Vomiting, or Dehydration, regardless of hospitalization 
 
11.8 
Reporting of Adverse Events for commercial agents – AdEERS abbreviated pathway 
 
The following are expedited reporting requirements for adverse events experienced by patients on study 
who have not received any doses of an investigational agent on this study.  Commercial reporting 
requirements are provided in Table B.  
 
 COG requires the AdEERS report to be submitted within 5 calendar days of learning of the event. 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
 
 
 
 
 
 
 
 
 
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Toxicity monitoring is also the responsibility of the study committee and any unexpected frequency of 
serious events on the trial are to be brought to the attention of the DSMC. The study statistician is 
responsible for the monitoring of the interim results and is expected to request DSMC review of any 
protocol issues s/he feels require special review. Any COG member may bring specific study concerns to 
the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to implementation 
(e.g., termination, dropping an arm based on toxicity results or other trials reported, increasing target 
sample size, etc.). The DSMC determines whether and to whom outcome results may be released prior to 
the release of study results at the time specified in the protocol document. 
 
12.3 
CRADA/CTA 
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s) Covered by a 
Clinical Trials Agreement (CTA) or a Cooperative Research and Development Agreement (CRADA), 
hereinafter referred to as Collaborative Agreement: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA) between the Pharmaceutical Company(ies) (hereinafter 
referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment and Diagnosis.  Therefore, 
the following obligations/guidelines, in addition to the provisions in the “Intellectual Property Option to 
Collaborator” (http://ctep.cancer.gov/industry) contained within the terms of award, apply to the use of 
the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) data for 
Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained as such by 
the investigators. The protocol documents for studies utilizing investigational Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI.  If a copy of this protocol is requested by a patient or patient’s family member participating 
on the study, the individual should sign a confidentiality agreement. A suitable model agreement 
can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with (an)other 
investigational Agent(s), each the subject of different collaborative agreements , the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use shall 
hereinafter be referred to as "Multi-Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational Agent. 
 
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3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will be 
made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order. Additionally, all Clinical Data and Results 
and Raw Data will be collected , used and disclosed consistent with all applicable federal statutes 
and regulations for the protection of human subjects, including, if applicable, the Standards for 
Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to the NCI, 
who will then notify the appropriate investigators (Group Chair for Cooperative Group studies, or 
PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP for 
immediate delivery to Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  Collaborator 
shall have the right to request that publication be delayed for up to an additional 30 days in order 
to ensure that Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP for 
forwarding to Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or publication in 
the proceedings. Press releases and other media presentations must also be forwarded to CTEP 
prior to release. Copies of any manuscript, abstract and/or press release/ media presentation 
should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, manuscript 
or other form of public disclosure shall contain any of Collaborator(s) confidential/ proprietary 
information. 
 
 
13.0 
NEUROSURGICAL GUIDELINES 
 
13.1 
Neurosurgical Procedures 
There are no standard neurosurgical procedures for high-grade astrocytomas.  The extent of surgical resection 
will depend upon the location of the tumor within the brain, and its vascularity.  Patients potentially eligible 
for this study will undergo a neurosurgical procedure in which the diagnosis will be pathologically 
confirmed.  When feasible, an attempt will be made to carry out a "gross total" tumor removal; if not feasible, 
an attempt will be made to remove as much tumor as possible without jeopardizing the patient.  If even a 
subtotal or partial resection is considered hazardous to the patient, then a biopsy procedure must be 
performed in order to make a pathologic diagnosis.  No patient will be eligible for this study without a 
pathologic diagnosis.  
 
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13.2 
Definitions of Extent of Resection 
 
13.2.1 Biopsy Only 
An open surgical removal or closed (e.g. needle) removal of tissue for the sole purpose of making a 
pathologic diagnosis.  If tumor removal is less than 10% of the total tumor mass, this will be considered a 
biopsy only. 
 
13.2.2 Partial Resection 
The surgical removal of greater than 10% but less than 50% of the tumor mass. 
 
 
13.2.3 Subtotal Resection 
The surgical removal of greater than or equal to 50% but less than 90% of the tumor mass. 
 
 
13.2.4 Near Total Resection (Extensive Subtotal Resection) 
Resection of greater than or equal to 90% of the tumor mass, but residual disease apparent on inspection. 
 
13.2.5 Gross Total Resection 
Resection of all visible tumor. 
 
13.2.6 
An attempt should be made to estimate the volume of the residual tumor in cm2. 
 
13.3 
Imaging Confirmation of Extent of Resection 
See Section 18.0 for Neuroimaging Guidelines.  All patients must have confirmation of the neurosurgical 
staging of the extent of resection with a postoperative MRI with and without contrast.  Post-operative 
imaging of the brain should be done within 72 hours of surgery if possible (preferably within 24 hours of 
surgery), and prior to the onset of edema or gliosis which can make measurements of residual tumor 
difficult. If imaging cannot be obtained at this time or is difficult to interpret, the scan should be repeated 
10 or more days after surgery. 
 
13.4 
Peri-operative Corticosteroids 
Some patients with large tumors may require initiation of corticosteroid therapy pre-operatively to reduce 
associated cerebral edema or improve neurologic function. 
 
Usual corticosteroid dosage is 0.25 to 1 mg/kg/day of, dexamethasone in divided doses every 4-6 hours. 
Corticosteroids may be continued during the peri-operative period; however, every attempt should be made to 
taper and discontinue corticosteroid therapy as soon as clinically feasible (7 days). 
 
13.5 
Special Precautions for Bevacizumab 
Black box warning includes risk of gastrointestinal perforation and wound healing complications (fatal 
results have occurred). Suspend dosing at least 28 days prior to elective surgery. Do not initiate 
bevacizumab for at least 28 days after a major surgery (eg, organ resection, exploratory laparotomy, 
thoractomy) or 14 days after intermediate surgical procedure (eg, paracentesis or thoracocentesis) and 
until the surgical wound is fully healed. Minor surgical procedures (eg, biopsies, infusaport, or Broviac 
line placement) need to have fully healed and occurred > 7 days prior to initiation of bevacizumab.  
 
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14.0 
RADIATION THERAPY GUIDELINES  
 
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT facilities 
(per COG Administrative Policy 3.9).   
 
General Guidelines 
Radiation therapy will be given concurrently with chemotherapy (vorinostat, temozolomide, or 
bevacizumab) in newly diagnosed patients with localized high-grade glioma. The primary site will be 
irradiated even if gross-total resection was achieved. This study mandates the use of conformal or 
intensity-modulated radiation therapy; the use of CT-MR registration to define the target volumes, and 
electronic data submission. Given the infiltrative nature of high-grade glioma, patients presenting with 
extensive disease and large tumor volumes may be treated with simple beam arrangements.  
 
Required Benchmark and Questionnaires: 
3D-conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy (IMRT) using photons are 
required for this study. Patients may not receive proton therapy on this protocol.  Centers participating 
in this protocol using 3D-CRT are required to complete the 3D Benchmark; those using IMRT must 
complete the IMRT questionnaire and benchmark or phantom (see Section 14.8). All centers participating 
in this protocol must complete the QARC CT/MR image fusion benchmark. Benchmark materials and 
questionnaires may be obtained from the Quality Assurance Review Center (www.qarc.org) and must be 
submitted 
before 
patients 
on 
this 
protocol 
can 
be 
evaluated. 
Contact 
the 
RPC 
(http://rpc.mdanderson.org/rpc) for information regarding their IMRT phantoms.   
 
Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed for the use of IMRT 
in National Cancer Institute sponsored cooperative group trials. These guidelines are available through 
www.qarc.org. These guidelines require that the protocol explicitly state their requirements and methods 
for localization and immobilization; the use of volumetric imaging; target and organ motion management; 
nomenclature, definitions and rationale for targets and organs at risk; target volume coverage and normal 
tissue dose constraints; effects of heterogeneity in tissues; and quality assurance. 
 
14.1 
Indications for Radiation Therapy  
 
14.1.1 Treatment 
All patients will be irradiated and volumetric targeting for radiation therapy planning is required. 
 
14.1.2 Timing of Radiation Therapy  
Radiation therapy must start within 31 days of the definitive surgical procedure.  
 
14.1.3 Criteria to Start Radiation Therapy 
There are no contraindications to radiation therapy. Patients taking phenytoin should be weaned and/or 
switched to a different anticonvulsant as soon as feasible.  
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care.  Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  
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14.2 
Emergency Irradiation 
Patients are not allowed to have received radiation therapy prior to enrollment on this protocol. Patients who 
require urgent irradiation after protocol enrollment may initiate treatment using a simple beam’s eye view 
treatment approach. The treatment may then be modified to improve conformity or normal tissue sparing as 
soon as feasible.  
 
14.3 
Equipment 
 
Modality: X-rays with a nominal energy of  4MV. In the unusual circumstance of a superficial lesion, 
electron fields may be used. Conformal and IMRT techniques are allowed in this study. Patients may not 
receive proton beam therapy on this protocol. 
 
Calibration: The calibration of therapy machines used in this protocol shall be verified by the 
Radiological Physics Center (RPC). 
 
CT treatment planning: All patients will undergo CT treatment planning for this protocol. Image section 
thickness < 3mm should be taken throughout the extent of the irradiated volume. 
 
14.4 
Target Volumes 
 
The International Commission on Radiation Units and Measurements (ICRU-50 and 62)145,146  
www.icru.org prescription methods and nomenclature shall be utilized for this study. Although the MRI 
obtained immediately prior to radiation therapy should be used for treatment planning, the target volumes 
for this study will be determined by the collective information that delineates the extent of disease before 
and after surgical resection or biopsy. Most patients with high-grade glioma require a combination of pre- 
and post-operative MR sequences to delineate the full extent of disease.  MR pre- and post-gadolinium 
contrast T1, T2, and FLAIR sequences should be reviewed. The sequence that best defines the extent of 
initial disease should be used to determine GTV1 and registered to the treatment planning CT. The GTV, 
CTV and PTV and normal tissues must be outlined on all axial imaging slices on which the structures 
exist.    
 
14.4.1 Gross Tumor Volume 1 (GTV1) 
 
GTV1 will include all the tissues initially involved with disease and the entirety of residual tumor defined 
by the pre-operative and post-operative MRI. GTV1 will include both enhancing and non-enhancing areas 
of the tumor, MR T2-weighted imaging abnormality, and the resection bed.  The GTV1 will take into 
account changes in brain anatomy resulting from tumor resection or CSF shunting.  
 
 
GTV1 is the volume of tissue containing the highest concentration of tumor cells. 
 
GTV1 includes disease defined by neuroimaging before and after surgery. 
 
GTV1 is corrected volumetrically after surgical resection. 
 
GTV1 includes the pre and post-contrast MR T1 and T2 abnormality. 
 
 
Special Circumstances (GTV1) 
 
 
The surgical corridor should not be included in the delineation of the GTV unless suspected to 
contain tumor. 
 
In cases where there is discrepancy between imaging studies or intra-operative findings, the larger 
volume will define GTV1. 
 
 
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14.4.2 Gross Tumor Volume 2 (GTV2) 
There are several options to define GTV2. GTV2 may be determined based on extent of resection prior to 
radiation therapy, residual enhancing or non-enhancing residual tumor by T1-weighted MRI or may be 
the same as GTV1 when the resultant PTV2 is considered by the treating radiation oncologist to be 
tolerable for treatment to 5940cGy.  
 
GTV2 Option 1 
GTV2 = post-operative tumor bed after gross-total resection. 
 
GTV2 Option 2 
 
GTV2 = residual tumor as determined by pre- and post-contrast T1-weighted MRI. 
 
GTV2 Option 3 
 
GTV2 = GTV1 when the resultant PTV2 is considered relatively small and the treating radiation 
oncologist determines that the patient will tolerate 5940cGy to this volume. 
 
14.4.3 Clinical Target Volume 1 (CTV1) 
 
CTV1 is defined as the volume of tissue containing subclinical microscopic disease. 
 
CTV1 for this protocol is the GTV1 with an anatomically confined margin of 2cm. 
 
CTV1 should be tailored at tissue interfaces where invasion/infiltration is not likely. 
 
The CTV may be manually moved inward to the inner table of the bony calvarium. 
 
14.4.4 Clinical Target Volume 2 (CTV2) 
 
The CTV2 margin should be an expansion of the GTV2 to encompass microscopic disease. 
 
The CTV2 for this protocol is the GTV2 with an anatomically confined margin of 1 cm. 
 
The CTV2 should be tailored at tissue interfaces where invasion/infiltration is not likely. 
 
The CTV may be manually moved inward to the inner table of the bony calvarium. 
 
 
14.4.5 Planning Target Volume 1 (PTV1) 
 
The PTV includes the CTV with an added margin that is intended to account for patient movement and 
set-up variability.  The treating radiation oncologist will select a margin between 3 and 5mm that reflects 
the appropriate set-up uncertainty and internal margin for the individual patient and treatment facility. 
 
The PTV-1 will include the CTV-1 plus a 3-5 mm margin in all dimensions.  The PTV may extend 
beyond bone margins, and may extend beyond the skin surface. 
 
The PTV-2 will include the CTV-2 plus a 3-5 mm margin in all dimensions.  The PTV may extend 
beyond bone margins, and may extend beyond the skin surface.   
 
Motion Management and Margins to Account for Target Volume and Organ Motion 
Considering motion of normal tissues and target volumes is important. The internal target volume (ITV) 
is defined as the CTV surrounded by the IM component of the PTV and is meant to account for potential 
motion of the CTV. The planning organ at risk volume (PRV) includes the corresponding organ at risk 
(OAR) volume surrounded by a margin to compensate for motion or physiologic change in the tissue 
volume. If adequate clinical data do not exist to define the IM component of the PTV or the PRV margin, 
the following suggestions are provided: 
 
 
A margin matching the PTV margin may be added to any OAR to form the PRV. 
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clinical target volumes occupying significant proportions of whole brain volume, opposed lateral beam 
approaches may be offered when more complex approaches and beam arrangements demonstrate limited 
benefit. 
 
Patient Position: Reproducible setups are critical and the use of immobilization devices is strongly 
encouraged. Use of anesthesia is permitted if necessary for proper positioning. 
Field Shaping: Field shaping shall be done with either customized cerrobend blocking or multileaf 
collimation. 
 
14.7 
Organs at Risk 
The organs at risk (OAR) guidelines in this section are recommendations. If the recommended doses to a 
particular OAR are exceeded because of target volume coverage requirements or other conditions, an 
explanation should be included in the quality assurance documentation. In some cases, IMRT may be 
preferred to meet these recommendations and the required target volume coverage guidelines. 
 
14.7.1 Cochleae 
 
D50% <  3500cGy – Goal (single cochlea) 
 
Comment – There is no dose limit for the cochleae. 
 
Structure definition - Each cochlea will be contoured on the treatment planning CT as a circular 
structure within the petrous portion of the temporal bone.  The contour should appear on at least 
two successive CT images. 
 
14.7.2 Optic Globes 
 
D50% < 1000cGy and D10% < 3500cGy – Goal 
 
D50% < 2000cGy and D10% < 5400cGy – Maximum 
 
Comment – Effort should be made to avoid direct treatment of the anterior chamber of the eye 
and minimize dose to the entire eye without compromising target volume coverage during 
treatment of PTV1. In the event that the recommended constraints provided in this section would 
be exceeded as a result of treatment of PTV2, the treating radiation oncologist may use their 
discretion to reduce target volume coverage. 
 
Structure definition - Each eye should be separately contoured on the treatment planning CT or 
MR as a circular structure from the most superior to inferior aspect. 
 
14.7.3 Optic Nerves and Chiasm 
 
D50% < 5400cGy and D10% < 5600cGy – Goal 
 
D50% < 5600cGy and D10% < 5800cGy – Maximum 
 
Comment – Effort should be made to avoid direct treatment of the optic nerves and chiasm 
without compromising target volume coverage during treatment of PTV1. In the event that the 
recommended constraints provided in this section would be exceeded as a result of treatment of 
PTV2, the treating radiation oncologist may use their discretion to reduce target volume 
coverage. 
 
Structure definition – The optic nerve may be contoured on CT or MR.  The contour should 
appear on at least two successive CT or MR images. 
 
14.7.4 Spinal Cord147  
 
D50% < 2600cGy and D10% < 5700cGy - Goal 
 
D50% < 5000cGy and D10% < 5900cGy – Maximum 
 
Comment – Effort should be made to minimize dose to the spinal cord without compromising 
target volume coverage during treatment of PTV1. If any portion of the spinal cord receives the 
prescription dose during the treatment of PTV1, it is preferable to allow that portion of the spinal 
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cord to receive 5400cGy during the first 30 fractions of treatment. During treatment of PTV2; 
however, the entire spinal cord volume should receive no more than 70% or 126cGy per fraction 
during each of the last three treatments to achieve the recommended constraints provided in this 
section. 
 
Structure Definition - For the purposes of this study, the upper aspect of the spinal cord begins at 
the inferior border of the foramen magnum and should be contoured on the treatment planning 
CT. For purposes of comparison and consistency with dose volume data, the spinal cord should 
be contoured on a number of images to be determined by the image section thickness (CT section 
thickness, n=number of images; 2mm, n=30; 2.5 mm, n=24; 3 mm, n=20). 
 
14.7.5 Brainstem148 
 
D50% < 6100cGy and D10% < 6300cGy - Goal 
 
D50% < 6200cGy and D10% < 6400cGy – Maximum 
 
Comment – Effort should be made to minimize dose to the brainstem without compromising 
target volume coverage during treatment of PTV1. In the event that the recommended constraints 
provided in this section would be exceeded as a result of treatment of PTV2, the treating radiation 
oncologist may use their discretion to reduce target volume coverage. 
 
Structure Definition - The brainstem may be contoured on the treatment planning CT or MR and 
will include the midbrain, pons and medulla. The cranial extent will be inferior to the IIIrd 
ventricle and optic tracts. The caudal extent will end at the foramen Magnum. 
 
14.8 
Dose Calculations and Reporting 
 
Prescribed Dose  
The dose prescription and fractionation hsall be reported on the RT-1/IMRT Dosimetry Summary Form. 
If IMRT is used, the monitor units generated by the IMRT planning system must be independently 
checked prior to the first treatment.  Measurements in a QA phantom can suffice for a check as long as 
the patient’s plan can be directly applied to a phantom geometry. The total dose delivered shall be 
reported on the RT-2 Radiotherapy Total Dose Record.  
 
 
Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are directly included in a 
radiation field. The total dose shall be calculated and reported on the RT-2 Radiotherapy Total Dose 
Record form.  The appropriate dose-volume histograms should be submitted.  If IMRT is used, a DVH 
must be submitted for a category of tissue called “unspecified tissue,” which is defined as tissue 
contained within the skin, but which is not otherwise identified by containment within any other structure. 
In addition, a DVH for “Body” shall be submitted in all cases to enable calculation of the required 
volumes in Table 14.8b. 
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14.9 
Quality Assurance Documentation 
 
On-treatment review is NOT required for this study. Within one week of the completion of radiation 
therapy, detailed treatment data shall be submitted. 
 
Digital Submission: 
 
Submission of treatment plans in digital format (either DICOM RT or RTOG format) is required. 
 
Digital data must include CT scans, structures, plan, and dose files. Submission may be by either  
 
sFTP or CD. Instructions for data submission are on the QARC web site at www.qarc.org under 
 
"Digital Data."  Any items on the list below that are not part of the digital submission may be 
 
included with the transmission of the digital RT data via sFTP or submitted separately.  Screen 
 
captures are preferred to hard copy for items that are not part of the digital plan. 
 
Treatment Planning System Output: 
 
Digitally reconstructed radiographs (DRR) or simulator films for each treatment field. .  
Please include two sets, one with and one without overlays of the target volumes and 
organs at risk. When using IMRT, orthogonal setup images are sufficient. 
 
RT treatment plan including CT, structures, dose, and plan files.  These items are included 
in the digital plan. 
 
Dose volume histograms (DVH) for the composite treatment plan for all target volumes and 
required organs at risk. This shall include GTV1, CTV1, PTV1, and GTV2, CTV2 and 
PTV2, when indicated. A DVH shall be submitted for the organs at risk specified in section 
14.8.  When using IMRT, a DVH shall be submitted for a category of tissue called 
“unspecified tissue.” This is defined as tissue contained within the skin, but which is not 
otherwise identified by containment within any other structure. DVH's are included in the 
digital plan. 
 
Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics. 
 
Supportive Data: 
 
 
All diagnostic imaging, corresponding radiology reports, and operative report used to plan 
the target volume. This includes CT and MRI scans PRIOR to attempted surgical resection 
of the primary tumor. Digital format is preferred. 
 
Radiotherapy record (treatment chart) including prescription and daily and cumulative 
doses to all required areas and organs at risk. 
 
Documentation of an independent check of the calculated dose when IMRT is used. 
 
If the recommended doses to the organs at risk are exceeded, an explanation should be 
included for review by the QARC and the radiation oncology reviewers. 
 
If emergency RT is administered, documentation should be provided in the form of the RT-
2 Total Dose Record Form and the radiotherapy record (treatment chart). 
 
Forms: 
 
RT-1/IMRT Dosimetry Summary Form. 
 
The RT-2 Radiotherapy Total Dose Record Form. 
 
 
 
 
 
 
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These data should be forwarded to: 
Quality Assurance Review Center 
640 George Washington Highway, Suite 201 
 Lincoln, RI  02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
Quality Assurance Review Center 
640 George Washington Highway, Suite 201 
 Lincoln, RI  02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
14.10 Definitions of Deviations in Protocol Performance 
 
DEVIATION 
 
Minor 
Major 
Prescription Dose 
 
Difference in prescribed or computed 
dose is 6-10% of protocol specified dose 
Difference in prescribed or computed dose 
is > 10% of protocol specified dose 
Dose Uniformity 
 
>10% PTV received > 110% 
of the protocol dose 
or 
95% isodose covers < 100% of CTV 
90% isodose covers < 100% of CTV 
Volume 
 
CTV or PTV margins are less than the 
protocol specified margins in the 
absence of anatomic barriers to tumor 
invasion (CTV) or without written 
justification (PTV) 
GTV does not encompass MR-visible 
residual tumor 
Organs at Risk 
 
Will be assessed at time of data review 
Will be assessed at time of data review 
 
 
15.0 
NEUROPATHOLOGY GUIDELINES AND CENTRAL PATHOLOGY REVIEW 
SPECIMEN REQUIREMENTS 
 
15.1 
Central Review  
A retrospective central pathology review will be performed for all patients. The review outcome will not 
alter the patient’s status on the study. The aim of the central pathology review is to provide confirmation 
of the diagnosis and to ensure accuracy and fidelity of the data. The classification and grading of the 
tumors will be performed according to the WHO criteria. The submission of pathology material shall be 
made directly from the participating institutions. The review pathologist may utilize unstained sections for 
a variety of supplemental tests. The remaining slides shall be kept as back-up material, or shall be used to 
perform additional staining as needed. 
 
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15.2 
Specimen Handling 
Optimal and standardized evaluation of each case necessitates handling according to the below guidelines, as 
possible: 
 
The treating institution should perform a panel of immunohistochemical (IHC) stains on the best /most 
representative block to aid in diagnostic work up. It is highly recommended that this panel include: GFAP 
(also S100, if GFAP-is weak, focal or negative appearing) Synaptophysin, Neurofilament protein, EMA, 
MIB-1 (Ki-67) and p53: Ideally, these institutional IHC stained slides could/ should be made available for 
central review. In the event all IHC stains are negative or IHC stain results are equivocal, electron 
microscopy, performed by the institution, may be of benefit if a sample was fixed for this at the time of 
surgery. A copy of any electron microscopy report should be included with the institution's pathology report 
sent for central review, as described in 15.3. Ideally, the institutional IHC stained slides could/should be made 
available for central review and would be returned upon completion of review. 
 
Solid tumor cytogenetic study results (i.e. karyotyping) may also be of benefit, if sufficient sample is 
available, to be performed by the referring institution; if a report of these results is available, it should 
also be included with the institution's pathology report sent for central review. All tissue received by 
institutional pathology and not utilized for recommended special studies, should be prepared for light 
microscopy sections. 
 
15.3 
Required Pathology Review Material 
The following specimens must be received prior to the start of maintenance.   
 
Representative paraffin-embedded tissue blocks from each representative lesion.  Blocks 
will be retained at the Biopathology Center unless return is requested by the institution.  If 
blocks are unavailable, then from each representative block the following are REQUIRED: 
-Two H & E stained sections 
-Four unstained sections prepared for immunohistochemistry.    
 
Institutional neuropathologist's report. (Also include any outside consultant's report.) 
 
Operative Report(s) 
 
Institutional Neuropathology Worksheet 
- 
Any history of pre-operative (pre-biopsy or pre-resection) medical therapy (i.e. 
corticosteroids, radiation or other) should be noted; some may impact and alter 
histopathology 
- 
Cytogenetics report, if done 
- 
Any CSF cytology reports, if applicable  
- 
Electron Microscopy Report, if done 
 
ACNS0822 Specimen Transmittal Form to accompany each shipment.   
 
15.4 
Specimen Shipping 
All pathology review materials must be labeled with the patient's COG Patient ID Number and the 
Surgical Path ID (SPID Number) from the corresponding pathology report. Cases for Standard Central 
Review are shipped by regular mail or using your institution’s courier prior to the start of Maintenance: 
 
COG Biopathology Center 
Nationwide Children's Hospital 
700 Children's Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2894 
Fax: (614) 722-2865 
*Be sure to include the room number. Packages received without the room number may be returned to the 
sender. 
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16.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS   
 
Participation in optional biology studies is strongly encouraged. In addition, institutions are 
strongly encouraged to enroll and submit specimens for ACNS02B3. If enough material is available 
to meet the biology requirements of this protocol and still have enough material left to meet 
minimal banking requirement for ACNS02B3, then the institution could receive credit for both this 
therapeutic trial and ACNS02B3.  
 
All specimens will be banked and processed at the COG Biopathology Center (BPC) and 
distributed from there as well. 
 
