Randomized Phase 3 Trial Evaluating the Addition of the IGF-1R Monoclonal Antibody Ganitumab (AMG 479, NSC# 750008) to Multiagent Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma
Phase: PHASE3
Conditions: Metastatic Ewing Sarcoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Bone Marrow, Metastatic Malignant Neoplasm in the Lung, Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone, Peripheral Primitive Neuroectodermal Tumor of Soft Tissues
Sponsor: National Cancer Institute (NCI)

  
 
i 
 
Group Chair 
Peter C. Adamson, M.D. 
adamson@email.chop.edu  
 
Group Statistician 
Todd Alonzo, Ph.D. 
talonzo@childrensoncology 
group.org 
 
Group Vice Chair 
Susan Blaney, M.D. 
smblaney@txch.org  
 
Chief Operating Officer 
Elizabeth O’Connor, M.P.H. 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, M.S. 
crabtreed@email.chop.edu 
 
Group Chair’s Office 
The Children's Hospital 
of Philadelphia 
3501 Civic Center Blvd 
CTRB 10060 
Philadelphia, PA 19104 
 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Statistics & Data Center 
Headquarters 
222 E. Huntington Drive 
Suite 100 
Monrovia, CA 91016 
 
P 626 447 0064 
F 626 445 4334 
 
Gainesville Office 
6011 NW 1st Place 
Gainesville, FL 32607 
 
P 352 273 0556 
F 352 392 8162 
 
 
 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
 
May 1, 2019 
 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
The study committee for AEWS1221, Randomized Phase 3 Trial Evaluating the Addition of 
the IGF-1R Monoclonal Antibody Ganitumab (AMG 479, NSC# 750008, IND#) to Multiagent 
Chemotherapy for Patients with Newly Diagnosed Metastatic Ewing Sarcoma, has provided 
Amendment 6 for CTEP review. 
 
This amendment is submitted in response to FDA comments from Dr. Julie Rhie dated 
April 11, 2019 and a Request for Rapid Amendment (RRA) from Dr. Helen Chu dated April 
23, 2019. In this amendment, the protocol provides guidance to investigators for managing 
suspected cases of pneumonitis, the addition of oxygen saturation in follow-up vital sign 
assessments for patients who have previously received whole lung radiotherapy, and the 
revised CAEPR for ganitumab (Version 2.1, March 26, 2019). This study was closed to 
patient accrual on March 20, 2019. The risk information in the informed consent document 
has been updated to include the risk of pneumonitis. Additional administrative updates have 
been made to the protocol. Revisions to the protocol and consent documents are detailed 
in the pages below.  
 
The AEWS1221 study committee looks forward to approval of this amendment. Please 
contact me with any questions or concerns. 
 
 
Sincerely,  
 
Tiffany Liu, MS, MA, Protocol Coordinator (for) 
 
Steven DuBois, MD, AEWS1221 Study Chair 
Peter Adamson, MD, Children’s Oncology Group Chair 
 

 
 
 
 
ii 
 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
    # 
Section 
Page(s) 
Change 
1.  
Title Page & 
Throughout 
1 
• 
Updated version date and amendment number.  
• 
Inserted study closure date. 
2.  
Table of Contents 3-5 
Updated to reflect current pagination and headings. 
3.  
Study Committee 7 
Updated study committee member’s contact information 
4.  
Experimental 
Design Schema 
10 
Added the following statement:  
“NOTE: As of March 20, 2019, the study closed 
to accrual and institutions were instructed to 
immediately discontinue ganitumab for patients 
on Regimen B.” 
5.  
2.16 
23 
Provided background information for why study is being 
amended. This information was communicated to sites in 
an investigator memo dated March 20, 2019.  
6.  
4.1.1 
 
 
 
31-33 
 
 
 
• 
Added/modified text to reflect that study has closed to 
accrual and that institutions were instructed to 
immediately discontinue ganitumab for Regimen B 
patients.  
• 
Updated Treatment and Regimen B Consolidation 
Schemas to indicate that ganitumab administration has 
been discontinued. 
7.  
4.1.1.1 
33-34 
• 
Modified text to reflect the discontinuation of ganitumab 
for Regimen B patients. 
• 
Added a statement that the sequence of Consolidation 
cycles may be adjusted at the physician’s discretion to 
avoid resuming doxorubicin shortly after completing a 
course of radiation.   
8.  
4.1.1.2 
4.1.1.3 
34-35 
36 
Modified text to reflect the discontinuation of ganitumab for 
Regimen B patients. 
9.  
4.2.2 
4.2.3 
36 
36 
• 
Removed corticosteroid therapy information because it 
pertained to ganitumab administration, which has been 
discontinued. 
• 
Renumbered to reflect the removal of the original 
Section 4.2.2 
10. 
4.4.1.1 
4.4.1.2 
4.4.2.1 
4.4.2.2 
43 
50 
60 
68 
Clarified that both filgrastim and pegfilgrastim biosimilar 
products are permitted:  
“Begin myeloid growth factor support (filgrastim biosimilar 
products or pegfilgrastim or biosimilar products 
according to institutional standards for patients receiving 
interval compressed chemotherapy) at least 24-36 hours 
after the last dose of chemotherapy.” 

 
 
 
 
iii 
 
    # 
Section 
Page(s) 
Change 
11. 
4.4.1.1 
4.4.1.3 
4.4.2.1 
4.4.2.3 
44-46 
54-56 
62-64 
72-74 
Removed fasting metabolic labs from Therapy Delivery 
Maps due to discontinuation of ganitumab. Re-lettered 
required observations to reflect change.   
12. 4.4.2 
57 
Added/modified text to reflect that institutions were 
instructed to immediately discontinue ganitumab for 
Regimen B patients. 
13. 
4.4.2.1 
4.4.2.2 
4.4.2.3 
62-64 
72-74 
74 
Removed ganitumab information from Therapy Delivery 
Maps and Administration Schedule instructions. 
Maintenance was removed in its entirety. Re-numbered to 
reflect removal of the Therapy Delivery Map for 
Maintenance. 
14. 4.4.2.3 
 
69 
 
Added the following End of Therapy instructions for 
Regimen B patients:  
“Following completion of Metastatic Site Radiation, 
patients on Regimen B will have completed all 
prescribed protocol therapy. See Sections 7.1.3 for 
observations due at End of Therapy and Section 
7.3 for recommended observations during follow-
up.” 
15. 
5.1.1 
5.1.2 
5.3.2 
5.5 
5.7 
5.7.1 
5.10 
75 
75 
77 
78 
80 
80 
81 
Removed dose modification information specific to 
ganitumab-related toxicities.  
16. 5.10 
81 
Added new Section 5.10 with additional guidance for 
patients who develop pneumonitis.  

 
 
 
 
iv 
 
    # 
Section 
Page(s) 
Change 
17. 6.1 
82-84 
 
Inserted revised CAEPR for ganitumab (Version 2.1, March 
26, 2019) to replace Version 2.0. Specific changes are as 
follows:  
 
• 
Added New Risk: 
• 
Also Reported on Ganitumab Trials But With 
Insufficient Evidence for Attribution: Agitation; 
Alkaline phosphatase increased; Anal fistula; Anal 
mucositis; Atrial fibrillation; Back pain; Bone pain; 
Blood and lymphatic system disorders - Other 
(pancytopenia); Cardiac disorders - Other (diastolic 
dysfunction); Constipation; Cough; Creatinine 
increased; Dysphagia; Ejection fraction decreased; 
Epistaxis; Esophagitis; Febrile neutropenia; Heart 
failure; Hematoma; Hepatobiliary disorders - Other 
(hepatic function abnormal); Hepatobiliary 
disorders - Other (jaundice cholestatic); 
Hyperkalemia; Hypocalcemia; Hypophosphatemia; 
Hypoxia; Infections and infestations - Other 
(pneumococcal infection); Investigations - Other 
(electrocardiogram abnormal); Malaise; Myelitis; 
Oral pain; Palmar-plantar erythrodysesthesia 
syndrome; Pleural effusion; Rectal fistula; Rectal 
hemorrhage; Skin infection; Skin ulceration; Soft 
tissue infection; Syncope; Tremor; Typhlitis; 
Urinary tract infection; Urinary tract obstruction; 
Vascular access complication; Weight loss 
 
• 
Increase in Risk Attribution: 
• 
Changed to Likely from Less Likely: Fatigue 
• 
Changed to Less Likely from Also Reported on 
Ganitumab Trials But With Insufficient Evidence for 
Attribution: Lymphocyte count decreased; Myalgia  
• 
Changed to Rare But Serious from Also Reported 
on Ganitumab Trials But With Insufficient Evidence 
for Attribution: Pneumonitis  
 
• 
Provided Further Clarification: 
• 
Footnote #4 has been added: “The rate and 
severity of radiation-associated pneumonitis may 
be increased in patients who receive ganitumab 
shortly before or after radiation to the lungs.” 
• 
Enterocolitis (CTCAE 4.0 language) is now 
reported as Gastrointestinal disorders - Other 
(enteritis).  
• 
Nervous system disorders - Other (sciatica) 
(CTCAE 4.0 language) is now reported as 
Radiculitis.  
• 
Dyspnea has been deleted and is now reported as 
part of footnote #3. 
 
18. 6.11 
102-103 
Monograph has been updated. 

 
 
 
 
v 
 
    # 
Section 
Page(s) 
Change 
19. 7.1.1 
106-107 
 
Removed fasting metabolic labs, including its respective 
footnote, from the list of studies to be obtained due to 
discontinuation of ganitumab. 
 
20. 7.1.2 
7.1.3 
108-109 
110 
 
• 
Removed Table 7.1.3 that contained evaluations during 
Metastatic Site Radiation and Maintenance. 
Table 7.1.2 now includes evaluations during Metastatic 
Site Radiation.  
• 
Removed fasting metabolic labs, including its 
respective footnote, from the list of studies to be 
obtained due to discontinuation of ganitumab. 
• 
Removed information pertaining to Maintenance. 
• 
Added the following footnote:  
o 
 “13   Submission of imaging demonstrating 
the first episode of disease 
progression/suspected relapse is required 
for central review (see Section 16.3). For 
times other than suspected relapse, follow 
recommended disease evaluation schedule 
for all patients in Regimens A and B in 
Section 7.3 timed from end-Consolidation. 
This includes disease restaging 3 months 
and 6 months from end-Consolidation.” 
 
21. 7.3 
111-112 
 
• 
Added oxygen saturation by pulse oximetry to the list of 
follow-up observations and included the following new 
footnote 1:  
“For patients treated with whole lung radiation.” 
• 
Renumbered footnotes to reflect the addition of the 
above footnote.  
 
22. 11.10 
11.11 
148 
149 
 
Modified CTEP-AERS reporting instructions:  
“CTEP-AERS 24-hour Notification is required for ≥ Grade 2 
1 pneumonitis.” 
 
23. 15.4 
169 
 
Modified bone marrow collection and delivery information:  
“Material must arrive fresh in the laboratory. Marrow 
samples collected on Monday-Friday Thursday are eligible 
for submission such that samples arrive in the laboratory 
Tuesday-Saturday Friday. Weekday deliveries are 
preferred, if possible. For patients undergoing clinical 
biopsies on a Friday, do not submit marrow samples 
from that biopsy for this correlative study.” 
 
 
 

 
 
AEWS1221 
 
Version date: 05/01/19 
 
1 
 
 
 
 
CHILDREN'S ONCOLOGY GROUP 
 
 
AEWS1221 
 
Randomized Phase 3 Trial Evaluating the Addition of the IGF-1R Monoclonal Antibody 
Ganitumab (AMG 479, NSC# 750008, IND#) to Multiagent Chemotherapy for Patients with Newly 
Diagnosed Metastatic Ewing Sarcoma 
 
 
An Intergroup NCTN Phase 3 Study 
 
 
NCI Supplied Agent: Ganitumab (NSC# 750008, IND#) 
 
IND sponsor for ganitumab: DCTD, NCI 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR ANY 
OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT INCLUDED TO 
AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH MEANS A SYSTEMATIC 
INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO DEVELOP OR 
CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH PLAN DEVELOPED BY THE 
CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR SET OF STUDY QUESTIONS AND 
SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR TO PROVIDE INDIVIDUALIZED 
MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE PROCEDURES IN THIS PROTOCOL 
ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY STRUCTURED SETTINGS, AND MAY NOT 
PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON WHO REQUIRES MEDICAL CARE IS URGED TO 
CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN OR VISIT THE NEAREST LOCAL HOSPITAL OR 
HEALTHCARE INSTITUTION. 
 
 
 
STUDY CHAIR 
 
Steven DuBois, MD, MS 
Pediatric Oncology 
Dana-Farber Cancer Institute 
450 Brookline Avenue, Dana 3 
Boston, MA 02215 
Phone: (617) 632-5460 
Fax: 
(617) 632-4811 
Email: steven_dubois@dfci.harvard.edu 
 
 
 
 
Activated: 
12/8/14 
Version Date: 
05/01/2019 
Closed: 
03/20/2019 
Amendment: 
6 

 
 
AEWS1221 
 
Version date: 05/01/19 
 
2 
 
Participating Organizations 
 
COG / Children's Oncology Group 
 
NRG / NRG Oncology 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
 
SWOG / SWOG 
 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: (Sign 
in at www.ctsu.org, and select the 
Regulatory Submission sub-tab under 
the Regulatory tab.)  
 
Institutions with patients waiting that 
are unable to use the Portal should 
alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 to 
receive further instruction and 
support. 
 
Contact  the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
Data collection for this study 
will be done exclusively through 
Medidata Rave. Please see the 
Data Submission Schedule in the 
CRF packet for further 
instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. Access to 
the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program - Identity and 
Access Management (CTEP-IAM) registration system and requires user log on with CTEP-IAM username 
and password. Permission to view and download this protocol and its supporting documents is restricted and 
is based on person and site roster assignment housed in the CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data submission) 
contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 

 
 
AEWS1221 
Version date: 05/01/19 
 
3 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
11 
1.1 
Primary Objective 
11 
1.2 
Secondary Objective 
11 
1.3 
Exploratory Objectives 
11 
2.0 
BACKGROUND 
12 
2.1 
Metastatic Ewing Sarcoma 
12 
2.2 
Interval Compressed Chemotherapy in Ewing Sarcoma 
12 
2.3 
Role of IGF-1R Inhibition in Ewing Sarcoma 
12 
2.4 
Clinical Experience with IGF-1R Monoclonal Antibodies in Patients with Ewing 
Sarcoma 
13 
2.5 
Rationale for Combining IGF-1R Inhibition and Chemotherapy in Ewing Sarcoma 
13 
2.6 
Clinical Experience with Ganitumab 
14 
2.7 
Rationale for Proposed Ganitumab Starting Dose and Pharmacokinetic Evaluation 
15 
2.8 
Rationale for Open-Label Study Design 
16 
2.9 
Rationale for Maintenance Phase with Ganitumab 
16 
2.10 
Rationale for FDG-PET Imaging of Bone Metastases 
17 
2.11 
Rationale for Imaging Aims 
17 
2.12 
Rationale for Evaluation of Hypofractionated Stereotactic Body Radiotherapy (SBRT) 
for Bone Metastases 
18 
2.13 
Rationale for Dexrazoxane Cardioprotection 
19 
2.14 
Rationale for Correlative Biology Studies 
19 
2.15 
Rationale for Amendment #2 
22 
2.16 
Rationale for Amendment #6 
23 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
23 
3.1 
Study Enrollment 
23 
3.2 
Patient Eligibility Criteria 
26 
4.0 
TREATMENT PROGRAM 
31 
4.1 
Overview of Treatment Plan 
31 
4.2 
Concomitant Medications 
36 
4.3 
General Approach to Local Control of the Primary Tumor 
37 
4.4 
Chemotherapy Administration Schedule 
39 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
75 
5.1 
Slow Blood Count Recovery 
75 
5.2 
Renal Toxicity 
75 
5.3 
Cardiac Toxicity 
77 
5.4 
Neurological Toxicity 
77 
5.5 
Mucositis 
78 
5.6 
Hematuria or Hemorrhagic Cystitis 
78 
5.7 
Hepatotoxicity 
79 
5.8 
Dermatologic Toxicity 
80 
5.9 
Allergy to Etoposide 
81 
5.10 
Pneumonitis 
81 

 
 
AEWS1221 
Version date: 05/01/19 
 
4 
5.11 
Any Other Grade 3 or 4 Toxicities 
81 
6.0 
DRUG INFORMATION 
82 
6.1 
GANITUMAB 
82 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
86 
6.3 
DACTINOMYCIN 
88 
6.4 
DEXRAZOXANE 
89 
6.5 
DOXORUBICIN 
91 
6.6 
ETOPOSIDE - INJECTION 
93 
6.7 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
95 
6.8 
IFOSFAMIDE 
97 
6.9 
MESNA - INJECTION 
99 
6.10 
MESNA - ORAL 
100 
6.11 
PEGFILGRASTIM, PEGFILGRASTIM-JMDB, PEGFILGRASTIM-CBQV 
102 
6.12 
VINCRISTINE SULFATE 
104 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
106 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
106 
7.2 
Correlative Biology Studies 
110 
7.3 
Follow-up 
111 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
113 
8.1 
Criteria for Removal from Protocol Therapy 
113 
8.2 
Off Study Criteria 
113 
9.0 
STATISTICAL CONSIDERATIONS 
114 
9.1 
Statistical Design 
114 
9.2 
Patient Accrual and Expected Duration of Trial 
114 
9.3 
Gender and Minority Accrual Estimates 
130 
10.0 
EVALUATION CRITERIA 
130 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
130 
10.2 
Disease Assessment Requirements and Definitions 
130 
10.3 
Disease Response Criteria 
131 
10.4 
Demonstration of Residual Viable Tumor 
139 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
140 
11.1 
Purpose 
140 
11.2 
Determination of reporting requirements 
140 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
141 
11.4 
Special Situations for Expedited Reporting 
141 
11.5 
Reporting Requirements for Specialized AEs 
144 
11.6 
Exceptions to Expedited Reporting 
144 
11.7 
Reporting Requirements - Investigator Responsibility 
145 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
145 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
147 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
148 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
 
148 
11.12 Routine Adverse Event Reporting 
149 
12.0 
STUDY REPORTING AND MONITORING 
149 
12.1 
CDUS 
149 
12.2 
Data and Safety Monitoring Committee 
150 
12.3 
CRADA/CTA 
150 

 
 
AEWS1221 
Version date: 05/01/19 
 
5 
13.0 
SURGICAL GUIDELINES 
152 
13.1 
Surgical Guidelines for Biopsy 
152 
13.2 
Surgical Guidelines for Consideration of Amputation at Diagnosis 
153 
13.3 
Surgical Guidelines for Primary Bone Lesions 
154 
13.4 
Anatomic Guidelines for Resectability 
155 
13.5 
Resection of Residual Lung Metastases 
160 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
160 
14.1 
Biopsy Specimen 
161 
14.2 
Molecular and Cytogenetic Studies for Initial Diagnosis 
161 
14.3 
Specimen from Surgical Resection 
162 
14.4 
Pathology Specimen Requirements 
163 
14.5 
Consultation 
163 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
164 
15.1 
Serum Markers of IGF-1R Pathway 
164 
15.2 
Tissue Markers 
166 
15.3 
EGFR Promoter Polymorphisms 
167 
15.4 
Bone Marrow Micrometastatic Disease 
169 
15.5 
Ganitumab Pharmacokinetic Study 
170 
15.6 
Circulating Tumor DNA Analysis 
172 
15.7 
Additional correlative studies 
173 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
174 
16.1 
Imaging Guidelines 
174 
16.2 
Correlative Imaging Aims 
175 
16.3 
Instructions for Submitting Imaging for Correlative Imaging Aims 
175 
17.0 
RADIATION THERAPY GUIDELINES 
176 
17.1 
General Guidelines 
176 
17.2 
Indications for Radiation Therapy 
178 
17.3 
Timing of Radiotherapy 
179 
17.4 
Emergency Radiation Therapy 
180 
17.5 
Equipment and Methods of Delivery and Verification 
180 
17.6 
Target Volumes 
181 
17.7 
Target Dose 
188 
17.8 
Treatment Technique 
191 
17.9 
Organs at Risk – Conventional Fractionation 
198 
17.10 Organs at Risk – SBRT 
200 
17.11 Dose Calculations and Reporting 
202 
17.12 Quality Assurance Documentation 
203 
17.13 Definition of Minor and Major Deviations 
205 
17.14 Evaluation of SBRT Plans For Deviations 
205 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
207 
APPENDIX II:  REFERENCE GUIDE FOR REQUIRED AND RECOMMENDED CORRELATIVE 
STUDIES 
210 
APPENDIX III:  YOUTH INFORMATION SHEETS 
212 
APPENDIX IV:  POSSIBLE DRUG INTERACTIONS 
216 
APPENDIX V:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
220 
REFERENCES 
222 

 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AEWS1221 
Version date: 05/01/19 
 
6 
 
STUDY COMMITTEE 
 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Steven DuBois, MD, MS 
Heike E. Daldrup-Link, MD  
Hematology/Oncology 
Diagnostic Imaging 
Dana-Farber Cancer Institute 
Lucile Packard Children's Hospital Stanford University 
450 Brookline Avenue 
Division of Pediatric Radiology 
Boston, MA 02215 
725 Welch Road 
Phone: (617) 632-5460 
Palo Alto, CA 94304 
Fax: 
(617) 632-5710 
Phone: (650) 497-8601 
E-mail: steven_dubois@dfci.harvard.edu 
Fax: 
(650) 724-2521 
 
E-mail: heiked@stanford.edu 
STUDY VICE CHAIR 
 
Julia Glade Bender, MD  
Katherine Anne Janeway, MD  
Hematology/Oncology 
Hematology/Oncology 
Memorial Sloan Kettering Cancer Center 
Dana-Farber Cancer Institute 
1275 York Avenue 
Pediatric Oncology 
New York, NY 10065 
450 Brookline Ave Street 
Phone: (212) 639-6729  
Dana 3 
E-mail: gladebej@mskcc.org 
Boston, MA 02215 
 
Phone: (617) 632-4994 
STUDY STATISTICIAN 
Email: katherine_janeway@dfci.harvard.edu 
Mark Krailo, PhD 
 
Statistics 
Edward Anders Kolb, MD  
Children's Oncology Group - Operations Center 
Hematology/Oncology 
222 E. Huntington Drive; Suite 100 
Alfred I duPont Hospital for Children 
Monrovia, CA 91016 
BBMT 
Phone: (626) 241-1529 
1600 Rockland Road 
Fax: 
(626) 445-4334 
Wilmington, DE 19803 
E-mail: mkrailo@childrensoncologygroup.org 
Phone: (302) 651-5567 
 
Fax: 
(302) 651-4918 
Carola A. S. Arndt, MD  
Email: eakolb@nemours.org 
Hematology/Oncology 
 
Mayo Clinic, Pediatric Hem-Onc, E-9 
Damon Russell Reed, MD  
200 First Street SW 
Hematology/Oncology 
Rochester, MN 55905 
Johns Hopkins All Children's Hospital 
Phone: (507) 284-2652  
Hematology/Oncology 
Fax: 
(507) 284-0727 
601 5th Street South 
E-mail: carndt@mayo.edu 
St Petersburgh, FL 33701 
 
Phone: (813) 745-6161 
Richard G. Gorlick, MD  
Fax: 
(813) 745-8337 
Hematology/Oncology 
Email: dreed29@jhmi.edu 
M D Anderson Cancer Center 
 
Division Head of Pediatrics 
 
1515 Holcombe Blvd. 
 
Houston, TX 77030 
 
Phone: (713) 792-6620 
 
Fax: 
(713) 794-5042 
 
Email: rgorlick@mdanderson.org  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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7 
STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
Nadia Nicole Laack, MD  
Stephanie Terezakis, MD 
Radiation Oncology 
Radiation Oncology 
Mayo Clinic 
University of Minnesota/Masonic Cancer Center  
200 First St SW 
Department of Radiation Oncology 
Rochester, MN 55905 
516 Harvard St. Southeast, PWB-1 
Phone: (507) 284-4561 
Minneapolis, MN 55455 
Fax: 
(507) 284-0079 
Phone: (612) 626-6710   
Email: laack.nadia@mayo.edu 
E-mail: sterezak@umn.edu 
 
 
Stephen L. Lessnick, MD PhD  
Lisa A. Teot, MD  
Hematology/Oncology 
Pathology 
Nationwide Children’s Hospital 
Dana-Farber Cancer Institute 
Hematology/Oncolcogy/BMT 
Staff Pathologist 
700 Children’s Drive 
Children’s Hospital Boston 
WA5011 
300 Longwood Avenue Bader 110 
Columbus, OH 43205 
Boston, MA 02115 
Phone: (614) 355-2633 
Phone: (857) 218-4962 
Fax: 
(614) 355-2927 
Fax: 
(617) 730-0207 
Email: stephen.lessnick@nationwidechildrens.org 
Email: lisa.teot@childrens.harvard.edu 
 
 
Dinesh Rakheja, MD  
Richard Womer, MD 
Pathology 
Hematology/Oncology 
University of Texas Southwestern Medical Center 
CHOP Division of Oncology 
Pathology 
324 South 34th St 
5323 Harry Hines Boulevard 
Philadelphia, PA 19104 
Dallas, TX 75390-9073 
Phone: (215) 590-2229 
Phone: (214) 456-2877 
Fax: 
(215) 590-4183 
Fax: 
(214) 456-6199 
Email: rwomer@pennmedicine.upenn.edu 
Email: dinesh.rakheja@utsouthwestern.edu 
 
 
Andrea A. Hayes-Jordan, MD 
Robert Lor Randall, MD FACS  
Surgery 
Surgery 
UNC Lineberger Comprehensive Cancer Center 
University of California Davis Comprehensive Cancer 
Pediatric Surgery 
Center 
Physicians Office Building Campus Box 7223 
Dept. of Orthopaedic Surgery 
170 Manning Drive 
4860 Y Street, Suite 3800 
Chapel Hill, NC 27599  
Sacramento, CA 95817 
Phone: (919) 966-4643 
Phone: (916) 734-2958 
Fax: 
(919) 843-2497 
Fax: 
(916) 734-7904 
Email: andrea_hayes-jordan@med.unc.edu 
Email: rlrandall@ucdavis.edu 
 
 
STUDY NURSE 
Joel M. Reid, PhD 
Stacy Whiteside, RN MS CPNP  
Pharmacology 
Nursing 
Mayo Clinic 
Nationwide Children's Hospital 
19-365 Gonda Building 
700 Children's Drive 
200 First Street SW 
Columbus, OH 43205 
Rochester, MN 55905 
Phone: (614) 722-8870 
Phone: (507) 284-0822 
Fax: 
(614) 722-8820 
Fax: 
(507) 284-3906 
E-mail: Stacy.Whiteside@nationwidechildrens.org 
E-mail: reid.joel@mayo.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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8 
 
STUDY COMMITTEE MEMBERS 
 
STUDY COMMITTEE MEMBERS 
Christine Hill-Kayser 
Hsiao-Ming Lu, Ph. D. 
Radiation Oncology- Proton Therapy 
Medical Physics- Proton Therapy 
Children’s Hospital of Philadelphia 
Director of Clinical Physics 
3400 Spruce Street, 2 Donner 
Massachusetts General Hospital 
Philadelphia, Pennsylvania 19146 
Francis H. Burr Proton Therapy Center, Room 112 
Phone: (215) 850-7903 
30 Fruit Street 
Fax: 
(507) 349-5445 
Boston, MA 02114 
E-mail: hill@uphs.upenn.edu 
Phone: (617) 726-6924 
 
Fax: 
(617) 724-9532 
Brian Crompton, MD 
E-mail: hmlu@partners.org 
Hematology/Oncology 
 
Dana-Farber Cancer Institute 
STUDY CLINICAL RESEARCH ASSOCIATE 
450 Brookline Avenue 
Carol Tustin 
Boston, MA 02215 
Children’s Hospital of Philadelphia 
Phone: (617) 582-8553 
Division of Oncology 
Fax: 
(617) 632-4811 
3501 Civic Center Blvd, CTRB /10300 - 19 
Email: brian.crompton@childrens.harvard.edu 
Philadelphia, Pennsylvania 19104 
 
Phone: (215) 590-2811 
Eric P. Eutsler, MD 
Fax: (215) 590-4183 
Diagnostic Imaging 
Email: tustinc@email.chop.edu 
Washington University School of Medicine 
 
501 S. Kingshighway Blvd. 
PROTOCOL COORDINATOR 
Campus Box 8131 
Tiffany Liu, MS, MA 
St. Louis, MO 63110 
Children’s Oncology Group – Operations Center 
Phone (314) 454-6229 
222 E. Huntington Drive, Suite 100 
E-mail eeutsler@wustl.edu 
Monrovia, CA 91016 
 
Phone: (626) 241-1616 
STUDY PHARMACIST 
Fax: 
(626) 445-4334 
Brandy Strickland Snyder, PharmD 
E-mail: tliu@childrensoncologygroup.org 
Pharmacy 
 
Wake Forest University Health Sciences 
 
Medical Center Blvd 
 
Winston Salem, North Carolina 
 
Phone: (336) 713-6555 
 
Fax: 
(336) 713-3401 
 
E-mail: bstrickl@wakehealth.edu 
AGENT  
 
NCI Supplied Agent: Ganitumab, NSC# 750008 
RESEARCH COORDINATOR 
Other Agents: Vincristine, NSC# 67574, Commercial 
Justin Davis 
Doxorubicin, NSC# 123127, Commercial 
Children’s Oncology Group – Operations Center 
Cyclophosphamide, NSC# 26271, Commercial 
222 E. Huntington Drive, Suite 100 
Ifosfamide, NSC# 109724, Commercial 
Monrovia, CA 91016 
Etoposide, NSC# 141540, Commercial 
Phone: (626) 241-1509 
Dexrazoxane, NSC# 169780, Commercial 
Fax: 
(626) 445-4334 
MESNA, NSC# 113891, Commercial 
E-mail: jdavis@childrensoncologygroup.org 
IND #:   
 
IND sponsor for Ganitumab: DCTD/NCI  
 
 
 
 
 
 
 
 
 
 
 
SEE SECTION 15.0 FOR SPECIMEN SHIPPING ADDRESSES 
 
 

 
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9 
 
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 
 
Despite improvements in outcomes for patients with localized Ewing sarcoma, patients with newly 
diagnosed metastatic Ewing sarcoma continue to have poor outcomes with standard multiagent 
chemotherapy. A large body of preclinical data supports a role for IGF-1R inhibition in the treatment of 
Ewing sarcoma. More recently, clinical trials of IGF-1R monoclonal antibodies have demonstrated single-
agent activity in patients with relapsed Ewing sarcoma. Ganitumab is a fully human monoclonal antibody 
directed against IGF-1R. In this phase 3 randomized trial, patients with newly diagnosed metastatic Ewing 
sarcoma are randomized at study entry to the comparator arm with interval compressed multiagent 
chemotherapy or to the experimental arm with interval compressed multiagent chemotherapy and the 
addition of ganitumab. The primary endpoint is event-free survival. Feasibility of this approach and 
evaluation of stereotactic body radiotherapy to sites of bone metastasis are additional clinical objectives. 
300 eligible and evaluable patients will enroll. A series of correlative biology studies will explore markers 
of response to IGF-1R inhibition. These studies include serum markers of the IGF-1 pathway, IGF-1R 
expression on bone marrow micrometastatic tumor cells, and polymorphisms in EGFR as a potential 
resistance mechanism. 
 
