Conditions: Medulloblastoma
Keywords: Wnt Medulloblastoma Chemotherapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
Participants enrolling on this study will receive standard of care chemotherapy for Wnt positive medulloblastoma without the radiation therapy or the weekly chemotherapy that is given during radiation therapy.

Detailed description:
There will be 9 cycles of chemotherapy. There are two different kinds of cycles given. They are referred to as A and B.

Cycle A lasts for 6 weeks and Cycle B lasts for 4 weeks. B cycles are given after the completion of two A cycles.

Below are the details of the drugs and schedules for A and B cycles.

Cycle A (This cycle lasts 42 days)

* Lomustine (CCNU) is given by mouth on Day 1.
* Vincristine is given directly into a vein (IV) over one minute or using a minibag over several minutes by some institutions on Days 1, 8, and 15.
* Cisplatin is given directly into a vein over 8 hours on Day 1

Cycle B (This cycle lasts 28 days)

* Cyclophosphamide is given into a vein over 1 hour on Days 1 and 2.
* MESNA, a drug to protect the bladder from the effects of cyclophosphamide, will be given 15 minutes before each dose of cyclophosphamide and repeated at 3 and 6 hours.
* Vincristine is given directly into a vein directly into the vein (IV) over one minute or using a minibag over several minutes by some institutions on Days 1 and 8.

You may also get a supportive care drug called a myeloid growth factor (filgrastim or pegfilgrastim). This drug will help your blood counts recover after the chemotherapy is given.

Arms:
arm 1: Chemotherapy Cycle A Lomustine (CCNU) is given by mouth on Day 1. Vincristine is given directly into a vein (IV) over one minute or using a minibag over several minutes by some institutions on Days 1, 8, and 15. Cisplatin is given directly into a vein over 8 hours on Day 1. This cycle lasts 42 days.

Chemotherapy Cycle B Cyclophosphamide is given into a vein over 1 hour on Days 1 and 2. MESNA, a drug to protect the bladder from the effects of cyclophosphamide, will be given 15 minutes before each dose of cyclophosphamide and repeated at 3 and 6 hours. Vincristine is given directly into a vein directly into the vein (IV) over one minute or using a minibag over several minutes by some institutions on Days 1 and 8.This cycle lasts 28 days

Interventions: intervention 1: Lomustine intervention 2: Vincristine intervention 3: Cisplatin intervention 4: Cyclophosphamide intervention 5: Mesna intervention 6: Vincristine
Intervention descriptions: intervention 1: Chemotherapy Cycle A Lomustine (CCNU) is given by mouth on Day 1. intervention 2: Chemotherapy Cycle A Vincristine is given directly into a vein (IV) over one minute or using a minibag over several minutes by some institutions on Days 1, 8, and 15. intervention 3: Chemotherapy Cycle A Cisplatin is given directly into a vein over 8 hours on Day 1. intervention 4: Chemotherapy Cycle B Cyclophosphamide is given into a vein over 1 hour on Days 1 and 2. intervention 5: Chemotherapy Cycle B MESNA, a drug to protect the bladder from the effects of cyclophosphamide, will be given 15 minutes before each dose of cyclophosphamide and repeated at 3 and 6 hours. intervention 6: Chemotherapy Cycle B Vincristine is given directly into a vein directly into the vein (IV) over one minute or using a minibag over several minutes by some institutions on Days 1 and 8.

Protocol document:
ICF_002.pdf: 
 
 
 
 
 
 
 
 
 
 
J1403 - Pilot Study of a Surgery and Chemotherapy-Only 
Approach in the Upfront Therapy of Children with Wnt Positive 
Standard Risk Medulloblastoma 
 
NCT02212574 
 
May 11, 2016 
 


Approved May 11, 2016
Date: May 11, 2016
Principal Investigator: Kenneth J. Cohen, MD, MBA
Application No.: NA_00091840
Page 1 of 14
Combined Informed Consent/Authorization June 2015 Version 15
 
 
 
RESEARCH PARTICIPANT INFORMED CONSENT AND PRIVACY 
AUTHORIZATION FORM 
Protocol Title:  
Pilot Study of a Surgery and Chemotherapy-Only Approach in 
the Upfront Therapy of Children with Wnt Positive Standard 
Risk Medulloblastoma 
Application No.:   
NA_00091840 
 
Sponsor: 
 
 
Matthew Larson Foundation 
Principal Investigator: Kenneth Cohen, MD, MBA  
Johns Hopkins Hospital   
Bloomberg 11379 
1800 Orleans St. 
Baltimore, MD  21287  
Phone 410-614-5055  
Fax 410-955-0028 
1. 
What you should know about this study:   
x You are being asked to join a research study. This consent form explains the research study and your 
part in it. Please read it carefully and take as much time as you need. Ask your study doctor or the 
study team to explain any words or information that you do not understand. 
x You are a volunteer.  If you join the study, you can change your mind later.  There will be no penalty 
or loss of benefits if you decide to quit the study.
x During the study, we will tell you if we learn any new information that might affect whether you 
wish to continue to participate. 
x If we think your participation in this study may affect your clinical care, information about your 
study participation will be included in your medical record, which is used throughout Johns Hopkins.   
Doctors outside of Johns Hopkins may not have access to this information.  You can ask the research 
team to send this information to any of your doctors. 
x When Johns Hopkins is used in this consent form, it includes The Johns Hopkins University, The 
Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, Howard County General Hospital, 
Johns Hopkins Community Physicians, Suburban Hospital, Sibley Memorial Hospital and All 
Children’s Hospital. 
If you are using Epic for this study, fax a copy 
of the signed consent form to 410-367-7382.
Patient I.D. Plate
                               
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x Biospecimens will be collected in this study.  Biospecimens may include any of the following: 
blood, tissue, saliva, urine, bone marrow, cells, etc.  Most biospecimens contain DNA, which is the 
genetic code for each person. 
x A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search this Web site at any time. 
x If you would like to review the information for this study, or a summary of the results, ask the study 
team doctor for the ClinicalTrials.gov study registration number. 
x If children and adults can join this study, the word “you” in this consent form will refer to both you 
and your child. 
2. 
Why is this research being done? 
This research is being done to see if children with Wnt-positive medulloblastoma can be treated 
successfully without the use of radiation therapy. 
Your brain tumor has been tested and shown to be Wnt-positive.  Children with Wnt-positive 
medulloblastoma are almost always cured when given radiation therapy and chemotherapy after the 
removal of their tumor.  However, radiation therapy to the brain and spinal cord results in a number of 
side effects including hair loss, irritation or redness of the skin, inflammation and irritation of the areas 
of the ear canal, and balance problems. Long-term side effects include increased risk of radiation 
induced high grade cancers, increased risk of inflammation to the blood vessels of the brain, with risk of 
stroke, growth failure, vision problems, partial hearing loss, memory loss, and learning difficulties.  
Researchers are testing whether the total amount of treatment received after surgery can be safely 
reduced to try and decrease some of the side effects of treatment, and still maintain this excellent 
outcome. There are different ways this can be done including: 
x Giving some radiation, but less than is usually given 
x Giving some chemotherapy, but less than is usually given 
x Giving no radiation 
In this study, we will test the third option (giving no radiation). Children with Wnt-positive 
medulloblastoma may join. 
How many people will be in this study? 
Up to 13 children may join this study across participating centers.  At Johns Hopkins, only one person is 
expected to enroll.  
3. 
What will happen if you join this study? 
If you agree to join this study, we will ask you to do the following things: 
The only difference between the research therapy and the standard treatment for Wnt-positive 
medulloblastoma you will receive is that you will not receive radiation therapy or the weekly 
chemotherapy that is given during radiation treatment.  All of the chemotherapy that is standardly given 
following radiation will occur, along with the normal monitoring during the chemotherapy treatment 
This is shown in the following pictures: 
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Information about the standard chemotherapy and associated monitoring is included at the end of this 
consent form. 
How long will you be in the study? 
The chemotherapy treatment will last for about one year. After the completion of treatment, you will be 
followed for an additional 5 years. 
4. 
What are the risks or discomforts of the study? 
The major risk of this study is that by not giving the radiation treatment, your tumor will come back.  If 
this happens, more treatment could be given including more surgery, radiation therapy and more 
chemotherapy.  However, it is possible that despite given more treatment if the tumor comes back, your 
doctors will not be able to treat the tumor and you would die of your disease or a complication of this 
treatment. 
Information about the risks of the standard chemotherapy are included at the end of this consent form.  
These risks would be the same whether you agree to participate in this study or not. 
5. 
Are there risks related to pregnancy? 
Women should not become pregnant and men should not father a baby while on this study because the 
drug(s) in this study can be bad for an embryo or fetus. If you or your partner can get pregnant, it is 
important for you to use birth control or not have sex while on this study. Check with your study doctor 
about what kind of birth control methods to use and how long to use them. Some birth control methods 
might not be approved for use in this study.  
Women should not breastfeed a baby while on this study. Also check with your doctor about how long 
you should not breastfeed after you stop the study treatment(s). 
6. 
Are there benefits to being in the study? 
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You may or may not benefit from joining this research study.  If we are able to successfully treat your 
tumor without the use of radiation, you will not have any of the short term or long term side effects of 
radiation treatment.  
We hope the information learned from this study will benefit other patients with medulloblastoma in the 
future. 
7. 
What are your options if you do not want to be in the study? 
If you do not want to participate in this study, your alternative is to receive the standard therapy for Wnt-
positive medulloblastoma or to participate in a different research study.  Your doctor(s) will discuss 
these options with you. 
You do not have to join this study.  If you do not join, your care at Johns Hopkins will not be affected. 
8. 
Will it cost you anything to be in this study? 
No. 
9. 
Will you be paid if you join this study? 
No. 
10. 
Can you leave the study early? 
x 
You can agree to be in the study now and change your mind later.   
x 
If you wish to stop, please tell us right away. 
x 
Leaving this study early will not stop you from getting regular medical care.  
x 
If you leave the study early, Johns Hopkins may use or give out your health information that it already 
has if the information is needed for this study or any follow-up activities. 
11. 
Why might we take you out of the study early? 
You may be taken out of the study if: 
x Your cancer gets worse or the side effects from the study drug are too dangerous. 
x Staying in the study would be harmful. 
x It is not in your best interest to do so. 
x You need treatment not allowed in this study. 
x You fail to follow instructions. 
x You become pregnant. 
x The study is cancelled. 
There may be other reasons that we don’t know at this time to take you out of the study.
12. 
How will your privacy be protected?  
We have rules to protect information about you.  Federal and state laws and the federal medical Privacy 
Rule also protect your privacy.  By signing this form you provide your permission, called your 
“authorization,” for the use and disclosure of information protected by the Privacy Rule.
The research team working on the study will collect information about you.  This includes things learned 
from the procedures described in this consent form.  They may also collect other information including 
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your name, address, date of birth, and information from your medical records ([which may include 
information about HIV, drug, alcohol or STD treatment, genetic test results, or mental health treatment).
The research team will know your identity and that you are in the research study.  Other people at Johns 
Hopkins, particularly your doctors, may also see or give out your information. We make this information 
available to your doctors for your safety.    
People outside of Johns Hopkins may need to see or receive your information for this study.  Examples 
include government agencies (such as the Food and Drug Administration), safety monitors, other sites in 
the study and companies that sponsor the study. If you are in a cancer study that receives federal 
funding, the National Cancer Institute (NCI) now requires that we report identifiable information (such 
as, zip code) about your participation.  You may contact the NCI if you have questions about how this 
information is used.  
We cannot do this study without your authorization to use and give out your information.  You do not 
have to give us this authorization.  If you do not, then you may not join this study. 
We will use and disclose your information only as described in this form and in our Notice of Privacy 
Practices; however, people outside Johns Hopkins who receive your information may not be covered by 
this promise or by the federal Privacy Rule.  We try to make sure that everyone who needs to see your
information keeps it confidential – but we cannot guarantee that your information will not be re-
disclosed. 
The use and disclosure of your information has no time limit. You may revoke (cancel) your permission 
to use and disclose your information at any time by notifying the Principal Investigator of this study by 
phone or in writing.  If you contact the Principal Investigator by phone, you must follow-up with a 
written request that includes the study number and your contact information.  The Principal 
Investigator’s name, address, phone and fax information are on page one of this consent form. 
If you do cancel your authorization to use and disclose your information, your part in this study will end 
and no further information about you will be collected. Your revocation (cancellation) would not affect 
information already collected in the study, or information we disclosed before you wrote to the Principal 
Investigator to cancel your authorization. 
13. 
Will the study require any of your other health care providers to share your health 
information with the researchers of this study?    
As a part of this study, the researchers may ask to see your health care records from your other health 
care providers.   
x You will be asked to give us a list of other health care providers that you use.  
14. 
What treatment costs will be paid if you are injured in this study?  
Johns Hopkins does not have a program to pay you if you are hurt or have other bad results from being 
in the study. However, medical care at Johns Hopkins is open to you as it is to all sick or injured people. 
x If you have health insurance: The costs for any treatment or hospital care you receive as the 
result of a study-related injury will be billed to your health insurer. Any costs that are not paid 
for by your health insurer will be billed to you. 
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x If you do not have health insurance: You will be billed for the costs of any treatment or hospital 
care you receive as the result of a study-related injury. 
By signing this form you will not give up any rights you have to seek compensation for injury. 
15. 
What other things should you know about this research study? 
a. What is the Institutional Review Board (IRB) and how does it protect you?  
The Johns Hopkins Medicine IRB is made up of: 
x Doctors
x Nurses
x Ethicists
x Non-scientists
x and people from the local community. 
The IRB reviews human research studies. It protects the rights and welfare of the people taking part 
in those studies.  You may contact the IRB if you have questions about your rights as a participant or 
if you think you have not been treated fairly.  The IRB office number is 410-955-3008. You may 
also call this number for other questions, concerns or complaints about the research. 
When the Johns Hopkins School of Medicine Institutional Review Board (IRB) reviews a study at 
another site, that site (institution) is solely responsible for the safe conduct of the study and for 
following the protocol approved by the Johns Hopkins IRB.   
b. What do you do if you have questions about the study?    
Call the principal investigator, Dr. Kenneth Cohen at 410-614-5055. If you wish, you may contact 
the principal investigator by letter or by fax.  The address and fax number are on page one of this 
consent form. If you cannot reach the principal investigator or wish to talk to someone else, call the 
IRB office at 410-955-3008.   
If you are taking part at All Children’s Hospital, call Dr. Stacie Stapleton at 727-767-4176.
c. What should you do if you are injured or ill as a result of being in this study?  
If you think you are injured or ill because of this study, call Dr. Kenneth Cohen at 410-614-5055
during regular office hours.  
If you have an urgent medical problem related to your taking part in this study, call 410-955-6070 
and ask for the Pediatric Oncologist on-call.  This number is available 24 hours a day including 
weekends and holiday.  
If you are taking part at All Children’s Hospital and you have a medical problem related to your 
taking part in this study, call Dr. Stacie Stapleton at 727-767-4176. If this doctor is not available, the 
operator will page the “on call physician.”
d. What happens to Data and Biospecimens that are collected in the study?  
Johns Hopkins and our research partners work to understand and cure diseases.  The biospecimens 
and/or data you provide are important to this effort. 
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If you join this study, you should understand that you will not own your biospecimens or data, and 
should researchers use them to create a new product or idea, you will not benefit financially.  
With appropriate protections for privacy, Johns Hopkins may share your biospecimens and 
information with our research sponsors and partners.   
16. 
Assent Statement 
This research study has been explained to my child in my presence in language my child can understand.  
He/she has been encouraged to ask questions about the study now and at any time in the future.
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17. 
What does your signature on this consent form mean?  
Your signature on this form means that: You understand the information given to you in this form; you accept the 
provisions in the form and you agree to join the study. You will not give up any legal rights by signing this 
consent form.
WE WILL GIVE YOU A COPY OF THIS SIGNED AND DATED CONSENT FORM
________________________________________________________________________________________________________________________ 
Signature of Parent                                                                           (Print Name)                                                 
 
