Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Phase: PHASE2
Conditions: Brain and Central Nervous System Tumors
Sponsor: St. Jude Children's Research Hospital

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
SJCRH 
SJYC07 CTG# - NCT00602667 
Initial version, dated:  7/25/2007, Resubmitted to CPSRMC 9/24/2007 and 10/6/2007 
(IRB Approved: 11/09/2007)  Activation Date: 11/27/2007 
 
Amendment 1.0 dated January 23, 2008, submitted to CPSRMC: January 23, 2008, IRB Approval: March 10, 2008    
Amendment 2.0 dated April 16, 2008, submitted to CPSRMC: April 16, 2008,   (IRB Approval:  May 13, 2008)   
Revision 2.1 dated April 29, 2009 (IRB Approved:  April 30, 2009   )    
Amendment 3.0 dated June 22, 2009, submitted to CPSRMC: June 22, 2009 (IRB Approved: July 14, 2009)    
Activated: August 11, 2009 
Amendment 4.0 dated March 01, 2010 (IRB Approved: April 20, 2010)   Activated: May 3, 2010      
Amendment 5.0 dated July 19, 2010 (IRB Approved:  Sept 17, 2010) Activated: September 24, 2010 
Amendment 6.0 dated August 27, 2012 (IRB approved: September 24, 2012) Activated: October 18, 2012 
Amendment 7.0 dated February 22, 2013 (IRB approved: March 13, 2013) Activated: April 4, 2013 
Amendment 8.0 dated March 20, 2014. Resubmitted to IRB May 20, 2014 (IRB approved: May 22, 2014) Activated: May 30, 2014 
Amendment 9.0 dated August 26, 2014.  (IRB approved: October 14, 2014) Activated: November 4, 2014 
Un-numbered revision dated March 22, 2018. (IRB approved: March 27, 2018)  
Un-numbered revision dated October 22, 2018 (IRB approved: 10-24-2018) 
 
 
RISK-ADAPTED THERAPY FOR YOUNG CHILDREN WITH EMBRYONAL BRAIN TUMORS, 
HIGH-GRADE GLIOMA, CHOROID PLEXUS CARCINOMA OR EPENDYMOMA (SJYC07) 
 
Principal Investigator 
Amar Gajjar, M.D. 
Division of Neuro-Oncology 
Department of Oncology 
 
Section Coordinators 
David Ellison, M.D., Ph.D. 
Department of Pathology 
 
Thomas E. Merchant, D.O., Ph.D. 
Department of Radiation Oncology 
 
Eugene Reddick, Ph.D. 
Department of Diagnostic Imaging 
 
Arzu Onar-Thomas, Ph.D. 
Department of Biostatistics 
 
Heather Conklin, Ph.D. 
Department of Psychology 
 
Clinton F. Stewart, Pharm.D. 
Department of Pharmaceutical Sciences 
 
Other Investigators 
Giles Robinson, M.D. 
Ibrahim Qaddoumi, M.D. 
Division of Neuro-Oncology 
Department of Oncology 
 
Greg Armstrong, M.D. 
Department of Epidemiology & Cancer Control 
 
Catherine Billups, M.S. 
Jie Huang, M.S.  
Department of Biostatistics 
 
Matthew J. Krasin, M.D. 
Department of Radiation Oncology 
 
Noah Sabin, M.D. 
Zoltan Patay, M.D., Ph.D 
Department of Diagnostic Imaging 
 
 
Fredrick Boop, M.D.  
Department of Neurosurgery 
 
 
Brent Orr, M.D. Ph.D. 
Department of Pathology 
St. Jude Children's Research Hospital 
262 Danny Thomas Place 
Memphis, Tennessee  38105-2794 
Telephone:  (901) 595-3300 
This is a confidential research document.  No information may be extracted without permission of the Principal Investigator  

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
UNIVERSITY OF FLORIDA INVESTIGATORS 
 
 
Robert B. Marcus, Jr., M.D. 
Professor 
Department of Radiation Oncology 
University of Florida  
 
 
Nancy P. Mendenhall, M.D. 
Medical Director, UFPTI 
Professor & Associate Chairman 
Department of Radiation Oncology 
University of Florida 
 
 
Daniel J. Indelicato, M.D. 
Assistant Professor 
Department of Radiation Oncology 
University of Florida 
 
 
Zuofeng Li, D.Sc. 
Associate Professor 
Department of Radiation Oncology 
University of Florida 
  
 
 
 

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
COLLABORATING INVESTIGATORS: 
 
 
 
Daniel Bowers, MD 
University of Texas Southwestern Medical Center at Dallas  
Dallas, Texas 
 
Sonia Partap, MD 
Stanford University 
Palo Alto, California 
 
Anne Bendel, MD 
Children's Hospitals and Clinics of Minnesota  
Minneapolis, Minnesota 
 
Tim Hassall, MBBS, FRACP 
Royal Children’s Hospital in Brisbane 
Brisbane, Qld AUSTRALIA 
 
John Crawford, MD, MS 
University of California, San Diego  
San Diego, California 
 

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
Protocol summary 
SJYC07, Risk-Adapted Therapy for Young Children with Embryonal Brain Tumors, 
High-Grade Glioma, Choroid Plexus Carcinoma or Ependymoma 
Principal Investigator:  Amar Gajjar, M.D. 
IND holder:  Not applicable, non-IND study 
Brief overview:  Children younger than 3 years of age with newly diagnosed medulloblastoma, 
supratentorial primitive neuroectodermal tumor (PNET), atypical teratoid/rhabdoid tumor 
(ATRT), high-grade glioma, choroid plexus carcinoma (CPC) or ependymoma. Children ≥ 3 and 
< 5 years of age with newly diagnosed non-metastatic medulloblastoma are also eligible  
Intervention:  multi-modality, according to risk assignment 
Drugs:  Methotrexate, vincristine, cisplatin, cyclophosphamide, vinblastine, carboplatin, 
etoposide, topotecan, erlotinib 
Other:  Focal radiation therapy, craniospinal irradiation 
Brief outline of treatment plan:   
All participants will receive 4 identical cycles of induction chemotherapy including high-dose (5 
g/m2 or 2.5g/m2 for patients less than or equal to 31 days of age at enrollment) intravenous 
methotrexate and standard dose vincristine, cisplatin, and cyclophosphamide.  Patients enrolled 
on the high-risk arm will also receive low-dose vinblastine between induction cycles.  Induction 
will be followed by risk-adapted consolidation therapy: low-risk patients will receive further 
conventional chemotherapy with carboplatin, cyclophosphamide, and etoposide; intermediate 
risk patients will receive focal radiotherapy (RT) to the tumor bed; high-risk patients will receive 
either chemotherapy with targeted intravenous topotecan and cyclophosphamide or optional 
craniospinal irradiation (CSI).  CSI will be offered only to patients who reach 3 years of age by 
the end of induction only.   After consolidation, all patients will receive 6 cycles of oral 
maintenance chemotherapy with cyclophosphamide, topotecan, and depending on the diagnosis, 
either erlotinib or etoposide (VP-16). 
 
            Induction                       Consolidation                                Maintenance  
           (16 weeks)                         (8 weeks)                                     (24 weeks)  
 
 MTX/VCR/CDDP/CPM         CPM/Carbo/VP16 (Low Risk)                  PO CPM/Topo alternating      
   (+VBL for High-risk)           Focal RT (Intermediate Risk)                      with Erlotinib or VP16 
                                                  Topo/CPM or CSI (High Risk)   
            

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
Study design:  Exploratory study utilizing risk-adapted multi-modality treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample size:  Target accrual is 90 medulloblastoma patients.  The projected total accrual for 
the entire study including patients with other tumor types is 315. 
Data management:  Data management and statistical analysis will be provided locally by the 
Division of Neuro-Oncology and the Department of Biostatistics at St. Jude Children’s 
Research Hospital. 
Human subjects:  The main risk to research participants will be the potential toxicities 
associated with the use of the multi-modality therapy.  The research participants will be 
informed of the toxicities that have been associated with the study drugs and potential side 
effects of procedures recommended in this study.  Adverse events will be monitored, treated, 
and reported following institutional and federal guidelines and regulations. 
M Stage 
Diagnosis 
Extent of Resection 
Histologic Subtype 
Age at Diagnosis 
High Risk 
Intermediate Risk 
Low Risk 
M1+
M0 
Other                
(PNET, ATRT, 
Medulloblastoma 
High Grade 
Glioma 
< GTR 
 GTR 
Other       
(Classical, 
anaplastic) 
Nodular 
Desmoplastic 
>3 to 
<5 yrs 
< 3 yrs  

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
TABLE OF CONTENTS 
   
1.0 
OBJECTIVES ......................................................................................................................... 1 
1.1 PRIMARY OBJECTIVES .............................................................................................. 1 
1.2 SECONDARY OBJECTIVES ......................................................................................... 1 
2.0 
BACKGROUND AND RATIONALE .................................................................................. 4 
2.1 OVERVIEW ............................................................................................................... 4 
2.2 RESULTS OF CLINICAL TRIALS FOR INFANTS AND YOUNG CHILDREN WITH BRAIN 
TUMORS ................................................................................................................... 6 
2.3 RATIONALE FOR TUMOR BIOLOGY STUDIES .......................................................... 16 
2.4 RATIONALE FOR TREATMENT ................................................................................ 21 
2.5 RATIONALE FOR PHARMACOKINETIC/PHARMACOGENETIC STUDIES ...................... 44 
2.6 RATIONALE FOR CNS NEUROTRANSMITTER STUDIES ............................................ 52 
2.7 RATIONALE FOR NEUROCOGNITIVE STUDIES ......................................................... 54 
2.8 RATIONALE FOR DIAGNOSTIC IMAGING STUDIES ................................................... 57 
2.9 RATIONALE FOR GROWTH HORMONE SECRETION TESTING BEFORE AND AFTER 
RADIATION THERAPY ............................................................................................ 59 
3.0 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ............................................ 60 
3.1 INCLUSION CRITERIA FOR ALL PATIENTS............................................................... 60 
3.2 CRITERIA FOR ASSIGNMENT TO THE LOW-RISK ARM OF THE PROTOCOL ............... 61 
3.3 CRITERIA FOR ASSIGNMENT TO THE INTERMEDIATE-RISK ARM OF THE PROTOCOL62 
3.4 CRITERIA FOR ASSIGNMENT TO THE HIGH-RISK ARM OF THE PROTOCOL .............. 63 
3.5 SYNCHRONOUS EXTRANEURAL ATRT ................................................................... 63 
3.6 ENROLLMENT ON STUDY ....................................................................................... 63 
4.0 
TREATMENT PLAN ........................................................................................................... 64 
4.1 SURGICAL MANAGEMENT ...................................................................................... 66 
4.2 INDUCTION ............................................................................................................. 66 
4.3 CONSOLIDATION .................................................................................................... 70 
4.4 MAINTENANCE TREATMENT ................................................................................... 74 
4.5 DOSE MODIFICATIONS DURING TREATMENT .......................................................... 77 
4.6 RADIOTHERAPY GUIDELINES ................................................................................. 81 
4.7 CONCURRENT TREATMENT AND SUPPORTIVE CARE GUIDELINES .......................... 94 
5.0 
DRUG INFORMATION ...................................................................................................... 96 
5.1 METHOTREXATE .................................................................................................... 96 
5.2 LEUCOVORIN (FOLINIC ACID) ................................................................................. 98 
5.3 VINCRISTINE (ONCOVIN) .................................................................................... 98 
5.4 CISPLATIN (PLATINOL-AQ) ................................................................................ 99 
5.5 CYCLOPHOSPHAMIDE (CYTOXAN) .................................................................... 100 
5.6 MESNA (MESNEX) ............................................................................................ 101 
5.7 G-CSF (FILGRASTIM) (NEUPOGEN) .................................................................. 102 
5.8 VINBLASTINE (VELBAN) ................................................................................... 102 
5.9 CARBOPLATIN (PARAPLATIN) ........................................................................... 103 
5.10 ETOPOSIDE (VP-16) (VEPESID) ..................................................................... 104 
5.11 TOPOTECAN (HYCAMTIN) ............................................................................. 105 
5.12 ERLOTINIB HYDROCHLORIDE (TARCEVA) ..................................................... 106 

Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
6.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS ..................................................... 108 
6.1 EVALUATIONS TO BE OBTAINED AT ENROLLMENT .............................................. 108 
6.2 EVALUATIONS DURING THERAPY ........................................................................ 109 
6.3 LONG-TERM FOLLOW-UP EVALUATIONS ............................................................. 111 
7.0 
NEUROPATHOLOGY GUIDELINES ............................................................................ 112 
7.1 CENTRAL REVIEW OF PATHOLOGY ...................................................................... 112 
7.2 METHODS ............................................................................................................ 112 
8.0 
CORRELATIVE STUDIES ............................................................................................... 113 
8.1 BIOLOGICAL STUDIES ON TUMOR TISSUE ............................................................ 113 
8.2 PHARMACOKINETIC AND PHARMACOGENETIC STUDIES ....................................... 122 
8.3 CSF NEUROTRANSMITTER STUDIES ..................................................................... 129 
8.4 NEUROCOGNITIVE STUDIES.................................................................................. 132 
8.5 DIAGNOSTIC IMAGING STUDIES ........................................................................... 140 
     8.6 ENDOCRINE STUDIES FOR PATIENTS RECEIVING PROTON BEAM RADIATION….. 142  
9.0 
EVALUATION CRITERIA .............................................................................................. 143 
9.1 RESPONSE CRITERIA ............................................................................................ 143 
9.2 TOXICITY EVALUATION CRITERIA ....................................................................... 143 
10.0 
OFF THERAPY AND OFF STUDY CRITERIA ........................................................ 145 
10.1 OFF THERAPY CRITERIA .................................................................................. 145 
10.2 OFF STUDY CRITERIA ...................................................................................... 146 
11.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ................... 146 
11.1 REPORTING ADVERSE EVENTS AND DEATHS ON TREATMENT ......................... 146 
11.2 REPORTING TO IRB .......................................................................................... 149 
12.0 
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY ..... 150 
      12.1   DATA COLLECTION AT ST. JUDE AND COLLABORATING SITES ……………….147 
12.2 STUDY MONITORING ........................................................................................ 150 
12.3 MONITORING FEASIBILITY OBJECTIVES ........................................................... 151 
12.4  MONITORING FOR EXCESSIVE TOXICITY IN THE PRESENCE OF PROTON BEAM 
RADIATION THERAPY (PBRT) ............................................................................. 152 
12.5 CONFIDENTIALITY ........................................................................................... 152 
13.0 
STATISTICAL CONSIDERATIONS .......................................................................... 155 
13.1 PRIMARY OBJECTIVES ...................................................................................... 155 
13.2 ANALYSIS PLAN FOR SECONDARY OBJECTIVES ............................................... 179 
14.0 
OBTAINING INFORMED CONSENT ........................................................................ 197 
14.1 INFORMED CONSENT PRIOR TO RESEARCH INTERVENTIONS ............................ 197 
14.2 CONSENT WHEN ENGLISH IS NOT THE PRIMARY LANGUAGE .......................... 197 
14.3 COLLECTION OF COLLABORATING INSTITUTION CONSENT FORMS .................. 197 
15.0 
REFERENCES ................................................................................................................ 198 
Appendices 
Appendix I: 
Drugs That May Affect Cyclophosphamide/4-HCY or Erlotinib/OSI-420 Metabolism 
Appendix II:  Lansky Performance Scale  
Appendix III: Treatment of Synchronous Extraneural ATRT 
Appendix IV: Ototoxicity Grading Criteria  
Appendix V: High-tyramine Foods to Avoid 72 Hours Prior to CSF Neurotransmitter Sampling 
Appendix VI:  Recommended Treatment for Patients with Progressive Disease 
Appendix VII:  Required Data and Time Table for Submission 
Appendix VIII:  RSV Treatment Guidelines 

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Page 1 of 221 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
1.0 
OBJECTIVES 
 
1.1 
PRIMARY OBJECTIVES 
 
1.1.1 Biology: To identify patterns of   methylation profiling  that are associated 
with progression-free survival among young patients with medulloblastoma 
treated with risk-adapted therapy. 
Responsible Investigators: Amar Gajjar, Giles. Robinson 
 
Responsible Biostatistician: Arzu Onar-Thomas, Tong Lin 
 
1.1.2 Therapeutic: To estimate the event free survival distribution of young 
medulloblastoma patients treated with risk-adapted therapy. 
Responsible Investigator: Amar Gajjar 
 
Responsible Biostatistician: Arzu Onar-Thomas 
 
1.2 
SECONDARY OBJECTIVES 
 
1.2.1 Biological aims 
Responsible Investigatords: Amar Gajjar, Giles Robinson 
Responsible Biostatistician: Arzu Onar-Thomas, Tong Lin 
• To perform high resolution genome-wide analyses of chromosomal 
abnormalities and gene expression patterns, and evaluate the relationship 
of these to other clinicopathological variables. 
 
• To evaluate specific tumor types for molecular abnormalities with 
suspected prognostic or therapeutic significance.  
 
• To evaluate the feasibility of collecting frozen and fixed tumor samples 
for analysis using high-resolution molecular biology tools. 
 
1.2.2 Therapeutic aims 
Responsible Investigator: Amar Gajjar 
 
Responsible Biostatistician: Arzu Onar-Thomas 
• To estimate the event free and overall survival of patients treated with 
the proposed risk-adapted therapy regimen, and to descriptively compare 
these survival rates to historical controls. 
 
• To estimate the rates of local and distant disease progression in patients 
treated with focal radiotherapy (RT) to the post-operative tumor bed 
using a 5 mm clinical target volume margin. 
 
• To estimate the objective response rate (sustained for 8 weeks) to 
induction chemotherapy including high-dose intravenous methotrexate 
for patients with residual or metastatic disease. 
 

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IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
• To evaluate the feasibility and toxicity of administering low dose 
intravenous vinblastine in conjunction with induction chemotherapy to 
patients with metastatic disease. 
 
• To evaluate the feasibility and toxicity of administering consolidation 
therapy including cyclophosphamide and pharmacokinetically targeted 
topotecan to patients with metastatic disease, and to estimate the 
sustained (for 8 weeks) objective response rate (complete response and 
partial response, as defined in section 9.1) to such therapy in patients 
with measurable residual disease after induction. 
 
• To evaluate the feasibility and toxicity of administering oral 
maintenance therapy in young children. 
 
• To use quantitative MR measures (volumetric, diffusion, and perfusion) 
of young brain tumor patients receiving chemotherapy including high-
dose intravenous methotrexate to assess impact of treatment on 
developing brain. 
 
• Investigate the feasibility of using PET as an in-vivo dosimetric and 
distal edge verification system for patients treated with proton beam 
therapy (for participants enrolled at St Jude only). 
 
1.2.3 Pharmacologic Aims 
Responsible Investigator: Clinton Stewart 
Responsible Biostatistician: Arzu Onar-Thomas 
 
• To develop a population pharmacokinetic model containing covariates 
which explain inter- and intra-patient pharmacokinetic variability for 
high-dose methotrexate in young children with brain tumors, and to 
explore the relationship between clinical effect (toxicity and antitumor 
efficacy) and methotrexate pharmacokinetics. 
 
• To assess the extent of inter-patient variability in the pharmacokinetics 
of intravenous and oral cyclophosphamide and metabolites in young 
children with brain tumors, and to explore possible associations between 
cyclophosphamide pharmacokinetic parameters and patient specific 
covariates (e.g., age, sex, race, weight). 
 
• To assess the ability to achieve the target systemic exposure of 
intravenous topotecan in young patients with metastatic brain tumors. 
 
• To assess the extent of inter-patient variability in the pharmacokinetics 
of intravenous and oral topotecan in young children with brain tumors, 
and explore possible associations between topotecan systemic exposure 
and patient specific covariates (e.g., age, sex, race, weight). 

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Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
• To assess the extent of inter-patient variability in the pharmacokinetics 
of oral erlotinib in young children with medulloblastoma and 
ependymoma, and explore possible associations between erlotinib 
pharmacokinetic parameters and patient specific covariates (e.g., age, 
sex, race, weight). 
 
• For St. Jude patients enrolled on the PGEN5 protocol, to assess the 
relation between pharmacogenetic variation in drug metabolizing 
enzymes and drug transporters, and the pharmacokinetics of 
methotrexate, cyclophosphamide, topotecan, and erlotinib in young 
children with brain tumors. 
 
1.2.4 Cancer control aims 
 
• To explore possible associations between cerebrospinal fluid (CSF) 
neurotransmitter concentrations, with emphasis placed upon 
concentrations of dopamine and its metabolites, and the development of 
neurocognitive deficits as identified by standardized tests. 
Responsible Investigator: Clinton Stewart; Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 
• To explore the association between genetic polymorphisms affecting 
central dopaminergic transmission and specific phenotypes, including 
CNS neurotransmitter and neurocognitive performance phenotypes. 
Responsible Investigators: Clinton Stewat; Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 
• To investigate changes in neuropsychological performance among 
patients enrolled in the study, and examine the impact of the proposed 
treatment regimen and other disease related factors (e.g., hydrocephalus) 
on neuropsychological performance. 
Responsible Investigator: Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 
o Hypothesis 1: There will be a decline (negative slope) in global 
cognitive functioning for the group as a whole. 
 
o Hypothesis 2: Hydrocephalus (correcting for CSF diversion) will be 
associated with a steeper decline in global cognitive functioning. 
 
o Hypothesis 3: Higher radiation doses to specified structures (e.g., the 
frontal lobes) will be associated with steeper declines on related 
functions (e.g., attention and working memory). 
 

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Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
• To assess the impact of changes in quantitative MR measures in the 
frontal lobe on neurocognitive performance in attention, working 
memory, and fluency. 
Responsible Investigator: Eugene Reddick, Heather Conklin 
Responsible Biostatistician: Hui Zhang 
• To assess the impact of changes in quantitative MR measures in the right 
frontal-parietal regions on neurocognitive performance on visual-spatial 
reasoning and processing speed. 
Responsible Investigator: Eugene Reddick, Heather Conklin 
Responsible Biostatistician: Hui Zhang 
• To assess the incidence of endocrinopathy after radiation therapy using 
photons or protons (for participants enrolled at St Jude only). 
Responsible Investigator: Thomas Merchant 
Responsible Biostatistician: Arzu Onar-Thomas 
 
• To estimate the rate of longitudinal change in growth hormone secretion 
after conformal, intensity-modulated and proton beam radiation therapy 
(for participants enrolled at St Jude only). 
Responsible Investigator: Thomas Merchant 
Responsible Biostatistician: Arzu Onar-Thomas 
  
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
OVERVIEW 
 
Medulloblastoma and other embryonal tumors such as ATRT and supratentorial 
PNET are the most common malignant brain tumors to arise in children.1 Treatment 
which includes craniospinal irradiation (CSI) has significantly improved the long-
term survival of older children with medulloblastoma;2-4 however, CSI damages the 
developing brain resulting in severe neurocognitive5 and endocrine6,7 sequelae. 
Thus, CSI is generally not administered to children less than three years of age. 
Because of this limitation in therapy, and likely also because of inherent differences 
in tumor biology, children less than three years old with embryonal tumors 
generally have a poor prognosis.8,9  In order to limit the long-term sequelae of CSI, 
clinical trials in young children have attempted to substitute or delay CSI with 
intensive adjuvant chemotherapy.  This approach has resulted in improved survival 
for selected groups of patients, most notably those with localized, completely 
resected medulloblastoma.  For the majority of young patients, however, long-term 
survival rates remain poor, despite very aggressive treatment.  Furthermore, these 
chemotherapeutic regimens may also be associated with significant toxicity, with 
toxic death rates exceeding 10% in some trials.10  New treatment strategies will be 
needed in order to improve survival without further increasing toxicity. 
 

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IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
A variety of novel treatments are now being developed which have more specific 
activity against tumor cells than standard cytotoxic agents, and thus avoid many of 
the typical toxicities of conventional cytotoxic chemotherapy.  Among the most 
promising are molecularly targeted agents such as the small molecule tyrosine 
kinase inhibitors,11 and treatments directed against the tumor vasculature.12  It is 
anticipated that such specific therapies may eventually replace conventional 
cytotoxic agents entirely, but this will be a gradual process, and must be based on a 
firm understanding of tumor biology.  For this transition to occur, molecular targets 
which are critical for tumor proliferation or survival must be identified first.  The 
use of molecular targeted therapies for the treatment of young patients is likely to 
be especially challenging since the cell signal pathways that are dysregulated during 
tumorigenesis often control normal development. Once appropriate targets are 
identified, drugs with activity against these targets must be developed, and clinical 
trials then conducted to evaluate the toxicity and efficacy of these agents, and to 
determine the appropriate means of integrating them with standard therapies. 
 
For medulloblastoma and the other brain tumors of young children, molecularly 
targeted therapies are in early development, because little is known about the 
molecular pathophysiology of these tumors.  The focus of the current protocol will 
therefore be a comprehensive study of genome-wide patterns of gene expression 
and chromosomal alteration in medulloblastomas arising in children younger than 
three years, with the following goals: 
 
• Increased understanding of molecular pathways implicated in tumor 
development 
• Detection of molecular subtypes of potential biological, clinicopathological, 
or therapeutic significance 
• Identification of potential molecular therapeutic targets 
 
The backbone of the treatment plan will include the therapies that have been the 
most effective and least toxic in prior clinical trials involving this patient 
population.  The intensity of therapy will be based on the known prognostic factors 
of stage, extent of resection, and histopathological variant.  Novel therapies will be 
included throughout the treatment regimen for patients with high risk (metastatic) 
disease, and in a maintenance phase for all patients. 
 
In addition to biological studies involving tumor tissue, a variety of other 
correlative studies will be included.  These studies will help us to optimize the 
treatment of brain tumors in children younger than 3 years of age by thoroughly 
examining the factors which affect drug pharmacokinetics and activity, treatment 
toxicity, and patient outcome. 

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Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
2.2 
RESULTS OF CLINICAL TRIALS FOR INFANTS AND YOUNG CHILDREN WITH BRAIN 
TUMORS 
 
Clinical trials for infants and young children with brain tumors have been 
characterized by small sample sizes and considerable heterogeneity in both 
enrollment criteria and treatment strategies, thus making it difficult to directly 
compare results between studies. Investigators have often used the term “infant” to 
describe the patient population treated, but in fact these trials vary substantially in 
the age of patients enrolled, with some including only patients younger than 18 
months of age,13 and others enrolling children as old as 6 years of age.10  In the 
following discussion the phrase “infants and young children” will be used to refer 
generally to children considered too young to receive CSI, keeping in mind that the 
threshold for routine use of CSI has been defined differently in different trials.  The 
specific age range included in a particular trial will be noted whenever it is 
pertinent.  Treatments have also varied considerably among different trials, as has 
the terminology used to describe those treatments.   CSI consistently refers to 
irradiation of the whole brain and spine, and implies the use of an additional 
“boost” dose to the tumor bed or surrounding area.  However, the dose of CSI, and 
the dose and target volume of boost therapy vary considerably between trials and 
patients.  As discussed in detail below, one strategy for avoiding CSI has been to 
eliminate the RT dose to the whole brain and spine, and administer RT only to the 
tumor bed and/or surrounding area.  This more restricted RT administration has 
been described variously as “focal (or local) RT,” “tumor bed irradiation,” 
“posterior fossa irradiation,”or “involved-site RT.”  The dose to the tumor bed has 
varied (generally between 45.0 and 54.0 Gy), as have the clinical target volume 
(CTV; 1.0 to 2.0 cm), and, for posterior fossa tumors, the dose to the entire 
posterior fossa (none to 36.0 Gy).  In order to simplify the following discussion, 
“CSI” will be used to refer to any RT regimen which includes the entire brain and 
spine, regardless of dose, and “focal RT” will refer to any RT regimen which does 
not include the entire brain and spine, regardless of the dose, CTV, or inclusion of 
additional RT to the entire posterior fossa.   
 
2.2.1 Medulloblastoma results 
 
The results of major clinical trials conducted among infants and young children 
with medulloblastoma are summarized in Table 1.   

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Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
 
 
2.2.1.1 Delayed RT trials 
 
Once the severe long-term neurocognitive sequelae associated with the use of CSI 
in infants and young children became recognized in the 1980s, investigators began 
to explore alternatives to the immediate postoperative CSI used in older children.     
Early trials for infants and young children with medulloblastoma attempted to use 
chemotherapy to delay CSI, with mixed results.  Based on encouraging results from 
a pilot study by van Eys, et al.,20 the Pediatric Oncology Group (POG) implemented 
the delayed CSI approach in the POG 8633/34 (Baby POG-1) trial.14,15  In Baby 
POG-1, children younger than 3 years of age were treated with chemotherapy 
consisting of vincristine, cyclophosphamide, etoposide, and cisplatin, followed by 
CSI at one or two years post-diagnosis, depending on age.  CSI was successfully 
delayed in only 40% of patients, 5-year PFS for all medulloblastoma patients was 
31.8±8.3% and 5-year was OS 39.7±6.9%.  Medulloblastoma patients treated on 
TABLE 1 RESULTS OF PROSPECTIVE CLINICAL TRIALS FOR INFANTS AND YOUNG CHILDREN WITH  
MEDULLOBLASTOMA 
 
Event Free Survival  
(%±SE) 
Overall Survival 
(%±SE) 
Reference 
Trial 
n 
1 year 
5 year 
5 year 
 
M0 No Residual 
Baby POG 
13 
 
 
69 
14,15 
CCG 9921 
38 
66 ± 8 
41 ± 8 
54 ± 8 
16 
SFOP  
47 
 
29  
(95% CI 18-44) 
73 
(95% CI 59-84) 
17 
HIT-SKK92 
17 
 
82 ± 9 
93 ± 6 
18 
Head Start I+II (age <3) 
14 
 
64 ± 13 
86 ± 9 
ISPNO 2006 
PBTC-001 
20 
70 ± 10 
 
 
PBTC 2006 
M0 With Residual 
CCG9921 
23 
43 ± 10 
26 ± 9 
40 ± 11 
16 
SFOP 
17 
 
6  
(95% CI 1-27) 
41 
(95% CI 22-64) 
17 
HIT-SKK92 
14 
 
50 ± 13 
56 ± 14 
18 
Head Start I+II (age <3) 
7 
 
29 ± 17 
57 ± 19 
ISPNO 2006 
PBTC-001 
7 
51 ± 18 
 
 
PBTC 2006 
M0 All Resections 
Head Start I+II (age <3) 
21 
86 ± 8 
52 ± 11 
75 ± 10 
ISPNO 2006 
99703 
24 
 
3-yr EFS ~70 
 
COG 2006 
PBTC-001 
27 
66± 9   
 
 
PBTC 2006 
St. Jude  
(1998 and later) 
20 
78.7 
(95% CI 63-99.7) 
67.0 
(95% CI 48-93) 
 
 
M+ 
CCG-9921 
31 
42 ± 9 
25 ± 8 
31 ± 9 
16 
SFOP 
15 
 
13 (95%CI 4-38) 
13 (95%CI 4-38) 
17 
HIT-SKK92 
12 
 
33 ± 14 
38 ± 15 
 
Head Start II  (age< 6) 
21 
 
 3-yr EFS 49 
(95%CI 27-72) 
3-yr OS 60 
(95%CI 36-84) 
19 

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Baby POG-1 with M0 disease and gross total resection had a relatively good 
prognosis, with a 5-year OS of 69%.  The subsequent POG study 9233/34 (Baby 
POG-2) attempted to improve survival by intensifying the chemotherapy regimen; 
patients were randomly assigned to receive either standard Baby POG-1 treatment 
or an intensified version of Baby POG-1 therapy in which the drugs were 
administered at higher doses and more frequently. There was no difference in event 
free or overall survival between patients receiving standard or intensified Baby 
POG therapy (POG 9233/34 final progress report, spring 2003 COG meeting).   
 
A delayed RT approach was also used in the Children’s Cancer Group CCG-921 
trial, which ran concurrently with Baby POG-1.  The CCG-921 treatment plan 
called for children younger than 18 months of age to receive the “8 drugs in 1 day” 
chemotherapy regimen, followed by delayed CSI or focal RT.  In fact, only 9 of 91 
patients < 18 months of age at diagnosis received RT as planned.  Three-year PFS 
was 22% for all posterior fossa PNET (medulloblastoma) patients, and posterior 
fossa PNET patients with completely resected M0 disease had a 5-year PFS of 
30%.13  As in the POG, the subsequent CCG trial (CCG-9921) attempted to 
improve survival through the use of more intensive chemotherapy.  CCG-9921 
enrolled children younger than 3 years of age; patients were randomly assigned to 
receive one of two 5-cycle induction chemotherapy regimens, followed by a 
uniform regimen of maintenance chemotherapy for 56 weeks.  Patients with 
residual or metastatic disease were to receive CSI or focal RT at the end of 
maintenance or at 3 years of age, whichever came earlier.  As in the prior CCG trial, 
only a minority (40%) of patients received RT as planned.  There was no difference 
in EFS or OS between chemotherapy arms, and outcomes were similar to Baby 
POG-1, with a 5-year EFS for all medulloblastoma patients of 32±5% and 5-year 
OS for completely resected M0 medulloblastoma of 54±8%.16    
 
The above studies demonstrated that CSI can be delayed without compromising 
survival in a subset of medulloblastoma patients younger than 3 years of age at 
diagnosis.  It has subsequently become apparent, however, that delaying CSI does 
not result in substantially better neurocognitive outcomes than administering CSI 
immediately after resection.  During the 1980s and early 1990s, medulloblastoma 
patients younger than 3 years of age were treated at St. Jude with delayed CSI 
according to the Baby POG trials or very similar St. Jude institutional protocols, 
with OS and EFS comparable to that achieved on the POG and CCG trials.8,9    In a 
review of the St. Jude experience with delayed radiation, median IQ for survivors of 
infant medulloblastoma fell from a baseline median of 88 (range 50 to 111) to a 
median 62 (range 44 to 86) at a median follow up time of 4.8 years (range 2 to 10.6 
years).9 The suboptimal survival and neurocognitive results attained with delayed 
CSI have prompted investigators to look for alternative approaches.   
 
2.2.1.2 Alternatives to CSI 
 
One potential alternative to delayed CSI is to administer RT only when 
chemotherapy is ineffective.  This approach was used in the French BBSFOP trial, 

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in which medulloblastoma patients younger than 4 years of age received 
chemotherapy for one year, with RT only in cases of recurrence or progression.  
The BBSFOP chemotherapy regimen was relatively mild, and failures were 
frequent; the 5-year PFS was 29% (95% CI 18-44) for completely resected M0 
medulloblastoma.  Many patients were effectively salvaged with RT (either CSI or 
focal RT, depending on the extent of disease) and high-dose chemotherapy.  The 
salvage regimen resulted in 5-year OS for completely resected M0 medulloblastoma 
which was similar to Baby POG-1 (73%, 95% CI 59-84).17  
 
Another strategy to avoid CSI is to include methotrexate in the chemotherapy 
regimen.  Two small trials incorporating methotrexate-based chemotherapy as have 
demonstrated improvements in long-term survival compared to the POG and CCG 
trials.  The best published results for medulloblastoma patients without macroscopic 
metastasis come from the German HITSKK92 trial, which included a combination 
of intraventricular and high-dose intravenous methotrexate, in addition to standard 
chemotherapy.18 Patients aged less than 3 years old with completely resected 
M0/M1 medulloblastoma (n=17) had a 5-year PFS of 82±9%, and 5-year OS of 
93±6%.  Outcomes in patients with residual disease (n=14, 5-year PFS 50±13%, 
and 5-year OS of 56±14%) and macroscopic metastasis (n=12, 5-year PFS 33±14%, 
and 5-year OS of 38±15%) were also somewhat better than in prior series.  
However, 19 of 23 evaluated HITSKK92 patients had evidence of 
leukoencephalopathy on MRI.  These results suggest that the apparent improvement 
in survival gained through the incorporation of both intravenous and 
intraventricular methotrexate came at the cost of neurotoxicity.  The best published 
results for young children with metastatic medulloblastoma were generated by the 
Head Start II trial, which used five cycles of induction chemotherapy including IV 
methotrexate (400mg/kg), followed by a consolidation regimen of myeloablative 
chemotherapy with autologous stem cell rescue (ASCR).  The majority of patients 
(82%) had a CR to induction chemotherapy, and 3-year EFS and OS were 49% 
(95%CI 27-72) and 60% (95%CI 36-84), respectively.  While encouraging, 
interpretation of these results is limited by the small size of the study and inclusion 
of older children (only 9 patients under age 3 years at diagnosis were enrolled).21   
The use of high-dose chemotherapy with ASCR has been advocated as an 
alternative to craniospinal irradiation.  The Head Start I and II trials treated patients 
with localized medulloblastoma with 5 induction cycles very similar to regimen A 
of CCG-9921, followed by a single consolidation course of high-dose carboplatin, 
thiotepa, and etoposide with ASCR. The toxicity associated with the Head Start 
regimen was substantial, with toxic death occurring in 6% of patients during 
induction; of the patients who went on to receive consolidation with ASCR, an 
additional 8% died from treatment complications.10  Final results from the Head 
Start I and II trials were reported in abstract form at the Spring 2006 International 
Symposium on Pediatric Neuro-Oncology (ISPNO); for the 14 patients with 
completely resected medulloblastoma, 5-year EFS was 64±13%, and 5-year OS 
86±9%.  The Head Start regimen became the basis for the recent CCG 99703 trial, 
in which patients received three cycles of intensive standard chemotherapy 
followed by three cycles of high dose chemo with ASCR.  Preliminary results 

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suggest an improvement in 3-year EFS and OS for patients with medulloblastoma 
when compared with CCG-9921, but final assessment of the relative efficacy of 
99703 versus 9921 will depend on longer follow-up and formal analysis of 
prognostic factors. An important limitation of this trial is that the use of RT was left 
to the discretion of the investigator.  Data regarding which patients received RT, 
how long RT was delayed, and the dose and extent of RT (focal vs. CSI) were not 
collected as a component of this trial, thus making it difficult to draw conclusions 
about the effectiveness of this chemotherapy regimen.   
 
One additional alternative to CSI is the use of focal RT for patients with localized 
disease.  This strategy has been implemented in two recent trials.  The COG P9934 
study included focal RT after 16 weeks of induction chemotherapy for patients with 
localized, completely resected medulloblastoma.  Survival results from this trial 
have not yet been reported.  In PBTC-001, patients received standard chemotherapy 
plus intrathecal mafosfamide for twenty weeks, followed by focal RT, and then 
twenty weeks of maintenance chemotherapy.  Early outcome results were reported 
at the PBTC Fall 2006 meeting, and are encouraging, with 1-year EFS for 20 
patients with completely resected M0 medulloblastoma of 70 ± 10%.  These 
preliminary results suggest no difference in EFS between patients who received 
mafosfamide and those who did not.  Additional support for the use of focal RT 
comes from the French BBSFOP trial, in which focal RT was used successfully as 
salvage therapy for patients with local recurrence, in combination with high-dose 
chemotherapy.  On that trial, 25 of 34 patients with local relapse were given 
busulfan/thiotepa and focal RT, 5 received CSI, and 4 progressed quickly with no 
further therapy.  Three-year overall survival after local relapse or progression was 
61% (95% CI 45-76).17  The St. Jude experience provides further evidence of the 
efficacy of focal RT.  Between 1983 and 1997, St. Jude patients with M0 
medulloblastoma were treated with the Baby POG-1 regimen or similar treatment 
plans utilizing delayed CSI.  A total of 12 patients with M0 medulloblastoma were 
treated in this early cohort; extent of resection prior to treatment was gross total 
(n=8), near-total (n=1) or subtotal (n=3), and 1-year and 5-year EFS were both 
33.3% (95% CI 15.0-74.2) (Figure 1).  Since 1998, all St. Jude patients with M0 
medulloblastoma have been treated with a regimen based on focal RT, including 3 
enrolled on the PBTC-001 pilot study BB98, 10 enrolled on PBTC-001, 3 treated as 
per PBTC-001, and 4 enrolled on P9934.  Extent of resection prior to treatment was 
gross total (n=15), near total (n=3), or subtotal (n=2).  Results have been very 
encouraging for these 20 patients, with a 1-year EFS of 78.7% (95% CI 62.2-
99.7%), and 5-year EFS 67.0% (95% CI 48.4-92.8%).    
 

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Figure 1:  Event Free Survival for St. Jude Patients with M0 Medulloblastoma by 
Treatment Era 
EFS (Years)
Proportion
0
5
10
15
20
0.0
0.2
0.4
0.6
0.8
1.0
Era=1998 and later
Era=pre-1998
 
 
Although other changes have occurred between the two eras, including 
improvements in imaging and surgical technology and better ability to diagnose 
ATRT, these results suggest that focal RT may play an important role in the 
treatment of children younger than 3 years of age with localized medulloblastoma.   
 
2.2.1.3 Rationale for chemotherapy and focal RT in medulloblastoma patient’s ≥3 - 
< 5 years of age 
 
Age at diagnosis and dose of neuraxis irradiation are key determinants of 
neurocognitive outcome in medulloblastoma survivors. Children younger than 7 
years of age are particularly vulnerable to side effects of whole brain irradiation. 
Published data from the SJMB 96 protocol has documented significant decline in 
standard risk medulloblastoma patients (≥3-7 yrs of age) treated with 23.4 Gy 
craniospinal irradiation (CSI) across the following domains: Intelligence Quotient 
(IQ); Reading; Spelling, and Math as compared to older children treated with 
identical therapy (Table 1a). With longer follow up of this patient cohort, therapy 
inflicted neurocognitive deficits have impaired these children from completing high 
school and seeking higher education. 
 
In our current study SJMB03, 23 patients between the ages of 3-5 have been 
treated. The 1 and 2 year EFS for this cohort with chemotherapy and neuraxis 
irradiation are 86±7% and 76±10%, respectively. Thus in order to preserve the 
neurocognitive function we propose to treat this group of young children between 
3-5 years of age, who are particularly vulnerable to irradiation induced damage, 
with chemotherapy and focal irradiation to the tumor bed and avoid irradiating the 
whole brain and spinal cord.  
 

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This cohort of patients will be limited to average risk medulloblastoma patients 
defined as those having a gross total resection with no metastatic disease. The 
outcome data will be closely monitored for early progressive disease failures as 
outlined in the statistical section. 
 
 
 
 
 
 
2.2.2 Supratentorial PNET results 
 
TABLE 2  RESULTS OF PROSPECTIVE CLINICAL TRIALS FOR SUPRATENTORIAL PNET 
 
Event Free Survival  
(%±SE) 
Overall Survival 
(%±SE) 
Reference 
Trial 
n 
1 year 
5 year 
5 year 
 
All Stages and Resections 
CCG 9921 
46 
26 ± 6 
17 ± 6 
31 ± 7 
16 
HIT-SKK-87 and -92 
29 
 
3 year 14.9 
3 year 17.2 
22 
 
 
 
 
 
 
M0 No Residual 
CCG 9921 
20 
25 ± 10 
15 ± 8 
30 ± 10 
16 
PBTC-001 
2 
50 ± 25 
 
 
PBTC 2006 
 
M0 With Residual 
CCG9921 
17 
29 ± 11 
18 ± 9 
33 ± 12 
16 
PBTC-001 
7 
71 ± 16 
 
 
PBTC 2006 
 
M+ 
CCG-9921 
9 
22 ± 14 
0 
0 
16 
Table 1a: Estimated intercepts and slopes of Intellect and Achievement for Age and Risk Groups 

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PNET arising outside the posterior fossa is rare in children less than 3 years of age, 
and has generally connoted a poor prognosis (Table 2), especially in patients with 
pineal tumors (pineoblastoma).    CCG-921 included 8 patients with pineoblastoma 
and 11 with non-pineal supratentorial PNET.  Pineoblastoma patients had a dismal 
prognosis, with a 3-year PFS of 0%, while those with other supratentorial PNETs 
had a 3-year PFS of  55±16%.13  In the subsequent CCG-9921 trial, 46 patients with 
supratentorial PNET, including pineoblastoma, had a 5-year EFS and OS of 17±6% 
and 31±7%, respectively.  Extent of resection did not appear to be prognostically 
important, as M0 patients with completely resected disease (n=20, 5-yr EFS 
15±8%, 5-yr OS 30±10%) had similar outcomes to those with residual disease 
(n=17, 5-yr EFS 18±9%, 5-yr OS 33±12%).  No patient with M+ supratentorial 
PNET survived 5 years (n=9).16  Similar results were reported by the German 
cooperative group for patients less than 3 years of age treated on the HITSKK87 
and HITSKK92 trials, which included intravenous and combined 
intravenous/intraventricular methotrexate, respectively.  A total of 29 patients with 
supratentorial PNET were enrolled on the two trials, with no significant difference 
in outcome detected between trials; 3-year OS for the combined cohort was 17.2%, 
and 3-year PFS 14.9%.  Administration of RT was the only significant positive 
predictor of survival.22  Preliminary results from PBTC-001 have demonstrated less 
difference in outcome between medulloblastoma and supratentorial PNET.  As 
discussed at the fall 2006 PBTC Meeting, the 9 M0 supratentorial PNET patients on 
that trial had a 1-year PFS of 67±15%, and the 27 M0 medulloblastoma patients had 
a 1-year PFS of 66±9%.  Longer follow-up will be necessary to see if this apparent 
improvement in survival for patients with PNET persists. 
 
2.2.3 ATRT results 
 
TABLE 3  RESULTS OF PROSPECTIVE CLINICAL TRIALS FOR ATRT 
 
Event Free Survival  
(%±SE) 
Overall Survival 
(%±SE) 
Reference 
Trial 
n 
1 year 
5 year 
5 year 
 
M0 No Residual 
CCG 9921 
13 
31 ± 13 
15 ± 10 
38 ± 13 
16 
PBTC-001 
10 
33 ± 16 
 
 
PBTC 2006 
 
M0 With Residual 
CCG9921 
5 
20 ± 18 
0 
0 
16 
PBTC-001 
6 
17 ± 11 
 
 
PBTC 2006 
 
M+ 
CCG-9921 
10 
40 ± 15 
20 ± 13 
30 ± 14 
16 
 
ATRT is a distinct and highly aggressive neoplasm which has been recognized 
fairly recently.23,24  These tumors have a typical histologic pattern which includes 
cells with “rhabdoid” features such as eosinophilic cytoplasm, eccentric nuclei, and 

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prominent nucleoli.  The histologic findings within a particular ATRT can be quite 
heterogeneous, however, and the typical histology may not be present.  Areas of a 
tumor, and in some cases entire tumors, may be morphologically indistinguishable 
from medulloblastoma or PNET.  It is likely that in the past, many ATRTs were 
misclassified as medulloblastoma or PNET.  ATRT is characterized by alterations 
in the hSNF5/INI1 gene on chromosome 22q11, also known as SMARCB1.  Eighty-
five percent of ATRTs contain homozygous deletions of the SMARCB1 gene, or 
loss of one allele and mutation of the other copy.25,26  More frequent utilization of 
molecular diagnostic techniques such as FISH or immunohistochemistry in recent 
years has permitted more accurate diagnosis of ATRT based on the detection of 
SMARCB1/hSNF5/INI1 abnormalities.27  ATRTs occur primarily in children 
younger than 2 years of age, and are frequently metastatic at presentation.  While 
older children may be successfully treated with complete resection, CSI, and high-
dose chemotherapy with ASCR, outcomes for children younger than 3 years of age 
are dismal (Table 3).28  In the St. Jude experience reported by Tekautz, et al.  2-year 
EFS for the 22 children under 3 years of age at diagnosis was 11±6%.  Similarly, 2-
year EFS for 28 children < 3years old treated on the CCG-9921 trial was 14±7%.16  
Use of sarcoma-type therapy based on the IRS-III study has resulted in long-term 
survival in a few cases, but includes a combination of early radiation, intrathecal 
chemotherapy and doxorubicin with substantial potential for acute and long-term 
toxicity.29,30  Results of PBTC-001 suggest no improvement over prior studies, with 
a 1-year EFS for M0 ATRT patients of 17±11%.  Among the 12 St. Jude ATRT 
patients on PBTC-001, 10 have experienced recurrence or progression to date, and 
all relapses occurred by 20 weeks of therapy.  Because of the dismal prognosis 
associated with this diagnosis, patients with ATRT are good candidates for novel 
treatment approaches.  
 
2.2.4 Clinical trial results for other diagnoses 
 
High-grade gliomas are rare in children < 3 years of age.1 To date, three small 
prospective studies have described the outcome of young children with high-grade 
glioma.31-33  They reported long term OS rates from 50% to 59%, and PFS rates 
from 31% to 43%.  Several children in each series survived without ever receiving 
RT, and the extent of surgical resection was not a significant prognostic factor in 
any of these studies.  These results suggest that young children have a more 
favorable prognosis than older patients with histologically identical neoplasms, 
perhaps due to differences in tumor biology.31-33.  We recently reviewed the St. Jude 
experience with high-grade astrocytoma in 16 children younger than three years, 
and documented survival rates similar to the prior publications, with a 5 year OS of 
66.3% and 5 year EFS of 28.6%.34  No specific treatment regimen that is 
particularly effective for high-grade glioma in young children has been identified, 
but in the St. Jude experience, as in the other published reports, patients were 
treated with the same chemotherapy regimens as young children with other brain 
tumors such as medulloblastoma.  Three St. Jude patients have survived at least 2 
years without receiving RT, and all three received chemotherapy including 
carboplatin, cyclophosphamide, and etoposide. 34 Infants and young children with 

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high-grade gliomas who progress on chemotherapy will be offered radiation therapy 
per section 4.0. 
While rare overall, ependymoma represents one of the more common CNS 
malignancies in very young children.35  Early clinical trials treated ependymomas 
with the same delayed chemotherapy approach used for medulloblastoma, with 
some success.  The Baby POG 1 trial resulted in a 66% 5 year OS for patients 
younger than 3 years of age with completely resected ependymoma.15  Patients with 
subtotal resections fared poorly, however, with a 5 year OS of 25%.  For the older 
patients on the trial (24 to 36 months of age), radiation was only delayed by 1 year, 
and 5 year OS was 62.3%.  Patients younger than 24 months received RT after a 
delay of 2 years, with a 5 year OS of only 25.7%, prompting the authors to conclude 
that delaying RT more than 1 year adversely affected survival.15  The CCG 9921 
trial also utilized delayed RT and achieved similar results; with 5 year OS of 67% 
for patients with completely resected M0 disease.  Five-year PFS for this group was 
only 32%, however, again emphasizing the importance of RT for this disease.16 
Among best results for localized ependymoma treated with RT have been recently 
reported by Merchant et al.36 The 7 yr event free survival was 69.1% (95% CI 56.9 
– 81.3). Among the factors that impacted local disease control were extent of 
resection [gross total vs. near total or subtotal: hazard ratio (HR) 0.16 (0.067-0.38); 
p<0.0001], sex [male vs. female: HR 3.85 (1.10-13.52); p=0.035]; and age [<3 
years vs. ≥3 years: HR 3.25 (1.30 – 8.16); p=0.012]. The study included patients 
with a median age of 2.9 yrs (range 0.9 – 22.9 yrs). Infants < 1 yr of age, 
irrespective of the extent of resection are treated with chemotherapy and hence will 
continue to be eligible for the current protocol. Since several series have 
demonstrated that extent of resection is a key prognostic factor it is essential for 
achieving a gross total resection (GTR) in newly diagnosed patients. The addition 
of chemotherapy has post operatively facilitated a GTR in patients with residual 
disease. This strategy was used successfully in the recently closed COG trial 
(ACNS 121) and in our institutional experience (personal communication – F.A 
Boop). Adjuvant post-operative chemotherapy devascularizes the tumor and makes 
surgical resection much easier and less risky for the patient. Recent data from a 
closed trial (CCG – 9942) has demonstrated that 4 cycles of pre-irradiation 
chemotherapy (including cisplatin, vincristine, cyclophosphamide and etoposide) in 
patients with residual disease after surgery may improve the cure rate for this subset 
of children.36a Of the 41 patients enrolled on the study – 34 patients were fully 
evaluable for response to chemotherapy: 14 (42%) had a complete response (CR) 
and 6 (18%) had a partial response (PR); 9 had a minor response or stable disease 
(SD) and 5 (15%) patients had progressive disease (PD) prior to radiation. 
Interestingly the 3 yr EFS for all patients with incomplete resections and 
chemotherapy was 58%, which was not significantly different than the 62% 3 yr 
EFS for the completely resected patients who received radiation therapy alone. The 
patients who achieved a CR to chemotherapy had a 3 yr EFS of 86% and those with 
a PR had a 3 yr EFS of 83%. These data suggest that the use of pre-radiation 
chemotherapy may in fact have a beneficial effect on the EFS of this high risk 
group of patients with residual disease after the initial surgical resection. Hence 

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infants and young children < 3 years of age with residual disease after initial 
surgical resection will be eligible to be enrolled on the trial.  
 
Patients with metastatic disease are not amenable to focal RT alone and are treated 
with chemotherapy regimens similar to what is being proposed on this trial and thus 
infants and young children < 3 years of age with metastatic ependymoma will be 
eligible for this trial. 
 
Rare tumors like choroid plexus carcinoma (CPC) and the PNET variants (CNS 
neuroblastoma, ependymoblastoma, etc.) occurring in very young children have 
traditionally been treated like medulloblastoma, with maximal resection followed 
by chemotherapy and sometimes radiation.  Wolff, et al. performed a meta-analysis 
of CPC trials and case reports, and found that complete resection and radiation were 
significantly associated with prolonged survival in patients of all ages, although 
these associations were not statistically significant for very young children, 
probably because of the small number of patients included.37,38  In the absence of a 
standard treatment approach for these rare tumors, it is reasonable to continue to 
treat them on trials designed for patients with embryonal tumors which include 
surgical resection and radiotherapy.  Enrolling these patients in the trial will also 
facilitate evaluation of the biology of these rare tumors. 
 
2.2.5 Summary of clinical trials 
 
Trials which have attempted to delay or avoid CSI in children younger than 3 years 
of age with embryonal tumors, ATRT, PNET, high-grade glioma, CPC and 
ependymoma have demonstrated that some children can be cured with fairly limited 
adjuvant therapy.  Patients with medulloblastoma whose tumor is completely 
resected and non-metastatic have a relatively good prognosis, even with less 
intensive chemotherapy, such as that used in the CCG-921 and BBSFOP trials.  
Small studies suggest that high-dose and intraventricular methotrexate may improve 
outcomes, but at the risk of neurotoxicity. Early results also suggest that focal RT 
may be an effective component of treatment for patients with localized disease.  
The efficacy of high-dose chemotherapy with ASCR has not been conclusively 
established, but the toxicity associated with this approach has been substantial in 
most studies. For patients with residual or metastatic disease of any histology, even 
the best outcomes to date leave much room for improvement. 
 
2.3 
RATIONALE FOR TUMOR BIOLOGY STUDIES 
 
2.3.1 Rationale for examination of genetic abnormalities in tumor samples from 
young children with medulloblastoma 
 
No molecular alterations are used in current clinical practice to predict disease risk 
or treatment response among children with brain tumors. This lack of knowledge 
reflects the relatively limited characterization of pediatric brain tumors that has 
been conducted to date. Brain tumors arising in very young children (< 3 years old) 
are relatively rare, and have hence been especially poorly characterized.  

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Medulloblastoma (MB) has been associated with several molecular abnormalities.39  
These include gains and losses of large chromosomal regions (e.g. loss of 8p, loss of 
9q22, loss of 17p, gain of 17q), amplifications of specific genes (e.g., MYCC and 
MYCN), and point or frameshift mutations (e.g., TP53, CTNNB1, PTCH1). 
Inactivating mutations in PTCH1 and SUFU activate the sonic hedgehog (SHH) cell 
signal pathway, while mutations in CTNNB1 promote signaling through the canonical 
WNT pathway. Certain abnormalities have been associated with prognosis of 
medulloblastoma, such as high expression levels of ERBB2 and MYCC and MYCN 
amplification (poor prognosis) and nuclear accumulation of the CTNNB1 gene 
product, β-catenin (good prognosis).40-43 However, these data have been derived 
mainly from retrospective analyses of tumors removed from children older than three 
years of age; the incidence and  prognostic significance of these molecular 
characteristics in tumors arising in patients less than 3 years is not known.   
 
The SJYC07 protocol offers an excellent opportunity to collect and study 
medulloblastoma samples from young children. Generated data will increase our 
understanding of the molecular development of these tumors and can be correlated 
with key clinicopathological variables, such as histopathological subtype and 
outcome. Obtaining and storing freshly frozen tissue from these tumors will allow 
isolation of high quality RNA (including microRNA), DNA, and protein for 
subsequent analysis. Tumor RNA will be used for gene expression studies, as 
discussed further in section 2.3.2.  Tumor DNA will be analyzed using array 
technology (methylation profiling), and protein extractions will be used for western 
blotting or proteomic analysis. This broad strategy will be augmented by an analysis 
of MBs for molecular abnormalities recognized to have specific associations with 
clinicopathological variables, particularly prognosis. This can be accomplished both 
by using data from the microarray studies and by using methods, such as interphase 
fluorescence in situ hybridization (iFISH), gene sequencing and 
immunohistochemistry (IHC), to demonstrate specific abnormalities, such as MYC 
amplification in clones of cells, SMARCB1 mutation or WNT pathway activation, 
respectively. All of these methods can be applied also to the analysis of formalin-
fixed paraffin-embedded (FFPE) tissue.  FFPE tissue is obtained for diagnostic 
purposes in virtually all brain tumor resections, unlike frozen tumor material, which 
is obtained at the discretion of the neurosurgeon.  Surplus FFPE tissue is therefore 
frequently available for research purposes.  The efficiency of molecular assays that 
analyze intact tissue sections is increased markedly by the incorporation of multiple 
samples of FFPE tumors into tissue microarrays (TMA). We will construct and 
analyze TMA from FFPE material collected from patients treated on SJYC07. 
 
2.3.2 Rationale for analysis of gene expression profiles in young children with 
medulloblastoma 
 
The limited molecular data that are available regarding medulloblastoma in young 
children have been obtained from traditional molecular biological approaches which 
usually evaluate a single gene or cell signal pathway at one time.  The advent of 

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microarray technology now permits the simultaneous evaluation of thousands of 
genes in each tumor.44  This approach can therefore interrogate genes previously 
implicated in the biology of medulloblastoma as well as identifying potentially new 
causative alterations. Gene expression profiles have been generated for a variety of 
adult and pediatric tumor types. These profiles have unmasked subtypes of 
histologic tumor types that provide important insight into the various molecular 
alterations that can generate these diseases. Best studied are the acute leukemias 
including pediatric ALL45,46 and AML.47 In studies of renal cell carcinoma, gene 
expression profiles were found to be distinct in patients with aggressive disease 
versus those with more indolent tumors.  When the use of this molecular distinction 
as a prognostic tool was simulated in the clinical setting, the prediction was 
accurate in 96% of the cases tested, exceeding the accuracy of prediction by 
staging.48  Additional studies involving renal cell carcinoma identified a gene 
signature associated with metastatic disease,49 and other studies in patients with 
ovarian cancer identified a gene signature associated with response to 
chemotherapy.50  More recently, Liu and colleagues identified an “Invasiveness 
Gene Signature” (IGS) based on analysis of breast tumor samples.  Interestingly, 
the IGS was also found to be associated with prognosis in lung cancer, prostate 
cancer, and medulloblastoma.51  Taken together, these results provide support for 
the general approach of using gene expression profiling to identify genes associated 
with the clinical behavior of tumors and patient survival.  This approach must be 
used cautiously, however, as the analysis of large numbers of genes will always 
yield apparent distinctions among groups of tumors or patients.   
 
