Clinical trial NCT02017964
Conditions: Desmoplastic/Nodular Medulloblastoma Medulloblastoma Medulloblastoma With Extensive Nodularity Nevoid Basal Cell Carcinoma Syndrome
Sponsor: Children's Oncology Group
Start date: 2013-12-24; Completion date: 2022-12-31
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well combination chemotherapy works in treating younger patients with newly diagnosed, non-metastatic desmoplastic medulloblastoma. Drugs used in chemotherapy, such as vincristine sulfate, cyclophosphamide, methotrexate, etoposide, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description:
PRIMARY OBJECTIVES:

I. Estimate of the progression free survival (PFS) distribution for patients 0-\<4 years of age with M0 desmoplastic medulloblastoma (nodular desmoplastic or medulloblastoma with extensive nodularity) treated with the modified HIT SKK regimen (excluding the use of intraventricular methotrexate).

OTHER PRE-SPECIFIED OBJECTIVES:

I. Evaluate the feasibility of a rapid central pathology screening review for treatment allocation according to histology and assess agreement between institutional and central pathology review diagnoses as well as among central pathology review diagnoses.

II. Prospectively evaluate the molecular profile of nodular desmoplastic (ND)/medulloblastoma with extensive nodularity (MBEN) medulloblastoma in young children.

III. Monitor and describe the neurocognitive and adaptive functioning of young children with ND/MBEN medulloblastoma treated on this protocol using the ALTE07C1 protocol.

OUTLINE:

INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) over 1 minute or infused via minibag on days 1, 15, and 29; cyclophosphamide IV over 1 hour on days 1-3; methotrexate IV over 24 hours on days 15 and 29; etoposide IV over 60-120 minutes on days 43-45; and carboplatin IV over 1 hour on days 43-45. Treatment repeats every 63 days for 3 courses in the absence of disease progression or unacceptable toxicity.

CONTINUATION THERAPY: Patients receive vincristine sulfate IV over 1 minute or infused via minibag on day 1, cyclophosphamide IV over 1 hour on days 1-3, etoposide IV over 60-120 minutes on days 21-23, and carboplatin IV over 1 hour on days 21-23. Treatment repeats every 42 days for 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 16, 20, 24, 36, 48, 60, and 72 months.

Arms: arm 1: INDUCTION THERAPY: Patients receive vincristine sulfate IV over 1 minute or infused via minibag on days 1, 15, and 29; cyclophosphamide IV over 1 hour on days 1-3; methotrexate IV over 24 hours on days 15 and 29; etoposide IV over 60-120 minutes on days 43-45; and carboplatin IV over 1 hour on days 43-45. Treatment repeats every 63 days for 3 courses in the absence of disease progression or unacceptable toxicity.

CONTINUATION THERAPY: Patients receive vincristine sulfate IV over 1 minute or infused via minibag on day 1, cyclophosphamide IV over 1 hour on days 1-3, etoposide IV over 60-120 minutes on days 21-23, and carboplatin IV over 1 hour on days 21-23. Treatment repeats every 42 days for 2 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carboplatin intervention 2: Cognitive Assessment intervention 3: Cyclophosphamide intervention 4: Etoposide intervention 5: Laboratory Biomarker Analysis intervention 6: Methotrexate intervention 7: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Optional ancillary studies intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies intervention 6: Given IV intervention 7: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 ACNS1221 
Version Date: 
1/6/17 
Activated:    December 23, 2013 
Closed:        July 27, 2016
Amendment #: 
3 
CHILDREN'S ONCOLOGY GROUP 
ACNS1221 
A Phase II Study For The Treatment Of Non-Metastatic Nodular Desmoplastic 
Medulloblastoma In Children Less Than 4 Years Of Age  
A Groupwide Phase II Study 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY
OTHER PURPOSE.  MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY.  RESEARCH MEANS A
SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO
DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE.  THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED
BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY
QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE
INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT.  THE PROCEDURES IN 
THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS,
AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT.  ANY PERSON WHO REQUIRES MEDICAL
CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST 
LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
TABLE OF CONTENTS 
2 
STUDY COMMITTEE 
5 
ABSTRACT 
8 
EXPERIMENTAL DESIGN SCHEMA 
9 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
10 
1.1 
Primary Aims 
10 
1.2 
Correlative Science Objectives 
10 
2.0 
BACKGROUND 
10 
2.1 
Medulloblastoma Trials of Infancy and Early Childhood 
10 
2.2 
The Nodular Desmoplastic (ND)/Medulloblastoma with extensive nodularity  
(MBEN) histological subtype in infants 
11 
2.3 
Treatment of ND Medulloblastoma/MBEN and Outcome 
13 
2.4 
The Issue of Age Cut Off for Infant Medulloblastoma 
15 
2.5 
Surgical Management of ND Medulloblastoma/MBEN 
16 
2.6 
Neurocognitive and Adaptive Functioning Studies 
17 
2.7 
Molecular Characterization of Infant Medulloblastoma 
18 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
21 
3.1 
Study Enrollment 
21 
3.2 
Patient Eligibility Criteria 
23 
4.0 
TREATMENT PROGRAM 
26 
4.1 
Overview of Treatment Plan 
26 
4.2 
Age Specific Dose Reductions 
27 
4.3 
Neurocognitive Function 
27 
4.4 
Concomitant Therapy Restrictions 
27 
4.5 
Administration Guidelines for Induction Therapy Cycles 1, 2, 3 (63 Day 
Cycles) 
28 
4.5.1 
Therapy Delivery Map for Induction Therapy (Cycles 1, 2, 3) 
34 
4.6 
Administration Guidelines for Continuation Therapy (42 Days) Cycles 1, 2 
36 
4.6.1 
Therapy Delivery Map for Continuation Therapy (Cycles 1, 2) 
39 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
40 
5.1 
Hematological Toxicity 
40 
5.2 
Carboplatin 
40 
5.3 
Cyclophosphamide 
41 
5.4 
Etoposide (VP-16) 
41 
5.5 
High-Dose Methotrexate (HDMTX) and Leucovorin Rescue 
42 
5.6 
Vincristne 
43 
6.0 
DRUG INFORMATION 
44 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
44 
7.1 
Required Clinical, Laboratory and Disease Evaluations During Protocol 
Therapy 
45 
7.2 
Required Observations Following Completion of Protocol Therapy 
46 


 
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7.3 
Required Studies 
46 
7.4 
Optional Studies 
47 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
48 
8.1 
Criteria for Removal from Protocol Therapy 
48 
8.2 
Off Study Criteria 
48 
9.0 
STATISTICAL CONSIDERATIONS 
48 
9.1 
Sample Size and Study Duration 
48 
9.2 
Accrual Duration 
50 
9.3 
Analysis Plan for the Primary Objective 
51 
9.4 
Correlative Science Objectives 
51 
9.5 
Gender and Minority Accrual Estimates 
55 
10.0 
EVALUATION CRITERIA 
55 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
55 
10.2 
Methodology to Determine Tumor Measurement 
55 
10.3 
Selection of Target Lesions 
58 
10.4 
Response Criteria for Target Lesions 
58 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
59 
11.1 
Purpose 
59 
11.2 
Determination of Reporting Requirements 
59 
11.3 
Reporting of Adverse Events for Commercial Agents - CTEP-AERS abbreviated 
pathway 
60 
11.4 
Routine Adverse Event Reporting 
61 
12.0 
STUDY REPORTING AND MONITORING 
61 
12.1 
CDUS 
61 
12.2 
Data and Safety Monitoring Committee 
61 
13.0 
SURGICAL GUIDELINES 
62 
13.1 
Assessment of Residual Tumor 
62 
13.2 
Size of Post-Surgical Residual Tumor 
62 
13.3 
Extent of Tumor Resection 
62 
13.4 
Imaging Confirmation of Extent of Resection 
62 
13.5 
Peri-operative Corticosteroids 
62 
13.6 
Second Surgery 
62 
14.0 
PATHOLOGY GUIDELINES AND SPECIAL STUDIES 
63 
14.1 
Required Rapid Central Pathology Screening Review (See Appendix III) 
63 
14.2 
Virtual Microscopy (VIPER) System 
64 
14.3 
Required Special Studies Specimen Requirements 
64 
14.4 
Rationale for Biology Studies 
66 
14.5 
Methods 
66 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
67 
15.1 
Timing of MRIs 
67 
15.2 
Whole Brain MRI With and Without Contrast 
67 
15.3 
Spine MRI With Contrast 
68 
16.0 
RADIATION THERAPY GUIDELINES 
69 


 
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17.0 
NEUROPSYCHOLOGICAL FUNCTION STUDY 
69 
APPENDIX I: HIGH DOSE METHOTREXATE FLOW CHART 
70 
APPENDIX II: LIST OF ANTICONVULSANTS BASED ON CYP3A4/5 ENZYME 
INDUCTION 
71 
APPENDIX III: ACNS1221 RAPID CENTRAL PATHOLOGY SCREENING REVIEW 
SCHEMA (PRIOR TO STUDY ENROLLMENT) 
71 
APPENDIX IV:  CTEP AND CTSU REGISTRATION PROCEDURES 
74 
APPENDIX V:  POSSIBLE DRUG INTERACTIONS 
76 
REFERENCES 
80 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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AGENT NSC# AND IND#’s 
 
AGENT                           NSC#      IND# 
 
Carboplatin                      241240    Exempt 
 
Cyclophosphamide          026271    Exempt 
 
Etoposide                         141540    Exempt 
 
Filgrastim (G-CSF)          614629    Exempt 
  
Leucovorin                       003590    Exempt 
 
 
Mesna                               113891    Exempt 
      
Methotrexate                    000740    Exempt 
 
Vincristine                        067574    Exempt 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 14.0 FOR SPECIMEN SHIPPING ADDRESSES 


 
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, 
which will help us protect the privacy of our research subjects.  The Certificate protects against the 
involuntary release of information about your subjects collected during the course of our covered studies.  
The researchers involved in the studies cannot be forced to disclose the identity or any information collected 
in the study in any legal proceedings at the federal, state, or local level, regardless of whether they are 
criminal, administrative, or legislative proceedings.  However, the subject or the researcher may choose to 
voluntarily disclose the protected information under certain circumstances.  For example, if the subject or 
his/her guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure.  Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to 
self or others 
 
 
ABSTRACT 
The ACNS1221 study is a single arm multi institutional trial for newly diagnosed young children (0-<4 
years of age at study enrollment) with nodular desmoplastic or medulloblastoma with extensive nodularity  
(M0 ND/MBEN medulloblastoma). The primary objective is estimating the PFS distribution associated 
with treatment as per HITSKK 2000 protocol without intraventricular methotrexate. Eligibility for this 
protocol will be based on central rapid screening pathology review. While the primary objective is 
estimating the PFS distribution associated with the proposed treatment for the purpose of determining the 
sample size the design utilizes a binomial endpoint to look for evidence that the 2-year PFS rate is less than 
90%. The 90% threshold is both desirable for this patient population and is relatively comparable to that 
achieved with HIT SKK 2000 regimen. 
 
 
 
 
 
 
 
 


 
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ENROLLMENT ON  
ALTE07C1 STRONGLY 
RECOMMENDED 
SECOND LOOK SURGERY 
Strongly recommended  
EXPERIMENTAL DESIGN SCHEMA 
         SURGERY 
 
 
 
                                           M0 MEDULLOBLASTOMA           Obtain Prior  
                                                       
 
 
 
 
 
    To Enrollment 
 
      RAPID CENTRAL PATHOLOGY 
          SCREENING REVIEW SEE APPENDIX III 
 
 
ND/MBEN HISTOLOGY CONFIRMED  
           RESERVATION & STUDY ENROLLMENT 
 
 
          INDUCTION THERAPY (CYCLE 1) 
     
 
 
CPM, VCR, CARBO, ETOP, HD MTX 
 
 
RESPONSE EVALUATION 
 
 
          INDUCTION THERAPY (CYCLES 2 & 3) 
     
 
 
CPM, VCR, CARBO, ETOP, HD MTX 
 
 
RESPONSE EVALUATION 
 
 
 
RESIDUAL 
 
              CR  
DISEASE 
 
 
 
 
 
 
 
 
 
 
END OF THERAPY 
 
 
 
 
 
 
                    RESPONSE EVALUATION 
 
 
 
 
 
 
 
 
     
        CONTINUATION THERAPY (2 CYCLES) 
CPM, VCR, ETOP, CARBO 
 
 
                                     RESPONSE EVALUATION/END OF THERAPY 
    M0 – No evidence of metastasis 
ND/MBEN – Nodular desmoplastic or medulloblastoma with extensive nodularity 
    CPM – Cyclophosphamide 
    VCR – Vincristine 
    CARBO – Carboplatin 
    ETOP – Etoposide 
    HD MTX – High Dose Methotrexate 
CR – Complete Response 


 
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aims 
Estimate of the PFS distribution for patients 0-<4 years of age with M0 desmoplastic 
medulloblastoma (nodular desmoplastic or medulloblastoma with extensive nodularity) 
treated with the modified HIT SKK regimen (excluding the use of intraventricular 
methotrexate). 
 
We hypothesize that the PFS distribution associated with treatment as per HIT SKK 2000 
protocol without intraventricular methotrexate in newly diagnosed young children (0-<4 
years of age at diagnosis) with M0 ND/MBEN medulloblastoma will be comparable to the 
outcome observed on HIT SKK 2000 protocol with intraventricular methotrexate. Note 
however that this trial is an independent assessment of the efficacy associated with the 
proposed therapeutic approach and any comparisons of outcome between this study and 
HIT SKK 2000 can only be made in a descriptive fashion. 
1.2 
Correlative Science Objectives 
 
1.2.1 
Evaluate the feasibility of a rapid central pathology screening review for treatment 
allocation according to histology and assess agreement between institutional and 
central pathology review diagnoses as well as among central pathology review 
diagnoses. 
 
1.2.2 
Prospectively evaluate the molecular profile of ND/MBEN medulloblastoma in 
young children. 
 
1.2.3  
Monitor and describe the neurocognitive and adaptive functioning of young 
children with ND/MBEN medulloblastoma treated on this protocol using the 
ALTE07C1 protocol. 
 
 
2.0 
BACKGROUND 
 
2.1 
Medulloblastoma Trials of Infancy and Early Childhood 
Medulloblastoma (MB) in infancy and early childhood (<5 years) are relatively rare and 
constitute a significant therapeutic challenge because of the greater vulnerability of the 
developing brain to treatment related toxicity specifically to cranial radiation. Craniospinal 
radiation, which is a major component of the standard treatment of medulloblastoma, is 
usually avoided or delayed in this age group. More recently, limiting RT to focal radiation 
has been attempted and the final results of these approaches are pending. However, overall, 
the outcome of medulloblastoma in infancy and early childhood is traditionally poorer than 
in older children.   
 


 
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The past 3 decades of clinical trials in infant brain tumors have explored the use of 
chemotherapy to delay the use of extended field of radiation in order to preserve 
neurocognitive function. Early infant study protocols were initially applied to all CNS 
tumor types in this age group. Over time, separate treatment strategies have emerged for 
histologically-determined sub-groups, such as ependymomas, rhabdoid tumors, choroid 
plexus tumors and medulloblastoma. The most recent era of trials have demonstrated 
improved survival rates and provided early evidence of reduced neuro-toxicity, compared 
to historical data. These clinical trials have also brought to light new prognostic factors that 
can be used to risk stratify brain tumors in early childhood. Among these, the 
nodular/desmoplastic histological subtype is prognostic only in the infant medulloblastoma 
cohort unlike the extent of resection and the metastatic status which have been shown to 
be associated with outcome in both infants and older children with medulloblastoma.1-3  
 
The favorable outcome of the ND/MBEN subgroup was initially reported by the German 
group (HIT SKK 92) and was later confirmed in retrospective analyses of most of the 
contemporary infant trials.1,2,4,5 However, all these studies have analyzed histology as a 
prognostic factor in a retrospective manner. Therefore, the logical next step is to 
incorporate the histologic subtype into the clinical risk stratification at the time of diagnosis 
and to tailor treatment according to the known prognostic factors (histology, extent of 
resection and metastatic status). 
 
The trial will focus on non-metastatic (M0) medulloblastoma with nodular 
desmoplastic/extensive nodularity (ND/MBEN). The aim is to achieve similar excellent 
outcome with reduced treatment related neurotoxicity. 
 
2.2 
The Nodular Desmoplastic (ND)/Medulloblastoma with extensive nodularity 
 
(MBEN) histological subtype in infants  
Previous series indicate that the nodular/desmoplastic histology is more common in the 
infant group. Reported rates vary widely among studies, ranging from 29% to 75%. The 
rate reported in the metaanalysis conducted by Rutkowski et al.5 was 41%. The 9934 
protocol had the highest percentage of desmoplastic patients based on central pathology 
review compared to all other published series. In the CCG-9921 protocol, the frequency of 
desmoplastic histology4 amongst centrally reviewed tumors was 22 of the 76 patients 
(29%). Table 1 provides a summary of reported frequencies in several large infant trials.  
 
 


 
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Table 1: Summary of Reported Frequencies of Desmoplastic Medulloblastoma 
 
Trial 
Desmoplastic 
N (%) 
Non Desmoplastic 
N  
SFOP1    
25 (33%) 
50 
HIT SKK 925  
20 (46%) 
23 
HIT SKK 20006  
19 (42%) 
26 
Head Start III (ASCO 2011) 
28 (30%) 
64 (70%) 
CCG-99214 
22 (29%) 
54 
P99347  
39 (75%) 
13 
CCG-99703 (Cohen,  personal 
communication) 
13 (56%) 
10 
Meta-analysis5  
108 (41%) 
 
France 
33 (45%) 
41 
Germany 
29 (40%) 
43 
USA 
10 (32%) 
21 
UK 
17 (61%) 
11 
Italy 
19 (36%) 
36 
 
HIT SKK, HeadStart I, II; CCG 9921 and 9934 are the only trials providing 
frequency  for Non metastatic Medulloblastoma 
 
Part of the explanation in the varying rates of desmoplasia may be related to selection bias 
among the various infant medulloblastoma series such as different ages for inclusion, 
different eras of diagnostic tools and awareness of the diagnosis, as well as absence of the 
requirement for specifying desmoplastic medulloblastoma diagnosis in the protocol. 
However, there is also evidence that lack of consensus on the definition of desmoplastic 
medulloblastoma is also contributing to this discrepancy. Therefore, it appears essential in 
the context of a protocol that is intending to treat according to histologic subtype to 
incorporate a rapid central pathology screening review process rather than relying on 
institutional diagnosis. This study will include pre-screening and rapid central pathology 
screening review to confirm eligibility. In addition, the study will use vitrual microscopy 
(VIPER) online automated pathology review system at the COG Biopathology Center 
(BPC) for the rapid screening central review.  This automated system will notify the 
pathologists and track the rapid central review. Representative H&E and reticulin slides 
will be scanned at the BPC into an ACNS1221 digital tissue review database for use by the 
review pathologists.  
 