16.1 
Overview of Biology Specimen Requirements  
 
 
Study 
 
Blood (all blood to be sent to BPC) 
 
Tumor tissue (all tumor to be sent to BPC) 
Telomerase 
activity, hTert 
and hTR 
expression, and 
telomere length 
Send blood only if frozen tumor tissue sent: 
4 ml in purple top (EDTA) tube prior to start of 
protocol therapy 
 
 
Snap frozen 
Gene expression 
and miRNA 
profiling 
n/a 
Snap frozen 
Genome 
Allelotype and 
SNP Analyses 
Send blood only if tumor tissue sent: 
5 ml in a green top tube (sodium heparin) and 5 
mL in a purple top tube (EDTA) prior to start of 
protocol therapy 
 
 
Snap frozen; or 
 If frozen tumor not available but block sent for pathology, no 
extra samples need be sent.  
 
If frozen tumor or block not sent for pathology, send 1) 
formalin-fixed block or 3-10 50 µm scrolls and 10 unstained 
slides and 2) ten 20 µm paraffin sections mounted on plain 
slides (not PLUS) unbaked AND ten 4 µm paraffin sections 
mounted on PLUS slides 
MGMT and 
other markers 
5 ml in purple top (EDTA) tube prior to start of 
protocol therapy 
 
 
Tissue blocks (if sent for pathology); otherwise: 
-Ten 4 micron sections (unstained slides) from a representative 
block  
-Three 20-micron scrolls in a sterile  microfuge (Eppendorf  type) 
tube from a formalin-fixed, paraffin-embedded tumor sample. 
TOTAL of 
SPECIMENS 
4 mL purple top (not sent if no tumor sent) 
5 mL purple top (not sent if no tumor sent) 
5 mL green top (not sent if no tumor sent) 
5 mL purple top 
 
Snap frozen (as much as possible) 
Block 
If no block, then: 
a) 
3-10 50 µm scrolls and 10 unstained slides;  
b) 
Ten 20 µm paraffin sections mounted on plain 
slides (not PLUS) unbaked AND 
ten 4 µm paraffin sections mounted on PLUS 
slides; 
c) 
Ten unstained slides and three 20-micron scrolls 
 
 
 
16.2 
Snap Frozen Tumor Specimens  
Process tumor specimens from first and any subsequent surgery according to the guidelines below. Send 
snap frozen tumor specimens to the Biopathology Center (BPC) in Columbus, Ohio. Portions of the tissue 
will be used for the correlative biology studies according to the priority list of biology studies in Section 
16.2.2. 
 
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As many 100 mg pieces of tissue as possible should be frozen in foil in liquid nitrogen within 10 minutes 
after tumor removal. Frozen tissue should be sent on dry ice to the BPC. A minimum tumor tissue of 
> 0.5 cm3 is preferred.  
 
Note:  It is recommended that the pathologist bring a liquid N2 container up to the frozen section room, so 
that if adequate tissue is available at the time of frozen section, some is immediately snap frozen at that 
time for possible COG studies and/ or tumor banking. The neurosurgeon(s) OR personnel, and Pathology 
lab personnel may well need to be informed/ educated regarding the importance of rapid receipt and snap 
freezing of tumor once removed from the patient. If there is insufficient tumor received for rapid 
processing/ snap freezing during frozen section evaluation, as described above, then any subsequent parts 
of tumor removed for this purpose should still be snap frozen within 20 minutes of removal/ resection 
from the patient.  
 
Frozen tumor specimens should only be dispatched on Monday through Thursday for delivery Tuesday 
through Friday to the BPC (see Section 16.2.1 for shipping address).   
 
All tumor samples will be banked and processed by the COG Biopathology Center (BPC) and 
distributed from there. 
 
16.2.1 Specimen Shipment 
When frozen and room temperature specimens are shipped together, they can be shipped to the BPC in a 
Specimen Procurement Kit. This dual chambered kit allows for the shipment of either cold or room 
temperature specimens AND frozen specimens in the same container. Dry ice may be placed in either 
compartment of the kit, but should not be put in both. This kit contains most of the supplies necessary for 
shipping specimens to the BPC.  The Specimen Procurement Kit should only be used when frozen tissue 
is included in the shipment. Blood with a cold pack will need to be submitted separately in your own 
packaging. To request a Specimen Procurement Kit, click on the ‘Biopathology Center Application’ link 
on either the Protocol or the CRA Home Page of the COG web site. On the Biopathology Center 
Applications page, select the BPC Kit Management link to enter the Kit Management application. For 
packing and shipping instructions please see Shipping Specimens in a Dual Chambered Kit at 
https://members.childrensoncologygroup.org/prot/biology.asp. Ship to: 
 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
 
*Be sure to include the room number. Packages received without the room number may be returned to the 
sender. 
 
16.2.2 Priority List of Biology Studies  
In the event of limited snap frozen tumor sample availability, sample studies will be prioritized as 
follows:   
1) Assessment of telomerase activity, hTert and hTR expression, and telomere length analyses 
2) Gene expression profiling and miRNA analyses 
3) Genome Allelotype and SNP Array analyses 
 
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16.3 
Telomerase activity, hTert expression, and telomere length studies  
Tumor tissue and peripheral blood will be obtained from all consenting patients, and will be analyzed for 
telomerase activity, hTert and hTR expression, and telomere length. The blood sample should only be sent 
if frozen tumor tissue was sent. 
 
Snap Frozen Tumor Tissue: Snap frozen tissue will be distributed by the BPC, according to the priority 
list of biology studies (see Section 16.2.2). A minimum of 100 mg tumor tissue is preferred. 
 
Peripheral Blood: Four (4) mL of peripheral blood will be collected in a purple top tube (EDTA) prior to 
the start of protocol therapy. 
 
Label the specimens with the patient’s BPC number, the specimen type and collection date. The blood 
specimen must be sent the same day it was drawn with a completed ACNS0822 Specimen Transmittal 
Form. Blood may be shipped Monday through Friday for delivery Tuesday through Saturday.  Frozen 
tumor tissue must be shipped Monday through Thursday for delivery Tuesday through Friday. Ship 
specimens to the BPC at the address listed in 16.2.1. 
 
16.4 
Gene expression and miRNA profiling 
Tumor tissue from all consenting patients will be analyzed for gene expression and miRNA profiling. 
 
Snap Frozen Tumor Tissue: Snap frozen tissue will be distributed by the BPC, according to the 
priority list of biology studies (see Section 16.2.2). A minimum of 100 mg tumor tissue is preferred. 
 
16.5 
Genome Allelotype and SNP Array Analyses 
Frozen tumor tissue, paraffin embedded and peripheral mononuclear cells (PBMCs) will be obtained from 
all consenting patients prior to starting treatment for studies of angiogenic gene expression. The blood 
sample should only be sent if tumor tissue was sent. 
 
 
Snap Frozen Tumor Tissue: Frozen tumor tissue will be distributed by the BPC, according to 
priority list of biology studies (see Section 16.2.2). A minimum tumor tissue > 0.5 cm3 is 
preferred. Paraffin-embedded material should be submitted in addition to the frozen tissue 
sample. 
 
-If frozen tumor was not sent to the BPC but formalin-fixed blocks were sent, then the 
materials will be processed from the blocks by the BPC and the institution does not need to 
send slides, scrolls, or micron sections. 
-If neither frozen tumor nor blocks were sent to the BPC, formalin-fixed block with 
> 80% tumor should be sent although this will compromise the studies being performed. 
(Paraffin blocks will be returned upon request only.) 
-If neither frozen tumor nor blocks were sent to the BPC and the institution cannot 
release blocks, three to ten 50 µm scrolls should be sent and 10 unstained slides (Please 
indicate percent tumor represented.) 
 
Paraffin Sections: These sections will be prepared by the BPC if blocks were sent to the 
BPC. 
Ten 20 µm paraffin sections mounted on plain slides (not PLUS) unbaked should be submitted 
for laser capture microdissection and ten 4 µm paraffin sections mounted on PLUS slides should 
be submitted for possible FISH confirmation of gene copy number changes. These sections will 
be prepared by the BPC if blocks were sent to the BPC. 
 
Peripheral Blood: 5 mL of peripheral blood in a green top tube (sodium heparin) and 5 mL of 
blood in a purple top tube (EDTA) will be collected any time before the initiation of therapy. Do 
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not send if the patient has had a whole blood transfusion. Do not send if a tumor specimen is not 
sent. If tumor is submitted, it is strongly encouraged that the peripheral blood be sent as well.  
 
Label all specimens and the accompanying paperwork with the patient’s BPC number, the collection date and 
specimen type. An ACNS0822 Specimen Transmittal Form must accompany each shipment. Blood 
samples should be stored and shipped AT ROOM TEMPERATURE. Ship specimens to the BPC via 
Federal Express, Priority Overnight to the address listed in Section 16.2.1. Blood may be shipped Monday 
through Friday for delivery Tuesday through Saturday.   All other specimens must be shipped Monday 
through Thursday for delivery Tuesday through Friday.  
 
16.6 
MGMT status and immmunohistochemical marker studies 
Tumor tissue and peripheral blood will be obtained prior to starting treatment from consenting patients 
enrolled on this study to evaluate a series of immunohistochemical markers associated with outcome in 
previous pediatric high-grade glioma studies. 
 
 
 
Tumor Tissue:  
 
If tissue blocks were sent to the Biopathology Center for Pathology Review, then the materials 
will be processed from the blocks by the BPC and the institution does not need to send slides or 
micron sections. 
 
If tissue blocks were not sent for Pathology Review then the following materials for the MGMT 
biology study must be received: 
 
Ten unstained slides from a representative block  
 
Three 20-micron sections from a formalin-fixed, paraffin-embedded tumor sample.  
These three sections should be in a sterile microfuge (Eppendorf type) tube. 
Peripheral Blood: 5 mL of blood will be collected into a purple top tube (EDTA) prior to the 
start of protocol therapy. 
 
Label all specimens with the patient’s BPC number, specimen type and collection date.  A completed 
ACNS0822 Specimen Transmittal Form must accompany each shipment. Ship slides and sections in 
padded envelopes via Federal Express Priority Overnight.  Ship blood via Federal Express Priority Overnight 
at ROOM TEMPERATURE any time before the initiation of therapy.   Ship all specimens to the BPC using 
the address listed in Section 16.2.1.  Blood may be shipped Monday through Friday for delivery Tuesday 
through Saturday.   All other specimens must be shipped Monday through Thursday for delivery Tuesday 
through Friday.  
 
16.7 
Description of Biology Studies 
 
16.7.1 Assessment of telomerase activity, hTert and hTR expression, and telomere length  
Tumor tissue will be obtained from all consenting patients enrolled on all treatment arms of this study 
prior to starting treatment. Tumor samples will be analyzed for TERT and hTR subunits expression using 
quantitative real time PCR. Telomerase enzyme activity will be assessed using the TRAP assay. Telomere 
length will be assessed by Southern blot and/or flow cytometry.   
 
16.7.2 Gene expression profiling and SNP Arrays 
 
SNP Array Analysis 
With the availability of normal blood DNA as a reference, LOH in the corresponding tumor sample can 
be measured very precisely at a single SNP locus. One of the advantages of using SNP array for whole 
genome scanning is that it not only provides locus-specific genotypes but also accurately quantify the 
copy number of each allele. Genomic DNA will be obtained from fresh tumor tissue biopsies frozen in 
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liquid nitrogen and stored at -80oC using TRIzol Reagent (Life Technologies, GibcoBRL) according to 
the manufacturer’s recommendations. Where frozen tissue is not available, DNA extraction will be 
obtained from formalin-fixed, paraffin-embedded tissue scrolls. For normal DNA, genomic DNA will 
extracted from matched peripheral blood leukocytes using Wizard Genomic DNA Purification Kit 
(Promega) according to the manufacturer’s recommendations. Isolated DNA is then loaded on Affymetrix 
arrays and scanned as per the manufacturer’s protocol. All data analysis will be carried out using 
Affymetrix software.  
 
Expression Array Analysis 
Total RNA will be isolated from fresh frozen tumor tissue using TRIzol Reagent (Life Technologies). 
RNA integrity will be confirmed with the Agilent 2100 Bioanalyzer (Agilent Technologies). We will use 
HG_U133plus2 or Genechip® Human Gene 1.0 ST array (Affymetrix, Santa Clara, CA) for expression 
analysis. Preparation of cRNA, hybridization, scanning, and image analysis of the arrays will be 
performed according to manufacturer’s protocols. Briefly, five g of total RNA will be used to generate 
cRNA probes and combined with a mixture of control cRNAs (made from bacterial genes BioB, BioC, 
BioDN and CreX) before hybridization. The U133plus2 arrays consist of more than 47,000 gene probe 
sets, each representing a transcript. Each probe set consists of 16 perfectly complementary 25 base long 
probes (PMs) as well as 16 mismatch probes (MMs) that are identical except for an altered central base. 
All GeneChip images will be visually inspected for irregularities and analyzed by dChip or GCOS 
software. 
 
MicroRNA analysis 
Total RNA from expression array analysis (see above) will also be used for this study. The presence of an 
intact miRNA population will be confirmed with the Bioanalyzer (Agilent Technologies). After labeling, 
samples will be hybridized to the Human miRNA Microarray v3 (Agilent Technologies, Santa Clara, CA) 
or superior version depending on what is available at the time of sample processing. The v3 chip contains 
probes for 866 human miRNAs and 89 human viral miRNAs identified from the Sanger database v12.0.  
 
16.7.3 Exploration of the prognostic significance of MGMT and other markers of potential treatment 
resistance   
Tumor tissue will be obtained prior to starting treatment from consenting patients enrolled on this study to 
evaluate a series of immunohistochemical markers associated with outcome in previous pediatric high-
grade glioma studies. Particular emphasis will be placed on examining MGMT expression, which has 
been associated with response to alkylator-based therapy in the CCG-945 and ACNS0126 cohort.  
Additional markers to be examined include p53, MIB1 (a marker of proliferation status), and pAkt and 
pMAPK, growth signaling intermediates that have been associated with an adverse prognosis in recent 
studies.103 Tumor samples (unstained slides) will be analyzed using immunoperoxidase labeling 
techniques, as previously applied in ACNS0126 and ACNS0423. In addition to assessment of MGMT 
expression using immunohistochemical methods, tumors will be identified in which MGMT expression is 
silenced by determining promoter CpG methylation in DNA isolated from formalin-fixed, paraffin-
embedded tumor samples. 
 
16.8 
Optional Imaging Studies (MR Perfusion and MR Diffusion Tensor Imaging)  
 
Optional imaging studies will be performed only in patients with evidence of residual tumor on the 
MRI performed to determine extent of resection prior to start of therapy. 
 
For subjects who provide consent, MR perfusion and diffusion studies will be obtained at the following 
timepoints: 
1) 
Prior to the start of protocol therapy 
2) 
Prior to the start of maintenance therapy 
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3) 
Prior to cycle 3 of maintenance therapy  
4) 
Subsequent to completion of maintenance therapy 
 
16.8.1 Perfusion Studies:  
The EPI-GRE imaging sets will be analyzed at the centralized reading location with an automated method 
which uses the global arterial input function with deconvolution techniques to yield parametric maps of 
cerebral blood volume (CBV), flow (CBF) and mean transit times (MTT) or equivalent measures using 
standard clinical software and in-house software for perfusion analysis. ROI assessment of regions of 
highest tumoral CBV compared with contralateral hemispheric white matter will be used to establish 
rCBV ratios for baseline and follow-up purposes. 
 
Perfusion: 
 
GRE- EPI Perfusion sequence.  EPI GRE sequence, FA: 35 degrees, 128 x 128 matrix, FOV = 26, 
TR: 1500 ms or less, TE: minimum. ASSET (SENSE) use if possible. Contrast injection optimally by 
power injector (1-3ml/sec) or by hand injection if not possible.  Slice number as allowable by scanner 
to at least cover the tumor.  At least 50 phases are acquired. 
 
16.8.2 Diffusion Studies: 
Diffusion weighted imaging will be performed using diffusion tensor imaging. This will allow for 
quantitative analysis of tumor diffusion in areas in close proximity to normal looking brain in order to 
better estimate tumor invasiveness into adjacent white matter as well as to assess diffusion characteristics 
of tumor tissue before and during treatment. Standard maps produced are Mean diffusivity, Fractional 
anisotropy, and Trace diffusion. Imaging processing will be performed at the centralized reading location 
using standard clinical software and in-house software for diffusion analysis. Region-of-interest analysis 
of tumor and peritumoral regions will be performed. Primary assessment will be by ROI analysis of 
diffusivity within the solid components of the tumor. 
 
Diffusion Tensor Imaging: 
 
 
DTI Imaging sequence:  12 – 25 direction (depending upon scanner) 3mm slice thickness, 
 
gap:0, b=1000, 128 x 128 matrix, FOV 38.4 cm. (isotropic dataset), ASSET (SENSE) use 
 
if possible. 
 
The optional perfusion and diffusion MR imaging will be reviewed by the study neuroradiologist, Dr. 
James Leach. 
 
Address Information 
Copies of scans and the corresponding radiology reports of the optional studies for central review should 
be forwarded to: 
Quality Assurance Review Center 
640 George Washington Highway, Suite 201 
  
Lincoln, RI  02865-4207 
 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
 
Submission of Diagnostic Imaging data in digital format is required.  Digital files must be in Dicom format.  
These files can be burned to a CD and mailed to QARC.  Multiple studies for the same patient may be 
submitted on one CD; however, please submit only one patient per CD.  Electronic submission of the scans is 
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acceptable via Dicommunicator.  Contact QARC at Dicommunicator@QARC.org for further information.  
Alternative electronic methods, e.g., sFTP are possible.  Contact QARC for more information. 
 
 
17.0 
NEUROIMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
 
 
 
17.1 
Timing of MRIs 
To document the degree of residual tumor, standard whole brain MRI with and without contrast (gadolinium) 
and spine MRI with and without contrast (gadolinium) must be performed at the following time points: 
 
within 4 weeks preceding enrollment into the study 
 
prior to each odd numbered cycle of maintenance therapy 
 
when patient is removed from protocol therapy (upon completion of therapy or at progression) 
 
17.2 
Whole Brain MRI With and Without Contrast  
Preoperative brain MRI with and without contrast (gadolinium) is required. To document the degree of 
residual tumor, postoperative brain MRI with and without contrast must be done. 
 
Postoperative brain MRI (with and without contrast) preferably within 48 hours of surgery is encouraged, 
but if unable to be done at that time (or postoperative changes obscure potential residual tumor) 
postoperative imaging should be done within 28 days of surgery.  
 
Required sequences: 
1. Sagittal T1 localizer; 4 mm skip 0.4 mm 
2. Axial FSE T2; 4 mm,  skip 0.4 mm  
3. Axial T2 FLAIR; 4 mm skip 0.4  
4. Axial diffusion; 4-5 mm skip 0 (single shot, matrix 128 x 128 or 128 x 192, B=1000) 
5. Axial T1; 4 mm skip 0.4 mm  
6. Axial gradient echo (susceptibility sequence); 4-5 mm skip 1-2 mm. TE=20, flip angle =20.   
7. Axial T1 with contrast; 4 mm skip 0.4 mm 
8. Sagittal T1 with contrast; 4 mm skip 0.4 mm 
9. Axial T2 FLAIR with contrast; 4 mm skip 0.4  
 
Optional sequences (depending on tumor) 
Precontrast : 
1. Sagittal or coronal FSET2; 4 mm skip 0.4 mm, depending on tumor configuration/orientation 
2. Axial diffusion tensor (see optional sequences, Section 16.8) 
 
Post contrast : 
1. Coronal T1 : 4mm skip 0.4 
2. T1-weighted gradient echo volume sequence (SPGR or equivalent) 
3. Axial Perfusion (see optional sequences, Section 16.8) 
 
NOTES:  
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care.  
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 
(except where explicitly prohibited within the protocol).  
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1. DO NOT INTERLEAVE T1 weighted sequences 
2. Flow compensation should not be used / not on all T1 enhanced sequences 
3. Fat Saturation not necessary 
 
For patients who have provided consent, see details for optional perfusion and diffusion imaging in Section 
16.8. 
 
17.3 
Spinal MRI With and Without Contrast 
 
The MRI scan must be performed of the entire spine with and without contrast, and must be performed in 
at least two planes. Exception: The spine imaging can be performed with contrast only, if it immediately 
follows the enhanced brain MRI. If there is significant motion artifact and/or hemorrhage, then the scan is 
not evaluable and must be repeated or the patient is not eligible for study.   
 
1. Whole spine sagittal T1; 3 mm skip 0 – 0.3 mm.  
Technical notes: 
- 
Phase direction AP, frequency direction SI 
- 
Acquire 2 separate acquisitions (one cervical and upper thoracic, the second lower thoracic and 
lumbosacral) to optimize placement of presaturation pulse.  
- 
Place anterior saturation pulse close to the anterior margin of the spinal column - to minimize 
motion artifacts from chest/abdomen. 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
- 
Keep TE to minimum (<15 msecs) 
- 
Do not use fat saturation 
2. Axial T1 images through the entire spine; 4-5 mm thick, skip 1-2mm.  
Technical notes: 
- 
Phase direction RL, frequency direction AP 
- 
Keep TE to minimum (< 15 msecs) 
- 
DO NOT INTERLEAVE 
 
For primary tumors of the spinal cord, add: 
1. Whole spine sagittal T2; 3 mm skip 0mm.  
Technical notes: 
- 
Can keep Phase direction AP, frequency direction SI, with anterior saturation pulses; or switch 
phase direction SI, frequency direction AP, with inferior and superior saturation pulses if that 
produces better images (less CSF pulsation artefacts) 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
2. Axial FSE T2, 4-5mm skip 0-1 mm, through tumor 
 
NOTE: 
In the routine evaluation for subarachnoid metastatic dissemination from brain tumors to the spine: 
1. High quality T1 images are essential - without artefacts from physiologic motion (cardiac, 
respiratory) or from CSF pulsation.  
2. T2 weighted sequences (sagittal or axial) are not needed. They are optional.  
 
17.4 
Tumor Response Assessment 
For the response assessment, MRI scans obtained prior to each odd numbered maintenance cycle will be 
compared to the baseline MRI scan.  Exception: In cases of progressive disease, the reference scan 
should be the MRI with the smallest product observed since the start of treatment (not necessarily at week 
8). 
 
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17.5 
Central Review for Phase II and III 
Central review will be performed for all patients with reported responses of CR or PR. Submit the following 
studies with their corresponding reports to the address below.  
 
If Brain Measurable Disease: 
 
Brain MRI with and without contrast performed within 4 weeks prior to enrollment 
 
Brain MRI with and without contrast to document best response (subsequent evaluations do not need 
to be submitted if no change from earliest best response). 
 
If Spine Measurable Disease: 
 
Spine MRI with and without contrast performed within 4 weeks prior to enrollment 
 
Spine MRI with and without contrast to document best response (subsequent evaluations do not need 
to be submitted if no change from earliest best response). 
 
17.6 
Address Information 
Copies of scans of the required studies for central review should be forwarded to: 
 
Quality Assurance Review Center 
640 George Washington Highway, Suite 201 
  
Lincoln, RI  02865-4207 
 
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
 
 
 
Submission of Diagnostic Imaging data in digital format is required.  Digital files must be in Dicom format.  
These files can be burned to a CD and mailed to QARC.  Multiple studies for the same patient may be 
submitted on one CD; however, please submit only one patient per CD.  Electronic submission of the scans is 
acceptable via Dicommunicator.  Contact QARC at Dicommunicator@QARC.org for further information.  
Alternative electronic methods, e.g., sFTP are possible.  Contact QARC for more information. 
 
 
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Page 114 
 
APPENDIX I: 90th and 95th PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT IN 
GIRLS AGE 1-17 YEARS 
 
Age  
BP  
 
Systolic BP (mmHg) 
 
 
Diastolic BP (mmHg) 
(Year) 
Percentile 
 
Percentile of Height 
 
 
 
Percentile of Height 
 
 
 
5th 
10th 
25th
50th
75th
90th
95th
5th
10th
25th 
50th 
75th
90th
95th
1 
90th 
95th 
97  
100  
97  
101 
98 
102 
 100 
104 
101 
105 
102 
106 
103 
107  
52 
56 
53  
57  
53  
57  
54  
58  
55 
59 
55 
59 
56 
60 
2 
90th 
95th 
98  
102  
99 
103  
100 
104 
 101 
105 
103 
107 
104 
108 
105 
109 
 57 
61 
58  
62  
58  
62  
59 
63  
60 
64 
61 
65 
61 
65 
3 
90th 
95th 
 
100  
104  
100  
104  
102 
105 
103 
107 
104 
108 
106 
109 
106 
110 
 61 
65 
62  
66  
62  
66  
63  
67  
64 
68 
64 
68 
65 
69 
4 
90th 
95th 
101  
105  
102  
106  
103 
107 
104 
 108 
106 
 110 
107 
 111 
108 
 112 
64 
 68 
64 
68  
65 
69  
66  
70  
67 
71 
67 
71 
68 
72 
5 
90th 
95th 
103 
107  
    103  
107 
105 
 108 
 106 
 110 
107 
111 
109 
 112 
109 
 113 
66 
 70 
67 
 71 
67 
 71  
68  
 72  
69 
 73 
69 
73  
70 
74 
6 
90th 
95th 
104 
108  
105 
109 
106 
 110 
108 
 111 
109 
 113 
110 
114 
111 
 115 
68 
 72 
68  
 72  
69  
 73 
70  
 74 
70 
 74  
71 
75 
72 
76 
7 
90th 
95th 
106 
110  
 107  
111  
108 
112 
109 
 113 
111 
 115 
112 
 116 
113 
 116 
 69 
 73 
70  
74 
70  
 74  
71 
75  
72 
76  
72 
76  
73 
77 
8 
90th 
95th 
108 
112  
109  
112  
110 
 114 
111 
115 
113 
 116 
114 
 118 
114 
 118  
71 
75 
71  
75  
71  
 75   
72  
76  
73 
77 
74 
78 
74 
78 
9 
90th 
95th 
110 
114  
 110 
 114  
 112 
 115 
 113 
 117 
 114 
 118 
 116 
 119 
 116 
 120 
 72 
 76 
 72 
 76  
 72 
 76 
 73 
 77  
 74 
 78 
 75 
 79 
 75 
 79 
10 
90th 
95th 
112 
 116  
 112 
116  
114 
 117 
115 
 119 
116 
 120 
118 
 121 
 118 
 122 
 73 
 77 
 73 
 77 
 73 
 77  
 74 
 78 
 75 
 79 
 76 
 80 
 76 
 80  
11  
90th 
95th 
114  
118  
114 
118 
116 
119 
117 
121 
118 
122 
119 
123 
120 
124 
74 
 78  
74 
78  
74  
78  
75  
79  
76 
80 
77 
81  
77 
81 
12 
90th 
95th 
116  
119  
116  
120  
117 
121 
119 
123 
120 
124 
121 
125 
122 
126 
75 
79 
75  
79  
75  
79  
76  
80  
77 
81 
78 
 82 
78 
82 
13  
90th 
95th 
117  
121  
118 
122  
119 
123 
121 
124 
122 
126 
123 
127 
124 
128 
76 
80 
76  
80  
76  
80 
77 
81 
 78 
 82 
79 
83  
79 
83 
14  
90th 
95th 
119  
123 
120  
123 
121 
125 
122 
126 
124 
127 
125 
129 
125 
129 
77 
81 
77  
81 
77  
 81  
78 
82   
 79 
83  
80 
84  
80 
84 
15  
90th 
95th 
120  
124  
121 
125  
122 
126 
123 
127 
125 
129 
126 
130 
127 
131 
 78 
 82 
78  
 82  
78  
82  
 79  
83   
80 
84 
81 
 85 
81 
85 
16  
90th 
95th 
121 
125  
122  
126  
123 
127 
124 
128 
126 
130 
127 
131 
 128 
 132 
 78 
 82 
78  
 82  
79  
83  
 80  
 84  
81 
85 
81 
85 
82 
86 
17  
90th 
95th 
122 
125 
122  
126 
123 
127 
125 
129 
126 
130 
127 
131 
 128 
132 
 78 
82 
79 
 83  
  79  
 83  
80 
 84 
 81 
 85  
81 
85 
82 
86 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source:  Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents; NIH Publication No. 05-5267. 
Use of this document is governed by the terms of use on the first page of this document.