Date/Time  
________________________________________________________________________________________________________________________ 
Signature of Person Obtaining Consent                                                  (Print Name)                                               
 
Date/Time 
________________________________________________________________________________________________________________________ 
Signature of Legally Authorized Representative (LAR)                        (Print Name) 
 
Date/Time  
For CHILD PARTICIPANT 
________________________________________________________________________________________________________________________ 
Description of LAR’s authority under state or applicable local law to act as surrogate health care                                               
Date/Time 
decision-maker for child research participant (for example, Legal Guardian, court-ordered representative) 
________________________________________________________________________________________________________________________ 
Signature of Parent #2                                                                            (Print Name) 
 
Date/Time 
(required if DHHS 45 CFR 46.406 or   46.407/FDA 21 CFR 50.53 or 50.54 study)   
________________________________________________________________________________________________________________________ 
Signature of Child Participant (optional unless IRB required)              (Print Name)                                        
 
Date/Time 
________________________________________________________________________________________________________________________ 
Signature of Witness to Consent Procedures                                         (Print Name) 
 
Date/Time 
(optional unless IRB or Sponsor required) 
I have received the separate Insurance and Research Participant Financial Responsibility Information Sheet.   
___________________________________________________________________________________________________________ 
Signature of Participant, LAR or Parent/Guardian                               (Print Name)                                                        Date/Time 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN 
TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC 
A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED). 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT OF RESEARCH 
PARTICIPANTS. 
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DOCUMENTATION OF PHYSICIAN/MID-LEVEL PROVIDER CONSENT 
My signature below indicates that I have discussed the risks, benefits, and alternatives, answered any 
questions, and believe the participant is able to make an informed choice to join the study.
________________________________________________________________________________________________________________________ 
Signature of Physician/Mid-Level Provider                     (Print Name)                                                                     
 
Date/Time   
 
________________________________________________________________________________________________________________________ 
Signature of Parent                                                 (Print Name)                                                                    
 
Date/Time 
________________________________________________________________________________________________________________________ 
Signature of Legally Authorized Representative (LAR)                        (Print Name) 
 
Date/Time  
For CHILD PARTICIPANT 
________________________________________________________________________________________________________________________ 
Description of LAR’s authority under state or applicable local law to act as surrogate health care                                               
Date/Time 
decision-maker for child research participant (for example, Legal Guardian, court-ordered representative) 
________________________________________________________________________________________________________________________ 
Signature of Parent #2                                                                            (Print Name) 
 
Date/Time 
(required if DHHS 45 CFR 46.406 or   46.407/FDA 21 CFR 50.53 or 50.54 study)   
________________________________________________________________________________________________________________________ 
Signature of Child Participant (optional unless IRB required)              (Print Name)                                        
 
Date/Time 
________________________________________________________________________________________________________________________ 
Signature of Witness to Consent Procedures                                         (Print Name) 
 
Date/Time 
(optional unless IRB or Sponsor required) 
 
 
NOTE: A COPY OF THE SIGNED, DATED CONSENT FORM MUST BE KEPT BY THE PRINCIPAL INVESTIGATOR; A COPY MUST BE GIVEN 
TO THE PARTICIPANT; IF YOU ARE USING EPIC FOR THIS STUDY A COPY MUST BE FAXED TO 410-367-7382; IF YOU ARE NOT USING EPIC 
A COPY MUST BE PLACED IN THE PARTICIPANT’S MEDICAL RECORD (UNLESS NO MEDICAL RECORD EXISTS OR WILL BE CREATED). 
ONLY CONSENT FORMS THAT INCLUDE THE JOHNS HOPKINS MEDICINE LOGO CAN BE USED TO OBTAIN THE CONSENT OF RESEARCH 
PARTICIPANTS. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Addendum to Consent Form Describing the Standard of Care Chemotherapy 
As explained in the consent form above, all of the chemotherapy being given on this protocol will be recommended 
whether you choose to participate in this study or not.   
For this research, standard chemotherapy should begin within 30 days from the time of surgery.  
There will be 9 cycles of chemotherapy. There are two different kinds of cycles given. They are referred to as A and B. 
Cycle A lasts for 6 weeks and Cycle B lasts for 4 weeks. B cycles are given after the completion of two A cycles.  
Below are the details of the drugs and schedules for A and B cycles. 
Cycle A (This cycle lasts 42 days) 
x 
Lomustine (CCNU) is given by mouth on Day 1. 
x 
Vincristine is given directly into a vein (IV) over one minute or using a minibag over several minutes by some 
institutions on Days 1, 8, and 15. 
x 
Cisplatin is given directly into a vein over 8 hours on Day 1 
Cycle B (This cycle lasts 28 days) 
x 
Cyclophosphamide is given into a vein over 1 hour on Days 1 and 2. 
x 
MESNA, a drug to protect the bladder from the effects of cyclophosphamide, will be given 15 minutes before 
each dose of cyclophosphamide and repeated at 3 and 6 hours. 
x 
Vincristine is given directly into a vein directly into the vein (IV) over one minute or using a minibag over several 
minutes by some institutions on Days 1 and 8. 
You may also get a supportive care drug called a myeloid growth factor (filgrastim [G-CSF] or pegfilgrastim). This drug 
will help your blood counts recover after the chemotherapy is given.  
Procedures that are part of regular cancer care and will be done even if you do not join the study: 
Before treatment on this study begins and while receiving treatment, you will be given a series of standard medical 
tests. These include: 
• 
Physical exams 
• 
Blood tests  
• 
Tests of kidney function  
• 
Tests of liver function  
• 
Tests of hormone function 
• 
Hearing tests  
• 
Magnetic Resonance Imaging (MRI) of brain and spine.  
• 
Evaluation of cerebral spinal fluid (CSF) taken by lumbar puncture* 
• 
Neuropsychological testing 
What are the risks or discomforts of the standard chemotherapy? 
While on the study, you are also at risk for the side effects described below. You should discuss these with the study 
doctor and/or your regular doctor. There also may be other side effects that we cannot predict. Other drugs will be 
given to make side effects less serious and uncomfortable. Many side effects go away shortly after the therapy is 
completed, but in some cases side effects can be serious or long-lasting or permanent. In rare cases, the side effects 
can lead to death.  Other unknown side effects may occur. You will be watched closely and the treatment will be 
discontinued if serious side effects develop. 
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H,5%XSORDGHG
Template Version Date April 2010 
 
Insurance and Research Participant Financial Responsibility 
Information Sheet  
 
Clinical Research Study Title:  
Pilot Study Assessing the Feasibility of a Surgery and Chemotherapy-Only Approach in the Upfront 
Therapy of Children with Wnt Positive Standard Risk Medulloblastoma 
Principal Investigator: Kenneth Cohen MD MBA  
  
eIRB # : NA_00091840  
 
 
  
Date: 04/23/2014 
PRA Review and Date: 09/26/2014 – CIR00004694 v2
 
The following procedures, tests, drugs or devices are part of this research and will be supplied free of 
charge by the study:
o
Pathology Central Review 
o
Radiology Central Review 
o
Central Neuropathologic Analysis (Wnt 
Tumor Testing) 
o
Sequencing of Tumor Samples for 
Mutations of ȕ-Catenin, optional 
o
Storage of Tumor Samples & Blood for 
Future Research Studies, optional 
You and/or your health insurer will be responsible for all other procedures, tests, drugs or devices that are 
part of this study such as the following: 
o
MRI Brain (with contrast) 
o
MRI Spine 
o
CSF Evaluation 
o
Audiogram 
o
GFR or CrCl or Serum Creatinine based on 
age/gender 
o
CBC, Diff and Platelet 
o
Liver Function, BUN, Creatinine, 
Electrolytes (Ca, Mg) 
o
History & Physical Exam (with neurological 
exam) 
o
Endocrinology Review 
o
Pregnancy Test 
o
Central Venous Catheter 
o
Administration of Study Drugs 
o
Cisplatin IV 
o
Lomustine PO 
o
Vincristine IV 
o
Cyclophosphamide IV 
o
Mesna IV 
o
Filgrastim (G-CSF) or Pegfilgrastim 
o
Hydration 
o
Mannitol IV 
If you have health insurance, you will be responsible for any co-pays or deductibles not covered by your 
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J1403

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
J1403 - Pilot Study of a Surgery and Chemotherapy-Only 
Approach in the Upfront Therapy of Children with Wnt Positive 
Standard Risk Medulloblastoma 
 
NCT02212574 
 
September 12, 2016 
 


NA_00091840 (J1403) CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 

PILOT STUDY OF A SURGERY AND CHEMOTHERAPY-ONLY APPROACH IN THE 
UPFRONT THERAPY OF CHILDREN WITH WNT POSITIVE STANDARD RISK 
MEDULLOBLASTOMA 
JHU Protocol #: J1403/NA_00091840 
Study Phase: Pilot 
Study Products: None 
Protocol Chair/Principal Investigator: Kenneth J. Cohen, MD, MBA 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
 
Co-Principal Investigators:  Pratiti Bandopadhayay, MBBS, PhD 
 
 
 
 
 
 
 
 
 
 
Susan Chi, MD 
 
Dana-Farber Cancer Institute 
Harvard Medical School 
 
Co-Investigators: 
Dr Mark Kieran, Dana-Farber Cancer Institute   
Statistician: Dr Wendy London, Dana-Farber Cancer Institute   
Coordinating Center  
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University 
Bloomberg 11379 
1800 Orleans St. 
Baltimore, MD 21287 
Phone: 410-614-5055 
kcohen@jhmi.edu 
 
IRB: Institutional Review Board 
Johns Hopkins School of Medicine 
1620 McElderry Street 
Reed Hall, Suite B-130 
Baltimore, MD 21205-1911 
 
Protocol Revision Record 
Version #1: December 19, 2013 
Version #2: February 17, 2014 
Version #3: August 25, 2014 (Amendment #1) 
Version #4: September 14, 2015 (Amendment #2) 
Version #5: April 28, 2016 (Amendment #3) 
Version #6: September 12, 2016 (Amendment #4) 
 


 
 
 
 
NA_00091840 (J1403) CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Dr Amy Smith 
M D Anderson Cancer Center- Orlando 
 
Pediatric Hematology/Oncology 
 
92 West Miller MP 318 
Orlando, FL 32806 
 
 
USA 
 
Phon
e 
(321) 841-8588 
 
 
EMai 
amy.smith@orlandohealth.com 
 
 
Fax: 
(321) 841-8560 
 
 
Dr Kellie Nazemi 
Oregon Health and Science University 
 
Pediatric Hematology/Oncology 
 
3181 SW Sam Jackson Park Road 
Mail Code: CDRCP 
Portland, OR 97239-3098 
 
 
USA 
 
Phone: 
(503) 494-1543 
 
 
EMail: 
nazemik@ohsu.edu 
 
 
Fax: 
503 494-0714 
 
 
 
Dr Joshua Rubin 
 
Washington University School of Medicine 
 
Pediatric Hematology/Oncology 
 
1 Children's Place, 9 South 
St. Louis, MO 63110 
 
 
USA 
 
Phone: 
314 454-6018 
 
 
EMail: 
rubin_j@kids.wustl.edu 
 
 
Fax: 
314 454-2780 
 
 
Dr Sarah Leary 
Seattle Children's Hospital 
 
Hematology/Oncology 
 
4800 Sand Point Way NE 
M/S B-6553 
Seattle, WA 98105 
 
 
USA 
 
Phone: 
(206) 987-2106 
 
 
EMail: 
sarah.leary@seattlechildrens.org 
 
 
Fax: 
(206) 987-3946 
 
 
 
Dr Kathleen Dorris 
 
Children's Hospital Colorado 
 
Center for Cancer & Blood Disorders 
 
13123 East 16th Avenue B115 
Aurora, CO 80045 
 
 
USA 
 
Phone: 
720 777-6772 
 
 
EMail: 
kathleen.dorris@childrenscolorado.org 
 
 
Fax: 
720 777-7279 
 
 
 
Dr Stacie Stapleton 
All Children's Hospital 
 
Pediatric Hematology/Oncology 
 
601 5th Street South 
Suite 140 
St. Petersburg, FL 33701 
 
USA 
 
Phone: 
727 767-4176 
 
 
EMail: 
Stacie.Stapleton@allkids.org 
 
 
Fax: 
727 767-4379 
 
 
Dr Jason Fangusaro 
 
Ann and Robert H Lurie Children's Hospital of Chicago 
 
Hematology/Oncology 
 
225 E Chicago Ave Box # 30 
Chicago, IL 60611 
 
USA 
 
Phone: 
(312) 227-4844 
 
 
EMail: 
JFangusaro@luriechildrens.org 
 
 
Fax: 
(312) 227-9756 
 
 
 
Dr Tobey MacDonald 
Children's Healthcare of Atlanta - Egleston 
 
Pediatric Neuro-Oncology 
 
Aflac Cancer Ctr & Blood Disorders Service 
2015 Uppergate Drive NE, Suite 442 
Atlanta, GA 30322 
 
USA 
 
Phone: 
(404) 727-1447 
 
 
EMail: 
tobey.macdonald@emory.edu 
 
 
Fax: 
(404) 727-4455 
 
 
 
Dr. Derek Hanson 
   Hackensack University Medical Center 
Program Head, Pediatric Neuro-oncology 
Institute for Pediatric Cancer and Blood 
Disorders 
Joseph M. Sanzari Children’s Hospital 
30 Prospect Avenue 
Hackensack, NJ 07601 
USA 
Phone:   
551-996-5437 
Fax:   
 
201-487-7340 
Email:   
dhanson@hackensackumc.org 


NA_00091840 (J1403) CONFIDENTIAL 
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1
1.   
 