 
 
 

 
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EXPERIMENTAL DESIGN SCHEMA 
NOTE: As of March 20, 2019, the study closed to accrual and institutions were instructed to 
immediately discontinue ganitumab for patients on Regimen B. 
 
 
 
# Patients will be randomized at study entry to receive either Regimen A or Regimen B. The first 10 patients < 21 years old randomized to 
Regimen B will submit mandatory trough serum samples for ganitumab concentrations (completed as of July 2015). 
 
RANDOMIZATION 
AT STUDY ENTRY# 
to 
REGIMEN A or 
REGIMEN B 
END OF PROTOCOL 
THERAPY 
OFF PROTOCOL 
THERAPY 
Progressive disease 
Progressive disease 
(or residual bone marrow 
metastatic disease) 
OFF PROTOCOL 
THERAPY 
Progressive disease 
MAINTENANCE 
Ganitumab 
Every 3 weeks x 24 weeks 
REGIMEN B  
EVALUATIONS 
CONSOLIDATION 
4 Cycles (8 weeks) 
VDC/IE + Ganitumab 
EVALUATIONS 
CONSOLIDATION 
4 Cycles (8 Weeks) 
VC/IE + Ganitumab 
EVALUATIONS 
INDUCTION 
6 Cycles (12 weeks) 
VDC/IE + Ganitumab 
LOCAL CONTROL 
Surgery and/or XRT 
EVALUATIONS 
METASTATIC SITE 
RADIATION 
METASTATIC SITE 
RADIATION 
REGIMEN A  
CONSOLIDATION 
4 Cycles (8 weeks) 
VDC/IE
CONSOLIDATION 
4 Cycles (8 Weeks) 
VC/IE
EVALUATIONS 
EVALUATIONS 
LOCAL CONTROL 
Surgery and/or XRT 
INDUCTION 
6 Cycles (12 weeks) 
VDC/IE 
EVALUATIONS 
EVALUATIONS 
VDC: 
 
vincristine-doxorubicin-cyclophosphamide 
IE: 
 
ifosfamide-etoposide 
Ganitumab: 
 IGF-1R monoclonal antibody 
XRT: 
 
radiation therapy 

 
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11 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Objective 
To determine if event-free survival (EFS) in patients with newly diagnosed metastatic Ewing 
sarcoma treated with multiagent chemotherapy is improved with the addition of ganitumab 
(AMG 479). 
 
1.2 
Secondary Objective 
1.2.1 
To describe the toxicity of the addition of ganitumab to multimodality therapy for 
patients with newly diagnosed metastatic Ewing sarcoma. 
1.2.2 
To compare overall survival in patients with newly diagnosed metastatic Ewing 
sarcoma treated with multiagent chemotherapy with and without the addition of 
ganitumab. 
 
1.3 
Exploratory Objectives 
1.3.1 
To compare bone marrow response rates in patients with newly diagnosed 
metastatic Ewing sarcoma treated with multiagent chemotherapy with and without 
the addition of ganitumab. 
1.3.2 
To describe the toxicity of 6 months of ganitumab monotherapy as Maintenance 
therapy following multimodality therapy in patients with newly diagnosed 
metastatic Ewing sarcoma. 
1.3.3 
To describe trough levels of ganitumab in a cohort of patients with Ewing sarcoma 
< 21 years of age treated with 18 mg/kg. 
1.3.4 
To describe the feasibility of and local failure rates following hypofractionated 
stereotactic body radiotherapy (SBRT) directed at bone metastases in patients with 
newly diagnosed metastatic Ewing sarcoma. 
1.3.5 
To determine if EFS, overall survival, bone marrow response rates, and toxicity 
differ based on serum markers of the IGF-1 pathway in patients with newly 
diagnosed metastatic Ewing sarcoma treated with interval compressed 
chemotherapy with and without the addition of ganitumab.  
1.3.6 
To determine if EFS, overall survival, and bone marrow response rates differ based 
on protein, DNA, and RNA markers in patients with newly diagnosed metastatic 
Ewing sarcoma treated with interval compressed chemotherapy with and without 
the addition of ganitumab. 
1.3.7 
To evaluate bone marrow micrometastatic disease and tumor cell surface IGF-1R 
expression at diagnosis and after 3 and 6 cycles of study therapy in patients with 
newly diagnosed metastatic Ewing sarcoma. 
1.3.8 
To determine if the presence of germline polymorphisms in EGFR correlate with 
response to multiagent therapy with and without ganitumab. 
1.3.9 
To investigate the ability of FDG-PET to augment conventional response 
assessment of primary Ewing sarcoma tumors by MRI. 
1.3.10 To explore FDG-PET response at the primary tumor as a prognostic marker and as 
a predictive biomarker of clinical activity of IGF-1R inhibition in patients with 
newly diagnosed metastatic Ewing sarcoma. 
1.3.11 To collect data on institutional testing for EWSR1 translocation status in patients 
enrolling on study. 
1.3.12 To explore the capacity of plasma cell-free DNA analysis to detect tumor-specific 
genetic changes at initial diagnosis and after initiation of protocol therapy. 
1.3.13 To collect a population of bone marrow metastatic tumor cells by flow cytometry 
for genomic profiling. 
 
 

 
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2.0 
BACKGROUND 
2.1 
Metastatic Ewing Sarcoma 
There has been considerable improvement in the outcome of patients with localized Ewing 
sarcoma over the last two decades. In contrast, the overall survival for patients with initially 
metastatic disease continues to be less than 30% across multiple studies.1-5 Some groups 
have reported that patients with isolated lung metastases have a better outcome than 
patients with bone and/or bone marrow metastases.4,5  
 
2.2 
Interval Compressed Chemotherapy in Ewing Sarcoma 
Standard therapy for Ewing sarcoma in COG protocols includes alternating cycles of 
vincristine/doxorubicin/cyclophosphamide (VDC) with ifosfamide/etoposide (IE).6 With 
the positive results of COG protocol AEWS0031, the new standard remains VDC 
alternating with IE, with cycles now given on an interval-compressed basis every 2 weeks 
for a total of 14 cycles.7 Of note, the standard arm of AEWS1031 includes a total of 
17 cycles of chemotherapy in order to maintain uniformity in treatment length with the 
experimental arm of that study. The effect of the addition of 3 cycles on outcomes is not 
clear and therefore 14 cycles of therapy per the interval compressed arm of AEWS0031 
has been chosen for the chemotherapy backbone of this study. 
 
Sub-analysis of AEWS0031 demonstrated that older patients were able to receive interval-
compressed chemotherapy as prescribed. Specifically, the median cycle length for patients 
≥ 18 years of age was 15 days compared to 15 days for patients < 18 years of age (R. 
Womer, personal communication). 
 
AEWS0031 only included patients with localized Ewing sarcoma. Therefore, the 
tolerability and activity of interval-compressed VDC/IE in patients with metastatic disease 
remains unclear. This issue will be addressed in this study.  
 
2.3 
Role of IGF-1R Inhibition in Ewing Sarcoma 
Several lines of evidence indicate that targeting the insulin like growth factor receptor-1 
(IGF-1R) will be an effective strategy in the treatment of Ewing sarcoma. All but one 
Ewing sarcoma cell line evaluated in 2 early studies demonstrated expression of both IGF-
1 and IGF-1R.8,9 In contrast to wild-type fibroblasts, fibroblasts lacking the IGF-1R were 
not transformed after transfection with EWS/FLI1.10 EWS/FLI1 appears to repress 
expression of IGF binding protein-3 (IGF-BP3), an endogenous inhibitor of the IGF-1 
pathway.11 Several small molecule inhibitors of IGF-1R have demonstrated activity in 
preclinical models of Ewing sarcoma.12-14 In one study, Ewing sarcoma was among the 
solid tumor histologies most sensitive to inhibition by one such inhibitor, GSK1904529A.14 
 
Early studies demonstrated that a neutralizing antibody against the IGF-1R inhibited the 
growth of all Ewing sarcoma cell lines tested.8,9,15 This effect was also observed in Ewing 
sarcoma mouse xenografts.16 Compared to 43% of control-treated mice, no antibody-
treated mice developed lung metastases. The Pediatric Preclinical Testing Program (PPTP) 
has evaluated two IGF-1R monoclonal antibodies (SCH 717454 and IMC-A12) in a panel 
of Ewing sarcoma cell lines and xenografts17,18 SCH 717454 demonstrated little in vitro 
activity. In contrast, 2 of 5 Ewing sarcoma xenografts demonstrated significant 
prolongation of time to event and significant inhibition of tumor growth after treatment 
with SCH 717454. One of these xenografts showed tumor regression in response to SCH 
717454 and met criteria for “high” level activity.18 IMC-A12 demonstrated both in vitro 

 
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and in vivo activity. Two of 4 Ewing sarcoma cell lines demonstrated more than 50% 
reduction in cell growth. Two of 5 Ewing sarcoma xenografts showed reductions in tumor 
size and 3 of 5 showed prolongation in time to event.17 Ganitumab has also been evaluated 
in preclinical models of Ewing sarcoma, with demonstrated activity both as a single agent 
and in combination with rapamycin.19  
 
2.4 
Clinical Experience with IGF-1R Monoclonal Antibodies in Patients with Ewing 
Sarcoma 
Based on these promising preclinical studies, several groups have evaluated anti-IGF-1R 
monoclonal antibodies in patients with relapsed or refractory Ewing sarcoma. A phase 2 
study of ganitumab included 18 patients with Ewing sarcoma treated with 12 mg/kg IV 
every two weeks. One patient had a confirmed partial response (6% response rate).20 Closer 
evaluation of the data demonstrated that 6/18 (33%) patients had regressions of at least 
10%. A phase 2 study of R1507 included 115 patients with relapsed or refractory Ewing 
sarcoma and demonstrated an objective response rate of 10%.21 In COG protocol 
ADVL0712, one of 10 patients with Ewing sarcoma treated with IMC-A12 at the 6 mg/kg 
dose level had a confirmed partial response and 4 additional patients had stable disease for 
at least 3 cycles.22 At the 9 mg/kg dose level, 2 of 20 patients had RECIST partial 
responses.23 Of 16 patients with Ewing sarcoma treated on a phase 1 study of figitumumab 
(20 mg/kg IV every 3-4 weeks), one patient had a complete response, one patient had a 
partial response, and 6 patients had stable disease for more than 4 months (12.5% response 
rate).24 A phase 2 study of figitumumab in 106 patients with relapsed or refractory Ewing 
sarcoma recently demonstrated a 14% response rate.25 A phase 1 study of MK-0646 
included 6 patients with Ewing sarcoma, one of whom had a mixed response. 26 These 
studies indicate that IGF-1R monoclonal antibodies have single agent activity in patients 
with relapsed or refractory Ewing sarcoma, with objective response rates of approximately 
10%.  
 
2.5 
Rationale for Combining IGF-1R Inhibition and Chemotherapy in Ewing Sarcoma 
Several preclinical studies have evaluated the strategy of IGF-1R inhibition in combination 
with chemotherapy. These studies have demonstrated that treatment with an IGF-1R 
inhibitor increases the sensitivity of Ewing sarcoma cells to the effects of chemotherapy. 
In one study, the addition of an IGF-1R monoclonal antibody enhanced the cytotoxic 
effects of doxorubicin (synergistic effect) or vincristine (additive effect) on Ewing sarcoma 
cells.27 This effect was observed when cells were treated with IGF-1R monoclonal antibody 
with concomitant or sequential chemotherapy. Synergistic and additive antiproliferative 
effects in in vitro and in vivo Ewing sarcoma studies have also been reported with the 
combination of chemotherapy and small molecule IGF-1R inhibitors13,28 or with an IGF-
1R dominant negative construct.29 
 
IGF-1R monoclonal antibodies have started to undergo evaluation in combination with 
chemotherapy in adults and children. COG protocol ARST08P1 is evaluating intensive 
chemotherapy with and without the addition of IMC-A12 in children and young adults with 
newly diagnosed high-risk rhabdomyosarcoma. The chemotherapy backbone in 
ARST08P1 is similar to the chemotherapy backbone of this study, including cycles of VDC 
alternating every two weeks with IE. Toxicity has been consistent with the expected 
toxicity during intensive chemotherapy alone, though 3 cases of sinusoidal obstruction 
syndrome (SOS) at the highest dose level of IMC-A12 prompted dose reduction to the 
equivalent of the adult recommended phase 2 dose (Doug Hawkins, personal 

 
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communication). With regard to risk of cardiac toxicity, 1 of 20 patients treated with IMC-
A12 at a dose of 3 mg/kg developed Grade 3 congestive heart failure and 1 of 19 patients 
treated without IMC-A12 developed Grade 3 or 4 left ventricular systolic dysfunction. 
None of the 13 patients treated with IMC-A12 at a dose of 6 mg/kg has developed Grade 
3 or 4 cardiac toxicity. Detailed data on Grade 1 and 2 toxicities are not collected on 
ARST08P1. The addition of IMC-A12 has not impacted the ability to administer interval 
compressed chemotherapy cycles. The median duration of each reporting period has been 
similar for patients on ARST08P1 treated with and without IMC-A12 (J. Anderson/S. 
Malempati, personal communication). 
 
IMC-A12 has been evaluated in combination with doxorubicin in adults with soft tissue 
sarcoma (median age 64 years with range 29-80 years).30 In this phase 1 study, 2 dose-
limiting toxicities (mucositis and hyperglycemia) were seen among 13 patients treated with 
3 mg/kg IMC-A12. The dose was escalated to the maximum planned dose of 6 mg/kg IMC-
A12 in 10 evaluable patients, none with dose-limiting toxicity. Two of 13 patients treated 
with 3 mg/kg IMC-A12 developed Grade 3 left ventricular systolic dysfunction after a 
minimum of 4 courses of combination therapy. 
 
Figitumumab has also been evaluated in combination with cytotoxic chemotherapy in 
patients with non-small cell lung cancer. Patients in a phase 1 study were treated with 
paclitaxel, carboplatin, and escalating doses of figitumumab.31 A maximum tolerated dose 
was not identified. A phase 2 study randomized 156 patients to paclitaxel and carboplatin, 
with or without figitumumab.32 The response rate was higher in patients randomized to 
receive figitumumab. The combination was tolerable, with the rates of Grade 3 or 4 
neutropenia and hyperglycemia somewhat higher in patients receiving figitumumab. With 
this experience, a phase 3 trial was initiated in patients with newly diagnosed advanced 
NSCLC.33 Patients were randomized to receive paclitaxel and carboplatin either with or 
without figitumumab. The study was discontinued early when a planned interim analysis 
met futility limits. 
 
2.6 
Clinical Experience with Ganitumab 
Ganitumab is a fully human monoclonal antibody directed against IGF-1R. The drug has 
high affinity for IGF-1R, with a KD of 0.3 nM (Ganitumab Investigator’s Brochure; 
October 4, 2011). The drug inhibits binding of IGF-1 and IGF-2 to the extracellular domain 
of IGF-1R. The IC50 for blocking IGF-1R phosphorylation in the presence of IGF-1 or IGF-
2 is 0.6 nM.  
 
A phase 1 study included 53 patients with advanced solid cancers treated twice weekly.34 
A maximum tolerated dose was not reached and 20 mg/kg IV every 2 weeks was deemed 
tolerable, though biochemical blockade was achieved at levels of 12 mg/kg IV every 
2 weeks. Four of 23 patients treated at the 20 mg/kg dose level developed Grade 3 
thrombocytopenia. The only other Grade 3 toxicities noted across dose levels were 
arthralgia (n=1); diarrhea (n=1); and fatigue (n=1).  
 
Aside from the aforementioned study of single agent ganitumab in Ewing sarcoma (and 
desmoplastic small round cell tumor or DSRCT), most phase 2 studies of this agent have 
focused on combination approaches. Preliminary reports have demonstrated the tolerability 
of ganitumab at doses ≥ 12 mg/kg IV every 2 weeks when used in combination with 
erlotinib, sorafenib, AMG 655, and gemcitabine.35-37 The combination of ganitumab 
(12 mg/kg IV every 2 weeks) to gemcitabine improved 6-month overall survival in patients 

 
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with advanced pancreatic cancer in a phase 2 trial,36 though a randomized phase 3 trial 
testing this combination in advanced pancreatic cancer was stopped early when futility 
stopping rules were met. 
 
The pharmacokinetic profile of ganitumab appears to differ somewhat between adult 
patients with various solid tumors and adult patients with Ewing sarcoma and DSRCT 
treated on a phase 2 trial.20 Specifically, patients on this phase 2 trial treated with 12 mg/kg 
every 2 weeks had lower trough concentrations after their first and third doses of ganitumab 
compared to patients with relapsed solid tumors treated on 2 other studies with this same 
dose and schedule. The mean ± SD trough concentration after Cycle 1 was 17.5 ± 8.52 
µg/mL for EWS/DSRCT vs. 22 ± 11 µg/mL and 26.1 ± 12.5 µg/mL for other solid tumors. 
The mean ± SD trough concentration after Cycle 3 was 15.9 ± 33.6 µg/mL for 
EWS/DSRCT vs. 27 ± 15.9 µg/mL and 42.2 ± 18.5 µg/mL for other solid tumors 
(Ganitumab Investigator’s Brochure; October 4, 2011). 22 of 29 patients (75%) with 
EWS/DSRCT had ganitumab trough concentrations > 10 µg/mL after a single dose of 
12 mg/kg.20  
 
While a pediatric phase 1 clinical trial of ganitumab has not been performed, several points 
suggest that proceeding with the proposed pediatric and adult study based on the adult 
experience with this drug is reasonable. First, IGF-1R monoclonal antibodies as a class 
have been well tolerated in both adults and children. Second, of the compounds in this class 
in which adult and pediatric phase 1 studies have been performed, the recommended 
pediatric dose has not been lower than the adult dose. For example, the recommended 
pediatric phase 2 dose of IMC-A12 is 9 mg/kg weekly,23 which compares favorably to the 
adult recommended phase 2 dose of 6 mg/kg weekly.38 Likewise, for dalotuzumab, the 
recommended pediatric phase 2 dose (900 mg/m2 IV every 3 weeks) was similar to the 
recommended adult phase 2 dose.39 Third, the dose used in this study is below the 
maximum dose evaluated and deemed tolerable in the adult single agent phase 1 study. 
Fourth, the study includes a pharmacokinetics cohort to confirm that pediatric patients 
achieve adequate serum levels of ganitumab with the planned starting dose of 18 mg/kg 
(see Section 2.7).  
 
2.7 
Rationale for Proposed Ganitumab Starting Dose and Pharmacokinetic Evaluation 
The starting dose of ganitumab for this study will be 18 mg/kg. This dose was selected for 
several reasons. First, biochemical blockade of IGF-1R signaling is observed at serum 
concentrations > 10 µg/mL.40 Blockade of IGF-1R epitope binding on neutrophils also 
begins to saturate at serum concentrations of 10 µg/mL (Ganitumab Investigator’s 
Brochure; October 4, 2011). Trough serum concentrations in excess of this target trough 
concentration value of 10 µg/mL are anticipated using 18 mg/kg, extrapolating from the 
experience from the phase 2 trial of young adults with relapsed Ewing sarcoma treated with 
12 mg/kg (see above). These trough serum concentrations compare favorably with the IC50 
of ganitumab in 2 Ewing sarcoma cell lines of 1.6 and 3.7 nanomolar (0.54 µg/mL and 0.23 
µg/mL).19 In in vivo studies of ganitumab against mouse Ewing sarcoma xenografts, 
activity was noted at doses of ganitumab that yield steady state serum concentrations of 4.7 
µg/mL.19 Second, experience with ganitumab and other IGF-1R monoclonal antibodies 
have demonstrated clinical activity in patients with Ewing sarcoma at doses below maximal 
evaluated dose levels of 20 mg/kg.23,41 For example, the phase 2 trial of ganitumab in 
patients with relapsed Ewing sarcoma used 12 mg/kg IV every 2 weeks.41 Third, 
combination studies have evaluated doses of 12-20 mg/kg every 2 weeks.36 Fourth, given 
the risk of thrombocytopenia that has been observed with IGF-1R monoclonal 

 
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antibodies,21,23,34 use of maximal studied doses of ganitumab (20 mg/kg) may not be 
feasible in combination with interval compressed chemotherapy used for patients with 
Ewing sarcoma.  
 
Ganitumab has not been formally studied in children. Based on the phase 2 experience with 
ganitumab in Ewing sarcoma, it appears as though adults with Ewing sarcoma have higher 
clearance compared to adults with other solid tumors. While the starting dose of ganitumab 
has been increased to 18 mg/kg to account for this possibility, it is nevertheless possible 
that younger patients will not meet the goal trough concentration of 10 µg/mL. In order to 
assess this possibility, the first 10 patients < 21 years of age randomized to receive 
ganitumab in Regimen B provided trough serum samples for pharmacokinetics of 
ganitumab in Induction and Maintenance. These data demonstrated trough levels of 
ganitumab given at 18 mg/kg every 2 or 3 weeks appear to be adequate. 
 
2.8 
Rationale for Open-Label Study Design 
The study committee considered the possibility of a double-blind placebo-controlled study 
design. Such a design might have the advantage of reducing bias in the assessment of 
toxicity associated with protocol therapy. Another potential benefit of a placebo-controlled 
design might be reduction in early withdrawal of patients randomized to receive 
chemotherapy alone. 
 
However, it is not clear that these general benefits of a placebo-control apply to this specific 
clinical context. First, the toxicity assessments of greatest interest (depth and duration of 
myelosuppression; reduction in left ventricular systolic function) are objective test 
measures rather than subjective symptom-based toxicities. Likewise, the ascertainment of 
the primary study endpoint (disease progression) is typically clear in this patient population 
and therefore less likely to be influenced by bias compared to more subjective endpoints. 
Second, patients who are randomized to receive chemotherapy alone will receive a 
chemotherapy regimen that has become standard in the community outside of a clinical 
trial. Importantly, the effect of interval compression on outcomes in metastatic Ewing 
sarcoma has not been studied. It is therefore possible that patients randomized to receive 
chemotherapy alone will have superior outcomes compared to patients treated with 
previous regimens solely as a result of interval compression. Moreover, the study 
committee is not aware of a competing trial for patients with newly diagnosed metastatic 
Ewing sarcoma who have already started chemotherapy and have not had disease 
progression. Third, the investigator blind associated with a placebo control would be 
threatened by anticipated hyperglycemia following ganitumab. For all of these reasons, the 
added cost and complexity associated with adding a placebo control does not appear 
justified and this study will utilize an open label design.   
 
2.9 
Rationale for Maintenance Phase with Ganitumab 
Several pieces of data suggest that use of single-agent ganitumab as Maintenance therapy 
may be beneficial in patients with advanced Ewing sarcoma. First, preclinical data indicate 
that IGF-1R inhibition reduces formation of bone metastases in an experimental metastasis 
xenograft model of Ewing sarcoma.12 These findings have implications for using 
ganitumab to slow the progression of minimal residual disease. Second, as described above, 
ganitumab has single-agent preclinical and clinical activity in Ewing sarcoma.19,41 Third, 
the strategy of using biological therapy to eradicate minimal residual disease has been used 
successfully in the treatment of patients with high-risk neuroblastoma.42,43 This strategy 

 
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has not previously been used in the treatment of metastatic Ewing sarcoma and the current 
trial provides an opportunity to evaluate this approach in this high-risk population. Based 
on pharmacokinetic modeling in adults with solid tumors, use of ganitumab at a dose of 18 
mg/kg given every 3 weeks is anticipated to yield adequate trough serum concentrations 
(Ganitumab Investigator Brochure; October 4, 2011) and this protocol includes an 
assessment of trough concentrations with this dosing schedule.  
 
2.10 
Rationale for FDG-PET Imaging of Bone Metastases 
Previous COG trials for patients with metastatic Ewing sarcoma have relied upon 
technetium-based radionuclide whole body bone scans to detect and evaluate bone 
metastases. Since the inception of those previous trials, multiple studies have been 
published that detail the superior performance of FDG-PET scans for the diagnosis and 
evaluation of bone metastases in patients with Ewing sarcoma.44-49 For example, one report 
noted sensitivity and specificity for identifying bone metastases in Ewing sarcoma as 100% 
and 96% for FDG-PET vs. 68% and 87% for bone scan.45 Results were more striking in 
another analysis of 17 patients with Ewing sarcoma and paired bone scans and FDG-PET 
scans.48 The sensitivity for detecting bone metastases was 88% for FDG-PET and only 
37% for bone scan. 
 
Therefore, the current trial will utilize FDG-PET imaging to detect bone metastasis. A 
collateral benefit of this change is that FDG-PET allows detection of soft tissue sites of 
metastasis48, provides information about response at the primary tumor (see below), and 
may serve as a biomarker of response to IGF-1R inhibition (see below).  
 
