T,, - ., ,, - ' NOT,, - , .: Research Means A Systematic

ACNS0423
Activated: 03/21/05 Version Date: 10/23/15

Closed: 10/26/07 Amendment #: 3
Privileged Communication
FOR INVESTIGATIONAL USE ONLY
CHILDREN'S ONCOLOGY GROUP
ACNS0423
A Phase II Study of Concurrent Radiation and Temozolomide Followed by Temozolomide and

Lomustine (CCNU) in the Treatment of Children with High Grade Glioma
An Intergroup Study for Participation by COG and the Dutch Childhood Oncology Group –
SKION (Stichting Kinderoncologie Nederland)
Target Tumors
1. Anaplastic Astrocytoma (WHO III)
2. Glioblastoma Multiforme (WHO IV)
3. Gliosarcoma
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY
OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC
INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR
CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND
SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED
MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL
ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT PROVE
TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT
WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE
STUDY CHAIR
Kenneth Cohen, M.D.
Hematology/Oncology
Johns Hopkins Hospital
Pediatric Oncology
Bloomberg 11379; 1800 Orleans St.
Baltimore, MD 21287
Phone: (410) 614-5055
Fax: (410) 955-0028
E-mail: kcohen@jhmi.edu
For Group Operations and Statistics and Data Center Contacts See:
https://www.members.childrensoncologygroup.org
Version Date: 10/23/15 Page 1

ACNS0423
TABLE OF CONTENTS
SECTION PAGE
TABLE OF CONTENTS 2
STUDY COMMITTEE 5
ABSTRACT 7
EXPERIMENTAL DESIGN SCHEMA 8
1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 9
2.0 BACKGROUND 10
2.1 Introduction/Rationale for Development 10
2.2 Rationale for CCNU 11
2.3 Rationale for Temozolomide 11
2.4 Rationale for Combination 12
2.5 Biology studies/correlates 13
2.6 Gender and Race Differences 16
3.0 PATIENT ELIGIBILITY AND STUDY ENTRY 16
3.1 Study Enrollment 16
3.2 Timing of Enrollment and Start of Treatment 16
3.3 Patient Status 17
3.4 Prior Therapy 17
3.5 Contraindicated Medications 17
3.6 Organ Function Requirements 17
3.7 Pregnancy/Contraception 18
3.8 Regulatory 18
4.0 TREATMENT PLAN 18
4.1 Treatment Plan Overview 18
4.2 Chemoradiotherapy 19
4.3 Maintenance 22
5.0 DOSE MODIFICATIONS BASED ON TOXICTY 25
5.1 Dose Reduction During Chemoradiotherapy 25
5.2 Dose Reduction During Maintenance 25
6.0 DRUG INFORMATION 26
6.1 Temozolomide (Temodar ) NSC # 362856 (082005) 26
6.2 Lomustine (CCNU,Ceenu) NSC #79037 27
6.3 Maximum BSA for Obese Patients 28
7.0 REQUIRED OBSERVATIONS 28
7.1 Required Observations Before and During Protocol Therapy 28
7.2 Required Observations Following Completion of Protocol Therapy 28
8.0 SUPPORTIVE CARE 29
8.1 Venous Access 29
8.2 Antiemetics 29
8.3 Cytokine Support 29
8.4 Fever and Neutropenia 29
8.5 Prophylactic Antibiotics 29

ACNS0423
8.6 Blood Products 29

8.7 Steroids 30
9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 30
9.1 Criteria for Removal From Protocol Therapy 30
9.2 Off Study Criteria 30
10.0 STATISTICAL CONSIDERATIONS 30
10.1 Design Considerations 30
10.2 Patient Accrual 31
10.3 Study Duration 31
10.4 Study Endpoints 31
10.5 Comparison of Short-Term EFS Rate With Historical Baseline 31
10.6 Interim Monitoring 32
10.7 Analysis of Prognostic Significance of MGMT and MMR 33
10.8 Statistical Section for the Optional Biology Section 33
10.9 Gender and Ethnicity Considerations 34
11.0 EVALUATION CRITERIA 34
11.1 This Study Will Utilize The CTCAE Version 3.0 For Toxicity And Performance
Reporting 34
11.2 Methodology to Determine Tumor Measurement 34
11.3 Selection of Target and Non-Target Lesions 36
11.4 Response Criteria for Target Lesions 36
11.5 Response Criteria for Non-target Lesions 37
12.0 ADVERSE EVENT REPORTING REQUIREMENTS 37
12.1 Purpose 37
12.2 Determination of Reporting Requirements 37
12.3 Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway 38
12.4 Reporting Secondary AML/MDS 38
13.0 RECORDS AND REPORTING 39
13.1 Categories Of Research Records 39
13.2 CDUS 39
14.0 NEUROSURGICAL GUIDELINES 39
14.1 Neurosurgical Procedures 39
14.2 Definitions of Extent of Resection 40
14.3 MRI Scan Confirmation of Extent of Resection 40
14.4 Peri-operative Corticosteroids 40
15.0 RADIATION THERAPY GUIDELINES 40
15.1 Equipment 41
15.2 Target Volumes 41
15.3 Target Dose 42
15.4 Treatment Technique 43
15.5 Normal Tissue Sparing 43
15.6 Dose Calculation and Reporting 44
15.7 QA Documentation 44
15.8 Definitions of Deviations in Protocol Performance 47
16.0 NEUROPATHOLOGY GUIDELINES/BIOLOGY SPECIMEN REQUIREMENTS 47

ACNS0423
16.1 Eligible Tumors 47

16.2 Central Review 47
16.3 Required Biology Studies 48
16.4 Optional Biology Studies (strongly encouraged) 49
REFERENCES 53
APPENDIX I: PERFORMANCE STATUS SCALES/SCORES 57
APPENDIX II: TEMOZOLOMIDE AND LOMUSTINE (CCNU) DOSING 58
APPENDIX III: TEMOZOLOMIDE ADMINISTRATION AND MEDICATION DOCUMENTATION
FORM FOR CHEMORADIOTHERAPY 61
APPENDIX IV: TEMOZOLOMIDE AND LOMUSTINE (CCNU) ADMINISTRATION AND
MEDICATION DOCUMENTATION FORM FOR MAINTENANCE 63
APPENDIX V: INSTRUCTIONS FOR ADMINISTRATION OF TEMODAR AND LOMUSTINE FOR
PATIENTS UNABLE TO SWALLOW CAPSULES 66

THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY ACNS0423
STUDY COMMITTEE
STUDY CHAIR STUDY COMMITTEE MEMBERS
Kenneth Cohen, M.D. Richard Heideman, M.D.
Hematology/Oncology Hematology/Oncology
Johns Hopkins Hospital University of New Mexico School of Medicine
Pediatric Oncology MSC 10-5590
Bloomberg 11379; 1800 Orleans St. Albuquerque, NM 87131-5311
Baltimore, MD 21287 Phone: (505) 272-4461
Phone: (410) 614-5055 Fax: (505) 272-8699
Fax: (410) 955-0028 E-mail: rheideman@salud.unm.edu
E-mail: kcohen@jhmi.edu
Murali Chingtagumpala
Hematology/Oncology
Texas Children’s Cancer Center at Baylor College of
Medicine
STUDY STATISTICIAN 6621 Fannin Street CC1510
Mark Krailo, PhD Houston, TX 77030-2399
Statistics Phone: (832) 822-4200
Children’s Oncology Group Fax: (832) 825-1502
222 E. Huntington Drive, Suite 100 E-mail: mxchinta@txch.org
Monrovia, CA 91016
Phone: (626) 241-1529
Fax: (626) 445-4334
E-mail: mkrailo@childrensoncologygroup.org
Ian Pollack, M.D.

Surgery
Children's Hospital of Pittsburgh
Department of Neurosurgery
STUDY COMMITTEE MEMBERS One Children’s Hospital Drive
Peter Burger, M.D. Pittsburgh, PA 15224
Pathology Phone: (412) 692-5881
Johns Hopkins Hospital Fax: (412) 692-5921
Pathology/NeuroPathology E-mail: ian.pollack@chp.edu
600 North Wolfe Street
Pathology 7 Allen Buxton, M.A.
Baltimore, MD 21287 Statistics
Phone: (410) 955-8378 Children's Oncology Group - Operations Center
Fax: (410) 614-9310 222 E. Huntington Dr., Suite 100
E-mail: pburger@jhmi.edu Monrovia, CA 91016
Phone: (626) 241-1524
Fax: (626) 445-4334
E-mail: abuxton@childrensoncologygroup.org

Marc Rosenblum, M.D. Del Stringham, PharmD

Pathology Pharmacy
Memorial Sloan Kettering Cancer Center Childrens Hospital of Orange County
Department of Pathology Department of Pharmacy
1275 York Avenue 1201 West La Veta
New York, NY 10065 Orange, CA 92868
Phone: (212) 639-8410 Phone: (714) 509-8344
Fax: (212) 772-8521 Fax: (714) 509-8386
E-mail: rosenbl1@mskcc.org E-mail: dstringham@choc.org
Susan Fiore Shaw, RN

Nursing
SUNY Upstate Medical University
Pediatric Hematology/Oncology
750 East Adams Street Chris Williams-Hughes (Protocol Coordinator)
Syracuse, NY 13210 Children’s Oncology Group – Operations Center
Phone: (315) 464-5294 222 E. Huntington Dr., Suite 100
Fax: (315) 464-7238 Monrovia, CA 91016
E-mail: shaws@upstate.edu Phone: (303) 904-8527
Fax: (303) 904-8407
E-mail: cwilliams@childrensoncologygroup.org
Ingrid Shieh (Research Coordinator)

Children’s Oncology Group – Operations Center For Group Operations and Statistics and
222 E. Huntington Dr., Suite 100 Data Center Contacts See:
Monrovia, CA 91016 http://members.childrensoncologygroup.org
Phone: (626) 241-1533 (626) 447-0064
Fax: (626) 445-4334
E-mail: ishieh@childrensoncologygroup.org AGENT AND NSC#
Temozolomide (Temodar ) NSC# 362856
CCNU (Lomustine) NSC# 79037

STATEMENT 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 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
Children with high-grade gliomas (HGG) continue to have a poor prognosis, despite the use of
multimodality therapy including surgery, XRT and chemotherapy. Surgery alone is rarely, if ever
curative. Radiation clearly prolongs survival time but has a limited impact on long-term overall survival.
Clinical trials have provided data to support the use of adjuvant therapy in the treatment of patients with
high-grade glioma; however, the optimal agents and combination of agents remains unsettled. The
nitrosoureas have long been considered the most active chemotherapeutic agents against high-grade
gliomas, initially of interest because of their lipid solubility and ability to cross the blood-brain barrier.
Temozolomide, an oral alkylating agent, has shown significant pre-clinical and clinical activity against
high-grade gliomas, is well tolerated in children, and responses in CNS tumors have been seen in
pediatric trials. Synergistic effects of temozolomide and BCNU have been seen in mice with human
brain tumor xenografts and the combination of BCNU/temozolomide has been piloted in adults with
high-grade gliomas. A recent pediatric Phase I study (ADVL0011) determined the MTD for the
combination of temozolomide and CCNU in newly diagnosed patients with high-grade gliomas.
This trial will determine whether temozolomide given during radiation therapy followed by the
combination of temozolomide and CCNU as adjuvant therapy results in an improvement in event-free
survival compared to historical control cohorts. Temozolomide will be given concurrently with radiation
therapy to newly diagnosed children with HGG, on a 42-day schedule. Four weeks following the
completion of radiation therapy the patient will receive CCNU on day 1 and temozolomide daily for 5
days, beginning a new cycle every 42 days for a total of 6 cycles.
Biology Studies on the tumor tissue and peripheral blood are an important component of the study and
results will be correlated with outcome.

EXPERIMENTAL DESIGN SCHEMA
SURGERY
ON STUDY
CHEMORADIOTHERAPY
Radiation Therapy Dose: 54.0 Gy
with a Boost of 5.4 Gy
Temozolomide 90mg/m2/day
Daily for 42 Days
4 WEEK REST
MAINTENANCE
CCNU 90 mg/m2
Temozolomide 160mg/m2/day x 5
Every 42 Days
Total = 6 Cycles
FOLLOW-UP

1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)
1.1
To determine whether temozolomide given during radiation therapy followed by the combination of
temozolomide and CCNU as adjuvant therapy results in an improvement in event-free survival compared
to historical control cohorts.
Target tumors are:

• Anaplastic Astrocytoma
• Glioblastoma Multiforme
• Gliosarcoma
1.2
To further assess the toxicity of adjuvant treatment with CCNU and temozolomide following XRT and
concurrent temozolomide in a larger group of patients.
1.3 Laboratory Correlates
1.3.1
Investigate MGMT expression in formalin-fixed, paraffin-embedded biopsy specimens of brain tumors
using immunohistochemical methods.
1.3.2
Identify those tumors in which MGMT expression is silenced by determining promoter CpG methylation in
DNA isolated from formalin-fixed, paraffin-embedded tumor samples.
1.3.3
Investigate whether a functional MMR system is present in tumor cells by using microsatellite instability
assays to compare DNA isolated from formalin-fixed paraffin-embedded tumor samples with DNA isolated
from the patient’s peripheral blood white cells.
1.3.4
Determine p53 expression using standardized immunohistochemical techniques. p53 mutation analysis
will incorporate microdissection-based topographic genotyping and direct sequence analysis.
1.3.5
Determine MIB-1 indices in tumor samples using standardized immunohistochemical techniques.
1.3.6
Determine the frequencies of GSTM1, GSTT1, and GSTP1 allelic variants in patients with high grade
glioma.
1.3.7
Determine the level of protein expression of GSTP1 in tumor specimens.