Currently 3 COG CNS studies (ACNS0831 for Ependymoma; ACNS0333 for the ATRT 
and ACNS0334 for the High Risk Medulloblastoma in infants) have a rapid central 
pathology screening review process in place to confirm the tumor histology after enrolling 
on the study.  Although the timing of the rapid central pathology reviews is not an objective 
of the studies, for ACNS0831 and ACNS0334 approximately 80% of the reviews were 
completed within the indicated time frame of 12 days on ACNS0831 (5 days for tissue 
submission after study enrollment and 1 week for review) and 19 days on ACNS0334 (3 
working days for tissue submission after study enrollment and 2 weeks for review). In most 


 
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cases, the delays were due to inadequate tissue submission from the institution. Although 
the timing of the rapid review for ACNS0333 is identical to ACNS0334, the percent is 
lower possibly due to the fact frozen tissue is required. 
 
2.3 
Treatment of ND Medulloblastoma/MBEN and Outcome  
 
Table 2 Summary of EFS data for infant M0  medulloblastoma 
 
M0Mb 
ND/MBEN 
 
Non Desmoplastic 
  
  
N 
5 y EFS 
N 
5y EFS 
p 
HIT 
SKK 
2000 
19 (42%) 
95% 
23 
30% 
< 0.01 
HS I, II 
9 (43 %) 
67% 
12 
42% 
=0.34 
CCG 9921 
18 (37%) 
72% 
31 
16% 
< 0.0001 
P9934 $ 
39(53% ) 
58%* 
13 
23%* 
0.008 
99703 
13 (56%) 
   85 % ** 
10 
60%** 
NS 
*4y EFS  
** 3y EFS 
$  based on 52 patients with central pathology review  
 
 
The German group was the first to report the favorable outcome associated with nodular 
desmoplastic histology in infants using a conventional chemotherapy approach with high 
dose methotrexate and repeated intraventricular injections of methotrexate (HIT SKK 92). 
In their initial report3, the 3 year PFS for patients with desmoplastic and classic 
medulloblastoma were 85%±8 and 34%±10, respectively. They further confirmed their 
findings in the subsequent protocol HIT SKK 2000, which was using the same 
chemotherapy backbone with the addition of 2 cycles of conventional chemotherapy 
following complete response to therapy. The 5 year EFS for patients with localized 
ND/MBEN and classic medulloblastoma were 95%±5 and 30% ±11, respectively.6  
 
In the meta-analysis conducted by Rutkowski et al., data from Germany, France, UK, Italy 
and Headstart I and II protocols were pooled.5  The 8 year EFS and OS for patients with 
desmoplastic histology were 55% and 76%, respectively. The prognostic value of 
desmoplasia has also been retrospectively reviewed in several recent North American 
infant trials. In the CCG-9921 protocol, infants with desmoplastic medulloblastoma4  
showed an excellent outcome using conventional therapy, without radiation and without 
high dose methotrexate. Out of 18 M0 patients with desmoplastic medulloblastoma treated 
with this regimen, only 4 required radiation. The 5 year EFS for this group was 72%±11 (5 
year OS of 83%±9), which is comparable to the results of the HIT SKK 92 protocol that 
used both HD MTX and intraventricular methotrexate (82%±9).  
 
Similarly preliminary results from the Head Start III protocol using an intensive high dose 
methotrexate based induction followed by a consolidation with high dose chemotherapy 
and autologous stem cell rescue confirmed the high survival rate of patients with a 
nodular/desmoplastic histology with a 3 year EFS of 89%±6.2  
 
The P9934 protocol included infants aged 8 months to < 3 years with non metastatic 
medulloblastoma, with and without residual disease. This protocol used conventional 


 
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chemotherapy (oral etoposide, cyclophosphamide, cisplatin and vincristine) and early 
radiation to the tumor bed.7  Children with nodular desmoplastic histology fared better than 
non-desmoplastic patients. However the 4 year EFS for the nodular desmoplastic group 
was only 58%±8 with a 4 year OS of 79%±7 (this protocol did not include high dose 
methotrexate). 
 
The COG 99703 phase I/II trial used a sequential high dose chemotherapy and autologous 
stem cell rescue backbone. This study did not demonstrate a significant survival benefit for 
patients with nodular desmoplastic histology. However the results from this protocol are 
still preliminary and the statistical analysis is limited by the small number of patients with 
medulloblastoma (10 with nodular desmoplastic and 13 classic medulloblastoma). 
Furthermore the lack of reliable data collection on the use of adjuvant radiation in this 
protocol precludes any meaningful comparison. 
 
Based on these data, there is now clear evidence that a majority of young patients with 
nodular desmoplastic medulloblastoma can be successfully treated with conventional 
chemotherapy. Based on the outcome information summarized above, 2 regimens were 
considered for this current COG study:   
1) 
the 9921 regimen involving prolonged conventional chemotherapy  
2) 
the German HIT SKK  regimen, which has a shorter duration  
 
The 2 regimens are compared below in Table 3 in terms of cumulative dose of drugs used. 
 
Table 3 Comparison of 9921 and HIT SKK  Regimens with respect to 
Duration and Cumulative Drug Dose 
 
 
The 9921 regimen had a longer duration of treatment (71 weeks).  The large cumulative 
dose of cisplatin is likely to induce significant hearing loss and subsequent speech 
development problems in these very young patients. Additionally, as infants with nodular 
desmoplastic medulloblastoma are expected to be long term survivors, the very high 
cumulative doses of cyclophosphamide and ifosfamide incorporated in this regimen are of 
concern since they increase the risk of infertility. Overall although this regimen appears to 
be associated with similar favorable outcome, its toxicity profile raises significant concern 
especially with regard to fertility and ototoxicity. Thus we chose to use a modified version 
of the HIT SKK regimen in the proposed study. 
 
9921 Regimen A 
9921 Regimen B 
Duration of treatment
71 weeks (15 weeks induction +56 
weeks maintenance)
24 weeks (3 cycles of 2 months each)
Drugs used 
VCR, CDDP, CPM, VP16, CB 
VCR, CB, IFOS, VP16, CPM
MTX, IT MTX, CPM, VCR, CB VP-16
Cumulative dose of 
drugs 
VCR
47 doses 
47 doses 
9 doses ( * +  2 doses) 
CPM 
32.1 g/m2 
15.6 g/m2
7.2 g/m2 ( *+ 2.4g/m2) 
CDDP 
510 mg/m2
0
0
CB 
4.32 g/m2 
5.8 g/m2
1.8 g/m2  (* + 1.2g/m2) 
VP16
3.52 g/m2 
3.6 g/m2
1.35 g/m2*+ 0.9g/m2 
IFOS 
0
36 g/m2 
0
MTX
0
0
30 g/m2 
IT  MTX
0
0
36 x 2 mg 
HIT SKK 92 or * SKK 2000 


 
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Building on the initial results of the HIT SKK 92 protocol, the German group expanded its 
experience with the protocol HIT SKK 2000, using the same backbone with the addition 
of 2 more cycles of chemotherapy. For patients with persistent residual disease after 5 
cycles of chemotherapy, recommendation was made to proceed to CSI and further 
consolidation chemotherapy. However, with the strategy, none of the patients with 
ND/MBEN received more than 5 cycles of chemotherapy, as described in the current 
protocol and no patient underwent radiation for residual disease.6   
 
Although the HIT SKK 2000 regimen still has a much shorter duration compared to the 
9921 regimen, it includes methotrexate delivered both intraventricularly (through an 
Ommaya reservoir for a total of 32 doses of 2 mg) as well as high dose methotrexate 
delivered systemically. The use of intraventricular MTX poses considerable technical 
issues, especially for children with ventriculo-peritoneal shunts and carries significant risk 
of chemical peritonitis. More concerning is the evidence of MRI findings of 
leucoencephalopathy described in the Rutkowski publication.3  A significant correlation 
was reported between the grade of leukoencephalopathy and the cumulative dose of 
intraventricular methotrexate (correlation coefficient, 0.53; P<0.01), but there was no 
correlation between the leukoencephalopathy grade and doses of systemic methotrexate.  
 
Although the authors stated that the leukoencephalopathy were not associated with 
clinically evident symptoms, the neurocognitive performance of these children was 
significantly lower than that of control group of healthy children but higher than that of 
historical group treated with craniospinal irradiation. There was also a trend toward a 
higher neurocognitive status in children who received only systemic methotrexate as 
compared with children who received both systemic and intraventricular methotrexate.3  In 
the absence of detailed information on the long term neurocognitive outcome of the 
German cohort, it is felt that intraventricular methotrexate should not be incorporated in 
the current proposal.  
 
Therefore the intent of the current study is to investigate in a North American multi-
institutional setting whether a similar progression free survival reported in the HIT 
SKK 2000 protocol can be achieved without incorporating intraventricular 
methotrexate injections to limit the risk of leukoencephalopathy and the potential 
associated neurocognitive impairment. Note however this trial is not designed to make 
a formal comparison with HIT SKK 2000 and any such comparison in outcome can 
only be made descriptively.  
 
Additionally, while discussions within the different European pediatric oncology groups 
are ongoing to build on the German experience and to establish a common European 
protocol of treatment for ND/MBEN medulloblastoma in infants, it is felt that having a 
similar backbone chemotherapy regimen in North America will facilitate future 
collaborations particularly for molecular biology studies that appear increasingly essential 
for the development of future protocols. 
 
2.4 
The Issue of Age Cut Off for Infant Medulloblastoma  
The historical definition of “infant” since the inception of so called “baby brain” clinical 
trials has usually been all children less than 3 years of age. However, the upper limit of 
baby brain protocols varies across studies and some clinical trials for young children are 
enrolling patients up to the age of 5 years1  or even up to the age of 10 years as in the 
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The nodular desmoplastic subtype has predominantly been described in the group of 
children under the age of 3 years. However, it is estimated that between 10 and 20% of the 
medulloblastomas seen in children aged 3-5 years will be of nodular desmoplastic 
histology. (Michael Taylor personal communication) 
 
In light of the favorable outcome of patients with nodular desmoplastic medulloblastoma, 
the German group has recently extended the age range of the infant group to 4 years. On 
their protocol HIT 2000, which involved patients enrolled on the trial from January 2001 
to December 2005, there were 11 patients older than 3 years of age. Though the sample 
size is small, three (27%) of these 11 had nodular desmoplastic medulloblastoma, 
suggesting a similar rate of desmoplastic histology to that observed in the group of children 
less than 3 years old (10 out of 34 29%).  
 
Looking at their entire cohort, i.e. including histology-based subtypes (classic, nodular 
desmoplastic, anaplastic), patients between 3 to 4 years of age had a similar OS and EFS 
to those less than 3 years (age limit of the previous HIT-SKK 92 trial). Specifically 5-year 
OS rates: 71±14%vs. 82±6%, (p=0.420) and 5y EFS: 62±15% vs. 56±9%., (p=0.981), 
respectively. No events were reported for the 3 patients older than3 year with nodular 
desmoplastic histology.  (Von Bueren, personal communication) 
 
Similarly the French and Italian groups have included in their infant protocols children up 
to the age of 5 years without suggestion of worse outcome in the subgroup of 3-5 year olds 
with desmoplastic medulloblastoma compared to the 0 to 3 years group. The 8 year EFS 
of 55% reported in the medulloblastoma meta-analysis5 is based on a cohort including all 
children aged from 0 to 5 years with desmoplastic medulloblastoma.   
 
The current COG protocol for older children with medulloblastoma (ACNS0331) will soon 
be closed to accrual. It is well described that in the group of older children (> 3 years old) 
receiving craniospinal radiation, younger patients (less than 7 or 8 years) are at greater risk 
for cognitive decline8,9, and considering the expected excellent cure rate associated with 
the ND/MBEN subtype, it appears reasonable to offer a non radiation approach for the 
youngest of the older children with medulloblastoma. Therefore we extended the age of 
eligibility of the current study to 4 years. 
 
2.5 
Surgical Management of ND Medulloblastoma/MBEN 
Gross total surgical resection is clearly a significant prognostic factor in medulloblastoma 
irrespective of the age group.10  In the ND medulloblastoma/MBEN subgroup, gross total 
or near total resection is often achievable. In the 9921 cohort of desmoplastic children, STR 
(>90%) was achieved in 72.7% of the patient with ND/MBEN subtype. Similarly Von 
Bueren et al described no residual tumor in 14 out of the 19 (73.6%) patients with 
ND/MBEN.6  
 
Although a complete resection is achievable in the vast majority of the cases at the time of 
definitive surgery, it has to be kept in mind that the ND/MBEN subtype is chemosensitive. 
Complete response after initial chemotherapy in HIT SKK 2000 series was achieved in 3/5 
DMB/MBEN with residual disease.  
 
In some instances, ND/MBEN medulloblastoma can present with diffuse involvement of 
the cerebellum in absence of distant metastatic seeding, which may not render them 


 
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Page 17 
amenable to upfront complete surgical resection.  Therefore radical operations in tumors 
localized in areas with an increased risk of postoperative neurological deficits should be 
avoided in patient with ND/MBEN subtype. It is important to be cognizant of the age at 
presentation and radiological features suggestive of the ND/MBEN before the initial 
surgical procedure.  
 
Figure 1 MRI Imaging of Nodular Medulloblastoma 
 
 
                       
  
On T2-weighted and post-gadolinium sequences, the tumor shows an extensive nodular 
grape- like appearance.11  
 
However in patients with significant residual tumor after first surgery and initial 
chemotherapy, maximal safe secondary surgery will strongly be recommended.  
 
2.6 
Neurocognitive and Adaptive Functioning Studies 
Although the major intent of the infant brain tumor treatment strategy has been to protect 
this very young and vulnerable population from the radiation related neurocognitive 
impairment, the prior track record for neurocognitive evaluation in previous COG brain 
tumor protocols has not been impressive.  Therefore limited neurocognitive data in an 
infant population are available to document the benefit of such strategies in the infant 
population. 
 
However, since the inception of the ALTE07C1 protocol, the Behavioral Science 
Committee (BSC) of COG has demonstrated significantly improved rates of 
neurocognitive data collection. According to the most recent study progress report for  
ALTE07C1, the compliance rate for the time one (T1) evaluations is approximately 90% 
and the compliance rate for the time two (T2) evaluations is 82%. Because of this success, 
ALTE07C1 is now paired with 5 separate therapeutic trials that have primary or secondary 
aims to examine neurocognitive outcomes. As it is well agreed that the preservation of 
neurocognitive outcome in very young children with brain tumors is of paramount 
importance, the descriptive evaluation of neurocognitive and functional outcomes for these 
survivors is vital to the scientific aims of this study. Therefore enrollment on ALTE07C1 
will be strongly recommended for the patients enrolled on the current protocol ACNS1221. 
 


 
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While enrolled on ALTE07C1, ACNS1221 patients will be assessed at 3 time points: T1 
(9 months), T2 (30 months), and T3 (60 months) post diagnosis (all assessments are ± 3 
months).  
 
It is anticipated that mean neurocognitive and adaptive functioning will be within the 
average range for normative data at T1 and that scores will not significantly decline over 
time (T2 and T3). One measure of neurocognitive and one measure of adaptive functioning 
will be used as primary outcomes for measuring children’s performance over time.  
 
To evaluate overall adaptive functioning, the General Adaptive Composite score (GAC) 
from the Adaptive Behavior Assessment System–II (ABAS-II) will be used, which is a 
parent-report measure that provides a comprehensive assessment of adaptive behavior 
skills.12  
 
Given that this measure has norms starting at birth, these serial data will be obtained for all 
children enrolled on this study.  The standardization sample for the ABAS-II consisted of 
2100 individuals stratified by gender, race/ethnicity, and educational level according to 
year 2000 US Census data.  Data focusing on reliability are very strong (Cronbach alpha, 
test re-test, and inter-rater).  Satisfactory content, construct, and criterion-validity have 
been reported. With an emphasis on the ABAS-II, we will have potential data from 3 time 
points for all participating children.  Interpretation of these data can utilize scores over time 
(slopes) and comparison to measure norms.   
 
Beginning at age 2 years 6 months, Full Scale IQ (FSIQ) will be evaluated using key 
subtests (Vocabulary and Block Design) from the age-appropriate version of the Wechsler 
Intelligence Scale.13  These 2 subtests allow for a reasonably accurate measure of estimated 
IQ (rss= .91).   Since ALTE07C1 obtains data at  9, 30, and 60 months after diagnosis, all 
participating children will have potential data at 30 and 60 months after diagnosis (2 time 
points), and any child on this clinical trial diagnosed at 18 months or older will have data 
from 3 time points.  Interpretation of these data will use scores over time (slopes) and 
comparison to measure norms.   
 
2.7 
Molecular Characterization of Infant Medulloblastoma 
In recent years, medulloblastoma has been shown to be a heterogeneous disease divisible 
into distinct molecular and clinical subtypes that behave more predictably in response to 
therapy than current classification systems based on clinical risk.14-19 This has fostered a 
movement of using subtype stratification to improve risk assignment and better tailor 
therapy.16-18 Based on Northcott et al.’s and others16 findings, medulloblastoma can be 
divided into 4 subgroups according to their genomic profile (WNT, SHH, Group C and 
Group D) with a significant correlation with outcome (Figure 1A). The SHH and the WNT 
driven medulloblastomas are associated with an excellent survival outcome (≥ 80%). 
However the complexity of these tumors goes beyond subtype divisions and, even though 
subtyping groups together biologically common tumors, there still exists biologic and 
clinical variability even within the subtypes. For example, medulloblastomas of the SHH 
subtype, grouped together because of common gene expression data, are some of the most 
heterogeneous medulloblastomas.20  These tumors harbor a diversity of mutations in both 
the expected SHH genes but also in genes not immediately associable with the SHH 
pathway.21-24 Additionally there are certain cytogenetic features, like MYCN amplification, 
chromosome 17p loss, chromosome 10q loss, chromosome 3q gain which may associate 
with a worse prognosis.25  


 
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Page 19 
 
In the infant population, most medulloblastomas are Sonic Hedgehog (SHH) driven (Figure 
1B). There is a certain level of overlap between the nodular desmoplastic subgroup and the 
SHH group but the extent of overlap is still uncertain. About 60% of desmoplastic 
medulloblastomas are SHH driven.14 Although most of the SHH driven medulloblastomas 
are nodular desmoplastic by histology, some classic or even anaplastic medulloblastomas 
may be SHH driven. 
 
These observations suggest that an improved understanding of tumor biology even within 
the subtypes of the disease will be critical to maximally tailoring therapy. Currently most 
of our knowledge on molecular characterization of medulloblastoma have been generated 
from tissue samples from retrospective cohorts with limited information on treatment 
modalities and in the absence of homogeneous treatment. There is a need for a prospective 
validation of these molecular markers in a cohort of infants uniformly treated. The 
ACNS1221 protocol offers an excellent opportunity to collect and study a well-defined 
subset of medulloblastomas. 
 
We hypothesize that disease variability arises from characteristic molecular abnormalities 
which carry prognostic implications These findings will help constitute a rationale for 
integrating targeted therapy in future trials for newly diagnosed patients, such as sonic 
hedgehog inhibitors which are currently undergoing phase I and phase II evaluation in 
recurrent patients. 
  
 
 
 


 
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Figure 1A 
 
 
 
 
 
 
 
 
 
 
 
Figure 1B: Molecular subgroup distribution of medulloblastoma in children 
less than 3 years of age as per Northcott et al14 
 
 
 
 
Blue : WNT pathway driven Medulloblastoma  
Red  SHH driven Medulloblastoma  
Yellow: Group C  
Green: Group D 
 
 
 


 
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3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the COG Registry system once authorization 
for the release of protected health information (PHI) has been obtained. The COG 
patient ID number is used to identify the patient in all future interactions with 
COG. If you have problems with the registration, please refer to the online help.   
 