 
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Page 115 
 
APPENDIX II: 90th and 95th PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT 
IN BOYS AGE 1-17 YEARS 
Age  
BP  
 
Systolic BP (mmHg) 
 
 
Diastolic BP (mmHg) 
(Year) 
Percentile 
 
Percentile of Height 
 
 
 
Percentile of Height 
 
 
 
5th 
10th 
25th
50th
75th
90th
95th
5th
10th
25th 
50th 
75th
90th
95th
1 
90th 
95th 
94 
98 
95 
99 
97 
101 
99 
103 
100 
104 
102 
106 
103 
106 
49 
54 
50 
54 
51 
55 
52 
56 
53 
57 
53 
58 
54 
58 
2 
90th 
95th 
97 
101 
99 
102 
100 
104 
102 
106 
104 
108 
105 
109 
106 
110 
54 
59 
55 
59 
56 
60 
57 
61 
58 
62 
 58 
63 
59 
63 
3 
90th 
95th 
100 
104 
101 
105 
103 
107 
105 
109 
107 
110 
108 
112 
109 
113 
59 
63 
59 
63 
60 
64 
61 
65 
62 
66 
63 
67 
63 
67 
4 
90th 
95th 
102 
106 
103 
107 
105 
109 
107 
111 
109 
112 
110 
114 
111 
115 
62 
66 
63 
67 
64 
68 
65 
69 
66 
70 
66 
71 
67 
71 
5 
90th 
95th 
104 
108 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
112 
116 
65 
69 
66 
70 
67 
71 
68 
72 
69 
73 
69 
74 
70 
74 
6 
90th 
95th 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
113 
117 
113 
117 
68 
72 
68 
72 
69 
73 
70 
74 
 71 
75 
72 
76 
72 
76 
7 
90th 
95th 
106 
110 
107 
111 
109 
113 
111 
115 
113 
117 
114 
118 
115 
119 
70 
74 
70 
74 
71 
75 
72 
76 
73 
77 
74 
78 
74 
78 
8 
90th 
95th 
107 
111 
109 
112 
110 
114 
112 
116 
114 
118 
115 
119 
116 
120 
71 
75 
72 
76 
72 
77 
73 
78 
74 
79 
75 
79 
76 
80 
9 
90th 
95th 
109 
113 
110 
114 
112 
116 
114 
118 
115 
119 
117 
121 
118 
121 
72 
76 
73 
77 
74 
78 
75 
79 
76 
80 
76 
81 
77 
81 
10 
90th 
95th 
111 
115 
 112 
 116 
114 
117 
115 
119 
117 
121 
119 
122 
119 
123 
73 
77 
73 
78 
74 
79 
75 
80 
76 
81 
77 
81 
78 
82 
11 
90th 
95th 
113 
117 
114  
118 
115 
 119 
117 
121 
119 
123 
 120 
 124 
 121 
125 
74 
78 
74 
78 
75 
 79  
76  
 80  
77 
81  
78 
82 
78 
82 
12 
90th 
95th 
115 
119  
116  
120 
118 
 122 
120 
 123 
121 
125 
 123 
 127 
123 
 127 
74 
78 
75 
 79 
75  
80 
76 
 81 
77 
 82  
78 
82  
79 
83 
13 
90th 
95th 
117  
121 
118  
 122  
120 
124 
 122 
126 
124 
128 
125 
129 
126 
 130 
75 
79 
75 
79 
76 
80  
77 
81  
78 
82 
79 
83 
79 
83 
14 
90th 
95th 
120  
124 
121  
 125 
123 
 127 
125 
 128 
126 
 130 
128 
 132 
128 
 132 
75 
80 
76 
80   
 77 
81   
78  
82  
79 
83 
79 
84 
80 
84 
15 
90th 
95th 
122  
126  
124  
127  
125 
129 
127 
131 
129 
133 
130 
134 
131 
135 
76 
81  
77 
81   
78  
82  
79  
83  
80 
84  
80 
85 
81 
85 
16 
90th 
95th 
125  
129  
126  
130  
128 
132  
130 
134 
131 
135 
133 
137 
134 
137 
78 
82 
78 
 83 
79 
83  
80  
 84  
81 
85 
82 
86 
82 
87 
17 
90th 
95th 
127  
131  
 128  
132  
130 
134 
132 
136 
134 
 138 
135 
139 
  136 
140 
 80 
84 
  80 
85 
 81 
86   
82  
87 
83 
 87 
84 
88 
84 
89 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents; NIH Publication No. 05-5267. 
Use of this document is governed by the terms of use on the first page of this document.

Use of this document is governed by the terms of use on the first page of this document.

 
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APPENDIX IV:  TEMOZOLOMIDE DOSING DURING CHEMORADIOTHERAPY 
 
TEMOZOLOMIDE DOSING TABLE for STARTING DOSE - 90 mg/m2 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.48-0.52 
43-47 
45 
0.53-0.58 
48-52 
50 
0.59-0.63 
53-57 
55 
0.64-0.69 
58-62 
60 
0.70-0.75 
63-67 
65 
0.76-0.80 
68-72 
70 
0.81-0.86 
73-77 
75 
0.87-0.91 
78-82 
80 
0.92-0.97 
83-87 
85 
0.98-1.02 
88-92 
90 
1.03-1.08 
93-97 
95 
1.09-1.13 
98-102 
100 
1.14-1.19 
103-107 
105 
1.20-1.25 
108-112 
110 
1.26-1.30 
113-117 
115 
1.31-1.36 
118-122 
120 
1.37-1.41 
123-127 
125 
1.42-1.47 
128-132 
130 
1.48-1.52 
133-137 
135 
1.53-1.58 
138-142 
140 
1.59-1.63 
143-147 
145 
1.64-1.69 
148-152 
150 
1.70-1.75 
153-157 
155 
1.76-1.80 
158-162 
160 
1.81-1.86 
163-167 
165 
1.87-1.91 
168-172 
170 
1.92-1.97 
173-177 
175 
1.98-2.02 
178-182 
180 
2.03-2.08 
183-187 
185 
2.09-2.13 
188-192 
190 
2.14-2.19 
193-197 
195 
2.20-2.25 
198-202 
200 
2.26-2.30 
203-207 
205 
2.31-2.36 
208-212 
210 
2.37-2.40 
213-217 
215 
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TEMOZOLOMIDE DOSING TABLE for REDUCED DOSE= 60 mg/m2 
 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.46-0.54 
28-32 
30 
0.55-0.62 
33-37 
35 
0.63-0.70 
38-42 
40 
0.71-0.79 
43-47 
45 
0.80-0.87 
48-52 
50 
0.88-0.95 
53-57 
55 
0.96-1.04 
58-62 
60 
1.05-1.12 
63-67 
65 
1.13-1.20 
68-72 
70 
1.21-1.29 
73-77 
75 
1.30-1.37 
78-82 
80 
1.38-1.45 
83-87 
85 
1.46-1.54 
88-92 
90 
1.55-1.62 
93-97 
95 
1.63-1.70 
98-102 
100 
1.71-1.79 
103-107 
105 
1.80-1.87 
108-112 
110 
1.88-1.95 
113-117 
115 
1.96-2.04 
118-122 
120 
2.05-2.12 
123-127 
125 
2.13-2.20 
128-132 
130 
2.21-2.29 
133-137 
135 
2.30-2.37 
138-142 
140 
2.38-2.40 
143-147 
145 
 
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APPENDIX V:  TEMOZOLOMIDE DOSING DURING MAINTENANCE 
 
TEMOZOLOMIDE DOSING TABLE for MAINTENANCE STARTING DOSE= 200 mg/m2 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.49-0.51 
98-102 
100 
0.52-0.53 
104-106 
105 
0.54-0.56 
108-112 
110 
0.57-0.58 
114-116 
115 
0.59-0.61 
118-122 
120 
0.62-0.63 
124-126 
125 
0.64-0.66 
128-132 
130 
0.67-0.68 
134-136 
135 
0.69-0.71 
138-142 
140 
0.72-0.73 
144-146 
145 
0.74-0.76 
148-152 
150 
0.77-0.78 
154-156 
155 
0.79-0.81 
158-162 
160 
0.82-0.83 
164-166 
165 
0.84-0.86 
168-172 
170 
0.87-0.88 
174-176 
175 
0.89-0.91 
178-182 
180 
0.92-0.93 
184-186 
185 
0.94-0.96 
188-192 
190 
0.97-0.98 
194-196 
195 
0.99-1.01 
198-202 
200 
1.02-1.03 
204-206 
205 
1.04-1.06 
208-212 
210 
1.07-1.08 
214-216 
215 
1.09-1.11 
218-222 
220 
1.12-1.13 
224-226 
225 
1.14-1.16 
228-232 
230 
1.17-1.18 
234-236 
235 
1.19-1.21 
238-242 
240 
1.22-1.23 
244-246 
245 
1.24-1.26 
248-252 
250 
1.27-1.28 
254-256 
255 
1.29-1.31 
258-262 
260 
1.32-1.33 
264-266 
265 
1.34-1.36 
268-272 
270 
1.37-1.38 
274-276 
275 
1.39-1.41 
278-282 
280 
1.42-1.43 
284-286 
285 
1.44-1.46 
288-292 
290 
1.47-1.48 
294-296 
295 
1.49-1.51 
298-302 
300 
1.52-1.53 
304-306 
305 
1.54-1.56 
308-312 
310 
1.57-1.58 
314-316 
315 
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1.59-1.61 
318-322 
320 
1.62-1.63 
324-326 
325 
1.64-1.66 
328-332 
330 
1.67-1.68 
334-336 
335 
1.69-1.71 
338-342 
340 
1.72-1.73 
344-346 
345 
1.74-1.76 
348-352 
350 
1.77-1.78 
354-356 
355 
1.79-1.81 
358-362 
360 
1.82-1.83 
364-366 
365 
1.84-1.86 
368-372 
370 
1.87-1.88 
374-376 
375 
1.89-1.91 
378-382 
380 
1.92-1.93 
384-386 
385 
1.94-1.96 
388-392 
390 
1.97-1.98 
394-396 
395 
1.99-2.01 
398-402 
400 
2.02-2.03 
404-406 
405 
2.04-2.06 
408-412 
410 
2.07-2.08 
414-416 
415 
2.09-2.11 
418-422 
420 
2.12-2.13 
424-426 
425 
2.14-2.16 
428-432 
430 
2.17-2.18 
434-436 
435 
2.19-2.21 
438-442 
440 
2.22-2.23 
444-446 
445 
2.24-2.26 
448-452 
450 
2.27-2.28 
454-456 
455 
2.29-2.31 
458-462 
460 
2.32-2.33 
464-466 
465 
2.34-2.36 
468-472 
470 
2.37-2.38 
474-476 
475 
2.39-2.40 
478-480 
480 
 
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 TEMOZOLOMIDE DOSING TABLE for MAINTENANCE STARTING DOSE= 150 mg/m2 
 
BSA (m2) 
Calculated daily dose (mg) 
Administered daily dose (mg) 
0.50-0.51 
75-76 
75 
0.52-0.55 
78-82 
80 
0.56-0.58 
84-87 
85 
0.59-0.61 
88-91 
90 
0.62-0.65 
93-97 
95 
0.66-0.68 
99-102 
100 
0.69-0.71 
103-106 
105 
0.72-0.75 
108-112 
110 
0.76-0.78 
114-117 
115 
0.79-0.81 
118-121 
120 
0.82-0.85 
123-127 
125 
0.86-0.88 
129-132 
130 
0.89-0.91 
133-136 
135 
0.92-0.95 
138-142 
140 
0.96-0.98 
144-147 
145 
0.99-1.01 
148-151 
150 
1.02-1.05 
153-157 
155 
1.06-1.08 
159-162 
160 
1.09-1.11 
163-166 
165 
1.12-1.15 
168-172 
170 
1.16-1.18 
174-177 
175 
1.19-1.21 
178-181 
180 
1.22-1.25 
183-187 
185 
1.26-1.28 
189-192 
190 
1.29-1.31 
193-196 
195 
1.32-1.35 
198-202 
200 
1.36-1.38 
204-207 
205 
1.39-1.41 
208-211 
210 
1.42-1.45 
213-217 
215 
1.46-1.48 
219-222 
220 
1.49-1.51 
223-226 
225 
1.52-1.55 
228-232 
230 
1.56-1.58 
234-237 
235 
1.59-1.61 
238-241 
240 
1.62-1.65 
243-247 
245 
1.66-1.68 
249-252 
250 
1.69-1.71 
253-256 
255 
1.72-1.75 
258-262 
260 
1.76-1.78 
264-267 
265 
1.79-1.81 
268-271 
270 
1.82-1.85 
273-277 
275 
1.86-1.88 
279-282 
280 
1.89-1.91 
283-286 
285 
1.92-1.95 
288-292 
290 
1.96-1.98 
294-297 
295 
1.99-2.01 
298-301 
300 
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2.02-2.05 
303-307 
305 
2.06-2.08 
309-312 
310 
2.09-2.11 
313-316 
315 
2.12-2.15 
318-322 
320 
2.16-2.18 
324-327 
325 
2.19-2.21 
328-331 
330 
2.22-2.25 
333-337 
335 
2.26-2.28 
339-342 
340 
2.29-2.31 
343-346 
345 
2.32-2.35 
348-352 
350 
2.36-2.38 
354-357 
355 
2.39-2.40 
358-360 
360 
 
 
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 APPENDIX VI: INSTRUCTIONS FOR ADMINISTRATION OF TEMOZOLOMIDE 
(PATIENTS UNABLE TO SWALLOW CAPSULES AND CANNOT OBTAIN A SUSPENSION) 
 
 
If the person giving this medicine is pregnant or thinks she may be pregnant, she should not touch this 
medicine. 
 
Temozolomide is an anti-cancer medicine, and special precautions must be taken when handling it.  There 
is potential hazard to anyone who handles these medicines once the protective capsule is opened.  If your 
child cannot swallow the capsule you will be required to open the capsules and mix the contents of the 
capsule into apple sauce or apple juice.  This process must be done according to the following guidelines 
to make sure the medicine is given safely. 
 
 
Find a place to work that is free from drafts or wind and is not a place where food is stored or 
prepared. 
 
Cover the area with foil with a paper towel over it. 
 
Temozolomide can be mixed into apple sauce or apple juice.   
 
Put the apple sauce or apple juice into a container (or cup) that you can throw away. 
 
Put on gloves and mask.  
 
Open each capsule and put the powder in the apple sauce or apple juice and give IMMEDIATELY.  
The medicine may not dissolve completely if mixing in apple juice so make sure you have extra apple 
juice to add if you need to. 
 
If you need to add more juice or apple sauce, remove your gloves before touching the main food 
container, then place new gloves on before adding the extra juice or apple sauce to the medicine. 
(You do not want any medicine that may be on your gloves to get into the main food container of 
juice or apple sauce.).  
 
You must be able to throw away anything that the medicine touches, such as the spoon used for 
mixing or eating the apple sauce or the cup used for juice. 
 
Once all of the medicine is taken, throw away the following in a plastic bag:  medicine cup, the 
container the medicine was mixed in, the cover you used for the work area, mask, gloves and 
anything else that the medicine has touched. 
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APPENDIX VII:  ENZYME INDUCING AND NON-ENZYME INDUCING 
ANTICONVULSANTS 
 
 
 
Non-enzyme inducing anticonvulsants 
 
Generic Name 
Trade Name 
Gabapentin 
Neurontin 
Lamotrigine 
Lamictal 
Levetiracetam  
Keppra 
Tigabine 
Gabitril 
Topiramate 
Topamax 
Zonisamide 
Zonegran 
 
Enzyme inducing anticonvulsants 
 
Generic Name 
Trade Name 
Carbamazepine 
Tegretol 
Phenobarbital 
Phenobarbital 
Phenytoin 
Dilantin 
Primidone 
Mysoline 
Oxycarbazepine 
Trilepta 
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APPENDIX VIII: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0822 (Feasibility study) 
(for children from 7 through 12 years of age) 
 
A Study of Adding a Drug to Treatment for Newly Diagnosed Brain Tumors that Grow Quickly 
 
1. We have been talking with you about your glioma.  A glioma is a type of cancer that grows in 
your brain.  After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you were just diagnosed with a type of 
brain tumor that is more likely to grow fast. A research study is when doctors work together to try 
out new ways to help people who are sick. This study will see if a new treatment will work better 
to shrink or get rid of the tumor than other treatment often used. 
 
3. There is no “normal” treatment for glioma tumors that grow fast. But, often an operation to take 
out the tumor is done. Then, high-energy x-rays are used to kill any cancer cells left in the brain. 
Many children also get anti-cancer medicines to kill the cancer cells. These treatments do not 
work very well at getting rid of the tumor. Study doctors want to see if giving a drug during the x-
ray treatments will help get rid of cancer cells. Study doctors also want to see if giving 2 drugs 
after x-ray treatment can help get rid of the tumor. Study doctors hope this new treatment will 
work better to kill cancer cells than a treatment that is often used. 
 
Children who are part of this study will be given an anti-cancer medicine called vorinostat. 
Vorinostat is a medicine that you will swallow. You will take vorinostat during the time you are 
having the x-ray treatments. Because we are not sure how much vorinostat is best to give during 
x-ray treatment, you may get more or less of the drug than another child on the study. At the end 
of the x-ray treatment you will have a rest for 4 weeks where no treatment is given. Then you will 
be given 2 more anti-cancer medicines for about 11 more months. You will have about 8 scans 
done during these 11 months to see how the tumor reacts to the treatment. You will also have x-
rays taken of your knees every 12 weeks to check how you are growing. Then you will be 
finished with the treatments.  
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is that the 
new medicine during radiation treatment will work better to make your tumor get smaller or go 
away. Because the 2 anti-cancer medicines you will get after radiation treatment is a new 
treatment, we hope a benefit is that this part of treatment will work better to make your tumor 
shrink or go away. But, we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  The risks to you from this study are that you may get a treatment that is not as 
good at shrinking or getting rid of the tumor as the commonly used treatment and you may have 
bad health problems from the new medicine. Because the 2 anti-cancer medicines you will get 
after radiation treatment is a new treatment, there is a risk that you may have more bad health 
problems from the new combination of medicines. Other things may happen to you that we do not 
yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have. 
Use of this document is governed by the terms of use on the first page of this document.

 
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ACNS0822 
Page 126 
 
7. We are asking your “okay” to collect some extra blood and pieces of tumor, and to do some 
special scans.  We want to see if there are ways to tell how the tumor will react to treatment. The 
blood would be collected when other standard blood tests are being done, so there would not be 
any extra needle sticks.  The tumor samples would be taken at the time you have any operation. 
We will not do an operation just to get pieces of tumor. The special scans will be done when 
regular scans are done.  You can still take part in this study even if you do not allow us to collect 
the extra blood or tumor samples for research or to do the special scans. 
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INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0822 (Feasibility study) 
(for teens from 13 through 17 years of age) 
 
A Study of Adding a Drug to Treatment for Newly Diagnosed Brain Tumors that Grow Quickly 
 
1. We have been talking with you about your glioma. A glioma is a type of cancer that grows in the 
brain.  After doing tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have a “high-grade” glioma. This 
means the tumor is more likely to grow quickly and to spread. A research study is when doctors 
work together to try out new ways to help people who are sick. This study will see if a new 
treatment will work better to shrink or get rid of high-grade glioma than a commonly used 
treatment for this disease. 
 
Most children and teens with gliomas have surgery to take out the tumor and then get radiation 
therapy (powerful x-rays directed at the tumor location). Many children and teens also get 
chemotherapy drugs (anti-cancer medicines). Treatments for gliomas do not work very well at 
shrinking or getting rid of the tumor. Study doctors want to see if giving chemotherapy during 
radiation therapy will work better than radiation therapy alone to get rid of the tumor. They also 
want to see if giving two chemotherapy drugs after radiation therapy will help get rid of the tumor 
for as long as possible. 
 
3. Children and teens who are part of this study will be treated with a drug called vorinostat during 
the time radiation treatments are given, for 6 weeks. Because we are not sure how much 
vorinostat is best to give during x-ray treatment, you may get more or less of the drug than 
another child or teen on the study. Then you will have a rest for 4 weeks where no treatment is 
given. Then you will be given more chemotherapy with a combination of 2 drugs for about 11 
more months. This combination of drugs is experimental. You will have about 8 scans done 
during these 11 months to see how the tumor is reacting to the treatment. If you have not yet 
stopped growing, every 12 weeks during treatment you will also have x-rays taken of your knees 
to check how you are growing.  
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.”  We hope that a benefit to you of being part of this study is that the 
new drug given during radiation treatment will be better at shrinking or getting rid of the tumor 
than the commonly used treatment. We hope that the new combination of drugs given after 
radiation treatment will work better to shrink or get rid of the tumor than the commonly used 
treatment. However, we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  One risk to you from this study is that you may have side effects from the 
combination of radiation therapy with the vorinostat. Some possible side effects include things 
like being very tired, an upset stomach, and not being able to keep food down. Another risk to 
you is that you may have more side effects from the 2 drug combination that is given after 
radiation therapy. Some of these side effects may include high blood pressure, bleeding problems, 
and feeling sick to your stomach. Other things may happen to you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not.  Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have.  
 
Use of this document is governed by the terms of use on the first page of this document.

 
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ACNS0822 
Page 128 
7. We are asking your permission to collect additional blood and tumor samples, and to do special 
scans.  We want to see if there are ways to tell how the cancer will respond to treatment. The 
blood samples would be taken when other standard blood tests are being performed, so there 
would be no extra needle sticks. The tumor samples would be taken during surgeries you had. We 
would not do a surgery just to get these samples. The special scans would be done when other 
normal scans are done. You can still be treated on this study even if you do not allow us to collect 
the extra blood or tumor samples for research or to do the special scans.  
Use of this document is governed by the terms of use on the first page of this document.

 
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ACNS0822 
Page 129 
 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0822 (Phase II) 
(for children from 7 through 12 years of age) 
A Study Comparing 3 Treatments for Newly Diagnosed Brain Tumors That Grow Quickly 
1. We have been talking with you about your glioma.  A glioma is a type of cancer that grows in 
your brain.  After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have a tumor that is more likely to 
grow fast. A research study is when doctors work together to try out new ways to help people 
who are sick. Most children with gliomas have an operation to take out the tumor and then get 
radiation therapy (powerful x-rays directed at the tumor location). Many children also get anti-
cancer medicines. Treatments for gliomas do not work very well at shrinking or getting rid of the 
tumor. Study doctors want to try two new treatments to see if they will work better than a 
commonly used treatment. 
 
3. Children who are part of this study will be given an anti-cancer medicine and have radiation 
treatments for 6 weeks. Some children will get one of two new medicines during radiation 
treatment. Some children will get a commonly used medicine during radiation treatment. Then 
you will have a rest for 4 weeks where no treatment is given. Then you will be given 2 more anti-
cancer medicines for about 11 more months. You will have about 8 scans done during these 11 
months to see how the tumor reacts to the treatment. You will also have x-rays taken of your 
knees every 12 weeks to check how you are growing. Then you will be finished with the 
treatments.  
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.” If you get one of the new medicines during radiation treatment, we 
hope that a benefit to you of being part of this study is that you will get a treatment that works 
better to make your tumor get smaller or go away. If you get the medicine that is not new, we 
hope a benefit to you is helping study doctors learn more about how to treat brain tumors. 
Because the 2 anti-cancer medicines you will get after radiation treatment is a new treatment, we 
hope a benefit is that this part of the treatment will work better to make your tumor shrink or go 
away. However, we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  Another risk to you is that you may have more side effects from the 2 drug 
combination that is given after radiation therapy. Some of these side effects may include high 
blood pressure, bleeding problems, and feeling sick to your stomach. Other things may happen to 
you that we do not yet know about. Other things may happen to you that we do not yet know 
about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your “okay” to collect some extra blood and pieces of tumor, and to do some 
special scans.  We want to see if there are ways to tell how the tumor will react to treatment. The 
tumor samples would be taken at the time you would normally have any operation, so there 
would be no extra operations. The blood would be collected when other regular blood tests are 
done, so there would be no extra needle sticks.  The special scans would be done when other 
regular scans are done.  You can still take part in this study even if you do not allow us to collect 
the extra blood or tumor samples for research or to do the special scans. 
Use of this document is governed by the terms of use on the first page of this document.