2.11 
Rationale for Imaging Aims 
FDG-PET in addition to MRI to evaluate primary tumor response 
Conventional response assessment of primary Ewing sarcoma tumors involves anatomic 
imaging, most commonly with MRI. For those patients undergoing surgical local control, 
histologic response to neoadjuvant chemotherapy can also be assessed. Recent reports have 
raised concern that response by MRI may not correlate with histologic response to 
neoadjuvant chemotherapy in patients with Ewing sarcoma. For example, one report noted 
similar changes in tumor volume by MRI between patients with good histologic response 
and patients without a good histologic response.50 Another study reached the same 
conclusion using tumor cross-sectional area by MRI.51 
 
FDG-PET imaging has been shown to be a useful tool for monitoring the response to 
neoadjuvant chemotherapy in patients with newly diagnosed Ewing sarcoma. Several 
reports have noted that response by FDG-PET correlates with histologic response at the 
time of definitive surgical resection of the primary Ewing sarcoma tumor.44,50-53 Moreover, 
at least one report observed that favorable response by FDG-PET after neoadjuvant 
chemotherapy correlated with improved progression-free survival.53  
 
However, it is important to note that the majority of patients in these previous studies had 
localized Ewing sarcoma. The ability of FDG-PET to aid in primary tumor response 
assessment in patients with metastatic disease has been less well studied and differences in 
FDG-PET imaging may exist between these 2 populations. Indeed, one group has reported 
that baseline primary tumor standardized uptake values (SUVs) are higher in patients with 
metastatic Ewing sarcoma compared to localized Ewing sarcoma.54  
 

 
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Since patients will undergo serial whole body FDG-PET imaging to evaluate their 
metastatic disease, this study provides an opportunity to evaluate the utility of FDG-PET 
imaging in assessing primary tumor response in metastatic Ewing sarcoma. Non-invasive 
measures of tumor response are particularly important in this patient population given 
lower rates of surgical local control. 
 
FDG-PET as a potential biomarker of response to IGF-1R inhibition 
Agents that inhibit the IGF-1R pathway may result in hyperglycemia due to impairments 
in cellular uptake of glucose. Not surprisingly, then, FDG-PET imaging has been explored 
as a potential biomarker of response to IGF-1R inhibition. In preclinical studies of a small 
molecule IGF-1R/insulin receptor inhibitor, drug exposure impeded FDG uptake in cells 
expressing IGF-1R, but not in cells that lack IGF-1R expression.55 This effect also 
correlated with direct measures of IGF-1R pathway inhibition, including lower phospho-
AKT levels. A similar effect on FDG uptake was observed in a preclinical study following 
treatment with an antibody directed against IGF-1 and IGF-2 ligand.56 Finally, in a phase 
1 trial of IMC-A12 plus temsirolimus for adults with advanced solid tumors, change in 
SUV showed a suggestive correlation with clinical benefit from that drug combination. 57  
 
2.12 
Rationale for Evaluation of Hypofractionated Stereotactic Body Radiotherapy 
(SBRT) for Bone Metastases 
Conventional external beam radiotherapy (EBRT) for Ewing sarcoma requires 31 daily 
treatments totaling 55.8 Gy. Bone metastases are currently recommended to receive the 
same dose and fractionation using EBRT, with some evidence of efficacy of this 
approach.58,59 Because of the volume of bone marrow in the radiation field and concerns 
about ability to complete chemotherapy, treatment of the metastatic sites is often delayed 
until after treatment of the primary site and often at the end of therapy. Local control after 
radiotherapy to metastatic sites is largely unknown, as many patients with multiple or 
extensive sites of disease are often treated with palliative doses of radiation which are not 
expected to provide long-term durable tumor control.  
 
Hypofractionated stereotactic radiation therapy has been shown to be a highly effective 
treatment for brain metastases in both the adult and pediatrics population.60,61 Intracranial 
stereotactic radiation treatments are often complete in 1 to 5 fractions with similar or 
improved local control outcomes as conventional fractionation and the benefit of minimal 
interruption to systemic therapy treatments and smaller irradiated volumes. Until recently, 
treatment of extracranial sites with radiosurgery has not been possible due to inadequate 
immobilization and image-guidance to safely administer large doses of highly-targeted 
radiotherapy.62 Recent technologic advances including full-body immobilization devices, 
robotic treatment tables, and stereotactic image-guidance are now available and have been 
used to treat extracranial metastases with stereotactic radiotherapy in adults.63 Doses range 
from 18-30 Gy in a single fraction to 24-60 Gy in 5 fractions. Local control rates in excess 
of 75-90% have been reported using extracranial SBRT for metastatic tumors of the spine64, 
lung and liver, which is significantly higher than conventional moderate dose radiation in 
these locations.65 Toxicity has been minimal in these reports despite the use of very high 
biological equivalent doses and now over 10 years of experience with this technology.66,67 
 
SBRT has a particularly strong rationale for application in pediatrics given that high 
biologically effective doses have been shown to increase local control in more 
radioresistant histologies, such as sarcomas.68,69 With stereotactic radiation therapy 
techniques, both patient immobilization and rapid dose fall-off result in a reduction in 

 
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normal tissue dose surrounding the target lesion of interest and may result in lower 
toxicity.65 Reduction in irradiated volumes may also facilitate earlier administration of 
local control. In addition, the convenience of a 5-fraction treatment course is expected to 
improve compliance with the recommendation for definitive radiotherapy at known sites 
of disease. We hypothesize that aggressive treatment of bone metastases with SBRT will 
be possible within the context of a COG groupwide study and may improve outcomes by 
preventing progression at known sites of disease compared with standard EBRT.  
 
2.13 
Rationale for Dexrazoxane Cardioprotection 
IGF-1 appears to protect cardiac myocytes from doxorubicin-induced apoptosis.70,71 At 
least part of this effect involves signaling through the PI3-kinase/AKT pathway.72 IGFBP-
3, which sequesters IGF-1, promotes doxorubicin-induced apoptosis in cardiac myocytes.73 
Therefore, a theoretical risk of increased cardiac toxicity exists with the combination of an 
IGF-1R monoclonal antibody and doxorubicin-based chemotherapy. 
 
Dexrazoxane is a cardioprotectant that is recommended for use in adult patients receiving 
> 300 mg/m2 cumulative doxorubicin doses.74 Several studies in children and adults with 
sarcoma have demonstrated a role for dexrazoxane in reducing the risk of anthracycline-
induced cardiomyopathy.75-79 In COG protocol AEWS1031 for patients with newly 
diagnosed localized Ewing, dexrazoxane is used as a cardioprotectant during the last 
2 courses of doxorubicin-based therapy. In COG trials of agents that may increase the risk 
of doxorubicin-induced cardiomyopathy (AOST0121 with trastuzumab for osteosarcoma; 
ARST08P1 with IMC-A12 for rhabdomyosarcoma), dexrazoxane has been utilized from 
the start of doxorubicin-based chemotherapy. The addition of dexrazoxane in these studies 
has not appeared to impact the ability to deliver intensive multi-agent chemotherapy, 
including a similar chemotherapy regimen in ARST08P1 to the regimen used in the current 
protocol.  
 
Patients in both arms of the trial will receive dexrazoxane cardioprotection prior to each 
dose of doxorubicin. This therapy will be administered to patients randomized to 
chemotherapy alone in order to standardize the therapy received by both treatment groups 
and also due to the anticipated high rates of whole lung radiation to be employed in the 
treatment of this patient population.  
 
2.14 
Rationale for Correlative Biology Studies 
2.14.1 Serum Markers of IGF-1 Pathway as Predictors of Response to IGF-1R Inhibition 
Given the heterogeneous response to IGF-1R monoclonal antibodies in patients 
with relapsed Ewing sarcoma, identifying predictive biomarkers of response is 
critical in the development of these agents for patients with Ewing sarcoma. 
Peripheral blood markers of the IGF-1 pathway are among the most promising 
putative response biomarkers in adults with carcinoma treated with IGF-1R 
monoclonal antibodies. For example, preliminary data suggest that patients with 
non-small cell lung cancer and elevated serum free IGF-1 levels have reduced 
toxicity and increased survival when treated with figitumumab.80 Similarly, 
patients with advanced pancreatic cancer and elevated total IGF-1 blood levels 
appeared to have improved outcomes when treated with ganitumab.81 
 
Recent data have emerged that also support an association between IGF-1 levels 
and outcome after anti-IGF-1R therapy in patients with relapsed Ewing sarcoma. 

 
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These studies demonstrated that elevated baseline and Week 6 total serum IGF-1 
as well as higher relative increase in serum IGF-1 correlated with outcomes in 
patients with relapsed Ewing sarcoma treated with R1507.21 Total and free serum 
IGF-1 levels also correlated with outcomes in patients with relapsed Ewing 
sarcoma treated with figitumumab.25 Increases in growth hormone, insulin, and 
IGFBP3 have also been reported in patients with Ewing sarcoma treated with IGF-
1R monoclonal antibodies, though the impact of these changes on outcomes have 
not yet been reported.23,25 In preclinical studies, upregulation of IGF-2 expression 
has been described as a mechanism of resistance to IGF-1R inhibition in Ewing 
sarcoma, though not yet evaluated as a potential biomarker of resistance in clinical 
studies.82 
 
These results were obtained from uncontrolled trials in patients with relapsed 
Ewing sarcoma. These results may therefore indicate a role for IGF-1 levels as a 
prognostic factor rather than a predictive biomarker of response to anti-IGF-1R 
therapy. Moreover, the extent to which these findings will apply to patients with 
newly diagnosed Ewing sarcoma remains to be established.  
 
2.14.2 Tumor IGF-1R Expression as Predictor of Response to IGF-1R Inhibition 
Preclinical data from the PPTP suggest that Ewing sarcoma xenograft tumors with 
higher IGF-1R expression may be more likely to respond to an IGF-1R monoclonal 
antibody.18 A cohort of 16 patients with Ewing sarcoma treated with an IGF-1R 
monoclonal antibody had tumor IGF-1R levels measured.23 There was no 
association between tumor IGF-1R expression and response to IGF-1R inhibition 
in this small cohort. In contrast, in a cohort of 37 patients with non-small cell lung 
cancer, higher tumor IGF-1R expression correlated with higher response rate to 
therapy that included an IGF-1R monoclonal antibody.83 The association between 
markers of tumor IGF-1R activation and clinical response to IGF-1R inhibitors has 
not been evaluated. Therapeutic IGF-1R monoclonal antibodies both inhibit IGF-
1R function and reduce levels of IGF-1R protein present at the cell surface.84 As 
such, clearance of cell surface IGF-1R would be anticipated to serve as a 
pharmacodynamic marker of IGF-1R effect, but also potentially as a predictive 
biomarker of response to IGF-1R monoclonal antibody treatment. 
 
A flow cytometry approach for detecting occult Ewing sarcoma cells amidst a 
background of hematopoietic cells has been developed and depends upon the 
CD99-postive / CD45-negative (CD99+CD45-) immunophenotype of these 
cells.85 Among 42 patients with newly diagnosed Ewing sarcoma and no clinical 
evidence of bone marrow metastases, 45% of patients had CD99+CD45- bone 
marrow cell levels greater than observed in controls. In the current study, flow 
cytometric evaluation of occult bone marrow tumor cells will be evaluated as a 
possible early marker of minimal residual disease in patients with metastatic Ewing 
sarcoma. Moreover, bone marrow micrometastatic cell IGF-1R co-expression will 
be evaluated as a potential biomarker of response to ganitumab therapy. This assay 
provides an ideal platform for evaluating tumor IGF-1R expression, activation, and 
clearance as markers of response to ganitumab.  
 
The current study will utilize this flow cytometry assay as well as evaluation of 
paraffin-embedded diagnostic tumor material to quantify IGF-1R expression at 
diagnosis and following initiation of protocol therapy.  

 
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2.14.3 EGFR Expression and Germline EGFR Promoter Polymorphism as Predictors of 
Response to IGF-1R Inhibition 
Increased EGFR pathway signaling may represent one mechanism of resistance to 
the anticancer effects of IGF-1R inhibitors.86 In head and neck cancer, IGF-
induced signaling is enhanced by EGFR activation and/or EGFR/IGF-1R 
scaffolding.87 Reciprocal activation of EGFR and IGF-1R has been reported after 
inhibition of either receptor.88 Inducible signaling through EGFR in response to 
IGF-1R inhibition has been observed in hepatocellular carcinoma.89 In cell lines 
resistant to a small molecule inhibitor of IGF-1R (BMS-536924), EGFR is 
constitutively over-expressed. Additive activity was observed for BMS-536924 
used in combination with gefitinib, a small molecule inhibitor of EGFR, in the 
Rh26 rhabdomyosarcoma cell line.90 
 
Preclinical studies have demonstrated that the presence of a germline 
polymorphism (G/G) at site -216 in the EGFR promoter has been associated with 
Induction of EGFR gene expression in response to IGF-1R inhibition (E. Anders 
Kolb, personal communication). The presence of the G/G genotype at this locus 
correlated with resistance to IGF-1R inhibition in a panel of Ewing sarcoma 
xenografts. Whether this promoter polymorphism correlates with EGFR 
expression and response to IGF-1R inhibition has not been studied in patients 
treated with IGF-1R monoclonal antibodies. This protocol includes a correlative 
study to test the hypothesis that the presence of this polymorphism is associated 
with resistance to IGF-1R directed therapy.   
 
2.14.4 Evaluation of EWSR1 and Other Translocations 
As detailed above, Ewing sarcoma appears to be particularly sensitive to IGF-1R 
inhibition and there is a link between the EWSR1 translocation and increased IGF-
1R signaling. Recently, Ewing-like sarcomas have been described that are 
characterized by translocations involving genes other than EWSR1.91,92 It is not 
known to what extent these other sarcomas will be sensitive to IGF-1R inhibition. 
It is also not known what proportion of patients enrolling to clinical trials for 
Ewing sarcoma harbor alternative translocations. 
 
Two aims will help to address these gaps in our knowledge. First, data on clinical 
testing performed to assess for the presence of an EWSR1 translocation will be 
collected in patients enrolling to this study. Second, new technology has emerged 
that enables detection of tumor-specific genetic aberrations in cell free DNA 
collected from the plasma. This technology enables detection of a range of 
potential translocations of interest, as well as other potential mutations of interest 
in this disease (eg. STAG2 and TP53).93-95 This testing will be explored on a 
research basis to assess for EWSR1 translocations, other translocations, and other 
potential tumor-specific genetic changes of interest at the time of study enrollment 
and in response to therapy.   
 
Expansion of plasma cell free DNA assessment with Amendment #3C: 
Preliminary data from other groups suggest that circulating tumor DNA may clear 
rapidly after treatment.96,97 In order to more fully characterize the dynamics of 
ctDNA clearance in this population, additional timepoints have been added with 
Amendment #3C. In addition, emerging data suggest that EDTA may not be the 

 
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optimal collection tube for evaluation of plasma cell free DNA in the context of a 
multicenter clinical trial. With Amendment #3C, blood for this aspect of the study 
will be collected in specialized Streck tubes.98 
 
2.14.5 Genomic Testing of Tumor Cells 
The flow cytometry approach described above (Section 2.14.2) provides the 
potential to isolate bone marrow metastatic tumor cells for potential future testing. 
As proof of principle, fluorescent activated cell sorting using the CD99+CD45- 
immunophenotype has been used to isolate and then test bone marrow metastatic 
tumor cells for the presence of the characteristic EWSR1 translocation by 
fluorescent in situ hybridization (FISH). On both samples tested, the presence of 
this translocation was detected in ≥ 88% of the isolated cells. It is not known to 
what extent the genomic profile of metastatic Ewing sarcoma mirrors that of 
localized Ewing sarcoma. The current protocol provides an ideal opportunity to 
assess the genomic profile of metastatic Ewing sarcoma by using bone marrow 
metastatic tumor cells as the source of DNA for detailed genomic analysis.     
 
With Amendment #3C, tumor DNA and RNA sequencing via next generation 
sequencing methods is being added as an optional study to expand the number of 
somatic markers evaluated as part of Aim 1.3.6. Sequencing data will provide an 
opportunity to explore potential relationships between key somatic mutations 
described in a subset of Ewing sarcoma tumors (e.g., STAG2 and TP53) and 
clinical outcome.93-95 Moreover, the RNA sequencing data will provide an 
opportunity to explore potential relationships between expression of key genes of 
interest (e.g., genes encoding IGF-1R, IGFBP3, PTEN, insulin receptors) and 
clinical outcome as well as potential relationships between gene expression 
profiles and clinical outcome. Finally, the RNA sequencing data will allow 
orthogonal ascertainment of translocation status, with determination of both gene 
partners involved in the translocation. 
 
2.15 
Rationale for Amendment #2 
AEWS1221 was originally designed as a phase 2 randomized screening trial. This design 
was chosen over a definitive phase 3 trial due to concerns about the potential to complete 
a definitive phase 3 trial in a timely manner. Specifically, 3.5 patients/month were expected 
to be available. In the context of a screening trial requiring 126 patients, 3 years of accrual 
were expected. Moreover, at the time the study was designed, it was not clear that sufficient 
ganitumab would be available to support a larger trial.   
 
AEWS1221 activated to enrollment in December 2014 and there have been no suspensions 
to enrollment. As of May 6, 2016, 96 patients have enrolled over 17 months for an average 
monthly accrual rate of 5.6 patients/month. Since the study was activated, an additional 
supply of ganitumab has become available.   
 
Given the strong interest in this trial and its underlying rationale along with increased drug 
supply, the study committee has amended the trial to determine definitively the role of IGF-
1R inhibition in this patient population. The study committee is not aware of competing 
trials in development that would impact interest in this trial. 
 

 
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2.16 
Rationale for Amendment #6 
The COG DSMC reviewed outcomes to date as of March 2019. The DSMC recommended 
closure to accrual and discontinuation of ganitumab for all patients on Regimen B on active 
therapy. These recommendations were based upon lack of significant benefit of the 
addition of ganitumab to interval compressed chemotherapy in this population as well as 
the potential for increased risk of toxicity in patients on Regimen B. Specifically, an 
imbalance between Regimen A and Regimen B was observed in the number of patients 
with pneumonitis (1 case on Regimen A and 6 cases on Regimen B). 
 
The changes recommended by DSMC were implemented via an urgent COG groupwide 
memo dated March 20, 2019. Amendment #6 now makes these changes to the protocol and 
adds guidance for the diagnosis and management of pneumonitis.   
 
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 Patient Registry module in OPEN 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. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in ACCRN07, 
Protocol for the Enrollment on the Official COG Registry, The Childhood Cancer 
Research Network (CCRN) or APEC14B1, Project:EveryChild A Registry, Eligibility 
Screening, Biology and Outcome Study.  
 
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 I 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 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 

 
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• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
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. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally.  The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in 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 
Reservation Requirements 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in the Oncology Patient 
Enrollment Network (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.  
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’. 

 
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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 
 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps above. Reservations may be obtained 24 hours a day 
through the OPEN system. 
 
3.1.4 
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://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
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. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.  If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
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. 
 

 
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3.1.5 
Timing 
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 this study prior 
to study enrollment will be considered ineligible.  
 
3.1.6 
Institutional Pathology Report  
Immediately following enrollment, the institutional pathology report for the 
diagnosis under which the patient is being enrolled must be uploaded into RAVE. 
The report must include the associated study number and COG patient registration 
and accession numbers. Personal identifiers, including the patient’s name and 
initials must be removed from the institutional pathology report prior to 
submission. 
 
3.1.7 
Participation in Biology Studies. 
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative 
therapies will be carefully explained to the patient or the patient’s parents or 
guardian if the patient is a child. In order to minimize the potential for non-
compliance once enrolled, patients/guardians must be made aware that a number 
of the biology research studies are mandatory and understand that a significant 
number of non-standard blood samples will be required.  
 
3.1.8 
Randomization and Treatment Assignment 
Randomization will take place at the time a patient is enrolled via OPEN. Patients 
will be assigned to either the comparator arm (Regimen A) with the interval 
compressed VDC/IE, or the experimental arm (Regimen B) with VDC/IE and 
ganitumab.  
 
Randomization will be stratified according to age at date of enrollment (< 21 years 
vs. ≥ 21 years) and extent of metastatic disease (lung only vs. any other metastatic 
site). 
 
The first 10 patients < 21 years of age at study entry assigned to Regimen B will 
submit required ganitumab trough serum samples in Induction and Maintenance (see 
Section 15.5). Note: enrollment to this cohort completed as of July 2015. 
 
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.  
 
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 

 
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27 
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. Imaging, bone marrow and ECHO/MUGA must be 
performed within 4 weeks prior to start of protocol therapy (repeat if necessary). 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Patients ≤ 50 years of age at enrollment will be eligible for this study. 
 
Note:  
• 
Infants and small children are eligible for this study, however, the treating 
physicians and family must be prepared to deliver adequate local control as 
required in this study (see Section 13.0 and 17.0). 
 
3.2.2 
Diagnosis 
Patients with histologic diagnosis (by institutional pathologist) of newly diagnosed 
Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) arising from 
bone or soft tissue and with metastatic disease involving lung, bone, bone marrow, or 
other metastatic site. 
 
For the purpose of this study, metastatic disease is defined as one or more of the 
following: 
• 
Lesions which are discontinuous from the primary tumor, are not regional 
lymph nodes, and do not share a bone or body cavity with the primary tumor. 
Skip lesions in the same bone as the primary tumor do not constitute metastatic 
disease. Skip lesions in an adjacent bone are considered bone metastases. If 
there is any doubt whether lesions are metastatic, a biopsy of those lesions 
should be performed. 
• 
Contralateral pleural effusion and/or contralateral pleural nodules. 
• 
Distant lymph node involvement. 
• 
Patients with pulmonary nodules are considered to have metastatic disease if 
the patient has: 
o 
Solitary nodule ≥ 0.5 cm or multiple nodules of ≥ 0.3 cm unless lesion 
is biopsied and negative for tumor; 
o 
Patients with solitary nodule < 0.5 cm or multiple nodules < 0.3 cm 
are not considered to have lung metastasis unless biopsy documents 
tumor. 
• 
Bone marrow metastatic disease is based on morphologic evidence of Ewing 
sarcoma based on H&E stains. In the absence of morphologic evidence of 
marrow involvement on H&E, patients with bone marrow involvement 
detected ONLY by flow cytometry, RT-PCR, FISH, or immunohistochemistry 
will NOT be considered to have clinical bone marrow involvement for the 
purposes of this study. 
 

 
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This study requires bilateral bone marrow biopsies at study entry. The 
suggested approach for patients with large pelvic tumors in which a posterior 
iliac crest bone marrow biopsy would track through the tumor is to instead 
undergo 2 marrow biopsies on the contralateral side (either 2 posterior biopsies 
or one posterior and one anterior biopsy). 
 
• 
Bone metastasis: This study utilizes whole body FDG-PET scans to screen 
patients for bone metastases. Areas suspicious for bone metastasis based on 
FDG-PET scans require confirmatory anatomic imaging with either MRI or 
CT (whole body FDG-PET/CT or FDG-PET/MR scan acceptable). Whole 
body technetium bone scans may be performed at the discretion of the 
investigator and are not required. For patients without other sites of metastatic 
disease whose sole metastatic site to qualify for study entry is a single area 
suspicious for bone metastasis identified by FDG-PET, confirmatory biopsy 
or anatomic imaging evidence of an associated soft tissue mass at that site is 
required for study entry. 
 
3.2.3 
Adequate Tumor Tissue for Submission 
Patients must have adequate tumor tissue to meet the minimum requirement for 
submission (see Section 15.2). 
 
Enrolling institutions are reminded that submission of pre-treatment serum, tumor 
tissue and whole blood according to Sections 15.1, 15.2, and 15.3 is required. 
 
3.2.4 
Prior Therapy: Surgery 
Patients should only have had a biopsy of the primary tumor without an attempt at 
complete or partial resection. Patients will still be eligible if excision was 
attempted or accomplished as long as adequate anatomic imaging (MRI for most 
primary tumor sites) was obtained prior to surgery. 
 
3.2.5 
Organ Function Requirements 
 
3.2.5.1 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 
< 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR99 (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
 

 
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29 
3.2.5.2 Adequate Liver Function Defined As: 
- 
Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- 
SGPT (ALT) < 3 x upper limit of normal (ULN) for age (except for 
patients with liver metastasis who may enroll if ALT < 5 times ULN 
for age). 
 
3.2.5.3 Adequate Cardiac Function Defined As: 
- 
Shortening fraction of  27% or 
- 
Ejection fraction of ≥ 50%  
 
 
 
 
3.2.5.4 Normal blood glucose for age 
Patients must have a normal blood sugar level for age to participate. If an 
initial random draw (ie. non-fasting) blood glucose value is out of range, 
it is acceptable to repeat this test as a fasting draw.   
 
3.2.6 
Exclusion Criteria 
 
3.2.6.1 Patients with regional node involvement as their only site of disease 
 
beyond the primary tumor will not be eligible. 
 
3.2.6.2 Patients whose primary tumors arise in the intra-dural soft tissue (eg. 
 
brain and spinal cord) are not eligible. 
 
3.2.6.3 Patients who have received prior chemotherapy or radiation therapy are 
 
not eligible. 
 
3.2.6.4 Pregnancy and Breast Feeding 
Female patients of childbearing potential are not eligible unless a negative 
pregnancy test result has been obtained. Lactating females are not eligible 
unless they have agreed not to breastfeed their infants for the duration of 
protocol therapy. Sexually active patients of reproductive potential are not 
eligible unless they have agreed to use an effective contraceptive method 
for the duration of protocol therapy. 
 
3.2.6.5 Patients with known pre-existing diabetes mellitus will be excluded from 
study. 
 
3.2.6.6 Concomitant Medications Restrictions 
(Please see Section 4.2 for the concomitant therapy restrictions for patients 
during treatment.) 
 
Patients receiving chronic pharmacologic doses of corticosteroids are not 
eligible. For the purposes of eligibility, chronic exposure is defined as 
anticipated exposure of > 3 weeks, including the sum of both pre-
enrollment and anticipated post-enrollment dosing. Patients on acute 
corticosteroid therapy (≤ 3 weeks of total planned exposure) must still 
meet the normal blood glucose requirement in Section 3.2.5.4. Patients 
receiving chronic inhaled corticosteroids or chronic physiologic 
replacement doses of corticosteroids are eligible. 

 
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3.2.7 
Regulatory Requirements 
 
3.2.7.1 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.7.2 All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
 

 
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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 (except 
where explicitly prohibited within the protocol). 
 
 
4.1 
Overview of Treatment Plan 
 
4.1.1 
Overview 
NOTE: As of March 20, 2019, the study closed to accrual and institutions were 
instructed to immediately discontinue ganitumab for patients on Regimen B.  
 
At study entry, patients will be randomized to Regimen A (VDC/IE) or Regimen B 
(VDC/IE + ganitumab).  
 
Treatment will consist of 4 phases of therapy: Induction; Local Control; 
Consolidation; and Metastatic Site Irradiation. (Originally a 5th phase of therapy, 
Maintenance was administered to patients on Regimen B only. However, 
Maintenance therapy was discontinued effective March 20, 2019.) The 
chemotherapy backbone for this study is based on the interval compressed arm of 
AEWS0031. All patients will first receive a total of 14 cycles of chemotherapy; 
each cycle will be of 2 weeks duration. Induction consists of 6 cycles (12 weeks) 
of chemotherapy. Induction will be delivered prior to local control therapy, which 
may involve surgery and/or radiation therapy. Consolidation therapy will consist 
of 8 cycles (16 weeks) of chemotherapy.  
 
Patients randomized to Regimen A will receive Induction, Local Control, 
Consolidation, and Metastatic Site Irradiation. These patients will then enter 
follow-up after completion of Metastatic Site Irradiation.  
 
Prior to March 20, 2019, patients randomized to Regimen B received this same 
therapy with the addition of ganitumab 18 mg/kg/dose IV every 2 weeks for a total 
of 6 doses during Induction and for a total of 5 doses during Consolidation. In order 
to avoid jeopardizing local control measures, ganitumab was not to be given 
immediately prior to, during, or immediately after local control. After completion 
of Metastatic Site Irradiation, patients in Regimen B received an additional 8 doses 
of ganitumab 18 mg/kg given every 3 weeks as monotherapy during Maintenance. 
These patients then entered follow-up after completion of Maintenance.     
 
Post March 20, 2019: patients on Regimen B discontinued ganitumab and instead 
receive the same therapy as patients on Regimen A. 
 
Given theoretical concerns of possible additive cardiac toxicity of IGF-1R 
inhibition with doxorubicin, dexrazoxane will be given with each dose of 
doxorubicin in both regimens. Evaluation of cardiac function will be obtained at 
baseline, after cumulative doxorubicin dose of 150 mg/m2, and then prior to each 
doxorubicin cycle. See also Section 7.0 for required time points. 

 
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The first 10 patients < 21 years of age at study entry assigned to Regimen B will 
submit required ganitumab trough serum samples in Induction and Maintenance 
(see Section 15.5). Registering sites will be notified of the need to obtain these 
samples at the time of randomization. (Enrollment to this cohort completed as of 
July 2015; for patients previously assigned to this cohort, continue to collect 
samples as detailed in Section 15.5.) 
 