SCHEMA 
 
 
Chemotherapy dosing, schedule and administration will be the same as was used for the COG 
ACNS0331 standard risk medulloblastoma. 
Patients with classical non-metastatic Wnt positive medulloblastoma will be identified by the 
presence of monosomy 6 by array CGH, and gene transcript detection by NanoString. 
Pathology samples will be centrally analyzed at Johns Hopkins to confirm Wnt-positivity and 
radiology studies will be prospectively reviewed at DFCI.  Results of central review will be 
released within fourteen days, and before the chemotherapy is due to start (by day 31 following 
definitive surgery). 
 


 
 
 
 
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2
Local teams should proceed with radiation planning so that if central analysis does not confirm 
Wnt-positivity or patient/family elect not to forego irradiation there is no delay in the 
commencement of standard therapy. 
 
 
 
 
 
 


 
 
 
 
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3
 
Table of Contents 
1. SCHEMA
1
2. OBJECTIVES
6
2.1 STUDY DESIGN
6
2.2 PRIMARY OBJECTIVES
6
2.3 SECONDARY OBJECTIVES
6
3. BACKGROUND AND RATIONALE
7
3.1 BACKGROUND
7
3.2 RATIONALE
10
4. PARTICIPANT SELECTION
10
4.1 ELIGIBILITY CRITERIA
11
4.2 SCREENING FOR ENROLLMENT ON TREATMENT PORTION
11
4.3 INCLUSION OF WOMEN, MINORITIES AND OTHER UNDERREPRESENTED POPULATIONS
13
4.4 NEUROPATHOLOGICAL GUIDELINES AND SPECIMEN REQUIREMENTS.
13
4.5 MANDATORY SUBMISSION OF TISSUE FOR RAPID CENTRAL PATHOLOGY REVIEW
14
4.6 CENTRAL RADIOLOGY REVIEW
14
5. REGISTRATION PROCEDURES
17
5.1 REGISTRATION FOR SCREENING
17
5.2 REGISTRATION FOR TREATMENT
17
6. MULTICENTER GUIDELINES
18
7. QUALITY ASSURANCE
19
8. DATA SUBMISSION
20
9. ADVERSE EVENT REPORTING
20
10. TREATMENT PLAN
23
10.1 PRE-TREATMENT HEMATOLOGIC CRITERIA (PLEASE SEE SECTION 11.2 FOR OTHER 
CRITERIA FOR DOSE MODIFICATIONS OR DELAYS)
26
10.1.1 CYCLE 1, DAY 1
26
10.1.2 SUBSEQUENT CYCLES
26
10.2 AGENT ADMINISTRATION
26
10.2.1 LOMUSTINE
26
10.2.2 CISPLATIN
26
10.2.3 VINCRISTINE
27


 
 
 
 
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4
10.2.4 CYCLOPHOSPHAMIDE
27
10.2.5 MESNA
28
10.3 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES
28
10.4 DURATION OF THERAPY
29
10.5 DURATION OF FOLLOW UP
29
10.6 CRITERIA FOR REMOVAL FROM STUDY
29
11. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS
30
11.1 ANTICIPATED TOXICITIES
30
11.1.1 ADVERSE EVENT LISTS FOR LOMUSTINE
30
11.1.2 ADVERSE EVENT LIST FOR CISPLATIN
32
11.1.3 ADVERSE EVENT LIST FOR VINCRISTINE
33
11.1.4 ADVERSE EVENT LIST FOR CYCLOPHOSPHAMIDE
34
11.2 TOXICITY MANAGEMENT, DOSE MODIFICATIONS AND DELAYS
35
11.2.1 NEUROTOXICITY
35
11.2.2 HEPATOTOXICITY
35
11.2.3 HEMATOLOGICAL TOXICITY
35
11.2.4 HEMORRHAGIC CYSTITIS (HEMATURIA)
36
11.2.5 NEPHROTOXICITY
38
11.2.6 OTOTOXICITY
39
12. DRUG FORMULATION AND ADMINISTRATION
39
12.1 CISPLATIN
39
12.2 CYCLOPHOSPHAMIDE
41
12.3 LOMUSTINE
43
12.4 VINCRISTINE
45
13. REQUIRED AND RECOMMENDED EVALUATIONS
48
13.1 EVALUATIONS DURING THERAPY THAT MUST BE REPORTED TO THE COORDINATING CENTER48
13.2 RECOMMENDED EVALUATIONS DURING THERAPY THAT ARE NOT REPORTED TO THE 
COORDINATING CENTER
49
13.3 REQUIRED EVALUATIONS FOLLOWING COMPLETION OF THERAPY THAT MUST BE REPORTED 
TO THE COORDINATING CENTER
50
13.4 RECOMMENDED EVALUATIONS FOLLOWING THERAPY THAT ARE NOT REPORTED TO THE 
COORDINATING CENTER
51
14. MEASUREMENT OF EFFECT
52
14.1 ANTITUMOR EFFECT
52
14.1.1 RESPONSE ASSESSMENT, DEFINITIONS
52
15. ADVERSE EVENT REPORTING REQUIREMENTS
53
15.1 DEFINITIONS
53
15.1.1 ADVERSE EVENT (AE)
53
15.1.2 SERIOUS ADVERSE EVENT (SAE)
53
15.1.3 EXPECTEDNESS
55
15.1.4 ATTRIBUTION
55


 
 
 
 
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5
15.2 PROCEDURES FOR SAE RECORDING AND REPORTING
56
15.3 REPORTING REQUIREMENTS
57
15.4 REPORTING TO THE STUDY TEAM
57
15.4.1 SERIOUS ADVERSE EVENT REPORTING
57
15.4.2 NON-SERIOUS ADVERSE EVENT REPORTING
58
15.5 REPORTING TO THE INSTITUTIONAL REVIEW BOARD (IRB)
59
15.6 REPORTING TO THE FOOD AND DRUG ADMINISTRATION (FDA)
59
15.7 REPORTING TO THE NIH OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA)
59
15.8 REPORTING TO THE INSTITUTIONAL BIOSAFETY COMMITTEE (IBC)
59
15.9 REPORTING TO HOSPITAL RISK MANAGEMENT
59
15.10 MONITORING OF ADVERSE EVENTS AND PERIOD OF OBSERVATION
60
16. DATA AND SAFETY MONITORING
60
16.1 DATA REPORTING
60
16.1.1 DATA SUBMISSION
61
16.2 SAFETY MEETINGS
61
16.3 AUDITING/MONITORING
62
17. REGULATORY CONSIDERATIONS
63
17.1 PROTOCOL REVIEW AND AMENDMENTS
63
17.2 INFORMED CONSENT
64
17.3 ETHICS AND GOOD CLINICAL PRACTICE (GCP)
64
17.4 STUDY DOCUMENTATION
65
17.5 RECORDS RETENTION
65
17.6 MULTI-CENTER GUIDELINES
67
18. STATISTICAL CONSIDERATIONS
68
19. PUBLICATION PLAN
69
20. APPENDIX A: PERFORMANCE STATUS CRITERIA
70
21. REFERENCES
71
 
 
 
 


 
 
 
 
NA_00091840 (J1403) CONFIDENTIAL 
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6
2. 
OBJECTIVES 
This is a prospective, single arm, multi-center international pilot study designed to assess the 
effectiveness based on progression free survival (PFS) of a surgery and chemotherapy only 
approach for the treatment of children with non-metastatic Wnt positive medulloblastoma. This 
protocol tests the hypothesis that children with Wnt positive medulloblastoma can be treated 
effectively with maximum surgery and chemotherapy only without the need for radiation. Ten 
evaluable children will be enrolled to this study.  This pilot study will provide information 
regarding the safety of this approach to allow for the planning of a larger clinical trial to assess 
the outcomes of children treated without radiation.   Chemotherapy will be based on the current 
standard chemotherapy approach for average risk medulloblastoma. Primary outcome measure 
will be progression free survival.   
2.1 
Study Design 
This is a prospective, single arm pilot study which will enroll ten evaluable children (it is 
anticipated that up to three children might be inevaluable, such that 13 children may be 
enrolled).  Children will be treated with maximal surgical resection followed by chemotherapy.  
Pathology and radiology will be centrally reviewed at enrollment to ensure only children 
confirmed to have a Wnt-positive, non-metastatic medulloblastoma are enrolled on study. 
2.2 
Primary Objectives 
To determine the occurrence of relapse, progression, or death due to disease in the 
first two years after study enrollment of newly diagnosed children with non-metastatic, 
standard risk, Wnt positive medulloblastoma with a chemotherapy-only approach.  
Primary outcome measure of this study will be progression-free survival.
2.3 
Secondary Objectives 


 
 
 
 
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7
1. To describe overall survival of children with newly diagnosed non-metastatic, 
standard risk, Wnt positive medulloblastoma who are treated with a maximal 
surgical resection and chemotherapy-only approach. 
2. To determine the pattern of failure in those children with progressive disease. 
3. To correlate the frequency of nuclear E-catenin with other measures of Wnt-
positivity 
3. 
Background and Rationale 
3.1 
Background  
Medulloblastoma is the most common malignant central nervous system tumor in 
childhood.  Historically the tumors have been classified according to Chang staging and 
histological appearance.  It has been recently recognized that medulloblastoma includes a 
heterogeneous group of tumors that carry distinct genomic signatures and prognostic 
features (1-5). 
Children with Wnt positive medulloblastoma have been recognized to have an excellent 
prognosis.  Wnt positive medulloblastomas account for approximately 10% of all pediatric 
medulloblastomas, are most commonly of the classical histology subtype and carry a 
favorable prognosis when compared to other molecular signatures such as MYC 
amplification (4, 6).  Children with Wnt positive medulloblastoma are generally older, with a 
median age at diagnosis of 10.4 years (range 6-20)(6).   Retrospective analysis has 
demonstrated long term progression free survival rates of up to 90% in children with non-
metastatic Wnt positive medulloblastoma (7, 8).   
The Wnt positive subgroup of tumors can be identified by immunohistochemistry staining 
for nuclear E-catenin accumulation (5, 7-9).  This provides an easily reproducible method of 


 
 
 
 
NA_00091840 (J1403) CONFIDENTIAL 
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8
identifying Wnt positive medulloblastoma with paraffin embedded material. However, 
findings and interpretation can be challenging, leading to inconsistent results. 
The current therapeutic approach to standard risk medulloblastoma involves maximal 
surgical resection, adjuvant radiation (focal boost of 30.6Gy with craniospinal irradiation of 
23.40Gy and concurrent Vincristine) followed by maintenance chemotherapy comprising 
vincristine, cisplatin, CCNU and cyclophosphamide.  This approach is for treatment of 
children with standard risk medulloblastoma and currently includes all of the molecular 
subtypes.   
Treatment results for five year overall survival rates in standard risk medulloblastoma range 
between 70-80% (10, 11), however long term morbidity from therapy, in particular radiation 
therapy remains of concern.  Treatment with radiation therapy has been correlated with 
neurocognitive morbidity[Ris, 2001 #8, 12) increases the risk of secondary radiation 
induced tumors including meningiomas and high grade gliomas (13, 14), endocrinopathy, 
vasculopathy and growth deficits.  
Accordingly, strategies to reduce doses of craniospinal and posterior fossa radiation have 
been investigated.  The current COG study for standard risk medulloblastoma ACNS 0331 
is investigating further reduction in craniospinal doses of irradiation with a randomization of 
CSI doses of 23.40 Gy or 18 Gy. 
In young children, infant protocols have demonstrated that radiation can be safely delayed 
or omitted with the use of post-operative chemotherapy.  Studies have shown that a large 
number of children can be salvaged on relapse after upfront chemotherapy only treatment 
(15-17).  Using a chemotherapy regimen containing carboplatin, procarbazine, etoposide, 
cisplatin, vincristine and cyclophosphamide, the French SFOP trial treated children with 
medulloblastoma with a chemotherapy only approach.  These children were infants and 
thus unlikely to be Wnt positive.  Salvage therapy included high dose chemotherapy with 


 
 
 
 
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9
busulfan and thiotepa followed by involved field irradiation therapy.  Using this approach, 
children with non-metastatic disease with no radiological residual disease at diagnosis had 
a progression free survival of 29% (95% CI 18-44) with a 5 year overall survival of 73% (59-
84%)(16).  Importantly although the event free survival was low for these children with non 
Wnt medulloblastoma, this study was important in demonstrating that children with 
medulloblastoma who progressed after treatment with a chemotherapy only approach were 
able to be salvaged with further chemotherapy and involved field irradiation therapy (18). 
Head Start I and II protocols comprising maximal surgical resection followed by five cycles 
of induction chemotherapy with Cyclophosphamide, Etoposide, Cisplatin and Vincristine 
followed by myeloablative stem cell support consolidation were tested in an endeavor to 
omit irradiation therapy in young children (15).  Using this treatment approach, the five year 
event free survival for children with non-metastatic medulloblastoma was 52% (r11) and 
again children that relapsed were able to be salvaged, with the overall five year survival of 
children treated with this approach of 70% (r10)(15). 
Given the good outcomes reported in children with Wnt positive medulloblastoma with the 
current standard therapy, the possibility of reducing long-term therapy related morbidity by 
reducing radiation therapy is being considered in this protocol.  Treatment strategies that 
omit radiation are attractive as they stand to reduce the devastating long term morbidity 
associated with radiation therapy including neuro-cognitive deficits, radiation induced 
malignancies, endocrinopathy, vasculopathy and growth deficits.  
Children will be treated on this protocol with chemotherapy for standard risk 
medulloblastoma.  The chemotherapy is as per the COG ACNS0331 clinical trial for standard 
risk medulloblastoma.  Dosing and modification for toxicity is based on the chemotherapy 
regimen of COG ACNS0331.  This chemotherapy is the standard approach in the USA as 


 
 
 
 
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10
the chemotherapy regimen for children with standard risk medulloblastoma, and thus will be 
able to be administered by all centers.   
 
3.2 
Rationale 
 
The rationale for this study is as follows: 
 
1. Children with Wnt positive medulloblastoma have an excellent overall survival and can 
be easily identified at diagnosis. 
2. The current treatment strategy for standard risk medulloblastoma includes radiation 
therapy, which carries significant long-term morbidity including neuro-cognitive deficits, 
secondary high-grade malignancy, vasculopathy, endocrinopathy, and growth deficit. 
3. Chemotherapy only approaches for medulloblastoma in infants have demonstrated that 
many children with medulloblastoma can be cured without radiation.  For those that 
relapse, they can be salvaged with therapy including radiation therapy.  
We will therefore examine the progression free survival of children with non-metastatic 
Wnt positive medulloblastoma treated without radiation.  If children progress without 
radiation, radiation therapy can then be used as a component of salvage strategy.  
 