In order for an institution to maintain COG membership requirements, every newly 
diagnosed patient needs to be offered participation in ACCRN07, Protocol for the 
Enrollment on the Official COG Registry, The Childhood Cancer Research Network 
(CCRN).  
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol.  
 
Please see Appendix IV for detailed CTEP Registration Procedures for Investigators 
and Associates, and CTSU Registration Procedures including: how to download site 
registration documents; requirements for site registration, submission of regulatory 
documents and how to check your site’s registration status. 
 
3.1.2 
IRB Approval 
Sites must obtain IRB/REB approval for this protocol and submit IRB/REB 
approval and supporting documentation to the Cancer Trials Support Unit (CTSU) 
Regulatory Office before they can be approved to enroll patients. Allow 3 business 
days for processing. The submission must include a fax coversheet (or optional 
CTSU IRB Transmittal Sheet) and the IRB approval document(s). The CTSU IRB 
Certification Form may be submitted in lieu of the signed IRB approval letter. All 
CTSU forms can be located on the CTSU web page (https://www.ctsu.org). Any 
other regulatory documents needed for access to the study enrollment screens will 
be listed for the study on the CTSU Member’s Website under the RSS Tab.  
 
IRB/REB approval documents may be faxed (1-215-569-0206), E-mailed 
(CTSURegulatory@ctsu.coccg.org) or mailed to the CTSU Regulatory office.  
 
When a site has a pending patient enrollment within the next 24 hours, this is 
considered a “Time of Need” registration. For Time of Need registrations, in 
addition to marking your submissions as ‘URGENT’ and faxing the regulatory 
documents, call the CTSU Regulatory Helpdesk at: 1-866-651-CTSU. For general 
(non-regulatory) questions call the CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 


 
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Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. This information will be provided to the CTSU Regulatory 
Office from the CIRB at the time the site’s Signatory Institution accepts the CIRB 
approval. The Signatory site may be contacted by the CTSU Regulatory Office or 
asked to complete information verifying the participating institutions on the study. 
Other site registration requirements (i.e., laboratory certifications, protocol-
specific training certifications, or modality credentialing) must be submitted to the 
CTSU Regulatory Office or compliance communicated per protocol instructions. 
 
 
3.1.3 
Mandatory Submission of Tissue for Rapid Central Pathology Screening Review  
See Appendix III. All patients must have RAPID CENTRAL PATHOLOGY 
SCREENING REVIEW PRIOR TO STUDY ENROLLMENT, in order to 
avoid discordant diagnoses and to verify diagnosis criterion for treatment 
stratification. Pathology slides from the time of diagnosis must be sent to the COG 
Biopathology Center within 15 days of surgery for all potential M0 patients.  
 
Pathology slides must be marked RAPID REVIEW and submitted by Federal 
Express Priority Overnight to the Biopathology Center (See Section 14.0 for 
information regarding specimen submission).  PLEASE DO NOT SEND 
SPECIMENS FOR BIOLOGY STUDIES (SECTION 14.3) UNTIL 
ELIGIBILITY HAS BEEN CONFIRMED AND PATIENT IS ENROLLED. 
Results of rapid central review will be available within 10 calendar days of the 
receipt of pathology review materials.   
 
Please Note: Patients should have no metastatic disease on spinal MRI. Patients 
with a pending result of the CSF cytology are eligible for the rapid central 
pathology screening review. Confirmation of the CSF negativity is needed for 
enrollment on the ACNS1221 protocol unless contraindicated.  
 
3.1.4 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system.  
 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system OPEN. Prior to discussing 
protocol entry with the patient, site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available for the patient. 
Once a slot-reservation confirmation is obtained, site staff may then proceed to 
enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  


 
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2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF 
 
3.1.5 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at < https://eapps-ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on 
either the lead protocol organization (LPO) or participating organization roster. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org.  
 
Prior to accessing OPEN, site staff  and the results from the rapid central pathology 
screening review have confirmed the patient is eligible. 
• 
All eligibility criteria have been met within the protocol stated timeframes. 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and 
cannot be waived (per COG policy posted 5/11/01). All clinical and laboratory data 
required for determining eligibility of a patient enrolled on this trial must be available 
in the patient's medical/research record which will serve as the source document for 
verification at the time of audit.  
 


 
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All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy.  
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
3.2.1 
Age 
Patient must be less than 48 months (4 years) of age at time of definitive surgery. 
 
3.2.2 
Diagnosis  
Patients must be newly diagnosed and have a confirmed histologic diagnosis 
of nodular desmoplastic (ND) medulloblastoma or medulloblastoma with 
extensive nodularity (MBEN) from rapid central pathology screening review.  
 
Please Note: Patients with Gorlin syndrome are eligible. 
 
Please see exclusion criteria regarding metastatic disease below. 
 
3.2.3 
CSF Cytology 
Patient must have negative lumbar CSF cytology (lumbar CSF must be obtained 
unless medically contraindicated). CSF cytology for staging should be performed 
preferably no sooner than 14 days post operatively to avoid false positive CSF, 
Ideally, CSF should be obtained between Day 14 and Day 21 to allow for final 
staging status before enrollment onto the study. 
 
Note: Patients with positive CSF cytology obtained prior to 14 days after surgery 
may have cytology repeated to determine eligibility and final CSF status. 
 
3.2.4 
Imaging 
Patients must have: 
• 
Pre-operative cranial MRI (recommended with gadolinium) or pre-
operative CT (recommended with contrast) 
• 
Post-operative cranial MRI with and without gadolinium within 72 hours 
of surgery 
• 
Spinal MRI pre-op with and without gadolinium or post-op with and 
without gadolinium preferably within 72 hours of surgery 
 
3.2.5 
Timing 
Patients must be enrolled on study within 31 days of definitive surgical resection 
at which time tissue is acquired to determine a diagnosis.  


 
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Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. Patients who are started on protocol therapy on a Phase II study 
prior to study enrollment will be considered ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section. 
 
3.2.6 
Performance Level  
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 
2. 
Use 
Lansky 
for 
patients 
≤ 16 years 
of 
age. 
See 
https://members.childrensoncologygroup.org/prot/reference_materials.asp under 
Standard Sections for Protocols. 
 
3.2.7 
Life Expectancy 
Patients must have a life expectancy of ≥ 8 weeks. 
 
3.2.8 
Concomitant Medications Restrictions 
(Please see Section 4.4 for the concomitant therapy restrictions for patients during 
treatment.) 
 
Steroids: Patients who are receiving dexamethasone must be on a stable dose for 
at least 1 week prior to study entry. 
 
3.2.9 
Organ Function Requirements 
3.2.9.1 
Adequate Bone Marrow Function Defined As: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1000/µL 
- 
Platelet count ≥ 100,000/µL (transfusion independent) 
- 
Hemoglobin ≥ 10.0 g/dL (may receive RBC transfusions) 
 
3.2.9.2 
Adequate Renal Function Defined As: 
- Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or 
- A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR26 utilizing child length and stature data published 
by the CDC. 
 
 


 
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3.2.9.3 
Adequate Liver Function Defined As: 
- 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and 
- 
SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) 
for age. 
3.2.9.4 
Central Nervous System Function Defined As: 
- 
Patients with seizure disorder may be enrolled if on anticonvulsants 
and well controlled. 
- 
Patients must not be in status, coma or assisted ventilation prior to 
study enrollment. 
 
EXCLUSION CRITERIA 
 
3.2.10  Metastatic Disease 
Patients with metastatic disease by either MRI evaluation (brain and spine) or 
lumbar CSF cytology are not eligible. 
 
3.2.11 Prior Therapy 
Patients must not have received any prior tumor-directed therapy other than 
surgical intervention and corticosteroids. 
 
REGULATORY REQUIREMENTS 
 
3.2.11 
Parents or legal guardians must sign a written informed consent. 
 
3.2.12 
All institutional, FDA, and NCI requirements for human studies must be met. 
 
 
4.0 
TREATMENT PROGRAM 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
Patients will be enrolled on the study after central rapid pathology screening confirmation 
of ND/MBEN and start chemotherapy within 36 days of definitive surgery.  They will 
receive a total of 3 to 5 cycles of chemotherapy.  Three cycles of Induction Therapy (63 
Day Cycle) will include Methotrexate, Cyclophosphamide, Vincristine, Etoposide, and 
Carboplatin. Each cycle will begin when ANC > 750/µL and platelets > 75,000/µL and when 
off filgrastim (G-CSF) for at least 48 hours.  


 
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Patients will then have a response evaluation. For patients with complete response the 
treatment is complete and the patient will begin follow-up. For patients with persistent 
residual disease, second look surgery is strongly recommended after completion of 
induction (See Section 13.0) followed by 2 cycles of Continuation Therapy (42 Day Cycle) 
to include Cyclophosphamide, Vincristine, Carboplatin and Etoposide. 
 
4.2 
Age Specific Dose Reductions 
Age specific dose reductions will be made for cyclophosphamide, vincristine and 
carboplatin. Dose reductions must be calculated based on the patient’s age at the 
beginning of each cycle and continued for that cycle. No age specific dose reductions 
will be made for methotrexate or etoposide. See table below. 
 
Age at the Beginning of Each Cycle 
Dosage 
≤ 6.99 months of age 
2/3 (67%) of the m2 dosage 
7-12.99 months of age 
4/5 (80%)  of the m2 dosage 
≥ 13 months of age 
Full m2 dosage 
 
4.3 
Neurocognitive Function 
Enrollment 
onto 
the 
neuropsychological 
function 
study 
ALTE07C1, 
Neuropsychological, Social, Emotional, and Behavioral Outcomes in Children with 
Cancer, is strongly encouraged. If the family agrees to participate in ALTE07C1, a 
separate informed consent for ALTE07C1 must be signed. Please refer to the ALTE07C1 
protocol for eligibility requirements. 
 
4.4 
Concomitant Therapy Restrictions 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general 
supportive care are to be used as necessary. Antiemetics may be used per institutional 
guidelines.  
 
High Dose Methotrexate 
Hold trimethoprim/sulfamethoxazole (Bactrim) on the day of HDMTX infusion and 
continue to hold until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M). 
 
Avoid probenecid, penicillins, aspirin, proton pump inhibitors and NSAIDS on the day of 
methotrexate and continue until the methotrexate level is less than 0.1 micromolar (1 x 10-
7 M) as renal excretion of methotrexate is inhibited by these agents.  
 
Avoid IV contrast media, urinary acidifiers, phenytoin, and fosphenytoin on the day of 
methotrexate and until the methotrexate level is less than 0.1 micromolar (1 x 10-7 M). 
 
Vincristine 
Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and 
carbamazepine) should be avoided. See Appendix II.  
 
Clinically significant drug interactions have been reported when using vincristine with 
strong CYP450 3A4 inhibitors and inducers. Selected strong inhibitors of cytochrome P450 
3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, 
ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, 


 
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Page 28 
phenobarbitol, carbamazepine, and St. John’s wort. The use of these drugs should be 
avoided with vincristine.   
 
The clinical outcome and significance of CYP450 interactions with cyclophosphamide and 
etoposide are less clear. CYP450 3A4 stimulators or inhibitors should be avoided or used 
with great caution.  
 
Additional 
inducers 
or 
inhibitors 
of 
CYP450 
enzymes 
can 
be 
found 
at 
http://medicine.iupui.edu/clinpharm/ddis/.  
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
4.5 
Administration Guidelines for Induction Therapy Cycles 1, 2, 3 (63 Day Cycles) 
Cycle 1 will begin when ANC ≥ 1000/µL and platelet count ≥ 100,000/µL. Subsequent 
cycles will begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL and when off filgrastim (G-
CSF) for at least 48 hours.  
 
For the administration of Carboplatin/ Etoposide and of Cyclophosphamide/Vincristine if 
ANC <750/µL or platelet <75,000/µL, delay chemotherapy for 1 week and until the 
threshold value have been reached. If despite the use of filgrastim, there is subsequent 
episode of delayed recovery, omit the Day 3 of the next similar cycle. 
 
Begin administration of methotrexate on Days 15 and 29 when ANC ≥ 250/µL and platelets 
≥ 50,000/µL. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional 
policy 
Days: 1, 15, 29 
Dose: Age Based Dosing below (Maximum single dose 2 mg). Dose reductions must be 
calculated based on the patient’s age at the beginning of each cycle and continued for that 
cycle.  Administer vinCRIStine prior to cyclophosphamide. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
1 mg/m2/day  
7-12.99 months of age  
1.2 mg/m2/day  
≥ 13 months of age  
 
1.5 mg/m2/day 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement “Do not remove covering until moment of injection. For intravenous 
use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.  VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®).  Use conventional vincristine only; the 
conventional and liposomal formulations are NOT interchangeable. 
 


 
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Cyclophosphamide (CPM): IV over 1 hour  
Days: 1-3 
Dose: Age Based Dosing below. Dose reductions must be calculated based on the patient’s 
age at the beginning of each cycle and continued for that cycle. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
533 mg/m2/day  
7-12.99 months of age  
640 mg/m2/day  
≥ 13 months of age 
 
800 mg/m2/day 
 
Suggested Hydration: 
Prehydrate at least 2 hours at 125mL/m2/hour before and post hydrate for at least 18 hours 
IV at 125 mL/m2/hour.   
 
Mesna: IV (short or continuous infusion) 
Days: 1-3 
Dose: Age Based Dosing below. Dose reductions must be calculated based on the patient’s 
age at the beginning of each cycle and continued for that cycle. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
533 mg/m2/day for patients  
7-12.99 months  of age  
640 mg/m2/day  
≥ 13 months of age 
 
800 mg/m2/day 
 
IV short or continuous infusion: For prophylaxis of hemorrhagic cystitis, the total daily 
mesna dose is equal to 100% of the daily cyclophosphamide dose. Mesna can be 
administered in 5 divided doses by short intravenous infusion over 15 to 30 minutes. The 
initial bolus dose of mesna may be administered 15 minutes before or at the same time as 
the cyclophosphamide dose; subsequent doses are given 3, 6, 9, and 12 hours after the start 
of cyclophosphamide.   
 
For example: if the cyclophosphamide dose is 1000 mg, then the total daily mesna dose 
is 1000 mg; 200 mg of mesna will be given 15 minutes before or with the 
cyclophosphamide  dose (Hour 0) and 4 boluses of 200 mg each will be given at Hours 3, 
6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
cyclophosphamide and finished no sooner than 12 hours after the end of the 
cyclophosphamide infusion.   
 
For example: if the cyclophosphamide dose is 1000 mg, then the total daily mesna dose 
is 1000 mg; the 1000 mg mesna continuous infusion will start 15-30 minutes before or at 
the same time as the cyclophosphamide and be completed no sooner than 12 hours after 
the end of the cyclophosphamide  infusion.  
 
Methotrexate: IV over 24 hours 
Days: 15, 29 
Dose:  5,000 mg/m2 
See Appendix I for a flowchart of the HDMTX/LCV guidelines. 
 


 
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Hold any nonsteroidal anti-inflammatory medications, penicillins, proton pump inhibitors 
or aspirin-containing medications on the day of HDMTX infusion and for at least 72 hours 
after the start of the HD MTX infusion and until the MTX level is less than 0.4 μM. In the 
presence of delayed clearance continue to hold these medications until MTX level is less than 
0.1 µM. 
 
Suggested Hydration: 
Prehydrate with D5 ¼ NS with 30 mEq NaHCO3/L at 125 mL/m2/hour until urine specific 
gravity is ≤ 1.010 and pH is ≥ 7.0 and ≤ 8.0. Ringers Lactate may be used as the initial 
fluid if a bicarbonate containing solution is unavailable. Adjust fluid volume and sodium 
bicarbonate to maintain urine specific gravity and pH at above parameters. A bicarbonate 
bolus (25 mEq/m2 over 15 min) may be given to raise the urine pH relatively quickly, a 
normal saline bolus may also be helpful in facilitating hydration. Continue hydration and 
alkalinization throughout HDMTX infusion, and for a minimum of 48 hours after its 
completion and until serum methotrexate level less than 0.1 micromolar (1 x 10-7 molar).  
 
Hour 0: MTX 500 mg/m2 IV infused over 30 minutes. This is followed, immediately, by 
MTX 4500 mg/m2 given by continuous IV infusion over 23.5 hours. Be certain that the 
HDMTX infusion is completed in the 24 hour period. Unintentional prolongation to as long 
as 26 hours though not encouraged is acceptable. 
 
Hours 24, (36), 42 and 48: Draw MTX level and serum creatinine; NOTE: 36 hour level 
is only drawn if needed (see below) 
 
 
For MTX levels that exceed these expected values modify the rescue regimen as noted 
below and increase hydration to 200 mL/m2/hr, monitor urine pH to assure a value ≥ 7.0 
and monitor urine output to determine if volume is ≥ 80% of the fluid intake, measured 
every 4 hours. If serum creatinine rises significantly, at any time point, assure appropriate 
urine pH and urine volume as above and draw a 42 hour level. If urine output fails to 
continue at 80% of the fluid intake, consider furosemide. Regardless of urine output, also 
consider glucarpidase (carboxypeptidase G2) (see below). For patients with delayed 
clearance during a previous course, begin the following course with the increased hydration 
(200 mL/m2/hr). If subsequent course is not associated with delayed clearance, attempt to use 
standard hydration. 
 
If the 24 hour level is < 150 µM draw the next level at hour 42 and refer to table below.  
 
If the 24 hour level is ≥ 150 µM and/or creatinine > 125% baseline, repeat level if MTX 
contamination is possible. If the value is “real” refer to the changes in hydration, etc 
described above and repeat the level with a serum Cr at hour 36. Then refer to the table 
below.  
 
If the 42 and 48 hour levels are ≤ 1 and 0.4 µM, respectively, give Leucovorin at 15 
mg/m2 IV/PO at 42, 48 and 54 hours post the start of methotrexate loading dose. No 
additional levels are needed, nor is additional leucovorin. 
 
 


 
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** If the 36 hour level exceeds 3 µM, increase hydration to 200 mL/m2/hr, monitor urine pH to assure a 
value > 7.0 and monitor urine output to determine if volume is > 80% of the fluid intake, measured every 4 
hours. If urine output fails to continue at 80% of the fluid intake, consider furosemide. Regardless of urine 
output, also consider glucarpidase if 36 hour MTX level exceeds 10 µM. 
++ If the level is high at hour 36 or 42, but then the patient “catches up” and the level falls to the expected 
values of ≤ 1 and/or ≤ 0.4 µM at hours 42 and 48, respectively, resume standard leucovorin and hydration as 
long as urine output remains satisfactory.  
 
Special precautions: IV leucovorin and sodium bicarbonate are incompatible. 
 
Selected drug interactions: Avoid NSAIDs, TMP/SMX, penicillins, probenicid, IV contrast 
media, proton pump inhibitors, phenytoin and fosphenytoin. Urinary acidifiers can cause 
methotrexate to precipitate in the urinary tract.  
 
Leucovorin: IV or PO (See Appendix I and guidelines for HD MTX above) 
Days: 17, 31 (42 hours after the start of methotrexate infusion)  
Dose: 15 mg/m2 at hrs 42, 48, & 54 until serum methotrexate levels are less than 0.1 
micromolar (1 x 10-7 molar). 
 
Inject by IV push over a minimum of 3 minutes or by short infusion over 15 to 120 minutes. 
Because of the calcium content of the leucovorin solution, no more than 160 mg of 
leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL solution per 
minute). IV leucovorin and sodium bicarbonate are incompatible.   
 