Treatment Schema  
 
 
Drugs 
Dose 
V 
VinCRIStine 
2 mg/m2/day IV x 1 day (max dose 2 mg) 
D 
Doxorubicin 
37.5 mg/m2/day x 2 days IV (with dexrazoxane for all doses) 
C 
Cyclophosphamide 
1200 mg/m2/day IV x 1 day 
I 
Ifosfamide 
1800 mg/m2/day IV x 5 days 
E 
Etoposide 
100 mg/m2/day IV x 5 days  
G 
Ganitumab 
18 mg/kg IV x 1 day (Only in Regimen B)* 
* As of March 20, 2019, institutions were instructed to immediately discontinue 
ganitumab for patients on Regimen B. 
 
  
 

 
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Regimen A 
 
Induction 
 
 
Post-Induction Local Control: See Sections 4.3, 13.0 and 17.0. 
 
Consolidation 
 
Post-Consolidation Metastatic Site Radiation 
See Sections 4.1.1.2 and 17.0. No systemic therapy is given during this phase of therapy. 
 
Maintenance: Patients in Regimen A do not receive Maintenance therapy. 
 
Regimen B 
NOTE: As of March 20, 2019, the study closed to accrual and institutions were instructed to 
immediately discontinue ganitumab for patients on Regimen B. This led to the removal of 
Maintenance therapy. 
 
Induction 
 
Post-Induction Local Control: See Sections 4.3, 13.0 and 17.0. 
 
Consolidation 
 
Post-Consolidation Metastatic Site Radiation 
See Sections 4.1.1.2 and 17.0. No systemic therapy is given during this phase of therapy. 
 
4.1.1.1 Local Control 
Local control will take place once patients have recovered from Induction 
chemotherapy. If surgery is the primary local control, it should be 
scheduled at the time of recovery from the sixth cycle of Induction 
chemotherapy- usually at chronological Week 13. When surgery is 
performed, the next cycle of chemotherapy should be given as soon as 
possible post-operatively. The passing of more than 6 weeks between 
 
Cycle 
1 
2 
3 
4 
5 
6 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
VDC 
 
IE 
 
VDC 
 
IE 
 
VDC 
 
IE 
 
Cycle 
1 
2 
3 
4 
5 
6 
7 
8 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
VDC 
 
IE 
 
IE 
 
VDC 
 
VC 
 
IE 
 
VC 
 
IE 
 
Cycle 
1 
2 
3 
4 
5 
6 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
VDC 
 
IE 
 
VDC 
 
IE 
 
VDC 
 
IE 
 
 
G 
 
G 
 
G 
 
G 
 
G 
 
G 
 
Cycle 
   1 
2 
3 
4 
5 
6 
7 
8 
Week 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
VDC 
 
IE 
 
IE 
 
VDC 
 
VC 
 
IE 
 
VC 
 
IE 
 
 
 
 
 
G 
 
G 
 
G 
 
G 
 
G 
 

 
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chemotherapy cycles for reasons other than surgical complications and/or 
severe chemotherapy toxicity should be avoided. 
 
Note: If logistical issues (such as surgeon availability) prevent surgery 
from taking place after completion of the sixth cycle of Induction, then the 
first cycle of Consolidation chemotherapy should be administered while 
awaiting surgery 
 
For patients who will have radiation alone, Consolidation chemotherapy 
should be initiated concurrently with the radiation therapy, upon recovery 
from Induction chemotherapy. Administration of ifosfamide-etoposide 
chemotherapy concurrently with radiation is allowed and the schedule of 
chemotherapy in Consolidation is designed to accommodate primary site 
radiotherapy during the first part of Consolidation. If radiation to the 
primary tumor must occur at a different time for a compelling clinical 
indication, then the sequence of chemotherapy cycles should be adjusted 
to account for this change and to avoid concomitant doxorubicin and 
radiation administration. For example, if radiation is ongoing at the time 
Cycle 4 of Consolidation is due, Cycles 4 and 5 should be swapped. 
Likewise, the sequence of chemotherapy cycles may be adjusted at 
investigator discretion to avoid resuming doxorubicin shortly after a 
course of radiation completes.   
 
Radiation may begin concurrently or immediately after Cycle 1 of 
Consolidation (VDC). Otherwise, doxorubicin should not be given during 
radiation treatment.  
 
If radiation therapy is to follow surgery, radiation therapy should be 
scheduled to start as soon as recovery from surgery permits.  
 
4.1.1.2 Metastatic Site Radiation 
Patients with lung metastases at diagnosis will receive whole lung 
irradiation in 1.5 Gy daily fractions after the completion of Consolidation 
chemotherapy. Bone metastatic sites will also be radiated during this time. 
The recommended form of radiotherapy will be SBRT (40 Gy in 
5 fractions over 5 days) rather than standard EBRT.  
 
Metastatic site radiation will begin once patients have recovered from the 
last cycle of Consolidation chemotherapy, but no earlier than 3 weeks from 
the start of Week 15 of Consolidation.  
 
In rare scenarios, whole lung radiation might occur early due to 
overlapping fields. If whole lung radiation will occur at the time of primary 
site radiation due to overlapping fields, then the timing of local control and 
sequence of Consolidation cycles should be modified to avoid receipt of 
doxorubicin after whole lung radiation. Consolidation Cycle 4 should be 
moved to Week 1 Consolidation and radiation delayed by two weeks. 
When radiation begins, a VDC cycle can be given at the start of radiation 
followed by two IE cycles (original Consolidation Cycles 1, 2, and 3). 

 
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Post-radiation, patients can resume chemotherapy with Cycle 5 
Consolidation.   
 
4.1.1.3 Evaluations 
Patients will undergo full disease evaluation with MRI or CT of primary 
tumor site, chest CT, FDG-PET scan, and bilateral bone marrow aspirates 
and biopsies at study entry. If whole body PET/CT is obtained with thin 
cuts through chest, this scan may also substitute for required chest CT scan 
(see Section 10.3.2.1). The suggested approach for patients with large 
pelvic tumors in which a posterior iliac crest bone marrow biopsy would 
track through the tumor is to instead undergo 2 marrow biopsies on the 
contralateral side (either 2 posterior biopsies or one posterior and one 
anterior biopsy). Tumors with associated soft-tissue mass are 
recommended to undergo evaluation with MRI as MRI is superior at 
delineating soft-tissue extent. Chest CT to evaluate for lung metastasis 
should NOT be omitted for patients who undergo thoracic MRI as part of 
evaluation of the primary tumor. Patients with primary bone tumors are 
also recommended to undergo plain film of the primary tumor site at study 
entry as part of good clinical care. Sites suspicious for bone or soft tissue 
metastasis identified by FDG-PET scan at study entry should be imaged 
further with MRI or CT (whole body CT obtained as part of PET/CT scan 
is acceptable). For patients without other sites of metastatic disease whose 
sole metastatic site to qualify for study entry is a single area suspicious for 
bone metastasis identified by FDG-PET, confirmatory biopsy or anatomic 
imaging evidence of an associated soft tissue mass at that site is required 
for study entry. 
 
All patients will undergo MRI or CT of primary tumor site (ideally with 
the same modality used at study entry), chest CT, and FDG-PET (or 
PET/CT) scan at the end of Induction prior to local control. Tumors with 
associated soft-tissue mass, including chest wall tumors are recommended 
to undergo evaluation with MRI as MRI is superior at delineating soft-
tissue extent. Previous sites of bone or soft tissue metastasis and any new 
sites of concern for bone or soft tissue metastasis based on FDG-PET 
should be imaged further with MRI or CT (whole body CT obtained as 
part of PET/CT scan is acceptable). 
 
All patients will undergo MRI or CT of primary tumor site, chest CT, and 
FDG-PET (or PET/CT) scan before Week 9 of Consolidation and at the 
end of Consolidation chemotherapy. Tumors with associated soft-tissue 
mass, including chest wall tumors, are recommended to undergo 
evaluation with MRI as MRI is superior at delineating soft-tissue extent. 
Plain film of the primary tumor site may be substituted for MRI or CT for 
patients who have undergone surgical resection with metallic implants 
though modern MRI techniques may still allow adequate imaging even in 
the presence of metallic implants. Previous sites of bone or soft tissue 
metastasis and any new sites of concern for bone or soft tissue metastasis 
based on FDG-PET should be imaged further with MRI or CT (whole 
body CT obtained as part of PET/CT scan is acceptable). 
 

 
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Following completion of Consolidation chemotherapy, patients in both 
arms of the study are recommended to undergo MRI or CT of primary 
tumor site, chest CT, and FDG-PET (or PET/CT) every 3 months 
following the schedule in Section 7.3. This schedule applies to patients in 
Regimen B who received Maintenance ganitumab. Previous sites of bone 
or soft tissue metastasis and any new sites of concern for bone or soft tissue 
metastasis based on FDG-PET should be imaged further with MRI or CT 
(whole body CT obtained as part of PET/CT scan is acceptable). 
 
Patients with clinical evidence of bone marrow involvement at study entry 
(per Section 3.2.2) will undergo repeat bilateral bone marrow aspirates and 
biopsies after 3 cycles of Induction chemotherapy. For patients with 
clinically evident persistent bone marrow metastatic disease, repeat 
bilateral bone marrow aspirates and biopsies will be performed prior to 
local control and then every 4 cycles until clear. See Sections 10.3.4 and 
10.4 for definitions of marrow response and note off-protocol therapy 
criteria for residual bone marrow involvement at end of Consolidation). 
Once clear and in the absence of clinical concern for relapsed disease, no 
repeat bone marrow aspirates / biopsies are required until these patients 
undergo their disease evaluations at the end of Consolidation 
chemotherapy.  
 
Please see Section 15.4 for submission instructions for the recommended 
bone marrow correlative biology study. 
 
4.1.2 
Dose Adjustment for Obesity 
There will be no dose adjustments for obese patients. 
 
4.2 
Concomitant Medications 
No other cancer chemotherapy or immunomodulating agents will be used. 
 
4.2.1 
Cytochrome P450 drug interaction 
 
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 specific azole antifungals (such as voriconazole, 
itraconazole, ketoconazole) and strong inducers include drug such as rifampin, 
phenytoin, phenobarbitol, carbamazepine, and St. John’s wort (see Appendix V for 
list of agents). These drugs should be avoided with vincristine.  
 
The clinical outcome and significance of CYP450 interactions with 
cyclophosphamide, doxorubicin, etoposide and ifosfamide are less clear. 
CYP450 3A4 inducers or inhibitors should be avoided or used with great caution. 
Multi-day aprepitant regimen also interacts with CYP3A4 and should be used with 
caution with etoposide, ifosfamide, or vincristine chemotherapy. 
 
 
4.2.2 
Other supportive care 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and 
general supportive care are to be used as necessary.  
 

 
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For COG Supportive Care Guidelines see: 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
4.3 
General Approach to Local Control of the Primary Tumor 
This study requires definitive treatment of the primary tumor with complete surgical 
excision, a combination of surgical excision and radiation therapy for microscopic residual 
disease, or full-dose radiation therapy. A multidisciplinary approach to primary tumor 
treatment involving the oncologist, the radiation oncologist, and the surgeon is 
indispensable, and planning should begin immediately upon diagnosis.  
 
The guiding principle for local control should be to eradicate the primary tumor and avoid 
local recurrence with the least amount of functional loss, while minimizing delays in 
systemic therapy in this metastatic patient population. This will require careful consultation 
between the oncologist, the orthopedic or surgical oncologist, and the radiation oncologist.  
 
Even for patients anticipated to undergo surgical local control of the primary tumor, early 
radiation oncology referral is recommended to facilitate planning for metastatic site 
radiation, including the need for institutional credentialing to administer SBRT to bone 
metastases (see Section 17.1.2). 
 
4.3.1 
Primary Tumor Treatment Modalities 
4.3.1.1 Surgery 
Surgical excision should be considered for all tumors which respond to 
Induction chemotherapy. Surgery is the local therapy modality of choice 
if the lesion can be resected with negative microscopic margins (R0) and 
a reasonable functional result. If surgical expertise is not available at a 
given institution, it is strongly suggested that consultation be made with 
an experienced orthopedic or surgical oncologist at another institution. 
Patients with unresectable lesions or inadequate margins after surgery will 
receive radiation therapy.  
 
The aim of surgery is to achieve a wide (R0) surgical excision which 
leaves a clear margin of normal tissue surrounding the lesion. Patients with 
complete resections (R0) with a clear margin (defined in next section) will 
not require radiation therapy. Currently there is no reliable way to assess 
tumor responsiveness non-invasively. Therefore, in most cases, a wide 
cuff of normal tissue will surround the tumor consistent with the planned 
reconstruction. In rare cases, the margin may be closer if an important 
structure such as a major growth plate, a joint or a structure such as the 
acetabulum can be preserved. A marginal (R1) excision leaves 
inflammatory tissue containing residual tumor cells. The pathologic 
margin is microscopic. The patient requires post operative radiation 
therapy.  
 
Intralesional or debulking (R2) operations leaves gross residual tumor. 
This type of surgical procedure is never indicated. Recovery from 
complicated surgical procedures will delay the resumption of 
chemotherapy. Since gross residual tumor remains, the patient will require 
full dose radiation therapy (the same dose as if no surgical procedure was 

 
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38 
performed). Radiation will be less effective in the hypoxic post surgical 
bed and the radiation field size will be larger than if surgery was not 
attempted.  
 
For details on the surgical approach to the biopsy and excision, see 
Section 13.0. 
 
4.3.1.2 Margins 
At the time of resection, the surgeon should mark all margins and orient 
the specimen at the operative field, so that margin evaluation is precise. 
Narrow margins are unavoidable in some areas. In these situations, the 
surgeon should take a number of separate biopsies of the “normal” tissue 
around the margins of resection and these should be marked and submitted 
separately for pathologic review. Communication with the pathologist is 
mandatory to assure accuracy of margin examination. Consideration 
should be given to having the pathologist inspect the specimen in the 
operating theatre to help with orientation. The tumor should not be 
bisected or cut into separate specimens prior to this discussion.  
 
The aim of surgery is to achieve a wide (R0) surgical excision which 
leaves a clear margin of normal tissue surrounding the lesion. Patients with 
complete resections (R0) with a clear margin (defined as no viable tumor 
at the cut surface) will not require radiation therapy. In most instances this 
will be normal non-reactive tissue. In some instances when resected 
tumors have greater than 90% overall necrosis, the tissue at the margin 
may be bland scar or loose fibrous tissue. This will be considered a clear 
margin and no postoperative radiation therapy will be required. If 
specimens with greater than 90% overall necrosis have inflammatory 
tissue or coagulative tumor necrosis at the margin, (the cytoarchitecture of 
the tumor cells is preserved) the margin will be considered 
microscopically positive and require post operative radiation therapy. If 
the tumor specimen has less than 90% overall necrosis, the cut surface of 
the resected tumor must be normal non-reactive tissue in order to be 
considered pathologically negative. If there is ambiguity about the margin 
status, investigators should strongly consider post-operative radiotherapy. 
 
4.3.1.3 Surgery plus Radiation Therapy 
Most patients will have either surgery alone, surgery with radiation 
therapy for positive microscopic margins, or radiation therapy alone.  
 
When surgery is done first, followed by radiation therapy, surgery should 
occur as soon as possible after recovery from Induction Cycle 6 
chemotherapy and radiation therapy should begin as soon as feasible 
thereafter. 
 
Pre-operative radiotherapy is not indicated. This approach may result in 
considerable delays in chemotherapy: thus the benefits must be weighed 
against risk in each patient. The final decision regarding the best treatment 
is dependent on patient and tumor characteristics and is left to the 
consultants at the patient’s institution. 

 
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39 
 
In patients with unresectable tumors treated with definitive radiation, 
delayed excision is not typically indicated and therefore discouraged. 
 
For details on the surgical approach to the biopsy and excision, see 
Section 13.0. For details on radiotherapy, see Section 17.0. 
 
4.3.1.4 Radiation Therapy Only 
Candidates for radiotherapy alone will include patients with bulky lesions 
in surgically difficult sites such as the spine, skull and periacetabular 
pelvis, patients with a poor response to Induction chemotherapy, or those 
patients in whom surgery would result in unacceptable functional results. 
Sites which, if removed, would result in significant impairment of function 
include the skull, facial bones, vertebrae and pelvic bones about the 
acetabulum. In some cases, resection even in these sites may be feasible 
in combination with radiation therapy, and decisions regarding a specific 
patient must be individualized. 
 
Patients who are to be treated with radiotherapy alone should be treated 
with radiotherapy at the start of Consolidation Week 1 chemotherapy. 
Proton therapy is allowed as part of this study. For details regarding 
radiotherapy, see Section 17.0. 
 
4.4 
Chemotherapy Administration Schedule 
Chemotherapy will be administered on an interval-compressed schedule every 2 weeks, as 
allowed by recovery from previous cycles. Recommended guidelines for administering 
interval-compressed chemotherapy include checking a CBC with differential on Day 1 and 
8 of each cycle and then every Monday, Wednesday and Friday (or 3 other nonconsecutive 
days per week) after Day 12, until the criteria for starting the next cycle are satisfied.  
 
 
Note: See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG 
website at: 
https://cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for special 
precautions and suggestions for patient monitoring during the infusion. As applicable, also 
see the CAGs for suggestions on hydration, or hydrate according to institutional guidelines. 
 
4.4.1 
Administration Schedules for Induction and Consolidation in Regimen A 
 
Patients in Regimen A do not receive ganitumab. 
 
Patients in Regimen A do not receive a Maintenance phase.  
 
4.4.1.1 Administration Schedule: Induction (Weeks 1-12) Regimen A 
Criteria to start Induction: No count criteria are required to start Induction 
Week 1 therapy.  
 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count 
≥ 75,000/µL post nadir (without transfusion). The ANC often falls after 
discontinuing myeloid growth factor support. If the ANC has risen 

 
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40 
to ≥ 750/µL after the nadir but then falls the next cycle should be given 
despite ANC < 750/ µL. To maintain dose intensity, administration of 
subsequent cycles of chemotherapy should not be delayed as along as the 
patient meets count recovery criteria, regardless of myeloid growth factor 
utilized. 
 
See Section 5.1 for exceptions in Weeks 1 and 3 for patients with bone 
marrow metastatic disease.  
 
 
If a cycle of chemotherapy is delayed due to toxicity, see Section 5.0 for 
criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age, chemotherapy should be 
calculated by weight rather than by surface area. Dose/kg = dose/m2 
divided by 30 kg/m2. Example: If patient is less than 1 year of age and 
weight is 15 kg and dose of Etoposide is 100 mg/m2, then the dose of 
Etoposide is based on mg/kg = 100 mg/m2 divided by 30 kg/m2 = 
3.3 mg/kg x15 kg = 49.5 mg.  
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day 1 of Weeks 1, 5 and 9 
Dose: 2 mg/m2/dose. (Maximum dose is 2 mg.) For patients < 1 year old, 
the dose is 0.067 mg/kg/dose. 
 
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. Fatal if given by other routes. For intravenous use only.” 
 
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. 
 
Dexrazoxane: Slow IV Push (eg, over 5-15 minutes) given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1, 5 and 9 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of 
DOXOrubicin). For patients < 1 year old, the dose is 12.5 mg/kg/dose. 
Note: Administer DOXOrubicin after completing the infusion of 
dexrazoxane and every effort should be made to keep the total combined 
infusion time for dexrazoxane and doxorubicin to ≤ 30 minutes. 
 
DOXOrubicin: IV push/infusion over 1-15 minutes.  
Days: 1 and 2 of Weeks 1, 5 and 9 
Dose: 37.5 mg/m2/dose. For patients < 1 year old, the dose is 
1.25 mg/kg/dose. 

 
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41 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing 
solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion 
between DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in 
a liposomal formulation. Use conventional DOXOrubicin only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
Cyclophosphamide: IV over 30-60 minutes 
Day 1 of Weeks 1, 5 and 9 
Dose: 1,200 mg/m2/dose. For patients < 1 year old, the dose is 
40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 
0.9% NaCl only to avoid hypotonic solution) or further diluted.  
 
Mesna must be administered in conjunction with cyclophosphamide 
(see below). Hydrate per institutional guidelines or according to 
recommendations below.   
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days: 1-5 of Weeks 3, 7 and 11 
Dose: 1,800 mg/m2/dose. For patients < 1 year old, the dose is 
60 mg/kg/dose. 
 
Mesna must be administered in conjunction with ifosfamide (see below). 
Hydrate per institutional guidelines or according to recommendations 
below.  
 
Suggested hydration for cyclophosphamide/ifosfamide: Administer 
3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start 
of cyclophosphamide/ifosfamide. May use diuretics (eg, furosemide) to 
increase urine output. Consider adding potassium and magnesium to 
prevent electrolyte deficiencies.  
 
Mesna with Cyclophosphamide 
Administer MESNA by IV infusion or IV/PO on Day 1 of Weeks 1, 5 and 
9. 
Total IV Dose: 720 mg/m2/day. For patients < 1 year old, the IV dose is 
24 mg/kg/day. 
 
Mesna with Ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-5 of Weeks 3, 7 
and 11. 
Total IV Dose: 1,080 mg/m2/day. For patients < 1 year old, the IV dose 
is 36 mg/kg/day. 
 
Mesna IV short or continuous infusion:  

 
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42 
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal 
to 60% of the daily ifosfamide/cyclophosphamide dose. Mesna can be 
administered in 3 divided doses by short 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 ifosfamide/cyclophosphamide dose; subsequent 
doses 
are 
given 
4 
and 
8 hours 
after 
the 
start 
of 
ifosfamide/cyclophosphamide).  
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; 200 mg of mesna will be given 
15 minutes before or at the start of the cyclophosphamide/ifosfamide dose 
(Hour 0) and 2 boluses of 200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous 
infusion (CI). The continuous infusion should be started 15-30 minutes 
before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide 
infusion.   
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; the 600 mg mesna continuous 
infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours 
after the end of the ifosfamide/cyclophosphamide infusion. If 
ifosfamide/cyclophosphamide is administered over 1 hour and mesna is 
started 30 minutes before the cyclophosphamide/ifosfamide infusion, the 
total mesna infusion will last at least 9 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral 
mesna may receive the last TWO bolus doses (originally at Hours 4 and 
8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral doses 
will be administered at Hours 2 and 6. 
 
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
200 mg of mesna will be given IV 15 minutes before or with the 
cyclophosphamide/ifosfamide dose (Hour 0) and the TWO oral doses of 
400 mg each will be given at Hours 2 and 6. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, 
dilute mesna parental solution before oral administration. The solution can 
be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, 
apple, tomato and orange) or plain or chocolate milk. The most palatable 
is chilled grape juice. Tablets are 400 mg and can be divided into 
200 mg/0.5 tabs so dosing can be rounded up to nearest 200 mg. 
Administer doses on a schedule as determined by timing of 
cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to 
the original dosing schedule. Do not deviate from the original schedule. 
Notify provider if a dose is delayed or missed. If the patient vomits within 

 
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43 
2 hours following an oral dose, repeat the oral dose or administer an IV 
dose of mesna. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days: 1-5 of Weeks 3, 7 and 11 
Dose: 100 mg/m2/dose. For patients < 1 year old, the dose is 
3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of 
administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested for prolonged infusion due to risk of precipitation. 
 
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. 
 
Growth Factor Support 100-106 
Begin myeloid growth factor support (filgrastim or pegfilgrastim or 
biosimilar products according to institutional standards for patients 
receiving interval compressed chemotherapy) at least 24-36 hours after the 
last dose of chemotherapy. If given daily then continue a minimum of 
7 days and until ANC ≥ 750/µL post nadir and discontinue at least 
24 hours prior to next cycle of chemotherapy.  
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Induction in Regimen A are provided in the 
following 3 pages. Local Control will follow Induction (see Section 4.3 
for details). See Section 7.1.1 for observations prior to Local Control.  
 
Details of Consolidation chemotherapy in Regimen A are provided in 
Section 4.4.1.2. 
 

 
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AEWS1221 
Regimen A:  Induction (Weeks 1-12) 
Induction consists of 6 two-week cycles (84 days in total). The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 1 and 2 (Weeks 1-4); one VDC cycle followed by one IE cycle. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
No count criteria are required to start Induction Week 1 therapy. Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If the ANC has risen 
to ≥ 750/µL after the nadir but then falls the next cycle should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the 
next chemotherapy cycle. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine  
(VCR) 
IV push over 1 min$ 
2 mg/m2/dose OR  
0.067 mg/kg/dose for pt < 1 yo 
1 
$ Or infusion via minibag as per institutional policy.  
Maximum dose: 2 mg. See Section 4.4.1.1. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total bilirubin  
e. Albumin, EKG, Urine pregnancy test* 
f. ECHO* or MUGA* 
g. Plain film primary tumor (bone tumors only) 
h. MRI or CT of primary tumor, Chest CT, FDG-PET scan. 
(See Sections 7.1.1 & 16.0) 
i. MRI or CT and FDG-PET submission* 
j. Required BMA aspirates and biopsies 
k. Unstained slides* 
l.  Required baseline blood samples* 
m.Optional BMA submission* 
n. Optional sample in Streck* 
 
*See Section 7.1.1 
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push over  
5-15 mins‡ 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 1 yo 
1 and 2 
‡ Given immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
should be ≤ 30 min. See Section 4.4.1.1. 
DOXOrubicin 
(DOXO) 
IV push/infusion over  
1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 1 yo 
1 and 2 
See Section 4.4.1.1 for details. 
Cyclophosphamide 
(CPM) 
IV over  
30-60 mins  
1200 mg/m2/dose OR  
40 mg/kg/dose for pt < 1 yo 
1 
See Section 4.4.1.1 for details. 
Mesna (MESNA)  
IV or IV/PO 
Total IV dose: 720 mg/m2/day 
OR 
24 mg/kg/day for pt < 1 yo 
1 
Administer with CPM, see Section 4.4.1.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for < 1 yo  
15 - 19 
See Section 4.4.1.1 for details. 
Mesna (MESNA)  
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day 
OR 36 mg/kg/day for pt < 1 yo 
15 - 19 
Administer with IFOS, see Section 4.4.1.1 
Etoposide (ETOP) 
IV over  
1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo  
15 - 19 
Slow rate of administration if hypotension occurs. 
See Section 4.4.1.1 for details. 
 
Cycle 1:  Ht__________cm Wt__________kg  
BSA__________m2  
 
Cycle 2:  Ht__________cm Wt__________kg BSA__________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
______mg 
DXRZ  
_______mg 
DOXO 
________mg 
CPM 
________mg 
MESNA (with CPM)  
____________mg/day% 
IFOS 
_______mg 
MESNA (with IFOS)  
___________mg/day% 
ETOP  
______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
1 
______mg _______mg ________mg ________mg ____________mg/day%  
 
 
a – n 
 
 
 
 
2 
 
_______mg ________mg  
 
 
 
 
 
 
 
 
 
3-4# 
 
Growth factor used: _______________ Dose: ___________ Date of first dose: ___________  
Date of last dose: __________ 
 
 
2 
8 
 
 
 
 
 
 
 
 
b* 
 
 
 
3 
15 
 
 
 
 
 
_______mg ___________mg/day% ______mg a – d, n 
 
 
 
 
16 
 
 
 
 
 
_______mg ___________mg/day% ______mg  
 
 
 
 
17 
 
 
 
 
 
_______mg ___________mg/day% ______mg  
 
 
 
 
18 
 
 
 
 
 
_______mg ___________mg/day% ______mg  
 
 
 
 
19 
 
 
 
 
 
_______mg ___________mg/day% ______mg  
 
 
 
 
20-21#  
Growth factor used: ________________ Dose: ___________ 
Date of first dose: ___________  
Date of last dose: __________ 
 
 
4 
22 
 
 
 
 
 
 
 
 
b* 
 
 
 
 
28 
 
 
 
 
 
 
 
 
b* 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.1. 
The therapy delivery map for Induction continues on the next 2 pages. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 1 of 3 

 
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AEWS1221 
Regimen A:  Induction Continued 
Induction consists of 6 two-week cycles (84 days in total).The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 3 and 4 (Weeks 5-8); one VDC cycle followed by one IE cycle. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 3 and 4 should be given despite 
ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt < 1 yo 
29 
$ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.1.1. 
a. History and physical exam, height, 
weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), 
Total bilirubin  
e. Required BMA and biopsies if marrow 
involved at baseline* 
f. Optional bone marrow aspirate 
submission* 
g. Required serum sample*  
h. Optional sample in Streck* 
 
* See Section 7.1.1 for details. 
 