4. 
Participant Selection 
Children with non-metastatic completely resected medulloblastoma will be enrolled on study.  
Wnt positive medulloblastoma will be identified by the presence monosomy 6 by array CGH and 
by gene transcript detection by NanoString.  Central review of pathology and imaging will be 
performed after enrollment, prior to the commencement of therapy to confirm eligibility criteria. 


 
 
 
 
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11
4.1 
Eligibility Criteria 
The study will be conducted in two parts: 
Screening:  To determine if the tumor meets protocol criteria for non-metastatic Wnt 
positive medulloblastoma 
Treatment: For those subjects whose tumor meets protocol criteria for non-metastatic 
Wnt positive medulloblastoma based on Screening. 
Patients will be consented to Treatment only after screening confirmation of Wnt positive 
medulloblastoma. Patients must be enrolled before chemotherapy commences.  
Treatment must begin by day 31 following definitive surgery. 
4.2 
Screening for enrollment on treatment portion 
Participants must meet the following criteria at Screening to be potential candidates 
for the Treatment portion of the study: 
x 
Children at least 3 years of age and less than or equal to 18 years of age at diagnosis  
x 
Participants must have classical histology posterior fossa medulloblastoma as 
determined by institutional neuro-pathological evaluation.  
x 
Sufficient pathologic material must be available for central analysis and review (see 
Section 4.5 below)  
 
Tumors will be deemed Wnt positive if, at the time of central analysis, there is: 
 
 
 
- Monosomy 6 as determined by array CGH 
- Gene transcript detection by NanoString supporting Wnt+ medulloblastoma  
    - Absence of large-cell, anaplastic histology  
  
- Nuclear E-catenin IHC result will be determined, but not required for the diagnosis 


 
 
 
 
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Participants who meet the Screening requirements must meet the following eligibility 
criteria to participate in the Treatment portion of the study: 
x 
Absence of residual or disseminated disease as defined by the following criteria: 
- Minimal residual disease as determined by post-operative imaging preferably 
performed within 48 hours of resection (and at most 28 days post-surgery), i.e. 
gross total resection or residual disease of <1.5cm2 on post-operative imaging. 
- No evidence of metastatic disease in the brain, spine or CSF.  Assessments must 
include MRI imaging of the brain and spine with and without contrast and a lumbar 
puncture for CSF cytology 
x 
Diagnostic imaging (pre and post contrast) must be forwarded to DFCI for central review 
to confirm eligibility. 
x 
Patients must not have had any radiation therapy or chemotherapy for medulloblastoma 
prior to study enrollment
x 
Patients must have a Lansky performance status of t 30 for children d 10 years of age 
or a Karnofsky performance status of > 30 for children > 10 years of age. 
x 
Participants must have normal organ and marrow function as defined below: 
  
-Hemoglobin greater than 10gm/dL (can be transfused).   
-Hemoglobin < 10gm/dL due to operative blood loss is permitted. 
  
-Absolute neutrophil count > 1,000/uL 
  
-Platelets > 100,000/uL (non-transfused) 
  
-Total bilirubin <1.5 x upper limit normal  
  
-SGOT (AST) or SGPT (ALT) <2.5 x upper limit normal for age 
-Creatinine clearance or radioisotope GFR >70 ml/min/1.73m2 or normal serum 
creatinine for patient’s age and gender


 
 
 
 
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x 
The effects of cisplatin, lomustine, vincristine and cyclophosphamide on the developing 
human fetus are presumed to be teratogenic. For this reason women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier 
method of birth control; abstinence) for the duration of study participation. Should a 
woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. Pregnant or breast-feeding females 
are not eligible for study enrollment.  All females of child-bearing age must have a 
negative pregnancy test before being enrolled on study.  All patients of child-bearing age 
must practice an effective method of birth control whilst undergoing chemotherapy on 
study. 
x 
No history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to cisplatin, lomustine, vincristine or cyclophosphamide. 
x 
Ability to understand and the willingness to sign a written informed consent document for 
both Screening and Treatment.  Signed informed consent must be obtained prior to 
screening or treatment. 
x 
All Institutional, FDA and NCI requirements for human studies must be met. 
x 
Eligibility criteria cannot be waived. 
4.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
 
 
This protocol is open to males and females of all races.
4.4 
Neuropathological guidelines and specimen requirements. 
Tumors will be classified according to the World Health Organization classification of 
central nervous system brain tumors. 
At the time of central neuropathologic analysis, the following criteria will used to classify 
the tumor as a Wnt-positive medulloblastoma (all criteria must be met): 


 
 
 
 
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14
1. 
Histological classification of medulloblastoma that is not large cell/anaplastic 
2. 
Monosomy 6 as determined by array CGH 
3. 
Gene transcript detection by NanoString consistent with Wnt+ medulloblastoma 
4.5 
Mandatory Submission of Tissue for Rapid Central Pathology Review 
Pathology slides (mandatory) should be submitted for rapid central pathology review and 
molecular analyses on all consenting patients with an institutional diagnosis of 
medulloblastoma to confirm eligibility for Treatment.   
The following samples are required: 
1.  Two (2) representative H&E slide supporting the diagnosis of medulloblastoma 
and either: 
2.  Tissue block 
or: 
3. Ten (10) unstained slides on plus glass and ten (10) 10 um shavings 
Results of rapid central review of pathology and molecular classification will be 
available within 14 days of submission. 
Pathology Samples should be sent to: 
Dr. Fausto Rodriguez 
The Johns Hopkins Hospital 
Department of Pathology 
Sheikh Zayed Tower M2101 
1800 Orleans St. 
Baltimore, MD   21231 
Phone 410-955-8378 
Fax 410-614-9310
4.6 
Central radiology review 
Mandatory Submission of Imaging for Rapid Central Radiology Review 


 
 
 
 
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15
The following imaging is required and must be submitted for central review within 
sufficient time to allow for all centralized testing and review to take place prior to Day 
30 following surgery 
1. Pre-operative MRI of the brain with contrast 
2. Post-operative MRI of the brain with contrast 
3. Either pre-operative MRI of the total spine or post-operative MRI of the total spine 
obtained at least 10 days, but no more than 21 days following surgery. 
Results of rapid central review of radiology will be available within 7 days of 
submission. 
De-identified MRI images should be saved on a CD disk (DICOM format) and sent by 
FedEx or courier to: 
Dana-Farber Cancer Institute 
Mark Kieran, MD, PhD, D3154 
450 Brookline Ave 
Boston, MA 02215 
Treating physicians should also notify the investigational team by emailing: 
Pratiti_Bandopadhayay@dfci.harvard.edu 
MRI Brain – Imaging Guidelines (recommended in the absence of an institutional 
standard) 
Recommended sequences: 
 
-Sagittal T1 localizer, 4-5mm skip 1mm 
-Axial FSE T2:4-5mm, skip 0-1mm 
-Axial FLAIR:4-5mm skip 0 (may also do post contrast). Can substitute 2 and 3 with 
axial spin echo proton density/T2, 5mm skip 1mm(if FSET2/FLAIR not available) 
-Axial diffusion:4-5mm skip 0 (single shot, matrix 128 x 128 or 128 x 192, B=1000) 
-Axial T1:4mm skip 1mm 
 


 
 
 
 
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16
Contrast 
-Axial T1: 4-5mm skip 0-1mm 
-Coronal T1:4-5mm skip 0-1mm 
 
Optional sequences: 
Precontrast: 
-sagittal or coronal FSET2, 4-5mm skip 0-1mm, depending on tumor 
configuration/orientation 
 
MRI Spine with contrast – Imaging Guidelines 
1, Whole spine-sagittal T1:3mm skip 0mm 
Technical notes: 
-Acquire 2 separate acquisitions (one cervical and upper thoracic, the second lower 
thoracic and lumbosacral) to optimize placement of presaturation pulse. 
-Phase direction AP, frequency direction SI 
-Place anterior saturation pulse close to the anterior margin of the spinal column-to 
minimize motion artifacts from chest/abdomen. 
-Pixel size 1mm2 or less (example: for 26cm FOV, use 256 x 256 matrix) 
-Keep TE to minimum (<15msecs) 
-Fat saturation not necessary 
 
2, Axial T1 images through the entire spine, 4-5mm thick, skip 1-2mm 
Technical notes: 
-Phase direction RL, frequency direction AP 
-Keep TE to minimum (<15 msecs) 
-Do not interleave 


 
 
 
 
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5. 
REGISTRATION PROCEDURES  
This study will be conducted in accordance with the Sidney Kimmel Comprehensive Cancer 
Center’s Coordinating Center Protocol.
Patient Registration 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an 
institutionally approved IRB consent form.   
All patients must be registered centrally at the Sidney Kimmel Comprehensive Cancer Center.  
5.1 
Registration for Screening 
To register a patient for screening, the following documents must be completed and faxed (443-
287-3975) or e-mailed (Tammy Scott scottta@jhmi.edu) at the Coordinating Center: 
Signed patient consent form for Screening 
x 
Screening registration Form 
The Coordinating Center will review the documents to confirm eligibility.  To complete the 
registration process, the Coordinating Center will: 
x 
assign a patient study number 
x 
register the patient on the study with the Sidney Kimmel Comprehensive 
Cancer Center’s Clinical Research Office 
x 
fax or e-mail the patient study number to the participating site. 
 
5.2 
Registration for Treatment 
To enroll a patient for treatment who has met the screening criteria, the following documents 
must be completed and faxed (443-287-3975) or e-mailed (Tammy Scott scottta@jhmi.edu) at 
the Coordinating Center: 


 
 
 
 
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x 
Signed patient consent form for Treatment 
x 
Treatment eligibility checklist 
The Coordinating Center will review the documents to confirm eligibility.  To complete the 
registration process for Treatment, the Coordinating Center will: 
x 
Register the patient on the Treatment portion of the study with the Sidney 
Kimmel Comprehensive Cancer Center’s Clinical Research Office 
x 
Send a fax or e-mail to the institution confirming eligibility and the last eligible 
start date for treatment. 
 
6. 
Multicenter Guidelines 
 
Protocol Chair 
 
The Protocol Chair is responsible for performing the following tasks: 
x 
Coordinating, developing, submitting, and obtaining approval for the protocol as well 
as its subsequent amendments 
x 
Assuring that all participating institutions are using the correct version of the protocol. 
x 
Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study. 
x 
Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
x 
Reviewing data from all sites 
 
Coordinating Center 
 
The Coordinating Center is responsible for performing the following tasks: 
x 
Ensuring that IRB approval has been obtained at each participating site prior to the 
first patient registration at that site, and maintaining copies of IRB approvals from 
each site. 
x 
Managing central patient registration. 


 
 
 
 
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x 
Collecting and compiling data from each site. 
x 
Establishing procedures for documentation, reporting, and submitting of AE’s and 
SAE’s to the Protocol Chair, and all applicable parties. 
x 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
 
Participating sites are responsible for performing the following tasks: 
x 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
x 
Submitting data to the Coordinating Center. 
x 
Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly. 
x 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol. 
x 
Maintaining regulatory binders on site and providing copies of all required documents 
to the Coordinating Center. 
x 
Collecting and submitting data according to the schedule specified by the protocol. 
7. 
Quality Assurance 
This is a Level 1 study under the SKCCC Data Safety Monitoring Plan.  Data monitoring of this 
protocol will occur on a regular basis with the frequency dependent on the rate of subject 
accrual and the progress of the study.  The protocol will be monitored internally at SKCCC by 
Kenneth J. Cohen, MD, MBA monthly and externally by the SKCCC CRO in accordance with 
SKCCC guidelines.  Trial monitoring and reporting will be done through the Safety Monitoring 
Committee at SKCCC. 
 
Authorized representatives of the Coordinating Center may visit participating sites to perform 


 
 
 
 
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20
audits or inspections, including source data verification.  The purpose of these audits or 
inspections is to systematically and independently examine all trial related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), and 
any applicable regulatory requirements. 
8. 
Data Submission 
Data and/or completed eCRFs must be transmitted to the Coordinating Center following the 
completion of each cycle as detailed in Section 16.1.1.  
9. 
Adverse Event Reporting 
Definition of Adverse Event (AE) 
 
An adverse event is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram).  In clinical trials, from the time of signing an informed 
consent, an AE can include an undesirable medical condition occurring at any time, 
including run-in or washout periods, even if no trial treatment has been administered. 
Definition of Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any trial phase (i.e., run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or 
placebo, that fulfills one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires in-patient hospitalization or prolongation of existing hospitalization 


 
 
 
 
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21
x 
Results in persistent or significant disability or incapacity 
x 
Is a congenital abnormality or birth defect 
x 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
Protocol Chair 
The Protocol Chair is ultimately responsible for the required reporting of all serious 
adverse events. 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance of 
documentation of serious adverse events and is responsible for submitting serious 
adverse event reports to the Protocol Chair promptly.  The Coordinating Center will 
maintain documentation of all serious adverse event reports for each participating site.  
Adverse event reports submitted to the Coordinating Center must be signed and dated 
by the participating site’s Principal Investigator.  The Coordinating Center will provide 
appropriate forms to be used by all participating sites for reporting serious adverse 
events.  Information to be provided must include: 
x 
Subject ID number, and initials 
x 
Date of the event 
x 
Description of the event 
x 
Description of site's response to the event 
x 
Assessment of the subject's condition 
x 
Subject's status on the study (on study, off study, etc.) 
x 
Attribution of event to study drug 
 
Participating Sites 


 
 
 
 
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22
Participating sites are responsible for reporting serious adverse events to their IRB 
according to its specific requirements and to the Coordinating Center as follows: 
Fatal Events whether anticipated or unanticipated, and whether or not related to the 
study must be reported to the Coordinating Center within 24 hours of the 
participating site Principal Investigator's learning of the event. 
 
Progressive Disease as defined as recurrence or progression of medulloblastoma 
within the brain, spine or CSF must be reported within 7 days. 
 
Serious and Unanticipated Adverse Events (considered an adverse event of 
special interest by the treating physician) as defined above must be reported to the 
Coordinating Center within 24 hours of the participating site Principal Investigator's 
learning of the event.  
 
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be reported 
within three (3) working days of the participating site Principal Investigator's 
learning of the event.  
 
Serious adverse event reports are to be faxed to the Coordinating Center at SKCCC. 
Follow-up reports are faxed, mailed, or sent electronically to the Coordinating Center 
as necessary. 
The investigator must also report follow-up information about SAEs within the same 
time frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information 
must also be provided within the same time frames described above. 