Gene expression analysis of high-grade gliomas has revealed the value of this 
approach for building new hypotheses and identifying new paths for research in 
brain tumor patients. Such studies have shown that expression profiles may provide 
better prognostic information than features such as histology, and may facilitate the 
development of novel therapeutic targets. For example Freije, et al. found that gene 
expression profiles were strongly predictive of survival in adults with infiltrating 
gliomas, independent of histologic subtype.52  In the largest glioma gene expression 
study to date Phillips, et al. evaluated 115 high-grade astrocytoma samples from 
adults, and identified previously undescribed prognostic subclasses which resemble 
stages in neurogenesis.  A tumor class displaying markers of neuronal 
differentiation showed longer survival, while tumor classes exhibiting markers of 
proliferation or angiogenesis/mesenchymal differentiation were associated with 
shorter survival.53  Associations between gene expression and survival were also 
demonstrated by Rich, et al.  They examined subsets of genes associated with 
survival in patients > 50 years old with glioblastoma, and identified three particular 
genes (SPARC, Doublecortex, and Semaphorin3B) which were dominant 
contributors to regression models associating gene profiles and survival.  These 
genes are involved in cellular migration, and suggest a new set of therapeutic 
targets which are distinct from more established targets involving cell proliferation 
and apoptotic pathways.54 Faury, et al. conducted a similar study with pediatric 
glioblastomas.  They found that a gene expression profile associated with Ras and 
Akt pathway activation was also associated with poor prognosis.  In addition, they 

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demonstrated that YB1, a gene involved in brain embryogenesis which contributes 
to oncogenesis in epithelial cancers, was overexpressed in a majority of pediatric, 
but not adult, glioblastomas.55   
The few medulloblastoma gene expression studies performed to date have evaluated 
small numbers of tumor samples using microarray platforms which assess relatively 
few genes compared to the platforms now available.  Pomeroy, et al. obtained 
expression profiles from 99 patient samples using a microarray which included 
6817 genes, and were able to distinguish medulloblastomas from other brain tumors 
including PNETs, ATRTs, and malignant gliomas.  They were also able to identify 
genes that are differentially expressed between classic medulloblastomas and those 
with desmoplastic histology, and found evidence to support the association between 
desmoplastic medulloblastoma and abnormalities of the SHH/PTCH pathway.56  A 
subsequent analysis of the same patient samples found that gene expression profiles 
were the only significant predictor of outcome in a multivariate analysis that 
included standard clinical prognostic markers such as stage and age at diagnosis.57  
While these results are intriguing, the patient population evaluated (60 patients 
total) included only 10 patients younger than three years of age at diagnosis.  A 
recent publication from Richard Gilbertson’s laboratory described gene expression 
analyses of 46 medulloblastoma samples, including 11 from patients less than three 
years old, using a microarray that analyzes the expression level of 18,400 
transcripts and variants.  In that study unsupervised analysis of gene profiles 
partitioned medulloblastomas into 5 subgroups, two of which were enriched for 
specific genetic alterations in pathways known to be involved in medulloblastoma 
(WNT and SHH).  The majority of tumors (n=6) from young children were in the 
subgroup associated with SHH abnormalities, while no tumors from young children 
were in the subgroup associated with WNT abnormalities.58  A similar analysis 
performed by investigators in the Netherlands also found that MBs clustered into 4 
‘gene expression’ subgroups.  In that analysis, the 14 tumors from children < 3 
years old clustered into two of these subgroups:  9 tumors in the subgroup 
associated with SHH pathway abnormalities and 5 tumors in a “retinal gene” 
subgroup.  As in the Gilbertson group’s study, none of the tumors from young 
children was in the subgroup associated with WNT pathway abnormalities 
(personal communication, Marcel Kool). 
 
The above studies suggest that gene expression profiling may be a valuable tool for 
examining the biology of medulloblastoma in young children.  While very few 
tumor samples from patients in this population have been analyzed to date, results 
from other patient populations demonstrate that this type of analysis can identify 
molecular signatures that predict tumor behavior better than stage or histology.  
Such analyses may also provide new insights into the molecular pathophysiology of 
these tumors, and may yield novel therapeutic targets.  This analysis will therefore 
be an integral component of the current trial.  Gene expression studies of 
medulloblastoma samples will be complemented by comprehensive analysis of 
chromosome gain and loss through the use of 500K single nucleotide polymorphism 
(SNP) gene mapping arrays, as well as other emerging techniques for 

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comprehensive molecular characterization of tumor samples, including expression 
analysis of microRNAs. 
 
In addition to expression arrays that can only be conducted from snap frozen tissue, 
DNA methylation profiling can be done from DNA extracted from FFPE tissue 
blocks. DNA methylation profiling in cancer has prognostic potential. DNA 
extracted from FFPE material will be used for methylation profiling. The current 
platform available at SJCH for methylation profiling is the Illumina Infinium 
Human Methylation 450 Bead Chip which will be used according to the 
manufacturer’s recommendations.  How methylation subgoups may correlate with 
RNA expression subgroups is an area of great interest especially given the 
numerous mutations to epigenetic modifying genes found amongst the current 
molecular subgroups. 
 
2.3.3 Additional tumor biology studies 
 
Although the focus of the SJYC07 trial is the treatment and molecular 
characterization of medulloblastoma in young children, patients with other 
diagnoses will be eligible for enrollment on this trial. Very little is known about the 
biological features of these tumors.  ATRT is the second most common CNS 
embryonal tumor of infancy, and is recognized to have a poor prognosis. 
Monosomy 22 and mutations of the SMARCB1 (INI1) gene located on 22q set 
ATRTs apart from other embryonal tumors,59 but any specific associations between 
these two genetic abnormalities and tumor morphology, age at presentation or other 
molecular alterations have yet to be determined. In addition, it appears that 
mutation of genes other than SMARCB1 can cause the ATRT phenotype.60 ATRTs 
and choroid plexus carcinomas (CPCs) are associated as part of a syndrome of 
familial posterior fossa tumors of infancy.61 CPCs may also demonstrate SMARCB1 
mutations,26 but their frequency and nature in infant CPCs and whether distinct 
SMARCB1 mutations occur in CPCs and ATRTs have not been determined.  
Ependymomas arise from radial glia, and exhibit different profiles at the levels of 
genome and transcriptome depending on site and histopathological features.62  
However, little is known about the relationship between molecular abnormalities 
and biological behavior. Gain of 1q has been associated with a poor outcome in 
pediatric posterior fossa tumors,63 but whether this or undiscovered molecular 
abnormalities will be useful to stratify patients for therapy is yet to be determined.  
For rarer tumors like the non-cerebellar PNETs and high-grade gliomas, few 
molecular data exist.64   
 
While molecular characterization of medulloblastomas in very young children is the 
primary objective of the SJYC07 trial, this trial provides an excellent opportunity to 
characterize the molecular features of other brain tumors in this patient population.  
It is important to note that the density of gene expression and SNP arrays can allow 
for the identification of novel gene alterations even when analyzing relatively small 
numbers of tumor samples. 62  The same comprehensive series of molecular studies 

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proposed for medulloblastoma samples will therefore also be performed for the 
other tumor samples obtained through this trial. 
 
2.4 
RATIONALE FOR TREATMENT 
 
2.4.1 Rationale for risk stratification 
 
The risk stratification schema for this trial is demonstrated in Figure 2.  Clinical 
trials have consistently demonstrated better event-free and overall survival for 
medulloblastoma patients with localized disease (M0).  Among these patients, those 
with completely resected tumors (GTR) have a particularly good prognosis.  In the 
Baby POG 1 trial,15 patients with GTR/M0 medulloblastoma had a 5-year OS of 
69% with standard chemotherapy and delayed craniospinal irradiation.  On the more 
recent SFOP trial, despite less intensive chemotherapy and reduced PFS in all strata 
compared to other trials, 29% of GTR/M0 medulloblastoma patients remained 
progression-free at 5 years without irradiation.17  These results suggest that a 
subgroup of GTR/M0 medulloblastoma patients can be cured without radiotherapy.  
Results of other trials suggest that desmoplastic histology is associated with a much 
better prognosis than other histologic subtypes of medulloblastoma (Table 4).  In the 
German HIT-SKK’92 trial, 20 patients with desmoplastic medulloblastoma had a 5-
year PFS of 85±8%, compared to 23 patients with classical medulloblastoma (5-year 
PFS 34±10%, p<0.001).18  Similarly, in the combined results of the Head Start I and 
II trials, 5-year EFS for desmoplastic (n=9) and classical (n=12) medulloblastoma 
patients with localized disease were 67±17% and 42±14%, respectively.(Abstract 
MB-03, ISPNO 2006).  On the British UKCCSG 9204 trial, 1-year EFS was 82.2% 
(95% CI 72.9-100%) for 17 patients with desmoplastic medulloblastoma of all 
stages, and 18.2 (95% CI 0–41.0%) for 11 patients with classical or large cell 
anaplastic histology (personal communication, Richard Grundy).  Finally, a recent 
combined analysis of data from 5 national groups included 253 patients with early 
childhood medulloblastoma, and found that desmoplasia was an independent 
favorable prognostic factor in a multivariable analysis (p<0.001, personal 
communication, Stefan Rutkowski).  In the current study, patients with GTR/M0 
medulloblastoma and nodular desmoplastic histology will be considered low-risk, 
and treated without RT.  Patients with all other histologic subtypes of localized 
medulloblastoma will be considered intermediate risk. 
 
While high-grade gliomas are very rare in children younger than 3 years of age, all 
published reports suggest that these patients have a better prognosis than older 
children and adults with the same tumor types.31-34 Neither complete resection nor 
treatment with RT has been demonstrated to improve survival in these series.  In 
recent years, clinical practice at St. Jude has been to treat children < 3 years of age 
with high-grade glioma with chemotherapy (typically cyclophosphamide, 
carboplatin, and etoposide), and to administer RT only in cases of disease 
progression or recurrence.  Using this approach, 3 patients have avoided RT and 
survived more than 2 years without disease progression.  Based on this experience 

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and the available literature, we will enroll all M0 high-grade glioma patients on the 
low-risk arm, regardless of the extent of surgical resection. 

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Figure 2 Risk Stratification Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M Stag e 
Diagnosis 
Exte nt of Resection
Hist ologic Subt ype 
Age at Diagnosis 
High Risk 
Inte rmediate  Risk 
Low Risk 
M1+ 
M 0 
Other                
(PN ET, A TRT,
M edullobl as tom a 
H igh G rade 
G liom a 
< G TR 
 G TR 
Other       
(Cl as si cal, 
anaplastic) 
Nodular 
Desmopl asti c 
>3 to 
<5 yrs 
< 3 yrs  

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All patients on the intermediate risk arm will receive focal RT.  Medulloblastoma 
patients with incompletely resected M0 tumors have a higher rate of relapse than 
those with GTR, with 5-year PFS rates of less than 50% in published trials.16,18   
Patients with residual medulloblastoma will therefore undergo re-resection prior to 
treatment whenever possible.  Those patients with residual disease which cannot be 
completely resected by the start of treatment will also be considered intermediate 
risk, regardless of histologic subtype. All patients between ≥3-<5 years of age 
diagnosed with non-metastatic medulloblastoma having a gross total resection will 
be considered as intermediate risk irrespective of histology. Patients with M0 
supratentorial PNET and ATRT have a poor prognosis compared to those with 
desmoplastic medulloblastoma, and will be treated on the intermediate risk arm.  
Finally, although there is no standard treatment for patients with rare CNS tumors 
such as choroid plexus carcinoma or the PNET/medulloblastoma variants, these 
patients have often been treated with therapy similar to that used for 
medulloblastoma, and complete resection and irradiation have been associated with 
better outcomes in some series.37,38  Patients with these diagnoses and no evidence 
of metastasis will therefore be assigned to the intermediate risk arm.  Patients with 
ependymoma have been included in prior infant brain tumor chemotherapy 
studies.14,16,65 Results of these studies have documented that approximately 1/3 of 
infants with ependymoma can be cured with chemotherapy alone. At the current 
time we do not feel proton beam RT alone is the best way to treat these patients 
because anecdotal evidence of recurrent tumors in the anterior 3rd ventricle. Hence 
we will treat all infants up to 3 years of age on the protocol based on their risk 
stratification. 
 
Patients with metastatic brain tumors have a poor prognosis, and will be treated on 
the high risk arm of this study.  High-risk patients who reach the age of 3 years by 
TABLE 4  EFFECT OF DESMOPLASTIC HISTOLOGY ON PROGNOSIS 
 
n 
5 year EFS (%±SE) 
5 year OS (%±SE) 
Reference 
HIT-SKK92 (All Stages) 
Classical 
23 
34 ± 10 
41 ± 11 
 
Desmoplastic 
20 
85 ± 8 
95 ± 5 
 
 
p 
<0.001 
<0.001 
18 
Head Start 1 + 2 (M0 only) 
Classical 
12 
42 ± 14 
75 ± 13 
 
Desmoplastic 
9 
67 ± 16 
78 ± 14 
ISPNO 
2006 
UKCCSG  9204 (All Stages) 
Classical/Large Cell 
Anaplastic 
11 
18.2 (95% CI 0–41) 
18.2 (95% CI 0-41) 
 
Desmoplastic 
17 
35.3 (95% CI 13-58) 
52.9 (95% CI 29-77) 
* 
*Personal Communication, Richard Grundy 

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week 17 of treatment will be offered craniospinal irradiation, with the neuraxis dose 
based on response to induction chemotherapy. Patients whose parents choose not to 
pursue RT and those younger than 3 will undergo intensive consolidation with 
topotecan and cyclophosphamide.  
 
2.4.2 Rationale for use of high-dose intravenous methotrexate 
 
2.4.2.1 Clinical experience with methotrexate in medulloblastoma 
 
NOTE: Readers are urged to exercise caution when comparing methotrexate doses 
between trials.  Some published clinical trials have dosed methotrexate by patient 
weight (doses given in mg/kg), while others have used body surface area (doses 
given in mg/m2).  Doses have traditionally been converted via the “rule of 30,” in 
which 1 mg/kg is approximately equivalent to 30 mg/m2.  In the literature, BSA 
doses of methotrexate are typically given in grams per square meter, while weight-
based doses are given in milligrams per kg. 
 
The first clinical experience with methotrexate in medulloblastoma was reported by 
Rosen, et al. in 1977.66  Seven patients with recurrent medulloblastoma were treated 
with 300 mg/kg to 500 mg/kg IV methotrexate, and 5 of these patients had objective 
responses to 2 or 3 cycles, including one CR.  Mooney, et al. subsequently treated 5 
patients with recurrent medulloblastoma with 1 to 5 doses of IV methotrexate at 
2500 mg/m2/dose, with no objective responses..67  Allen et al. treated two adult 
patients and one 10 year-old child with newly diagnosed medulloblastoma or 
pineoblastoma with 8000 to 11,000 mg/m2 iv methotrexate.  One patient had a CR, 
one a PR, and one stable disease after 2 to 4 cycles.68  These early series provided 
the rationale for the use of high-dose methotrexate in the Head Start II trial, in 
which 400 mg/kg methotrexate was given in conjunction with each of 5 cycles of 
induction cisplatin/cyclophosphamide/ vincristine/etoposide to patients with 
metastatic (M1+) medulloblastoma.  Although limited by small patient numbers and 
the inclusion of patients up to 6 years of age, this trial has achieved the best 
outcome for patients with metastatic disease, with 3-year EFS of 49%.  Detailed 
neurocognitive outcomes have not been reported, but patients who “avoided 
irradiation retained normal intellectual function and quality of life.”19  The German 
HITSKK92 treatment regimen included six doses of intravenous methotrexate at 
5000 mg/m2/dose, in addition to 36 doses of intraventricular methotrexate at 2 
mg/dose.  Survival was better than in prior studies across all risk categories; 5-year 
EFS was 82%, 50%, and 33% for medulloblastoma patients with M0/1 completely 
resected, M0/1 incompletely resected, and M2+ disease, respectively (Figure 3).  
Leukoencephalopathy was common, however (19 of 23 evaluated patients), and 
long-term neurocognitive outcomes were significantly worse for patients treated 
with this approach than for healthy age-matched controls.  A significant correlation 
between the grade of leukoencephalopathy and the cumulative dose of 
intraventricular methotrexate was found (correlation coefficient 0.53, p<0.01), but 
there was no correlation between leukoencephalopathy grade and intravenous 
methotrexate dose.18  The Head Start II and HITSKK92 trials resulted in the best 

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reported survival for young children with medulloblastoma to date, and provide 
evidence that methotrexate may play an important therapeutic role in this 
population.  These studies were small, however, and many important questions 
about the use of methotrexate in this population remain unanswered. In order to 
maximize therapeutic benefit and limit toxicity, it will be important to gain a better 
understanding of the pharmacokinetics of methotrexate in very young children, and 
to evaluate the relationships between dose, antitumor effect, and toxicity.   
 
Figure 3 Survival with Methotrexate-Based Therapy on the German HIT-SKK92 Trial for 
Children <3 years old with Medulloblastoma (Adapted from Rutkowski, et al) 18  
 
 
2.4.2.2 Clinical experience with methotrexate in other tumors 
 
The published experience with high-dose methotrexate in other CNS tumors in very 
young children is quite limited.  Results for ATRT patients treated on the Head 
Start II trial were presented in abstract form at the 2004 ISPNO meeting, and 
suggest that methotrexate has some activity in this disease.  On Head Start II, 
ATRT patients were generally treated with high-dose methotrexate 400 mg/kg/dose 
x 5 in conjunction with the Head Start chemotherapy regimen described above.  
Three of 6 ATRT patients had no evidence of disease at 12, 24, and 46 months from 
diagnosis, including two patients who received methotrexate and one patient who 
did not.  This contrasts with the results from Head Start I, in which none of the 6 
ATRT patients received methotrexate; they were otherwise treated identically to 

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those on Head Start II, and none of the 6 patients in the Head Start I trial survived.69  
The Head Start regimen was generally not very effective for the treatment of 
ependymoma, but results for patients with metastatic disease suggest that 
methotrexate may have some activity.  Five patients with metastatic ependymoma 
received the methotrexate-containing Head Start II regimen, with one toxic death 
during induction, as well as one disease progression and three complete responses 
detected at the end of induction.  The patient with progressive disease was 
effectively treated with CSI, so that all 4 patients who completed induction have 
survived, with follow-up durations of 2.1 to 7.8 years; survivors include one patient 
who was 2.4 years old at diagnosis and has not received RT.65  The German 
cooperative group reported results for patients with supratentorial PNET treated on 
HITSKK87 and HITSKK92.  Both regimens contained intravenous methotrexate at 
5 g/m2/dose, and results were similar to those from contemporary trials without 
methotrexate, with a 3-year PFS of 14.9%.22   
 
High-dose methotrexate (8g/m2) given in combination with cyclophosphamide and 
vincristine resulted in an objective response rate of 47% in a series of children with 
high-grade glioma.70 
 
2.4.2.3 Rationale for methotrexate dosing 
 
The current trial, as well as planned future medulloblastoma trials in the Children’s 
Oncology Group, will utilize only intravenous methotrexate.  Administration of 
intraventricular methotrexate in this patient population is problematic, as many 
patients (~40% of patients on PBTC-001) have hydrocephalus requiring placement 
of a ventriculoperitoneal shunt.  This prevents the effective administration of 
intraventricular chemotherapy, unless the shunt can be temporarily turned off.  
While placement of a shunt with an on/off valve is technically possible, life-
threatening elevation in intracranial pressure can result if the shunt is turned off 
inadvertently or for too long.  Additionally, there is some evidence to suggest that 
the risk of neurocognitive dysfunction associated with combined intravenous and 
intrathecal methotrexate administration is greater than that associated with high-
dose intravenous administration alone.71,72  As discussed above, the severity of 
leukoencephalopathy on the HITSKK92 trial was significantly correlated with 
cumulative intraventricular, but not intravenous, methotrexate dose.18 
 
A standard intravenous methotrexate dosing regimen for medulloblastoma in young 
children has not been established. Given the potential for neurotoxicity, particularly 
in patients who go on to receive RT, it is important to avoid using more of this 
agent than necessary, while still giving enough to achieve a therapeutic benefit. 
Although clinical evidence of therapeutic efficacy has been documented at 
methotrexate doses of 400 mg/kg (~12,000 mg/m2, on Head Start II) and 5,000 
mg/m2 (~167mg/kg, given in addition to intraventricular methotrexate on 
HITSKK92), no prospective comparison of different methotrexate doses has been 
conducted, and substantial differences between the patient populations studied in 
Head Start II and HITSKK92 make it difficult to compare their results directly. 

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Comparison of these results is also complicated by the use of different methotrexate 
infusion lengths.  The Head Start II regimen utilized a 4 hour infusion, as is the 
common practice in the treatment of osteosarcoma.19  In HITSKK92, each 
methotrexate dose was infused over 24 hours, as is typically done in the treatment 
of childhood ALL.  In ALL, HDMTX is an effective component of CNS-directed 
therapy, and it therefore seems reasonable to use the same administration approach 
for brain tumor patients.  The relationship between plasma and CSF methotrexate 
levels has been studied extensively for a variety of ALL treatment regimens, and 
investigators have shown that methotrexate penetration into the CSF is slow,73 
requiring up to 8 hours to reach a steady state concentration.74  A prolonged 
infusion may therefore result in better methotrexate delivery to the CNS.  Hence, 
for the current protocol, methotrexate will be administered as a 24 hour infusion.   
 
While ALL studies have demonstrated that 24-hour methotrexate infusions are well 
tolerated in very young children at doses as high as 33,600 mg/m2,75,76 investigators 
have shown that increasing the dose beyond 8.0 g/m2 does not result in a 
proportional increase in CSF levels.77  These and other results78 suggest that there is 
a saturable carrier system for methotrexate and its metabolite 7-OH methotrexate 
between serum and CSF.  If this is the case, increasing the dose of methotrexate 
beyond the doses that are typically used clinically may provide little additional 
therapeutic benefit.  Indeed, ALL patients treated with very high dose methotrexate 
(33.6 g/m2) on the CCG trials had a higher than expected rate of CNS relapse, 
although these results may be at least partially explained by excessive leucovorin 
rescue and decreased intensity CNS therapy in other components of the protocol.79 
As a methotrexate dose of 5 g/m2 over 24 hours was administered safely and 
effectively in the German HITSKK92 infant medulloblastoma trial,18and there is 
limited rationale for exceeding this dose, the 5 g/m2 dose will be used for all 
patients in the current trial.   
 
2.4.2.4 Rationale for reduced MTX dosage for patients enrolled at ≤ 31 days of age  
 
Currently, the methotrexate dosage for all patients enrolled on SJYC07 is 5 g/m2 
administered over 24 hours. Recently we have studied two children that were less 
than one month of age when they received methotrexate therapy.  Since no data 
were available regarding methotrexate disposition in children this young, we 
empirically reduced their dosage to 2.5 g/m2 over 24 hours. This was primarily 
because patients ≤ 1 month of age have reduced renal function, and in particular a 
reduced glomerular filtration rate. Both infants tolerated therapy well with 
methotrexate concentrations similar to what we have observed in our other patients 
treated at full dosage and without any significant toxicities.  
 
Since no data are published regarding methotrexate clearance in these very young 
infants, we contacted Dr. Stefan Rutkowski, the lead author of the study upon 
which the use of methotrexate is based for his guidance in dosing methotrexate in 
very young infants.  Dr. Rutkowski indicated that they have not used methotrexate 
in children with brain tumors that young, so he was unable to provide any insights. 
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have been ≤ 1 month of age when starting induction therapy. Their methotrexate 
clearances were 13.2 and 54.8 L/h/m2, compared to a mean (SD) of 96.9 (32) 
L/h/m2 for patients older than 1 month.  
 
Although these patients will be older than 1 month by the start of the second course 
of methotrexate, we propose to keep the methotrexate dosage at 2.5 g/m2 in 
subsequent courses. Interestingly, in a preliminary analysis of all children enrolled 
on SJYC07 we noted a decrease in the MTX clearance between course 1 (median = 
101.6 L/h/m2) and course 2 (median = 86.3 L/h/m2). We hypothesize that the reason 
for the drop in clearance after course 1 is the administration of cisplatin, which is 
nephrotoxic. Although clearance did not drop further in subsequent courses, we 
have very little experience in administering MTX to patients this young. We 
therefore will adopt a conservative approach and administer the reduced 
methotrexate dosage (2.5 g/m2 over 24 hours) for all 4 courses. 
 
2.4.2.5 Rationale for leucovorin rescue  
Table 5 Comparison of Leucovorin Rescue on Current Trial and Other Recent HDMTX Trials  
Trial 
MTX 
Dose 
Infusion 
(hours) 
LV dose 
First LV 
Last LV 
Cumulative LV 
Dose* 
SJYC07 
5 g/m2 
24 
15 mg/m2 q6h 
Hour 42 
Hour 66 
45 to 75 mg/m2† 
Proposed COG 
High-risk Infant 
MB 
400 mg/kg 
4 
10 mg (fixed dose) q6h 
Hour 24 
MTX level <0.1μM 
50 mg 
(fixed dose) 
 
 
 
 
 
 
 
CCG-191P, -134P, 
144P (Infant ALL) 
33.6 g/m2 
24 
200  mg/m2 bolus,  
then 12  mg/m2 q 3h x 6, 
then 12 mg/m2 q 6h 
Hour 36 
MTX level < 0.08  
μM 
~300  mg/m2 
P9754 
(Osteosarcoma) 
12 g/m2 
4 
15 mg/m2 q6h 
Hour 24 MTX level <0.1 μM 75 to 135 mg/m2 
AOST0331 
(Osteosarcoma) 
12 g/m2 
4 
15 mg/m2 q6h 
Hour 24 MTX level <0.1 μM 75 to 135 mg/m2 
HITSKK'92 
5 g/m2 
24 
15 mg/m2 q6h 
Hour 42 
MTX level <0.25 
μM 
90 mg/m2 
Interfant99  
(Infant ALL) 
5 g/m2** 
24 
15 mg/m2 q6h 
Hour 36 
Hour 48 
45 mg/m2 
IFNT06  
(Infant ALL) 
5 g/m2** 
24 
15 mg/m2 q6h 
Hour 42 
Hour 54 
45 mg/m2 
POG 9917 (NHL) 
5 g/m2 
24 
75 mg/m2 initial, 
then 15 mg/m2 q6h 
Hour 36 MTX level <0.1 μM 
105 to 165 
mg/m2 
POG 9404 (T-cell 
ALL) 
5 g/m2 
24 
75 mg/m2 initial, 
then 15 mg/m2 q6h 
Hour 36 MTX level <0.1 μM 
105 to 165 
mg/m2 
NHL-BFM 95 
(NHL) 
5 g/m2 
4 vs. 24 30 mg/m2 initial, then 15 
mg/m2 q6h x 2 
Hour 42 
Hour 54 
60 mg/m2 
TOTAL XV (ALL) 
5 g/m2 
24 
15 mg/m2 q6h 
Hour 42 MTX level <0.1 μM 45 to 75 mg/m2 
LV, leucovorin; *Assumes normal clearance, leucovorin continued until hour 48 to 72 without dose modifications;  
** doses reduced for children < 12 months of age;  
 

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As experience with the use of intravenous HDMTX in very young children with 
medulloblastoma is limited, there is no standard regimen for leucovorin rescue in 
this setting.  Similar doses of HDMTX have been used extensively in other 
pediatric malignancies, however, including infant ALL.  For comparison, 
leucovorin regimens from several recent clinical trials are presented in Table 5.  
The leucovorin regimen for the current protocol is the same as that used at St. Jude 
Children's Research Hospital for patients with ALL receiving an identical dose and 
infusion length.   
 
2.4.3 Rationale for conventional chemotherapy 
 
In order to allow consistent dose calculations within the trial, and facilitate 
comparisons with other studies, all drug doses will be based on body surface area 
(BSA).  While many past trials have utilized weight-based dosing or a combination 
of weight and BSA-based dosing for very young children, BSA-based dosing has 
been utilized safely and effectively in some recent trials, including the trial with the 
best outcome for medulloblastoma in this population to date, the German 
HITSKK92 study.18,81  BSA-based dosing has also been utilized safely and 
effectively in infant leukemia trials.75 The optimal conversion between weight and 
BSA-based doses is not well established for any drug, and likely varies by a number 
of drug and patient factors.  In selecting the doses for this treatment plan, we have 
relied on published BSA doses from trials including patients < 3 years old 
whenever possible.  When no such doses were available, we selected BSA-based 
doses from trials involving older children.  In those cases, we attempted to choose 
doses that would result in similar weight-based doses (as calculated by the “rule of 
30”) to those used in other infant brain tumor trials.  
 
Cisplatin, cyclophosphamide, and vincristine have been included in almost all 
successful chemotherapeutic regimens for infants with embryonal tumors.14-16,18,19  
These drugs will form the backbone of chemotherapy for all patients.  The Baby 
POG-2 trial randomized patients to receive  chemotherapy regimen A, which 
included 1 dose of cyclophosphamide per cycle (65 mg/kg/dose, ~2 g/m2/dose), or 
regimen B, which included 2 doses of cyclophosphamide per cycle (65mg/kg/dose), 
and revealed no difference in overall survival between the two groups.  Our 
regimen will therefore only include a single 1.5 g/m2 dose of cyclophosphamide per 
cycle. Similarly, Baby POG-2 showed no advantage to increasing the cisplatin dose 
from 4 mg/kg to 5 mg/kg, and subsequent studies16,19 have achieved reasonable 
outcomes using a dose of 3.5 mg/kg.  A cisplatin dose of 75 mg/m2 will 
consequently be used in this study.  This dose has been used safely and successfully 
in two recent medulloblastoma trials.2,4  Because of the potential for nephrotoxicity 
and ototoxicity with cisplatin, some groups have replaced cisplatin with carboplatin, 
with mixed results.17,18  In the current trial, all patients will receive four induction 
cycles of high-dose methotrexate, vincristine, cisplatin, and cyclophosphamide.  In 
low-risk patients this will be followed by consolidation consisting of two cycles of 
carboplatin, cyclophosphamide and etoposide.  The low-risk consolidation doses are 

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very similar to those administered on the St. Jude CNS-14 trial.  This combination 
was well tolerated, and has been used extensively for very young brain tumor 
patients receiving non-protocol treatment at St. Jude in recent years.   
 
Etoposide has been included in all of the large prospective chemotherapy trials for 
very young children with medulloblastoma, but the use of this agent in other solid 
tumors has been associated with the occurrence of second malignancies,82 and it is 
therefore important that this drug be used judiciously, especially in the low-risk 
group of patients with a high likelihood of long-term survival.  Furthermore, recent 
data suggest that inclusion of this agent may not be absolutely necessary for 
treatment of these diseases.  For example, the recent St. Jude (SJMB96) and COG 
A9961 trials for older medulloblastoma patients treated with craniospinal irradiation 
and adjuvant chemotherapy resulted in excellent survival rates, and included no 
etoposide.2,4  The total dose of etoposide administered on SJYC07 will therefore be 
quite limited in comparison to prior trials.  Patients treated on the most recent COG 
low-risk infant medulloblastoma protocol (P9934) received a total of 285.6 mg/kg 
(~8568 mg/m2) of oral etoposide, while patients treated on the most recent PBTC 
infant brain tumor protocol (PBTC-001) received 142.8 mg/kg (~4284 mg/m2) of 
oral etoposide.  Patients treated on the recently opened COG high-risk infant 
medulloblastoma protocol (ACNS0334) will receive a total of 22.5 mg/kg (~675 
mg/m2) of intravenous etoposide.  On SJYC07, by contrast, low-risk patients will 
receive 400 mg/m2 (~13.3 mg/kg) of intravenous etoposide during consolidation, 
and no etoposide during maintenance.  Intermediate and high-risk patients with 
medulloblastoma or ependymoma will receive no etoposide at any time, while 
intermediate and high-risk patients with other diagnoses will receive no etoposide 
during consolidation, and a total of 3150 mg/m2 (~ 105 mg/kg) of oral etoposide 
during maintenance.   
 
2.4.4 Rationale for use of G-CSF in Induction and Consolidation 
 
Because the drugs used in this treatment plan are expected to cause substantial 
myelosuppression, G-CSF support will be administered during all induction and 
consolidation chemotherapy courses.  Numerous clinical trials and meta-analyses 
have now demonstrated that the prophylactic use of G-CSF decreases the duration 
of neutropenia, incidence of febrile neutropenia, length of hospitalization, and 
length of antibiotic use, and some, but not all, trials have demonstrated a decrease in 
documented infections and infection-related mortality.83-85  The American Society 
of Clinical Oncology (ASCO) clinical practice guidelines have recently been 
revised to recommend that prophylactic G-CSF be used in all treatment regimens 
with an expected incidence of febrile neutropenia of > 20%.86  During the recent 
PBTC-001 trial, which used similar drug doses to those used in this trial, patients 
experienced febrile neutropenia in 29-44% of courses (PBTC-001 progress report, 
Spring 2006). 
 

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2.4.5 Rationale for Consolidation with pharmacokinetically-targeted topotecan 
and cyclophosphamide in high-risk patients 
 
Topotecan is a topoisomerase I inhibitor with extensive antitumor activity in 
preclinical studies, including xenograft models of pediatric CNS tumors such as 
medulloblastoma.87-89  The antitumor activity of topotecan has been found to be 
highly dose and schedule dependent.  Clinical trials have also demonstrated a high 
degree of inter- and intrapatient variability in topotecan pharmacokinetics.90  
Topotecan has substantial CSF penetration, which is augmented by prolonged 
infusion.  Zamboni, et al. demonstrated that increasing the length of topotecan 
infusion from 30 minutes to 4 hours results in higher CSF topotecan lactone 
levels.91,92   
 
The recent SJMB96 trial for patients 3 years of age or older with medulloblastoma 
and other embryonal tumors included an upfront phase II window for high-risk 
patients consisting of topotecan targeted to an AUC of 120 to 160 ng/mL*hr, daily 
for 5 doses in each of two 3-week cycles.  Of 36 assessable patients, four patients 
(11.1%) had a complete response, six (16.6%) showed a partial response, four 
(11.1%) had a marginal response, and disease was stable in 17 patients (47.2%). 
Toxicity was mostly hematological, with only one patient experiencing treatment 
delay.  Cyclophosphamide is also highly active against medulloblastoma and other 
embryonal tumors,14,93 and the combination of cyclophosphamide and topotecan has 
been effective in the treatment of  metastatic Ewing’s sarcoma and other pediatric 
solid tumors.94,95  In this protocol,  the combination of topotecan and 
cyclophosphamide will be administered in a consolidation phase for high risk 
patients who do not receive craniospinal irradiation.  Two cycles of this 
combination will be given.  Topotecan will be administered as a 4 hour infusion on 
days 1-5 of each cycle, with the topotecan dose targeted to achieve an AUC of 
140±20 ng/mL*hr.  Cyclophosphamide will be administered on day 4 and 5 at a 
dose of 600 mg/m2/day.  Based on the SJMB96 experience with single agent 
topotecan, count recovery is expected within 21-28 days with this regimen.  
 
2.4.6 Rationale for anti-angiogenic therapy 
 
2.4.6.1 Overview 
 
In the early 1970’s, Judah Folkman observed that tumors must have an adequate 
blood supply in order to grow beyond minimal size, and proposed that targeting the 
tumor blood supply would provide an alternative means of limiting tumor growth.96  
In the subsequent decades, considerable research effort has been devoted to 
exploring the mechanisms by which tumors induce angiogenesis, and identifying 
aspects of tumor angiogenesis which might be targeted for therapeutic benefit.12,97-
100 It is now clear that tumor angiogenesis is a complex process, involving multiple 
interactions between tumor and endothelial cells, intra- and intercellular signals, 
and the extracellular matrix.101,102  There remains considerable interest in the 

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vasculature as a therapeutic target but the development of effective anti-angiogenic 
treatments remains in its infancy.97,98,100,103 
 
2.4.6.2 Tumor angiogenesis 
 
The underlying mechanisms of tumor angiogenesis have been explored extensively 
during the past three decades.  One component of Folkman’s hypothesis which has 
drawn particular attention is the concept of the angiogenic switch.96  The 
development of solid tumors was thought to include an avascular dormant stage, in 
which tumors remained less than 1-2mm in size, and received adequate oxygen and 
nutrients through diffusion from adjacent normal vasculature.  Tumors could exist 
in this dormant phase for prolonged periods of time, and evidence for this concept 
came from the frequent identification of small, non-lethal tumor nodules in autopsy 
studies.104  It was only when a tumor “switched on” the angiogenic phenotype that 
the tumor could induce the development of its own vasculature.  Tumors that made 
the transition to the angiogenic phenotype gained the potential to grow much larger, 
metastasize, and become lethal.103,105  This hypothesis required the presence of a 
soluble factor which allowed the tumor to initiate angiogenesis, and the 
identification of the first such factor, basic fibroblast growth factor (bFGF)106 in 
1984 helped Folkman’s ideas gain wider acceptance.103  Other pro-angiogenic 
factors such as vascular endothelial growth factor (VEGF) were soon isolated, and 
the list of angiogenic activators continues to grow.  Eventually a number of 
endogenous anti-angiogenic factors including thrombospondin-1, endostatin, and 
angiostatin were also identified.  Current models of tumor angiogenesis suggest that 
the angiogenic phenotype may be turned on or off at various points in the life of a 
tumor, depending on the tumor type and microenvironment,101,107,108 and may be 
induced by changes in gene expression, rather than progressive genetic 
derangements.109 The switch to the angiogenic phenotype is thought to be 
controlled by the balance of activators and inhibitors in a particular tumor at any 
given time, and is mediated by interactions among tumor and endothelial cells, 
pericytes, and the extracellular matrix.102  While a full understanding of the 
mechanisms and regulation of tumor angiogenesis will take many more years of 
study, the basic research insights gained to date have led to substantial progress in 
the development of anti-angiogenic treatments.12,97-100 
 
Tumor angiogenesis is an attractive therapeutic target for several reasons.  From a 
theoretical standpoint, dependence on adequate blood supply for progressive growth 
is a hallmark of cancer,110so effective anti-angiogenic therapies can potentially be 
utilized for a wide variety of tumor types.  Also, because many tumors must trigger 
angiogenesis to grow beyond minimal size or metastasize, anti-angiogenic therapy 
administered to patients with limited tumor burden could prevent this switch, and 
maintain the tumor in a chronic dormant state.111-114  Furthermore, intriguing new 
research suggests that anti-angiogenic therapy may target tumor stem cells.  Like 
stem cells in normal tissues, cancer stem cells (CSCs) have the capacity to divide 
and differentiate into more mature tumor cells.  Traditional cancer therapies may 
fail to effectively kill cancer stem cells.  A small number of residual CSCs may thus 

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allow tumor repopulation, and play a role in resistance to therapy and 
relapse.62,109,115  The CSC represents an attractive therapeutic target, but no 
therapies have yet been developed which specifically target these cells. Recent 
work from the laboratory of Richard Gilbertson suggests that brain tumor stem cells 
exist in a vascular niche, and that anti-angiogenic therapy may target the CSC 
population by disrupting this niche.  In this series of experiments CSCs were 
identified in brain tumor cell lines and primary tumors by the expression of Nestin 
and CD133.  Nestin+ cells were found in close proximity to tumor vasculature, and 
CD133+ cells isolated from primary medulloblastoma and ependymoma specimens 
interacted physically with endothelial cells in culture.  Endothelial cells maintained 
self-renewing and undifferentiated brain tumor cells in culture via secreted factors, 
and promoted the propagation of brain tumor cells in an orthotopic mouse xenograft 
model.  Perhaps most interestingly, when orthotopic xenografts of ERBB2-
transfected Daoy cells were utilized as a model of aggressive medulloblastoma, 
antiangiogenic therapy with the anti-VEGF antibody bevacizumab or the 
EGFR/ERRB2 antagonist erlotinib depleted tumor vasculature, ablated the self-
renewing tumor cell population, and inhibited tumor growth.116  In a similar series 
of studies from Duke University, Bao et. al demonstrated that a glioma stem cell 
population (stem cell-like glioma cells, or SCLGCs) secretes VEGF and supports 
tumor angiogenesis, and that this effect is abrogated by bevacizumab.  They also 
demonstrated that bevacizumab therapy limited growth of tumors derived from 
SCLGCs in a xenograft model.117  Most recently, investigators in the Kerbel lab 
demonstrated that the combination of cytotoxic chemotherapy and anti-angiogenic 
therapy inhibited tumor growth and reduced the tumor stem-cell-like fraction in a 
nude mouse glioma xenograft model.118  Taken together, these results suggest that 
tumor stem cells and tumor endothelial cells are interdependent, and that anti-
angiogenic therapy may target both populations.  
 
Anti-angiogenic therapy is also attractive on a practical basis.  As endothelial cells 
are far more genetically stable than tumor cells, it was initially believed that the 
development of resistance to anti-angiogenic therapy was unlikely.119 As clinical 
experience accumulates, it is becoming apparent that resistance based on acquired 
mutations in endothelial cells is indeed rare, but that tumors can develop resistance 
to anti-angiogenic therapy by other mechanisms, including the use of alternative 
angiogenic signaling pathways.  Such resistance may, however, be surmountable 
through the use of combinatorial anti-angiogenic approaches.12 Another practical 
advantage of anti-angiogenic therapy is that these treatments have a different 
pattern of toxicity than standard cytotoxic regimens, and can thus be used in 
conjunction with standard therapy, or in patients who have been heavily pretreated 
with cytotoxic drugs.12  Finally, as will be discussed in detail below, many existing 
chemotherapeutic agents have been found to have anti-angiogenic activity.99,120  
Some anti-angiogenic strategies can therefore be developed based on alternative 
scheduling of agents that are readily available and have well-established 
pharmacologic characteristics and toxicities. 
 

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The complexity of tumor angiogenesis allows for a wide variety of potential 
therapeutic strategies.  One general approach is to target receptors or signaling 
molecules that are specific to an angiogenic pathway.  The most successful of these 
to date has been bevacizumab (Avastin®), a humanized monoclonal antibody to 
VEGF.12  As monotherapy, bevacizumab has been efficacious only in metastatic 
renal cell carcinoma, where it improved progression free, but not overall survival.121 
It has, however, been considerably more effective when used in combination with 
cytotoxic chemotherapy.  The combination of bevacizumab and standard 
chemotherapy resulted in improved progression free and overall survival in 
colorectal cancer patients in two large Phase III trials,122,123 and the drug has 
consequently been approved by the FDA for combination first-line therapy in 
colorectal cancer. The combination of bevacizumab and chemotherapy has also 
been effective in non-small cell lung cancer, metastatic breast cancer,123 and 
recurrent high-grade glioma,124 and is being evaluated in ongoing clinical trials in 
many other malignancies, including recurrent or refractory pediatric high-grade 
glioma and diffuse pontine glioma in the PBTC 22 trial.  Bevacizumab has 
generally been well tolerated, with common toxicities consisting primarily of mild 
proteinuria and hypertension. It has, however, also been associated with rare but 
severe adverse events including hemorrhage, thrombosis, gastrointestinal 
perforation and reversible posterior leukoencephalopathy syndrome 
(RPLS).122,123,125 While the efficacy of bevacizumab provides substantial support 
for the concept of anti-angiogenic therapy, we have chosen not to incorporate 
bevacizumab into this frontline treatment protocol because of the lack of experience 
with this agent in very young children and the potential for severe toxicity.  Other 
novel agents include receptor tyrosine kinase inhibitors designed to interfere with 
signaling pathways involved in tumor angiogenesis.  A large number of agents in 
this category are under development, and two of these, sunitinib and sorefinib, have 
been approved by the FDA for monotherapy of renal cell carcinoma.126  These anti-
angiogenic tyrosine kinase inhibitors offer considerable promise for future 
applications in pediatric oncology.  As with bevacizumab, however, none of these 
agents have been studied in young children.  Furthermore, most of these drugs are 
only available in oral formulations (e.g., unbreakable tablets or capsules) that 
cannot be administered to infants.  The oral tyrosine kinase inhibitor erlotinib was 
designed to diminish tumor cell proliferation mediated by abnormal EGFR and 
ERBB2 signaling,127 but has also been found to down-regulate VEGF expression in 
vivo and in vitro in cells overexpressing ERBB2.116  As discussed in detail in 
section 2.4.6, erlotinib has been well tolerated in two pediatric phase I studies, and 
is commercially available in a tablet formulation which can be crushed for 
administration to young children.  Erlotinib will be administered to all 
medulloblastoma, high-grade glioma and ependymoma patients in the maintenance 
phase of this protocol.  Although this agent was included in the treatment regimen 
primarily because of its potential anti-proliferative activity in ERBB2 
overexpressing tumors, it may also have anti-angiogenic activity.116 
 

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2.4.6.3 Low-dose (metronomic) chemotherapy 
 
The most feasible strategy for targeting tumor angiogenesis in very young children 
at the present time is to use standard chemotherapeutic agents at low doses with 
frequent administration.  A growing body of preclinical research has demonstrated 
that this “metronomic” dosing strategy inhibits tumor angiogenesis.99,120,128,129  
Browder, et al. first showed that cyclophosphamide given at both the standard 
maximum tolerated dose (MTD) and in frequent low doses induced endothelial and 
tumor cell apoptosis in an experimental model of drug resistant cancer.130  The 
continuous low dose regimen, however, produced a more prolonged anti-angiogenic 
effect, and suppressed tumor growth more effectively.   Subsequent preclinical and 
early clinical studies have demonstrated the activity of metronomic chemotherapy 
against a variety of adult and pediatric tumor types (a partial list is provided in 
Table 6).   
 
TABLE 6 – RESULTS OF CLINICAL TRIALS INVOLVING 
METRONOMIC CHEMOTHERAPY IN RELAPSED/ REFRACTORY CANCER 
Adult Trials 
Disease 
Chemotherapy 
n 
Results 
Ref. 
Metastatic Breast 
Cancer 
Cyclophosphamide and Methotrexate 
64 
2 CR, 10 PR 
131 
Non Small-Cell 
Lung Cancer 
Etoposide 
17 
1 PR, 6 SD (8-32 wks) 
132 
Non-Hodgkin’s 
Lymphoma 
Cyclophosphamide and Celexocib 
35 
2 CR, 9 PR 
Median PFS 4.7 months 
133 
Melanoma 
Treosulfan and Rofecoxib 
12 
1 PR, 4 SD (24-36 wks) 
134 
Prostate Cancer 
Cyclophosphamide and Dexamethasone 
17 
Reduced PSA in 74% of patients 
135 
Pediatric Trials 
Disease 
Chemotherapy 
n 
Results 
Ref. 
Brain Tumors 
Temozolomide dose escalation x 42 days on, 
14 days off 
28 
MTD 85 mg/m2 
2CR, 2 PR 
136 
Solid Tumors 
(Phase I) 
Cyclophosphamide 50 mg/m2/d and Topotecan 
0.8mg/m2/d 
17 
Recommended duration 14 days; 
1 PR, 1 SD 
137 
Solid Tumors 
(Pilot/PK) 
Celecoxib with either Cyclophosphamide 30 
mg/m2/d or Vinblastine 1 mg/m2 3x/wk 
33 
Anti-angiogenic levels of 
cyclophosphamide and vinblastine 
attained,  
4 SD >28 wks 
138 
Solid Tumors 
(Feasibility) 
Celecoxib, Thalidomide, Cyclophosphamide 
2.5 mg/kg/d alternating cycles with Etoposide 
50 mg/m2/d 
20 
8 patients completed 6 months 
therapy,  
4 SD >123 wks 
139 
PK – Pharmacokinetics; CR – complete response; PR – Partial Response; SD – Stable Disease; PFS – Progression 
Free Survival; PSA – Prostate Specific Antigen 
 
The anti-angiogenic effect often occurs at drug concentrations substantially lower 
than those achieved by standard tumor cytotoxic doses.  Administering drugs in this 
manner can therefore result in minimal toxicity to normal tissues, and may allow 
the use of metronomic chemotherapy in conjunction with standard MTD therapy or 
other anti-angiogenic agents.140,141 Because metronomic chemotherapy can prevent 

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repopulation of endothelial cells damaged by MTD treatment, it may actually be 
most effective when used in combination with MTD chemotherapy, and indeed 
some preclinical evidence suggests that this is the case.  In studies utilizing the 
RIP1-Tag2 transgenic mouse model of pancreatic cancer, Pietras and Hanahan142 
demonstrated that a “chemo-switch” strategy (MTD followed by metronomic 
cyclophosphamide) produced more prolonged tumor growth suppression than MTD 
cyclophosphamide alone.  Interestingly, the combination of chemo-switch 
cyclophosphamide with SU11248, a tyrosine kinase inhibitor with activity against 
PDGFR, VEGFR-1 and -2, c-Kit, FGFR-1, and EGFR, resulted in complete 
responses and unprecedented survival for that model.  The chemo-switch strategy of 
intensive cytotoxic treatment followed by prolonged administration of low dose 
chemotherapy is also strikingly similar to the treatment approach utilized in 
pediatric acute lymphoblastic leukemia, one of the pediatric cancers with the best 
rates of long-term survival.99  Furthermore, as discussed above, recent evidence 
from glioma xenograft studies in the Kerbel laboratory suggests that a reduction in 
the tumor stem-cell-like fraction may be achieved through the combined use of 
cytotoxic and anti-angiogenic treatments, including low dose metronomic 
cyclophosphamide.118 The current protocol will utilize metronomic chemotherapy 
in three components of the treatment plan:  1) For patients with high-risk 
(metastatic) disease, low-dose vinblastine will be administered between cycles of 
MTD chemotherapy.  2)  Low-dose cyclophosphamide and topotecan will be used 
in the maintenance phase for all patients.  3) For patients with diagnoses other than 
medulloblastoma, high-grade glioma and ependymoma, low-dose oral etoposide 
will be used in place of erlotinib in the maintenance phase. 
 
2.4.6.4 Rationale for use of vinblastine as an anti-angiogenic agent 
 
Vinblastine was one of the first standard chemotherapeutic agents to have 
recognized anti-angiogenic activity.  Vacca, et al. showed that picomolar 
concentrations of vinblastine inhibited proliferation, chemotaxis, and adhesion to 
fibronectin of cultured human endothelial cells.  The drug was not cytotoxic to 
endothelial cells at these concentrations, and did not inhibit proliferation of cultured 
tumor cells.  The same vinblastine concentrations inhibited angiogenesis reversibly 
in vivo in the chick embryo chorioallantoic membrane model.128  Klement, et al. 
subsequently confirmed that low dose vinblastine inhibited endothelial cell 
proliferation in culture, and showed that it inhibited angiogenesis in vivo in a 
subcutaneous matrigel plug assay.  They also demonstrated that low-dose 
vinblastine diminished the growth rate, perfusion, and vascularity of  tumors in a 
CB-17 SCID mouse xenograft model of neuroblastoma, and caused dramatic tumor 
regression in the same assay when used in combination with an anti-VEGF 
receptor-2  antibody.143  
 
In the clinical setting, weekly low-dose vinblastine was reported to induce a long-
lasting remission in 8 of 13 patients with relapsed childhood anaplastic large cell 
lymphoma.144  This preclinical and retrospective clinical data prompted two 
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anti-angiogenic agent.  In the recently published pilot study by Stempak, et al.,138 
children with recurrent or refractory solid tumors were treated with celecoxib in 
combination with either intravenous vinblastine 1 mg/m2 3x/week (n=17) or 
metronomic oral cyclophosphamide 30 mg/m2 daily (n=16).  Both regimens were 
well tolerated.  In these heavily pretreated patients, there were only 3 episodes of 
grade III or IV neutropenia lasting <5 days (2 in the vinblastine arm and 1 in the 
cyclophosphamide arm).  Pharmacokinetic analysis demonstrated that these dosing 
regimens achieved serum concentrations consistent with those shown to have 
antiangiogenic effects in preclinical studies.  Although clinical outcome was not a 
primary goal of the study, approximately 20% of patients had stable disease lasting 
3 to 6 months, and extended periods of stable disease (7-18 months) were noted in 4 
patients.  In the ongoing Children’s Oncology Group trial AEWS02P1, patients 
with metastatic Ewing’s sarcoma receive celecoxib and intravenous vinblastine 
1mg/m2 3x/week continuously throughout a treatment regimen consisting of 
standard MTD chemotherapy (vincristine/doxorubicin/ cyclophosphamide 
alternating with ifosfamide/etoposide) and focal RT.  This regimen has been 
similarly well tolerated, with rates of myelosuppression comparable to prior 
Ewing’s studies, and no novel toxicities (Children’s Oncology Group Fall 2006 
Meeting AEWS02P1 Progress Report and personal communication with study 
principal investigator Judy Felgenhauer, MD).  Since these trials began, celecoxib 
has been associated with an increased risk of fatal cardiovascular events in adults, 
although no such toxicity has been documented in children.  Due to concerns about 
the continued availability of the drug, the difficulty of administering the available 
capsule formulation to young children, and the potential for nephrotoxicity when 
used in conjunction with other nephrotoxic agents in our protocol, we have chosen 
not to include celecoxib in this treatment regimen. 
 
In summary, low-dose vinblastine has anti-angiogenic effects in preclinical models 
at non-cytotoxic levels.  Administration of the dose to be used in this protocol 
(1mg/m2 3x/week) has been shown to achieve serum levels consistent with anti-
angiogenic activity in children with recurrent/refractory solid tumors.  This dosing 
regimen caused minimal myelosuppression when used in combination with 
celecoxib, and no apparent additive myelotoxicity when used with an intensive 
MTD chemotherapy/radiation regimen in children with Ewing’s sarcoma.  Because 
vinblastine is administered intravenously, it will be an ideal agent for use in infants 
and young children, who are typically unable to swallow capsules/tablets, and may 
suffer significant nausea from the other agents used in this protocol.  As most MTD 
chemotherapy has an anti-angiogenic effect of limited duration,120,130,145 vinblastine 
will be administered only during the breaks between MTD cycles, rather than 
simultaneously with MTD chemotherapy, as is being done in the AEWS02P1 
protocol.  This strategy should also limit the potential for undesirable 
pharmacokinetic interactions between vinblastine and standard chemotherapeutic 
agents.  
 

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2.4.6.5 Rationale for maintenance therapy with low dose cyclophosphamide and 
topotecan 
 
Lower intensity, prolonged duration chemotherapy is an integral component of the 
successful management of childhood acute lymphoblastic leukemia.99 The role of 
maintenance therapy in other tumors is not well established, but several prior infant 
medulloblastoma protocols have incorporated a maintenance phase.  In the era of 
delayed radiation studies, chemotherapy was continued for up to two years before 
patients were irradiated.14,16  Subsequent trials have utilized various strategies, 
including a shorter maintenance phase (P9934), continued moderate intensity 
therapy for 6-12 months (HIT-SKK92 and BBSFOP),17,18or termination of therapy 
after an induction phase followed by consolidation with high dose chemotherapy 
and stem cell rescue (Head Start and 99703).10,19  In this study, a 24 week 
maintenance phase will be included for all patients.  This will provide an 
opportunity to evaluate the feasibility and toxicity of administering oral metronomic 
and molecularly targeted therapy in this patient population.  Cyclophosphamide and 
topotecan are active against medulloblastoma and other embryonal tumors when 
given as single agents at  maximum tolerated doses,14,93,146 and against metastatic 
Ewing’s sarcoma and other pediatric solid tumors when given in combination.94,95  
Both agents have also been demonstrated to have anti-angiogenic activity,130,147-149 
and the combination of these drugs is therefore a natural choice for the metronomic 
component of this maintenance regimen.  
 
As described above, cyclophosphamide was one of the first agents shown to have 
anti-angiogenic activity when administered in frequent low doses,130 and remains 
the best-studied metronomic agent.99,150,150-152  In adult studies, metronomic 
cyclophosphamide is typically given at a dose of 50 mg per day, (roughly 30mg/m2) 
either continuously or in 21-day cycles, followed by a 7-day rest period.  Toxicity 
consists primarily of mild, reversible myelosuppression.133,153In children, daily oral 
cyclophosphamide has been administered in several regimens.  Kieran, et al. tested 
the feasibility of administering a four drug anti-angiogenic regimen to 20 children 
with recurrent or progressive pediatric cancer.  Patients received continuous oral 
thalidomide and celecoxib, with alternating 21 day cycles of oral etoposide and oral 
cyclophosphamide (2.5mg/kg/day to a maximum of 100mg/day).  21 episodes of 
grade III and no episodes of grade IV neutropenia occurred within the first six 
months of therapy.  During the same interval, 4 episodes of grade III anemia 
occurred, with no grade IV anemia and no grade III or IV thrombocytopenia. One 
quarter of patients remained progression free more than 123 weeks from starting 
therapy, including the single patient in the study with medulloblastoma.139  In 
addition, as described above, Stempak et al. administered cyclophosphamide 
30mg/m2/day in combination with BID celecoxib to 16 pediatric patients with 
recurrent/refractory solid tumors.  Toxicity was minimal, and prolonged stable 
disease was observed in 1 patient.138  Heavily pretreated pediatric solid tumor 
patients have therefore tolerated oral cyclophosphamide in combination with other 

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agents at doses ranging from 30 mg/m2/day (approximately 1 mg/kg/day) to 
2.5mg/kg/day (approximately 75 mg/m2/day). 
Topotecan has activity in medulloblastoma and PNET,146 and has also been shown 
to have anti-angiogenic activity when administered in frequent low doses in 
preclinical models of Wilms tumor and neuroblastoma.147-149  In a retrospective 
study from Memorial Sloan Kettering Cancer Center, Kramer, et al. reported that 20 
patients with relapsed/refractory neuroblastoma were treated with 21 day cycles of 
daily oral topotecan, generally at 1 mg/m2/d in two divided doses.  Toxicity 
including diarrhea (n=12) and myelosuppression (n=11), both requiring dose 
adjustment in several cases.  Anti-neuroblastoma activity was seen in 7 patients, 
lasting 4 to 12 months.154  
 
In a pediatric Phase I study, Bowers, et al. administered cyclophosphamide 50 
mg/m2/day in combination with topotecan 0.8mg/m2/day to 17 children with 
recurrent or refractory malignant solid tumors.  A partial response was observed in 
one neuroblastoma patient, and prolonged stable disease was observed in 1 of 3 
medulloblastoma patients enrolled in the trial.  Myelosuppression was the DLT, and 
the maximum tolerated duration of combined therapy was 14 days out of a cycle 
lasting 21 to 28 days.137 To optimize the anti-angiogenic effect, it will be preferable 
to administer chemotherapy for a greater proportion of each cycle, and limit the 
duration of the rest period.  In the maintenance phase of this protocol, oral 
cyclophosphamide will be given at 30 mg/m2/day for 21 days, followed by a 7 day 
rest. Topotecan will be given at 0.8 mg/m2/day for the first 10 days of each 28 day 
cycle containing cyclophosphamide.  If patients experience delays in therapy due to 
myelosuppression, the dose of cyclophosphamide, and if necessary, duration of 
topotecan will be adjusted in subsequent courses (see section 4.5.4 for details).  
Cyclophosphamide/topotecan cycles will be alternated with cycles of single-agent 
erlotinib or etoposide (see below). 
 
2.4.7 Rationale for molecularly-targeted therapy with erlotinib 
 
2.4.7.1 ERBB Family expression in medulloblastoma and other brain tumors 
 
The receptor tyrosine kinase I (RTK I), also known as ERBB, family of 
transmembrane receptors includes EGFR (also known as ERBB1), ERBB2 (also 
known as HER2), ERBB3 and ERBB4.  These receptors participate in cell signaling 
pathways which control a variety of  cell processes including proliferation and 
apoptosis.155  Abnormalities of ERBB family proteins have been detected in a 
number of tumor types, including breast, lung, and pancreatic cancer.156  
Overexpression of ERRB2 results in abnormal receptor homodimerization which 
causes constitutive receptor activation and stimulates cell proliferation mediated 
through the PI3K/AKT pathway.  Gilbertson, et al. detected ERBB2 expression by 
immunohistochemistry in 80% of medulloblastoma tumor samples from pediatric 
patients, and ERBB4 in 66%.  ERBB1 and ERBB3 were rarely expressed.  Patients 
with high levels of ERBB2 expression (≥ 50% immunoreactive tumor cells) had a 
significantly worse prognosis, and co-expression of ERBB2 and ERBB4 was 
associated with particularly poor survival.157  Further studies in the Gilbertson 

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laboratory have shown that ERBB2 overexpression in medulloblastoma is 
associated with increased proliferative activity, tumor invasiveness, and metastatic 
potential,158-161 and other investigators have reported an association between 
ERRB2 expression and survival.162-164  As a component of the current SJMB03 trial 
for medulloblastoma patients ≥ 3 years of age, evaluation of ERBB2 protein 
expression by Western blot is being performed on snap frozen tumor samples.  In 
the pilot study which preceded SJMB03, ERBB2 protein expression was an 
independent predictor of  poor prognosis, and the combination of ERBB2 
expression and clinical disease characteristics provided a highly accurate means of 
risk stratification for children three years of age or older at diagnosis.  This pilot 
study included 15 samples from children younger than three years of age.  ERBB2 
expression was detected in 8 of 15 tumors, but the small number of samples 
available precluded survival analysis within the younger cohort.  Interestingly, 
ERBB2 expression and nodular desmoplastic histology were not mutually 
exclusive, as ERBB2 was expressed in 5 of 9 young children with nodular 
desmoplastic medulloblastoma, and 3 of 6 young patients with classical or 
anaplastic histology.40  The frequent expression of ERBB2 in medulloblastoma of 
all histologic subtypes, and its association with aggressive clinical behavior, make it 
an attractive therapeutic target. 
 
The frequency of ERBB family abnormalities in other tumors eligible for this trial 
has not been investigated as thoroughly.  Overexpression of the ERBB family 
member EGFR has been detected in approximately 80% of pediatric high-grade 
gliomas,165although the expression of EGFR has not been evaluated in high-grade 
gliomas from children younger than three years of age.  ERBB2 and ERBB4 have 
been found to be co-expressed in approximately 75% of ependymomas, and high-
level co-expression has been associated with increased tumor cell proliferation and 
aggressive clinical behavior.166  In contrast, one small series demonstrated that 
EGFR expression was not detected by immunohistochemistry in any of  9 ATRT 
samples.167  Similarly, preliminary analysis of gene expression profiles from ATRT 
samples collected on the St. Jude NBTP01 biology study has revealed no evidence 
of alterations in expression of ERBB family genes (personal communication, Amar 
Gajjar, NBTP01 principle investigator).  No studies of ERBB family alterations in 
pediatric supratentorial PNET have been published, to our knowledge. 
 