OBTAIN 
OTHER STUDIES 
AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push over  
5-15 mins‡ 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 1 yo 
29 and 30 
‡ Given immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
should be ≤ 30 min. See Section 4.4.1.1. 
DOXOrubicin 
(DOXO) 
IV 
push/infusion 
over 1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 1 yo  
29 and 30 
See Section 4.4.1.1 for details. 
Cyclophosphamide 
(CPM)  
IV over 30-60 mins  1200 mg/m2/dose OR  
40 mg/kg/dose for pt < 1 yo 
29 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
29 
Administer with CPM, see Section 4.4.1.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt or < 1 yo 
43-47 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
43-47 
Administer with IFOS, see Section 4.4.1.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo 
43-47 
Slow rate of administration if hypotension occurs. 
See Section 4.4.1.1 for details. 
 
 
 
Cycle 3: Ht__________cm Wt__________kg  
BSA__________m2  
 
 
Cycle 4: Ht__________cm Wt__________kg  
BSA__________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
______mg 
DXRZ  
____mg 
DOXO 
______mg 
CPM 
______mg 
MESNA (with CPM) 
__________mg/day% 
IFOS 
______mg 
MESNA (with IFOS)  
_________mg/day% 
ETOP 
______mg 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
5 
29 
______mg ______mg ______mg ______mg _________mg/day%  
 
 
a – d, g, h  
 
 
 
30 
 
______mg ______mg  
 
 
 
 
 
 
 
 
 
31-32#  
Growth factor used: __________________ Dose: ________ Date of first dose: ___________ Date of last dose: ____________ 
 
 
6 
36 
 
 
 
 
 
 
 
 
b* 
 
 
 
7 
43 
 
 
 
 
 
______mg __________mg/day% ______mg a – f 
 
 
 
 
44 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
45 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
46 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
47 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
48-49#  
Growth factor used: ___________________ Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
8 
50 
 
 
 
 
 
 
 
 
b* 
 
 
 
 
56 
 
 
 
 
 
 
 
 
b* 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.1  
The therapy delivery map for Induction continues on the next page. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 2 of 3 

 
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46 
AEWS1221 
Regimen A:  Induction Continued 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 5 and 6 (Weeks 9-12); one VDC cycle followed by one IE cycle. 
 
____________________________ 
Patient ID 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 5 and 6 should be given despite ANC < 750/µL. 
Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
57 
$ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.1.1 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++,  
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubin 
e. ECHO/MUGA (prior to Week 9 chemotherapy). 
f. MRI or CT of primary tumor, chest CT, FDG-
PET scan. (See Sections 7.1.1 & 16.0) 
g. MRI or CT and FDG-PET submission* 
h. Required BMA and biopsies if marrow still 
positive at last eval * 
i. Optional BMA submission* 
j. Optional sample in Streck* 
*See Section 7.1.1 for details. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Dexrazoxane(DXRZ) Slow IV push over  
5-15 mins‡ 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 1 yo 
57 and 58 
‡ Given immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
should be ≤ 30 min. See Section 4.4.1.1. 
DOXOrubicin 
(DOXO) 
IV 
push/infusion 
over 1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 1 yo 
57 and 58 
See Section 4.4.1.1 for details. 
Cyclophosphamide 
(CPM) 
IV over 30-60 mins  1200 mg/m2/dose OR 
 40 mg/kg/dose for pt < 1 yo  
57 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
57 
Administer with CPM, see Section 4.4.1.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 1 yo  
71-75 
See Section 4.4.1.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR  
36 mg/kg/day for pt < 1 yo 
71-75 
Administer with IFOS, see Section 4.4.1.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo 
71-75 
Slow rate of administration if hypotension occurs. See 
Section 4.4.1.1 for details. 
 
 
Cycle 5: Ht __________cm Wt __________kg 
BSA__________m2  
 
 
Cycle 6: Ht __________cm Wt __________kg 
BSA__________m2 
 
 
Date 
Due 
Date 
Given 
Week Day 
VCR 
______mg 
DXRZ  
_____mg 
DOXO 
______mg 
CPM 
______mg 
MESNA (with CPM) 
__________mg/day% 
IFOS 
______mg 
MESNA (with IFOS)  
__________mg/day% 
ETOP 
______mg 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
9 
57 
______mg _____mg ______mg ______mg _________mg/day%  
 
 
a - e 
 
 
 
 
58 
 
_____mg ______mg  
 
 
 
 
 
 
 
 
 
59-60#  
Growth factor used: ______________ Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
 
 
 
 
 
 
 
 
b* 
 
 
 
11 
71 
 
 
 
 
 
______mg __________mg/day% ______mg a – d  
 
 
 
 
72 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
73 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
74 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
75 
 
 
 
 
 
______mg __________mg/day% ______mg  
 
 
 
 
76-77#  
Growth factor used: _____________  Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
12 
78 
 
 
 
 
 
 
 
 
b* 
 
 
 
 
84 
 
Local Control will follow Induction therapy. See Section 4.3 for Local Control options. See Section 7.1 for 
observations prior to Local Control. 
a, b, f – j  
% Enter total daily dose as mg/day by CI or intermittent infusion. 
 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.1  
SEE SECTION 5.0 FOR DOSE MODIFICATIONS FOR TOXICITIES AND THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINE
Page 3 of 3 

 
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47 
 
4.4.1.2 Administration Schedule: Consolidation Therapy (Weeks 1-16) Regimen A 
Ensure adequate time for healing following surgical local control. 
Consolidation will not begin until 2 weeks post-operatively. For patients 
receiving radiation therapy for local control, radiation therapy should 
begin concomitantly with Week 1 of Consolidation therapy. 
DOXOrubicin may be administered concurrently with radiation therapy 
only at Week 1 of Consolidation chemotherapy.  
 
See Section 4.1.1.2 for modifying order of Consolidation for patients who 
receive early whole lung radiation due to overlapping radiation fields with 
the primary tumor. 
 
Criteria to start Consolidation: ANC ≥ 750/µL and platelet ≥ 75,000/µL 
post nadir (without transfusion). The ANC often falls after discontinuing 
myeloid growth factor support. If the ANC has risen to ≥ 750/µL after the 
nadir but then falls the next cycle should be given despite ANC < 750/µL. 
To maintain dose intensity, administration of subsequent cycles of 
chemotherapy should not be delayed as along as the patient meets count 
recovery criteria, regardless of myeloid growth factor utilized. 
 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count 
≥ 75,000/µL post nadir (without transfusion). The ANC often falls after 
discontinuing myeloid growth factor support. If the ANC has risen to 
≥ 750/µL after the nadir but then falls the next cycle should be given 
despite ANC < 750/µL. To maintain dose intensity, administration of 
subsequent cycles of chemotherapy should not be delayed as along as the 
patient meets count recovery criteria, regardless of myeloid growth factor 
utilized. 
 
If a cycle of chemotherapy is delayed due to toxicity, see Section 5.0 for 
criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age chemotherapy should be 
calculated by weight rather than by surface area. Dose/kg = dose/m2 
divided by 30 kg/m2. Example: If patient is less than 1 year of age and 
weight is 15 kg and dose of Etoposide is 100mg/m2, then the dose of 
Etoposide is based on mg/kg = 100mg/m2 divided  by 30 kg/m2 = 3.3 
mg/kg x15 kg = 49.5 mg. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day 1 of Weeks 1, 7, 9, and 13 
Dose: 2 mg/m2/dose (Maximum dose is 2 mg). For patients < 1 year old, 
the dose is 0.067 mg/kg/dose. 
 
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. 
Fatal if given by other routes. For intravenous use only.” 

 
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48 
 
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. 
 
Dexrazoxane: Slow IV Push (eg, over 5-15 minutes) given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1 and 7 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of 
DOXOrubicin). For patients < 1 year old, the dose is 12.5 mg/kg/dose. 
Note: Administer DOXOrubicin after completing the infusion of 
dexrazoxane and every effort should be made to keep the total combined 
infusion time for dexrazoxane and doxorubicin to ≤ 30 minutes.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes  
Days: 1 and 2 of Weeks 1 and 7 
Dose: 37.5 mg/m2/dose. For patients < 1 year old, the dose is 
1.25 mg/kg/dose. 
 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing 
solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion 
between DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in 
a liposomal formulation. Use conventional DOXOrubicin only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
Cyclophosphamide: IV over 30-60 minutes 
Day 1 of Weeks 1, 7, 9 and 13 
Dose: 1,200 mg/m2/dose. For patients < 1 year old, the dose is 
40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 
0.9% NaCl only to avoid hypotonic solution) or further diluted.  
 
Mesna must be administered in conjunction with Cyclophosphamide (see 
below). Hydrate per 
institutional guidelines or according to 
recommendations below.   
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days 1-5 of Weeks 3, 5, 11 and 15 
Dose: 1,800 mg/m2/dose. For patients < 1 year old, the dose is 
60 mg/kg/dose. 
Mesna must be administered in conjunction with IFOS (see below). 
Hydrate per institutional guidelines or according to recommendations 
below.   
 

 
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49 
Suggested hydration for cyclophosphamide/ifosfamide: Administer 
3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start 
of cyclophosphamide/ifosfamide. May use diuretics (eg, furosemide) to 
increase urine output. Consider adding potassium and magnesium to 
prevent electrolyte deficiencies.  
 
Mesna with cyclophosphamide 
Administer MESNA by IV infusion or IV/PO on Day 1 of Weeks 1, 7, 9 
and 13. 
Total IV Dose: 720 mg/m2/day. For patients < 1 year old, the IV dose is 
24 mg/kg/day. 
 
Mesna with ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-5 of Weeks 3, 5, 
11 and 15. 
Total IV Dose: 1,080 mg/m2/day. For patients < 1 year old, the IV dose 
is 36 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal 
to 60% of the daily ifosfamide/cyclophosphamide dose. Mesna can be 
administered in 3 divided doses by short 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 ifosfamide/cyclophosphamide dose; subsequent 
doses 
are 
given 
4 
and 
8 hours 
after 
the 
start 
of 
ifosfamide/cyclophosphamide).  
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; 200 mg of mesna will be given 
15 minutes before or at the start of the cyclophosphamide/ifosfamide dose 
(Hour 0) and 2 boluses of 200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous 
infusion (CI). The continuous infusion should be started 15-30 minutes 
before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide 
infusion.  For example: if the cyclophosphamide/ifosfamide dose is 
1,000 mg, then the total daily mesna dose is 600 mg; the 600 mg mesna 
continuous infusion will start 15-30 minutes before or at the same time as 
the ifosfamide/cyclophosphamide and be completed no sooner than 
8 hours after the end of the ifosfamide/cyclophosphamide infusion. If 
ifosfamide/cyclophosphamide is administered over 1 hour and mesna is 
started 30 minutes before the cyclophosphamide/ifosfamide infusion, the 
total mesna infusion will last at least 9 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral 
mesna may receive the last TWO bolus doses (originally at Hours 4 and 

 
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50 
8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral doses 
will be administered at Hours 2 and 6. 
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
200 mg of mesna will be given IV 15 minutes before or with the 
cyclophosphamide/ifosfamide dose (Hour 0) and the TWO oral doses of 
400 mg each will be given at Hours 2 and 6. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, 
dilute mesna parental solution before oral administration. The solution can 
be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, 
apple, tomato and orange) or plain or chocolate milk. The most palatable 
is chilled grape juice. Tablets are 400 mg and can be divided into 
200 mg/0.5 tabs so dosing can be rounded up to nearest 200 mg. 
Administer doses on a schedule as determined by timing of 
cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to 
the original dosing schedule. Do not deviate from the original schedule. 
Notify provider if a dose is delayed or missed. If the patient vomits within 
2 hours following an oral dose, repeat the oral dose or administer an IV 
dose of mesna. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days 1-5 of Weeks 3, 5, 11 and 15 
Dose: 100 mg/m2/dose. For patients < 1 year old, the dose is 
3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of 
administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested for prolonged infusion due to risk of precipitation. 
 
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. 
 
Growth Factor Support 
Begin myeloid growth factor support (filgrastim or pegfilgrastim or 
biosimilar products according to institutional standards for patients 
receiving interval compressed chemotherapy) at least 24-36 hours after the 
last dose of chemotherapy. If given daily then continue a minimum of 7 
days and until ANC ≥ 750/µL post nadir and discontinue at least 24 hours 
prior to next cycle of chemotherapy.  
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Consolidation in Regimen A are provided 
on the following 5 pages. See Section 7.1.2 for observations required 
during Consolidation. 
 

 
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51 
Following recovery from Consolidation chemotherapy and no earlier than 
3 weeks from start of Week 15 of Consolidation, patients proceed to 
Metastatic Site Radiation (see Section 17.0). No systemic therapy is given 
during Metastatic Site Radiation.  
 
4.4.1.3 End of Therapy for Patients on Regimen A 
Following completion of Metastatic Site Radiation, patients on Regimen 
A will have completed all prescribed protocol therapy. See Sections 7.1.3 
for observations due at End of Therapy and Section 7.3 for recommended 
observations during follow-up. 

 
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52 
 
AEWS1221 
Regimen A:  Consolidation Chemotherapy  
Consolidation chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycle 1 (Weeks 1 and 2) of Consolidation chemotherapy  
 
____________________________Patient ID 
 
______________________ 
DOB  
 
Begin Consolidation when ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). Myeloid growth factor support should be stopped a minimum of 24 hours 
prior to the administration of a chemotherapy cycle. If radiation is the primary local control measure or will be given pre-operatively then Consolidation chemotherapy should be 
initiated concurrently with the radiation therapy, i.e. both radiation and Cycle 1 Consolidation should start at the same time. DOXOrubicin may be administered concurrently with 
radiation therapy only at Week 1 of Consolidation chemotherapy. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
1 
$ Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg. See Section 
4.4.1.2. 
a. History and physical exam, height, weight, 
BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubin 
e. ECHO or MUGA (prior to DOXOrubicin)* 
f.  Unstained slides if surgical local control* 
g. Submission of percent tumor necrosis if 
surgical local control 
 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push  
(eg, over 5-15 min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt <1 yo 
1 and 2 
Administer immediately prior to DOXO. The 
combined infusion time for DXRZ + DOXO 
should be ≤ 30 min. See Section 4.4.1.2. 
DOXOrubicin 
(DOXO) 
IV push over  
1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt <1 yo 
1 and 2 
See Section 4.4.1.2.for details.  
Cyclophosphamide 
(CPM) 
IV over 30-60 mins 1200 mg/m2/dose OR 
40 mg/kg/dose for pt <1 yo 
1 
See Section 4.4.1.2. 
Mesna (MESNA) IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
1 
Administer with CPM, see Section 4.4.1.2. 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA_________m2 
 
 
%Enter total daily dose as mg/day by CI or intermittent infusion. 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
The therapy delivery map for Consolidation continues on the next page.  
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
________mg 
DXRZ 
________mg 
DOXO 
_______mg 
CPM 
_______mg 
MESNA (with CPM) 
__________________mg/day% 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
1 
_________mg 
_________mg 
_________mg 
________mg 
__________________mg/day% 
a – g 
 
 
 
 
2 
 
_________mg 
_________mg 
 
 
 
 
 
 
 
3-4# 
Growth factor used: _______________ Dose: ________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
2 
8 
 
 
 
 
 
b* 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
b* 
 
Page 1 of 5 

 
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53 
AEWS1221 
Regimen A:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycles 2 and 3 (Weeks 3 - 6) of Consolidation chemotherapy 
____________________________ 
Patient ID 
____________________________ 
DOB 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 2 and 
3 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next cycle.  
 
Cycle 2: Ht__________cm Wt__________kg  
BSA______m2  
 
 
Cycle 3: Ht__________cm     Wt__________kg 
BSA__________m2 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See 
Section 4.4.1.2.  
The therapy delivery map for Consolidation continues on the next page. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 
1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt  < 1 yo 
15–19 and 
29-33 
See Section 4.4.1.2. for 
details. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total bilirubin 
 
* See Section 7.1.2 for details. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD PATIENT 
CARE 
Mesna 
(MESNA) 
IV or IV/PO Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
15–19 and 
29-33 
Administer with IFOS, see 
Section 4.4.1.2. 
Etoposide 
(ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo 
15–19 and 
29-33 
Slow rate of administration 
if hypotension occurs. See 
Section 4.4.1.2. 
Date Due 
Date 
Given 
Week 
Day 
IFOS 
_________mg 
MESNA (with IFOS) 
__________________mg/day% 
ETOP 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
3 
15 
_________mg 
__________________mg/day% 
________mg 
a – d 
 
 
 
 
16 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
17 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
18 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
19 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
20-21# 
Growth factor used: ________________ Dose: ________    Date of first dose: ___________ 
 Date of last dose: ____________ 
 
 
4 
22 
 
 
 
b* 
 
 
 
5 
29 
_________mg 
__________________mg/day% 
________mg 
a – d 
 
 
 
 
30 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
31 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
32 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
33 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
34-35# 
Growth factor used: ________________ Dose: _________   Date of first dose: ___________  
Date of last dose: ____________ 
 
 
6 
36 
 
 
 
b* 
 
 
 
 
42 
 
 
 
b* 
 
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AEWS1221 
Regimen A:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycles 4 and 5 (Weeks 7-10) of Consolidation chemotherapy 
 
 ____________________________ 
Patient ID 
__________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 4 and 5 should be 
given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next cycle. 
 
Cycle 4: Ht__________cm Wt__________kg  
BSA______m2  
 
 
Cycle 5: Ht__________cm     Wt__________kg 
BSA__________m2 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
________mg 
DXRZ 
________mg 
DOXO 
_______mg 
CPM 
_________mg 
MESNA (with CPM) 
____________mg/day% 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
7 
43 
_________mg ________mg _______mg __________mg ____________mg/day% a - e 
 
 
 
 
44 
 
________mg ______mg 
 
 
 
 
 
 
 
45-46# 
 
Growth factor used: ________ Dose: _____ 
Date of first dose: ___________ Date of last dose: : __________ 
 
 
8 
50 
 
 
 
 
 
b* 
 
 
 
9 
57 
_________mg  
 
_____mg 
____________mg/day% a – d, f – i  
 
 
 
58-59# 
 
Growth factor used: ________ Dose: _____ 
Date of first dose: ___________ Date of last dose: : __________ 
 
 
10 
64 
 
 
 
 
 
b* 
 
 
 
 
70 
 
 
 
 
 
b* 
 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
# Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
43 and 57  
$ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.1.2. 
a. History and physical exam, height, weight, 
BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubin 
e. ECHO or MUGA (prior to Wk 7 
DOXOrubicin)* 
f. MRI or CT Scan of primary tumor, Chest CT, 
FDG PET scan (prior to Wk 9 chemotherapy). 
See Sections 7.1.2 & 16.0. 
g. Bilat. BMA and biopsies (prior to Wk 9 
therapy) if marrow still positive at last eval * 
h. Optional marrow aspirate submission* 
i. Optional sample in Streck* 
 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Dexrazoxane (DXRZ) 
Slow IV push  
(eg, over 5 15min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt <1 yo 
43 and 44 
Administer immediately prior to DOXO. The combined 
infusion time for DXRZ+ DOXO should be ≤ 30 min.  
See Section 4.4.1.2. 
DOXOrubicin (DOXO) 
IV push 
over 1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt <1 yo 
43 and 44 
See Section 4.4.1.2.for details. 
Cyclophosphamide 
(CPM) 
IV over 
30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 1 yo 
43 and 57 
See Section 4.4.1.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
43 and 57 
Administer with CPM, see Section 4.4.1.2. 
 
Page 3 of 5 

 
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AEWS1221 
Regimen A:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycles 6 and 7 (Weeks 11-14) of Consolidation chemotherapy. 
 
____________________________ 
Patient ID 
__________________ 
DOB  
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 6 and 7 should be 
given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt <1 yo 
71-75 See Section 4.4.1.2 for hydration guidelines. 
a. History and physical exam, height, weight, 
BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubin 
e. ECHO or MUGA * 
 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT CARE 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
71-75 Administer with IFOS, see Section 4.4.1.2 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt <1 yo 
71-75 Slow rate of administration if hypotension 
occurs. 
VinCRIStine (VCR) IV push over 1 min$ 2.mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
85 
$ Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg See Section 
4.4.1.2 
Cyclophosphamide 
(CPM) 
IV over 30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt <1 yo 
85 
See Section 4.4.1.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
85 
Administer with CPM, see Section 4.4.1.2 
 
Cycle 6: Ht __________cm Wt __________kg 
BSA______m2  
 
 
Cycle 7: Ht __________cm Wt __________kg 
BSA__________m2 
 
 
Date 
Due 
Date 
Given 
Week Day 
IFOS 
_______mg 
MESNA (with IFOS) 
__________mg/day% 
ETOP 
________mg 
VCR 
_______mg 
CPM 
_______mg 
MESNA (with CPM) 
__________mg/day% 
 
Studies Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
11 
71 
_______mg 
__________mg/day% ________mg 
 
 
 
a – e 
 
 
 
 
72 
_______mg 
__________mg/day% ________mg 
 
 
 
 
 
 
 
 
73 
_______mg 
__________mg/day% ________mg 
 
 
 
 
 
 
 
 
74 
_______mg 
__________mg/day% ________mg 
 
 
 
 
 
 
 
 
75 
_______mg 
__________mg/day% ________mg 
 
 
 
 
 
 
 
 
76-
77# 
 
Growth factor used: ______________ Dose: ______    Date of first dose: ___________ Date of last dose: ____________ 
 
 
12 
78 
 
 
 
 
 
 
b* 
 
 
 
13 
85 
 
 
 
_______mg 
_______mg __________mg/day% 
 
a – d 
 
 
 
 
86-
87# 
 
Growth factor used: ______________ Dose: ______    Date of first dose: ___________ Date of last dose: ____________ 
 
 
14 
92 
 
 
 
 
 
 
b* 
 
 
 
 
98 
 
 
 
 
 
 
b* 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
# Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Page 4 of 5 

 
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AEWS1221 
Regimen A:  Consolidation Chemotherapy 
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycle 8 (Weeks 15 and 16) of Consolidation chemotherapy. 
 
 ____________________________ 
Patient ID 
__________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to  ≥ 750/µL after nadir but then falls, Cycles 8 and 
9 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt <1 yo 
99-103 
See Section 4.4.1.2 for details. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total bilirubin 
e. ECHO or MUGA* 
f. MRI or CT of primary tumor, chest CT, FDG-PET 
scan (See Sections 7.1.2 & 16.0) 
g. Bilateral BMA and biopsies (end-Consolidation for 
all patients if positive at study entry)* 
h. Optional bone marrow aspirate submission* 
i. Unstained slides (if late surgical resection)* 
j. Pulmonary function test (if lung mets at study 
entry)* 
k. Optional sample in Streck* 
l. Required end Consolidation serum sample* 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
99-103 
Administer with IFOS, see Section 
4.4.1.2 
Etoposide (ETOP) 
IV over 1-2 
hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt <1 yo 
99-103 
Slow rate of administration if 
hypotension occurs. 
Cycle 8: Ht__________cm Wt__________kg  
BSA______m2 
 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
__________mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
_________mg 
Studies 
Comments 
(Include 
any 
held 
doses, or 
dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
15 
99 
__________mg 
______________mg/day% 
_________mg 
 
a – d 
 
 
 
 
100 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
101 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
102 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
103 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
104-105# 
Growth factor used: ______________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________  
 
 
16 
106 
 
 
 
b* 
 
 
 
 
112 
 
 
 
(a – l)‡ 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
# Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.1.2. 
‡ End of Consolidation/Pre-Metastatic Site Radiation  
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
Page 5 of 5 

 
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57 
 
4.4.2 
Administration Schedules for Induction and Consolidation in Regimen B 
 
NOTE: As of March 20, 2019, institutions were instructed to immediately 
discontinue ganitumab for patients on Regimen B. 
 
Prior to March 20, 2019: Patients in Regimen B received ganitumab in 
Induction, Consolidation, and Maintenance.   
 
The first 10 patients < 21 years of age at study entry randomized to Regimen B 
must submit required serum samples for measurement of ganitumab trough 
concentrations in Induction and Maintenance. Registering sites will be notified of 
the need to obtain these samples at the time of randomization. (Enrollment to this 
cohort completed as of July 2015; for patients previously assigned to this cohort, 
continue to collect samples as detailed in Section 15.5.)    
 
4.4.2.1 Administration Schedule: Induction (Weeks 1-12) Regimen B 
Criteria to start Induction: No count criteria are required to start Induction 
Week 1 therapy.  
 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count 
≥ 75,000/µL post nadir (without transfusion). The ANC often falls after 
discontinuing myeloid growth factor support. If the ANC has risen 
to ≥ 750/µL after the nadir but then falls the next cycle should be given 
despite ANC < 750/µL. To maintain dose intensity, administration of 
subsequent cycles of chemotherapy should not be delayed as along as the 
patient meets count recovery criteria, regardless of myeloid growth factor 
utilized. 
 
See Section 5.1 for exceptions in Weeks 1 and 3 for patients with bone 
marrow metastatic disease.  
 
If a cycle of chemotherapy is delayed due to toxicity, see Section 5.0 for 
criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age, chemotherapy should be 
calculated by weight rather than by surface area. Dose/kg = dose/m2 
divided by 30 kg/m2. Example: If patient is less than 1 year of age and 
weight is 15 kg and dose of Etoposide is 100 mg/m2, then the dose of 
Etoposide is based on mg/kg = 100 mg/m2 divided by 30 kg/m2 = 
3.3 mg/kg x15 kg = 49.5 mg.  
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day 1 of Weeks 1, 5 and 9 
Dose: 2 mg/m2/dose. (Maximum dose is 2 mg.) For patients < 1 year old, 
the dose is 0.067 mg/kg/dose. 
 
Special precautions: FOR INTRAVENOUS USE ONLY. The container 
or the syringe containing vinCRIStine must be enclosed in an overwrap 

 
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58 
bearing the statement “Do not remove covering until moment of injection. 
Fatal if given by other routes. For intravenous use only.” 
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. 
 
Dexrazoxane: Slow IV Push (eg, over 5-15 minutes) given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1, 5 and 9 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of 
DOXOrubicin). For patients < 1 year old, the dose is 12.5 mg/kg/dose. 
Note: Administer DOXOrubicin after completing the infusion of 
dexrazoxane and every effort should be made to keep the total combined 
infusion time for dexrazoxane and doxorubicin to ≤ 30 minutes. 
 
DOXOrubicin: IV push/infusion over 1-15 minutes.  
Days: 1 and 2 of Weeks 1, 5 and 9 
Dose: 37.5 mg/m2/dose. For patients < 1 year old, the dose is 
1.25 mg/kg/dose. 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing 
solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion 
between DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in 
a liposomal formulation. Use conventional DOXOrubicin only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
Cyclophosphamide: IV over 30-60 minutes 
Day 1 of Weeks 1, 5 and 9 
Dose: 1,200 mg/m2/dose. For patients < 1 year old, the dose is 
40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 
0.9% NaCl only to avoid hypotonic solution) or further diluted.  
 
Mesna must be administered in conjunction with cyclophosphamide 
(see below). Hydrate per institutional guidelines or according to 
recommendations below.   
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days: 1-5 of Weeks 3, 7 and 11 
Dose: 1,800 mg/m2/dose. For patients < 1 year old, the dose is 
60 mg/kg/dose. 
 
Mesna must be administered in conjunction with ifosfamide (see below).  
Hydrate per institutional guidelines or according to recommendations 
below.  
 

 
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59 
Suggested hydration for cyclophosphamide/ifosfamide: Administer 
3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start 
of cyclophosphamide/ifosfamide. May use diuretics (eg, furosemide) to 
increase urine output. Consider adding potassium and magnesium to 
prevent electrolyte deficiencies.  
 
Mesna with Cyclophosphamide 
Administer MESNA by IV infusion or IV/PO on Day 1 of Weeks 1, 5 and 
9. 
Total IV Dose: 720 mg/m2/day. For patients < 1 year old, the IV dose is 
24 mg/kg/day. 
 
