Conditions: Central Nervous System Neoplasm Pineoblastoma Recurrent Medulloblastoma Recurrent Primitive Neuroectodermal Tumor Refractory Medulloblastoma Refractory Peripheral Primitive Neuroectodermal Tumor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies how well giving temozolomide and irinotecan hydrochloride together with or without bevacizumab works in treating young patients with recurrent or refractory medulloblastoma or central nervous system (CNS) primitive neuroectodermal tumors. Drugs used in chemotherapy, such as temozolomide and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether temozolomide and irinotecan hydrochloride are more effective with or without bevacizumab in treating medulloblastoma or CNS primitive neuroectodermal tumors.

Detailed description:
PRIMARY OBJECTIVES:

l. To compare the overall survival (OS) of subjects receiving the combination of temozolomide and irinotecan with that of subjects receiving temozolomide, irinotecan (irinotecan hydrochloride), and bevacizumab for recurrent medulloblastoma (MB)/primitive neuroectodermal tumor (PNET) of childhood.

SECONDARY OBJECTIVES:

I. To assess the response rate for each treatment arm amongst patients who are enrolled with measurable disease.

II. To determine event-free survival (EFS) for each patient compared across regimens.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive temozolomide orally (PO) and irinotecan hydrochloride IV over 90 minutes on days 1-5.

ARM II: Patients receive temozolomide PO and irinotecan hydrochloride IV as in arm I and bevacizumab IV over 30-90 minutes on days 1 and 15.

In both arms, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 5 years.

Arms:
arm 1: Patients receive temozolomide PO and irinotecan hydrochloride IV over 90 minutes on days 1-5. arm 2: Patients receive temozolomide PO and irinotecan hydrochloride IV as in arm I and bevacizumab IV over 30-90 minutes on days 1 and 15.

Interventions: intervention 1: Bevacizumab intervention 2: Irinotecan Hydrochloride intervention 3: Temozolomide
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
June 23, 2014 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Attached is Amendment #4 to ACNS0821, Temozolomide with Irinotecan versus 
Temozolomide, Irinotecan plus Bevacizumab (NSC# 704865, BB-IND# 7921) for 
Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, A COG Randomized 
Phase II Screening Trial. 
. 
The amendment is being submitted in response to an RA from Dr. Helen Chen 
(helen.chen@nih.gov) dated May 9, 2014.  The bevacizumab monograph has been 
modified to reflect the incorporation of the revised Comprehensive Adverse Events and 
Potential Risks (CAEPR) list for bevacizumab provided by the NCI. The changes made 
due to this request are detailed below.  
 
In addition, the eligibility criteria have been revised regarding measurable disease. 
Liberalizing the eligibility requirement will allow the study to enroll more patients with 
recurrent/refractory disease and will offer these patients the opportunity for study 
participation when other therapeutic options are quite limited.   
 
The primary objective of the study is to compare the overall survival (OS) of subjects 
receiving the combination of temozolomide and irinotecan with that of subjects receiving 
temozolomide, irinotecan and bevacizumab for recurrent medulloblastoma (MB)/PNET of 
childhood.  Measurable disease is a vital eligibility criterion only if the primary objective is 
tumor response and EFS.  However, with OS as the primary outcome of the study, it is 
not imperative that patients have measurable disease at the time of enrollment.  Patients 
with leptomeningeal disease or patients with clear residual disease following resection of 
recurrence will be enrolled and still be assessable for OS.  The Study committee will 
stratify patients for randomization to each treatment arm according to whether or not they 
have measurable disease.  Thus, exposure to each treatment arm will be similar for an 
equal number of patients that have no measurable disease at the time of enrollment.  
While power may be limited, the investigators will test for a differential effect on outcome 
based on whether or not measurable disease was present at enrollment. 
 
 
In addition, administrative changes have also been included.  
 
Specific changes are detailed below. 
 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Chief Administrative Officer 
Maria Hendricks, M.S.N, R.N. 
C.C.R.P. 
hendricksm@email.chop.edu  
 
Group Statistician 
Meenakshi Devidas, Ph.D. 
mdevidas@cog.ufl.ed 
 
Associate Group  
Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
P 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
A National Cancer Institute  
supported clinical cooperative 
group and Equal Opportunity 
Affirmative Action Institutions 
 
 
 
 
 
 
 


ii 
 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol.  
Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
 Title Page 
1 
The version date and amendment number have been 
updated. 
2. 
 Table of Contents 
2-3 
The table of contents has been updated since the 
protocol has been repaginated. 
3. 
 Study Committee 
4-5 
The contact information for Drs.Krailo and Chris 
Williams-hughes have been updated. Dr. Jakacki has 
been replaced by Dr. Chi as the Vice-chair. Dr. Turner 
and Ingrid Shieh have been removed and Sung Tse has 
been added. 
4. 
 Abstract  
6 
The last paragraph has been revised to include 
evaluable disease. 
5. 
 1.2.1 
8 
The objective has been revised as below. 
 
To assess the response rate for each treatment arm 
amongst patients who are enrolled with measurable 
disease. 
 
6. 
 3.1.5 
14 
The following statement has been added. 
 
Patients will be stratified for randomization to each 
treatment arm according to whether or not they 
have measurable disease. 
7. 
 3.2.2.3 
14 
The section has been revised as below. 
 
Patients must have clear residual disease, defined 
as tumor that is measurable in two perpendicular 
diameters on MRI OR diffuse leptomeningeal 
disease OR clear MRI evidence of disease that may 
not be measurable in two perpendicular diameters. 
Patients must have measurable residual disease, 
defined 
as 
tumor 
that 
is 
measurable 
in 
two 
perpendicular diameters on MRI. Diffuse leptomeningeal 
disease is not considered measurable. 
 
8. 
 6.0 
31 
The following statement was added, “Please see 
Appendix VIII for drug interactions associated with 
the drugs used in this study”. 
 
9. 
 6.1 
31-38 
The Bevacizumab monograph has been updated as 
requested by the RA to include the updated CAEPR 
(Version 2.3).  
 
• 
Added New Risk:  
• 
Less Likely:  Dehydration; Wound complication  
• 
Rare But Serious:  Infections and infestations 


iii 
 
– Other (necrotizing fasciitis) 
• 
Also Reported on Bevacizumab Trials But 
With the Relationship to Bevacizumab Still 
Undetermined:  Acidosis; Activated partial 
thromboplastin time prolonged; Agitation; 
Alopecia; Anxiety; Arachnoiditis; Arterial injury; 
Arthritis; Ascites; Ataxia; Atelectasis; 
Atrioventricular block complete; Atrioventricular 
block first degree; Back pain; Bladder spasm; 
Blood antidiuretic hormone abnormal; Blurred 
vision; Bone marrow hypocellular; Bone pain; 
Breast pain; Bruising; Burn; Carbon monoxide 
diffusing capacity decreased; Cardiac arrest; 
Cataract; CD4 lymphocytes decreased; 
Central nervous system necrosis; 
Cerebrospinal fluid leakage; Chelitis; Chest 
wall pain; Cholecystitis; Chronic kidney 
disease; Cognitive disturbance; Colonic 
stenosis; CPK increased; Cystitis noninfective; 
Death NOS; Depressed level of 
consciousness; Depression; Dermatitis 
radiation; Dry eye; Dry mouth; Dry skin; 
Dysesthesia; Dysphagia; Dysphasia; Ear and 
labyrinth disorders – Other (tympanic 
membrane perforation); Edema face; Edema 
limbs; Edema trunk; Electrocardiogram QT 
corrected interval prolonged; Encephalopathy; 
Enterocolitis; Erectile dysfunction; Esophageal 
pain; Esophageal stenosis; Extraocular muscle 
paresis; Extrapyramidal disorder; Eye 
disorders – Other (blindness); Eye disorders – 
Other (conjunctival hemorrhage); Eye 
disorders – Other (corneal epithelial defect); 
Eye disorders – Other (floaters); Eye disorders 
– Other (ischemic CRVO); Eye disorders – 
Other (macular pucker); Eye disorders – Other 
(transient increased IOP > or = 30 mm Hg); 
Eye disorders – Other (vitreous hemorrhage); 
Eye pain; Facial nerve disorder; Facial pain; 
Fever; Fibrosis deep connective tissue; 
Flatulence; Flu like symptoms; Flushing; 
Forced expiratory volume decreased; 
Fracture; Gallbladder necrosis; Gallbladder 
obstruction; Gastrointestinal disorders – Other 
(peritonitis); Generalized muscle weakness; 
GGT increased; Head soft tissue necrosis; 
Hearing impaired; Hemolysis; Hepatic 
necrosis; Hot flashes; Hydrocephalus; 
Hypercalcemia; Hyperglycemia; Hyperhidrosis; 
Hyperkalemia; Hypermagnesemia; 
Hypernatremia; Hyperthyroidism; 
Hypertriglyceridemia; Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; 
Hypophosphatemia; Hypotension; 


iv 
 
Hypothyroidism; Hypoxia; Injection site 
reaction; INR increased; Insomnia; Irregular 
menstruation; Joint effusion; Keratitis; 
Leukoencephalopathy; Libido decreased; 
Lipase increased; Localized edema; 
Lymphocele; Lymphocyte count decreased; 
Memory impairment; Multi-organ failure; 
Muscle weakness lower limb; Muscle 
weakness upper limb; Musculoskeletal and 
connective tissue disorder – Other 
(polymyalgia rheumatic); Myocarditis; Nail 
loss; Nasal congestion; Neck pain; Nervous 
system disorders – Other (increased 
intracranial pressure); Optic nerve disorder; 
Oral pain; Pain in extremity; Pain of skin; 
Pancreatitis; Paresthesia; Pelvic pain; Pelvic 
soft tissue necrosis; Phlebitis; Photophobia; 
Photosensitivity; Proctitis; Psychosis; 
Pulmonary fibrosis; Purpura; Pyramidal tract 
syndrome; Rash acneiform; Rectal mucositis; 
Rectal stenosis; Renal and urinary disorders – 
Other (dysuria); Renal and urinary disorders – 
Other (ureterolithiasis); Renal hemorrhage; 
Respiratory failure; Respiratory, thoracic and 
mediastinal disorders – Other (dry nares); 
Respiratory, thoracic and mediastinal 
disorders – Other (pulmonary infarction); 
Restrictive cardiomyopathy; Retinal 
detachment; Retinal tear; Retinopathy; Right 
ventricular dysfunction; Serum amylase 
increased; Skin and subcutaneous tissue 
disorders – Other (diabetic foot ulcer); Skin 
and subcutaneous tissue disorders – Other 
(skin breakdown/ decubitus ulcer); Skin 
hyperpigmentation; Skin induration; Soft tissue 
necrosis lower limb; Somnolence; Stevens-
Johnson syndrome; Tinnitus; Tremor; Tumor 
pain; Typhlitis; Urinary frequency; Urinary 
incontinence; Urinary retention; Urinary tract 
obstruction; Urinary tract pain; Vaginal 
discharge; Vasculitis; Vasovagal reaction; 
Watering eyes; Weight gain 
 
• 
Increase in Risk Attribution: 
• 
Changed to Likely from Less Likely:  
Neutrophil count decreased 
• 
Changed to Less Likely from Reported But 
Undetermined:  Platelet count decreased 
 
• 
Decrease in Risk Attribution: 
• 
Changed to Reported But Undetermined from 
Less Likely:  Vertigo   
 
• 
Provided Further Clarification: 
• 
Supraventricular tachycardia is now reported 


v 
 
as Cardiac disorders – Other (supraventricular 
arrhythmias) and the following footnote (#3) 
was added, “Supraventricular arrhythmias may 
include supraventricular tachycardia, atrial 
fibrillation and atrial flutter.” 
• 
Gastrointestinal anastomotic leak is now 
reported as Injury, poisoning and procedural 
complications – Other (anastomotic leak) and 
the following footnote (#10) was added, 
“Anastomotic leak may include 
Gastrointestinal anastomotic leak; Gastric 
anastomotic leak; Large intestinal anastomotic 
leak; Rectal anastomotic leak; Small intestinal 
anastomotic leak; Urostomy leak; Vaginal 
anastomotic leak.” 
 
• 
Modified Specific Protocol Exceptions to Expedited 
Reporting (SPEER) reporting requirements:   
• 
Added:  Dehydration; Platelet count 
decreased; Wound complication 
 
• 
Deleted Risk:  
• 
Also Reported on Bevacizumab Trials But 
With the Relationship to Bevacizumab Still 
Undetermined:  Pneumonitis; Pneumothorax 
 
 
In addition, the version date and agent ordering 
information have been updated. 
10. 
 9.2 
45 
The following statement was added.  
Patients will be stratified for randomization to each 
treatment arm according to whether or not they 
have measurable disease. 
 
11. 
 9.3.3 
47 
The following statement has been added. 
 
Only patients who are enrolled with measurable 
disease will be considered in the evaluation of 
response rate. 
 
12. 
 9.5 
48 
The section title has been revised. 
13. 
 10.2 
49-52 
The section has been revised and separated into 
sections 10.2.1, 10.2.2 and 10.2.3. The title of Table 
10.2 has been revised and Table 10.2b has been added. 
14. 
 10.4 
53 
Item 5 was added for patients with measurable disease. 
15. 
 10.5 
53 
The following statement was added.  
Non-target lesions will only be evaluated in patients 
with measurable disease. 
 
16. 
 11.0 
55-62 
The AE Reporting guidelines have been updated using 
the new CTEP AERS Reporting. 


vi 
 
17. 
 Appendix VIII  
77-78 
The Appendix was added to include possible drug 
interactions for each agent used in the study. 
 
 
SUMMARY OF CHANGES: INFORMED CONSENT DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol.  
Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
 WHAT 
ARE 
THE RISKS OF 
THE 
STUDY 
AND HOW ARE 
THE 
RISKS 
DIFFERENT 
FROM 
TREATMENT? 
 
 
7-8 
The side effects of bevacizumab have been updated using 
the COG format. 
 
The bevacizumab monograph has also been revised to 
include the following changes according to the Request for 
Amendment for bevacizumab from CTEP. 
 
• 
Added New Risk:   
• 
Occasional:  Dehydration; Delay in healing of 
wounds or spontaneous opening of wounds 
• 
Rare:  Flesh-eating bacteria syndrome, an 
infection in the deep layers of skin 
 
• 
Decrease in Risk Attribution:   
• 
Changed to Reported But Undetermined from 
Less Likely (i.e., removed from the Risk Profile):  
Feeling of spinning or whirling 
 
The condensed risk profile has been modified to include 
the following. 
Added to to “Common” 
• Low white cell count that may increase the risk 
of infection 
• 
Absence of menstrual cycles (periods) and 
damage to the ovaries that may decrease the 
ability to have children in the future 
 
Added to “Occasional” 
• 
Abnormal bone changes which may interfere 
with growth 
• 
Increased blood level of liver tests which may 
mean there has been damage to the liver 
 
In addition, the following statement was added. 
Some drugs or supplements may interact with your 
treatment plan. Talk to your doctor, pharmacist, or 
study team before starting any new prescription 
drugs, 
over-the-counter 
drugs, 
herbals, 
or 
supplements and before making a significant change 
in your diet.  Supplements may come in many forms, 
such as teas, drinks, juices, liquids, drops, capsules, 
pills, or dried herbs. All forms should be avoided. 
 


vii 
 
2. 
 WHAT 
ARE 
THE COSTS? 
 
 
The fourth paragraph has been revised. 
3. 
 WHAT ARE MY 
RIGHTS AS A 
PARTICIPANT? 
 
11 
The fourth paragraph has been updated and revised 
regarding follow-up visits. 
4. 
 Attachment #2 
14-15 
The possible side effects of irinotecan have been updated 
using the COG format. In addition, the drug interactions for 
temozolomide have been removed and included in 
Appendix VIII. 
 
 
Please let me know if we can offer further information. 
 
Sincerely, 
 
Chris Williams-Hughes, Protocol Coordinator (for) 
Adam Levy, MD, MS, Study Chair, ACNS0821 
Peter Adamson, MD, Group Chair, Children’s Oncology Group 
 
 
 


 
 
 
ACNS0821 
 
 
Page 1 
 
Activated: 
November 22, 2010 
Version Date: 
6/23/14 
Closed: 
      
Amendment # 
4 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
ACNS0821 
 
 
Temozolomide with Irinotecan versus Temozolomide, Irinotecan plus Bevacizumab (NSC# 704865, 
BB-IND# 7921) for Recurrent/Refractory Medulloblastoma/CNS PNET of Childhood, A COG 
Randomized Phase II Screening Trial 
 
 
A Groupwide Phase II Study 
 
NCI Supplied Agent: Bevacizumab (IND# 7921, NSC#704865) 
 
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 
INSTITUTION. 
 