2.4.7.2 Erlotinib 
 
The amplification, overexpression and mutation of ERBB family receptors in a 
number of different tumor types have prompted the development of several new 
drugs that target these signal proteins.  One of the most advanced in clinical 
development is erlotinib (Tarceva, OSI-774), an orally available small-molecule 
inhibitor of the ERBB1 and ERBB2 tyrosine kinases.  Erlotinib has been approved 
by the FDA for use in non-small cell lung cancer and pancreatic cancer, 156 and is 
being evaluated in ongoing clinical trials in a number of other cancer types, 
including the St. Jude SJHG04 study for children with high grade glioma.  While 
this agent was originally developed because of its activity against EGFR (ERBB1), 

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more recent preclinical work has demonstrated that erlotinib also blocks signaling 
by ERBB2.116,127  A study from Richard Gilbertson’s laboratory demonstrated that 
erlotinib significantly inhibited ERBB2 phosphorylation and expression of the 
downstream target S100A4 in the Daoy medulloblastoma cell line, and inhibited 
migration of Daoy.2 cells in vitro.  Erlotinib also inhibited pro-metastatic gene 
expression in Daoy.2 cells grown as s.c. xenografts in nude mice.161 
 
Erlotinib has been generally well tolerated in adult clinical trials.  Toxicity has 
consisted primarily of rash and diarrhea.  Diarrhea has been the dose limiting 
toxicity in adult studies, and the adult MTD has been established at 150 mg daily.  
While interstitial lung disease (ILD) was a rare but sometimes fatal adverse event in 
early clinical trials, the BR-2 study, a randomized, double blinded, placebo 
controlled study involving 731 adult patients with incurable advanced stage 
NSCLC, found no difference in the incidence of ILD between the treatment and 
control groups (0.8% in each group).168  The Children’s Oncology Group 
ADVL0214 trial was a pediatric Phase I study for patients with selected 
recurrent/refractory solid tumors, including brain tumors.  46 patients were enrolled, 
including 23 younger than 12 years of age.  Patients received an initial 28 day 
course of single-agent erlotinib, followed by repeated courses of erlotinib in 
combination with temozolomide 180 mg/m2, administered on the first five days of 
each course.  Myelosuppression was minimal during the single agent erlotinib 
phase, with only one episode of grade 3 leukopenia.  Dose limiting toxicities were 
rash, diarrhea, and hyperbilirubinemia, and the MTD of erlotinib for both the single 
agent and combination phases was 85 mg/m2.  No pulmonary toxicity was reported 
in this pediatric phase I trial (COG Spring 2006 Meeting Progress Report). 
 
In the SJHG04 trial for children older than three years of age with high grade 
glioma, erlotinib is given concurrently with focal irradiation and as a single agent 
thereafter.  During the initial phase I component of this trial, the dose of erlotinib 
was escalated to the maximum planned dose level of 120 mg/m2 once daily, and no 
MTD was reached.  An amended version of the trial which opened subsequently 
allowed further dose escalation.  While no MTD was reached, pharmacokinetic 
studies demonstrated that serum erlotinib levels reached a plateau at higher doses.  
As in prior studies, toxicity consisted primarily of rash and diarrhea (personal 
communication, Alberto Broniscer).  An 8-year old patient on this trial required 
externalization of a ventriculoperitoneal shunt due to infection, and provided an 
opportunity for simultaneous evaluation of plasma and CSF erlotinib 
pharmacokinetics.  At a dose of 78 mg/m2/day, CSF penetration for erlotinib and its 
metabolite OSI-420 were 7% and 9%, respectively.169 
 
In summary, expression of EGFR or ERBB2 is detectable in a large proportion of 
medulloblastomas, high-grade gliomas and ependymomas, and is associated with 
aggressive clinical behavior.  Erlotinib is a receptor tyrosine kinase inhibitor with 
activity against ERBB2 and good CSF penetration.  As discussed in section 2.4.5.2, 
it may also have anti-angiogenic activity in ERBB2 overexpressing tumors.  It has 
been well tolerated in pediatric phase I trials which include brain tumor patients.  

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Furthermore, unlike many other molecularly targeted agents, erlotinib tablets can be 
crushed, and can thus be given more readily to very young children.  This trial will 
evaluate the feasibility and toxicity of administering this drug to young children  
with medulloblastoma, high-grade glioma or ependymoma as a component of 
maintenance therapy.  Erlotinib will be given at a dose of 90 mg/m2 by mouth daily 
for 28-day cycles, in alternation with cycles of metronomic 
cyclophosphamide/topotecan. 
 
ERBB2 expression has not been detected in ATRT, and has not been evaluated in 
supratentorial PNET or the rarer tumors eligible for this trial.  There is therefore 
minimal rationale for administering erlotinib to patients with tumors other than 
medulloblastoma, high-grade glioma or ependymoma.  Oral etoposide will be 
substituted for erlotinib for these patients at a dose of 50 mg/m2 daily for the first 21 
days of each maintenance cycle B.  This dose of etoposide has been shown to 
produce clinical responses and prolonged disease stabilization in patients with 
recurrent medulloblastoma and other brain tumors, as well as non-CNS solid 
tumors.170-173  This regimen has also been successfully administered to very young 
children with medulloblastoma and other embryonal CNS tumors on the recent 
P9934 and PBTC-001 trials.  It has been well tolerated in this population, with the 
primary adverse effect being manageable myelosuppression (COG Fall 2006 
Meeting P9934 Progress Report). 
 
2.4.8 Rationale for RT 
 
RT is an essential component of treatment for medulloblastoma and other CNS 
tumors in older patients, but investigators have attempted to limit the use of this 
modality in very young children due to unacceptable toxicity.174,175  While results 
have varied by trial, even the most effective chemotherapy regimens have not 
allowed the omission of RT in all patients.  RT therefore remains a necessary 
component of treatment for many patients in this population.  Fortunately, attempts 
to limit the late effects of RT by reducing the dose to normal brain structures have 
met with some success.  These improvements have been achieved through the use 
of smaller target volumes and conformal treatment planning.  Implementation of 
these strategies has resulted in effective disease control for ependymoma patients as 
young as 12 months, with good neurocognitive outcomes.36  As described in section 
2.2.1, preliminary results from treatment regimens utilizing local RT in very young 
patients with M0 medulloblastoma have also produced encouraging survival rates. 
 
Patients enrolled on this trial will be at risk for neurocognitive sequelae from a 
variety of insults, including direct tumor effects, hydrocephalus, surgery, and 
chemotherapy.  Accordingly, this treatment plan will attempt to limit the toxicity of 
RT in several ways.  For patients with low-risk disease (those with M0 completely 
resected nodular desmoplastic medulloblastoma), RT will be omitted entirely.  For 
patients with intermediate risk disease (all other M0 patients), focal RT will be 
required; in order to minimize damage to normal brain, we will use a clinical target 
volume margin of 5 mm.  Given the high likelihood of neurocognitive dysfunction 

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associated with CSI in children less than 3 years of age, we will not routinely 
administer CSI to high-risk patients on this protocol.  Some patients with high-risk 
disease will, however, reach the age of 3 years while on treatment, and as it is a 
component of standard therapy for children older than 3 years, CSI will be offered 
to these patients.  For patients whose parents do elect CSI, we will use a clinical 
tumor volume margin of 5 mm for the primary tumor site boost, and adjust the 
neuraxis dose based on the response to induction chemotherapy.  Proton beam RT is 
an emerging technology which has the potential to reduce the radiation dose to 
normal structures to a greater extent than is possible with conformal photon therapy 
techniques.176  The use of proton RT may ultimately result in decreased 
neurocognitive toxicity, and this modality is being used with increasing frequency 
in the treatment of pediatric tumors, including brain tumors.  As this technology is 
not currently available at St. Jude, patients enrolled on this protocol will be allowed 
to receive proton radiotherapy at other institutions; all such cases should be 
discussed with the principal investigator or radiation oncology section coordinator 
prior to the initiation of RT. 
 
2.5 
RATIONALE FOR PHARMACOKINETIC/PHARMACOGENETIC STUDIES 
 
NOTE:  Methotrexate pharmacokinetic studies will be obtained for all patients at 
all sites as a component of standard care, and topotecan pharmacokinetics will be 
evaluated for all patients at all sites who are treated on the high-risk arm and 
receive consolidation with targeted topotecan and cyclophosphamide.  During the 
maintenance phase, trough levels will be obtained at two time points for all patients 
at all sites receiving oral cyclophosphamide and erlotinib in order to assess 
compliance.  All other pharmacokinetic studies will be optional, and will be offered 
only to patients treated at St. Jude. 
 
2.5.1 Methotrexate studies 
 
Methotrexate, a folic acid antagonist, is structurally similar to folic acid and acts by 
reversibly inhibiting dihydrofolate reductase, ultimately interfering with the 
synthesis of DNA and cell reproduction.  Renal excretion constitutes the major 
route of methotrexate elimination, with renal clearance accounting for 60-80% of 
total body clearance. Following an intravenous methotrexate dose, between 40 and 
90% of the dose is recovered unchanged in the urine.177  Considerable evidence has 
been published that the pharmacokinetic parameters (e.g., systemic clearance) of 
high-dose methotrexate (HDMTX) are highly variable among children and that this 
variability can influence event-free survival of pediatric patients with ALL.178,179  A 
greater risk of ALL relapse was observed in children with a lower systemic 
exposure to MTX due to more rapid systemic clearance of HDTMX.180,181  Seidel 
and colleagues also noted that higher MTX clearance was associated with a worse 
outcome in pediatric patients with ALL.182 
 
A number of factors may explain at least part of the observed variability in 
methotrexate pharmacokinetic parameters, particularly systemic clearance. 

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Different studies have shown that hydration and urinary alkalinization regimens, 
renal function, as well as emesis and concomitant drug administration can 
significantly affect HDMTX disposition in children.183  Aumente and colleagues184 
have published the results of a population pharmacokinetic study using NONMEM 
analysis involving 49 pediatric patients with newly diagnosed ALL aged 6 months 
to 17 years receiving HDMTX (3 g/m2 infused over 24 hours). The investigators 
propose that age is an important factor that explains part of the inter-individual 
variability of methotrexate pharmacokinetics. For the same total body weight, 
children younger than 10 years had a total CL 30% higher than in children older 
than 10 years. These data supports the previous reports demonstrating that systemic 
methotrexate CL decreases progressively as a function of age.185 
 
At birth and up to approximately 2 months, glomerular filtration rate is 
approximately 40 ml/min/1.73 m2. As methotrexate is primarily eliminated by 
glomerular filtration, very young infants might be expected to have diminished 
methotrexate clearance.  Of the few data published on methotrexate 
pharmacokinetics in infants with acute lymphoblastic leukemia, results are mixed. 
In children receiving  high-dose MTX, Donelli and colleagues186 found no 
significant differences in MTX pharmacokinetics when comparing infants aged less 
than 1 year and older children aged up to 10 years in a small series. By contrast, 
McLeod and colleagues showed that infants (n=4) between 3-12 months had a 
significantly lower clearance of 80 ml/min/m2 compared to 103 ml/min/m2 in 108 
children aged 1-19 years (p=0.01), but observed no increased toxicity in the 
infants.187 Thompson and colleagues also reported a modest difference in clearance 
when comparing very young pediatric patients (less than 6 months old, 89 ± 32 
ml/min/m2) to older infants aged 7-12 months (111 ± 40 ml/min/m2).188 These 
authors also observed a difference in the average methotrexate clearance when 
comparing very young infants (0-3 months) to infants between 7 and 12 months old. 
In this study, very young infants (0 to 3 months) had greater renal toxicity (all 
grades) than the older infants, but no significant differences were noted in 
hepatoxicity or mucositis between the age groups.  The authors urged caution in 
interpretation of the toxicity results since the study was not designed to collect data 
on other factors that might contribute to methotrexate toxicity (e.g., aminoglycoside 
usage, etc.).  
 
The intra- and inter-patient variability reported in methotrexate pharmacokinetics 
remains largely unexplained in patients with normal renal function and sufficient 
hydration. A well-documented methotrexate efflux transporter is the ABC 
transporter ABCC2 or MRP2/cMOAT, which is expressed in the luminal membrane 
of hepatocytes and proximal tubular cells of kidney. The involvement of ABCC2 in 
methotrexate transport has been documented in vitro as well as in vivo. 189,190 The 
methotrexate plasma area under the curve between 36 and 48h (AUC36-48) was 
higher in female patients as well as in patients who carry at least one -24T allele. 
Moreover, a significant interaction between genotype and gender was found, 
leading to a hypothesis that a gender-specific effect could exist for the -24C>T 
ABCC2 polymorphism on high-dose methotrexate pharmacokinetics.191   

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Considering the potential importance of MTX in treating very young children with 
brain tumors, and the possible influence of infant physiology on MTX disposition, 
the present study aims to characterize MTX pharmacokinetics and toxicity in 
infants as important steps toward improving the safety and efficacy of future 
therapy for this vulnerable patient population.  For St. Jude patients enrolled on the 
institutional PGEN5, the relationship between pharmacogenetic and 
pharmacokinetic variables will also be explored. 
 
2.5.2 Rationale for cyclophosphamide pharmacokinetic and pharmacogenomic 
studies 
 
Wide inter-patient variability in cyclophosphamide systemic clearance is observed 
in both adult and pediatric patients. Although many factors may account for this 
difference, the relatively increased hepatic cytochrome activity in children 
compared with adults is thought to account for much of the difference in 
pharmacokinetics parameters between adults and children.192,193  Pediatric patients 
have also demonstrated considerable inter-patient variability in their exposures to 
cyclophosphamide metabolites DCCY and CEPM,194 but inter-patient variability in 
systemic exposure to the metabolite HCY has not been evaluated in children. In 
previous studies, variations in DCCY and CEPM exposure could not be attributed 
to a child’s body surface area, age, gender, glomerular filtration rate, or hepatic 
function,195,196 which suggests the contribution of other factors to the variability in 
cyclophosphamide metabolite exposure.  Although a few studies have previously 
described cyclophosphamide pharmacokinetics in children, none have used recently 
developed, highly sensitive analytical techniques to assess inter- and intra-patient 
variability in cyclophosphamide exposure.  In fact, intra-patient variability in 
cyclophosphamide exposure has not been addressed thoroughly by any means in 
pediatric patients, much less very young children.  Thus, in this study we propose to 
describe the pharmacokinetics of cyclophosphamide and its metabolites (i.e., HCY) 
in very young children receiving intravenous and oral cyclophosphamide, using a 
recently developed LC MS/MS analytical method.  We will also assess the extent of 
inter-patient variability in the pharmacokinetics of cyclophosphamide and 
metabolites, and the effects of patient specific covariates upon the 
pharmacokinetics.   
 
Cyclophosphamide is a known inducer of its own metabolism, and variable 
increases in cyclophosphamide clearance have been described after repeated 
administration.197  Unfortunately, autoinduction may confound the pharmacokinetic 
analysis by contributing to intra-patient variation between oxazophosphorine 
courses, as was observed with ifosfamide, a related isomer of cyclophosphamide.  
We therefore propose to evaluate intra-patient pharmacokinetic variation by 
conducting pharmacokinetic studies in selected patients (those receiving 
consolidation with IV topotecan plus cyclophosphamide 600 mg/m2/day IV on 2 
consecutive days).  The results of these studies will be very interesting to compare 
with those from a similar study performed in older children with medulloblastoma, 

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but at a much higher cyclophosphamide dosage.  In that study, cyclophosphamide 
65 mg/kg/d (~1950 mg/m2/day) IV was administered on 2 consecutive days, and 
results of detailed pharmacokinetic studies showed cyclophosphamide clearance 
was increased on the second day by an average of  32%.   
 
Concomitant medications, particularly those affecting CYP isozymes, have been 
shown to influence the half-life of cyclophosphamide,198 but the effect of these 
compounds upon the systemic exposure of the metabolites has not been explored.  
The half-life of cyclophosphamide has been extended by allopurinol and 
chlorpromazine, while shortened by etoposide, dexamethasone,199 and enzyme-
inducing anticonvulsants.200  The mechanisms of these interactions have not been 
evaluated, although dexamethasone may shorten the half-life of cyclophosphamide 
by induction of cytochrome P450 3A activity,201 while fluconazole and itraconazole 
are thought to increase cyclophosphamide half-life by inhibiting CYP2C8, CYP2C9 
and CYP3A4.202,203  Patients receiving inducers or inhibitors of CYP enzymes, such 
as glucocorticoids, enzyme-inducing anticonvulsants, azole anti-fungals, or 
macrolide antibiotics (see Appendix I) will be analyzed and the impact of such 
drugs upon cyclophosphamide / HCY pharmacokinetics will be described.  As we 
expect that very few patients enrolled on SJYC07 will be receiving inhibitors or 
inducers of metabolizing enzymes, any analysis of the effects of concurrent 
medications upon cyclophosphamide or metabolite pharmacokinetics will be purely 
descriptive. 
 
Genetic polymorphisms have been identified as factors influencing variability in 
drug exposure and response amongst patients, particularly with anti-neoplastic 
agents.204-206  Recent in-vitro evidence has suggested that polymorphisms in 
CYP2B6 and CYP2C9 can affect formation of cyclophosphamide metabolites, 
notably the formation of the active 4-OH metabolite.207-209  Moreover, 
polymorphisms in CYP3A4/5, the most abundant cytochrome P-450 isoforms in 
humans, are suspected of impacting the rates of cyclophosphamide metabolite 
formation both in-vitro and in-vivo.210  Previous studies from Petros et al. have 
demonstrated an association between polymorphisms in CYP3A4/5, 
cyclophosphamide disposition, and overall survival in breast cancer patients.211  
Recent evidence has also suggested that alkylating agents are substrates for 
MRP2/cMOAT, and this transporter is responsible for their distribution in the 
body.212,213  These studies suggest that a high-efflux MRP2/cMOAT phenotype 
could influence systemic HCY exposure, thus affecting anti-tumor efficacy and/or 
the toxicity profile of cyclophosphamide/HCY.  In light of these data, we propose to 
study the distribution of polymorphisms in cytochrome P450 enzymes and ABC 
transporters amongst St. Jude patients enrolled on the institutional pharmacogenetic 
protocol PGEN5.  The associations between the selected genetic polymorphisms 
and pharmacokinetic phenotypes will be investigated in an exploratory manner. 
 
To characterize the pharmacokinetics of cyclophosphamide and its metabolites 4-
OH-cyclophosphamide and carboxyethylphosphoramide mustard (CEPM) in infants 
with brain tumors, we have performed studies in all consenting patients during the 

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induction phase (i.e., all risk groups), and also during consolidation for high-risk 
patients. Thus far cyclophosphamide pharmacokinetic studies have been completed 
in 23 infants during induction, and in 3 out of 6 infants with high-risk tumors during 
consolidation (with the other 3 patients going off-study prior to consolidation). 
 
The hepatic metabolism of cyclophosphamide is very complex involving several 
cytochrome P450 enzyme systems including CYPB6, CYP2C9, and CYP3A4/5, 
which undergo a rapid maturation process in children less than 3 years of 
age.213a,b,c,d  In general, these studies have shown that CYP3A4/5 activity can 
rapidly increase in the first year of life to a level that is actually higher than adult 
CYP3A4/5 activity. CYP3A4 activity varies over 3-fold within the three years from 
birth to 3 years of age. 213a,d CYP2C9 liver expression and activity also increase 
rapidly in the first year of life, but remain below adult values.213b The 
developmental changes in hepatic CYP450 expression may lead to a difference in 
cyclophosphamide pharmacokinetics between induction and consolidation in our 
patient population. In particular, changes in CYP isoform expression during the four 
months that the patient matures may lead to different activation of CTX to the 4-
OHCTX form, possibly resulting in altered pharmacologic effect (e.g., decreased 
efficacy or increased toxicity).  
 
Initially, we planned to address the question of whether cyclophosphamide 
clearance changed between induction and consolidation by studying patients during 
induction and consolidation for the high-risk group; however, our experience shows 
that we are unlikely to accrue sufficient numbers of high risk patients for an 
adequate analysis. Thus, we propose to expand our studies of cyclophosphamide 
pharmacokinetics to include the group of children in the low-risk arm that receive 
cyclophosphamide during consolidation. This will enable us to accrue adequate 
patient numbers as exemplified by the power analysis detailed below.  
 
Total accrual on the protocol is estimated to be ~400 patients, and current estimates 
as well as SJ historical data suggests that approximately 50% of patients enrolled 
will be either LR or HR.  Hence 200 total LR+HR patients are expected to be 
enrolled on this protocol. Thirty eight (38) of these have already been enrolled, so 
we expect to have 162 additional enrollees in these two risk groups. The 
investigators expect that 50-60% of these patients will be treated at SJ and the rest 
will be treated at the collaborating sites, which is consistent with prior SJ-initiated 
multi-institutional brain tumor protocols, such as SJMB03. Based on current 
accrual, we estimate that 50% of the LR+HR patients will be LR and 50% will be 
HR. Thus of the approximately 81-98 additional patients treated at SJ, 40-50 are 
expected be LR and 40-50 to be HR. The EFS rate at 4 months for HR is ~60%. We 
don’t have a good estimate of the EFS rate for LR group (since so few were in the 
SJ historical cohort) but we may conservatively estimate the EFS rate at 4 months 
as 90%. Hence 36-45 of the LR patients and 24-30 of the HR patients are expected 
to reach consolidation without progression. The investigators expect that 90% of 
patients treated at SJ will consent to these optional PK studies, as was observed in 
prior studies. Thus we estimate that an additional 32-40 LR and 22-27 HR patients 

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will be enrolled on the protocol and will have both induction and consolidation 
samples available. 
 
We do not know a priori whether the change in cyclophosphamide clearance 
between induction and consolidation (ΔCL) vs. age is linear or even monotonic. If 
the observed relationship is linear, or can be linearized via a transformation such as 
log, and the data does not deviate substantially from bivariate normality, then the 
Pearson’s correlation coefficient will be used to test the existence of a relationship. 
The following table provides power estimates based on Pearson’s Correlation for 
various sample sizes and for two population correlation values, ρ=0.4 and ρ =0.5. 
The power values provided in the table below are in the acceptable range (≥80%) 
for most cases. If the observed data are grossly non-normal and/or the relationship 
between ΔCL and age cannot be linearized, then we will use Spearman’s rank 
correlation instead, which may lead to some loss of power. While it is difficult to 
estimate the magnitude of the loss in power, it is relatively safe to assume that the 
power associated with n=35 in the table below would approximately correspond to 
the power associated with n=40 for the Spearman’s rank correlation. 
 
Power estimates based on testing ρ=0 vs. ρ≠0, where   ρ 
is Pearson’s Correlation Coefficient with α=0.05 
Sample 
Size 
Association Value 
to be detected 
Power for Pearson’s 
Correlation-based 
Test 
35 
0.4 
68.07% 
35 
0.5 
88.27% 
40 
0.4 
74.15% 
40 
0.5 
92.22% 
45 
0.4 
79.24% 
45 
0.5 
94.91% 
65 
0.4 
91.93% 
65 
0.5 
99.17% 
65 
0.3 
68.99% 
 
This table shows that if we perform cyclophosphamide pharmacokinetic studies 
during consolidation separately for LR and HR patients, we will have adequate 
power to address the question of how clearance changes between induction and 
consolidation and how these changes relate to age. Combining the two cohorts 
would allow us to have higher power overall, detect smaller correlation values and 
mediate the loss of power in the event that we may have to use Spearman’s rank 
correlation due to non-linearity or non-normality in the data. We therefore propose 
to study the pharmacokinetics of cyclophosphamide during consolidation in LR 
patients as well as HR patients. 
 
2.5.3 Rationale for topotecan pharmacokinetic and pharmacogenomic studies 
 
As described in Section 2.4.5.5, “Rationale for consolidation with 
pharmacokinetically-targeted topotecan and cyclophosphamide in high-risk 

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patients”, these two very active agents will be combined and administered for two 
cycles of consolidation therapy.  We have extensive experience with 
pharmacokinetically guided dosing of topotecan in children with cancer.  Most of 
this experience was to attain a plasma systemic exposure; however, in children with 
medulloblastoma and other embryonal tumors we used our pharmacokinetically 
guided approach to topotecan dosing to attain a target exposure duration threshold 
(EDT) in the vCSF defined as 1 ng/ml for 8 hours.  In a subsequent 
pharmacokinetic analysis of the data from this clinical trial, we demonstrated that a 
plasma pharmacokinetic model could be used to estimate vCSF topotecan 
concentrations in children with medulloblastoma.214 Furthermore, we showed that 
as the plasma topotecan AUC increased, so did the likelihood of exceeding the 
EDT. Whereas previous studies have validated the three-compartment 
pharmacokinetic model used to evaluate the topotecan plasma and vCSF 
disposition, this was the first study to evaluate the ability of a plasma 
pharmacokinetic model to provide an estimate of vCSF exposure that was based 
solely on plasma topotecan data. 
 
We have conducted many individual pharmacokinetic studies of topotecan in 
children with cancer, and our results have shown wide inter-individual variability in 
topotecan clearance215-217.  In order to better understand the inter- and intra-patient 
variability in topotecan lactone disposition, we have conducted a population 
pharmacokinetic analysis using NONMEM.  This analysis included 220 children 
divided into a model building and a validation set. The modeling building set 
included 162 children that participated in four Phase I and three Phase II clinical 
trials of topotecan, and the validation set, which included 58 children in one clinical 
trial.  The patient covariates that were evaluated included continuous (e.g., age) and 
categorical variables (e.g., sex).  Although our analysis included children from 0.04 
to 22.0 years, we noted no continuous relation with age and topotecan clearance. 
When evaluated as a linear continuous variable, age was not a significant covariate 
(p>0.1).  However, for infants less than 0.5 years (10 studies in 1 patient), BSA-
normalized topotecan clearance was 40% less than that observed in patients greater 
than 0.5 years of age (p<0.001).  The results of this larger study would suggest that 
unless a child is in the first months of life, the topotecan clearance will be similar to 
older patients. We speculate that maturation of renal function during the first weeks 
of life, leading to a change in glomerular filtration rate, produces this observed 
change in topotecan clearance with age (up to 6 months).  However, in our 
population of 162 children, only 4 children were ≤ 1 yr of age and 14 ≤ 2 yr of age.  
Thus, to gain a better understanding of the variability of topotecan disposition in 
very young children it is crucial to study the pharmacokinetics and 
pharmacogenomics of topotecan in this population. 
 
Currently the sampling times for targeting topotecan studies are pre, and 5 min, 1 
hour, and 4 hours after the end of a four-hour infusion.  With the processing time 
required for the whole blood topotecan assay used in this protocol, it requires a 
minimum of ten hours to complete a targeting study (time from start of study to 
reporting AUC results). Even when patients are started very early in the Medicine 

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Room this makes for a long day for patients and families. Thus, we have performed 
simulation studies to assess the effect of moving the last sample time point from 4 
hours up sooner. The results of these simulation studies showed that collecting the 
last sample at 2 hrs post-infusion resulted in a biased estimate of the topotecan 
AUC, but collecting the last sample at 3 hrs post-infusion allowed us to estimate the 
topotecan AUC as accurately as the 4-hr time point. Thus, we recommend adjusting 
the sample time points for the topotecan targeting studies to change the 4-hour 
sample to a 3-hour sample. 
 
2.5.3.1 Rationale for stratifying topotecan initial dosage by age  
 
During Consolidation, patients that are high-risk receive two cycles of 
pharmacokinetically-guided topotecan therapy. For those children who were treated 
on non-protocol treatment plans as per SJYC07 and for patients enrolled on the 
study, a topotecan dosage of 3.5 mg/m2 was selected for day 1 of course 1.  With 
this initial dosage, only three of 12 patients (9 patients treated as per SJYC07 on 
non-protocol treatment plans and 3 SJYC07 patients) had topotecan AUC values 
within the desired topotecan lactone AUC range of 140±20 ng*hr/ml on day 1 of 
course 1. Out of 3 SJYC07 patients, only 1 has been in the AUC target range. It was 
noted that the two patients with the highest topotecan AUC values (277 and 234 
ng*hr/ml), were also the youngest (8 months and 11 months, respectively). 
Topotecan is primarily cleared by renal elimination213f and it is known that renal 
function, and in particular glomerular filtration, develops over the first year of life. 
213a We do not yet have adequate data from SJYC07 patients and as per SJYC07 
non-protocol treatment plan patients to determine the relationship between age and 
topotecan clearance because most patients thus far have been older than 1 year.  
 
We therefore examined data from SJRET5, another clinical protocol in which 
topotecan is administered intravenously to young children. Preliminary analysis of 
data from SJRET5 shows that topotecan systemic clearance is linearly related to age 
for the first year of life, then reaches a plateau after 1 year.  The relationship of 
topotecan systemic clearance and age mirrors renal development.213a Thus, we used 
combined data from SJRET5, SJYC07 and NPTP patients to determine the initial 
dosage of topotecan that is the most likely to result in patients being within the 
target AUC range on day 1 of course 1. We recommend that patients ≥12 months of 
age continue to receive 3.5 mg/m2, patients 6-11.9 months of age should receive 2.5 
mg/m2 as the initial course 1 day 1 topotecan dosage, and patients <6 months of age 
receive 2 mg/m2 as the initial course 1 day 1 topotecan dosage.  With this 
adjustment in the course 1 day 1 topotecan dosage, we expect a reduction in the 
number of topotecan targeting pharmacokinetic studies that will be necessary to get 
patients within the target topotecan AUC range. 
 
2.5.4 Rationale for erlotinib pharmacokinetic and pharmacogenetic studies 
 
Currently no data are published on the pharmacokinetics of erlotinib and its 
metabolites in children.  We have conducted a clinical pharmacokinetic study of 

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erlotinib in children with high grade glioma enrolled on SJHG04.  These patients 
received escalating erlotinib dosages (70, 90, and 120 mg/m2/d) along with 
radiation therapy.  We measured erlotinib and OSI-420 pharmacokinetics on days 1, 
2, 3, and 8 of course 1 (the erlotinib dose on day 2 was held).  The preliminary 
results of the pharmacokinetic studies show at the 70 mg/m2/d dosage level, the 
median (range) erlotinib and OSI-420 Cmax and Tmax were 1405 ng/ml (937 to 2180) 
and 4.1 hr (2.2 to 8.2) and 158.5 ng/ml (45 to 203) and 4.1 hr (2.2 to 7.9), 
respectively.  The youngest child on that clinical trial was 3 years of age, so that it 
is crucial to study the pharmacokinetics of erlotinib in this very young patient group 
to assess the inter- and intra-patient variability in erlotinib disposition. 
 
Erlotinib is extensively metabolized by hepatic CYP3A4 and CYP3A5. It is also 
metabolized in minor amounts by CYP1A2 and CYP2C8, by pulmonary CYP1A1 
and by CYP1B1 in tumor tissue. Because erlotinib is largely metabolized by 
CYP3A4/5, drugs that induce or inhibit this isoenzyme may interact to decrease the 
efficacy or increase associated toxicities, respectively (see Appendix I).  By 
evaluating the pharmacogenetics in this patient group (for St. Jude patients enrolled 
on the institutional protocol PGEN5 only) as well as collecting patient specific data, 
we can assess for covariates that will explain the variability that we observe in the 
erlotinib pharmacokinetic parameters. 
 
2.6 
RATIONALE FOR CNS NEUROTRANSMITTER STUDIES 
 
Morbidity associated with the treatment of brain tumors in young children is well 
known.  Patients receiving standard therapies often demonstrate late neurocognitive 
deficits, especially in the area of attention.218-220  Declines in cognitive ability 
indicated by diminished intelligence quotients often continue for 10 or more years 
after therapy.221  Studies have also described an association between late 
neurocognitive deficits and decreases in normal cerebral white matter volume.222-224  
While the exact mechanism of white matter damage is still unknown, both 
radiotherapy and chemotherapy have been implicated.225  It is generally accepted, 
however, that therapy-induced microvasculature damage may precipitate cerebral 
white matter injury.226,227 Ischemic injury, including that resulting from 
microvasculature damage, has been shown to induce alterations in striatial 
dopamine distribution and depress dopamine D2 receptor activity in animals.228,229  
It is unclear whether such a phenomenon occurs in young children after therapy for 
medulloblastoma and other tumors, but accruing evidence suggests perturbations in 
central dopaminergic transmission may play a role in the cognitive deficits seen 
after medulloblastoma therapy in older children.  The role of dysfunctional 
dopaminergic transmission has not been investigated in very young children 
receiving treatment for CNS malignancies. 
  
A recent study by Reddick et al. has demonstrated that the primary consequence of 
cerebral white matter damage in children treated for brain tumors was a decrease in 
attentional ability.230  Other investigators have also described similar attention and 
working memory deficits in pediatric brain tumor and leukemia patients.231-233  

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Similarly, deficits in sustained attention and working memory are classical findings 
associated with attention deficit hyperactivity disorder (ADHD): a condition often 
attributed to defective central dopaminergic transmission.  Moreover, patients 
exhibiting neurocognitive deficits after cancer therapy have responded to 
methylphenidate, an amphetamine derivative used to treat ADHD.234,235  
Methylphenidate is thought to improve attentional abilities by releasing stored 
dopamine from the presynaptic vesicular pool, decreasing dopamine reuptake via 
transporter inhibition, and by inhibiting monoamine oxidase.  The increased 
extracellular dopamine is believed to activate inhibitory autoreceptors in the 
striatum, thus improving attention.  It has also been demonstrated that increasing 
the availability of dopamine in the prefrontal cortex facilitates performance on 
working memory tasks known to be dependent on this brain region.236 These data 
suggest that neurocognitive deficits observed after cancer therapy may share a 
pathophysiological basis with ADHD; that is, defective central dopaminergic 
transmission.   
 
To validate the link between ADHD and central dopaminergic defects, studies have 
investigated the relationship between CSF monoamine concentrations and behavior 
in ADHD patients.237,238  A significant positive correlation between CSF 
homovanillic acid (HVA), a dopamine metabolite, and inattention has been made.239  
Another study demonstrated that higher CSF HVA concentrations prior to stimulant 
therapy predicted better drug response in one group of ADHD patients.240  The 
results of these studies provide support for the relationship between ADHD and 
defective central dopaminergic transmission.  Similarly, we propose exploring CSF 
dopamine and metabolite concentrations in young children with medulloblastoma 
and other brain tumors to determine the role impaired dopaminergic transmission 
may play in the genesis of therapy-related neurocognitive deficits.  We propose to 
correlate the CSF neurotransmitter phenotype with expression of inattentiveness, 
working memory deficits and cognitive impairment as quantified by standardized 
psychological measures.  It is our hypothesis that neurocognitive deficits after 
anticancer therapy in the young child with a central nervous system tumor result 
from iatrogenically induced disturbances in central dopamine transmission. 
 
2.6.1 Rationale for genotyping for dopamine-related gene polymorphisms in 
patients enrolled on SJYC07 
 
As mentioned previously, we hypothesize that the neurocognitive deficits observed 
after cancer therapy are related to defects in central dopaminergic transmission.  
Such neurocognitive deficits after therapy manifest themselves as an inattentive 
phenotype similar to that observed in ADHD, a disorder arising from defective 
dopaminergic transmission.  To date, several studies have investigated the 
dopaminergic hypothesis of ADHD from a genetic perspective, with significant but 
variable genotype-phenotype relationships described. 
 
The gene encoding the dopamine transporter DAT1 has been studied extensively, 
and significant correlations between a variant found in the 3’ un-translated region of 

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the gene and ADHD have been made.241-244  This DAT1 polymorphism is referred 
to as the 480 bp DAT1 variant or DAT1*10.  In population analyses, the DAT1*10 
allele has demonstrated a high expression frequency of approximately 0.7, 
depending on ethnicity.245,246 The DAT1*10 allele was also associated with poor 
response to methylphenidate in children with ADHD247,248.  It is believed that this 
polymorphism leads to either a hyperactive dopamine transporter249 or an increased 
transporter density250, both of which ultimately result in decreased extracellular 
dopamine.  The presence of such a polymorphism in patients may identify a 
predilection towards developing an inattentive phenotype after brain tumor therapy.  
Therefore, we propose to study the expression of the 10-repeat DAT1 (DAT1*10) 
allele amongst young children with medulloblastoma and other brain tumors, and to 
correlate patient DAT1 genotypes with neurocognitive and CSF neurotransmitter 
phenotypes.   
 
Polymorphisms in dopamine receptor genes have also been correlated with ADHD 
in several studies.  The most studied polymorphism in dopamine receptors is the 7-
repeat DRD4 (dopamine D4 receptor) variant found in exon 3, known as DRD4*7, 
which exhibits an allelic frequency of approximately 0.17 to 0.2.251,252  This 
polymorphism, which results in a diminished inhibitory response to dopamine,253 
has been correlated with ADHD in numerous investigations.254-258  On the contrary, 
other studies have found no association between the 7-repeat DRD4 allele and 
ADHD.259-261 Studies also suggest that dopamine D5 and D2 receptor 
polymorphisms are associated with the ADHD phenotype, specifically the 148 bp 
DRD5 and TaqI poly DRD2 variants.262-265  Many investigators believe that these 
polymorphisms in dopamine receptors and DAT1 transporter lead to decreased 
central dopaminergic transmission, and thus an ADHD phenotype.  It is likely that 
such polymorphisms may somehow be related to the development of 
neurocognitive deficits that occur after brain tumor therapy, particularly the 
inattentive phenotype.  We hypothesize that specific genetic polymorphisms may 
result in an increased susceptibility to iatrogenically-induced neurocognitive 
impairment.  Therefore, we propose to study the expression of such polymorphisms 
in very young children with brain tumors, and to correlate genotypes with 
neurocognitive and CSF phenotypes.  In particular, we have chosen to focus upon 
two specific polymorphisms in the DAT1 and DRD4 genes, DAT1*10 and 
DRD4*7, for correlative analyses.   
 
2.7 
RATIONALE FOR NEUROCOGNITIVE STUDIES  
 
2.7.1 Neuropsychological evaluation 
 
Young children treated for CNS malignancies experience not only a significantly 
poorer response to treatment, as evidenced by decreased survival rates,266-268 but 
also increased treatment-related toxicities including neuropsychological 
impairment.269,270 They may be particularly at risk for neuropsychological deficits 
due to increased vulnerability of the developing brain to therapeutic interventions. 
As survival rates improve for infants treated for CNS malignancies, the late effects 

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of treatment and their impact on quality of life become paramount. 
Neuropsychological deficits are of great concern as they have been shown to 
associate with academic failure, high unemployment rates and a reduced quality of 
life.271 
 
The few studies that have investigated neuropsychological outcomes in children 
treated for CNS malignancies in infancy have been inconsistent in their findings. 
Several studies have found radiation therapy to be associated with a decline in 
neurocognitive functioning.8,17,272-275  Some studies found that any treatment 
resulted in neurocognitive impairment,276,277 whereas others found that children 
treated with chemotherapy but without radiation therapy were within the average 
range with respect to cognitive outcome.273-275,278,279 These studies have generally 
been limited by small sample sizes, heterogeneous treatment approaches, lack of 
longitudinal cognitive data and short-term follow-up durations.9,18,36,273-275,278-280 By 
improving upon these study limitations, we will be better able to assess longitudinal 
change in neuropsychological functioning following treatment and identify those 
disease (e.g., tumor type, tumor location and presence of hydrocephalus) and 
treatment- related (e.g., chemotherapy agents and radiation dosimetry) factors most 
predictive of cognitive risk. These investigations are essential for identifying 
treatment interventions that are both effective and associated with the fewest 
treatment-related toxicities.  
 
For this study, children will be assessed at baseline, six months and yearly 
following treatment. Therefore, the assessment battery needs to span the years from 
infancy to 8 years of age. An effort was made to select measures that could assess 
the widest age range possible. Nonetheless, as no single measure exists that covers 
this entire age spectrum, separate test batteries are needed for children less than 3 
years of age and another for children 3 years of age and older. Children less than 3 
years of age will be administered a single comprehensive battery, the Bayley Scales 
of Infant and Toddler Development, Third Edition (Bayley-III).281 All children 3 
and older will be administered a separate battery, listed in section 8.4. These 
batteries are comparable in the domains assessed such that some longitudinal 
analyses will be possible across batteries. 
 
2.7.2 Neurological evaluation 
 
Adverse neuro-cognitive and neurological outcomes are well recognized in patients 
who were previously treated as infants for CNS cancer.  However, a prospective 
assessment of neurological development in children younger than three years of age 
treated for embryonal brain tumors, high-grade glioma, CPC, or ependymoma has 
not been well documented.  Better understanding of this developmental process 
may inform future treatment trials.  Based on experience with older children, we 
expect neurological deficits (including expressive language, oculomotor 
dysfunction, facial weakness, difficulty with swallowing, motor paresis, motor 
ataxia, and impaired gait) to be maximally apparent just after surgery and then 
stabilize or improve over time.       

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2.7.3 Hydrocephalus measurements 
 
Hydrocephalus resulting from tumor or treatment-related complications may affect 
the biologic, neuroimaging and cancer control objectives of this study. 
Hydrocephalus measurements (evans index, cella media index, ventricular angle 
and frontal horn diameter) corresponding to the time of diagnosis, enrollment, 
completion of therapy and two years after the initiation of therapy will be recorded 
for each patient along with clinical information about CNS diversion (presence or 
absence of ventriculostomy, CSF shunting and shunt revisions). The dynamics of 
hydrocephalus measurements and their value as a clinical co-variate will be studied. 
 
2.7.4 Radiation dosimetry: correlation with failure and toxicity 
 
Variability is expected in the distribution of dose to target and normal tissues 
resulting from differences in the size and location of the tumor bed, the method and 
modality of treatment delivery (3-dimensional conformal radiation therapy, 
intensity modulated radiation therapy, proton beam radiation therapy) and clinical 
and technical factors including hydrocephalus, post-operative brain shift, 
immobilization, target conformity and normal tissue dose constraints. The CTV 
margin of 5 mm was chosen for this protocol to minimize dose to normal tissues 
and to encompass microscopic disease in continuity with the tumor bed. The 
variability in the distribution of dose about the targeted volume may both 
incidentally and therapeutically irradiate normal tissue beyond the CTV. The 
following technical factors may be investigated in the evaluation of rate and pattern 
of failure: planning target volume, dose conformity, and modality of delivery. The 
pattern of failure may be further investigated by registration of the specific imaging 
sequence demonstrating failure to the treatment planning CT or MR study, 
volumetric contouring of the recurrent tumor, and dose-volume histogram and 
conformity assessment of the recurrent tumor volume. Normal tissue dosimetry may 
be compared across patients and correlated with functional outcomes by mean 
doses, mean doses weighted for biologic effect (equivalent uniform dose) or 
discrete dose-volume elements representing low, intermediate and high-doses 
relative the prescribed doses in this protocol. The cumulative form of the dose-
volume histogram, for each normal tissue volume, has a characteristic shape. 
Without spatial specificity, these histograms describe the proportion of a normal 
tissue volume that receives a particular dose. The derivative of the cumulative dose 
volume histogram generates a frequency versus dose plot. The plot may be binned 
into discrete dose-volume elements and integrated to derive variables for correlative 
analyses and comparison of treatment techniques. Our goal is to use dose-volume 
data to estimate the change in functional outcomes as a function of time after 
radiation therapy. We will contribute dose-volume variables to the proposed 
primary and specific aims of this protocol, including the analysis of endocrine, 
cognitive, neurologic and audiometric effects. Dose-volume data will be generated 
for the functional elements and the lobes of the brain as described in the RT section 
as well as volume elements segmented for the neuroimaging objectives. We will 
compare conformal, intensity-modulated and proton beam radiation therapy 

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methods using the same dose-volume elements and statistical methods employed in 
prior analyses. 
  
2.8 
RATIONALE FOR DIAGNOSTIC IMAGING STUDIES 
 
2.8.1 Assessing brain structure and developing models relating therapy and 
neuroimaging 
 
Aggressive CNS therapy is associated with increased risk for neurotoxicity which is 
often evidenced by cognitive delays or deficits and negatively affect quality of life 
of survivors.282-285 These deficits in cognitive processing are thought to be 
dependent upon the integrity of widely distributed neural networks supported by 
interhemispheric and intrahemispheric white matter tracts.286 In very young 
children, cranial RT is often delayed by first treating with aggressive chemotherapy 
including methotrexate which is also associated with structural alteration of cerebral 
white matter.287-289 Other potential sources of white matter damage include 
increased intracranial pressure and treatment with steroids.290 These relationships 
suggest that white matter damage may represent a useful index of the cumulative 
impact of multiple sources of CNS insult.  
 
The pathophysiology of late CNS damage induced by radiation or chemotherapy is 
not fully understood, especially with regard to the vulnerability of white matter to 
injury. Some hypotheses attribute primary mechanisms of CNS damage to the death 
of neuronal cells, oligodendrocytes, or endothelial cells and the subsequent 
microvascular damage. Ultimately, this damage seems to be a primary or secondary 
effect associated with administration of treatment to the CNS.291 Secondary 
processes, such as damage to the myelin membrane as a result of oxidative stress 
after radiotherapy, have also been proposed as putative mechanisms of CNS 
damage.292 Furthermore, study of the adverse effects of irradiation on the 
microenvironment of neural precursor cells has helped to integrate the findings 
from these competing hypotheses.293 CNS damage from methotrexate is 
hypothesized to induce reversible leukoencephalopathy by inhibiting turnover of 
myelin lipids and proteins; this inhibition results in intramyelinic splits and 
intralamellar formation of vacuoles that can accumulate interstitial fluid.  Increases 
in free water content and decreases in myelin would greatly affect both the T1 and 
the T2 relaxation times of the tissue, and such effects would result in contrast 
changes in the image.294 
 
Most recent protocols containing methotrexate routinely use MR imaging to 
qualitatively evaluate neurotoxicity with a subjective grading scale.  This subjective 
grading, however, precludes comparison of therapy-induced changes between 
clinical trials and does not provide any continuous measure of the intensity or extent 
of changes as a function of other influential factors. Our own experience with 
children treated for ALL without irradiation have demonstrated higher prevalence, 
extent and intensity of white matter changes associated with higher doses and more 
courses of methotrexate.295,296 A recent study of white matter anisotropy using 

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diffusion tensor imaging (DTI) has investigated patients post-treatment for 
childhood cancer compared to age-matched controls to assess myelin damage.297 
This study found significant relationships between percentage difference in white 
matter fractional anisotropy  (FA) for each patient relative to the age-matched 
control and full-scale, verbal, and performance IQ. These preliminary findings 
suggested that white matter FA may be a clinically useful biomarker for the 
assessment of treatment related atypical maturation. The use of dynamic 
susceptibility contrast perfusion imaging has been central in the evaluation of 
vascular impact of CRT. One such study demonstrated highly significant reduction 
of CBV in the first two years post therapy in both gray and white matter of adults 
treated for astrocytoma.298 This reduction in CBV was correlated to total dose 
delivered to a tissue area with higher doses causing the largest changes. A more 
recent report assessed the changes in the recirculation phase of normal-appearing 
brain tissue two months post therapy in adults treated for grade III/IV glioma.299 
Their results suggested a dose-dependent reduction in vessel density and increase in 
permeability. While many of these studies have been performed in adults, few have 
focused on children and the impact of radiation and chemotherapy on normal 
myelin maturation. 
 
2.8.2 Susceptibility-weighted MR imaging (SWI) 
 
This technique was originally developed to assess the vascular architecture of brain 
parenchyma noninvasively. The unique potential of SWI lies in its ability to 
exquisitely highlight vascular structures, based on differences between the magnetic 
susceptibility in blood (BOLD effect) and surrounding tissues. Arteriograms and 
venograms with spatial resolution in the order of a few hundred microns may 
therefore be obtained by SWI. SWI also has the potential to detect, perhaps even 
quantify extremely small amounts of magnetically susceptible substances within 
brain parenchyma therefore detect the presence of microscopic hemorrhages. 
Potential uses of SWI include therefore tissue characterization through visualization 
of microvascular architecture within brain lesions (including but not limited to 
tumors) and monitor possible changes to that as a response to treatment or indicator 
of disease progression, as well as detection of small, otherwise likely undetectable 
amounts of blood degradation products within tumor lesions which may be relevant 
in novel treatment options (e.g. antioangiogenesis drugs) for both patient selection 
and monitoring under treatment. Additional benefits of the technique may comprise 
early detection of radiation induced vascular changes within brain, such as venous 
anomalies and associated cavernous angiomas and prevent hemorrhagic 
complications of those. 
 
2.8.3 Positron emission tomography for dose verification after proton beam 
therapy (PBT) (for participants enrolled at St Jude only) 
 
Conventional radiation therapy uses x-rays to deposit dose within a patient. Dose 
deposition occurs predominantly through photon-electron interactions in tissue. 
Proton beam therapy (PBT) uses a subatomic particle known as a proton. Protons 

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interact with electrons in tissue to deposit dose; however, because of their physical 
characteristics, protons also interact with atomic nuclei. During PBT it is possible to 
convert stable 16O, 14N and 12C atoms within tissue to the short-lived positron 
emitters299a  15O, 13N and 11C.  These positron emitters (primarily 11C) can be 
imaged using a clinical PET299b,c system.  A correlation between the dose deposited 
by protons and the PET image can be modeled via Monte Carlo simulations,299d 
leading to in-vivo dosimetric and distal edge verification of PBT. 
 
2.9 
RATIONALE FOR GROWTH HORMONE SECRETION TESTING BEFORE AND AFTER 
RADIATION THERAPY  
 
(participants enrolled at St Jude only) 
 
Growth hormone (GH) deficiency (GHD) may occur following irradiation of the 
hypothalamic-pituitary axis (HPA).299e,f We have modeled the effects of radiation 
dose and time after irradiation on pituitary growth hormone secretion. 299g,h The data 
used to derive these models was obtained from serial provocative tests of GH 
secretion in patients with localized brain tumors treated by photon-based conformal 
radiation therapy.  These models suggest that low-dose irradiation, even in the 
dosing range that is unavoidable due to internally scattered photon-electron 
interactions, increases the near-term risk for GHD.  Although GHD is treatable, 
somatotropin (rDNA origin) therapy is expensive and invasive.  Moreover, 
untreated GHD contributes to the cognitive decline observed after irradiation and 
causes abnormal growth, development and metabolism. The mitogenic effects of 
somatropin replacement are potentially adverse in cancer survivors, and the 
risk/benefit ratio of this therapy remains controversial in the presence of active 
cancer. 
 
Proton beam therapy (PBT) may be capable of sparing children from radiation-
induced GHD because the dose to normal tissues, including the hypothalamus, is 
often reduced when compared to photon conformal radiation therapy. 299i The 
difference between protons and photons is the physical characteristic of dose 
deposition in normal tissue.  Protons display unique stopping power and less 
internal scatter compared to photons.  Investigating whether proton beam therapy 
will reduce the incidence of growth hormone deficiency requires baseline and serial 
assessment of GH release in patients treated with PBT.  No current models of 
radiation dose and effect are applicable for patients treated with protons.  
Comparable low dose data, as low as achievable with proton beam therapy, has not 
been available from photon-treated patients.   
 
To estimate the rate of longitudinal change in GH secretion by reducing the dose to 
the hypothalamus, consenting patients on the intermediate risk arm of this protocol 
will undergo pre- and post-irradiation provocative endocrine testing.  These data 
will be combined with the calculated hypothalamic dose to estimate the effect of 
radiation dose and relevant clinical variables on GH secretion abnormality in both 
photon and proton beam therapy intermediate risk patients. 

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3.0 
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
 
3.1 
INCLUSION CRITERIA FOR ALL PATIENTS 
 
3.1.1 Newly diagnosed tumor of the CNS, to include patients with:  
• medulloblastoma (all histologic subtypes) 
• supratentorial PNET (including CNS neuroblastoma or 
ganglioneuroblastoma, medulloepithelioma, and ependymoblastoma) 
• pineoblastoma 
• atypical teratoid rhabdoid tumor (ATRT) 
• choroid plexus carcinoma 
• high-grade glioma, including anaplastic astrocytoma (WHO grade 
III), anaplastic oligodendroglioma (WHO grade III), anaplastic 
oligoastrocytoma (WHO grade III), anaplastic ganglioglioma (WHO 
grade III), pleomorphic xanthoastrocytoma with anaplastic features 
(WHO grade III), high-grade astroblastoma , anaplastic pilocytic 
astrocytoma (WHO grade III), malignant glioneuronal tumor, 
glioblastoma multiforme (WHO grade IV) or gliosarcoma (WHO 
grade IV) 
• Patients with ependymoma (including all ependymoma histological 
variants)   
 
Histologic diagnosis has been verified by institutional pathologist and 
classified according to the WHO (2007) system. 
 
3.1.2 Age < 3 years at time of diagnosis for all histological diagnosis.  
 
Medulloblastoma patients ≥ 3 and < 5years old at diagnosis who have non-
metastatic disease (as defined in section 3.2.1.2) with no more than 1cm2 of 
residual tumor are also eligible.  Medulloblastoma patients in the ≥ 3 and < 
5years old age group with anaplastic or large cell histology or with MYC or 
MYCN amplification are excluded. Pathology from collaborating 
institutions must be centrally reviewed prior to enrollment for confirmation. 
 
3.1.3 No previous radiotherapy or chemotherapy other than corticosteroid therapy. 
 
3.1.4 Patients must begin treatment as outlined in the protocol within 31 days of 
definitive surgery. 
 
3.1.5 Patients with adequate organ function as defined by the following 
parameters obtained prior to study entry:  
 
• Normal renal function as defined by a serum creatinine concentration 
< 3X the institutional upper limit of normal (ULN). 
 

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• Normal liver function as defined by SGPT (ALT) concentration <5X 
the institutional ULN and a total bilirubin concentration <3X the 
institutional ULN. 
• Normal bone marrow function as defined by a hemoglobin 
concentration >8 g/dL (with or without support); white blood cell 
(WBC) >2000/mm3; absolute neutrophil count (ANC) >500/mm3; 
platelets >50,000/mm3 (without support). 
 
3.1.6 Adequate performance status as defined by Lansky Score ≥ 30 (except for 
Posterior Fossa Syndrome; see Appendix II). 
 
3.2 
CRITERIA FOR ASSIGNMENT TO THE LOW-RISK ARM OF THE PROTOCOL 
 
Note: the low risk medulloblastoma cohort closed to accrual on December 2, 2015 
due to lack of efficacy.  Please see section 13.1.4 
 
3.2.1 Low-risk medulloblastoma (patients must meet all of the following criteria): 
 
• Histologic diagnosis of nodular desmoplastic medulloblastoma (includes 
medulloblastoma with extensive nodularity).  Patients with focal areas of 
anaplasia or other atypical features suggesting a more aggressive 
phenotype in a tumor which would otherwise be considered nodular 
desmoplastic should be treated on the intermediate risk arm.  In such 
unusual cases, final risk stratification will be at the discretion of the 
principal investigator and study pathologist. 
 
• No evidence of CNS metastasis as indicated by MR images of the brain 
and spine and by cytologic examination of lumbar CSF 7 to 28 days 
after surgery.  If lumbar puncture is medically contraindicated, 
ventricular CSF from a shunt or Ommaya reservoir may be used to rule 
out M1 disease.  If CSF sampling is not possible and the patient has no 
other evidence of metastasis, the patient should be assigned to the 
intermediate risk arm. 
 
• Gross total resection as determined by the intraoperative observations of 
the neurosurgeon of record and confirmed by postoperative MR 
imaging. Gross total resection is defined as residual tumor or imaging 
abnormality (not definitive for residual tumor) whose size is <1 cm2 on 
postoperative CT or MR images. 
 
• If there is brain stem invasion by the tumor in the absence of imaging 
evidence of residual tumor (tumor size <1 cm2) and the patient otherwise 
meets criteria for enrollment on the low-risk arm, the patient will be 
classified as low-risk. 
 

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• Desmoplastic medulloblastoma patients who are ≥3 -<5 years of age will 
NOT be eligible for the low risk arm of the protocol. 
 
 
3.2.2 Low-risk high-grade glioma (patients must meet all of the following criteria): 
 
• Histologic diagnosis of high-grade glioma, including anaplastic 
astrocytoma (WHO grade III), anaplastic oligodendroglioma (WHO 
grade III), anaplastic oligoastrocytoma (WHO grade III), anaplastic 
ganglioglioma (WHO grade III), pleomorphic xanthoastrocytoma with 
anaplastic features (WHO grade III), high-grade astroblastoma (WHO 
grade III), anaplastic pilocytic astrocytoma (WHO grade III), malignant 
glioneuronal tumor, glioblastoma multiforme (WHO grade IV) or 
gliosarcoma (WHO grade IV). 
 
• No evidence of CNS metastasis as indicated by MR images of the brain 
and spine and by cytologic examination of lumbar CSF 7 to 28 days after 
surgery.  If lumbar puncture is medically contraindicated, ventricular CSF 
from a shunt or Ommaya reservoir may be used to rule out M1 disease.  If 
CSF sampling is not possible and the patient has no other evidence of 
metastasis, the patient will be assigned to the low risk arm. 
 
3.3 
CRITERIA FOR ASSIGNMENT TO THE INTERMEDIATE-RISK ARM OF THE PROTOCOL 
 
 
3.3.1 Patients less than 3 years of age at diagnosis must meet one of the two 
following criteria: 
 
• Histologic diagnosis of nodular desmoplastic medulloblastoma with less 
than gross total resection (as defined in section 3.2.1), but with no 
evidence of metastasis (as defined in section 3.2.1). 
 
• Any eligible histologic diagnosis other than desmoplastic 
medulloblastoma, with no evidence of CNS metastasis (as defined in 
section 3.2.1). 
 
3.3.2 Medulloblastoma patients who are ≥3 and < 5 years of age with no more 
than 1cm2 of residual tumor and with no evidence of CNS metastasis (as 
defined in section 3.2.1.2).  Medulloblastoma patients in the ≥ 3 and < 5 
years old age group with anaplastic histology, large cell histology,  
melanotic differentiation, or myogenic differentiation or tumors with MYC 
or MYCN gain or amplification are excluded. Pathology from collaborating 
institutions’ patients must be centrally reviewed prior to enrollment for 
confirmation. 
 

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3.4 
CRITERIA FOR ASSIGNMENT TO THE HIGH-RISK ARM OF THE PROTOCOL 
 
 
3.4.1 Any eligible histologic diagnosis, with evidence of CNS metastasis (as 
defined in section 3.2.1.2). 
 
3.4.2 Patients with extraneural metastasis are eligible for treatment on the high-
risk arm.   
Extraneural metastasis at initial diagnosis is extremely rare in patients with 
medulloblastoma or PNET, occurring in none of the 84 newly diagnosed St. 
Jude patients younger than 3 years of age with these diagnoses, and 1 of 283 
older patients (this patient had a spinal cord PNET with metastasis to bone).  
Accordingly, testing for extraneural metastasis by bone scan or bone 
marrow biopsy will not be performed routinely on this protocol.  In the 
unlikely event that extraneural metastasis is detected on an evaluation 
performed at an outside institution prior to referral or because of clinical 
suspicion, such M4 patients will be eligible for protocol treatment on the 
high-risk arm.    
 
3.5 
SYNCHRONOUS EXTRANEURAL ATRT 
 
Although it is uncommon, ATRT may occur at sites outside the CNS.  The most 
frequent site for synchronous ATRT is the kidney, but other sites have been 
reported.  At St. Jude, 4 of 40 patients younger than 3 years of age with ATRT have 
had synchronous extraneural tumors, including 2 with renal tumors, 1 with a soft 
tissue mass in the scapular region, and 1 with an adrenal tumor.  The patient with 
the adrenal tumor is currently undergoing treatment with no evidence of disease 
eight months after diagnosis, but the other 3 patients have died from disease.  
Patients with synchronous extraneural ATRT are eligible for treatment on this 
protocol.  Treatment will be based on the extent of both CNS and extraneural 
disease.  See Appendix III for details. 
 
3.6 
ENROLLMENT ON STUDY 
 
St. Jude enrollments. A member of the study team will confirm potential participant 
eligibility as defined in Section 3.1-3.2, complete and sign the ‘Participant 
Eligibility Checklist’.  The study team will enter the eligibility checklist information 
into the Patient Protocol Manager (PPM) system. Eligibility will be reviewed, and a 
research participant-specific consent form and assent document (where applicable) 
will be generated. The complete signed consent/assent form(s) must be faxed or 
emailed to the CPDMO at 
 to complete the enrollment process. 
 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A staff 
member is on call Saturday, Sunday, and holidays from 8:00 am to 5:00 pm.  
Enrollments may be requested during weekends or holidays by calling the CPDMO 
“On Call” cell phone 
 or referencing the “On Call Schedule” on the 
intranet). 

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Collaborating site enrollments:  Collaborating Site research participants should be 
registered at St. Jude within 24 hours of enrollment at the site.  Email notification 
should be sent to the PI or to the Neuro-Oncology Research Office 
 upon enrollment. The completed eligibility 
checklist and entire signed consent form should be faxed to the Neuro-Oncology 
Research Office at 
 within 3 working days of obtaining consent and 
confirming eligibility.  Follow with a phone call to 
 or email to 
 to ensure the fax has been received. The Neuro-
Oncology Research Office is staffed 8:00 am to 5:00 pm Central time Monday – 
Friday, excluding holidays.  St. Jude research staff will then complete enrollment 
with the St. Jude CPDMO. 
 