 
 
 
 
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23
 
All SAEs must be collected whether or not they are considered causally related to the 
protocol therapy.  Investigators and other site personnel are responsible for reporting all 
casually related SAEs to their IRB and the Protocol Chair. 
10. TREATMENT PLAN  
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from 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. 
 
Treatment will be administered on an inpatient or outpatient basis. Expected toxicities and 
potential risks as well as dose modifications for vincristine, cisplatin, CCNU and 
cyclophosphamide are described in Section 11 (Expected Toxicities and Dosing 
Delays/Dose Modification). No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant’s 
malignancy. 
The chemotherapy backbone of this protocol is the current standard chemotherapy for 
average risk medulloblastoma, which is currently administered widely in multiple centers in 
North America.  Chemotherapy must begin within thirty days of definitive surgery.  A central 
venous catheter is recommended prior to commencement of chemotherapy.  Each cycle 
will begin at full dose when ANC >1000/Pl and platelet count t 75,000/Pl.  Granulocyte 
colony stimulating factor (GCSF) will be used if there is a delay in two consecutive weeks in 
initiating chemotherapy due to neutropenia.   Chemotherapy will be given according to the 


 
 
 
 
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24
following schema of cycles/regimens: 1A, 2A, 3B, 4A, 5A, 6B, 7A, 8A, 9B. Cycle A is for 42 
days and cycle B is for 28 days. 


 
 
 
 
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25
Week/Cycle 
Regimen 
Chemotherapy 
Week 1, Cycle 1 
A (42 Days) 
Cisplatin (75mg/m2) IV over 6 hours day 1 
Lomustine (CCNU) (75mg/m2) orally day 1 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8, 15 
Week 7, Cycle 2 
A (42 Days) 
Cisplatin (75mg/m2) IV over 6 hours day 1 
Lomustine (CCNU) (75mg/m2) orally day 1 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8, 15 
Week 13, Cycle 3 
B (28 Days) 
Cyclophosphamide (1000mg/m2) IV over 1 hour days 1 and 2 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8 
Mesna (360mg/m2/dose) IV infusion over 15-30 minutes starting 15 
minutes prior to, or at the same time as cyclophosphamide (based on 
institutional standards) and then repeated at 4 or 8 hours 
Week 17, Cycle 4 
A (42 Days) 
Cisplatin (75mg/m2) IV over 6 hours day 1 
Lomustine (CCNU) (75mg/m2) orally day 1 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8, 15 
Week 23, Cycle 5 
A (42 Days) 
Cisplatin (75mg/m2) IV over 6 hours day 1 
Lomustine (CCNU) (75mg/m2) orally day 1 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8, 15 
Week 29, Cycle 6 
B (28 Days) 
Cyclophosphamide (1000mg/m2) IV over 1 hour days 1 and 2 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8 
Mesna (360mg/m2/dose) IV infusion over 15-30 minutes starting 15 
minutes prior to, or at the same time as cyclophosphamide (based on 
institutional standards) and then repeated at 4 or 8 hours  
Week 33, Cycle 7 
A (42 Days) 
Cisplatin (75mg/m2) IV over 6 hours day 1 
Lomustine (CCNU) (75mg/m2) orally day 1 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8, 15 
Week 39, Cycle 8 
A (42 Days)
Cisplatin (75mg/m2) IV over 6 hours day 1 
Lomustine (CCNU) (75mg/m2) orally day 1 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8, 15 
Week 45, Cycle 9 
B (28 Days) 
Cyclophosphamide (1000mg/m2) IV over 1 hour days 1 and 2 
Vincristine (1.5mg/m2, maximum 2.0mg) IV push day 1, 8 
Mesna (360mg/m2/dose) IV infusion over 15-30 minutes starting 15 
minutes prior to, or at the same time as cyclophosphamide (based on 
institutional standards) and then repeated at 4 or 8 hours 


 
 
 
 
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10.1 Pre-treatment Hematologic Criteria (please see Section 11.2 for other criteria for 
dose modifications or delays)
10.1.1 Cycle 1, Day 1 
10.1.1.1 ANC >1000/Pl  
10.1.1.2  Platelet count t 75,000/Pl.   
10.1.2 Subsequent Cycles 
10.1.2.1 ANC >1000/Pl  
10.1.2.2  Platelet count t 75,000/Pl.   
10.2 Agent Administration 
10.2.1 Lomustine 
x 
75mg/m2 given orally on day 1 per institutional guidelines 
x 
Doses will be rounded up or down to the nearest 10mg.  Round down for 
doses < *5 and round up for doses  *5 (e.g. 84 mg round to 80 mg; 85 
mg round to 90 mg) 
x 
Doses will be administered on an empty stomach, 1 hour before or 2 
hours after a meal, with oral fluids.  
x 
Doses are usually administered at bedtime.  
10.2.2  Cisplatin 
x 
75mg/m2 given intravenously over 6 hours x 1 dose on Day 1 
x 
Suggested hydration and supportive care 


 
 
 
 
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x 
-2 to 0 hours prehydration 500ml/m2 D5 1/2NS with mannitol 10 GM/m2 at 
250ml/ m2/hr 
x 
0 to 6 hours Cisplatin 75mg/m2 with 10 GM/m2 mannitol in D5 ½ NS 
1000ml/m2 IV at 167 ml/m2/hr for 6 hours. 
x 
6 to 24 hours 
Continue hydration with D5 ½ Normal Saline with 
magnesium sulfate 0.5-1mEq/kg in post-hydration fluid to run at 
125ml/m2/hr for at least 6 hours.  If children tolerating oral intake after 6 
hours the remainder of post hydration can be given orally.  24 hours after 
the cisplatin continue magnesium supplementation. 
x 
Urine output must be monitored during administration of cisplatin. If the 
urine output falls below 3ml/kg/hr for two hours consecutively, mannitol 
0.5g/kg with a 10ml/kg bolus of normal saline are recommended.   
x 
Children are likely to require magnesium supplementation after 
commencing treatment with cisplatin.  Aluminum containing needles and 
giving sets should be avoided because of the risk of precipitation.  
10.2.3 Vincristine 
x 
1.5mg/m2 (maximum dose 2mg) given as an IV push on days 1, and 8 
and 15 (Day 15 dose for Regimen A only).  Doses are to be rounded 
down to the nearest 0.1mg. 
x 
Vincristine is vesicant and should be administered through a central line 
to prevent extravasation 
SPECIAL PRECAUTIONS: Intrathecal injection of vincristine is FATAL.   
10.2.4 Cyclophosphamide 
x 
1000mg/m2 IV over 1 hour day 1 and 2 


 
 
 
 
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x 
Prehydrate with D5W and ½ Normal Saline for 2 hours pre and 6 hours 
post cyclophosphamide at 125ml/m2/hr or as per local institutional 
guidelines 
 
10.2.5 Mesna 
x 
360mg/m2/dose intravenously over 15-30 minutes on days 1 and 2. 
x 
Administer either 15 minutes before or during the cyclophosphamide 
infusion (based on institutional standards) and then repeat at hours 4 and 
8.   
x 
The total dose of Mesna can also be given as a continuous infusion, 
starting at the same time as the cyclophosphamide infusion and 
continuing for at least eight hours post cyclophosphamide (or given as per 
institutional policy).
10.3 General Concomitant Medication and Supportive Care Guidelines
If a cycle of chemotherapy is delayed for over 2 weeks due to neutropenia, subsequent 
cycles of chemotherapy should include filgrastim (G-CSF) or pegfilgrastrim. Filgrastim 
(G-CSF) may be used to maintain treatment schedule if there is a 2 week delay in 
initiation of subsequent chemotherapy cycles due to low ANC. The standard dose of 
filgrastim is 5mcg/kg/day subQ to commence 24 hours after the completion of 
chemotherapy.  Filgrastim must be stopped at least 24 hours before the next 
chemotherapy cycle but may be continued without regard to vincristine administration.  
Pegfilgrastim can be used instead of GCSF for children greater than 1 year of age (and 
greater than 10kg).  The recommended dose is one subQ injection of 0.1mg/kg at least 
24 hours after completion of chemotherapy (maximum 6 mg).   


 
 
 
 
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10.4 Duration of Therapy 
Duration of protocol therapy will depend on individual response, evidence of disease 
progression and tolerance. In the absence of treatment delays due to adverse 
events, treatment may continue until the prescribed chemotherapy course of nine 
cycles is complete or until one of the following criteria applies: 
x 
Disease progression 
x 
Intercurrent illness that prevents further administration of treatment 
x 
Unacceptable adverse event(s) 
x 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
x 
Participant decides to withdraw from the study, or 
x 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
x 
Completion of prescribed therapy 
10.5 Duration of Follow Up  
Participants will be followed for 5 years following enrollment.  In the event the patient is 
taken off study protocol therapy, survival outcomes will still be collected, unless the 
patient denies consent. 
10.6 Criteria for Removal from Study  
Participants will be removed from study in the following events:  a, patient/family 
no longer wish to participate or b, the treating physician deems it is not in the 
patient’s best interest to remain on study.   
 


 
 
 
 
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In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator (or Protocol Chair), Dr Kenneth 
Cohen at 410-614-5055. 
11. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS 
Dose delays and modifications will be made using the following recommendations. Toxicity   
assessments will be done using the CTEP Version 4 of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
11.1 Anticipated Toxicities  
A list of the adverse events and potential risks associated with the agents 
administered in this study appear below and will determine whether dose delays and 
modifications will be made or whether the event requires expedited reporting in 
addition to routine reporting. 
  
11.1.1 Adverse Event Lists for Lomustine 
 
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 
 
Nausea, vomiting 
 
 
Disorientation, lethargy, ataxia, 
and dysarthria  
Prompt(within 
2-3 weeks 
prior to next 
course 
 
 
 
Liver dysfunction (Ĺ alkaline 
phosphatase, SGOT (AST) and 
bilirubin) (L), stomatitis  


 
 
 
 
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Delayed: Any 
time later 
during 
therapy, 
excluding the 
above 
conditions  
 
 
Pulmonary fibrosis and/or 
infiltrates ( usually with high 
cumulative dose  1100mg/m² 
(L), progressive renal 
dysfunction, renal failure (large 
doses)(L), decrease in kidney 
size, optic atrophy, visual 
disturbances, blindness,  
Late: Any 
time after 
completion of 
treatment 
 
 
 
Secondary malignancy, death 
secondary to pulmonary fibrosis  
Unknown 
Frequency 
and Timing: 
Fetal and teratogenic toxicities: Lomustine is embryotoxic and teratogenic in 
rats and embryotoxic in rabbits at dose levels equivalent to the human dose. It is 
not known whether this drug is excreted in human milk.  
* (L) Toxicity may also occur later.  


 
 
 
 
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11.1.2 Adverse Event List for Cisplatin 
 
 
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 
 
 
Nausea (L), vomiting 
(L)  
 
 
Metallic taste (L)  
 
Anaphylactic reaction (facial 
edema, wheezing, 
tachycardia, and 
hypotension), phlebitis, 
extravasation (rare) but if 
occurs = local ulceration (only 
in concentration > 0.5mg/mL)  
Prompt(withi
n 2-3 weeks 
prior to next 
course 
Anorexia (L), 
myelosuppression,  
hypomagnesemia (L), 
high frequency hearing 
loss (L), nephrotoxicity 
(Ĺ Cr, BUN, Uric Acid) 
(L)  
Electrolyte 
disturbances (L)  
(hypocalcemia, 
natremia, kalemia, & 
phosphatemia)  
peripheral neuropathy, 
(paresthesias in a 
stocking-glove 
distribution) (L)  
Vestibular dysfunction, 
tinnitus (L), rash, seizure (L), 
elevated liver function tests 
(L)  
Delayed: 
Any time 
later during 
therapy, 
excluding 
the above 
conditions  
 
Hearing loss in the 
normal hearing range  
Areflexia, loss of 
proprioception and vibratory 
sensation, (very rarely loss of 
motor function) (L), optic 
neuritis, papilledema, cerebral 
blindness, blurred vision and 
altered color perception 
(improvement or total 
recovery usually occurs after 
discontinuing), chronic renal 
failure, deafness  
Late: Any 
time after 
completion 
of treatment 
 
 
Secondary malignancy  
Unknown 
Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of cisplatin have been noted in animals and 
cisplatin can cause fetal harm in humans. Cisplatin is excreted into breast milk.  
* (L) Toxicity may also occur later.  
 
 


 
 
 
 
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11.1.3 Adverse Event List for Vincristine 
 
 
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 
 
 
 
 
Jaw pain, headache  
 
Extravasation (rare) but if 
occurs = local ulceration, 
shortness of breath, and 
bronchospasm  
Prompt(withi
n 2-3 weeks 
prior to next 
course 
 
Alopecia, constipation  
 
 
Weakness, abdominal 
pain, mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia)  
 
Paralytic ileus, ptosis, 
diplopia, night blindness, 
hoarseness, vocal cord 
paralysis, SIADH, seizure, 
defective sweating  
Delayed: 
Any time 
later during 
therapy, 
excluding 
the above 
conditions  
Loss of deep tendon 
reflexes  
Peripheral 
paresthesias including 
numbness, tingling and 
pain; clumsiness; wrist 
drop, foot drop, 
abnormal gait  
Difficulty walking or inability to 
walk; sinusoidal obstruction 
syndrome (SOS, formerly 
VOD) (in combination); 
blindness, optic atrophy; 
urinary tract disorders 
(including bladder atony, 
dysuria, polyuria, nocturia, 
and urinary retention); 
autonomic neuropathy with 
postural hypotension; 8th 
cranial nerve damage with 
dizziness, nystagmus, vertigo 
and hearing loss  
Unknown 
Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination 
with other antineoplastic agents) have been noted in humans. The toxicities 
include: chromosome abnormalities, malformation, pancytopenia, and low birth 
weight. It is unknown whether the drug is excreted in breast milk.  
 
 
 


 
 
 
 
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11.1.4 Adverse Event List for Cyclophosphamide 
 
 
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 
 
 
Anorexia, nausea & 
vomiting (acute and 
delayed)  
 
Abdominal discomfort, 
diarrhea  
 
Transient blurred vision, nasal 
stuffiness with rapid 
administration, arrhythmias 
(rapid infusion), skin rash, 
anaphylaxis, SIADH  
Prompt(withi
n 2-3 weeks 
prior to next 
course 
 
Leukopenia, alopecia, 
immune suppression  
 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L)  
 
Cardiac toxicity with high 
dose (acute – CHF 
hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail 
changes, impaired wound 
healing, infection secondary 
to immune suppression  
Delayed: 
Any time 
later during 
therapy, 
excluding 
the above 
conditions  
Gonadal dysfunction: 
azoospermia or 
oligospermia 
(prolonged or 
permanent)1 (L)  
Amenorrhea1
Gonadal dysfunction: ovarian 
failure1 (L), interstitial 
pneumonitis, pulmonary 
fibrosis2 (L)  
Late: Any 
time after 
completion 
of treatment 
 
 
Secondary malignancy (ALL, 
ANLL, AML), bladder 
carcinoma (long term use > 2 
years), bladder fibrosis  
Unknown 
Frequency 
and Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in 
combination with other antineoplastic agents) have been noted in humans. 
Toxicities include: chromosomal abnormalities, multiple anomalies, pancytopenia, 
and low birth weight. Cyclophosphamide is excreted into breast milk. 
Cyclophosphamide is contraindicated during breast feeding because of reported 
cases of neutropenia in breast fed infants and the potential for serious adverse 
effects.  
 