Etoposide: IV over 60-120 minutes 
Days: 43-45 
Dose: 150 mg/m2/dose 
 
Infuse diluted solution (concentration  ≤ 0.4 mg/mL) over at least 60-120 minutes; slow rate 
of administration if hypotension occurs. Rate should not exceed 300 mg/m2/hour 
(10 mg/kg/hour) (hypotension risk). The use of an in-line filter during the infusion is 
suggested. Administer etoposide prior to carboplatin. 
 
36 Hr MTX Level 
42 hr MTX 
level 
48 hr MTX 
level 
Leucovorin Rescue++ 
Only required if 24 
hr level is ≥ 150 µM. 
See 
below 
for 
guidelines** 
1.01 to 9.9 
µM  
0.41 to 5.9 
µM 
Continue 15 mg/m2 q 6h until MTX 
level < 0.1 µM (draw q12-24 h). 
 
10 to 19.9 µM 6 to 9.9 µM 
Increase to 15 mg/m2 q 3h until MTX 
level < 0.1 µM (draw q 6-24 h). 
Consider glucarpidase. 
 
20 to 200 µM 10 to 100 µM Increase to 100 mg/m2 q 6h until MTX 
level < 0.1 µM (draw q 6-24 h). 
Consider glucarpidase. 
 
> 200 µM 
> 100 µM 
Increase to 1000 mg/m2 q 6h until MTX 
level < 0.1 µM (draw q 6-24 h). 
Consider glucarpidase. 


 
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Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large 
volumes of D5W due to potential development of hyponatremia. 
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred with etoposide 
0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare the etoposide solution as close 
as possible, preferably within 4 hours, to the time of administration or alternatively as per 
institutional policy. Glass or polyethylene-lined (non-PVC) containers and polyethylene-lined 
tubing may be used. 
 
CARBOplatin: IV over 1 hour 
Days: 43-45 
Dose: Age Based Dosing below. Dose reductions must be calculated based on the patient’s 
age at the beginning of each cycle and continued for that cycle. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
133 mg/m2/day   
7-12.99 months  of age  
160 mg/m2/day  
≥ 13 months of age 
 
200 mg/m2/day 
 
IV: Avoid use of aluminum containing needles or administration sets. 
 
Medication errors have occurred due to confusion between CISplatin (Platinol®) and 
CARBOplatin (PARAplatin®). 
 
Filgrastim: Subcutaneous (preferred) or IV 
Days: Daily, starting on Day 4 and Day 46 and continue for at least 7 days, or until ANC 
≥ 750/µL after the expected nadir whichever comes last. Note that an ANC ≥ 750 on or 
before Day 7 of a cycle is not sufficient for discontinuing G-CSF, as the ANC may rise 
before Day 7 and then fall to its nadir. 
Dose: 5 mcg/kg/dose. 
 
Note: The use of filgrastim is strongly recommended, however, patients receiving PEG-
filgrastim will not be excluded. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
For those patients who have not achieved a complete response after 3 cycles Induction 
therapy, another attempt at complete resection, if at all feasible, is strongly recommended. 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuideli
nes.pdf for special precautions and suggestions for patient monitoring during the infusion. 
As applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
The therapy delivery maps (TDMs) for Induction Therapy are on the following pages.  


 
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Following completion of this course, the next course starts on Day 64 or when ANC > 750/µL 
and platelets > 75,000/µL whichever occurs later and when off filgrastim (G-CSF) for at least 
48 hours. 


 
 
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Page 1 of 2 
 
4.5.1 
Therapy Delivery Map for Induction Therapy (Cycles 1, 2, 3)  
Induction Therapy will be given for Cycles 1, 2 and 3. 
Each Cycle lasts 9 weeks (63 days). 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Cycle 1 will begin when ANC ≥ 1000/µL and platelet count ≥ 100,000/µL. Subsequent cycles will begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL 
and when off filgrastim (G-CSF) for at least 48 hours.  For the administration of Carboplatin/Etoposide and of Cyclophosphamide/Vincristine if ANC 
<750/µL or platelet <75,000/µL, delay chemotherapy for 1 week and until the threshold value have been reached. If despite the use of filgrastim, 
there is subsequent episode of delayed recovery, omit the Day 3 of the next similar cycle. Begin administration of methotrexate on Days 15 and 29 
when ANC ≥ 250/µL and platelets ≥ 50,000/µL. 
Extensive details are in Section 4.0 (treatment overview). Each cycle lasts 63 days and the TDM for this cycle is on 2 pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
minute or infusion 
via minibag as per 
institutional policy 
Age                        Dose 
≤ 6.99 months       1 mg/m2/day  
7-12.99 months     1.2 mg/m2/day 
≥ 13 months          1.5 mg/m2/day 
1, 15, 29 
Note age based dosing. 
Maximum single dose 2 mg. 
a. History, PE (Ht, Wt, VS) 
with Neurologic Exam, 
b.Performance Status 
c. CBC (differential, 
platelets) 
d. Urinalysis and Serum 
Creatinine or GFR 
e. Electrolytes (including 
BUN, Calcium, PO4, 
Magnesium, Sodium, 
Potassium) 
f. Brain and spine MRI with 
and without gadolinium 
g. Audiogram or BAER 
h. CSF cytology 
OBTAIN OTHER 
STUDIES AS REQUIRED 
FOR GOOD PATIENT 
CARE 
Cyclophosphamide 
(CPM) 
IV over 1 hour 
Age                        Dose 
≤ 6.99 months       533 mg/m2/day  
7-12.99 months     640 mg/m2/day 
≥ 13 months           800 mg/m2/day 
1-3 
Note age based dosing. 
Mesna 
IV (short or 
continuous 
infusion) 
 
Age                         Dose 
≤ 6.99 months       533 mg/m2/day  
7-12.99 months     640 mg/m2/day 
≥ 13 months          800 mg/m2/day 
1-3 
Note age based dosing. 
Administer with 
Cyclophosphamide See Section 
4.5 
Filgrastim 
(G-CSF) 
SubQ (preferred) 
or IV 
5 mcg/kg/dose 
Daily, 
starting on 
Day 4 and 
Day 46  
Continue for at least 7 days, or 
until ANC ≥ 750/µL after the 
expected nadir whichever comes 
last 
Methotrexate 
(MTX) 
IV over 24 hours 
5,000 mg/m2/day 
15, 29 
See guidelines and Appendix I. 
Leucovorin (LCV) 
IV or PO 
15 mg/m2/dose  
17, 31 
Begin 42 hours after start of 
methotrexate infusion. every 6 
hours until serum methotrexate 
levels are less than 0.1 
micromolar (1 x 10-7 molar).See 
guidelines and Appendix I 
Etoposide (ETOP) 
IV over 60-120 
minutes 
150 mg/m2/dose 
43-45 
See guidelines. Administer prior 
to CARBOplatin. 
CARBOplatin 
(CARBO)  
IV over 1 hour 
Age                        Dose 
≤ 6.99 months       133 mg/m2/day  
7-12.99 months     160 mg/m2/day 
≥ 13 months          200 mg/m2/day 
43-45 
 
Note age based dosing. 
 


 
 
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Page 2 of 2 
 
 
 
 
4.5.1 
Therapy Delivery Map for Induction Therapy (Cycles 1, 2, 3)  
Induction Therapy will be given for Cycles 1, 2 and 3. 
Each Cycle lasts 9 weeks (63 days). 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Cycle 1 will begin when ANC ≥ 1000/µL and platelet count ≥ 100,000/µL. Subsequent cycles will begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL 
and when off filgrastim (G-CSF) for at least 48 hours.  For the administration of Carboplatin/ Etoposide and of Cyclophosphamide/Vincristine if ANC 
<750/µL or platelet <75,000/µL, delay chemotherapy for 1 week and until the threshold value have been reached. If despite the use of filgrastim, 
there is subsequent episode of delayed recovery, omit the Day 3 of the next similar cycle. Begin administration of methotrexate on Days 15 and 29 
when ANC ≥ 250/µL and platelets ≥ 50,000/µL. 
Extensive details are in Section 4.0 (treatment overview). Each cycle lasts 63 days and the TDM for this cycle is on 2 pages. 
 
Enter Cycle #: _____ Ht _________cm 
 
Wt _________kg 
 
BSA _________m2 
 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
MESNA 
_____mg/dose  
OR by CI 
_______mg/day 
VCR 
____mg 
MTX 
_____mg 
LCV 
_____mg 
CARBO 
_____mg 
ETOP 
_____mg 
G-CSF 
_____mcg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
____mg 
____mg 
 
 
 
 
 
a, b, c, d, e, f# 
 
 
 
2 
____mg 
____mg 
 
 
 
 
 
 
 
 
 
 
3 
____mg 
____mg 
 
 
 
 
 
 
 
  
 
 
4 
 
 
 
 
 
 
 
____mcg 
 
Indicate last day of  
G-CSF _____ 
 
 
15 
 
 
____mg 
____mg 
 
 
 
 
a , c, d, e 
 
 
 
17 
 
 
 
 
____mg 
 
 
 
 
Indicate last day of  
LCV ______    
 
 
29 
 
 
____mg 
____mg 
 
 
 
 
a , c, d, e 
 
 
 
31 
 
 
 
 
____mg 
 
 
 
 
Indicate last day of  
LCV ______    
 
 
43 
 
 
 
 
 
____mg 
____mg 
 
a, c, d, e, g& 
 
 
 
44 
 
 
 
 
 
____mg 
____mg 
 
 
 
 
 
45 
 
 
 
 
 
____mg 
____mg 
 
 
 
 
 
46 
 
 
 
 
 
 
 
____mcg 
 
Indicate last day of  
G-CSF _____ 
 
 
62 
 
 
 
 
 
 
 
 
[a, b, c,  e, f, g, 
h]$ 
 
 
 
64 
Begin the next Cycle on Day 64 when blood count parameters have been met and the patient has been off G-CSF for at least 48 hours.   
# - Obtain prior to Cycle 2 
 
 
 
& - Obtain for Cycles 2 and 3. 
$ - Obtain following Cycle 3  
 
See Section 5.0 for Dose Modifications for Toxicities and the COG website posted materials for Supportive Care Guidelines. 
 


 
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4.6 
Administration Guidelines for Continuation Therapy (42 Days) Cycles 1, 2 
Only patients with persistent disease will receive Continuation Therapy of 
chemotherapy. Cycles will begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL and when 
off filgrastim (G-CSF) for at least 48 hours and patient has recovered from second surgery (if 
done). 
For 
the 
administration 
of 
Carboplatin/ 
Etoposide 
and 
of 
Cyclophosphamide/Vincristine if ANC <750/µL or platelet <75,000/µL, delay 
chemotherapy for 1 week and until the threshold value have been reached. If despite the 
use of filgrastim, there is subsequent episode of delayed recovery, omit the Day 3 of the 
next similar cycle. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional 
policy 
Day: 1 
Dose: Age Based Dosing below (Maximum single dose 2 mg).  Dose reductions must be 
calculated based on the patient’s age at the beginning of each cycle and continued for that 
cycle. Administer vinCRIStine prior to cyclophosphamide. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
1 mg/m2/day   
7-12.99 months  of age  
1.2 mg/m2/day  
≥ 13 months of age  
 
1.5 mg/m2/day 
 
Special precautions: FOR INTRAVENOUS USE ONLY.   
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement “Do not remove covering until moment of injection. For intravenous 
use only - Fatal if given by other routes.” 
 
Medication errors have occurred due to confusion between vinCRIStine and 
vinBLAStine.  VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate 
liposomal injection, VSLI, Marqibo®).  Use conventional vincristine only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
Cyclophosphamide (CPM): IV over 1 hour  
Days: 1-3 
Dose: Age Based Dosing below. Dose reductions must be calculated based on the patient’s 
age at the beginning of each cycle and continued for that cycle. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
533 mg/m2/day   
7-12.99 months  of age  
640 mg/m2/day  
≥ 13 months of age 
 
800 mg/m2/day 
 
Suggested Hydration: 
Prehydrate at least 2 hours at 125mL/m2/hour before and post hydrate for at least 18 hours 
IV at 125 mL/m2/hour.   
 
 


 
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Mesna: IV (short or continuous infusion) 
Days: 1-3 
Dose: Age Based Dosing below. Dose reductions must be calculated based on the patient’s 
age at the beginning of each cycle and continued for that cycle. 
 
Age 
 
 
 
Dose 
≤ 6 months of age 
 
533 mg/m2/day   
7-12 months 
 
 
640 mg/m2/day  
≥ 13 months of age 
 
800 mg/m2/day 
 
IV short or continuous infusion: For prophylaxis of hemorrhagic cystitis, the total daily 
mesna dose is equal to 100% of the daily cyclophosphamide dose. Mesna can be 
administered in 5 divided doses by short intravenous infusion over 15 to 30 minutes. The 
initial bolus dose of mesna may be administered 15 minutes before or at the same time as 
the cyclophosphamide dose; subsequent doses are given 3, 6, 9, and 12 hours after the start 
of cyclophosphamide.   
 
For example: if the cyclophosphamide dose is 1000 mg, then the total daily mesna dose 
is 1000 mg; 200 mg of mesna will be given 15 minutes before or with the 
cyclophosphamide  dose (Hour 0) and 4 boluses of 200 mg each will be given at Hours 3, 
6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
cyclophosphamide and finished no sooner than 12 hours after the end of the 
cyclophosphamide infusion.   
 
For example: if the cyclophosphamide dose is 1000 mg, then the total daily mesna dose 
is 1000 mg; the 1000 mg mesna continuous infusion will start 15-30 minutes before or at 
the same time as the cyclophosphamide and be completed no sooner than 12 hours after 
the end of the cyclophosphamide  infusion.  
 
Etoposide: IV over 60-120 minutes 
Days: 21-23 
Dose: 150 mg/m2/dose 
 
Infuse diluted solution (concentration  ≤ 0.4 mg/mL) over at least 60-120 minutes; slow rate 
of administration if hypotension occurs. Rate should not exceed 300 mg/m2/hour 
(10 mg/kg/hour) (hypotension risk). The use of an in-line filter during the infusion is 
suggested. Administer etoposide prior to carboplatin. 
 
Special precautions: Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large 
volumes of D5W due to potential development of hyponatremia. 
 
Stability: Leaching of diethylhexyl phthalate (DEHP) from PVC bags occurred with etoposide 
0.4 mg/mL in 0.9% NaCl solution. To avoid leaching, prepare the etoposide solution as close 
as possible, preferably within 4 hours, to the time of administration or alternatively as per 
institutional policy. Glass or polyethylene-lined (non-PVC) containers and polyethylene-lined 
tubing may be used. 
 
 


 
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CARBOplatin: IV over 1 hour 
Days: 21-23 
Dose: Age Based Dosing below. Dose reductions must be calculated based on the patient’s 
age at the beginning of each cycle and continued for that cycle. 
 
Age 
 
 
 
Dose 
≤ 6.99 months of age 
 
133 mg/m2/day  
7-12.99 months  of age  
160 mg/m2/day  
≥ 13 months of age 
 
200 mg/m2/day 
 
IV: Infuse the diluted solution over 15-60 minutes. Avoid use of aluminum containing 
needles or administration sets. 
 
Medication errors have occurred due to confusion between CISplatin (Platinol®) and 
CARBOplatin (PARAplatin®). 
 
Filgrastim: Subcutaneous (preferred) or IV 
Days: Daily, starting on Day 4 and Day 24 and continue for at least 7 days, or until ANC 
≥ 750/µL after the expected nadir whichever comes last. Note that an ANC ≥ 750 on or 
before Day 7 of a cycle is not sufficient for discontinuing G-CSF, as the ANC may rise 
before Day 7 and then fall to its nadir. 
Dose: 5 mcg/kg/dose. 
 
Note: The use of filgrastim is strongly recommended, however, patients receiving PEG-
filgrastim will not be excluded. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 
See the Parenteral Chemotherapy Administration Guidelines (CAG) on the COG website 
at: 
https://members.childrensoncologygroup.org/_files/disc/Pharmacy/ChemoAdminGuideli
nes.pdf for special precautions and suggestions for patient monitoring during the infusion. 
As applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
 
For COG Supportive Care Guidelines see:  
https://members.childrensoncologygroup.org/prot/reference_materials.asp under Standard 
Sections for Protocols. 
 
The therapy delivery maps (TDMs) for Continuation Therapy are on the following pages.  
 


 
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Page 1 of 1 
 
4.6.1 Therapy Delivery Map for Continuation Therapy (Cycles 1, 2)  
Continuation Therapy will be given for Cycles 1 and 2. 
Each Cycle lasts 6 weeks (42 days). 
____________________________ 
Patient name or initials 
____________________________ 
DOB 
Each cycle will begin when ANC ≥ 750/µL and platelets ≥ 75,000/µL and when off filgrastim (G-CSF) for at least 48 hours.  For the 
administration of Carboplatin/Etoposide and of Cyclophosphamide/Vincristine if ANC <750/µL or platelet <75,000/µL, delay 
chemotherapy for 1 week and until the threshold value have been reached. If despite the use of filgrastim, there is subsequent episode of 
delayed recovery, omit the Day 3 of the next similar cycle. Extensive details are in Section 4.0 (treatment overview). Each cycle lasts 42 
days and the TDM for this cycle is on 1 page. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT 
NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 
minute or infusion 
via minibag as per 
institutional policy 
Age                        Dose 
≤ 6.99 months      1 mg/m2/day  
7-12.99 months    1.2 mg/m2/day 
≥ 13 months         1.5 mg/m2/day 
1 
Note age based dosing. 
Maximum single dose 2 
mg. 
a. History, PE (Ht, Wt, 
VS) with Neurologic 
Exam, b.Performance 
Status 
c. CBC (differential, 
platelets) 
d. Urinalysis and Serum 
Creatinine or GFR 
e. Electrolytes (including 
BUN, Calcium, PO4, 
Magnesium, Sodium, 
Potassium) 
f. Brain and spine MRI 
with and without 
gadolinium 
g. Audiogram or BAER 
h. CSF Cytology 
OBTAIN OTHER 
STUDIES AS 
REQUIRED FOR 
GOOD PATIENT 
CARE 
Cyclophosphamide 
(CPM) 
IV over 1 hour 
Age                        Dose 
≤ 6.99 months       533 mg/m2/day  
7-12.99 months     640 mg/m2/day 
≥ 13 months          800 mg/m2/day 
1-3 
Note age based dosing. 
Mesna 
IV (short or 
continuous 
infusion) 
 
Age                        Dose 
≤ 6.99 months       533 mg/m2/day  
7-12.99 months     640 mg/m2/day 
≥ 13 months          800 mg/m2/day 
1-3 
Note age based dosing. 
Administer with 
Cyclophosphamide See 
guidelines. 
Filgrastim 
(G-CSF) 
SubQ (preferred) 
or IV 
5 mcg/kg/dose 
Daily, 
starting 
on Day 4 
and Day 
24  
Continue for at least 7 
days, or until ANC ≥ 
750/µL after the expected 
nadir whichever comes last 
Etoposide (ETOP) 
IV over 60-120 
minutes 
150 mg/m2/dose 
21-23 
See  guidelines. 
Administer prior to 
CARBOplatin. 
CARBOplatin 
(CARBO)  
IV over 1 hour 
Age                        Dose 
≤ 6.99 months       133 mg/m2/day  
7-12.99 months     160 mg/m2/day 
≥ 13 months          200 mg/m2/day 
21-23 
 
Note age based dosing. 
 