4.0 
TREATMENT PLAN  
Figure 4 Treatment Schema 
 

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TABLE 7  - OVERVIEW OF DRUG DOSES 
Induction 
All Patients: 
                            Methotrexate 5 g/m2 day 1 over 24 hours (for patient > 31 days at enrollment), or 
                                                 
2.5 g/m2 day 1 over 24 hours (for patients ≤ 31 days at enrollment) 
                            Leucovorin 15 mg/m2 IV/PO q6hr x 5 doses starting at hour 42 from start of MTX 
                            Vincristine 1 mg/m2 IV day 8 and day 15 (±2) days 
                            Cisplatin 75 mg/m2 IV day 8 
                            Cyclophosphamide 1.5 g/m2 IV day 9 
                            Mesna 375 mg/m2 IV x 4 doses 
                            Filgrastim 5 mcg/kg IV/SQ starting day 10, continue until ANC >2000 post-nadir 
 
High-risk patients only:   
                            Vinblastine 1 mg/m2 IV days 17, 19, 22, 24, 26 
 
Repeat for 4  cycles 16 weeks  total 
 
Consolidation 
Low-risk 
Cyclophosphamide 1.5 g/m2 IV day 1 
Mesna 375 mg/m2 IV x 4 doses day 1 
Carboplatin (AUC 5) day 2 
Etoposide 100 mg/m2 IV days 1, 2 
Filgrastim 5 mcg/kg IV/SQ starting 
 
day 3, continue until ANC >2000 
 
post-nadir 
 
Repeat for 2 cycles total 
 
Intermediate-risk 
 
Focal RT (54 Gy) 
 
High-risk 
Topotecan IV over 4 hours targeted to  
    AUC 140±20 ng/mL*hr days 1-5 
Cyclophosphamide 600 mg/m2 IVdays 4, 5 
Mesna 200 mg/m2  IV x 3 doses day 4, 5 
Filgrastim 5 mcg/kg IV/SQ starting day 6, 
 
continue until ANC >2000 post-nadir 
Repeat for 2 cycles total 
              OR 
Optional for patients > 3 years old at end of 
induction only:  
CSI (dose based on induction response) 
    
Maintenance 
               Cycle A 
                        Cyclophosphamide 30 mg/m2 PO daily on days 1-21 
                        Topotecan 0.8 mg/m2 PO daily on days 1-10 
                        Rest day 22-28 
              Cycle B 
                        Erlotinib 90 mg/m2 PO daily on days 1-28 (Medulloblastoma, High-Grade Glioma and 
Ependymoma  Patients Only) 
                     OR 
                        Etoposide 50 mg/m2 PO daily on days 1-21 (All other diagnoses) 
                                                        Repeat for 3 cycles each (A1-B1-A2-B2-A3-B3) 24 weeks total 

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4.1 SURGICAL MANAGEMENT 
 
In patients with localized medulloblastoma and other brain tumors, gross total resection 
results in a substantial survival benefit.  For patients with nodular desmoplastic 
medulloblastoma, the presence of residual tumor will require enrollment on the 
intermediate risk arm of the study, thereby exposing patients to the additional long-term 
sequelae of RT.  For these reasons, the maximal resection that can be achieved without 
undue risk to the patient should be attempted prior to trial enrollment.  Decisions about 
initial resectability will be at the discretion of the local neurosurgeon.  In rare instances, 
the feasibility of completely resecting residual tumor may change as a result of 
induction chemotherapy; in these cases a “second-look” operation may be performed 
prior to consolidation therapy, after discussion with the principal investigator.  Second-
look surgery will not affect subsequent treatment; patients who undergo such surgery 
will continue therapy on the intermediate risk arm. 
 
4.2 
INDUCTION 
 
Each induction cycle may begin when: 
 
 ANC >500/mm3 (after G-CSF discontinued)  
 Hgb >8 g/dL (with or without transfusion support),  
 Platelets >50,000/mm3 (without support), and  
 Total bilirubin < 3X the institutional ULN.   
 
Induction cycles are expected to last 28 days, but cycles may start early (prior to 
day 29 of the previous cycle) in order to accommodate scheduling concerns, as long 
as the above criteria are met. 
 
4.2.1 High-dose methotrexate (day 1) 
 
4.2.1.1 Methotrexate administration  
 
Hydration for methotrexate should be given according to institutional standard of 
care; the following are recommended: 
 
 Whenever possible, pre-hydration should start the day prior to HDMTX 
administration and consist of D5W + 40 mEq NaHCO3/L + 20 mEq KCl/L 
to run at 125 mL/m2/hour and continue until MTX level is < 0.5 microM. 
 
 If prehydration is not started before admission, pre-hydrate with D5W + 40 
mEq/L NaHCO3/L + 20 mEq KCl/L at 200 mL/m2/hr for at least two hours 
(hours -2 to 0) prior to start of methotrexate.  Decrease hydration rate to 125 
mL/m2/hour when MTX starts and continue until MTX level is < 0.5 
microM.   
 

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 
Hr 0-24:  Methotrexate 5 g/m2 TOTAL DOSE for patients > 31 days of 
age at enrollment 
 
Hr 0-24:  Methotrexate 2.5 g/m2 TOTAL DOSE for patients ≤ 31 days 
of age at enrollment 
 
 Dilute with D5W to a final concentration of 10 mg/mL. Set pump volume 
limit for loading dose, then reset for remaining 23 hr infusion.  Methotrexate 
to run simultaneously (piggyback) with IV hydration. 
 
Patients > 31 days of age at enrollment: 
 
- Hrs 0-1:  Loading dose =10% of total dose = 500 mg/m2 over 1 hour. 
- Hrs 1-24:  Maintenance dose = 90% of total dose = 4500 mg/m2 over 
23 hours. 
 
Patients ≤31 days of age at enrollment: 
 
- Hrs 0-1:  Loading dose =10% of total dose = 250 mg/m2 over 1 hour. 
- Hrs 1-24:  Maintenance dose = 90% of total dose = 2250 mg/m2 over 
23 hours 
 
 Check urine pH with each void while inpatient.  If urinary pH=6.0, give 
NaHCO3 12.5 mEq/m2 IV push.  If urinary pH <6.0, give NaHCO3 25 
mEq/m2 IV push.  Notify physician or clinical pharmacist if 2 or more 
consecutive urine pH still <6.5 (for further NaHCO3) or if pH >9 or if no 
urine output x 4 hours for additional IV fluids. 
 
Figure 5:  Methotrexate Administration Schema 
 
IV fluids                                                                                        (Continue fluids until MTX <0.5 microM) 
MTX 
MTX levels       ◊        ◊                      ◊                          ◊ 
Leucovorin                                                                      ♦        ♦       ♦      ♦       ♦_  
Hour           -2    0       6     12     18     24     30     36     42     48     54     60     66 
 
 
4.2.1.2 Leucovorin rescue 
 
Leucovorin should be administered starting at hour 42 at a dose of 15 mg/m2 IV/PO 
(IV is preferred) every 6 hours for 5 doses.   
 
Leucovorin rescue should be adjusted based upon the patient’s methotrexate plasma 
concentrations (i.e., increased if > 1.0 microMolar and continued until the 
methotrexate concentration is < 0.1 microMolar at 24 hours after the end of the 24 
hour infusion).  Additional measures, such as hydration, hemoperfusion, or 
carboxypeptidase will be considered in the event of a 42-hour methotrexate level 
>10 microM.  If a patient has Grade 3 or 4 gastrointestinal toxicity with prior MTX 

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or a history of typhlitis with any chemotherapy, leucovorin should begin at 36 hours 
with all subsequent MTX; if toxicity recurs, the baseline leucovorin dosage should 
also be increased.   
 
4.2.2  Criteria for proceeding to day 8 chemotherapy with vincristine and   
cyclophosphamide 
 
Day 8 chemotherapy may begin when: 
 
• ANC >500/mm3 
• Hgb >8 g/dL (with or without transfusion support) 
• Platelets >50,000/mm3 (without support) 
 
Dose modifications for vincristine or cisplatin may be required in the event of 
hyperbilirubinemia or renal dysfunction, respectively, as detailed in section 4.4.  
Transient elevations in ALT and AST are expected with high-dose methotrexate 
administration and do not require delay or modification of day 8 or 9 chemotherapy.  
Patients who experience mucositis with methotrexate administration should proceed 
with day 8 chemotherapy as long as severity at day 8 is ≤ grade 2, symptoms are 
improving, and plasma methotrexate level is undetectable.  Day 8 chemotherapy 
may be given one day early or up to 3 days late at the discretion of the treating 
physician as long as the above criteria are met. 
 
4.2.3 Vincristine (Days 8 & 15) 
 
• 1 mg/m2 (max dose 2 mg) given by IV push prior to cisplatin on day 8. 
• Repeat vincristine on day 15 (±2 days). 
 
4.2.4 Cisplatin (Day 8) 
 
Hydration for cisplatin should be given according to institutional standard of care; 
the following are recommended: 
 
• Pre-hydrate with 200 mL/m2/hr of D5W½ NS for at least 2 hours and 
until UOP > 2 mL/kg/hr. 
• Hour 0-0.25:  Mannitol 10 g/m2 infused over 15 min. 
• Hour 0.25-6.25: Cisplatin 75 mg/m2 IV over 6 hrs in D5W½ NS 1000 
mL/m2 + mannitol 10 g/m2. 
• Hour 6.25-24: Continue hydration with D5W½ NS + 10 mEq KCl/L at 
125 mL/m2/hr I.V. 
 
Urine output:  Calculate input and output (I/O) q 8 hrs x 24 hrs post completion of 
cisplatin.  Urine output should be at least 2 mL/kg/hr x 24 hrs post completion of 
cisplatin. 
 

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If output falls below 2 mL/kg/hr and no fluid deficit, give a mannitol bolus of 6 
g/m2 over 15 min.  If no response within 2 hours, call physician. 
 
If negative fluid balance within the previous 8 hrs and not overall fluid positive 
within the previous 24 hrs, replace any deficits with ½ NS 1 mL: 1 mL over the 
next 4 hrs. 
 
4.2.5 Cyclophosphamide (Day 9) 
 
Hydration:  Patients will be receiving post-cisplatin hydration, which should 
provide adequate pre-hydration for cyclophosphamide. Monitor electrolytes and 
make appropriate changes in hydration, if necessary.  Cyclophosphamide should not 
be started until urine specific gravity is ≤ 1.010 and urine RBC <50/HPF. 
 
• -15 min:  Mesna 375 mg/m2 IV in D5W over 15 min. 
• Hour 0-1:  Cyclophosphamide 1500 mg/m2 IV in D5W over one hour 
(NOTE:  Cyclophosphamide dose is lower in cycles with topotecan; see 
section 4.3.3.1.2 for cyclophosphamide dosing during those cycles). 
• Hour 1-24:  Continue hydration with D5 W½ NS + 10 mEq KCl/L at 125 
mL/m2/hr + KCl 20 mEq/L. 
• Hours 3, 6, and 9: Mesna 375 mg/m2 IV in D5W over 15 min.  
• Maintain urine output >2 mL/kg/hour to prevent hemorrhagic cystitis. 
 
4.2.6 Filgrastim (beginning Day 10) 
 
Begin filgrastim, 5 mcg/kg/day SQ/IV daily, 24 to 36 hrs after cyclophosphamide 
infusion is complete.  Continue until the absolute neutrophil count is greater than 
2000/µL after nadir. Filgrastim must be stopped at least 48 hours before the next 
cycle of chemotherapy, and may be administered at home after proper instruction. 
 
4.2.7 Vinblastine (high-risk patients only) 
 
• 1 mg/m2 given by IV push on days 17, 19, 22, 24, 26. 
• Scheduling of vinblastine may be adjusted as long as all 5 doses are 
administered and at least 36 hours elapses between doses. 
 
4.2.8 Carboplatin substitution for cisplatin Day 8 for ototoxicity (see section 4.5.5) 
 
• Hour 0-1:  Carboplatin; Total dose to be given in D5W over 1 hour with 
the dose based on an AUC of 5.5 mg/mL/min according to the following 
formula: 
 
Dose (in mg/m2) = AUC x [(0.93 x GFR) + 15] 
NOTE: GFR is given in mL/min/m2 
 

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4.3 
CONSOLIDATION 
 
Consolidation may begin when: 
 
• ANC >500/mm3 (after G-CSF discontinued) 
• Hgb >8 g/dL (with or without transfusion support) 
• Platelets >50,000/mm3 (without support)  
 
4.3.1 Consolidation for low-risk patients 
 
4.3.1.1 Cyclophosphamide and Etoposide (Day 1) 
 
Hydration for cyclophosphamide should be given according to institutional standard 
of care; the following are guidelines: 
 
• Prehydrate with D5 W½ NS at 125 mL/m2/hour for at least 2 hours. 
• 15 min:  Mesna 375 mg/m2 IV in D5W over 15 min. 
• Hour 0-1:  Cyclophosphamide 1500 mg/m2 IV in D5W over 1 hour  
• (NOTE:  Cyclophosphamide dose is different in cycles with topotecan; see 
section 4.3.3.1.2 for cyclophosphamide dosing during those cycles). 
• Hour 1-2:  Etoposide 100 mg/m2 IV in NS over 1 hour. 
• Hour 2-24:  Continue hydration with D5W½ NS + KCl 10 mEq/L at 125 
mL/m2/hr x 22 hours, then decrease rate to 65 mL/m2/hour .   
• Hour 3, 6 and 9: Mesna 375 mg/m2 IV in D5W over 15 min.  
• Maintain urine output >2 mL/kg/hour x 24 hours from the start of the 
cyclophosphamide infusion to prevent hemorrhagic cystitis. 
 
4.3.1.2 Carboplatin and Etoposide (Day 2) 
 
• Hour 0-1:  Carboplatin; Total dose to be given in D5W over 1 hour with the 
dose based on an AUC of 5 mg/mL/min according to the following formula: 
 
Dose (mg/m2) = AUC x [(0.93 x GFR) + 15] 
NOTE: GFR is given in mL/min/m2 
 
• Hour 1-2:  Etoposide100 mg/m2 IV in NS over 1 hour 
 
4.3.1.3 Filgrastim (Beginning Day 3) 
 
Begin filgrastim, 5 mcg/kg/day SQ/IV daily, 24 to 36 hrs after carboplatin infusion 
is complete.  Continue until the absolute neutrophil count is greater than 2000/µL 
after nadir. Filgrastim must be stopped at least 48 hours before the next cycle of 
chemotherapy, and may be administered at home after proper instruction. 

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4.3.2  Consolidation for intermediate-risk patients 
 
Consolidation for intermediate risk patients will consist of focal irradiation to the 
tumor bed. (See section 4.6 for RT guidelines).  Intermediate risk patients who have 
not reached 12 months of age by week 17 of treatment should receive consolidation 
and maintenance therapy according to the low-risk treatment plan in order to delay 
RT until the age of 12 months.  They should then receive focal RT, followed by 
further maintenance therapy to complete a total of six courses of maintenance 
therapy.  For example, a patient who is 9 months old at week 17 should receive both 
cycles of low-risk consolidation chemotherapy 
(carboplatin/cyclophosphamide/etoposide), followed by one cycle of maintenance 
therapy (PO cyclophosphamide/topotecan), then focal RT, and then the remaining 
five courses of maintenance therapy, starting with cycle B1. Radiation therapy 
should begin no later than 6 weeks after the start of the last cycle of chemotherapy. 
Additional time will be allowed for patients who require surgery following 
induction chemotherapy and those who experience medical complications. 
 
 
4.3.3  Consolidation for high-risk patients 
 
4.3.3.1 Topotecan and cyclophosphamide chemotherapy 
 
Topotecan/cyclophosphamide will be administered to all patients <3 years of age at 
week 17, and patient ≥ 3 years of age at week 17 whose parents have elected not to 
pursue CSI. 
 
Topotecan (Days 1 - 5): 
 
Hr 0-4:  Topotecan will be given at an initial dose based on the patient’s age at the 
time of receiving chemotherapy in 200 mL D5W to infuse over 4 hours at 50 mL/hr.  
 
 
 
Topotecan pharmacokinetic studies will be performed for all patients.  Day 1 
plasma topotecan concentrations will be used to adjust dosage, if needed, to attain 
a target topotecan lactone AUC of 140±20ng/mL*hr.  Blood samples (1 to 2 mL) 
will be obtained prior to the topotecan infusion, and at 5 minutes, 1 hour and 3 
hours after the end of the infusion.  Dose changes should be made as soon as the 
results of pharmacokinetic analysis are available.  For St. Jude patients, dose 
adjustments will typically be made for the topotecan doses administered on Day 2 
and thereafter.  For all patients, pharmacokinetic analysis must be completed and 
any dose adjustment instituted no later than the Day 4 topotecan dose.  Please see 
Section 8.2.3 for details of pharmacokinetic studies.     
Age time of receiving 
chemotherapy 
<6 months 
6 - 11.9 
months 
≥12 months 
Topotecan dose 
2 mg/m2 
2.5 mg/m2 
3.5 mg/m2 

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Cyclophosphamide (Day 4 and 5) 
 
Cyclophosphamide will be given after the topotecan infusion on days 4 and 5 of 
each consolidation cycle.   
 
Hydration for cyclophosphamide should be given according to institutional 
standard of care; the following are guidelines: 
 
• Prehydrate with D5W½ NS plus 10 mEq KCl/L at 125 mL/m2/hr I.V., 
starting after day 3 topotecan infusion complete and continuing for 24 hours 
after the completion of day 5 cyclophosphamide. 
• Hr 3:45 Mesna 200 mg/m2 IV in D5W over 15 min 
• Hr 4-5:  Cyclophosphamide 600 mg/m2 IV in 100 mL D5W to infuse over 1 
hour on days 4 and 5 only.  (NOTE:  cyclophosphamide dose is different in 
cycles with cisplatin/vincristine or carboplatin/etoposide; see sections 4.2.5 
and 4.3.1.1 respectively for cyclophosphamide dosing during those cycles). 
• Hr 7 and 10 (3 and 6 hrs from start of cyclophosphamide):  Mesna 200 
mg/m2 IV in D5W over 15 min.  
• Cyclophosphamide pharmacokinetic studies will be performed for patients 
enrolled in the optional cyclophosphamide PK component of the trial.  For 
those patients only, PK levels will be drawn immediately prior to the 
infusion, at the end of the 1 hr infusion, and 3 and 6 hours after the end of 
the infusion on both days, and 24 hours after the end of the day 5 infusion.  
See section 8.2.2 for details. 
 
Filgrastim (Beginning Day 6) 
 
Begin filgrastim, 5 mcg/kg/day SQ/IV daily, 24 to 36 hrs after day 5 
cyclophosphamide infusion is complete.  Continue until the absolute neutrophil 
count is greater than 2000/µL after nadir. Filgrastim must be stopped at least 48 
hours before the next cycle of chemotherapy, and may be administered at home 
after proper instruction. 
 

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TABLE 8 TREATMENT PLAN AND TESTING FOR TOPOTECAN AND 
CYCLOPHOSPHAMIDE CONSOLIDATION 
DOSE DAY 
1 
2 
3 
4 
5 
6 
Topotecan IV 
X 
X 
X 
X 
X 
 
Cyclophosphamide IV 
 
 
 
X 
X 
 
Topotecan Blood Samples* 
(required for all patients) 
X* 
 
 
 
 
 
Cyclophosphamide Blood Samples** 
(for St. Jude patients who consent to 
optional PK study) 
 
 
 
X** 
X** 
 
Dose Adjustment  
 
 X 
 
 
 
 
G-CSF 
 
 
 
 
 
X 
* Topotecan PK samples will be taken before infusion begins and at 5 minutes, 1 hour, and 3 hours 
after the end of the infusion for all patients.  
** For St. Jude patients enrolled on the optional cyclo PK component of the trial, samples will be 
taken pre-infusion, at the end of infusion, and 3 and 6 hours after the end of the infusion on days 4 and 
5, and 24 hours after the end of the day 5 infusion. 
 
4.3.3.2 Craniospinal irradiation 
 
Patients ≥ 3 years of age at week 17 will be offered craniospinal irradiation (See 
section 4.6 for RT guidelines).   

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4.4 
MAINTENANCE TREATMENT 
 
 
Each maintenance cycle may begin when ANC >500/mm3, Hgb >8 g/dL (with or 
without transfusion support), platelets >50,000/mm3 (without support), total 
bilirubin <1.5X the institutional ULN, and ALT <3X the institutional ULN.  For 
patients receiving CSI, maintenance should be started 28 (± 3) days after the last RT 
dose.  No break in treatment is required for patients receiving focal RT 
(intermediate risk patients); these patients should start maintenance within 14 days 
of the last RT dose, as long as the above criteria are met.  Patients receiving 
consolidation chemotherapy on the low-risk or high-risk arm should start 
maintenance within 8 weeks of the start of consolidation chemotherapy.  If criteria 
for starting maintenance are not met within 7 days of the planned start date, contact 
the principal investigator, Dr. Amar Gajjar.  
 
4.4.1 Drug doses for Maintenance 
 
Patient diaries should be maintained for all oral drugs.  Caretakers should be 
interviewed to assess drug compliance when patient drug diaries are unavailable. In 
such cases, documentation will be provided by the study team in lieu of a diary. 
 
Table 9   Maintenance Therapy 
Cycle A 
Day 
Treatment 
1-10 
Cyclophosphamide 30 mg/m2 PO daily PO and Topotecan 0.8 mg/m2 PO daily  
11-21 
Cyclophosphamide 30 mg/m2 PO daily 
22-28 
Rest 
Cycle B 
1-28 
Erlotinib 90 mg/m2 PO daily  
      (Medulloblastoma, High-Grade Glioma and Ependymoma Patients Only) 
1-21 
Etoposide 50 mg/m2 PO daily  (All Other Diagnoses) 
Maintenance cycles will be repeated for a total of 24 weeks (A1-B1-A2-B2-A3-B3) 
 

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4.4.2 Specific drug administration guidelines 
 
For all oral drugs, if the patient vomits within 30 minutes of taking the dose, the 
dose should be repeated. If vomiting occurs between 30 minutes and 5 hours of 
taking the dose, this should be recorded on the patient diary but the dose should not 
be repeated.   
 
Oral drug administration represents a particular challenge in young children.  In 
order to assess compliance with the oral treatment regimen, a trough level will be 
drawn for all patients at all sites during the routine blood draw at week 2 or 3 of 
cycles A1 (cyclophosphamide) and B1 (erlotinib).  See sections 8.2.2 and 8.2.4 for 
details. 
 
Cyclophosphamide 
 
For all patients at all sites, required cyclophosphamide trough levels will be drawn 
to assess compliance during week 2-3 of cycle A1 and again during week 2-3 of 
cycle A3. 
 
For St. Jude patients enrolled in the optional cyclophosphamide PK component of 
the trial, cyclophosphamide pharmacokinetic studies will be performed during cycle 
A1.  For those patients only, PK levels will be drawn prior to the dose and at 0.5, 
1.75, 3, and 6 hours after cyclophosphamide administration on day 1 of cycle A1.  
As administering oral medications to very young children can be challenging, 
flexibility in the timing of drug administration and PK sampling is necessary; every 
effort should be made to obtain samples within 15 minutes before or after the 
schedule time point.  On the day of PK testing, cyclophosphamide must be 
administered prior to topotecan administration.  See Table 9 and section 8.2.2. 
 
Topotecan 
 
The IV topotecan formulation will be administered orally during the maintenance 
phase.  The drug may be mixed with a liquid or flavored syrup (e.g., cherry, 
chocolate) of the patient’s choice.  The specific diluent used should be recorded on 
the patient diary. 
 
Topotecan pharmacokinetic studies will be performed during cycle A1 for St. Jude 
patients enrolled in the optional oral topotecan PK component of the trial.  For those 
patients only, PK levels will be drawn prior to the dose and at 0.25, 1.5, and 6 hours 
after topotecan administration on day 1 of cycle A1.  As administering oral 
medications to very young children can be challenging, flexibility in the timing of 
drug administration and PK sampling is necessary; every effort should be made to 
obtain samples within 15 minutes before or after the scheduled time point.  See 
Figure 6 and section 8.2.3. 
 

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Figure 6:  Treatment Plan and Testing for Oral Cyclophosphamide and  
 
 
Topotecan  
 
 
 
4.4.2.3 Erlotinib 
 
Erlotinib should be preferentially taken with water at the same time each day at 
least 1 hour before or 2 hours after a meal. Patients who are unable to swallow 
whole tablets may take crushed tablets dispersed in a small amount of applesauce, 
flavored syrup (e.g., cherry, chocolate), or other liquid, depending on patient 
preference.  The specific diluent used should be recorded on the patient diary. The 
erlotinib dose will be calculated based on the body-surface area at the start of each 
cycle of treatment. The calculated dose should be rounded to the nearest 25 mg.  
 
For all patients at all sites, required erlotinib trough levels will be drawn to assess 
compliance during week 2-3 of cycle B1 and again during week 2-3 of cycle B3. 
 
For St. Jude patients enrolled in the optional erlotinib PK component of the trial, 
erlotinib pharmacokinetic studies will be performed during cycle B2.  For those 
patients only, PK levels will be drawn prior to erlotinib administration and at 1, 2, 
4, 8 and 24(±2) hours after erlotinib administration on day 1 of cycle B2.  Erlotinib 
should be held until after the 24 hour PK level has been drawn. See section 8.2.4. 
Pre  
Samples 
Cyclo TPT 
TPT 0.25 hr  
CTX 0.5 hr 
TPT 1.5 hr  
CTX 1.75 hr 
CTX 3 hr 
CTX 6 hr 
TPT 6 hr  
 
Sample  
Times 
(±15 min.): 
Drug  
Administration: 

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4.5 
DOSE MODIFICATIONS DURING TREATMENT 
 
4.5.1 Methotrexate dose modifications 
 
Hepatotoxicity:  If total bilirubin is >3X the institutional ULN, obtain direct 
bilirubin and proceed with chemotherapy if direct bilirubin is <1.5X the 
institutional ULN.  If direct bilirubin is ≥1.5X the institutional ULN the 
methotrexate dose may be held or reduced after consultation with the study 
principal investigator. 
 
Nephrotoxicity:  Substantial nephrotoxicity from high-dose methotrexate 
administration is not expected, but nephrotoxicity due to cisplatin administration 
may affect methotrexate administration.  If serum creatinine is >1.5X the upper 
limit of normal by age-appropriate institutional laboratory standards, creatinine 
clearance should be measured by a Technetium 99 plasma clearance study, and dose 
adjustments made as follows: 
 
• Creatinine clearance >75% of institutional lower limit of normal (LLN):  
proceed with methotrexate without dose adjustment.  Monitor plasma MTX 
levels and clinical status closely and consider additional hydration and/or 
early leucovorin. 
 
• Creatinine clearance 50-75% of institutional LLN: Reduce the calculated 
methotrexate dose by 50% until GFR >75% of institutional LLN and then 
resume full dose. 
 
• 
Creatinine clearance <50% of institutional LLN: withhold 
methotrexate until the creatinine clearance rises above 50% of institutional 
LLN.  If methotrexate dose is delayed >7 days due to creatinine clearance < 
50% of institutional LLN omit methotrexate dose and proceed with 
vincristine/cisplatin/cyclophosphamide with appropriate cisplatin dose 
adjustment when creatinine clearance is adequate (see section 4.5.5). 
 
4.5.2 Vincristine toxicity 
 
Seizures: hold one dose, then reinstitute at 0.5 mg/m2 (1 mg maximum) while 
anticonvulsants are continued.  If seizures do not recur, return to full dosage at the 
time of next scheduled dose. 
 
Neurotoxicity (grade 3/4, foot drop, severe paresis, disabling paresthesias) or ileus:  
Hold one dose, resume vincristine at 0.5 mg/m2 (1 mg maximum), and then return 
to full dosage when symptoms resolve. 
 
Jaw Pain:  Treat with analgesics (NOT salicylates).  Do not hold or reduce 
vincristine. 

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Hepatotoxicity:  If total bilirubin is >1.5X the institutional ULN, hold vincristine 
dose.  If total bilirubin is > institutional ULN but ≤1.5X institutional ULN, 
administer vincristine at 0.5 mg/m2. 
 
4.5.3 IV cyclophosphamide administered during induction or low-risk 
consolidation: 
 
Hematopoietic toxicity: Delay cyclophosphamide until the ANC is >500/mm3 and 
platelet count >50,000/mm3.   
 
Hemorrhagic cystitis: The patient should be taken off treatment if patient has Grade 
4 toxicity. 
 
4.5.4 PO cyclophosphamide administered with topotecan during maintenance: 
 
Check CBC weekly during first cycle.  If ANC < 250/mm3 or platelets 
(unsupported) <50,000/mm3, hold cyclophosphamide until counts recover to ANC 
>500/mm3 and platelets >50,000/mm3, then restart at 75% of prior dose.  Missed 
doses should not be made up, and dose reduction should be maintained for the next 
cycle of oral cyclophosphamide/topotecan.  If no significant myelosuppression as 
defined above occurs during first maintenance course, CBC may be checked every 
two weeks during subsequent courses.  If myelosuppression as defined above recurs 
during a subsequent course, the duration of oral topotecan should be reduced to 7 
days for all remaining courses. 
 
4.5.5 Cisplatin toxicity 
 
Ototoxicity:  A decrease in auditory acuity at frequencies above the normal hearing 
range (4000-8000 Hz) is expected.  For Chang Grade 1a or 1b ototoxicity, do not 
modify dose. For Chang Grade 2b ototoxicity, reduce cisplatin dose by 50% for all 
subsequent courses.  For Chang Grade 3 ototoxicity hold cisplatin and do not restart 
unless follow-up audiograms show improved hearing function.  See Appendix IV 
for Chang ototoxicity grading.  Although we have changed the grade levels for dose 
modification in amendment 5.0, we are dose reducing based on approximately the 
same hearing loss as measured at the specified frequencies as indicated in the 
previous grading scale.  A comparison of the CCG and Chang scales is provided in 
Appendix IV.  
 
Carboplatin may be substituted for cisplatin during induction for patients having 
Grade 4 ototoxicity or bi-lateral hearing loss after having prior cisplatin dose 
reduction.  The PI must approve of the substitution on a case by case basis.  
Carboplatin should be administered as per section 4.2.8.   
 
Nephrotoxicity:  If serum creatinine is >1.5X the upper limit of normal by age-
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measured by a Technetium 99 plasma clearance study, and dose adjustments made 
as follows: 
• 
Creatinine clearance >75% of institutional lower limit of normal (LLN): 
Proceed with cisplatin without dose adjustment. 
• Creatinine clearance 50-75% of institutional LLN: Reduce the calculated 
cisplatin dose by 50% until GFR >75% of institutional LLN and then 
resume full dose. 
• Creatinine clearance <50% of institutional LLN: withhold cisplatin until the 
creatinine clearance rises above 50% of baseline value – repeat Tc99 plasma 
clearance weekly until clearance is adequate to start cisplatin. 
 
If the cisplatin dose is delayed >14 days due to creatinine clearance <50% of 
institutional LLN delete cisplatin.  If cisplatin is deleted from therapy then 
carboplatin may be substituted at an AUC of 5.5 after consulting with the PI. 
 
4.5.6 Vinblastine toxicity 
 
Peripheral neuropathy: Hold until resolution for grade 3 or 4 foot drop, severe 
paresis, disabling paresthesias. Resume at 50% dose and then escalate to full dosage 
when symptoms resolve. 
 
Hepatic toxicity: If total bilirubin is >1.5X the institutional ULN, hold vinblastine 
dose.  If total bilirubin is > institutional ULN but ≤1.5X institutional ULN, 
administer vinblastine at 0.5 mg/m2. 
 
Fever/neutropenia: Vinblastine should be given through periods of febrile 
neutropenia or infection, as long as there is no evidence of life-threatening 
consequences (e.g., acidosis, hypotension, septic shock) and signs of local infection 
are well-controlled with appropriate treatment. 
 
Myelosuppression:  As blood counts are expected to drop due to the effects of 
cisplatin and cyclophosphamide, vinblastine should not be held for 
myelosuppression.  If chemotherapy if delayed more than 7 days due to 
myelosuppression, the vinblastine dose should be reduced by 25% for subsequent 
cycles. 
 
4.5.7 Carboplatin toxicity 
 
Hold carboplatin for a serum creatinine compatible with a grade 3 renal toxicity 
(>3X -6X the age-appropriate institutional ULN).  When creatinine returns to pre-
treatment values, repeat Tc99 DTPA plasma clearance and recalculate carboplatin 
dosing.   
 
4.5.8 IV etoposide administered during consolidation (for low-risk patients only): 
 
Hypersensitivity reactions of grade 3 or less which are preventable using 
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who develop an anaphylactic reaction to etoposide can be switched to etoposide 
phosphate. The dose of etoposide phosphate is the same as the dose of etoposide. 
4.5.9 Oral etoposide administered during maintenance (for patients with any 
diagnosis other than medulloblastoma, high-grade glioma or ependymoma): 
 
Check CBC weekly during first cycle.  If ANC < 250/mm3 or platelets 
(unsupported) <50,000/mm3, hold etoposide until counts recover to ANC 
>500/mm3 and platelets >50,000/mm3, then restart at 75% of prior dose.  Missed 
doses should not be made up, and dose reduction should be maintained for all 
subsequent cycles of oral etoposide.  If no significant myelosuppression as defined 
above occurs during first maintenance course, CBC may be checked every two 
weeks during subsequent courses. 
 
4.5.10 Erlotinib 
 
Hepatotoxicity:   
 
If total bilirubin is >1.5X the institutional ULN, obtain direct bilirubin and proceed 
with chemotherapy if direct bilirubin is <1.5X the institutional ULN.  If direct 
bilirubin is ≥ 1.5X the institutional ULN, reduce erlotinib dose by 50%.  If direct 
bilirubin does not improve to < 1.5X the institutional ULN within 7 days of dose 
reduction, hold erlotinib for the remainder of the cycle and restart at 45 mg/m2 with 
the subsequent erlotinib cycle.  If hyperbilirubinemia recurs, contact the PI, Dr. 
Amar Gajjar. 
 
If ALT ≥3X the institutional ULN, reduce erlotinib dose to 45 mg/m2.  If ALT does 
not improve to <3X within 7 days, hold erlotinib for the remainder of the cycle and 
restart at 45 mg/m2 with the subsequent erlotinib cycle.  If ALT elevation ≥ 3X the 
institutional ULN recurs, contact the PI. 
 
Diarrhea and rash: 
 
Grade 2 diarrhea and skin rash often resolve despite continued treatment with the 
drug. Therefore, supportive care should be instituted for grade 2 diarrhea or rash 
(see Section 4.7) and erlotinib should be continued at the same dose.  If the toxicity 
persists for >7 days and the patient finds the toxicity intolerable despite supportive 
care, erlotinib should be held until the toxicity improves to ≤grade 1, then restarted 
at 75% of the original dose.  If grade 2 intolerable toxicity lasting >7 days recurs 
after 2 dose reductions, contact the study PI.  In the event of grade 3 or higher 
diarrhea or rash, hold erlotinib until resolution to ≤grade 1; re-start erlotinib at 75% 
of the original dose if resolution ≤7 days.  Contact the study PI if grade 3 toxicity 
persists for >7 days or if grade 3 toxicity recurs after 1 dose reduction. 
 
Interstitial Lung Disease (ILD): 
 
Although quite rare, ILD can be life threatening. Therefore, patients should be 
monitored closely for symptoms consistent with ILD, such as new onset dyspnea 

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without an obvious cause. In the event that ILD is suspected, erlotinib treatment 
should be discontinued and the patient should receive appropriate medical 
management. Although there is no proven therapy, systemic corticosteroids are 
often provided. Erlotinib should not be restarted in those patients suspected of 
having drug-related ILD. On the other hand, erlotinib therapy can be resumed in 
patients with improved symptoms where ILD has been ruled out. 
 
4.6 
RADIOTHERAPY GUIDELINES 
 
4.6.1 Overview 
 
This protocol includes very young children with CNS embryonal tumors who 
receive multi-agent chemotherapy prior to the administration of radiation therapy. 
The guidelines for radiation therapy have been developed to ensure target volume 
coverage and reduce the side effects of treatment. Unique to this protocol is primary 
site irradiation using a 5mm clinical target volume (CTV) margin for intermediate 
and high-risk patients. Intermediate risk patients receive only primary site 
irradiation. High risk patients, older than the age of 3 years after induction 
chemotherapy, will be offered craniospinal irradiation (CSI) using response-based 
dosing. CSI will be followed by primary and metastatic site irradiation, when 
applicable. The primary site dose will be 54Gy for all patients. CSI doses will be 
23.4Gy after complete response and 36-39.6Gy for less than complete response. 
Risk-classification has been defined as follows: intermediate-risk – non-metastatic 
and either residual primary site disease at enrollment or non-desmoplastic 
medulloblastoma (0 - <3 yrs of age); all medulloblastoma histological subtypes (≥3 
- <5 yrs of age), ATRT, PNET, CPC, or ependymoma; high-risk: metastatic M1-3 
tumor regardless of primary tumor location. 
 
Electronic Data Transfer and Submission 
 
For quality assurance, participating institutions will be required to submit radiation 
therapy planning data. Efforts will be made to streamline this process and to protect 
patient identity. After the completion of treatment, the final or composite treatment 
plan will be submitted electronically to St. Jude for clinical and research purposes. 
 
The CSI component of treatment will be planned and administered in a 
conventional manner; however, irradiation of the primary site is amenable to a 
spectrum of conformal planning and delivery methods available at the collaborating 
institutions. Proton beam radiation therapy will be allowed; if this treatment 
modality is not available at another collaborating site, patients may receive such 
treatment at other institutions depending on family preference. For patients at 
collaborating sites who chose to receive proton beam irradiation it is recommended 
(but not required) that these patients get treated at the University of Florida Proton 
Therapy Institute (UFPTI).  Participants from collaborating sites may be referred to 
other radiation oncology facilities that have the capability to deliver PBT.  The 
guidelines for this study are generalized to provide consistency in the targeting, 
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aspects of treatment including the spinal dose for M2 patients, cranial dose for M3 
(spine disease only), treatment of metastatic sites and residual pineal region tumor 
after 54 Gy; such treatment decisions should comply with the guidelines detailed in 
Table 10. 
 
Guidelines and requirements for the use of proton beam therapy (PBT) 
 
As of October 29, 2015 the option to proton beam therapy was withdrawn from the 
protocol due to safety reasons.  Please see section 12.4 
 
Proton beam therapy (PBT) will be allowed for intermediate-risk patients treated on 
this protocol at all participating sites.  Patients enrolled at St. Jude may receive PBT 
by referral to the University of Florida Proton Therapy Institute (UFPTI) in 
Jacksonville, Florida. Only patients on the intermediate-risk arm will be referred for 
PBT at UFPTI. At the present time, investigators using PBT will be required to 
comply with the guidelines for the use of protons in National Cancer Institute 
sponsored cooperative group trials which specify that (1) only passively or actively 
scattered proton beams will be used; (2) the International Atomic Energy Agency 
IAEA TRS 398 protocol shall be used for beam calibration; (3) dose reporting will 
be in Cobalt Gy equivalent (1 CGE = 1 proton Gy * 1.1) which is the same as ICRU 
78 DRBE (RBE-weighted absorbed dose)300a; and that (4) radiation doses shall be 
prescribed to protocol specified definitions for gross and clinical target volumes. 
Throughout this protocol, CGE is to be used instead of Gy when referring to proton 
dose. For set-up uncertainties and target motion, additional margin, smearing, range 
of modulation will be added on a per beam basis.  Whereas dose is to be specified 
in centigray (cGy)-to-muscle for photons, for PBT, the absorbed dose is specified 
with respect to water. In the event that scanning PBT becomes available, the 
guidelines will be amended after consideration by participating investigators. 
 
The use of proton beam therapy remains experimental and as such, is offered as an  
optional, special research treatment modality as an alternative to standard photon 
therapy.  Moreover, information is lacking about the combined effects of PBT and 
chemotherapy in young children. PBT may reduce side effects in children with 
brain tumors by sparing normal tissue compared with conformal or intensity 
modulated radiation therapy.  Of note, we have seen changes in the MRI images of 
about half of the patients who have received proton beam radiation on this protocol 
to date (intermediate risk arm only367).  These MRI changes are mostly transient 
signal abnormalities and enhancement in brain parenchyma, consistent with 
radiation-induced effects on normal-apearing tissue. There is a risk these changes 
could progress to radiation necrosis which is a radiation form of cell damage that 
results in the early death of those cells in living tissue. We are not sure what the 
changes on MRI mean.  In many cases those changes resolve. In general, the 
affected patients did not manifest symptoms; however, in the case of one patient, 
those changes progressed to radiation necrosis and were manifested clinically based 
on the involved area of the brain.   
 

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Patients sent to UFPTI for PBT may have a component of their treatment simulated 
at St. Jude prior to referral. This procedure may include imaging using CT, MRI 
and PET, and the contouring or creation of target volumes and normal tissue 
structures. This may facilitate the treatment planning process at UFPTI and will 
create protocol specified target and normal tissue volumes to be used for research. 
Imaging data and target and normal tissue contours in electronic form will be 
provided to UFPTI collaborators with relevant clinical information and supportive 
imaging. 
 
4.6.2 Target volume definitions 
 
The volumes that will be targeted and treated are defined in this section.  The 
definitions for the 3-dimensional target volumes and treatment dosimetry should 
adhere as closely as possible to the ICRU Report-50300 and Report 62301 definitions 
whenever possible.  Examples of target volumes for supratentorial and infratentorial 
tumors are provided in Figure 7. 
 
Craniospinal Irradiation (CSI): The CSI volume includes the entire subarachnoid 
volume with special attention to identification and inclusion of the cribriform plate 
and temporal fossae; the full width of the spinal subarachnoid space and the inferior 
aspect of the thecal sac. 
 
Gross Tumor Volume (GTV): The GTV includes all gross residual tumor and/or the 
tumor bed at the primary site based on the initial pre-operative imaging examination 
that defines the tissues initially involved with disease anatomically and the post-
operative and pre-irradiation neuroimaging examinations that identify residual 
disease and/or the tumor bed.  The GTV in most cases will be a contracted or 
collapsed tumor bed. Tissue defects resulting from surgical approaches will not be 
included as part of the GTV when not previously involved by tumor. Investigators 
are strongly encouraged to register pre-operative MR imaging sequences that 
demonstrate tumor to assist in the delineation of the GTV. 
 
Clinical Target Volume (CTV): The CTV includes the GTV with an added margin 
that is meant to treat subclinical microscopic disease and is anatomically confined 
(i.e., the CTV is limited to the confines of the bony calvarium, falx and tentorium 
where applicable or extends up to but not beyond neuroanatomic structures through 
which tumor extension or invasion is certain not to have occurred); the CTV margin 
will be 5mm for all patients. When the GTV approaches the boundary of an 
anatomic compartment, the CTV will extend up to and include the boundary. The 
CTV margin chosen for this study requires treatment planning MR and/or 
diagnostic MR imaging data with image section thickness ≤ 5mm. 
 
Planning Target Volume (PTV): A margin is added to the CTV in 3-dimensions to 
create the PTV. The PTV is geometric and not anatomically defined. The purpose 
of the PTV is to account for uncertainty in immobilization, image registration and 
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Given that the CTV is generally confined to the intracranial space, the PTV may 
extend into or beyond bone but is unlikely to extend beyond the surface of the 
patient.  The GTV, CTV and PTV for patients treated with protons will be identical 
to those contoured or created for treatment using photons.  The PTV margin chosen 
by the treating investigator requires treatment planning MR and/or diagnostic MR 
imaging data with imaging section thickness ≤ the chosen PTV margin. 
 
Metastatic Target Volume (MTV): Overt metastatic disease >5mm in maximal 
diameter at the time of treatment planning will define a volume or volumes for 
potential boost irradiation. The MTV will include the contoured lesion(s) with a 
geometric margin of 5mm. The treating investigator should be concerned about 
excessive irradiation of the intracranial or spinal volume and consider measures to 
minimize the aggregate volume of the combined MTV+PTV.  The investigator has 
the option to evaluate the brain or spine with MR imaging near the completion of 
CSI and exclude metastatic sites that measure ≤ 5mm. 
 
 
Figure 7  Target Volume Examples  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-contrast transverse T1-weighted MR images. Gross tumor (GTV=blue), 
clinical target (CTV=magenta) and planning target (PTV=yellow) volumes defined 
for post-operative, post-induction tumor/tumor bed in patients with supratentorial 
(left) and infratentorial (right) CNS tumors. Protocol specified CTV and PTV 
margins are 5mm and 3mm, respectively. 
 
4.6.3 Dosimetry and logistics 

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Craniospinal dosimetry: Dose will be measured at the midplane of the cranial 
volume and at the posterior border of the vertebral body the spinal field(s) including 
the dose at the central ray. Effort should be made to minimize inhomogeneity at the 
craniocervical junction when possible and the gradient of dose across the spinal 
cord.  
 
3-D dosimetry – target coverage:  
 
Photons: The prescription point for each 3-dimensional target volume is at or near 
the center of the volume and may be a point other than the central axis. The goal is 
to prescribe to the highest isodose surface that encompasses the PTV with the least 
inhomogeneity.  The entire PTV should be encompassed within the 100% isodose 
surface, although 95% is acceptable (i.e., 100% of the PTV receives at least 95% of 
the prescription dose). When inhomogeneity of the treatment plan delivers more 
than 105% of the prescription dose to more than 10% of the protocol defined spinal 
cord, optic chiasm or optic nerve, a reduction in the targeted volume or avoidance 
of the critical structure should be considered after 50.4 Gy even when coverage of 
the PTV, CTV or GTV is compromised. It has been observed that the dosimetry of 
superficial tumors can be problematic. Treatment planning systems demonstrate 
poor PTV coverage based on proximity to the skin surface. In such cases, bolus is 
not required and efforts should be made to verify coverage of the targeted volumes 
by other means. 
 
Protons - The PTV, CTV and GTV will be used for dose prescription and reporting; 
however, dose coverage of the PTV using protons will differ compared to treatment 
using photons. The goal will be to deliver 100% of prescribed dose to 95% of the 
PTV (D95% = 54Gy). The PTV will be used to select the appropriate beam size and 
beam arrangements to achieve lateral coverage of the targeted volume and to 
minimize heterogeneity.  The PTV will not be used to determine the distal range for 
the individual proton beams. The proton distal target margin will be determined per 
beam based on following distances and margins: 
 
Proton Distal Target Margin = CTV + Range Uncertainty + Internal Margin 
 
• CTV -the distal aspect of the CTV 
• Range uncertainty - 1.5% of the water-equivalent range of the CTV at 
maximal depth (> 1mm) 
• Internal margin - compensates for all variations in site, size and shape of the 
tissues contained in or adjacent to the CTV (> 1mm) 
 
The proton distal range may be adjusted at the discretion of the treating radiation 
oncologist based on normal tissue dose concerns.  
 
Motion management 
 

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Motion of the target volume is not anticipated for patients treated on this protocol; 
however, if target volume change is anticipated based on tumor cyst formation or 
expansion, post-operative brain shift, subdural fluid collections or hydrocephalus, 
MR or CT imaging will be prescribed during the six week course of treatment. 
  
Field shaping and beam configuration 
 
Field shaping for photons will be done with either customized cerrobend blocking 
or multileaf collimation. Field shaping for PBRT will rely on customized brass 
apertures. Every attempt should be made to minimize dose to organs at risk and 
limit heterogeneity of the high-dose volume without compromising coverage of the 
target volume. Three-dimensional conformal therapy (coplanar or non-coplanar), 
IMRT and PBT are required to minimize dose to normal surrounding structures. 
Due to uncertainties in the distal range of the proton beam in which the RBE may 
be greater than 1.1, single proton beam plans which stop in a critical organ will not 
be allowed.  Individual proton beams which are a component of a multi-field proton 
beam, which stop within such an organ, may be allowed. Beam angles will be 
chosen to minimize range uncertainty; however, this will not be the sole criteria for 
beam angle selection.  
 
3-D dosimetry - uniformity: Tissue inhomogeneity corrections are required. No 
more than 10% of the PTV should receive greater than 110% of the prescription 
dose. Whenever possible, treatment dosimetry should spare the spinal cord, 
brainstem, optic chiasm, and optic nerves from receiving more than the prescribed 
daily dose when not intimately associated with the target. It has been observed that 
the dosimetry of superficial tumors can be problematic. Treatment planning systems 
demonstrate poor target coverage based on proximity to the skin surface. In such 
cases, superficial compensators are not required and efforts should be made to 
verify coverage of the targeted volumes by other means. 
 
Dose fractionation: Patients will receive one fraction of 1.8 Gy per day, five days 
per week. Exceptions will include logistical considerations owing to holidays, 
weather, equipment failure and the need to complete the course of treatment in the 
least number of elapsed days. This is typically 42 + 2 days.  

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Table 10:  Radiation Doses (Gy) by Treatment Volume 
Disease Location 
And Risk Classification 
CSI Dose 
Primary Site 
Dose (†) 
Brain/Spine 
Metastases 
INFRATENTORIAL 
Intermediate Risk 
0 
54 
NA 
 
High Risk (CR) 
 
23.4 
 
54 
 
NA 
 
High Risk (<CR) 
                  M1 
      M2 
 
      M3 
 
 
36 
36-39.6 (brain) 
36-39.6 (spine) 
36-39.6 (brain)  
36-39.6 (spine) 
 
 
54 
54 
 
54 
 
 
NA 
54 
 
54 (brain) 
50.4 (spine) 
SUPRATENTORIAL 
Intermediate Risk 
0 
54 
NA 
High Risk (CR) 
 
23.4 
 
54 
 
NA 
 
High Risk (<CR) 
                  M1 
      M2 
 
      M3 
 
 
36 
36-39.6 (brain) 
36-39.6 (spine) 
36-39.6 (brain) 
36-39.6 (spine) 
 
 
54 
54 
 
54 
 
 
NA 
54 
 
54 (brain) 
50.4 (spine) 
(†) Optional local boost for patients with residual pineal region disease after external beam 
radiation therapy (section 4.6.4.1) 
 
Treatment interruptions:  CSI may be interrupted as necessary for medical status 
(e.g., ANC <500, fever/neutropenia, VP shunt surgery, neurologic or general 
medical problems). Treatment may be interrupted for platelet count <20,000 if the 
count cannot be supported to a level of >40,000.  Interruption shall be defined as 
missing >4 consecutive days during the course of irradiation. 
 
Sequencing contingencies:  When required, CSI will generally be given first, 
followed by supplemental irradiation (“boost therapy”) to the primary and 
metastatic sites (when applicable). Boost therapy may be initiated prior to 
craniospinal irradiation if required by the medical condition. In all cases when CSI 
is deferred, it should be initiated as soon as medically feasible, before the 
completion of boost therapy if feasible.   
 
4.6.4 Treatment planning and delivery techniques 
 

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Craniospinal irradiation: Patients may be simulated and treated in the prone or supine 
position using customized immobilization devices that allow for verification of 
cranial and spinal field junctions. Treatment will be given using standard techniques, 
encompassing the entire subarachnoid volume. The technique should assure coverage 
at the cribriform plate and temporal fossae; the full width of the spinal subarachnoid 
space (dosimetrically to include the medial aspect of the neural foramina) down to the 
bottom of the thecal space (as indicated by sagittal spinal MR). 
 
Craniospinal irradiation-CT planning: CT studies obtained uniquely for the CSI 
planning process are allowed and may also serve as the basis for planning boost 
treatment. CT studies will be performed whenever possible and the information 
used for craniocaudal intensity modulation. For the cranial component of treatment, 
the external contours of the skull and neck are viewed in the AP direction and 
points are chosen to divide the cranial field into 2-4 fields to achieve a field-within-
a-field plan and lateral homogeneity over the craniocervical junction. For the spinal 
component of treatment, the spinal cord and canal are contoured and viewed 
laterally and points are chosed to divide the spinal field into 4-6 fields to achieve 
field-within-a-field plan and antero-posterior homogeneity over the spinal cord and 
thecal sac. The following parameters are suggested: volume - cranial vertex to 
perineum; section thickness < 5mm; image matrix - 5122. The administration of IV 
contrast is not required.  
 
Craniospinal irradiation-prescribed doses: As noted in Table 10 high-risk patients 
who have a complete response to induction chemotherapy will receive 23.4Gy and 
others 36-39.6Gy. Investigator discretion will be used to determine the spinal dose 
for M2 patients and cranial dose for M3 patients. For example, a patient with M2 
disease might receive 39.6 Gy to the cranial volume and 36Gy to the spine; a 
patient with M3 disease (spine only) might receive 36Gy to the cranium and 39.6Gy 
to the spine. The decision to decrease the dose from 39.6Gy to 36Gy for a portion 
of the craniospinal volume in either case may be driven by patient age or other 
factors. In the M3 example, primary site irradiation should commence with the first 
fraction after 36Gy. 
 
Primary site irradiation: The treatment planning objectives for the primary site 
component of treatment are to ensure target volume (PTV) coverage, minimize 
inhomogeneity, respect normal tissue tolerances and minimize dose to the 
supratentorial brain, cochleae and hypothalamic-pituitary unit. The full spectrum of 
conformal treatment techniques may be used including forward or inverse planned 
beam’s eye view conformal radiation therapy and step and shoot or dynamic MLC 
intensity modulated radiation therapy. Proton beam radiation therapy is allowed.  
 
Primary site irradiation – CT and MR planning:  Patients may be simulated and 
treated in the supine or prone position. A treatment planning CT is required 
(contrast is optional) and should be performed as close to the start of primary or 
boost treatment as possible and will typically occur during the last week of CSI in 
those cases that require CSI. The following parameters are suggested: volume - 

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cranial vertex to thoracic inlet; section thickness – 2mm; image matrix 5122. 
Registration of MR to CT is encouraged using a 3-dimensionally acquired post-Gd 
T1-weighted data set or T2-weighted MR imaging data set formatted in the 
transverse plane and matching as closely as possible the section thickness of the CT 
study. Other data sets representing alternative MR sequences may be registered and 
used as needed. Whenever feasible the MR studies for RT planning should be 
obtained as close as possible to the start of treatment and about the time of 
simulation to account for changes in ventricular volumes, the operative site and 
extra-axial fluid collections. CT ONLY PLANNING - When MR registration is not 
available the following structures will be contoured: GTV, CTV, PTV, the outer 
(skin) surface of the head and neck regions, entire brain, eyes, optic nerves, optic 
chiasm, pituitary, hypothalamus, temporal lobes, spinal cord, cochleae.  
 
CT AND MR PLANNING - When MR registration is available the following 
structures will be contoured on both CT and MR: outer (skin) surface of the head 
and neck regions, eyes and spinal cord. The outer surface volumes will be available 
for dose and unspecified tissue calculations, the ocular volumes may be used to 
verify laterality and the spinal cord volumes can be compared to assure similar 
flexion and extension which is critical in planning treatment for infratentorial 
tumors. For reporting purposes, only the cochleae, spinal cord and outer (skin) 
structures will be contoured on CT. It is preferred that the remainder of the 
structures will be contoured on MR including the GTV, CTV, PTV, entire brain, 
eyes, optic nerves, optic chiasm, brainstem (entire brainstem, brainstem surface and 
brainstem core) pituitary, hypothalamus, hippocampi and temporal lobes.  An 
example of the hypothalamus is given in Figure 8.  Examples and normal tissue 
tolerances for other critical structures are discussed in section 4.6.5. 
 
Figure 8 Transverse post-
contrast T1-weighted MR 
images. The hypothalamus 
is contoured on four 
successive MR images as a 
bi-lobed structure 
bordering the anterior IIIrd 
ventricle (red). 
 
 
 
 
 
 
 
 
 
 
 

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Infratentorial primary site irradiation: The GTV is the post-operative residual tumor 
and/or tumor bed as defined in section 4.6.2, the CTV includes an anatomically 
confined 5mm margin in adjacent brain as defined in section 4.6.2 and the PTV 
includes a 3-dimensional geometric margin as defined in section 4.6.2. If the GTV 
is not anterior to the posterior aspect of the brainstem, the anterior border of the 
CTV may be limited to the center of the brainstem in axial extent. The primary site 
PTV will receive a cumulative dose of 54Gy. 
 
Supratentorial primary site irradiation: The GTV is the post-operative residual 
tumor and/or tumor bed as defined in section 4.6.2, the CTV includes an 
anatomically confined 5mm margin in adjacent brain as defined in section 4.6.2 and 
the PTV includes a 3-dimensional geometric margin as defined in section 4.6.2. The 
primary site PTV will receive a cumulative dose of 54Gy; an additional local boost 
will be considered at the investigator's option for patients with residual pineal 
region tumor after external beam radiation therapy. 
 
Radiosurgery options 
 
Metastatic site irradiation: Intracranial metastatic disease meeting the size criteria 
for treatment (> 5mm at the time of irradiation) should be treated concurrently with 
the primary site and when feasible joined to the primary site volume. The decision 
to treat separate or combined primary and metastatic boost volumes should be based 
on normal tissue irradiation. Spinal metastatic disease meeting the size criteria for 
boost treatment should be treated concurrently with the primary site treatment. As 
noted previously, aggregate intracranial boost volumes (MTV+PTV) should be 
minimized.  
 
4.6.5 Normal tissue tolerances 
 
Spinal cord:  For the purposes of this study, the upper aspect of the spinal cord 
begins at the inferior border of the foramen magnum and should be contoured on 
the treatment planning CT. For purposes of comparison and consistency with dose 
volume data, the spinal cord should be contoured on a number of images to be 
determined by the image section thickness (CT section thickness, n=number of 
images; 2mm, n=30; 2.5 mm, n=24; 3 mm, n=20; 4 mm, n=15). The treatment 
should be planned without compromising the prescription guidelines, to minimize 
the dose to the spinal cord and to avoid inhomogeneity that would have the spinal 
cord receiving > 1.8 Gy per day. An example of the spinal cord defined for image 
section thickness of 3.0 mm is included in Figure 10. 
 
Dose guidelines based on Figure 9: 
 
• D90% < 2Gy, D50% < 28Gy and D10% < 55Gy - Goal 
• D90% < 16Gy, D50% < 50Gy and D10% < 56Gy – Maximum 

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0
10
20
30
40
50
60
70
80
90
100
0
5
10
15
20
25
30
35
40
45
50
55
60
Dose (Gy)
% Volume
 
Figure 9: Spinal Cord Dose-Volume Histogram:  Average brainstem dose volume 
histogram (+SD) corresponding to a low-risk of spinal cord myelopathy. These 
data are derived from the treatment of children with infratentorial ependymoma 
using a prescribed dose of 54Gy. 
 
 
Figure 10: Spinal Cord:  
Sagittal radiograph digitally 
reconstructed from treatment 
planning CT scan. Spinal cord 
(red) is contoured on 30 
successive CT slices with 
superior aspect at the level of 
the foramen magnum. Protocol 
specified number of CT slices is 
dependent on slice thickness: 
2mm = 30 slices, 3mm = 20 
slices. 
  
 
 
 
 
 
Optic chiasm:  The mean dose to the optic chiasm should not exceed 56.7Gy and 
should be defined on CT or MR appearing on at least two consecutive images. If the 
mean dose may exceed 56.7Gy, the chiasm should be excluded from the treatment 
after 52.2Gy and receive no more than 1.25 Gy per fraction for the final treatment. 
These guidelines allow for the coverage of the target volumes to be compromised in 
selected cases. An example of the chiasm is included in Figure 11a. 
 

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Cochleae:  Each cochlea will be contoured on the CT data as a circular structure 
within the petrous portion of the temporal bone. The size and position of the 
contoured cochlea will be confirmed by viewing the structures in three dimensions 
using the treatment planning system.  The contour should appear on at least two 
successive CT images. The mean dose to the cochleae should be limited to 35Gy for 
intermediate risk patients and 45Gy for high-risk patients. An example of the 
cochleae is included in Figure 11a. 
 
Figure 11a: Optic Chiasm and Cochleae 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A) Post-contrast transverse T1-weighted MR images. The optic chiasm is contoured for the 
protocol with portions of the optic pathway on two successive MR images (yellow). 

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B) Transverse CT images. The cochleae are contoured for the protocol on two successive CT 
images (red). 
 
 
Brainstem 
 
 
 
 
The brainstem will be contoured on the treatment planning CT and will include the 
midbrain, pons and medulla. The cranial extent will be inferior to the 3rd ventricle and 
optic tracts. The caudal extent will end at the foramen magnum. For photon planning the 
entire brainstem will be contoured. For proton planning the entire brainstem, brainstem 
surface and core will be contoured. The surface will include the superficial aspect of the 
brainstem to a depth of 3mm. The brainstem core will be the brainstem volume with the 
surface removed. 
 