 
STUDY CHAIR 
 
Adam Levy, MD 
Montefiore Medical Center 
Pediatric Hematology/Oncology 
3415 Bainbridge Avenue 
Rosenthal 3rd floor 
Bronx, New York 10467-2490 
United States 
Phone: 718 741-2342 
Fax: 718 920-6506 
e-mail: adlevy@montefiore.org 
 
 
For Statistics and Data Center Contact Person see:  http://members.childrensoncologygroup.org 


 
 
 
ACNS0821 
 
 
Page 2 
TABLE OF CONTENTS 
SECTION 
PAGE 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
4 
ABSTRACT 
6 
EXPERIMENTAL DESIGN SCHEMA 
7 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
8 
1.1 
Primary Objective 
8 
1.2 
Secondary Objectives 
8 
2.0 
BACKGROUND 
8 
2.1 
Introduction/Rationale for Development 
8 
2.2 
Bevacizumab 
9 
2.3 
Temozolomide 
10 
2.4 
Irinotecan 
10 
2.5 
Combination of Temozolomide and Irinotecan 
11 
2.6 
Justification for the Addition of Bevacizumab to Chemotherapy 
12 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
13 
3.1 
Study Enrollment 
13 
3.2 
Patient Criteria 
14 
4.0 
TREATMENT PROGRAM 
19 
4.1 
Overview of Treatment Plan 
19 
4.2 
Concomitant therapy restrictions 
20 
4.3 
TEMO+IRIN Course 
21 
4.4 
TEMO+IRIN+BEVA Course 
24 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
27 
5.1 
Dose Reduction 
27 
5.2 
Hematologic Toxicity 
30 
5.3 
Non-Hematologic Toxicity 
30 
6.0 
DRUG INFORMATION 
31 
6.1 
Bevacizumab 
31 
6.2 
IRINOTECAN 
39 
6.3 
TEMOZOLOMIDE 
41 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
42 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
42 
7.2 
Follow-up 
44 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA44 
8.1 
Criteria for Removal from Protocol Therapy 
44 
8.2 
Off Study Criteria 
44 
9.0 
STATISTICAL CONSIDERATIONS 
44 
9.1 
Sample Size and Study Duration 
44 
9.2 
Study Design 
44 
9.3 
Methods of Analysis 
45 
9.4 
Interim Safety Monitoring 
47 


 
 
 
ACNS0821 
 
 
Page 3 
9.5 
Detection of Progression 
48 
9.6 
Gender and Minority Accrual Estimates 
49 
10.0 
EVALUATION CRITERIA 
49 
10.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
49 
10.2 
Methodology to Determine Tumor Measurement 
49 
10.3 
Selection of Target and Non-Target Lesions 
52 
10.4 
Response Criteria for Target Lesions 
52 
10.5 
Response Criteria for Non-target Lesions 
53 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
54 
11.1 
Purpose 
54 
11.2 
Determination of reporting requirements 
54 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
54 
11.4 
Special Situations for Expedited Reporting 
55 
11.5 
Reporting Requirements for Specialized AEs 
57 
11.6 
Exceptions to Expedited Reporting 
58 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
60 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
61 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway62 
11.12 Routine Adverse Event Reporting 
62 
12.0 
STUDY REPORTING AND MONITORING 
63 
12.1 
CDUS 
63 
12.2 
Data and Safety Monitoring Committee 
63 
12.3 
CRADA/CTA 
63 
13.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
65 
13.1 
Timing of MRIs 
65 
13.2 
Whole Brain MRI With and Without Contrast 
65 
13.3 
Spine MRI With Contrast 
66 
13.4 
Tumor Response Assessment 
67 
APPENDIX I: 90TH AND 95TH PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT IN 
GIRLS AGE 1-17 YEARS 
68 
APPENDIX II: 90TH AND 95TH PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT IN 
BOYS AGE 1-17 YEARS 
69 
APPENDIX III: TEMOZOLOMIDE DOSING TABLE - STARTING DOSE= 150 MG/M2 
70 
APPENDIX IV: TEMOZOLOMIDE DOSING TABLE-REDUCED DOSE = 112.5 MG/M2 
72 
APPENDIX V: TEMOZOLOMIDE DOSING TABLE - REDUCED DOSE= 75 MG/M2 
73 
APPENDIX VI: RECOMMENDATIONS FOR ADMINISTRATION OF TEMOZOLOMIDE 
(PATIENTS WHO ARE UNABLE TO SWALLOW CAPSULES AND CANNOT OBTAIN A 
SUSPENSION) 
74 
APPENDIX VII: YOUTH INFORMATION SHEETS 
75 
APPENDIX VII: POSSIBLE DRUG INTERACTIONS 
77 
REFERENCES 
79 
 


 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
ACNS0821 
 
 
Page 4 
 
STUDY COMMITTEE 
 
STUDY CHAIR 
Julia Glade Bender, M.D. 
Adam Levy, M.D. 
Hematology/Oncology 
Hematology/Oncology 
Columbia University Medical Center 
Montefiore Medical Center 
Pediatric Oncology 
Pediatric Hem/Onc 
161 Fort Washington Avenue 
3415 Bainbridge Avenue 
IP7 
Rosenthal 3rd floor 
New York, NY  10032 
Bronx, NY  10467-2490 
Phone: (212) 305-5808 
Phone: (718) 741-2342 
Fax: 
(212) 305-5848 
Fax: 
(718) 920-6506 
E-mail: jg589@columbia.edu 
E-mail: adlevy@montefiore.org 
 
 
Ian Pollack, M.D. 
STUDY VICE CHAIR 
Surgery 
Susan Chi, M.D. 
Children’s Hospital of Pittsburgh of UPMC 
Hematology/Oncology 
Department of Neurosurgery 
Dana-Farber Cancer Institute  
One Children’s Hospital Drive 
Pediatric Oncology 
4401 Penn Ave, Faculty Pavilion Bldg, 8th Floor 
44 Binney Street 
Pittsburgh, PA  15224 
Boston, MA  02115 
Phone: (412) 692-5881 
Phone: (617) 632-4386 
Fax: 
(412) 692-5921 
Fax: 
(617) 632-4897 
E-mail: ian.pollack@chp.edu 
E-mail: susan_chi@dfci.harvard.edu 
 
 
Marily Lesher, BS CCRP 
 
Clinical Research Associates 
 
University of Minnesota Medical Center 
STUDY STATISTICIAN 
Pediatric Hematology-Oncology & BMT 
Mark Krailo, Ph.D. 
420 Delaware St. SE,  MMC 484/Mayo D5482 
Statistics 
Minneapolis, MN  55455 
Children's Oncology Group - Operations Center 
Phone: (612) 626-3915 
Statistics 
Fax: 
(612) 626-2815 
222 E. Huntington Drive, Suite 100 
E-mail: mblesher@umn.edu  
Monrovia, CA 91016 
 
Phone: (626) 241-1529 
Nancy Rollins, M.D. 
Fax: 
(626) 445-4334 
Diagnostic Imaging 
E-mail: mkrailo@childrensoncologygroup.org 
UT Southwestern Medical Center 
 
Children's Medical Center-Dallas 
STUDY COMMITTEE MEMBERS  
1935 Medical District Drive 
Michele Lynn VanSoelen, MSN 
Dallas, TX  75235 
Nursing 
Phone: (214) 456-2809 
Helen DeVos Children’s Hospital at Spectrum Health 
Fax: 
(214) 456-6015 
Div of Pediatric Hem/Onc 
E-mail: nancy.rollins@childrens.com 
100 Michigan St., NE    MC# 85 
 
Grand Rapids, MI  49503-2560 
 
Phone: (616) 391-2086 
 
Fax: 
(616) 391-9430 
 
E-mail: michele.vansoelen@devoschildrens.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Page 5 
 
 
Daniel Hamstra, MD, PhD 
 
Radiation Oncology 
RESEARCH COORDINATOR 
C S Mott Children’s Hospital 
Sung Tse, BA 
UH B2C490, SPC-5010 
Children’s Oncology Group – Operations Center 
1500 East Medical Center Drive 
222 E. Huntington Drive, Suite 100 
Ann Arbor, Michigan  48109-5010 
Monrovia, CA 91016 
Phone: 734 936-4300 
Phone: (626) 241-1663 
Fax: 734 763-7370 
Fax: (626) 445-4334 
E-mail: dhamm@med.umich.edu 
E-mail: stse@childrensoncologygroup.org 
 
 
Royston Browne, RPh 
 
Pharmacy 
PROTOCOL COORDINATOR 
Montefiore Medical Center 
Chris Williams-Hughes   
Pharmacy Department 
Children's Oncology Group - Operations Center 
111 East 210th St. 
222 E. Huntington Drive, Suite 100 
Bronx, NY  10467 
Monrovia, CA 91016 
Phone: (718) 920-5778 
Phone: (660) 553-5049 
Fax: 
(718) 515-9529 
Fax: 
(626) 445-4334 
E-mail: RBrowne@montefiore.org 
E-mail: 
cwilliams@childrensoncologygroup.org 
or 
chrismwhughes@att.net 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For Group Operations (GOC) and  
 
Statistics and Data Center (SDC) contacts see: 
 
http://members.childrensoncologygroup.org 
 
 
 
AGENT NSC# AND IND#’s 
 
Bevacizumab (Supplied by the NCI)  NSC# 704865  IND# 
7921 
 
Irinotecan  
 
NSC #616348 
 
Temozolomide   
NSC# 362856 
 
 
 
 
 
 
 
 


 
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Page 6 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects.  The Certificate protects 
against the involuntary release of information about subjects collected during the course of our covered 
studies.  The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings.  However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances.  For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure.  Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against 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 
 
Temozolomide is an orally administered alkylating agent of the imidazotetrazine derivatives with excellent 
CNS penetration.  Phase II studies have shown variable response rates of 16-47% in children and adolescents 
with recurrent medulloblastomas/PNET. Irinotecan is a water-soluble campothecin derivative that inhibits 
topoisomerase I (topo I), an enzyme involved in DNA repair, transcription and replication.1-3 Irinotecan has 
been shown to have single agent activity against recurrent medulloblastomas.4  A British study found a 40% 
objective response rate to the combination of irinotecan and temozolomide in patients with recurrent 
MB/PNET.  Bevacizumab is a humanized monoclonal neutralizing antibody binding all five isoforms of 
human vascular endothelial growth factor (VEGF). CNS tumors are potentially excellent targets for anti-
angiogenic therapy given the presence of tumor neo-vascularization and high concentrations of pro-angiogenic 
factors.5-7  
 
Both irinotecan and temozolomide have activity against recurrent MB/PNET and the combination has 
been well tolerated in heavily pre-treated patients.8 The addition of bevacizumab theoretically may 
increase the efficacy of chemotherapy. Therefore, a phase II trial evaluating the addition of bevacizumab 
to the combination of irinotecan and temozolomide in MB/PNET of childhood will be performed.  
 
This study will use a randomized phase II screening design4,9 to compare temozolomide 
(150 mg/m2 PO for 5 days) with irinotecan (50 mg/m2 IV for 5 days) to temozolomide, irinotecan plus 
bevacizumab (10 mg/kg IV on Days 1 and 15), in children with recurrent MB/PNET. Patients must have 
measurable or evaluable disease. Response will be evaluated prior to every other course.  Therapy can be 
continued for up to 12 courses in the absence of disease progression or unacceptable side effects. 
 
 


 
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EXPERIMENTAL DESIGN SCHEMA 
 
 
TEMO = Temozolomide 150 mg /m 2 / day PO on Days 1 - 5
IRIN = Irinotecan 50 mg / m 2 /day IV on Days 1 -5 
BEVA = Bevacizumab 10 mg/ kg IV on Days 1 and 15
PD = Progressive Disease 
SD = Stable disease 
PR = Partial Response 
CR = Complete Response 
SD, CR, or PR 
Study Entry 
And
Randomization
TEMO + IRIN 
( Courses 1 and 2 )*
TEMO + IRIN 
( Courses 3 and 4 )*
PD
SD, CR , or PR 
Therapy may continue for up to 12 courses , as 
long as no unacceptable toxicities and no PD 
PD
Response 
Evaluation 
Response 
Evaluation 
Response 
Evaluation 
Response 
Evaluation 
* Each course is 28 days 
Off protocol 
therapy 
Off protocol 
therapy 
TEMO + IRIN 
+ 
BEVA 
( Courses 1
 
and 2)* 
TEMO + IRIN 
+ 
BEVA 
( Courses 3
 
and 4)* 


 
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Page 8 
 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Objective 
To compare the overall survival (OS) of subjects receiving the combination of 
temozolomide and irinotecan with that of subjects receiving temozolomide, irinotecan 
and bevacizumab for recurrent medulloblastoma (MB)/PNET of childhood.  
 
1.2 
Secondary Objectives 
1.2.1 
To assess the response rate for each treatment arm amongst patients who are 
enrolled with measurable disease. 
. 
1.2.2 
To determine event-free survival (EFS) for each patient compared across 
regimens. 
 
 
2.0 
BACKGROUND 
 
2.1 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Redacted


 
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2.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Redacted


 
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2.3 
Temozolomide  
Temozolomide is an orally administered alkylating agent of the imidazotetrazine 
derivatives with excellent CNS penetration. It is the prodrug of the cytotoxic triazine, 
monomethyl triazenoimidazole carboxamide (MTIC), which is the active metabolite of 
dacarbazine (DTIC).20  Temozolomide is currently FDA approved for the treatment of 
recurrent anaplastic astrocytomas and newly diagnosed glioblastoma multiforme. The 
Children’s Cancer Group (CCG) conducted a phase I study of temozolomide in children 
and adolescents with recurrent solid tumors. In this study, responses were seen in 
medulloblastomas and supratentorial PNETs.21 A complete response to temozolomide 
has also been reported in a patient with leptomeningeal recurrence of a 
medulloblastoma.22  An Italian multicenter study of temozolomide in patients with 
recurrent or refractory MB/PNET following craniospinal radiation therapy and multiple 
chemotherapy regimens found an objective response rate of 47%, including 6 of 34 
patients with a complete response.23  A COG phase 2 study of temozolomide in children 
and adolescents with recurrent CNS tumors found temozolomide to be modestly active as 
a single agent for recurrent MB/PNET with an overall response rate of 16%.  Of 29 
patients with MB/PNET, 25 were evaluable with 1 CR (4%) and 3 PR (12%).1  Thus, 
temozolomide appears to be active as a single agent for recurrent medulloblastoma 
although the reported response rates are highly variable. 
 
2.4 
Irinotecan  
Irinotecan is a water-soluble campothecin derivative that inhibits topoisomerase I (topo 
I), an enzyme involved in DNA repair, transcription and replication.2,3,24 In xenograft 
models of childhood tumors including neuroblastoma, sarcomas and brain tumors, single 
agent irinotecan has demonstrated anti-tumor activity.25-27 Irinotecan demonstrated potent 
therapeutic activity in medulloblastoma xenografts in nude mice.28 Irinotecan is a 
prodrug that is metabolized by carboxylesterase enzymes to form SN-38 which is 100-
1000 times more potent as a topo I inhibitor than irinotecan.29-33 Major common 
toxicities include diarrhea, altered liver function, and myelosuppression when given in 
combination with other chemotherapeutic agents. IRIN activity is schedule-dependent in 
mouse xenograft models,and a low-dose protracted schedule administered daily x 5 for 2 
consecutive weeks in preclinical studies was most efficacious and demonstrated less 
hematological toxicity than higher-dose bolus regimens. 
 
Redacted


 
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Many doses and schedules of irinotecan have been studied.  A phase I pediatric study of 
irinotecan given as a 2-hour infusion once every 3 weeks reported 1 partial response, 1 
minor response, and 2 patients with stable disease out of the 19 previously treated 
medulloblastoma patients.34 A COG phase II trial evaluated irinotecan 50 mg/m2/day for 
5 days every 21 days in children with refractory tumors.4 Irinotecan on this schedule was 
generally well tolerated. The best response rate was seen in the recurrent 
medulloblastoma stratum (16%). In a separate pediatric phase II study of irinotecan 
dosed at 125 mg/m2 per week given IV for four weeks followed by a two week rest, two 
of three patients with MB/PNET had stable disease for 9 and 13 months.35 Based on the 
preclinical experience suggesting enhanced irinotecan activity when given on a 
protracted daily schedule and the responses seen in the phase II COG study, the current 
study will utilize daily irinotecan given on the first 5 days of each course. 
 
2.5 
Combination of Temozolomide and Irinotecan  
The combination of temozolomide with irinotecan was studied in xenograft models of 
neuroblastoma, rhabdomyosarcoma and glioblastoma.36 The activity of the combination 
suggested schedule-dependent synergistic efficacy, and pharmacokinetic studies 
demonstrated no interactions between the agents. To the contrary, administration of 
irinotecan with temozolomide appeared to reduce temozolomide toxicity in this mouse 
model. The combination of temozolomide with irinotecan has been evaluated in adult 
solid tumors using a variety of schedules.  Jones et al.37 reported partial responses in 
patients with GBM, head and neck carcinoma and colorectal carcinoma in a phase I trial 
utilizing three different dosing schedules. A total of 49 patients were enrolled and the 
ideal dosing schedule could not be determined. Another study for patients with recurrent 
malignant glioma combined temozolomide 200 mg/m2 daily for 5 days and irinotecan 
given at different doses and schedules.38 Limited accrual precluded determining an 
advantage of one schedule over the other. Toxicity was mild, and only rare Grade 4 
leukopenia and thrombocytopenia were noted. A phase I trial for adults with recurrent 
malignant glioma determined an MTD of temozolomide 200 mg/m2/day on Days 1-5 
plus intravenous IRIN 125 mg/m2  (325 mg/m2 for patients receiving enzyme-inducing 
antiepileptic drugs) administered Weeks 1, 2, 4, and 5 of each 6-week cycle. The DLTs 
were hematologic, gastrointestinal, and hepatic.39 
 
Pooled data from children with Ewing sarcoma treated according to a phase I trial 
schedule using temozolomide 100 mg/m2/day on Days 1-5 and intravenous irinotecan 
10-20 mg/m2/day on Days 1-5 and 8-12 every 21-28 days reported the combination to be 
generally well tolerated with minimal myelosuppression in heavily pre-treated patients. 
Grade 3-4 diarrhea was seen in 11% of courses.40 The MTD in a pediatric phase I trial of 
temozolomide and irinotecan using a protracted daily irinotecan schedule was 
temozolomide 100 mg/m2/day for five days combined with 10 mg/m2/day irinotecan IV 
daily for 5 days for 2 consecutive weeks. Temozolomide was not dose-escalated beyond 
100 mg/m2/day. No pharmacokinetic interactions were seen between the agents, and 
myelosuppression was minimal and noncumulative.41 Patients who had previously 
received craniospinal radiation were not eligible. Using a simpler schedule, Kushner et 
al. published results in children with refractory or relapsed neuroblastoma using 150 
mg/m2/day of temozolomide in combination with intravenous irinotecan 50 mg/m2/day 
for 5 consecutive days every 3-4 weeks.8 Hematologic and GI toxicities were easily 
manageable and no cumulative toxicities were seen. Responses and prolonged stable 
disease were seen in this heavily pre-treated group of patients with poor bone marrow 
reserve. 


 
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Page 12 
 
The preliminary results of an ongoing phase 2 open label study of irinotecan and 
temozolomide in children with recurrent or refractory medulloblastoma were presented at 
the International Society of Pediatric Neuro-Oncology meeting in early July 2008. The 
study utilizes temozolomide 100 mg/m2/day on days 1-5 and intravenous irinotecan 10 
mg/m2/day on days 1-5 and 8-12 every 3 weeks with planned escalation of temozolomide 
to 125 mg/m2/day for patients that tolerate the initial dosing. There were 6 reported 
responses within the first 15 enrolled patients, with central review ongoing.42 The 
proposed COG study utilizes the doses and schedule of temozolomide and irinotecan 
administered by Kushner et al8 and found to be tolerable in heavily pre-treated patients.  
 
In summary, considering the single-agent activity of both agents in recurrent MB, the 
non-overlapping toxicity profiles for temozolomide and irinotecan, and the proven 
feasibility of using this regimen in heavily pre-treated patients, further evaluation of this 
combination in a phase II study is warranted.  Preclinical data suggests that a protracted 
schedule of irinotecan enhances efficacy but this has not been borne out at least in 
patients with recurrent rhabdomyosarcomas where similar efficacy was seen in patients 
randomized to the 5 day regimen as compared to the 5 days x 2.43  The current study will 
utilize 150 mg/m2/day of temozolomide with intravenous irinotecan 50 mg/m2/day for 5 
consecutive days every 28 days. 
 
2.6 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
Redacted


 
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Page 13 
 
3.0 
ENROLLMENT PROCEDURES AND ELIGIBILITY CRITERIA 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration  
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the eRDE system once authorization for the 
release of protected health information (PHI) has been obtained. The COG 
patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help. 
  
 
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.  
 
3.1.2 
IRB Approval 
Local IRB/REB approval of this study must be obtained by a site prior to 
enrolling patients. Sites must submit IRB/REB approvals to the NCI’s Cancer 
Trials Support Unit (CTSU) Regulatory Office and allow 3 business days for 
processing. The submission must include a fax coversheet (or optional CTSU 
IRB Transmittal Sheet) and the IRB approval document(s).  The CTSU IRB 
Certification Form may be submitted in lieu of the signed IRB approval letter.  
All CTSU forms can be located on the CTSU web page (https://www.ctsu.org). 
Any other regulatory documents needed for access to the study enrollment 
screens will be listed for the study on the CTSU Member’s Website under the 
RSS Tab.   
 