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY 
ACNS0822 
Page 130 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0822 (Phase II) 
(for teens from 13 through 17 years of age) 
 
A Study Comparing 3 Treatments for Newly Diagnosed Brain Tumors that Grow Quickly 
 
 
1. We have been talking with you about your glioma. A glioma is a type of cancer that grows in the 
brain.  After doing tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have a “high-grade” glioma. This 
means the tumor is more likely to grow quickly and to spread. A research study is when doctors 
work together to try out new ways to help people who are sick. Most children and teens with 
gliomas have surgery to take out the tumor and then get radiation therapy (powerful x-rays 
directed at the tumor location). Many children and teens also get chemotherapy drugs (anti-cancer 
medicines). Treatments for gliomas do not work very well at shrinking or getting rid of the tumor. 
Study doctors want to try two new treatments to see if they will work better than a commonly 
used treatment. 
 
3. Children and teens who are part of this study will be given chemotherapy and have radiation 
treatments for 6 weeks. Some children and teens will receive 1 of 2 new drugs during radiation 
treatment, while others will receive a commonly used drug. You have a 1 in 3 chance of getting 
each drug. Then you will have a rest for 4 weeks where no treatment is given. Then you will be 
given more chemotherapy with a combination of 2 drugs for about 11 more months. This 
combination is experimental. Then you will be given more chemotherapy with 2 different drugs 
for about 11 more months. (These 2 drugs will be new for everyone). You will have about 8 scans 
done during these 11 months to see how the tumor is reacting to the treatment. If you have not yet 
stopped growing, every 12 weeks during treatment you will also have x-rays taken of your knees 
to check how you are growing.  
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.”  We hope that a benefit to you of being part of this study if you get 
one of the new drugs during radiation treatment is that the new treatment will be better at 
shrinking or getting rid of the tumor than the commonly used treatment. If you receive the 
commonly used treatment, we hope that a benefit to you is knowing that you will help doctors 
learn more about how to treat gliomas. For all children and teens in this study, we hope that the 
new combination of drugs given after radiation treatment will work better to shrink or get rid of 
the tumor than the commonly used treatment. However, we do not know for sure if there is any 
benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  If you receive one of the 2 new drugs during radiation treatment, one risk to 
you from this study is that you may receive a treatment that is not as good as the common 
treatment in shrinking or getting rid of the tumor. Another risk is that you may have more side 
effects from the new treatment than the common treatment. These side effects include headaches, 
high blood pressure, tiredness, diarrhea, vomiting and loss of appetite. If you receive the 
commonly used drug during radiation treatment, the risk to you is that you may receive a 
treatment that is not as good as the new treatment at shrinking or getting rid of your tumor. There 
is the risk that the new treatment given after radiation treatment will not work as well as the 
common treatment to shrink or get rid of the tumor, and you may have more side effects from the 
2 drugs used. Some of these side effects are high blood pressure, bleeding problems, and feeling 
sick to your stomach. Other things may happen to you that we do not yet know about. 
Use of this document is governed by the terms of use on the first page of this document.

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY 
ACNS0822 
Page 131 
 
6. Your family can choose to be part of this study or not.  Your family can also decide to stop being 
in this study at any time once you start.  There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have.  
 
7. We are asking your permission to collect additional blood and tumor samples, and to do special 
scans.  We want to see if there are ways to tell how the cancer will respond to treatment. The 
blood samples would be taken when other standard blood tests are being performed, so there 
would be no extra needle sticks. The tumor samples would be taken during any surgeries you had, 
so you would have no extra surgeries. The special scans would be done when other regular scans 
are done. You can still be treated on this study even if you do not allow us to collect the extra 
blood or tumor samples for research or to do the special scans.  
Use of this document is governed by the terms of use on the first page of this document.

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY 
ACNS0822 
Page 132 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0822 (Phase III) 
(for children from 7 through 12 years of age) 
A Study Comparing 2 Treatments for Newly Diagnosed Brain Tumors That Grow Quickly 
1. We have been talking with you about your glioma.  A glioma is a type of cancer that grows in 
your brain.  After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have a tumor that is more likely to 
grow fast. A research study is when doctors work together to try out new ways to help people 
who are sick. Most children with gliomas have an operation to take out the tumor and then get 
radiation therapy (powerful x-rays directed at the tumor location). Many children also get anti-
cancer medicines. Treatments for gliomas do not work very well at getting rid of the tumor. Study 
doctors want to try a new treatment to see if it will work better than a commonly used treatment. 
 
3. Children who are part of this study will be given an anti-cancer medicine and have radiation 
treatments for 6 weeks. Some children will get one new medicine during radiation treatment. 
Some children will get a commonly used medicine during radiation treatment. Then you will have 
a rest for 4 weeks where no treatment is given. Then you will be given 2 more anti-cancer 
medicines for about 11 more months. You will have about 8 scans done during these 11 months 
to see how the tumor reacts to the treatment. You will also have x-rays taken of your knees every 
12 weeks to make sure you are growing normally. Then you will be finished with the treatments.  
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.” If you get the new medicine during radiation treatment, we hope that 
a benefit to you of being part of this study is that you will get a treatment that works better to 
make your tumor get smaller or go away. If you get the medicine that is not new, we hope a 
benefit to you is helping study doctors learn more about how to treat brain tumors. Because the 
anti-cancer medicines you will get after radiation treatment is a new treatment, we hope a benefit 
is that this part of the treatment will work better to make your tumor shrink or go away. However, 
we do not know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  If you get the new medicine during radiation treatment, the risks to you from 
this study are that you may get a treatment that is not as good at shrinking or getting rid of the 
tumor as the commonly used treatment, and you may have more health problems from the new 
medicine. If you do not get the new medicine during radiation treatment, the risk to you is that 
you may not get a treatment that works better to make your tumor shrink or go away. Because the 
2 anti-cancer medicines you will get after radiation treatment is a new treatment, there is a risk 
that that you may have bad health problems from the new combination of medicines. Other things 
may happen to you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your “okay” to collect extra blood and pieces of tumor, and to do some special 
scans.  We want to see if there are ways to tell how the tumor will react to treatment. The tumor 
samples would be taken at the time you have any operation, so there would be no extra 
operations. The blood would be collected when other regular blood tests are being done, so there 
would be no extra needle sticks.  The special scans would be done when other regular scans are 
done.  You can still take part in this study even if you do not allow us to collect the extra blood or 
tumor samples for research or to do the special scans. 
Use of this document is governed by the terms of use on the first page of this document.

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY 
ACNS0822 
Page 133 
INFORMATION SHEET REGARDING RESEARCH STUDY – ACNS0822 (Phase III) 
(for teens from 13 through 17 years of age) 
 
A Study Comparing 2 Treatments for Newly Diagnosed Brain Tumors that Grow Quickly 
 
 
1. We have been talking with you about your glioma. A glioma is a type of cancer that grows in the 
brain.  After doing tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have a “high-grade” glioma. This 
means the tumor is more likely to grow quickly and to spread. A research study is when doctors 
work together to try out new ways to help people who are sick. Most children and teens with 
gliomas have surgery to take out the tumor and then get radiation therapy (powerful x-rays 
directed at the tumor location). Many children and teens also get chemotherapy drugs (anti-cancer 
medicines). Treatments for gliomas do not work very well at shrinking or getting rid of the tumor. 
Study doctors want to try a new treatment to see if it will work better than a commonly used 
treatment. 
 
3. Children and teens who are part of this study will be given chemotherapy and have radiation 
treatments for 6 weeks. Some children and teens will receive a new drug during radiation 
treatment, while others will receive a commonly used drug. You have a 50-50 chance of getting 
either drug. Then you will have a rest for 4 weeks where no treatment is given. Then you will be 
given more chemotherapy with a combination of 2 drugs for about 11 more months. This 
combination is experimental. You will have about 8 scans done during these 11 months to see 
how the tumor is reacting to the treatment. If you have not yet stopped growing, every 12 weeks 
during treatment you will also have x-rays taken of your knees to check how you are growing.  
 
4. Sometimes good things can happen to people when they are in a research study.  These good 
things are called “benefits.”  We hope that a benefit to you of being part of this study if you get 
the new drug during radiation treatment is that the new treatment will be better at shrinking or 
getting rid of the tumor than the commonly used treatment. If you receive the commonly used 
treatment, we hope that a benefit to you is knowing that you will help doctors learn more about 
how to treat gliomas. For all children and teens in this study, we hope that the new combination 
of drugs given after radiation treatment will work better to shrink or get rid of the tumor than the 
commonly used treatment. However, we do not know for sure if there is any benefit of being part 
of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study.  These bad things 
are called “risks.”  If you receive the new drug during radiation treatment, one risk to you from 
this study is that you may receive a treatment that is not as good as the common treatment in 
shrinking or getting rid of your tumor. Another risk is that you may have more side effects from 
the new treatment than the common treatment. These side effects include headaches, high blood 
pressure, tiredness, vomiting and loss of appetite. If you receive the commonly used drug during 
radiation treatment, the risk to you is that you may receive a treatment that is not as good as the 
new treatment at shrinking or getting rid of your tumor. There is the risk that the new treatment 
given after radiation treatment will not work as well as the common treatment to shrink or get rid 
of the tumor, and you may have more side effects from the 2 drugs used. Some of these side 
effects are high blood pressure, bleeding problems, and feeling sick to your stomach. Other things 
may happen to you that we do not yet know about. 
 
Use of this document is governed by the terms of use on the first page of this document.

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY SEE PAGE 1 FOR USAGE POLICY 
ACNS0822 
Page 134 
6. Your family can choose to be part of this study or not.  Your family can also decide to stop being 
in this study at any time once you start.  There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have.  
 
7. We are asking your permission to collect additional blood and tumor samples, and to do special 
scans.  We want to see if there are ways to tell how the cancer will respond to treatment. The 
blood samples would be taken when other standard blood tests are being performed, so there 
would be no extra needle sticks. The tumor samples would be taken during any surgeries you had, 
so you would have no extra surgeries. The special scans would be done when other regular scans 
are done. You can still be treated on this study even if you do not allow us to collect the extra 
blood or tumor samples for research or to do the special scans.  
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150  Ree AH, Dueland S, Folkvord S, et al. Vorinostat, a histone deacetylase inhibitor, combined with 
pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat 
(PRAVO) phase 1 study. Lancet Oncol 11:459-464, 2010 
 
 
 
 
 
 
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SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH – FEASIBILITY STUDY 
 
As of Amendment #1 the feasibility study was completed. 
 
 
 
 
 
 
 
 
 
 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM  
 
ACNS0822, 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 
 
PART 1 – Feasibility Study of Vorinostat with Radiation Therapy 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required. When we say “you” 
in this consent form, we mean you or your child; “we” means the doctors and other staff. 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY? 
 
This study is called a clinical trial. A clinical trial is a research study involving treatment of a 
disease in human patients. This study is organized by Children’s Oncology Group (COG). COG 
is an international research group that conducts clinical trials for children with cancer. More than 
200 hospitals in North America, Australia, New Zealand, and Europe are members of COG. 
 
You are being asked to take part in this research study because you have been diagnosed with 
a type of brain tumor called a high-grade glioma. A “high-grade” glioma is a tumor that grows 
fast and is more likely to spread.  
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard treatment for high-grade gliomas and this clinical trial.  
 
Please take your time to make your decision. Discuss it with your friends and family. We 
encourage parents to include their child in the discussion and decision to the extent that the 
child is able to understand and take part. 
 
 
WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE? 
 
Standard treatment for high-grade gliomas includes surgery to remove as much tumor as 
possible followed by radiation therapy (treatment with high-dose x-rays). Treatment may also 
include chemotherapy (anti-cancer drugs) during and after radiation treatment. Temozolomide is 
This model informed consent form has been reviewed by the DCT/NCI and is the official consent 
document for this study. Institutions should use the sections of this document which are in bold type 
in their entirety. Editorial changes to these sections may be made as long as they do not change 
information or intent. If the local IRB insists on making deletions or more substantive modifications 
to any of the sections in bold type, they must be justified in writing by the investigator at the time of 
the institutional audit.  
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one of the chemotherapy drugs often used during radiation therapy to treat newly diagnosed 
high-grade glioma. Anti-cancer drugs, such as temozolomide, are also commonly used in 
Maintenance therapy for newly diagnosed high-grade glioma. Maintenance therapy is therapy 
given after radiation therapy. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
High-grade gliomas are hard to treat successfully. Study doctors want to find treatments that will 
be better at getting rid of or shrinking high-grade gliomas. One thing they want to do is try using 
different chemotherapy drugs during radiation therapy. Treatment that combines chemotherapy 
and radiation therapy at the same time is called “chemoradiotherapy”. Two drugs that will be 
used in this study are vorinostat and bevacizumab.  
 
Early studies have shown that vorinostat and bevacizumab may help radiation therapy work 
better to get rid of cancer cells. One study of adults with high-grade glioma found that vorinostat 
helped keep the cancer from getting worse over 6 months. Recently, a study was completed to 
find the highest dose of vorinostat that can be given safely to children. Another study of adults 
with high-grade glioma found that bevacizumab combined with radiation therapy helped get rid 
of or shrink tumors.  
 
Study doctors also want to see if using different drugs during maintenance therapy will be better 
than treatment with temozolomide in helping to get rid of or shrink high-grade gliomas. Another 
drug that they want to try together with temozolomide is bevacizumab. Temozolomide is 
commonly used in maintenance therapy for brain tumors. It is well-tolerated and has fewer side 
effects than other drugs commonly used in maintenance therapy. Study doctors want to find out 
if adding bevacizumab to treatment with temozolomide during maintenance therapy will work 
better than temozolomide alone. Bevacizumab is a drug that works differently than traditional 
chemotherapy drugs. Cancer cells need to have a blood supply just as normal body cells do. 
Bevacizumab is an antibody that works to stop the growth of blood vessels in the tumor.  
 
In studies of adults with different types of cancer, patients who had bevacizumab added to their 
chemotherapy treatments did better than those who did not. Other studies of adults with high-
grade gliomas suggest that adding bevacizumab to treatment with other drugs is well-tolerated 
and works better than either the bevacizumab or the other drugs alone to help keep the cancer 
from getting worse. Bevacizumab was recently approved for use in adults with recurrent high-
grade glioma. Early results are available from an ongoing study of children with newly-
diagnosed brain tumors. These children are being treated with the combination of 
temozolomide, irinotecan and bevacizumab during maintenance therapy and the results to date 
suggest the combination is well-tolerated. Study doctors think the combination of temozolomide 
and bevacizumab will be well-tolerated by children who take part in this study, and that the 
combination may work better than temozolomide alone to get rid of or shrink high-grade 
gliomas. 
 
This study is being done in 3 parts. Part 1 of this study is to find the dose of vorinostat that can 
be given safely to children during radiation therapy. Once this dose is known, the study will 
continue to Part 2. Part 2 of the study will test and compare 3 treatments. Part 3 of this study will 
compare the 2 best treatments from Part 2. People who are in Part 1 of this study will not be in 
Part 2 or 3. We are now doing Part 1 of the study. You are being asked to enroll on Part 1 of this 
study.  
 
 
 
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The goals of Part 1 of this study are to:  
 
 Find out the dose of vorinostat that can be given safely to children while they are 
receiving radiation therapy. The combination of vorinostat with radiation therapy is 
experimental.   
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
The total number of people enrolled on this study is expected to be 248. We will enroll between 
6 and 12 people on Part 1 of this study. 
 
 
WHAT WILL HAPPEN ON THIS STUDY THAT IS RESEARCH? 
 
This is a 3-part study, and different parts of this study will be done to test different treatments. In 
Part 1 of this study some subjects may be given a different dose of vorinostat than the subjects 
treated with vorinostat in Parts 2 and 3 of the study. Subjects are people who agree to be 
treated on this study. 
 
Part 1 
We will try to find out the highest dose of vorinostat that can be given in combination with 
radiation therapy without causing side effects that are too severe. This dose is called the 
maximum tolerated dose, or MTD. 
 
From 6 to 12 subjects will take part in Part 1. The dose of vorinostat for the first 6 subjects will 
be 230 mg/m2. If that dose doesn’t cause too many side effects, then that dose will be the dose 
used in the rest of the study. But, if the dose of 230 mg/m2 causes too many side effects, then 
the next 3 subjects will get vorinostat at a lower dose (180 mg/m2). If the lower dose does not 
cause too many side effects, then another 3 subjects will receive the lower dose. If the lower 
dose doesn’t cause too many side effects in these 6 subjects, it will be the dose used in the rest 
of the study. If the lower dose does cause too many side effects, we will change the study. 
 
In Part 2, we will treat more subjects to find out how effective the MTD of vorinostat found in 
Part 1 is against newly diagnosed high-grade gliomas, when it is given in combination with 
radiation therapy. We will compare treatment with vorinostat during radiation therapy to two 
other treatments each using a different drug during radiation therapy. 
 
In Part 3, we will compare the two treatments found to work the best during Part 2 to see which 
one is more effective against newly diagnosed high-grade gliomas. 
 
The remainder of this informed consent will discuss what will happen on Part 1 of this study. 
 
Treatment Plan  
 
The treatment plan involves cancer fighting medicine called chemotherapy and radiation 
therapy. The treatment on this clinical trial takes about 12 to 14 months. It is divided into 2 
phases.  
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The first phase of treatment is called “chemoradiotherapy”. This phase lasts about 70 days, or 
10 weeks. During this first phase, you will be given radiation therapy to the brain 5 days a week 
for 6 weeks. On the days that you receive radiation therapy, you will take vorinostat 1 to 2 hours 
before the radiation therapy. After you complete radiation therapy and treatment with vorinostat, 
you will have a 4-week rest, during which no treatment is given.  
 
The second phase of treatment, called Maintenance therapy, begins after the 4-week rest 
period. During Maintenance therapy, you will not receive any further radiation therapy but you 
will have more chemotherapy. Maintenance therapy consists of 1 cycle of treatment repeated 
for up to a total of 12 cycles. Each cycle is 28 days long. During each cycle, you will receive two 
drugs, called bevacizumab and temozolomide. Temozolomide will be given on 5 days and 
bevacizumab will be given on 2 days during each cycle. Maintenance therapy lasts about 336 
days or 11 months. 
 
 
There is one treatment arm in Part 1 of this study. It is: 
 
 Arm A: Chemoradiation with vorinostat followed by maintenance chemotherapy with 
bevacizumab and temozolomide. 
 
 
Diagram of Treatment 
 
A diagram of treatment on Part 1 of this study can be seen below.  
 
 
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Treatment Plan Tables 
 
Treatment that is commonly used for newly diagnosed high-grade gliomas is described in 
Attachment #1. This includes the standard radiation therapy that all subjects will receive while 
part of this study and temozolomide commonly used during radiation therapy and during 
maintenance 
therapy. 
The 
following 
drug 
therapies 
relate 
to 
the 
experimental 
chemoradiotherapy and maintenance therapy in this study. 
 
Various methods will be used to give drugs: 
 
PO - Drug is given by tablet or liquid swallowed through the mouth. 
 
IV - Drug is given using a needle or tubing inserted into a vein. It can be given by IV push 
over several minutes or by infusion over minutes or hours. 
 
Most drugs on this study will be given using a needle or tubing inserted into a vein (IV). 
 
Chemoradiotherapy Treatment for All Subjects  
All subjects will receive vorinostat during the chemoradiotherapy phase of treatment. The 
experimental treatment is using vorinostat instead of temozolomide. 
 
Drug 
How the drug will be given  
Days 
Vorinostat 
PO 
(1 to 2 hours before radiation 
therapy) 
1-5, 8-12, 15-19, 
22-26, 29-33, 36-40 
 
Study Entry
Chemoradiotherapy:
Radiation therapy ( 5 days each week) for 6 weeks
And 
Vorinostat ( 5 days each week)
And 
4 week rest
Maintenance Therapy:
with 
Bevacizumab and Temozolomide
(for up to 12 cycles)
and scans every other cycle
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All subjects will receive the standard radiation therapy for high-grade gliomas. Standard 
radiation therapy is described in Attachment #1.  
 
Maintenance Chemotherapy Treatment for All Subjects 
All subjects on this study will receive the same chemotherapy drugs during Maintenance 
chemotherapy. These drugs are bevacizumab and temozolomide. The purpose of Maintenance 
chemotherapy is to kill any remaining glioma cells that may regrow and cause a relapse (cancer 
coming back). Each Maintenance cycle lasts about 28 days and the cycle may be repeated for up 
to a total of 12 cycles. Maintenance lasts about 11 months. The experimental treatment is using 
bevacizumab and temozolomide instead of temozolomide alone as maintenance therapy.  
 
Drug 
How the drug will be given  
Days 
Bevacizumab 
IV over 90 minutes* 
1 and 15 
Temozolomide 
PO 
1-5 
*The first dose will be given over 90 minutes. If you tolerate it well and do not have any bad side effects, the second dose 
may be given over 60 minutes. Again, if tolerated, each remaining dose may be given over 30 minutes. 
 
During maintenance chemotherapy, you will have several scans done so the study doctors can 
see how the tumor is responding to treatment. You will have scans before you begin, and scans 
after you finish this part of your treatment.  You will also have scans after every two cycles of 
maintenance chemotherapy, to see if the tumor has changed.  If the tumor has not gotten larger, 
you will get more cycles of maintenance chemotherapy, up to a possible total of 12 cycles.  
 
If at any time your disease gets worse or you have serious side effects from the treatment, you 
will be taken off study therapy.  If this happens, your doctor will discuss other treatment options 
with you at that time. 
 
Research Study Tests and Procedures 
 
The following tests will be done because you are part of this study. These tests are not part of 
standard care.  
 
Some of the tissue already taken and used to make the diagnosis of your disease and some of 
the scans used to check your response to treatment will be sent to a central review center as 
part of COG quality control. 
 
If you have not yet stopped growing, you will have X-rays taken of your right knee every 12 
weeks during maintenance chemotherapy to check for normal bone growth. If the study doctors 
think it is necessary, you may also have MRI scans of both knees done after one or more of 
these X-rays. 
 
Optional Research Tests 
 
In addition to the treatment goals, we would like to use tumor and blood samples collected on 
this study to answer some research questions that might benefit future patients.  You can 
choose to be in this clinical trial without taking part in the optional biology research portion. 
Biology studies will help us find out more about how the study drugs work to destroy cancer 
cells and help us understand why some people may respond better or worse to the treatments.  
 
Tumor tissue removed during your surgery will be sent to a central lab to document the type of 
tumor you have. We would like to do some extra tests on your tumor tissue, and take some 
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extra blood and do some tests on it. We would also like to do some extra imaging studies, or 
scans (special MRI scans) to study physical changes in the tumor that happen during treatment.  
 
The goals of the optional research studies are: 
 
 To study DNA from tumor and blood samples to see if certain genetic characteristics (the 
hereditary information that is passed on from cell to cell and tells the cell how to function) 
can be used to help identify people who are more likely to have a better treatment response.  
 
 To study tumor tissue and blood to see if the biological characteristics of the tissue and 
blood relate to how well a subject responds to treatment. We want to look at the amount of 
certain enzymes (proteins that help with chemical reactions in the body) found in the tumor 
that help protect it from the effects of chemotherapy. This information will help us to target 
more effective therapies against high grade glioma in the future. 
 
 To use special MRI scanning techniques that give more information about the blood flow, 
structure, and functioning of the tumor. These scans are called perfusion MRIs and diffusion 
MRIs. They will be used together with the standard MRI scans to see if they can help 
identify people who are more likely to have a better treatment response.  
 
 
The table below gives information about the samples we would like to use for the optional 
research studies. 
 
 
Samples for Optional Research Studies  
 
Who will we ask for 
a sample? 
What Sample(s) are we 
asking for? 
When will we ask for the sample(s)? 
All subjects 
Blood 
(about 2 teaspoonfuls if 
you do not agree to allow 
us to collect tumor tissue 
and about 3 teaspoonfuls, 
if you do allow us to collect 
tumor tissue) 
 
 
Before treatment begins 
 
All subjects 
Tumor tissue 
At the time of surgery  
Subjects with tumor 
visible 
on 
post-
surgery scan done 
before 
treatment 
begins 
Special MRI scans  
Before treatment begins, 
Before maintenance therapy begins, prior to 
cycle 
3 
of 
Maintenance 
and 
at 
the 
completion of therapy. 
 
Although these studies are very important to understanding more about treatments for high-
grade glioma, the results of these studies will not directly affect your treatment. The test results 
will not be given back to you. 
 
 
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HOW LONG IS THE STUDY? 
 
Subjects in this clinical trial are expected to receive treatment on this study for about 12 to 14 
months.  After treatment, subjects will have follow-up examinations and medical tests. We would 
like to continue to find out about your health for about 10 years after you enter the study. 
Keeping in touch with you and checking on how your health is every year for a while after you 
complete treatment helps us understand the long-term effects of the study.  
 
 
Your doctor or the study doctor may decide to take you off this study under the following 
circumstances: 
 
if he/she believes that it is in your best interest 
 
if your disease comes back during treatment 
 
if you experiences side effects from the treatment that are considered too severe 
 
if new information becomes available that shows that another treatment would be better for 
you 
 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the study doctor and your regular doctor first. They will help you 
stop safely.  
 
 
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WHAT ARE THE RISKS OF THE STUDY AND HOW ARE THE RISKS 
DIFFERENT FROM TREATMENT? 
 