1.Dependent on dose, age, gender, and degree of pubertal development at time of treatment.  
2 Risk increased with pulmonary chest irradiation and higher doses. 
* (L) Toxicity may also occur later.  
 


 
 
 
 
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35
11.2 Toxicity Management, dose modifications and delays 
11.2.1 Neurotoxicity 
11.2.1.1 For grade 3 to 4 neurotoxicity including foot drop, paresthesia, ileus or 
paresis, withhold the next dose of Vincristine and then resume at lower 
dose (1mg/m2, maximum dose 1.5mg) and then escalate to full dose 
when symptoms resolve. 
11.2.1.2 For seizures, withhold dose then recommence at reduced dose 
(1mg/m2, maximum dose 1.5mg) and then escalate to full dose (if 
seizures do not recur) whilst continuing anticonvulsants.  Exclude 
syndrome of inappropriate secretion of antidiuretic hormone (SIADH) as a 
cause of seizures. 
11.2.1.3 Vincristine should not be withheld for jaw pain which should be treated 
symptomatically with analgesics (not salicylates). 
11.2.2 Hepatotoxicity 
11.2.2.1 Vincristine should be withheld for a direct bilirubin of greater than 
1.9mg/dL.  For direct bilirubin levels of 1.5mg/dL to 1.9mg/dL a reduced 
dose (1mg/m2, maximum dose 1.5mg) should be administered. 
11.2.3 Hematological toxicity 
 
If chemotherapy is due and the absolute neutrophil count remains below 750/ L the 
next cycle of chemotherapy should be delayed.  Repeat CBC weekly. 
 


 
 
 
 
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If the next cycle of Maintenance is due and ANC < 750/ L hold chemotherapy 
until ANC  750/ L. 
x 
If the patient is due to receive Regimen A, the dose of Lomustine (CCNU) 
should be reduced to 20 mg/m2 
x 
If the patient is due to receive Regimen B, the dose of Cyclophosphamide 
should be reduced by 50% on Days 1 and 2
If the next cycle of Maintenance is due and ANC is above or equal to 750/ L but 
below 1,000/L or the platelet count is < 75,000/ L: 
x 
If the patient is due to receive Regimen A, the dose of Lomustine (CCNU) 
should be reduced by 50% (38 mg/m2) 
x 
If the patient is due to receive Regimen B, the dose of Cyclophosphamide 
should be reduced by 25% (750 mg/m2/day) on Days 1 and 2. 
x 
If the ANC is less than 750/ L when the next cycle is due, despite the dose 
reduction in CCNU, hold chemotherapy until the ANC is greater than or equal 
to 750/ L. For the next cycle of Regimen A, reduce Lomustine (CCNU) to 
20mg/m2. 
 
If a cycle of chemotherapy is delayed for over 2 weeks due to neutropenia, 
subsequent cycles of chemotherapy should include filgrastim (G-CSF). Filgrastim 
(G-CSF) will be used to maintain treatment schedule if there is a delay in initiation of 
chemotherapy due to low white cell count (see section 10.3). 
 
11.2.4 Hemorrhagic Cystitis (Hematuria) 
11.2.4.1  Microscopic Hematuria 


 
 
 
 
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For transient microscopic hematuria (no more than 2 abnormal urinalyses on 2 
separate days during a cycle of therapy), there is no modification of the 
cyclophosphamide or mesna. 
For persistent microscopic hematuria (> 2 abnormal urinalyses during a cycle 
of therapy), increase hydration to 3500-4000 mL/m2/day. 
11,2,4,2  Gross Hematuria 
All episodes of gross hematuria should be evaluated in conjunction with a 
pediatric surgical consult. Further testing, such as cystoscopy, urine culture, 
excretory urogram, and voiding cystogram should be considered based on 
good clinical judgment. 
For transient gross hematuria (only 1 episode, which clears to less than gross 
hematuria) during or following a cycle of therapy, do not modify 
cyclophosphamide dose. Use continuous infusion mesna, at 100% of the 
cyclophosphamide dose. Start the mesna infusion 15-30 min prior to or at the 
same time as cyclophosphamide and continue for 24 hours after the 
completion of the cyclophosphamide infusion. 
 
For persistent gross hematuria after completion of a cycle of therapy, hold 
subsequent cyclophosphamide until the urine clears to less than gross 
hematuria. Reinstitute cyclophosphamide at full dose, with the mesna 
changed to a continuous infusion. 
 
For persistent gross hematuria occurring during a cycle of cyclophosphamide, 
interrupt the cyclophosphamide. Withhold further cyclophosphamide until the 
next cycle of therapy or until urine clears. For subsequent cycles give mesna 


 
 
 
 
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by continuous infusion. For occurrence of a second episode of gross 
hematuria or persistence of microscopic hematuria on the continuous infusion 
regimen, continue the cyclophosphamide when the urine clears to less than 
gross hematuria. 
 
For persistent gross hematuria on the mesna continuous infusion regimen, 
discontinue the cyclophosphamide. 
11.2.5 Nephrotoxicity 
11.2.5.1 
If the creatinine clearance or GFR is less than 50% of baseline value, then the 
cisplatin should not be administered. It should be held until the creatinine 
clearance rises above 50% of baseline value. 
11.2.5.2 
If the creatinine clearance or GFR is less than 75% of baseline value, then the 
cisplatin dose should be reduced by 50% of the calculated dose. 
11.2.5.3 
If the creatinine clearance or GFR does not rise above 30 ml/min/1.73 m2, the 
cisplatin should be deleted from treatment. 
11.2.5.4 
Following transient renal dysfunction, as defined above, the cisplatin should be 
reinstituted at 50% dosage until the creatinine clearance or GFR has maintained 
above 50% of baseline value for two cycles of chemotherapy. After two cycles of 
therapy with acceptable creatinine clearance, cisplatin should be given at full 
doses. 
 


 
 
 
 
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11.2.6 Ototoxicity 
11.2.6.1  For a decrease in auditory acuity of  30 decibels at 4,000 – 8,000 Hz, 
a 50% reduction in cisplatin dosage should be made.  For a  20 decibel loss at 
500-3,000 Hz, a 50% reduction in cisplatin dosage should be made.  For Grade 4 
ototoxicity, cisplatin should be held and not restarted unless follow-up 
audiograms show an improvement in hearing function. 
12. DRUG FORMULATION AND ADMINISTRATION 
12.1 Cisplatin 
Description 
Cisplatin (Cis-diamminedichloroplatinum II, CDDP, cis-DDP, Platinol-AQ) NSC #119875  is an 
inorganic, water-soluble complex containing a central platinum atom, 2 chlorine atoms, and 2 
ammonia molecules. In aqueous solution, the chloride ions are slowly displaced by water 
generating a positively charged aquated complex. This activated complex is then available to 
react with nucleophilic sites on DNA, RNA, or protein resulting in the formation of bi-functional 
covalent links, very similar to alkylating reactions. The intra-strand cross-links, in particular with 
guanine and cytosine, change DNA conformation and inhibit DNA synthesis leading to the 
cytotoxic and anti-tumor effects of cisplatin. Cisplatin has synergistic cytotoxicity with radiation 
and other chemotherapeutic agents. Cisplatin has a rapid distribution phase of 25-80 minutes 
with a slower secondary elimination half-life of 60-70 hours. The platinum from cisplatin, but not 
cisplatin itself, becomes bound to several plasma proteins including albumin, transferrin, and 
gamma globulin. Three hours after a bolus injection and two hours after the end of a three hour 
infusion, 90% of the plasma platinum is protein bound. The complexes between albumin and the 
platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a 
minimum half-life of five days or more. Platinum is present in tissues for as long as 180 days 


 
 
 
 
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after the last administration. Both cisplatin and platinum are excreted through the kidneys 
ranging from 10-50%. Fecal elimination is minimal. Cisplatin’s penetration into the CNS is poor.
Form
Available as an aqueous solution containing 1 mg/mL of cisplatin and 9 mg (1.54 mEq)/mL of 
sodium chloride in 50 mL, 100 mL, and 200 mL multi-dose non-preserved vials. 
Storage and Stability 
Store at 15°-25°C (68º-77ºF). Do not refrigerate. Protect unopened container from light. The 
cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from 
light or for 7 days under fluorescent room light. Cisplatin removed from its amber container 
should be protected from light if not used within 6 hours
Compatibility
Cisplatin is incompatible with sodium bicarbonate and alkaline solutions. Needles or intravenous 
sets containing aluminum parts that may come in contact with cisplatin should not be used for 
preparation or administration. Aluminum reacts with cisplatin causing precipitate formation and a 
loss of potency  
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
Preparation 
Cisplatin may be further diluted in dextrose and saline solutions provided the solution contains 
>0.3% sodium chloride. The final infusion solution should contain  0.2% sodium chloride. 
Dextrose/saline/mannitol containing solutions, protected from light, are stable refrigerated or at 
room temperature for 24 to 72 hours, however, cisplatin solutions should not be stored in the 
refrigerator to avoid precipitation.  
Administration


 
 
 
 
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75mg/m2 given intravenously over 6 hours x 1 dose on Day 1. 
Suggested hydration and supportive care 
-2 to 0 hours Prehydration 500ml/m2 D5 1/2NS with mannitol 10 GM/m2 at 250ml/m2/hr 
0 to 6 hours 
Cisplatin 75mg/m2 with 10 GM/m2 mannitol in D5 ½ NS 1000ml/m2 IV at 167 
ml/m2/hr for 6 hours. 
6 to 24 hours Continue hydration with D5 ½ Normal Saline with magnesium sulfate 0.5-
1mEq/kg in post-hydration fluid at 125ml/m2/hr for at least 6 hours.  If children are tolerating oral 
intake after 6 hours the remainder of post hydration can be given orally. 
 
Urine output must be monitored during administration of cisplatin. If the urine output falls below 
3ml/kg/hr for two hours consecutively, mannitol 0.5g/kg with a 10ml/kg bolus of normal saline 
are recommended.  
Ordering
Commercially available from various manufacturers. See package insert for more detailed 
information.  
12.2 Cyclophosphamide 
Description
Cyclophosphamide (Cytoxan) NSC #26271 is an alkylating agent related to nitrogen mustard. 
Cyclophosphamide is inactive until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, 
and CYP3A4) in the liver to active compounds. The initial product is 4-
hydroxycyclophosphamide (4-HC) which is in equilibrium with aldophosphamide which 
spontaneously releases acrolein to produce phosphoramide mustard. Phosphoramide mustard, 
which is an active bifunctional alkylating species, is 10 times more potent in vitro than is 4-HC 
and has been shown to produce interstrand DNA cross-link analogous to those produced by 
mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the urine 


 
 
 
 
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as the inactive carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life 
ranges from 4.1 to 16 hours after IV administration. 
Form:  Cyclophosphamide for injection is available as powder for injection or lyophilized powder 
for injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 75 mg 
mannitol/100 mg cyclophosphamide.  
Storage and Stability: Storage at or below 25ºC (77ºF) is recommended. The product will 
withstand brief exposures to temperatures up to 30ºC (86ºF). 
Compatibility NA 
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment. 
Availability
Commercially available from various manufacturers. See package insert for more detailed 
information. 
Preparation 
Cyclophosphamide for Injection: Reconstitute with NS, SWFI, or Bacteriostatic Water for 
Injection (paraben preserved only) to a concentration of 20 mg/mL. If administered as undiluted 
drug at the 20 mg/mL concentration, reconstitute with NS only to avoid a hypotonic solution. 
Solutions reconstituted with preservative should be used within 24 hours if stored at room 
temperature or within 6 days if stored under refrigeration.  
Administration
1000mg/m2 IV over 1 hour day 1 and 2 
Prehydrate with D5W and ½ Normal Saline for 1 hour pre and 6 hours post cyclophosphamide 
at 125ml/m2/hr 


 
 
 
 
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Ordering
Commercially available from various manufacturers. See package insert for more detailed 
information.  
12.3 Lomustine 
Description
Lomustine (Cyclohexylchloroethylnitrosourea CCNU, CeeNU®) NSC #79037) alkylates DNA 
and RNA, causes interstrand cross-linking of DNA, prevents the repair of DNA, and alters the 
structure of RNA and the structure and function of many proteins and enzymes. It is not cross 
resistant with other alkylators and it may also inhibit several key enzymatic processes by 
carbamoylation of amino acids in proteins. Lomustine is cell-cycle non-specific and is thought to 
act in the late G1 or early S phase. Time to peak concentration after oral administration is 1 to 4 
hours. Lomustine is rapidly and completely absorbed. Metabolism of lomustine is through 
hydroxylation of the cyclohexyl moiety by hepatic microsomal enzymes. The parent drug 
lomustine has not been detected in blood, but the peak concentrations of the ring hydroxylated 
metabolites are approximately 3 ȝM after doses of 130 mg/m2. Following oral administration of 
radioactive lomustine at doses ranging from 30 mg/m2 to 100 mg/m2, about half of the 
radioactivity given was excreted in the urine in the form of degradation products within 24 hours. 
Approximately 10% is excreted through the lungs and 5% through the feces. The serum half-life 
of the metabolites ranges from 16 hours to 2 days. Tissue levels are comparable to plasma 
levels. Due to the high lipid solubility and the relative lack of ionization at physiological pH, 
lomustine crosses the blood-brain barrier. Levels of radioactivity in the CSF are 50% or greater 
than those measured concurrently in plasma  
Form 


 
 
 
 