IRB/REB approval documents may be faxed (1-215-569-0206), emailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.  
 
When a site has a pending patient enrollment within the next 24 hours, this is 
considered a “Time of Need” registration.  For Time of Need registrations, in 
addition to marking your submissions as  ‘URGENT’ and faxing the regulatory 
documents, call the CTSU Regulatory Helpdesk  at: 1-866-651-CTSU. For 
general (non-regulatory) questions call the CTSU General Helpdesk at: 1-888-
823-5923. 
 
3.1.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the 
study have been met. Study enrollment is accomplished by going to the 
Enrollment application in the RDE system. If you have problems with 
enrollment, refer to online help in the Applications area of the COG website.  
 
3.1.4 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five calendar days after the date of study 
enrollment. Patients who are started on protocol therapy on a Phase II study 
prior to study enrollment will not be entered on study.  
 


 
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Page 14 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
If a patient will have a port placed, the patient should be enrolled a few days 
after placement (see Section 3.2.5.3). 
 
3.1.5 
Randomization 
Randomization will take place at the time a patient is entered On Study via RDE. 
Patients will be assigned to receive one of two regimens with equal probability: 
temozolomide with irinotecan (TEMO+IRIN), or temozolomide with irinotecan plus 
bevacizumab (TEMO+IRIN+BEVA). Patients will be stratified for randomization to 
each treatment arm according to whether or not they have measurable disease. 
 
3.2 
Patient Criteria 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data 
required for determining eligibility of a patient enrolled on this trial must be 
available in the patient's medical/research record which will serve as the source 
document for verification at the time of audit.  
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Patients must be no greater than 21 years of age at the time of study enrollment. 
 
3.2.2 
Diagnosis  
 
3.2.2.1 
Medulloblastoma (CTEP SDC=10027107) or PNET of childhood (CTEP 
SDC=10056672) that has relapsed or become refractory to standard chemotherapy. 
Patients with pineoblastoma are eligible. 
 
3.2.2.2 
Patients must have had histologic verification of the malignancy at original 
diagnosis or at the time of recurrence. 
 
3.2.2.3 
Patients must have clear residual disease, defined as tumor that is measurable in 
two perpendicular diameters on MRI OR diffuse leptomeningeal disease OR 
clear MRI evidence of disease that may not be measurable in two perpendicular 
diameters. 
 
3.2.2.4 Brain and Spine MRI 
To document the degree of residual tumor, the following must be obtained (see 
Section 13.0 for complete details): 
 


 
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Page 15 
All patients must have a brain MRI with and without gadolinium and a spine 
MRI with gadolinium performed within 2 weeks prior to study enrollment. 
 
3.2.3 
Performance Level 
Patients must have a Lansky or Karnofsky performance status score of  ≥ 50%, 
corresponding to ECOG 
categories of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky 
for patients £ 16 years of age. For Performance Status Scoring see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under 
Standard Sections for Protocols. 
 
3.2.4 
Life Expectancy 
Patients must have a life expectancy of ³ 8 weeks. 
 
3.2.5 
Prior Therapy 
 
3.2.5.1 
Patients must have experienced at least one and at most two relapses prior to 
study enrollment.  Patients with primary refractory disease are eligible. 
 
3.2.5.2 
Patients must have fully recovered from the acute toxic effects of all prior 
chemotherapy, immunotherapy, or radiotherapy prior to entering this study. 
a. Myelosuppressive chemotherapy: Must not have received within 3 
weeks of entry onto this study (6 weeks if prior nitrosourea). 
b. Biologic (anti-neoplastic agent): At least 7 days since the completion 
of therapy with a biologic agent; at least 3 weeks for biologic 
agents with a long half life, such as antibodies. 
c. XRT: Must not have received craniospinal radiotherapy within 24 
weeks prior to study entry. The tumor designated as 
“measurable” for protocol purposes must not have received 
radiation within 12 weeks prior to study entry); focal radiation to 
areas of symptomatic metastatic disease must not be given 
within 14 days of study entry. 
d. Stem Cell Transplant (SCT): For autologous SCT, ≥ 3 months must 
have elapsed prior to study entry.  
e. Study specific limitations on prior therapy: 
1) Patients must not have previously received bevacizumab, 
irinotecan, temozolomide or other anti-VEGF inhibitor.  
2) Patients must not be taking enzyme-inducing antiepileptic 
medicines within 1 week of study entry.  
 
3.2.5.3 
Patients must have recovered from any surgical procedure before enrolling on 
this study (see Table below for examples of major, intermediate, and minor 
surgical procedures): 
a) 
Patients with a major surgical procedure within 28 days prior to 
enrollment should be excluded.  
b) 
Patients with an intermediate surgical procedure within 14 days 
prior to enrollment should be excluded.  


 
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Page 16 
c) 
For minor surgical procedures (including Broviac line or 
infusaport placement), patients should not receive the first planned 
dose of bevacizumab until the wound is healed and at least 7 days 
have elapsed.  
d) 
There should be no anticipation of need for major surgical 
procedures during the course of the study. 
 
Examples of Major, Intermediate, or Minor Surgical Procedures 
Major Procedures 
Intermediate Procedures 
Minor Procedures 
Major craniotomy for 
tumor resection 
VP-shunt placement 
Incision and drainage of 
superficial skin abscesses 
Organ resection 
Stereotactic brain biopsy 
Punch biopsy of skin lesions 
Bowel wall anastomosis 
 
Superficial skin wound suturing 
Arteriovenous grafts 
 
Bone marrow aspirate and/or 
biopsy 
Exploratory Laparotomy 
 
Fine needle aspirations 
Thoracotomy 
 
Broviac line or infusaport 
placement 
 
 
Paracentesis or thoracocentesis 
 
Please note: Lumbar punctures or placement of PICC lines are not considered 
minor procedures and may occur at any time prior to or during therapy. 
 
3.2.6 
Cardiac Disease or Hypertension 
a. 
Hypertension must be well controlled (≤ 95th percentile for age and 
height if patient is ≤ 17 years) on stable doses of medication. (See 
Appendices I and II for tables of blood pressure based on age and 
gender.) 
 
Please see exclusion criteria in 3.2.15 – 3.2.16. 
 
3.2.7 
Concomitant Medications Restrictions  
 
(Please see Section 4.2 for the concomitant therapy restrictions for patients while on 
study.) 
a. 
Growth factor(s): Must not have received within 7 days of entry onto 
this study. 
b. 
Steroids: Patients who are receiving corticosteroids must be on a stable 
or decreasing dose for at least 7 days. 
c. 
Study Specific: Patients must not be currently taking NSAIDs, 
clopidrogel, dipyridamole or aspirin therapy > 81 mg/day. 


 
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3.2.8 
Organ Function Requirements 
All patients must have: 
 
3.2.8.1 Adequate Bone Marrow Function (including status post SCT) Defined 
As 
- 
Peripheral absolute neutrophil count (ANC) ³ 1000/µL (must not 
have received G-CSF within the prior 7 days) 
- 
Platelet count ³ 100,000/µL (transfusion independent) 
- 
Hemoglobin ³ 8.0 gm/dL (may receive PRBC transfusions) 
 
3.2.8.2 Adequate Renal Function Defined As 
- 
Creatinine clearance or radioisotope GFR ³ 70ml/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived 
from the Schwartz formula for estimating GFR (Schwartz 
et al. J. Peds, 106:522, 1985) utilizing child length and 
stature data published by the CDC. 
 
 
3.2.8.3 Urine protein should be screened by dipstick analysis. If protein ≥ 2+ on 
dipstick, then Urine Protein Creatinine (UPC) ratio should be calculated. 
If UPC ratio > 0.5, 24-hour urine protein should be obtained and the 
level should be < 1000 mg/24 hours for patient enrollment. 
 
Note: UPC ratio of spot urine is an estimation of the 24 urine protein 
excretion – a UPC ratio of 1 is roughly equivalent to a 24-hour urine 
protein of 1 gm.  UPC ratio is calculated using one of the following 
formulae: 
- [urine protein]/[urine creatinine] – if both protein and creatinine are 
reported in mg/dL 
- [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is 
reported in mmol/L 
 
3.2.8.4 Adequate Liver Function Defined As 
- 
Total bilirubin £ 1.5 x upper limit of normal (ULN) for age, 
- 
SGPT (ALT) ≤ 3 x upper limit of normal (ULN) for age, 


 
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3.2.8.5 Central Nervous System Function Defined As 
- 
Patients with a seizure disorder may be enrolled if well-
controlled and on non-enzyme inducing anticonvulsants.  
3.2.8.6 Adequate Coagulation Defined As 
- 
INR/PT ≤ 1.5 x upper limit of normal 
 
Please see coagulation exclusion criteria in 3.2.11 – 3.2.12. 
 
EXCLUSION CRITERIA 
 
3.2.9 
Patients with a serious or non-healing wound, ulcer, or bone fracture are not eligible for this 
study. 
 
3.2.10 
Patients must not have a history of abdominal fistula, gastrointestinal perforation or intra-
abdominal abscess within 6 months prior to study entry.  
 
3.2.11   
Patients must not have a known bleeding diathesis or coagulopathy. 
 
3.2.12 
Patients must not have had significant vascular disease (eg, aortic aneurysm requiring 
surgical repair, deep venous or arterial thrombosis) within the last 6 months prior to 
study entry. 
 
3.2.13 
Patients must not have a known thrombophilic condition (i.e. protein S, protein C or 
antithrombin III deficiency, Factor V Leiden, Factor II G20210A mutation, 
homocysteinemia or antiphospholipid antibody syndrome). Testing is not required in 
patients without thrombophilic history.  
 
3.2.14 
Patients must not have evidence of new CNS hemorrhage on baseline MRI obtained 
within 14 days prior to study enrollment.   
 
3.2.15 
Patients with a history of stroke, myocardial infarction, transient ischemic attack (TIA), 
severe or unstable angina, peripheral vascular disease, or grade II or greater congestive 
heart failure within the past 6 months are not eligible. 
 
3.2.16 
Patients must not have serious and inadequately controlled cardiac arrhythmia. 
 
3.2.17 
Female patients who are pregnant are not eligible for this study. 
 


 
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3.2.18 
Female patients who are breastfeeding are not eligible for this study unless they agree not to 
breastfeed. 
 
3.2.19 
Female patients of childbearing potential must have a negative pregnancy test. 
 
3.2.20 
Sexually active patients of childbearing potential must agree to use an effective method of 
contraception during the study and for at least 6 months after the completion of bevacizumab 
therapy. 
 
3.2.21  
Patients with known hypersensitivity to Chinese hamster ovary cell products or other 
recombinant human antibodies. 
 
REGULATORY 
 
3.2.22 
All patients and/or their parents or legal guardians must sign a written informed consent. 
 
3.2.23 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
 
4.0 
TREATMENT PROGRAM 
 
 
 
 
 
 
 
 
 
 
4.1 
Overview of Treatment Plan 
Patients will be randomized at enrollment to one of two study arms: temozolomide with 
irinotecan (TEMO+IRIN) or temozolomide with irinotecan plus bevacizumab 
(TEMO+IRIN+BEVA). The primary study endpoint is overall survival. Therapy may 
continue for a maximum of 12 courses, in the absence of disease progression (see Section 
10.4. for definition) if off protocol criteria have not yet been satisfied (see Section 8.1).  
 
Each course of therapy will last 28 days. The temozolomide dose will be 150 mg/m2/day 
by mouth daily for the first 5 days of each course. Irinotecan 50 mg/m2/day will be given 
intravenously for the first 5 days of each course. For patients receiving bevacizumab, the 
dose will be 10 mg/kg intravenously on Days 1 and 15 of each course.  
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care.  
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 
(except where explicitly prohibited within the protocol).  


 
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Page 20 
Disease status will be assessed prior to the initiation of therapy and at the end of every 
other course of treatment. In the absence of disease progression (see definition in Section 
10.4) and unacceptable toxicities, patients can begin subsequent courses of therapy once 
the following criteria have been met:  
- 
ANC ≥ 1,000/µL  
- 
Platelets ≥ 100,000/µL (transfusion independent) 
 
Following completion of a course, the next course begins on Day 29 or when blood 
count parameters are met (whichever occurs later).  
 
See Section 7.1 for required observations prior to starting protocol therapy. 
 
 
4.2 
Concomitant therapy restrictions 
 
4.2.1 
No other cancer chemotherapy or immunomodulating agents are permitted. The use of 
alternative or complementary therapies is discouraged. 
 
4.2.2 
Radiotherapy is not permitted. 
 
 
4.2.3 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary.   
 
4.2.4 
Corticosteroid therapy is permissible only for treatment of increased intracranial pressure 
or for hormonal replacement and should not be used as a prophylactic antiemetic. 
 
4.2.5 
Irinotecan is a substrate for CYP3A4 (major) and CYP2B6 (major). CYP3A4 and 
CYP2B6 inhibitors may increase the level/effects of irinotecan and inducers may 
decrease the level/effect of irinotecan. Strong inhibitors of cytochrome CYP3A4, include 
azole antifungals (such as fluconazole, voriconazole, itraconazole, ketoconazole) 
rifampin, phenytoin, phenobarbital, carbamazepine, and St. John’s Wort. Additional 
drugs and inducers or inhibitors of CYP3A4 and CYP2B6 can be found at 
http://medicine.iupui.edu/clinpharm/ddis. Interacting drugs with irinotecan should be 
avoided or used with great caution. 
 
4.2.6 
The use of NSAIDS, clopidogrel, dypiridamole, or aspirin therapy > 81 mg/day is not 
permitted. 
 
4.2.7 
The routine use of growth factors is not recommended for the initial course of therapy, 
but may be used as clinically indicated at the discretion of the investigator. 
 
 


 
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Page 21 
For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under 
Standard Sections for Protocols. 
 
4.3 
TEMO+IRIN Course  
The TEMO+IRIN treatment course will be repeated every 28 days at the same dose, 
provided there are no dose limiting toxicities. Temozolomide will be administered first, 
followed by irinotecan. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuideli
nes.pdf for special precautions and suggestions for patient monitoring during the 
infusion. As applicable, also see the CAGs for suggestions on hydration, or hydrate 
according to institutional guidelines. 
 
Dose calculations should be based on actual BSA. There is no maximum dosing. 
 
Temozolomide:  PO 
Days: 1 through 5. 
Dose: 150 mg/m2/dose. 
Note: Temozolomide given IV is not permitted.  Temozolomide will be given on an 
empty stomach (to improve absorption and reduce the incidence of nausea and vomiting) 
at least one hour before irinotecan administration. The temozolomide dose should be 
rounded off to the nearest 5 mg (round 2.5 mg down [see Appendix III]). For patients 
with a BSA < 0.5 m2, temozolomide should be given at a dose of 5 mg/kg/day rounded 
off to the nearest 5 mg (round 2.5 mg down [see example in Appendix III]). If emesis 
occurs within 20 minutes of taking a given dose, then the dose may be repeated once. If 
emesis occurs after 20 minutes, the dose should not be repeated. Guidelines for 
administration of oral temozolomide to patients who are unable to swallow capsules or 
tablets are provided in Appendix VI and instructions for the preparation of 
extemporaneous suspension are available in the drug monograph (section 6.3). 
Antiemetics should be given 30 minutes prior to each temozolomide dose. 
 
Pharmacy note: Temozolomide capsules are available in 6 different strengths. Daily 
doses are usually comprised of multiple capsules of different strengths. To prevent 
errors, each strength of temozolomide capsules must be dispensed in a separate bottle 
and the total number of each strength of capsules needed for the full course must be 
dispensed at one time. See drug monograph for additional details and examples. 
 
Irinotecan:  IV, infuse the diluted solution over 90 minutes 
Days: 1 through 5. 
Dose: 50 mg/m2/dose. 
Note: Irinotecan will be given at least one hour after temozolomide administration. 
Higher incidence of cholinergic symptoms has been reported with more rapid infusion 
rates. To avoid extravasation; the use of a central line is suggested. 
 
Following administration of irinotecan, monitor for signs and symptoms of diarrhea and 
dehydration.  For diarrhea related to irinotecan therapy, the use of atropine for early-
onset diarrhea and the use of loperamide for late-onset diarrhea are recommended. See 


 
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Page 22 
the 
COG 
Supportive 
Care 
Guidelines 
at 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
under 
Standard Sections for Protocols for dosing and schedule information. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for this TEMO+IRIN course is on the next page.  
 
Following completion of the first TEMO+IRIN course, the TEMO+IRIN course is 
repeated 
for 
up 
to 
12 courses, as tolerated and in the absence of disease progression (see Section 10.4 for 
Response Evaluation). Subsequent TEMO+IRIN courses should begin on Day 29 or 
when blood parameters recover (whichever occurs later). 
 
 


 
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Page 23 
 
4.3.1   Temozolomide with Irinotecan (TEMO+IRIN) 
Four consecutive weeks (28 days) will constitute one course. 
This therapy delivery map relates to all courses of TEMO+IRIN. 
Use a copy of this page once for each course. (Please note course number below.) 
 
__________________________ 
             Patient name or initials 
____________________________ 
DOB   
Criteria to start this course: ANC ≥ 1000/µL and platelet count ≥ 100,000/µL. Details are in Section 4.0 (Treatment 
Overview). This course lasts 28 days and the TDM for this course is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Temozolomide 
(TEMO) 
PO 
150 mg/m2/dose 
or  
5 mg/kg/dose* for 
patients 
< 0.5 m2 
 
1–5 
Administer at least one 
hour prior to IRIN 
administration. 
 
*Round off to the nearest 
5mg. 
 
See Dosing Table in 
Appendix III and admin. 
guidelines in Section 4.3. 
a) 
History & PE (Ht, Wt, VS) 
b) 
CBC (diff/ platelets) 
c) 
Electrolytes (Ca++, PO4, Mg++) 
d) 
ALT, AST, BUN, creatinine (or 
creatine clearance or radioisotope 
GFR), bilirubin 
e) 
MRI of the Head with and without 
gadolinium  
f) 
MRI of the Spine with gadolinium 
g) 
CSF cytology  
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE. 
Irinotecan 
(IRIN) 
IV over 90 
minutes 
50 mg/m2/dose 
1–5 
 
 
Please enter Course # ________ 
Ht_____cm 
        Wt____kg 
         BSA____m2 
 
Date Due 
Date Given 
Day 
TEMO 
_____mg 
IRIN 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose 
above and actual dose 
administered below 
 
 
 
 
1 
_____mg 
_____mg 
a, b, c, d, e#, f^, g† 
 
 
 
2 
_____mg 
_____mg 
 
 
 
 
3 
_____mg 
_____mg 
 
 
 
 
4 
_____mg 
_____mg 
 
 
 
 
5 
_____mg 
_____mg 
 
 
 
 
8 
 
 
b 
 
 
 
15 
 
 
b 
 
 
 
21 
 
 
b 
 
 
 
28 
 
 
 
See Section 7.1 for studies to be performed 
when patient is removed from protocol 
therapy. 
 