1.3.8
Determine whether polymorphisms in GSTP1, GSTM1 and GSTT1 genes and tumor GSTP1 protein
expression are associated with survival, hypothesizing that patients with inherent low activity GST
genotypes and low GSTP1 protein expression will have increased survival time.
1.3.9
Assess whether germline polymorphisms of the GST genes are correlated with severity of chemotherapy
toxicity, hypothesizing that patients with low activity GST genotypes will have decreased clearance of the
metabolites of chemotherapy agents, and thus will have higher degree of toxicity.
1.3.10
Characterize allelic imbalance and copy number changes associated with high-grade gliomas by
Affymetrix SNP arrays.
1.3.11
Characterize gene expression changes associated with high-grade gliomas by Affymetrix U133plus2
arrays.
1.3.12
To correlate any identified chromosomal abnormalities and differentially expressed genes with clinical
parameters such as age, tumor location, degree of resection, histological grade, p53 expression,
progression free survival, overall survival, treatment responses to determine their prognostic significance.
1.3.13
Identify oncogenes and tumor suppressor genes involved in the pathogenesis and malignant phenotype of
pediatric high grade gliomas
2.0 BACKGROUND
2.1 Introduction/Rationale for Development

Children with high-grade gliomas (HGG) continue to have a poor prognosis, despite the use of
multimodality therapy including surgery, XRT and chemotherapy. Surgery is not only necessary for
histologic diagnosis, but there is general consensus that extent of tumor resection correlates with outcome
in children.1,2 However, surgery alone is rarely, if ever curative – wide regional tumor infiltration beyond
the primary tumor frustrates complete resections in all but the occasional tumor confined to polar
locations. For older children and adults, radiation therapy (RT) remains the mainstay of therapy for
HGG. With the exception of very young children, where an attempt has been made to eliminate or delay
the use of RT because of concerns regarding neurodevelopmental morbidity, all patients are considered
candidates for RT following surgery. Radiation clearly prolongs survival time,3 but has a limited impact
on long-term overall survival.
The impact of adjuvant chemotherapy on survival is somewhat controversial. The best that can be
claimed for adults is that adjuvant nitrosoureas increase the proportion of patients surviving longer than
18 months from 5-15%.3-6 The initial pediatric high-grade glioma study (CCG-943) appeared to show a
clear benefit with the addition of CCNU and vincristine to radiation therapy,7 although a later review of
the pathology showed a significant percentage of low-grade gliomas in the survivors.8 Results from the
more recent pediatric high-grade glioma study (CCG-945) indicated that an intensive 8-drug regimen
given over 18 hours (8-in-1 regimen) provided no improvement compared with the
CCNU/vincristine/prednisone regimen (p > 0.52). Among patients with centrally reviewed high-grade
histologies, 5-year progression-free survival (PFS) was 19% ± 3%.9 Among patients with centrally
reviewed high-grade gliomas whose tumors were not completely resectable (<90% of the tumor
removed), 5-year progression-free survival (PFS) was 11% ± 4%.10 Therefore, there is clearly a need for
more effective regimens.
2.2 Rationale for CCNU

The nitrosoureas have long been considered the most active chemotherapeutic agents against high-grade
gliomas, initially of interest because of their lipid solubility and ability to cross the blood-brain barrier.
The response rate from studies done in the pre-CT era in patients with recurrent malignant gliomas,
ranged between 20-50%. A prospective, randomized study of newly diagnosed patients found that the
addition of BCNU following surgery and radiation therapy resulted in a statistically significant difference
in the percentage of survivors at 18 months (19% for the combination versus 4% for those treated with
radiation therapy alone, p<0.01).4 A subsequent prospective randomized trial found that patients treated
with post-radiation BCNU had a significant increase in median survival compared to those treated with
post-radiation methylprednisone.11 A meta-analysis of more recent published randomized trials
comparing radiation therapy alone to radiation plus adjuvant nitrosourea-based chemotherapy in newly
diagnosed patients with malignant gliomas found that adjuvant chemotherapy resulted in an increase in
survival of 10.1% at 1 year and 8.6 % at 2 years.6 However, a recent large randomized trial of patients
with high-grade gliomas found no difference between patients treated with radiation therapy alone versus
those treated with radiation therapy followed by PCV chemotherapy.12 Regardless, no other
chemotherapeutic agent or biologic response modifier has produced better results and a meta-review of
the published clinical trials of adults with recurrent high-grade gliomas found that treatment with
nitrosoureas resulted in a statistically significant increase in time to tumor progression as compared to
any other drug (p=0.018).13
CCNU has the advantage of having excellent oral bioavailability and less pulmonary toxicity than BCNU
and has been used extensively in pediatric trials. In the initial pediatric high-grade glioma study (CCG-
943) appeared to show a clear benefit with the addition of CCNU and vincristine to radiation therapy.7
Although a later review of the pathology showed a significant percentage of low-grade gliomas in the
survivors,8 a subset analysis of those patient deemed to have high-grade gliomas by central review still
confirmed a significant improvement in PFS and OS in those patients treated with adjuvant
chemotherapy (R. Sposto, personal communication).
2.3 Rationale for Temozolomide

Temozolomide, an oral alkylating agent, is a prodrug of the cytotoxic triazine MTIC, which is the active
metabolite of dacarbazine (DTIC), but unlike DTIC, temozolomide spontaneously degrades to the active
compound MTIC under physiological conditions.14 The mechanism of action of temozolomide appears
to be site-specific DNA cross-linking, resulting from methylation at the O6-position of guanine.15
Temozolomide has shown significant pre-clinical16 and clinical activity against high-grade gliomas.17,18
In a Phase II study in adult patients with newly diagnosed and recurrent high-grade astrocytomas,17
major responses were seen in 5 of 10 (50%) recurrent astrocytomas and 4 of 7 (57%) newly diagnosed
patients. An additional Phase II study was reported for patients with anaplastic astrocytoma or anaplastic
oligoastrocytoma at first relapse.18 Patients with no prior exposure to chemotherapy received dosing at
200 mg/m2/day x 5 days and those with prior chemotherapy began at 150 mg/m2/day x 5 days (the dose
could be increased to 200 mg/m2/day in the absence of grade 3/4 toxicity). Objective responses were
noted in 35% patients (8% CR, 27% PR) with an additional 26% with SD. An adult trial reported by
Stupp and colleagues administered daily temozolomide during radiation therapy and on the standard 5-
day schedule in the adjuvant setting to 64 patients with newly diagnosed glioblastomas. Results were
encouraging with a median survival of 16 months and a one-year survival of 58%.19
Temozolomide is well tolerated in children, and responses in CNS tumors have been seen in pediatric
trials.20 For children without prior craniospinal radiotherapy, the recommended Phase II dose was 200

mg/m2/day x 5 days. While not the primary endpoint of the trial, stable disease or partial responses were
seen in brainstem gliomas and high-grade gliomas with 7 of 16 (64%) demonstrating stable disease or a
partial response after two cycles. One high-grade astrocytoma had a CR after 10 cycles. A European
Phase II study evaluated temozolomide in pediatric patients with recurrent high-grade gliomas. The best
response rate for patients with non-brainstem gliomas was 12% (95% CI 2-31%). The response rate
increased to 30% if stabilization of disease was included in the definition of response.21
Based on the results reported by Stupp et al in adults, a multi-institutional Phase I trial in children
utilizing a 42-day dosing schedule of TMZ during radiation therapy was done and has shown this
regimen to be well tolerated.22 With this information, COG began a group-wide Phase II study of
involved field RT with concurrent temozolomide followed by 10 cycles of adjuvant temozolomide (200
mg/m2/day x 5) in patients with newly diagnosed high-grade gliomas. The study remains in progress and
results are yet blinded.
2.4 Rationale for Combination

Plowman et al.23 reported synergistic effects of temozolomide and BCNU in mice with human brain
tumor xenografts. In mice implanted subcutaneously with advanced stage SF-295 glioblastoma cells,
single agent temozolomide, single agent BCNU, or the combination of BCNU and temozolomide resulted
in tumor growth delays of 190%, 258%, and > 492%, respectively. The BCNU/temozolomide regimen
also induced complete tumor regression in all 5 mice treated; 4 of the 5 remained tumor free when the
experiment was terminated at day 61. Furthermore, in studies of athymic mice bearing O6MGMT-positive
intracranial human CNS tumor xenografts, temozolomide showed increased activity against O6MGMT-
positive tumors compared with the activity of BCNU or procarbazine, suggesting that temozolomide may
be useful for treatment of human tumors resistant to these conventional agents.24
Five partial responses were seen among 25 adult patients with recurrent glioblastomas in a Phase I trial
of BCNU and a single dose of temozolomide.25 A Phase II study in adult patients with recurrent
glioblastomas using the MTD from the Phase I study was recently reported. BCNU 150 mg/m2 was
followed two hours later by a single oral dose of 550 mg/m2 temozolomide. Of 36 evaluable patients,
there were 2 partial responses, 2 minor responses and 19 cases of stable disease. The 6 month
progression free survival was 21% with a median overall survival of 34 weeks. Both of these were
superior to that of the historical database of patients with recurrent high-grade gliomas enrolled in prior
Phase II trials, although they did not appear different than what was seen in patients treated with the
standard 5 day regimen of temozolomide alone.26 Temozolomide has been shown to exhibit marked
schedule-dependency,27 with a greater therapeutic effect and a higher response rate when given over 5
days compared to 1 day,28 so that the comparison of a 5 day schedule of temozolomide to the
combination of BCNU with a single dose of temodar is not tremendously informative. An adult Phase I
trial evaluating the combination of BCNU and the standard 5 day regimen of temozolomide included 7
patients with recurrent high-grade gliomas. Of these, two patients had prolonged stable disease and one
patient with a recurrent glioblastoma had an 83% decrease in the size of his tumor for 19 months before
he died of an unrelated cause.29
COG recently completed a Phase I study of CCNU and temozolomide in patients with newly diagnosed
incompletely resected high-grade gliomas. Two courses of CCNU/temozolomide were given 4 weeks
apart prior to radiation therapy so that response could be assessed. Up to six additional courses of
CCNU/temozolomide were administered post-radiation therapy to patients who had at least stable
disease following the first two courses of chemotherapy. All patients received 90 mg/m2 of CCNU, while
the dose of temozolomide was escalated in cohorts using a standard Phase I design. Thirty-two patients
were enrolled and 28 were eligible for toxicity evaluation. Two of three patients receiving a
temozolomide dose of 200 mg/m2/day x 5 days with 90 mg/m2 CCNU developed hematologic DLTs.

Zero of six patients developed DLT at the next lower dose level (temozolomide dose of 160 mg/m2 with
90 mg/m2 of CCNU), which was therefore determined to be the MTD. A total of 14 evaluable patients
were accrued at the MTD, one of whom experienced a DLT (thrombocytopenia). The initial two courses
were able to be administered at 4 weeks intervals in the majority of patients at the MTD.
Myelosuppression was cumulative, with increasing need for transfusions during courses 7 and 8, which
were administered at a median of 45 and 42.5 days apart.
Twenty-six patients were evaluable for response. Fourteen patients had glioblastomas, eleven had
anaplastic astrocytomas and one patient had an anaplastic oligodendroglioma (AO). Twelve patients had
thalamic or bithalamic primaries. Following the first two courses of chemotherapy, there was one
complete response, one near complete response, one partial response (at the first dose level), three
minor/objective responses (including the patient with the AO, which was 1p negative), one mixed
response (PR at the primary site with concomitant development of metastases) and 10 patients had stable
disease. Five patients progressed early during the first four weeks of therapy, while four others were
found to have progressive disease after receiving two courses of chemotherapy.
Given the extremely high-risk patient population enrolled in this Phase I study where not all patients
received the optimal doses of drugs, the responses to the CCNU/temozolomide combination after two
courses of chemotherapy, are encouraging. The combination is well tolerated and can be given on an
outpatient basis. A study evaluating the combination of CCNU/temozolomide at the established MTD as
the maintenance chemotherapy regimen is the logical successor to the current COG study utilizing
temozolomide alone. Given the cumulative myelosuppression encountered in the Phase I trial, 6 courses
of CCNU/temozolomide (rather than 8) given 6 weeks apart will be administered starting 4 weeks after
the completion of radiation therapy.
This protocol will be the second in a series of planned clinical trials piloting new therapeutic strategies in
a small number of patients and comparing their outcome to those of historical controls. This approach
should allow for the rapid assessment of new regimens in children with HGG.
The design of this study takes into account the fact that, in addition to the therapeutic challenges posed
by these tumors, malignant gliomas have historically proven difficult to reliably classify by institutional
neuropathologists. This factor has complicated analyses of prior studies of malignant glioma (MG), in
which the frequency of discrepancies between institutional and central review diagnoses has been as high
as 30%. This can, and has, resulted in incorrect conclusions regarding response and survival. A
mechanism to address this issue prospectively is essential to ensure that the results of this study will
establish a reliable baseline against which other adjuvant approaches for these tumors can be compared.
Accordingly, all patients will have central review of their tumor by a panel of review pathologists. Final
diagnosis will require a consensus opinion.
2.5 Biology studies/correlates
2.5.1 MGMT/MMR Analysis

Known mechanisms of resistance to the DNA methylating action of both CCNU and temozolomide include both
both O6-methylguanine methyltransferase (MGMT, also referred to as alkylguanine-DNA alkyltransferase
(AGT) and DNA mismatch repair (MMR) deficiency. MGMT is the proximal mechanism of resistance;
removal of the methyl group from the O6 position of guanine to a cysteine residue within MGMT restores DNA
to the intact state, thus abolishing the cytotoxicity of chloroethylating and methylating agents such as the
nitrosoureas, procarbazine, and temozolomide. MGMT is frequently increased in malignant gliomas, and human
human studies have suggested that there is a relationship between the response to nitrosoureas and tumor MGMT
MGMT levels.30,31 Unlike chloroethylating agents like CCNU, the DNA adduct resulting from temozolomide

requires the presence of an intact MMR system. The ultimate cytotoxic event associated with temozolomide is
the initiation of futile repair efforts and subsequent induction of apoptosis. In vitro and early clinical studies
strongly suggest that a similar relationship exists between MMR32,33 and tumor response.34,35 Thus, an issue to
explore in the treatment of malignant gliomas is the potential relationship between outcome and drug resistance
resistance phenotype (tumor MMR and MGMT status). A report by Friedman et al suggested a relationship
between response to temozolomide and the immunocytochemical quantitation of MMR proteins (MSH2, MLH1)
MLH1) and MGMT among a small group of newly diagnosed adults with glioblastoma multiforme.34 To better
understand these relationships and their impact on the outcome of patients treated with temozolomide and CCNU,
CCNU, the current study will incorporate a biologic analysis of these resistance mechanisms as potential
correlates of clinical response. The information obtained may be of future value for predicting patient response to
to CCNU and/or temozolomide and suggesting the use of alternative treatments in those with unfavorable biologic
biologic profiles.
2.5.2 MIB-1/p53 analysis

This study will also provide correlative data on tumor biological and genotypic factors that may be
associated with treatment response. In particular, recent publications from the group36-38 based on the
CCG-945 clinical study cohort have demonstrated that several biological markers are strongly associated
with outcome in childhood malignant gliomas. In particular, a significant association was apparent
between p53 overexpression and outcome. Five-year progression-free survival was 44 +/- 6 percent in 74
tumors with low levels of p53 expression versus 17 +/- 6 percent in 41 tumors with p53 overexpression
(P< 0.001).36 A weaker association was observed between TP53 mutations and outcome, although a
strong interaction between age and frequency of p53 mutations was noted.37 The association between
p53 overexpression and adverse outcome was apparent even after stratifying for histologic subgrouping
(e.g., anaplastic astrocytoma or glioblastoma multiforme, P = 0.005), as well as age, extent of resection,
and tumor location (P<0.001.36 A similarly strong association was observed between MIB-1 labeling
and outcome. Five-year event-free survival was 44% +/- 6% among 71 tumors with MIB-1 indices <
18%, 30% +/- 8% in 33 tumors with indices between 18 and 36%, and 10% +/- 6% in 29 with indices >
36% (P < 0.0001).38 Prognostic value transcended histologic subgroups (P < 0.0001), and was apparent
in tumors classified as anaplastic astrocytoma (AA) (P = 0.002) and glioblastoma multiforme (GBM) (P
= 0.002), notwithstanding the independent association between MIB- 1 labeling index and histologic
diagnosis (18.2 +/- 2.36 for AA versus 29.2 +/- 2.82 for GBM, P = 0.004).
2.5.3 Glutathione Gene Analysis