Mesna with Ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-5 of Weeks 3, 7 
and 11. 
Total IV Dose: 1,080 mg/m2/day. For patients < 1 year old, the IV dose 
is 36 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal 
to 60% of the daily ifosfamide/cyclophosphamide dose. Mesna can be 
administered in 3 divided doses by short 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 ifosfamide/cyclophosphamide dose; subsequent 
doses 
are 
given 
4 
and 
8 hours 
after 
the 
start 
of 
ifosfamide/cyclophosphamide).  
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; 200 mg of mesna will be given 
15 minutes before or at the start of the cyclophosphamide/ifosfamide dose 
(Hour 0) and 2 boluses of 200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous 
infusion (CI). The continuous infusion should be started 15-30 minutes 
before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide 
infusion.   
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; the 600 mg mesna continuous 
infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours 
after the end of the ifosfamide/cyclophosphamide infusion. If 
ifosfamide/cyclophosphamide is administered over 1 hour and mesna is 
started 30 minutes before the cyclophosphamide/ifosfamide infusion, the 
total mesna infusion will last at least 9 hours and 30 minutes. 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral 
mesna may receive the last TWO bolus doses (originally at Hours 4 and 

 
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60 
8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral doses 
will be administered at Hours 2 and 6. 
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
200 mg of mesna will be given IV 15 minutes before or with the 
cyclophosphamide/ifosfamide dose (Hour 0) and the TWO oral doses of 
400 mg each will be given at Hours 2 and 6. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, 
dilute mesna parental solution before oral administration. The solution can 
be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, 
apple, tomato and orange) or plain or chocolate milk. The most palatable 
is chilled grape juice. Tablets are 400 mg and can be divided into 
200 mg/0.5 tabs so dosing can be rounded up to nearest 200 mg. 
Administer doses on a schedule as determined by timing of 
cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to 
the original dosing schedule. Do not deviate from the original schedule. 
Notify provider if a dose is delayed or missed. If the patient vomits within 
2 hours following an oral dose, repeat the oral dose or administer an IV 
dose of mesna. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days: 1-5 of Weeks 3, 7 and 11 
Dose: 100 mg/m2/dose. For patients < 1 year old, the dose is 
3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of 
administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested for prolonged infusion due to risk of precipitation. 
 
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. 
 
Growth Factor Support 
Begin myeloid growth factor support (filgrastim or pegfilgrastim or 
biosimilar products according to institutional standards for patients 
receiving interval compressed chemotherapy) at least 24-36 hours after the 
last dose of chemotherapy. If given daily then continue a minimum of 
7 days and until ANC ≥ 750/µL post nadir and discontinue at least 
24 hours prior to next cycle of chemotherapy.  
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Induction in Regimen B are provided in the 
following 3 pages. Local Control will follow Induction (see Section 4.3 
for details). See Section 7.1.1 for observations prior to Local Control.  
 

 
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61 
Details of Consolidation chemotherapy in Regimen B are provided in 
Section 4.4.2.2. 
 

 
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Regimen B:  Induction (Weeks 1-12) 
Induction consists of 6 two-week cycles (84 days in total). The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 1 and 2 (Weeks 1-4)  
 
_______________________                             _______________________ 
Patient ID                                                           DOB 
 
No count criteria are required to start Induction Week 1 therapy. Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If the ANC has risen 
to ≥ 750/µL after the nadir but then falls the next cycle should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the 
next chemotherapy cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) IV push over 1 min$ 
2 mg/m2/dose OR  
0.067 mg/kg/dose for pt < 1 yo 
1 
$ Or infusion via minibag as per institutional policy.  
Maximum dose: 2 mg. See Section 4.4.1.1. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total bilirubin,  
e. Albumin, EKG, Urine pregnancy test* 
f. ECHO* or MUGA* 
g. Plain film primary tumor (bone tumors only) 
h. MRI or CT of primary tumor, Chest CT, FDG-PET 
scan. (See Sections 7.1.1 & 16.0) 
i. MRI or CT and FDG-PET submission* 
j. Required BMA aspirates and biopsies 
k. Unstained slides* 
l.  Required baseline blood samples* 
m.Optional BMA submission* 
n. PK blood sample (ONLY for 1st 10 patients < 21 yo; 
see Section 15.5) 
o. Optional Sample in Streck* 
 
*See Section 7.1.1    
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push over  
5-15 mins‡ 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 1 yo 
1 and 2 
‡ Given immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO should 
be ≤ 30 min. See Section 4.4.2.1. 
DOXOrubicin 
(DOXO) 
IV push/infusion over  
1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 1 yo 
1 and 2 
See Section 4.4.2.1 for details. 
Cyclophosphamide 
(CPM) 
IV over  
30-60 mins  
1200 mg/m2/dose OR  
40 mg/kg/dose for pt < 1 yo 
1 
See Section 4.4.2.1 for details. 
Mesna (MESNA)  
IV or IV/PO 
Total IV dose: 720 mg/m2/day 
OR 
24 mg/kg/day for pt < 1 yo 
1 
Administer with CPM, see Section 4.4.2.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for < 1 yo  
15 - 19 
See Section 4.4.2.1 for details. 
Mesna (MESNA)  
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day 
OR 36 mg/kg/day for pt < 1 yo 
15 - 19 
Administer with IFOS, see Section 4.4.2.1 
Etoposide (ETOP) 
IV over  
1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo  
15 - 19 
Slow rate of administration if hypotension occurs. 
See Section 4.4.2.1 for details. 
 
 
 
 
 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA__________m2  
 
Cycle 2: Ht__________cm Wt__________kg BSA__________m2 
 
Date 
Due 
Date 
Given 
Week Day 
VCR 
____mg 
DXRZ  
____mg 
DOXO 
____mg 
CPM 
____mg 
MESNA (with CPM) 
________mg/day% 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
ETOP  
_____mg 
 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
1 
____mg _____mg ____mg ____mg ________mg/day% 
 
 
 
 
a – o 
 
 
 
 
2 
 
_____mg ____mg  
 
 
 
 
 
 
 
 
 
 
3-4# 
 
Growth factor used: _______________ Dose: ___________ Date of first dose: ___________  
Date of last dose: __________ 
 
 
2 
8 
 
 
 
 
 
 
 
 
 
b* 
 
 
 
3 
15 
 
 
 
 
 
_____mg 
_________mg/day% _____mg 
 
a - d, n, o 
 
 
 
 
16 
 
 
 
 
 
_____mg 
_________mg/day% _____mg 
 
 
 
 
 
 
17 
 
 
 
 
 
_____mg 
_________mg/day% _____mg 
 
 
 
 
 
 
18 
 
 
 
 
 
_____mg 
_________mg/day% _____mg 
 
 
 
 
 
 
19 
 
 
 
 
 
_____mg 
_________mg/day% _____mg 
 
 
 
 
 
 
20-21#  
Growth factor used: ________________ Dose: ___________ 
Date of first dose: ___________  
Date of last dose: __________ 
 
 
4 
22 
 
 
 
 
 
 
 
 
 
b* 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
b* 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.1. 
The therapy delivery map for Induction continues on the next 2 pages. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
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Regimen B:  Induction Continued 
Induction consists of 6 two-week cycles (84 days in total). The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 3 and 4 (Weeks 5-8) 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 3 and 4 should be given despite 
ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt < 1 yo 
29 
$ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg. See Section 4.4.2.1. 
a. History and physical exam, height, 
weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), 
Total bilirubin,  
e. Required BMA and biopsies if marrow 
involved at baseline* 
f. Optional bone marrow aspirate 
submission* 
g. Required serum sample*  
h. PK blood sample (ONLY for 1st 10 
patients < 21 yo; see Section 15.5) 
i. Optional sample in Streck* 
 
 
* See Section 7.1.1 for details. 
 
OBTAIN 
OTHER 
STUDIES 
AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push over  
5-15 mins‡ 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 1 yo 
29 and 30 
‡ Given immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO should 
be ≤ 30 min. See Section 4.4.2.1. 
DOXOrubicin 
(DOXO) 
IV push/infusion 
over 1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 1 yo  
29 and 30 
See Section 4.4.2.1 for details. 
Cyclophosphamide 
(CPM)  
IV over 30-60 mins  1200 mg/m2/dose OR  
40 mg/kg/dose for pt < 1 yo 
29 
See Section 4.4.2.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
29 
Administer with CPM, see Section 4.4.2.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt or < 1 yo 
43-47 
See Section 4.4.2.1 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
43-47 
Administer with IFOS, see Section 4.4.2.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo 
43-47 
Slow rate of administration if hypotension occurs. See 
Section 4.4.2.1 for details. 
 
 
 
 
 
 
 
Cycle 3: Ht__________cm Wt__________kg  
BSA__________m2  
 
 
Cycle 4: Ht__________cm Wt__________kg  
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week Day 
VCR 
____mg 
DXRZ  
____mg 
DOXO 
____mg 
CPM 
_____mg 
MESNA (with CPM) 
__________mg/day% 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
ETOP 
_____mg 
 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
5 
29 
____mg ____mg ____mg _____mg _________mg/day%  
 
 
 
a – d, g, h, i  
 
 
 
30 
 
____mg ____mg  
 
 
 
 
 
 
 
 
 
 
31-32#  
Growth factor used: __________________ Dose: ________ Date of first dose: ___________ Date of last dose: ____________ 
 
 
6 
36 
 
 
 
 
 
 
 
 
 
b* 
 
 
 
7 
43 
 
 
 
 
 
_____mg ________mg/day% 
_____mg  
a – f 
 
 
 
 
44 
 
 
 
 
 
_____mg ________mg/day% 
_____mg  
 
 
 
 
 
45 
 
 
 
 
 
_____mg ________mg/day% 
_____mg  
 
 
 
 
 
46 
 
 
 
 
 
_____mg ________mg/day% 
_____mg  
 
 
 
 
 
47 
 
 
 
 
 
_____mg ________mg/day% 
_____mg  
 
 
 
 
 
48-49#  
Growth factor used: ___________________ Dose: _________    Date of first dose: ___________ Date of last dose: ____________  
 
 
8 
50 
 
 
 
 
 
 
 
 
 
b* 
 
 
 
 
56 
 
 
 
 
 
 
 
 
 
b* 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.1. 
 
The therapy delivery map for Induction continues on the next page. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
 
 
Page 2 of 3 

 
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Regimen B:  Induction Continued 
Induction consists of 6 two-week cycles (84 days in total). 
The therapy delivery map presents Induction therapy on 3 pages. 
This therapy delivery map relates to Cycles 5 and 6 (Weeks 9-12) 
 
____________________________ 
Patient ID 
____________________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after the nadir but then falls, Cycle 5 and 6 should be given despite ANC < 750/µL. 
Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next chemotherapy cycle. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
57 
$ Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg. See Section 4.4.2.1 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++,  
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubin 
e. ECHO/MUGA (prior to Week 9 chemotherapy). 
f. MRI or CT of primary tumor, chest CT, FDG-
PET scan. (See Sections 7.1.1 & 16.0) 
g. MRI or CT and FDG-PET submission* 
h. Required BMA and biopsies if marrow still 
positive at last eval * 
i. Optional BMA submission* 
j. PK blood sample (ONLY for 1st 10 patients    
< 21 yo; see Section 15.5) 
k. Optional sample in Streck* 
 
*See Section 7.1.1 for details. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push over  
5-15 mins‡ 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt < 1 yo 
57 and 58 ‡ Given immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + 
DOXO should be ≤ 30 min. See Section 4.4.2.1. 
DOXOrubicin 
(DOXO) 
IV push/infusion 
over 1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt < 1 yo 
57 and 58 
See Section 4.4.2.1for details. 
Cyclophosphamide 
(CPM)  
IV over 30-60 mins  1200 mg/m2/dose OR 
 40 mg/kg/dose for pt < 1 yo  
57 
See Section 4.4.2.1for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
57 
Administer with CPM, see Section 4.4.2.1 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt < 1 yo  
71-75 
See Section 4.4.2.1for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR  
36 mg/kg/day for pt < 1 yo 
71-75 
Administer with IFOS, see Section 4.4.2.1 
Etoposide (ETOP) 
IV over 1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo 
71-75 
Slow rate of administration if hypotension occurs. 
See Section 4.4.2.1 for details. 
 
 
 
 
 
 
 
Cycle 5: Ht __________cm Wt __________kg 
BSA__________m2  
 
 
Cycle 6: Ht __________cm Wt __________kg 
BSA__________m2 
Date 
Due 
Date 
Given 
Week Day 
VCR 
_____mg 
DXRZ  
____mg 
DOXO 
____mg 
CPM 
____mg 
MESNA (with CPM)  
________mg/day% 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
ETOP 
_____mg 
 
Studies 
Comments (Include any held 
doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
9 
57 
_____mg _____mg ____mg ____mg ________mg/day%  
 
 
 
a - e 
 
 
 
 
58 
 
_____mg ____mg  
 
 
 
 
 
 
 
 
 
 
59-60#  
Growth factor used: ______________ Dose: _________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
 
 
 
 
 
 
 
 
 
b* 
 
 
 
11 
71 
 
 
 
 
 
_____mg _________mg/day% _____mg  
a – d, j  
 
 
 
 
72 
 
 
 
 
 
_____mg _________mg/day% _____mg  
 
 
 
 
 
73 
 
 
 
 
 
_____mg _________mg/day% _____mg  
 
 
 
 
 
74 
 
 
 
 
 
_____mg _________mg/day% _____mg  
 
 
 
 
 
75 
 
 
 
 
 
_____mg _________mg/day% _____mg  
 
 
 
 
 
76-77#  
Growth factor used: _____________  Dose: _________    Date of first dose: ___________ Date of last dose: ____________  
 
 
12 
78 
 
 
 
 
 
 
 
 
 
b* 
 
 
 
 
84 
Local Control will follow Induction therapy. See Section 4.3 for Local Control options. See Section 7.1 for observations 
prior to Local Control. 
a, b, f – i, k 
 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
 
#Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.1  
SEE SECTION 5.0 FOR DOSE MODIFICATIONS FOR TOXICITIES AND THE COG MEMBER WEBSITE FOR SUPPORTIVE CARE GUIDELINE
Page 3 of 3 

 
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4.4.2.2 Administration Schedule:  Consolidation Therapy (Weeks 1-16) 
Regimen B 
Ensure adequate time for healing following surgical local control. 
Consolidation will not begin until 2 weeks post-operatively. For patients 
receiving radiation therapy for local control, radiation therapy should 
begin concomitantly with Week 1 of Consolidation therapy. 
DOXOrubicin may be administered concurrently with radiation therapy 
only at Week 1 of Consolidation chemotherapy.  
 
See Section 4.1.1.2 for modifying order of Consolidation for patients who 
receive early whole lung radiation due to overlapping radiation fields with 
the primary tumor. 
 
Criteria to start Consolidation: ANC ≥ 750/µL and platelet ≥ 75,000/µL 
post nadir (without transfusion). The ANC often falls after discontinuing 
myeloid growth factor support. If the ANC has risen to ≥ 750/µL after the 
nadir but then falls the next cycle should be given despite ANC < 750/µL. 
To maintain dose intensity, administration of subsequent cycles of 
chemotherapy should not be delayed as along as the patient meets count 
recovery criteria, regardless of myeloid growth factor utilized. 
 
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count 
≥ 75,000/µL post nadir (without transfusion). The ANC often falls after 
discontinuing myeloid growth factor support. If the ANC has risen to 
≥ 750/µL after the nadir but then falls the next cycle should be given 
despite ANC < 750/µL. To maintain dose intensity, administration of 
subsequent cycles of chemotherapy should not be delayed as along as 
patient meets count recovery criteria, regardless of myeloid growth factor 
utilized.   
 
If a cycle of chemotherapy is delayed due to toxicity, see Section 5.0 for 
criteria to resume chemotherapy. 
 
Note: for children less than 1 year of age chemotherapy should be 
calculated by weight rather than by surface area. Dose/kg = dose/m2 
divided by 30 kg/m2. Example: If patient is less than 1 year of age and 
weight is 15 kg and dose of Etoposide is 100mg/m2, then the dose of 
Etoposide is based on mg/kg = 100mg/m2 divided  by 30 kg/m2 = 
3.3 mg/kg x15 kg = 49.5 mg. 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per 
institutional policy 
Day 1 of Weeks 1, 7, 9 and 13 
Dose: 2 mg/m2/dose (Maximum dose is 2 mg). For patients < 1 year old, 
the dose is 0.067 mg/kg/dose. 
 
Special precautions: FOR INTRAVENOUS USE ONLY. The container 
or the syringe containing vinCRIStine must be enclosed in an overwrap 

 
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bearing the statement “Do not remove covering until moment of injection. 
Fatal if given by other routes. For intravenous use only.” 
 
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. 
 
Dexrazoxane: Slow IV Push (eg, over 5-15 minutes) given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1 and 7 
 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of 
DOXOrubicin). For patients < 1 year old, the dose is 12.5 mg/kg/dose. 
Note: Administer DOXOrubicin after completing the infusion of 
dexrazoxane and every effort should be made to keep the total combined 
infusion time for dexrazoxane and doxorubicin to ≤ 30 minutes.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes  
Days: 1 and 2 of Weeks 1 and 7 
Dose: 37.5 mg/m2/dose. For patients < 1 year old, the dose is 
1.25 mg/kg/dose. 
 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing 
solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion 
between DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in 
a liposomal formulation. Use conventional DOXOrubicin only; the 
conventional and liposomal formulations are NOT interchangeable. 
 
Cyclophosphamide: IV over 30-60 minutes 
Day 1 of Weeks 1, 7, 9 and 13 
Dose: 1,200 mg/m2/dose. For patients < 1 year old, the dose is 
40 mg/kg/dose. 
May be administered as undiluted drug (20 mg/mL, reconstitute with 
0.9% NaCl only to avoid hypotonic solution) or further diluted.  
 
Mesna must be administered in conjunction with Cyclophosphamide (see 
below). Hydrate per 
institutional guidelines or according to 
recommendations below.   
 
Ifosfamide: IV, infuse the diluted solution over 1 hour 
Days 1-5 of Weeks 3, 5, 11 and 15 
Dose: 1,800 mg/m2/dose. For patients < 1 year old, the dose is 
60 mg/kg/dose. 
Mesna must be administered in conjunction with IFOS (see below). 
Hydrate per institutional guidelines or according to recommendations 
below.   

 
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Suggested hydration for cyclophosphamide/ifosfamide: Administer 
3,000 mL/m²/day (125 mL/m²/hour) using fluid containing D5W/0.45% 
NaCl or 0.9% NaCl. Achieve urine specific gravity ≤ 1.010 prior to start 
of cyclophosphamide/ifosfamide. May use diuretics (eg, furosemide) to 
increase urine output. Consider adding potassium and magnesium to 
prevent electrolyte deficiencies.  
 
Mesna with cyclophosphamide 
Administer MESNA by IV infusion or IV/PO on Day 1 of Weeks 1, 7, 9 
and 13 
Total IV Dose: 720 mg/m2/day. For patients < 1 year old, the IV dose is 
24 mg/kg/day. 
 
 
Mesna with ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-5 of Weeks 3, 5, 
11 and 15 
Total IV Dose: 1,080 mg/m2/day. For patients < 1 year old, the IV dose 
is 36 mg/kg/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal 
to 60% of the daily ifosfamide/cyclophosphamide dose. Mesna can be 
administered in 3 divided doses by short 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 ifosfamide/cyclophosphamide dose; subsequent 
doses 
are 
given 
4 
and 
8 hours 
after 
the 
start 
of 
ifosfamide/cyclophosphamide).  
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; 200 mg of mesna will be given 
15 minutes before or at the start of the cyclophosphamide/ifosfamide dose 
(Hour 0) and 2 boluses of 200 mg each will be given at Hours 4 and 8. 
 
This total daily dose of mesna can also be administered as IV continuous 
infusion (CI). The continuous infusion should be started 15-30 minutes 
before or at the same time as ifosfamide/cyclophosphamide and finished 
no sooner than 8 hours after the end of the ifosfamide/cyclophosphamide 
infusion.   
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
the total daily mesna dose is 600 mg; the 600 mg mesna continuous 
infusion will start 15-30 minutes before or at the same time as the 
ifosfamide/cyclophosphamide and be completed no sooner than 8 hours 
after the end of the ifosfamide/cyclophosphamide infusion. If 
ifosfamide/cyclophosphamide is administered over 1 hour and mesna is 
started 30 minutes before the cyclophosphamide/ifosfamide infusion, the 
total mesna infusion will last at least 9 hours and 30 minutes. 
 

 
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Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral 
mesna may receive the last TWO bolus doses (originally at Hours 4 and 
8) orally at 40% of the ifosfamide/cyclophosphamide dose. The oral doses 
will be administered at Hours 2 and 6. 
 
For example: if the cyclophosphamide/ifosfamide dose is 1,000 mg, then 
200 mg of mesna will be given IV 15 minutes before or with the 
cyclophosphamide/ifosfamide dose (Hour 0) and the TWO oral doses of 
400 mg each will be given at Hours 2 and 6. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, 
dilute mesna parental solution before oral administration. The solution can 
be diluted 1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, 
apple, tomato and orange) or plain or chocolate milk. The most palatable 
is chilled grape juice. Tablets are 400 mg and can be divided into 
200 mg/0.5 tabs so dosing can be rounded up to nearest 200 mg. 
Administer doses on a schedule as determined by timing of 
cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to 
the original dosing schedule. Do not deviate from the original schedule. 
Notify provider if a dose is delayed or missed. If the patient vomits within 
2 hours following an oral dose, repeat the oral dose or administer an IV 
dose of mesna. 
 
Etoposide: IV, infuse the diluted solution over at least 1-2 hours 
Days 1-5 of Weeks 3, 5, 11 and 15 
Dose: 100 mg/m2/dose. For patients < 1 year old, the dose is 
3.3 mg/kg/dose. 
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of 
administration if hypotension occurs. The use of an in-line filter during the 
infusion is suggested for prolonged infusion due to risk of precipitation. 
 
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. 
 
Growth Factor Support 
Begin myeloid growth factor support (filgrastim or pegfilgrastim or 
biosimilar products according to institutional standards for patients 
receiving interval compressed chemotherapy) at least 24-36 hours after the 
last dose of chemotherapy. If given daily then continue a minimum of 7 
days and until ANC ≥ 750/µL post nadir and discontinue at least 24 hours 
prior to next cycle of chemotherapy.  
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 

 
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The therapy delivery maps for Consolidation in Regimen B are provided 
on the following 5 pages. See Section 7.1.2 for observations required 
during Consolidation. 
 
Following recovery from Consolidation chemotherapy and no earlier than 
3 weeks from start of Week 15 of Consolidation, patients proceed to 
Metastatic Site Radiation (see Section 17.0). No systemic therapy is given 
during Metastatic Site Radiation.  
 
4.4.2.3 End of Therapy for Patients on Regimen B 
Following completion of Metastatic Site Radiation, patients on Regimen 
B will have completed all prescribed protocol therapy. See Sections 7.1.3 
for observations due at End of Therapy and Section 7.3 for recommended 
observations during follow-up. 
 
 

 
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Regimen B:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycle 1 (Weeks 1 and 2) of Consolidation chemotherapy  
 
____________________________Patient ID 
 
______________________ 
DOB  
 
Begin Consolidation when ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). Myeloid growth factor support should be stopped a 
minimum of 24 hours prior to the administration of a chemotherapy cycle. If radiation is the primary local control measure or will be given pre-operatively then 
Consolidation chemotherapy should be initiated concurrently with the radiation therapy, i.e. both radiation and Cycle 1 Consolidation should start at the same 
time. DOXOrubicin may be administered concurrently with radiation therapy only at Week 1 of Consolidation chemotherapy. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine 
(VCR) 
IV push over 1 min$ 2 mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
1 
$ Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg.  
See Section 4.4.2.2. 
a. History and physical exam height, weight, 
BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubin 
e. ECHO or MUGA (prior to DOXOrubicin)* 
f. Unstained slides if surgical local control* 
g. Submission of percent tumor necrosis if 
surgical local control 
 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Dexrazoxane 
(DXRZ) 
Slow IV push  
(eg, over 5-15 min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt <1 yo 
1 and 2 
Administer immediately prior to DOXO. The 
combined infusion time for DXRZ + DOXO 
should be ≤ 30 min. See Section 4.4.2.2. 
DOXOrubicin 
(DOXO) 
IV push over  
1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt <1 yo 
1 and 2 
See Section 4.4.2.2.for details.  
Cyclophosphamide 
(CPM) 
IV over 30-60 mins 1200 mg/m2/dose OR 
40 mg/kg/dose for pt <1 yo 
1 
See Section 4.4.2.2. 
Mesna (MESNA) IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
1 
Administer with CPM, see Section 4.4.2.2. 
 
Cycle 1: Ht__________cm Wt__________kg  
BSA_________m2 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. # Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 
4.4.2.2. 
The therapy delivery map for Consolidation continues on the next page.  
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
Date Due 
Date 
Given 
Week 
Day 
VCR 
________mg 
DXRZ 
 
________mg 
DOXO 
 
_____mg 
CPM 
 
_______mg 
MESNA (with CPM) 
 
__________mg/day% 
Studies 
Comments (Include any held doses, 
or dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
1 
1 
_________mg 
_________mg 
_________mg 
__________mg 
___________mg/day% 
a – g 
 
 
 
 
2 
 
_________mg 
_________mg 
 
 
 
 
 
 
 
3-4# 
Growth factor used: _______________ Dose: ________    Date of first dose: ___________ Date of last dose: ____________ 
 
 
2 
8 
 
 
 
 
 
b* 
 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
b* 
 
Page 1 of 5 

 
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AEWS1221 
Regimen B:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycles 2 and 3 (Weeks 3 - 6) of Consolidation chemotherapy 
____________________________ 
Patient ID 
____________________________ 
DOB 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 2 
and 3 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next cycle.  
 
Cycle 2: Ht__________cm Wt__________kg BSA______m2  
Cycle 3: Ht__________cm Wt__________kg BSA__________m2 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. # Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2.  
The therapy delivery map for Consolidation continues on the next page. 
 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 
1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt  < 1 yo 
15–19 and 
29-33 
See Section 4.4.2.2. for 
details. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total bilirubin 
 
* See Section 7.1.2 for details. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD PATIENT CARE 
Mesna 
(MESNA) 
IV or IV/PO Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
15–19 and 
29-33 
Administer with IFOS, see 
Section 4.4.2.2. 
Etoposide 
(ETOP) 
IV over  
1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt < 1 yo 
15–19 and 
29-33 
Slow rate of administration 
if hypotension occurs. See 
Section 4.4.2.2. 
Date Due 
Date 
Given 
Week 
Day 
IFOS 
_________mg 
MESNA (with IFOS) 
__________________mg/day% 
ETOP 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
3 
15 
_________mg 
__________________mg/day% 
________mg 
a – d 
 
 
 
 
16 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
17 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
18 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
19 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
20-21# 
Growth factor used: ________________ Dose: ________    Date of first dose: ___________ 
 Date of last dose: ____________ 
 
 
4 
22 
 
 
 
b* 
 
 
 
5 
29 
_________mg 
__________________mg/day% 
________mg 
a – d 
 
 
 
 
30 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
31 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
32 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
33 
_________mg 
__________________mg/day% 
________mg 
 
 
 
 
 
34-35# 
Growth factor used: ________________ Dose: _________   Date of first dose: ___________  
Date of last dose: ____________ 
 
 
6 
36 
 
 
 
b* 
 
 
 
 
42 
 
 
 
b* 
 
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AEWS1221 
Regimen B:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). 
This Therapy Delivery Map is on 5 pages.  
This page relates to Cycles 4 and 5 (Weeks 7-10) of Consolidation chemotherapy 
 
 ____________________________ 
Patient ID 
__________________ 
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 4 and 
5 should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to the administration of the next cycle. 
Cycle 4: Ht__________cm Wt__________kg  
BSA______m2  
 
 
Cycle 5: Ht__________cm     Wt__________kg 
BSA__________m2 
 
Date 
Due 
Date 
Given 
Week 
Day 
VCR 
______mg 
DXRZ 
_______mg 
DOXO 
_______mg  
CPM 
_______mg 
MESNA (with CPM) 
__________mg/day% 
 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
7 
43 
_______mg ________mg _______mg _______mg _________mg/day% 
 
a - e 
 
 
 
 
44 
 
________mg _______mg  
 
 
 
 
 
 
 
45-46# 
 
Growth factor used: ________ Dose: _____ 
Date of first dose: ___________ Date of last dose: : __________ 
 
 
8 
50 
 
 
 
 
 
 
b* 
 
 
 
9 
57 
_______mg  
 
_______mg __________mg/day% 
 
a – d, f – h  
 
 
 
58-59# 
 
Growth factor used: ____________ Dose: _____   Date of first dose: ___________ Date of last dose: ____________ 
 
 
10 
64 
 
 
 
 
 
 
b* 
 
 
 
 
70 
 
 
 
 
 
 
b* 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
 
# Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See 
Section 4.4.2.2. The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
VinCRIStine (VCR) 
IV push over 1 min$ 
2 mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
43 and 57  
$ Or infusion via minibag as per institutional 
policy. Maximum dose: 2 mg. See Section 
4.4.2.2. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total 
bilirubinECHO or MUGA (prior to Wk 7 
DOXOrubicin)* 
e. MRI or CT Scan of primary tumor, Chest CT, FDG 
PET scan (prior to Wk 9 chemotherapy). See 
Sections 7.1.2 & 16.0. 
f. Bilat. BMA and biopsies (prior to Wk 9 therapy) if 
marrow still positive at last eval * 
g. Optional marrow aspirate submission* 
h. Optional sample in Streck* 
 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
Dexrazoxane (DXRZ) 
Slow IV push  
(eg, over 5 15min) 
375 mg/m2/dose OR 
12.5 mg/kg/dose for pt <1 yo 
43 and 44 
Administer immediately prior to DOXO. The 
combined infusion time for DXRZ+ DOXO 
should be ≤ 30 min.  
See Section 4.4.2.2. 
DOXOrubicin (DOXO) IV push 
over 1-15 mins 
37.5 mg/m2/dose OR 
1.25 mg/kg/dose for pt <1 yo 
43 and 44 
See Section 4.4.2.2.for details. 
Cyclophosphamide 
(CPM) 
IV over 
30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt < 1 yo 
43 and 57 
See Section 4.4.2.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day OR 
24 mg/kg/day for pt < 1 yo 
43 and 57 
Administer with CPM, see Section 4.4.2.2. 
 