Treatment Risks 
All people who receive cancer treatment are at risk of having side effects. In addition to 
killing tumor cells, cancer chemotherapy can damage normal tissue and produce side 
effects. Side effects are usually reversible when the medication is stopped but 
occasionally persist and cause serious complications. A person can die from these and 
other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be 
given to prevent or decrease nausea and vomiting. Hair loss is usually temporary but on 
very rare occasions it may be permanent. Some chemotherapy may lead to sterility. 
Sterility is the inability to have children. There is also the possibility that a second cancer 
may develop years later as a result of the chemotherapy.  
 
The risks of temozolomide, which is commonly given as treatment, and risks of standard 
radiation therapy are listed in the tables in Attachment #2.  
 
Side effects can be increased when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of 
blood cells resulting in anemia, increased chance of infection, and bleeding tendency. 
Low blood counts are described in the COG Family Handbook for Children with Cancer. You will 
be taught more about caring for your child when his or her blood counts are low.  
 
There is a risk that the treatment plan will not cure the cancer or that the cancer can go 
away after the treatment and then come back at a later date.  
 
For Women: 
The treatment on this study can affect an unborn child.  You should not become pregnant 
or breast feed your baby while being treated on this study.  If you are sexually active and are at 
risk of getting pregnant, you and your male partner(s) must use an effective method to avoid 
pregnancy or you must not have sex.  The study doctor will talk to you about acceptable 
methods to avoid pregnancy while you are being treated on this study.  You will have to use the 
chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole time you 
are being treated on this study. You may need to continue this for a while, even after you finish 
the cancer treatment, so talk to your doctors about the length of time you need to avoid 
pregnancy or abstain. Natural family planning and the rhythm method will not be permissible 
means of avoiding pregnancy during study participation.  If you have questions about this or 
want to change your method to avoid pregnancy during therapy, please ask your doctor.  If you 
become pregnant during the research study, please tell the study doctor and your regular doctor 
immediately. 
 
If you are nursing a baby, the drugs used in this research could pass into the breast milk. You 
should not nurse your baby for the whole time you are getting the study medicines. You may 
need to continue this for a while, even after you finish the cancer treatment, so talk to your 
doctors about the length of time you need to avoid nursing. 
 
For Men: 
The treatment on this study can damage sperm.  You should not father a child while on this 
study as the treatment may indirectly affect an unborn child.  If you are sexually active and are 
at risk of causing a pregnancy, you and your female partner(s) must use a method to avoid 
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pregnancy that works well or you must not have sex.  The study doctor will talk to you about the 
acceptable methods to avoid pregnancy while you are being treated on this study.  You will 
have to use the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the 
whole time you are being treated on this study. You may need to continue this for a while, even 
after you finish the cancer treatment, so talk to your doctors about the length of time you need to 
avoid pregnancy or abstain. Natural family planning and the rhythm method will not be 
permissible means of avoiding pregnancy during study participation. If you have questions 
about this or want to change your method to avoid pregnancy during therapy, please ask your 
doctor.  If your partner becomes pregnant during the research study, please tell the study doctor 
and your regular doctor immediately. 
 
Risks of Study 
There is a risk that the experimental chemoradiotherapy treatment with vorinostat may 
not work as well as the common chemoradiotherapy treatment with temozolomide. There 
is also a risk that you may have more side effects from the experimental 
chemoradiotherapy treatment.  
 
There is also a risk that the experimental combination of bevacizumab and temozolomide 
during maintenance therapy may not be as effective as the commonly used maintenance 
therapy with temozolomide. There is also the risk that you may have more side effects 
from the bevacizumab and temozolomide than you would from temozolomide alone. The 
major concerns with bevacizumab are high blood pressure, protein in the urine that may 
mean kidney damage, bleeding, blood clots, heart damage and poor healing after 
surgery. These side effects are usually mild, but they can be life-threatening. 
Bevacizumab may make the side effects from temozolomide worse.  
 
The risks of the commonly used temozolomide are listed in the table on Attachment #2. The 
risks and side effects related to the study drugs vorinostat and bevacizumab are shown 
in the tables below. 
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Risks and side effects related to vorinostat include those which are: 
 
 
 
 
 
Likely 
Less Likely
Rare but serious
 
Fewer red blood cells and 
platelets in the blood  
o 
a low number of red 
blood cells can 
make you feel tired 
and weak 
o 
a low number of platelets 
that may cause you to 
bruise and bleed more 
easily 
 
A feeling of extreme 
tiredness, weakness, 
sleepiness, or not feeling well 
that is not relieved by sleep 
 
Loss of appetite 
 
Diarrhea 
 
Nausea 
 
Vomiting 
 
 
Low numbers of white blood 
cells called lymphocytes 
and / or neutrophils that 
may make it easier to get 
infections.  The infections 
may be life threatening 
 
Low number of white blood cells 
can make it easier to get 
infections 
 
Fever (high temperature) 
 
Hair loss  
 
Constipation 
 
Excessive loss of water from the 
body  
 
Dry mouth 
 
Acid or upset stomach (heartburn) 
 
Change in the way things taste 
 
Infection 
 
Abnormally low level of the 
protein albumin in the blood.  Low 
albumin may result in leaking of 
fluid from the blood into the 
tissue  
 
Increased levels of a chemical 
(creatinine) in the blood which 
could mean kidney damage 
 
Increase in the blood of certain 
enzymes or bilirubin (a substance 
that comes from the liver 
breaking down waste products) 
which could indicate liver 
irritation or damage 
 
Increase in the level of sugar in 
the blood that may require 
treatment 
 
Abnormally low levels of certain 
salts (electrolytes) like phosphate 
and/or calcium and/or sodium, 
and/or potassium in the body 
which may require that you take 
supplements by mouth or vein  
 
An involuntary and abnormal 
contraction of muscle 
 
Loss of strength in the muscles  
 
Dizziness (or sensation of 
lightheadedness, giddiness, 
spinning or rocking) 
 
Abdominal pain  
 
Cough 
  Feeling short of breath 
 
Weight loss 
 
 
Death of skin tissue which 
could lead to surgical 
treatment and be life-
threatening 
 
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Risks and side effects related to Bevacizumab include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Absence of 
menstrual cycles 
(periods) and 
damage to the 
ovaries that may 
decrease the ability 
to have children in 
the future 
 
High blood pressure 
 
 
 
Fever with a low white blood cell 
count which could indicate 
infection and may require 
hospitalization and treatment 
with antibiotics 
 
Fewer white blood cells and red 
blood cells in the blood 
o 
a low number of white blood 
cells can make it easier to 
get infections* 
o 
a low number of red blood 
cells can make you feel tired 
and weak 
 
Fast heart rate usually originating 
in an area located above the 
ventricles 
 
Vertigo; sensation of a spinning 
movement 
 
General pain, pain in the chest 
(not heart-related), in the 
abdomen (belly), in the muscles, 
or in the joints 
 
Inflammation of the part of the 
intestines known as the colon 
which can lead to infection, blood 
in the stools and abdominal 
(belly) pain 
 
Constipation 
 
Diarrhea 
 Acid or upset stomach (heartburn) 
 Bleeding in some organ(s) of the 
digestive system 
 
Blockage in an organ(s)/part(s) of 
the digestive tract 
 
Partial or complete blockage of 
the small and/or large bowel. The 
block is a functional rather than 
actual blockage of the bowel. 
 
Inflammation and/or sores in the 
mouth that may make swallowing 
difficult and are painful (painful 
mouth sores) 
 
Nausea  
 
Vomiting 
 
A feeling of weakness and/or 
tiredness 
 
Reaction that can occur during or 
following infusion of the drug. 
The reaction may include fever, 
chills, rash, low blood pressure, 
and difficulty breathing 
 
Allergic reaction by your body to 
the drug product that can occur 
 
Damage of or clots in small blood 
vessels in the kidney that can cause 
complications, some of which are 
serious including abnormal destruction 
of red blood cells (hemolysis) or 
platelets (that help to clot blood) and 
kidney failure 
 
Collection of signs and symptoms that 
indicate sudden heart disease in which 
the heart does not get enough oxygen. 
Sudden symptoms such as chest pain, 
shortness of breath, or fainting could 
indicate heart disease and should be 
reported right away. Signs such as 
abnormal heart electrocardiogram 
(EKG) and blood tests can confirm 
damage to the heart. 
 
Heart failure: inability of the heart to 
adequately pump blood to supply 
oxygen to the body 
 
Decrease in heart's ability to pump 
blood during the "active" phase of the 
heartbeat (systole) 
 
Heart attack caused by a blockage or 
decreased blood supply to the heart 
 
Irregular heartbeat resulting from an 
abnormality in one of the lower 
chambers of the heart (ventricle) 
 
Ventricular fibrillation: irregular 
heartbeat that involves the lower 
chambers of the heart (ventricles) that 
results in uncoordinated contraction of 
the heart; life threatening and 
potentially fatal, needing immediate 
attention 
 
Abnormal hole between an organ of the 
digestive tract and another organ of 
tissue 
 
A tear or hole in the stomach or gut 
that can lead to serious complications 
and may require surgery to repair 
 
Development of ulcers (erosion 
(ulceration) of the lining of the 
intestines which can result in pain 
and/or bleeding 
 
Allergic reaction which can be life 
threatening and potentially fatal. This 
reaction requires immediate medical 
treatment. It may include fever, chills 
and skin rash. Less commonly 
wheezing, shortness of breath, 
swelling of the throat, drop in blood 
pressure, and rapid heart rate may 
occur. 
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immediately or may be delayed. 
The reaction may include hives, 
low blood pressure, wheezing, 
swelling of the throat, and 
difficulty breathing 
 
Infection including infection 
(collection of pus) around the 
rectum 
 
Premature opening of a wound 
along surgical stitches after 
surgery 
 
Delayed or poor wound healing 
after surgery 
 
Increase in the blood of certain 
enzymes or bilirubin (a 
substance that comes from the 
liver breaking down waste 
products) which could indicate 
liver irritation or damage 
 
Increase in the level of liver or 
bone enzyme called alkaline 
phosphatase indicating bone 
disease or liver irritation or 
damage 
 
Increased blood level of a heart 
muscle protein (troponin I) 
indicating damage to the heart 
muscle 
 
Loss of weight 
 
Loss of appetite 
 
Aches and pains in the muscles 
and joints 
 
Abnormal changes in the growth 
plate that may affect the growth 
of long bones in very young 
children.  This side effect 
appeared to be reversible after 
the treatment was stopped but 
has not been assessed with long-
term use of this drug.  
 
Destruction or death of jawbone 
 
Dizziness (or sensation of 
lightheadedness, unsteadiness, 
or giddiness) 
 
Headache or head pain 
 
Nerve damage that may cause 
pain, burning, numbness, and 
tingling in the hands and feet and 
may affect the ability to perform 
tasks that require fine 
movements 
 
Fainting 
 
Blood in the urine 
 
Protein in the urine which may 
indicate kidney damage 
 
Bleeding in the vagina 
 
Runny or stuffy nose, sneezing 
 
Leakage from stomach due to 
breakdown of an anastomosis (surgical 
connection of two separate body 
structures) 
 
Severe bleeding which can occur in the 
brain, lungs, and other parts of the 
body and which may be life threatening 
 
Stroke caused by decreased blood flow 
to the brain 
 
Damage to the brain which may lead to 
difficulty thinking, carrying out normal 
tasks, seizures (convulsions), difficulty 
seeing, blindness, or other visual 
changes, which if caught early can be 
reversed 
 
Sudden decrease in kidney function 
 
Damage to the kidneys that causes 
protein to be lost from the blood by 
leaking from the kidneys into the urine 
and causing swelling usually in the 
legs and ankles from fluid build-up in 
body tissues 
 
Severe damage to the kidneys causing 
then to stop working and resulting in 
the buildup of waste products, fluids, 
salts and minerals in the body. The 
damage may be permanent and can be 
life-threatening. 
 
Abnormal hole between part of the 
urinary system and another organ or 
tissue 
 
Abnormal hole between the vagina and 
another organ or tissue 
 
Abnormal hole between the lower 
breathing tube and the body cavity that 
surrounds the lungs 
 
An abnormal hole in the nasal septum, 
the wall inside the nose that runs down 
the middle and divides the nose into 
two sides. The presence of the hole 
can cause frequent crusting, blockage, 
bleeding, whistling while breathing, 
and running nose 
 
An abnormal hole between the tube 
that connects the mouth with the 
stomach (esophagus) AND the lining of 
the windpipe (trachea). This is a rare, 
life-threatening and potentially fatal 
complication. 
 
 
Blood clots in the arteries which can 
block the blood flow to such areas as 
the brain leading to strokes, the heart 
with possible heart attack, the 
intestines or the legs. The lack of blood 
flow can damage these organs. These 
are more common in older people with 
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 
Cough 
 
Shortness of breath 
 
Nose bleed 
 
Hoarseness or other change in 
voice 
 
Itching 
 
Skin rash  
 
Hives 
 
Formation of a blood clot that 
plugs the blood vessel and can 
lead to pain and swelling in the 
area of the clot. Such clots may 
also break loose and travel to 
another area. They can cause 
damage or be life-threatening 
depending on where they go. 
 
pre-existing problems such as heart or 
blood vessel disease. 
 
*Neutropenia (decrease in white blood cells) is a common side effect of chemotherapy 
drugs. The incidence of this event may be increased when bevacizumab is added to 
chemotherapy; there was also an increase in neutropenia-related fever and infections, 
including rare incidences of infection with fatal outcomes. 
 
In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
We hope that you will get personal medical benefit from participation in this clinical trial, but we 
cannot be certain. These potential benefits could include getting rid of the cancer for as long as 
possible. We expect that the information learned from this study will benefit other patients in the 
future.  
 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
 
 
Current standard therapy even if you do not take part in the study. Standard therapy 
is described on page 1.   
 
Taking part in another study. 
 
Please talk to your doctor about these and other options. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
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The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is included in Attachment #3. 
 
Organizations that may look at and/or copy your research or medical records for 
research, quality assurance and data analysis include: 
 
 The Children's Oncology Group 
 Representatives of the National Cancer Institute (NCI), Food and Drug  Administration  
(FDA), and other U.S. and international governmental regulatory agencies involved in  
overseeing research  
 The Institutional Review Board (IRB) of this hospital 
 The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute 
 The drug company that makes vorinostat and the drug company that makes 
bevacizumab. 
 
 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance company. There are 
no plans for the study to pay for medical treatment. Please ask about any expected added costs 
or insurance problems. Staff will be able to assist you with this. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. However by signing this form, you are not giving up any legal rights to 
seek to obtain compensation for injury. 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
If you choose to enroll on this study, this institution will receive some money from the Children’s 
Oncology Group to perform the research. You will not be paid for participation in this study.  
 
This study includes providing specimens to the researchers; there are no plans for you to profit 
from any new products developed from research done on your specimens.   
 
The NCI will supply the vorinostat and bevacizumab at no charge while you take part in this 
study. The NCI does not cover the cost of getting the vorinostat and bevacizumab ready and 
giving it to you, so you or your insurance company may have to pay for this. 
 
It is also possible that the manufacturers may not continue to provide vorinostat and/or 
bevacizumab to the NCI for some reason. If this would occur, other possible options are: 
 
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 
You might be able to get the vorinostat and/or bevacizumab from the 
manufacturers or your pharmacy but you or your insurance company may have 
to pay for it. 
 
 
If there is no vorinostat and/or bevacizumab available at all, no one will be able 
to get more and the study would close. 
 
If a problem with getting vorinostat and/or bevacizumab occurs, your study doctor will talk to you 
about these options.  
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not 
to be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled.  You will still receive medical care.   
 
You can decide to stop being in the study at any time. Leaving the study will not result in any 
penalty or loss of benefits to which you are entitled. Your doctor will still take care of you. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies institutions 
if changes must be made to the study. Members of COG meet twice a year to evaluate results 
of treatment and to plan new treatments.  
 
During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years from now since all of the people on 
the study need to have completed treatment.   
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or if you have a research related problem or you think you have 
been injured in this study, contact Dr. XXXX or your doctor at XXXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX IRB Administrator at XXXX. 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX. 
 
WHERE CAN I GET MORE INFORMATION? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor can get you this Handbook, or you can get it at www.curesearch.org/. 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615.  
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Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
 
Optional Research Questions 
 
Please note: This section of the informed consent form is about the optional research tests of 
this study. You may take part in this additional research if you want to. You can still be a part of 
the treatment study even if you say ‘no’ to taking part in these additional research tests. 
 
Please read the sentences below and think about your choice. After reading each sentence, 
check "Yes" or "No" then add your initials and date after your answer.  
 
1. You may have tumor samples from any biopsies or surgeries I may have had. I 
understand that this tissue will be used to study certain proteins and gene changes in 
high-grade glioma tumors. I understand the results will not be reported to me or to my 
doctor and will not become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
 
2. You may take samples of my blood prior to starting treatment for research about certain 
proteins and gene changes in high-grade glioma tumors. I understand the results will not 
be reported to me or to my doctor and will not become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
 
3. I agree to have special MRI scans taken for research studies at the time standard MRI 
scans are taken for my treatment if I have residual tumor on the MRI before starting 
therapy. I understand the results will not be reported to me or to my doctor and will not 
become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 
 Initials          Date 
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SIGNATURE 
 
I have been given a copy of all _____ pages of this form.  The form includes three (3) 
attachments. 
 
I have reviewed the information and have had my questions answered. I agree to take part in 
this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
 
IRB# 
IRB Approved: 
 
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Attachment #1 
Treatment and Procedures Common to all Patients with High-Grade Gliomas 
 
Central Line 
For drugs to be given by vein, your doctor will likely recommend that you have a central venous 
line placed. A description of the types of central lines is in the COG Family Handbook for 
Children with Cancer. 
 
Methods for Giving Drugs 
Drugs will be given by tablet or liquid swallowed through the mouth (PO).  
 
Chemoradiotherapy with Temozolomide  
Chemotherapy with temozolomide is commonly used during radiation therapy for newly diagnosed 
high-grade glioma. The table below shows this chemotherapy treatment.  
 
Drug  
How the drug will be given 
Days  
Temozolomide 
PO (preferably at bedtime) 
Every Day, for 42 
days 
 
Maintenance Therapy with Temozolomide 
Temozolomide is commonly used during maintenance therapy for newly diagnosed high-grade 
glioma. Each cycle of maintenance therapy lasts about 28 days. The table below shows this 
maintenance chemotherapy treatment. 
 
Drug  
How the drug will be given 
Days  
Temozolomide 
PO (preferably at bedtime) 
1 – 5 of each cycle  
 
The risks of temozolomide are shown in Attachment #2. 
 
Standard Radiation Therapy for Subjects on All Treatment Arms 
All subjects will receive standard radiation therapy while on this study. Standard radiation 
therapy for high-grade glioma is radiation therapy to the brain 5 days a week for 6 weeks. The 
amount of radiation you receive on this study will be the standard amount used to treat newly 
diagnosed high-grade glioma. The risks of standard radiation therapy are shown in Attachment 
#2.  
 
Standard Tests and Procedures 
The following tests and procedures are part of regular cancer care and may be done even if you 
do not join the study: 
 
 
Frequent labs to monitor blood counts and blood chemistries. 
 
Urine tests to measure how your kidneys are functioning. 
 
Pregnancy test for females of childbearing age before treatment begins. 
 
MRI scans to monitor your response to treatment. 
 
Tests to monitor liver functioning. 
 
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Attachment #2 
Risks of Chemotherapy Drugs and Radiation Used to Treat High-Grade Gliomas 
 
Risks and side effects related to temozolomide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Fewer red and white blood 
cells and platelets in the 
blood  
o 
a low number of red 
blood cells can make 
you feel tired and weak 
o 
a low number of white 
blood cells can make it 
easier to get infections 
o 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Loss of appetite 
 
 
 
 
Diarrhea 
 
Headache 
 
Tiredness 
 
Difficulty swallowing 
 
Dizziness 
 
Anxiety or depression 
 
Difficulty sleeping 
 
Rash 
 
Itching 
 
Increased need to urinate 
 
Urinary tract infections 
 
Mouth sores 
 
Fluid build-up in legs and 
arms 
 
Hair loss 
 
Elevation in the blood of 
certain enzymes found in 
the liver 
 
Visual disturbances that 
may cause double vision 
 
Forgetfulness or confusion 
 
Aches and pains in muscles 
and joints 
 
Pain in the abdomen 
 
Convulsions 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, 
low blood pressure, rapid 
heart rate, chills and fever 
 
Low numbers of white blood 
cells called lymphocytes 
that may last a long time and 
make it easier to get 
infections which may be 
life-threatening 
 
Partial paralysis or weakness 
of one side of the body 
 
Blood clots which may be 
life-threatening 
 
A new cancer or leukemia 
resulting from this treatment
 
 
 
Radiation Risks   
All types of radiation therapy have side effects. Some side effects depend on the location 
of the tumor.  Some go away during or soon after treatment (short-term effects), and 
others may appear later (long-term effects). In addition, the side effects of radiation can 
be made worse by other treatments that are given (surgery, chemotherapy, or other 
medicine).  There may be side effects that we do not know about yet.  The list below 
gives possible short-term and long-term side effects.  
 
Short-term: Possible short–term side effects of radiation therapy include nausea and 
vomiting; fatigue (tiredness) and loss of appetite; irritation or redness of the skin and hair 
loss corresponding to the entrance and exit points of the radiation beams; rarely there is 
peeling of the skin at the site of irradiation; if the ear canal or middle ear receives a 
significant doses there may be an increase in the amount of ear wax (cerumen), there may 
also be a feeling of fullness that may last for weeks or months although this should be 
uncommon; in general, blood counts are not reduced by treatment of small volumes of the 
brain, for those children who have received chemotherapy and G-CSF prior to radiation 
therapy there may be a transient lowering of counts during treatment although this would 
most likely be due to the prior chemotherapy. Hospitalization should not be required during 
radiation therapy. In the event that you require general anesthesia or sedation during 
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radiation therapy, the short term side effects of treatment listed above may be slightly 
worse, including fatigue and loss of appetite.  
 
Long-term: The occurrence and severity of long-term side effects of radiation therapy to the 
brain depend on the age of the patient at the time of treatment, the area of the brain that 
requires treatment, complications that arise from the tumor or treatments prior to radiation 
therapy such as surgery and chemotherapy. Growth hormone deficiency after radiation 
therapy is common. Less common are deficiencies in thyroid hormone, stress (adrenal) 
hormone, and the hormones required for puberty. Any type of hearing loss after radiation 
therapy alone occurs only in the minority of cases and many years after treatment. 
Combined with chemotherapy such as that used in this study, hearing loss maybe seen 
within one to two years after radiation therapy. Radiation therapy may affect the ability to 
learn and, generally speaking, overall performance in school. Radiation therapy may also 
affect growth and development by decreasing the growth of bone and soft tissues that are 
in the field of treatment. Permanent hair loss occurs rarely. The doses of radiation used in 
this study are generally accepted as safe, meaning that the chance of breakdown of normal 
tissue (necrosis) or significant blood vessel damage that would result in stroke or 
permanent neurologic damage is very rare. With any type of radiation therapy there is 
always the chance that another tumor may appear years later in tissues that are in the field 
of radiation. 
 
 
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Attachment #3 
Certificate of Confidentiality 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate 
protects against the involuntary release of information about subjects collected during the 
course of our covered studies.  The researchers involved in the studies cannot be forced to 
disclose the identity or any information collected in the study in any legal proceedings at 
the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject 
or his/her guardian requests the release of information in writing, the Certificate does not 
protect against that voluntary disclosure.  Furthermore, federal agencies may review our 
records under limited circumstances, such as a DHHS request for information for an audit 
or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital 
staff of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others. 
 
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SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH – PHASE II STUDY 
 
 
 
 
 
 
 
 
 
 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM  
 
ACNS0822, 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 
 
PART 2 – Comparing Three Treatments 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required. When we say “you” 
in this consent form, we mean you or your child; “we” means the doctors and other staff. 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY? 
 
This study is called a clinical trial. A clinical trial is a research study involving treatment of a 
disease in human patients. This study is organized by Children’s Oncology Group (COG). COG 
is an international research group that conducts clinical trials for children with cancer. More than 
200 hospitals in North America, Australia, New Zealand, and Europe are members of COG. 
 
You are being asked to take part in this research study because you have been diagnosed with 
a type of brain tumor called a high-grade glioma. A “high-grade” glioma is a tumor that grows 
fast and is more likely to spread.  
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard treatment for high-grade gliomas and this clinical trial.  
 
Please take your time to make your decision. Discuss it with your friends and family. We 
encourage parents to include their child in the discussion and decision to the extent that the 
child is able to understand and take part. 
 
 
WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE? 
 
Standard treatment for high-grade gliomas includes surgery to remove as much tumor as 
possible followed by radiation therapy (treatment with high-dose x-rays). Treatment may also 
include chemotherapy (anti-cancer drugs) during and after radiation treatment. Temozolomide is 
one of the chemotherapy drugs often used during radiation therapy to treat newly diagnosed 
high-grade glioma. Anti-cancer drugs, such as temozolomide, are also commonly used in 
This model informed consent form has been reviewed by the DCT/NCI and is the official consent 
document for this study. Institutions should use the sections of this document which are in bold type 
in their entirety. Editorial changes to these sections may be made as long as they do not change 
information or intent. If the local IRB insists on making deletions or more substantive modifications 
to any of the sections in bold type, they must be justified in writing by the investigator at the time of 
the institutional audit.  
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Maintenance therapy for newly diagnosed high-grade glioma. Maintenance therapy is therapy 
given after radiation therapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
High-grade gliomas are hard to treat successfully. Study doctors want to find treatments that will 
be better at getting rid of or shrinking high-grade gliomas. One thing they want to do is try using 
different chemotherapy drugs during radiation therapy. Treatment that combines chemotherapy 
and radiation therapy at the same time is called “chemoradiotherapy”. Two drugs that will be 
used in this study are vorinostat and bevacizumab.  
 
Early studies have shown that vorinostat may help radiation therapy work better to get rid of 
cancer cells. One study of adults with high-grade glioma found that vorinostat helped keep the 
cancer from getting worse over 6 months. Recently, a study was completed to find the highest 
dose of vorinostat that can be given safely to children.  
 