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Lomustine is supplied as 100 mg capsules, 40 mg capsules and 10 mg capsules. Inactive 
ingredients in lomustine capsules are: magnesium stearate and mannitol.  
Storage and Stability
Store in well-closed containers at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F). 
Avoid excessive heat (over 40°C or 104°F). 
Compatibility -NA 
Handling
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  Patients should be 
told to wear gloves when handling lomustine capsules. 
Availability
Commercially available from various manufacturers. See package insert for more detailed 
information. 
Preparation and Administration
Round dose to the nearest 10mg. Round down for doses < *5 and round up for doses  *5 (e.g. 
84 mg round to 80 mg; 85 mg round to 90 mg). Give orally no more frequently than every 6 
weeks. Give with fluids on an empty stomach and at bedtime to reduce nausea and vomiting. 
No food or drink should be given for at least 2 hours after administration. In order to provide the 
proper dose of lomustine patients should be aware: that there maybe two or more different 
types and colors of capsules in the container dispensed by the pharmacist; lomustine is given 
as a single oral dose and will not be repeated for at least 6 weeks; and patients should be told 
to wear gloves when handling lomustine capsules.
Ordering


 
 
 
 
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Commercially available from various manufacturers. See package insert for more detailed 
information.  
12.4 Vincristine 
Description
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, 
disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. 
The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours respectively; 
however, the range of the terminal half-life in humans is from 19 to 155 hours. The liver is the 
major excretory organ in humans and animals; about 80% of an injected dose of vincristine 
sulfate appears in the feces and 10% to 20% can be found in the urine. The p450 cytochrome 
involved with vincristine metabolism is CYP3A4. Within 15 to 30 minutes after injection, over 
90% of the drug is distributed from the blood into tissue, where it remains tightly, but not 
irreversibly bound. It is excreted in the bile and feces. There is poor CSF penetration.  
Form 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine sulfate 1 mg 
(1.08 ȝmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are added for pH control. 
The pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. This product is a sterile, 
preservative free solution. 
Storage and Stability
Store refrigerated at 2Û-8ÛC or 36Û-46ÛF. Protect from light and retain in carton until time of use
Compatibility
Do not mix with any IV solutions other than those containing dextrose or saline 
Handling


 
 
 
 
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Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
Administration
1.5mg/m2 (maximum dose 2mg) given as an IV push on days 1, and 8 and 15 (Day 15 dose for 
Regimen A only).  Doses are to be rounded down to the nearest 0.1mg. 
Vincristine is vesicant and should be administered through a central line to prevent exravasation 
The World Health Organization, the Institute of Safe Medicine Practices (United States) and the 
Safety and Quality Council (Australia) all support the use of minibag rather than syringe for the 
infusion of vincristine. Vincristine should NOT be delivered to the patient at the same time with 
any medications intended for central nervous system administration. Vincristine is fatal if 
given intrathecally. Injection of vincristine sulfate should be accomplished as per institutional 
policy. Vincristine sulfate must be administered via an intact, free-flowing intravenous needle or 
catheter. Care should be taken to ensure that the needle or catheter is securely within the vein 
to avoid extravasation during administration. The solution may be injected either directly into a 
vein or into the tubing of a running intravenous infusion.  
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap bearing 
the statement: ʊDo not remove covering until moment of injection. For intravenous use only - 
Fatal if given by other routes. 
PLEASE NOTE:  
The warning statement in the vincristine USP monograph has been revised as stated above to 
the following: "Do not remove covering until moment of injection. For intravenous use only. Fatal 
if given by other routes." The prescribing information for the product by Teva USA has been 


 
 
 
 
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47
revised to reflect this information. At the writing of this monograph, the Hospira prescribing 
information had not yet been revised.  
This revision can be found in Pharmacopeial Forum 36(6) which is available free of charge on 
the USP website at http://www.usp.org/USPNF/pf/. The notice of intent to revise can be found at 
the following website: http://www.usp.org/USPNF/compendialNotices/vincristineSulfate.html. 
The official FDA-approved labeling can be found at the NIH’s DailyMed website: 
http://dailymed.nlm.nih.gov/dailymed/search.cfm?startswith=vincristine.
Ordering
Commercially available from various manufacturers. See package insert for more detailed 
information.  
 


 
 
 
 
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13. Required and Recommended Evaluations 
13.1 Evaluations During Therapy that must be reported to the Coordinating Center 
Test 
At Diagnosis/Prior 
to Cycle 1 
Prior to Each Cycle of Chemotherapy 
Completion of Treatment 
MRI Brain 
Pre-op and Post-
Op2 
X Prior to cycle 4 and 7) 
X 
MRI Spine 
Pre or post-op1 
X (Prior to Cycles 4 and 7) 
X 
CSF evaluation 
Post-op3 
 
 
Audiogram 
X 
X (Prior to Cycles 4, and 7) 
 
Height/Weight 
X 
 
 
Performance 
Status 
X 
 
 
GFR or CrCl or 
serum creatinine 
based on 
age/gender 
X 
 
X 
Complete Blood 
Count, Diff and 
Platelet count 
X 
X 
X 
Liver Function, 
BUN Creatinine, 
electrolytes (Ca, 
Mg) 
X 
 
 
History and 
Physical Exam  
X 
 
 
Pathology 
Central Review 
X 
 
 
Radiology 
Central Review 
X 
 
 
Neuropsych 
testing** 
Timing based on institutional standards and subject readiness 
1 - Spinal MRI to include an enhanced complete (cervical, thoracic, lumbar and sacral) pre-op or post-op between 10 and 21 days 
after surgery.  2 - Assessment must include pre-op and post-op MRI performed with and without contrast preferably within 48 hours 
and at most 21 days after surgery.  3 – Lumbar CSF evaluation should occur no sooner than 10 days following surgery and no later 
than 21 days following surgery .  **-neuropsychologic testing should be obtained based on institutional standards and available 
resources as a standard of care procedure.  If testing is obtained, results should be reported 
 


 
 
 
 
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13.2 Recommended Evaluations During Therapy that are not reported to the 
Coordinating Center 
Note:  The following observations are considered standard of care for children undergoing 
treatment for medulloblastoma.  It is anticipated that most/all of these data points will be 
obtained as part of good clinical care but they will not be reported centrally to the coordinating 
center since they do not impact the interpretation of the primary or secondary objectives and 
associated statistical analyses of this protocol 
Test 
Prior to Each Cycle of Chemotherapy 
(beginning with Cycle 2 of treatment) 
Completion of Treatment 
Height/Weight 
X 
 
History and 
Physical Exam  
X 
X 
GFR or CrCl or 
serum creatinine 
based on 
age/gender 
X (Prior to Cycles 4 and 7) 
X 
Liver Function, 
BUN Creatinine, 
electrolytes (Ca, 
Mg) 
X 
 
 
 
 


 
 
 
 
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13.3 Required Evaluations Following Completion of Therapy that must be reported to 
the Coordinating Center 
 
3 
m 
6 
m 
9 
m 
1 
year 
1.5 
years 
2 
years 
2.5 
years 
3 
years 
Annual 
after 3 
years 
until 
year 5 
At relapse/disease 
progression 
MRI Brain 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI Spine 
(complete spine) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
CSF Evaluation 
 
 
 
 
 
 
 
 
 
X 
Audiogram (per 
institutional 
standards) 
 
 
 
X 
 
 
 
 
 
 
Complete Blood 
Count, Diff and 
platelet count 
X 
 
 
 
 
 
 
 
 
 
Neuropsych 
testing** 
Timing based on institutional standards and subject readiness 
**-neuropsychologic testing should be obtained based on institutional standards and available resources as a standard of care 
procedure.  If testing is obtained, results should be reported 
 
 


 
 
 
 
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13.4 Recommended Evaluations Following Therapy that are not reported to the 
Coordinating Center 
Note:  The following observations are considered standard of care for children who have 
completed treatment for medulloblastoma.  It is anticipated that most/all of these data points 
will be obtained as part of good clinical care but they will not be reported centrally to the 
coordinating center since they do not impact the interpretation of the primary or secondary 
objectives and associated statistical analyses of this protocol 
 
3 
m 
6 
m 
9 
m 
1 
year 
1.5 
years 
2 
years 
2.5 
years 
3 
years 
Annual 
after 3 
years 
until 
year 5 
At relapse/disease 
progression 
History and 
physical with 
neurological 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height/Weight 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Audiogram (per 
institutional 
standards) 
 
 
 
 
 
 
 
X 
 
 
Complete Blood 
Count, Diff  
X 
 
 
 
 
 
 
 
 
 
Endocrinology 
evaluation (per 
institutional 
standards) 
 
 
 
X 
 
X 
 
X 
X 
 
 


 
 
 
 
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14. MEASUREMENT OF EFFECT 
14.1 Antitumor Effect 
For the purposes of this study, participants should be re-evaluated for response prior 
to cycle 4 and 7 (while on therapy) and then as described in section 13.3. 
14.1.1  Response Assessment, Definitions  
14.1.1.1 Definition of a New Lesion 
The finding of a new lesion should be unequivocal (i.e. not due to 
difference in scanning technique, imaging modality, or findings thought to 
represent something other than tumor (ex: new bone lesions may be 
healing or flare of pre-existing lesions). However, a lesion identified on a 
follow-up scan in an anatomical location that was not scanned at baseline 
is considered new and will indicate PD. If a new lesion is equivocal 
(because of small size, etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be 
declared using the date of the initial scan on which the lesion was 
discovered.  Demonstration of CSF cytopathology positive for 
medulloblastoma will also be evidence of tumor recurrence independent 
of any associated imaging findings on MRI. 
 
 


 
 
 
 
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15. ADVERSE EVENT REPORTING REQUIREMENTS 
15.1 Definitions 
15.1.1 Adverse Event (AE) 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is 
not considered to be related to the study.  
Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
15.1.2 Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and 
regardless of causality that:  
x 
Results in death 
x 
Is life-threatening. Life-threatening means that the person was at 
immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
x 
Prolongs inpatient hospitalization (prolonged a hospitalization beyond the 
expected length of stay). Hospitalization admissions and/or surgical 
operations scheduled to occur during the study period, but planned prior 
to study entry are not considered SAEs if the illness or disease existed 


 
 
 
 
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before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial (e.g., surgery 
performed earlier than planned).  Routine febrile neutropenia admissions 
(less than one week duration, no requirement of ICU admission) are 
expected toxicity of the therapy and will not be considered a serious 
adverse event 
x 
Results in persistent or significant disability/incapacity. Disability is 
defined as a substantial disruption of a person’s ability to conduct normal 
life functions. 
x 
Is a congenital anomaly or birth defect; or 
x 
Is an important medical event when, based upon appropriate medical 
judgment, it may jeopardize the participant and require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
 
Events not considered to be serious adverse events are hospitalizations for: 
x 
routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures 
x 
elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
x 
emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission 


 
 
 
 
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55
x 
respite care 
x 
Routine febrile neutropenia admissions (less than one week duration, no 
requirement of ICU admission)  
15.1.3 Expectedness 
Adverse events can be 'Expected' or 'Unexpected.'  
15.1.3.1 Expected adverse event 
Expected adverse events are those that have been previously identified 
as resulting from administration of the agent. For the purposes of this 
study, an adverse event is considered expected when it appears in the 
current adverse event list, the Investigator’s Brochure, the package 
insert or is included in the informed consent document as a potential 
risk.   
Refer to Section 6.1 for a listing of expected adverse events 
associated with the study agent(s). 
15.1.3.2 Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered 
unexpected when it varies in nature, intensity or frequency from 
information provided in the current adverse event list, the Investigator’s 
Brochure, the package insert or when it is not included in the informed 
consent document as a potential risk.   
15.1.4 Attribution 
 


 
 
 
 
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56
Attribution is the relationship between an adverse event or serious adverse event 
and the study treatment. Attribution will be assigned as follows: 
 
x Definite – The AE is clearly related to the study treatment. 
x Probable – The AE is likely related to the study treatment. 
x Possible – The AE may be related to the study treatment.  
x Unlikely - The AE is doubtfully related to the study treatment. 
x Unrelated - The AE is clearly NOT related to the study treatment. 
15.2 Procedures for SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points during the study.  
 
All SAEs whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be 
recorded in the participant’s medical record and on the appropriate study-specific 
eCRFs. AEs, unless deemed to be of special interest by the treating investigator, will 
not be reported since the toxicity of standard of care medulloblastoma therapy is well 
defined and previously reported. 
.  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website at: 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  


 
 
 
 
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15.3 Reporting Requirements
Each investigative site will be responsible to report SAEs that occur at that institution 
to their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below.  
15.4 Reporting to the Study Team 
15.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be reported 
to the Principle Investigator on the local institutional SAE form. This includes 
events meeting the criteria outlined in Section 11.1.2, as well as the following: 
 
x 
Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with 
the intervention. 
x 
All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting. 
x 
All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
x 
Progressive disease will be reported within 7 days 
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  


 
 
 
 
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58
 
Participating investigators must report each serious adverse event to the overall 
Principal Investigator within one business day of learning of the occurrence. In 
the event that the participating investigator does not become aware of the 
serious adverse event immediately (e.g., participant sought treatment 
elsewhere), the participating investigator is to report the event within one 
business day of learning of it and document the time of his or her first awareness 
of the adverse event.  
 
Report serious adverse events by telephone, email or facsimile to: 
 
 
 
Kenneth J. Cohen, MD, MBA  
 
 
Telephone Number: 410-614-5055  
 
 
Email: kcohen@jhmi.edu  
 
 
Fax: 410-955-0028 
 
 
Emergency Contact #: 410-375-8281 (mobile)  
 
Within the subsequent 1-2 business day from initial report, the participating 
investigator must provide follow-up information on the serious adverse event. 
Follow-up information should describe whether the event has resolved or 
continues, if and how the event was treated, and whether the participant will 
continue or discontinue study participation. 
15.4.2 Non-Serious Adverse Event Reporting  
 


 
 
 
 
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59
Non-serious adverse events will not be reported since the chemotherapy regimen 
is standard of care. 
15.5 Reporting to the Institutional Review Board (IRB)
Investigative sites should report serious adverse events to their respective IRB 
according to the local IRB’s policies and procedures in reporting serious adverse 
events. A copy of the submitted institutional SAE form should be forwarded to: 
 
 
 
Kenneth J. Cohen, MD, MBA  
 
 
Telephone Number: 410-614-5055  
 
 
Email: kcohen@jhmi.edu  
 
 
Fax: 410-955-0028 
 
 
Emergency Contact #: 410-375-8281 (mobile) 
 
15.6 Reporting to the Food and Drug Administration (FDA)
N/A 
 
 
15.7 Reporting to the NIH Office of Biotechnology Activities (OBA) 
N/A 
15.8 Reporting to the Institutional Biosafety Committee (IBC) 
N/A 
 
15.9 Reporting to Hospital Risk Management 


 
 
 
 
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60
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
15.10 Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered 
from initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution SAEs (with dates) should be documented on the appropriate eCRF and 
recorded in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, 
and/or monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Overall Investigator or respective IRB of any unanticipated death or adverse 
event occurring after a participant has discontinued or terminated study participation 
that may reasonably be related to the study.   
 