GSTs belong to a family of isoenzymes that catalyze the glutathione conjugation of a variety of
electrophilic compounds including carcinogens, mutagens, cytotoxic drugs and their metabolites.39 They
catalyze detoxification of many alkylating agents including nitrosoureas.40-43 They also detoxify the free
radicals formed by chemotherapy drugs such as procarbazine and radiation or can sequester alkylating
agents and steroids by direct binding.39 Cytosolic GSTs are soluble dimeric proteins divided into eight
classes, alpha through sigma, on the basis of amino acid sequence and immunoreactivity.39,44 They are
highly heterogeneous proteins expressed virtually in all tissues, including brain.45 Polymorphism in
GSTM1 was reported by Board, who described three alleles, GSTM1*0, GSTM1*A and GSTM1*B.46
The common GSTM1*0 is deleted and homozygotes (null genotype) who comprise 42 to 60% of the
Caucasian population express no GSTM1 protein.47,48 GSTM1*A and GSTM1*B differ by one base in
exon 7 and have similar catalytic activity.49 GSTT1 is polymorphic and 13 to 26% of the Caucasian
population have homozygous deletion, and thus lack GSTT1 function.47,50 Red cells from individuals
with the null phenotype cannot conjugate glutathione with methyl bromide, dichloromethane and
ethylene oxide.51 GSTP1 polymorphisms are characterized by single nucleotide substitutions at A1404G
(exon 5), and C2294T (exon 6) resulting in amino acid changes Ile105Val and Ala114Val, respectively.52
Four alleles have been described: GSTP1*A (Ile105Ile and Ala114Ala), GSTP1*B (Ile105Val and Ala114Ala),
GSTP1*C (Ile105Val and Ala114Val), and GSTP1*D (Ile105Ile) and Ala114Val).52,53 Forty-four percent of

the Caucasian population carry GSTP1*A/*A.23 In GSTP1 variants, corresponding amino acid transitions
cause a steric change at the substrate-binding site of the enzyme, without affecting the glutathione
binding site.52 Therefore, enzyme function towards electrophilic compounds is significantly different for
the particular alleles for different substrates. For example, 1-chloro-2,4-dinitrobenzene, thiotepa and
chlorambucil, GSTP1*A allele has significantly higher activity, compared to GSTP1*B, and GSTP1*C
alleles.52,54,55
Due to their major functional importance, polymorphisms in the GST enzyme family have been
suggested to have a role in susceptibility to cancer and, in part for individual differences in response to
cancer treatment.56 Higher levels of GST pi protein expression and nuclear localization have been related
to poor outcome in adult primary glioma patients.57 Recently, in a study of 282 adult patients with
malignant glioma, the effect of GSTM1, GSTT1 and GSTP1 polymorphisms on survival and
chemotherapy toxicity was evaluated.58 In patients with anaplastic astrocytoma and anaplastic
oligodendroglioma we observed that patients who were GSTM1 null and GSTP1*A/*A had significantly
better survival (median survival not reached vs. 41 months, respectively, p=0.06). In addition patients
with the same genotype combination were 5.7 (95% CI 0.9-37.4) times more likely to experience toxicity
secondary to nitrosourea-based chemotherapy compared to the patients with other genotypes. This is the
first study that showed a relationship, albeit with borderline significance, between a drug metabolism
polymorphism and outcomes in malignant glioma. Factors such as GST polymorphisms may identify
subgroup of patients with high grade glioma who would benefit from currently available chemotherapy
regimens.
Similar relationships between GST polymorphisms and outcome have also been reported in childhood
and adult leukemia, breast and colon cancer.59-63
Individual variation in response to chemotherapeutic agents at the level of the host, and the tumor is an
understudied clinical problem. Such variability is in part genetically determined and noted to contribute to
widely disparate outcomes including complete responsiveness, toxicity, severe toxicity and drug withdrawal
and in the worst case therapeutic failure.64 We hypothesize that host germline and/or tumor variability
determines the bioavailability of certain chemotherapeutic agents. A better understanding of the role of these
metabolic polymorphisms will ultimately improve both the efficacy and safety of currently used cancer
therapeutics. There is a large gap of knowledge regarding the role of metabolic polymorphisms in regulating
the consequences of cancer treatment. Drug metabolism genes may explain individual patient differences as
well as varying response to treatment among patients. As more information is gained, genetic testing of these
polymorphisms may facilitate the development of individualized treatment approaches, selecting patients who
can tolerate higher doses of chemotherapy without increased toxicity, possibly resulting in a better outcome.
2.5.4 Genome Allelotype Analysis

Previous studies have shown that pediatric high-grade gliomas have chromosomal imbalances distinct
from those in adults and the gain of chromosome 1q may be correlated with a worse prognosis.65 The
altered transcript levels in cancer genomes are often related to gene copy number changes such as
amplification of oncogenes, and the loss of tumor suppressor genes as detected by homozygous deletion
or LOH. In the past, LOH patterns have been detected by allelotyping using restriction fragment length
polymorphism (RFLP), and later by microsatellite markers. However, due to the relative low abundance
of microsatellite markers, the resolution for whole genome scanning is limited to 5-10 cM with
commercially available primer sets, and the process for whole genome analysis is long and tedious.
Additionally, microgram quantities of genomic DNA are needed for whole genome allelotyping. With the
discovery of more than 1.4 million single nucleotide polymorphisms (SNPs) distributed throughout the
human genome at an average density of one SNP per kilobase of DNA sequence, high-resolution
genome-wide allelotyping becomes a reality. The use of high-density single nucleotide polymorphic

allele (SNP) arrays allows parallel genotyping of over 10K SNPs using a one-primer assay.66 The utility
of Affymetrix 10K SNP array in identifying LOH and copy number changes simultaneously with high
resolution in clinical samples has been confirmed.67 In an analysis of 9 pairs of blood and high-grade
glioma DNA samples, all the cytogenetic changes detected by metaphase comparative genomic
hybridization were detected based on the mapped location of all the SNPs with LOH. Several cytobands
were found to have a high frequency of LOH. Additionally, using the signal intensities from 110 normal
reference samples, the regions with chromosome copy number gains and losses at the cytoband levels
were also detected.
We hypothesize that histologically comparable gliomas exhibit diverse patterns of gene expression and
genomic alterations which may correspond with certain prognostic factors. In this study, we propose to
apply a novel whole genome allelic imbalance analysis to characterize the changes typical of high-grade
malignant gliomas, and ultimately correlate these changes with clinical outcomes in order to develop a
useful prognostic tool, as well as identify potential new targets for treatment. Additionally, we also
propose to generate expression profiles and integrate the data with whole genome LOH and copy number
changes for the identification of oncogenes and tumor suppressor genes.
2.6 Gender and Race Differences

Differences in ethnicity or gender from previous clinical trials have not been analyzed to date for response rate.
3.0 PATIENT ELIGIBILITY AND STUDY ENTRY
3.1 Study Enrollment
3.1.1 IRB Approval

Upon receipt of local IRB approval for a COG study, fax the officially signed copy to the Group
Operations Center (GOC) at: (626) 445-6715. The COG IRB Approval Fax Cover Sheet is required to
be faxed with the official approval. A copy of this cover memo can be obtained from the protocol links
area of the Protocol Section on the COG website. After this approval is recorded by GOC staff, the
institution will have access to the RDE enrollment screens.
3.1.2 Patient Registration

Prior to study enrollment, all patients must have been registered via the RDE system into the COG
Cancer Registry (Diagnosis/Registry). The patient registration application is available 24 hours a day, 7
days a week. The assigned COG patient identification number will be used to identify the patient in all
future interactions with the COG. If you have problems with registration, please refer to the online help
in the eRDE area of the COG website.
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. Please use this number as part of the labeling
information on all banking and biology specimens sent to the Biopathology Center or a COG Reference
Laboratory. If you have a question about a patient’s BPC Number, please call the Biopathology Center at (800)
347-2486.
3.2 Timing of Enrollment and Start of Treatment
3.2.1
Patients must be scheduled to begin treatment within 31 days from the time of surgical resection. If more than
one surgical resection is performed, treatment must begin within 31 days of the most recent surgical resection.

3.2.2
Patients must be enrolled before treatment begins. The date protocol therapy is projected to start must
be no later than 14 calendar days after the date of study enrollment.
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.
3.3 Patient Status
3.3.1 Age
Patients must be ≥ 3 years and < 22 years at the time of enrollment.
3.3.2 Histologic Diagnosis

Patients must have a newly diagnosed CNS tumor with one of the following histologies: Anaplastic
Astrocytoma, Glioblastoma Multiforme, Gliosarcoma. Patients must have histologic verification of
diagnosis. Patients with primary spinal cord malignant gliomas are eligible. Patients with primary
brainstem tumors are not eligible. Patients with tumors with any component of oligodendroglioma
are NOT eligible.
Patients with M+ disease (defined as evidence of neuraxis dissemination) are not eligible. Spine
MRI and CSF cytology need only be done if clinically indicated.
3.3.3
Patients must have a pre-operative and post-operative brain MRI with and without contrast or pre and post-
operative spine MRI for spinal cord primaries. The requirement for a post-operative MRI is waived for patients
who undergo biopsy only (see Section 7.1).
3.3.4 Ability to Take Oral Medication

Patients must be able to take oral medications. Medications can be given through a G-tube.
3.3.5 Performance Level

Karnofsky ≥ 50% for patients >16 years of age and Lansky ≥ 50 for children ≤ 16 years of age
(Appendix I). 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.
3.3.6 Life Expectancy

Patients must have a life expectancy of ≥ 8 weeks.
3.4 Prior Therapy

Patients must have received no prior treatment other than surgery and corticosteroids.
3.5 Contraindicated Medications

Patients on phenobarbitol (which has been shown to reduce the tumor activity of CCNU in rats) or
cimetidine (Tagamet) (which potentiates CCNU myelotoxicity) are not eligible.
3.6 Organ Function Requirements

All patients must have:
3.6.1 Adequate Bone Marrow Function Defined As

- Peripheral absolute neutrophil count (ANC) ≥ 1000/µL
- Platelet count ≥ 100,000/µL (transfusion independent)
- Hemoglobin ≥ 8 gm/dL (may be transfused)
3.6.2 Adequate Renal Function Defined As

- Serum creatinine ≤ 1.5 x institutional upper limit of normal for age or
- Creatinine clearance or radioisotope GFR ≥ lower limit of normal for age.
3.6.3 Adequate Liver Function Defined As

- Total bilirubin ≤ 1.5 x institutional upper limit of normal for age
- SGPT (ALT) ≤ 2.5 x institutional upper limit of normal for age and albumin ≥ 2 g/dL.
3.6.4 Central Nervous System Function Defined As

- Patients with seizures may be enrolled if on anticonvulsants and the seizures are well
controlled.
3.6.5 Adequate Pulmonary Function Defined As:

- No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry ≥ 94% if
there is clinical indication for determination.
3.7 Pregnancy/Contraception
Temozolomide and CCNU are potentially mutagenic and cytotoxic. Therefore, there is reason to believe
it can be harmful to a developing fetus. It is not known whether Temozolomide is excreted in human
milk and therefore, should not be used by nursing women.
Females > 13 years of age or who have achieved menarche must have a negative pregnancy test
within 2 weeks of starting treatment (urine or serum) to be eligible. Patients must agree not to
become pregnant during the trial and for 2 months afterwards. Patients who have recently delivered an
infant must agree not to breast feed while on study.
Male patients who are sexually active must agree to use an effective method of contraception.
3.8 Regulatory
3.8.1
All patients and/or their parents or legal guardians must sign a written informed consent.
3.8.2
All institutional, FDA, and NCI requirements for human studies must be met.
4.0 TREATMENT PLAN
4.1 Treatment Plan Overview

All patients must begin therapy within 31 days of surgery. Radiation will be given in standard fractions
(total dose 59.4 Gy). (See Section 15.0). During radiation, patients will receive temozolomide daily for
42 days. Patients will begin Maintenance therapy with temozolomide and lomustine (CCNU) 4 weeks
after the completion of the 42 day course of Temozolomide.
Please note that different temozolomide doses and schedules will be used during the
Chemoradiotherapy and Maintenance Phases.
There have been multiple episodes of pneumocystis carinii pneumonia reported in patients receiving
temozolomide, particularly when taking corticosteroids. For this reason, patients should receive
Pneumocystis carinii pneumonia 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 TMP/SMX prophylaxis. For this reason, TMP/SMX may not be
utilized as PCP prophylaxis during chemoradiotherapy. Monthly inhaled or IV pentamidine or an
appropriate alternative must be administered during chemoradiotherapy.
TMP/SMX may be substituted during adjuvant 5-day temozolomide. PCP prophylaxis should be
discontinued 3 months after chemotherapy has discontinued.
4.2 Chemoradiotherapy
4.2.1 Radiation Therapy

The goal of treatment planning and dose prescription is that dose to the ICRU reference point shall be 54.0 Gy
given over 6 weeks. The boost volume, when present, will receive an additional 5.4 Gy for a total of 59.4 Gy.

Reg # Accession # Reporting Period Page 1 of 2

4.2.2 Administration Schedule for a Reporting Period
Drug Route Dose Days Important Notes
Temozolomide PO 90 mg/m2/day Daily Temozolomide must begin by Day 5 of XRT. See Appendix II,
(TEMO) or for III and Appendix V for dosing and administration guidelines.
3 mg/kg/day 42 days The 42 days of temozolomide should be given regardless of the
for patients end date of XRT. It is recommended that temozolomide be
≤ 0.5 m2 given at bedtime with an antiemetic given 30 minutes prior to
the temozolomide dose. The temozolomide dose should be
rounded to the nearest 5 mg (temozolomide is available in 5
mg, 20 mg, 100 mg and 250 mg capsules).
TMP/SMX 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
8.5).
4.2.3 Therapy Delivery Map

Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on
the Therapy Delivery Map below. Make a copy of this page (record 3 weeks on each page). Enter the week,
date and day starting with day one. XRT is to be given for 6 weeks and TEMO should be given for 42 days.
Week ______ Note Patient’s: Wgt ___________kg Hgt_______cm BSA ______m2

DATE
DAY
XRT
TEMO

DATE
DAY
XRT
TEMO

DATE
DAY
XRT
TEMO
Weeks 7-11 Rest Period

Required Observations
See Section 7.1 for additional pre-study and follow-up required observations.
Observation During ChemoRadiotherapy
History, Physical Exam X1

CBC, Differential, Platelets X2
Bun, Creatinine X1
SGPT, SGOT, Bilirubin X1
1- Perform at week 7
2- Perform Weekly
OBTAIN ADDITIONAL STUDIES AS REQUIRED FOR GOOD PATIENT CARE
Comments
For Institutional Use:

COMMENTS (Must be dated; document any change from required therapy):

4.3 Maintenance
Maintenance consists of six cycles of combination chemotherapy with lomustine and temozolomide.
Maintenance will commence four weeks after the completion of radiation. The temozolomide dose (160
mg/m2) should be rounded to the nearest 5 mg (temozolomide is available in 5 mg, 20 mg, 100 mg and
250 mg capsules). The lomustine dose (90 mg/m2) should be rounded to the nearest 10 mg. See
Appendix II, IV, V for guidelines for dosing and administration of temozolomide and lomustine.
Five days of temozolomide (Days 1-5) and one dose of lomustine (on Day 1) followed by 36 days of rest
will be considered one treatment cycle. Cycles will be repeated every 42 days provided the patient has
met the following criteria:
• Peripheral absolute neutrophil count (ANC) ≥1000/µL

• Platelet Count ≥ 100,000/µL (transfusion independent)
• Serum creatinine ≤1.5 x normal for age
• Total bilirubin ≤ 1.5 x normal for age, and SGPT (ALT) or SGOT (AST) ≤ 2.5 x normal for
age.