Study doctors also want to see if using different drugs during maintenance therapy will be better 
than treatment with temozolomide in helping to get rid of or shrink high-grade gliomas. Another 
drug that they want to try together with temozolomide is bevacizumab. Temozolomide is 
commonly used in maintenance therapy for brain tumors. It is well-tolerated and has fewer side 
effects than other drugs commonly used in maintenance therapy. Study doctors want to find out 
if adding bevacizumab to treatment with temozolomide during maintenance therapy will work 
better than temozolomide alone. Bevacizumab is a drug that works differently than traditional 
chemotherapy drugs. Cancer cells need to have a blood supply just as normal body cells do. 
Bevacizumab is an antibody that works to stop the growth of blood vessels in the tumor.  
 
In studies of adults with different types of cancer, patients who had bevacizumab added to their 
chemotherapy treatments did better than those who did not. Other studies of adults with high-
grade gliomas suggest that adding bevacizumab to treatment with other drugs is well-tolerated 
and works better than either the bevacizumab or the other drugs alone to help keep the cancer 
from getting worse. Bevacizumab was recently approved for use in adults with recurrent high-
grade glioma. Early results are available from an ongoing study of children with newly-
diagnosed brain tumors. These children are being treated with the combination of 
temozolomide, irinotecan and bevacizumab during maintenance therapy and the results to date 
suggest the combination is well-tolerated. Study doctors think the combination of temozolomide 
and bevacizumab will be well-tolerated by children who take part in this study, and that the 
combination may work better than temozolomide alone to get rid of or shrink high-grade 
gliomas. 
 
This study is being done in 3 parts. In Part 1 of this study we found the dose of vorinostat that 
can be given safely to subjects during radiation therapy. This dose will now be used in this part 
of the study, Part 2. Part 2 of this study will test and compare 3 treatments. Part 3 of this study 
will compare the 2 best treatments from Part 2. People who are in Part 2 of this study will not be 
in Part 3. We are now doing Part 2 of the study. You are being asked to enroll on Part 2 of this 
study.  
 
The goals of Part 2 of this study are to:  
 
 Find out what effects, good and/or bad, chemoradiotherapy with vorinostat followed 
by maintenance therapy with bevacizumab and temozolomide has on people with 
newly diagnosed high-grade gliomas. The combination of vorinostat with radiation 
therapy is experimental.  Maintenance therapy with bevacizumab and temozolomide 
is experimental. 
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 Find out what effects, good and/or bad, chemoradiotherapy with bevacizumab 
followed by maintenance therapy with bevacizumab and temozolomide has on 
people with newly diagnosed high-grade gliomas. The combination of bevacizumab 
with radiation therapy is experimental.  Maintenance therapy with bevacizumab and 
temozolomide is experimental. 
 
 Find out what effects, good and/or bad, chemoradiotherapy with temozolomide 
followed by maintenance therapy with bevacizumab and temozolomide has on 
people with newly diagnosed high-grade gliomas. The combination of temozolomide 
with radiation therapy is not experimental.  Maintenance therapy with bevacizumab 
and temozolomide is experimental. 
 
 
Compare the effects of the three treatments above to find out which is better at 
getting rid of or shrinking tumors and has the least amount of side effects. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
The total number of people enrolled on this study is expected to be up to 268. We enrolled 6 
patients on Part 1.  We will enroll up to 120 people on Part 2 of this study. Later, we will enroll 
up to 142 more people on Part 3 of this study. 
 
WHAT WILL HAPPEN ON THIS STUDY THAT IS RESEARCH? 
 
Random Assignment 
 
Subjects (people participating in the study) will receive one of 3 different treatment plans. The 
treatment plan they receive is decided by a process called randomization. Randomization 
means that the treatment is assigned based on chance. It is a lot like flipping a coin, except that 
it is done by computer to make sure that there are about the same number of people on each 
treatment plan of the study. The randomization process is described in the COG Family 
Handbook for Children with Cancer. 
 
Treatment Plan  
 
The treatment plans involve cancer fighting medicine called chemotherapy and radiation 
therapy. The treatment on this clinical trial takes about 12 to 14 months. It is divided into 2 
phases.  
 
The first phase of treatment is called “chemoradiotherapy”. This phase lasts about 70 days, or 
10 weeks. During this first phase, you will be given radiation therapy to the brain 5 days a week 
for 6 weeks. Within the first week of starting radiation therapy, you will begin taking one of 3 
drugs (bevacizumab, vorinostat, or temozolomide) during this phase. You will continue taking 
the drug while you receive radiation therapy. After you complete radiation therapy and the 
treatment with the drug, you will have a 4-week rest, during which no treatment is given.  
 
The second phase of treatment, called Maintenance therapy, begins after the 4-week rest 
period. During Maintenance therapy, you will not receive any further radiation therapy but you 
will have more chemotherapy. Maintenance therapy consists of 1 cycle of chemotherapy 
treatment repeated for up to a total of 12 cycles. Each cycle is 28 days long. During each cycle, 
you will receive two drugs, called bevacizumab and temozolomide. Temozolomide will be given 
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on 5 days and bevacizumab will be given on 2 days during each cycle.  Maintenance therapy 
lasts about 336 days or 11 months. 
 
The 3 treatment plans are the same except for a difference in what drug you will receive during 
chemoradiotherapy. All treatment plans will use the same radiation therapy. All treatment plans 
will use the same Maintenance chemotherapy.  
 
The 3 treatment arms are called Arm A, Arm B, and Arm C as follows: 
 
 Arm A: Chemoradiotherapy with vorinostat followed by maintenance chemotherapy 
with bevacizumab and temozolomide. 
 
 Arm B: Chemoradiotherapy with temozolomide followed by maintenance 
chemotherapy with bevacizumab and temozolomide. 
 
 Arm C: Chemoradiotherapy with bevacizumab followed by maintenance 
chemotherapy with bevacizumab and temozolomide. 
 
Randomization 
 
Randomization: Subjects will be randomized to either Arm A with vorinostat, Arm B with 
temozolomide, or Arm C with bevacizumab. The radiation therapy itself will be the same in all 
groups of subjects. Maintenance therapy will also be the same in all groups of subjects. 
 
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Chemoradiotherapy Treatment for Subjects who are on Treatment Arm A 
Subjects on Arm A will receive vorinostat during the chemoradiotherapy phase of treatment. The 
experimental treatment is using vorinostat instead of temozolomide. 
 
Drug 
How the drug will be given  
Days 
Vorinostat 
PO 
(1 to 2 hours before radiation 
therapy is given) 
1-5, 8-12, 15-19, 
22-26, 29-33, 36-40 
 
If you vomit the dose within 30 minutes and the pill is visible, repeat the same dose. If you vomit 
30 minutes after taking the dose or take the liquid dose do not repeat it.  
 
Subjects on Arm A will receive the standard radiation therapy for high-grade gliomas. Standard 
radiation therapy is described in Attachment #1.  
 
Chemoradiotherapy Treatment for Subjects who are on Treatment Arm B 
Subjects on Arm B will receive temozolomide during the chemoradiotherapy phase of treatment.  
See Attachment #1. 
 
Subjects on Arm B will receive the standard radiation therapy for high-grade gliomas. Standard 
radiation therapy is described in Attachment #1.  
 
 
Chemoradiotherapy Treatment for Subjects who are on Treatment Arm C 
Subjects on Arm C will receive bevacizumab during the chemoradiotherapy phase of treatment. 
The experimental treatment is using bevacizumab instead of temozolomide. 
 
Drug 
How the drug will be given  
Days 
Bevacizumab 
IV over 90 minutes*, 2 hours 
before radiation therapy is given 
22 and 36 
*The first dose will be given over 90 minutes. If you tolerate it well and do not have any bad side effects, the second dose 
may be given over 60 minutes. Again, if tolerated, each remaining dose may be given over 30 minutes. 
 
Subjects on Arm C will receive the standard radiation therapy for high-grade gliomas. Standard 
radiation therapy is described in Attachment #1.  
 
Maintenance Chemotherapy Treatment for ALL SUBJECTS on ALL Treatment Arms 
All subjects on this study will receive the same chemotherapy drugs during Maintenance 
chemotherapy. These drugs are bevacizumab and temozolomide. The purpose of Maintenance 
chemotherapy is to kill any remaining glioma cells that may regrow and cause a relapse (cancer 
coming back). Each Maintenance cycle lasts about 28 days and the cycle may be repeated for 
up to a total of 12 cycles. Maintenance lasts about 11 months. The experimental treatment is 
using bevacizumab and temozolomide instead of temozolomide alone as maintenance therapy.  
 
Drug 
How the drug will be given  
Days 
Bevacizumab 
IV over 90 minutes* 
1 and 15 
Temozolomide 
PO 
1-5 
*The first dose will be given over 90 minutes. If you tolerate it well and do not have any bad side effects, the second dose 
may be given over 60 minutes. Again, if tolerated, each remaining dose may be given over 30 minutes. 
 
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During maintenance chemotherapy, you will have several scans done so the study doctors can 
see how the tumor is responding to treatment. You will have scans before you begin, and scans 
after you finish this part of your treatment.  You will also have scans after every two cycles of 
maintenance chemotherapy, to see if the tumor has changed.  If the tumor has not gotten larger, 
you will get more cycles of maintenance chemotherapy, up to a possible total of 12 cycles.  
 
If at any time your disease gets worse or you have serious side effects from the treatment, you 
will be taken off study therapy.  If this happens, your doctor will discuss other treatment options 
with you at that time. 
 
Research Study Tests and Procedures 
 
The following tests will be done because you are part of this study. These tests are not part of 
standard care.  
 
Some of the tissue already taken and some of the scans used to check your response to 
treatment will be sent to a central review center as part of COG quality control. 
 
If you have not yet stopped growing, you will have X-rays taken of your right knee every 12 
weeks during maintenance chemotherapy to check for normal bone growth. If the study doctors 
think it is necessary, you may also have MRI scans of both knees done after one or more of 
these X-rays. 
 
Optional Research Tests 
 
In addition to the treatment goals, we would like to use tumor and blood samples collected on 
this study to answer some research questions that might benefit future patients.  You can 
choose to be in this clinical trial without taking part in the optional biology research portion. 
Biology studies will help us find out more about how the study drugs work to destroy cancer 
cells and help us understand why some people may respond better or worse to the treatments.  
 
Tumor tissue removed during your surgery will be sent to a central lab to document the type of 
tumor you have. We would like to do some extra tests on your tumor tissue, and take some 
extra blood and do some tests on it. We would also like to do some extra imaging studies, or 
scans (special MRI scans) to study physical changes in the tumor that happen during treatment.  
 
The goals of the optional research studies are: 
 
 To study DNA from tumor and blood samples to see if certain genetic characteristics (the 
hereditary information that is passed on from cell to cell and tells the cell how to function) 
can be used to help identify people who are more likely to have a better treatment response.  
 
 To study tumor tissue and blood to see if the biological characteristics of the tissue and 
blood relate to how well a subject responds to treatment. We want to look at the amount of 
certain enzymes (proteins that help with chemical reactions in the body) found in the tumor 
that help protect it from the effects of chemotherapy. This information will help us to target 
more effective therapies against high grade glioma in the future. 
 
 To use special MRI scanning techniques that give more information about the blood flow, 
structure, and functioning of the tumor. These scans are called perfusion MRIs and diffusion 
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MRIs. They will be used together with the standard MRI scans to see if they can help 
identify people who are more likely to have a better treatment response.  
 
The table below gives information about the samples we would like to use for the optional 
research studies. 
 
Samples for Optional Research Studies  
 
Who will we ask for 
a sample? 
What Sample(s) are we 
asking for? 
When will we ask for the sample(s)? 
All subjects 
Blood 
(about 2 teaspoonfuls if 
you do not agree to allow 
us to collect tumor tissue 
and about 3 teaspoonfuls, 
if you do allow us to collect 
tumor tissue) 
 
Before treatment begins 
 
All subjects 
Tumor tissue 
At the time of surgery  
 Subjects with tumor 
visible 
on 
post-
surgery scan done 
before 
treatment 
begins 
Special MRI scans  
Before treatment begins, 
Before maintenance therapy begins, prior to 
cycle 3 and at the end of treatment. 
Although these studies are very important to understanding more about treatments for high-
grade glioma, the results of these studies will not directly affect your treatment. The test results 
will not be given back to you. 
 
 
HOW LONG IS THE STUDY? 
 
Subjects in this clinical trial are expected to receive treatment on this study for about 12 to 14 
months.  After treatment, subjects will have follow-up examinations and medical tests. We would 
like to continue to find out about your health for about 10 years after you enter the study. 
Keeping in touch with you and checking on how your health is every year for a while after you 
complete treatment helps us understand the long-term effects of the study.  
 
 
Your doctor or the study doctor may decide to take you off this study under the following 
circumstances: 
 
if he/she believes that it is in your best interest 
 
if your disease comes back during treatment 
 
if you experiences side effects from the treatment that are considered too severe 
 
if new information becomes available that shows that another treatment would be better for 
you 
 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the study doctor and your regular doctor first. They will help you 
stop safely.  
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WHAT ARE THE RISKS OF THE STUDY AND HOW ARE THE RISKS 
DIFFERENT FROM TREATMENT? 
 
Treatment Risks 
All people who receive cancer treatment are at risk of having side effects. In addition to 
killing tumor cells, cancer chemotherapy can damage normal tissue and produce side 
effects. Side effects are usually reversible when the medication is stopped but 
occasionally persist and cause serious complications. A person can die from these and 
other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be 
given to prevent or decrease nausea and vomiting. Hair loss is usually temporary but on 
very rare occasions it may be permanent. Some chemotherapy may lead to sterility. 
Sterility is the inability to have children. There is also the possibility that a second cancer 
may develop years later as a result of the chemotherapy.  
 
The risks of temozolomide, which is commonly given as treatment, and risks of standard 
radiation therapy are listed in the tables in Attachment #2.  
 
Side effects can be increased when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of 
blood cells resulting in anemia, increased chance of infection, and bleeding tendency. 
Low blood counts are described in the COG Family Handbook for Children with Cancer. You will 
be taught more about caring for your child when his or her blood counts are low.  
 
There is a risk that the treatment plan will not cure the cancer or that the cancer can go 
away after the treatment and then come back at a later date.  
 
Reproductive risks 
Women should not become pregnant and men should not father a baby while on this 
study because the drug(s) in this study can be bad for an unborn baby. If you or your 
partner can get pregnant, it is important for you to use birth control or not have sex while 
on this study. Check with your study doctor about what kind of birth control methods to 
use and how long to use them. Some birth control methods might not be approved for use 
in this study. Women should not breastfeed a baby while on this study. Also check with 
your doctor about how long you should not breastfeed after you stop the study 
treatment(s). 
 
Risks of Study 
If you are assigned to Arm B with temozolomide, there is a risk that you may not receive 
a chemoradiotherapy treatment that is better at getting rid of your cancer.  
 
If you are assigned to Arm A with vorinostat or to Arm C with bevacizumab, there is a 
risk that the experimental chemoradiotherapy treatment may not work as well as the 
chemoradiotherapy treatment with temozolomide. There is also a risk that you may have 
more side effects from the experimental chemoradiotherapy treatment.  
 
For all subjects in this study, there is the risk that the experimental combination of 
bevacizumab and temozolomide during maintenance therapy may not be as effective as 
the commonly used maintenance therapy with temozolomide alone. There is also the risk 
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that you may have more side effects from the bevacizumab and temozolomide than you 
would from temozolomide alone. The major concerns with bevacizumab are high blood 
pressure, protein in the urine that may mean kidney damage, bleeding, blood clots, heart 
damage and poor healing after surgery. These side effects are usually mild, but they can 
be life-threatening. Bevacizumab may make the side effects from temozolomide worse.  
 
The risks of the commonly used temozolomide are listed in the table on Attachment #2. The 
risks and side effects related to the study drugs bevacizumab and vorinostat are shown 
in the tables below. 
 
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Risks and side effects related to Bevacizumab include those which are: 
 
 
Likely 
Less Likely 
Rare But Serious 
 
Absence of 
menstrual cycles 
(periods) and 
damage to the 
ovaries that may 
decrease the ability 
to have children in 
the future 
 
High blood pressure 
 
 
 Fever with a low white blood 
cell count which could indicate 
infection and may require 
hospitalization and treatment 
with antibiotics 
 Fewer white blood cells and red 
blood cells in the blood 
o 
a low number of white 
blood cells can make it 
easier to get infections* 
o 
a low number of red blood 
cells can make you feel 
tired and weak 
 Fast heart rate usually 
originating in an area located 
above the ventricles 
 
Vertigo; sensation of a 
spinning movement 
 General pain, pain in the chest 
(not heart-related), in the 
abdomen (belly), in the 
muscles, or in the joints 
 Inflammation of the part of the 
intestines known as the colon 
which can lead to infection, 
blood in the stools and 
abdominal (belly) pain 
 Constipation 
 
Diarrhea 
 Acid or upset stomach 
(heartburn) 
 Bleeding in some organ(s) of 
the digestive system 
 Blockage in an organ(s)/part(s) 
of the digestive tract 
 
Partial or complete blockage of 
the small and/or large bowel. 
The block is a functional rather 
than actual blockage of the 
bowel. 
 Inflammation and/or sores in 
the mouth that may make 
swallowing difficult and are 
painful (painful mouth sores) 
 
Nausea  
 
Vomiting 
 
A feeling of weakness and/or 
tiredness 
 Reaction that can occur during 
 Damage of or clots in small blood 
vessels in the kidney that can cause 
complications, some of which are 
serious including abnormal 
destruction of red blood cells 
(hemolysis) or platelets (that help to 
clot blood) and kidney failure 
 Collection of signs and symptoms 
that indicate sudden heart disease in 
which the heart does not get enough 
oxygen. Sudden symptoms such as 
chest pain, shortness of breath, or 
fainting could indicate heart disease 
and should be reported right away. 
Signs such as abnormal heart 
electrocardiogram (EKG) and blood 
tests can confirm damage to the 
heart. 
 Heart failure: inability of the heart to 
adequately pump blood to supply 
oxygen to the body 
 Decrease in heart's ability to pump 
blood during the "active" phase of 
the heartbeat (systole) 
 Heart attack caused by a blockage or 
decreased blood supply to the heart 
 Irregular heartbeat resulting from an 
abnormality in one of the lower 
chambers of the heart (ventricle) 
 Ventricular fibrillation: irregular 
heartbeat that involves the lower 
chambers of the heart (ventricles) 
that results in uncoordinated 
contraction of the heart; life 
threatening and potentially fatal, 
needing immediate attention 
 Abnormal hole between an organ of 
the digestive tract and another organ 
of tissue 
 A tear or hole in the stomach or gut 
that can lead to serious 
complications and may require 
surgery to repair 
 Development of ulcers (erosion 
(ulceration) of the lining of the 
intestines which can result in pain 
and/or bleeding 
 Allergic reaction which can be life 
threatening and potentially fatal. This 
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or following infusion of the 
drug. The reaction may include 
fever, chills, rash, low blood 
pressure, and difficulty 
breathing 
 Allergic reaction by your body 
to the drug product that can 
occur immediately or may be 
delayed. The reaction may 
include hives, low blood 
pressure, wheezing, swelling of 
the throat, and difficulty 
breathing 
 Infection including infection 
(collection of pus) around the 
rectum 
 Premature opening of a wound 
along surgical stitches after 
surgery 
 Delayed or poor wound healing 
after surgery 
 Increase in the blood of certain 
enzymes or bilirubin (a 
substance that comes from the 
liver breaking down waste 
products) which could indicate 
liver irritation or damage 
 Increase in the level of liver or 
bone enzyme called alkaline 
phosphatase indicating bone 
disease or liver irritation or 
damage 
 Increased blood level of a heart 
muscle protein (troponin I) 
indicating damage to the heart 
muscle 
 Loss of weight 
 Loss of appetite 
 Aches and pains in the muscles 
and joints 
 Abnormal changes in the 
growth plate that may affect the 
growth of long bones in very 
young children.  This side effect 
appeared to be reversible after 
the treatment was stopped but 
has not been assessed with 
long-term use of this drug.  
 Destruction or death of jawbone
 Dizziness (or sensation of 
lightheadedness, unsteadiness, 
or giddiness) 
 
Headache or head pain 
 Nerve damage that may cause 
reaction requires immediate medical 
treatment. It may include fever, chills 
and skin rash. Less commonly 
wheezing, shortness of breath, 
swelling of the throat, drop in blood 
pressure, and rapid heart rate may 
occur. 
 Leakage from stomach due to 
breakdown of an anastomosis 
(surgical connection of two separate 
body structures) 
 Severe bleeding which can occur in 
the brain, lungs, and other parts of 
the body and which may be life 
threatening 
 Stroke caused by decreased blood 
flow to the brain 
 Damage to the brain which may lead 
to difficulty thinking, carrying out 
normal tasks, seizures (convulsions), 
difficulty seeing, blindness, or other 
visual changes, which if caught early 
can be reversed 
 Sudden decrease in kidney function 
 Damage to the kidneys that causes 
protein to be lost from the blood by 
leaking from the kidneys into the 
urine and causing swelling usually in 
the legs and ankles from fluid build-
up in body tissues 
 Severe damage to the kidneys 
causing then to stop working and 
resulting in the buildup of waste 
products, fluids, salts and minerals 
in the body. The damage may be 
permanent and can be life-
threatening. 
 Abnormal hole between part of the 
urinary system and another organ or 
tissue 
 Abnormal hole between the vagina 
and another organ or tissue 
 Abnormal hole between the lower 
breathing tube and the body cavity 
that surrounds the lungs 
 An abnormal hole in the nasal 
septum, the wall inside the nose that 
runs down the middle and divides the 
nose into two sides. The presence of 
the hole can cause frequent crusting, 
blockage, bleeding, whistling while 
breathing, and running nose 
 An abnormal hole between the tube 
that connects the mouth with the 
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pain, burning, numbness, and 
tingling in the hands and feet 
and may affect the ability to 
perform tasks that require fine 
movements 
 Fainting 
 Blood in the urine 
 Protein in the urine which may 
indicate kidney damage 
 Bleeding in the vagina 
 Runny or stuffy nose, sneezing 
 Cough 
 Shortness of breath 
 Nose bleed 
 Hoarseness or other change in 
voice 
 Itching 
 Skin rash  
 Hives 
 Formation of a blood clot that 
plugs the blood vessel and can 
lead to pain and swelling in the 
area of the clot. Such clots may 
also break loose and travel to 
another area. They can cause 
damage or be life-threatening 
depending on where they go. 
 
stomach (esophagus) AND the lining 
of the windpipe (trachea). This is a 
rare, life-threatening and potentially 
fatal complication. 
 
 Blood clots in the arteries which can 
block the blood flow to such areas as 
the brain leading to strokes, the heart 
with possible heart attack, the 
intestines or the legs. The lack of 
blood flow can damage these organs. 
These are more common in older 
people with pre-existing problems 
such as heart or blood vessel 
disease. 
 
 
 
 
 
 
 
*Neutropenia (decrease in white blood cells) is a common side effect of chemotherapy 
drugs. The incidence of this event may be increased when bevacizumab is added to 
chemotherapy; there was also an increase in neutropenia-related fever and infections, 
including rare incidences of infection with fatal outcomes. 
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Risks and side effects related to vorinostat include those which are:  
 
 
 
 
Likely 
Less Likely
Rare but serious
 
Fewer red blood cells and 
platelets in the blood  
o 
a low number of red 
blood cells can 
make you feel tired 
and weak 
o 
a low number of platelets 
that may cause you to 
bruise and bleed more 
easily 
 
A feeling of extreme 
tiredness, weakness, 
sleepiness, or not feeling well 
that is not relieved by sleep 
 
Loss of appetite 
 
Diarrhea 
 
Nausea 
 
Vomiting 
 
 
Low numbers of white blood 
cells called lymphocytes 
and / or neutrophils that 
may make it easier to get 
infections.  The infections 
may be life threatening 
 
Low number of white blood cells 
can make it easier to get 
infections 
 
Fever (high temperature) 
 
Hair loss  
 
Constipation 
 
Excessive loss of water from the 
body  
 
Dry mouth 
 
Acid or upset stomach (heartburn) 
 
Change in the way things taste 
 
Infection 
 
Abnormally low level of the 
protein albumin in the blood.  Low 
albumin may result in leaking of 
fluid from the blood into the 
tissue  
 
Increased levels of a chemical 
(creatinine) in the blood which 
could mean kidney damage 
 
Increase in the blood of certain 
enzymes or bilirubin (a substance 
that comes from the liver 
breaking down waste products) 
which could indicate liver 
irritation or damage 
 
Increase in the level of sugar in 
the blood that may require 
treatment 
 
Abnormally low levels of certain 
salts (electrolytes) like phosphate 
and/or calcium and/or sodium, 
and/or potassium in the body 
which may require that you take 
supplements by mouth or vein  
 
An involuntary and abnormal 
contraction of muscle 
 
Loss of strength in the muscles  
 
Dizziness (or sensation of 
lightheadedness, giddiness, 
spinning or rocking) 
 
Abdominal pain  
 
Cough 
  Feeling short of breath 
 
Weight loss 
 
 
Death of skin tissue which 
could lead to surgical 
treatment and be life-
threatening 
 
 
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In addition to the risks described above, there may be unknown risks, or risks that we did not 
anticipate, associated with being in this study. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
We hope that you will get personal medical benefit from participation in this clinical trial, but we 
cannot be certain. These potential benefits could include getting rid of the cancer for as long as 
possible. We expect that the information learned from this study will benefit other patients in the 
future.  
 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
 
 
Current standard therapy even if you do not take part in the study. Standard therapy 
is described on page 1.   
 
Taking part in another study. 
 
Please talk to your doctor about these and other options. 
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WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is included in Attachment #3. 
 
Organizations that may look at and/or copy your research or medical records for 
research, quality assurance and data analysis include: 
 
 
The Children's Oncology Group 
 Representatives of the National Cancer Institute (NCI), Food and Drug  Administration  
(FDA), and other U.S. and international governmental regulatory agencies involved in  
overseeing research  
 The Institutional Review Board (IRB) of this hospital 
 The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute 
 The drug company that makes vorinostat and the drug company that makes 
bevacizumab. 
 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance company. There are 
no plans for the study to pay for medical treatment. Please ask about any expected added costs 
or insurance problems. Staff will be able to assist you with this. 
 