 
 
29 
Start next course on Day 29 or when blood count 
parameters are met (whichever occurs later). 
 
OBSERVATION NOTES: 
#Obtain within 1 week prior to the third course of therapy and prior to every other subsequent course of therapy (ie, 5th, 7th, etc.), 
up to 12 courses of therapy.  
^ Obtain within 1 week prior to the third course of therapy and prior to every other subsequent course of therapy (ie, 5th, 7th, etc.) 
only if initially positive or clinically indicated.   
† If baseline test is negative, repeat only if there is disease progression. If positive at baseline, repeat prior to every other course 
(ie, 3rd, 5th, etc.) until there are two negative cytologies. CSF cytology can be waived for patients where a lumbar puncture is 
not deemed to be safe.  
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 


 
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Page 24 
4.4 
TEMO+IRIN+BEVA Course 
 
The TEMO+IRIN+BEVA treatment course will be repeated every 28 days at the same dose, 
provided there are no dose limiting toxicities. Temozolomide will be administered first, followed 
by irinotecan and bevacizumab. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf 
for special precautions and suggestions for patient monitoring during the infusion. As applicable, 
also see the CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
Dose calculations should be based on actual BSA. There is no maximum dosing. 
 
Temozolomide:  PO 
Days: 1 through 5. 
Dose: 150 mg/m2/dose. 
Note:  Temozolomide given IV is not permitted.  Temozolomide will be given on an empty 
stomach (to improve absorption and reduce the incidence of nausea and vomiting) at least one 
hour before irinotecan administration. The temozolomide dose should be rounded off to the 
nearest 5 mg (round 2.5 mg down [see Appendix III]). For patients with BSA < 0.5 m2, 
temozolomide should be given at a dose of 5 mg/kg/day rounded off to the nearest 5 mg (round 
2.5 mg down [see example in Appendix III]). If emesis occurs within 20 minutes of taking a 
given drug dose, then the dose may be repeated once. If emesis occurs after 20 minutes, the dose 
should not be repeated. Guidelines for administration of oral temozolomide to patients who are 
unable to swallow tablets are provided in Appendix VI and instructions for the preparation of 
extemporaneous suspension are available in the drug monograph (section 6.3). It is recommended 
that antiemetics be given 30 minutes prior to the temozolomide dose. 
 
Pharmacy note: Temozolomide capsules are available in 6 different strengths. Daily doses are 
usually comprised of multiple capsules of different strengths. To prevent errors, each strength of 
temozolomide capsules must be dispensed in a separate bottle and the total number of each 
strength of capsules needed for the full course must be dispensed at one time. See drug 
monograph for additional details and examples. 
 
Irinotecan:  IV, infuse the diluted solution over 90 minutes 
Days: 1 through 5. 
Dose: 50 mg/m2/dose. 
Note: Irinotecan will be given at least one hour after temozolomide administration. Higher 
incidence of cholinergic symptoms has been reported with more rapid infusion rates. To avoid 
extravasation; the use of a central line is suggested. 
 
Following administration of irinotecan, monitor for signs and symptoms of diarrhea and 
dehydration.  For diarrhea related to irinotecan therapy, the use of atropine for early-onset 
diarrhea and the use of loperamide for late-onset diarrhea are recommended. See 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
for 
dosing 
and 
schedule information. 


 
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Page 25 
 
Bevacizumab:  IV over 90 minutes* 
Days: 1 and 15. 
Dose: 10 mg/kg/dose. 
Note: *Infuse first dose over 90 minutes. If tolerated without infusion-related side effects, the 
second dose may be given over 60 minutes. Again, if tolerated, the third dose and all subsequent 
doses may be given over 30 minutes. Check vital signs prior to infusion and monitor for 
infusion-related reactions every 30 minutes (during 60 and 90 minute infusions) and at the end of 
the infusion. Monitor every 15 minutes while the infusion rate is being adjusted. Routine 
premedication is not required for the first dose of bevacizumab. If infusional reactions occur, 
acetaminophen [10-15 mg/kg (max 650 mg)], diphenhydramine [1 mg/kg (max 50 mg)], or other 
medications may be given for symptom control and for premedication as needed. (See Section 
4.2 for concomitant therapy restrictions.) Anaphylactic precautions should be observed during 
bevacizumab administration. If an infusion reaction occurs, subsequent doses of bevacizumab 
should be administered over the shortest period that was well-tolerated. Bevacizumab is 
incompatible with D5W (the drug is inactivated). 
 
Special precautions: Black box warning includes risk of gastrointestinal perforation and wound 
healing complications (fatal results have occurred). Suspend dosing at least 28 days prior to 
elective surgery. Do not initiate bevacizumab for at least 28 days after a major surgery, for at 
least 14 days after intermediate surgical procedure, and until the surgical wound is fully healed.  
Minor surgical procedures (eg, biopsies, infusaport or Broviac line placement) need to have fully 
healed and occurred > 7 days prior to initiation of bevacizumab.  
 
See Table in Section 3.2.5.3 for examples of major, intermediate, and minor surgical procedures.  
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The therapy delivery map (TDM) for the TEMO+IRIN+BEVA course is on the next page.  
 
Following completion of the first TEMO+IRIN+BEVA course the TEMO+IRIN+BEVA course 
is repeated for up to 12 courses, as tolerated and in the absence of disease progression (see 
Section 10.4 for Response Evaluation). 
 
Subsequent TEMO+IRIN+BEVA Courses should begin on Day 29 or when blood parameters 
recover (whichever occurs later). 
 
 
 


 
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Page 26 
4.4.1  TEMO+IRIN+BEVA Course 
Four consecutive weeks (28 days) will constitute one course. 
This therapy delivery map relates to all courses of TEMO+IRIN+BEVA. 
Use a copy of this page once for each course. (Please note course number below.) 
                   
 ____________________________ 
             Patient name or initials 
____________________________ 
DOB   
Criteria to start this course: ANC ≥ 1000/µL and platelet count ≥ 100,000/µL. Details are in Section 4.0 (Treatment 
Overview). This course lasts 28 days and the TDM for this course is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Temozolomide 
(TEMO) 
 
PO 
150 
mg/m2/dose 
or  
5 mg/kg/dose* 
for patients 
 < 0.5 m2 
 
1-5 
 
Administer at least one hour 
prior to IRIN administration. 
 
*Round 
off 
to 
the 
nearest 
5 mg. 
 
See Dosing Table in Appendix 
III and admin. guidelines in 
Section 4.4. 
a) History & PE (Ht, Wt, VS) 
b) CBC (diff/ platelets) 
c) Electrolytes (Ca++, PO4, Mg++) 
d) ALT, AST, BUN, creatinine (or 
creatine clearance or radioisotope 
GFR) , bilirubin 
e) Urinalysis for protein (urine 
dipstick or UPC ratio) 
f) MRI of the Head with and without 
gadolinium  
g) MRI of the Spine with gadolinium 
h) CSF cytology 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD 
PATIENT CARE 
Irinotecan 
(IRIN) 
IV over  
90 minutes 
50 mg/m2/dose  
1-5 
 
Bevacizumab 
(BEVA) 
BB-IND#7921 
IV over 90* 
minutes 
10 mg/kg/dose 
1 and 15 
*May be given over shorter 
duration if well-tolerated.  
See admin. guidelines in Section 
4.4. 
 
Please enter Course # _______  
Ht_____cm 
        Wt____kg 
         BSA____m2 
Date 
Due 
Date 
Given 
Day 
TEMO 
____mg 
IRIN 
_____mg 
BEVA 
_____mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and 
actual dose administered below 
 
 
 
 
1 
____mg 
____mg 
____mg 
a, b, c, d, e#, f*, g^, h† 
 
 
 
2 
____mg 
____mg 
 
 
 
 
 
3 
____mg 
____mg 
 
 
 
 
 
4 
____mg 
____mg 
 
 
 
 
 
5 
____mg 
____mg 
 
 
 
 
 
8 
 
 
 
b 
 
 
 
15 
 
 
____mg 
a$, b 
 
 
 
21 
 
 
 
b 
 
 
 
28 
 
 
 
 
See Section 7.1 for studies to be performed 
when patient is removed from protocol 
therapy. 
 
 
29 
Start next course on Day 29 or when blood count 
parameters are met (whichever occurs later). 
 
OBSERVATION NOTES: 
# Prior to the start of each course of bevacizumab. If urine dipstick is 2+ or greater for protein, hold bevacizumab and obtain UPC ratio. See 
bevacizumab dose modifications for proteinuria (Section 5.1). 
* Obtain within 1 week prior to the third course of therapy and prior to every other subsequent course of therapy (ie, 5th, 7th, etc.), up to 12 
courses of therapy.  
^ Obtain within 1 week prior to the third course of therapy and prior to every other subsequent course of therapy (ie, 5th, 7th, etc.) if initially 
positive or clinically indicated.  
† If baseline test is negative, repeat only if there is disease progression. If positive at baseline, repeat prior to every other course (ie, 3rd, 5th, etc.) 
until there are two negative cytologies. CSF cytology can be waived for patients where a lumbar puncture is not deemed to be safe.  
$ Obtain BP only. 
See Section 5.0 for Dose Modifications for Toxicities. For general Supportive Care Guidelines see 
https://members.childrensoncologygroup.org/prot/reference_materials.asp 
under 
Standard 
Sections 
for 
Protocols. 


 
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Page 27 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Dose Reduction  
There will be no dose reduction for bevacizumab. Treatment should be interrupted or 
discontinued for certain adverse events, as described in the table below. 
 
If bevacizumab is interrupted for toxicities listed in the table below for > 4 weeks (unless 
otherwise specified), the patient should discontinue bevacizumab and be taken off protocol 
therapy. 
 
DOSE MODIFICATIONS FOR BEVACIZUMAB RELATED ADVERSE EVENTS  
 
Event 
          CTCAE v 4.0 Grade 
Action to be Taken 
Allergic reactions, 
Or 
Infusion-related reactions 
OR 
Anaphylaxis 
Grade 1-2 
Infusion 
of 
bevacizumab 
should 
be 
interrupted for subjects who develop dyspnea 
or clinically significant hypotension.  
For infusion-associated symptoms not 
specified above, infusion should be slowed to 
50% or less or interrupted. Upon complete 
resolution of the symptoms, infusion may be 
continued at no more than 50% of the rate 
prior to the reaction and increased in 50% 
increments every 30 minutes if well 
tolerated. Infusions may be restarted at the 
full rate during the next cycle.  
If infusional reactions occur, acetaminophen 
[10-15 mg/kg (max 650 mg)], 
diphenhydramine [1 mg/kg (max 50 mg)], or 
other medications may be given for symptom 
control and for premedication as needed.  
(See Section 4.2 for concomitant therapy 
restrictions.) 
 
Subjects who experience bronchospasm 
(regardless of grade) should discontinue 
bevacizumab. 
Grade 3-4 
Discontinue bevacizumab. 
Thromboembolic Event 
(Arterial); arterial ischemia 
- 
Cardiac ischemia 
- 
Myocardial infarction 
- 
CNS ischemia (TIA, CVA) 
- 
Any peripheral or visceral arterial 
ischemia/thrombosis 
 
Grade 2 
(if new or worsened since 
bevacizumab therapy) 
Discontinue bevacizumab. 
Grade 3-4 
Discontinue bevacizumab. 


 
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Page 28 
Event 
          CTCAE v 4.0 Grade 
Action to be Taken 
Thromboembolic Event 
(Venous) 
Grade 3 
OR 
asymptomatic Grade 4 
§ 
Hold bevacizumab treatment. If the 
planned duration of full-dose 
anticoagulation is < 2 weeks, 
bevacizumab should be held until the 
full-dose anticoagulation period is over. 
 
§ 
If the planned duration of full-dose 
anticoagulation is > 2 weeks, 
bevacizumab may be resumed during 
the period of full-dose anticoagulation 
IF all of the criteria below are met:  
- 
The subject must not have 
pathological conditions that carry 
high risk of bleeding (e.g. tumor 
involving major vessels or other 
conditions). 
- 
The subject must not have had 
hemorrhagic events while on 
study. 
- 
The subject must be on stable dose 
of heparin or have an in-range INR 
(usually 2-3) on a stable dose of 
warfarin prior to restarting 
bevacizumab. 
 
§ 
If 
thromboemboli 
worsen/recur 
upon resumption of study therapy, 
discontinue bevacizumab. 
Grade 4  
(symptomatic) 
Discontinue bevacizumab. 
Hypertension  
 
Use age and height appropriate normal 
values > 95th percentile ULN for pediatric 
patients (see Appendices I and II) 
[Treat with anti-hypertensive medication as needed. The goal of BP control should 
be consistent with general medical practice.] 
Grade 1 
If age ≤ 17 years: Asymptomatic, 
transient (< 24 hrs) BP increase 
>ULN; intervention not indicated. 
If age > 17 years:  (SBP 120-139 
mmHg or DBP 80-89 mmHg) 
Consider increased BP monitoring; start anti-
hypertensive medication if appropriate 
Grade 2 asymptomatic: 
If age ≤ 17 years: Recurrent or 
persistent (> 24 hrs) BP > ULN;  
If age > 17 years: (SBP 140-159 
mmHg or DBP 90-99 mmHg) 
If age ≤ 17 years: monotherapy indicated. 
Continue bevacizumab. 
 
If age > 17 years: Begin anti-hypertensive 
therapy and continue bevacizumab. 
Grade 2 symptomatic: 
OR 
Grade 3: 
>17 years: SBP >160 mmHg or 
DBP >100 mmHg) 
requiring more than one drug or 
more intensive therapy than 
previously (all ages) 
• 
Start or adjust anti-hypertensive therapy 
• 
Hold 
bevacizumab 
until 
symptoms 
resolve AND BP < 95th percentile ULN 
for age and height, if age ≤ 17 years; or 
BP < 160/90mmHg if age > 17 years. 
Grade 4: (all ages) 
 life threatening (e.g. hypertensive 
crisis or malignant hypertension) 
Discontinue bevacizumab. 
Heart Failure or LV dysfunction 
Heart failure > grade 2 
Discontinue bevacizumab. 
LV dysfunction >  grade 3 
Discontinue bevacizumab. 


 
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Page 29 
Event 
          CTCAE v 4.0 Grade 
Action to be Taken 
Proteinuria 
Proteinuria will be monitored by urine analysis 
for urine protein creatinine (UPC) ratio, or 
dipstick If Dipstick > 2+ proteinuria or UPC 
ratio > 1, 24 hour urine protein should be 
obtained 
If 24-h urine protein < 2.0gm  
Continue bevacizumab 
If 24-h urine protein > 2.0 gm 
• Hold bevacizumab until 24-h urine protein 
< 2.0 gm.   
• Discontinue bevacizumab if urine protein 
does not recover to < 2.0 after 8 weeks of 
bevacizumab interruption 
Nephrotic syndrome 
Discontinue bevacizumab. 
Hemorrhage (intracranial or pulmonary) 
Grade 1 
• 
Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
• 
For patients not on full-dose 
anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- 
the bleeding has resolved and 
Hb is stable;  
- 
there is no bleeding diathesis 
that would increase the risk of 
therapy; 
- 
there is no anatomic or 
pathologic condition that could 
increase the risk of 
hemorrhage recurrence. 
 
Grade 2-4 
Discontinue bevacizumab. 
 
Hemorrhage (any other organ systems) 
Grade 3 
 
 
• 
Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
• 
For patients not on full-dose 
anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- 
the bleeding has resolved and 
Hb is stable;  
- 
there is no bleeding diathesis 
that would increase the risk of 
therapy; 
- 
there is no anatomic or 
pathologic condition that could 
increase the risk of 
hemorrhage recurrence. 
• 
Patients who experience recurrence of 
Grade 3 hemorrhage should discontinue 
study therapy. 
 
Grade 4 
Discontinue bevacizumab. 
RPLS (Reversible Posterior Leukoencephalopathy syndrome or PRES (Posterior 
Reversible Encephalopathy Syndrome) 
• 
Hold bevacizumab in patients with 
symptoms/signs suggestive of RPLS; 
subsequent management should include 
MRI  scans and control of HTN. 
• 
Discontinue bevacizumab upon 
diagnosis of RPLS. 
Wound dehiscence requiring medical or 
surgical intervention or wound complications 
Grade 2 
 
Hold bevacizumab until healing 
 


 
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Page 30 
Event 
          CTCAE v 4.0 Grade 
Action to be Taken 
Grade 3-4 
Discontinue bevacizumab. 
Perforation (GI or any other organ) 
Discontinue bevacizumab. 
Fistula (GI, pulmonary or any other organ) 
Discontinue bevacizumab. 
Obstruction of GI tract 
Grade 
2 
requiring 
medical 
intervention 
• 
Hold bevacizumab until complete 
resolution. 
 
Grade 3-4 
• 
Hold bevacizumab until complete 
resolution. 
• 
If surgery is required, patient may 
restart bevacizumab after full recovery 
from surgery, and at investigator’s 
discretion. 
Other Unspecified bevacizumab-related AEs 
(except controlled nausea/vomiting). 
Grade 3 
• Hold bevacizumab until symptoms resolve 
to < grade 1 
Grade 4 
• Discontinue bevacizumab. 
 
 
5.2 
Hematologic Toxicity 
 
If ANC is < 1,000/µL and platelets are < 100,000/µL at Day 28, further therapy should 
be delayed and counts should be checked at least weekly until counts recover. If the 
ANC 
is 
< 
1,000/µL 
or 
platelets 
< 100,000/µL more than seven days beyond the time for the next treatment (ie, the 
subsequent course is delayed by > 7 days due to myelosuppression), reduce the 
temozolomide dose by 25% (112.5 mg/m2 for BSA ≥ 0.5 m2 or 3.75 mg/kg for BSA < 
0.5 m2; see Appendix IV). If a patient again experiences prolonged myelosuppression 
delaying the ability to deliver the subsequent course by Day 35 of a treatment course, the 
dose of temozolomide should be reduced again by 25% of the original dose (total of 50% 
dose reduction [75 mg/m2 for BSA ≥ 0.5 m2 or 2.5 mg/kg for BSA < 0.5 m2; see 
Appendix V]). If, despite a 50% dose reduction, myelosuppression prevents delivery of 
the subsequent course by Day 35, the patient should be taken off protocol therapy. 
 
5.3 
Non-Hematologic Toxicity 
Patients who experience Grade 3 or greater non-hematologic toxicity (NHT) (with the 
exception of diarrhea, alopecia, nausea or vomiting that occurs without anti-emetic 
treatment, infection or fever) which returns to Grade 1 or less by Day 35 will have the 
doses of irinotecan and temozolomide reduced by 25% of the original dose in subsequent 
courses (to 37.5 mg/m2/dose for irinotecan, see Appendix IV for temozolomide doses). 
If, at the reduced dose, a patient again experiences Grade 3 or greater non-hematologic 
toxicity, (with the exception of diarrhea, alopecia, nausea or vomiting, infection or 
fever), the irinotecan and temozolomide doses will be reduced by an additional 25% of 
the original dose (ie, 50% of the original dose to 25 mg/m2/dose for irinotecan, see 
Appendix V for temozolomide doses). If Grade 3 or higher NHT recurs despite the 50% 
dose 
reduction, 
the 
patient 
should 
be 
taken 
off 
protocol 
therapy. 
 