 
 
 
 
 
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Regimen B:  Consolidation Chemotherapy  
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total).This Therapy Delivery Map is on 5 pages.  
This page relates to Cycles 6 and 7 (Weeks 11-14) of Consolidation chemotherapy. 
 
_______________________             _____________________ 
     Patient ID  
DOB  
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 6 and 7 
should be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt <1 yo 
71-75 
See Section 4.4.2.2 for hydration guidelines. 
a. History and physical exam, height, 
weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, 
Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), 
Total bilirubin 
e. ECHO or MUGA* 
 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day 
OR 36 mg/kg/day for pt < 1 yo 
71-75 
Administer with IFOS, see Section 4.4.2.2 
Etoposide (ETOP) IV over 1-2 hours 
100 mg/m2/dose OR  
3.3 mg/kg/dose for pt <1 yo 
71-75 
Slow rate of administration if hypotension occurs. 
VinCRIStine 
(VCR) 
IV push over 1 min$ 
2.mg/m2/dose OR 
0.067 mg/kg/dose for pt <1 yo 
85 
$ Or infusion via minibag as per institutional policy. 
Maximum dose: 2 mg See Section 4.4.2.2 
Cyclophosphamide 
(CPM) 
IV over 
 30-60 mins 
1200 mg/m2/dose OR 
40 mg/kg/dose for pt <1 yo 
85 
See Section 4.4.2.2 for details. 
Mesna (MESNA) 
IV or IV/PO 
Total IV dose: 720 mg/m2/day 
OR 24 mg/kg/day for pt < 1 yo 
85 
Administer with CPM, see Section 4.4.2.2 
 
 
 
 
 
 
Cycle 6: Ht __________cm Wt __________kg 
BSA______m2  
 
 
Cycle 7: Ht __________cm        Wt __________kg       BSA__________m2 
 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
_____mg 
MESNA (with IFOS) 
_______mg/day% 
ETOP 
____mg 
VCR 
_____mg 
CPM 
_____mg 
MESNA (with CPM) 
_______mg/day% 
 
Studies 
Comments (Include any held doses, or 
dose modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
11 
71 
_____mg _______mg/day% 
_____mg 
 
 
 
 
a – e 
 
 
 
 
72 
_____mg _______mg/day% 
_____mg 
 
 
 
 
 
 
 
 
 
73 
_____mg _______mg/day% 
_____mg 
 
 
 
 
 
 
 
 
 
74 
_____mg _______mg/day% 
_____mg 
 
 
 
 
 
 
 
 
 
75 
_____mg _______mg/day% 
_____mg 
 
 
 
 
 
 
 
 
 
76-77# 
 
Growth factor used: ______________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________ 
 
 
12 
78 
 
 
 
 
 
 
 
b* 
 
 
 
13 
85 
 
 
 
_____mg 
_____mg __________mg/day%  
a – d 
 
 
 
 
86-87# 
 
Growth factor used: ______________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________ 
 
 
14 
92 
 
 
 
 
 
 
 
b* 
 
 
 
 
98 
 
 
 
 
 
 
 
b* 
 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
# Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See 
Section 4.4.2.2.  
The therapy delivery map for Consolidation continues on the next page. 
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines. 
 
 
 
Page 4 of 5 

 
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Regimen B:  Consolidation Chemotherapy 
Consolidation Chemotherapy consists of 8 two-week cycles (112 days in total). This Therapy Delivery Map is on 5 
pages. This page relates to Cycle 8 (Weeks 15 and 16) of Consolidation chemotherapy. 
 
_______________________             _____________________ 
     Patient ID  
DOB 
 
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir (without transfusion). If ANC has risen to ≥ 750/µL after nadir but then falls, Cycles 8 and 9 should 
be given despite ANC < 750/µL. Myeloid growth factor support should be stopped a minimum of 24 hours prior to administration of the next cycle.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide (IFOS) 
IV over 1 hour 
1800 mg/m2/dose OR 
60 mg/kg/dose for pt <1 yo 
99-103 
See Section 4.4.2.2 for details. 
a. History and physical exam, height, weight, BSA 
b. CBC, differential, platelets* 
c. Electrolytes, including Ca++, PO4, Mg++ 
d. Urinalysis, Creatinine, SGPT (ALT), Total bilirubin 
e. ECHO or MUGA* 
f. MRI or CT of primary tumor, chest CT, FDG-PET scan (See 
Sections 7.1.2 & 16.0) 
g. Bilateral BMA and biopsies (end-Consolidation for all 
patients if positive at study entry)* 
h. Optional bone marrow aspirate submission* 
i. Unstained slides (if late surgical resection)* 
j. Pulmonary function test (if lung mets at study entry)* 
k. Optional sample in Streck* 
l. Required end Consolidation serum sample* 
* See Section 7.1.2 for details. 
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
Mesna (MESNA) 
IV or IV/PO 
Total IV Dose: 1,080 mg/m2/day OR 
36 mg/kg/day for pt < 1 yo 
99-103 
Administer with IFOS, see 
Section 4.4.2.2 
Etoposide (ETOP) 
IV over 1-
2 hours 
100 mg/m2/dose OR 
3.3 mg/kg/dose for pt <1 yo 
99-103 
Slow rate of administration if 
hypotension occurs. 
 
 
 
 
 
Cycle 8: Ht__________cm Wt__________kg  
BSA______m2 
 
 
Date 
Due 
Date 
Given 
Week 
Day 
IFOS 
__________mg 
MESNA (with IFOS) 
______________mg/day% 
ETOP 
_________mg 
 
Studies 
Comments 
(Include 
any 
held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
15 
99 
__________mg 
______________mg/day% 
_________mg 
 
a – d 
 
 
 
 
100 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
101 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
102 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
103 
__________mg 
______________mg/day% 
_________mg 
 
 
 
 
 
 
104-105# 
Growth factor used: ______________ Dose: _____    Date of first dose: ___________ Date of last dose: ____________  
 
 
16 
106 
 
 
 
 
b* 
 
 
 
 
112 
 
 
 
 
(a – l)‡ 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. # Begin myeloid growth factor support at least 24- 36 hours after the last dose of chemotherapy. See Section 4.4.2.2. 
‡ End of Consolidation/Pre-Metastatic Site Radiation  
See Section 5.0 for Dose Modifications for Toxicities and the COG Member website for Supportive Care Guidelines.  
Page 5 of 5 

 
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Slow Blood Count Recovery 
This section includes separate instructions for modifying myelosuppressive chemotherapy 
(Section 5.1.1), for modifying ganitumab during induction and consolidation 
(Section 5.1.2), and for modifying ganitumab during maintenance (Section 5.1.3) in the 
setting of slow blood count recovery.  
 
 
5.1.1 
Chemotherapy Dose Modifications for Slow Blood Count Recovery 
Recovery of absolute neutrophil count to > 750/µL, and platelet count to 
> 75,000/µL is required at the start of each myelosuppressive chemotherapy cycle. 
The ANC often falls after discontinuing myeloid growth factor support. If the ANC 
has risen to > 750/µL after the nadir but then falls the next cycle can be given 
despite ANC < 750/µL. If a cycle is delayed for more than 7 days, the next time 
the chemotherapy combination causing the delay is administered doses of 
myelosuppressive chemotherapy agents (doxorubicin/cyclophosphamide and 
ifosfamide/etoposide) should be reduced by 25%. Vincristine does not require dose 
modification for slow blood count recovery. 
 
For patients who have chemotherapy dose reduction, re-escalation in 
chemotherapy dose in 25% increments should be attempted if the next cycle with 
the chemotherapy combination causing the initial delay is administered at reduced 
dose and does not result in treatment delay.  
 
If the bone marrow is involved at diagnosis, the above guidelines for ANC and 
platelet counts do not apply during the first 2 cycles of chemotherapy. In patients 
who have bone marrow involvement at the time of initial diagnosis and in whom 
chemotherapy has been delayed for more than 14 days due to persistent 
neutropenia or thrombocytopenia, obtain a bone marrow aspirate and biopsy. If 
bone marrow shows persistent tumor, proceed with next scheduled cycle of 
chemotherapy regardless of counts. Repeat bone marrow aspirate after this cycle 
to rule out progressive marrow involvement. Also, if a patient had achieved a 
complete response in the bone marrow and presents with prolonged 
myelosuppression, early repeat bone marrow aspirate and biopsy should be 
considered. If marrow had previously cleared and then becomes positive, the 
patient is considered to have progressive disease and should be removed from 
protocol therapy. 
 
5.2 
Renal Toxicity 
5.2.1 
Ifosfamide  
Renal toxicity is the primary, long-term dose-limiting side effect of ifosfamide. 
Available information indicates that the renal injury produced by ifosfamide may 
be permanent, and in some cases progressive. Renal irradiation, young age 
(< 3 years of age), and absence of one kidney are risk factors for severe renal 
toxicity. The elements below define incomplete and significant Fanconi’s 
syndrome for the purposes of this study. In the event a patient appears to have 
evidence of Fanconi’s syndrome, the investigator may consider evaluation as 
detailed below and consider modifying therapy as detailed below. 
 

 
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Elements of Fanconi Syndrome include: 
1. Renal phosphorus wasting with hypophosphatemia. (serum phosphate 
< 2.5 mg/dL = 0.8 mmol/L). 
2. Renal bicarbonate wasting with acidosis (Bicarbonate < 16). 
3. Renal potassium wasting with hypokalemia (< 3.0 mEq/L). 
4. 1+ glycosuria with serum glucose < 150 mg/dL. 
5. Proteinuria: a ratio of urine protein: urine creatinine > 0.2 occurring in the 
absence of significant malnutrition and acidosis due to sepsis/infection.  
 
Incomplete Fanconi Syndrome, with only one or a few of these elements, is 
common. Over time, these abnormalities may resolve, remain static, or progress. 
 
For the purposes of this study, significant Fanconi Syndrome will be defined as: 
1. GFR is < 50 mL/min/1.73 m2, not due to other causes such as aminoglycoside 
toxicity, amphotericin B, etc., in the presence of mineral/electrolyte wasting, 
OR 
2. The GFR is any level, but there is significant evidence of persistent Renal 
Tubular Acidosis (RTA) as evidenced by serum bicarbonate less than 
16 mmol/L and serum phosphate ≤ 2 mg/dL (or < 0.6 mmol/L) without 
supplementation on measurements taken before the next ifosfamide cycle. 
 
Modify therapy for significant Fanconi syndrome as follows: 
Delete ifosfamide from all subsequent cycles and substitute cyclophosphamide 
440 mg/m2/day or 15 mg/kg/day for those < 1 year old with Mesna uroprotection 
(60% of the cyclophosphamide dose = 265 mg/m2/day or 9 mg/kg/day for those 
< 1 year old) for 5 days to be given together with 5 days of etoposide. This 
schedule of fractionated cyclophosphamide has previously been used in National 
Wilms Tumor Trial V, Regimen I. 
 
5.2.2 
Etoposide 
If Grade 2 or greater renal toxicity (creatinine > 1.5 X ULN) occurs, nephrotoxic 
agents should be discontinued, chemotherapy held and renal function tests repeated 
in one week. If toxicity persists a GFR or creatinine clearance should be obtained. 
The following initial dose modification should be considered based on measured 
creatinine clearance: for CrCl > 50 mL/min/1.73 m2 give full dose, for CrCl of 15-
50 mL/min/1.73m2 give 75% of the dose (a 25% dose reduction). Etoposide should 
be held if CrCl < 15 mL/min/1.73 m2. 
 
5.2.3 
Cyclophosphamide 
If Grade 2 or greater renal toxicity (creatinine >1.5 X ULN) occurs, nephrotoxic 
agents should be discontinued. Cyclophosphamide, since it is subject to renal 
clearance, should be held and renal function repeated in one week. If estimated 
creatinine clearance (eGFR) drops by ≥ 33% (1/3) from the eGFR at study baseline 
or if the eGFR drops into the abnormal range, cyclophosphamide will require dose 
modifications. Prior to dose adjustment the local investigator should confirm the 
subject was well-hydrated when renal chemistries were obtained and a validated 
24-hour creatinine clearance or a radionuclide GFR should be obtained.  
 
The following initial dose modification should be instituted:  
 
Renal function 
Cyclophosphamide dose 
If drop in eGFR < 33% AND CrCl > 40 mL/min/1.73m2 
Full dose 

 
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If drop in eGFR > 33% BUT CrCl > 40 mL/min/1.73m2 
90% dose 
If drop in eGFR > 33% BUT CrCl < 40 but > 10 mL/min/1.73m2 
50% dose 
If CrCL < 10 mL/min/1.73m² 
Withhold until toxicity resolves 
 
5.3 
Cardiac Toxicity 
Dexrazoxane will be used as a cardioprotecant prior to each dose of doxorubicin. 
 
5.3.1 
Monitoring 
An electrocardiogram and echocardiogram with determination of shortening 
fraction, or radionuclide angiogram for ejection fraction should be performed 
before treatment and then according to the schedule in Section 7.0. Use the same 
test each time for consistency in evaluation. 
 
5.3.2 
Management 
If prolongation of the QTc interval (> 0.48 sec), a decrease in the ejection fraction 
to < 50%, or a decrease in the left ventricular shortening fraction to < 27%, the 
doxorubicin-containing chemotherapy should be postponed 1 week, any existing 
electrolyte or micronutrient deficiencies corrected and the tests repeated. If the 
abnormalities persist during that 1 week delay or at any time patients have 
Grade ≥ 3 (symptomatic) left ventricular systolic dysfunction, doxorubicin should 
be 
PERMANENTLY 
DISCONTINUED. 
Substitute 
dactinomycin 
0.045 mg/kg/day (max dose 2.5 mg) for 1 day, IV slow push on Day 1 only of the 
VDC cycle. The chemotherapy cycle administered following dactinomycin-
contianing cycles should be administered after 21-days (and not 14 days) since 
interval compression is not possible when dactinomycin is administered (a 2-week 
interval may still be maintained following I/E cycles). No change in doxorubicin 
dosing is recommended for an asymptomatic decrease in cardiac ejection or 
shortening fraction provided they remain at or above 50% and 27% respectively. 
 
 
5.4 
Neurological Toxicity 
Neurological toxicity can result from two of the agents used in this study, vincristine and 
ifosfamide. 
 
5.4.1 
Vincristine Neuropathy 
Grade 1 and 2 neuropathy requires no dose modification. For Grades 3 and 4 
(interfering with activities of daily living) hold indefinitely until symptoms 
decrease to Grade 1 (present on exam/testing but not symptomatic) or less and 
resume at 50% dose. Increases to 75% and full dose should be considered at the 
start of each vincristine containing cycle based on patient’s symptoms.  
 
Anticipate autonomic neuropathy resulting in constipation. Laxatives and/or stool 
softeners should be used preemptively during vincristine containing cycles. If 
severe paralytic ileus occurs vincristine should be stopped until normal bowel 
movements are re-established and then resumed at 50% dose. Mild to moderate 
constipation (< 4 days) is not an indication for interrupting vincristine. 
 
 
5.4.2 
Ifosfamide Neurotoxicity 
This is an organic brain syndrome that ranges from mild confusion and 
disorientation to seizures, ataxia, and coma. It may be aggravated by impaired renal 
function. It usually, but does not always, resolve spontaneously, and it may or may 
not recur with subsequent doses. If symptoms are mild and transient cycle may 

 
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continue with strict avoidance of potentially aggravating co-administered 
medications such as sedatives and anticholinergic drugs. If Grade 4 neurotoxicity 
occurs 
during 
ifosfamide 
administration, investigators 
may 
consider 
administration of methylene blue.  
 
Patients who have experienced mild symptoms (≤ Grade 2) may receive ifosfamide 
in subsequent cycles. If patients with ≤ Grade 2 neurotoxicity are to be re-treated, 
the ifosfamide infusion may be prolonged at the investigator’s discretion. If 
neurotoxicity > Grade 2 occurs or symptoms are prolonged, delete ifosfamide from 
all subsequent cycles and substitute cyclophosphamide 440 mg/m2 per day with 
Mesna uroprotection (60% of the cyclophosphamide dose = 265 mg/m2/day or 
9 mg/kg/day for those < 1 year old) for 5 days, with 5 days of etoposide. This 
schedule of fractionated cyclophosphamide has previously been used in National 
Wilms Tumor Trial V, Regimen I. 
 
5.5 
Mucositis 
 
A few simple remedies for mucositis are available, and all should be pursued before doses 
are reduced. The incidence and severity of mucositis have been related to degree of pre-
existing mucosal disease and oral hygiene. Good mouth care, including use of mouth rinses 
should be considered. Medications include the following: 
 
Glutamine: Oral swish-and-swallow glutamine suspension at 2 gram/m2 swish-
and-swallow twice daily has been shown to reduce the severity and duration of 
mucositis associated with chemotherapy and radiotherapy in a randomized 
controlled trial.  
 
Sucralfate: Though its effectiveness is controversial, sucralfate suspension 
1 gram/10 mL (40-80 mg/kg/day, max 1 gram per dose) swish-and-swallow 
4 times daily may reduce the symptoms or severity of mucositis from 
chemotherapy and radiation therapy. 
 
Chemotherapy doses should not be reduced for mucositis unless all supportive care 
remedies outlined above have been exhausted. 
 
For Grade 3 or 4 mucositis (mouth or throat pain interfering with ability to hydrate or 
aliment adequately or diarrhea resulting in incontinence and interfering with daily 
activities) which persists more than 15 days after a vincristine-doxorubicin-
cyclophosphamide cycle, and is unresponsive to the measures described, decrease the 
doxorubicin dose by 25% in subsequent cycles. Do not decrease the doses of the other 
drugs.  
 
For Grade 3 or 4 mucositis which persists more than 15 days after an ifosfamide-etoposide 
cycle, reduce both the ifosfamide and etoposide doses by 25% in subsequent cycles. Re-
escalation should be attempted if mucosal toxicity > Grade 2 does not recur. 
 
5.6 
Hematuria or Hemorrhagic Cystitis 
5.6.1 
Microscopic Hematuria 
For treatment modifications, microscopic hematuria is a count defined as 
> 50 RBCs/HPF without visible blood in the urine. 
 

 
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For transient microscopic hematuria (no more than 2 abnormal urinalyses on 
2 separate 
days 
during a 
cycle 
of therapy), do 
not modify the 
cyclophosphamide/ifosfamide dose. Administer with increased hydration 
(3500-4000 mL/m2/day) using a total daily mesna dose equal to 60% of the daily 
cyclophosphamide/ifosfamide dose as a continuous infusion over at least 9 hrs. For 
example, if the full cyclophosphamide dose is 1200 mg, then administer at least 
720 mg of mesna by continuous infusion. 
 
For persistent microscopic hematuria (more than 2 abnormal urinalyses during a 
cycle of therapy), do not modify the cyclophosphamide/etoposide dose. 
Administer with increased hydration (3500-4000 mL/m2/day) using a total daily 
mesna dose equal to 100% of the daily cyclophosphamide/ifosfamide dose as a 
continuous infusion over at least 9 hrs. 
 
5.6.2 
Gross Hematuria 
Gross hematuria is defined as visible blood in the urine. 
 
All episodes of gross hematuria should be evaluated in conjunction with a pediatric 
surgical or urologic consult. Further testing, such as cystoscopy, urine culture, 
excretory urogram, and voiding cystogram should be considered based on good 
clinical judgment. 
 
For transient gross hematuria (only 1 episode, which clears to less than gross 
hematuria) 
during 
or 
following 
a 
cycle 
of 
therapy, 
hold 
cyclophosphamide/ifosfamide indefinitely until hematuria clears. When hematuria 
clears, restart at 50% of the previous cyclophosphamide/ifosfamide dose. 
Use hydration of 3500-4000 mL/m2/day and mesna at 100% of the 
cyclophosphamide/ifosfamide dose as a continuous infusion over 24 hrs/day. The 
cyclophosphamide/ifosfamide dose may be escalated back to 100% if tolerated. 
 
For persistent gross hematuria after completion of a cycle of therapy, hold 
subsequent cyclophosphamide/ifosfamide doses until the urine clears to less than 
gross hematuria. Reinstitute cyclophosphamide/ifosfamide at 50% of the initial 
dose, with hydration of 3500-4000 mL/m2/day and the mesna at 100% of the 
cyclophosphamide/ifosfamide dose given as a continuous infusion over 24 hours. 
If this regimen is tolerated, the cyclophosphamide/ifosfamide dose may be 
escalated back to the original dose (100%). For persistent or recurrent gross 
hematuria 
on 
the 
mesna 
continuous 
infusion 
regimen, 
discontinue 
cyclophosphamide/ifosfamide. 
 
5.7 
Hepatotoxicity 
Hepatotoxicity is not expected to occur frequently on this study and if observed, 
causes should be investigated. However, abnormal liver function may be 
associated with increased vincristine and doxorubicin toxicity. Dose adjustments 
for vincristine, doxorubicin and etoposide should be made based on the level of 
direct bilirubin. Vincristine doses omitted due to toxicity will not be replaced. 
 
 
 

 
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Hepatotoxicity 
Vincristine 
adjustment 
Doxorubicin 
adjustment 
Etoposide 
adjustment 
Grade 1  
(Direct bilirubin < 1.5 X ULN) 
 
Full Dose 
 
Full Dose 
 
Full Dose  
 
Grade 2 
(Direct bilirubin 1.5-3 X ULN) 
Delay 1 week. Full 
dose if resolved to 
Grade 1 or less. 
50% if still Grade 2. 
Delay 1 week. Full 
dose if resolved to 
Grade 1 or less.  
50% if still Grade 2. 
Delay 1 week. Full 
dose if resolved to 
Grade 1 or less.  
50% if still Grade 2. 
Grade 3, 4 
 
Delay 1 week and 
until resolved to 
Grade 1, then resume 
at full dose. 
Delay 1 week and 
until resolved to 
Grade 1, then resume 
at full dose.   
Delay 1 week and 
until resolved to 
Grade 1, then 
resume at full dose.  
 
5.7.1 
Sinusoidal Obstruction Syndrome (SOS, Formerly Known as Veno-occlusive 
Disease [VOD]) of the Liver (Hepatopathy) 
 
Treating physicians are advised to monitor closely for signs of SOS.   
 
Criteria for diagnosis of sinusoidal obstruction syndrome of the liver 
a. Pathologic confirmation by liver biopsy OR 
b. Reversal of portal venous flow by ultrasound OR 
c. Two or more of the following: 
• 
Serum Total Bilirubin > 2.0 mg/dL 
• 
Unexplained weight gain greater than 10% of baseline weight or ascites 
• 
Hepatomegaly or RUQ pain without other explanation 
 
SOS is graded as below. 
 
MILD 
MODERATE 
SEVERE 
Total Bilirubin 
< 6 mg/dL 
> 6 and < 20 mg/dL 
> 20 mg/dL 
Weight Gain 
< 5% of baseline of 
noncardiac origin 
> 5% of baseline of 
noncardiac origin 
 
Ascites 
None 
Clinical or radiologic 
documentation 
Compromising 
respiratory function 
Hepatic 
Dysfunction 
Reversible 
Reversible 
Hepatic 
encephalopathy 
 
For any SOS (mild, moderate, or severe), a CTEP-AERS report must be filed 
per Section 11.10 and 11.11. 
 
5.8 
Dermatologic Toxicity 
 
5.8.1 
Nails 
Patients receiving interval compressed chemotherapy may rarely slough their 
fingernails. This is painless and reversible, and no countermeasures are indicated. 
 

 
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5.8.2 
Palms and Soles 
Patients may rarely experience painful inflammation and desquamation of the 
palms and soles, more often after ifosfamide-etoposide cycles. If this occurs, allow 
a 21-day interval in the next cycle, and attempt a 14-day cycle again subsequently. 
 
5.9 
Allergy to Etoposide 
Pre-medication (such as diphenhydramine, +/- ranitidine and +/- hydrocortisone) and 
slowing of the rate of infusion with etoposide can be tried. Substitution with etoposide 
phosphate should be considered if a patient develops a reaction that would put him/her at 
risk if further etoposide were given. Etoposide phosphate may be substituted for etoposide 
with pre-medication and administered given at the same dose and rate.  
 
 
5.10 
Pneumonitis 
Thoracic radiation may be used in this patient population for management of primary tumor 
(e.g., chest wall primary site) or for management of metastatic disease (e.g., whole lung 
radiation for patients with lung metastasis). The extent to which ganitumab may increase 
the risk or severity of pneumonitis is not known, though an interim analysis in March 2019 
showed a higher number of cases of pneumonitis in patients treated with ganitumab.  
 
 
Investigators should be vigilant for development of pneumonitis in patients treated with or 
without ganitumab. Oxygen saturation evaluation at time of protocol mandated physical 
examinations is required for patients who have been treated with whole lung radiation. 
Investigators should consider additional evaluations in patients who have been treated with 
whole lung radiation who present with unexplained cough, dyspnea, or physical exam 
findings on lung auscultation. 
 
Pneumonitis will be managed according to local practice, individualized to each patient’s 
clinical scenario:  
 
Grade 1: Patients with Grade 1 pneumonitis (asymptomatic) should be monitored 
according to local practice for potential worsening to higher grade pneumonitis 
(symptomatic).  
 
Grade 2 or higher: A typical approach to Grade 2 and higher radiation pneumonitis includes 
a protracted course (2-4 weeks) of high dose corticosteroids (prednisone) followed by a 
slow taper over 3 to 12 weeks. Prophylaxis for pneumocystis pneumonia (PCP) is required 
for patients receiving > 20 mg prednisone daily. Consultation with pulmonology is 
strongly encouraged. For questions about radiation pneumonitis, sites may reach out to the 
study chair (Steven DuBois), vice-chair (Julia Glade-Bender), and lead radiation oncologist 
(Nadia Laack). 
 
Sites are to report pneumonitis of any grade in an expedited manner via CTEP-AERS and 
through routine reporting (see Section 11). 
 
5.11 
Any Other Grade 3 or 4 Toxicities 
Delay chemotherapy until toxicity has resolved to Grade 1. Dose reduction of 25% may be 
considered at investigator’s discretion. Attempts should be made to re-escalate dose if 
toxicity does not recur. 
 
 

 
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6.0 
DRUG INFORMATION  
6.1 
GANITUMAB  
(AMG 479) IND #, NSC 750008 
 
 
 
 
(04/25/19) 
 
Source and Pharmacology: 
Ganitumab is a fully human recombinant IgG1 monoclonal antibody against human IGF-1R. 
Ganitumab exerts its anti-tumor activity by blocking ligand binding (IGF-1 and IGF-2) and 
inducing receptor internalization and degradation without cross-reacting with the insulin receptor. 
Ganitumab is produced in Chinese hamster ovary cells by recombinant DNA technology. 
 