In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. However by signing this form, you are not giving up any legal rights to 
seek to obtain compensation for injury. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
If you choose to enroll on this study, this institution will receive some money from the Children’s 
Oncology Group to perform the research. You will not be paid for participation in this study.  
 
This study includes providing specimens to the researchers; there are no plans for you to profit 
from any new products developed from research done on your specimens.   
 
The NCI will supply the vorinostat and bevacizumab at no charge while you take part in this 
study. The NCI does not cover the cost of getting the vorinostat and bevacizumab ready and 
giving it to you, so you or your insurance company may have to pay for this. 
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It is also possible that the manufacturers may not continue to provide vorinostat and/or 
bevacizumab to the NCI for some reason. If this would occur, other possible options are: 
 
 
You might be able to get the vorinostat and/or bevacizumab from the 
manufacturers or your pharmacy but you or your insurance company may have 
to pay for it. 
 
 
If there is no vorinostat and/or bevacizumab available at all, no one will be able 
to get more and the study would close. 
 
If a problem with getting vorinostat and/or bevacizumab occurs, your study doctor will talk to you 
about these options.  
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not 
to be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled.  You will still receive medical care.   
 
You can decide to stop being in the study at any time. Leaving the study will not result in any 
penalty or loss of benefits to which you are entitled. Your doctor will still take care of you 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies institutions 
if changes must be made to the study. Members of COG meet twice a year to evaluate results 
of treatment and to plan new treatments.  
 
During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years from now since all of the people on 
the study need to have completed treatment.   
 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or if you have a research related problem or if you think you have 
been injured in this study, you may contact Dr. XXXX or your doctor at XXXXX. 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX IRB Administrator at XXXX 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX 
 
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WHERE CAN I GET MORE INFORMATION? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor can get you this Handbook, or you can get it at www.curesearch.org/. 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237).  
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 
 
A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
Optional Research Questions 
Please note: This section of the informed consent form is about the optional research tests of 
this study. You may take part in this additional research if you want to. You can still be a part of 
the treatment study even if you say ‘no’ to taking part in these additional research tests. 
 
Please read the sentences below and think about your choice. After reading each sentence, 
check "Yes" or "No" then add your initials and date after your answer.  
 
1. You may have tumor samples from any biopsies or surgeries I may have had. I 
understand that this tissue will be used to study certain proteins and gene changes in 
high-grade glioma tumors. I understand the results will not be reported to me or to my 
doctor and will not become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
 
2. You may take samples of my blood prior to starting treatment for research about certain 
proteins and gene changes in high-grade glioma tumors. I understand the results will not 
be reported to me or to my doctor and will not become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
 
3. I agree to have special MRI scans taken for research studies at the time standard MRI 
scans are taken for my treatment if I have residual tumor on the MRI before starting 
therapy. I understand the results will not be reported to me or to my doctor and will not 
become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
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SIGNATURE 
I have been given a copy of all _____ pages of this form.  The form includes three (3) 
attachments. 
 
I have reviewed the information and have had my questions answered. I agree to take part in 
this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
 
IRB# 
IRB Approved: 
 
 
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Attachment #1 
Treatment and Procedures Common to all Patients with High-Grade Gliomas 
 
Central Line 
For drugs to be given by vein, your doctor will likely recommend that you have a central venous 
line placed. A description of the types of central lines is in the COG Family Handbook for 
Children with Cancer. 
 
Methods for Giving Drugs 
Drugs will be given by tablet or liquid swallowed through the mouth (PO).  
 
Temozolomide Chemoradiotherapy for Subjects on Treatment Arm B 
Subjects on Arm B will receive a commonly used chemotherapy for newly diagnosed high-grade 
glioma during chemoradiotherapy treatment. The table below shows the chemotherapy that 
subjects on Arm B will receive.  
 
Drug  
How the drug will be given 
Days  
Temozolomide 
PO (preferably at bedtime) 
Every Day, for 42 
days 
 
Maintenance Therapy with Temozolomide 
Temozolomide is commonly used during maintenance therapy for newly diagnosed high-grade 
glioma. Each cycle of maintenance therapy lasts about 28 days. The table below shows this 
maintenance chemotherapy treatment. 
 
Drug  
How the drug will be given 
Days  
Temozolomide 
PO (preferably at bedtime) 
1 – 5 of each cycle 
 
The risks of temozolomide are shown in Attachment #2. 
 
Standard Radiation Therapy for Subjects on All Treatment Arms 
All subjects will receive standard radiation therapy while on this study. Standard radiation 
therapy for high-grade glioma is radiation therapy to the brain 5 days a week for 6 weeks. The 
amount of radiation you receive on this study will be the standard amount used to treat newly 
diagnosed high-grade glioma. The risks of standard radiation therapy are shown in Attachment 
#2.  
 
Standard Tests and Procedures 
The following tests and procedures are part of regular cancer care and may be done even if you 
do not join the study: 
 
 
Frequent labs to monitor blood counts and blood chemistries. 
 
Urine tests to measure how your kidneys are functioning. 
 
Pregnancy test for females of childbearing age before treatment begins. 
 
MRI scans to monitor your response to treatment. 
 
Tests to monitor liver functioning. 
 
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Attachment #2 
Risks of Chemotherapy Drugs and Radiation Used to Treat High-Grade Gliomas 
 
Risks and side effects related to temozolomide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Fewer red and white blood 
cells and platelets in the 
blood  
o 
a low number of red 
blood cells can make 
you feel tired and weak 
o 
a low number of white 
blood cells can make it 
easier to get infections 
o 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Loss of appetite 
 
 
 
 
Diarrhea 
 
Headache 
 
Tiredness 
 
Difficulty swallowing 
 
Dizziness 
 
Anxiety or depression 
 
Difficulty sleeping 
 
Rash 
 
Itching 
 
Increased need to urinate 
 
Urinary tract infections 
 
Mouth sores 
 
Fluid build-up in legs and 
arms 
 
Hair loss 
 
Elevation in the blood of 
certain enzymes found in 
the liver 
 
Visual disturbances that 
may cause double vision 
 
Forgetfulness or confusion 
 
Aches and pains in muscles 
and joints 
 
Pain in the abdomen 
 
Convulsions 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, 
low blood pressure, rapid 
heart rate, chills and fever 
 
Low numbers of white blood 
cells called lymphocytes 
that may last a long time and 
make it easier to get 
infections which may be 
life-threatening 
 
Partial paralysis or weakness 
of one side of the body 
 
Blood clots which may be 
life-threatening 
 
A new cancer or leukemia 
resulting from this treatment
 
 
 
Radiation Risks   
All types of radiation therapy have side effects. Some side effects depend on the location 
of the tumor.  Some go away during or soon after treatment (short-term effects), and 
others may appear later (long-term effects). In addition, the side effects of radiation can 
be made worse by other treatments that are given (surgery, chemotherapy, or other 
medicine).  There may be side effects that we do not know about yet.  The list below 
gives possible short-term and long-term side effects.  
 
Short-term: Possible short–term side effects of radiation therapy include nausea and 
vomiting; fatigue (tiredness) and loss of appetite; irritation or redness of the skin and hair 
loss corresponding to the entrance and exit points of the radiation beams; rarely there is 
peeling of the skin at the site of irradiation; if the ear canal or middle ear receives a 
significant doses there may be an increase in the amount of ear wax (cerumen), there may 
also be a feeling of fullness that may last for weeks or months although this should be 
uncommon; in general, blood counts are not reduced by treatment of small volumes of the 
brain, for those children who have received chemotherapy and G-CSF prior to radiation 
therapy there may be a transient lowering of counts during treatment although this would 
most likely be due to the prior chemotherapy. Hospitalization should not be required during 
radiation therapy. In the event that you require general anesthesia or sedation during 
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radiation therapy, the short term side effects of treatment listed above may be slightly 
worse, including fatigue and loss of appetite.  
 
Long-term: The occurrence and severity of long-term side effects of radiation therapy to the 
brain depend on the age of the patient at the time of treatment, the area of the brain that 
requires treatment, complications that arise from the tumor or treatments prior to radiation 
therapy such as surgery and chemotherapy. Growth hormone deficiency after radiation 
therapy is common. Less common are deficiencies in thyroid hormone, stress (adrenal) 
hormone, and the hormones required for puberty. Any type of hearing loss after radiation 
therapy alone occurs only in the minority of cases and many years after treatment. 
Combined with chemotherapy, such as that used in this study, hearing loss maybe seen 
within one to two years after radiation therapy. Radiation therapy may affect the ability to 
learn and, generally speaking, overall performance in school. Radiation therapy may also 
affect growth and development by decreasing the growth of bone and soft tissues that are 
in the field of treatment. Permanent hair loss occurs rarely. The doses of radiation used in 
this study are generally accepted as safe, meaning that the chance of breakdown of normal 
tissue (necrosis) or significant blood vessel damage that would result in stroke or 
permanent neurologic damage is very rare. With any type of radiation therapy there is 
always the chance that another tumor may appear years later in tissues that are in the field 
of radiation. 
 
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Attachment #3 
Certificate of Confidentiality 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate 
protects against the involuntary release of information about subjects collected during the 
course of our covered studies.  The researchers involved in the studies cannot be forced to 
disclose the identity or any information collected in the study in any legal proceedings at 
the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject 
or his/her guardian requests the release of information in writing, the Certificate does not 
protect against that voluntary disclosure.  Furthermore, federal agencies may review our 
records under limited circumstances, such as a DHHS request for information for an audit 
or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital 
staff of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others. 
  
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SAMPLE INFORMED CONSENT/PARENTAL PERMISSION FOR PARTICIPATION IN 
RESEARCH – PHASE III STUDY 
 
 
 
 
 
 
 
 
 
 
SAMPLE RESEARCH INFORMED CONSENT/PARENTAL PERMISSION FORM  
 
ACNS0822, 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 
 
PART 3 – Comparing Two Treatments 
 
If you are a parent or legal guardian of a child who may take part in this study, permission from 
you is required. The assent (agreement) of your child may also be required. When we say “you” 
in this consent form, we mean you or your child; “we” means the doctors and other staff. 
 
 
WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY? 
 
This study is called a clinical trial. A clinical trial is a research study involving treatment of a 
disease in human patients. This study is organized by Children’s Oncology Group (COG). COG 
is an international research group that conducts clinical trials for children with cancer. More than 
200 hospitals in North America, Australia, New Zealand, and Europe are members of COG. 
 
You are being asked to take part in this research study because you have been diagnosed with 
a type of brain tumor called a high-grade glioma. A “high-grade” glioma is a tumor that grows 
fast and is more likely to spread.  
 
It is common to enroll children and adolescents with cancer in a clinical trial that seeks to 
improve cancer treatment over time. Clinical trials include only people who choose to take part. 
You have a choice between a standard treatment for high-grade gliomas and this clinical trial.  
 
Please take your time to make your decision. Discuss it with your friends and family. We 
encourage parents to include their child in the discussion and decision to the extent that the 
child is able to understand and take part. 
 
 
WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE? 
 
Standard treatment for high-grade gliomas includes surgery to remove as much tumor as 
possible followed by radiation therapy (treatment with high-dose x-rays). Treatment may also 
include chemotherapy (anti-cancer drugs) during and after radiation treatment. Temozolomide is 
one of the chemotherapy drugs often used during radiation therapy to treat newly diagnosed 
This model informed consent form has been reviewed by the DCT/NCI and is the official consent 
document for this study. Institutions should use the sections of this document which are in bold type 
in their entirety. Editorial changes to these sections may be made as long as they do not change 
information or intent. If the local IRB insists on making deletions or more substantive modifications 
to any of the sections in bold type, they must be justified in writing by the investigator at the time of 
the institutional audit.  
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high-grade glioma. Anti-cancer drugs, such as temozolomide, are also commonly used in 
Maintenance therapy for newly diagnosed high-grade glioma. Maintenance therapy is therapy 
given after radiation therapy. 
 
WHY IS THIS STUDY BEING DONE? 
 
High-grade gliomas are hard to treat successfully. Study doctors want to find treatments that will 
be better at getting rid of or shrinking high-grade gliomas. One thing they want to do is try using 
different chemotherapy drugs during radiation therapy. Treatment that combines chemotherapy 
and radiation therapy at the same time is called “chemoradiotherapy”.  
 
Early studies have shown that vorinostat may help radiation therapy work better to get rid of 
cancer cells. One study of adults with high-grade glioma found that vorinostat helped keep the 
cancer from getting worse over 6 months. Recently, a study was completed to find the highest 
dose of vorinostat that can be given safely to children.  
 
Study doctors also want to see if using different drugs during maintenance therapy will be better 
than treatment with temozolomide in helping to get rid of or shrink high-grade gliomas. Another 
drug that they want to try together with temozolomide is bevacizumab. Temozolomide is 
commonly used in maintenance therapy for brain tumors. It is well-tolerated and has fewer side 
effects than other drugs commonly used in maintenance therapy. Study doctors want to find out 
if adding bevacizumab to treatment with temozolomide during maintenance therapy will work 
better than temozolomide alone. Bevacizumab is a drug that works differently than traditional 
chemotherapy drugs. Cancer cells need to have a blood supply just as normal body cells do. 
Bevacizumab is an antibody that works to stop the growth of blood vessels in the tumor.  
 
In studies of adults with different types of cancer, patients who had bevacizumab added to their 
chemotherapy treatments did better than those who did not. Other studies of adults with high-
grade gliomas suggest that adding bevacizumab to treatment with other drugs is well-tolerated 
and works better than either the bevacizumab or the other drugs alone to help keep the cancer 
from getting worse. Bevacizumab was recently approved for use in adults with recurrent high-
grade glioma. Early results are available from an ongoing study of children with newly-
diagnosed brain tumors. These children are being treated with the combination of 
temozolomide, irinotecan and bevacizumab during maintenance therapy and the results to date 
suggest the combination is well-tolerated. Study doctors think the combination of temozolomide 
and bevacizumab will be well-tolerated by children who take part in this study, and that the 
combination may work better than temozolomide alone to get rid of or shrink high-grade 
gliomas. 
 
This study is being done in 3 parts. Parts 1 and 2 are now finished. In Part 1, we found the dose 
of vorinostat that can be given safely to subjects during radiation therapy. In Part 2, we tested 
and compared two experimental treatments (one using vorinostat and one using bevacizumab) 
with treatment using temozolomide. Results from Part 2 showed that [insert bevacizumab or 
vorinostat] worked better than treatment with temozolomide to help keep the cancer from getting 
worse over one year. We are now doing Part 3 of the study. In Part 3, study doctors want to test 
and 
compare 
chemoradiotherapy 
using 
[insert 
bevacizumab 
or 
vorinostat] 
with 
chemoradiotherapy using temozolomide. By comparing the two treatments in another group of 
patients, study doctors hope to confirm the results seen in Part 2. You are being asked to enroll 
on Part 3 of this study.  
 
 
 
 
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The goals of Part 3 of this study are to:  
 
 
Compare the effects of two treatments to find out which is better at getting rid of or 
shrinking tumors and has the least amount of side effects. The two treatments are: 
 
 
Chemoradiotherapy with [insert either bevacizumab or vorinostat] 
followed by maintenance therapy with bevacizumab and temozolomide 
has on people with newly diagnosed high-grade gliomas. The 
combination of [insert either bevacizumab or vorinostat] with radiation 
therapy is experimental.  Maintenance therapy with bevacizumab and 
temozolomide is experimental. 
 
 
Chemoradiotherapy with temozolomide followed by maintenance therapy 
with bevacizumab and temozolomide has on people with newly 
diagnosed high-grade gliomas. The combination of temozolomide with 
radiation therapy is not experimental.  Maintenance therapy with 
bevacizumab and temozolomide is experimental. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
The total number of people enrolled on this study is expected to be up to 268. We enrolled 6 
patients on Part 1 and up to 120 people on Part 2 of this study. Now we are enrolling up to 142 
more people on Part 3 of this study. 
 
 
WHAT WILL HAPPEN ON THIS STUDY THAT IS RESEARCH? 
 
Random Assignment 
 
Subjects (people participating in the study) will receive one of 2 different treatment plans. The 
treatment plan they receive is decided by a process called randomization. Randomization 
means that the treatment is assigned based on chance. It is a lot like flipping a coin, except that 
it is done by computer to make sure that there are about the same number of people on each 
treatment plan of the study. The randomization process is described in the COG Family 
Handbook for Children with Cancer. 
 
Treatment Plan  
 
The treatment plans involve cancer fighting medicine called chemotherapy and radiation 
therapy. The treatment on this clinical trial takes about 12 to 14 months. It is divided into 2 
phases.  
 
The first phase of treatment is called “chemoradiotherapy”. This phase lasts about 70 days or 10 
weeks. During this first phase, you will be given radiation therapy to the brain 5 days a week for 
6 weeks. Within the first week of starting radiation therapy, you will begin taking one of the 2 
drugs (either [insert bevacizumab or vorinostat] or temozolomide) used during this phase. You 
will continue taking the drug while you receive radiation therapy. After you complete radiation 
therapy and treatment with the drug, you will have a 4-week rest, during which no treatment is 
given.  
 
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The second phase of treatment, called Maintenance therapy, begins after the 4-week rest 
period. During Maintenance therapy, you will not receive any further radiation therapy but you 
will have more chemotherapy. Maintenance therapy consists of 1 cycle of treatment repeated 
for up to a total of 12 cycles. Each cycle is 28 days long. During each cycle, you will receive two 
drugs called bevacizumab and temozolomide. Temozolomide will be given on 5 days and 
bevacizumab will be given on 2 days during each cycle.  Maintenance therapy lasts about 336 
days or 11 months. 
 
The 2 treatment plans are the same except for a difference in what drug you will receive during 
chemoradiotherapy. All treatment plans will use the same radiation therapy. All treatment plans 
will use the same Maintenance chemotherapy.  
 
The 2 treatment arms are called Arm A and Arm B as follows: 
 
 Arm A: Chemoradiation with [insert bevacizumab or vorinostat] followed by 
maintenance chemotherapy with bevacizumab and temozolomide. 
 
 Arm B: Chemoradiation with temozolomide followed by maintenance chemotherapy 
with bevacizumab and temozolomide. 
 
 
Randomization 
 
Participants will be randomized to receive either [insert bevacizumab or vorinostat] or 
temozolomide during radiation therapy. The radiation therapy itself will be the same in all groups of 
subjects. Maintenance therapy will also be the same in all groups of subjects. 
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Diagram of Treatment 
 
A diagram of treatment on Part 3 of this study can be seen below.  
 
 
 
 
Study Entry
ARM A
Chemoradiotherapy :
Radiation therapy (5 days each week) for 6 weeks
And
[ Vorinostat or Bevacizumab] 
And 4 week rest 
Maintenance Therapy
With
Bevacizumab and  Temozolomide
(for up to 12 months)
And scans every other cycle
ARM B
Chemoradiotherapy:
Radiation therapy (5 days each week) for 6 weeks
with
Temozolomide 
And 4 week rest 
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Treatment Plan Tables 
 
Treatment that is commonly used for newly diagnosed high-grade gliomas is described in 
Attachment #1. This includes the radiation therapy that all subjects will receive, and also the 
commonly used temozolomide chemotherapy that subjects on study treatment Arm B will 
receive during radiation therapy and that all subjects will receive during maintenance therapy. 
The following drug therapy relates to the experimental comparison of the treatment group in this 
study, and to the experimental Maintenance therapy for all subjects. 
 
Various methods will be used to give drugs: 
 
PO - Drug is given by tablet or liquid swallowed through the mouth. 
 
IV - Drug is given using a needle or tubing inserted into a vein. It can be given by IV push 
over several minutes or by infusion over minutes or hours. 
 
Most drugs on this study will be given using a needle or tubing inserted into a vein (IV). 
 
Chemoradiotherapy Treatment for Subjects on Treatment Arm A 
Subjects on Arm A will receive [insert bevacizumab or vorinostat] during the chemoradiotherapy 
phase of treatment. The experimental treatment is using [insert bevacizumab or vorinostat] 
instead of temozolomide. 
 
[insert only the row for bevacizumab or vorinostat] 
Drug 
How the drug will be given  
Days 
Vorinostat 
PO (1 to 2 hours before 
radiation therapy is given) 
1-5, 8-12, 15-19, 
22-26, 29-33, 36-40  
Bevacizumab 
IV over 90 minutes* 2 hours 
before radiation therapy is given 
22 and 36 
*The first dose will be given over 90 minutes. If you tolerate it well and do not have any bad side effects, the second dose 
may be given over 60 minutes. Again, if tolerated, each remaining dose may be given over 30 minutes. 
 
Subjects on Arm A will receive the standard radiation therapy for high-grade gliomas. Standard 
radiation therapy is described in Attachment #1.  
 
Chemoradiotherapy Treatment for Subjects who are on Treatment Arm B 
Subjects on Arm B will receive temozolomide during the chemoradiotherapy phase of treatment.  
See Attachment #1. 
 
Subjects on Arm B will receive the standard radiation therapy for high-grade gliomas. Standard 
radiation therapy is described in Attachment #1.  
 
Maintenance Chemotherapy Treatment for ALL SUBJECTS on ALL Treatment Arms 
All subjects on this study will receive the same chemotherapy drugs during Maintenance 
chemotherapy. These drugs are bevacizumab and temozolomide. The purpose of Maintenance 
chemotherapy is to kill any remaining glioma cells that may regrow and cause a relapse (cancer 
coming back). Each Maintenance cycle lasts about 28 days and the cycle may be repeated for up 
to a total of 12 cycles. Maintenance lasts about 11 months. The experimental treatment is using 
bevacizumab and temozolomide instead of temozolomide alone as maintenance therapy.  
 
 
 
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Drug 
How the drug will be given  
Days 
Bevacizumab 
IV over 90 minutes* 
1 and 15 
Temozolomide 
PO 
1-5 
*The first dose will be given over 90 minutes. If you tolerate it well and do not have any bad side effects, the second dose 
may be given over 60 minutes. Again, if tolerated, each remaining dose may be given over 30 minutes. 
 
During maintenance chemotherapy, you will have several scans done so the study doctors can 
see how the tumor is responding to treatment. You will have scans before you begin, and scans 
after you finish this part of your treatment.  You will also have scans after every two cycles of 
maintenance chemotherapy, to see if the tumor has changed.  If the tumor has not gotten larger, 
you will get more cycles of maintenance chemotherapy, up to a possible total of 12 cycles.  
 
If at any time your disease gets worse or you have serious side effects from the treatment, you 
will be taken off study therapy.  If this happens, your doctor will discuss other treatment options 
with you at that time. 
 
Research Study Tests and Procedures 
 
The following tests will be done because you are part of this study. These tests are not part of 
standard care.  
 
Some of the tissue already taken and some of the scans used to check your response to 
treatment will be sent to a central review center as part of COG quality control. 
 
If you have not yet stopped growing, you will have X-rays taken of your right knee every 12 
weeks during maintenance chemotherapy to check for normal bone growth. If the study doctors 
think it is necessary, you may also have MRI scans of both knees done after one or more of 
these X-rays. 
 
Optional Research Tests 
 
In addition to the treatment goals, we would like to use tumor and blood samples collected on 
this study to answer some research questions that might benefit future patients. You can 
choose to be in this clinical trial without taking part in the optional biology research portion. 
Biology studies will help us find out more about how the study drugs work to destroy cancer 
cells and help us understand why some people may respond better or worse to the treatments.  
 
Tumor tissue removed during your surgery will be sent to a central lab to document the type of 
tumor you have. We would like to do some extra tests on your tumor tissue, and take some 
extra blood and do some tests on it. We would also like to do some extra imaging studies, or 
scans (special MRI scans), to study physical changes in the tumor that happen during 
treatment.  
 
The goals of the optional research studies are: 
 
 To study DNA from tumor and blood samples to see if certain genetic characteristics (the 
hereditary information that is passed on from cell to cell and tells the cell how to function) 
can be used to help identify people who are more likely to have a better treatment response.  
 
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 To study tumor tissue and blood to see if the biological characteristics of the tissue relate to 
how well a subject responds to treatment. We want to look at the amount of certain enzymes 
(proteins that help with chemical reactions in the body) found in the tumor that help protect it 
from the effects of chemotherapy. This information will help us to target more effective 
therapies against high grade glioma in the future. 
 
 To use special MRI scanning techniques that give more information about the blood flow, 
structure, and functioning of the tumor. These scans are called perfusion MRIs and diffusion 
MRIs. They will be used together with the standard MRI scans to see if they can help 
identify people who are more likely to have a better treatment response.  
 
The table below gives information about the samples we would like to use for the optional 
research studies. 
 
Samples for Optional Research Studies  
 
Who will we ask for 
a sample? 
What Sample(s) are we 
asking for? 
When will we ask for the sample(s)? 
All subjects 
Blood  
(about 2 teaspoonfuls if 
you do not agree to allow 
us to collect tumor tissue 
and about 3 teaspoonfuls, 
if you do allow us to collect 
tumor tissue) 
 
Before treatment begins 
All subjects 
Tumor tissue 
At the time of surgery 
Subjects with tumor 
visible 
on 
post-
surgery scan done 
before 
treatment 
begins 
Special MRI scans  
Before treatment begins, 
Before maintenance therapy begins, prior to 
cycle 3 and at the end of treatment. 
 
Although these studies are very important to understanding more about treatments for high-
grade glioma, the results of these studies will not directly affect your treatment. The test results 
will not be given back to you. 
 
HOW LONG IS THE STUDY? 
 
Subjects in this clinical trial are expected to receive treatment on this study for about 12 to 14 
months.  After treatment, subjects will have follow-up examinations and medical tests. We would 
like to continue to find out about your health for about 10 years after you enter the study. 
Keeping in touch with you and checking on how your health is every year for a while after you 
complete treatment helps us understand the long-term effects of the study.  
 