4.3.1 Administration Schedule for a Reporting Period
Drug Route Dose Days Important Notes

Temozolomide PO 160 mg/m2/day Days 1-5 of An anti-emetic should be administered 30
(TEMO) or each 42 day minutes prior to administration. See
5.3 mg/kg/day cycle Appendix II, IV, and V for dosing and
for patients administration. The temozolomide dose
≤ 0.5m2 should be rounded to the nearest 5 mg
(temozolomide is available in 5 mg, 20
mg, 100 mg and 250 mg capsules).
Lomustine PO 90 mg/m2 or Day 1 of each 42 CCNU can be given at the same time as the
(CCNU) 3mg/kg/day day cycle. temozolomide, using the same anti-emetic
for patients (i.e. first day of given 30 minutes prior to administration.
≤ 0.5m2 temozolomide See Appendix II, IV, and V for dosing and
administration) administration. The lomustine dose should
be rounded to the nearest 10 mg
(lomustine is available in 10 mg, 40 mg
and 100 mg capsules).
4.3.2 Therapy Delivery Map

Use a copy of this page to track each patient’s cycle by entering the actual dates and doses administered on
the Therapy Delivery Map below. Make a copy of this page for every 2 cycles. Enter the week, cycle, date and
day starting with day one. This cycle should be repeated six times.
Week ______ Cycle ______

Note Patient’s: Wgt ___________kg Hgt_______cm BSA ______m2
DATE
DAY 1 2 3 4 5 6-42
TEMO Rest
CCNU Period
Week ______ Cycle ______

Note Patient’s: Wgt ___________kg Hgt_______cm BSA ______m2
DATE
DAY 1 2 3 4 5 6-42
TEMO Rest
CCNU Period

Required Observations
See Section 7.1and 7.2 for additional pre-study and follow-up required observations.
Observation During Maintenance At Completion of

Chemotherapy Therapy
History X1 X
Physical Exam X1 X
CBC, differential, Platelets X2 X4
BUN, Creatinine X1 X4
SGPT, SGOT,bilirubin X1 X4
MRI of brain with gadolinium X3 X5
1 - Prior to each cycle

2 - Weekly
3 - Prior to every other cycle
4 - Obtain on Day 42 of maintenance cycle 6. Repeat weekly until results are normal
5 – Obtain 6 weeks following the administration of cycle 6
Comments
For Institutional Use:

COMMENTS (Must be dated; document any change from required therapy):

ACNS0423
5.0 DOSE MODIFICATIONS BASED ON TOXICTY
5.1 Dose Reduction During Chemoradiotherapy
5.1.1 Non-Hematologic
If Grade 3 non-hematologic toxicity occurs which is at least possibly related to the temozolomide,
discontinue temozolomide and restart at 60 mg/m2 when the toxicity has resolved (Grade I or less). The
dose should not be re-escalated. If the toxicity recurs or does not resolve within 7 days temozolomide
should not be restarted. If grade 4 non-hematologic toxicity occurs, temozolomide should be
discontinued and not restarted and the patient should receive CCNU alone (without temozolomide) as
maintenance chemotherapy.
5.1.2 Hematologic
Grade 4 hematologic toxicity requires discontinuation of temozolomide. CBCs should be checked twice
weekly until:
Absolute neutrophil count (ANC) > 1000/µL
Platelet count > 100,000/µL (transfusion independent)
Once the counts recover, temozolomide can be restarted at 75 mg/m2. Please the Study Chair if counts
have not recovered to the above criteria within 14 days.
5.2 Dose Reduction During Maintenance

Both the Temozolomide and lomustine doses will be reduced by 25% (i.e. CCNU to 67.5 mg/m2 and
temozolomide to 120 mg/m2/day x 5) if platelets do not recover to > 100,000/µL or ANC does not
recover to > 1,000/µL by Day 49 of that course. If the ANC does not recover to > 1,000/µL and the
platelets to > 100,000/µL by day 49 on the reduced dose, no further lomustine should be given. If
lomustine is discontinued, the dose of Temozolomide in subsequent courses may be given at full dose
and the cycles administered every 4 weeks instead of every 6 weeks, provided the ANC is > 1000/µL
and platelets are > 100,000/µL prior to starting each course. The total number of maintenance courses
remains the same (i.e. six) even if temozolomide is given alone. If the ANC does not recover to ≥
1,000/µL and the platelets to ≥ 100,000/µL by day 49 of the course without lomustine, no further
chemotherapy should be given and the patient is off protocol therapy. Prophylactic G-CSF should not
be used.
Patients who experience Grade 3 or greater non-hematologic toxicity, (with the exception of nausea or
vomiting, infection or fever) which returns to Grade I or less by Day 49 will have the doses of both
lomustine and Temozolomide reduced by 25% in subsequent courses and the dose should not be re-
escalated. If drug-related non-hematologic toxicity recurs and does not improve to meet the pre-
treatment eligibility criteria by Day 49 on the reduced doses, no further chemotherapy should be given.

ACNS0423
6.0 DRUG INFORMATION
6.1 Temozolomide (Temodar ) NSC # 362856 (082005)

Source and Pharmacology: An orally administered alkylating agent, a second generation
imadazotetrazine. 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 1.13hr
(intraperitoneally) and 1.29hxr (orally) with an oral bioavailability of 0.98. Total apparent body
clearance is 100ml/min/m2 and plasma elimination half-life is ~100 minutes.
Toxicity:
Common Occasional Rare
Happens to 21-100 Happens to 5-20 children out of Happens to <5 children out of every 100
children out of every 100 every 100
Immediate: Anorexia, constipation, Abdominal pain, diarrhea, Convulsions, hemiparesis, dizziness,
Within 1-2 nausea, vomiting headache, rash, itching, urinary ataxia, confusion, dysphagia, anxiety,
days of frequency and/or infection thrombo-embolism (L)
receiving drug
Prompt: Myelosuppression Mucositis, lethargy, peripheral Prolonged l ymphopenia with increased
Within 2-3 edema risk of infection or death, amnesia,
weeks, prior to insomnia, depression, myalgia, diplopia,
next course visual changes
Delayed: Alopecia, hepatotoxicity
Anytime later
during therapy
Late: Secondary tumors or cancer
Anytime after
completion of
therapy
(L) Toxicity may also occur later.
Formulation and Stability: 5mg, 20mg, 100mg, 250mg capsules, stored at room temperature.
Guidelines for Administration: Dose should be rounded to the nearest 5mg. See Treatment and Dose
Modifications sections and Appendix II, III, IV, and V.
There is a potential for medication errors involving Temodar 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.
Temodar capsules are available in four different strengths, each a different size, and are color coded
according to strength. All capsules are available in 5-count and 20-count packages.
Capsule Strength COLOR
5 mg Green Imprint
20 mg Brown Imprint
100 mg Blue Imprint
250 mg Black Imprint
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

ACNS0423
for the course, and clearly indicate how many days of dosing the patient will have and how many days
are without Temodar 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 Temodar. It is also
important for the patient/parent to understand the number of days that they will be off the medication.
Each strength of Temodar 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 Temodar 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 Temodar from each bottle or vial to equal the total daily dose prescribed by the physician.
Supplier: Commercially available. See package insert for more detailed information.
6.2 Lomustine (CCNU,Ceenu) NSC #79037
Source and Pharmacology: CCNU is one of the orally active nitrosoureas exhibiting antitumor effect.
It alkylates DNA and RNA, and is not cross-resistant with other alkylators.
Toxicity:
Common Occasional Rare
Happens to 21-100 children out Happens to 5-20 children out Happens to <5 children out of every
of 100 of every 100 100
Immediate: Nausea, vomiting Diarrhea, stomatitis, alopecia,
Within 1-2 days of confusion, lethargy, ataxia and
receiving drug cortical blindness.
Prompt: Myelosuppression Anorexia Elevation of liver enzymes
Within 2-3 weeks, prior to
next course
Delayed: Pulmonary toxicity (L), renal
Any time later during toxicity (L), cumulative
therapy myelosuppression
Late: Cumulative myelosuppression
Any time after completion
of treatment
(L) Toxicity may also occur later
Formulation and Stability: Lomustine is supplied in the form of a white powder in 10, 40, and 100mg
capsules. The encapsulated drug is stable at room temperature for 2 years when stored in tightly closed
containers. Avoid excessive heat (> 40°C).
Guidelines for Administration: Dose should be rounded to the nearest 10 mg. See Appendix II, IV, and
V
Contraindicated Medications: Phenobarbitol (which has been shown to reduce the tumor activity of
lomustine in rats) and cimetidine (Tagamet) (which potentiates lomustine (CCNU) myelotoxicity).
Supplier: Commercially available. See package insert for more detailed information.

ACNS0423
6.3 Maximum BSA for Obese Patients

Body surface area should be capped at 2.5 m2 for both lomustine (CCNU) and temozolomide.
7.0 REQUIRED OBSERVATIONS
7.1 Required Observations Before and During Protocol Therapy

Prior to During At time of
During At Completion
Observation Study Maintenance Progression
ChemoRT of Therapy
Entry Chemo
History X Week 7 Prior to each
cycle X X
Physical Exam including Ht, Wt, X Week 7 Prior to each
BSA, VS cycle X X
Performance Status X
CBC, differential, platelets X3 Weekly Weekly X1
BUN, Creatinine X3 Week 7 Prior to each X1
cycle
SGPT, SGOT, bilirubin X3 Week 7 Prior to each X1
cycle
MRI of brain with and without X3,4 NA Prior to every X2 X7
gadolinium other cycle
MRI of spine with gadolinium X6
Pregnancy Test (Urine or Serum) X3
Required Specimens for Pathology X5 X5
(see Section 16.2) and Biology
Studies (see Section 16.3)
1. - Obtain on Day 42 of maintenance cycle 6. Repeat weekly until results are normal.
2. - Obtain 6 weeks following the administration of cycle 6.
3. - Obtain within 4 weeks of starting treatment.
4. –Obtain pre-op MRI and baseline post-op MRI needs to be done within 4 weeks of starting treatment. Post-op
MRI is not required if the patient underwent biopsy only.
5- Pathology and biology specimens must be submitted prior to starting Maintenance chemotherapy. The
blood sample (see Section 16.3) needs to be drawn prior to starting chemoradiotherapy.
6- Obtain if patient has spinal primary or if clinically indicated.
7- Submit cranial (and spinal if obtained) MRI to QARC for review. Because of the high incidence of
disseminated disease at the time of relapse, spinal MRI’s are encouraged.
7.2 Required Observations Following Completion of Protocol Therapy

Observation
3 6 9 1 1.5 2 2.5 3 3.5 Annually
Months Months Months Year Years Years Years Years Years
History X X X X X X X X X X
Physical X X X X X X X X X X
Exam
including Ht,
MRI of Brain X X X X X X X X X X
with
Gadolinium

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8.0 SUPPORTIVE CARE
8.1 Venous Access

An indwelling central venous access catheter may be necessary to facilitate the use of blood drawing in
young children.
8.2 Antiemetics
An oral serotonin receptor antagonist should be given 30-60 minutes prior to each dose of temozolomide
and CCNU and prn thereafter. Corticosteroids should not be used as an antiemetic due to the effect
on the blood-brain barrier.
8.3 Cytokine Support

Prophylactic growth factor support should not be used. Therapeutic use in patients with serious
neutropenic complications such as sepsis, fungal infection, etc. may be considered at the investigator’s
discretion.
8.4 Fever and Neutropenia

Patients who develop a fever should be evaluated for neutropenia and infection. Antibiotics should be
administered based on institutional policy.
8.5 Prophylactic Antibiotics

There have been multiple episodes of pneumocystis carinii pneumonia 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
TMP/SMX prophylaxis. For this reason, TMP/SMX should not be utilized as PCP prophylaxis during
chemoradiotherapy. Monthly inhaled or IV pentamidine or an appropriate alternative must be
administered during chemoradiotherapy.
TMP/SMX may be used as PCP prophylaxis during maintenance chemotherapy. PCP prophylaxis
should be discontinued 3 months after the completion of chemotherapy.
8.6 Blood Products
8.6.1 Platelets
Patients will be transfused as necessary with platelets to maintain the platelet count > 30,000/µL (or
higher if clinically indicated). All blood products will be irradiated to prevent graft-versus-host disease.
Filters to remove leukocytes should be used to prevent WBC sensitization. CMV seronegative patients
should receive CMV-safe blood products.
8.6.2 Red Blood Cells

Patients will be transfused as necessary with irradiated packed red blood cells to maintain a hematocrit >
20-25%. Hematocrit should be maintained at > 30% during Radiation Therapy. Blood products will be
irradiated to prevent graft-versus-host disease. Filters should be used to prevent WBC sensitization.
8.6.3 Irradiation
Blood products should be irradiated following the current FDA guidelines found at:
http://www.fda.gov/cber/gdlns/gamma.htm

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8.7 Steroids
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 anti-emetic.
9.0 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY
CRITERIA
9.1 Criteria for Removal From Protocol Therapy

a) Progressive disease (See Section 11.4)
b) Parent/patient request
c) Completion of Chemoradiotherapy and Maintenance therapy
d) Inability to recover ANC to > 1,000/µL or platelets to > 100,000/µL by day 49 of any
maintenance course of chemotherapy given after lomustine has been discontinued due to
myelosuppression (see Section 5.2)
e) Hypersensitivity to temozolomide
f) Non-compliance with study medication
g) Patient withdrawal from protocol therapy due to physician’s choice
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.
9.2 Off Study Criteria

a) Death
b) Lost to follow-up
c) Entry into another COG therapeutic study
d) Withdrawal of consent for any further data submission
e) Tenth anniversary of study closure to accrual
10.0 STATISTICAL CONSIDERATIONS
This protocol is intended to pilot therapeutic strategies for treatment of children with high-grade gliomas
(HGG). The study is the second in possibly a series of trials that will treat a small number of patients and
compare their outcome to those of historical controls. The primary objectives of the statistical analysis will be
to determine whether there is compelling early evidence that this treatment will result in a significant
improvement in outcome compared to the historical data. A second objective is to assess the significance of
MGMT (i.e., AGT) and of MMR deficiency, as mechanisms of TMZ resistance and hence markers of poor
prognosis.
10.1 Design Considerations

This pilot study described herein is viewed as part of a long-term strategy for screening potential treatments for
HGG in children. In order to take into consideration the possibility that in the near future other treatment
approaches worthy of piloting will become available, the size of the current pilot studies will be limited to a
number of patients that is adequate for reasonably precise statistical inference, and that can be enrolled within
1 year to 18 months. If a successor high-grade glioma study is not ready to open after this time period, the
current pilot will continue to accrue patients in order to achieve greater precision in analyses of MGMT and
MMR relationship to prognosis.