Gastrointestinal Toxicity Secondary to Irinotecan 
Patients with Grade 3-4 diarrhea will receive antibiotics and anti-diarrheals to prevent 
irinotecan induced diarrhea, per the COG supportive care guidelines; for detailed 
information 
please 
refer 
to 
(https://members.childrensoncologygroup.org/_files/protocol/Standard/SupportiveCareG
uidelines.pdf). Patients who develop diarrhea and require antibiotics should continue to 


 
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receive antibiotics for every course of irinotecan during the study period. If patients 
continue to experience  ≥ Grade 3 diarrhea despite maximum supportive care measures 
with prophylactic antibiotics and anti-diarrheals, subsequent irinotecan doses should be 
reduced by 25% of the original dose (to 37.5 mg/m2/dose). If diarrhea persists further 
reduce irinotecan dose by 50% of original dose for subsequent cycles (to 25 
mg/m2/dose). If Grade 3 diarrhea persists despite the 50% dose reduction, the patient 
should be taken off protocol therapy. 
 
Febrile Neutropenia  
Uncomplicated febrile neutropenia is not a reason for dose reduction. 
 
 
6.0 
DRUG INFORMATION  
The drugs are presented in alphabetical order.  
 
Please see Appendix VIII for drug interactions associated with the drugs used in this study. 
 
 
6.1 
Bevacizumab   
 
(rhuMAb VEGF, Avastin®) NSC# 704865  IND # 7921  (5/9/14) 
 
Source and Pharmacology:  
Bevacizumab is a recombinant humanized anti-vascular endothelial growth factor (anti-
VEGF) monoclonal antibody, consisting of 93% human and 7% murine amino acid 
sequences. The agent is composed of human IgG framework and murine antigen-binding 
complementarity-determining regions. Bevacizumab approximate molecular weight is 
149,000 daltons. Bevacizumab blocks the binding of VEGF to its receptors resulting in 
inhibition of angiogenesis. 
 
The estimated half-life of bevacizumab is approximately 20 days (range 11-50 days). The 
predicted time to reach steady state was 100 days in 491 patients who received 1 to 20 
mg/kg weekly, every 2 weeks, or every 3 weeks. The clearance and the central volume of 
distribution are higher in males than females. Clearance was higher in those patients with 
a higher tumor volume. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Bevacizumab (rhuMAb VEGF, NSC 704865) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 3540 patients. Below is the CAEPR for 
bevacizumab (rhuMAb VEGF). 


 
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NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 Version 2.3, August 1, 20131 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
 
 
Blood 
and 
lymphatic 
system 
disorders 
- 
Other 
(renal 
thrombotic microangiopathy) 
  
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Acute coronary syndrome2 
  
 
Cardiac disorders - Other 
(supraventricular 
arrhythmias)3 
 
 Cardiac 
disorders 
- 
Other 
(supraventricular arrhythmias)3 (Gr 3) 
 
 
Heart failure 
  
 
 
Left 
ventricular 
systolic 
dysfunction 
  
 
 
Myocardial infarction2 
  
 
 
Ventricular arrhythmia 
  
 
 
Ventricular fibrillation 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Colitis 
 
 Colitis (Gr 3) 
 
Constipation 
 
 Constipation (Gr 3) 
 
Diarrhea 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula4 
  
 
Gastrointestinal 
hemorrhage5 
 
 Gastrointestinal hemorrhage5 (Gr 2) 
 
 Gastrointestinal obstruction6  
  
 
 
Gastrointestinal perforation7 
  
 
 
Gastrointestinal ulcer8 
  
 
Ileus 
 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
 
Nausea 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Infusion related reaction 
 
 Infusion related reaction (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 3) 
 
Pain 
 
 Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction 
 
 Allergic reaction (Gr 2) 
 
 
Anaphylaxis 
  


 
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INFECTIONS AND INFESTATIONS 
  
 
Infection9 
 
 Infection9 (Gr 3) 
 
 
Infections and infestations - Other 
(necrotizing fasciitis) 
  
 
Infections and infestations - 
Other (peri-rectal abscess) 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Injury, poisoning and procedural 
complications 
– 
Other 
(anastomotic leak)10 
  
 
Wound complication 
 
 Wound complication (Gr 2) 
 
Wound dehiscence 
 
 Wound dehiscence (Gr 2) 
INVESTIGATIONS 
  
 
Alanine 
aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 3) 
 
Alkaline 
phosphatase 
increased 
 
 Alkaline phosphatase increased (Gr 
3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Blood bilirubin increased 
 
 Blood bilirubin increased (Gr 2) 
 
Cardiac troponin I increased  
  
Neutrophil 
count 
decreased 
 
 
 Neutrophil count decreased (Gr 3) 
 
Platelet count decreased 
 
 Platelet count decreased (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased  
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 3) 
 
Musculoskeletal 
and 
connective tissue disorder - 
Other 
(bone metaphyseal 
dysplasia)11 
 
  
 
Myalgia 
 
 Myalgia (Gr 3) 
 
Osteonecrosis of jaw12 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
 
 
Ischemia cerebrovascular2 
  
 
Peripheral 
sensory 
neuropathy13 
 
  
 
 
Reversible 
posterior 
leukoencephalopathy syndrome 
  
 
Syncope 
 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
Hematuria 
 
 Hematuria (Gr 3) 
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Renal and urinary disorders - 
Other (Nephrotic Syndrome) 
  
 
 
Urinary fistula 
  


 
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REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
Reproductive system 
and breast disorders - 
Other 
(ovarian 
failure)14 
 
 
  
 
 
Vaginal fistula 
  
 
Vaginal hemorrhage 
 
 Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Allergic rhinitis 
 
 Allergic rhinitis (Gr 3) 
 
 
Bronchopleural fistula 
  
 
 
Bronchopulmonary hemorrhage 
  
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
Epistaxis 
 
 Epistaxis (Gr 3) 
 
Hoarseness 
 
 Hoarseness (Gr 3) 
 
 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
- 
Other 
(nasal-septal perforation) 
  
 
 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
- 
Other 
(tracheo-esophageal fistula) 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event 
 
 Thromboembolic event (Gr 3) 
 
 
Vascular 
disorders 
- 
Other 
(arterial thromboembolic event)2,15 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased in elderly patients and in 
patients with a history of diabetes. 
 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial fibrillation and atrial flutter. 
 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Gastric fistula, Gastrointestinal fistula, Rectal fistula, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal hemorrhage, Esophageal 
hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Intra-
abdominal hemorrhage, Oral hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal obstruction, Esophageal 
obstruction, Ileal obstruction, Jejunal obstruction, Rectal obstruction, Small intestinal obstruction, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 


 
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7Gastrointestinal perforation may include: Colonic perforation, Duodenal perforation, Esophageal 
perforation, Gastric perforation, Jejunal perforation, Rectal perforation, Small intestinal perforation, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric ulcer, and other sites 
under the GASTROINTESTINAL DISORDERS SOC. 
 
9Infection may include any of the 75 infection sites under the INFECTIONS AND INFESTATIONS SOC. 
 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal anastomotic leak; Large 
intestinal anastomotic leak; Rectal anastomotic leak; Small intestinal anastomotic leak; Urostomy leak; 
Vaginal anastomotic leak 
 
11Metaphyseal dysplasia was observed in young patients who still have active epiphyseal growth plates. 
 
12Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients in association with 
bevacizumab treatment, the majority of whom had received prior or concomitant treatment with i.v. 
bisphosphonates. 
 
13Increased rate of peripheral sensory neuropathy has been observed in trials combining bevacizumab 
and chemotherapy compared to chemotherapy alone.  
 
14Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-stimulating hormone (FSH) 
elevation (≥30 mIU/mL), was increased in patients receiving adjuvant bevacizumab plus mFOLFOX compared to 
mFOLFOX alone (34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and an FSH level 
<30 mIU/mL was demonstrated in 22% (7/32) of these women.  Long term effects of bevacizumab exposure on 
fertility are unknown. 
 
15Arterial thromboembolic event includes visceral arterial ischemia, peripheral arterial ischemia, heart 
attack and stroke. 
 
 
Also reported on bevacizumab (rhuMAb VEGF) trials but with the relationship to bevacizumab 
(rhuMAb VEGF) still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(idiopathic thrombocytopenia purpura); Bone marrow hypocellular; Disseminated intravascular 
coagulation; Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block first degree; Cardiac 
arrest; Myocarditis; Pericardial effusion; Restrictive cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other (tympanic membrane 
perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle paresis; Eye disorders - Other 
(blindness); Eye disorders - Other (conjunctival hemorrhage); Eye disorders - Other (corneal epithelial 
defect); Eye disorders - Other (floaters); Eye disorders - Other (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm Hg); Eye disorders - Other 
(vitreous hemorrhage); Eye pain; Keratitis; Optic nerve disorder; Photophobia; Retinal detachment; 
Retinal tear; Retinopathy; Watering eyes 
GASTROINTESTINAL DISORDERS - Ascites; Chelitis; Colonic stenosis; Dry mouth; Dysphagia; 
Enterocolitis; Esophageal pain; Esophageal stenosis; Flatulence; Gastrointestinal disorders - Other 
(peritonitis); Oral pain; Pancreatitis; Proctitis; Rectal mucositis; Rectal stenosis;Typhlitis 


 
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GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death NOS; Edema face; 
Edema limbs; Edema trunk; Facial pain; Fever; Flu like symptoms; Gait disturbance; Injection site 
reaction; Localized edema; Multi-organ failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; Gallbladder obstruction; Hepatic 
failure; Hepatic necrosis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic meningitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; Bruising; Burn; 
Dermatitis radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood antidiuretic hormone 
abnormal; CD4 lymphocytes decreased; CPK increased; Carbon monoxide diffusing capacity decreased; 
Electrocardiogram QT corrected interval prolonged; Forced expiratory volume decreased; GGT 
increased; INR increased; Lipase increased; Lymphocyte count decreased; Serum amylase increased; 
Weight gain 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Acidosis; 
Hypercalcemia; 
Hyperglycemia; 
Hyperkalemia; 
Hypermagnesemia; 
Hypernatremia; 
Hypertriglyceridemia; 
Hyperuricemia; 
Hypoalbuminemia; Hypocalcemia; Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; 
Chest wall pain; Fibrosis deep connective tissue; Generalized muscle weakness; Head soft tissue 
necrosis; Joint effusion; Muscle weakness lower limb; Muscle weakness upper limb; Musculoskeletal and 
connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and connective tissue 
disorder - Other (myasthenia gravis); Musculoskeletal and connective tissue disorder - Other 
(polymyalgia rheumatica); Neck pain; Pain in extremity; Pelvic soft tissue necrosis; Soft tissue necrosis 
lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous system necrosis; 
Cerebrospinal fluid leakage; Cognitive disturbance; Depressed level of consciousness; Dysesthesia; 
Dysgeusia; Dysphasia; Encephalopathy; Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; 
Leukoencephalopathy; Memory impairment; Nervous system disorders - Other (increased intracranial 
pressure); Paresthesia; Peripheral motor neuropathy; Pyramidal tract syndrome; Seizure; Somnolence; 
Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Libido decreased; 
Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; Cystitis noninfective; 
Renal and urinary disorders - Other (dysuria); Renal and urinary disorders - Other (ureterolithiasis); Renal 
hemorrhage; Urinary frequency; Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary 
tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile dysfunction; Irregular 
menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Atelectasis; Hypoxia; Nasal congestion; Pulmonary fibrosis; Pulmonary hypertension; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic and mediastinal 
disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Hyperhidrosis; Nail loss; Pain 
of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Purpura; Rash acneiform; Skin 
and subcutaneous tissue disorders - Other (diabetic foot ulcer); Skin and subcutaneous tissue disorders - 
Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; Skin induration; Skin ulceration; 
Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; Phlebitis; Vasculitis  
 
 
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 
 
PLEASE NOTE:  The potential risks listed in the CAEPR whose relationship to bevacizumab is still undetermined are not required by CTEP to 
be described in the ICD; however, they may be communicated to patients according to local IRB requirements. 


 
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Effect in Pregnancy and Lactation: 
Bevacizumab has been shown to be teratogenic in rabbits when administered in doses that are 
two-fold greater than the recommended human dose on a mg/kg basis. Observed effects 
included decreases in maternal and fetal body weights, an increased number of fetal 
resorption, and an increased incidence of specific gross and skeletal fetal alterations. Adverse 
fetal outcomes were observed at all doses tested. Angiogenesis is critical to fetal development 
and the inhibition of angiogenesis following administration of Bevacizumab is likely to result 
in adverse effects on pregnancy. It is not known whether Bevacizumab is secreted in human 
milk. Because human IgG1 is secreted into human milk, the potential for absorption and harm 
to the infant after ingestion is unknown. 
 
A prospective study of 179 premenopausal women with stage II or III colorectal cancer 
given adjuvant therapy with mFOLFOX alone (n= 84) or mFOLFOX with bevacizumab 
(n=95) suggests that the use of bevaciumab with chemotherapy may result in ovarian 
failure. In this study, ovarian failure was defined as amenorrhea lasting 3 or more 
months, FSH level ≥ 30 mIU/mL and a negative serum β-HCG pregnancy test. A new 
onset of ovarian failure was documented in 34% (32/95) of women who received 
bevacizumab with chemotherapy compared to 2% (2/84) of women given chemotherapy 
alone [relative risk of 14 (95% CI 4, 53)]. Recovery of ovarian function occurred in 22% 
(7/32) of these women after discontinuation of bevacizumab. Additional long term 
effects of bevacizumab on fertility are unknown. 
 
Effect on Growth and Development: 
Studies of bevacizumab in animals showed a decrease in ovarian function and abnormal 
bone growth. These and other effects of bevacizumab may potentially impair growth and 
development.  Abnormal changes in the bones after treatment with bevacizumab have 
been observed in young children with growing bones.  This side effect appeared to be 
reversible after the treatment was stopped, but has not been assessed with long-term use 
of the drug. 
 
Formulation and Stability: Bevacizumab is supplied as a clear to slightly opalescent, 
sterile liquid ready for parenteral administration. Each 400 mg (25 mg/mL, 16 mL fill) 
glass vial contains bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile 
Water for Injection, USP. Upon receipt, refrigerate the intact bevacizumab vials at 2-8°C 
(36-46°F). Store in the outer carton to protect bevacizumab vials from light. Do not 
freeze. Do not shake. 
 
Bevacizumab vials contain no antibacterial preservatives and are labeled for single use. 
Discard any unused portion left in the vial immediately after use.  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
Do not administer as an intravenous (IV) push or bolus. Prior to administration, dilute 
the dose in 0.9% sodium chloride for injection to a final concentration of 1.4-16.5 
mg/mL. Inspect visually for particulate matter and discoloration prior to administration.   
 
The chemical and physical stability of the diluted solution in 0.9% sodium chloride is 48 
hours at 2°C-30°C. From a microbiological point of view, the product should be used 
immediately. If not used immediately, in-use storage times and conditions are the 


 
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responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, 
unless dilution has taken place in controlled and validated aseptic conditions. 
Bevacizumab is incompatible with D5W. 
 
To ensure complete delivery of bevacizumab IV infusion line must be flushed with 0.9% 
sodium chloride. The following are two recommended methods for flushing the line: 
1. 
When the bevacizumab infusion is complete, while maintaining a closed system, 
add an additional 50 mL of 0.9% sodium chloride for injection to the 
bevacizumab infusion bag. Continue the infusion until a volume equal to that of 
the volume contained in the tubing has been administered. 
2. 
Replace the empty bevacizumab infusion bag with a 50 mL bag of 0.9% sodium 
chloride for injection and infuse a volume equal to the volume contained in the 
tubing.  
 
Please note: the flush is not included in the total recommended infusion times. 
 
Supplier: Supplied by Genentech and distributed by the NCI DTCD. Do not use 
commercially available drug. 
 
Agent Ordering 
NCI supplied agent   may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution. Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If 
there are several participating investigators at one institution, CTEP supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
 
 Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees must submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application < https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx 
>. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account < https://eapps-ctep.nci.nih.gov/iam/ > and the maintenance 
of an “active” account status and a “current” password. For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 
the CTEP home page at http://ctep.cancer.gov for the Procedures for Drug 
Accountability and Storage and http://ctep.cancer.gov/forms/default.htm to obtain a copy 
of the DARF and Clinical Drug Request form.) 
 
Agent Returns 


 
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Investigators/Designees must return unused DCTD supplied investigational agent to the 
NCI clinical repository as soon as possible when: the agent is no longer required because 
the study is completed or discontinued and the agent cannot be transferred to another 
DCTD sponsored protocol; the agent is outdated or the agent is damaged or unfit for use. 
Regulations require that all agents received from the DCTD, NCI be returned to the 
DCTD, NCI for accountability and disposition. Return only unused vials/bottles. Do 
NOT return opened or partially used vials/bottles unless specifically requested otherwise 
in the protocol. See the CTEP web site for Policy and Guidelines for Investigational 
agent Returns at: http://ctep.cancer.gov/protocolDevelopment/default.htm#agents_drugs. 
The appropriate forms may be obtained at:  http://ctep.cancer.gov/forms/default.htm. 
 
6.2 
IRINOTECAN  
[CPT-11,Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-
camptothecin), Camptosar®],   NSC #616348 
 
 
 
(05/09/11) 
Source and Pharmacology:  
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant alkaloid 
isolated from Camptotheca acuminata). Irinotecan is a prodrug that requires conversion, 
by the carboxylesterase enzyme to the topoisomerase-I inhibitor, SN-38 in order to exert 
anti-tumor activity. SN-38 is approximately 1000 times more potent than irinotecan. 
Camptothecins interact specifically with the enzyme topoisomerase I which relieves 
torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its 
active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent 
religation of these single-strand breaks. Current research suggests that the cytotoxicity of 
irinotecan is due to double-strand DNA damage produced during DNA synthesis when 
replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, 
and either irinotecan or SN-38. Renal excretion is a minor route of elimination of 
irinotecan. The majority of the drug is metabolized in the liver. SN-38 is conjugated to 
glucuronic acid and this metabolite has no anti-tumor activity. The extent of conversion 
of SN-38 to its glucuronide has been inversely correlated with the risk of severe diarrhea, 
because the other major route of SN-38 excretion is biliary excretion by canalicular 
multispecific organic anion transporter (cMOAT) which presumably leads to mucosal 
injury. In addition, APC and NPC are oxidative metabolites of irinotecan dependent on 
the CYP3A4 isoenzyme. After intravenous infusion of irinotecan in humans, irinotecan 
plasma concentrations decline in a multiexponential manner, with a mean terminal 
elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of 
the active metabolite SN-38 is about 10 to 20 hours. Irinotecan is 30% to 68% bound to 
albumin and SN-38 is approximately 95% bound to albumin. 