Your doctor or the study doctor may decide to take you off this study under the following 
circumstances: 
 
if he/she believes that it is in your best interest 
 
if your disease comes back during treatment 
 
if you experiences side effects from the treatment that are considered too severe 
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 
if new information becomes available that shows that another treatment would be better for 
you 
You can stop participating at any time. However, if you decide to stop participating in the study, 
we encourage you to talk to the study doctor and your regular doctor first. They will help you 
stop safely.  
 
 
WHAT ARE THE RISKS OF THE STUDY AND HOW ARE THE RISKS 
DIFFERENT FROM TREATMENT? 
 
Treatment Risks 
All people who receive cancer treatment are at risk of having side effects. In addition to 
killing tumor cells, cancer chemotherapy can damage normal tissue and produce side 
effects. Side effects are usually reversible when the medication is stopped but 
occasionally persist and cause serious complications. A person can die from these and 
other complications. 
 
Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be 
given to prevent or decrease nausea and vomiting. Hair loss is usually temporary but on 
very rare occasions it may be permanent. Some chemotherapy may lead to sterility. 
Sterility is the inability to have children. There is also the possibility that a second cancer 
may develop years later as a result of the chemotherapy.  
 
The risks of temozolomide, which is commonly given as treatment, and risks of radiation therapy 
are listed in the tables in Attachment #2.  
 
Side effects can be increased when chemotherapy drugs are combined. 
 
The most common serious side effect from cancer treatment is lowering of the number of 
blood cells resulting in anemia, increased chance of infection, and bleeding tendency. 
Low blood counts are described in the COG Family Handbook for Children with Cancer. You will 
be taught more about caring for your child when his or her blood counts are low.  
 
There is a risk that the treatment plan will not cure the cancer or that the cancer can go 
away after the treatment and then come back at a later date.  
 
Reproductive risks 
Women should not become pregnant and men should not father a baby while on this study 
because the drug(s) in this study can be bad for an unborn baby. If you or your partner can 
get pregnant, it is important for you to use birth control or not have sex while on this 
study. Check with your study doctor about what kind of birth control methods to use and 
how long to use them. Some birth control methods might not be approved for use in this 
study. Women should not breastfeed a baby while on this study. Also check with your 
doctor about how long you should not breastfeed after you stop the study  
 
Risks of Study 
If you are assigned to Arm B with temozolomide, there is a risk that you may not receive 
a chemoradiotherapy treatment that is better at getting rid of your cancer.  
 
If you are assigned to Arm A with [insert bevacizumab or vorinostat], there is a risk that 
the experimental chemoradiotherapy treatment may not work as well as the 
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chemoradiotherapy treatment with temozolomide.  There is also a risk that you may have 
more side effects from the experimental chemoradiotherapy treatment.  
 
For all subjects in this study, there is the risk that the experimental combination of 
bevacizumab and temozolomide during maintenance therapy may not be as effective as 
the commonly used maintenance therapy with temozolomide. There is also the risk that 
you may have more side effects from the bevacizumab and temozolomide that you would 
from temozolomide alone. The major concerns with bevacizumab are high blood 
pressure, protein in the urine that may mean kidney damage, bleeding, blood clots, heart 
damage and poor healing after surgery. These side effects are usually mild, but they can 
be life-threatening. Bevacizumab may make the side effects from temozolomide worse.  
 
The risks of the commonly used temozolomide are listed in the table on Attachment #2. The 
risks and side effects related to the study drugs bevacizumab [if vorinostat then insert 
“and vorinostat”] are shown in the tables below. 
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Risks and side effects related to Bevacizumab include those which are: 
 
 
 
 
Absence of 
menstrual cycles 
(periods) and 
damage to the 
ovaries that may 
decrease the ability 
to have children in 
the future 
 
High blood pressure 
 
 
 Fever with a low white blood 
cell count which could indicate 
infection and may require 
hospitalization and treatment 
with antibiotics 
 Fewer white blood cells and red 
blood cells in the blood 
o 
a low number of white 
blood cells can make it 
easier to get infections* 
o 
a low number of red blood 
cells can make you feel 
tired and weak 
 Fast heart rate usually 
originating in an area located 
above the ventricles 
 
Vertigo; sensation of a 
spinning movement 
 General pain, pain in the chest 
(not heart-related), in the 
abdomen (belly), in the 
muscles, or in the joints 
 Inflammation of the part of the 
intestines known as the colon 
which can lead to infection, 
blood in the stools and 
abdominal (belly) pain 
 Constipation 
 
Diarrhea 
 Acid or upset stomach 
(heartburn) 
 Bleeding in some organ(s) of 
the digestive system 
 Blockage in an organ(s)/part(s) 
of the digestive tract 
 
Partial or complete blockage of 
the small and/or large bowel. 
The block is a functional rather 
than actual blockage of the 
bowel. 
 Inflammation and/or sores in 
the mouth that may make 
swallowing difficult and are 
painful (painful mouth sores) 
 
Nausea  
 
Vomiting 
 
A feeling of weakness and/or 
tiredness 
 Reaction that can occur during 
or following infusion of the 
drug. The reaction may include 
fever, chills, rash, low blood 
 Damage of or clots in small blood 
vessels in the kidney that can cause 
complications, some of which are 
serious including abnormal 
destruction of red blood cells 
(hemolysis) or platelets (that help to 
clot blood) and kidney failure 
 Collection of signs and symptoms 
that indicate sudden heart disease in 
which the heart does not get enough 
oxygen. Sudden symptoms such as 
chest pain, shortness of breath, or 
fainting could indicate heart disease 
and should be reported right away. 
Signs such as abnormal heart 
electrocardiogram (EKG) and blood 
tests can confirm damage to the 
heart. 
 Heart failure: inability of the heart to 
adequately pump blood to supply 
oxygen to the body 
 Decrease in heart's ability to pump 
blood during the "active" phase of 
the heartbeat (systole) 
 Heart attack caused by a blockage or 
decreased blood supply to the heart 
 Irregular heartbeat resulting from an 
abnormality in one of the lower 
chambers of the heart (ventricle) 
 Ventricular fibrillation: irregular 
heartbeat that involves the lower 
chambers of the heart (ventricles) 
that results in uncoordinated 
contraction of the heart; life 
threatening and potentially fatal, 
needing immediate attention 
 Abnormal hole between an organ of 
the digestive tract and another organ 
of tissue 
 A tear or hole in the stomach or gut 
that can lead to serious 
complications and may require 
surgery to repair 
 Development of ulcers (erosion 
(ulceration) of the lining of the 
intestines which can result in pain 
and/or bleeding 
 Allergic reaction which can be life 
threatening and potentially fatal. This 
reaction requires immediate medical 
treatment. It may include fever, chills 
and skin rash. Less commonly 
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pressure, and difficulty 
breathing 
 Allergic reaction by your body 
to the drug product that can 
occur immediately or may be 
delayed. The reaction may 
include hives, low blood 
pressure, wheezing, swelling of 
the throat, and difficulty 
breathing 
 Infection including infection 
(collection of pus) around the 
rectum 
 Premature opening of a wound 
along surgical stitches after 
surgery 
 Delayed or poor wound healing 
after surgery 
 Increase in the blood of certain 
enzymes or bilirubin (a 
substance that comes from the 
liver breaking down waste 
products) which could indicate 
liver irritation or damage 
 Increase in the level of liver or 
bone enzyme called alkaline 
phosphatase indicating bone 
disease or liver irritation or 
damage 
 Increased blood level of a heart 
muscle protein (troponin I) 
indicating damage to the heart 
muscle 
 Loss of weight 
 Loss of appetite 
 Aches and pains in the muscles 
and joints 
 Abnormal changes in the 
growth plate that may affect the 
growth of long bones in very 
young children.  This side effect 
appeared to be reversible after 
the treatment was stopped but 
has not been assessed with 
long-term use of this drug.  
 Destruction or death of jawbone
 Dizziness (or sensation of 
lightheadedness, unsteadiness, 
or giddiness) 
 
Headache or head pain 
 Nerve damage that may cause 
pain, burning, numbness, and 
tingling in the hands and feet 
and may affect the ability to 
wheezing, shortness of breath, 
swelling of the throat, drop in blood 
pressure, and rapid heart rate may 
occur. 
 Leakage from stomach due to 
breakdown of an anastomosis 
(surgical connection of two separate 
body structures) 
 Severe bleeding which can occur in 
the brain, lungs, and other parts of 
the body and which may be life 
threatening 
 Stroke caused by decreased blood 
flow to the brain 
 Damage to the brain which may lead 
to difficulty thinking, carrying out 
normal tasks, seizures (convulsions), 
difficulty seeing, blindness, or other 
visual changes, which if caught early 
can be reversed 
 Sudden decrease in kidney function 
 Damage to the kidneys that causes 
protein to be lost from the blood by 
leaking from the kidneys into the 
urine and causing swelling usually in 
the legs and ankles from fluid build-
up in body tissues 
 Severe damage to the kidneys 
causing then to stop working and 
resulting in the buildup of waste 
products, fluids, salts and minerals 
in the body. The damage may be 
permanent and can be life-
threatening. 
 Abnormal hole between part of the 
urinary system and another organ or 
tissue 
 Abnormal hole between the vagina 
and another organ or tissue 
 Abnormal hole between the lower 
breathing tube and the body cavity 
that surrounds the lungs 
 An abnormal hole in the nasal 
septum, the wall inside the nose that 
runs down the middle and divides the 
nose into two sides. The presence of 
the hole can cause frequent crusting, 
blockage, bleeding, whistling while 
breathing, and running nose 
 An abnormal hole between the tube 
that connects the mouth with the 
stomach (esophagus) AND the lining 
of the windpipe (trachea). This is a 
rare, life-threatening and potentially 
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perform tasks that require fine 
movements 
 Fainting 
 Blood in the urine 
 Protein in the urine which may 
indicate kidney damage 
 Bleeding in the vagina 
 Runny or stuffy nose, sneezing 
 Cough 
 Shortness of breath 
 Nose bleed 
 Hoarseness or other change in 
voice 
 Itching 
 Skin rash  
 Hives 
 Formation of a blood clot that 
plugs the blood vessel and can 
lead to pain and swelling in the 
area of the clot. Such clots may 
also break loose and travel to 
another area. They can cause 
damage or be life-threatening 
depending on where they go. 
 
fatal complication. 
 
 Blood clots in the arteries which can 
block the blood flow to such areas as 
the brain leading to strokes, the heart 
with possible heart attack, the 
intestines or the legs. The lack of 
blood flow can damage these organs. 
These are more common in older 
people with pre-existing problems 
such as heart or blood vessel 
disease. 
 
 
*Neutropenia (decrease in white blood cells) is a common side effect of chemotherapy 
drugs. The incidence of this event may be increased when bevacizumab is added to 
chemotherapy; there was also an increase in neutropenia-related fever and infections, 
including rare incidences of infection with fatal outcomes. 
 
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[if vorinostat, then include this table] 
Risks and side effects related to vorinostat include those which are:  
 
 
 
Likely 
Less Likely
Rare but serious
 
Fewer red blood cells and 
platelets in the blood  
o 
a low number of red 
blood cells can 
make you feel tired 
and weak 
o 
a low number of platelets 
that may cause you to 
bruise and bleed more 
easily 
 
A feeling of extreme 
tiredness, weakness, 
sleepiness, or not feeling well 
that is not relieved by sleep 
 
Loss of appetite 
 
Diarrhea 
 
Nausea 
 
Vomiting 
 
 
Low numbers of white blood 
cells called lymphocytes 
and / or neutrophils that 
may make it easier to get 
infections.  The infections 
may be life threatening 
 
Low number of white blood cells 
can make it easier to get 
infections 
 
Fever (high temperature) 
 
Hair loss  
 
Constipation 
 
Excessive loss of water from the 
body  
 
Dry mouth 
 
Acid or upset stomach (heartburn) 
 
Change in the way things taste 
 
Infection 
 
Abnormally low level of the 
protein albumin in the blood.  Low 
albumin may result in leaking of 
fluid from the blood into the 
tissue  
 
Increased levels of a chemical 
(creatinine) in the blood which 
could mean kidney damage 
 
Increase in the blood of certain 
enzymes or bilirubin (a substance 
that comes from the liver 
breaking down waste products) 
which could indicate liver 
irritation or damage 
 
Increase in the level of sugar in 
the blood that may require 
treatment 
 
Abnormally low levels of certain 
salts (electrolytes) like phosphate 
and/or calcium and/or sodium, 
and/or potassium in the body 
which may require that you take 
supplements by mouth or vein  
 
An involuntary and abnormal 
contraction of muscle 
 
Loss of strength in the muscles  
 
Dizziness (or sensation of 
lightheadedness, giddiness, 
spinning or rocking) 
 
Abdominal pain  
 
Cough 
  Feeling short of breath 
 
Weight loss 
 
 
Death of skin tissue which 
could lead to surgical 
treatment and be life-
threatening 
 
In addition to the risks described above, there may be unknown risks, or risks that we did not anticipate, associated 
with being in this study. 
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ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
We hope that you will get personal medical benefit from participation in this clinical trial, but we 
cannot be certain. These potential benefits could include getting rid of the cancer for as long as 
possible. We expect that the information learned from this study will benefit other patients in the 
future.  
 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Instead of being in this study, you have these options: 
 
 
Current standard therapy even if you do not take part in the study. Standard therapy 
is described on page 1.  
 
Taking part in another study 
 
Please talk to your doctor about these and other options. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee 
absolute confidentiality. Your personal information may be disclosed if required by law. 
 
The Children’s Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. Information about 
the certificate is included in Attachment #3. 
 
Organizations that may look at and/or copy your research or medical records for 
research, quality assurance and data analysis include: 
 
 
The Children's Oncology Group 
 Representatives of the National Cancer Institute (NCI), Food and Drug  Administration  
(FDA), and other U.S. and international governmental regulatory agencies involved in  
overseeing research  
 The Institutional Review Board (IRB) of this hospital 
 The Pediatric Central Institutional Review Board (CIRB) of the National Cancer 
Institute 
 The drug company that makes [insert if vorinostat is used: vorinostat] and the drug 
company that makes bevacizumab. 
 
WHAT ARE THE COSTS? 
 
Taking part in this study may lead to added costs to you or your insurance company. There are 
no plans for the study pay for medical treatment. Please ask about any expected added costs or 
insurance problems. Staff will be able to assist you with this. 
 
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In the case of injury or illness resulting from this study, emergency medical treatment is 
available but will be provided at the usual charge. No funds have been set aside to compensate 
you in the event of injury. However by signing this form, you are not giving up any legal rights to 
seek to obtain compensation for injury. 
 
You or your insurance company will be charged for continuing medical care and/or 
hospitalization.  
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
If you choose to enroll on this study, this institution will receive some money from the Children’s 
Oncology Group to perform the research. You will not be paid for participation in this study.  
 
This study includes providing specimens to the researchers; there are no plans for you to profit 
from any new products developed from research done on your specimens.   
 
The NCI will supply the [insert if vorinostat used in phase 3: vorinostat and] bevacizumab at no 
charge while you take part in this study. The NCI does not cover the cost of getting the [If 
vorinostat: vorinostat and] bevacizumab ready and giving it to you, so you or your insurance 
company may have to pay for this. 
 
Even though it probably won’t happen, it is possible that the manufacturers may not continue to 
provide the [insert if vorinostat used in phase 3: vorinostat and/or] bevacizumab to the NCI for 
some reason. If this does happen, other possible options are: 
 
 
You might be able to get the [insert if vorinostat used in phase 3: vorinostat 
and/or] bevacizumab from the manufacturers or your pharmacy but you or your 
insurance company may have to pay for it. 
 
 
If there is no [insert if vorinostat used in phase 3: vorinostat and/or] bevacizumab 
available at all, no one will be able to get more and the study would close. 
 
If a problem with getting [insert if vorinostat used in phase 3: vorinostat and/or] bevacizumab 
occurs, your study doctor will talk to you about these options.  
 
WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary. You may choose not to be in this study. If you decide not 
to be in this study, you will not be penalized and you will not lose any benefits to which you are 
entitled.   You will still receive medical care.   
 
You can decide to stop being in the study at any time. Leaving the study will not result in any 
penalty or loss of benefits to which you are entitled.  Your doctor will still take care of you 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay 
in this study. A committee outside of COG closely monitors study reports and notifies institutions 
if changes must be made to the study. Members of COG meet twice a year to evaluate results 
of treatment and to plan new treatments.  
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During your follow-up visits after treatment, you may ask to be given a summary of the study 
results after they are written up. This may be several years from now since all of the people on 
the study need to have completed treatment.   
 
 
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about the study or if you have a research related problem or if you think you have 
been injured in this study, you may contact Dr. XXXX or your doctor at XXXXX 
 
If you have any questions about your rights as a research participant or any problems that you 
feel you cannot discuss with the investigators, you may call XXXX IRB Administrator at XXXX 
 
If you have any questions or concerns that you feel you would like to discuss with someone who 
is not on the research team, you may also call the Patient Advocate at XXXX 
 
 
 
 
WHERE CAN I GET MORE INFORMATION? 
 
The COG Family Handbook for Children with Cancer has information about specific cancers, 
tests, treatment side effects and their management, adjusting to cancer, and resources.  Your 
doctor can get you this Handbook, or you can get it at www.curesearch.org/. 
 
Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/. 
 
If you are in the United States, you may call the NCI's Cancer Information Service at: 
1-800-4-CANCER (1-800-422-6237).  
 
Information about long term follow-up after cancer treatment can be found at: 
http://www.survivorshipguidelines.org/. 
 
A description of this clinical trial will be available at: http://www.ClinicalTrials.gov, as required by 
U.S. Law. This web site will not include information that can identify you. At most, the web site 
will include a summary of the results. You can search this web site at any time. 
 
You will get a copy of this form. You may also ask for a copy of the protocol (full study plan). 
 
Optional Research Questions 
 
Please note: This section of the informed consent form is about the optional research tests of 
this study. You may take part in this additional research if you want to. You can still be a part of 
the treatment study even if you say ‘no’ to taking part in these additional research tests. 
 
Please read the sentences below and think about your choice. After reading each sentence, 
check "Yes" or "No" then add your initials and date after your answer.  
 
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1. You may have tumor samples from any biopsies or surgeries I may have had. I 
understand that this tissue will be used to study certain proteins and gene changes in 
high-grade glioma tumors. I understand the results will not be reported to me or to my 
doctor and will not become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
2. You may take samples of my blood during treatment for research about certain proteins 
and gene changes in high-grade glioma tumors. I understand the results will not be 
reported to me or to my doctor and will not become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
 
3. I agree to have special MRI scans taken for research studies at the time standard MRI 
scans are taken for my treatment if I have residual tumor on the MRI before starting 
therapy. I understand the results will not be reported to me or to my doctor and will not 
become part of my health record. 
 
 
 
Yes_____ 
No_____ 
 
________ / _______  
 
 
 
 
 
 
 
 
 Initials          Date 
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SIGNATURE 
 
I have been given a copy of all _____ pages of this form.  The form includes three (3) 
attachments. 
 
 
I have reviewed the information and have had my questions answered. I agree to take part in 
this study. 
 
Participant 
Date  
 
 
Parent/Guardian 
Date  
 
 
Parent/Guardian 
Date  
 
 
Physician/PNP obtaining consent 
Date  
 
 
IRB# 
IRB Approved: 
 
 
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Attachment #1 
Treatment and Procedures Common to all Patients with High-Grade Gliomas 
 
Central Line 
For drugs to be given by vein, your doctor will likely recommend that you have a central venous 
line placed. A description of the types of central lines is in the COG Family Handbook for 
Children with Cancer. 
 
Methods for Giving Drugs 
Drugs will be given by tablet or liquid swallowed through the mouth (PO).  
 
Temozolomide Chemoradiotherapy for Subjects on Treatment Arm B 
Subjects on Arm B will receive a commonly used chemotherapy for newly diagnosed high-grade 
glioma during chemoradiotherapy treatment. The table below shows the chemotherapy that 
subjects on Arm B will receive.  
 
Drug  
How the drug will be given 
Days  
Temozolomide 
PO (preferably at bedtime) 
Every Day, for 42 
days 
 
 
Maintenance Therapy with Temozolomide 
Temozolomide is commonly used during maintenance therapy for newly diagnosed high-grade 
glioma. Each cycle of maintenance therapy lasts about 28 days. The table below shows this 
maintenance chemotherapy treatment. 
 
Drug  
How the drug will be given 
Days  
Temozolomide 
PO (preferably at bedtime) 
1 – 5 of each cycle 
 
The risks of temozolomide are shown in Attachment #2. 
 
Standard Radiation Therapy for Subjects on All Treatment Arms 
All subjects will receive standard radiation therapy while on this study. Standard radiation 
therapy for high-grade glioma is radiation therapy to the brain 5 days a week for 6 weeks. The 
amount of radiation you receive on this study will be the standard amount used to treat newly 
diagnosed high-grade glioma. The risks of standard radiation therapy are shown in Attachment 
#2.  
 
Standard Tests and Procedures 
The following tests and procedures are part of regular cancer care and may be done even if you 
do not join the study. 
 
Frequent labs to monitor blood counts and blood chemistries. 
 
Urine tests to measure how your kidneys are functioning. 
 
Pregnancy test for females of childbearing age before treatment begins. 
 
MRI scans to monitor your response to treatment. 
 
Tests to monitor liver functioning. 
 
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Attachment #2 
Risks of Chemotherapy Drugs and Radiation Used to Treat High-Grade Gliomas 
 
Risks and side effects related to temozolomide include those which are: 
Likely 
Less Likely 
Rare But Serious 
 
Fewer red and white blood 
cells and platelets in the 
blood  
o 
a low number of red 
blood cells can make 
you feel tired and weak 
o 
a low number of white 
blood cells can make it 
easier to get infections 
o 
a low number of 
platelets causes you to 
bruise and bleed more 
easily 
 
Nausea 
 
Vomiting 
 
Constipation 
 
Loss of appetite 
 
 
 
 
Diarrhea 
 
Headache 
 
Tiredness 
 
Difficulty swallowing 
 
Dizziness 
 
Anxiety or depression 
 
Difficulty sleeping 
 
Rash 
 
Itching 
 
Increased need to urinate 
 
Urinary tract infections 
 
Mouth sores 
 
Fluid build-up in legs and 
arms 
 
Hair loss 
 
Elevation in the blood of 
certain enzymes found in 
the liver 
 
Visual disturbances that 
may cause double vision 
 
Forgetfulness or confusion 
 
Aches and pains in muscles 
and joints 
 
Pain in the abdomen 
 
Convulsions 
 
Severe allergic reaction 
which can be life threatening 
with shortness of breath, 
low blood pressure, rapid 
heart rate, chills and fever 
 
Low numbers of white blood 
cells called lymphocytes 
that may last a long time and 
make it easier to get 
infections which may be 
life-threatening 
 
Partial paralysis or weakness 
of one side of the body 
 
Blood clots which may be 
life-threatening 
 
A new cancer or leukemia 
resulting from this treatment
 
 
 
Radiation Risks   
All types of radiation therapy have side effects. Some side effects depend on the location 
of the tumor.  Some go away during or soon after treatment (short-term effects), and 
others may appear later (long-term effects). In addition, the side effects of radiation can 
be made worse by other treatments that are given (surgery, chemotherapy, or other 
medicine).  There may be side effects that we do not know about yet.  The list below 
gives possible short-term and long-term side effects.  
 
Short-term: Possible short–term side effects of radiation therapy include nausea and 
vomiting; fatigue (tiredness) and loss of appetite; irritation or redness of the skin and hair 
loss corresponding to the entrance and exit points of the radiation beams; rarely there is 
peeling of the skin at the site of irradiation; if the ear canal or middle ear receives a 
significant doses there may be an increase in the amount of ear wax (cerumen), there may 
also be a feeling of fullness that may last for weeks or months although this should be 
uncommon; in general, blood counts are not reduced by treatment of small volumes of the 
brain, for those children who have received chemotherapy and G-CSF prior to radiation 
therapy there may be a transient lowering of counts during treatment although this would 
most likely be due to the prior chemotherapy. Hospitalization should not be required during 
radiation therapy. In the event that you require general anesthesia or sedation during 
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radiation therapy, the short term side effects of treatment listed above may be slightly 
worse, including fatigue and loss of appetite.  
 
Long-term: The occurrence and severity of long-term side effects of radiation therapy to the 
brain depend on the age of the patient at the time of treatment, the area of the brain that 
requires treatment, complications that arise from the tumor or treatments prior to radiation 
therapy such as surgery and chemotherapy. Growth hormone deficiency after radiation 
therapy is common. Less common are deficiencies in thyroid hormone, stress (adrenal) 
hormone, and the hormones required for puberty. Any type of hearing loss after radiation 
therapy alone occurs only in the minority of cases and many years after treatment. 
Combined with chemotherapy, such as that used in this study, hearing loss maybe seen 
within one to two years after radiation therapy. Radiation therapy may affect the ability to 
learn and, generally speaking, overall performance in school. Radiation therapy may also 
affect growth and development by decreasing the growth of bone and soft tissues that are 
in the field of treatment. Permanent hair loss occurs rarely. The doses of radiation used in 
this study are generally accepted as safe, meaning that the chance of breakdown of normal 
tissue (necrosis) or significant blood vessel damage that would result in stroke or 
permanent neurologic damage is very rare. With any type of radiation therapy there is 
always the chance that another tumor may appear years later in tissues that are in the field 
of radiation. 
 
 
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Attachment #3 
Certificate of Confidentiality 
 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate 
protects against the involuntary release of information about subjects collected during the 
course of our covered studies.  The researchers involved in the studies cannot be forced to 
disclose the identity or any information collected in the study in any legal proceedings at 
the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings.  However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances.  For example, if the subject 
or his/her guardian requests the release of information in writing, the Certificate does not 
protect against that voluntary disclosure.  Furthermore, federal agencies may review our 
records under limited circumstances, such as a DHHS request for information for an audit 
or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against the required reporting by hospital 
staff of information on suspected child abuse, reportable communicable diseases, and/or 
possible threat of harm to self or others. 
 
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