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10.2 Patient Accrual

From past experience, it is reasonable to expect that accrual of eligible HGG patients will be at least 50
per year from COG institutions, with higher accrual rates possible. The Dutch accrual rate for eligible
HGG patients will be around 8 per year.
10.3 Study Duration

This study will accrue 50 eligible patients with assessable tumor tissue and with minimum follow-up of
six months after the end of radiation therapy. Accrual will continue until there is reasonable assurance
that this goal has been achieved. Ineligibility and drop-out rates are unlikely to exceed 20%, and
probably will be much less than this, so that at most 60 patients will likely be required to achieve this
goal. Accrual will therefore require 12 months, although the rapidity with which the study is activated in
different COG institutions will lengthen the time for completion of the first pilot study.
Observed vs Predicted EFS Percent

All Eligible CCG-945 Patients 3 Years and Over.
100% Lognormal Pi=.11, Lambda=0.62, gamma=0.842
90%
Event-free Survival Percent
80%
70%
60%
50%
40%
30%
20%
10%
0%
- 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Time
In the event that a successor pilot therapy is not available, this study will continue accrual until at most
100 eligible patients with assessable tumor tissue and adequate follow-up is reasonably assured.
10.4 Study Endpoints
10.4.1 Efficacy Endpoints

The primary endpoint for the evaluation of treatment efficacy will be event-free survival, defined as the time to
disease progression, disease relapse, occurrence of a second malignant neoplasm, or death from any cause.
The secondary endpoints include survival, which is defined as the time to death from any cause.
10.4.2 Safety and Toxicity Endpoints

The primary endpoint for patient safety monitoring is toxic death, which is a death primarily attributable to
complications of treatment.
10.5 Comparison of Short-Term EFS Rate With Historical Baseline
10.5.1 Parametric Model of the Event-Free Survival Function

The main study analysis will be based on a non-mixture parametric cure model (PCM) of the form

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S (t ) = e F (t ) ln π
where S (t ) is the event-free survival function, π is the long-term EFS (cure) rate, and
(
F (t ) = Φ ln ( λt )
γ
)
is a lognormal distribution function with shape parameter γ and scale parameter λ.46
This PCM describes outcome in a series of 129 eligible randomized HGG patients (based on review
histopathological diagnosis) aged 3 and over who were treated on CCG-945, with maximum likelihood
estimates π̂ =0.11 (95% CI: 0.05, 0.17), λ̂ =0.61/year (0.44, 0.88), γ̂ =0.84 (0.71,1.0). The product limit
estimate and parametric model fit are shown in the figure.
The PCM will serve as an historical baseline of comparison with the pilot series. The primary early comparison
will be for 1-year EFS. The comparison of 1-year EFS in the pilot study compared to the historical control
percent at that time will be based on a lower, one-sided, 95% confidence bound on the differences in EFS
percent estimated from the non-mixture PCM.
10.5.2 Precision of Estimate of Short-Term EFS as a Function of Pilot Cohort Maturity

Based on the cohort size of 50, at any given time T from the start of the enrollment of a pilot series, the
estimate of T-1 year EFS percent will have a standard error of 8% to 8.5%. Hence, 1 year from the time that
patient enrollment ends at 1 year, the precision of 1-year EFS will be approximately that specified, so that in
comparison to the 1-year EFS of approximately 45% in the historical series, an observed 1-year EFS of
approximately 57% will be significant at the one-sided p=0.1 level, and there will be 90% power against an
improvement to about 64%. Based on a cohort size of 100, the standard errors and detectable differences will
decrease by a factor of approximately 1/1.414. The analysis will be adjusted for extent of resection and
histology.
In addition to the 1-year EFS comparison described above, a number of PCM-based comparisons between
pilot series and historical baseline may be possible depending on the maturity of the data.68
10.6 Interim Monitoring
10.6.1 Monitoring for Efficacy

There will be no monitoring for efficacy before the 50th evaluable patient has been enrolled, since this
accrual goal will have been completed before sufficient information to allow such monitoring is available.
In the event that this study will proceed to an accrual goal of 100 patients, an interim analysis will be
performed when the 50th evaluable patient has been enrolled. A one-sided, one-degree of freedom PCM-
based likelihood-ratio test of a proportional-hazards decrease in efficacy from the historical baseline will
be performed at the overall 5% Type I level, with adjustment based on the methods of Tsiatis et al.69 A
significant result will constitute compelling evidence that the outcome is significantly worse than
predicted, and will likely result in a decision to discontinue the pilot.
10.6.2 Monitoring for Toxic Death, for Delays in Completion of XRT Due to TMZ-Related Toxicity,
and for Delays in the Start of Maintenance Chemotherapy.
No serious problems are expected with toxic death or with significant delays in treatment due to TMZ. We
will nevertheless monitor rates of toxic death during XRT and during maintenance. We will also monitor
significant delays in completion of XRT or in the start of maintenance courses. Statistical monitoring rules will
not be used. Rather, a careful review of treatment and patient safety will be undertaken whenever observed

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rates nominally exceed the maximum acceptable rate, or when there is a large observed difference in these
rates between the treatment groups.
The following measures will be computed:

1. Cumulative incidence of toxic death during therapy. The maximum acceptable rate is 5%.
2. Cumulative incidence of occurrence of significant delays in the start of any course of maintenance
chemotherapy. A greater than 2-week delay will be considered significant. The maximum acceptable rate
is 10%.
10.7 Analysis of Prognostic Significance of MGMT and MMR

The analysis of the prognostic significance of MGMT and MMR will be based on all patients in this
series who are treated with a TMZ-containing regimen. We will assume that at least 75 patients are
available for analysis of 3-year EFS, either from this pilot or from a combined series of TMZ-containing
pilots.
Based on data in adults22,48 it is expected that MGMT will be absent in approximately 26% of tumors,
and it is expected that these patients will have a better prognosis. Assume 3-year EFS of approximately
25% overall, and using a one-sided, 5% Wald test of difference in 3-year EFS, there will be 80% power
to detect a difference of 31% in 3-year EFS (i.e., 49% in MGMT negative vs. 17% in MGMT positive).
This is a reasonably-sized difference to expect for a useful distinction in prognosis based on MGMT.
Based on data in adults26 it is expected that MMR will be present in approximately 79% of tumors, and it
is expected that these patients will have a better prognosis. Assume as above 3-year EFS of
approximately 25% overall, and using a one-sided, 5% Wald test of difference in 3-year EFS, there will
be 80% power to detect a difference of 22% in 3-year EFS (i.e., 30% in MMR positive vs. 8% in MMR
negative). This also is a reasonably-sized different to expect for a useful distinction in prognosis based on
MMR.
These considerations will depend ultimately on the cutpoint used to distinguish positive vs negative tumors
with respect to MGMT and MMR.
10.8 Statistical Section for the Optional Biology Section

For glutathione gene analysis, we will compute frequencies for GSTM1, GSTT1 and GSTP1 variants and
distribution of GSTP1 protein expression. We will evaluate the data with all patients together, and then
by histology of the tumor separately. We will compute Cox proportional hazard regression method to
estimate the effect of GST polymorphisms and tumor GSTP1 protein expression on survival in the
presence of other known or potential prognostic factors.70 We will explore interaction between individual
GST polymorphisms. Unconditional logistic regression analysis will be used to estimate ORs and 95% CI
for the effect of GST genotypes on the occurrence of adverse events secondary to chemotherapy.
For genome allelotype analysis, LOH data generated in this study will be binary (loss of one allele or
retain of both alleles). To distinguish the biologically significant changes from the random changes, we
will compute the frequency of allelic loss (FAL) statistic. FAL for a cytoband is the number of tumors
that exhibit LOH at the SNP loci divided by the number of tumors in which at least on SNP loci is
informative. The expected FAL between tumors of different covariates will be tested using Fisher’s exact
test or a chi-squared test. SNP loci will be ranked based on the FAL statistics and LOH will be validated
by PCR amplification and direct sequencing analysis. SNP with copy number changes will be validated
by quantitative real-time PCR. Validated SNP markers will be subject to Kaplan-Meier analysis. The log
rank test will be used to test for association between PFS and prognostic factors and genetic alterations.

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Similar analysis will be done with expression profiles data. Differential gene expression will be validated
by real-time quantitative RT-PCR.
10.9 Gender and Ethnicity Considerations

Review of outcome data from previous CCG 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.
We will, however, contrast therapeutic outcomes in two situations. First, across subgroups defined by gender,
viz., males v. females. Second, across subgroups defined by ethnicity, viz., white v. black v. Hispanic.
Expected Accrual by Sex and Race/Ethnicity

(Total N=100)
SEX/RACE White Black Hispanic Asian Other/Mixed
Female 42 6 3 1 1
Male 33 6 4 1 -
Total 75 12 7 2 1
11.0 EVALUATION CRITERIA
11.1 This Study Will Utilize The CTCAE Version 3.0 For Toxicity And Performance Reporting
A copy of the CTCAE Version 3.0 can be downloaded from the CTEP home page
(http://ctep.info.nih.gov). Additionally, the toxicities are to be reported on the appropriate data collection
forms.
11.2 Methodology to Determine Tumor Measurement

Tumor response criteria are determined by changes in size using all 3 dimensional measurements: width
(W), transverse (T), and length (L) measurements. Thus for all tumors these 3 measurements need to be
recorded, using either T1 or T2 weighted images (which ever gives the best estimate of tumor size). The
following section describes the methodology.
(See drawing below for illustration)

1. Longest diameter of target lesion(s) should be selected in the axial plane only for CT. For MRI
imaging, the longest diameter can be measured from the axial plane or the plane in which the tumor
is best seen or measured, provided the same plane is used in follow ups.
2. The longest measurement of the tumor (or width, W) should be determined.
3. The 2 perpendicular measurements should be determined (transverse (T) measurement-
perpendicular to the width in the selected plane, and the length (L) – tumor extent in the plane
perpendicular to the selected plane)

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A COG GUIDELINE: TUMOR SIZE

X-Y MEASUREMENT BASED ON
PLANE CROSS-SECTIONAL IMAGING
B • A, B, C, D, & E are contiguous

parallel slices in the X-Y plane
T (usually axial) showing the tumor
L • W and T are the maximal
perpendicular diameters on the slice
W (C in this example) showing the
largest surface area
C
• Tumor length in the Z-axis (L)
Z (perpendicular to X-Y plane) can be
AXIS obtained either by the [a] (difference
in table position of the first and last
D slices showing the tumor + one slice
thickness), or [b] the product of (slice
thickness + gap) and the number of
slices showing the tumor
E
4. The cystic or necrotic components of a tumor are not considered in tumor measurements. Therefore
only the solid component of cystic/necrotic tumors should be measured. If cysts/necrosis compose the
majority of the lesion, the lesion may not be “measurable”. Options:
- if the cyst/necrosis is eccentric, the W, T and L of the solid portion should be measured, the
cyst/necrosis excluded from measurement
- if the cyst/necrosis is central but represents a small portion of the tumor (<25%), disregard and
measure the whole lesion
- if the cyst/necrosis is central but represents a large portion of the tumor, identify a solid aspect of the
mass that can be reproducibly measured
5. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be measured
accurately. Presence and location of leptomeningeal tumor spread should be noted, change in
extent/thickness assessed on follow up studies.
6. Overall Response Assessment

The overall response assessment takes into account response in both target and non-target lesion, and the
appearance of new lesions, where applicable, according to the criteria described in the table below. The
overall response assessment is shown in the last column, and depends on the assessments of target, non-
target, and new lesions in the preceding columns.

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Overall
Target Lesions Non-target Lesions New Lesions Response
CR CR No CR
CR IR/SD No PR
PR Non-PD No PR
CR or PR Non-PD No PR
SD Non-PD No SD
PD Any Yes or No PD
Any PD Yes or No PD
Any Any Yes PD
The sections that follow discuss the selection and evaluation of each of these types of lesions.
11.3 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.
2. If multiple measurable lesions are present, up to 5 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.
11.4 Response Criteria for Target Lesions

1. Response criteria are assessed in 3 dimensions – the product of LxWxT. An elliptical model volume
(=0.5LxWxT) is used.
2. To assess response/progression, the ratio is calculated:

LxWxT (current scan)
LxWxT (reference scan)
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.
3. Response Criteria for target lesions:
Complete Response (CR): Disappearance of all target lesions.

Partial response (PR): ≥65% decrease in the sum of the products of the three perpendicular diameters
of all target lesions (up to 5), taking as reference the initial baseline measurements.
Stable Disease (SD): Neither sufficient decrease in the sum of the products of the three perpendicular
diameters of all target lesions to qualify for PR (taking as reference the initial baseline measurements),

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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): 40% or more increase in the product of perpendicular diameters of ANY
target lesion, taking as reference the smallest product observed since the start of treatment, or the
appearance of one or more new lesions.
In the rare circumstance that the length of a lesion cannot be determined, then comparison of 2
dimensional measurements, TxW (product of the longest diameter and its longest perpendicular
diameter) can be used. Please submit scans documenting Progressive Disease to QARC for Review.
See Section 7.1.
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
all target lesions (up to 5), taking as reference the initial baseline measurements
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% or more increase in the product of perpendicular diameters of ANY
target lesion, taking as reference the smallest product observed since the start of treatment, or the
appearance of one or more new lesions.
11.5 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.
12.0 ADVERSE EVENT REPORTING REQUIREMENTS
12.1 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.
12.2 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.
Commercial agents are those agents not provided under an IND but obtained instead from a commercial
source. In some cases an agent obtained commercially may be used for indications not included in the
package label. In addition, NCI may on some occasions distribute commercial supplies for a trial. Even
in these cases, the agent is still considered to be a commercial agent and the procedures described below
should be followed.

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Determine the prior experience Expected events are those that have been previously identified as
resulting from administration of the agent. An adverse event is considered unexpected, for reporting
purposes only, when either the type of event or the severity of the event is not listed in:
• the current NCI Agent-Specific Adverse Event List (provided in the Drug
Information Section of this protocol); or
• the drug package insert (for treatments with commercially available agents).
12.3 Reporting of Adverse Events for Commercial Agents - AdEERS abbreviated pathway
Commercial reporting requirements are provided in Table B. The commercial agent(s) used in this study
are listed in the Drug Information Section of this protocol.
• COG requires the AdEERS report to be submitted within 5 calendar days of learning of the
event.
• Use the NCI protocol number and the protocol-specific patient ID provided during trial
registration on all reports.
Table B
Reporting requirements for adverse events experienced by patients on study who have NOT
received any doses of an investigational agent on this study.
AdEERS Reporting Requirements for Adverse Events That Occur During Therapy With a
Commercial Agent or Within 30 Days1
Attribution Grade 4 Grade 5

Unexpected Expected
Unrelated or AdEERS
Unlikely
Possible,
Probable, AdEERS AdEERS
Definite
1
This includes all deaths within 30 days of the last dose of treatment with a
commercial agent, regardless of attribution. Any death that occurs more
than 30 days after the last dose of treatment with a commercial agent
which can be attributed (possibly, probably, or definitely) to the agent and
is not due to cancer recurrence must be reported via AdEERS.
12.4 Reporting Secondary AML/MDS
All cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) that occur in patients on
NCI-sponsored trials following their chemotherapy for cancer must be reported to the Investigational Drug
Branch (IDB) of the NCI Cancer Therapy Evaluation Program (CTEP) and included as part of the second
malignant neoplasm reporting requirements for this protocol (see data submission packet). Submit the
following information within two weeks of an AML/MDS diagnosis occurring after treatment for cancer on
NCI-sponsored trials:
• a completed NCI/CTEP Secondary AML/MDS Report Form (do not use AdEERS);

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• a copy of the pathology report confirming the AML/MDS; and

• a copy of the cytogenetics report (if available).
Submit the information via fax to:
NCI (fax # 301-230-0159) and
COG (fax # 626-445-6715; attention AE Coordinator)
Note: If a patient has been enrolled in more than one NCI-sponsored study, the NCI/CTEP Secondary
AML/MDS Report Form must be submitted for the most recent trial. The COG must also be provided
with a copy of the report even if the study was not the patient’s most recent trial.
13.0 RECORDS AND REPORTING
13.1 Categories Of Research Records

Research records for this study can be divided into three categories:
1. Non-computerized Information: Pathology Narrative Reports and Surgical Reports. These forms
are faxed to the Statistics and Data Center at: (626) 445-4334.
2. Reference Labs’ required records and QARC data. These data accompany submissions to these
centers, which forward their review data electronically to the COG Research Data Center.
3. Computerized Information Electronically Submitted: All other computerized data will be entered
in the COG Remote Data Entry System with the aid of schedules and worksheets (essentially
paper copies of the RDE screens) as provided in the data form packet.
See separate Data Form Packet which includes submission schedule.
13.2 CDUS
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data will
be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, July 31 and
October 31. This is not a responsibility of institutions participating in this trial.
14.0 NEUROSURGICAL GUIDELINES
14.1 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 and
sufficient specimens for the required biologic studies.