Enter Cycle #: _____ Ht _________cm 
Wt _________kg 
BSA _________m2 
Date 
Due 
Date 
Given 
Day 
CPM 
____mg 
MESNA 
_____mg/dose  
OR by CI 
_______mg/day 
VCR 
____mg 
CARBO 
_____mg 
ETOP 
_____mg 
G-CSF 
_____mcg 
Studies 
Comments 
(Include any held 
doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
____mg 
____mg 
____mg 
 
 
 
a, b, c, d, e 
 
 
 
2 
____mg 
____mg 
 
 
 
 
 
 
 
 
3 
____mg 
____mg 
 
 
 
 
 
  
 
 
4 
 
 
 
 
 
____mcg 
 
Indicate last day 
of  G-CSF ____ 
 
 
21 
 
 
 
____mg 
____mg 
 
a, c, d, e, g 
 
 
 
22 
 
 
 
____mg 
____mg 
 
 
 
 
 
23 
 
 
 
____mg 
____mg 
 
 
 
 
 
24 
 
 
 
 
 
____mcg 
 
Indicate last day 
of  G-CSF ____ 
 
 
42 
 
 
 
 
 
 
[a, b, c, e, f, g, h]$ 
 
 
 
43 
Begin Cycle 2 on Day 43 when blood count parameters have been met and the patient has been off G-CSF for at least 48 hours. 
$ - Obtain following Cycle 2  
See Section 5.0 for Dose Modifications for Toxicities and the COG website posted materials for Supportive 
Care Guidelines. 


 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Hematological Toxicity 
For the administration of Carboplatin/ Etoposide and of Cyclophosphamide/Vincristine 
if ANC <750/µL or platelet <75,000/µL, delay chemotherapy for 1 week and until the threshold 
value have been reached. If despite the use of filgrastim, there is subsequent episode of delayed 
recovery, omit the Day 3 of the next similar cycle. 
 
5.2 
Carboplatin 
5.2.1 
Nephrotoxicity 
The estimation of GFR must be performed before every carboplatin containing block.  If 
serum creatinine > 1.2 mg/dL (100 µM) or > 1.5 ULN or Creatinine clearance < 80 mL/min 
x 1.73 m²: Delay chemotherapy for 1 week  
 
In case of no improvement: Perform estimation of GFR by clearance of radioisotope:  
If the Isotope GFR ≥ 60 and < 80 mL/min x 1.73 m², reduce carboplatin dose to 125 
mg/m²/dose. Perform estimation of GFR by clearance of radioisotope before next course.  
Isotope GFR < 60 mL/min/1.73 m², replace carboplatin by cyclophosphamide at the 
calculated dose for age for cyclophosphamide. 
 
Note: Institutions should verify with Nuclear Medicine Department or lab to ensure 
correct units are reported. 
 
Both formulas are listed so that you can use either the Corrected GFR (that is corrected to the 
adult clearance of 1.73 m2) or the Uncorrected GFR (that is the raw GFR).  Use the correct 
version of the formula dependent on the units of measurement reported for the GFR. The GFR 
corrected or uncorrected is reported in the units as below: 
Corrected GFR reported in mL/min/1.73 m2 
Uncorrected (Raw) GFR reported in mL/min 
(To Convert Corrected to Uncorrected GFR the following formula is used:     Corrected GFR 
x BSA   = Uncorrected (Raw) GFR 
 
5.2.2 Ototoxicity 
Careful monitoring of children by expert audiologist and by serial audiometry throughout 
the treatment with carboplatin is recommended as clinically indicated. Otoacoustic 
emissions (OAE) are the clinical methodology of choice for initial testing. If not feasible 
BAER is suggested. Do not adjust dose for unilateral hearing loss related to initial or second 
surgery. Adjust dose as below for unilateral or bilateral hearing loss. 
If  decrease threshold ≤ 15 dB at 1000-3000 Hz or ≤ 40 dB at 4000-8000 Hz : No dose 
modification needed 
If decrease threshold between >15- ≤ 30 dB at 1000-3000 Hz or > 40 dB at 4000-8000 Hz–
Reduce carboplatin from 200 mg/m2 to 125 mg/m²/day prior to adjusting dose for age. 
 
If decrease threshold > 30 dB at 1000-3000 Hz: Replace carboplatin by cyclophosphamide 
at the calculated dose for age for cyclophosphamide. 
 
5.2.3 Allergic Reactions 
In subsequent cycles of carboplatin, it is recommended to infuse carboplatin over 2 hours 


 
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and premedicate with diphenhydramine 1mg/kg (max dose 50 mg) and steroids (if reaction 
is more than a mild reaction), and ranitidine 1 mg/kg/dose IV (max dose 50 mg) or 
equivalent H2-receptor antagonist (e.g., famotidine dose 0.5 mg/kg, maximum single dose 
20 mg) if unresponsive to diphenhydramine and steroid. 
 
5.3 
Cyclophosphamide 
5.3.1 
Microscopic Hematuria 
For transient microscopic hematuria (no more than 2 abnormal urinalyses on 2 separate 
days during a cycle of therapy), do not modify the cyclophosphamide dose. If mesna 
originally given as short infusion boluses, change to continuous infusion.  If mesna 
originally given as 100% via continuous infusion, increase hydration for subsequent doses. 
 
Hydration: administer 3000 mL/m²/day (125 mL/m²/hour) using fluid containing at least 
0.45% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start of cyclophosphamide. 
May use diuretics (like furosemide) to increase urine output. 
 
For persistent microscopic hematuria (> 2 abnormal urinalyses during a cycle of therapy), 
increase hydration to 3500-4000 mL/m2/day and daily mesna dose to 120% of the 
cyclophosphamide dose at the next cycle. 
 
5.3.2 
Gross Hematuria 
All episodes of gross hematuria should be evaluated in conjunction with a pediatric surgical 
consult. Further testing, such as cystoscopy, urine culture, excretory urogram, and voiding 
cystogram should be considered based on good clinical judgement. 
 
For transient gross hematuria (only 1 episode, which clears to less than gross hematuria) 
during or following a cycle of therapy, do not modify dose. Use hydration and continuous 
infusion mesna at 120% of the cyclophosphamide dose. 
 
5.4 
Etoposide (VP-16) 
5.4.1 
Allergic Reaction  
Premedicate with diphenhydramine (1-2 mg/kg slow IV push, maximum dose is 50 mg). 
If symptoms persist, add hydrocortisone 100-300 mg/m2. Continue to use premedication 
before etoposide in future. Also consider substituting an equimolar amount of etoposide 
phosphate, in the face of significant allergy and/or hypotension. Etoposide phosphate is a 
water soluble prodrug that does not contain polysorbate 80 and polyethyleneglycol, the 
solubilizing agent in etoposide that may induce allergic reactions and hypotension. 
Etoposide phosphate is rapidly converted to etoposide in vivo and provides total drug 
exposure, as represented by AUC (0-infinity), that is statistically indistinguishable from 
that measured for etoposide at equimolar doses. 
 
To substitute etoposide with etoposide phosphate, doses should always be expressed and 
calculated as the desired ETOPOSIDE dose, not as the etoposide phosphate (salt) 
dose.  Etoposide phosphate 113.5 mg is equivalent to etoposide 100 mg; each vial of 
Etopophos contains 100 mg of etoposide.  An etoposide dose of 100 mg/m2 is equal to 
Etopophos 100 mg/m2.   
 
 


 
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5.4.2 
Hypotension  
If diastolic or systolic blood pressure (BP) falls 20 mm Hg during infusion, reduce infusion 
rate by 50%. Start a simultaneous infusion of NS 10 mL/kg if BP fails to recover or falls 
further. Stop infusion if BP does not recover, continue NS. If the patient has had any 
episode of hypotension, prehydrate with 0.9% NaCl at 10 mL/kg/hr for 2 hours prior to any 
subsequent infusion. 
 
5.5 
High-Dose Methotrexate (HDMTX) and Leucovorin Rescue  
5.5.1 
Nephrotoxicity 
Postpone course if pre-treatment (MTX) serum creatinine is > 1.5 x baseline or GFR 
creatinine clearance < 65 mL/minute/1.73m2. If renal function does not recover, omit 
MTX. Do not give HDMTX to a patient with this degree or renal impairment, assuming 
that prolonged excretion can be managed with glucarpidase. 
 
NOTE: For patients who have markedly delayed MTX clearance secondary to renal 
dysfunction, consider using glucarpidase (carboxypeptidase G2, Voraxaze). ASD 
Healthcare is the sole supplier of glucarpidase (carboxypeptidase G2, Voraxaze) in the 
US. To obtain supplies of glucarpidase in the US contact the Voraxaze 24-hour Customer 
Service 
line 
at 
855-786-7292. 
Additional 
information 
can 
be 
found 
at 
http://www.btgplc.com/products/specialty-pharmaceuticals/voraxaze. 
Canadian 
sites 
should contact McKesson at (877) 384-7425 for further information. Sites in Australia and 
New 
Zealand 
should 
contact 
Hospira 
at 
1300-046-774 
(local) 
or 
medicalinformationAUS@hospira.com. 
 
5.5.2 Liver Dysfunction 
Samples for the determination of ALT value must be drawn within 72 hours, PRIOR to a 
course of intravenous MTX. Blood samples for ALT should not be drawn following the 
start of MTX infusions as MTX causes significant short term elevation in ALT levels. 
ALT 
IV MTX 
< 10 X ULN 
Continue with therapy as scheduled 
10 – 20 X ULN 
Continue with therapy as scheduled for 1 cycle 
10 – 20 X ULN for 2 
consecutive cycles 
Discontinue TMP/SMX* 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point 
of interruption. 
 
> 20 X ULN 
Hold therapy until ALT < 10 X ULN, then resume at full doses at point 
of interruption.  
 
> 20 X ULN for > 2 weeks Evaluate with AST, Bili, Alkaline phosphatase, PT, albumin, total 
protein, and hepatitis A, B, C, CMV, and EBV serologies. 
Consider liver biopsy before additional therapy given. Notify Study 
Chair. 
* 
Please 
see 
COG 
Supportive 
care 
Guidelines 
at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp for TMP/SMX substitutions. 
 
Hold IV MTX for direct hyperbilirubinemia of > 2.0 mg/dL. 
 
 


 
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5.5.3 Mucositis  
For Grade 3-4 mucositis, withhold IV MTX until resolved. Increase leucovorin rescue 
following the next course from 3 to 5 doses on a q6 hr schedule. If subsequent course is 
not associated with Grade 3-4 mucositis, attempt to decrease the leucovorin. If mucositis 
recurs despite the extended leucovorin, decrease the dose of MTX by 25%, increase 
hydration to 200 mL/m2/hr and continue increased leucovorin as above. Should subsequent 
courses be well tolerated, use a stepwise approach to resuming a standard approach to drug 
delivery. Consider culturing lesions for herpes simplex if mucositis persists or recurs. 
 
5.6 
Vincristne 
5.6.1 
Vincristine Neurotoxicity 
Seizures: Hold one (1) dose of vincristine, then reinstitute at 1 mg/m2  (1.5 mg maximum 
dose) while anticonvulsants are continued. If seizures do not recur, then escalate to full 
dosage. Rule out syndrome of inappropriate secretion of antidiuretic hormone (SIADH) as 
a cause of seizures.  
 
Severe neuropathic pain (Grade 3 or greater): Hold dose(s). When symptoms subside, 
resume at 50% previous dose, then escalate to full dose as tolerated. However, since 
vincristine is an important component of curative therapy, and the majority of neuropathies 
are ultimately reversible, treating physicians may choose to deliver full dose therapy.  
 
Foot Drop, paresis: Should be Grade 4 to consider holding or decreasing dose. These 
toxicities are largely reversible, though possibly over months to years. Accordingly, 
holding doses of vincristine and/or lowering the dose may not result in rapid resolution of 
symptoms and may compromise cure. Drugs such as gabapentin may be of value. 
 
Vocal Cord Paralysis: Hold dose(s). When symptoms subside, resume at 50% of previous 
dose, then escalate to full dose as tolerated.  
 
5.6.2 
Jaw Pain 
Treat with analgesics; do not modify vincristine dose unless determined to be in the best 
interest of the patient by the treating physician. 
 
5.6.3 
Constipation or Ileus  
Every effort should be made to prevent the development of constipation and ileus through 
judicious use of stool softeners/laxatives to prevent dose alterations.  For greater than Grade 3 
toxicity, hold vincristine dose(s). Institute aggressive regimen to treat constipation, if 
present. When symptoms abate then resume vincristine at 50% dose and escalate to full 
dosage as tolerated.   
 
 
 


 
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6.0 
DRUG INFORMATION  
 
See the consent document for toxicities. All other information is available on the COG website in the 
commercial agent monographs manual titled “Drug Information for Commercial Agents used by the 
Children’s Oncology Group.” This manual is provided under Standard Sections for Protocols at: 
https://members.childrensoncologygroup.org/prot/reference_materials.asp. 
 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable per COG 
administrative Policy 5.14 (except where explicitly prohibited within the protocol). 
 


 
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7.1 
Required Clinical, Laboratory and Disease Evaluations During Protocol Therapy 
All baseline studies must be performed prior to starting protocol therapy unless otherwise indicated 
below. Obtain other studies prior to start of phase unless otherwise indicated.   
STUDIES 
TO BE 
OBTAINED 
Baseline 
Prior to 
Each 
Cycle of 
Induction 
Therapy  
During 
Each 
Cycle of  
Induction 
Therapy 
Following 
Completion 
of Induction 
Therapy 
(Cycle 3) 
Following 
Second 
Look 
Surgery 
Prior to Each 
Cycle of 
Continuation 
Therapy 
During 
Continuation 
Therapy 
Completion 
of 
Continuation 
Therapy 
History 
X 
X 
X (Day 15, 
29, 43) 
X 
 
X  
X (Day 21) 
X 
Physical 
Exam (Ht, 
Wt, VS)  
X 
X 
X (Day 15, 
29, 43) 
X 
 
X 
X (Day 21) 
X 
Performance 
Status 
X 
X 
 
X 
 
X 
 
X 
CBC 
(differential, 
platelets) 
X 
X  
X (Day 15, 
29, 43) 
X 
 
X  
X (Day 21) 
X 
Urinalysis 
X 
X 
X (Days 
15, 29) 
 
 
X 
X (Day 21) 
 
Electrolytes 
(including 
BUN, 
Calcium, 
PO4, 
Magnesium, 
Sodium, 
Potassium)  
X 
X  
X (Day 15, 
29, 43) 
X 
 
X 
X (Day 21) 
X 
Serum 
Creatinine, 
Creatinine 
Clearance or 
GFR  
X 
X 
X (Day 15, 
29, 43) 
 
 
X 
X (Day 21) 
 
Audiogram or 
BAER 
X 
 
X (Day 
43)4 
X 
 
 
X (Day 21) 
X 
Brain MRI 
with and 
without 
gadolinium 
X1  
X (Prior 
to Cycle 
2)3 
 
X3 
X3 
 
 
X3 
Spinal MRI 
with and 
without 
gadolinium 
X2 
X (Prior 
to Cycle 
2) 3 
 
X3 
X3 
 
 
X3 
CSF cytology 
X 
 
 
X 
 
 
 
X 
Tissue 
Submission 
for Biology 
Studies (See 
Sections 
7.3and 14.3 
 
X 
 
 
 
 
X 
 
 
 
1- 
The pre-operative MRI evaluation will include an MRI of the brain (recommended with gadolinium) or pre-operative CT 
(recommended with contrast). The brain MRI should be repeated within 72 hours of surgery with and without gadolinium and this 
study will serve as the baseline for future comparisons.  
2- 
The spinal MRI will include pre-op with and without gadolinium or post-op with and without gadolinium preferably within 72 
hours of surgery. 
3- 
Required for disease evaluation. 
4- 
Obtain for Cycles 2 and 3. 
This table only includes evaluations necessary to answer the primary and secondary aims. Obtain other studies 
as indicated for good clinical care.  


 
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7.2 
Required Observations Following Completion of Protocol Therapy 
 
 
Observation 
 
 
3 Months, 6 
Months, 9 
Months 
 
Every 4 Months 
up to 24 
Months 
(Months 12, 16, 
20, 24) 
Annually up to 
72 Months 
(Months  36, 48, 
60, 72) 
Physical Exam with 
neurologic exam 
including growth curve 
(Height and Weight) 
X 
X 
X 
Brain MRI with and 
without gadolinium 
X 
X 
X 
Spine MRI with and 
without gadolinium 
X 
X 
X1 
Audiogram or BAER 
 
X2 
X1 
1 – Obtain if clinically indicated or if abnormal at completion of therapy. 
2 – Obtain at 12 and 24 months. 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) schedule. 
 
7.3 
Required Studies  
7.3.1 
Biology Specimens 
The following specimens are required. Send tumor tissue and peripheral blood according 
to collection and shipping instructions in Section 14.0.  NOTE: Biology specimens should 
not be submitted until after the rapid central pathology screening review has been 
completed and the patient is found to be eligible for and enrolled on ACNS1221.  
 
 
 


 
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Sample 
When Obtained 
Study 
Peripheral Blood 
(5 ml of blood in 
a purple top tube 
[EDTA]) 
Prior to treatment 
and at the time of 
second surgery. 
 
 
Germline DNA and SNP 
analysis 
 Formalin Fixed 
Paraffin Embeded  
(FFPE) Sections: 
 25 (5µm) 
unstained slides 
and up to 10 
(10µm) scrolls  
At time of diagnosis 
and second surgery 
1)IHC: 9 GAB1, βcatenin, 
Filamin A, and YAP1 
2) FISH studies:   
Loss of 9q and 10q 
Isochromosome 17q 
MYCN and MYCC 
amplification, GLI2 
amplification 
 
 
7.4 
Optional Studies  
 
7.4.1 
Neurocognitive Evaluations 
Patients who consent to participate on ALTE07C1 will be assessed at three times points, 
in accordance with the COG Standard Neuropsychological Battery: At 9 months (± 3 
months) post cancer diagnosis; at 30 months (± 3 months) post diagnosis, and again at 60 
months (± 3 months) post diagnosis. Age appropriate tests will be used and will include 
measures of broad cognitive functioning (IQ) and specific areas of neuropsychological 
functioning, emotional-behavioral functioning, and quality of life. Total testing time 
should be approximately 1 hour at each assessment point.  
 