Dose guidelines based on Figure 11b: 
 
• D90% < 35Gy, D50% < 54Gy and D10% < 56Gy - Goal 
• D90% < 54Gy, D50% < 56Gy and D10% < 58Gy – Maximum 
 
 
Figure 11b: Brainstem Dose-Volume Curves:  average brainstem dose volume histogram 
(+SD) corresponding to a low-risk of brainstem-related side effects for a 30 fraction 
treatment regimen. 300b 

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0
10
20
30
40
50
60
70
80
90
100
0
5
10
15
20
25
30
35
40
45
50
55
60
Dose (Gy)
% Volume
 
 
4.7 
CONCURRENT TREATMENT AND SUPPORTIVE CARE GUIDELINES 
 
Hypomagnesemia: Can occur as a result of renal tubular wastage of magnesium 
caused by cisplatin.  Symptoms include paresthesias, muscle cramps, weakness, and 
occasionally disorientation and seizures. If this occurs, give magnesium IV or PO. 
 
Magnesium:  Start supplementation 24 hrs after patient starts cisplatin therapy.  
Recommended doses for magnesium sulfate are 0.5-1.0 mEq/kg/day, starting with 
the first course of cisplatin (1 gm of magnesium sulfate equals 8.0 mEq). 
Alternative oral forms of magnesium (magnesium gluconate 90-150 mg/kg/day and 
magnesium oxide 10-30 mg/kg/day) are allowable by investigator's preference.  
Close monitoring of magnesium levels and magnesium supplementation are 
recommended throughout therapy. 
 
Blood product support:  All blood products will be irradiated with 1500-3000 cGy 
to prevent graft-versus-host disease. Filters to remove leukocytes should be used to 
prevent WBC sensitization.  CMV-seronegative patients should receive CMV-
negative blood products. 
 
 Platelets:  Transfuse as necessary to maintain the platelet count at 
>30,000/mm3 following chemotherapy.  This threshold may be adjusted 
based on individual patient factors (e.g., history of hemorrhage, subdural 
fluid collections, expected imminent count recovery). 
 
 Red blood cells: Therapy-induced anemia and reticulocytopenia are 
expected.  Patients will be transfused as necessary with irradiated packed 
red blood cells to maintain a hemoglobin >8 g/dL.  This threshold may be 
adjusted based on institutional practice and individual patient factors (e.g., 
symptomatic anemia). 
 

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Pneumocystis prophylaxis: All patients will receive trimethoprim/ sulfamethoxazole 
(Septra). The following schedule is recommended, with doses given b.i.d. on Mon, 
Tues, and Weds. Septra prophylaxis should start during the first round of 
chemotherapy. Patients allergic to Septra may be treated either with Dapsone, 
monthly aerosolized pentamidine or monthly intravenous pentamidine or 
investigator preference.  
 
TABLE 12 SEPTRA DOSE 
BSA (m2) 
Num of Single Strength Tablets* 
Liquid Suspension (ml)** 
< 0.3 
--- 
2.5 
0.3 to 0.79 
0.5 
5 
0.8 to 1.39 
1 
10 
1.4 to 1.89 
1.5 
15 
> 1.89 
2 
20 
 
*(sulfamethoxazole 400 mg  
and trimethoprim 80 mg) 
**(sulfamethoxazole 40 mg/ml  
and trimethoprim 8 mg/ml) 
Neutropenia/fever:  Patients with fever (>38°C) and ANC <500 will be evaluated 
promptly, cultured, and treated with broad-spectrum antibiotics with an attempt to 
avoid nephrotoxic drugs.  Antifungal treatment will be considered in patients who 
have had at least 5-7 days of IV broad spectrum antibiotics in the face of persistent 
fevers or with documented fungal colonization or CT evidence of systemic fungal 
infection. 
 
Venous access:  All patients will have a central line placed prior to starting 
chemotherapy.  Placement of a double-lumen Hickman line or equivalent venous 
access is highly recommended. 
 
Nutritional management:  Any patient with greater than 10% weight loss over 
pretreatment baseline should begin enteral or parenteral nutritional support.  Enteral 
support is preferred, and consideration of gastrostomy tube placement is encouraged 
for patients requiring more than transient nutritional support.  For patients with 
weight loss < 10% compared to pretreatment baseline, the use of cyproheptadine 
(Periactin) as an appetite stimulant is encouraged.  Megestrol acetate (Megace) may 
cause adrenal suppression when used for more than very brief intervals; the use of 
this drug as an appetite stimulant is strongly discouraged. 
 
Antiemetics: The preferred antiemetic for cisplatin and cyclophosphamide is 
ondansetron (0.15-0.20 mg/kg) given 1/2 hr prior to infusion and every 6-8 hours 
thereafter for at least 3 doses. The use of dexamethasone as an antiemetic is 
strongly discouraged during chemotherapy. The preferred antiemetic regimen for 
radiation therapy is ondansetron (0.15-0.20 mg/kg) given prophylactically every 8 
hours during radiation therapy and beginning before the first treatment. The 
prophylactic use of dexamethasone during radiation therapy is discouraged. 
 

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Anticonvulsants:  Non-enzyme-inducing anticovulsant use is allowed at any point 
during this therapy. Preferentially, patients should not receive CYP3A inducers or 
inhibitors during therapy.  A list of all CYP3A inhibitors and inducers is provided 
in Appendix I. Every effort should be made to avoid placing patients on any drug 
listed in Appendix I during therapy. However, one of these medications may be 
used if no effective alternative drug is available, after discussion with the principal 
investigator. 
 
Histamine-receptor 2 (H2) antagonists, proton-pump inhibitors and antacids for 
patients on erlotinib:  H2 antagonists should be used only when deemed clinically 
necessary, but their administration should be at least 4 hours apart from that of 
erlotinib. Proton-pump inhibitors and antacids can be used only if symptoms are not 
controlled by H2 antagonists at least 4 hours apart from erlotinib administration. 
 
Anti-diarrheal medications:  Diarrhea is one of the most common adverse events 
described with the use of erlotinib. Loperamide or other anti-diarrheal medication 
should be considered for grade 1 diarrhea, and definitely used for any diarrhea 
≥grade 2. The recommended doses of loperamide are shown in Table 13 below. 
 
Table 13 – Weight-Specific Guidelines for Therapeutic Use of Loperamide 
Weight 
Initial (loading) 
loperamide dose 
Subsequent daytime 
loperamide dose 
Subsequent nighttime 
loperamide dose 
8-10 kg 
1 mg 
0.5 mg q 3h 
0.75 mg q 4h 
10-20 kg 
1 mg 
1 mg q 3h 
1 mg q 4h 
20-30 kg 
2 mg  
1 mg q 3h 
2 mg q 4h 
30-43 kg 
2 mg 
1 mg q 2h 
2 mg q 4h 
> 43 kg 
4 mg 
2 mg q 2h 
4 mg q 4h 
 
Rash:  Skin toxicities will be monitored by routine physical examination and 
managed symptomatically. Because secondary bacterial infections are common and 
can lead to more serious complications, topical or systemic antibiotics may be 
considered. Anecdotally, topical corticosteroids or a short course of systemic 
corticosteroids can be helpful for rash secondary to erlotinib. 
 
RSV:  RSV treatment should be initiated as per institutional guidelines.  Please see 
Appendix VIII for recommendations. 
 
5.0 
DRUG INFORMATION 
 
5.1 
METHOTREXATE 
 
Source and pharmacology:  Methotrexate is a folate analogue that acts by inhibiting 
dihydrofolate reductase.  Dihydrofolate reductase is an enzyme important in the 
conversion of folic acid to tetrahydrofolic acid, which is necessary in the synthesis 
of purine nucleotides and thymidylate.  By inhibiting the production of 
tetrahydrofolic acid, methotrexate interferes with DNA, RNA and protein synthesis.  
Methotrexate is poorly and variably absorbed orally, with an average of ≈ 40% for 

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doses of < 30 mg/m2.  At higher dosages, the extent of absorption decreases.  
Methotrexate is approximately 50% protein bound.  It distributes widely into body 
tissues and fluids with sustained concentrations in the kidney and the liver.  
Methotrexate undergoes metabolism by cytosolic aldehyde oxidase to hydroxy 
methotrexate.  It is excreted mainly in the urine as unchanged drug with small 
amounts being excreted in the bile and feces. The percent recovered as unchanged 
drug in the urine is higher with short infusions than with prolonged infusions.  
Methotrexate has a biphasic elimination with an initial half-life of ≈ 2-3 hours and a 
terminal half-life of 10-12 hours. Methotrexate may be “sequestered” in body fluid 
collections and eliminated slowly from these areas. Patients with effusions or GI 
obstruction should have plasma levels monitored closely for delayed excretion 
following high-dose methotrexate. 
 
Formulation and stability:  Methotrexate is supplied in single-dose vials containing 
50mg, 100mg, 200mg, and 250 mg of methotrexate as a 25 mg/ml preservative-free 
solution and in vials containing 20mg, 50 mg, 100mg, 250 mg and 1000mg of 
lyophilized drug.  It is also available in 2.5 mg tablets. Methotrexate preservative-
free solution and lyophilized drug should be stored at room temperature and 
protected from light.  Methotrexate tablets can also be stored at room temperature. 
The vials containing 20, 50, 100 and 250 mg of lyophilized product can be 
reconstituted by adding sterile water, 0.9% NaCl or D5W to a final concentration 
not exceeding 25 mg/ml.  The 1000mg vials containing lyophilized product are 
reconstituted to a final concentration of 50 mg/ml. 
 
Supplier:  Commercially available 
 
Toxicity:    The dose limiting toxicities of methotrexate are generally bone marrow 
suppression, ulcerative stomatitis, severe diarrhea or acute nephrotoxicity.  
Toxicities reported frequently include nausea and vomiting, diarrhea, anorexia, 
hepatic toxicity and alopecia.  Less common side effects include blurred vision, 
photosensitivity, anaphylaxis, headache, pneumonitis, skin depigmentation or 
hyperpigmentation, rash, vasculitis and encephalopathy.   During high-dose 
methotrexate therapy, most patients experience a transient decrease in GFR, but 
renal failure can occur, particularly if the patient does not receive urinary 
alkalinization and aggressive hydration before, during and after receiving high dose 
methotrexate.  Leucovorin rescue should be initiated within 48 hours of starting 
high-dose methotrexate and adjusted based on MTX levels to prevent bone marrow 
toxicity and mucositis.  Leucovorin may also be necessary after IT administration, 
especially if IT methotrexate therapy is given to patients with renal dysfunction.  
Patients with Down’s Syndrome have a tendency to have delayed methotrexate 
clearance and a greater risk of toxicity, despite increased leucovorin rescue. 
 
Dosage and route of administration:  Methotrexate will be given at a dose of 5 
g/m2/dose as an intravenous infusion over 24 hours on day 1 of each induction cycle 
except in patients ≤ 31 days of age at enrollment.  These young infants will receive 

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methotrexate at a reduced dose of 2.5g/m2/dose.  See treatment plan (section 4.2) 
for details. 
 
5.2 
LEUCOVORIN (FOLINIC ACID) 
 
Source and pharmacology:  Leucovorin is a racemic mixture of tetrahydrofolic acid, 
which is involved as a cofactor for 1-carbon transfer reactions in the synthesis of 
purine and pyrimidines.  Leucovorin is a potent antidote for both the hematopoietic 
and reticuloendothelial toxic effects of folic acid antagonists by replenishing 
reduced folate pools.  It is postulated that in some cancers, leucovorin enters and 
“rescues” normal cells from the toxic effects of folic acid antagonists, in preference 
to tumor cells, because of differences in membrane transport and affinity for 
polyglutamylation. Leucovorin is converted in the intestinal mucosa and the liver to 
5-methyl-tetrahydrofolate, which is also active as a reduced folate.  It is excreted 
primarily in the urine with minor excretion occurring in the feces. 
 
Formulation and stability:  Leucovorin is supplied in 5, 15 and 25 mg tablets and 
vials containing 50, 100 or 350 mg of leucovorin as a lyophilized powder.   The 
tablets and the lyophilized powder can be stored at room temperature.  The 50 mg 
and 100 vials can be reconstituted by adding 5 or 10 ml of sterile water or 
bacteriostatic water for injection respectively to yield a final concentration of 10 
mg/ml.  The 350 mg vials can be reconstituted with 17 ml of sterile water or 
bacteriostatic water for injection to yield a final concentration of 20 mg/ml.  The 
reconstituted solution is stable for at least 7 days at room temperature.  Leucovorin 
may be further diluted in 5% dextrose or 0.9% NaCl containing solutions.   
 
Supplier:  Commercially available 
 
Toxicity:  Leucovorin is generally well tolerated.  Toxicities that have been reported 
uncommonly include rash, mild nausea, headache, and wheezing (possible allergic 
reaction).   Intrathecal leucovorin is contraindicated and has caused neurotoxic 
deaths.  There have been rare reports of leucovorin promoting seizures. 
 
Dosage and route of administration:  Leucovorin rescue will be given starting at 
hour 42 from the start of each methotrexate infusion.  See treatment plan (section 
4.2) for details. 
 
5.3 
VINCRISTINE (ONCOVIN) 
 
Source and pharmacology:  Vincristine is an alkaloid obtained from the periwinkle 
(Vinca rosea) plant.  It reversibly binds to microtubule and spindle proteins causing 
metaphase arrest.  Vincristine has poor penetration into the CSF.  It is 
approximately 75% protein bound.  Extensive metabolism occurs in the liver.  
Excretion is primarily in the bile.  A dosage decrease is recommended in patients 
with a bilirubin > 3 mg/dl.  
 

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Formulation and stability:  Vincristine is supplied in multiple-dose 1 mg/ml vials 
containing 1 ml, 2 ml and 5 ml. The intact vials should be stored under refrigeration 
and protected from light.   
 
Supplier:  Commercially available 
 
Toxicity:  Dose limiting toxicity is neurotoxicity.  This can be characterized by 
constipation and/or paralytic ileus, ptosis, vocal cord paralysis, weakness, jaw pain, 
abdominal pain, peripheral neuropathies, loss of deep tendon reflexes and “foot 
drop”.  Peripheral neuropathy is often the first sign of neurotoxicity and is initially 
reversible.  Other toxicities reported include alopecia, mild nausea and vomiting, 
SIADH, myelosuppression, orthostatic hypotension, optic atrophy, transient cortical 
blindness, and auditory damage.  Acute shortness of breath and severe 
bronchospasms have been reported following the administration of vinca alkaloids.  
Myelosuppression is rare at usual doses.  Vincristine is a vesicant and may cause 
severe tissue damage if extravasation occurs.  
 
Dosage and route of administration:  Vincristine 1 mg/m2 will be administered by 
intravenous push on days 8 and 15 of each induction cycle.  See treatment plan 
(section 4.2) for details. 
 
5.4 
CISPLATIN (PLATINOL-AQ) 
 
Source and Pharmacology:  Cisplatin is an inorganic heavy metal coordination 
complex that has biochemical properties similar to those of a bifunctional alkylating 
agent. It must undergo activation, by aquation, to form positively charged platinum 
complexes that react with nucleophilic sites on DNA.  Cisplatin is cell-cycle, phase 
non-specific.  Cisplatin rapidly distributes into tissues with the highest 
concentrations being present in the prostate, liver, and kidney and is highly protein 
bound (>90%).  Cisplatin has an elimination half-life of 30-90 minutes. Platinum is 
bound to plasma constituents. Cisplatin is excreted predominantly via glomerular 
filtration, and dosage adjustments are necessary for patients with renal dysfunction. 
 
Formulation and stability:  Cisplatin is available in an amber multi-dose vial 
containing 100 mg of cisplatin at a concentration of 1 mg/ml.  The unopened vial 
should be stored at room temperature and protected from light. The undiluted 
solution should not be refrigerated as a precipitate will form. Once opened, the vial 
should be discarded after 28 days if protected from light, or 7 days if not protected 
from light.  Cisplatin should be further diluted in NS or 1/2 NS prior to 
administration.   
 
Supplier:  Commercially available 
 
Toxicity:  Nephrotoxicity is one of the major dose-limiting side effects of cisplatin.  
This toxicity may be irreversible and can be minimized by providing adequate 
hydration before, during and after cisplatin therapy.  Other dose limiting toxicities 

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include myelosuppression, neuropathies and ototoxicity.  Nausea and vomiting are 
common and can be severe.   Delayed nausea and vomiting (occurring > 24 hours 
after drug administration) can occur.  Diarrhea, anorexia, electrolyte disturbances 
(especially hypomagnesemia), cardiac abnormalities, allergic reactions and transient 
elevations in liver enzymes can occur. Secondary cancers have been reported. 
 
Dosage and route of administration:  Cisplatin 75 mg/m2 will be administered by 
intravenous infusion over 6 hours on day 8 of each induction cycle.  See treatment 
plan (section 4.2) for details. 
 
5.5 
CYCLOPHOSPHAMIDE (CYTOXAN) 
 
Source and pharmacology:  Cyclophosphamide is a nitrogen mustard derivative.  It 
acts as an alkylating agent that causes cross-linking of DNA strands by binding with 
nucleic acids and other intracellular structures, thus interfering with the normal 
function of DNA.  Cyclophosphamide is cell-cycle, phase non-specific.  
Cyclophosphamide is well absorbed from the GI tract with a bioavailability of > 
75%.  Cyclophosphamide is a prodrug that requires activation.  It is metabolized by 
mixed-function oxidases in the liver to 4-hydroxycyclophosphamide, which is in 
equilibrium with aldofosfamide.  Aldofosfamide spontaneously splits into 
cyclophosphamide mustard, which is considered to be the major active metabolite, 
and acrolein.  In addition, 4-hydroxycyclophosphamide may be enzymatically 
metabolized to 4-ketocyclophosphamide and aldofosfamide may be enzymatically 
metabolized to carboxyphosphamide which are generally considered to be inactive.  
Cyclophosphamide and its metabolites are excreted mainly in the urine.  Dosage 
adjustments should be made in patients with a creatinine clearance of < 50 ml/min.     
 
Formulation and stability:  Cyclophosphamide is available in 25 and 50 mg tablets.  
Cyclophosphamide is also available in vials containing 100, 200, 500, 1000 and 
2000mg of lyophilized drug and 75 mg mannitol per 100 mg of cyclophosphamide.  
Both forms of the drug can be stored at room temperature.  The vials are 
reconstituted with 5, 10, 25, 50 or 100 ml of sterile water for injection respectively 
to yield a final concentration of 20 mg/ml.  Reconstituted solutions may be further 
diluted in either 5% dextrose or 0.9% NaCl containing solutions.  Diluted solutions 
are physically stable for 24 hours at room temperature and 6 days if refrigerated, but 
contain no preservative, so it is recommended that they be used within 24 hours of 
preparation. Cyclophosphamide oral elixir can be compounded from simple syrup 
for administration to small children not able to swallow tablets.  The simple syrup 
oral compound is stable for 8 weeks if refrigerated at 4oC and is stable for 8 days at 
room temperature.302, 302b   
 
Supplier:  Commercially available 
 
Toxicity:  Dose limiting toxicities of cyclophosphamide are bone marrow 
suppression and cardiac toxicity.  Cardiac toxicity is typically manifested as 
congestive heart failure, cardiac necrosis or hemorrhagic myocarditis and can be 

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fatal.  Hemorrhagic cystitis may occur and necessitates withholding therapy.  The 
incidence of hemorrhagic cystitis is related to cyclophosphamide dose and duration 
of therapy.  Forced fluid intake and/or the administration of mesna decrease the 
incidence and severity of hemorrhagic cystitis.  Other toxicities reported commonly 
include nausea and vomiting (may be mild to severe depending on dosage), 
diarrhea, anorexia, alopecia, immunosuppression and sterility.  Pulmonary fibrosis, 
SIADH, anaphylaxis and secondary neoplasms have been reported rarely. 
 
Dosage and route of administration:  Cyclophosphamide will be administered 
during four distinct phases of this treatment plan.  See the appropriate sections of 
the treatment plan for details: 
 
• Induction (all patients):  1500 mg/m2 given by intravenous infusion over 1 
hour on day 9 of each cycle.  See section 4.2 
• Consolidation (low-risk patients only):  1500 mg/m2 given by intravenous 
infusion over 1 hour on day 1 of each cycle.  See section 4.3 
• Consolidation (high-risk patients not electing CSI only):  600 mg/m2 
intravenous infusion over 1 hour on day 4 and 5 of each cycle.  See section 4.3 
• Maintenance (all patients):  30 mg/m2 by mouth on days 1 to 21 of each A 
cycle.  See section 4.4. 
 
5.6 
MESNA (MESNEX) 
 
Source and pharmacology:  Mesna is a synthetic sulfhydryl (thiol) compound.  Mesna 
contains free sulfhydryl groups that interact chemically with urotoxic metabolites of 
oxazaphosphorine derivatives such as cyclophosphamide and ifosfamide. Oral 
bioavailability is ≈50%. Upon injection into the blood, mesna is oxidized to mesna 
disulfide, a totally inert compound.  Following glomerular filtration, mesna disulfide 
is rapidly reduced in the renal tubules back to Mesna, the active form of the drug. 
Mesna and mesna disulfide are excreted primarily via the urine. 
 
Formulation and stability:  Mesna is available in 2 ml, 4 ml and 10 ml amps 
containing 100 mg/ml of mesna solution.  The intact vials can be stored at room 
temperature.  Mesna may be further diluted in 5% dextrose or 0.9% NaCl containing 
solutions to a final concentration of 1-20 mg/mL.  Diluted solutions are physically 
and chemically stable for at least 24 hours under refrigeration.   
 
Supplier:  Commercially available 
 
Toxicity:  Mesna is generally well tolerated.  Nausea and vomiting, headache, 
diarrhea, rash, transient hypotension and allergic reactions have been reported.  
Patients may complain of a bitter taste in their mouth during administration.  Mesna 
may cause false positive urine dipstick readings for ketones.   
 

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Dosage and Administration:  Mesna will be administered by intravenous infusion 
over 15 minutes in association with all intravenous cyclophosphamide doses.  See 
sections 4.2 and 4.3 for details. 
 
5.7 
G-CSF (FILGRASTIM) (NEUPOGEN) 
 
Source and pharmacology:  G-CSF (granulocytic colony stimulating factor), is a 
biosynthetic hematopoietic agent that is made using recombinant DNA technology 
in cultures of Escherichia coli.  G-CSF stimulates production, maturation and 
activation of neutrophils.  In addition, endogenous G-CSF enhances certain 
functions of mature neutrophils, including phagocytosis, chemotaxis and antibody--
dependent cellular cytotoxicity. 
 
Formulation and stability:  G-CSF is supplied in vials containing 300 mcg and 480 
mcg of G-CSF at a concentration of 300 mcg/ml.  The intact vials should be stored 
under refrigeration.   The vials can be left out of refrigeration for 24 hours, but 
should be discarded if left at room temperature for longer periods of time.  G-CSF 
can be drawn up into tuberculin syringes for administration and stored under 
refrigeration for up to 7 days prior to usage.  G-CSF can be further diluted for IV 
infusion in 5% dextrose.  Do not dilute in saline---precipitate may form.  If the final 
concentration of this product is < 15 mcg/ml, it is recommended that albumin be 
added to a final concentration of 2mg/ml (0.2%) to minimize adsorption of the drug 
to infusion containers and equipment.   
 
Supplier:  Commercially available 
 
Toxicity:  G-CSF causes marked leukocytosis.  Adverse reactions reported 
commonly include bone pain, thrombocytopenia, diarrhea, nausea, rash, alopecia, 
fever, anorexia and pain or bruising at the injection site.  Allergic reactions, MI, 
atrial fibrillation, and splenomegaly have been reported rarely.  G-CSF is 
contraindicated in patients with allergy to E. Coli derived products. 
 
Dosage and route of administration:  filgrastim 5 mcg/kg will be administered daily 
by subcutaneous or intravenous injection after all courses of myelosuppressive 
intravenous chemotherapy, and continue until the ANC > 2000/mm3 post-nadir.  
See sections 4.2 and 4.3 for details. 
 
5.8 
VINBLASTINE (VELBAN) 
 
Source and pharmacology:  Vinblastine is an alkaloid extracted from the periwinkle 
plant (Vinca Rosea).  It reversibly binds to microtubule and spindle proteins causing 
metaphase arrest.  It may also block cellular utilization of glutamic acid, thereby 
inhibiting purine synthesis and urea formation via the citric acid cycle.  Vinblastine 
is highly protein bound and poorly penetrates the CSF.  Metabolism in the liver is 
extensive with one metabolite, deacetyl vinblastine, being more active than the 

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parent drug.  The major route of elimination is via the bile. Dosages should be 
adjusted for patients with impaired liver function (bilirubin > 3 mg/dl).     
 
Formulation and stability:  Vinblastine is available in 10 ml vials containing 
1mg/ml of vinblastine in solution. Intact vials of vinblastine solution and 
lyophilized vinblastine should be stored under refrigeration.  
 
Supplier:  Commercially available 
 
Toxicity:  The dose limiting toxicity is myelosuppression.  Other toxicities reported 
commonly include alopecia, mild nausea and vomiting and constipation.  
Vinblastine is a vesicant and may cause severe tissue damage if extravasation 
occurs.  Vinblastine rarely produces neurotoxicity characterized by peripheral 
neuropathy, loss of deep tendon reflexes, weakness, jaw pain and “foot drop”.  This 
toxicity is much less common than with vincristine.  Acute shortness of breath and 
severe bronchospasms have been reported following the administration of vinca 
alkaloids. 
 
Dosage and route of administration:  Vinblastine 1 mg/m2 will be given 
intravenously on days 17, 19, 22, 24, and 26 of each induction cycle for high-risk 
patients only.  See section 4.2 for details. 
 
5.9 
CARBOPLATIN (PARAPLATIN) 
 
Pharmacology:   Carboplatin is an inorganic heavy metal coordination complex that 
has biochemical properties similar to those of a bifunctional alkylating agent. 
Carboplatin must undergo activation, by aquation, to form positively charged 
platinum complexes that react with nucleophilic sites on DNA, producing 
predominantly intrastrand DNA cross-links.  Carboplatin is widely distributed in 
body tissues and fluids with highest concentrations in the kidney, liver, skin and 
tumor tissue.  Carboplatin does not bind significantly to plasma proteins, but the 
activated form does bind to tissue and plasma proteins.  In adults with normal renal 
function, the plasma elimination half-life is ≈2-3 hours.  The elimination of 
carboplatin and its platinum-containing products is primarily dependent on 
glomerular filtration rate; therefore dosages may be adjusted for renal function. 
 
Formulation and stability:  Carboplatin is supplied in 20-ml amber vials containing 
50, 150 or 450 mg of carboplatin as a white lyophilized powder. Vials should be 
reconstituted with sterile water for injection, D5W or 0.9% NaCl to give a 
concentration of 10 mg/ml and further diluted with D5W or 0.9% NaCl to 
concentration of 0.5 mg to 1.0 mg per ml.  It is recommended that the reconstituted 
solution be discarded 8 hours after preparation. 
 
Supplier:  Commercially available. 
 

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Toxicity:  Dose limiting toxicity is bone marrow suppression with 
thrombocytopenia being prominent.  Nausea and vomiting of moderate severity are 
common. Hepatic dysfunction (after high doses), alopecia, ototoxicity, peripheral 
neuropathies, reversible renal toxicity, visual disturbances, and allergic reactions 
have all been reported less commonly.  Pulmonary fibrosis is rare, but occurs most 
commonly in patients treated with cumulative doses > 1400 mg/m2 or receiving 
bone marrow transplant dosages.  Electrolyte abnormalities including 
hyponatremia, hypomagnesemia, hypocalcemia and hypokalemia can occur.  
Secondary cancers have been reported rarely. 
 
Dosage and route of administration:   Carboplatin targeted to an AUC of 5 (by the 
Calvert formula) will be administered intravenously over 1 hour on day 2 of each 
consolidation cycle for low-risk patients only.  See treatment plan (section 4.3) for 
details.  Carboplatin will be used as a substitute for cisplatin in patients with ≥ 
Grade 3 ototoxicity.  See section 4.2.8 for details. 
 
5.10 
ETOPOSIDE (VP-16) (VEPESID) 
 
Source and pharmacology:  Etoposide is an epipodophyllotoxin derived from 
Podophyllum pelatatum. It is thought to act mainly by inhibiting topoisomerase II, 
causing double and single strand DNA breaks.  Etoposide is cell cycle, phase-
specific, with activity in the G2 and S phases.  Absorption of etoposide is 
approximately 30-40% and is highly variable and somewhat dose-dependent.  It is 
extensively bound to serum proteins and is metabolized in the liver, including 
cytochrome P450 3A metabolism to several moieties that include a reactive 
oxidized species.  Etoposide and its metabolites are excreted mainly in the urine 
with a smaller amount excreted in the feces.  Dosage adjustments should be 
considered in patients with liver dysfunction, kidney dysfunction or 
hypoalbuminemia. 
     
Formulation and stability:  Etoposide is available in multi-dose vials containing 
100mg, 150mg, 500mg and 1000mg of etoposide as a 20mg/ml solution and 30% 
alcohol.   Etoposide is also available as a 50 mg capsule.  The intact vials of 
etoposide solution should be stored at room temperature. The capsules should be 
stored under refrigeration.  Etoposide solution should be diluted in D5W or 0.9% 
NaCl prior to administration.  Solutions with a final concentration of 0.2 and 0.4 
mg/ml are stable at room temperature for 96 hours and 24 hours respectively. 
 
Supplier:  Commercially available 
 
Toxicity:  Dose limiting toxicity is myelosuppression.  Nausea and vomiting 
(usually of low to moderate severity), diarrhea, mucositis (particularly with high 
doses), alopecia and anorexia are fairly common.  Hypotension can occur with rapid 
infusions.  Other side effects reported less commonly include hepatitis, fever and 
chills, anaphylaxis and peripheral neuropathy. Secondary leukemia has been 
reported. 

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Dosage and route of administration:  Etoposide 100 mg/m2 will be administered 
intravenously over 1 hour on days 1 and 2 of each consolidation cycle for low-risk 
patients only.  See section 4.3 for details.  Etoposide 50 mg/m2 will be given by 
mouth daily on days 1 through 21 of each maintenance cycle B for all patients with 
diagnoses other than medulloblastoma, high-grade glioma or ependymoma.  See 
section 4.4 for details. 
 
5.11 
TOPOTECAN (HYCAMTIN) 
 
Source and pharmacology:  Topotecan is a semi-synthetic derivative of 
camptothecin that inhibits topoisomerase I activity. Topoisomerase I relieves 
torsional strain in the DNA helix during replication by inducing reversible single 
strand DNA breaks.   Topotecan binds to the topoisomerase I-DNA complex and 
prevents relegation of single strand breaks.  This results in double-strand DNA 
breaks during DNA synthesis when replication enzymes interact with the ternary 
complex formed by topotecan, topoisomerase I and DNA.  Topotecan undergoes a 
rapid, pH-dependent opening of the lactone ring to yield a relatively inactive, 
hydroxy acid in plasma.  At physiologic pH, topotecan exists mainly as the hydroxy 
acid.  Metabolism occurs via a pH dependent hydrolysis of the lactone moiety.  
Metabolism to an N-demethylated metabolite represents a minor metabolic 
pathway.  Mean elimination half-life is three hours.  Approximately 30% of a dose 
is excreted in the urine.  Dosage adjustment is recommended for patients with 
moderate to severe renal dysfunction).   
 
Formulation and stability:  Topotecan is available in single-dose vials containing 4 
mg of topotecan as a lyophilized light yellow to greenish powder and 48 mg of 
mannitol.  The intact vials should be stored at room temperature and protected from 
light.  Each vial may be reconstituted with 4 ml of sterile water for injection to yield 
a final concentration of 1 mg/ml. Because the reconstituted solution does not 
contain a preservative, it is recommended that it be used immediately after 
reconstitution. The reconstituted solution can be further diluted with 5% dextrose or 
0.9% NaCl containing solutions.  Once diluted for administration, the drug is stable 
for at least 24 hours at room temperature and ambient lighting. 
 
Topotecan for injection when reconstituted to 4 mg/4 mL with Bacteriostatic Water 
for Injection is chemically and physically stable for up to 28 days in amber colored 
plastic prescription bottles at both 5 degrees and 25 degrees centigrade.  
 
Supplier:  Commercially available 
 
Toxicity:  The dose-limiting toxicity is myelosuppression.  Other toxicities reported 
commonly include nausea and vomiting, diarrhea, mucositis, abdominal pain, fever, 
rash, alopecia, anorexia, headache and flu-like symptoms. Toxicities reported less 
commonly include elevated liver function tests and paresthesias. 
 
Dosage and route of administration:  Topotecan will be administered by intravenous 
infusion over 4 hours on days 1-5 of each consolidation cycle for high risk patients 

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not receiving craniospinal irradiation.  The initial dose of Topotecan will be based 
on patient’s age as outlined in section 4.3.3.1.1 with subsequent doses adjusted, if 
necessary, to achieve a topotecan lactone AUC of 140 ± 20 ng/mL*hr.  See section 
4.3 for details.  Topotecan will be also be administered orally at a dose of 0.8 
mg/m2 daily for the first 10 days of each cycle A of maintenance therapy for all 
patients.  See section 4.4 for details. 
 
5.12 
ERLOTINIB HYDROCHLORIDE (TARCEVA) 
 
Source and pharmacology: Erlotinib hydrochloride (erlotinib, Tarceva) is an 
orally active anti-tumor agent being developed for the treatment of a variety of solid 
tumors. Erlotinib acts through direct and reversible inhibition of the EGFR and 
ERBB2 tyrosine kinase.  
 
Formulation and stability: Tablets containing 25mg, 100mg, and 150mg of erlotinib 
are available. In addition to the active ingredient, tablets also contain lactose 
monohydrate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl 
sulfate, and magnesium stearate. The oral tablets are conventional, 
immediate-release tablets containing erlotinib as the hydrochloride salt.  
 
Supplier:  Commercially available 
 
The dose limiting toxicity after intermittent or continuous dosing of erlotinib in 
adults with cancer has been diarrhea.  The dose limiting toxicities in a pediatric 
phase I trial were rash, diarrhea and hyperbilirubinemia (COG Spring 2006 
Meeting, ADVL0214 Progress Report). 
 

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Table 14: Erlotinib - Known Toxicities and DLT 
Common (21-100% 
Frequency) 
Occasional (5-20% 
Frequency) 
Rare (< 5% Frequency) 
Skin rash/erythema Grade 
1/2 (48-80%) 
Diarrhea Grade 1/2 (20-
60%) 
Nausea (2-30%) 
Vomiting (10-22%) 
Fatigue (lethargy, malaise, 
asthenia) (20-30%) 
Dry skin 
Dry mouth 
Anorexia 
Headache 
Pruritus 
Stomatitis 
Cough 
Decreased appetite 
Grade 3/4 transaminase 
elevation 
Grade 3/4 skin rash 
Grade 3/4 diarrhea 
Eyelash ingrowth/corneal 
pain or redness 
Corneal erosions 
Uveitis 
Tearing 
Renal Toxicity 
Desquamation 
Dry eye 
Pneumonitis 
Pulmonary infiltrates, 
pulmonary fibrosis 
Blurry vision and 
hypersensitivity/allergic 
reaction 
Stevens-Johnson 
syndrome 
 
Other side effects reported on erlotinib trials but with the relationship to erlotinib still 
undetermined include: anemia, leukopenia, neutropenia, leukocytosis, eosinophilia, 
thrombocytopenia, osteonecrosis, pulmonary embolism, deep vein thrombosis, rigors, 
pyrexia, alopecia, acne, sore throat, glossodynia, taste disturbance, chelitis, 
constipation, abdominal pain or cramping, gastric ulceration and perforation, flatulence, 
dehydration, dysphagia, ischemic bowel, dyspepsia, pancreatitis, hematuria, epistaxis, 
melena, hemoptysis, GI bleeding, hyperbilirubinemia, transaminitis, increased alkaline 
phosphatase, pneumonia, urinary tract infection, infection with or without neutropenia, 
hypokalemia, hyponatremia, nasal dryness, rhinitis, depression, anxiety, insomnia, 
paresthesia, dizziness, cerebrovascular ischemia, uveitis, back pain, abdominal pain, 
dyspnea, increased creatinine, elevated BUN, proteinuria, renal failure, and 
endometritis. 
 
Dosage and route of administration: Erlotinib will be administered at a dose of 90 
mg/m2 daily for 28 days during each cycle B of maintenance therapy for all patients 
with medulloblastoma, high-grade glioma or ependymoma.  See section 4.4 for details. 
 

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6.0 
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS 
 
6.1 
EVALUATIONS TO BE OBTAINED AT ENROLLMENT  
 
Table 15 Baseline Evaluations 
To Be Obtained Prior to Enrollment 
To Be Obtained Within 2 Weeks of 
Enrollment 
 
Required for All Patients: 
 
History and physical exam with height (cm), 
weight (kg), and BSA 
Lansky performance status (See Appendix II) 
Institutional diagnosis of medulloblastoma, 
medulloblastoma variant, PNET, PNET 
variant, ATRT, high-grade glioma, CPC, or 
ependymoma 
MRI of brain with and without contrast 
MRI of spine with contrast 
CSF cytology from lumbar spinal fluid*  
Operative Report 
Laboratory Studies:  CBC with Diff, Chem 18  
Renal ultrasound to rule out synchronous renal 
rhabdoid tumor (required for ATRT patients 
only) 
 
Required if Parent Consents to Optional 
Correlative Study: 
 
CSF for neurotransmitter studies 
 
 
Required for All Patients: 
 
Auditory brainstem response (ABR)† 
Formalin-Fixed Paraffin-Embedded (FFPE) 
Tumor Block Specimen for Central Pathology 
Review 
Blood Sample for Genomic DNA 
 
Required if Parent Consents to Optional 
Correlative Study: 
 
Neuropsychology Evaluation** 
 
 
Obtain as Clinically Indicated: 
 
Urinalysis , PT, PTT  
Ophthalmologic Evaluation  
Nutrition Evaluation 
Physical Therapy 
Occupational Therapy 
Speech Therapy 
 
* Obtain CSF cytology from lumbar puncture even if the patient has a VP shunt or Ommaya 
reservoir; CSF from a VP shunt or Ommaya reservoir may be included only if lumbar puncture 
is medically contraindicated 
§ Baseline neurological evaluation may be obtained within 4 weeks of enrollment 
† Every effort should be made to obtain ABR prior to first dose of cisplatin on day 8 
 

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6.2 
EVALUATIONS DURING THERAPY 
 
Table 16 Evaluations During Induction and Consolidation 
 
Prior to Each 
Induction 
Cycle 
Prior to 
Induction 
Cycle 3 
End of Induction / 
Prior to 
Consolidation 
Weekly During 
Induction and 
Consolidation 
CLINICAL EVALUATIONS 
Complete history 
X 
 
X 
 
Physical exam 
X 
 
X 
X 
Height, weight, BSA 
X 
 
X 
X 
Auditory brainstem 
response (ABR) 
 
X 
X 
 
Tc-99 glomerular filtration 
rate (GFR) or creatinine 
clearance 
 
 
Low risk 
 
Radiation oncology 
consult 
 
 
High risk receiving 
CSI Intermediate risk 
 
LABORATORY STUDIES 
CBC with differential 
X 
 
X 
X† 
Serum creatinine and 
electrolytes (including 
Ca++, Mg++, Phos) 
X 
 
X 
X** 
ALT, AST, BUN, total 
bilirubin 
X 
 
X 
 
Urinalysis 
X 
 
 
 
Endocrine screen and GH 
provocative test #(for 
consenting St Jude 
patients) 
 
 
Intermediate risk 
 
Lumbar spinal fluid for 
CSF cytology* 
 
X 
X 
 
CSF for neurotransmitter 
studies (if enrolled in 
optional correlative study) 
 
X 
X 
 
IMAGING STUDIES 
MRI brain with and 
without contrast 
 
X 
X 
 
MRI spine 
 
X 
X 
 
RT simulation 
 
 
High risk receiving 
CSI Intermediate risk 
 
RT CT scan 
 
 
High risk receiving 
CSI Intermediate risk 
 
# per section 8.6 
*CSF from VP shunt or Ommaya may be substituted only if lumbar puncture is medically contraindicated 
†Obtain CBC with diff. twice weekly while patient is receiving G-CSF 
**Weekly chemistry studies are not required during consolidation for patients receiving RT - obtain other 
studies as clinically indicated See Table20, Section 8.2 for PK studies 
 

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Table 17 Evaluations During Maintenance and at End of Therapy 
Obtain studies prior to start of cycle except as noted 
 
A1 
B1 
A2 
B2 
A3 
B3 
End of 
Therapy 
Complete history 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Height, weight, BSA 
X 
X 
X 
X 
X 
X 
X 
CBC with differential+ 
q wk 
q wk 
q wk 
q wk 
q wk 
q wk 
X 
Serum creatinine and 
electrolytes (including Ca++, 
Mg++, Phos) 
q 2wk 
q 2wk 
q 2wk 
q 2wk 
q 2wk 
q 2wk 
X 
ALT, AST, BUN, total 
bilirubin 
q 2wk 
q 2wk 
q 2wk 
q 2wk 
q 2wk 
q 2wk 
X 
Urinalysis* 
q 2wk 
X 
q 2wk 
X 
q 2wk 
X 
X 
Endocrine Studies (TSH, Free
T4, am cortisol, others as 
clinically indicated), 
including GH provocative 
test  (for intermediate risk 
consenting St Jude patients) # 
 
 
 
 
 
 
X 
Trough PK level to assess 
compliance  
(all patients at all sites) 
Cyclo  
wk 2 or 3 
Erlotinib 
wk 2 or 3** 
 
 
Cyclo  
wk 2 or 3 
Erlotinib 
wk 2 or 3** 
 
Optional PK Studies (if 
enrolled in optional PK 
component)**  
X 
 
 
X 
 
 
 
Lumbar spinal fluid for CSF 
cytology† 
X 
 
 
X 
 
 
X 
CSF for neurotransmitter 
studies (if enrolled in 
optional correlative study) 
X 
 
 
X 
 
 
X 
MRI brain with and without 
contrast 
X 
 
 
X 
 
 
X 
MRI spine 
X 
 
 
X 
 
 
X 
Auditory brainstem 
response (ABR) 
X 
 
 
 
 
 
X 
Neuropsychology 
evaluation § 
X 
 
 
 
 
 
X 
+ If no significant myelosuppression as defined as ANC < 250/mm3 or platelets (unsupported) <50,000/mm3,  occurs 
during first maintenance course, CBC may be checked every two weeks during subsequent courses. 
* Schedule for urinalysis may be modified per treating physician’s discretion  
 # per section 8.6 
**See Table 20, Section 8.2, for details regarding PK studies; †CSF from VP shunt or Ommaya may be substituted 
only if lumbar puncture is medically contraindicated; **Medulloblastoma, high-grade glioma and ependymoma 
patients only. 
§ Obtain time 2 evaluation 6 months (+/- 60 days) after baseline evaluation. Yearly assessments should be 
scheduled from time of enrollment (+/- 60 days). 
   Obtain other studies as clinically indicated 
 

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6.3 
LONG-TERM FOLLOW-UP EVALUATIONS  
 
Table 18 Long-Term Follow-up Evaluations# 
 
Months Off Therapy # 
EVALUATION 
3 
6 
9 
12 
16 
20 
24 
30 
36 
Follow-up  
(to 60 months) 
Complete history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 6mo 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 6mo 
Height, weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 6mo 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 6mo 
Serum creatinine and electrolytes 
(including Ca++, Mg++, Phos) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 6mo 
ALT, AST, BUN, total bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 6mo 
MRI brain with and without 
contrast 
X 
X 
X 
X 
X 
X 
X 
X 
X 
q 12mo 
MRI spine 
X 
X 
X 
X 
X 
 
X 
 
X 
q 12mo 
Lumbar spinal fluid for CSF 
cytology* 
X 
X 
X 
X 
X 
 
X 
 
X 
 
CSF neurotransmitter studies  
(if enrolled in optional correlative 
study) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Auditory brainstem response 
(ABR) 
 
 
 
X 
 
 
X 
 
X 
q 12mo 
Neuropsychology evaluation §  
 
 
 
X 
 
 
X 
 
X 
q 12mo 
Endocrine Studies (TSH, Free T4, 
am cortisol, others as clinically 
indicated) # 
 
X## 
 
X 
 
 
X## 
 
X 
q 12mo 
*CSF from VP shunt or Ommaya may be substituted only if lumbar puncture is medically contraindicated 
# All evaluations allow for ± 1 month from the stated schedule 
§ Yearly assessments should be scheduled from time of enrollment (+/- 60 days) 
# per section 8.6 
Please obtain additional studies for optimal patient care 
 

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7.0 
NEUROPATHOLOGY GUIDELINES 
 
7.1 
CENTRAL REVIEW OF PATHOLOGY 
 
Central review of pathology will be performed for all patients in order to: 
 
• Confirm trial eligibility based on the diagnosis of embryonal tumor, high-grade 
glioma, choroid plexus carcinoma, or ependymoma, with classification 
according to the WHO (2007) system 
• Identify nodular / desmoplastic medulloblastomas for patient stratification 
• Facilitate distribution of tissue for approved biological studies 
 
7.2 
METHODS 
 
The working histological diagnosis will be provided by the local pathologist, but 
formalin-fixed paraffin-embedded (FFPE) tumor blocks and a copy of the 
pathology report should be submitted to St. Jude Children’s Research Hospital for 
pathological review as soon as possible after finalization of the report.  
 
The blocks chosen for central pathology review (and trial biological studies – see 
8.1.2.2) should contain plenty of representative tumor. The address for submission 
of FFPE blocks is: 
 
 
 
 
 
 
 
 
 
Neuropathology review will involve examination of standard histological 
preparations and, if required, immunohistochemistry (IHC) to look for the 
expression of neuroepithelial proteins (e.g. GFAP / synaptophysin / neurofilament 
protein / NEU-N) or non-neuroepithelial proteins (e.g. cytokeratins / smooth muscle 
actin / desmin / epithelial membrane antigen / Kir 7.1 protein). A Ki-67 
immunolabeling index will also be determined for certain tumors, and expression of 
the SMARCB1 (INI1) gene product will be evaluated in all tumors.  
 
Subclassifying infant medulloblastomas (MBs)  
 
Pediatric MBs are heterogeneous. Several histopathological variants are defined in 
the WHO classification of CNS tumors (2007), and data from several studies 
suggest that some of these variants have a distinctive biology and response to 
treatment.303 The large cell and anaplastic variants of MB have a more aggressive 
biological behavior than the classic MB,304,305 while the nodular / desmoplastic MB, 

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particularly the medulloblastoma with extensive nodularity (MBEN), has a more 
favorable outcome.306,307 The good prognosis of the nodular / desmoplastic MB has 
recently been shown in trial cohorts of young children,18 and provides an 
opportunity to treat patients with this MB variant using therapies designed to 
maximize cure, but reduce long-term adverse events. Thus, nodular / desmoplastic 
medulloblastomas in patients 0 - <3 yrs of age will be treated on a separate low risk 
arm of this protocol.  Patients diagnosed with desmoplastic medulloblastoma 
between the ages of 3-5 will be treated on the intermediate risk arm of the study. 
The diagnosis of this variant will be facilitated using reticulin preparations to 
highlight internodular desmoplasia.  
 
Figure 11  Nodular Desmoplastic Medulloblastoma 
 
 
 
 
 
Desmoplastic/nodular MB (H&E) 
Desmoplastic/nodular MB (reticulin) 
 
8.0 
CORRELATIVE STUDIES 
 
 
8.1 
BIOLOGICAL STUDIES ON TUMOR TISSUE 
 
8.1.1 Overview of studies on tumor tissue 
 
Tumor from trial patients is required for diagnosis and biological studies, though 
the priority for utilizing tissue should be a reliable diagnosis. Tissue surplus to 
diagnostic requirements should be processed for biological studies. In addition to 
fresh / frozen tissue, this may include FFPE tissue processed initially for diagnostic 
purposes. However, sufficient tissue should always be reserved in pathology blocks 
for further diagnostic tests or medicolegal examination in the originating 
department of pathology.  
 
Fresh frozen tumor samples will be analyzed using the most advanced methods 
available.  The techniques presented in the following sections are intended to be 
representative of those which will be used for the biological components of the trial.  
As microarray technology is evolving rapidly, it is likely that specific platforms and 
procedural details will be different from those described below.  Microarray 
platforms which may be used include the Human Genome U133 Plus 2.0 Array and 
Genome-Wide Human SNP Array 6.0. In addition, microRNAs will be studied at 

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the level of the genome and by expression profiling using an Illumina™ or 
Agilent™ platform. 
 
Studies on FFPE material under the SJYC07 protocol are described below in 
8.1.3. 
 
8.1.2 Tissue processing and storage 
 
Fresh-frozen tumor material 
 
Informed consent for the submission of tumor samples for all analyses will be 
obtained from parents. In order to simplify shipping requirements for partner sites 
and to facilitate tracking of submitted material, all samples from outside sites will 
be shipped to the principal investigator.  Once sample submission has been 
documented by Neuro-oncology research staff, samples will be immediately 
transported to the SJCRH Tumor Bank, in order to ensure that the MCTC remains 
blinded to patient identity and clinical characteristics (including outcome). All 
material will then be assigned a Tumor Bank number and forwarded to the MCTC 
for analysis. 
 
One or more ‘pea-sized’ aliquots of tumor should be collected from patients at the 
time of initial resection and any subsequent tumor surgery. Once removed from the 
patient, tissue elements degrade within 15-20 minutes, so liquid nitrogen for freezing 
the tissue should be available within close proximity to the operating room. 
Immediately following removal from the patient, divide tumor tissue into pea-sized 
aliquots (~50-100mg per aliquot, a total of 100-200mg is the preferred minimum, but 
please send as much tissue as available).  Wrap all aliquots in foil (or place in 
cryopreservation tubes, if the tumor is semi-liquid). Use a waterproof marker to label 
foil (or cryopreservation tubes) with the PATIENT ACCESSION NUMBER. Snap-
freeze the foil containing the tumor material in liquid nitrogen. For tissue obtained 
locally at LBCMC, A member of the NBTP will be present to transport the snap 
frozen samples to SJCRH.  If not shipped immediately, snap-frozen samples should 
be transferred under liquid nitrogen (or on dry ice) to a -80oC freezer until shipped 
(NOTE -20oC is inadequate for storage). Samples should be shipped on dry ice with 
the completed ‘FRESH FROZEN TISSUE SUBMISSION FORM’ to the Principal 
investigator: 
 
 
 
 
 
 
   
    
Frozen tumor will be processed subsequently to yield high quality DNA, RNA and 
protein. 

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Fixed tumor material 
 
FFPE tumor tissue for research IHC, iFISH, DNA extraction and construction of 
TMAs can be obtained at the same time as tissue sections are prepared for central 
histopathological review. Tissue blocks for this purpose should be obtained for all 
patients enrolled in this study and be submitted as for central pathology review and 
together with a completed ‘FIXED TISSUE SUBMISSION FORM’, to the 
principal investigator: 
 
 
 
 
 
 
 
 
 
Once sample submission has been documented by Neuro-oncology research staff, 
samples will be immediately transported to the SJCRH Pathology Department for 
processing and storage. 
  
Tissue blocks for this component of the biological studies will be processed as 
follows: 
 
• Sections (25 x 5 / 8µm) will be mounted on coated glass slides suitable for 
IHC & iFISH.  
• Tissue scrolls (10 x 25µm) will be obtained for extraction of tumor DNA 
and cell nuclei (iFISH). 
 
Constitutional DNA whole blood sample 
 
Informed consent for the submission of blood samples will be obtained from 
parents. In order to simplify shipping requirements for partner sites and to facilitate 
tracking of submitted material, all samples from outside sites will be shipped to the 
principal investigator.  Once sample submission has been documented by Neuro-
oncology research staff, samples will be immediately transported to the SJCRH 
tumor bank, in order to ensure that the MCTC remains blinded to patient identity 
and clinical characteristics (including outcome). All material will then be assigned a 
Tumor Bank number and forwarded to the MCTC for analysis. 
 
Five mls of whole blood should be submitted for analysis for each patient enrolled 
on SJYC07. Whole blood anti-coagulated with EDTA should be collected and kept 
at 4°C and shipped on wet ice. Using a waterproof marker, label the tubes with the 
patient identifying number and the date obtained, and send to:  
 
 

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8.1.3 Prioritization of tumor biology studies 
 
Frozen tissue studies 
 
If a limited amount of frozen tumor has been submitted, biological studies will be 
prioritized as follows: 
 
 
1. Microarray gene expression analysis. 
2. Methylation arrays  
 
2.  RT-PCR. 
 
3.  SNP array analysis. 
 
4.  Gene sequencing studies. 
 
5.  Western blot studies. 
 
6.  MicroRNA analysis and other studies. 
 
Note:  Gene expression studies will have the highest priority among biology studies.  
In cases where more than one block of frozen tissue has been obtained from a 
particular patient, extra material may be used for biology studies prior to the 
completion of accrual.  In all such cases at least one frozen tumor block will be 
retained for analysis of gene expression at the end of trial accrual.  In situations 
where only one block of frozen tumor has been obtained, no biology studies will be 
performed until the end of accrual, and RNA extraction for gene expression analysis 
and confirmatory RT-PCR studies will have the first priority when frozen tissue is 
analyzed.   
 
FFPE tissue studies 
 
FFPE tissue will be processed in Neuropathology according to a defined sequence. 
Submitted tissue blocks will first be processed for central pathology review, at 
which time standard (H&E) sections can be assessed for suitable regions that would 
contribute to the construction of a tissue microarray (TMA). If a tissue block 
appears sufficiently deep, cores will be taken for TMA construction. If not, this 
element of the studies will be omitted. A block will subsequently be sectioned as 
described below, prioritizing DNA extraction for methylation arrays over IHC  and 
iFISH.  
 

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It is a policy of the Neuropathology department at St. Jude to return FFPE tissue 
blocks borrowed from other institutions with sufficient tissue for further diagnostic 
or medicolegal use. If at any stage tissue within a block appears thin, then 
sectioning will stop and the block will be returned.  
 
8.1.4 Methods for tumor biology studies 
 
Methods for biological studies advance rapidly, especially in the area of microarray 
technology.  The availability of specific platforms and techniques is likely to 
change during the accrual phase of the trial, and the most advanced techniques 
available at the time of sample analysis will be utilized.  The methods presented 
below should therefore be considered to be representative of the techniques which 
will actually be performed in this trial. 
 
Immunohistochemistry (IHC) 
 
FFPE sections (5µm), including those for appropriate controls, will be taken to 
assess the following in medulloblastoma tumor samples: 
 
• 
activation of the wnt signaling pathway (β-catenin) 
• 
activation of the shh signaling pathway (Gli-1 / SFRP1) 
• 
ERBB2 
 
In addition and where appropriate antibodies are available, IHC will be used to 
validate novel patterns of gene expression revealed by the genome-wide approaches 
described below.  
 
Interphase fluorescence in situ hybridization (iFISH) 
 
FFPE sections (8µm) or cell nuclei extracted from tissue scrolls, including those for 
appropriate controls, will be taken to assess the following in medulloblastoma 
tumor samples: 
 
• loss of chromosomes 6, 8p, 9q22 
• isochromosome 17q  
• amplification of MYCC, MYCN, MYCL 
 
In addition, iFISH will be used to validate genetic abnormalities revealed by the 
genome-wide approaches described below.  
 
Tissue microarray 
 
Tissue microarrays will be constructed for tumor samples from patients with all 
diagnoses.   
 

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A maximum of four 1.0 mm diameter tissue cores will be extracted from 
representative tissue block(s) for the construction of tissue microarrays. H&E-
stained slides from each of the paraffin donor blocks will be utilized as guides in 
selecting morphologically representative areas, with the Pathology section 
coordinator designating appropriate areas for sampling. A maximum of three 1.0 
mm diameter tissue cores from each donor block will be precisely arrayed in the 
recipient TMA block using a tissue arrayer (Beecher Instruments, Silver Spring, 
MD) equipped with a thin-walled stainless steel tube (punch) with a sharpened end 
similar to a cork borer.  A stainless steel stylet will be used to transfer tissue cores 
into recipient (array) blocks at defined microarray coordinates.  Staggering of the 
first row of cores will be used to ensure reliable orientation of tissue sections and 
identification of each donor sample.  Subsequently, 4 µm-thick sections from the 
microarray blocks will be mounted on positively-charged slides for future 
immunohistochemical and FISH analysis.  Tissue cores will only be taken in cases 
where there is adequate tissue available and will not otherwise compromise the 
donor block for future diagnostic utility.  All original blocks will be promptly 
returned to the submitting institution, along with a copy of the central laboratory 
pathology report.  
 
A database will be generated identifying the microarray coordinates with individual 
donor cases (identifier of pathology case numbers only) with password protection 
for access by only the Pathology section coordinator.  The database will allow for 
parallel entries of subsequent FISH and immunohistochemical results. Any other 
patient-related documents (pathology reports) will be kept in a locked file in the 
Pathology section coordinator’s office.   
 
Microarray analysis 
 
We will construct gene expression-profiles for all tumor samples with 5-10µg RNA 
using microarray analysis.161 Briefly, first and second strand cDNA will be 
synthesized from 5-15 µg of total tumor cell RNA using the SuperScript Double-
Stranded cDNA Synthesis Kit (Gibco Life Technologies, Rockville, Maryland) and 
an oligo-dT24-T7 primer. This is then used to prepare cRNA that is labeled with 
biotinylated UTP and CTP by in vitro transcription using a T7 promoter coupled 
double stranded cDNA as template and the T7 RNA Transcript Labeling Kit 
(ENZO Diagnostics Inc., Farmingdale, NY). Following purification and 
precipitation at –20oC, 10 µg of this cRNA is fragmented by heat and ion-mediated 
hydrolysis at 95oC (200 mM Tris-acetate, pH 8.1, 500 mM KOAc, 150 mM 
MgOAc) and hybridized to the Human Genome U133 Plus 2.0 array. This contains 
almost 54,000 probe sets representing more than 47,000 transcripts derived from 
approximately 38,500 well-substantiated human genes. This set design uses 
sequences selected from GenBank®, dbEST, and RefSeq. Arrays are then washed 
at 25oC with 6 X SSPE (0.9M NaCl, 60 mMNaH2PO4, 6 mM EDTA + 0.01% 
Tween 20) followed by a stringent wash at 50oC with 100 mM MES, 0.1M [Na+], 
0.01% Tween 20. We will then stain arrays with phycoerythrein conjugated 
streptavidin (Molecular Probes, Eugene, OR) and the fluorescence intensities will 

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be determined using a laser confocal scanner (Hewlett-Packard, Palo Alto, CA). 
The scanned images are analyzed using Microarray software (Affymetrix). We 
will standardize for sample loading and variations in staining by scaling the average 
of the fluorescent intensities of all genes on an array to a constant target intensity 
(2500) for all arrays used. The signal intensity for each gene was calculated as the 
average intensity difference, represented by [(PM - MM)/(number of probe pairs)], 
where PM and MM denote perfect-match and mismatch probes. Microarray 
expression profiles will be analyzed as described in detail in the statistics section of 
the protocol. 
 
SNP array analysis 
 
SNP analysis will be performed using the Affymetrix Genome-wide human SNP 
array 6.0, or a similar platform, using the most appropriate technology available at 
the time of analysis. Such arrays are designed for high throughput parallel 
genotyping of almost one million SNPs that span the human genome with a median 
intermarker distance of 5.8 kb308,309. The sequence of each allele is determined 
using 40 tiled probes that span the SNP position, providing highly accurate 
(>99.5%) and reproducible (>99.9%) genotype calls310,311.  
 
Samples for SNP analyses will be submitted to the microarray core laboratory in the 
Hartwell Center for Bioinformatics and Biotechnology and assessed for DNA purity 
and integrity by using UV spectrophotometry and agarose gel electrophoresis. 
Samples with 260/270 ratios <1.1 (indicating residual phenol) or with 260/280 
ratios <1.8 (indicating residual protein) will be repurified using the Qiagen QiaAmp 
DNA mini-kit. Samples passing initial quality assessment will be processed as 
described below. 
 
Total genomic DNA (500 ng) is digested with Nsp I and Sty I restriction enzymes 
and ligated to adaptors that recognize the cohesive 4bp overhangs. All fragments 
resulting from restriction enzyme digestion, regardless of size, are substrates for 
adaptor ligation. A generic primer that recognizes the adaptor sequence is used to 
amplify adaptor-ligated DNA fragments. PCR conditions have been optimized to 
preferentially amplify fragments in the 200 to 1,100 bp size range. PCR 
amplification products for each restriction enzyme digest are combined and purified 
using polystyrene beads. The amplified DNA is then fragmented, labeled and 
hybridized to the array. Following hybridization, arrays are washed automatically 
using a GeneChip Fluidics Station 450 using high stringency conditions to remove 
non-hybridized labeled DNA. Arrays are incubated with Streptavidin Phycoerythrin 
(SAPE, Molecular Probes), washed, and then incubated with biotin-conjugated anti-
streptavidin antibody. After removal of the antibody solution, the arrays are 
restained using the SAPE, washed again, and then scanned using an Affymetrix 
GeneChip Scanner or similar platform. SNP array data will be analyzed as 
described in section 13.2.1. 
 