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14.2 Definitions of Extent of Resection
14.2.1 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.
14.2.2 Partial Resection

The surgical removal of greater than 10%, but less than 50%, of the tumor mass.
14.2.3 Subtotal Resection

The surgical removal of greater than or equal to 50%, but less than 90%, of the tumor mass.
14.2.4 Extensive Subtotal Resection

Resection of greater than or equal to 90% of the tumor mass, but residual disease apparent on inspection.
14.2.5 Gross Total Resection

Resection of all visible tumor.
14.2.6
An attempt should be made to estimate the volume of the residual tumor in cm³.
14.3 MRI Scan Confirmation of Extent of Resection

All patients must have confirmation of the neurosurgical opinion of the extent of resection by a post-operative
enhanced MRI scan. This scan should be carried out within the first three post-operative days (72 hours), if
possible, preferably within 24 hours of surgery.
14.4 Peri-operative Corticosteroids

Some patients with large tumors may require initiation of corticosteroid therapy pre-operatively to reduce
associated brain edema.
Usual corticosteroid dosage is 0.25 to 0.5 mg/kg/day of Decadron, 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.
15.0 RADIATION THERAPY GUIDELINES
Radiation therapy for patients on COG protocols can only be delivered at approved COG RT
facilities (see Administrative Policy 3.9, April 2004). Contact QARC for questions or further
information.
Submission of the radiation therapy treatment plan in digital format (either Dicom RT or RTOG
format) is strongly encouraged. See the QARC website (www.QARC.org) for digital data
submission information.

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Radiation Therapy is to start within 31 days of the definitive surgical procedure. Primary brain
malignant gliomas will receive a total dose of between 54.0 and 59.4 Gy in 30-33 fractions over 6-7
weeks. The total dose will be 54.0 Gy if if a gross total resection has been performed. If the tumor has
not been completely resected, the residual disease will be boosted to a total dose of 59.4 Gy. Primary
spinal cord malignant gliomas will receive a total dose of between 50.4-54 Gy in 28-30 fractions over 5 -
6 weeks, regardless of the extent of tumor resection. Centers participating in this protocol using 3D
conformal techniques are required to complete the 3D Benchmark; those treating with IMRT must
complete the IMRT Questionnaire and either the QARC Benchmark or irradiate the RPC’s IMRT head
and neck phantom. The Benchmark material can 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. The Proton
Questionnaire and Benchmark are required if protons are to be used for treatment.
15.1 Equipment
Modality: X-rays with nominal energy of 4 MV or greater or proton beam. Co-60 is not allowed on this
study.
Calibration: The calibration of therapy machines used in this protocol shall be verified by the
Radiological Physics Center (RPC).
15.2 Target Volumes

RT volumes for this study will be determined by the collective information that delineates the extent of
disease both prior to and following surgical resection or biopsy. The required imaging studies are a
contrast-enhanced pre-operative MRI scan, a contrast-enhanced post-operative MRI scan (unless only a
biopsy was performed), and a radiation treatment planning CT scan with IV contrast and the patient in
the treatment position. Use of fusion image registration software is encouraged, if available. If a spinal
cord tumor will be treated with a single PA or an opposed pair of AP and PA fields, it is not necessary to
obtain a treatment planning CT scan. These guidelines are intended to be comprehensive.
15.2.1 Gross Tumor Volumes (GTV)

The GTV-1 will include all the tissues initially involved with disease and the entire residual tumor
defined by the pre-operative and post-operative MRI scans. The GTV-1 will include both enhancing and
non-enhancing areas of the tumor. The GTV-1 will take into account any changes in brain anatomy that
have occurred as a result of tumor resection and/or CSF shunt placement. T-1, T-2, and FLAIR
sequences of the MRI scans should all be reviewed and the sequence that best defines the extent of initial
disease should be used to determine the GTV-1.
The GTV-2 will include only the residual tumor seen on the post-operative MRI scan. The GTV-2 will
include both enhancing and non-enhancing areas of the residual tumor. T-1, T-2, and FLAIR sequences
of the post-operative MRI scan should all be reviewed and the sequence that best defines the extent of
residual disease should be used to determine the GTV-2. If only a small biopsy has been performed, the
GTV-2 may be identical to the GTV-1. If the tumor has been completely resected, there will not be a
GTV-2 and the radiation therapy course will end with completion of the initial radiation fields.
15.2.2 Clinical Target Volumes (CTV)

The CTV includes the GTV with an added margin that is intended to treat subclinical microscopic
disease and is anatomically confined. This means that margins of the CTV may be manually moved
inward to the inner table of the bony calvarium or (for spinal cord tumors) the spinal canal.

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The CTV-1 will include the GTV-1 plus a 2 cm margin in all dimensions. For primary spinal cord
tumors, the CTV-1 will be expanded in the cranial and caudal directions to include 2 vertebral bodies
above and 2 vertebral bodies below the GTV-1.
The CTV-2 will include the GTV-2 plus a 1 cm margin in all dimensions. For primary spinal cord
tumors, the CTV-2 will be expanded in the cranial and caudal directions to include 1vertebral body
above and 1vertebral body below the GTV-2. If there is not a GTV-2, there will not be a CTV-2.
15.2.3 Planning Target Volumes (PTV)

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 5 mm that
reflects the variability appropriate for the individual patient and 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, but shall not 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, but shall not extend beyond the skin surface. If there is not a CTV-2, there will
not be a PTV-2.
15.3 Target Dose
15.3.1 Prescription Point

The prescription point is at or near the isocenter.
If IMRT is used, dose may be prescribed to an isodose surface that encompasses the PTV provided that
the dose uniformity requirements in Section 15.3.5 are satisfied.
15.3.2 Dose Definition

Dose is specified in Gy to muscle.
15.3.3 Tissue Heterogeneity

Calculations that take into account tissue heterogeneity are required for CT-based planning techniques.
15.3.4 Prescription Point and Fractionation

Planning Target Volume 1 (PTV-1)
For brain tumors, the total dose to the PTV-1 prescription point will be 54 Gy given in 30 fractions of
1.8 Gy each. For spinal cord tumors, the total dose to the PTV-1 prescription point will be 45 Gy given
in 25 fractions of 1.8 Gy each. The patient will be treated with one fraction per day. All fields will be
treated each day. The total dose to the prescription point will be 54 Gy given in 30 fractions. The patient
will be treated with one fraction per day with all fields treated per day. 1.80 Gy will be delivered to the
isocenter.
Planning Target Volume 2 (PTV-2)

This boost is delivered only to those patients with gross residual disease. For brain tumors with gross
residual disease, the total boost dose to the PTV-2 prescription point will be 5.4 Gy given in 3 fractions.
The cumulative dose to the prescription point will be 59.4 Gy. The patient will be treated with one

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fraction per day. All fields will be treated each day. For spinal cord tumors with gross residual disease,
the total boost dose to the PTV-2 prescription point will be between 5.4 Gy given in 3 fractions and 9 Gy
given in 5 fractions. The treating radiation oncologist will prescribe between 3 and 5 fractions based on
his/her practice. The cumulative dose to the prescription point will be between 50.4 and 54 Gy. If there
are any questions regarding the boost dose
15.3.5 Dose Uniformity

For standard planning techniques, the dose variation in the PTV shall be within +7% and -5% of the
prescribed dose. For conformal planning techniques (3D conformal and IMRT), the entire PTV shall be
encompassed within the 95% isodose surface and no more than 10% of the PTV should receive more than
110% of the prescription dose, as evaluated by dose volume histogram.
15.3.6 Treatment Interruptions

No treatment breaks in the radiation therapy component of this combined modality treatment are anticipated.
Skin reactions should be treated supportively. Low blood counts are generally related to systemic therapy and
are not caused or worsened by local field brain RT. In the case of severe or unusual toxicities, Dr. Robert
Lavey or the study chair should be notified. The reason for any interruptions greater than three treatment days
should be recorded in the patient’s treatment chart and submitted with the QA documentation.
15.4 Treatment Technique
15.4.1
Two-dimensional or conformal (three dimensional) planning may be used in this study.
15.4.2 Patient Position and Immobilization

Reproducible setups are critical and the use of immobilization devices such as thermoplast mask, bite-
block, etc. should be used for all pediatric patients and must be used for patients being treated with
IMRT.
15.4.3 Field Shaping

Field shaping can be done with blocks or multi-leaf collimation.
15.5 Normal Tissue Sparing
15.5.1 Lenses of the Eyes

The lenses of the eyes must be excluded from the primary beam by the use of shielding blocks that are at
least 5 HVL thick.
15.5.2 Optic Nerve and Chiasm

Whenever possible without shielding gross tumor, the dose to the optic nerves and chiasm should not
exceed 54.0 Gy and the dose to the retinas of the eyes should not exceed 45.0 Gy, including the dose
from the boost.
15.5.3 Spinal Cord

The dose to the spinal cord within the PTV shall not exceed 54 Gy. The dose to the spinal cord more
than 5 mm outside the PTV should not exceed 46 Gy.

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15.6 Dose Calculation and Reporting
15.6.1 Prescribed Dose

The monitor units required to deliver the prescribed dose shall be calculated and submitted using the RT-
1 or IMRT Dosimetry Summary Form.
If IMRT is used, the monitor units generated by the IMRT planning system must be independently checked
prior to the patient’s first treatment. Measurements in a QA phantom can suffice for a check as long as the
plan’s fluence distributions can be recomputed for a phantom geometry.

The maximum and minimum doses in the PTV shall be calculated and reported on the RT-1 or IMRT
Dosimetry Summary Form and on the RT-2 (Radiotherapy Total Dose Record Form). These may be extracted
from isodose distributions, calculated separately or derived from DVH’s.
15.6.3 Dose Specification Points

The daily dose reference point calculated on this study is the isocenter. The total dose to this point shall be
calculated and reported on RT-2.
The daily dose to the critical organs indicated in section 15.5 shall be calculated whenever they are included in
the radiation therapy treatment field. These doses must be recorded in the treatment records and submitted
with the QA documentation. For patients treated with volume-based techniques, the appropriate dose volume
histograms shall be submitted.
15.6.4 Isodose Distribution

An isodose plot of the dose distribution in the central transverse plane through the target volume shall be
submitted. The prescription point and the outlines of the planning target volume and critical organs shall be
shown. Isodose values must be clearly labeled. The effects of shielding blocks shall be included and corrections
for heterogeneity shall be shown.
For volume based treatment planning, a hard copy isodose distribution for the total dose plan in the
axial, sagittal, and coronal planes, which includes the isocenter of the planning target volume (PTV)
must be submitted. If sagittal and coronal planes are not available, then five axial distributions may be
submitted (central axis, two superior and two inferior planes). These dose distributions must include the
following:
A sufficient number of isodose contours should be shown to determine that the dose distribution
conforms to the protocol guidelines. These isodoses should be superimposed over treatment planning CT
or MR images. However, if such hard copy presents difficulty, similar plots without the gray scale image
are acceptable if enough critical contours are identifiable to verify the dose distribution to target volumes
and critical normal structures. Specifically, include those volumes for which there are dose volume
histograms.
15.7 QA Documentation
If conformal techniques are used to treat patients on this study an approved 3D benchmark must be on
file at QARC before a patient’s treatment can be evaluated. If IMRT techniques are used the institution

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must be approved to use IMRT techniques. To be approved for IMRT institutions must complete the
IMRT Questionnaire and either the QARC Benchmark or irradiate the RPC’s IMRT head and neck
phantom. The Benchmark material can 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. The Proton
Questionnaire and Benchmark are required if protons are to be used for treatment.
If possible, the radiation therapy treatment plan should be submitted in digital format (either Dicom RT
or RTOG format). See the QARC website (www.QARC.org) for digital data submission information.
Data submitted in digital format should include the treatment planning CT, structure contours, treatment
plans, 3D dose distributions, and DVH’s. All other radiotherapy data (i.e. RT-1 form or IMRT form,
calculations, DRR’s, BEV’s, port films or portal images, patient photo with treatment fields marked)
should be submitted in hard-copy format or as JPEG screen captures. We also request that you submit a
hard copy isodose distribution in 3 orthogonal planes through the isocenter and hard copy of DVH’s
corresponding to the plan you submit digitally.
Note: Black and white copies of color documentation are not acceptable.
15.7.1 On-Treatment Review

Within three days of the start of radiotherapy, the following data shall be submitted for on-treatment
review for patients using standard planning techniques:
• Copies of the pre-operative and post-operative MRI utilized in defining the gross target volume.
• Copies of the corresponding MRI and operative reports.
• Copies of simulator films and /or digitally reconstructed radiographs (DRRs) for each field. It is
strongly encouraged that the GTV, CTV and PTV1 and PTV2 be drawn on the simulator films.
• Copies of verification (portal) films or hard copy of real time portal images for each field.
• Pictures of the patient in the treatment position.
• Prescription sheet for the entire treatment course.
• RT-1 Dosimetry Summary Form
• Copies of worksheets and /or printouts used for calculations of monitor settings to give the
prescribed dose, and doses to all normal structures.
• Copies of isodose distributions to demonstrate that the dose variation is within specification. The
target volumes and the prescription point must be clearly shown.
15.7.2 On-Treatment Review for 3D Conformal Treatment Planning

If 3D-conformal or IMRT treatment planning is utilized, submit the following for on-treatment
review:
• Copies of the pre-operative and post-operative MRI utilized in defining the gross target
volume.
• Copies of the corresponding MRI and operative reports.
• Copies of the planning CT or MRI with target volumes and critical structures (see 15.5.2)
delineated.
• First day portal films (or hard copy of real time portal images) if achievable.
• Simulator films if used as part of the planning process, and digitally reconstructed
radiographs of each treatment portal.
• One set of orthogonal anterior/posterior and lateral films for isocenter localization for each
group of concurrently treated beams. If portals being submitted contain an orthogonal set,
this is sufficient.

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• Pictures of the patient in the treatment position.