 
7.4.2 
Optional Biology Specimens 
The following specimens are optional. Send snap frozen tumor tissue according to 
collection and shipping instructions in Section 14.0 
 
Sample 
When Obtained 
Study 
50-100  mg pieces 
Snap frozen tumor 
tissue  
At time of 
diagnosis and 
second surgery 
1) High throughput gene 
expression analysis  
2) SNP analysis on tumors  
3) Whole exome 
sequencing   
4) Targeted gene 
sequencing  
 
 


 
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) 
Progressive disease. 
b) 
Refusal of further protocol therapy by patient/parent/guardian. 
c) 
Completion of protocol therapy. 
d) 
Physician determines it is in patient’s best interest. 
e) 
Development of a second malignancy. 
f) 
Repeat eligibility studies (if required) are outside the parameters required for eligibility. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off Study (see 
below). Follow-up data will be required unless consent was withdrawn. 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The sixth anniversary of the date the patient was enrolled on this study. 
f) Patient did not receive protocol treatment after study enrollment. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size and Study Duration 
Background 
The primary objective of this trial is to estimate the PFS distribution of patients 0-<4 years of age 
with newly-diagnosed M0 desmoplastic (ND/MBEN) medulloblastoma treated with ACNS1221 
therapy. While this study is not designed for a formal comparison, outcome for patients treated on 
the current trial will be assessed for evidence that the 2-year PFS rate is unacceptably low given 
what was observed for patients treated on HIT SKK 2000 trial, which enrolled newly diagnosed 
non-metastatic medulloblastoma patients within this age group and treated them with a 
chemotherapy-only regimen.6   HIT SKK 2000 enrolled 19 evaluable desmoplastic patients (13 
ND+6 MBEN), 14 of whom were R0 (9 ND+5 MBEN) after initial surgery. All 19 patients have 
been followed for over 2 years and the only progression (local) was observed 1.7 years after 
diagnosis in a patient who was R0 after initial surgery. Hence the percentage of patients who were 
progression free during the first 2 years for this cohort is 94.74% with a Blyth-Still-Casella 95% 
lower bound estimate of 79.13%.  
 
While the follow-up is less complete, preliminary results from Head Start III trial for a similarly 
defined patient cohort indicate a similar outcome (G Dhall personal communication). Specifically, 
15 M0/R0 desmoplastic patients less than 4 years of age were enrolled on the Head Start III study 
and only 1 failure was observed during the first 2 years. Hence the percentage of patients who were 
progression free during the first 2 years in the associated Head Start III cohort is 93.33% with a 


 
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Blyth-Still-Casella 95% lower bound estimate of 75.29%, which is quite similar to the outcome 
observed in the HIT SKK 2000 trial. 
 
With respect to the COG studies, the recent report by Leary et al4 indicate that 18 M0 desmoplastic 
patients aged 0-3 years were treated on CCG-9921 protocol. All 18 were followed for at least 2 
years from on-treatment date and 4 failed during the first 2 years leading to a “proportion of 
success” estimate of 77.78%. In other words 77.78% of patients were failure free at the end of 2 
years with a standard error of 9.47%. The Blyth-Still-Casella 95% lower bound estimate of the 
proportion of patients who are failure free at the 2-year mark is 58.12%.  
 
Primary Endpoint and Sample Size 
The intent of the current study is to estimate the PFS distribution associated with the current 
treatment which uses the same chemotherapy regimen as HIT SKK 2000 but without the 
intraventricular MTX. Note however that this study is an independent assessment of the efficacy 
associated with the proposed treatment regimen and this trial is not designed to directly compare 
its outcome to the one observed on HIT SKK 2000 trial.  
 
While the primary objective is estimating the PFS distribution, for the purpose of sample size 
determination we will frame the design in the context of hypothesis testing with the following 
primary outcome: proportion of eligible patients who receive at least 1 dose of the chemotherapy 
regimen and who complete the first 2 years from diagnosis without progression or death. Since this 
trial proposes a reduction in treatment, we will base the design on a one-sided test and the following 
hypotheses: the true, unknown 2-year success rate is at least 90% (null) vs. less than 74% 
(alternative). The values for the null and the alternative hypotheses were chosen based on the 
outcome observed on recent trials especially HIT SKK 2000. Though 90% is slightly lower than 
what was achieved on HIT SKK 2000, this was felt to be a reasonable target taking into account 
the small sample sizes from which these outcome information were derived, the variability 
observed in the outcome across trials and the previous variability associated with identifying 
ND/MBEN medulloblastoma. Moreover the study team firmly believes that 90% 2-year PFS 
without IT-MTX would be a very desirable outcome for this patient population.  
 
Because the desirable outcome is stated in the null hypothesis which is consistent with the treatment 
reduction objective of this study, we used a relatively large α and a small β in order to maximize 
the power to detect erosion in PFS rates and control the risk of falsely concluding that the modified 
treatment is not associated with worse outcome. Based on the above-mentioned parameters, a 
sample size of 37 patients results in α=0.16 and power=0.945 for the associated 1-sided hypothesis 
which would lead us to declare the proposed treatment regimen as promising if no more than 5 
failures are observed during the first 2 years from diagnosis among the 37 patients. In other words, 
the 2-year PFS rate associated with the proposed treatment regimen will be considered desirable if 
32 or more of the 37 patients enrolled (86.5%) complete the two year observation period without 
an event. Otherwise the proposed regimen will be rejected. Final analysis will be conducted once 
37 eligible and evaluable patients have been enrolled and all have been followed for 2 years from 
diagnosis or until failure, whichever comes first. Considering the unlikely event of patients being 
declared ineligible or inevaluable after enrolling on the trial, we estimate that we will enroll at most 
42 patients in total. 
 
In the recent infant trials conducted by COG or its predecessors, namely CCG-9921, CCG-99703 
and P9934, there were no M0 medulloblastoma patients who were censored in the first 2 years of 
the study. In addition, based on the currently open trials whose eligibility criteria include 
medulloblastoma patients younger than 4 years of age, specifically ACNS0331, ACNS0332 and 


 
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ACNS0334, there was only 1 medulloblastoma patient younger than 4 years of age who was lost 
to follow-up within 2 years of enrollment. Hence we expect that in the current study no patient will 
be lost to follow-up within two years of diagnosis. This is important since the parameter on which 
this design is based is a proportion derived from a Binomial distribution. The definition of this 
proportion requires all patients who fail to be evaluated at the 2-year time point to be considered as 
failures. These would include patients who discontinue treatment due to toxicity and refuse further 
follow-up, withdraw from the study or who are lost to follow-up within the first two years. 
Definition of an “event” also includes second malignancy or death for any reason within the first 2 
years from diagnosis. 
 
9.2 
Accrual Duration 
The study team estimates that the accrual rate to this trial will be approximately15 patients/year. 
Hence we expect that accrual to this study will be complete in 2.5-3 years barring any unforeseen 
circumstances. 
 
To estimate our expected accrual we reviewed the enrollment profile of previous infant studies and 
extracted the number of M0 Desmoplastic patients enrolled per year according to the central 
pathology review of these trials. The following table summarizes the accrual of several infant 
studies which ran during the last 2 decades, some of which overlapped: 
 
Table 4: Accrual Summary of Infant M0 ND/MBEN  
Medulloblastoma Patients on Previous Trials 
 
Protocol  
Years of study 
No. of M0 ND/MBEN  No./year 
9934 
10/2000-6/2006 
30 
5 
9921 
4/1993-7/1997 
18 
4.5 
99703 
3/1998-10/2004 
13 
1.7 
Head Start I,II 
1991-2003 
21 
1.6 
Head Start III 
2003-2009 
28 
4.6 
 
The following facts are part of our rationale for anticipating higher accrual than what has been 
listed above: 
• 
The 9934 trial did not include patients < 8 months and was only opened in 33 out of 
the 250 COG institutions. Note that while the accrual rate for this study had to be 
adjusted from 25 patients/year to 16 patients/year, at the time the adjustment was made 
the study team had speculated that the slower accrual was likely related to the mandated 
XRT rather than competition from other studies. 
• 
99703 study was closed to accrual frequently as part of the study design to evaluate 
safety which resulted in many patients being treated off protocol. 
• 
The addition of 1 to 2 patients per year to account for accrual of patients aged between 
3 and 4 years (estimate based on A9961 series)  
 
Also based on CBTRUS data applied to the US population estimates (2004-2007) of children ages 
0-4 years, an annual incidence of approximately 185 cases of medulloblastoma would be expected. 
Based on the reported frequencies of desmoplastic medulloblastoma summarized in Table 1, we 
estimate that 40% of these 185 new cases annually will be ND/MBEN which results in a population 
size of 74 patients/year in the US alone with additional patients who would be eligible to enroll 
from COG member institutions in Canada and Australia. Although some concurrent studies will be 
competitive (next Head Start study and the currently open St Jude SJYC07 trial), we do not 


 
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anticipate that they will alter our ability to reach our target accrual rate of 15 patients/year. This 
trial is the only opportunity for many centers to treat ND/MBEN medulloblastoma patients with a 
regimen specific to their histology and without high dose chemotherapy, which we believe will 
help boost accrual. 
 
9.3 
Analysis Plan for the Primary Objective 
At the time of the final analysis, 95% exact confidence interval estimate of the binomial probability 
of completing two years of therapy free of failure will be calculated. In addition Kaplan-Meier 
estimates of PFS and overall survival distributions will be provided. PFS will be measured from 
diagnosis to the earliest of disease progression or death from any cause. Similarly OS will be 
measured from diagnosis to death from any cause.  Patients who have not experienced one of these 
events will be censored at their last date of contact. In the event that any patient experiences a 
second malignancy we will also provide an estimate of event free survival distribution. For patients 
with measureable disease we will assess response rates after induction therapy as well as at the end 
of continuation therapy. Estimates of response rates as well as the associated exact confidence 
intervals will be reported.  If accrual estimates as discussed above prove accurate, these analyses 
are expected 5-6 years after the trial is activated. 
 
Interim Analysis 
Given the excellent outcome which is being targeted, the long follow-up needed to assess the 
primary endpoint and the relatively small number of patients to be enrolled on this study, devising 
an interim analysis with reasonable operating characteristics is difficult. Keeping this limitation in 
mind, we will conduct an interim analysis once 15 patients have been enrolled and have been 
observed for the 2-year outcome. If 10 or fewer patients complete the 2-year observation period 
without progression/death, this would suggest that the modified therapy is inferior. Note however 
that unless these events occur relatively early or that the reduced treatment has a substantially lower 
success rate, it is likely that at the time of the interim analysis, most patients would have been 
accrued since accrual will not be suspended in order to wait for the interim analysis results. Based 
on this interim analysis rule, if the modified treatment has a 74% 2-year success rate, there is a 
34.7% chance that this boundary will be crossed at the interim analysis. However if the 2 year 
success rate is 60%, the trial will stop with 78.3% probability based on the proposed interim 
analysis rule. In addition since only 6 failures are needed overall in order to declare the proposed 
strategy a failure, this will also serve as a stopping rule. More specifically, we will stop accrual to 
the trial if at any point 6 failures have been observed within the first 2 years from diagnosis, which 
may be more effective than the interim analysis rule in stopping early if the proposed regimen is 
indeed inferior. Note that an earlier time point could not be considered for the design as no failures 
were observed on the HIT SKK 2000 study or on the CCG-9921 trial among patients who would 
have been eligible for this study during the first year of treatment and only 1 patient had failed by 
18 months.  
 
9.4 
Correlative Science Objectives 
Rapid Central Pathology Screening Review  
Evaluate the feasibility of a rapid central pathology screening review for treatment allocation 
according to histology and assess agreement between institutional and central pathology review 
diagnoses as well as among central pathology review diagnoses. 
 
While the nodular/desmoplastic histology subtype is more common among the infant group, the 
reported rates vary widely among studies, ranging from 29% to 75%. The discrepancy in the rates 
of desmoplasia may be related to selection bias among the various infant medulloblastoma series 


 
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(different ages for inclusion, different eras of diagnostic tools and awareness of the diagnosis) or 
may be due to under-reporting since most protocols to date did not have specific reporting 
requirements for subtypes of medulloblastoma. However, there is also evidence that lack of 
consensus on the definition of desmoplastic medulloblastoma is another contributing factor to this 
discrepancy. Therefore, a rapid central pathology screening review appears essential in the context 
of a protocol that is intending to treat according to histologic subtype.  Hence this protocol will 
require pre-screening and rapid central pathology screening review to confirm eligibility. 
 
Patients with an institutional diagnosis of medulloblastoma will undergo a rapid central review and 
only those with confirmed ND/MBEN histology will be eligible to be treated on the current study. 
The central pathology panel will include 3 pathologists who will review the pathology slides via a 
web-based system. All 3 pathologists are expected to review all cases and eligibility will be based 
on majority opinion. More specifically, if at least 2/3 pathologists agree that the patient has 
ND/MBEN medulloblastoma that patient will be declared eligible. In cases where one of the 3 
pathologists is not available and the remaining 2 pathologists are not in agreement, they will be 
expected to discuss the case and reach a consensus about eligibility. Given the web-based review 
system and the relatively long period allocated for review, the study team believes it is highly 
unlikely that there will be a case where more than one pathologist will be unavailable for review. 
 
The feasibility of this central prescreening process will be monitored and the central review results 
are expected to be made available within 10 days of the receipt of the slides at the Biopathology 
Center. We will monitor the success rate of timely central pathology review based on the 
expectation that at least 95% of the cases will be reviewed within 10 days. Note that while the 
sample size of this trial is 37 eligible and evaluable patients, up to 100 patients may have to be pre-
screened in order to achieve it. The following somewhat ad-hoc monitoring rules will be used to 
assess feasibility of this approach and if at any time one of the thresholds is met, a re-evaluation of 
the central pathology screening review process will be initiated so that corrective action can be 
taken. These thresholds are based on an exact binomial design with H0:p≥0.95 vs. HA:p<0.95 which 
leads to a sample size of 98 and is powered to detect an effect size of 9% (i.e. p=0.86) with an 
actual α=0.057 and actual power=0.943. The associated interim monitoring rules based on 
monitoring for rejection of H0 only are given in the table below:  
  
Number of 
Patients 
Screened 
Re-evaluate pathology review process 
if number of patients whose central 
path screening review is not complete 
within 10 days of receipt of slides at 
Biopathology Center 
Cumulative 
boundary 
crossing probability under 
the assumption that the true 
success rate ≤86% 
35 
≥8 
21.1% 
55 
≥9 
51.7% 
80 
≥10 
80.9% 
98 
≥10 
94.3% 
 
At the end of the trial the feasibility of such a prescreening process will be assessed by reporting 
various performance statistics including the percentage and the associated confidence interval of 
cases where the central review was obtained within 10 days from receipt of slides as well as 
summary statistics of the actual review times. Further frequency tables and other descriptive 
statistics will be provided summarizing the agreement between the site pathologists and the central 
pathology reviewers as well as among the central pathology reviewers. 
 
 


 
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Molecular Profile 
Prospectively evaluate the molecular profile of ND/MBEN medulloblastoma in young children 
The proposed secondary biology objective is quite broad and aims to scrutinize the available tumor 
material via a variety of molecular studies. Given the high dimensionality of the genomic 
information which will be generated from these samples, the optional nature of some of these 
studies and the relatively small sample size planned for this study, the number of patients with 
available tissue will be the limiting factor in determining the feasibility and the utility of these 
studies. The eligible cohort for this trial is relatively homogeneous from a clinical and histological 
perspective which will help reduce the number of other variables that may need to be 
accommodated in the resulting models.  
 
As indicated above accrual is expected to last approximately 3 years. Tumor tissue will be collected 
from consenting 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 available at that time. The same 
rapid emergence of new approaches is also true for statistical methodology regarding genomic data 
therefore the approaches detailed below reflect the current state of knowledge and may be modified 
at the time of analysis which is expected to be performed approximately 4 years after study 
initiation. At the time the protocol is closed to accrual but prior to the analysis of the procured 
samples, a  separate protocol (to include analytical and statistical methodology) will be developed 
for use of the samples collected for the ACNS1221 trial  for correlative biology studies and 
submitted and approved in accordance with the National Clinical Trials Network. The following 
therefore is an overview of studies which may be performed, though are subject to change based 
on above-outlined reasons: 
 
Unsupervised clustering algorithms, such as hierarchical clustering or non-negative matrix 
factorization27 may be used descriptively to explore the possibilities of discovering novel subgroups 
based on gene expression.  We may also combine our data with previously collected data for other 
medulloblastomas and perform subgroup discovery analysis on the combined cohort including 
bootstrap-based resampling of subjects28 to determine the stability of subgroup assignments.   
 
We may explore the association of gene expression with clinical features, histological features, and 
prognosis, via appropriate hypothesis tests and models.  We may use false discovery rate methods29 
or other similar approaches to address multiple testing. 
 
We may use SNP microarrays to identify copy number abnormalities in these tumors.  We will 
adjust for potential aneuploidy while normalizing signal data and then use an appropriate 
segmentation algorithms 30,31,32,33 to identify change-points in the series that may indicate regions 
of deletion or amplification.  We may also explore whether the constellation of deletions and 
amplifications appear to be associated with target specific pathways as well as with clinical features 
and prognosis.   
 
We may use sparse canonical correlation34 or similar approaches to characterize the association of 
genome-wide copy number alterations with genome-wide gene expression.   
 
Using the most appropriate methods available at the time, the whole exome sequencing data, will 
be mapped to the reference genome, will be transformed and adjusted for GC-effects, and then 
segmented to identify copy number changes.  Additionally, we may explore the presence of 


 
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translocations and other structural alterations in the whole exome data.  The clinical and prognostic 
relevance of copy number and structural abnormalities may be studied by screening their 
association with clinical and prognositic variables. 
 
All patients who enroll on this study will have FFPE tissue available for analysis. The percentage 
of tumor sub-types identified via expression of four IHC markers (GAB1, Bcatenin, Filamin A and 
Yap1) along with their exact confidence intervals will be provided.  Similar statistics will also be 
computed for percentage of patients with a variety of molecular aberrations such as loss of 
chromosome 9q, 10q and 17p, gain of chromosome 3q and 17q, amplification of MYCN and GLI2 
as well as other specific targets which may be identified in the near future.  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 tests. Significance will be determined 
using exact, permutation, or resampling methods. Finally associations of such abnormalities with 
outcome will be explored via Cox models. 
 
Neurocognitive Functioning 
Due to early closure of the study, the neuropsychological function studies were removed as 
part of Amendment #3. 
 
Monitor and describe the neurocognitive and adaptive functioning of young children with 
ND/MBEN medulloblastoma treated on this protocol using the ALTE07C1 protocol 
Neurocognitive and adaptive functioning outcome assessment is an important secondary objective 
of this trial and the intent is to provide preliminary evidence that the treatment regimen proposed 
in this study will not lead to substantial decline in neuropsychological and adaptive functioning as 
assessed in an exploratory fashion. The proposed assessments and time points (9, 30, and 60 months 
post diagnosis (± 3 months)) are consistent with the approved COG ALTE07C1 protocol. Since the 
proposed hypotheses are in the form of non-inferiority, it will not be possible to test these 
definitively. Instead provided adequate data is available to make such analyses viable, we will 
provide confidence intervals of the average scores obtained at each time point both for Full Scale 
IQ score (FSIQ) and General Adaptive Composite score (GAC) and see if these confidence 
intervals include the normative values. Additionally we will describe changes between T1 and T2, 
T2 and T3 and T1 and T3 via paired tests and confidence intervals both for FSIQ and GAC scores 
in order to capture any deterioration over time. We will also consider repeated measures analyses 
incorporating all three time points to describe change over time.  
 
Given the optional nature of these studies, the consent rate to participate in ALTE07C1 trial and 
compliance with data submission will determine whether adequate data will be available to provide 
meaningful information. Hence a monitoring rule will be in place to ensure that the consent and 
compliance rates are not unacceptably low. We will base this monitoring rule on T1 and on GAC 
score, since FSIQ score availability will be dependent on the age distribution of patients at T1 
whereas GAC will be potentially available on everyone since it is a parent report measure. Based 
on a 1-sample t-test and a null hypothesis that the mean GAC score for patients on this study will 
be similar to the norms vs. the mean  GAC score will be lower, we will need 27 patients to detect 
a 0.5 std dev drop in average GAC scores with 10% type 1 error and 90% power. This sample size 
requires approximately 75% consent and compliance rate. So we will check the consent and 
compliance rate after 20 patients have been enrolled on the study and have reached T1, if the 
number of patients who consented and provided data for GAC score is less than 15, then we will 
review and revise our approach to ensure that the compliance improves for future patients. 