 
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Toxicity: 
 
Common 
Happens to 21-100 children out of every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, anorexia, fever, asthenia, 
cholinergic symptoms: (rhinitis, increased 
salivation, miosis, lacrimation, diaphoresis, 
flushing, and intestinal hyperperistalsis that can 
cause abdominal cramping and early diarrhea)  
Constipation, headache, 
diarrhea (L)  
Anaphylaxis, dehydration with dizziness & 
hypotension, bradycardia, dyspnea and 
cough, disorientation/confusion, 
somnolence, pain at infusion site 
Prompt: 
Within 2-3 weeks, prior 
to the next course 
Neutropenia, alopecia, eosinophilia, elevations 
in transaminases, alkaline phosphatase, 
bilirubin, mucositis, infection 
Anemia, rash, 
dyspepsia, 
thrombocytopenia 
Colitis, renal failure (secondary to severe 
dehydration), thromboembolic events, ileus 
Delayed: 
Any time later during 
therapy 
 
 
Pneumonitis 
Late: 
Any time after 
completion of treatment 
 
 
 
Unknown 
Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at doses similar or less than those used 
in humans. Toxicities include: decreased skeletal ossification, multiple anomalies, low birth weight and increased fetal 
mortality. It is not known if irinotecan is excreted into breast milk but it is excreted into rat milk. 
(L) Toxicity may also occur later. 
 
 
 
 
Formulation & Stability:  
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the trihydrate 
salt), 45 mg sorbitol and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 
(range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan is available in 
single-dose amber glass vials in 40 mg (2 mL) and 100 mg (5 mL), 300 mg (15 mL), and 
500 mg (25 mL). Store at controlled room temperature 15°-30°C (59°-86°F). Protect 
from light. It is recommended that the vial (and backing/plastic blister) should remain in 
the carton until the time of use.  
 
Guidelines for Administration:  See Treatment and Dose Modifications sections of the 
protocol. 
 
Irinotecan must be diluted prior to infusion. Irinotecan should be diluted in 5% D5W, 
(preferred) or NS, to a final concentration range of 0.12-2.8 mg/mL. The solution is 
physically and chemically stable for up to 24 hours at room temperature (approximately 
25°C) and in ambient fluorescent lighting. Solutions diluted in D5W and stored at 
refrigerated temperatures (approximately 2°-8°C), and protected from light are physically 
and chemically stable for 48 hours. Refrigeration of admixtures using NS is not 
recommended due to a low and sporadic incidence of visible particulates. Care should be 
taken to avoid extravasation; the use of a central line is suggested. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
 
 


 
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6.3 
TEMOZOLOMIDE  
(Temodar®, Temodal®) NSC# 362856   
 
 
 
(05/10/11) 
 
Source and Pharmacology:  
An orally administered alkylating agent, a second generation imidazotetrazine. A prodrug 
of MTIC, temozolomide spontaneously decomposes to MTIC at physiologic pH. Exerts 
its effect by cross-linking DNA. This is likely a site specific alkylation at the O6-position 
of guanine with some effect at the N7 position. Temozolomide reaches its peak 
concentration in 1 hour. Food reduces the rate and extent of absorption. It has an 
elimination half-life of 1.13 hr (intraperitoneally) and 1.29 hr (orally) with an oral 
bioavailability of 0.98. Total apparent body clearance is 100 mL/min/m2 and plasma 
elimination half-life is ~ 100 minutes.  
 
Toxicity 
 
Common 
Happens to 21-100 subjects 
out of every 100 
Occasional 
Happens to 5-20 subjects out 
of every 100 
Rare 
Happens to < 5 subjects out of every 100 
Immediate: 
Within 
1-2 days of 
receiving drug 
Anorexia, constipation, 
nausea, vomiting, 
Abdominal pain, diarrhea, 
headache, rash, itching, urinary 
frequency and/or infection 
Convulsions, anaphylaxis, hemiparesis, 
dizziness, ataxia, confusion, dysphagia, 
anxiety, thrombo-embolism (L)  
Prompt: 
Within 
2-3 weeks, 
prior to next 
course 
Myelosuppression 
Mucositis, lethargy, peripheral 
edema 
Prolonged lymphopenia with increased 
risk of infection or death, amnesia, 
insomnia, depression, myalgia, diplopia, 
visual changes 
Delayed: 
Anytime later 
during therapy 
 
Alopecia, hepatotoxicity 
 
Late: 
Anytime after 
completion of 
therapy 
 
 
Secondary tumors or cancer 
 
Formulation and Stability: Temozolomide capsules are available in six different 
strengths (5, 20, 100, 
140, 180, 250 mg). The capsules vary in size, color, and imprint according to strength. In 
the US, capsules are packaged in 5-count and 14-count bottles. In other countries 
temozolomide may be packaged in 5-count, 14-count or 20-count bottles. Temozolomide 
capsules are stored at controlled room temperature. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
There is a potential for medication errors involving temozolomide capsules resulting in 
drug overdosages, which may have been caused by dispensing/taking the wrong number 
of capsules per day and/or product usage exceeding the prescribed dosing schedule. 
 
When dispensing, it is extremely important that prescribing and dispensing include clear 
instructions on which capsules, and how many of each capsule(s) are to be taken per day. 
Only dispense what is needed for the course, and clearly indicate how many days of 
dosing the patient will have and how many days are without temozolomide dosing. 


 
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Page 42 
When counseling patients, it is important for each patient/parent to understand the 
number of capsules per day and the number of days that they take temozolomide. It is 
also important for the patient/parent to understand the number of days that they will be 
off the medication.  
 
Each strength of temozolomide must be dispensed in a separate vial or in its original 
glass bottle. Based on the dose prescribed, determine the number of each strength of 
temozolomide capsules needed for the full course as prescribed by the physician. For 
example, 275 mg/day for 5 days would be dispensed as five 250 mg capsules, five 20 mg 
capsules, and five 5 mg capsules. Label each container with the appropriate number of 
capsules to be taken each day. Dispense to the patient/parent, making sure each container 
lists the strength (mg) per capsule and that he or she understands to take the appropriate 
number of capsules of temozolomide from each bottle or vial to equal the total daily dose 
prescribed by the physician. Institutions that have the capability to dispense 
temozolomide as daily doses in a blister pack may do so, taking specific precautions to 
ensure that the appropriate dose is provided and that the patient is educated to understand 
the daily dosing regimen. 
 
For children unable to swallow the capsules whole, the oral capsules may be formulated 
into a suspension. To prepare a 10mg/mL suspension triturate the contents of ten 100 mg 
capsules (1000 mg), 500 mg povidone K-30 and 25mg anhydrous citric acid dissolved in 
1.5mL purified water in a glass mortar to form a uniform paste. To the paste add 50 mL 
of Ora-Plus® by adding a small amount, mixing, and then adding the balance. Transfer 
to a glass graduated cylinder.  Add Ora-Sweet® or Ora-Sweet® SF to a total volume of 
100 mL by rinsing the mortar with small amounts of the syrup (Ora-Sweet® or Ora-
Sweet® SF).  Rinse at least four times. Package in an amber plastic prescription bottle. 
The 
packaged 
suspension 
is 
stable 
for 
7 days at room temperature or 60 days in the refrigerator. The suspension should be 
shaken well before each use. Procedures for proper handling and disposal of cytotoxic 
drugs should be used when preparing the suspension. (Trissel LA, Yanping Z, Koontz 
SE.  Temozolomide stability in extemporaneously compounded oral suspensions. Int J 
Pharm Compounding 10:396-9, 2006.) 
 
Alternatively, the capsules can be opened and mixed with apple sauce or juice (see 
Appendix VI). 
 
Supplier: Commercially available. See package insert for further information.  
 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
All baseline studies must be performed prior to starting protocol therapy unless otherwise 
indicated below.  
 
 
 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations  
 
Obtain prior to start of course unless otherwise indicated.   
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care.  Minor unavoidable departures (up to 72 hours) from protocol directed 
therapy and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and 
family logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per 
COG Administrative Policy 5.14 (except where explicitly prohibited within the protocol).  


 
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STUDIES TO BE OBTAINED 
Baseline 
Prior to 
Each 
Course 
 
During Each 
Course 
 
 
Prior to 
every 
other 
Course 
When Patient 
is Removed 
From Protocol 
Therapy 
History 
X 
X 
 
 
X 
Physical Exam (Ht, Wt, VS) 
X 
X 
BP: Prior to 
every dose of 
bevacizumabA 
 
X 
Performance Status 
X 
 
 
 
X 
CBC (differential, platelets) 
X 
X 
Weekly 
 
X 
Electrolytes, including Ca++, 
PO4, Mg++ 
X 
X 
 
 
X 
Urinalysis for dipstick protein 
and urine protein creatinine 
(UPC) ratio  
X B  
X B 
 
 
 
Creatinine (OR creatinine 
clearance OR radioisotope 
GFR), BUN, AST, ALT, 
bilirubin  
X 
X 
 
 
X 
INR/PT 
X 
 
 
 
 
Pregnancy test (for females of 
childbearing potential) 
X 
 
 
 
 
Brain MRI with and without 
gadolinium 
XC  
 
 
XD 
X 
Spine MRI with gadolinium 
XC 
 
 
XD 
XD 
CSF cytology 
XE 
 
 
XE 
XE 
A For patients receiving bevacizumab only.  
B Obtain prior to the start of each course of bevacizumab. If urine dipstick is 2+ or greater for protein, hold 
bevacizumab and obtain UPC ratio. See bevacizumab dose modifications for proteinuria (Section 5.1). 
C Obtain within 2 weeks prior to study enrollment.  
D Obtain within one week prior to the third course of therapy and prior to every other subsequent course of 
therapy (ie, 5th, 7th, etc.) for up to 12 courses of therapy. Repeat spine MRI only if initially positive or 
clinically indicated.  
E Obtain within 14 days prior to start of course 1 if feasible and not contraindicated. If baseline test is negative, 
repeat only if there is disease progression. If positive at baseline, repeat prior to every other course (ie, 3rd, 5th, 
etc.) until there are two negative cytologies. CSF cytology can be waived for patients where a lumbar puncture 
is not deemed to be safe. 
 
This table only includes evaluations necessary to answer the primary and secondary aims.  Obtain other 
studies as indicated for good clinical care.  


 
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Page 44 
 
 
7.2 
Follow-up  
See COG Late Effects Guidelines for recommended post treatment follow-up 
http://www.childrensoncologygroup.org/disc/LE/default.htm. 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
8.1 
Criteria for Removal from Protocol Therapy 
a) 
Progressive disease (see definition in Section 10.4). 
b) 
Grade 3 or higher non-hematologic toxicity despite two dose reductions (as stated in 
Section 5.0). 
c) 
Prolonged myelosuppression that prevents delivery of subsequent course by Day 35 
despite dose  
reductions (See Section 5.2). 
d) 
Adverse event requiring discontinuation of bevacizumab (as stated in Section 5.1). 
e) 
Refusal of further protocol therapy by patient/parent/guardian. 
f) 
Completion of 12 courses of therapy. 
g) 
Physician determines it is in patient’s best interest. 
h) 
Second Malignant Neoplasm (SMN) 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below).  Follow-up data will be required unless consent was withdrawn. 
 
8.2 
Off Study Criteria 
a) 
Death. 
b) 
Lost to follow-up. 
c) 
Pateint enrollment onto another COG study with tumor therapeutic intent (eg, at 
 recurrence). 
d) 
Withdrawal of consent for any further data submission. 
e) 
The fifth anniversary of date the patient was enrolled on this study 
 
9.0 
STATISTICAL CONSIDERATIONS  
 
9.1 
Sample Size and Study Duration 
Based on A09071, we estimate 36 eligible patients will be available for enrollment 
annually, at a rate of 3 patients per month for 36 months, for a total of approximately 108 
eligible patients. An additional 11 patients will be added to accommodate for a 10% 
inevaluable and ineligible rate to a maximum accrual of 120 patients. The last patient 
enrolled will be followed for six months after enrollment at which time the definitive 
analysis for the study will be conducted. 
 
9.2 
Study Design 
This is a randomized, phase II screening trial comparing temozolomide with irinotecan to 
temozolomide, irinotecan and bevacizumab, for the treatment of recurrent/refractory 
medulloblastoma/PNET. Patients will be randomized at the time of enrollment to receive 


 
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Page 45 
one of two regimens with equal probability: (1) temozolomide (TEMO) with irinotecan 
(IRIN), or (2) temozolomide with irinotecan plus bevacizumab (TEMO+IRIN+B). 
Treatment will continue for up to 12 courses as long as there is no tumor progression 
and/or untoward toxicity. Patients will be stratified for randomization to each treatment 
arm according to whether or not they have measurable disease. 
 
9.3 
Methods of Analysis 
Survival will be the primary outcome measure used to determine whether the addition of 
bevacizumab to temozolomide/irinotecan reduces the risk of death to warrant further study. 
The secondary objective includes estimation of the risk of disease progression and response 
rate for each treatment arm. 
 
9.3.1 
Efficacy Endpoint 
Any patient who dies will be considered to have experienced an event, regardless 
of the cause of death.  Otherwise, the patient will be considered censored at last 
contact. 
 
All eligible patients who are randomized and receive at least one dose of their 
assigned regimen will be considered in the analysis.  The primary analysis will 
be done with each patient’s outcome assigned to her or his randomized regimen. 
 A secondary analysis will be done with each patient’s outcome assigned to her 
or his actual treatment regimen, if there are any patients whose randomized 
regimen is switched. The risk of death of two regimens will be compared using 
the log-rank test. 
 
Patients will be enrolled for thirty-six months (108 eligible patients).  The last 
patient enrolled will be followed for six (6) months.  At that point, the primary 
study analysis can be accomplished. 
 
Data from patients enrolled on CCG-0962, P9761, P9963, A09713 and A09705 
provide an estimate of the median survival of 45 weeks from study enrollment 
for patients with recurrent medulloblastoma.  TEMO+IRIN+B will be considered 
of sufficient interest for further development if the one-sided test of equality of 
risk of death between TEMO+IRIN v. TEMO+IRIN+B has an associated p-value 
of 0.15 or less.  The power characteristics of this design are given in the 
following figure: 


 
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Page 46 
 
For example, this design has approximately 87% power for the alternative of a 
40% reduction in risk of death associated with TEMO+IRIN+B.  
 
Each regimen will be monitored for toxicity, however, as described below. 
 
In addition to overall survival, the event-free survival (EFS) will be determined 
for each patient and compared across regimens using the log-rank test.  The EFS 
interval for a patient will be defined to be the time from enrollment to: (1) 
disease progression; (2) second malignant neoplasm; (3) death regardless of 
cause; or (4) date of last contact, whichever comes first. Patients whose EFS 
follow-up is terminated because of reasons (1)-(3) above will be considered to 
have experienced an event; otherwise the patient will be considered censored at 
the conclusion of EFS-time.  Kaplan-Meier estimates of the EFS for each of the 
randomized regimens will be constructed. 
 
9.3.2 
Interim Montioring 
We will monitor for emerging differences between the randomized treatments 
using the Lan and DeMets spending function approach. 54 The test statistic used 
for this for interim monitoring will be: 
 
 
 
where the hazard ratio is estimated from a proportional hazards regression 
stratified according to the factors by which randomization is stratified.  The 
bevacizumab-containing therapy is considered the experimental therapy.  The 
spending function will be α(t)=αt2.  We will monitor for differences in survival 
across the regimens at the times shown below.  The projected expected 
information times are presented in the tables as well.  
 
{
}
ln Hazard Ratiofor Death for Experimental: Standard Therapy
Estimated VarianceoftheHazard Ratio
Power 
Hazard Ratio
0.4 
0.5 
0.6 
0.7 
0.8 
0.9 
1.0 
0.4
0.5 
0.6 
0.7 
0.8 
0.9 
Power as a Function of the Hazard Ratio Associated with Bevacizumab Containing Therapy 


 
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Monitoring Time (Years 
Since Study Opening) 
Expected 
Information 
Time 
Lower 
Monitoring 
Boundary 
Cumulative α 
1.5 
0.23 
-2.4 
0.008 
2.5 
0.51 
-1.8 
0.04 
3.5 
1.0 
-1.1 
0.15 
 
At each of the monitoring times above, we will test the alternative hypothesis.  If 
the p-value obtained by that procedure is less than or equal to 0.004, the study 
will be identified for possible closure of accrual because the alternative 
hypothesis is not tenable (‘futility monitoring’). 
 
9.3.3 
Response Rate for Each Regimen 
 
Only patients who are enrolled with measurable disease will be considered in the 
evaluation of response rate. 
 
Disease response will be assessed according to the response criteria described in 
Section 10.4.   
 
Any patient who receives at least one dose of protocol therapy will be considered 
for this assessment.  Any patient who demonstrates an overall response of 
complete or partial response at any time will be considered as a “responder”. All 
other evaluable patients who have had protocol therapy terminated will be 
considered non-responders. The response rate will be estimated separately for 
each regimen by the number of responders divided by the number of response-
evaluable patients.  The response rates will be compared by means of the exact 
conditional test of proportions, but decisions regarding the relative efficacy of 
the two regimens will be made based on the risk for adverse event as described 
above. 
 
The estimated response rate for patients with medulloblastoma treated with 
temozolomide (Temodar) from A09701 was 16%.  If this response rate holds for 
the two regimens in this study, the expected 95% confidence intervals for the 
response rates will be 7.36%-28.9%. The response rates will be compared by 
means of the exact conditional test of proportions, but decisions regarding the 
relative efficacy of the two regimens will be made based on the risk for death. 
 
9.4 
Interim Safety Monitoring  
The feasibility of these two regimens will be monitored as well. A patient will be 
considered to have experienced a feasibility- event if the patient dies while receiving 
protocol therapy and treatment is considered the principal cause of death or the patient is 
removed from protocol therapy prior to month four because of toxicity. If, at any time, 
seven or more patients experience feasibility-events, the regimen on which this occurs 
will be considered for modification or termination. If the true feasibility- event rate is 
21% and enrollment proceeds to the full 54 for a particular regimen, the regimen will be 
considered tolerable with probability 0.05.  In addition, each time the study is reported to 
the COG Data and Safety Monitoring Committee, the proportion of eligible patients on 
each therapy that have experienced a feasibility-event will be reported along with the 


 
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Page 48 
95% confidence interval for that rate.  If the lower boundary for the confidence interval 
exceeds 5%, the particular therapy will be identified for modification. 
 
Furthermore, the dosing regimen will be re-evaluated with consideration for a protocol 
amendment if: (1) > 30% of patients require a dose reduction on either arm by the 4-
month time point, or  (2) > 25% of patients need to discontinue bevacizumab by 4 
months for bevacizumab-related toxicity. 
 