Gene sequence analysis 

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We will use the polymerase chain reaction (PCR) and a combination of previously 
published and ‘in-house’ generated primers to amplify DNA extracted from each of 
the tumor samples; the products of these reactions will then be directly sequenced 
with the assistance of the Hartwell Center. Genes identified as potential oncogenes 
and tumor suppressor genes using SNP or expression microarrays will be subject to 
DNA sequence analysis. We will also conduct sequence analysis of constitutional 
DNA (extracted from white blood cells) taken from patients whose tumors contain 
gene mutations: this will be performed to confirm that the mutations have arisen 
somatically during tumor formation.  
 
Western blotting analysis 
 
We will analyze the expression of a number of cell signal proteins that have been 
implicated in the biology of medulloblastoma. Antibodies employed for western 
blotting will include: phospho-Y1248 ERBB2 (Upstate Biotechnology, Waltham, 
MA), phospho-Y204 ERK1/2 (Santa Cruz Biotechnology, Santa Cruz, CA) 
phospho-Ser473 of AKT1, phospho-β catenin, β-catenin (New England Biolabs, 
Beverly, MA), ERBB2 (Novacastra Ltd, Newcastle, UK), ERK1, PDGFRB (Santa 
Cruz Biotechnology), AKT1 (New England Biolabs), S100A4 (Dako, Carpinteria, 
CA), TP53 (Oncogene Science) and β-actin (Sigma Chemicals, St Louis, MO) 
commercially available primary antibodies. We will also study the expression of 
additional proteins encoded by genes associated through SNP and gene expression 
array analysis with clinical disease behavior.  
 
Western blot analysis will be performed using standard techniques. Briefly, 100 µg 
of tumor protein lysate will be analyzed by western blotting analysis as described in 
detail previously (10). The first three lanes of all blots will include three separate 
cell line controls: (lane 1) Daoy.V (expresses low-levels of ERBB2, S100A4, active 
β-catenin and moderate levels of PDGFRB), (lane 2) Daoy.2 (express high-levels of 
ERBB2, S100A4, active β-catenin and moderate levels of PDGFRA), (lane 3) 
D341 (negative for all ERBB receptors). Following probing for the protein of 
interest all blots will be re-probed with an antibody for β-actin to control for protein 
loading and transfer. The expression level of each protein of interest will be 
determined by densitometric analysis and normalized to the levels of cell line 
controls (lanes 1-3) and β-actin. This system allows for accurate inter-tumor 
assessment of specific protein expression. 
 
Real-time PCR analysis 
 
Real-time PCR will be performed using a 7900HT Sequence Detection System 
(ABI) and the TaqMan One Step PCR Master Mix Reagents Kit (ABI) as described 
previously.312 RT-PCR will be used to confirm the differential expression pattern of 
genes detected using microarray analysis. Real-time PCR reactions will be analyzed 
using SDS v2.0 software (ABI). Total RNA from human adult brain (Ambion) is 

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used to generate standard curves for relative quantitation. 18S rRNA is used for an 
endogenous control. 

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8.2 
PHARMACOKINETIC AND PHARMACOGENETIC STUDIES 
 
TABLE 19 OVERVIEW OF PHARMACOKINETIC STUDIES 
Drug 
Patients 
Course and Day 
Time points 
Sample volume 
(per level) 
Induction PK Studies 
Methotrexate IV 
 
All patients 
(any site) 
Each induction 
cycle - day 1 
Pre-infusion and 6, 
23, 42 hours from 
start of MTX, and as 
needed 
1-2 mL 
Cyclophosphamide IV   
Enrolled in optional 
PK study 
(St. Jude only) 
Induction cycle 1 
or cycle 2 –  day 9 
Pre-infusion, 
end of infusion, hours 
3, 6, and 24 from end 
of infusion 
1 mL 
Consolidation PK Studies 
Topotecan IV 
 
All high-risk receiving 
Cyclo/Topo 
consolidation 
(any site) 
Each 
consolidation 
cycle – day 1 and 
as needed 
Pre-infusion,  
5 min., 1, and 3 hours 
from end of infusion 
2 mL 
Cyclophosphamide IV 
 
Applies only to St Jude 
patients enrolled on 
optional PK study 
 
 
High-risk receiving 
Cyclo/Topo  
 
 
Low-risk pts 
receiving Cyclo/ 
Carbo /VP16 
Each 
consolidation 
cycle – day 4,5 
 
Each 
consolidation 
cycle – day 1 
 
Pre-infusion, 
end of infusion, hours 
3, 6 and 24 from end 
of infusion  
2mL for day 4 
and 24 level 
 
1 mL for all 
other levels 
Maintenance PK Studies 
Cyclophosphamide 
trough to assess 
compliance 
All patients  
(any site) 
Cycle A1  and A3 –  
during week 2 or 3 
Trough level; obtain 
during routine lab 
draw 
1 mL 
Cyclophosphamide PO  
Enrolled in optional 
PK study  
(St. Jude only) 
Cycle A1 – 
   day 1 
Pre-dose, 0.5, 1.75, 3 
and 6 hours post-dose 
1 mL 
Topotecan PO 
 
Enrolled in optional 
PK study  
(St. Jude only) 
Cycle A1 –  
   day 1 
Pre-dose,  
0.25, 1.5 and 6 hours 
post-dose 
2 mL 
Erlotinib trough to 
assess compliance 
All patients  
receiving erlotinib 
(any site) 
Cycle B1 and B3 – 
during week 2 or 3 
Trough level; obtain 
during routine lab 
draw 
2 mL 
Erlotinib PO 
 
Enrolled in optional 
PK study  
(St. Jude only) 
Cycle B2 –  
   day 1 
Pre-dose, 
1, 2, 4, 8,  
and 24 (±2) hours 
post-dose 
2 mL 
Alpha-1-Acid 
Glycoprotein (AAGP) 
Studies 
Enrolled in optional 
PK study  
(St. Jude only) 
Cycle B2 – day 1 
One sample only 
(record time on PK 
data collection form) 
3 mL 

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8.2.1 Shipping information all PK studies: 
 
All PK samples obtained at sites other than St. Jude should be shipped to the 
principal investigator at this address: 
 
 
 
 
 
 
 
 
 
8.2.2 Methotrexate studies 
 
All Collaborating Sites:  Pharmacokinetic studies will be conducted in all patients 
enrolled on this protocol. Pharmacokinetic samples will be drawn prior to the start 
of the infusion and at 6, 23 and 42 hours after the start of each methotrexate 
infusion.  Additional levels may be drawn in the event of delayed clearance or 
unexpected toxicity.  
 
Methotrexate plasma sampling strategy 
 
The plasma sampling strategy has been designed to take advantage of the routine 
clinical monitoring of methotrexate therapy, but also to utilize optimal sampling 
time points.  The total blood volume collected for the pharmacokinetic studies for 
methotrexate (1-2 ml per sample) is no more than 6 ml per cycle.   
 
Serial blood samples for pharmacokinetic studies will be collected prior to the start 
of the infusion and 6, 23 and 42 hours after the start of the methotrexate infusion. 
 
Sample collection and processing instructions 
 
Draw 1-2 ml of venous blood for pharmacokinetic studies. Record the exact time of 
sample collection and methotrexate administration on the Pharmacokinetic Data 
Collection Form. Centrifuge the sample at room temperature (7000X G for 10 min) 
within 30 to 60 minutes of blood draw. Transfer the plasma sample to individually 
labeled tubes and store at -20°C. 
 
CSF pharmacokinetic studies 
 
Rarely, patients will require placement of an externalized ventricular drain or 
Ommaya reservoir during treatment.  In these cases, parents will be asked to 
consent to an optional CSF pharmacokinetic study.  For patients enrolled in this 
component of the trial, CSF samples will be collected prior to the start of the 

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infusion and at 6, 23, and 42 hours from the start of the methotrexate infusion 
during the relevant cycle. 
 
Description of methotrexate assay 
 
Plasma and CSF samples will be assayed for methotrexate using fluorescence 
polarization immunoassay (FPIA) technology in the Clinical PK Lab, Department 
of Pharmaceutical Sciences, St. Jude Children's Research Hospital.  This assay will 
be run on the TDx-FLx clinical instrument using the Abbott Laboratories drug 
monitoring system specifically for methotrexate in patient serum or plasma. 
 
Description of pharmacokinetic data analysis 
 
Methotrexate plasma concentration-time data will be fit to a compartmental 
pharmacokinetic model using maximum likelihood estimation as implemented in 
ADAPT II (ADAPT II User’s Guide, 1997). Individual pharmacokinetic parameters 
estimated will include apparent volume of the central compartment (Vc/F), 
elimination rate constant (Ke), and half-life (t1/2). The methotrexate clearance will 
be calculated using the log-linear trapezoidal method.   
 
In addition to estimating individual pharmacokinetic parameters, we will also 
estimate the population parameters using nonlinear mixed effects modeling methods 
(NONMEM). This method estimates the population parameters and both the inter- 
and intra-subject variability. Once the population parameters and corresponding 
covariance matrix are estimated, individual estimates can be obtained using post 
hoc analysis. Thereafter the influence of patient specific covariates such as age, 
body-surface area, and sex on methotrexate pharmacokinetic parameters will be 
tested to obtain an optimal dosing schedule for children with cancer. 
 
8.2.3 Cyclophosphamide studies 
 
8.2.3.1 Sample collection 
 
Intravenous cyclophosphamide PK Studies (St. Jude only): 
 
Cyclophosphamide pharmacokinetic studies will be conducted after intravenous 
administration in all consenting patients.  
 
Induction:  For all cyclophosphamide pharmacokinetic studies after a single 
intravenous dose, a 1 mL blood sample will be drawn immediately prior to 
beginning the cyclophosphamide infusion, at the end of the 1 hour infusion, and at 
3, 6, and 24 hours after the end of cyclophosphamide infusion. 
   
Consolidation: For cyclophosphamide pharmacokinetic studies after 
cyclophosphamide administration on day 1 for low risk patients and days 4 and 5 
for high risk patients, a 1 mL blood sample will be drawn immediately prior to 

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beginning the cyclophosphamide infusion, at the end of the 1 hour infusion, and at 3 
and 6 hours after the end of cyclophosphamide infusion.  At 24-hours after the end 
of the cyclophosphamide infusion, a 2 mL blood sample will be obtained.  
 
Oral cyclophosphamide PK studies during maintenance:  
 
All patients:  A trough cyclophosphamide level will be drawn at the time of routine 
laboratory studies during week 2 or 3 of cycle A1 and week 2 or 3 of cycle A3.   
 
 St. Jude patients only:    Cyclophosphamide pharmacokinetic studies will be 
conducted after oral drug administration in consenting patients. For 
cyclophosphamide pharmacokinetic studies after oral administration, a 1 ml blood 
sample will be drawn immediately prior to cyclophosphamide administration and at 
0.5, 1.75, 3, and 6 hours after cyclophosphamide administration on day 1 of the 
cycle A1.  On the day of PK testing, cyclophosphamide must be administered prior 
to topotecan administration.  As administering oral medications to very young 
children can be challenging, flexibility in the timing of drug administration and PK 
sampling is necessary; every effort should be made to obtain samples within 15 
minutes before or after the schedule time point.  The PK nurse administering the 
drug should estimate the proportion of the drug swallowed.  If < 75% of the dose 
was swallowed, PK testing should be rescheduled for another day during week 1 of 
cycle A1.     
 
LC MS/MS assay methodology: 
 
Cyclophosphamide and its metabolites will be analyzed using a liquid 
chromotography mass spectroscopy method developed by Kalhorn and 
colleagues.313   
 
PK Studies for cyclophosphamide and metabolites (St. Jude patients enrolled in 
optional PK studies only):   
 
Blood samples will be removed from a non-CY infusion port of a central venous 
access catheter and aliquots of each sample will be placed into tubes containing 
either phenylhydrazine for analysis of 4-HCY or EDTA (ethylenediaminetetraacetic 
acid) for other analytes.  The blood - phenyhydrazine mixture will be mixed, 
refrigerated or kept on wet ice for up to 16-hours; then centrifuged. Plasma will be 
immediately removed, frozen, and stored at -80°C until analysis.  
 
Trough cyclophosphamide level to assess compliance (all patients at all sites): 
 
Draw 1 mL whole blood and place into a green top (sodium heparin) tube.  Record 
the exact date and time the sample was obtained.  Take blood from green top tube 
and place in a microcentrifuge tube using a transfer pipette.  Centrifuge for 2 
minutes at 10,000 RPM, then transfer plasma from the microcentrifuge tube into 1 

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screw top tube using a transfer pipette. Put on dry ice. If shipping sample store at -
80C until sample can be shipped.  Ship samples on dry ice.  
 
8.2.4 Topotecan studies  
 
Pharmacokinetic studies for intravenous topotecan therapy 
 
Blood samples for topotecan pharmacokinetic testing will be obtained with dose 1 
in all patients receiving consolidation therapy with topotecan/cyclophosphamide.  
Day 1 plasma topotecan concentrations will be used to adjust dosage, if needed, to 
attain a target topotecan lactone AUC of 140 ± 20 ng•hr/mL.  For St. Jude patients, 
topotecan PK analysis will ordinarily be performed immediately, so that the day 2 
topotecan dose may be adjusted as necessary.  For patients at other sites, topotecan 
PK samples will be shipped to St. Jude by overnight delivery for processing and 
analysis.  All day 1 samples should be shipped together immediately after the 3-
hour post infusion level is obtained.  Analysis will be performed in the Stewart 
laboratory, and results communicated to the treating physician as soon as possible, 
but no later than the start of the day 4 topotecan dose.  Modification of the plasma-
sampling plan may be required periodically to optimize topotecan pharmacokinetic 
parameter estimation. After the first course of therapy, the first dose of the 
subsequent topotecan course will be based on the dosage required in the preceding 
course to attain the target topotecan AUC.  If plasma samples are unable to be 
obtained on the scheduled day for technical reasons, then the patient will be 
restudied on the next possible day. 
 
A limited sampling model will be used, with blood samples obtained prior to the 
infusion, and at 5 minutes, 1, and 3 hours after the end of the topotecan infusion.  
When possible, samples should be obtained from a different lumen than that used 
for drug administration.   
 
St. Jude patients:  At least 45 minutes before drawing blood sample or starting 
chemotherapy page the PK technician on call (pager 2252) in the Stewart 
Laboratory to have personnel available to process samples.  Blood samples of 2 mL 
each will be collected in green-top, sodium heparin tubes.  The exact date and time 
the sample was collected must be recorded.  Immediately after the sample is 
collected, pipette 1 mL whole blood from the green top tube into a screw top tube (2 
tubes per time point), place the tubes on dry ice, and transport to the Stewart 
laboratory. 
 
Patients at all other North American sites:  Blood samples of 2 mL each will be 
collected in green-top, sodium heparin tubes.  The exact date and time the sample 
was collected must be recorded.  Immediately after the sample is collected, pipette 
1mL whole blood from the green top tube into a screw top tube (2 tubes per time 
point) and place the tubes on dry ice. Store at -80C until the sample can be shipped.  
Ship on dry ice.  
 
 

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Pharmacokinetic studies for oral topotecan phase 
 
St. Jude patients only.  In all consenting patients, oral topotecan pharmacokinetic 
studies will be conducted on day 1 of the first course of oral topotecan.  On the day 
of PK testing, cyclophosphamide must be administered prior to topotecan 
administration.  Serial blood samples (2 mL each) for topotecan will be drawn prior 
to the dose and at 0.25, 1.5, and 6 hours after topotecan administration on day 1 of 
cycle A1.  Modification of the plasma-sampling plan may be required periodically 
to optimize topotecan pharmacokinetic parameter estimation.  As administering oral 
medications to very young children can be challenging, flexibility in the timing of 
drug administration and PK sampling is necessary; every effort should be made to 
obtain samples within 15 minutes before or after the schedule time point.  The PK 
nurse administering the drug should estimate the proportion of the drug swallowed.  
If < 75% of the dose was swallowed, PK testing should be rescheduled for another 
day during week 1 of cycle A1. 
 
At least 45 minutes before drawing blood sample or starting chemotherapy page the 
PK technician on call (pager 2252) in the Stewart Laboratory to have personnel 
available to process samples.  Blood samples of 2 mL each will be collected in 
green-top, sodium heparin tubes.  The exact date and time the sample was collected 
must be recorded.  Immediately after the sample is collected, pipette 1 mL whole 
blood from the green top tube into a screw top tube (2 tubes per time point), place 
the tubes on dry ice, and transport to the Stewart laboratory. 
 
HPLC fluorescence Assay for Topotecan Lactone 
 
Plasma samples will be assayed for topotecan lactone by an isocratic high 
performance liquid chromatography assay with fluorescence detection as 
implemented in the Stewart Laboratory. 
 
8.2.5 Erlotinib studies 
 
All patients:  A trough erlotinib level will be drawn at the time of routine laboratory 
studies during week 2 or 3 of cycle B1 and week 2 or 3 of cycle B3. 
 
St. Jude patients only:  Pharmacokinetic studies will be conducted in all consenting 
patients enrolled on this protocol. Pharmacokinetic samples will be drawn on day 1 
of the cycle B2. If unable to collect samples on day 1, then pharmacokinetic 
sampling can be collected on one of the next 2 consecutive weekdays. 
 
Plasma sampling strategy 
 
The plasma sampling strategy has been designed to produce pediatric erlotinib data 
that will give estimates for the single dose and steady-state pharmacokinetic 
parameters of erlotinib.   
 

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Serial blood samples for pharmacokinetic studies will be collected before and 1, 2, 
4, 8 and 24 (±2) hours after the first dose of erlotinib in the second erlotinib cycle.  
As administering oral medications to very young children can be challenging, 
flexibility in the timing of drug administration and PK sampling is necessary; every 
effort should be made to obtain samples within 15 minutes before or after the 
schedule time point.  The PK nurse administering the drug should estimate the 
proportion of the drug swallowed.  If < 75% of the dose was swallowed, PK testing 
should be rescheduled for another day during week 1 of cycle B2. 
 
Sample collection and processing instructions 
 
Draw 2 ml of venous blood and place in purple top tubes for pharmacokinetic 
studies. Record the exact time of sample collection and erlotinib administration on 
the Pharmacokinetic Data Collection Form. Centrifuge the sample at room 
temperature (7000X G for 10 min) within 30 to 60 minutes of blood drawn. 
Transfer the plasma sample to individually labeled tubes and store at -20°C.  
Samples from sites other than St. Jude should be shipped on ice to the principal 
investigator at the address in section 8.2.1. 
 
Description of erlotinib assay 
 
Plasma and tumor samples will be analyzed for the determination of erlotinib and 
its metabolites OSI-420/413 by an isocratic high-performance liquid 
chromatography assay with tandem mass spectrometry implemented and validated 
in the Stewart Laboratory.  
 
Description of pharmacokinetic data analysis 
 
Erlotinib plasma concentration-time data will be fit to a compartmental 
pharmacokinetic model using maximum likelihood estimation as implemented in 
ADAPT II (ADAPT II User’s Guide, 1997). Individual pharmacokinetic parameters 
estimated will include apparent volume of the central compartment (Vc/F), 
elimination rate constant (Ke), and half-life (t1/2). The apparent oral erlotinib 
clearance will be calculated as erlotinib dosage/AUC, and AUC0-∞ will be 
calculated using the log-linear trapezoidal method.   
 
In addition to estimating individual pharmacokinetic parameters, we will also 
estimate the population parameters using nonlinear mixed effects modeling methods 
(NONMEM). This method estimates the population parameters and both the inter- 
and intra-subject variability. Once the population parameters and corresponding 
covariance matrix are estimated, individual estimates can be obtained using post 
hoc analysis. Thereafter the influence of patient specific covariates such as age, 
body-surface area, and sex on erlotinib pharmacokinetic parameters will be tested to 
obtain an optimal dosing schedule for children with cancer. 
 
 

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Alpha-1-Acid Glycoprotein (AAGP) studies 
 
AAGP levels  
 
Since erlotinib is bound by AAGP and this may influence toxicity, AAGP will also 
be measured at the time of pharmacokinetic analysis on day 1 of the second 
erlotinib cycle.  
 
AAGP samples 
  
Collection of AAGP Specimens (It is important that plasma be collected): 
The appropriate volume of blood to yield about 1.0 ml of plasma 
(approximately 3 ml of whole blood) will be collected in tubes containing 
heparin. Actual sampling times will be recorded on the Pharmacokinetics Data 
Collection Form. Isolate plasma, freeze, and store samples as indicated above 
for pharmacokinetic samples. Once frozen, care should be taken NOT to allow 
samples to thaw. Sample labels should bear the following information: patient 
ID initials/number, sample time and date. 
 
Description of assay 
 
AAG concentrations in plasma will be determined by a validated 
immunoturbidometric assay (Tina-quant, Roche).  
 
8.2.6 Pharmacogenetic studies – St Jude patients only 
 
All St. Jude patients will be asked to enroll on the institutional protocol PGEN5 for 
the collection of blood to process for DNA.  Genotyping for genetic polymorphisms 
in cytochrome P450s and drug transporters will be assessed using standard 
molecular techniques used in the Department of Pharmaceutical Sciences, St. Jude 
Children’s Research Hospital.  We will correlate patient pharmacogenetic data with 
the pharmacokinetics of methotrexate, cyclophosphamide, topotecan, and their 
metabolites using the methodology described in sections 8.2.1-8.2.4.  Patients at 
collaborating sites will not participate in these studies. 
 
8.3 
CSF NEUROTRANSMITTER STUDIES 
 
 
 
8.3.1 CSF neurotransmitter and neurochemical assessment – St Jude Patients 
Only 
 
To verify our hypothesis that neurocognitive deficits after medulloblastoma therapy 
result from either iatrogenic or inherent (i.e., genetic) disturbances in central 
dopamine transmission, we propose to study CSF neurotransmitter concentrations 
in patients enrolled in SJYC07.  Focus will be upon dopamine and dopamine 
metabolite CSF concentrations since these neurochemicals are germane to our 
hypothesis.  However, concentrations of CSF serotonin and its major metabolite 5-

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HIAA will also be evaluated to estimate the contribution of lumbar puncture-
associated stress on CSF neurotransmitter concentrations.  In a study by Hill et al., 
the immediate post lumbar puncture CSF concentrations of dopamine and serotonin 
metabolites were roughly half the concentrations detected hours later314.  However, 
the ratio of metabolites remained constant, particularly the HVA:5-HIAA ratio.  
Since our proposed analytical technique is capable of evaluating a host of 
neurotransmitters from one CSF sample, we will also monitor other transmitter 
concentrations in a descriptive manner.  Such data will aid in our ability to evaluate 
our hypothesis.   
 
In consenting St. Jude patients, all CSF neurotransmitter/neurochemical samples 
will be collected during routine sampling for other clinical tests (e.g., CSF 
cytology).  No additional CSF tap procedures will be performed for the study.  A 2 
to 3 mL volume of CSF will be drawn for neurotransmitter/neurochemical 
evaluation during routine CSF samplings scheduled at the time of each disease 
evaluation (pre-treatment, week 8, 16, 24, 36, and 48).  Remaining CSF will be 
stored for future analyses.  Patients and mothers of nursing infant patients should 
follow a low tyramine diet for at least three days prior to CSF sampling and avoid 
caffeine for 24 hours prior to sampling.  (See Appendix V for a list of tyramine 
containing foods to be avoided). 
 
CSF processing and shipment information needed. 
 
8.3.2 CSF Handling and Storage 
 
For each consenting St. Jude patient, CSF will be collected for neurotransmitter 
studies at the same time the LP is done for clinical assessment of cytology.  The 
biological study specimens are taken when the patient is scheduled for their regular 
LP's (see section 6.0).   
 
1. Collect 2 - 3 mL of CSF into the 10 mL clear tube labeled “NT-CSF” that 
contains a pre-measured volume of antioxidant cocktail.  These tubes are 
supplied by the Stewart Laboratory at St Jude. 
 
2. After mixing by gentle inversion, immediately aliquot the specimen equally 
between two 1-2 mL amber screw top vials and freeze at -80ºC. If a freezer 
is not immediately available, freeze vials on dry ice. Please note that 
dividing each neurotransmitter CSF sample into 2 separate screw top tubes 
will reduce error in the analysis of neurotransmitter levels.   Samples will be 
transported to the Stewart Laboratory immediately after collection. 
 
8.3.3 Genotyping for dopamine-related gene polymorphisms 
 
 
All patients will be asked to enroll on the institutional protocol PGEN5 for the 
collection of blood to process for DNA, which will be extracted by standard 
techniques.  Genotyping for genetic polymorphisms (e.g. DAT1, DRD4, 

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COMT) will be assessed using standard molecular techniques used in the 
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital. 
 
8.3.4 Evaluation of neurocognitive deficits and assessment of the neurocognitive 
phenotype for correlative analyses 
 
Although numerous neurocognitive outcomes are available from routine evaluations 
of patients enrolled on SJYC07, we have chosen to limit ourselves to those most 
closely associated with deficient dopaminergic functioning in ADHD, the model of 
inattention which most closely mimics symptoms among survivors of 
medulloblastoma.  One recent review 315 described the neurocognitive phenotype as 
characterized by specific deficits in attentional functioning, including slowed 
processing speed, decreased perceptual sensitivity, and decreased “hit rate” on 
continuous performance tasks.  Our primary outcome measures will therefore be the 
Test of Variables of Attention (TOVA),316 WJ-III Auditory Attention, WJ-III 
Auditory Working Memory, 317  the SB-V Block Span318 and the BRIEF.319  Testing 
will be routinely conducted at baseline, 6 and 12 months post-diagnosis, and yearly 
after completion of therapy.  Additional, exploratory analyses will also be 
conducted with other neurocognitive outcomes. 
 
All neurocognitive outcomes used for primary, secondary, and exploratory analyses 
will result in scores that are normalized for age using a standardization sample from 
the general population.  These scores will comprise a continuous distribution at the 
interval level of measurement. 
 
8.3.5 CSF Neurochemical Assay Methodologies 
 
 
The proposed neurochemical assay is based on the method of Vaarman, Kask, and 
Maeorg 320, and utilizes an isocratic reverse-phase HPLC with electrochemical 
detection. This method has been used to quantitate a number of neurotransmitters in 
supernatants of acid precipitated brain homogenates (Table 20).  A modification of 
this method has been developed and validated within the Stewart laboratory at St. 
Jude Children’s Research Hospital.   
 
Table 20  Neurotransmitters and metabolites of interest measured by HPLC-EC 
detection 
 DOPAMINE 
DOPAMINE, HOMOVANILLIC ACID (HVA), 
DIHYDROXYPHENYLACETIC ACID (DOPAC) 
Serotonin 
Serotonin, hydroxyindoleacetic acid (5-HIAA) 
 
In addition to the HPLC with electrochemical detection method that will be used to 
quantitate CSF neurotransmitters, samples will also be analyzed by NMR 
spectroscopy. 

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8.4 
NEUROCOGNITIVE STUDIES  
 
8.4.1 Neuropsychological Studies 
 
8.4.1.1 Overview of neuropsychological studies 
 
Children will be assessed at baseline, six months and yearly following treatment 
until 5 years from the end of therapy. Therefore, the assessment battery needs to 
span the years from infancy to 8 years of age.  An effort was made to select 
measures that could assess the widest age range possible. Nonetheless, as no single 
measure exists that covers this entire age spectrum, separate test batteries are 
needed for children less than three years of age and another for children 3 years of 
age and older. Children less than three years of age will be administered a single 
comprehensive battery, the Bayley Scales of Infant and Toddler Development, 
Third Edition (Bayley-III). All children 3 and older will be administered a separate 
battery, listed in Table 21. These batteries are comparable in the domains assessed 
such that some longitudinal analyses will be possible across batteries. 
 
Another primary goal was to select a battery that could be administered in a 
circumscribed period of time to reduce the time burden for children, their parents 
and the research team. The administration time for the test battery is 1-3 hours, 
dependent on the age of the child and the speed with which they can complete tasks. 
It is anticipated that the average administration time will be 1.5 hours. The 
maximum administration time of 3 hours is only expected for older children (i.e., 7-
8 years of age) or children that are notably slow (e.g., unusually slow speed of 
cognitive and/or physical processing). Therefore, the administration length of the 
current battery readily lies within the standard length of typical clinical and research 
batteries. It is anticipated that parents will spend on average .5 hours completing 
questionnaires while their child is being assessed in a separate room.   
 
8.4.1.2  Neuropsychological assessment schedule 
 
Baseline neuropsychological assessments should be conducted at the time of 
enrollment (+ up to 60 days as needed). Time 2 evaluations should be six months 
from the time of enrollment (+/- 60 days). The time 2 evaluation does not need to be 
prior to the start of maintenance therapy; however, this may be the most feasible 
time point logistically based on other assessments and travel to the medical center 
providing care. There should be approximately six months (+/- 60 days) between 
baseline and time 2 evaluations. Yearly assessments should be scheduled from the 
time of enrollment (+/- 60 days). It is likely that medical management and health 
status of the patient will in part guide the timing of assessments as it is important 
that children be well enough to participate in an evaluation to ascertain valid 
neuropsychological data. 

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Table 21 Neurocognitive Measures for children > 3 years of age  
 
COGNITIVE 
DOMAIN 
MEASURE 
BROAD SKILL 
TEST CHARACTERISTICS 
AGE 
RANGE 
TIME 
IQ Estimate  
SB-V Routing 
subtests  
Global Cognitive 
Function  
Object Series/Matrices and 
Descriptive Vocabulary Subtests  
2+ 
15 min. 
 
 
 
 
 
 
Language  
Comprehension 
of Instructions, 
NEPSY  
Receptive Language  
Follow verbally presented directions 
of increasing length (with visual 
stimuli present) 
3-12 
5-10 min. 
 
 
 
 
 
 
Memory  
Narrative 
Memory, 
NEPSY 
Verbal Memory  
Children are read a short story and 
asked to recall as much of the story 
as possible (free and cued recall 
conditions) 
3-12 
10 min.  
 
 
 
 
 
 
 
Sentence 
Repetition, 
NEPSY 
Verbal Memory  
Verbatim repetition of sentences 
read by the examiner  
3-12 
5 min. 
 
 
 
 
 
 
 
SB-IV Bead 
Memory  
Visual Memory  
Children are shown a series of bead 
formations and then asked to recall 
the beads in the same formation 
2-24 
10 min.  
 
 
 
 
 
 
Attention & 
Executive 
Function  
SB-V Block 
Span subtest  
Nonverbal Attention 
Span  
The examiner taps a series of blocks 
and children then recall the same 
sequence of blocks 
2+ 
10 min.  
 
 
 
 
 
 
 
TOVA  
Sustained Attention  
Computerized task of attention. 
Records number of omission and 
commission errors, as well as 
reaction time (RT) and variability of 
RT 
4-80 
20 min.  
 
Auditory 
Attention, WJIII 
Selective Auditory  
Attention  
Children selectively listen for certain 
words on an audio recording that 
contains distracting background 
noise   
2+ 
10 min.  
 
 
 
 
 
 
 
Auditory 
Working 
Memory, WJIII 
Auditory Working 
Memory  
Repeat words and numbers after 
organizing based on a pre-
established rule 
3.6+  
5 min. 
 
 
 
 
 
 
 
Retrieval 
Fluency, WJIII 
Verbal Fluency  
Name foods, people and names & 
animals, each in 1 min. trial 
3+  
5 min.  
 
 
 
 
 
 

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Table 21 Neurocognitive Measures for children > 3 years of age (continued) 
 
COGNITIVE 
DOMAIN 
MEASURE 
BROAD SKILL 
TEST CHARACTERISTICS 
AGE 
RANGE 
TIME 
Achievement 
Bracken, School 
Readiness 
Composite 
(SRC)  
Pre-academic skills  
Tests knowledge of colors, 
letter/sounds, numbers/counting, as 
well as sizes and shapes.  
3-6:11 
15 min. 
 
 
 
 
 
 
 
Letter-Word 
Identification, 
WJIII 
Basic Reading  
Identify letters & single word 
reading  
2+  
5 min. 
 
 
 
 
 
 
 
Word Attack, 
WJIII 
Phonological 
Processing Skills 
Children read a series of nonwords  
3.8+ 
5 min. 
 
 
 
 
 
 
 
Applied 
Problems, WJIII 
Quantitative 
Reasoning and Math 
Calculation  
Children are presented a series of 
math problems to solve, which are 
orally presented and include visual 
diagrams  
2+ 
10 min. 
 
 
 
 
 
 
Visual Spatial 
& Visual 
Motor 
Beery VMI 
Visual Perception & 
Visual-Motor 
Integration  
Green – Match shapes of decreasing 
size  
Blue – Draw shapes of increasing 
complexity  
2-19 
10 min. 
 
 
 
 
 
 
 
Purdue Pegboard  
Fine Motor Speed & 
Dexterity 
Place pegs using dominant, non-
dominant & both hands, timed 
2.6+  
5 min.  
 
 
 
 
 
 
Processing 
Speed 
Visual Matching, 
WJIII 
Processing Speed 
Find matching pairs; timed  
2.6+  
3 min.  
 
 
 
 
 
 
 
Decision Speed, 
WJIII 
Processing Speed  
Find conceptually similar pairs; 
timed  
2.6+  
3 min.  
 
 
 
 
 
 
Parent Scales 
 
 
 
 
 
Executive 
Function  
BRIEF  
Executive Function  
Parent rating scales assessing the 
behavioral manifestation of 
executive functions 
2-
5:11/5-
18 
10 min.  
 
 
 
 
 
 
Social-
Emotional  
 
BASC-II 
Psychosocial 
Adjustment & 
Adaptive Function  
Questionnaire assessing 
internalizing, externalizing & 
attention problems  
2-22 
15 min. 

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8.4.1.3 Laboratory measures  
 
Intelligence/global measures of functioning  
 
Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III).281 
The Bayley-III will be used to assess children 0-3:0 years of age. This test assesses 
a wide range of function, including cognition, language, motor control, social-
emotional and adaptive behavior development. Cognition, language and motor 
function are assessed through tasks administered by an examiner, in which the child 
is presented with a variety of stimuli, asked to participate in various activities and 
asked to follow various commands. Social-emotional and adaptive behavior are 
measured with a parent questionnaire. This test is a well standardized instrument 
(normative sample size of 1,700 stratified by age), which is commonly used to 
assess development and cognitive function in infants. Reliability is adequate, as 
evidenced by the internal consistency of the Cognitive (.91), Expressive 
Communication (.91), Receptive Communication (.87), Gross Motor (.91) and Fine 
Motor (.86) scales. The validity of this measure can be found through its 
correlations with other well validated measures of infant development (e.g., the 
Bayley-II, the Preschool Language Scale-4, Peabody Developmental Motor Scale-2, 
and Adaptive Behavioral Assessment System-II).281 Additionally, scores on this 
measure have been shown to reliably differentiate among groups of children with 
clinical and medical conditions including Down Syndrome, Cerebral Palsy, 
prematurity and pervasive developmental disorders.281 Total administration time 
ranges from 30 to 90 minutes depending on age, and normative data exists for 
children ages 0-3.   
 
Stanford-Binet Intelligence Scales – Fifth Edition (SB:V, Abbreviated IQ).318 An 
abbreviated form of this test, consisting of two subtests, will be used to assess 
intellectual function in all children greater than 3 years of age. Normative data 
exists for individuals spanning 2-85 years of age (standardization sample size is 
4,800). Abbreviated IQ (AIQ) scores are derived from the Vocabulary and Object 
Series/Matrices subtests. The AIQ correlates highly with Full Scale IQ (.87 for 
individuals > 6 years of age and .81 for ages 2-5). This is a well standardized 
measure, with adequate internal consistency (.85-.96) and test-retest reliability (.84) 
for Abbreviated IQ. The SB:V abbreviated IQ score also correlates highly with 
other well validated measures of intelligence like the Wechsler Preschool and 
Primary Scale of Intelligence – Revised321 (WPPSI-R; .83) and the Wechsler 
Intelligence Scale for Children-Third Edition322 (WISC-III; .84). Total 
administration time for the AIQ is 15-20 minutes.   
 
Language measures 
 
NEPSY, A Developmental Neuropsychological Assessment (Comprehension of 
Instructions).323  Receptive language is assessed by determining the child’s ability 
to accurately follow a series of verbal instructions (commands) of increasing 

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complexity. This measure is well standardized with a normative sample of 1,000 
children stratified by age and gender. This subtest has adequate internal reliability 
(.88 for ages 3-4 and .73 for ages 5-12). Furthermore, this task correlates highly 
with other indices of verbal reasoning such as the Verbal IQ (.62) and Verbal 
Comprehension Index (.58) of the WISC-III. This subtest takes approximately 5-10 
minutes to administer and is normed for children 3-12 years of age. 
 
Memory measures 
 
NEPSY, A Developmental Neuropsychological Assessment (Narrative Memory).323 
For this task, the examiner reads as story and then asks the child to recall as much 
of the story as possible. This subtest assesses verbal memory (ability to retell the 
story) both under free and cued recall conditions (i.e., with true/false or multiple 
choice questions). This subtest has adequate internal consistency (.77-.85) and test-
retest reliability (.81). This subtest also correlates with the verbal memory indices 
of the Children’s Memory Scale324 (.43-.47). Administration time is approximately 
10 minutes and can be given to children 3-12 years of age. 
 
NEPSY, A Developmental Neuropsychological Assessment (Sentence 
Repetition).323 For this task, the examiner reads a series of sentences that become 
increasingly lengthy and complex. The child is required to repeat each sentence 
verbatim. The reliability of this subtest is adequate for internal consistency (.81-.91) 
and test-retest reliability (.89). This task also correlates with indices of other well 
validated memory measures such as the Children’s Memory Scale324 (.53-.59). 
Administration time is approximately 5-10 minutes and norms are available for 
children 3-12 years of age.  
 
Stanford-Binet Intelligence Scales – Fourth Edition (SB:IV) Bead Memory 
subtest.325  
This is a task of nonverbal memory. Children are shown a series of beads 
formations and afterwards are asked to recall the beads in the same formation as 
previously shown. This test has adequate test-retest reliability (.87) and internal 
consistency (.93-.97). Administration time is approximately 10 minutes and 
normative data exists for ages 2-24.   
 
Attention and executive function measures 
 
Stanford-Binet Intelligence Scales – Fifth Edition (SB:V) Block Span subtest.318  
This is a test of nonverbal attention span (i.e., spatial span). The examiner taps a 
number of blocks and children must recall the same sequence of blocks originally 
touched by the examiner. As the test progresses, the number of blocks the child has 
to recall increases. The subtest has high reliability (.90) and also correlates with 
nonverbal intelligence composites, such as performance IQ, of the WPPSI-R and 
WISC-III (.66-.72). Administration time is approximately 10 minutes and norms 
exist for ages 2 and older.  
 

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Test of Variables of Attention (TOVA):316 The TOVA is a computerized continuous 
performance test (CPT) of attention. This task presents one of either two stimuli, a 
target stimulus which requires a button to be pressed when shown, and a non-target 
stimulus requiring the button not be pressed when shown. Over a period of 
approximately twenty minutes, these stimuli are flashed (one at a time) on the 
computer monitor in succession at varying rates of speed. The number of omission 
and commission errors, as well as reaction time and variability of reaction time are 
recorded. Performance across these variables during the first, second, third and 
fourth time quartiles are also collected. Omission errors (failure to press the button 
when target stimuli appear) are indicative of not paying attention (inattention). In 
contrast, commission errors (pressing the button for non-target stimuli) are 
indicative of an impulsive response style. This task is similar to the Conner’s CPT 
but uses geometric shapes so as to exclude the use of lexical stimuli, it also includes 
a more reliable response method and assesses a larger age range (4-80). Research 
with children has found test-retest reliability coefficients to be adequate for 
omissions (.70), commissions (.78), reaction time (.84) and variability of reaction 
time (.87). The TOVA also has high correlations with other well validated 
computerized continuous performance tests such as the Conner’s CPT (.85).316 
 
The Woodcock Johnson Tests of Cognitive Abilities-Third Edition (WJIII; 
Auditory Attention):326 For this test, children point to a picture (among 4 choices) 
indicated by a word they hear on tape, while background noise increases over time 
making it more difficult to selectively attend to the stimulus word. This is a task of 
selective attention and speech discrimination.  Reliability for this measure is 
adequate (i.e., internal consistency ranges from .83 -.95) and it has been shown to 
correlate with other validated measures of auditory attention. This subtest takes 
approximately 10 minutes to administer and norms are available for ages 2 years 
and older.  
 
The Woodcock Johnson Tests of Cognitive Abilities-Third Edition (WJIII; 
Auditory Working Memory):326 This task presents a series of mixed word and 
number items to children that progressively increase in length. Children are 
required to repeat back the words and number using rules, in which they are 
required to recall items/things first followed by numbers. As such, this task assesses 
auditory working memory as well as auditory attention span. Reliability is adequate 
with internal consistency ranging from .80-.96. This measure also correlates with 
teacher ratings on the School Problems scale (-.37) from the Behavior Assessment 
System for Children (BASC),327 thus providing support linking the role of working 
memory to academic achievement. Norms are available for ages 3.6+ years of age 
and administration time is approximately 10 minutes.   
 
The Woodcock Johnson Tests of Cognitive Abilities-Third Edition (WJIII; 
Retrieval Fluency):326  The Retrieval Fluency task requires that the child name as 
many items as they can that belong to three semantic categories (foods/drinks, 
names, and animals) within one minute per category. This task assesses speed of 
verbal fluency and verbal retrieval. This task has been shown to be reliable both in 

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terms of its internal consistency (.70-.93) and test-retest reliability (.81-.85). Cluster 
scores on the WJIII, which contain this subtest, also correlate with composite scores 
from the Stanford Binet Intelligence Scale – Fourth Edition (SB-IV; .46-.69) 
Administration time is approximately 5 minutes and norms exist for ages 3 and 
older.    
 
Academic achievement measures  
 
The Bracken Basic Concepts Scale – Third Edition: Receptive (BBCS-3:R), School 
Readiness Composite (SRC):328  This composite assesses children’s knowledge of 
fundamental pre-academic skills, which include colors, letters, numbers and 
counting, sizes and comparisons, and shapes. Reliability data has found the SRC to 
have a high internal consistency (.95) as well as test-retest reliability (.84). This 
measure has been shown to differentiate between groups with lower or poor 
academic skills (e.g., mental retardation) from typically developing children. 
Administration time is approximately 10-15 minutes and norms exist for children 
ages 3-6:11 years old, although concept age equivalent values can be obtained for 
the entire study age spectrum of 3 and older. The Bracken will be administered first, 
and only if children demonstrate proficiency with pre-academic skills on this task 
will they be administered the achievement subtests from the Woodcock Johnson-III 
listed below.  
 
The Woodcock Johnson Tests of Academic Achievement-Third Edition (WJIII; 
Letter-Word identification):326  This task assesses single letter identification for 
younger children and word reading for older children, thereby testing basic letter 
recognition and word reading skills. This subtest has a high test-retest reliability 
(.88-.95). Additionally, the reading cluster composite score from the WJII correlates 
highly (.82) with the Reading Composite score of the Wechsler Individual 
Achievement Test (WIAT).329 Administration time is approximately 5 minutes and 
norms are available for ages 2 and older.  
 
The Woodcock Johnson Tests of Academic Achievement-Third Edition (WJIII; 
Word-Attack):326  Word-Attack requires that children read a list of nonwords to 
assess their phonological processing skills. This task has adequate test-retest 
reliability (.83) and the Basic Reading Skills cluster score on the WJIII, which is 
contains this subtest, correlates highly (.82) with the Reading Composite score of 
the WIAT. Administration time is approximately 5 minutes and norms exist for 
ages 3.8 and older.   
 
The Woodcock Johnson Tests of Academic Achievement-Third Edition (WJIII; 
Applied Problems):326  This subtest presents a series of problems, which gradually 
increase in difficulty, that assess basic quantitative reasoning skills and math 
specific achievement skills (i.e., for more difficult problems, the child needs to both 
identify the correct math calculation involved and correctly execute the operation). 
This subtest has a robust test-retest reliability (.86) and correlates with other 
validated math achievement measures, such the Math Composite score of the WIAT 

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(.60). Administration time is approximately 10 minutes and norms exist for ages 2 
and older.   
 
Measures of visual spatial reasoning and visual motor processing  
 
The Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI):330  
The VMI assesses visual-motor skills by requiring children to copy a series of 
increasingly complex shapes and figures as accurately as possible. A supplemental 
test of visual perception will also be administered, which requires children to match 
identical shapes that also become increasingly complex. As such, these two tests 
assess both visual-motor integration skills and visual perception skills alone, which 
allows one to better parse out the relative contribution of these two factors in a 
child’s visual motor integration skills. This test is reliable with demonstrated 
internal consistency for both the VMI (.88) and the supplemental visual perceptual 
test (.85). These tasks have been shown to correlate with other validated measures 
of fine motor skills (e.g., Movement Assessment Battery in Children and Clinical 
Observations of Motor and Postural Skills) and successfully differentiate children 
with motor skills deficits from those without.331 Administration time for these two 
tasks is approximately 10 minutes and norms are available for ages 2-19.  
 
The Purdue Pegboard Test:332-334  This test entails placing small pegs into a 
pegboard as quickly as possible with each hand separately and then using both 
hands together. The Purdue Pegboard is a test of fine motor dexterity and speed that 
allows for comparison between performance with the dominant versus nondominant 
hand. This measure has adequate test-retest reliability (.63-.82) and performance on 
this measure is sensitive in discriminating normal individuals from those with 
known motor impairment (e.g. cerebellar disease) as well as normal individuals 
with MRI white matter hyperintensities.335 Administration time is 5 minutes and 
norms are available for ages 2.6 and older.  
 
Processing speed measures 
 
The Woodcock Johnson Tests of Cognitive Abilities-Third Edition (WJIII; Visual 
Matching):326  The Visual Matching subtest requires that children find as many 
matching pairs as possible on a form in a 3-minute time period. This task assesses 
visual processing speed. Reliability is adequate for both internal consistency (.84-
.96) and test-retest coefficients (.78-86). The processing speed composite of the 
WJ-III correlates significantly with other similar measures such as the Processing 
Speed Index of the WISC-III (.59).  Administration time is 3 minutes and norms 
exist for ages 2.6 and older. 
 
The Woodcock Johnson Tests of Cognitive Abilities-Third Edition (WJIII; Decision 
Speed):326 
 
This task requires that children find as many conceptually similar pairs (e.g., fruits) 
as possible in a 3-minute time period in order to assess semantic processing speed. 

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Reliability is adequate for internal consistency (.78-.92) and test-retest (.78-.92) 
coefficients. Together, the Visual Matching and Decision Speed subtests comprise 
the Processing Speed Index of the WJIII. The Processing Speed Index of the WJ-III 
correlates significantly with other similar measures such as the Processing Speed 
Index of the WISC-III (.59). Administration time is 3 minutes and norms are 
available for ages 2.6 and older.  
 
8.4.1.3 Parent and child report measures 
 
The Behavior Rating Inventory of Executive Function (BRIEF):319 The BRIEF is a 
parent questionnaire designed to assess behavioral manifestations of executive 
functioning. Executive functions include goal-directed behaviors, such as the ability 
to plan, organize, sustain performance and change performance in response to 
feedback. The BRIEF questionnaire consists of 86 items from which eight clinical 
scales (Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, 
Organization of Materials and Monitor), two indices (Metacognition and Behavioral 
Regulation) and one composite score (Global Executive Composite) are derived. 
Scores are age and gender standardized with a mean of 50 and a standard deviation 
of 10. The measure requires 10-15 minutes of the parent’s time. 
 
Behavior Assessment System for Children, Second Edition (BASC-2):336 The 
BASC-2 is a questionnaire assessing behavioral, emotional and adaptive 
functioning. The parent form contains 10 clinical scales and 6 adaptive indices. The 
clinical scales include those of the externalizing problems composite (e.g., 
Hyperactivity, Aggression, Conduct Problems), the internalizing problems 
composite (e.g., Anxiety, Depression, Somatization), and the behavioral symptoms 
indices (Atypicality, Withdrawal, and Attention Problems). Adaptive scales include 
Overall Adaptive Skills, Functional Communication, Activities of Daily Living, 
Leadership, Social Skills and Adaptability. The reliability of the BASC-2 is strong 
with internal consistency averaging above .80 for all the age specific versions of 
this questionnaire (preschool, child, and adolescent), and average test-retest 
reliability is .89. This measure correlates strongly with other well-validated broad 
band child behavioral checklists such as the Child Behavior Checklist (CBCL). This 
measure will be used to assess both psychosocial function and adaptive functioning.   
 
8.5 
DIAGNOSTIC IMAGING STUDIES 
 
 
8.5.1 Quantitative MR measures of white matter volume and integrity 
 
MRI of the brain will occur at six time points: presentation, midpoint (week 8) and 
end of induction phase (week 16), end of consolidation phase (week 24), and 
midpoint (week 36) and end of maintenance phase (week 48). These studies were 
designed to yield longitudinal measures of white matter structure and integrity 
during treatment and to determine their relationship between therapy intensity and 
impact on normal brain development. These clinical MR scans consist of T1 sagittal 
for localization followed by 4 mm thick contiguous transverse T1, T2/PD, and 

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FLAIR images covering the entire cerebrum, cerebellum and brain stem. Contrast is 
then administered with acquisition of T2* perfusion imaging data during contrast 
bolus passage. Subsequently, 3D and coronal T1-weighted images are acquired, 
followed by a diffusion tensor imaging sequence, which acquires all the data 
necessary to fully evaluate the diffusion tensor. The full examination can be 
performed in approximately one hour and will require sedation. Scans will be 
evaluated by neuroradiologists for clinically relevant findings that will be captured 
in a data reporting form. The T1, T2/PD, and FLAIR images will be analyzed with 
a hybrid neural network segmentation algorithm that has been developed and 
validated specifically for quantification white matter changes.337-339  
 
Quantitative volumes (cc) of abnormal and normal appearing white matter, gray 
matter and CSF will be determined from the segmented maps. This method has 
been previously applied to investigate the impact of radiation dose, age at 
irradiation and time since irradiation on normal appearing white matter volumes in 
children surviving medulloblastoma. In addition, the diffusion images will fully 
define the diffusion tensor for each point in the images. The tensor will then be used 
to evaluate the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) 
for each point in the image.340,341 The ADC measures the average diffusion distance 
in a region which reflects the extracellular/intracellular volume ratio and is 
extremely sensitive to acute ischemia. Furthermore, the FA measures the directional 
organization of a region and reflects the myelin integrity. The T2* weighted 
imaging sets will be analyzed with an automated method which determines the 
global arterial input function then uses a truncated single value deconvolution 
combined with a standard form Tikhonov regularization with generalized cross 
validation to yield parametric maps of cerebral blood volume (CBV), flow (CBF) 
and mean transit times (MTT). The volumetric data set, diffusion parameter maps 
and perfusion parameter maps will be analyzed for a stack of transverse sections 
covering the full corpus collusum on the mid-sagittal view. To investigate regional 
changes in white matter structure and integrity, this volume of interest will then be 
divided into anatomical regions corresponding to frontal, temporal, parietal and 
occipital lobes.  Other brain structures of interest such as the caudate, putamen, 
cingulate, thalamus, insula, amygdala and hippocampus may also be segmented and 
assessed in relationship to treatment and neurocognitive performance. 
 
8.5.2 Positron emission tomography for dose verification after Proton Beam 
Therapy (for participants enrolled at St Jude only) 
 
Each consenting patient will receive 54 CGE at 1.8 CGE per fraction PBT for 30 
fractions as per the SJYC07 protocol.  The number of PET activation studies will 
equal the number of proton treatment beams, which is estimated to be 3 for the 
majority of cases.  On the day of the PET evaluation, the patient will be treated with 
a single beam corresponding to the activation beam under study. A separate plan 
will be developed to ensure the prescription dose to the target using a single beam 
on that day and that a critical normal tissue volume will not be compromised by the 
end of range uncertainty in RBE.  The beam on time and duration for each of the 
single field treatment fractions will be recorded.  The duration of the single beam 

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fraction is estimated to be 10 to 15 minutes shorter than the conventional fraction.  
At the end of the single beam fraction, the patient will be transported to the PET-
CT; estimated time required is 10 minutes.  For PET attenuation correction and 
anatomic localization purposes a CT of the cranium will be obtained, estimated time 
required is 5 minutes.  The PET activation study will then be acquired for 30 
minutes, the start time will be recorded.   
  
The treatment plan and PET-CT images will be imported into a Monte Carlo 
program in which the UFPTI proton therapy beam and patient specific apertures 
and collimators have been simulated.  Based on the treatment plan, a Monte Carlo 
simulation of the positron activation locations and intensities will be created.  The 
predicted image and acquired image will be compared and analyzed. 
 
8.6 
ENDOCRINE STUDIES FOR PATIENTS RECEIVING PROTON BEAM RADIATION RT  
 
(participants enrolled at St Jude only) 
 
Prior to radiation therapy, consenting patients will be evaluated for potential 
endocrine dysfunction.  GH provocative testing will be performed using arginine 
and carbidopa-levodopa.  ACTH secretion will be tested using the 1 µg ACTH test.  
Hypothalamic-pituitary axis  function will be assessed with static assessments of 
fasting serum: thyrotropin (TSH), free and total thyroxine (T4), total T3, cortisol 
(obtained by 0800 hours), prolactin, insulin-like growth factor binding protein-3 
(IGFBP-3), IGF-I, IGFBP-1 (as a marker of insulin resistance), and complete blood 
count. Similar evaluations will be repeated at the end of therapy and at 6 and 24 
months after completion of therapy. These screening tests resemble those drawn for 
routine evaluation prior to radiation therapy. Understanding the pan-endocrine 
status is critical to interpretation of the GH data. Exceptions to the endocrine testing 
procedures may be made at the discretion the treating physicians.  Testing 
procedures may be omitted or modified: 1) because the patient is receiving 
replacement therapy; 2) when the provocative agent is unavailable; or 3) when the 
procedure is deemed inappropriate based on patient’s clinical condition, the 
intraday timing of the drug administration, or phlebotomy is constrained by logistic 
problems. 
 
Comparison of GH secretion and hypothalamic radiation dosing data will follow 
procedures and criteria previously outlined and summarized in the statistical 
section.  A statistical model will be used to assess the cumulative effect of the dose 
distribution and mean dose to the hypothalamus on GH secretion.  Accurate 
assessment of the effect of a particular dose requires clinical and treatment 
information including: pre-existing medical conditions and medications; age of the 
patient at the time of diagnosis and irradiation; symptomatic interval and 
progression events prior to irradiation; tumor location and volume; hydrocephalus 
and its management; extent and number of surgical procedures and related 
morbidity; prior chemotherapy and related morbidity; neurological effects of tumor 
including seizures; technical factors of irradiation; neuro-imaging changes; the use 
of corticosteroids; auxology such as height and weight; common toxicity coding; 

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and the type and extent of adverse events. This information is included in the 
medical record of study patients and is often considered vital to routine medical 
care.  Within the constraints of the available sample size, these data will be used in 
the model to estimate the incidence and time to onset of GH deficiency defined at 
various levels including peak serum GH values < 10 ng/mL and < 7 ng/mL after 
provocation. 
 
9.0 
EVALUATION CRITERIA 
 
 
9.1 
RESPONSE CRITERIA 
 
9.1.1 Complete Response:  Disappearance of all radiologically discernable lesions 
and negative CSF cytologic examination. 
 
9.1.2 Partial Response: ≥50% reduction in tumor size as measured by the sum of 
the products of the maximum perpendicular diameters of all measurable 
lesions; or two consecutively negative CSF cytologies (if the initial cytology 
was positive) plus a <50% reduction in tumor size.  No progression in any 
lesion, and no new lesion. 
 
9.1.3 Stable Disease:  <50% reduction in the sum of the products of the maximum 
perpendicular diameters of all measurable lesions and persistently negative 
or positive CSF cytology.  No clinical progression or radiographic 
progression in any lesion, and no new lesion. 
 
9.1.4 Progressive Disease:  >25% increase in the size of any measurable lesion; 
the appearance of a new radiographically demonstrable lesion; or the 
conversion of negative CSF cytology to positive, confirmed by two 
consecutive positive cytologic evaluations following two consecutive 
negative CSF evaluations.   
 
 
Patients with progressive disease will continue on treatment, as described in 
section 10.1, and will continue to be followed until off study criteria are met 
(see section 10.2).  Recommended treatment for patients with progressive 
disease is discussed in Appendix VI.  
 
9.2 
TOXICITY EVALUATION CRITERIA 
 
Toxicity will be monitored and graded according to the Cancer Therapy Evaluation 
Program Common Terminology Criteria for Adverse Events, version 3.0 
(CTCAEv3.0). Adverse events not included in the CTCAEv3.0 should be reported 
and graded under the other adverse event within the appropriate category. A copy of 
the CTCAEv3.0 can be accessed from the CTEP home page: 
http://ctep.info.nih.gov 
 

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All adverse events grades 3, 4, and 5 (with the exception of those listed below) 
which occur during treatment and for 30 days after the end of treatment, and events 
which occur later than 30 days after the end of treatment which are felt to be at least 
possibly related to protocol treatment, are to be recorded on the case report forms.  
The date of resolution of the toxicity recorded on the case report forms should 
reflect the date the toxicity resolved to less than a grade 3.  The following adverse 
events will not be captured on the case report forms or in the study database: 
 
 Grade 3 and 4 hematologic toxicities which occur from the beginning of 
induction chemotherapy through the end of consolidation therapy with the 
exception of grade 3+ hematologic toxicities occurring in intermediate risk 
patients undergoing consolidation (i.e. during radiation therapy). 
 
 Grade 3 elevation in serum ALT (SGPT) or AST (SGOT) which occurs within 7 
days after the start of any high-dose methotrexate infusion. 
 
 Grade 3 and 4 electrolyte abnormalities which occur from the beginning of 
induction chemotherapy to the end of maintenance chemotherapy.  However, if 
the event results in a hospitalization or prolongation of an existing 
hospitalization, the event should be recorded on the case report form. 
Electrolyte abnormalities which occur after recovery from the last course of 
maintenance chemotherapy should be recorded on the case report forms.  
 
 TPN or IV fluids administered to prevent significant weight loss / malnutrition 
from the beginning of induction chemotherapy through the end of consolidation 
therapy.  If the patient experiences significant weight loss / malnutrition and 
receives TPN or IV fluids for this reason, this event should be recorded on the 
case report form and graded appropriately using the CTCAE v3.0.  Events that 
occur after the recovery from the last course of maintenance chemotherapy 
should be recorded on the case report forms. 
 
Ototoxicity will be graded according to the Chang Ototoxicity Grading Criteria 
found in Appendix IV.  All ototoxicities grades 0-4 are to be recorded on the case 
report forms. 
 
With amendment 5.0, the CCG ototoxicity grading scale is being replaced by the 
Chang scale.  A recent review of the Chang scale shows it to be more sensitive and 
specific in identifying clinically significant hearing loss and the need for 
amplification and/or assistive listening devices than the CCG and other older 
criteria.341b  
 Lead Audiologist at St. Jude and her 
staff will reevaluate the previously obtained audiograms so that the protocol 
database will be consistent in using the Chang scale for all ototoxicity data. 

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IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
10.0 
OFF THERAPY AND OFF STUDY CRITERIA 
 
10.1 
OFF THERAPY CRITERIA 
 
Patients can be taken off treatment under the following circumstances (survival, 
treatment, and disease status data will be collected annually until patient meets off 
study criteria—see section 10.2) 
 
• Disease progression in M0 patients at diagnosis are permitted to stay on 
therapy (see section 9.1.4). Please refer to * and **(below) 
• First disease progression in patients who are M+ at diagnosis  
• Second disease progression on any patients on therapy 
• Unacceptable toxicity 
• Physician request 
• Family request 
• Completed protocol treatment 
 
* Patients who are M0 at diagnosis and experience local disease progression during 
induction are permitted to stay on therapy.  These patients should have surgical 
resection of the residual tumor (if feasible) and continue consolidation therapy 
consisting of focal irradiation and consolidation chemotherapy with IV topotecan 
and cyclophosphamide followed by oral maintenance chemotherapy per their 
original tumor histology. 
 
** Patients who are M0 at diagnosis and experience metastatic or local and 
metastatic disease progression are permitted to stay on therapy. These patients 
should contine consolidation therapy on the high risk arm of the protocol followed 
by oral maintenance chemotherapy per original tumor histology. 
 
Please refer to Appendix VI for examples of potential patient scenarios. 
 
For patients who have changes consistent with progressive disease on imaging 
studies following completion of all therapy, it is recommended that in patients who 
do not require immediate surgical intervention, imaging studies be repeated in 4 
weeks’ time to rule out any imaging artifact due to therapy. For patients who have 
conversion of CSF cytology from negative to positive as the only sign of apparent 
progressive disease that the CSF examination repeated in 2-4 weeks prior to calling 
progressive disease.  
 
For patients who are treated at collaborating institutions it is recommended that 
each patient to be taken OFF TREATMENT be discussed with the PI of the study 
and if needed, pertinent studies sent for review to St. Jude. 

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Protocol version dated: 10-22-2018 
 
10.2 
OFF STUDY CRITERIA 
 
Patients can be taken off study under the following circumstances: 
 
• Family request (withdrawal of consent for further follow-up) 
• Death 
 
According to institutional procedures, patients will be deemed off study for the 
CPDMO upon written authorization by the principal investigator (PI). Collaborating 
institutions should submit the Off Study case report form accompanied by a copy of 
the clinic/progress note documenting that the patient was taken off study. 
 