 
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9.5 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
2 
3 
Not Hispanic or Latino 
17 
22 
39 
Ethnic Category: Total of all subjects 
18 
24 
42 
Racial Category 
 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
1 
2 
3 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
17 
22 
39 
Racial Category: Total of all subjects 
18 
24 
42 
 
 
 
 
This distribution was derived from enrollment patterns in prior COG trials with similar patient 
populations and incorporates the slightly larger likelihood of medulloblastoma in males. 
 
 
10.0 
EVALUATION CRITERIA 
 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
This study will utilize version 4.0 of the CTCAE of the National Cancer Institute (NCI) for toxicity 
and performance reporting. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v4.0’ is understood to represent the most current version of CTCAE v4.0 as 
referenced on the CTEP website (ie, v4.02 and all subsequent iterations prior to version 5.0). 
 
10.2 
Methodology to Determine Tumor Measurement 
In order to completely document the assessment of response, the measurements of the longest tumor 
dimension, and its perpendicular, of all target lesions upon which the assessments of tumor 
response are based should be explicitly noted in the radiology report for the baseline and all 
subsequent follow-up exams. Reports for the follow-up exams should reiterate the measurements 
obtained at baseline for each target lesion. Non-target lesions or newly occurring lesions should 
also be enumerated in these reports, and changes in non-target lesions should be described. 
 
Tumor response criteria are determined by changes in size using the longest tumor dimension, and 
its perpendicular. FLAIR, T2 or post contrast T1 weighted images may be used - whichever gives 
the best estimate of tumor size. 
 
Since many tumors contain nonenhancing components (or, in some cases, the tumor may not 
enhance at all), both the enhancing and the non-enhancing components must be evaluated – on post 
contrast T1 weighted images and on FLAIR/T2 weighted images respectively. Increase in 


 
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enhancement on T1 weighted images without accompanying increase in disease bulk on T2 or 
FLAIR images is not considered tumor progression. In return, enlarging areas of nonenhancing 
tumor (defined as mass effect/tissue thickening) are evidence of tumor progression. Conversely, 
decrease in enhancing tumor component without decrease in overall FLAIR/T2 extent may 
represent change in tumor permeability (commonly observed with antiangiogenic therapies) rather 
than represent tumor response. 
 
The following section describes the methodology. (See Figure 10.1 below for illustration.) 
 
1. For MRI imaging the longest measurement of the tumor (or width, W) should be determined. 
It can be measured from the axial plane or the plane in which the tumor is best seen or measured, 
provided the same plane is used in follow ups. Longest diameter of target lesion(s) should be 
selected in the axial plane only for CT. 
2. The measurement (transverse (T)) perpendicular to the width in the selected plane should be 
determined. NOTE: A measurable lesion should have a minimal transverse measurement that 
is at least twice the combined thickness of the image slice and the interslice gap. For example, 
with a 4 mm slice and a 0.4 mm gap, minimal measurable lesion diameter is 8.8 mm. Smaller 
lesions would not be measurable for study purpose. 
3. The cystic or necrotic components of a tumor are not considered in tumor measurements. 
Therefore only the solid component of cystic/necrotic tumors should be measured. If 
cysts/necrosis composes the majority of the lesion, the lesion may not be “measurable”. 
Options: 
- 
if the cyst/necrosis is eccentric, the W and T of the solid portion should be measured, 
the cyst/necrosis excluded from measurement 
- 
if the cyst/necrosis is central but represents a small portion of the tumor (< 25%), 
disregard and measure the whole lesion 
- 
if the cyst/necrosis is central but represents a large portion of the tumor, identify a solid 
aspect of the mass that can be reproducibly measured 
4. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be measured 
accurately. Presence and location of leptomeningeal tumor spread should be noted, and change 
in extent/thickness assessed on follow up studies. 
 
 


 
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Figure 10.1: COG Guidelines for Measurement of Tumor Size 
 
 
5. 
Overall Response Assessment 
The overall response assessment takes into account response in both target and non-target lesion, 
and the appearance of new lesions, where applicable, according to the criteria described in the table 
below. The overall response assessment is shown in the last column, and depends on the 
assessments of target, non-target, and new lesions in the preceding columns. 
 
 
Z
AXIS
W
T
A
B
C
D
E
COG GUIDELINE: TUMOR SIZE
MEASUREMENT BASED ON
CROSS-SECTIONAL IMAGING
• A, B, C, D, & E are contiguous
parallel slices in the X-Y plane
(usually axial) showing the tumor
• W and T are the maximal
perpendicular diameters on the slice
(C in this example) showing the
largest surface area
• Tumor length in the Z-axis (L)
(perpendicular to X-Y plane) can be
obtained either by the [a] (difference
in table position of the first and last
slices showing the tumor + one slice
thickness), or [b] the product of (slice
thickness + gap) and the number of
slices showing the tumor
X-Y
PLANE
L


 
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Overall Response Assessment 
 
 
Target Lesions 
 
New Lesions* 
 
Overall Response 
CR 
No 
CR 
PR 
No 
PR 
SD  
No 
SD  
PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR – Complete Response 
 
PD – Progressive Disease 
PR – Partial Response  
 
IR – Incomplete Response 
SD – Stable Disease 
*If CSF cytology becomes positive, it will be considered a new lesion and progressive disease. 
 
The sections that follow discuss the selection and evaluation of each of these types of lesions. 
10.3 
Selection of Target Lesions 
1. For most CNS tumors, only one lesion/mass is present and therefore is considered a “target” 
for measurement/follow up to assess for tumor progression/response.  
2. If multiple measurable lesions are present, a minimum of the 2 largest lesions should be 
measured; a maximum of 5 should be selected as “target” lesions. Target lesions should be 
selected on the basis of size and suitability for accurate repeated measurements.  
3. The lower size limit of the target lesion(s) should be at least twice the thickness of the slices 
showing the tumor to decrease the partial volume effect (eg, 8 mm lesion for a 4 mm slice). 
10.4 
Response Criteria for Target Lesions 
Response criteria are assessed in 2 dimensions – the product of WxT.  
 
To assess response/progression, the ratio is calculated: 
 
 
 
WxT (current scan)  
 
 
 
WxT (reference scan) 
 
Development of new disease or progression in any established lesions is considered progressive 
disease, regardless of response in other lesions – eg, when multiple lesions show opposite 
responses, the progressive disease takes precedence. 
 
Complete Response (CR): The disappearance of all target lesions. 
Partial Response (PR): ≥ 50% decrease in the sum of the products of the 2 perpendicular 
diameters of all target lesions (up to 5), taking as reference the initial baseline measurements. 
Stable Disease (SD): Neither sufficient decrease in sum of the products of the 2 perpendicular 
diameters of all target lesions to qualify for PR (taking as reference the initial baseline 
measurements), nor sufficient increase in a single target lesion to qualify for PD, (taking as 
reference the smallest disease measurement since the treatment started). 
Progressive Disease (PD): ≥ 25% increase in the product of perpendicular diameters of ANY 
target lesion, taking as reference the smallest product observed since the start of treatment, or 
the appearance of one or more lesions.  If CSF cytology becomes positive, it will be considered 
a new lesion and progressive disease. 
 
Local progression is defined as progression of known residual tumor or the appearance of tumor at 
known prior sites of disease that were at some point without evidence of disease. Distant 
progression is defined as the appearance of tumor at sites other than known prior sites of disease. 


 
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Distant progression most often occurs in the subarachnoid space and may occur at any point within 
the neuraxis. Although rare, extra-CNS metastasis represents distant failure. Combined local and 
distant progression is defined when evaluation of the entire neuraxis reveals local and distant 
progression. 
 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event data collection and reporting, which are required as part of every clinical trial, are 
done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents.  
 
11.2 
Determination of Reporting Requirements 
Reporting requirements may include the following considerations: 1) the characteristics of the 
adverse event including the grade (severity); 2) the relationship to the study therapy (attribution); 
and 3) the prior experience (expectedness) of the adverse event. 
  
Commercial agents are those agents not provided under an IND but obtained instead from a 
commercial source. In some cases an agent obtained commercially may be used for indications not 
included in the package label.  In addition, NCI may on some occasions distribute commercial 
supplies for a trial.  Even in these cases, the agent is still considered to be a commercial agent and 
the procedures described below should be followed. 
 
Determine the prior experience Expected events are those that have been previously identified as 
resulting from administration of the agent.  An adverse event is considered unexpected, for 
reporting purposes only, when either the type of event or the severity of the event is not listed in:  
 
• the current known toxicities for each commercial agent as provided in the Drug Information 
for Commercial Agents Used by the Children’s Oncology Group posted on the COG 
website; or 
• the drug package insert. 
 
11.2.1 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment 
with investigational agent/intervention, radiation or chemotherapy). A metastasis of the initial 
neoplasm is not considered a secondary malignancy.  
 
All secondary malignancies that occur following treatment need to be reported via CTEP-AERS. 
Three options are available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy   
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
 


 
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11.2.2 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
11.3 
Reporting of Adverse Events for Commercial Agents – via CTEP-AERS  
Expedited AE reporting must use CTEP-AERS (Adverse Event Expedited Reporting 
System), accessed via https://eapps-ctep.nci.nih.gov/ctepaers 
 
Commercial reporting requirements are provided in Table B.  The commercial agent(s) used in this 
study are listed in the front of this protocol immediately following the Study Committee roster.  
 
• 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of 
learning of the event.   
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting and are located on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who have NOT 
received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During Therapy With 
a Commercial Agent or Within 30 Days1 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated 
or 
Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution.  Any death that occurs more than 
30 days after the last dose of treatment with a commercial agent that can be 
attributed (possibly, probably, or definitely) to the agent and is not due to 
cancer recurrence must be reported via CTEP-AERS. 
 
 
 


 
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11.4 
Routine Adverse Event Reporting 
Note: The guidelines below are for routine reporting of study specific adverse events on the COG 
case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
The NCI defines both routine and expedited AE reporting.  Routine reporting is accomplished via 
the Adverse Event (AE) Case Report Form (CRF) within the study database.  For this study, routine 
reporting will include all toxicities reported via CTEP-AERS and all Grade 4 and higher Adverse 
Events.  
 
 
12.0 
STUDY REPORTING AND MONITORING  
 
The Case Report Forms and the submission schedule are posted on the COG web site with each protocol under 
“Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data 
will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 30, 
July 31 and October 31. This is not a responsibility of institutions participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research by the 
Children’s Oncology Group, the COG Data and Safety Monitoring Committee (DSMC) reviews 
reports of interim analyses of study toxicity and outcomes prepared by the study statistician, in 
conjunction with the study chair’s report. The DSMC may recommend the study be modified or 
terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected frequency 
of serious events on the trial are to be brought to the attention of the DSMC. The study statistician 
is responsible for the monitoring of the interim results and is expected to request DSMC review of 
any protocol issues s/he feels require special review. Any COG member may bring specific study 
concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping an arm based on toxicity results or other trials reported, 
increasing target sample size, etc.). The DSMC determines whether and to whom outcome results 
may be released prior to the release of study results at the time specified in the protocol document. 
 
 
 


 
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13.0 
SURGICAL GUIDELINES 
13.1 
Assessment of Residual Tumor 
The assessment of presence or absence of residual tumor will be based primarily on post-surgical MRI, 
with due consideration to the neurosurgeon's assessment of residual tumor from visual inspection of 
the tumor bed.  Tumor unequivocally detectable on MRI or by surgical impression is considered 
residual tumor. 
 
13.2 
Size of Post-Surgical Residual Tumor 
The size of residual tumor present after surgery will be based on post-surgical MRI, with due 
consideration to the neurosurgeon's assessment of residual tumor based upon visual inspection of the 
tumor bed.  
 
Measurements should include solid residual tumor or tumor cysts with enhancing walls only. Tumor 
cysts without enhancement in the wall should not be included in the measurements of residual.  
 
 
13.3 
Extent of Tumor Resection 
The extent of tumor resection will be based primarily on post-surgical MRI, with due consideration to 
the neurosurgeon's assessment of residual tumor from visual inspection of the tumor bed.   Extent of 
tumor resection will be categorized as follows: 
 
Biopsy:  An open surgical removal or closed (e.g., needle) removal of tissue for the purpose of 
establishing a pathological diagnosis, with tumor removal less than 10% of the total tumor mass. 
 
Partial:  Removal of 10 - 49% of the tumor mass. 
 
Subtotal Resection:  Removal of 50 - 95% of the tumor mass.   
 
Radical Subtotal Resection (Near Total):  Removal of > 95% but less than 100% of the tumor mass. 
 
Gross Total Resection:  No visible tumor is left at the time of surgery and this is confirmed by 
postoperative CT or MRI. 
 
13.4 
Imaging Confirmation of Extent of Resection 
All patients will have confirmation of the neurosurgical staging of the extent of resection with a 
postoperative MRI scan, with and without contrast. This scan should be carried out after surgery, 
within 72 hours. 
 
13.5 
Peri-operative Corticosteroids 
Some patients with large tumors may require initiation of corticosteroid therapy preoperatively to 
reduce associated cerebral edema. If possible, this should not be started until after the initial MRI 
scan, since corticosteroids may affect tumor contrast enhancement.   
 
13.6 
Second Surgery 
The purpose of the second operation is to remove as much tumor that persists after induction 
chemotherapy as safely possible.  As outlined in the Background section of this protocol, complete 


 
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resection of disease at diagnosis confers a survival advantage to patients.  The goal of this 
intervention is to confer the advantage of complete resection of disease to as many patients as 
possible.  If it is determined pre-operatively that residual tumor cannot be removed in its entirety, 
serious consideration should be made for tumor maximal safe debulking instead.  
 
Guidelines for this operation are similar to those for the first operation; however, control of 
increased intracranial pressure and ventriculomegaly should not be concerns at this time.  An 
approach most suitable to the child should be taken.  The direction of approach can be either similar 
to the first operation or different from it depending on the site of residual disease and the judgment 
of the surgeon. 
 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIAL STUDIES 
 
Before entering patients on this trial, clinicians should discuss this protocol with their pathologist 
and provide them with pathology section of the protocol and list of the required materials that will 
need to be submitted for the rapid central pathology screening review. (Requirements are listed on 
the Data Submission Schedule in the CRF packet and below.) 
 
It is the responsibility of the Principal Investigator at the institution to ensure that the pathologist is informed 
and to request that all M0 patients up to 4 year of age at definitive surgery specimens be forwarded to the 
COG Biopathology Center (BPC), as required. The BPC will NOT request materials. 
 
14.1 
Required Rapid Central Pathology Screening Review (See Appendix III) 
The pathologic classification of tumors is becoming increasingly complex since there is 
considerable variation in the histological features of patients.  Central review is therefore critical to 
ensuring that the diagnosis is accurate and that patients are treated appropriately. Central pathologic 
review will be performed on all diagnostic specimens (whether resected or biopsied). Results of 
the review will only be given to the treating institution for patients who receive rapid central 
pathology screening review. 
 
If there is a discrepancy between the institutional diagnosis and the diagnosis on the rapid screening 
central review of a patient, then a discussion between the local and study pathologists will take 
place to attempt to reach a consensus, however, the decision of the study pathologists will be used 
to confirm eligibility. Slides will be stored at the COG Biopathology Center for quality control 
purposes. 
 
Specimen Requirements 
Patients must have a centrally confirmed histologic diagnosis of nodular desmoplastic (ND) 
medulloblastoma or medulloblastoma with extensive nodularity (MBEN) to enroll on the 
ACNS1221 study. The tumor should show significant nodular features encompassing 10% or more 
of the overall specimen. Please do not submit tissue for Biology Studies (Section 14.3) until 
eligibility is confirmed and patient is enrolled on the study. 
 
 
Required Materials for Rapid Central Pathology Screening Review  
1) 
1 x H&E stained slide from ALL available paraffin blocks  
2)  
1 reticulin stained slide from a representative block 
3) 
1 synaptophysin stained slide if useful for institutional diagnosis 


 
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4) 
5 unstained slides from most representative block 
5) 
Institutional pathology reports  
6)  
Operative report(s)  
7) 
ACNS1221 Rapid Review Transmittal Form 
 
Please label all pathology review materials with patient’s COG ID number and the Surgical Path 
ID (SPID Number) and block number from the corresponding pathology report. 
 
 
 
 
 
Cases sent for Rapid Central Pathology Screening Review must be marked for RAPID 
REVIEW and shipped within 15 days of diagnosis by Federal Express Priority Overnight 
to: 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email: BPCParaffinTeam@nationwidechildrens.org 
*Be sure to include the room number. Packages received without the room number may be 
returned to the sender. 
 
Results of rapid central pathology screening review will be available within 10 calendar days 
of the receipt of pathology review materials.   
 
14.2 
Virtual Microscopy (VIPER) System 
This study will use virtual microscopy (VIPER) online automated pathology review system at the 
COG BPC for the rapid central pathology screening review.  Representative H&E and reticulin 
slides will be scanned at the BPC into an ACNS1221 digital tissue review database.  Synaptophysin 
stained slides will be scanned if available. The three study pathologists (Drs. Eberhardt, Hawkins 
and Horbinski) will be notified by email that a case is ready for central review.  If 2 of the 3 
pathologists confirm a diagnosis of nodular desmoplatic medulloblastoma or medulloblastoma with 
extensive nodularity using VIPER (Virtual Imaging for Pathology Education and Research), 
eligibility is confirmed.  The institution will be notified of patient eligibility by email within 10 
days of receipt of the slide at the Biopathology Center.  At that time the patient may be enrolled on 
the protocol if all eligibility criteria are met and consent has been obtained. 
 
14.3 
Required Special Studies Specimen Requirements 
Participation in biology studies is mandatory and specimens must be submitted no later than 
3 working days after enrollment on ACNS1221. In addition, institutions are encouraged to 
enroll and submit specimens for ACNS02B3.   
 
Required Materials: 
At the time of diagnosis and second surgery, tumor tissue should be sent to the Biopathology 
Center for Biology Studies: 
1)  
Peripheral Blood: 5 ml of peripheral blood in a purple top tube (EDTA) should be 
sent at kept at 4oC.  During warm weather, blood should be shipped on a cold pack. 
For second surgeries, please send blood at this time also. 


 
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2) 
Formalin Fixed Paraffin Embedded Material (FFPE): 25 (5um) unstained slides 
and up to 10 (10µm) scrolls should be sent  
3) 
COG Generic Specimen Transmittal Form must accompany each shipment.  Please 
use 
current 
form 
available 
at 
http://memberschildrensoncologygroup.org/prot/generic.asp.  
 
Optional Materials: 
It is highly recommended that snap frozen tumor tissue (a minimum of > 0.5 cm2 is preferred) be 
submitted if available. As many 50-100 mg pieces of tissue as possible should be frozen in foil in 
liquid nitrogen within 10 minutes of removal. Wrap the aliquots in foil or place in cryopreservation 
tube if the tumor is semi-liquid.  Use waterproof marker to label samples. Snap freeze the foil or 
cryopreservation tube containing the tumor material in vapor phase liquid nitrogen. Store in a -
80oC freezer until shipment. Samples should be shipped to the BPC on dry ice.  
 