Each regimen will be considered separately with respect to the incidence of intracranial 
hemorrhage.  Every patient considered evaluable for feasibility-event will also be 
considered for the assessment of rate of intracranial hemorrhage.  A feasibility-evaluable 
patient who experiences a grade 2 or greater intracranial hemorrhage at any time during 
protocol therapy will be considered to have experienced a CNS-hemorrhage event 
(CHE).  A feasibility-evaluable patient who terminates protocol therapy without 
experiencing a CHE at any time up to 30 days after the termination of protocol therapy or 
the patient’s death, whichever comes first, will be considered not to have experienced a 
CHE. 
 
If, at any time, three CHEs are observed on either regimen, the study will be identified 
for possible modification.  For either regimen, if the true CHE rate is 10%, the regimen 
will be identified as being associated with an excessive CHE rate with probability of at 
least 91%.  At each formal interim monitoring, the CHE-time will be calculated for every 
feasibility-evaluable patient. This will be the time from enrollment until CHE event, 30 
days after completion of protocol therapy or last patient status, whichever occurs first.  
Patients who experience a grade 2 or greater intracranial hemorrhage according to CTC 
version 4 will be considered to have experience a CHE; otherwise the patient will be 
considered censored for CHE at the end of the CHE-time.  The proportion of patients 
who experience a CHE event as a function of time since enrollment will be calculated 
according to the method of Kaplan and Meier, as well as the 95% confidence interval 
associated with that proportion. 
 
9.5 
Detection of Progression 
The administration of bevacizumab may modify the radiographic appearance of the 
tumor and mask anatomical progressive disease.  We will compare the sites of disease at 
recurrence to obtain preliminary data on this hypothesis.  At disease progression, the 
sites of recurrence will be classified as: (1) recurrence at the primary site only; or (2) 
recurrence at a site other than one initially involved at the time enrollment onto 
ACNS0821.  The cumulative incidence of each type of disease progression will be 
calculated for each regimen separately and compared using the methods of Fine and 
Gray53.  A higher cumulative incidence of  new sites of disease relative to those observed 
at enrollment will be taken to support the possibility that bevacizumab may mask 
anatomical progression.  Because the study is designed to obtain the target power for the 
overall survival comparison, the power for detecting differences in the modalities by 
which recurrence is detected will be limited when using a conventional statistical test of 
size 0.05.  
 


 
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9.6 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
7 
7 
Not Hispanic or Latino 
43 
70 
113 
Ethnic Category: Total of all subjects 
43 
77 
120 
Racial Category 
 
American Indian or Alaskan Native 
4 
6 
10 
Asian 
0 
4 
4 
Black or African American 
16 
6 
22 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
23 
61 
84 
Racial Category: Total of all subjects 
43 
77 
120 
 
 
 
This distribution was derived from A09071, A Phase II Study of Temodar (Temozolomide) 
in Children and Adolescents with Recurrent Central Nervous System Tumors. 
 
 
10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
This study will utilize the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
Additionally, toxicities are to be reported on the appropriate data collection forms. 
 
10.2 
Methodology to Determine Tumor Measurement 
Patients must have clear residual disease, defined as tumor that is measurable in two 
perpendicular diameters on MRI OR diffuse leptomeningeal disease OR clear MRI evidence 
of disease that may not be measurable in two perpendicular diameters. 
 
10.2.1  Assessments of Tumor that is Measurable in Two Perpendicular Diameters 
In order to completely document the assessment of response, the measurements of the 
longest tumor dimension, and its perpendicular, of all target lesions upon which the 
assessments of tumor response are based should be explicitly noted in the radiology 
report for the baseline and all subsequent follow-up exams. Reports for the follow-up 
exams should reiterate the measurements obtained at baseline for each target lesion. 
Non-target lesions or newly occurring lesions should also be enumerated in these 
reports, and changes in non-target lesions should be described. 


 
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Tumor response criteria are determined by changes in size using the longest 
tumor dimension, and its  perpendicular. Either T1 or T2 weighted images are 
used - whichever gives the best estimate of tumor size. 
 
The following section describes the methodology. (See Figure 10.1 below for 
illustration). 
 
1. For MRI imaging (preferred), 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. Longest diameter of target lesion(s) should be selected in 
the axial plane only for CT. 
2. The longest measurement of the tumor (or width, W) should be determined.  
3. The perpendicular measurement should be determined (transverse (T) measurement-
perpendicular to the width in the selected plane. 
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 and T 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. 
 
10.2.2 Assessments of Diffuse Leptomeningeal Disease or Disease that may not be 
measurable in Two Diameters  
Patients enrolled without measurable disease as defined above but with diffuse 
leptomeningeal disease OR clear MRI evidence of disease that is not  measurable 
in two perpendicular diameters (see Figure 10.1 below) will be assessed for 
disease response with scheduled MRI evaluations and CSF cytology as detailed 
in Section 7.1. Clear, unequivocal disease extension will be at the discretion of 
the clinical radiologist and must be noted in the MRI report.  If there is concern 
for disease extension that is not clear, CSF can be obtained and if newly positive 
for malignant cells should be considered disease progression.  Presence and 
location of leptomeningeal tumor spread should be noted, and change in 
extent/thickness assessed on follow up studies. 
 
 
10.2.3 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, as 
defined in Table 10.2a and 10.2b. Response classifications for target lesions, 
non-target lesions and disease not measurable in two perpendicular diameters are 
defined in Section 10.4.   
 
 
 
 


 
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Figure 10.1: COG Guidelines for Measurement of Tumor Size 
 
 
 
 
Table 10.1: RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER 
(RECIST) AND PRODUCT OF TWO DIAMETERS (WHO)  
(Modified from Appendix II, Table 2, JNCI 92:213, 2000) 
 
 
Diameter, 2R 
Product, (2R)2 
Response 
Decrease 
Decrease 
 
30% 
50% 
 
50% 
75% 
Disease 
Progression 
Increase 
Increase 
 
12% 
25% 
 
20% 
44% 
 
25% 
56% 
 
30% 
69% 
 
 
 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE
MEASUREMENT BASED ON
CROSS-SECTIONAL IMAGING
• A, B, C, D, & E are contiguous
parallel slices in the X-Y plane
(usually axial) showing the tumor
• W and T are the maximal
perpendicular diameters on the slice
(C in this example) showing the
largest surface area
• Tumor length in the Z-axis (L)
(perpendicular to X-Y plane) can be
obtained either by the [a] (difference
in table position of the first and last
slices showing the tumor + one slice
thickness), or [b] the product of (slice
thickness + gap) and the number of
slices showing the tumor
X-Y
PLANE
L


 
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Table 10.2a Overall Response Assessment for Target Tumor Measurable in Two Diameters 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
IR/SD 
No 
PR  
PR 
CR, IR/SD 
No 
PR 
SD  
CR, IR/SD 
No 
SD  
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR – Complete Response 
PD – Progressive Disease 
PR – Partial Response 
IR – Incomplete Response 
SD – Stable Disease 
 
Table 10.2b Overall Response Assessment for Disease Not Measurable in Two Perpendicular 
Diameters 
 
 
Target Lesions 
 
Non-target Lesions 
 
New Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
SD  
CR, IR/SD 
No 
SD  
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR – Complete Response 
PD – Progressive Disease 
PR – Partial Response 
IR – Incomplete Response 
SD – Stable Disease 
 
*New CSF positive for malignant cells will be considered Progressive Disease. Persistence of CSF 
positive for malignant cells will be considered Stable Disease even if target lesions demonstrate response. 
 
 
10.3 
Selection of Target and Non-Target Lesions 
1. 
For most CNS tumors, only one lesion/mass is present and therefore is 
considered a “target” for measurement/follow up to assess for tumor 
progression/response.  
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 (eg, 8 mm 
lesion for a 4 mm slice). 
4. 
Any change in size of non-target lesions should be noted, though does not need 
to be measured. 
 
10.4 
Response Criteria for Target Lesions 
1. 
Response criteria are assessed in 2 dimensions – the product of WxT.  
2. 
To assess response/progression, the ratio is calculated: 


 
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WxT (current scan)  
WxT (reference scan) 
 
3. 
Development of new disease or progression in any established lesions is 
considered progressive disease, regardless of response in other lesions – e.g. 
when multiple lesions show opposite responses, the progressive disease takes 
precedence. 
 
4. 
Response Criteria for target lesions: 
 
Complete Response (CR): 
The 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 sum of the products of the two 
perpendicular diameters of all target lesions to qualify for 
PR (taking as reference the initial baseline measurements), 
nor sufficient increase in a single target lesion to qualify for 
PD, (taking as reference the smallest disease measurement 
since the treatment started). 
Progressive Disease (PD): 
≥ 25% increase in the product of perpendicular 
diameters of ANY target lesion, taking as reference the 
smallest product observed since the start of treatment, or the 
appearance of one or more lesions.   
 
Local progression is defined as progression of known residual tumor or the appearance of 
tumor at known prior sites of disease that were at some point without evidence of 
disease. Distant progression is defined as the appearance of tumor at sites other than 
known prior sites of disease. Distant progression most often occurs in the subarachnoid 
space and may occur at any point within the neuraxis. Although rare, extra-CNS 
metastasis represents distant failure. Combined local and distant progression is defined 
when evaluation of the entire neuraxis reveals local and distant progression. 
 
5.  
For patients enrolled without “measurable disease” but with clear MRI evidence 
of recurrent disease:  
 
Complete Response (CR): Disappearance of all lesions.  
Stable Disease (SD) / Incomplete Response (IR): The persistence of one or more non-
target lesions but without evidence of progressive disease at any site.  
Progressive Disease (PD): The appearance of one or more new lesions and/or 
unequivocal progression of existing lesions. New CSF positive for malignant cells. 
 
10.5 
Response Criteria for Non-target Lesions 
Non-target lesions will only be evaluated in patients with measurable disease. 
 
Complete Response (CR): Disappearance of all non-target lesions.  
Stable Disease (SD) / Incomplete Response (IR): 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.  
 


 
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11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Certain adverse events must be reported 
in an expedited manner to allow for timelier monitoring of patient safety and care. The 
following sections provide information about expedited reporting. 
 
11.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), 
and the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of 
the trial; and 4) whether or not hospitalization or prolongation of hospitalization was 
associated with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply. 
• 
Concurrent administration: When an investigational agent is used in 
combination with a commercial agent, the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent 
and a commercial agent on the same study arm, but the commercial agent 
is given for a period of time prior to starting the investigational agent, 
expedited reporting of adverse events which occur prior to starting the 
investigational agent would follow the guidelines for commercial agents.  
Once therapy with the investigational agent is initiated, all expedited 
reporting of adverse events follow the investigational agent reporting 
guidelines. 
 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting tables 
assigned to the protocol, using the CTEP Adverse Event Reporting System (CTEP-
AERS). 
 


 
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Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are 
part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
11.4 
Special Situations for Expedited Reporting  
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of 
a possible, probable, or definite relationship to the study therapy must be 
reported according to the CTEP-AERS reporting tables in this protocol.  
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to as 
disabilities), congenital anomalies or birth defects, must be reported via CTEP-
AERS if it occurs at any time following treatment with an agent under a NCI 
IND/IDE since these are considered to be serious AEs. 
 
11.4.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with grade 5.  
o Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (incl cysts and polyps) - 
Other (Progressive Disease)” under the system organ class (SOC) of the 


 
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same name. Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) 
should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 
hours.  
 
Any death occurring greater than 30 days after the last dose of the 
investigational agent/intervention requires expedited reporting within 24 hours 
only if it is possibly, probably, or definitely related to the investigational 
agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a 
secondary malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) 
must also be reported via the routine reporting mechanisms outlined in this 
protocol. 
 
11.4.5 Pregnancy, Fetal Death, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy 
loss”, or “Neonatal loss”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to 301-230-0159. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 


 
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11.4.5.1 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of 
the fetus to agents that may be teratogenic. For this reason, pregnancy 
needs to be reported in an expedited manner via CTEP-AERS as 
Grade 3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the 
baby is born with a birth defect or anomaly, then a second CTEP-
AERS report is required. 
 
11.4.5.2 
Fetal Death 
Fetal death, defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle 
after expulsion from the uterus, without possibility of resuscitation”, 
needs to be reported expeditiously, as Grade 4 “Pregnancy, 
puerperium and perinatal conditions - Other (pregnancy loss)”. Do 
NOT report a fetal death as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death. 
 
11.4.5.3 
Death Neonatal  
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” needs to be 
reported expeditiously, as Grade 4 “General disorders and 
administration - Other (neonatal loss)” when the death is the result 
of a patient pregnancy or pregnancy in partners of men on study. 
Do NOT report a neonatal death resulting from a patient pregnancy or 
pregnancy in partners of men on study as a Grade 5 event since CTEP-
AERS recognizes any Grade 5 event as a patient death.  
 
11.5 
Reporting Requirements for Specialized AEs 
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (eg, elevated laboratory 
value, diarrhea). The baseline AE must be re-assessed throughout the study and 
reported if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the 
event to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 Persistent AEs 


 
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A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a 
subsequent cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
 
11.6 
Exceptions to Expedited Reporting 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered 
expected for CTEP-AERS reporting purposes. (Formerly referred to as the Agent 
Specific Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to 
the NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use 
the lower of the grades to determine if expedited reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under 
the CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE 
reports in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 


 
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11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting and are located 
on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate treatment areas should have access to a copy of the CTCAE. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted 
electronically 
to 
NCI 
via 
CTEP-AERS 
at: 
https://eapps-
ctep.nci.nih.gov/ctepaers.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is 
to be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-
897-7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of 
the report at the site.   
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be 
submitted within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect, 
or is an IME, which based upon the medical judgment of the investigator may 
jeopardize the patient and require intervention to prevent a serious AE, must be 
reported via CTEP-AERS if the event occurs following investigational agent 
administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE 
requires expedited reporting within 24 hours.  
 
CTEP-AERS Medical Reporting includes the following requirements as part of the 
report: 1) whether the patient has received at least one dose of an investigational agent on 
this study; 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.  
 
Any medical documentation supporting an expedited report (eg, H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours 
to the NCI. NOTE: English is required for supporting documentation submitted to 


 
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the numbers listed below in order for the NCI to meet the regulatory reporting 
timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied 
under a CTEP IND to: 301-230-0159 (back-up: 301-897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax # 626-
303-1768; email: COGAERS@childrensoncologygroup.org; Attention: COG AERS 
Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 
 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 


 
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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. This  
does not include hospitalizations that are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. (FDA, 21 CFR  
312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting 
in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 
Calendar 
Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional 
Special Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
• 
Grades 1-4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not 
require expedited reporting.  
• 
G3-4 Decreased neutrophil count/febrile neutropenia, regardless of 
hospitalization 


 
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• 
G3-4 Diarrhea, Nausea, Vomiting, or Dehydration, regardless of hospitalization 
 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this 
study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event. 
 
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. 
 
 
CTEP-AERS 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 Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This 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 CTEP-AERS. 
 
 
11.12 Routine Adverse Event Reporting 
 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS 
reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database.  For this study, routine reporting will include all CTEP-AERS 
reportable events and Grade 3 and higher Adverse Events. 
 


 
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12.0 
STUDY REPORTING AND MONITORING  
 
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”.  
 
12.1 
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. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. 
The study statistician is responsible for the monitoring of the interim results and is 
expected to request DSMC review of any protocol issues s/he feels require special 
review. Any COG member may bring specific study concerns to the attention of the 
DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior 
to implementation (e.g., termination, dropping an arm based on toxicity results or other 
trials reported, increasing target sample size, etc.). The DSMC determines whether and to 
whom outcome results may be released prior to the release of study results at the time 
specified in the protocol document. 
 
12.3 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of 
Cancer Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in 
addition to the provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industry) contained within the terms of award, apply to the use of 
the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the 
clinical study.  Collaborator(s) data  
 
for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators. The protocol documents for studies 
utilizing investigational Agents contain confidential information and should not 
be shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 


 
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ACNS0821 
 
 
 
Page 64 
study, the individual should sign a confidentiality agreement. A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in 
combination with (an)other investigational Agent(s), each the subject of different 
collaborative agreements , the access to and use of data by each Collaborator 
shall be as follows (data pertaining to such combination use shall hereinafter be 
referred to as "Multi-Party Data”): 
 
a. 
NCI will provide all Collaborators with prior written notice regarding 
the existence and nature of any agreements governing their collaboration 
with NIH, the design of the proposed combination protocol, and the 
existence of any obligations that would tend to restrict NCI's 
participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from 
the clinical trial by any other Collaborator solely to the extent necessary 
to allow said other Collaborator to develop, obtain regulatory approval 
or commercialize its own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that 
it will use the Multi-Party Data solely for development, regulatory 
approval, and commercialization of its own investigational Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and 
the FDA, as appropriate and unless additional disclosure is required by law or 
court order. Additionally, all Clinical Data and Results and Raw Data will be 
collected , used and disclosed consistent with all applicable federal statutes and 
regulations for the protection of human subjects, including, if applicable, the 
Standards for Privacy of Individually Identifiable Health Information set forth in 
45 C.F.R. Part 164. 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair 
for Cooperative Group studies, or PI for other studies) of Collaborator's wish to 
contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days 
from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided 
to CTEP for forwarding to Collaborator(s) for courtesy review as soon as 


 
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ACNS0821 
 
 
 
Page 65 
possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or  
 
publication in the proceedings. Press releases and other media presentations must 
also be forwarded to CTEP prior to release. Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
Executive Plaza North, Suite 7111 
Bethesda, Maryland  20892 
FAX 301-402-1584 
Email: anshers@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator(s) confidential/ proprietary information. 
 
 
13.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
 
 
 
 
 
 
 
 
13.1 
Timing of MRIs 
To document the degree of residual tumor, standard whole brain MRI with and without 
contrast (gadolinium) and spine MRI with contrast (gadolinium) must be performed at the 
following time points: 
• 
within 2 weeks preceding enrollment into the study 
• 
prior to every other course of therapy 
• 
when patient is removed from protocol therapy 
 
In addition, for patients who have undergone surgical tumor debulking prior to protocol 
therapy, pre-operative and post-operative imaging must be obtained preferably within 48 
hours of surgery.  
 
13.2 
Whole Brain MRI With and Without Contrast  
Recommended sequences: 
1. Sagittal T1 localizer; 4 mm skip 0.4 mm 
2. Axial FSE T2; 4 mm,  skip 0.4 mm  
3. Axial T2 FLAIR; 4 mm skip 0.4  
4. Axial diffusion; 4-5 mm skip 0 (single shot, matrix 128 x 128 or 128 x 192, 
B=1000) 
5. Axial T1; 4 mm skip 0.4 mm  
6. Axial gradient echo (susceptibility sequence); 4-5 mm skip 1-2 mm. TE=20, 
flip angle =20.   
7. Axial T1 with contrast; 4 mm skip 0.4 mm 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care.  
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 
(except where explicitly prohibited within the protocol).  