11.0 
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
REPORTING ADVERSE EVENTS AND DEATHS ON TREATMENT 
 
Only “unanticipated problems involving risks to participants or others” referred to 
hereafter as “unanticipated problems” are required to be reported to the St. Jude 
IRB promptly, but in no event later than 10 working days after the investigator first 
learns of the unanticipated problem. Regardless of whether the event is internal or 
external (for example, an IND safety report by the sponsor pursuant to 21 CFR 
312.32), only adverse events that constitute unanticipated problems are reportable 
to the St. Jude IRB.  As further described in the definition of unanticipated problem, 
this includes any event that in the PI’s opinion was: 
 
• Unexpected (in terms of nature, severity, or frequency) given (1) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document, as well as other relevant information available about the 
research; (2) the observed rate of occurrence (compared to a credible 
baseline for comparison); and (3) the characteristics of the subject 
population being studied; and 
• Related or possibly related to participation in the research; and 
• Serious; or if not serious suggests that the research places subjects or 
others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized.  
 
Unrelated, expected deaths do not require reporting to the IRB.  Though death is 
“serious”, the event must meet the other two requirements of “related or possibly 
related” and “unexpected/unanticipated” to be considered reportable. 
 
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of the 
death.  
 

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The following definitions apply with respect to reporting adverse experiences:  
 
Serious Adverse Event: Any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria: 
 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the 
event as it occurred); 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or 
• any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include:  any substantial disruption of the ability to 
conduct normal life functions, allergic bronchospasm requiring intensive 
treatment in the 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), a congenital anomaly/birth 
defect, secondary or concurrent cancer, medication overdose, or is any 
medical event which requires treatment to prevent any of the medical 
outcomes previously listed.   
 
Unexpected Adverse Event:  
 
• Any adverse event for which the specificity or severity is not consistent with 
the protocol-related documents, including the applicable investigator 
brochure, IRB approved consent form, Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) application, or other relevant 
sources of information, such as product labeling and package inserts; or if it 
does appear in such documents, an event in which the specificity, severity or 
duration is not consistent with the risk information included therein; or  
• The observed rate of occurrence is a clinically significant increase in the 
expected rate (based on a credible baseline rate for comparison); or  
• The occurrence is not consistent with the expected natural progression of 
any underlying disease, disorder, or condition of the subject(s) experiencing 
the adverse event and the subject’s predisposing risk factor profile for the 
adverse event.  
 
Internal events: Events experienced by a research participant enrolled at a site under 
the jurisdiction of St. Jude IRB for either multicenter or single-center research 
projects. 
External events: Events experienced by participants enrolled at a site external to the 
jurisdiction of the St. Jude Institutional Review Board (IRB) or in a study for which 
St. Jude is not the coordinating center or the IRB of record. 
 

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Unanticipated Problem Involving Risks to Subjects or Others: An unanticipated 
problem involving risks to subjects or others is an event which was not expected to 
occur and which increases the degree of risk posed to research participants.  Such 
events, in general, meet all of the following criteria:  
 
• unexpected;  
• related or possibly related to participation in the research; and  
• suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized.  An unanticipated problem involving risk 
to subjects or others may exist even when actual harm does not occur to any 
participant.  
 
Consistent with FDA and OHRP guidance on reporting unanticipated problems and 
adverse events to IRBs, the St. Jude IRB does not require the submission of external 
events, for example IND safety reports, nor is a summary of such events/reports 
required; however, if an event giving rise to an IND safety or other external event 
report constitutes an “unanticipated problem involving risks to subjects or others” it 
must be reported in accordance with this policy.  In general, to be reportable 
external events need to have implications for the conduct of the study (for example, 
requiring a significant and usually safety-related change in the protocol and/or 
informed consent form). 
 
Although some adverse events will qualify as unanticipated problems involving risks 
to subjects or others, some will not; and there may be other unanticipated problems 
that go beyond the definitions of serious and/or unexpected adverse events.  
Examples of unanticipated problems involving risks to subjects or others include: 
 
• Improperly staging a participant’s tumor resulting in the participant being 
assigned to an incorrect arm of the research study; 
• The theft of a research computer containing confidential subject information 
(breach of confidentiality); and  
• The contamination of a study drug.  Unanticipated problems generally will 
warrant consideration of substantive changes in the research protocol or 
informed consent process/document or other corrective actions in order to 
protect the safety, welfare, or rights of subjects or others.  
 
For St. Jude:  Serious and unexpected events are to be reported within five (5) 
working days.  Unexpected deaths are to be reported to the St Jude PI within 24 
hours of knowledge of the event. 
 
For Collaborating Sites: Serious and unexpected events related to therapy are to be 
reported to the St. Jude PI (Dr. Amar Gajjar) within five (5) working days via fax or 
email.  Unexpected deaths must be reported to the St. Jude PI via phone call or 
email within 24 hours of knowledge of the event.  A written report must follow.   

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In the event that the PI is unavailable, the study coordinator 
 
should be contacted regarding the event.  
 
 
 
 
 
 
 
 
 
 
 
For the purposes of this protocol, the following events will NOT be considered 
serious or unexpected adverse events: 
 
• Hospitalization for treatment related febrile neutropenia 
• Hospitalization for expected complications of treatment or expected 
toxicities of the commercially available agents used in this study (except for 
grade 4 non-hematologic toxicities). 
• Hospitalization for treatment of expected signs or symptoms of disease 
complications (line infections; shunt placement and revisions) or 
progression of disease 
• Death unequivocally related to disease progression. 
 
11.2 
REPORTING TO IRB 
 
 
In addition to the continuing review reports to the IRB, the Principal Investigator is 
responsible for reporting all serious and unexpected adverse events that impact the 
safety of or risk to study patients.  Unexpected deaths which occur while a patient is 
receiving therapy, and for 30 days after protocol therapy is discontinued, or any 
death more than 30 days after protocol treatment which is felt to be related to 
protocol treatment, are to be reported by Dr. Gajjar to the St. Jude IRB office within 
48 hours of knowledge of the event.  Serious and unexpected events related to 
therapy are to be reported to the St. Jude IRB within 10 working days.  All other 
events will be reported in the continuing review report. 
 
All participating investigators are responsible for submitting annual continuing 
review reports, and serious and unexpected adverse event information to their 
Institutional Review Board (IRB)/Ethics Committee according to local 
requirements.  

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12.0 
DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY 
 
12.1 
DATA COLLECTION AT ST. JUDE AND COLLABORATING SITES 
 
Case report forms (CRFs) will be completed by each participating site and 
submitted to SJCRH according to the data submission table distributed with the 
CRFs (see Appendix VII). CRFs can be either mailed or faxed to: 
 
 
 
 
 
 
 
The SJCRH CRA will review CRFs for accuracy and completeness. Data will then 
be entered into a secure database. 
 
12.2 
STUDY MONITORING 
 
The study team will hold monthly meetings and review case histories or quality 
summaries on participants.  
 
Source document verification of eligibility and informed consent for 100% of St. 
Jude participants will be performed by the Eligibility Coordinators within 10 
working days of completion of enrollment. 
 
The Clinical Research Monitor will perform monitoring of applicable essential 
regulatory documentation.  Also, reviewing for the timeliness of serious adverse 
event reporting (type, grade, attribution, duration, timeliness and appropriateness) 
for selected study participants semi-annually and track accrual continuously.  The 
monitor will verify those data points relating to the primary study objective for a 
certain number of study enrollees as specified in the Moderate Risk monitoring plan 
checklist for this study.  Protocol compliance monitoring will include participant 
status, safety assessments, eligibility, the informed consent process, participant 
protocol status, off-study, and off-therapy criteria.  The Monitor will generate a 
formal report which is shared with the Principal Investigator (PI), study team and 
the Internal Monitoring Committee (IMC). 
 
Monitoring may be conducted more frequently if deemed necessary by the CPDMO 
or the IMC.   
 
Continuing reviews by the IRB and CT-SRC will occur at least annually.  In 
addition, SAE reports in TRACKS (Total Research and Knowledge System) are 
reviewed in a timely manner by the IRB/ OHSP. 

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Protocol version dated: 10-22-2018 
12.3 
MONITORING FEASIBILITY OBJECTIVES 
 
This exploratory trial includes several feasibility objectives.  Feasibility criteria and 
monitoring intervals have been established for each of these objectives as described 
in sections 13.1 and 13.2 and summarized in Table 23.  The principal investigator 
will report the results of each feasibility assessment to the IRB and CPSRMC, along 
with a proposed response to such assessments, if criteria are not being met.  
Responses may include changes in methodology, revision of study objectives, or 
possibly deletion of secondary objectives. 
 
 
Table 23 Feasibility Monitoring Plans 
Objective 
Data to be Reviewed 
Feasibility 
Criteria 
Potential Responses to 
Failure to Meet Criteria 
Initial 
Assessment 
Subsequent Assessments 
1.1.1 and 
1.2.1.3 
Proportion of 
Enrolled Patients 
with Frozen Tissue 
> 40% of 
patients have 
frozen tissue 
Modify tissue acquisition 
procedures 
 
Re-evaluate feasibility 
of primary objective 
After 30 patients 
enrolled (any 
diagnosis) 
Every 30 patients 
1.2.1.3 
Proportion of Enrolled 
Patients with FFPE 
Tissue Available for 
Research Studies 
>60% of 
patients have 
FFPE tissue 
Modify tissue acquisition 
procedures 
 
Re-evaluate feasibility of 
objective 
 
After 30 patients 
enrolled (any 
diagnosis) 
Every 30 patients 
1.2.2.4 
Proportion of induction 
courses with delay >7 
days due to toxicity 
<25% of 
courses 
delayed >7 
days 
Reduce vinblastine dose 
 
Eliminate vinblastine 
After 10 high-risk 
patients have 
completed 
induction 
When every 10 high-risk 
patients complete 
induction 
1.2.2.5 
Proportion of 
topotecan/cyclo courses 
in which subsequent 
chemo is delayed > 7 
days 
< 25%  of 
courses 
delaye > 7 
days 
Reduce 
cyclophosphamide dose 
 
Re-evaluate feasibility of 
objective 
After 10 high-risk 
patients complete 
both consolidation 
courses 
When every 10 high-risk 
patients complete both 
consolidation courses 
1.2.2.6 
Proportion of oral 
chemotherapy doses 
received 
>75% of 
doses 
received 
Modify drug 
administration 
techniques 
 
Re-evaluate feasibility of 
objective 
After 20 patients 
complete 
maintenance 
After every 30 patients 
complete maintenance 
1.2.2.9 
Number of  
medulloblastoma 
patients between 3-5 yrs 
of age who have 
experienced an event 
among the first 21 
patients enrolled and 
followed for 1 year 
 >14 patients 
are event free 
at 1 year 
Stop enrollment of 
patients on this arm of  
the study 
After 21 patients 
are followed for 1 
year post 
enrollment 
After 35 patients  are 
followed for 1 year post 
enrollment 
1.2.3.3 
Proportion of courses in 
which target AUC is 
achieved 
Target 
achieved in > 
60% of 
courses 
Modify targeting 
strategy 
After 10 St. Jude 
high-risk patients 
complete both 
consolidation 
courses 
 
When every 10 St. Jude 
high-risk patients 
complete both 
consolidation courses (on 
amendment 3.0 or later) 
1.2.4.1, 
1.2.4.2 
Ability to formulate 
specific hypotheses for 
subsequent testing 
 
Test specific hypotheses 
in remaining subjects 
 
Eliminate CSF 
neurotransmitter studies 
After 30 patients 
enrolled (any 
diagnosis) and 
followed for 1 
year 
 

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12.4  
MONITORING FOR EXCESSIVE TOXICITY IN THE PPRESENCE OF PROTON BEAM 
RADIATION THERAPY (PBRT) 
 
Due to the concerns regarding the potential for excessive toxicity in patients 
receiving PBRT, amendment 9 of this protocol will implement a monitoring rule to 
alert the study team if excessive toxicities are observed in patients receiving PBRT. 
The following toxicities are of potential concern and will be incorporated into the 
monitoring rule. The participating sites were informed via a memorandum sent on 
June 12, 2014 that these toxicities must be entered into the CRIS database and will 
be monitored by the study team.  
 
 Neurology: CNS necrosis/cystic progression grades 3+ that begin after start of 
radiation. Patients would require HBO and necrosis would be noted in the MRI 
reports. 
 Neurology: CNS cerebrovascular ischemia grades 3+ that begin after start of 
radiation. These would be noted in the MRI reports. Patients would have TIAs, 
CVAs or strokes. 
 Vascular: Vessel injury-artery grades 3+ that begin after start of radiation. This 
would require re-vascular surgical repair. 
 Neurology: Ataxia (incoordination): grades 3+ that begin after start of radiation. 
 Neurology: Encephalopathy: grades 3+ that begin after start of radiation. 
 Neurology: Leukoencephalopathy: grades 3+ that begin after start of radiation. 
 Neurology: Neuropathy (cranial, motor or sensory): grades 3+ that begin after 
start of radiation. 
 Neurology: Seizure: grades 3+ that begin after start of radiation. 
In SJYC07 PBRT is an optional modality for patients enrolled on the intermediate 
risk arm. Patients who choose not to pursue PBRT are treated with photon-based 
RT approaches (conformal, IMRT, etc.). There are no suitable historical data 
available from a young patient cohort on which we can base the toxicity 
comparisons, however the cohort of patients who are being treated with photons on 
this protocol can serve as an informal ‘control group’ to aid our interpretations in 
the context of toxicity comparisons. It should be noted however that since the 
selection of patients for PBRT is not random and is based on 
patient/family/physician preferences, this comparison is not statistically optimal. 
 
As part of the effort to develop monitoring rules for excessive toxicity during or 
after PBRT, we analyzed the adverse event data for the intermediate risk patients 
using the data which were current as of 8/21/2014. At that time there were 117 
patients who were enrolled as intermediate risk and 1 whose risk group was 
changed from high to intermediate. For the purpose of toxicity monitoring, patients 
who were on the intermediate risk arm of SJYC07 at any time and who received 
focal radiation (i.e., not craniospinal radiation) will be included in the monitoring of 
excess toxicity related to proton beam radiation therapy. Furthermore intermediate 
risk patients enrolled prior to amendment 8 who were 3-5 years of age, had 

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anaplasia or MYCN gain or amplification and who received focal RT will also be 
included in these toxicity analyses. Per protocol, these patients will be excluded 
only from biology and therapeutic primary objectives. 
 
Of the 118 intermediate risk patients as defined above, 35 patients were excluded 
because they had no RT data available (23 came off treatment before receiving RT, 
3 were reassigned risk group, and 9 are pending RT) at the time of this analysis. 
The remaining 83 patients were included in this analysis; 45 of these patients 
received proton beam RT and 38 received photon-based RT.  Among the patients 
who are still alive, the median follow-up times (range) for those treated with 
photons vs. protons were 44.7 months (6.9-77.1 months) and 32.0 months (1.0-59.5 
months), respectively. We compared these two groups with respect to age at 
diagnosis, gender, tumor diagnosis and tumor location and noted no statistical 
differences with respect to these four characteristics.  
 
Four of the 45 patients who received proton beam had one of the adverse events of 
interest, compared to 0/38 patients who received photon-based RT. Please see the 
table below for details. Considering adverse events with attributions at least 
possibly related, 3/45 patients who received proton beam RT had one of the AE’s of 
interest (6.7%). 
 
List of intermediate risk patients with adverse events of interest 
Patient 
# 
Adverse Event 
Timeframe 
Grade 
AE relation 
1 
Vessel injury-artery, Carotid 
36 Months Off Therapy 
3 
3=Possible 
1 
CNS cerebrovascular 
ischemia 
36 Months Off Therapy 
3 
3=Possible 
2 
Ataxia (incoordination) 
Maintenance - Cycle 
B2 
3 
2=Remote 
3 
CNS necrosis/cystic 
progression 
3 Months Off Therapy 
3 
4=Probable 
4 
Seizure 
Maintenance – Cycle 
A1 
3 
3=Possible 
 
Safety monitoring for clinically significant necrosis or vasculopathy 
The occurrence of clinically significant necrosis or vasculopathy that is at least 
possibly related to PBRT will constitute a primary endpoint for this safety 
monitoring effort. More specifically, the events listed in the first 3 bullets above 
(grade 3+ CNS necrosis/cystic progression, grade 3+ CNS cerebrovascular 
ischemia, and grade 3+ vessel injury-artery) will be used for the primary safety 
monitoring. 
 
As noted above at the time of the analysis in preparation for this amendment, 38 
SJYC07 intermediate risk patients were treated with conformal photon radiation 
therapy and none of them experienced clinically significant necrosis or 

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vasculopathy. Though follow-up is not the same in all of these patients, using a 
binomial approach and based on the observed data, the exact 90% upper bound 
estimate of the proportion of patients who may experience these toxicities when 
treated with photon-based RT is 5.9%. These data are evolving however and thus 
are subject to change. 
 
Based on discussions with the study team, if adequate evidence accumulates to 
suggest that the percentage of patients who experience clinically significant 
necrosis or vasculopathy at least possibly related to RT exceeds 5%, this would be 
considered unacceptable. A Bayesian monitoring rule with prior density of 
Beta(1,15)  on the toxicity rate will be used as a trigger for careful assessment of the 
toxicity data. This prior has mean p=0.0625 and median p=0.0435, with 
approximately 90% of support for p<0.15. The monitoring criterion is met when the 
posterior probability P(p>0.05│data)>0.85 which indicates 85% certainty that the 
toxicity rate exceeds 5%  given the data and the assumed prior density. Using this 
approach, the following table summarizes the monitoring thresholds: 
  
Number of Intermediate Risk 
patients who complete  PBRT  
Initiate data review if the number of 
patients who experience clinically 
significant necrosis and/or 
vasculopathy associated with PBRT 
satisfies the following: 
40 
≥4 
50 
≥5 
60 
≥6 
70 
≥6 
80 
≥7 
90 
≥7 
100 
≥8 
 
Note that the monitoring thresholds listed above are based on number of patients 
and not number of events and thus a patient with two of these events will be 
counted only once. Based on the table above, the toxicity monitoring rule was not 
triggered at the time of this amendment since there were 2 patients in 45 treated 
with PBRT who experienced one of these events.  
 
Safety monitoring for permanent neurological conditions or deficits excluding 
the effects of necrosis and vasculopathy 
No formal monitoring rule is being proposed for the rest of the toxicities listed 
above since their attribution to PBRT can be less clear. We will however utilize a 
similar approach to monitor for permanent neurological conditions or deficits at 
least possibly associated with PBRT (excluding the effects of necrosis and 
vasculopathy) at the same time an assessment is conducted for necrosis and 
vasculopathy. Patients who have experienced necrosis or vasculopathy will be 
excluded from this cohort to allow a separate assessment, since those patients would 
have already counted towards the toxicity monitoring rule above. We will use the 

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same thresholds as above for these toxicities as well to trigger a more extensive 
review of the data.  
 
This safety monitoring for PBRT related toxicities will be incorporated into our 
monthly monitoring report and thus will be assessed monthly. If any of the 
monitoring thresholds above are crossed, a prompt and extensive review of the 
toxicity data will be undertaken. If a boundary is crossed, we will also compare the 
toxicities in the photon vs. proton intermediate risk cohorts from SJYC07 using 
cumulative incidence functions to better inform the decision making process. At 
that time a decision will also be made regarding whether protocol directed choice of 
allowing participants to receive photon radiation therapy would be temporarily 
suspended during this review.  
  
As of October 29, 2015 the option to receive proton beam therapy was withheld.  
 
The pre-planned stopping rule for toxicity for clinically significant necrosis or 
vasculopathy in the proton beam radiation cohort was met with the occurrence of a 
6th event in 55 evaluable patients (11%) who received proton beam radiation.  
 
Six participants treated with the proton beam therapy have experienced grade 3 
necrosis or grade 3 vasculopathy.  
 
• Three participants experienced grade 3 radiation necrosis within 4 – 6 
months after starting radiation. Two of these participants are alive without 
disease but with sequelae of radiation necrosis. The third participant died of 
progressive disease within 8 months of the onset of necrosis.  
 
• Three participants experienced grade 3 CNS vascular injury requiring re-
vascular surgery within 45-60 months after starting radiation. One 
participant required a second re-vascular surgery and is alive without 
disease with minimal sequelae. One participant was unable to be re-
vascularized and is alive on daily aspirin. The third participant had re-
vascular surgery on 
 and is alive without disease.  
 
 
12.5 
CONFIDENTIALITY 
 
Study numbers will be used in place of an identifier such as the name or medical 
record number. No research participant names will be recorded on the data 
collection forms. The list containing the study number and the medical record 
number will be maintained in a locked file and will be destroyed after all data have 
been analyzed. 
 
13.0 
STATISTICAL CONSIDERATIONS 
 
13.1 
PRIMARY OBJECTIVES 
 

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1.1.1 Biology: To identify patterns of tumor methylation profiling that are 
associated with progression-free survival among young medulloblastoma 
patients treated with risk-adapted therapy. 
Responsible Investigators: Amar Gajjar, Giles. Robinson 
Responsible Biostatistician: Arzu Onar-Thomas, Tong Lin 
 
1.1.2 Therapeutic: To estimate the event free survival distribution of young 
medulloblastoma patients treated with risk-adapted therapy 
Responsible Investigator: Amar Gajjar 
 
Responsible Biostatistician: Arzu Onar-Thomas 
 
All patients with medulloblastoma who were diagnosed prior to their 3rd birthday 
will contribute to both the biology and therapeutic primary objectives of this 
protocol. Furthermore patients who were ≥3 and <5 years old at the time of 
diagnosis will also be included in the cohort for these primary objectives as long as 
they meet the eligibility criteria listed in section 3.1.2 of version 8 of this protocol. 
Patients in the 3-5 year old age cohort who enrolled on previous versions of this 
protocol and who do not meet the criteria in section 3.1.2 listed in version 8 will be 
excluded from these analyses. 
 
The outcomes of interest for the biology and therapeutic primary objectives are 
progression-free survival and event free survival, respectively. PFS will be 
measured from date on treatment until the date of first progression, 
medulloblastoma-related death or date of last contact for patients who have not 
experienced an event (failed). EFS will be measured from date on treatment until 
the date of first progression, second malignancy or death due to any cause; or date 
of last contact for patients who have not experienced an event (failed). For both 
objectives the primary analyses will be consistent with ‘intent to treat’ and thus all 
eligible patients who receive any methotrexate will be included in these analyses. 
Patients who go off treatment due to toxicity or for any reason other than disease 
progression or medulloblastoma-specific death, will still be followed on study until 
disease progression, second malignancy or death. Patients who experience a second 
malignancy or die from other causes will be considered as having had a competing 
event in the analysis for the biology objective since the intent there is to look for 
associations between gene expression and tumor progression. Patients who remain 
progression free or are lost to follow-up will be treated as censored at the date of 
last contact.  
 
With respect to EFS, a subset analysis will also be done by removing patients who 
have died from unrelated causes. 
 
Protocol therapy will be risk directed based on the following three strata:  
 
Low risk:  
• Patients with gross-totally resected M0 medulloblastoma with nodular 
desmoplastic histology.  
• Patients with M0 high-grade glioma, regardless of extent of resection. 

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Intermediate risk: 
• Patients with M0 medulloblastoma with histology other than nodular 
desmoplastic; and/or patients with less than gross-totally resected tumors. 
• Patients with M0 PNET/pineoblastoma, ATRT and other diagnoses 
(ependymoma, CPC, etc.) 
Patients who are ≥3 and < 5 yrs of age with non-metastatic medulloblastoma 
and less than 1 cm2 of residual tumor. Patients with anaplastic histology, 
large cell histology,  melanotic differentiation, or myogenic differentiation 
or tumors with MYC or MYCN gain or amplification are excluded. 
 
High risk: 
• Patients with M+ medulloblastoma, PNET/pineoblastoma, ATRT or other 
diagnosis (high-grade glioma, ependymoma, CPC, etc.) 
 
Note that the intermediate and high-risk groups will also include patients with 
ATRT, PNET/pineoblastoma, PNET variants (ependymoblastoma, CNS 
neuroblastoma), high-grade glioma, ependymoma and choroid plexus carcinoma. 
Only medulloblastoma patients will contribute to the primary objectives.  Although 
patients with other eligible tumors will not contribute to answering the primary 
study objectives, they will contribute to the toxicity monitoring rule as well as to 
most of the secondary objectives. Further, tumor tissues from these patients will be 
subjected to similar exploratory genome-wide analysis of DNA abnormalities and 
analysis of gene expression profiles as indicated in the secondary objectives. 
 
 
 
As part of the risk directed therapy, patients in the high-risk stratum who are 3 years 
or older at the end of induction therapy will be offered optional craniospinal 
irradiation (CSI). CSI is expected to improve EFS for these patients and thus reduce 
the expected numbers of events on which the power of the proposed analyses is 
based. Nevertheless patients who elect to receive CSI will be included in the 
primary analyses. Provided the number of events is adequate, we will also perform 
a secondary subset analysis by considering these patients as censored on the date of 
their irradiation. 
 
It is also possible that there will be some very young patients enrolled on the 
intermediate-risk stratum for whom focal irradiation (which is part of the risk-
directed therapy) will not be appropriate. In this case, these patients will receive 
therapy consistent with the low-risk consolidation and maintenance phases until 
they reach one year of age, at which time they will undergo focal irradiation, 
followed by further maintenance therapy to complete six total maintenance courses. 
 
13.1.1 Overview of historical survival data: 
 
The Kaplan-Meier estimates of distributions of EFS from infant medulloblastoma 
studies in the literature reveal a ‘cure model’ pattern where early failures are 
followed by a long stabilization (cure) period in the EFS rates. Though somewhat 
less pronounced, this pattern also holds for EFS curves of PNET/pineoblastoma and 

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ATRT patients. Thus a model which captures this “cure pattern” is needed in order 
to estimate the expected number of failures and hence approximate the duration of 
the trial.  
 
There is considerable uncertainty in the historical data regarding when the above-
mentioned stabilization may be expected to occur. The historical St Jude data 
indicates that a vast majority of failures will be observed within the first year, 
whereas the data in the literature indicates that this period may be around 2 years. 
The following are the EFS curves from some of the relevant studies in the literature. 
Several of these plots also illustrate the effect of the factors being utilized in 
defining the risk strata on EFS: 
 
Figure 12:  EFS by Regimen in Medulloblastoma Patients Treated on CCG-992116 
 
 

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Figure 13:  EFS by Pathology for Patients Treated on CCG-992116 
 
 
Figure 14:  PFS in R0M0 Patients by Extent of Resection in Medulloblastoma Patients 
Treated on the French BBSFOP Trial17 
 
 
 
 
 
 
 
 
 
 

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Figure 15:  PFS and OS Curves for PNET Patients Treated on the German HITSKK’87 
and HITSKK’92 Trials22  
 
 
Figure 16:  EFS for Children < 3 Years of Age with Metastatic Medulloblastoma Treated 
on Headstart II19  
 
There were 9 children under 3 years of age at the time of diagnosis who were 
treated on this protocol (5 were M3 and 2 each were M2 and M1). The plot below 
was produced from the data presented in the paper. 
Time to Relapse (months)
EFS
0
10
20
30
40
50
60
0.0
0.2
0.4
0.6
0.8
1.0
 
 

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Figure 17: St Jude Historical Infant Medulloblastoma Data: 
 
This cohort includes 56 patients (33 M0, 23 M+) treated during 1984-2006. Follow-
up time was truncated at 10 years in order to enhance visualization. A few 
censoring times are available beyond this cutoff but no events were observed. 
Time to Event (Years)
EFS
0
2
4
6
8
10
0.0
0.2
0.4
0.6
0.8
1.0
MStage.C=M+
MStage.C=M0
 
 
Figure 18: St Jude Historical Infant PNET/Pineoblastoma and ATRT Data: 
 
This cohort includes 58 patients (37 ATRT, 8 Pineoblastoma and 13 PNET) treated 
during 1984-2006.  
EFS (years)
Proportion
0
2
4
6
8
10
12
14
0.0
0.2
0.4
0.6
0.8
1.0
SJDX=ATRT
SJDX=PINEOBLAST
SJDX=PNET
 
 
 

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Putting together the St Jude historical data for Medulloblastomas, 
PNET/pineoblastomas and ATRTs and incorporating M-status in light of the 
stratification proposed for this trial, leads to the following Kaplan-Meier Plot: 
 
Figure 19:  St Jude Historical Infant Medulloblastoma, PNET/Pineoblastoma and ATRT 
Data: 
 
EFS (Years)
Proportion
0
5
10
15
20
0.0
0.2
0.4
0.6
0.8
1.0
DXSJC=ATRT/PNET, MStage=M+
DXSJC=ATRT/PNET, MStage=MO
DXSJC=MEDULLO, MStage=M+
DXSJC=MEDULLO, MStage=M0
 
 
To enhance visualization, the x-axis of the plot below was truncated at 5 years to 
produce the following: 
 
Figure 20:  St Jude Historical Infant Medulloblastoma, PNET/Pineoblastoma and ATRT 
Data (Truncated): 
 
EFS (years)
Proportion
0
1
2
3
4
5
0.0
0.2
0.4
0.6
0.8
1.0
SJDX=ATRT/PNET, Mstage=M+
SJDX=ATRT/PNET, Mstage=M0
SJDX=MEDULLO, Mstage=M+
SJDX=MEDULLO, Mstage=M0
 
 

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The following table was produced based on the St. Jude Historical Infant Data and displays 
the EFS as well as accrual information available: 
 
Table 24:  Number (Percentage) of Patients by Histology and M-Status 
in SJ Historical Cohort 
 
Number (Percentage) 
of Patients  
1-Year EFS 
M0 Medulloblastoma 
33 (28.9%) 
61.7% (46.8-81.4) 
M0 PNET/Pineoblastoma 
10 (8.8%) 
60.0% (36.2-99.5) 
M0 ATRT 
22 (19.3%) 
13.6% (4.2-44.4) 
M+ Medulloblastoma 
23 (20.2%) 
21.7% (10.0-47.2) 
M+ PNET/Pineoblastoma 
11 (9.6%) 
21.2% (6.3-71.6) 
M+ ATRT 
15 (13.2%) 
14.4% (4.0-52.0) 
Total 
          114 (100%) 
 
 
Recall that the low-risk stratum includes M0 Medulloblastoma patients whose tumors are 
desmoplastic and are gross-totally resected. The following information was compiled from 
the historical St Jude medulloblastoma data in order to obtain some idea regarding the 
proportion of patients who can be expected to be treated in this stratum: 
 
 There were 40 medulloblastoma patients in the St Jude cohort whose tumors were 
tested for desmoplasia. The following table summarizes this information: 
 
Table 25:  Medulloblastoma Patients in the St Jude Cohort whose Tumors were 
Tested for Desmoplasia 
 
M0 
M+ 
Total 
Desmoplastic 
6 (15%) 
3 (7.5%) 
9 (22.5%) 
Non-desmoplastic 
16 (40%) 
15 (37.5%) 
31 (77.5%) 
All 
22 (55%) 
28 (45%) 
40 
 
All 6 M0 desmoplastic tumors were gross-totally resected. 
 
 The effect of desmoplasia on EFS was also investigated using the specimens 
collected during UKCCSG CNS 9204 trial from 31 infants. Based on personal 
communication with Dr. Richard Grundy, 17 (60.7%) of the 28 tumor specimens 
which had sufficient material for the necessary pathology studies were 
desmoplastic. The 1-year EFS rate for the 17 patients with desmoplastic tumors was 
88.2% (72.9-100%) compared to 18.2% (0.0-41.0%) for the 11 non-desmoplastic 
tumors. 
 
The table on the next page summarizes the relevant historical information that was 
reviewed in compiling the background information for this trial. 

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Table 26:  Historical Medulloblastoma, PNET/Pineoblastoma and ATRT Data 
 
Headstart II 
Chi et al. (2004 
JCO) 
Headstart I  
Mason et al.  
(1998 JCO) 
“The French 
Study” BBSFOP 
(Lancet 2005) 
“German Study” 
HITSKK’92 
(NEJM 2005)  
CCG-9921  
(JCO 2005) 
Historical St Jude Data 
Patients 
Medullo 
9 M+ patients  
N=13 “most with 
limited disease” 46% 
w/ complete resection 
75 patients 15 of 
whom were M+ 
43 patients 31 of whom 
were M0/M1 and 12 were 
M2/M3. 
92 patients 
38 M0 w/ min residual 
23 M0 other, 31 M+ 
56 patients 
(33 M0, 23 M+) treated 
during 1984-2006 
PNET 
NA 
14 patients 
NA 
13 treated on HIT-SKK87 
16 treated on HIT-SKK92 
20 M0 w/ min residual 
17 M0 other, 9 M+ 
21 PNET/Pineoblastoma 
11 M0, 10 M+ 
ATRT 
N=6 (2004 
ISPNO abstract) 
6 patients (from 
Reddy(2005) Neuro 
Oncol 75:309-313 
NA 
NA 
13 M0 w/ min residual 
5 M0 other, 10 M+ 
37 ATRT 
22 M0, 15 M+ 
Tx 
 
400mg/kg of 
Mtx + Other 
chemo 
Intensive Chemo and 
Bone Marrow Rescue 
Postoperative 
Chemo alone 
Chemo that included IT 
MTX. RT was an option 
for patients who did not 
achieve complete remission 
Multiagent Chemo 
with RT for patients 
with residual disease 
or M+ status 
Various 
1-year 
PFS/EFS 
(95% 
CI) 
Medullo 
PFS: 77.8% (54-
100) 
EFS: 69% (43-95) 
Not provided.  
5-year PFS: R0M0 
29%(18-44); 
R1M0 6% (1-27); 
RXM+ 13% (4-38) 
1 yr EFS (read from plots) 
- 
M2/M3: 40% (n=17) 
- 
M0/M1 no residual: 
100% (n=14) 
- 
M0/M1 with residual: 
85% (n=12) 
1-year EFS 
- M0 min resid 66% 
- M0 other: 43% 
- M+: 42% 
1-year EFS 
- M0: 61.7% (47-81.4) 
- M+: 21.7% (10.7-47.2) 
PNET 
NA 
1 yr EFS: 79% (57-
100); 2-year EFS: 
43% (17-69) 
NA 
1 yr EFS (read from plots) 
(not available separately for 
HIT-SKK87 and HIT-
SKK92): 45%  
1-year EFS 
- M0 min resid  25% 
- M0 other: 29% 
-    M+: 22% 
1-year EFS 
- M0: 60% (36-99.5) 
- M+: 42.4% (21-87) 
ATRT 
PFS: 50% at 1-, 
2-, 3- years 
(2004 ISPNO 
abstract) 
PFS, OS: 0% (though 
no time is given) 
(2004 ISPNO 
abstract) 
NA 
NA 
1-year EFS 
- M0 min resid  31% 
- M0 other: 20% 
-    M+: 40% 
1-year EFS 
- M0: 13.6% (4.2-44.4) 
- M+: 14.4% (4.0-52.0) 
Stable 
Medullo 
~2 years 
Not enough 
information 
All except 1 had 
PD w/n 2 yrs of dx. 
~ 2 years 
~2-3 years 
~1 Year 
PNET 
NA 
~ 2 years 
NA 
~ 2 years (but not much) 
~2 years 
~2 years 
ATRT 
~1 year 
NA 
NA 
NA 
~2 years 
~2 years 
Desmo- 
plasia 
Medullo 
NA 
NA 
25 desmo cases. 
Not signif. wrt EFS 
20 desmo cases. 1-year 
EFS desmo vs. not: 100% 
vs. 60%. Effect significant. 
NA 
1-year EFS: 
Desmo(n=9): 77.8% (39-100) 
Non(n=31):29% (11-50.3) 

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13.1.2 Background Information on Gene Expression for Medulloblastoma 
Patients: 
 
As stated previously, the primary biology objective of the study is perform 
molecular studies with the intent of assessing various biologic findings for their 
association with progression-free survival for very young medulloblastoma 
patients in the context of the risk-directed therapy proposed for this protocol. As 
the historical data summarized above indicate, progression-free survival is 
affected by M-stage, extent of resection and histologic subtype, and therefore 
these factors will have to be included in the same model before the effect of 
molecular aberrations on PFS can be properly studied. A typical model for such 
studies is the Cox proportional hazards model. 
 
Well-accepted statistical guidelines indicate that approximately 10 events are 
needed for each variable studied in a multi-variable Cox model. An important 
implication of this recommendation, i.e. 10 events per covariate, in the context of 
this trial is that in order to be able to study the association of a given biologic 
marker while simultaneously accounting for M-stage, extent of resection and 
histologic subtype, approximately 40 events will be needed. Note that it is 
possible even with 40 events that we may not be able to account for the 
association of all of these factors in a satisfactory fashion. For example, if we 
observe very few events in the low-risk stratum, it may be difficult to isolate the 
effect of desmoplasia from M0-status or GTR, depending on the number of events 
observed in the intermediate and high risk groups and the distribution of these 
factors among those patients. An alternative approach to accounting for these 
three factors in the same model as the biologic marker is to use risk-stratum as a 
proxy. Although this approach may limit the inference regarding surgical 
resection status, desmoplasia and M-stage, it may allow associations to be 
observed between biologic marker and PFS with fewer events, which is the 
primary goal. In the case where risk stratum is used, the model would include 3 
covariates (2 indicator variables for risk strata and gene expression) and thus 
approximately 30 events should be adequate.  
 
 
13.1.3  Background information on St Jude Historical Cohort  
 
St. Jude historical cohort treated during 1998-2006 were used in the initial design 
of this study and appropriate subsets of this cohort will be used as part of the 
outcome evaluation. The entire St Jude historical cohort includes 83 patients, 35 
of whom were medulloblastoma patients and 32 of whom were ATRT patients. 
The 1- and 5- year event-free survival rates of the historical cohort are 0.393 
(0.0548) and 0.325 (0.053), respectively; whereas 1- and 5- year overall survival 
rates of the historical cohort are 0.639 (0.0537) and 0.418 (0.0571). The 
corresponding Kaplan-Meier plot is given below: 
 
 

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Figure 21: Kaplan-Meier Plot of Event-Free and Overall Survival for St. Jude Historical Cohort 
(all histologies) 
Time (Years)
Proportion
0
2
4
6
8
0.0
0.2
0.4
0.6
0.8
1.0
EFS
OS
 
 
With respect to the risk strata defined in this study, 3 patients in the historical 
cohort would have been classified as low risk, 37 patients would have been 
graded as intermediate risk and 35 patients would have been grouped as high risk. 
Note that 8 of the 83 patients could not be classified into one of the three risk 
strata as these were medulloblastoma patients with M0 disease and gross total 
resection but the desmoplasia status of their tumor was unknown. Of the 35 
patients classified into the high risk stratum 14 were medulloblastoma patients; 
and of the 37 patients in the intermediate risk stratum 10 were medulloblastoma 
patients. The following tables and plots summarize the EFS and survival 
information for the St Jude historical cohort by risk stratum: 
 

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Table 27 Summary Statistics for Event-Free Survival of St Jude Historical 
Cohort by Risk-Stratum 
                  n.obs events mean se(mean) median 0.95LCL 0.95UCL  
RiskStratum=High   35    28   1.83    0.470  0.405  0.285    0.756         
RiskStratum=Int    37    23   3.39    0.727  0.485  0.422     NA              
RiskStratum=Low     3     1   4.24    1.650   NA    0.203     NA                
 
Table 28 Summary Statistics for Overall Survival of St Jude Historical 
Cohort by Risk-Stratum 
                  n.obs events mean se(mean) median  0.95LCL 0.95UCL  
RiskStratum=High    35    25   2.61    0.496   1.12     0.718   2.31 
RiskStratum=Int     37    18   4.68    0.748   1.49     1.074     NA 
RiskStratum=Low      3     1   4.40    1.525     NA     0.663     NA 
 
Table 29 One and Five-Year EFS and OS Rates of St Jude Historical 
Cohort by Risk-Stratum 
 
 
 
1-Year EFS   5-Year EFS 
1-Year OS 
 5-Year OS 
RiskStratum=High 0.286(0.076) 0.222(0.071)   0.510(0.085) 0.262(0.077) 
RiskStratum=Int 
0.365(0.083) 0.332(0.082)   0.680(0.080) 0.447(0.089) 
RiskStratum=Low 
0.667(0.272) 0.667(0.272)   0.667(0.272) 0.667(0.272) 
 
Figure 22 Kaplan-Meier Plot of Event-Free Survival for St. Jude Historical Cohort 
by Risk-Stratum (all histologies) 
 
EFS (Years)
Proportion
0
2
4
6
8
0.0
0.2
0.4
0.6
0.8
1.0
RiskStrata=High
RiskStrata=Intermediate
RiskStrata=Low
 

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Figure 23 Kaplan-Meier Plot of Overall Survival for St. Jude Historical Cohort by Risk Stratum 
(all histologies) 
 
OS (Years)
Proportion
0
2
4
6
8
0.0
0.2
0.4
0.6
0.8
1.0
RiskStrata=High
RiskStrata=Intermediate
RiskStrata=Low
 
 
Note however that the proposed primary therapeutic analysis will not be 
specific to risk group. In other words the EFS distribution of medulloblastoma 
patients will be estimated across all three risk groups. The following table and 
plot provide some summary information regarding the St. Jude historical 
medulloblastoma cohort. The 1- and 5 year EFS rates for this cohort are 
estimated as 0.593 (0.084) and 0.530 (0.086), whereas the 1- and 5 year OS 
rates are given as 0.737 (0.075) and 0.612 (0.085). 
 
Table 30 Summary Statistics for Event-Free and Ovarall Survival  
of St Jude Historical Medulloblastoma Cohort 
           
 
 
 
N Obs 
Events 
Mean 
SE 
(Mean) 
Median 
0.95 LCL 
.095 UCL 
EFS 
35 
17 
4.34 
0.661 
5.468 
0.416 
NA 
OS 
35 
13 
5.36 
0.613 
NA 
2.449 
NA 
 

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Figure 24 Kaplan-Meier Plot of Event Free and Overall Survival for St. Jude 
Historical Medulloblastoma Cohort 
Time (Years)
Proportion
0
2
4
6
8
0.0
0.2
0.4
0.6
0.8
1.0
EFS
OS
 
 
 
The unusual “cure model” shape of the EFS and survival curves for the 
medulloblastoma cohort makes it infeasible to use the typical one-parameter 
exponential distribution-based methods in describing this distribution. Note that 
the historical data that was initially used to design this trial did not come from a 
single study, rather the cohort consisted of patients mainly treated on BB98, 
P9934 and PBTC001, two of which were Phase I trials. Given the heterogeneity 
of these data as well as its relatively small size, a historical control based 
comparative design could not be employed. Further, a standard treatment does not 
exist for the patient population in question and thus there were no other more 
relevant data which could be used in planning this study at the time it was first 
designed. Therefore the objective of this study was not to perform a formal 
comparison; rather it was and is to estimate the EFS distributon for the cohort 
treated on this trial to provide efficacy information for the proposed regimen and 
to build an appropriate historical cohort for future studies. 
 
Update on Published Relevant Literature as of Amendment 8: 
Since the writing of this protocol, multiple studies reporting outcome of 
medulloblastoma occurring in young patients (<5 years at diagnosis) treated 
primarily with chemotherapy with the intent to avoid or delay radiation therapy 
have been published. The table below adapted from Leary et al. (2011)368 
summarizes the outcome reported in these studies: 

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Table 31. Summary of Studies Reporting Survival Comparing Desmoplastic Groups 
Trial 
Event-Free 
Survival 
Overall 
Survival 
Initial Treatment 
N 
PFS 
Time 
(yrs) 
DMB 
Non-
DMB 
DMB 
Non-
DMB 
CSI 
HDC 
ASCR 
HD 
MTX 
HIT-SKK2000 
45 
5 
95% 
30%a 
100% 
68% 
No 
No 
Yes 
HIT-SKK92  
43 
5 
85% 
34% 
95% 
41% 
No 
No 
Yes 
HIT-SKK87  
29 
10 
89% 
30% 
89% 
40% 
Yes 
No 
Yes 
UKCCSG/SIOP 
CNS9204  
31 
5 
35%a 
33%b 
53% 
33% 
No 
No 
Yes 
Meta-analysis  
270 
8 
55% 
27% 
77% 
42% 
Yesc 
Yesc 
Yesc 
CCG-9921 
76 
5 
77% 
17% 
85% 
29% 
No 
No 
No 
DMB indicates desmoplastic medulloblastoma, including desmoplastic nodular medulloblastoma 
and medulloblastoma with extensive nodularity; CSI, craniospinal irradiation; HDC ASCR, high-
dose chemotherapy with autologous stem cell rescue; HDMTX, high-dose methotrexate. 
a outcome for Non-DMB patients is based on classic medulloblastomas only. The trial only 
included 3 anaplastic patients. 
b All differences in survival are statistically significant except for UKCCSG/SIOP CNS9204 
event-free survival. 
c Patient cohorts in meta-analysis treated on six different regimens, including reverences HIT-
SKK 87 and 92 trials and UKCCSG/SIOP CNS9204 trials above in addition to Italian and Head-
Start regimens which used HDC ASCR. 
 
With the drastically reduced sample size of the revised trial (version 8 onwards) 
we will use published data to set monitoring rules for early stopping as detailed in 
relevant sections below.  
 
Enrollment of Medulloblastoma Patients 3-5 years of age 
With amendment 5.0, the eligibility for enrollment to SJYC07 was expanded to 
include patients ≥ 3 - <5 years of age in order to explore the possibility of treating 
these patients without Craniospinal Irradiation (CSI), which is known to have 
devastating neurocognitive effects in the long run. It is the investigators’ belief 
that the risk adapted therapy proposed for this trial would provide a comparable 
outcome to the one that can be achieved via CSI for patients with tumors that do 
not harbor high risk features. Starting with amendmet 6 of the current study 3-5 
year old medulloblastoma patients with anaplastic or large cell histology or C-
MYC or N-MYC amplification have been excluded from enrolling on this trial as 
these are well established adverse risk factors in these patients. With amendment 
8 patients with melanotic or myogenic differentiation have also been excluded as 
these subtypes are also thought to have worse outcome.  

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While the initial study design had proposed a separate stratum and a separate 
assessment for these patients, due to accrual limitations, with amendment 8, we 
chose to combine them with patients <3 years of age as have routinely been done 
with contemporary early childhood medulloblastoma protocols including HIT 
2000 from the German group as well as ACNS1221, the new COG study. 
 
13.1.4 Accrual estimates and expected trial duration 
 
Overview of accrual estimate and trial duration 
 
This study will be considered complete when 90 medulloblastoma patients have been 
enrolled and the last patient has been followed for 1-year. It is expected that the total 
enrollment period will last approximately 10 years. The planned total of 90 patients 
include an estimated 70 medulloblastoma patients < 3 years of age at the time of 
diagnosis as well as 20 medulloblastoma patients 3-5 years of age at the time of 
diagnosis.  
 
As of Feb 27, 2014 198 eligible patients have been enrolled on the study, 55 of whom 
are medulloblastoma patients (1 without central path review at the time of the writing 
amendment 8). While it is difficult to estimate the total accrual for the entire study (all 
histologies), based on the current information and expectations for future enrollment 
patterns, we project that total accrual to the trial will be approximately 315 patients (70 
<3 year-old medulloblastoma patients + 225 <3 year-old patients with other histologies 
and 20 ≥3-<5 year-old intermediate-risk medulloblastoma patients). Note that with the 
opening of SJATRT protocol, young ATRT patients who have been have historically 
been enrolled on this trial will enroll on that study instead. Hence we anticipate a slight 
drop in the number of non-medulloblastoma patients enrolled on this trial for the 
remainder of the accrual period. 
 
 
Accrual to Date (as of amendment 8) 
The initial accrual goal of this study was 140 <3-year old medulloblastoma 
patients to be enolled in approximately 7 years. However as of March 2014, 
approximately 6.5 years after the trial opened to accrual only 44 <3-year old 
medulloblastoma patients have been enrolled. Thus based on a recommendation 
of the St Jude CT-SRC we have dramatically revised the accrual goals as well as 
the planned analyses in order to complete this trial in a more timely fashion. The 
table below provides detailed accrual information in patients <3 years. We expect 
to accrue the remaining 26 patients in the next 3 years: 

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Table 32: SJYC07 Accrual by Year and Site, Diagnosis Age <3 Years of Age  
(as of 2/27/2014) 
Medullo 
2007 
2008 2009 
2010 
2011 
2012 
2013 
2014 
Grand 
Total 
Collab 
0 
1 
4 
5 
4 
5 
1 
0 
20 
St Jude 
1 
3 
3 
8 
5 
2 
2 
0 
24 
Grand Total 
1 
4 
7 
13 
9 
7 
3 
0 
44^ 
 
Non-Medullo 
2007 
2008 2009 
2010 
2011 
2012 
2013 
2014 
Grand 
Total 
Collab 
0 
0 
5 
8 
8 
7 
3 
0 
31 
St Jude 
0 
20 
20 
16 
14 
17 
16 
2 
105 
Grand Total 
0 
20 
25 
24 
22 
24 
19 
2 
136^ 
 
All Patients 
2007 
2008 2009 
2010 
2011 
2012 
2013 
2014 
Grand 
Total 
Collab 
0 
1 
9 
13 
12 
12 
5 
2 
54 
St Jude 
1 
23 
23 
24 
20 
20 
18 
3 
132 
Grand Total 
1 
24 
32 
37 
32 
32 
23 
5 
186^ 
^ 6 patients did not have central pathology results at the time of data extraction. These patients 
were not included in the medullo vs. non-medullo accrual numbers, but were included in the 
overall (All Patients) section. 
 
The following table summarizes the accrual rates observed to date in the 3-5 year old 
Medulloblastoma cohort. Note that accrual to this cohort was initiated in October 2010.  
 
Table 33: SJYC07 Accrual by Year and Site, Diagnosis Age ≥3-<5 Years of Age  
Medullo 
2007 
2008 
2009 
2010 
2011 
2012 
2013 
2014 
Grand 
Total 
Collab 
0 
0 
0 
0 
3 
2 
1 
0 
6 
St Jude 
0 
0 
0 
0 
1 
1 
2 
0 
4 
Grand Total 
0 
0 
0 
0 
4 
3 
3 
0 
10 
 
Non-
Medullo 
2007 
2008 
2009 
2010 
2011 
2012 
2013 
2014 
Grand 
Total 
Collab 
0 
0 
0 
0 
0 
0 
0 
0 
0 
St Jude 
0 
0 
0 
1 
0 
0 
0 
0 
1 
Grand Total 
0 
0 
0 
1 
0 
0 
0 
0 
1 
 
All Patients 
2007 
2008 
2009 
2010 
2011 
2012 
2013 
2014 
Grand 
Total 
Collab 
0 
0 
0 
0 
3 
2 
1 
0 
6 
St Jude 
0 
0 
0 
1 
1 
1 
2 
0 
5 
Grand Total 
0 
0 
0 
1 
4 
3 
3 
0 
11 
 

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Thus to date we have enrolled 10 intermediate ≥3-<5 year-old Medulloblastoma 
risk patients. With the projected timeline of 3 more years of accrual we expect to 
enroll approximately 10 more patients in this cohort, barring early stopping. Note 
that with amendment 8 of the protocol, rather than accrued to a separate stratum, 
these patients will be combined with <3-year old patients in the intermediate risk 
stratum. 
 
Accrual Patterns Observed to Date (Amendment 8 onwards): 
 
Of the 44 <3-year old medulloblastoma patients enrolled on this trial as of Feb 27, 
2014, 13 are high risk, 13 are intermediate risk and 18 are low risk. Note that this 
enrollment pattern is very different than the St Jude historical cohort on which the 
original design was based. In the historical cohort of 23 medulloblastoma patients 
14 were high risk, 10 were intermediate risk and 3 were low risk. Thus with this 
major amendment we will modify the analysis plan and monitoring approaches. 
Clearly with the above noted difference in accrual pattern across strata, it would 
not be reasonable to use a combine- cohort-based approach to monitor outcome. 
 
Barring early stopping based on various monitoring rules noted below, the trial 
will remain open until 90 medulloblastoma patients are enrolled which we 
anticipate will take another 3 years. The rationale for this sample size is pragmatic 
rather than statistical. While in the initial version of the protocol the biology 
primary objective was based on gene expression that required fresh frozen tissue, 
in this version the biology objective is being modified to utilize biologic data 
generated from fixed tissue. To date 95% of patients enrolled on the study 
(regardless of histology) have provided fixed tumor tissue. In our initial sample 
size justification of 140 <3-year old medulloblastoma patients, we had assumed 
that 40%, i.e. 56 patients, would provide good quality RNA for gene expression 
analyses. Further based on the SJ historical cohort, we had estimated that we 
would observe approximately 30 events in these 56 patients at the end of the trial. 
Based on 90-95% acquisition rate of FFPE tissue observed to date on this trial, we 
estimate that if 90 patients are enrolled approximately 80 (90%) patients will have 
adequate FFPE tissue for the planned biology analyses. If the accrual distribution 
across risk strata as well as outcome are similar to the one observed in the St Jude 
historical cohort and taking into account the longer observation period we have 
acquired due to slow accrual, in 90 patients we expect to observe a median of 47 
events (90% CI: 38-56). While it is not clear whether we will have similar power 
for the biology objective as the original design which was based on gene 
expression, we expect that these data will provide useful information since even 
with the smaller overall sample size we will have a larger number of events due to 
longer follow-up as well as tissue availability from a large majority of patients. 
Note that the current distribution of patients across risk strata is skewed towards 
the low risk patients and we expect to see fewer events in this stratum however 
the intermediate risk stratum in the SJ historical cohort (n=10) had only 1 event 
during the limited follow-up at the time of the original protocol design which 
appears to be very unusual based on published data from various large studies 
with much longer follow-up utilizing ‘chemotherapy only’ approaches to treat this 

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population and thus we anticipate that it is highly likely we will observe more 
than 30 events in the overall cohort. 
 
 
Monitoring Rules: 
Please note that the outcome data already available on this trial was not used in 
the modification of the trial design and monitoring rules that have been 
implemented as of amendment 8 of the protocol. 
 
Amendment 8 onwards: 
Note that with the drastically reduced target accrual the originally proposed 
approach to interim analysis becomes infeasible as the operating characteristics of 
that approach are inadequate. Furthermore, the differing proportions of patients 
allocated to various risk strata between the historical cohort and the current trial 
also make the original approach less than desirable. Thus we propose stratum 
specific monitoring rules based on recently published literature utilizing similar 
treatment approaches for young medulloblastoma patients.  
 
Published Data for Young Medulloblastoma Patients: 
The following KM plots are from a variety of papers displaying the outcome 
observed in similar patient cohorts based on chemotherapy dominated regimens 
with the intent to delay or avoid radiation. 
 
 

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Event-Free Survival for Medulloblastoma comparing Desmoplastic Groups (p < 
0.0001) from Leary et al.368 
 
 
Survival according to histology from van Beuren et al.369 . Nineteen patients (13 patients with 
desmoplastic medulloblastoma [DMB)] and 6 patients with medulloblastoma with extensive 
nodularity [MBEN]) had better event-free survival (EFS; panel A) and overall survival (OS; 
panel B) rates (5-year rates, 95% ± 5% and 100% ± 0%, respectively) than did 23 patients with 
classic medulloblastoma (CMB; 30% ± 11% [P < .001] and 68% ± 10% [P = .008], respectively). 
 
 
Survival according to postoperative residual tumor from van Beuren et al.369. Thirty-nine patients 
without residual tumor or with small residual tumor (≤1.5 cm2) had slightly better rates of event-
free survival (EFS; 5-year rates, 60% ± 9% vs 33% ± 19%; P = .110) (panel A) and overall 
survival (OS; 5-year rates, 84% ± 6% vs 50% ± 20%; P = .044) (panel B), compared with 6 
patients with residual tumor >1.5 cm2. 
 

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Event-free survival (EFS) and overall survival (OS) of patients with desmoplastic/nodular 
medulloblastoma (DNMB)/medulloblastoma with extensive nodularity (MBEN) versus 
classic medulloblastoma (CMB) within the clinical risk groups (A and B) M0R0, (C and 
D) M0R+, and (E and F) M+ from Rutkowski et al.370  
 
Monitoring Rule for Low Risk Medulloblastoma Patients (this monitoring rule has 
been in the protocol since its inception): 
 
One of the innovative parts of the proposed treatment regimen is to remove focal 
RT from the treatment of low risk medulloblastoma patients (M0 gross-totally 
resected nodular desmoplastic tumors). In order to guard against the possibility 
that the proposed treatment strategy may yield inferior outcome for this patient 
group an ad-hoc monitoring rule will be utilized. Note that sample size constraints 
make it infeasible to implement a formal monitoring strategy in this case. As part 
of the German Study (HITSKK’92) 20 patients with desmoplastic tumors were 
treated with IT methotrexate as part of that study’s regimen, all of whom were 
event free at one year. The 95% exact lower bound (Blyth-Still-Casella) of this 

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estimate is 87.4%. In contrast, the St. Jude historical data contains 9 patients with 
desmoplastic tumors whose 1-year EFS estimate is 77.8% (7 were event free at 1 
year) which leads to a 95% Blyth-Still-Casella lower bound of 48.5%. For the 
current trial we will monitor the 1-year EFS rates of low-risk medulloblastoma 
patients (those with M0 gross-totally resected desmoplastic tumors) starting with 
the 10th patient. If at any point, this estimate falls below 80%, we will consider 
revising our approach. This estimate will be updated after every 10 low-risk 
patients reach the 1-year time point.  
 
As of December 2, 2015 accrual to the low risk medulloblastoma cohort has been 
suspended based on the above stopping rule. Routine data monitoring found 8 of 
the 23 low risk medulloblastoma participants had events, bringing the 1-year EFS 
to 78.3%, which is below the 80% boundry.   
 
Monitoring Rule for Intermediate Risk Medulloblastoma Patients: 
 
The intermediate risk Medulloblastoma cohort in this protocol is composed of 
M0R+ patients or M0R0 non-desmoplastic patients. Rutkowski et al. panel C 
provides outcome information for a cohort that is similarly defined i.e. M0R+ 
patients. While this cohort does not include patients with LCA tumors who 
typically have worse outcomes and are included in our intermediate risk cohort, 
our cohort also includes M0R0 non-desmoplastic patients who have slightly better 
outcome as shown in panel A of the same plot. So on average we feel comfortable 
assuming for monitoring purposes that the outcome reported in panel C of 
Rutkowsi et al. for classic medulloblastoma patients may serve as an appropriate 
boundary. While the short-term, i.e. 1- or 2-year EFS rates are not formally 
reported in the manuscripts referenced above, this information can be 
approximated from the plots above. Based on the information from this plot, the 
2-year PFS rate is approximately 25%. So similar to the approach proposed for 
high risk patients we will use 20% 2-year EFS as threshold for the intermediate 
risk cohort. If at any point this threshold is crossed the study team will review all 
available data and may consider treatment revision or stopping accrual in this 
cohort. We will utilize this approach after 15 intermediate risk patients have been 
followed for 2 years and will repeat it with every 15 additional intermediate risk 
patients. 
 
Monitoring Rule for High Risk Medulloblastoma Patients: 
 
Based on published data summarized above, it appears that 2-year PFS/EFS rate 
of M+ non-Desmoplastic patients is approximately 25% (panel E of the KM plots 
in Rutkowski et al. above). While our high risk cohort (defined by M+ disease) 
includes Desmoplastic Nodular patients, it also includes large cell or anaplastic 
patients. While the former has been shown to have better EFS, the latter, albeit 
more rare, usually has worse EFS than desmoplastic patients. Thus taking all of 
these factors into account as well as the small number of patients which will be 
enrolled on our trial, for monitoring purposes we will use 20% 2-year EFS as 
threshold for the combined M+ cohort. If at any point this threshold is crossed the 

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study team will review all available data and may consider treatment revision or 
stopping accrual in this cohort. We will utilize this approach after 15 high risk 
patients have been followed for 2 years and will repeat it with every 15 additional 
high risk patients. 
Toxicity Monitoring Rule: 
 
An informal toxicity monitoring rule will be employed during the trial where the 
accrual will be stopped to reassess safety concerns in the event that a total of 3 
patients, regardless of histology, experience Grade 3 elevation in creatinine or 
decrease in glomerular filtration rate across all strata at any point during the study, 
as defined by CTCAE criteria (version 3.0).  See section 12.3 for a summary of 
monitoring plans. 
 
13.1.5 Analysis plan for the primary objectives: 
 
 
 
Biology objective: 
 
As indicated above total accrual on this trial is expected to last approximately 10 
years. Tumor tissue will be collected from patients during this time, however the 
sample and array processing will not be performed until the accrual is complete. 
This will eliminate various sources of variability which would otherwise be 
introduced into the data. Further, in light of the rapidly progressing sample and 
array processing methodologies, waiting until the end of the accrual period to 
perform the necessary analyses would allow us to utilize the most up-to-date 
methods at that time. Once all tumor samples have been accrued, study 
investigators, the Biostatistics Department, and the Hartwell Center will 
collaborate to develop the most informative design and analysis of the biologic 
data given the labor, material, and cost constraints at that time.  Topics to be 
decided include the selection of reference samples, replication, and associated 
plans for statistical analysis and inferences.   
 