Please label biology specimens with the COG Patient ID number, collection date and 
specimen type. For slides, document whether tissue is primary (P) or metastatic (M). 
 
Specimen Shipment 
If frozen tissue is submitted then biology specimens can be shipped together in a Specimen 
Procurement Kit. This dual chambered kit allows for the shipment of room temperature and frozen 
specimens in the same container. Dry ice may be placed in either compartment of the kit, but should 
not be put in both. This kit contains most of the supplies necessary for shipping specimens to the 
BPC.  To request a Specimen Procurement Kit, click on the ‘Biopathology Center Application’ link 
on either the Protocol or the CRA Home Page of the COG web site. On the Biopathology Center 
Applications page, select the BPC Kit Management link to enter the Kit Management application. 
For packing and shipping instructions please see Shipping Specimens in a Dual Chambered Kit 
at https://members.childrensoncologygroup.org/prot/biology.asp.  
 
Ship the kit by Priority Overnight using a FedEx shipping label obtained through the BPC Kit 
Management application. Specimen procurement kits are to be shipped Monday through Thursday 
for delivery Tuesday through Friday.  If blood is collected on a Friday, it may be shipped for 
Saturday delivery. Please do not ship tissue on Friday. 
 
Note: If frozen tissue is not submitted, then a shipping label for the blood sample can be obtained 
through the BPC Kit Management application, but slides must be shipped either by mail or using 
the institution’s courier account. 
 
Ship specimens to: 
 
COG Biopathology Center 
Nationwide Children’s Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH  43205 
Phone: (614) 722-2865 
Fax: (614) 722-2897 
Email:BPCBank@nationwidechildrens.org 
*Be sure to include the room number. Packages received without the room number may be 
returned to the sender. 
 


 
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All specimens will be processed and then banked at the COG Biopathology Center (BPC).   
Specimens will be forwarded to Dr. Giles Robinson for biology studies. 
 
14.4 
Rationale for Biology Studies 
High throughput molecular analysis on fresh frozen tumor tissue 
Studies detailing subtype differences have utilized high quality RNA and DNA from fresh frozen 
material.14-17,35  These studies have radically improved our understanding of medulloblastoma.  
Similarly, we plan to improve our understanding of this histologically defined subset of ND/MBEN 
medulloblastoma with high throughput gene expression analysis. SNP analysis on tumors and other 
upcoming new technologies that will be available at the time of analysis, where fresh frozen tissue 
is requested.  Isolation, collection and storage of genomic material on ND/MBEN tumors will allow 
for identification of currently identified and other candidate mutations via targeted sequencing 
studies or whole exome sequencing 
 
Rationale for Studies on FFPE 
The majority of medulloblastoma samples attained from surgery do not have fresh frozen tissue 
available on which to perform studies.  This current protocol will enroll patients from many 
different sites and, despite our emphasis on receiving fresh frozen tissue from every patient, we 
still anticipate to not have fresh frozen tissue on all of the medulloblastoma samples enrolled.   
Therefore, on this current protocol we will continue to collect and store FFPE upon which we aim 
to gather molecular and genomic information.  While we anticipate that rapidly changing 
technology will enhance extraction of molecular data from of this medium there remains a lot of 
valuable information that can currently be gained from already available testing.   
Immunohistochemistry (IHC) and interphase fluorescence in situ hybridization (FISH) can be used 
to identify molecular abnormalities associated with clinicopathologic variables.  These studies are 
robust, rapidly performed, and relatively inexpensive. IHC can be used to determine subtype 
classification.  On ACNS1221 expression of four IHC markers (GAB1, Bcatenin, Filamin A and 
Yap1) will be performed on all FFPE tumor samples.  Immunoreactivity profiles of these 4 markers 
will allow for the classification of ND/MBEN tumors into the WNT, SHH and non-WNT/non-SHH 
molecular subgroups. [27] Since we anticipate the majority of the ND/MBEN tumors will fall into 
the SHH subgroup36,37 this analysis will provide useful data on the exclusivity of this histology to 
the SHH subtype and may allow for improved identification of a SHH specific ND/MBEN 
subgroup. FISH can also be used to uncover specific molecular abnormalities with 
clinicopathologic associations.  Losses of chromosome 9q, 10q and 17p, gains of chromosome 3q 
and 17q, as well as amplification of MYCN and GLI2 will be assessed in this population.  In 
addition FISH and IHC will be used to validate and explore genetic abnormalities revealed by high 
throughput molecular studies on the entire ND/MBEN population.    
 
14.5 
Methods 
Methods for biology studies advance with technology and are subject to change.  Samples on this 
trial will be analyzed by the most advanced methods available and the following methods are to be 
considered representative of those which will be used. Current patient derived materials needed to 
perform these analyses include (1) Fresh Frozen tumor tissue (2) Formalin Fixed Paraffin 
Embedded Tumor Material (3) Constitutional DNA Whole Blood Sample.     
 
Fresh frozen tissue will be processed for RNA and DNA extraction. One or more pea sized aliquots 
of tumor should be collected from patients at time of initial resection and any subsequent tumor 
surgery.  
 


 
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Constitutional DNA Whole Blood Sample 5 mL of whole blood will be needed to extract germline 
DNA.  This will serve as a comparative germline sample to tumor for sequencing studies.  Whole 
blood anti-coagulated with EDTA will need to be collected, kept at 4oC and shipped on wet ice.  
Using waterproof marker, label the tubes with patient identifying number. 
 
Formalin Fixed Paraffin Embeded Material (FFPE) for IHC, FISH studies.  FFPE tissue will be 
processed by Neuropathology.  For IHC FFPE sections (5μm) will be taken to assess the following:  
• 
GAB1, Bcatenin, Filamin A, and YAP1 immunoreactivity for subtype classification 
For FISH FFPE sections (8 μm) will be taken to assess the following 
• 
Loss of 9q and 10q 
• 
Isochromosome 17q 
• 
MYCN and MYCC amplification, GLI2 amplification 
 
 
 
15.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
 
 
 
 
 
 
 
 
 
15.1 
Timing of MRIs 
To document the degree of residual tumor, standard whole brain MRI with and without contrast 
(gadolinium) and spine MRI with and without contrast (gadolinium) must be performed at the 
following time points: 
• 
Pre-operative to include an MRI of the brain (recommended with gadolinium) or pre-
operative CT (recommended with contrast).   
• 
Pre-operative Spinal MRI with and without gadolinium or post-op with and without 
gadolinium preferably within 72 hours of surgery 
• 
Post-operative cranial MRI within 72 hours of surgery 
• 
Prior to Cycle 2 of Induction Therapy 
• 
Completion of Induction Therapy 
• 
Post-operative MRI within 72 hours of second surgery if done. 
• 
Following Completion of Continuation Therapy 
 
15.2 
Whole Brain MRI With and Without Contrast  
Recommended sequences: 
1. Sagittal T1 localizer; 4 mm skip 0.4 mm 
2. Axial FSE T2; 4 mm,  skip 0.4 mm  
3. Axial T2 FLAIR; 4 mm skip 0.4  
4. Axial diffusion; 4-5 mm skip 0 (single shot, matrix 128 x 128 or 128 x 192, B=1000) 
5. Axial T1; 4 mm skip 0.4 mm  
6. Axial gradient echo (susceptibility sequence); 4-5 mm skip 1-2 mm. TE=20, flip angle =20.   
7. Axial T1 with contrast; 4 mm skip 0.4 mm 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care.  Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable per COG Administrative Policy 5.14 (except where 
explicitly prohibited within the protocol).  


 
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8. Sagittal T1 with contrast; 4 mm skip 0.4 mm 
9. Axial T2 FLAIR with contrast; 4 mm skip 0.4  
 
Optional sequences (depending on tumor) 
Precontrast : 
1. 
Sagittal or coronal FSET2; 4 mm skip 0.4 mm, depending on tumor 
 configuration/orientation 
2. 
Axial diffusion tensor  
Post contrast : 
1. 
Coronal T1 : 4mm skip 0.4 
2. 
T1-weighted gradient echo volume sequence (SPGR or equivalent) 
3. 
Axial Perfusion 
 
NOTES:  
1. 
DO NOT INTERLEAVE T1 weighted sequences 
2. 
Flow compensation should not be used / not on all T1 enhanced sequences 
3. 
Fat Saturation not necessary 
 
15.3 
Spine MRI With Contrast 
The MRI scan must be performed of the entire spine with and without contrast, and must be 
performed in at least two planes.  
 
1. 
Whole spine sagittal T1; 3 mm skip 0 – 0.3 mm.  
Technical notes: 
- 
Phase direction AP, frequency direction SI 
- 
Acquire 2 separate acquisitions (one cervical and upper thoracic, the second lower  
 
thoracic and lumbosacral) to optimize placement of presaturation pulse.  
- 
Place anterior saturation pulse close to the anterior margin of the spinal column – to 
minimize motion artifacts from chest/abdomen. 
- 
Pixel size 1 mm2 or less (example: for 26 cm FOV, use 256 x 256 matrix)  
- 
Keep TE to minimum (<15 msecs) 
- 
Do not use fat saturation 
2. 
Axial T1 images through the entire spine; 4-5 mm thick, skip 1-2mm.  
Technical notes: 
- 
Phase direction RL, frequency direction AP 
- 
Keep TE to minimum (< 15 msecs) 
- 
DO NOT INTERLEAVE 
 
 
 


 
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16.0 
RADIATION THERAPY GUIDELINES 
No radiation therapy is planned for this study. 
 
 
17.0 
NEUROPSYCHOLOGICAL FUNCTION STUDY 
Due to early closure of the study, the neuropsychological function studies were removed as part of 
Amendment #3. 
 
Enrollment onto the neuropsychological function study ALTE07C1 is strongly encouraged. If the family 
agrees to participate in ALTE07C1, a separate informed consent for ALTE07C1 must be signed. Please 
refer to the ALTE07C1 protocol for eligibility requirements. 
 
 
 
 


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Page 71 
APPENDIX II: CYP3A4 INDUCERS AND INHIBITORS 
 
The use of the following medications should be discontinued prior to initiation of protocol therapy and should be 
avoided during protocol therapy if reasonable alternatives exist. This is not an inclusive list; please refer to other 
resources such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx for additional information. 
 
 
CYP3A4 substrates  
Strong 
Inhibitors* 
Moderate 
Inhibitors 
Weak 
Inhibitors 
Inducers 
alfentanil  
amiodarone 
aprepitant 
benzodiazepines 
bortezomib 
brentuximab 
budesonide 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
glucocorticoids** 
crizotinib 
cyclosporine 
cyclophosphamide  
dapsone 
dasatinib 
dihydroergotamine 
docetaxel 
doxorubicin 
ergotamine 
erlotinib 
esomeprazole 
estrogens 
etoposide 
fentanyl 
fosaprepitant 
gefitinib 
haloperidol 
HIV antiretrovirals 
HMG Co-A inhibitors 
ifosfamide 
imatinib 
irinotecan  
itraconazole 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin 
macrolide antibiotics 
medroxyprogesterone 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
conivaptan 
delavirdine 
fosamprenavir 
indinavir 
itraconazole 
ketoconazole 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
atazanavir 
cimetidine 
crizotinib 
cyclosporine  
desipramine 
diltiazem 
erythromycin 
fluconazole 
fluvoxamine 
fosaprepitant 
grapefruit 
grapefruit 
juice 
imatinib 
norfloxacin 
tetracycline 
verapamil 
amiodarone 
ciprofloxacin 
doxycycline 
mifepristone 
metronidazole 
nicardipine 
propofol 
quinidine 
sertraline 
tacrolimus 
 
 
 
armodafinil 
barbiturates 
bosentan 
carbamazepine 
deferasirox 
efavirenz 
etravirine 
fosphenytoin 
glucocorticoids** 
modafinil 
nafcillin 
nevirapine 
oxcarbazepine 
phenobarbital 
phenytoin 
pioglitazone 
primidone 
rifabutin 
rifampin 
rifapentin 
ritonavir 
St. John’s wort 
topiramate 
 


 
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Page 72 
methadone 
midazolam 
modafinil 
monteleukast 
nefazodone 
nilotinib 
omeprazole 
ondansetron 
paclitaxel 
pazopanib 
quinidine  
sildenafil 
sirolimus  
sunitinib 
tacrolimus terfenadine 
telaprevir 
tamoxifen 
temsirolimus 
teniposide 
trimethoprim 
vinca alkaloids 
zolpidem 
 
* Certain fruits and fruit juices (star fruit, Seville oranges, pomegranate) may inhibit CYP 3A4 isozyme, however, 
the degree of that inhibition is unknown.  
**Refer to Section 3.2.8 regarding use of corticosteroids. 
 
 


 
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APPENDIX III: ACNS1221 RAPID CENTRAL PATHOLOGY SCREENING REVIEW SCHEMA (PRIOR 
TO STUDY ENROLLMENT) 
 
 
  
 
 
 
 
        
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7 DAYS 
 
 
 
 
 
WITHIN 10 DAYS OF RECEIPT 
 OF SLIDES AT BPC 
 
 
 
 
 
 
 
                     
 
 
SURGERY 
PATIENT DIAGNOSED WITH 
M0 MEDULLOBLASTOMA 
OBTAIN COG NUMBER VIA OPEN 
INSTITUTION SUBMITS SLIDES AND PATHOLOGY REPORT FOR RAPID 
CENTRAL PATHOLOGY SCREENING REVIEW TO BPC WITHIN 15 DAYS 
SLIDES RECEIVED AT BPC AND SCANNED  
INTO VIPER SYSTEM WITH PATHOLOGY REPORT 
PATHOLOGISTS NOTIFIED BY VIPER SYSTEM CASE 
IS AVAILABLE FOR REVIEW 
PATHOLOGISTS REVIEW CASE AND COMPLETE PATHOLOGY FORM 
(COMPLETE WHEN 2 OF 3 REVIEWS MATCH) 
STUDY COMMITTEE NOTIFIED BY VIPER SYSTEM OF FINAL RESULT  
FROM  RAPID PATHOLOGY SCREENING REVIEW 
NOTIFICATION TO INSTITUTION OF FINAL RAPID CENTRAL PATHOLOGY 
SCREENING REVIEW RESULT BY STUDY COMMITTEE 
CONFIRMED ND/MBEN 
MEDULLOBLASTOMA 
PATIENT IS ELIGIBLE FOR 
ENROLLMENT ON ACNS1221 
NOT ND or MBEN 
MEDULLOBLASTOMA 
PATIENT NOT ELIGIBLE FOR 
ENROLLMENT ON ACNS1221 


 
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Page 74 
 
 
  
APPENDIX IV:  CTEP AND CTSU REGISTRATION PROCEDURES 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
investigators participating in any NCI-sponsored clinical trial to register and to renew their registration 
annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
<http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>. For questions, please contact 
the CTEP Investigator Registration Help Desk by email at <pmbregpend@ctep.nci.nih.gov>. 
 
CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) application is a 
web-based application intended for use by both Investigators (i.e., all physicians involved in the conduct of 
NCI-sponsored clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and annual re-
registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See CTEP Investigator 
Registration Procedures above for information on registering with CTEP as an Investigator, which must be 
completed before a CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU (Cancer Trials Support 
Unit) websites and applications, including the CTSU members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>. For questions, please contact the CTEP 
Associate Registration Help Desk by email at <ctepreghelp@ctep.nci.nih.gov>. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for ACNS1221 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not participating via the NCI CIRB)  


 
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Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval to the CTSU Regulatory Office, where 
they will be entered and tracked in the CTSU RSS.  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 
215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS site registration status page of the 
members’ section of the CTSU website. (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
 


 
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Page 76 
APPENDIX V:  POSSIBLE DRUG INTERACTIONS 
 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or their 
Parents should be encouraged to talk to their doctors before starting any new medications, using over-the-
counter medicines, or herbal supplements and before making a significant change in diet. 
 
Carboplatin 
Drugs that may interact with carboplatin* 
• Antibiotics like gentamicin or tobramycin 
• Anti-seizure medications like fosphenytoin or phenytoin 
• Arthritis medications like leflunomide, tofacitinib 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Other medications like clozapine or natalizumab 
 
Food and supplements that may interact with carboplatin** 
• Echinacea 
*Sometimes these drugs are used with carboplatin on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, 
pills, or dried herbs. All forms should be avoided.   
 
Cyclophosphamide 
 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol* 
• 
Chloramphenicol 
• 
Cyclosporine* 
• 
Digoxin  
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Indomethacin 
• 
Nevirapine 
• 
Ondansetron* 
• 
Pentostatin  
• 
Tamoxifen 
• 
Trastuzumab  
• 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide** 
• 
St John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 


 
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*Sometimes these drugs are used with cyclophosphamide on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, 
or dried herbs. All forms should be avoided.   
 
 
Etoposide 
 
Drugs that may interact with etoposide* 
• Antibiotics  
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
• Aripiprazole, clozapine, nefazodone 
• Antifungals  
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
• Leflunomide, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, 
tipranavir 
• Anti-seizure medications  
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide, 
mifepristone, natalizumab, pimozide, sitaxentan 
 
Food and supplements that may interact with etoposide** 
• Echinacea 
• Glucosamine 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with etoposide on purpose.  Discuss all drugs with your doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, 
pills, or dried herbs. All forms should be avoided.   
 
 
 
 


 
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Page 78 
 
Methotrexate  
 
Drugs that may interact with methotrexate* 
• 
Some antibiotics (amoxicillin, Bactrim, chloramphenicol, ciprofloxacin, penicillin, 
piperacillin, tetracycline) 
• 
Some anti-inflammatory drugs (aspirin, acetaminophen, ibuprofen, naproxen, ketorolac) 
• 
Some heartburn medications (esomeprazole, lansoprazole, omeprazole, pantoprazole) 
• 
Several other specific agents, including the following: amiodarone, clozapine, 
cyclosporine, eltrombopag, leflunomide, phenytoin, pimecrolimus, probenecid, 
pyrimethamine, retinoids, theophylline, warfarin 
 
Food and supplements that may interact with methotrexate** 
• 
Alcohol 
• 
Echinacea 
• 
Some vitamins, including those that contain folic acid or high doses of vitamin C 
*Sometimes these drugs are used with methotrexate on purpose.  Discuss all drugs with your 
doctor. 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, 
pills, or dried herbs. All forms should be avoided.   
 
Leucovorin 
 
Drugs that may interact with leucovorin* 
• Some antiepileptics (fosphenytoin, phenobarbital, phenytoin, primidone) 
 
Food and supplements that may interact with leucovorin** 
• Folic acid 
 
*Sometimes these drugs are used with leucovorin on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, 
pills, or dried herbs. All forms should be avoided.   
 
 
 


 
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Page 79 
 
Vincristine 
 
Drugs that may interact with vincristine* 
• Antibiotics  
• Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
• Aripiprazole, nefazodone, trazodone 
• Antifungals  
• Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
• Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
• Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
• Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, 
fosamprenavir, indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 
Stribild, telaprevir, tenofovir, tipranavir 
• Anti-seizure medications  
• Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
• Amiodarone, digoxin, dronedenarone, propranolol, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
• Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, 
pimozide, warfarin  
 
Food and supplements that may interact with vincristine** 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
*Sometimes these drugs are used with vincristine on purpose.  Discuss all drugs with your 
doctor. 
 
**Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, 
capsules, pills, or dried herbs. All forms should be avoided.   
 
 
 


 
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