 
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Page 66 
8. Sagittal T1 with contrast; 4 mm skip 0.4 mm 
9. Axial T2 FLAIR with contrast; 4 mm skip 0.4  
 
Optional sequences (depending on tumor) 
Precontrast : 
1. Sagittal or coronal FSET2; 4 mm skip 0.4 mm, depending on tumor 
configuration/orientation 
2. Axial diffusion tensor (see optional sequences, Section 16.8) 
 
Post contrast : 
1. Coronal T1 : 4mm skip 0.4 
2. T1-weighted gradient echo volume sequence (SPGR or equivalent) 
3. Axial Perfusion (see optional sequences, Section 16.8) 
 
NOTES:  
1. DO NOT INTERLEAVE T1 weighted sequences 
2. Flow compensation should not be used / not on all T1 enhanced sequences 
3. Fat Saturation not necessary 
 
13.3 
Spine MRI With Contrast 
The MRI scan must be performed of the entire spine with contrast, and must be 
performed in at least two planes.  
 
1. Whole spine sagittal T1; 3 mm skip 0 – 0.3 mm.  
Technical notes: 
- 
Phase direction AP, frequency direction SI 
- 
Acquire 2 separate acquisitions (one cervical and upper thoracic, the second 
lower thoracic and lumbosacral) to optimize placement of presaturation pulse.  
- 
Place anterior saturation pulse close to the anterior margin of the spinal column - 
to minimize motion artifacts from chest/abdomen. 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
- 
Keep TE to minimum (<15 msecs) 
- 
Do not use fat saturation 
2. Axial T1 images through the entire spine; 4-5 mm thick, skip 1-2mm.  
Technical notes: 
- 
Phase direction RL, frequency direction AP 
- 
Keep TE to minimum (< 15 msecs) 
- 
DO NOT INTERLEAVE 
 
For primary tumors of the spinal cord, add: 
1. Whole spine sagittal T2; 3 mm skip 0mm.  
Technical notes: 
- 
Can keep Phase direction AP, frequency direction SI, with anterior saturation 
pulses; or switch phase direction SI, frequency direction AP, with inferior and 
superior saturation pulses if that produces better images (less CSF pulsation 
artifacts) 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
2. Axial FSE T2, 4-5mm skip 0-1 mm, through tumor 
 
NOTE: 


 
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ACNS0821 
 
 
 
Page 67 
In the routine evaluation for subarachnoid metastatic dissemination from brain tumors to 
the spine: 
1. High quality T1 images are essential - without artefacts from physiologic motion 
(cardiac, respiratory) or from CSF pulsation.  
2. T2 weighted sequences (sagittal or axial) are not needed. They are optional.  
 
13.4 
Tumor Response Assessment 
For the response assessment, MRI scans obtained within the first 8 weeks (after Course 
2) and within the first 16 weeks (after Course 4) will be compared to the baseline MRI 
scan.  Exception: In cases of progressive disease, the reference scan should be the MRI 
with the smallest product observed since the start of treatment (not necessarily at week 
8). 
 
 


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


 
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ACNS0821 
 
 
 
Page 69 
 
APPENDIX II: 90th and 95th PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT 
IN BOYS AGE 1-17 YEARS 
Age  
BP  
 
Systolic BP (mmHg) 
 
 
Diastolic BP (mmHg) 
(Year) 
Percentile 
 
Percentile of Height 
 
 
 
Percentile of Height 
 
 
¯ 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
90th 
95th 
94 
98 
95 
99 
97 
101 
99 
103 
100 
104 
102 
106 
103 
106 
49 
54 
50 
54 
51 
55 
52 
56 
53 
57 
53 
58 
54 
58 
2 
90th 
95th 
97 
101 
99 
102 
100 
104 
102 
106 
104 
108 
105 
109 
106 
110 
54 
59 
55 
59 
56 
60 
57 
61 
58 
62 
 58 
63 
59 
63 
3 
90th 
95th 
100 
104 
101 
105 
103 
107 
105 
109 
107 
110 
108 
112 
109 
113 
59 
63 
59 
63 
60 
64 
61 
65 
62 
66 
63 
67 
63 
67 
4 
90th 
95th 
102 
106 
103 
107 
105 
109 
107 
111 
109 
112 
110 
114 
111 
115 
62 
66 
63 
67 
64 
68 
65 
69 
66 
70 
66 
71 
67 
71 
5 
90th 
95th 
104 
108 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
112 
116 
65 
69 
66 
70 
67 
71 
68 
72 
69 
73 
69 
74 
70 
74 
6 
90th 
95th 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
113 
117 
113 
117 
68 
72 
68 
72 
69 
73 
70 
74 
 71 
75 
72 
76 
72 
76 
7 
90th 
95th 
106 
110 
107 
111 
109 
113 
111 
115 
113 
117 
114 
118 
115 
119 
70 
74 
70 
74 
71 
75 
72 
76 
73 
77 
74 
78 
74 
78 
8 
90th 
95th 
107 
111 
109 
112 
110 
114 
112 
116 
114 
118 
115 
119 
116 
120 
71 
75 
72 
76 
72 
77 
73 
78 
74 
79 
75 
79 
76 
80 
9 
90th 
95th 
109 
113 
110 
114 
112 
116 
114 
118 
115 
119 
117 
121 
118 
121 
72 
76 
73 
77 
74 
78 
75 
79 
76 
80 
76 
81 
77 
81 
10 
90th 
95th 
111 
115 
 112 
 116 
114 
117 
115 
119 
117 
121 
119 
122 
119 
123 
73 
77 
73 
78 
74 
79 
75 
80 
76 
81 
77 
81 
78 
82 
11 
90th 
95th 
113 
117 
114  
118 
115 
 119  
117 
121  
119 
123 
 120 
 124  
 121 
125  
74  
78  
74 
78 
75 
 79  
76  
 80  
77  
81   
78  
82  
78  
82  
12 
90th 
95th 
115 
119  
116  
120 
118  
 122 
120  
 123  
121 
125 
 123 
 127 
123  
 127  
74  
78 
75  
 79  
75  
80 
76 
 81 
77  
 82   
78  
82   
79  
83  
13 
90th 
95th 
117  
121 
118  
 122  
120 
124  
 122  
126  
124 
128  
125  
129 
126  
 130  
75  
79  
75 
79  
76 
80  
77 
81  
78  
82  
79  
83  
79  
83  
14 
90th 
95th 
120  
124 
121  
 125 
123 
 127 
125 
 128  
126  
 130  
128  
 132 
128  
 132 
75 
80  
76 
80   
 77 
81   
78  
82  
79  
83  
79  
84  
80  
84  
15 
90th 
95th 
122  
126  
124  
127  
125  
129  
127  
131  
129  
133  
130  
134  
131  
135  
76  
81   
77  
81   
78  
82  
79  
83  
80  
84   
80  
85  
81  
85  
16 
90th 
95th 
125  
129  
126  
130  
128 
132 
  
130  
134  
131  
135  
133 
137  
134  
137  
78  
82 
78  
 83  
79 
83  
80  
 84  
81 
85  
82  
86  
82  
87  
17 
90th 
95th 
127  
131  
 128  
132  
130  
134  
132 
136 
134  
 138  
135 
139  
  136  
140  
 80 
84  
  80 
85  
 81 
86   
82  
87 
83  
 87  
84  
88  
84  
89  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents; NIH Publication No. 05-5267. 


 
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Page 70 
APPENDIX III: TEMOZOLOMIDE DOSING TABLE - STARTING DOSE= 150 mg/m2 
For patients <0.5m2 use 5 mg/kg.  Round dose to the nearest 5mg.  Round 2.5 down. 
Example:  For a patient that is 0.3 m2 and weighs 5.3 kg, the calculated dose is 5.3 kg x 5mg/kg = 26.5 mg 
rounded to the nearest 5 mg = 25 mg temozolomide/day. 
 
BSA (m2) 
Administered daily dose (mg) 
0.50-0.51 
75 
0.52-0.55 
80 
0.56-0.58 
85 
0.59-0.61 
90 
0.62-0.65 
95 
0.66-0.68 
100 
0.69-0.71 
105 
0.72-0.75 
110 
0.76-0.78 
115 
0.79-0.81 
120 
0.82-0.85 
125 
0.86-0.88 
130 
0.89-0.91 
135 
0.92-0.95 
140 
0.96-0.98 
145 
0.99-1.01 
150 
1.02-1.05 
155 
1.06-1.08 
160 
1.09-1.11 
165 
1.12-1.15 
170 
1.16-1.18 
175 
1.19-1.21 
180 
1.22-1.25 
185 
1.26-1.28 
190 
1.29-1.31 
195 
1.32-1.35 
200 
1.36-1.38 
205 
1.39-1.41 
210 
1.42-1.45 
215 
1.46-1.48 
220 
1.49-1.51 
225 
1.52-1.55 
230 
1.56-1.58 
235 
1.59-1.61 
240 
1.62-1.65 
245 
1.66-1.68 
250 
1.69-1.71 
255 
1.72-1.75 
260 
1.76-1.78 
265 
Continue on next page 


 
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BSA (m2) 
Administered daily dose (mg) 
1.79-1.81 
270 
1.82-1.85 
275 
1.86-1.88 
280 
1.89-1.91 
285 
1.92-1.95 
290 
1.96-1.98 
295 
1.99-2.01 
300 
2.02-2.05 
305 
2.06-2.08 
310 
2.09-2.11 
315 
2.12-2.15 
320 
2.16-2.18 
325 
2.19-2.21 
330 
2.22-2.25 
335 
2.26-2.28 
340 
2.29-2.31 
345 
2.32-2.35 
350 
2.36-2.38 
355 
2.39-2.40 
360 
 


 
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Page 72 
 
APPENDIX IV: TEMOZOLOMIDE DOSING TABLE-REDUCED DOSE = 112.5 mg/m2 
For patients <0.5m2 use 3.75 mg/kg.  Round dose to the nearest 5mg.  Round 2.5 down. 
Example:  For a patient that is 0.3 m2 and weighs 5.3 kg, the calculated dose is 5.3 kg x 3.75mg/kg = 19.875mg 
rounded to the nearest 5 mg = 20 mg temozolomide/day. 
BSA (m2) 
Administered daily dose (mg) 
0.50-0.51 
55 
0.52-0.55 
60 
0.56-0.60 
65 
0.61-0.64 
70 
0.65-0.68 
75 
0.69-0.73 
80 
0.74-0.77 
85 
0.78-0.82 
90 
0.83-0.86 
95 
0.87-0.91 
100 
0.92-0.95 
105 
0.96-1.00 
110 
1.01-1.04 
115 
1.05-1.08 
120 
1.09-1.13 
125 
1.14-1.17 
130 
1.18-1.22 
135 
1.23-1.26 
140 
1.27-1.31 
145 
1.32-1.35 
150 
1.36-1.40 
155 
1.41-1.44 
160 
1.45-1.48 
165 
1.49-1.53 
170 
1.54-1.57 
175 
1.58-1.62 
180 
1.63-1.66 
185 
1.67-1.71 
190 
1.72-1.75 
195 
1.76-1.80 
200 
1.81-1.84 
205 
1.85-1.88 
210 
1.89-1.93 
215 
1.94-1.97 
220 
1.98-2.02 
225 
2.03-2.06 
230 
2.07-2.11 
235 
2.12-2.15 
240 
2.16-2.20 
245 
2.21-2.24 
250 
2.25-2.28 
255 
2.29-2.33 
260 
2.34-2.37 
265 
2.38-2.40 
270 
 


 
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APPENDIX V: TEMOZOLOMIDE DOSING TABLE - REDUCED DOSE= 75 mg/m2 
 
For patients <0.5m2 use 2.5mg/kg.  Round dose to the nearest 5mg.  Round 2.5mg down. 
Example:  For a patient that is 0.3 m2 and weighs 5.3 kg, the calculated dose is 5.3 kg x 2.5 mg/kg = 13.25mg 
rounded to the nearest 5 mg = 15 mg temozolomide/day. 
 
BSA (m2) 
Administered daily dose (mg) 
0.50 
35 
0.51-0.56 
40 
0.57-0.63 
45 
0.64-0.70 
50 
0.71-0.76 
55 
0.77-0.83 
60 
0.84-0.90 
65 
0.91-0.96 
70 
0.97-1.03 
75 
1.04-1.10 
80 
1.11-1.16 
85 
1.17-1.23 
90 
1.24-1.30 
95 
1.31-1.36 
100 
1.37-1.43 
105 
1.44-1.50 
110 
1.51-1.56 
115 
1.57-1.63 
120 
1.64-1.70 
125 
1.71-1.76 
130 
1.77-1.83 
135 
1.84-1.90 
140 
1.91-1.96 
145 
1.97-2.03 
150 
2.04-2.10 
155 
2.11-2.16 
160 
2.17-2.23 
165 
2.24-2.30 
170 
2.31-2.36 
175 
2.37-2.40 
180 
 


 
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APPENDIX VI: RECOMMENDATIONS FOR ADMINISTRATION OF TEMOZOLOMIDE 
(PATIENTS WHO ARE UNABLE TO SWALLOW CAPSULES AND CANNOT OBTAIN A 
SUSPENSION) 
 
Temozolomide is an oral cancer medicine that your child will be taking for treatment of his/her 
medulloblastoma/PNET. If your child is unable to swallow capsules, the following instructions must be 
followed for safe administration of this medicine. 
 
• 
Temozolomide must be kept in a dark container. 
• 
Temozolomide should be taken the same time every day. 
• 
If your child requires nausea medicine it should be taken prior to the temozolomide. 
• 
If the dose of temozolomide is vomited (which is unusual) within the first 20 minutes after it is 
taken, the dose should be repeated.  If your child vomits more than 20 minutes after the 
temozolomide has been taken, do not repeat the dose. 
• 
If the caregiver administering this medicine is pregnant or suspects she is pregnant she should not 
handle this medicine. 
 
Since temozolomide is an anti-cancer agent, special precautions must be taken when handling this 
medicine.  There is potential hazard to anyone who handles this medicine 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.  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. 
• 
Temozolomide can be mixed in apple sauce or apple juice. 
• 
Place the apple sauce or apple juice in a disposable container. 
• 
Put on gloves, mask and goggles (eye protection). 
• 
Open each capsule and place the powder in a medicine cup. 
• 
Add the whole contents of the medicine cup to either apple sauce or apple juice.  The medicine will 
not dissolve completely if mixing in apple juice so have extra apple juice on hand so you can add it 
to any remaining powder in the bottom of 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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APPENDIX VII: YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY 
(for children from 7 through 12 years of age) 
 
A Study of New Drug Combinations in Children and Teens with Brain Tumors 
 That are Difficult to Treat or Have Come Back after Treatment 
 
1. We have been talking with you about your brain tumor. Your brain tumor has either come back 
or not gone away with the treatments you already got. 
 
2. We are asking you to take part in a research study because other treatments did not get rid of 
your tumor. A research study is when doctors work together to try out new ways to help people 
who are sick. In this study, we are trying to find out if new combinations of anti-cancer 
medicines can make your tumor get smaller or go away. We do not know if one drug 
combination is better than the other. That is why we are doing this study.  
 
3. All children who are part of this study will be treated with two drugs. Half of the children in this 
study will also be treated with a third drug. You will either get two drugs or three drugs. How 
many drugs you will get is decided on by chance. This is like flipping a coin and saying, “Heads 
means I get the two-drug treatment, but tails means I get the three-drug treatment.” A computer 
decides which treatment you will get, not you or your doctor. 
 
4. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is that the 
drug combinations will work to make your tumor smaller or go away but we do not know for 
sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” One risk to you from this study is that the study treatments may not work as 
well as other treatments to get rid of the tumor for as long as possible. Another risk is that you 
may have more side effects from the three-drug treatment than the two-drug treatment. Other 
things may happen to you that we do not yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have. 
 


 
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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
A Study of New Drug Combinations in Children and Teens with Brain Tumors 
 That are Difficult to Treat or Have Come Back after Treatment 
 
 
1. We have been talking with you about medulloblastoma/PNET tumors. Medulloblastoma and 
PNET are types of cancer that grow in the brain. Your tumor has either come back or not gone 
away with previous treatments. 
 
2. We are asking you to take part in a research study because other treatments did not get rid of 
your medulloblastoma/PNET tumor. A research study is when doctors work together to try out 
new ways to help people who are sick. In this study, doctors want to try new combinations of 
anti-cancer drugs (chemotherapy) to see if these new drug combinations will work well to make 
your tumor get smaller or go away. 
 
3. All children and teens who are part of this study will be treated with a combination of two 
chemotherapy drugs, called temozolomide and irinotecan. This drug combination has been used 
to treat children and teens with other types of cancer. This study will also see if adding another 
drug to the combination will work better to make the tumor smaller or go away. This added drug 
is called bevacizumab. It has been used in studies of adults and children with other types of 
tumors.    
 
4. This study is called a randomized study, because you will be randomly assigned to get one drug 
combination or the other. This is like flipping a coin and saying, “Heads means I get the two-
drug chemotherapy, but tails means I get the three-drug chemotherapy.” A computer decides 
which chemotherapy plan you will be on, not you or your doctor. Studies like this one are done 
to learn which drug combination works best and to make sure the number of people is equal 
among the groups. We do not know if one drug combination is better than another.  
 
5. Sometimes good things can happen to people when they are in a research study. These good 
things are called “benefits.” We hope that a benefit to you of being part of this study is that the 
drug combinations will make your tumor get smaller or go away, but we don’t know for sure if 
there is any benefit of being part of this study. 
 
6. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” One risk to you from this study is that the treatment you get may not work as 
well as other treatments to get rid of the tumor for as long as possible. Another risk is that you 
may have more side effects from the drugs if you get the three-drug combination. Other things 
may happen to you that we don’t yet know about. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions you have.  
 
 


 
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APPENDIX VII: POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Bevacizumab 
 
Drugs that may interact with bevacizumab* 
• 
Clozapine 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
 
Food and supplements that may interact with bevacizumab** 
• 
Unknown 
 
*Sometimes these drugs are used with bevacizumab on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, 
or dried herbs. All forms should be avoided.   
 
 
 
Irinotecan 
 
Drugs that may interact with irinotecan* 
• 
Antibiotics  
• 
Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
• 
Citalopram, clozapine, desipramine, nefazodone, sertraline 
• 
Antifungals  
• 
Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications  
• 
Leflunomide, tofacitinib 
• 
Anti-rejection medications 
• 
Cyclosporine, tacrolimus 
• 
Antiretrovirals and antivirals  
• 
Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• 
Anti-seizure medications  
• 
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• 
Heart medications  
• 
Amiodarone, dronedenarone, diltiazem, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 


 
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Page 78 
• 
Bosentan, sitaxentan, aprepitant, dexamethasone, ivacaftor, lomitapide, mifepristone, natalizumab, 
succinylcholine 
 
Food and supplements that may interact with irinotecan** 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with irinotecan on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. 
All forms should be avoided.  
 
 
 
 
Temozolomide 
 
Drugs that may interact with temozolomide* 
• Clozapine, leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with temozolomide** 
• 0. 
 
*Sometimes these drugs are used with temozolomide on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, 
or dried herbs. All forms should be avoided.   


 
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