 
16. DATA AND SAFETY MONITORING
16.1 Data Reporting 


 
 
 
 
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61
eCRFs will be provided for all study mandated data points and should be 
submitted based on the deadlines detailed in Section 16.1.1 
16.1.1 Data Submission  
eCRFs will be submitted electronically via CRMS (information will be provided to 
each site for access to CRMS): 
The schedule for completion and submission of eCRFs  to the coordinating 
center is as follows: 
 
Form 
Submission Timeline 
Screening Registration Form 
Complete prior to registration with coordinating center 
Treatment eligibility checklist 
By Day 28 following surgery 
Start Cycle Form 
Within 14 days from the start of each cycle.  Note that 
Start Cycle Form for Cycles 4 and 7 will include 
response assessment information 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being taken 
off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up visit 
date or call 
16.2 Safety Meetings 


 
 
 
 
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62
The SKCCC Safety Monitoring Committee (SMC) will review and monitor toxicity and 
accrual data from this trial. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information 
that raises any questions about participant safety will be raised and addressed by the 
Principal Investigator and study team as needed. 
 
The SMC will meet according to SKCCC standards or more often if required to review 
toxicity and accrual data for the study. Information to be provided to the committee 
may include: up-to-date participant accrual; DLT information; all grade 2 or higher 
unexpected adverse events; summary of all deaths while being treated and during 
active follow-up; any response information; protocol deviations; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) 
will be provided upon request. 
 
16.3 Auditing/Monitoring  
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan 
(12/6/2012). The SKCCC Clinical Research Office QA Group will perform an audit 
after the first JHU research participant has enrolled. The JHU Study team 
(coordinating center) will then periodically audit data from participating satellite sites 
depending on the rate of accrual and prior audit results (this satellite site auditing will 
be accomplished remotely or via on-site visits as applicable). In addition, the SKCCC 
Data Safety Monitoring Committee will review every relapse in real time to ensure that 
the safety stopping rule is not triggered.  All trial monitoring and reporting will be 
reviewed annually by the SKCCC Safety Monitoring Committee. The PI at each site is 
responsible for internally monitoring the trial. Data must be reviewed to assure the 


 
 
 
 
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63
validity of data, as well as, the safety of the research participants. Each PI will also 
monitor the progress of the trial, review safety reports, and clinical trial efficacy 
endpoints and to confirm that the safety outcomes favor continuation of the study. 
JHU  agrees to (1) promptly notify Collaborating Investigator in writing promptly of 
information such as new and unexpected serious adverse safety events arising from 
JHU  monitoring of the Study that could affect the safety of Subjects, and (2) trends or 
patterns of non-serious or expected adverse events that occur at a specificity or 
severity that is inconsistent with prior observations, including results obtained for a 
period of two years after Study Conclusion or termination, that could affect the safety 
or medical care of subjects who were at any point enrolled in the Study, influence the 
conduct of the Study, or alter the IRB's approval. 
17. REGULATORY CONSIDERATIONS
17.1 Protocol Review and Amendments 
This protocol, the proposed informed consents, all forms of participant information 
related to the study and any other necessary documents must be submitted, 
reviewed and approved by a properly constituted IRB governing each study location. 
This will occur following approval by the Coordinating Center IRB. 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The overall Principal Investigator will disseminate protocol 
amendment information to all participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 


 
 
 
 
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64
17.2 Informed Consent 
All participants must be provided a consent form describing each portion of this 
study and providing sufficient information for participants to make an informed 
decision about their participation in this study. The formal consent of a 
participant, using the IRB approved consent form, must be obtained before the 
participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The participant must be 
given a copy of the signed and dated consent document. The original signed 
copy of the consent document must be retained in the medical record or research 
file.  
17.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
x 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
x 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  


 
 
 
 
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65
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
x 
State laws  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such 
case, the deviation must be reported to the IRB according to the local reporting 
policy.  
17.4 Study Documentation 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and 
the study data to be subsequently verified. 
 
Original source documents supporting entries in the eCRFs include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays.  
17.5 Records Retention 


 
 
 
 
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66
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
 


 
 
 
 
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67
17.6 Multi-center Guidelines 
x 
This protocol will adhere to the policies and requirements of the SKCCC. 
x 
Overall Principal Investigator/Coordinating Center is responsible for 
distributing all Safety Reports to all participating institutions for submission to 
their individual IRBs for action as required. 
x 
Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  
 
 


 
 
 
 
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18. STATISTICAL CONSIDERATIONS  
Overview: This is a single arm, prospective pilot study to explore the strategy of omitting 
radiation therapy in pediatric patients with standard risk, WNT positive standard risk 
medulloblastoma.  This is not an intent-to-treat design; some eligible patients will be excluded 
from the assessment of the primary objective due to receiving radiation or starting 
chemotherapy too late. 
Accrual and study duration: 10% of all medulloblastoma belong to the Wnt-positive subgroup.  
We would therefore anticipate there to be approximately 45 children diagnosed with Wnt-
positive medulloblastoma in the USA each year.  Ten ‘evaluable’ children will be required to 
provide adequate operating characteristics for the stopping rule below.   We estimate at most 3 
children will be inevaluable.  Therefore a total of up to 13 children will be enrolled (fewer, if there 
are less than 3 inevaluable patients).  At an accrual rate of 5-6 children per year, these 13 
children can be enrolled within 2-3 years.  Study duration will be at least 4-5 years (2-3 years for 
accrual, plus a minimum of 2 years follow up on the last patient enrolled).   
Endpoints: The primary endpoint will be the occurrence of relapse, progression, or death due 
to disease within the first two years after study enrollment.   Secondary endpoints are the 
patterns of failure in those children that do have progressive disease, progression-free survival 
(PFS) (calculated from the time of enrollment until the first occurrence of relapse, progressive 
disease or death due to disease, or until last contact if no event occurs), and overall survival 
(OS). 
Evaluability: To be evaluable for inclusion in the stopping rule for assessment of the primary 
objectives, children: 
a) must be eligible; 
b) must commence treatment with chemotherapy by day 31 after resection; 


 
 
 
 
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69
c) must not receive radiation therapy within two years after study enrollment.   However, any 
child who has a relapse or progression prior to receiving radiation therapy is evaluable. 
 
     Safety Monitoring and Stopping Rule 
To address the primary objective of the utility of eliminating radiation therapy, the following one-
stage monitoring rule will be used: Of the first 10 evaluable patients enrolled, if at any time 3 or 
more patients have an event (relapse, progression, or death due to disease), then the study will 
be stopped and we will conclude that removal of radiation therapy is unsafe in children with 
standard risk, Wnt-positive medulloblastoma.  If there are 2 or fewer children who have an event 
out of 10, then we will conclude that removal of radiation therapy in children with standard risk, 
Wnt-positive medulloblastoma is feasible.  This rule tests the null hypothesis that the proportion 
of patients with relapse/progression/disease-death by 2-years is 0.1versus the alternative that 
it is 0.45, with 90% power and alpha=0.07.  The choices of the null and alternative were based 
on the results of Packer et al (10). 
Methods to address study objectives:  To address the primary objective, the stopping rule 
above will be applied.  To address the secondary objectives, the data will be descriptively 
summarized.  Kaplan-Meier curves of PFS and OS will be generated.  Toxicities will be 
tabulated. 
19. PUBLICATION PLAN 
 
The study team will aim to publish the study results within 24 months of the end of data 
collection in a peer reviewed journal. 
 
 


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70 
20. Appendix A: Performance Status Criteria 
 
Lansky Play- Performance Status Scale 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
100 
fully active, normal  
100 
Normal, no complaints, no evidence of 
disease. 
 
90 
minor restrictions with strenuous physical 
activity 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
active, but gets tired more quickly 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
both greater restriction of, and less time 
spent in, active play 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
60 
up and around, but minimal active play; 
keeps busy with quieter activities 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
lying around much of the day, but gets 
dressed; no active play; participates in all 
quiet play and activities 
50 
Requires considerable assistance and 
frequent medical care. 
40 
mostly in bed; participates in quiet activities 
40 
Disabled, requires special care and 
assistance. 
30 
stuck in bed; needs help even for quiet play 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
often sleeping; play is entirely limited to very 
passive activities 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
does not play nor get out of bed 
10 
Moribund, fatal processes progressing 
rapidly. 
0 
unresponsive 
0 
Dead. 
 


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71
21. References 
1. Ellison DW, Kocak M, Dalton J, et al. Definition of disease-risk stratification groups in 
childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin 
Oncol; 29: 1400-7. 
2. Tamayo P, Cho YJ, Tsherniak A, et al. Predicting relapse in patients with medulloblastoma by 
integrating evidence from clinical and genomic features. J Clin Oncol; 29: 1415-23. 
3. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct 
molecular variants. J Clin Oncol; 29: 1408-14. 
4. Cho YJ, Tsherniak A, Tamayo P, et al. Integrative genomic analysis of medulloblastoma 
identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol; 29: 1424-30. 
5. Schwalbe EC, Lindsey JC, Straughton D, et al. Rapid diagnosis of medulloblastoma 
molecular subgroups. Clin Cancer Res; 17: 1883-94. 
6. Kool M, Koster J, Bunt J, et al. Integrated genomics identifies five medulloblastoma subtypes 
with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One 
2008; 3: e3088. 
7. Ellison DW, Onilude OE, Lindsey JC, et al. beta-Catenin status predicts a favorable outcome 
in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain 
Tumour Committee. J Clin Oncol 2005; 23: 7951-7. 
8. Fattet S, Haberler C, Legoix P, et al. Beta-catenin status in paediatric medulloblastomas: 
correlation of immunohistochemical expression with mutational status, genetic profiles, and 
clinical characteristics. J Pathol 2009; 218: 86-94. 
9. Taylor MD, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the 
current consensus. Acta Neuropathol; 123: 465-72. 
10. 
Packer RJ, Goldwein J, Nicholson HS, et al. Treatment of children with medulloblastomas 
with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's 
Cancer Group Study. J Clin Oncol 1999; 17: 2127-36. 
11. 
Merchant TE, Kun LE, Krasin MJ, et al. Multi-institution prospective trial of reduced-dose 
craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary 
site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int 
J Radiat Oncol Biol Phys 2008; 70: 782-7. 
12. 
Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE. Late neurocognitive sequelae 
in survivors of brain tumours in childhood. Lancet Oncol 2004; 5: 399-408. 
13. 
Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours 
after radiotherapy and antimetabolites. Lancet 1999; 354: 34-9. 
14. 
Mulhern RK, Kepner JL, Thomas PR, Armstrong FD, Friedman HS, Kun LE. 
Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive 
conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group study. J Clin 
Oncol 1998; 16: 1723-8. 
15. 
Dhall G, Grodman H, Ji L, et al. Outcome of children less than three years old at diagnosis 
with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II 
protocols. Pediatr Blood Cancer 2008; 50: 1169-75. 
16. 
Grill J, Sainte-Rose C, Jouvet A, et al. Treatment of medulloblastoma with postoperative 
chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 2005; 6: 573-
80.


NA_00091840 (J1403) CONFIDENTIAL 
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72
17. 
von Bueren AO, von Hoff K, Pietsch T, et al. Treatment of young children with localized 
medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 
confirming the prognostic impact of histology. Neuro Oncol; 13: 669-79. 
18. 
Ridola V, Grill J, Doz F, et al. High-dose chemotherapy with autologous stem cell rescue 
followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after 
conventional chemotherapy. Cancer 2007; 110: 156-63. 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
J1403 - Pilot Study of a Surgery and Chemotherapy-Only 
Approach in the Upfront Therapy of Children with Wnt Positive 
Standard Risk Medulloblastoma 
 
NCT02212574 
 
September 12, 2016 
 


 
 
 
 
NA_00091840 (J1403) CONFIDENTIAL 
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68 
18. STATISTICAL CONSIDERATIONS  
Overview: This is a single arm, prospective pilot study to explore the strategy of omitting 
radiation therapy in pediatric patients with standard risk, WNT positive standard risk 
medulloblastoma.  This is not an intent-to-treat design; some eligible patients will be excluded 
from the assessment of the primary objective due to receiving radiation or starting 
chemotherapy too late. 
Accrual and study duration: 10% of all medulloblastoma belong to the Wnt-positive subgroup.  
We would therefore anticipate there to be approximately 45 children diagnosed with Wnt-
positive medulloblastoma in the USA each year.  Ten ‘evaluable’ children will be required to 
provide adequate operating characteristics for the stopping rule below.   We estimate at most 3 
children will be inevaluable.  Therefore a total of up to 13 children will be enrolled (fewer, if there 
are less than 3 inevaluable patients).  At an accrual rate of 5-6 children per year, these 13 
children can be enrolled within 2-3 years.  Study duration will be at least 4-5 years (2-3 years for 
accrual, plus a minimum of 2 years follow up on the last patient enrolled).   
Endpoints: The primary endpoint will be the occurrence of relapse, progression, or death due 
to disease within the first two years after study enrollment.   Secondary endpoints are the 
patterns of failure in those children that do have progressive disease, progression-free survival 
(PFS) (calculated from the time of enrollment until the first occurrence of relapse, progressive 
disease or death due to disease, or until last contact if no event occurs), and overall survival 
(OS). 
Evaluability: To be evaluable for inclusion in the stopping rule for assessment of the primary 
objectives, children: 
a) must be eligible; 
b) must commence treatment with chemotherapy by day 31 after resection; 


 
 
 
 
NA_00091840 (J1403) CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
69 
c) must not receive radiation therapy within two years after study enrollment.   However, any 
child who has a relapse or progression prior to receiving radiation therapy is evaluable. 
 
     Safety Monitoring and Stopping Rule 
To address the primary objective of the utility of eliminating radiation therapy, the following one-
stage monitoring rule will be used: Of the first 10 evaluable patients enrolled, if at any time 3 or 
more patients have an event (relapse, progression, or death due to disease), then the study will 
be stopped and we will conclude that removal of radiation therapy is unsafe in children with 
standard risk, Wnt-positive medulloblastoma.  If there are 2 or fewer children who have an event 
out of 10, then we will conclude that removal of radiation therapy in children with standard risk, 
Wnt-positive medulloblastoma is feasible.  This rule tests the null hypothesis that the proportion 
of patients with relapse/progression/disease-death by 2-years is ≤0.1versus the alternative that 
it is ≥0.45, with 90% power and alpha=0.07.  The choices of the null and alternative were based 
on the results of Packer et al (10). 
Methods to address study objectives:  To address the primary objective, the stopping rule 
above will be applied.  To address the secondary objectives, the data will be descriptively 
summarized.  Kaplan-Meier curves of PFS and OS will be generated.  Toxicities will be 
tabulated. 
 
19. PUBLICATION PLAN 
 
The study team will aim to publish the study results within 24 months of the end of data 
collection in a peer reviewed journal.