• Prescription sheet for the entire treatment course.
• RT-1 or IMRT Dosimetry Summary Form, whichever is applicable.
• BEV’s of portals showing collimator, beam aperture, target volume and critical structures.
• A rooms eye view (REV), i.e., a composite illustration of all the fields and their angles, if
available from your planning system. Otherwise submit an overview diagram or illustration
of the patient with all beams and their orientation indicated.
• Copies of worksheets and /or printouts used for calculations of monitor settings to give the
prescribed dose, and doses to all normal structures.
• Copies of the isodose distributions for the total dose plan in the axial, sagittal and coronal
planes, which includes the isocenter of the planning target volume. The target volumes and
the prescription point must be clearly shown.
• Dose volume histograms for the entire treatment course or total prescribed dose for PTV1
(and PTV2, if treated) and any critical structures (see 15.5.2). If IMRT is used, a DVH shall
also 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.
• Documentation of an independent check of the calculated dose if IMRT is used.
15.7.3 Post-Treatment Review

Within one week of the completion of radiotherapy, the following data shall be submitted.
• A copy of the patient’s radiotherapy record including prescription, and the daily and
cumulative doses to all required areas and specified dose points.
• RT-2 Radiotherapy Total Dose Record
• A completed RT-1 or IMRT Dosimetry Summary Form if any changes have been made
subsequent to submission of the data for on-treatment review.
• Copies of additional DRR’s and portal films or hard copy of portal images for any field
modifications made subsequent to the on-treatment review.
• Copies of isodose distributions and calculations performed subsequent to the submission of
the on-treatment review.
• Dose volume histograms (DVH’s) for the target volume and normal tissue structures, if
modifications have been made subsequent to the on-treatment review.
15.7.4 Address
These data should be forwarded to:
Quality Assurance Review Center
272 West Exchange Street, Suite 101
Providence, Rhode Island 02903-1025
Phone: (401) 454-4301
Fax: (401) 454-4683
Note: Submission of Diagnostic Imaging data in digital format is preferred over hard copies of films.
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. Institutions with PACS systems may contact QARC if they are interested in installing
the COG Dicommunicator software that manages e-mailing studies securely to QARC. Contact
COG@QARC.org for further information.

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15.7.5 Questions
Questions regarding the dose calculations or documentation should be directed to:
COG Protocol Dosimetrist
Quality Assurance Review Center
272 West Exchange Street, Suite 101
Providence, Rhode Island 02903-1025
Questions regarding the radiotherapy section of this protocol should be directed to:
Robert Lavey, M.D.
Childrens Hospital Los Angeles
Radiation Oncology MS-54
4650 Sunset Blvd.
Los Angeles, CA 90027
Phone: (323) 669-2417
Fax: (323) 668-7978
E-mail: rlavey@chla.usc.edu
15.8 Definitions of Deviations in Protocol Performance
15.8.1 Prescription Dose

Minor Deviation: The dose to the prescription point differs from that in the protocol by between 6% and
10%.
Major Deviation: The dose to the prescription point differs from that in the protocol by more than 10%.

Minor Deviation:
Standard Planning: The variation of dose in one of the target volumes exceeds +7% or -5% of the
prescription dose.
Conformal Planning: The entire PTV receives less than 95% of the prescription dose, or more than
10% of the PTV receives more than 110% of the prescription dose.
15.8.3 Volume
Minor Deviation: Margins less than specified or fields excessively large as deemed by the study.
Major Deviation: Transection of tumor (GTV) or potentially tumor bearing area (CTV).
16.0 NEUROPATHOLOGY GUIDELINES/BIOLOGY SPECIMEN REQUIREMENTS
16.1 Eligible Tumors

The following non-brainstem high-grade gliomas are eligible:
a) Anaplastic astrocytoma (Grades 3)
b) Glioblastoma multiforme, all types and variants (Grade 4)
c) Gliosarcoma
16.2 Central Review

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16.2.1 Required Materials

The following specimens must be received prior to the start of maintenance. The neuropathologist at each
participating institution, at the completion of review of each case originating at his/her institution, should
submit the following to the COG Biopathology Center:
• 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
• Transmittal form
Label blocks (or slides), pathology report and transmittal form with the patient's COG Patient ID
Number and the corresponding institutional surgical pathology ID number.
16.2.2 Address
All materials should be submitted to:
COG Biopathology Center
Children's Hospital
700 Children's Drive, Room WA1340
Columbus, OH 43205
(614) 722-2894
16.2.3 Central Review Process

The primary review process will be performed by Dr. Peter Burger and a secondary review by Drs. Brat and
Rosenblum.
Three neuropathologists (Drs. Burger, Brat, and Rosenblum) have agreed to act as central reviewers for
this trial. Dr. Burger has agreed to do an initial review of the pathology by the completion date of XRT.
Should Dr. Burger’s diagnosis differ from that of the institutional pathologist, Drs. Brat and Rosenblum
will provide an expedited second opinion prior to the beginning of adjuvant therapy.
16.3 Required Biology Studies

Note: A Specimen Procurement Kit will be provided to facilitate shipping of all biology specimens
(required and optional) at the same time. Ship the specimens to the BPC by Federal Express Priority
Overnight using the BPC Federal Express Account (1290-2562-0). Participation on ACNS02B3 is
strongly encouraged. If the family/patient agrees to participate in both studies, a separate
consent for ACNS02B3 needs to be signed.
Unstained slides (see Section 16.3.1) must be submitted prior to the start of maintenance to the
Biopathology Center who will forward the slides to the Glioma Resource Laboratory at the University of
Pittsburgh. The formalin-fixed, paraffin-embedded specimens will be analyzed to determine MGMT
expression using immunohistochemical methods. In addition, 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. Microsatellite instability assays will be used to determine whether a
functional MMR system is present in tumor cells by comparing DNA isolated from formalin-fixed
paraffin-embedded tumor samples with DNA isolated from the patient’s peripheral blood white cells.

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MIB-1 expression analysis will be performed using a standardized immunohistochemical protocol, as

previously published28,30 to identify areas of maximal expression within the tumor sample. p53 mutation
analysis will incorporate microdissection-based topographic genotyping and direct sequence analysis, as
previously reported.28,29
16.3.1 Required Materials for Required Biology Studies

• A 5ml peripheral blood specimen in a green top tube (sodium heparin) must be shipped overnight
(Monday –Thursday) on wet ice (4°C) prior to the initiation of chemoradiotherapy. Blood must be
shipped to the BPC Monday through Thursday for delivery Tuesday through Friday since Saturday
delivery is not available. It is preferable that the peripheral blood NOT be drawn on a Friday;
however if blood is collected on a Friday, store in a refrigerator (4°C) until it can be shipped on the
following Monday.
• If tissue blocks were sent to the Biopathology Center for Pathology Review, then the required
materials will be processed from the blocks by the BPC and the institution does not need to send
slides or micron sections to meet the biology requirements for this protocol.
• If tissue blocks were not sent for Pathology Review then the following materials are required for
biology studies and must be received prior to the start of maintenance:
Ten unstained slides from a representative block for biology studies must be received
prior to the start of maintenance.
Three 20-micron sections from a formalin-fixed, paraffin-embedded tumor sample must
be received prior to the start of maintenance. These three sections should be in a sterile
microfuge (Eppendorf type) tube.
• A completed transmittal form must be sent with each shipment of specimens.
Label all specimens and the accompanying paperwork with the patient's BPC number, the collection date and
specimen type.
16.3.2 Address
All materials should be shipped to:
Biopathology Center
Children’s Hospital
700 Children’s Drive, WA1340*
Columbus, OH 43205
Phone: (614) 722-2810
* Be sure to include the room number. Packages without a room number may be returned to the sender.
16.4 Optional Biology Studies (strongly encouraged)
16.4.1 GST Studies
Multiplex GSTM1 and GSTT1 Genotyping

A multiplex PCR technique will be used to amplify both GSTM1and GSTT1 simultaneously in a single
PCR reaction.71 The PCR conditions consist of an initial melting temperature of 95 0C (5 min) followed
by 35 cycles of melting (95 0C, 30 sec), annealing (58 0C, 45 sec) and extension (72 0C, 1 min). The
PCR products from coamplification of GSTT1 (480 bp), DHFR (280 bp) and GSTM1 (215 bp) are then
viewed by an ethidium bromide-stained 2% Agarose gel for the presence or absence of GSTM1 and

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GSTT1 genes. In 10% of the samples PCR will be repeated. For statistical analyses, cases with null
genotypes will be compared with cases with non-null genotypes. We expect that, patients with null
genotypes will have longer survival and higher incidence of toxicity, since they will not be able to
metabolize chemotherapy agents.
GSTP1 Genotyping
A method similar to that described by Harries et al. will be used to determine the GSTP1 variant at
codon 105.72 The PCR conditions consist of an initial melting temperature of 95 0C (5 min) followed by
32 cycles of 95 0C (30 sec), 60 0C (45 sec) and 72 0C (45 sec) in 25 µl volume. A final polymerization step
of 72o C for 10 min is carried out to complete the elongation process and yield a 568 bp fragment. The PCR
product (8µl) is then digested with 5U BsmAI (New England Biolabs) for 16 hours at 580C. The samples are
analyzed by electrophoresis on an ethidium bromide-stained 1.5% agarose gel. The presence of the Ile/Ile allele
is revealed by 305, 135 and 128 bp fragments while the Val/Val allele is revealed by 222, 135, 128 and 83 bp
fragments. The Ile/Val allele is characterized by five fragments consisting of 305, 222, 135, 128 and 83 bp.
135 bp and 128 bp fragments cannot be separated. For codon 114 polymorphism, 170 bp genomic DNA is
amplified by PCR conditions as described above with an annealing temperature of 560C.48 The PCR
product (6µl) is then digested with 6U AciI (New England Biolabs) for 16 hours at 370C. The samples are
analyzed by electrophoresis on an ethidium bromide-stained 2.5% Nusieve3:Agarose1 gel. The presence of the
Ala/Ala allele is revealed by a completely digested single 144 bp fragment, while the Val/Val allele is revealed
by an indigestible fragment of 170 bp. The heterozygote Ala/Val allele will be characterized by two fragments
consisting of 170, and 144 bp. Ten per cent of all samples and all with Ala/Val and Val/Val polymorphisms
will be repeated. For statistical analyses, cases with homozygote *A/*A genotype will be compared with
cases with non-*A/*A genotypes, who will have at least one B,C or D allele. We expect that, patients
with *A/*A genotype will have longer survival and higher incidence of toxicity, since they will not be
able to metabolize chemotherapy agents.
Immunocytochemistry for GSTP1 Expression.

Paraffin sections will be pre-warmed to 60°C, deparaffinized in two exchanges of xylene, rinsed in
decreasing ethanol concentrations (100-70%), and rehydrated in PBS. Endogenous peroxidase will be
inactivated with 0.3% H2O2 in methanol, and the slides will be incubated overnight with a polyclonal
rabbit anti-human GST-π antibody at a 1:500 dilution. The slides will be rinsed with four exchanges of
cold (4°C) PBS and incubated with an avidin-conjugated mouse anti-rabbit antibody for 30 min. After
further rising with cold PBS, as described above, the slides will be treated with a solution of biotinylated
peroxidase (Vector Laboratories, Burlingame, CA) and will be developed with 0.05% diaminobenzidine
and 0.01% H2O2 in 50 mM Tris-HCI buffer (pH 7.5). Nonimmunized rabbit IgG will be used as a
negative control for the GSTP1 antibody. The MGR 3 glioblastoma cell line will be used as a positive
control for GSTP1 staining.
Following immunocytochemical staining, the level of GSTP1 expression in each specimen will be
determined by scoring the staining intensity of 600 cells (200 cells in each of three different microscopic
fields selected randomly at a 200-fold magnification). GSTP1 staining intensity will be assessed as low,
moderate, or high, based on the cytoplasmic staining intensity of 70% or greater of tumor cells.
Subcellular GSTP1 expression will be characterized as the presence or absence of GSTP1
immunoreactivity in the cytoplasm and/or nuclei of tumor cells in the same microscopic field evaluated
for the level of GSTP1 expression. The GSTP1 staining characteristics of other non-tumor cells, e.g.,
reactive astrocytes, endothelial cells, and infiltrating lymphocytes, will be noted but not used in the
evaluation of GSTP1 expression in the tumors. To validate the immunocytochemical staining procedure,
30 specimens will be randomly selected and independently evaluated for GSTP1 staining.

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16.4.2 Genome Allelotype analysis
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
liquid nitrogen and stored at -80oC using TRIzol Reagent (Life Technologies, GibcoBRL) according to
the manufacturer’s recommendations. 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. All data analysis will be carried out using Affymetrix software.
Expression Array Analysis

We will use HG_U133plus2 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 µg 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.
16.4.3 Required Materials for Optional Biology Studies
Materials required for GST Studies:

• 3 ml of peripheral blood in a green top tube (sodium heparin) should be shipped overnight. This
does not need to be drawn before therapy begins and should be sent on a Monday-Thursday.
The specimen can be sent at room temperature, along with the 2 unstained slides.
• 2 Unstained slides
• A completed transmittal form must be sent with each shipment of specimens.
It is strongly preferred that both blood and tissue be submitted for the GST studies. However, if both cannot
be sent, either blood or tissue will be accepted. Label all materials with the BPC Number, collection date and
specimen type.
Materials required for Genome Allelotype Analysis:

Snap frozen tissue and matched control blood specimens should be sent to the BPC in Columbus, Ohio.
Portions of the tissue will be used for the molecular genetic studies. It is strongly encouraged that
consent be obtained for the CNS Tumor Banking protocol ACNS02B3, so that whatever tumor is not
used for the above studies will be available for other approved biology studies.
• As many 100 mg pieces of tissue as possible should be frozen in sterile foil in liquid nitrogen
within 10 minutes of removal. Frozen tissue should be sent on dry ice to the BPC. A minimum
tumor tissue > 0.5 cm2 is preferred.
-If frozen tumor is not available, 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.)

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-If frozen tumor is not available and the institution cannot release blocks, three to ten 50
µm scrolls should be sent and 10 unstained slides (Please indicate percent tumor
represented.)
• Ten 10 µm paraffin sections mounted on plain slides (not PLUS) unbaked should be submitted
for laser capture microdissection and ten 4 um paraffin sections mounted on PLUS slides should
be submitted for possible FISH confirmation of gene copy number changes.
• 5 ml of peripheral blood in a green top tube (sodium heparin) and 5 cc of blood in a purple top
tube (EDTA) should be sent any time before the initiation of therapy. Do 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 materials with the BPC Number, collection date and specimen type.
16.4.3.1 Shipping Instructions

Ship materials to:
Biopathology Center
Children’s Hospital
700 Children’s Drive, WA1340*
Columbus, OH 43205
Phone: (614) 722-2810
* Be sure to include the room number. Packages without a room number may be returned to the sender.