The same rapid emergence of new approaches is also true for statistical 
methodology regarding genomic data hence we will not pre-specify a particular 
approach that we will use for analysis which is expected to be performed 
approximately 11 years after study initiation. In general terms we anticipate that 
we will fit a Cox-type survival model per gene while simultaneously accounting 
for M-stage, extent of resection and desmoplasia or alternatively the risk-group in 
which patients were treated on protocol. For these models patients who 
experience disease progression or medulloblastoma specific death will be counted 
as having had an event; whereas patients who remain progression free or are lost 
to follow-up will be treated as censored at the date of last contact.  If some of the 
patients experience competing events such as second malignancy or death by non-
tumor related causes including toxicity, we will utilize an appropriate competing 
risks model (for example the method of Fine and Gray (1999)) to provide an 
alternative look at the data.  
 

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Provided adequate numbers of events are available per risk-stratum, an alternative 
subset analysis may be performed where patients within each risk-directed 
stratum are analyzed separately via a cause-specific survival model using PFS as 
the endpoint. Based on this approach the analysis performed for the low-risk 
stratum will only have to adjust for the genomic variable as all patients in this 
stratum will have M0, gross totally resected nodular desmoplastic 
Medulloblastoma. The analysis performed for medulloblastoma patients treated in 
the intermediate- and high-risk strata will only have to be adjusted for 
desmoplasia and resection-status, as all patients within the intermediate-risk 
stratum will be M0 and all patients within the high-risk stratum will be M+. 
 
Further, in all these analyses we will adjust the p-values for multiplicity using an 
FDR-like approach in an effort to minimize the number of false positives.  
 
Therapeutic objective: 
 
As indicated previously, due to the lack of an adequate historical control to which 
the results of this trial can be compared, the primary therapeutic objective is to 
estimate the EFS distribution of the medulloblastoma cohort treated with the 
proposed risk directed therapy. Kaplan-Meier estimates of event-free survival 
(EFS) distribution for all eligible medulloblastoma patients treated on this trial 
will be provided. Following the ‘intent to treat’ principle, all medulloblastoma 
patients who receive at least one dose of methotrexate will be included in these 
estimates. EFS will be measured from date on treatment until the date of first 
progression, second malignancy or death due to any cause; or date of last contact 
for patients who have not experienced an event (failed). Patients who go off 
treatment due to toxicity or for any reason other than an event, as defined above, 
will still be followed on study until disease progression, second malignancy or 
death. Patients who remain progression free or are lost to follow-up will be treated 
as censored at the date of last contact.  
 
13.2 
ANALYSIS PLAN FOR SECONDARY OBJECTIVES 
 
The caveat regarding rapidly evolving statistical methodology applies to the 
secondary objectives also. The analysis plans given below represent the current 
knowledge and may be modified at the time of the analysis if better approaches 
become available. 
 
13.2.1 Biological aims  
Responsible Investigatords: Amar Gajjar, Giles Robinson 
Responsible Biostatistician: Arzu Onar-Thomas, Tong Lin 
 
To perform high resolution genome-wide analyses of chromosomal abnormalities 
and gene expression patterns, and evaluate the relationship of these to other 
clinicopathological variables. 
 

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For patients from whom fresh frozen tumor is available at the time of surgery 
microarray analysis will be performed on the tumor sample obtained at initial or 
repeat surgery prior to treatment. The association between clinicopathological 
variables (e.g., M-stage, desmoplasia, age etc.) and presence of mutations as well 
as gene expression profiles will be explored.  
 
To compare expression between known clinicopathological subtypes, the 
Kruskal-Wallis test350 for equal medians will be applied to the expression of each 
probe.  For large enough group sizes, the chi-square approximation to the 
sampling distribution of the Kruskal-Wallis statistic will be used to obtain a p-
value.  For small group sizes, p-values will be obtained by comparing the 
observed Kruskal-Wallis statistic to the set of Kruskal-Wallis statistics obtained 
by pairing all possible permutations of group labels (or a large sample of the 
possible permutations) with the ranks. 
 
To assess the association of expression with other uncensored continuous 
variables (such as age, levels of certain proteins or other biologically meaningful 
quantities), the Spearman rank correlation test will be used.351  For large enough 
sample sizes, the t-distribution approximation to the sampling distribution of the 
statistic will be used to obtain a p-value.  For smaller samples, p-values will be 
obtained by comparing the observed Spearman rank correlation to the set of 
Spearman rank correlation statistics obtained from pairing all possible 
permutations (or a large sample of these permutations) of the first n digits (e.g. 1, 
2, n) with the ordered first n digits, where n is the number of individuals under 
consideration. 
 
For each set of p-values obtained by testing one of the hypotheses mentioned 
above, multiplicity issues will be examined using the concepts introduced by 
Pounds and Morris.342 However, instead of using the beta-uniform mixture model 
to estimate the distribution of p-values, a cubic-spline approximation of the 
cumulative distribution function will be used to estimate the distribution of p-
values.352 The approach can be used to explore various measures of the expected 
occurrences of Type I and Type II errors for any selected significance threshold.  
Additionally, the q-value approach introduced by Storey et al. may be used to 
examine multiplicity issues.353 
 
Unsupervised clustering algorithms, such as k-means and hierarchical clustering, 
will be used descriptively to explore the possibilities of discovering novel 
subgroups based on gene expression. Additional descriptive analyses may include 
principle component analysis and discriminant analysis.354 
 
SNP chips are relatively new and rapidly developing technology designed to 
simultaneously measure the number of copies per cell of many genes at the DNA 
level.   We will collect germline and tumor samples from each subject for DNA 
SNP microarray analysis.  The method of Carvahlo et al.355 will be used to 
compute summary signals for each array by removing the effects of fragment 
length and DNA probe sequence.  Genotype calls will be generated using the 

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CRLMM algorithm355 and regions of loss of heterozygosity will be inferred via 
hidden Markov modeling of the within-subject comparison of genotype calls in 
tumor and germline samples.356  For copy number analysis, the summary signals 
will be reference marker normalized.357  Inferences of change in copy number will 
be generated via comparison of reference-marker normalized tumor signals and 
germline signals.  The copy number inferences will be obtained via median 
smoothing,358 hidden Markov modeling,359 or circular binary segmentation.360,361  
Biological considerations and the estimated prevalence of lesions will be used to 
select regions of inferred LOH or copy number change for laboratory verification.  
Finally, we will explore the association of germline genotypes and inferred copy 
number change and LOH with clinical presentation and outcome, 
pharmacokinetic and pharmacodynamic variables, and microarray gene 
expression values using previously described statistical methods362 and adjust for 
multiple testing by using methods to control or estimate the false discovery 
rate.363,364  As the field of statistical genomics changes rapidly, improved methods 
may be available and used at the time of analysis. 
 
To evaluate specific tumor types for molecular abnormalities with suspected 
prognostic or therapeutic significance  
 
Specific tumor types within medulloblastoma will be scrutinized for the presence 
of molecular abnormalities with putative prognostic or therapeutic significance 
such as the activation of the wnt or shh signaling pathways, loss of chromosomes 
6, 8p, 9q22, isochromosome 17q and amplification of MTCC, MYCN and 
MYCL. Contingency table analysis will be used to examine the association of 
molecular abnormalities with other categorical characterizations of tumors. If 
appropriate, associations of continuous markers with specific tumor types will be 
examined using ANOVA or the Kruskal-Wallis test to compare the mean or 
median of the continuous variable across subgroups as defined by this technique. 
Significance will be determined using exact, permutation, or resampling methods.  
 
To evaluate the feasibility of collecting frozen and fixed tumor samples suitable 
for analysis using high-resolution molecular biology tools. 
 
As indicated in the statistical design for the primary objective we estimate that 
approximately 60% of patients will have frozen tissue available and 
approximately 70% of the available frozen tumor tissue will be suitable for high-
quality RNA extraction. A similar proportion of samples are expected to yield 
high-quality protein, and a larger proportion to yield high-quality DNA.  It is 
anticipated that most of the fresh-frozen tumor tissue will be available in small 
amounts making it infeasible to use some of it to assess RNA, DNA, and protein 
quality upon arrival at the biology lab.  As discussed in the plan for the primary 
objective, we will estimate the proportion of patients with frozen tumor tissue 
after the first 30 patients (with any histologic diagnosis) have been enrolled on the 
study, and re-evaluate the feasibility of completing this objective of the trial if this 
proportion is below 40%.  See section 12.2.   
 

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Compared to the percentage of patients with frozen tissue, we anticipate that a 
much higher percentage of patients will have fixed tumor tissue available. 
Nevertheless we will consider it unacceptable if less than 60% of patients have 
fixed tissue available for biological studies as well as for pathological diagnosis. 
Note that whereas the primary objective concerns only medulloblastoma patients, 
this secondary objective involves all patients enrolled on the study. As will be 
done for frozen tissue, after the first 30 patients (of any histologic diagnosis) have 
been enrolled on the study we will estimate the proportion of patients with fixed 
tumor tissue. If this proportion is below 60%, we will re-evaluate the feasibility of 
completing this objective. Beyond the first 30 patients, the estimate of the 
proportion of patients with fixed tumor tissue will be updated with every 30 new 
patients enrolled on the trial and if this percentage falls below 60% we will re-
assess the feasibility of this objective.  See section 12.2 for further discussion.   
 
13.2.2 Therapeutic aims 
Responsible Investigator: Amar Gajjar 
 
Responsible Biostatistician: Arzu Onar-Thomas 
 
To estimate the event-free and overall survival for patients treated with the 
proposed risk-adapted therapy regimen, and to descriptively compare these 
survival rates to historical controls.  
 
Histology specific Kaplan-Meier estimates of distributions of survival and event-
free survival (EFS) for all eligible patients who received at least one dose of 
methotrexate will be provided separately for each stratum. EFS will be measured 
from the date of initial treatment to the earliest date of disease progression, second 
malignancy or death for patients who fail; and to the date of last contact for 
patients who remain at risk for failure.  Note that toxicity will not be treated as an 
event in these estimates. The distribution estimates will be consistent with intent-
to-treat. 
 
Provided the accrual for the proposed study allows a reliable analysis to be 
performed, EFS and OS distributions will be estimated for each group stratified 
based on the proposed risk directed therapy and possibly by histology (for the 
intermediate and high risk groups). These will then be compared to the St. Jude 
historical cohort using the Mantel-Haenszel Log-rank test for the intermediate and 
high risk strata. Clearly, regardless of the number of patients enrolled on the low 
risk arm of this study, a meaningful stratum-specific comparison with the 
historical cohort cannot be made due to the fact that the historical cohort includes 
only three patients who would have been classified as low risk. Note that the 
comparison with SJ historical cohort will be made based on updated historical 
data as available at the time of analysis. 
 
To estimate the rates of local and distant disease progression in patients treated 
with focal irradiation of the post-operative tumor bed using a 5 mm clinical target 
volume margin. 
 

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We will estimate the rate of local and distant disease progression in patients 
treated in the intermediate risk stratum (M0 non-desmoplastic medulloblastoma 
and other eligible tumors) after focal irradiation of the post-operative tumor bed 
using a 5 mm clinical target volume margin. This analysis will be done once all 
patients in this stratum have been followed for at least 1 year from the end of their 
radiation treatment. We will provide exact 95% confidence intervals for the local 
and distant failure rates for the overall group and in the cases where patient 
numbers are adequate to make such estimates meaningful, for histology-specific 
sub-groups.  Historical control data for this objective are limited.  In the St. Jude 
historical control group (treated since 1998), 13 M0 medulloblastoma patients 
received focal RT at doses of 45 to 54 Gy and subsequently remained disease-
free.  Six M0 medulloblastoma patients treated during this era experienced disease 
recurrence or progression; 4 of these events occurred before focal RT was 
scheduled to be given.  Two patients had events after RT; one experienced local 
recurrence after receiving a dose of 45 Gy to the tumor bed, and the other 
experienced disseminated recurrence after receiving low-dose CSI (18 Gy).  The 
St. Jude historical control group also included 27 M0 ATRT, PNET, and 
pineoblastoma patients.  Of these, only 5 reached the time of planned focal RT 
without experiencing disease progression, and among those 5 patients 3 became 
long-term event-free survivors and 2 developed disease recurrence (1 local and 1 
disseminated).  Both patients who experienced recurrence after focal RT received 
a tumor bed dose of 45 Gy.  Thus, in the St. Jude historical control group as a 
whole, only 3 patients experienced failure after receiving focal RT, and all 3 
received a tumor bed dose (45 Gy) substantially lower than the 54 Gy which will 
be used on SJYC07.  Unlike in SJYC07, patients in this historical control group 
also received a radiation dose to the entire posterior fossa ranging from 18 to 36 
Gy.  CTV margins were also larger in the historical control group, and ranged 
from 1 cm to 2 cm.  By the time SJYC07 is complete, results from PBTC-001 and 
P9934 should be available, and may provide additional historical control data 
relevant to this objective. 
 
The following variables will be considered in relation to the rate and patterns of 
disease progression: planning target volume margin (3mm or 4mm or 5mm), 
planning target volume conformity index (e.g., 80% or 95% or 100%), recurrent 
tumor volume dose-volume histogram, method-modality (3DCRT, IMRT, proton 
beam radiation therapy). 
 
To estimate the objective response rate (sustained for 8 weeks) to induction 
chemotherapy including high-dose intravenous methotrexate for patients with 
residual or metastatic disease. 
 
For patients treated in the intermediate and high risk strata with residual or 
metastatic disease we will estimate the stratum-specific objective response rate 
(CR or PR) as defined in Section 9.1. Consistent with intent to treat, all patients 
who receive at least 1-dose of methotrexate are evaluable for response. Objective 
responses must be sustained for at least eight weeks. Provided it is confirmed and 
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first noted, or (in the case of patients with M1 disease and no radiographically 
evident residual tumor), the date of the first negative CSF cytology sample. We 
will provide exact 95% confidence intervals for the objective response rate 
separately for each stratum and if patient numbers allow, for each histologic 
subtype within each stratum. From the definition of the risk strata, all M0 patients 
with residual disease are in the intermediate-risk group and all M+ patients are in 
the high-risk group. Very few patients are expected to be M1 (only 5 in the 
historical cohort, 1 medulloblastoma and 4 other tumors, and none of these had 
residual disease) and even fewer would have measureable residual disease which 
would make obtaining meaningful estimates for this sub-group quite difficult. 
Within the high risk stratum, we will provide estimates of objective response 
separately for the M1 and M2+ patients, if adequate M1 patients have been 
accrued. Otherwise we will provide response estimates for the M+ group with and 
without the M1 patients. According to the SJ historical cohort identified for this 
study, 13 out of the 47 M0 patients and 13 out of the 35 M+ patients had 
measureable residual disease. 
 
To evaluate the feasibility and toxicity of administering low dose intravenous 
vinblastine in conjunction with induction chemotherapy for patients with 
metastatic disease. 
 
In order to evaluate the feasibility of administering low dose intravenous 
vinblastine in conjunction with induction chemotherapy for patients with 
metastatic disease, after the first 10 patients with metastatic disease have 
completed induction therapy, we will estimate the proportion of courses during 
which subsequent therapy was delayed for more than 7 days due to toxicity. If this 
percentage is greater than 25%, we will consider it unacceptable and will consider 
re-evaluating our approach. This percentage will be updated when every 10 new 
patients with metastatic disease complete induction and will be compared against 
the 25% threshold. 
To evaluate the feasibility and toxicity of administering consolidation therapy 
including cyclophosphamide and pharmacokinetically targeted topotecan to 
patients with metastatic disease, and to estimate the sustained (for 8 weeks) 
objective response rate (complete response + partial response, as defined in 
section 9.1)  to such therapy in patients with measurable residual disease after 
induction. 
 
In order to evaluate the feasibility of administering consolidation therapy 
including cyclophosphamide and pharmacokinetically targeted topotecan to 
patients with metastatic disease, after the first 10 patients in the high-risk stratum 
have completed both courses of consolidation, we will estimate the proportion of 
courses during which subsequent chemotherapy administration was delayed for 
more than 7 days due to toxicity. If this percentage is greater than 25%, we will 
consider it unacceptable and will consider re-evaluating our approach. This 
percentage will be updated with every 10 new patients who complete both high-
risk consolidation courses and will be compared against the 25% threshold. 

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For patients on the high-risk stratum with measurable residual disease after 
induction treated with consolidation therapy including cyclophosphamide and 
pharmacokinetically targeted topotecan, we will estimate the objective response 
rate (CR or PR) as defined in Section 9.1. Consistent with intent to treat, all 
patients who receive at least 1-dose of cyclophosphamide or topotecan during 
consolidation are evaluable for response. Objective responses must be sustained 
for at least eight weeks. Provided it is confirmed and sustained, the date of 
response will be the imaging date at which the response was first noted. We will 
provide exact 95% confidence intervals for the objective response rate for each 
histologic subtype separately, if patient numbers allow.  
 
To evaluate the feasibility and toxicity of administering oral maintenance therapy 
in children younger than 3 years of age at diagnosis. 
 
The overall strategy of this protocol is to facilitate the development and 
implementation of novel therapies with more specific anti-tumor activity and less 
toxicity than standard cytotoxic agents.  The large majority of new drugs in 
oncology are designed to be administered orally.  The ability to receive oral 
therapy at home has tremendous appeal to adults and older children with cancer, 
but administration of oral medication of any kind to infants and toddlers can be 
quite difficult.  We therefore intend to evaluate the feasibility of administering 
oral chemotherapy for a prolonged period of time (24 weeks) to children in this 
population. 
 
After the first 20 patients complete maintenance therapy, we will assess the 
feasibility of this objective.  Based on patient diaries, we will estimate the 
percentage of total scheduled doses patients received per course for each of oral 
topotecan, cyclophosphamide, erlotinib and etoposide. We believe that if the 
average number of doses received per course is less than 75% of the scheduled 
number of doses due to toxicity or patient refusal to take the agent, then the 
feasibility of administering oral maintenance therapy in very young children may 
be in question.  The feasibility assessment will be repeated after every 30 patients 
complete maintenance therapy.  
 
To use quantitative MR measures (volumetric, diffusion, and perfusion) of brain 
tumor patients less than 3 years of age receiving chemotherapy including high-
dose intravenous methotrexate to assess impact of treatment on developing brain. 
 
Quantitative MRI measures of change in neurostructure (especially white matter 
volume and integrity) over time will be assessed using a random effects model 
incorporating various covariates. Covariates to be considered include age at 
diagnosis, time since diagnosis and risk-arm. Differences in quantitative MRI 
measures of neurostructure volume and integrity between patient groups will be 
evaluated as a metric of structural neurotoxicity of therapy. Exploratory analyses 
will also investigate the association between patterns of neurostructure changes 
and clinical and demographic variables. 
 

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Positron Emission Tomography for Dose Verification after Proton Beam Therapy 
(for participants enrolled at St Jude only) 
 
All intermediate risk patients treated at St Jude are eligible to receive proton beam 
therapy (PBT) and will be routinely referred to the University of Florida Proton 
Therapy Institute (UFPTI), though study investigators expect that family 
preferences (e.g. difficulties associated with relocating to Florida for 
approximately eight weeks, etc.) may play a role in determining the percentage of 
patients who will choose not to receive PBT. Reasons (clinical or family-based) 
for opting out of PBT will be documented and summarized. Additionally if 
adequate number of intermediate risk patients fall in the non-PBT category to 
make such a comparison meaningful, these patients will be compared to patients 
who received PBT based on relevant clinical and demographic characteristics 
such as age, tumor location, tumor type and extent of resection to investigate 
differences between the two groups.  
 
Based on St Jude historical data for the cohort who would have been eligible for 
SJYC07, approximately 50% of patients are expected to be classified as 
intermediate risk. This figure is consistent with the first 79 St Jude patients who 
have been enrolled on the protocol to date, 41 of whom are intermediate risk. The 
accrual goal of the protocol is 90 medulloblastoma patients. It is estimated that 
approximately 225 additional non-medulloblastoma patients will also be accrued 
during the same period. As indicated previously 50% of all patients are expected 
to be classified as intermediate risk, hence the estimated number of intermediate 
risk patients who will enroll on the protocol is 157 and we estimate that 50-60% 
of these patients (78-94) will be treated at St Jude. St Jude historical data suggests 
that EFS at 4 months, which is the end of induction for this cohort of patients is 
72.3% (s.e. 7.46%), hence approximately 56-67 patients will be available to be 
referred for PBT. The study investigators expect 50%-66% of these patients to 
receive PBT and to consent to participate in the required PET studies. Hence we 
estimate that images from 28-44 patients will be available for this secondary 
objective. 
 
This objective aims to assess the feasibility of using post-PBT PET as an in-
vivodosimetric and distal edge verification system in this patient population. To 
this end we will estimate the percentage of PET scans where loss of signal 
intensity or resolution were observed. The former may be due to activation decay 
of relevant isotopes and the latter due to biological washout and patient motion. In 
addition we will estimate the differences observed between the measured and 
simulated parameters such as positron activation locations and intensities.  
 
13.2.3 Pharmacologic aims 
Responsible Investigator: Clinton Stewart 
Responsible Biostatistician: Arzu Onar-Thomas 
 
To develop a population pharmacokinetic model containing covariates which 
explain inter- and intra-patient pharmacokinetic variability for high-dose 
methotrexate in young children with brain tumors, and to explore the relationship 

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between clinical effect (toxicity and antitumor efficacy) and methotrexate 
pharmacokinetics. 
 
A compartmental pharmacokinetic model will be fit to the methotrexate plasma 
concentration-time data using maximum likelihood estimation as implemented in 
ADAPT II (ADAPT II User’s Guide, 1997). Individual pharmacokinetic 
parameters estimated will include volume of the central compartment (Vd), 
elimination rate constant (Ke), and half-life (t1/2). The methotrexate clearance 
will be calculated using the log-linear trapezoidal method.   
 
In addition to estimating individual pharmacokinetic parameters, we will also 
estimate the population parameters using nonlinear mixed effects modeling 
methods (NONMEM). This method estimates the population parameters and both 
the inter- and intra-subject variability. Once the population parameters and 
corresponding covariance matrix are estimated, individual estimates can be 
obtained using post hoc analysis. Thereafter the influence of patient specific 
covariates such as age, body-surface area, and sex on methotrexate 
pharmacokinetic parameters will be evaluated.  
 
A Cox-type survival model, possibly with time dependent covariates, may be used 
to explore the relationships between toxicity and efficacy vs. PK parameters. 
 
To assess the extent of inter-patient variability in the pharmacokinetics of 
intravenous and oral cyclophosphamide and metabolites in young children with 
brain tumors, and explore possible associations between cyclophosphamide 
pharmacokinetic parameters and patient specific covariates (e.g., age, sex, race, 
weight). 
 
Previous studies by Yule et al. have failed to demonstrate a relationship between 
patient specific cofactors, such as a child’s body surface area, age, gender, 
glomerular filtration rate, or hepatic function, and  exposure  to 
cyclophosphamide metabolites DCCY and CEPM365,366.  However, the effects of 
such cofactors on the exposure to the active metabolite HCY have not been 
evaluated in children.  We will therefore estimate the population pharmacokinetic 
parameters for cyclophosphamide and metabolites (i.e. HCY) using nonlinear 
mixed effects modeling methods (NONMEM). This method estimates the 
population parameters and the inter-subject variability. Once the population 
parameters and corresponding covariance matrix are estimated, individual 
estimates can be obtained using post hoc analysis. Using such a method, the 
influence of patient specific covariates such as age, BSA, and sex on 
cyclophosphamide/4-HCY pharmacokinetic parameters will be tested to optimize 
dosing in children with medulloblastoma.   
 
To assess the ability to achieve the target systemic exposure of intravenous 
topotecan in children diagnosed with metastatic brain tumors at a young age. 
 
Based on the accrual as of amendment 5.0, we expect approximately 20-25% of 
the patients enrolled on this study to have metastatic brain tumors, which leads to 

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an estimated 18-23 patients from a total of 90 patients with medulloblastoma and 
another 45-57  patients from the non-medulloblastoma cohort. We anticipate that 
approximately 50-60% of these patients will be treated at SJ and only SJ patients 
will contribute to this objective. The 6-month EFS rate for the high-risk cohort is 
37.1% (s.e. 8.17%), hence we expect samples from 15-20 patients will be 
available for this objective. 
  
Pharmacokinetic studies will be performed on day 1 of IV topotecan therapy 
during the consolidation phase. If the systemic exposure (AUC) of topotecan 
lactone is not within the target range of 140±20 ng/ml*hr on day 1, the topotecan 
dosage will be adjusted on subsequent days to achieve this target.  If a dosage 
adjustment is made, another pharmacokinetic study will be performed to 
determine whether the target AUC has been achieved with the new dosage. If 
pharmacokinetic studies have been performed three times in one course and the 
AUC is still not within the target range, one final dosage adjustment will be made 
without further pharmacokinetic studies during that course. The final dosage from 
course 1 will be used for the initial day 1 dosage during course 2. The same 
pharmacokinetic studies will be performed during course 2 to achieve the target 
AUC. 
 
For analysis of our targeting success rate, we will consider AUC values resulting 
from a pharmacokinetically-guided dosage adjustment differently than those 
determined solely from a predetermined dosage, such as the first dose of cycle 1. 
In the latter instance, we will refer to the AUC value as a “dose success” or a 
“dose failure,” and will reserve the terms “pharmacokinetic targeting success” and 
“pharmacokinetic targeting failure,” respectively, for situations in which the 
dosage adjustment does or does not place the patient’s topotecan lactone AUC 
within the target range. The initial topotecan dosage of course 1 will not count 
towards this feasibility objective, since this dosage is predetermined. 
  
Based on prior experience with topotecan targeting at St. Jude, we expect to 
achieve the target exposure in approximately 70% of targeted PK studies. We will 
assess the targeting success rate (i.e., studies that are targeting successes/total 
number of eligible targeting studies) after the first 10 SJ patients have been 
treated with targeted topotecan on protocol version 3.0 or later. If the targeting 
success rate is less than 60%, we will modify the targeting strategy. See section 
12.2 for details. As part of the analysis we will also provide simple descriptive 
statistics for each group (e.g., dose success and failure, and pharmacokinetic 
targeting success and failure). 
 
To assess the extent of inter-patient variability in the pharmacokinetics of 
intravenous and oral topotecan in young children with brain tumors, and explore 
possible associations between topotecan systemic exposure and patient specific 
covariates(e.g., age, sex, race, weight). 
 
We have evaluated the relationship between patient specific cofactors, such as a 
child’s body surface area, age, gender, glomerular filtration rate, or hepatic 

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function, and topotecan systemic exposure in a population analysis.  However, 
this analysis focused on older children and only included 14 children less than 2 
years old.  Thus, we will estimate the population pharmacokinetic parameters for 
topotecan using nonlinear mixed effects modeling methods (NONMEM). This 
method estimates the population parameters and the inter-subject variability. Once 
the population parameters and corresponding covariance matrix are estimated, 
individual estimates can be obtained using post hoc analysis. Using such a 
method, the influence of patient specific covariates such as age, BSA, 
concomitant drugs, pharmacogenetic factors, and sex on topotecan 
pharmacokinetic parameters will be tested to optimize dosing in very young 
children with brain tumors.   
 
To assess the extent of inter-patient variability in the pharmacokinetics of oral 
erlotinib in young children with medulloblastoma, high-grade glioma and 
ependymoma,, and explore possible associations between erlotinib 
pharmacokinetic parameters and patient specific covariates (e.g., age, sex, race, 
weight). 
 
We will estimate the population pharmacokinetic parameters for erlotinib using 
nonlinear mixed effects modeling methods (NONMEM). This method estimates 
the population parameters and the inter-subject variability. Once the population 
parameters and corresponding covariance matrix are estimated, individual 
estimates can be obtained using post hoc analysis. Using such a method, the 
influence of patient specific covariates such as age, BSA, concomitant drugs, 
pharmacogenetic factors, and sex on erlotinib pharmacokinetic parameters will be 
tested to optimize dosing in very young children with brain tumors.   
 
For St. Jude patients enrolled on the PGEN5 protocol, to assess the relation 
between pharmacogenetic variation in drug metabolizing enzymes and drug 
transporters, and the pharmacokinetics of methotrexate, cyclophosphamide, 
topotecan, and erlotinib in young patients with brain tumors.   
 
All St. Jude patients will be asked to enroll on the institutional protocol PGEN5 
for the collection of blood to process for DNA.  PGEN5 is a non-therapeutic study 
that investigates the influence of genetic polymorphisms on the disposition or 
effects of therapeutic agents.  In this analysis, we will assess the relation between 
appropriate metabolism (e.g., CYP3A5*1) and transporter genotypes (e.g., 
ABCG2 34G>A), and pharmacokinetic metrics (e.g., AUC or clearance) for 
cyclophosphamide, topotecan, methotrexate, and erlotinib.  We will also explore 
the relation between genotype, pharmacokinetic phenotype, and patient outcome.   
 
13.2.4 Cancer control aims 
 
CSF neurotransmitter studies 
Responsible Investigator: Clinton Stewart; Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 

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Correlations between complex neurochemical CSF phenotypes and attentional 
functioning, as well as the effect of genotype on each these two outcomes have 
never been studied in young children with primary tumors of the central nervous 
system.  Because of the lack of data to formulate specific hypotheses, we will 
analyze the following two CNS neurotransmitter objectives after 30 patients have 
been followed for one year (approximately 3-4 CSF samples and 2-3 
neurocognitive scores).  The primary investigator as well as co-investigators from 
pharmaceutical sciences, cancer control, and biostatistics will review the data and 
analysis results for either formulating specific hypotheses to be tested in the 
remaining patients accruing to the study or to stop investigation because of the 
obvious futility of this research.  Results may be reported at a national or 
international meeting emphasizing the exploratory nature of the findings.  If the 
plan is to continue with the investigation, we will report the intention to confirm 
the results in an independent set of data from the same protocol, SJYC07. No 
changes in clinical practice will occur due to this initial unconfirmed analysis.  
 
To explore possible associations between CSF neurotransmitter concentrations, 
with emphasis placed upon concentrations of dopamine and its metabolites, and 
the development of neurocognitive deficits as identified by standardized tests. 
Responsible Investigator: Clinton Stewart; Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 
To investigate whether neurocognitive deficits after medulloblastoma therapy are 
associated with suspected iatrogenic disturbances in central dopamine 
transmission, an exploratory study of CNS neurotransmitters will be undertaken 
with particular focus placed upon dopamine and metabolite profiles. Short term 
relationships will be investigated by calculating differences in the pre-treatment 
and 1 year values for both the neurotransmitter and attentional outcomes.  
Appropriate regression analyses (parametric or nonparametric, e.g. splines) will 
be used to assess the relationship between the change in neurotransmitter values 
vs. the change in neurocognitive function. Long term effects, estimating the 
change in neurotransmitter values and the change in attentional function and 
working memory through treatment and post-treatment, will be investigated using 
random coefficient models or some other appropriate model for longitudinal data. 
Ideally all analyses must take into consideration risk group, neurocognitive 
intervention, and other covariates deemed important however sample size 
considerations may make this infeasible.  The effects of serotonin and its 
metabolite, 5-HIAA, will also be investigated in the same manner. 
 
To explore the association between genetic polymorphisms affecting central 
dopaminergic transmission and specific phenotypes, including CNS 
neurotransmitter and neurocognitive performance phenotypes. 
Responsible Investigator: Clinton Stewart; Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 
 

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Genotyping for genetic polymorphisms (e.g. DAT1, DRD4) will be assessed 
using standard molecular techniques.  Based on the observed allelic frequencies, 
we expect to analyze the genotypes on a homozygous/heterozygous 
categorization. If, however, low frequencies are observed, patients will be 
grouped by presence or absence of particular polymorphisms for analysis.  We 
will report the distribution of homozygosity and heterozygosity, as well as the 
distribution based on presence vs. absence for each polymorphism.   
 
To assess the effect of pharmacogenetic variation on CNS transmitters, we will 
initially consider only the dopamine and serotonin neurotransmitters and 
metabolites provided in Table 21.  Kruskal-Wallis tests will be used to evaluate 
differences in neurotransmitter concentrations at study enrollment by DAT1*10 
and DRD4*7 polymorphisms.  Random coefficient models or other models 
appropriate for longitudinal data will be used to evaluate the association of the 
DAT1*10 and DRD4*7 polymorphism with the change in neurotransmitter levels 
throughout treatment and post-treatment. 
 
To assess the correlation of pharmacogenetic variation with neurocognitive 
performance phenotypes, random coefficient models or other longitudinal models 
will be used to evaluate the association of genetic polymorphisms with changes in 
attentional functioning and working memory 
 
Neuropsychological objectives 
Responsible Investigator: Heather Conklin 
Responsible Biostatistician: Hui Zhang 
 
To investigate changes in neuropsychological performance among patients 
enrolled in the study, and examine the impact of the proposed treatment regimen 
and other disease related factors (e.g., hydrocephalus) on neuropsychological 
performance. 
 
 
 
 
Hypothesis 1: There will be a decline (negative slope) in global  
 
 
cognitive functioning for the group as a whole. 
 
 
Hypothesis 2: Hydrocephalus (correcting for CSF diversion) will   
 
be associated with a steeper decline in global cognitive              
 
 
functioning. 
 
 
Hypothesis 3: Higher radiation doses to specified structures (e.g.,   
 
the frontal lobes) will be associated with steeper declines on  
 
 
related  functions (e.g., attention and working memory). 
 
Patients treated on this protocol will be subjected to serial neuropsychological 
evaluations (baseline, 6- and 12-months from treatment initiation and yearly after 
the first year.) Random-coefficient models relating the longitudinal 
neuropsychological performance measures to demographic variables (e.g., gender, 
age at diagnosis) disease-related covariates (e.g., tumor type, tumor location, 

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number of surgeries, extent of resection, presence of hydrocephalus. duration of 
time between symptom onset and treatment, endocrine abnormalities [particularly 
growth hormone], presence of a shunt, number of shunt revisions) and treatment-
related factors (e.g., chemotherapy agents and radiation dosimetry) will be studied 
in single or multivariable models based on data availability. If the number of 
longitudinal measurements is deemed too small per patient to make longitudinal 
random coefficient models effective then an attempt will be made to associate 
disease and treatment related covariates to changes in neuropsychological 
performance measures via parametric or non-parametric regression approaches. 
Such regression models will also be used to study short term changes in 
neuropsychological performance measures (differences in the pre-treatment vs. 6-
month and pre-treatment vs. 1 year values) via their association with these 
covariates. 
 
 
Our ability to assess structure-function relationships (Hypothesis 3) will depend 
on the number of patients who receive a significant radiation dose to the 
structures of interest, and survive long enough to undergo repeated neurocognitive 
testing.  Anatomical structures of interest and their corresponding neurocognitive 
functions are presented in Table 34.  Assessment of relationships between 
posterior fossa RT dose and motor coordination should be quite feasible, given 
the expected preponderance of medulloblastoma patients enrolled on the trial; 
medulloblastomas are located in the posterior fossa by definition and have 
moderate survival rates.  We plan to evaluate each of the other relationships if the 
number of surviving patients with relevant radiation exposure permits.  Additional 
structure-function relationships may also be evaluated, if there is evidence from 
the available literature to suggest such a relationship. 
 
TABLE 34 POSSIBLE STRUCTURE-FUNCTION RELATIONSHIPS TO BE ASSESSED 
Anatomical Structure 
Neurocognitive Function 
Posterior Fossa 
Motor Coordination 
Frontal Areas 
Attention; Working Memory 
Medial Temporal Lobes 
Memory 
Left Temporal Lobe/Perisylvian Area 
Language; Reading 
Right Parietal/Occipital Lobes 
Visual-spatial Reasoning 
 
Variables for dose-volume analyses will include, for a specified normal tissue 
volume, representing the lobes of the brain and smaller functional elements, the 
mean dose and V0-5 Gy, V5-10 Gy, V10-15 Gy, V15-20 Gy, V20-25 Gy, V25-30 Gy, V30-35 Gy, 
V35-40 Gy, V40-45 Gy, V45-50 Gy, V50-55 Gy, V55-60 Gy. The latter variables represent the 
percent volume receiving dose over the specified interval which will be used for 
correlation with the magnitude and time to onset of clinically significant CNS 
effects including cognitive, endocrine, audiometric, neurologic and structural 
abnormalities.   
 

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Hydrocephalus measurements (evans index, cella media index, ventricular angle 
and frontal horn diameter) corresponding to the time of diagnosis, enrollment, 
completion of therapy and two years after the initiation of therapy will be 
recorded for each patient along with clinical information about CNS diversion 
(presence or absence of ventriculostomy, CSF shunting and shunt revisions). 
Correlations between hydrocephalus measurements and biologic, 
neuropsychological and neurostructural outcomes have not been studied in this 
patient population. We hypothesize that the baseline and longitudinal changes in 
hydrocephalus measurements, when corrected for temporary or permanent CSF 
diversion will influence the baseline biologic, neuropsychological and 
neurostructural measurements.  These data will be generated for use by study co-
investigators to study the magnitude and rate of change in hydrocephalus 
parameters and to determine their value as covariates in the secondary objective 
aims for this protocol. Results may be reported at a national or international 
meeting emphasizing the exploratory nature of the findings. 
 
Interim Analysis to assess neurocognitive development of young children: 
 
We are interested in conducting an interim analysis to take a preliminary look at 
the trajectory of neurocognitive development among children diagnosed with 
malignancies of the CNS in infancy and treated with risk-adapted therapy using a 
comprehensive battery to assist with planning for dissemination of findings 
through conference presentations and manuscripts. Any manuscript which results 
from the interim look at the data will clearly state that these results are 
preliminary. Furthermore, the manuscript that reports the final results from these 
data at the end of the trial will acknowledge the interim look at the data and 
reference the relevant manuscripts or presentations. 
 
Our primary domains of interest are detailed below: 
 
• Intelligence as measured by the Cognitive Scale Composite Score, Bayley 
Scales of Infant and Toddler Development, Third Edition or Abbreviated IQ 
from the Stanford-Binet Intelligence Scales, 5th Edition. 
• Attention as measured by the Test of Visual Attention, Auditory Attention 
from the Woodcock Johnson Tests of Achievement, 3rd Edition and Parent 
Report on the Behavior Assessment System for Children, Second Edition.  
• Executive Function as measured by Retrieval Fluency and Auditory Working 
Memory from the Woodcock Johnson Tests of Achievement, 3rd Edition, and 
Parent Report on the Brief Inventory of Executive Function.  
• Processing Speed as measured by the Visual Matching and Decision Speed 
subtests of the Woodcock Johnson Tests of Achievement, 3rd Edition. 
 
By assuming intelligence (as measured by the Cognitive Scale Composite Score, 
Bayley Scales of Infant and Toddler Development or Abbreviated IQ from the 
Stanford-Binet Intelligence Scales) drops by about 1/3 of a standard deviation 
from baseline to 3-year assessment, 73 subjects will be needed to obtain 80% 
statistical power and 5% type 1 error by paired t-test. Therefore, an interim 

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analysis will be performed once we have at least 73 patients who have completed 
their 3-year neuropsychology assessment and have been measured for at least one 
of the domains mentioned above at 3 years (+/- 3 months) since enrollment and at 
least one additional assessment prior to this one. Patients who may have missed 
their 3-year assessment but who have been assessed at a later time point will also 
be counted towards the 73 patients provided they have at least 1 more 
measurement before the 3-year time point. Although paired t-test was used to 
estimate sample size, a mixed-effect model will be employed to study change 
over time since treatment initiation in these data. While these 73 patients will 
determine the timing of the proposed interim analysis, our model will incorporate 
all the patients who have at least two neuropsychology assessments with the 
constraint that they must have at least 1 measurement at or beyond 1-year. To 
address the association of other factors (e.g., treatment intensity, patient age and 
presence/absence of posterior fossa syndrome), they will be included as covariates 
in the mixed-effect modeling. We may also consider other potential factors for 
inclusion in these models as appropriate. 
 
 

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Diagnostic imaging objectives 
Responsible Investigator: Eugene Reddick, Heather Conklin 
Responsible Biostatistician: Hui Zhang, Yimei Li 
 
To assess the impact of changes in quantitative MR measures in the frontal lobe 
on neurocognitive performance in attention, working memory, and fluency. 
 
Associations between changes in quantitative MR measures in the frontal lobe 
and changes in neurocognitive performance in attention, working memory, and 
fluency will be studied via random effects models if adequate longitudinal data is 
available.  Note that one test battery will be used to evaluate children younger 
than 3 years of age and and different battery will be used to assess children older 
than 3 years of age.  Some neurocognitive measures will only be included in the 
test battery for older children; for these measures, analyses will be performed 
based on data collected after patients reach 3 years of age. Several other measures 
(e.g.,  IQ, adaptive functioning and executive function) will be included in both 
batteries, and will be more amenable to longitudinal analysis. If the amount of 
longitudinal data for a particular measure is deemed inadequate for analysis, 
regression (parametric or nonparametric) type approaches may be utilized to study 
changes (e.g. baseline vs. 6-months; baseline vs. 1-year) in these variables.  
 
To assess the impact of changes in quantitative MR measures in the right frontal-
parietal regions on neurocognitive performance on visual-spatial reasoning and 
processing speed.   
 
Quantitative MRI measures of change in neurostructure may provide in vivo 
measures of the impact of therapy on the normal brain. Models incorporating 
measures of therapy (risk arm, radiation dose) and quantitative MRI of 
neurostructure (especially white matter volume and integrity) will be evaluated 
first to ensure conditions necessary to test for statistical inference by computing 
partial correlation coefficients, controlling for age at diagnosis and time since 
diagnosis in all analyses. Random effects models may also be utilized if the 
longitudinal nature of the data is deemed adequate. As discussed above, however, 
some neurocognitive measures will only be obtained in children older than 3 years 
of age, and the amount of longitudinal data for these measures may therefore be 
limited.  With sufficient sample size, it would be preferable to use path analysis or 
structural equation modeling (SEM) to examine each conceptual model. 
 
To evaluate endocrine function before and after radiation therapy (for 
participants enrolled at St Jude only) 
Responsible Investigator: Thomas Merchant 
Responsible Biostatistician: Arzu Onar-Thomas 
 
It is estimated that 66-80 St Jude patients will be eligible for referral for proton 
beam therapy (PBT) and the study investigators expect that 45-60 patients will 
receive PBT.  Serial GH testing (at baseline, the end of therapy, and at 6 and 24 

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months after completion of therapy) will be performed on consenting patients in 
order to estimate longitudinal change in GH secretion as measured by mean peak 
GH values, with the intent to explore associations with radiation dose to the 
hypothalamus.  Since determination of proton- or photon-based radiotherapy is 
not based on randomization, it will not be possible to compare the endocrine 
outcome between the patients with and without PBT.  However, the differences 
between these two clinical cohorts with respect to clinical and demographic 
variables of interest will be summarized via descriptive statistics.  Due to the 
same constraints, the results of the modeling exercises described below are 
exploratory and should be interpreted as hypothesis generating. 
 
The intent of this objective is to estimate the longitudinal change in abnormal GH 
secretion as measured by mean peak GH values via a mixed effects model for the 
patients who receive PBT.  If sample size is sufficient (n>10), a separate model 
will be developed for patients receiving photon-based radiation therapy, though 
no direct comparison between the two cohorts will be made. 
 
Within the constraints of the available sample size, it is also of interest to 
incorporate various clinical and treatment-related variables into the model.  These 
other variables include pre-existing medical conditions and medications, age of 
the patient at the time of diagnosis and irradiation, symptomatic interval and 
progression events prior to irradiation, tumor location and volume, hydrocephalus 
and its management, extent and number of surgical procedures and related 
morbidity, prior chemotherapy and related morbidity, neurologic effects of tumor 
including seizures, technical factors of irradiation, neuro-imaging changes, the use 
of corticosteroids, measures such as patient height and weight, common toxicity 
coding and the type and extent of adverse events.  Since sample size is expected 
to be a notable constraint in these analyses, it will not be possible to build a model 
which will include several of these variables simultaneously. A well-established 
convention in the statistical literature uses 10 patients per covariate included in 
the model6.  We will also use this approach to determine the number of covariates 
that can be simultaneously modeled.  Also, please note that the 6-month and 1-
year PFS estimates for the St Jude historical cohort for the intermediate risk 
patients are 46.3% and 36.5%, respectively.  Hence, significant missingness may 
be expected in the later time-points for the GH tests.  If this is observed, the effect 
of these missing values on the overall conclusions will be investigated via various 
imputation methods.  In the event that the percentage of patients with missing data 
at the later time points exceeds 50%, the longitudinal models will be solely based 
on the earlier time points.  Additional exploratory models will be used to 
investigate the effect of the above-mentioned clinical and treatment-related 
factors on the incidence and time to onset of GHD defined at various levels 
(including peak serum GH < 10 ng/mL and < 7 ng/mL. 

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14.0  OBTAINING INFORMED CONSENT 
 
The process of obtaining informed consent will follow institutional guidelines. Informed 
consent will be obtained by the attending physician or his/her designee in the presence of 
at least one witness. After the eligibility criteria have been confirmed and the research 
participant is deemed eligible, we will seek consent from the parents or guardians.  As all 
research participants enrolled on this trial will be less than 5 years old at the time of 
diagnosis, assent from the research participant will not be obtained. 
 
14.1 
INFORMED CONSENT PRIOR TO RESEARCH INTERVENTIONS 
 
Written informed consent must be obtained prior to performing any research 
interventions, evaluations or tests done as part of eligibility determination.  This 
can be accomplished by institutional screening consent or with SJYC07 IRB-
approved informed consent. 
 
14.2 
CONSENT WHEN ENGLISH IS NOT THE PRIMARY LANGUAGE 
 
When English is not the patient, parent, or legally authorized representative’s 
primary language, the Social Work department will determine the need for an 
interpreter.  This information documented in the participant’s medical record.  
Either a certified interpreter or the telephone interpreter’s service will be used to 
translate the consent information.  The process for obtaining an interpreter and for 
the appropriate use of an interpreter is outlined on the Interpreter Services, OHSP, 
and CPDMO websites. 
 
14.3 
COLLECTION OF COLLABORATING INSTITUTION CONSENT FORMS 
 
St. Jude research staff will fax signed collaborating institution’s consent forms to 
the CPDMO Eligibility Office at 
  
 
 

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15.0 
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 351.  Pagano M, Gauvreau K. Principles of biostatistics. 2nd ed. Australia: Brooks-Cole, 2000. 
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 364.  Cheng C, Pounds S. A review of FDR methods for microarray data analysis. 
Bionformation 2007; 1:436-446 
 365.  Yule SM, Boddy AV, Cole M, Price L, Wyllie R, Tasso MJ et al. Cyclophosphamide 
pharmacokinetics in children. Br J Clin Pharmacol 1996; 41:13-19 
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Oncol. 2009;11:201–210. 

SJYC07 
Appendix I 
 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
APPENDIX I: DRUGS THAT MAY AFFECT CYCLOPHOSPHAMIDE/4-HCY AND 
ERLOTINIB/OSI-420 METABOLISM. 
 
CYP 3A4/5 Moderate and Potent Inhibitors 
Cannabinoids 
Itraconazole** 
Cimetidine 
Ketoconazole** 
Clarithromycin** 
Nefazodone 
Cyclosporine 
Nelfinavir$ 
Delavirdine 
Nevirapine 
Diltiazem 
Ranitidine 
Erythromycin** 
Ritonavir**,$ 
Fluoxetine** 
Saquinavir$ 
Fluvoxamine** 
Sertraline 
Grapefruit juice** 
Zafirlukast 
Indinavir**,$ 
 
**Strong inhibitors 
$Protease inhibitors 
 
CYP3A4 Inducers 
Phenytoin 
Carbamazepine 
Rifampicin 
Phenobarbital 
St. John’s Wart 
Glucocorticoids (i.e. dexamethasone) 

SJYC07 
Appendix II 
 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
APPENDIX II:  LANSKY PERFORMANCE SCALE 
 
PERFORMANCE STATUS CRITERIA 
Lansky performance scores are intended to be multiples of 10 
Score 
Description 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed, but lies around much of the day; no active play, able to 
participate in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed. 

SJYC07 
Appendix III 
 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
APPENDIX III: TREATMENT OF SYNCHRONOUS EXTRANEURAL ATRT 
 
Occurrence of a synchronous extraneural tumor in patients with ATRT is an uncommon event 
associated with a dismal prognosis.  Patients with such tumors are eligible for treatment on this 
protocol.  In general, treatment will be based on CNS staging, so that patients with otherwise M0 
disease are treated according to the intermediate risk arm of the study, and those with M1-3 
disease are treated according to the high risk arm.  Local control of extraneural disease sites 
should also be performed in a manner appropriate for the disease site, including complete 
resection if possible and local RT.  RT dose should be chosen by disease site in coordination 
with the principal investigator and Radiation Oncology Section Head.  Examples are provided 
below: 
 
Example 1 – Patient with M0 CNS disease (no intracranial or spinal metastasis on MRI, negative 
CSF cytology) and synchronous renal rhabdoid tumor.  After initial complete resection of CNS 
tumor and nephrectomy, chemotherapy should be administered according to the intermediate risk 
arm.  Consolidation should consist of conformal RT to the intracranial tumor bed to 54.0 Gy as 
detailed in this protocol, plus appropriate flank or abdominal radiation.  Abdominal RT dose and 
field should be based on the current standard therapy for patients with high risk renal tumors 
(e.g., 19.8 Gy as per COG study AREN0321). 
 
Example 2 – Patient with M3 CNS disease and synchronous renal rhabdoid tumor.  After initial 
maximal safe resection of CNS tumor and nephrectomy, chemotherapy should be administered 
according to the high risk arm.  Consolidation should consist of craniospinal irradiation or 
topotecan/cyclophosphamide as detailed in this protocol.  Decisions regarding flank/abdominal 
RT will be made on a case by case basis. 

SJYC07 
Appendix IV 
 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
 
 
APPENDIX IV:  CHANG OTOTOXICITY GRADING CRITERIA 
 
Chang Ototoxicity Grading Scale* 
 
Chang Grade 
(New Scale) 
Sensorineural Hearing Threshold (dB HL) 
Bone conduction or air conduction with normal tympanogram 
CCG Grade 
(Old Scale) 
0 
≤ 20 dB at 1, 2, and 4 kHz 
No change from 
baseline is grade 0 
1a 
≥ 40 dB at any freq 6 to 12 kHz 
1 
1b 
> 20 and < 40 dB at 4kHz 
2 
2a 
≥ 40 dB at 4 kHz and above 
-- 
2b 
> 20 and < 40 dB at and freq below 4kHz 
3 
3 
≥ 40 dB at 2 or 3 kHz and above 
4 
4 
≥ 40 dB at 1 kHz and above 
Not defined 
 
 
 
 

SJYC07 
Appendix V 
 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
APPENDIX V: HIGH-TYRAMINE FOODS TO AVOID 72 HR PRIOR TO CSF 
NEUROTRANSMITTER SAMPLING 
 
Smoked, aged, or pickled meat or fish 
Sauerkraut 
Aged cheeses (e.g., swiss, cheddar, blue, boursault, camembert, emmenthaler, stilton) 
Yeast extracts 
Fava beans 
Beef or chicken liver 
Aged sausages (e.g., bologna, pepperoni, salami, summer sausage);  
Game meats (e.g., venison, rabbit) 
 

SJYC07 
 
 
Appendix VI 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
APPENDIX VI – RECOMMENDED TREATMENT FOR PATIENTS WITH 
PROGRESSIVE DISEASE 
 
Treatment of patients with progressive disease will vary based on the timing and site of disease 
progression.  In general, it is recommended that treatment include components of SJYC07 
therapy to which the patient has not yet been exposed.  In particular, the intravenous 
topotecan/cyclophosphamide regimen described in section 4.3.3 should be administered as 
consolidation therapy for patients with progressive disease who have not previously been treated 
with this regimen.  Treatment of St. Jude patients with progressive disease will be discussed at 
the weekly St. Jude multidisciplinary brain tumor conference.  For patients from other sites, it is 
strongly recommended that management of disease progression be discussed with the principal 
investigator.  Specific scenarios are discussed below. 
 
Local Recurrence or Progression:   
 
 
 Patients with M0 disease at initial diagnosis who experience local disease recurrence or 
progression should undergo maximal safe resection, followed by focal RT (if not already 
given) and consolidation with intravenous topotecan/cyclophosphamide, as detailed in the 
high-risk consolidation regimen (see section 4.3.3).  
 
 
 RT for patients with all diagnoses other than high-grade glioma should be given 
according to the RT guidelines in section 4.6.  Radiation therapy for patients with high-
grade glioma will include different targeting and dose guidelines. The gross tumor 
volume will be based on the combined MRI post-contrast T1- and T2-weighted imaging 
sequences with an anatomically constrained clinical target volume margin of 2cm. The 
planning target volume margin with include a geometric expansion of 0.3-0.5cm. The 
minimum dose prescribed to the planning target volume should be 54Gy. A total dose of 
59.4Gy may be prescribed to the same volume or a subvolume at the discretion of the 
treating physician. The normal tissue dose constraints will be similar to those specified 
for the embryonal tumor group.     
 
 
 Maintenance therapy according to the initial treatment plan (see section 4.4) may 
subsequently be administered, if it has not already been given. 
 
 
Example 1:  Patient with M0 classical medulloblastoma (initially intermediate risk) 
develops local recurrence after 2 induction cycles.  Recommended treatment would 
include resection followed by focal RT, then consolidation with two cycles of 
intravenous topotecan/cyclophosphamide as detailed in section 4.3.3, then maintenance 
with alternating oral cyclophosphamide/topotecan and erlotinib (see section 4.4). 
 
Example 2:  Patient with M0 ATRT (initially intermediate risk) develops local recurrence 
after maintenance cycle A2.  Recommended treatment would include resection followed 
by consolidation with two cycles of intravenous topotecan/cyclophosphamide (see 
section 4.3.3).   

SJYC07 
 
 
Appendix VI 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
Distant Recurrence or Progression: 
 
Patients with distant (M1+) recurrence or progression have a dismal prognosis.  The decision to 
pursue further treatment should be made only after careful discussion with the family which 
considers the patient’s age, functional status, tumor histology, and previous treatment.  For 
patients younger than 3 years of age at the time of disease progression, chemotherapy with 
intravenous topotecan/cyclophosphamide is recommended, if it has not been administered 
previously.  For patients older than 3 years at the time of disease progression, CSI may also be 
considered. 
 
The older cohort of medulloblastoma patients enrolled on the study (≥3-< 5 yrs of age) who have 
a distant recurrence should be treated with CSI as outlined in the HR arm of the study and 
continue with the oral chemotherapy portion of the study. 
 
 
 
 

SJYC07 
 
 
Appendix VII 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
APPENDIX VII – REQUIRED DATA AND TIME TABLE FOR SUBMISSION 
 
DATA 
SUBMISSION GUIDELINE 
On Study (All Pre-treatment Assessments) 
Within 14 days of enrollment 
Chemotherapy 
Within 14 days of completion of a course of treatment 
Disease Assessment  
Within 14 days of completion of disease evaluation 
Serious and Unexpected Adverse Events 
Within 5 working days of the event 
Death 
Within 24 hours of knowledge of the event 
Follow Up Evaluations 
Within 14 days of follow-up evaluation 
Off-Treatment 
Within 14 days of off-treatment date 
Off-Study 
Within 14 days of off-study date  
 

SJYC07 
 
 
Appendix VIII 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
APPENDIX VIII – RSV TREATMENT GUIDELINES 
 
PROPHYLAXIS  
 
Principles  
• Monoclonal anti-RSV antibody (palivizumab) has been proven effective in reducing 
severe RSV infection in premature infants and young children with chronic lung 
disease. While it has not been evaluated in randomized trials in immunocompromised 
children, judicious use of this compound for prevention of RSV disease in patients at 
high risk of RSV related morbidity and mortality is indicated.  
 
Candidates  
• Patients ≤ 2 years of age on SJYC07, during the RSV season (November – March), 
may be considered for prophylaxis on a case by case basis in consultation with the 
Department of Infectious Diseases.  
 
Recommended Procedure  
 
1. Palivizumab is administered intramuscularly at a dose of 15 mg/kg, monthly from the 
beginning of November to the beginning of March. While not FDA-approved, the 
intravenous route may be safe and well-tolerated. Contact the local pharmacy or review 
the online St Jude Formulary Handbook for more information on IV administration.  
2. If a patient who is receiving immunoprophylaxis has a breakthrough RSV infection, 
prophylaxis should continue through the RSV season because the patient can get re-
infected. RSV subtypes may show variable susceptibility to palvizumab and failure of 
immunoprophylaxis once is not necessarily a predictor of its success (or lack of) in the 
future.  
3. Palivizumab is packed in 100- and 50-mg vials that must be used within six hours after 
they have been opened. Coordination with the pharmacy is encouraged to cohort patients 
requiring prophylaxis and to minimize wastage of this expensive compound. For patients 
weighing less than 9 kg, the pharmacy will round the dose to the nearest 25 mg.  
4. For patients weighing equal to or more than 9 kg, the pharmacy will round the dose to the 
nearest 50 mg.  
 
TREATMENT  
 
Principles  
 
• RSV infected patients, especially those who are severely immunocompromised, 
frequently have co-infections. RSV upper respiratory tract infection (URTI) does not 
rule out  lower respiratory tract infction (LRTI) by another co-pathogen. In severely 
immunocompromised patients, further tests including bronchoalveolar lavage in 
patients with LRTI should be done as clinically indicated.  
 
• High morbidity and mortality result from LRTI (RSV pneumonia).  
 
• Risk factors for the progression of URTI to LRTI and LRTI to death include: 

SJYC07 
 
 
Appendix VIII 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
o Lymphopenia (<100/mm
3)  
 
o Age ≤ 2 years  
 
• In patients who meet the criteria for treatment, early treatment is beneficial.  
o Survival is better in patients treated > 24 hours prior to respiratory failure 
requiring mechanical ventilation versus those treated late.  
 
o Survival is better with preemptive treatment at the RSV URTI stage as 
compared to historical controls treated late.  
 
• There are no randomized clinical trials that examine the efficacy of palivizumab or 
ribavirin in immuncompromised pediatric patients. The recommendations shown in 
this guideline are based on experience with RSV infection at this institution, existing 
literature and expert opinion. These guidelines do not obviate the role of patient 
specific infectious disease consults and case by case decision making.  
 
• For purposes of these treatment guidelines:  
 
• LRTI is defined as hypoxia, tachypnea or apnea and/or radiographic evidence of 
pneumonia (infiltrates, consolidation). Clinical signs such as wheezing, cough or 
radiological signs such as parenchymal thickening, atelectasis and effusion alone do 
not fulfill criteria of LRTI.  
• Immunocompromised is defined as < 3 months post completion of cancer therapy or 
< two years post HSCT.  
 
Candidates  
 
• Immunocompromised patients with LRTI.  
 
• Patients with URTI who are ≤ 2 years of age and/or lymphopenic (absolute lymphocyte 
count < 100/ mm
3) and/or HSCT recipients (pre engraftment or < 2 months post 
engraftment or with grade 3 or 4 GvHD) and/or have SCIDS  
 
Recommended Procedures  
 
1. All cancer patients with respiratory symptoms should get a fresh, well-collected nasal 
wash sample sent for viral DFA and culture. A nasal wash is recommended over a nasal 
swab. Procedures for collecting a nasal wash or a nasal culture are available in the 
Nursing Policy and Procedure Manual (Volume II).  
 
2. Ribavirin: Ribavirin, 20 mg/ml (6 grams diluted in 300 ml distilled water) over 12 to 18 
hours OR administered as three 2 hour pulses aerosolized through a SPAG unit into a 
respiratory tent. Ribavirin therapy is generally given for 5-10 days but duration of therapy 
has to be determined on a case by case basis (see below).  
 

SJYC07 
 
 
Appendix VIII 
Amendment 9.0, dated: 08-26-2014 
 
IRB Approved date: 10-24-2018 
Protocol version dated: 10-22-2018 
Palivizumab: 25-30 mg/kg IV single dose. Further treatment doses must be approved in 
consultation with the Department of Infectious Diseases for patients at SCRH. 
 
3. For patients weighing less than 9 kg, the pharmacy will round the dose to the nearest 25 
mg.  
 
4. For patients weighing equal to or more than 9 kg, the pharmacy will round the dose to the 
nearest 50 mg.  
 
5. For patients meeting the criterion for anti-RSV treatment, discontinuation of treatment is 
based on clinical evidence of respiratory improvement in the context of documented 
evidence of improvement of the immune system.  
 
6. Discontinuation of therapy should not be based solely on presence or absence of RSV in 
the upper respiratory tract. A negative RSV DFA from an upper airway specimen does 
not rule out RSV lower airway disease and conversely a prolonged period of positive  
 
7. RSV DFA in a recovering, stable patient is not uncommon. Additionally, ribavirin usecan 
reduce the sensitivity of RSV culture from respiratory secretions.