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REFERENCES
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20. Nicholson HS, Krailo M, Ames MM, et al: Phase I study of temozolomide in children and
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21. Lashford LS, Thiesse P, Jouvet A, et al: A United Kingdom Children's Cancer Study Group and
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22. Cohen K, Aronson L, Siffert J, et al: Final Outcome Of A Phase I Trial Of Trial Of Low-Dose
Temozolomide Given Concurrently With Radiation Therapy In Children And Adolescents With
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23. Plowman J, Waud WR, Koutsoukos AD, et al: Preclinical antitumor activity of temozolomide in
mice: efficacy against human brain tumor xenografts and synergism with 1,3-bis(2- chloroethyl)-
1-nitrosourea. Cancer Res 54:3793-3799, 1994
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25. Schold SC, Kuhn JG, Bosik ME, et al: A Phase I trial of BCNU plus temozolomide. A North
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glioblastoma multiforme: North American Brain Tumor Consortium study. Neuro-Oncology
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27. Stevens MF, Hickman JA, Langdon SP, et al: Antitumor activity and pharmacokinetics in mice
of 8-carbamoyl-3-methyl- imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B
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28. Newlands ES, Blackledge GRP, Slack JA, et al: Phase I trial of temozolomide. Br J Cancer
65:287-291, 1992
29. Hammond LA, Eckardt JR, Kuhn JG, et al: A randomized Phase I and pharmacological trail of
sequences of 1-3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced
solid noeplasms. Clin Canc Res 10:1645-1656, 2004
30. Belanich M, Pastor M, Randall T, et al: Retrospective study of the correlation between the DNA
repair protein alkyltransferase and survival of brain tumor patients treated with carmustine.
Cancer Res 56(4):783-8, 1996
31. Jaeckle KA, Eyre HJ, Townsend JJ, et al: Correlation of tumor O6-methylguanine-DNA
methyltransferase levels with survival of malignant astrocytoma patients treated with bis-
chloroethylnitrosoure: a Southwest Oncology Group study. J Clin Oncol 16(10):3310-5, 1998
32. Liu L, Markowitz S, Gerson SL: Mismatch repair mutations override alkyltransferase in
conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea. Cancer Res
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33. Fink D, Aebi S, Howell SB: The role of DNA mismatch repair in drug resistance. Clin Cancer
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34. Friedman HS, McLendon RE, Kerby T, et al: DNA mismatch repair and O6-alkylguanine-DNA
alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin
Oncol 16(12):3851-7, 1998

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35. Friedman HS, Johnson SP, Dong Q, et al: Methylator resistance mediated by mismatch repair
deficiency in a glioblastoma multiforme xenograft. Cancer Res 57(14):2933-6, 1997
36. Pollack IF, Finkelstein SD, Woods J, et al: Expression of p53 and prognosis in malignant
gliomas in children. N Engl J Med 346:420-427, 2002
37. Pollack IF, Finkelstein SD, Burnham J, et al: Age and TP53 mutation frequency in childhood
gliomas. Results in a multi-institutional cohort. Cancer Res 61:7404-7407, 2001
38. Pollack IF, Hamilton RL, Burnham J, et al: The impact of proliferation index on outcome in
childhood malignant gliomas: Results in a multi-institutional cohort. Neurosurgery 50:1238-
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39. Hayes JD, Pulford DJ: The glutathione S-transferase supergene family: regulation of GST and
the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev
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41. Goto S, Iida T, Cho S, et al: Overexpression of glutathione S-transferase pi enhances the adduct
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47. Garte S, Gaspari L, Alexandrie AK, et al: Metabolic gene polymorphism frequencies in control
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the simultaneous analysis of the glutathione S-transferase GSTM1 and GSTT1 polymorphisms.
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49. Seidegard J, Vorachek WR, Pero RW, et al: Hereditary differences in the expression of the
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54. Pandya U, Srivastava SK, Singhal SS, et al: Activity of allelic variants of Pi class human
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55. Srivastava SK, Singhal SS, Hu X, et al: Differential catalytic efficiency of allelic variants of
human glutathione S-transferase Pi in catalyzing the glutathione conjugation of thiotepa. Arch
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2004

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APPENDIX I: PERFORMANCE STATUS SCALES/SCORES
PERFORMANCE STATUS CRITERIA

Karnofsky and Lansky performance scores are intended to be multiples of 10
ECOG (Zubrod) Karnofsky Lansky*
Score Description Score Description Score Description
100 Normal, no complaints, no 100 Fully active, normal.

evidence of disease
Fully active, able to carry on all
0 pre-disease performance
90 Able to carry on normal 90 Minor restrictions in physically
without restriction.
activity, minor signs or strenuous activity.
symptoms of disease.
80 Normal activity with effort; 80 Active, but tires more quickly

Restricted in physically some signs or symptoms of
strenuous activity but disease.
ambulatory and able to carry
1
out work of a light or sedentary
nature, e.g., light housework, 70 Cares for self, unable to carry 70 Both greater restriction of and
office work. on normal activity or do active less time spent in play activity.
work.
60 Required occasional 60 Up and around, but minimal

assistance, but is able to care active play; keeps busy with
Ambulatory and capable of all for most of his/her needs. quieter activities.
self-care but unable to carry out
2 any work activities. Up and
50 Requires considerable 50 Gets dressed, but lies around
about more than 50% of
assistance and frequent much of the day; no active play,
waking hours
medical care. able to participate in all quiet
play and activities.
40 Disabled, requires special care 40 Mostly in bed; participates in

and assistance. quiet activities.
Capable of only limited self-
3 care, confined to bed or chair
more than 50% of waking 30 Severely disabled, 30 In bed; needs assistance even for
hours. hospitalization indicated. quiet play.
Death not imminent.
20 Very sick, hospitalization 20 Often sleeping; play entirely

Completely disabled. Cannot indicated. Death not limited to very passive activities.
4 carry on any self-care. Totally imminent
confined to bed or chair. 10 Moribund, fatal processes 10 No play; does not get out of bed.
progressing rapidly.
*
The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.

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APPENDIX II: TEMOZOLOMIDE AND LOMUSTINE (CCNU) DOSING
Temozolomide Dosing
Chemoradiotherapy
(90 mg/m2/day)
BSA (m2) Calculated Dose Administered
(mg) Dose (mg)
0.2-0.5 3 mg/kg/Day 3 mg/kg/Day
0.51-0.58 45.9-52.2 50
0.59-0.63 53.1-56.7 55
0.64-0.69 57.6-62.1 60
0.70-0.75 63.0-67.5 65
0.76-0.80 68.4-72.0 70
0.81-0.86 72.9-77.4 75
0.87-0.91 78.3-81.9 80
0.92-0.97 82.8-87.3 85
0.98-0.99 88.2-89.1 90
1 90 90
1.1 99 100
1.2 108 110
1.3 117 120
1.4 126 125
1.5 135 135
1.6 144 145
1.7 153 155
1.8 162 160
1.9 171 170
2 180 180

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Maintenance (160mg/m2/day)
(mg) Dose (mg)
0.2-0.5 5.3 mg/kg/day 5.3 mg/kg/day
0.51 82 80
0.52-0.54 83 - 86 85
0.55-0.57 88- 91 90
0.58-0.6 93 - 96 95
0.61-0.64 98 - 102 100
0.65-0.67 104 - 107 105
0.68-0.7 108 - 112 110
0.71-0.73 114 - 117 115
0.74-0.76 118-122 120
0.77-0.79 123-126 125
0.8-0.82 128-131 130
0.83-0.85 133-136 135
0.86-.088 138 - 141 140
0.89-0.91 142 - 146 145
0.92-0.95 147 - 152 150
0.96-0.98 153 - 157 155
0.99- 1 158-160 160
1.1 176 180
1.2 192 190
1.3 208 210
1.4 224 225
1.5 240 240
1.6 256 255
1.7 272 270
1.8 288 290
1.9 304 305
2 320 320

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LOMUSTINE (CCNU) DOSING
Maintenance chemotherapy
(90 mg/m2 on day 1)
(mg) Dose (mg)
0.2-0.5 3 mg/kg//day 3 mg/kg/day
0.51-0.6 46-54 50
0.61-0.7 55-63 60
0.71-0.81 64-73 70
0.82-0.92 74-83 80
0.93-1 84-90 90
1.1 99 100
1.2 108 110
1.3 117 120
1.4 126 130
1.5 135 130
1.6 144 140
1.7 153 150
1.8 162 160
1.9 171 170
2 180 180

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APPENDIX III: TEMOZOLOMIDE ADMINISTRATION AND MEDICATION

DOCUMENTATION FORM FOR CHEMORADIOTHERAPY
• Temozolomide is an oral cancer medicine that your child will be taking for treatment of his brain
tumor. Important guidelines for taking this medicine include:
• Temozolomide must be kept in a dark container
• Temozolomide should be taken the same time everyday and the capsules must be swallowed whole.
It is recommended that Temozolomide be given at bedtime with antiemetics given 30 minutes prior
to the dose.
• Temozolomide capsules may not be crushed or chewed
• If the capsules must be opened, please refer to the instruction sheet for administration (see Appendix V)
• If your child requires nausea medicine it should be taken approximately 30 minutes prior to the
Temozolomide dose
• If the dose of Temozolomide is vomited within 30 minutes of administration and the capsules can be
seen in the vomit, the dose should be repeated.
Medication Record: Please fill in the table each day the medicine is given. Please bring this form to clinic
each visit so that your provider can review the information.
Day Date Dose Other Medicines Problems

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17

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18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42

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APPENDIX IV: TEMOZOLOMIDE AND LOMUSTINE (CCNU) ADMINISTRATION AND

MEDICATION DOCUMENTATION FORM FOR MAINTENANCE
• Temozolomide and Lomustine (CCNU) are oral cancer medicines that your child will be taking for
treatment of his brain tumor. Important guidelines for taking this medicine include:
• Temozolomide and Lomustine (CCNU) must be kept in a dark container
• Temozolomide should be taken the same time everyday. It is recommended that Temozolomide be
given at bedtime with antiemetics given 30 minutes prior to the dose. If Lomustine (CCNU) is to be
given also, it can be taken at the same time as Temozolomide. It is recommended that both drugs be
taken at least 1 hour before or 2 hrs after a meal.
• Temozolomide and Lomustine (CCNU) capsules may not be crushed or chewed
• If the capsules must be opened, please refer to the instruction sheet for administration (See
Appendix V)
• Nausea medicine should be taken approximately 30 minutes prior to the dose.
• If the dose of Temozolomide and/or Lomustine (CCNU) is vomited within 30 minutes of
administration and the capsules can be seen in the vomit, the dose should be repeated.
Medication Record: Please fill in the table each day the medicine is given. Please bring this form to clinic
each visit so that your provider can review the information.
Cycle 1
1
TEMO
CCNU
2
TEMO
3
TEMO
4
TEMO
5
TEMO
Cycle 2
1
TEMO
CCNU
2
TEMO
3
TEMO
4
TEMO
5
TEMO

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Cycle 3
1
TEMO
CCNU
2
TEMO
3
TEMO
4
TEMO
5
TEMO
Cycle 4
1
TEMO
CCNU
2
TEMO
3
TEMO
4
TEMO
5
TEMO
Cycle 5
1
TEMO
CCNU
2
TEMO
3
TEMO
4
TEMO
5
TEMO

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Cycle 6
1
TEMO
CCNU
2
TEMO
3
TEMO
4
TEMO
5
TEMO

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APPENDIX V: INSTRUCTIONS FOR ADMINISTRATION OF TEMODAR AND LOMUSTINE

FOR PATIENTS UNABLE TO SWALLOW CAPSULES
• If the person giving this medicine is pregnant or suspects she is pregnant she should not give this
medicine
Temodar and Lomustine (CCNU) are anti-cancer agents, and special precautions must be taken when
handling these medicines. There is potential hazard to anyone who handles these medicines once the
protective capsule is opened. Since your child is unable to swallow the capsule you will be required to
open the capsules and mix the contents of the capsule in apple sauce or apple juice (temodar). This
process must be done according to the following guidelines to ensure safe administration of this
medicine.
• Find a place that is free from drafts or wind and is not an area where food is stored or prepared.
• The work surface should be covered with an impermeable and disposable mat such as the one a
pharmacy uses to reduce exposure to other members of the family.
• Temodar can be mixed in apple sauce or apple juice. Lomustine (CCNU) is not easily dissolved in
liquid, so it is preferable to open the capsule and place the contents into a small amount of food.
• Place the apple sauce or apple juice or small amount of food in a disposable container.
• Put on gloves and mask
• Open each capsule and place the powder in the apple sauce, apple juice or food and give
IMMEDIATELY. The medicine may not dissolve completely if mixing in apple juice so have extra
apple juice on hand if needed) to add to any powder remaining in the cup.
• If you need to have additional juice or apple sauce remove your gloves before touching the main
container then place new gloves on before adding the additional juice or apple sauce to the medicine.
(You do not want to contaminate the main container with any powder that may be on your gloves).
• Anything that comes into contact with the medicine must be disposable, such as the spoon used for
mixing or eating the apple sauce.
• Once all of the medicine is taken, throw away the following in the plastic bags provided to you by
the clinic: medicine cup, the container the medicine was mixed in, the cover for the work surface,
mask, gloves and anything else that has been in contact with the medicine.
• Once a course of medicine is completed, bring the plastic bag with you to the clinic so it can be
disposed of properly.

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ACNS0423

Activated: 03/21/05 Version Date: 10/23/15

CHILDREN'S ONCOLOGY GROUP

A Phase II Study of Concurrent Radiation and Temozolomide Followed by Temozolomide and

1. Anaplastic Astrocytoma (WHO III)

2. Glioblastoma Multiforme (WHO IV)

Version Date: 10/23/15 Page 1

Version Date: 10/23/15 Page 2

8.6 Blood Products 29

Version Date: 10/23/15 Page 3

16.1 Eligible Tumors 47

Version Date: 10/23/15 Page 4

Ian Pollack, M.D.

Version Date: 10/23/15 Page 5

Marc Rosenblum, M.D. Del Stringham, PharmD

Susan Fiore Shaw, RN

Ingrid Shieh (Research Coordinator)

Version Date: 10/23/15 Page 6

Version Date: 10/23/15 Page 7

EXPERIMENTAL DESIGN SCHEMA

Version Date: 10/23/15 Page 8

1.0 GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

Target tumors are:

1.3 Laboratory Correlates

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2.1 Introduction/Rationale for Development

2.2 Rationale for CCNU

2.3 Rationale for Temozolomide

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2.4 Rationale for Combination

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2.5 Biology studies/correlates

2.5.1 MGMT/MMR Analysis

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2.5.2 MIB-1/p53 analysis

2.5.3 Glutathione Gene Analysis

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2.5.4 Genome Allelotype Analysis

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2.6 Gender and Race Differences

3.0 PATIENT ELIGIBILITY AND STUDY ENTRY

3.1 Study Enrollment

3.1.1 IRB Approval

3.1.2 Patient Registration

3.2 Timing of Enrollment and Start of Treatment

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3.3 Patient Status

3.3.2 Histologic Diagnosis

3.3.4 Ability to Take Oral Medication

3.3.5 Performance Level

3.3.6 Life Expectancy

3.4 Prior Therapy

3.5 Contraindicated Medications

3.6 Organ Function Requirements

3.6.1 Adequate Bone Marrow Function Defined As

3.6.2 Adequate Renal Function Defined As

3.6.3 Adequate Liver Function Defined As

3.6.4 Central Nervous System Function Defined As

3.6.5 Adequate Pulmonary Function Defined As:

4.0 TREATMENT PLAN

4.1 Treatment Plan Overview

4.2.1 Radiation Therapy

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Week Note Patient’s: Wgt _kg Hgt_cm BSA ____m2

Week Note Patient’s: Wgt _kg Hgt_cm BSA ____m2

Week Note Patient’s: Wgt _kg Hgt_cm BSA ____m2

Week Cycle

Week Cycle