Ganitumab is a heterotetramer composed of 2 heavy chains of the IgG1 subclass and 2 light chains 
of the kappa subclass. The molecule contains 12 intramolecular and 4 intermolecular disulfide 
bonds and has a typical bi-antennary glycosylation pattern in the Fc portion of the heavy chain. 
Each heavy chain, with its 4 predicted intramolecular disulfides, contains 449 amino acids. The 
heavy chain contains an N-linked glycan.  Each light chain contains 219 amino acids, with 2 
putative intramolecular disulfides. The molecular weight is approximately 146 kilodaltons (kD). 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Ganitumab (AMG 479, NSC 750008) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below). Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further 
clarification. Frequency is provided based on 334 patients. Below is the CAEPR for Ganitumab (AMG 479). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next 
to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
Version 2.1, March 26, 20191 
 
 Adverse Events with Possible  
 Relationship to Ganitumab (AMG 479) 
 (CTCAE 5.0 Term) 
[n= 334] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
Anemia 
 Anemia (Gr 3) 
EAR AND LABYRINTH DISORDERS 
  
Hearing impaired2 
  
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 Diarrhea (Gr 2) 

 
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 Adverse Events with Possible  
 Relationship to Ganitumab (AMG 479) 
 (CTCAE 5.0 Term) 
[n= 334] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
Nausea 
 Nausea (Gr 2) 
Vomiting 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 Fatigue (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
Infusion related reaction 3 
 Infusion related reaction3 (Gr 2) 
INVESTIGATIONS 
  
Alanine aminotransferase increased
 Alanine aminotransferase increased 
(Gr 2) 
Aspartate aminotransferase 
increased 
 Aspartate aminotransferase 
increased (Gr 2) 
Lymphocyte count decreased 
  
Neutrophil count decreased 
 Neutrophil count decreased (Gr 3) 
Platelet count decreased 
 Platelet count decreased (Gr 3) 
White blood cell decreased 
 White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 Anorexia (Gr 2) 
Hyperglycemia 
 Hyperglycemia (Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
Myalgia 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Pneumonitis4 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
Rash5 
 Rash5 (Gr 2) 
 
1This table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to all 
Principal Investigators at the time of revision. The current version can be obtained by contacting  
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Middle to high range sensorineural hearing loss has been reported in patients treated with monoclonal 
antibodies to Insulin-like Growth Factor-1 Receptor (IGF-1R). 
 
3Infusional reactions may include chills, fever, hypotension, dyspnea, arthralgia, joint swelling, headache, 
dizziness, and cardiac arrhythmia (e.g., atrial fibrillation, tachycardia). 
 
4The rate and severity of radiation-associated pneumonitis may be increased in patients who receive 
ganitumab shortly before or after radiation to the lungs. 
 
5Rash includes rash, rash acneiform, rash maculo-papular, skin lesions, and pruritus. 
 
 
Adverse events reported on ganitumab (AMG 479) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that ganitumab (AMG 479) caused the adverse 
event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Febrile neutropenia 

 
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CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (diastolic dysfunction); Heart failure; 
Myocardial infarction 
ENDOCRINE DISORDERS - Hypothyroidism 
EYE DISORDERS - Cataract; Keratitis 
GASTROINTESTINAL DISORDERS - Abdominal pain; Anal fistula; Anal mucositis; Constipation; 
Dysphagia; Esophagitis; Gastrointestinal disorders - Other (enteritis); Mucositis oral; Oral pain; Pancreatitis; 
Rectal fistula; Rectal hemorrhage; Small intestinal obstruction; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Malaise; Non-cardiac chest pain; 
Pain 
HEPATOBILIARY DISORDERS - Hepatobiliary disorders - Other (hepatic function abnormal); 
Hepatobiliary disorders - Other (jaundice cholestatic) 
INFECTIONS AND INFESTATIONS - Anorectal infections; Infections and infestations - Other 
(pneumococcal infection); Lung infection; Myelitis; Sepsis; Skin infection; Soft tissue infection; Urinary tract 
infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Vascular access complication 
INVESTIGATIONS - Alkaline phosphatase increased; Creatinine increased; Ejection fraction decreased; 
Investigations - Other (electrocardiogram abnormal); Weight loss 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Dehydration; Hyperkalemia; Hypoalbuminemia; 
Hypocalcemia; Hypoglycemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Generalized 
muscle weakness 
NERVOUS SYSTEM DISORDERS - Radiculitis; Reversible posterior leukoencephalopathy syndrome; 
Seizure; Stroke; Syncope; Transient ischemic attacks; Tremor 
PSYCHIATRIC DISORDERS - Agitation 
RENAL AND URINARY DISORDERS - Acute kidney injury; Urinary tract obstruction 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Cough; Epistaxis; Hypoxia; Pleural effusion; Respiratory, thoracic and mediastinal disorders - Other 
(respiratory hemorrhage) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Palmar-plantar erythrodysesthesia 
syndrome; Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypertension; Thromboembolic event (venous) 
 
 
Note: Ganitumab (AMG 479) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 
Formulation and Stability: 
Ganitumab will be supplied as a sterile, clear, colorless liquid with 70 mg/mL (210 mg/3 mL or 
700 mg/10 mL) vial of ganitumab. The single-use vials also contain the following excipients; 10 
mM sodium acetate, 5% w/v sorbitol, 0.004% w/v polysorbate 20, pH 5.2. Sites participating in 
Canada will utilize the 210 mg vial size. All other participating sites will use the 700 mg vial size. 
 
Guidelines for Administration: 
See Treatment and Dose Modification sections of the protocol. 
 
Preparation: 
The final concentration of ganitumab for administration should be between 3 mg/mL to 20 mg/mL 
in 0.9% sodium chloride (NS). Gently invert the infusion bag to mix. DO NOT SHAKE. Protect 
from light. 
 
Storage: Store refrigerated between 2°C to 8°C.  Do not shake or freeze. Protect from light. 

 
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Stability: 
Once the ganitumab is injected into the infusion bag, the infusion must be completed within 8 hours. 
The total time between removal of ganituamb intact vials from the refrigerator and completion of 
infusion must not exceed 24 hours.   
 
Vials contain no preservatives and any solution remaining in the vials after the dose is prepared 
should be discarded. 
 
Route of Administration: Intravenous infusion  
 
Administration: 
The infusion line should be thoroughly flushed with saline before and after administration of 
ganitumab to avoid mixing with other drug products or IV solutions. 
 
The first dose should be administered over 60 minutes without premedication. If well tolerated over 
60 minutes, subsequent infusions may be administered over 30 minutes, at the investigator’s 
discretion. Infusion times can be extended to a maximum of 120 minutes for subjects unable to 
tolerate the 60 minute infusion.   
 
Doses over 2100 mg should be infused over 120 minutes. If well tolerated over 120 minutes, 
subsequent infusions may be administered over 60 minutes at the investigator’s discretion.  
 
Supplier:  
Ganitumab will be supplied by NantBio and distributed by the PMB, CTEP, NCI. 
 
Agent Ordering: 
NCI supplied agent may be requested by the eligible participating investigator (or their authorized 
designee) at each participating institution. The CTEP assigned protocol number must be used for 
ordering all CTEP supplied investigational agents. The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual submission of 
FDA form 1572 (Statement of Investigator), NIH Biosketch, Agent Shipment Form, and Financial 
Disclosure Form (FDF). If there are several participating investigators at one institution, CTEP 
supplied investigational agents for the study should be ordered under the name of one lead 
participating investigator at that institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) application. 
Access to OAOP requires the establishment of a CTEP Identity and Access Management (IAM) 
account and the maintenance of an “active” account status, and a “current” password, and active 
person registration status. For questions about drug orders, transfers, returns, or accountability, call 
or email PMB any time. Refer to the PMB’s website for specific policies and guidelines related to 
agent management. 
 
Agent Accountability: 
Agent Inventory Records – The investigator, or a responsible party designated by the investigator, 
must maintain a careful record of the receipt, dispensing, and final disposition of all agents received 
from PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record Form 
(DARF) available on the CTEP forms page. Store and maintain separate NCI Investigational Agent 
Accountability Records for each agent, strength, formulation and ordering investigator on this 
protocol. 

 
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Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site investigators and research 
staff through the PMB Online Agent Order Processing (OAOP) application. Access to OAOP 
requires the establishment of a CTEP IAM account and the maintenance of an “active” account 
status, a “current” password, and active person registration status. Questions about IB access may 
be directed to the PMB IB coordinator via email. 
 
Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
• 
CTEP Identity and Access Management (IAM) account: https://ctepcore.nci.nih.gov/iam/ 
• 
CTEP Registration and IAM account help:  RCRHelpDesk@nih.gov  
• 
PMB email:  PMBAfterHours@mail.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov  
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 
am and 4:30 pm (ET) 
 
 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
(Cytoxan) NSC #26271  
 
 
 
 
 
(03/13/13) 
 
Source and Pharmacology:  
Cyclophosphamide is an alkylating agent related to nitrogen mustard. Cyclophosphamide is inactive 
until it is metabolized by P450 isoenzymes (CYP2B6, CYP2C9, and CYP3A4) in the liver to active 
compounds. The initial product is 4-hydroxycyclophosphamide (4-HC) which is in equilibrium with 
aldophosphamide which spontaneously releases acrolein to produce phosphoramide mustard. 
Phosphoramide mustard, which is an active bifunctional alkylating species, is 10 times more potent 
in vitro than is 4-HC and has been shown to produce interstrand DNA cross-link analogous to those 
produced by mechlorethamine. Approximately 70% of a dose of cyclophosphamide is excreted in the 
urine as the inactive carboxyphosphamide and 5-25% as unchanged drug. The plasma half-life ranges 
from 4.1 to 16 hours after IV administration.  
 

 
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Anorexia, nausea & vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid administration, 
arrhythmias (rapid infusion), skin 
rash, anaphylaxis, SIADH 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Leukopenia, alopecia, immune 
suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose (acute 
– CHF hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail changes, 
impaired wound healing, infection 
secondary to immune suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or oligospermia 
(prolonged or permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, ANLL, 
AML), bladder carcinoma (long term 
use > 2 years), bladder fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other 
antineoplastic agents) have been noted in humans. Toxicities include: chromosomal 
abnormalities, multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is 
excreted into breast milk. Cyclophosphamide is contraindicated during breast feeding because of 
reported cases of neutropenia in breast fed infants and the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Cyclophosphamide for injection is available as powder for injection or lyophilized powder 
for injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 82 mg sodium 
bicarbonate/100 mg cyclophosphamide and the lyophilized powder for injection contains 
75 mg mannitol/100 mg cyclophosphamide. Storage at or below 25ºC (77ºF) is 
recommended. The product will withstand brief exposures to temperatures up to 30ºC 
(86ºF). 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Cyclophosphamide for Injection: If the drug will be administered as undiluted drug at the 
20 mg/mL concentration, then reconstitute to 20 mg/mL with NS ONLY to avoid a 
hypotonic solution. If the drug will be further diluted prior to administration, then first 
reconstitute with NS, SWFI, or Bacteriostatic Water for Injection (paraben preserved only) 
to a concentration of 20 mg/mL. Following reconstitution, further dilute in dextrose or 
saline containing solutions for IV use.  
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 

 
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6.3 
DACTINOMYCIN 
(Actinomycin-D, Cosmegen®) NSC #3053 
 
 
 
(05/09/11) 
 
Source and Pharmacology:  
Dactinomycin is a member of a class of antibiotic compounds isolated from Streptomyces 
parvullus. Dactinomycin is composed of a planar tricyclic ring chromophore 
(phenoxazone) to which two identical cyclic polypeptides are attached. The compound 
binds to DNA by intercalation, depending on a specific interaction between the polypeptide 
chains and deoxyguanosine. This interaction blocks the ability of DNA to act as a template 
for RNA and DNA synthesis in a concentration-dependent manner. Low drug 
concentrations inhibit RNA synthesis more than higher drug concentrations, which block 
both RNA and DNA syntheses. Dactinomycin can also cause topoisomerase-mediated 
single-strand breaks in DNA. Dactinomycin is minimally metabolized and is concentrated 
in nucleated red blood cells with very little diffusion into the CNS. After an IV bolus, 
dactinomycin has a very short initial distribution half-life of about 1-minute but a prolonged 
terminal plasma half-life of 36 hours. Dactinomycin is primarily eliminated by renal and 
biliary excretion. Approximately 30% of the dose is recovered in urine and feces in one 
week. 
 
 
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting  
Anorexia  
Anaphylaxis, abdominal pain, 
extravasation (rare) but if 
occurs = local ulceration 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression, alopecia 
(L)  
Diarrhea, mucositis, 
cheilitis, radiation recall 
reactions, fatigue, 
lethargy, malaise 
Elevated LFTs, hepatitis, 
hepatomegaly, sinusoidal 
obstruction syndrome (SOS, 
formerly VOD) (L), proctitis, 
acne, skin eruptions, 
hypocalcemia, fever, 
ulcerative stomatitis, 
esophagitis and/or enteritis, 
myalgia 
Delayed: 
Any time later during 
therapy 
 
 
Growth retardation, 
pneumonitis 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancies 
Unknown frequency 
and timing:  
Fetal toxicities of dactinomycin have been noted in animal models. It is not known if 
dactinomycin is excreted into breast milk 
 
 
(L) Toxicity may also occur later. 
 
 
 
Formulation and Stability:  
Lyophilized powder, in vials containing 500 mcg of dactinomycin, with 20 mg of mannitol. 
Store at controlled room temperature, 25°C (77°F); excursions permitted to 15-30°C (59-
86°F). Protect from light and humidity.  
 
Reconstitute with 1.1 mL of sterile water without preservative to give a final concentration 
of 500 mcg/mL (0.5 mg/mL). The resulting solution should be clear to gold colored. 

 
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Preservatives may cause precipitation. Stable at room temperature, 25°C (77°F) protected 
from light for up to 24 hours.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Dactinomycin can be injected directly into the vein or preferably administered through the 
tubing of a rapidly infusing solution of D5W or NS. The line should be flushed thoroughly 
at the end of the dactinomycin infusion. Significant binding of dactinomycin by cellulose 
ester membrane filters used in some intravenous in-line filters has been reported.  
 
Supplier: Commercially available. See package insert for more detailed information. 
 
 
6.4 
DEXRAZOXANE  
(ICRF-187, ADR-529, ZINECARD, Totect) NSC #169780 
 
(11/17/17) 
 
 
 
Source and Pharmacology:   
Dexrazoxane is a synthetic chemical, a cyclic derivative of EDTA that readily penetrates 
cell membranes. Results of laboratory studies suggest that dexrazoxane is converted 
intracellularly to a ring opened chelating agent that interferes with iron mediated free 
radical generation thought to be responsible, in part, for anthracycline-induced 
cardiomyopathy. The disposition kinetics of dexrazoxane are dose-dependent with 
administered doses from 60 to 900 mg/m2. The plasma half-life is 2 to 2.5 hours. 
Qualitative metabolism studies have confirmed the presence of unchanged drug, a diacid-
diamide cleavage product, and two monoacid-monoamide ring products in the urine of 
animals and man. Metabolite levels were not measured in the pharmacokinetics studies. 
Urinary excretion plays an important role in the elimination of dexrazoxane: 42% of the 
drug (500 mg/m2) was excreted in the urine. In vitro studies have shown that dexrazoxane 
is not bound to plasma proteins. The pharmacokinetics of dexrazoxane have not been 
evaluated in patients with hepatic or renal insufficiency. There was no significant effect of 
dexrazoxane on the pharmacokinetics of doxorubicin (50 mg/m2) or its predominant 
metabolite, doxorubicinol, in a crossover study in cancer patients. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of 
every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Pain on injection, phlebitis, transient 
increases in triglycerides and 
amylase, increase in SGPT (ALT)/ 
SGOT (AST) and bilirubin, mild 
nausea, vomiting, diarrhea, increase 
in serum iron, decrease in serum 
zinc and calcium  
Anorexia, malaise, 
extravasation (rare) but if occurs 
may = ulceration 
Prompt: 
Within 2-3 weeks, prior to 
the next course 
Myelosuppression   
Prolongation of PT/PTT  
Late: 
Any time after completion 
of treatment 
 
 
Secondary malignancies 
(have been reported with oral 
razoxane; the racemic mixture, of 

 
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which dexrazoxane is the S(+)-
enantiomer) 
Unknown Frequency 
and Timing:   
Fetal toxicities and teratogenic effects have been noted in animals. Dexrazoxane was 
maternotoxic, embryotoxic, and teratogenic when given to pregnant rats and rabbits during the 
period of organogenesis. It is not known whether dexrazoxane is excreted in human milk. 
 
Formulation and Stability:  
 
Three products are available: 
1. Dexrazoxane for Injection (generic)  
a. Available as a sterile, pyrogen-free lyophilized powder in the following strengths: 
250 mg single dose vial packaged with a 25 mL vial of 0.167 Molar (M/6) Sodium 
Lactate Injection, USP, and 500 mg single dose vial packaged with a 50 mL vial of 
0.167 Molar (M/6) Sodium Lactate Injection, USP.  
b. Store protected from light at 25°C (77°F); excursions permitted to 15°-30°C (59°-
86°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Available in as a sterile, pyrogen-free lyophilized powder in 250 mg and 500 mg 
single use vials. Hydrochloric Acid, NF is added to the vials for pH adjustment. 
b. Intact vials should be stored at 25°C (77°F); excursions are permitted to 15° to 30°C 
(59° to 86°F). 
 
3. Totect® (dexrazoxane for anthracycline extravasation only)   
a. Totect is packaged as an emergency treatment carton for single patient use. Each 
carton contains 10 vials of Totect (dexrazoxane for injection) 500 mg and 10 vials 
of 50 mL diluent, which provides a complete three day treatment. 
 
Reconstitution and dilution requirements and expiration dating vary based on the 
product used.  Refer to package insert for additional details.   
 
 
1. Dexrazoxane (generic) 
a. Dexrazoxane (250 mg or 500 mg vials) must be reconstituted with a sufficient 
quantity of 0.167 Molar (M/6) Sodium Lactate Injection, USP, to a concentration 
of 10 mg dexrazoxane for each mL of sodium lactate.  
b. Further dilute solution in either D5W or NS to a final concentration of 1.3 to 5 
mg/mL.  
c. The final solution is stable for up to 6 hours at room temperature, 15°C to 30°C 
(59°F to 86°F), or under refrigeration, 2°C to 8°C (36°F to 46°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Reconstitute with Sterile Water for Injection, USP as follows:  
• 
For 250 mg vials, reconstitute with 25 mL.  
• 
For 500 mg vials, reconstitute with 50 mL.  
• 
The resultant reconstituted solutions will have a concentration of 
10 mg/mL.  
b. Following initial reconstitution, ZINECARD is stable for 30 minutes at room 
temperature or up to 3 hours when stored under refrigeration, 2° to 8°C (36° to 
46°F).  
c. The pH of the resultant solution is 1.0 to 3.0.  Further dilution with Lactated 
Ringer’s Injection, USP is required to achieve a final concentration range of 1.3 to 
3 mg/mL in intravenous infusion bags. The infusion solution has a pH of 3.5 to 5.5.  

 
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d. The infusion solution is stable for one (1) hour at room temperature or if storage is 
necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). 
 
3. Totect® (dexrazoxane for anthracycline extravasation only)   
a. Totect® must be reconstituted with supplied diluent to provide a final concentration 
of 10 mg/mL. The patient’s dose of Totect® (based on body surface area) should be 
injected into a 1000 mL bag of NS for infusion.  
b. This solution is stable for 4 hours (begin infusion within 2 hours of preparation) 
when stored at temperatures <25°C (<77°F).  
c. Stability studies indicate that Totect® is chemically and physically stable after 
reconstitution with sterile water for injection and dilution in Lactated Ringer’s 
Injection when stored in refrigerated conditions (2-8°C) for no more than 8 hours 
(email communication Cumberland Pharma). 
 
Guidelines for Administration:  See Treatment and Dose Modifications sections of the 
protocol. 
For the prevention of anthracycline-induced cardiomyopathy, administer IV immediately 
prior to anthracycline dose. Administer the anthracycline after completing the infusion of 
dexrazoxane but within 30 minutes of beginning of the dexrazoxane infusion.  
 
The first infusion of Totect® should be administered as soon as possible and within the 
first 6 hours following the extravasation. 
 
Supplier:  Commercially available. See package insert for further information. 
 
CANADIAN SITES 
In Canada, Pfizer brand of Zinecard® is the only product commercially available and now 
has the same reconstitution, dilution, and expiration dating as the USA Pfizer Zinecard® 
above.  
 
6.5 
DOXORUBICIN 
(Adriamycin®) NSC #123127  
 
 
 
 
(05/09/11) 
 
Source and Pharmacology:  
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The cytotoxic 
effect of doxorubicin on malignant cells and its toxic effects on various organs are thought 
to be related to nucleotide base intercalation and cell membrane lipid binding activities of 
doxorubicin. Intercalation inhibits nucleotide replication and action of DNA and RNA 
polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-cleavable 
complexes appears to be an important mechanism of doxorubicin cytocidal activity. 
Doxorubicin cellular membrane binding may affect a variety of cellular functions. 
Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases, and 
dehydrogenases generate highly reactive species including the hydroxyl free radical (OH•). 
Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu 
(II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been 
shown to manifest the characteristic morphologic changes associated with apoptosis or 
programmed cell death. Doxorubicin-induced apoptosis may be an integral component of 
the cellular mechanism of action relating to therapeutic effects, toxicities, or both. 
 

 
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Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 
5 minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours 
reflects a slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 
L/kg and are indicative of extensive drug uptake into tissues. Plasma clearance is in the 
range of 8 to 20 mL/min/kg and is predominately by metabolism and biliary excretion. The 
P450 cytochromes which appear to be involved with doxorubicin metabolism are CYP2D6 
and CYP3A4. Approximately 40% of the dose appears in the bile in 5 days, while only 5 
to 12% of the drug and its metabolites appear in the urine during the same time period. 
Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 
74 to 76% and is independent of plasma concentration of doxorubicin. 
 
Toxicity: 
 
Common 
Happens to 21-100 children out 
of every 100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink or red 
color to urine, sweat, tears, and 
saliva 
Hyperuricemia, facial 
flushing, sclerosis of the vein 
Diarrhea, anorexia, 
erythematous streaking of the 
vein (flare reaction), 
extravasation (rare) but if occurs 
= local ulceration, anaphylaxis, 
fever, chills, urticaria, acute 
arrhythmias 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression (leukopenia, 
thrombocytopenia, anemia), 
alopecia  
Mucositis (stomatitis and 
esophagitis), hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
Any time later during 
therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses 
≥ 450 mg/m²) (L) 
 
Cardiomyopathy1 (CHF occurs 
in < 5% at cumulative doses 
≤ 400 mg/m²) (L), ulceration 
and necrosis of colon, 
hyper-pigmentation of nail bed 
and dermal crease, onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac dysfunction CHF (on long term follow up 
in pediatric patients) 
Secondary malignancy (in 
combination regimens) 
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin have been 
noted in animal models. Doxorubicin is excreted into breast milk in humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
(L) Toxicity may also occur later  
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 
50 mg¹vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² 
vials. 
¹: Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF (rapid 
dissolution formula) also contains methylparaben, 1 mg per each 10 mg of doxorubicin, to enhance 
dissolution. 
² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
 
Aqueous Solution: Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in 
carton until contents are used. 

 
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Powder for Injection: Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). 
Retain in carton until contents are used. Reconstitute with preservative-free NS to a final 
concentration of 2 mg/mL. After adding the diluent, the vial should be shaken and the 
contents allowed to dissolve. The reconstituted solution is stable for 7 days at room 
temperature and 15 days under refrigeration, 2°-8°C (36°-46°F) when protected from light. 
Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is stable for up to 48 hours at 
room temperature (25°C) when protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol.  
 
 
Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl 
preferably into a large vein. Protect the diluted solution from sunlight. To avoid 
extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.6 
ETOPOSIDE - INJECTION 
(Toposar®, Etopophos®,VP-16) NSC #141540  
 
 
(11/15/16) 
 
Source and Pharmacology:  
A semisynthetic derivative of podophyllotoxin that forms a complex with topoisomerase 
II and DNA which results in single and double strand DNA breaks. Its main effect appears 
to be in the S and G2 phase of the cell cycle. The initial t½ is 1.5 hours and the mean terminal 
half-life is 4 to 11 hours. It is primarily excreted in the urine. In children, approximately 
55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance 
of etoposide is 7 to 10 mL/min/m² or about 35% of the total body clearance over a dose 
range of 80 to 600 mg/m². Etoposide, therefore, is cleared by both renal and non renal 
processes, i.e., metabolism and biliary excretion. The effect of renal disease on plasma 
etoposide clearance is not known. Biliary excretion appears to be a minor route of etoposide 
elimination. Only 6% or less of an intravenous dose is recovered in the bile as etoposide. 
Metabolism accounts for most of the non renal clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve (AUC) 
exhibit a high degree of patient variability. Etoposide is highly bound to plasma proteins 
(~94%), primarily serum albumin. Pharmacodynamic studies have shown that etoposide 
systemic exposure is related to toxicity. Preliminary data suggests that systemic exposure 
for unbound etoposide correlates better than total (bound and unbound) etoposide. There 
is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide which is rapidly and completely 
converted to etoposide in plasma. Pharmacokinetic and pharmacodynamic data indicate 
that etoposide phosphate is bioequivalent to etoposide when it is administered in molar 
equivalent doses. 
 
 
 

 
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension during 
infusion; anaphylaxis (chills, fever, 
tachycardia, dyspnea, 
bronchospasm, hypotension) 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression (anemia, 
leukopenia), alopecia 
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticaria 
Peripheral neuropathy, mucositis, 
hepatotoxicity, chest pain, 
thrombophlebitis, congestive heart 
failure, Stevens-Johnson Syndrome, 
exfoliative dermatitis 
Delayed: Any time 
later during therapy 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory cycles, 
hypomenorrhea, onycholysis of nails 
Late: Any time after 
completion of 
treatment 
 
 
Secondary malignancy (preleukemic 
or leukemic syndromes) 
 
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 1/20th of the 
human dose. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Etoposide for Injection is available as a 20 mg/mL solution in sterile multiple dose vials 
(5 mL, 25 mL, or 50 mL each). The pH of the clear, nearly colorless to yellow liquid is 3 
to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl alcohol, 80 mg 
modified polysorbate 80/tween 80, 650 mg polyethylene glycol 300, and 30.5 percent (v/v) 
alcohol. Vial headspace contains nitrogen. Unopened vials of etoposide are stable until 
expiration date on package at controlled room temperature (20˚-25˚C or 68˚-77˚F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 
100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide 
phosphate must be stored under refrigeration (2°-8°C or 36°-46°F). Unopened vials of 
etoposide phosphate are stable until the expiration date on the package. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
Etoposide: 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide infusions 
are stable at room temperature for 96 hours when diluted to concentrations of 0.2 mg/mL; 
stability is 24 hours at room temperature with concentrations of 0.4 mg/mL. The time to 
precipitation is highly unpredictable at concentrations > 0.4 mg/mL. Use in-line filter 
during infusion secondary to the risk of precipitate formation. However, the use of an in-
line filter is not mandatory since etoposide precipitation is unlikely at concentrations of 
0.1-0.4 mg/mL. Do not administer etoposide by rapid intravenous injection. Slow rate 
of administration if hypotension occurs.  
 
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags occurred 
with etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the etoposide solution as close 

 
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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 to minimize exposure to DEHP. 
 
Etoposide Phosphate: 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, NS, 
Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic Sodium Chloride 
for Injection with Benzyl Alcohol for a concentration equivalent to 20 mg/mL or 
10 mg/mL etoposide equivalent (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), 
respectively. Use diluents without benzyl alcohol for neonates and infants < 2 years of 
age or patients with hypersensitivity to benzyl alcohol.  
 
When reconstituted as directed, etoposide phosphate solutions can be stored in glass or 
plastic containers under refrigeration for 7 days. When reconstituted with a diluent 
containing a bacteriostat, store at controlled room temperature for up to 48 hours. 
Following reconstitution with SWFI, D5W, or NS store at controlled room temperature for 
up to 24 hours. 
 
Following reconstitution, etoposide phosphate may be further diluted to a concentration as 
low as 0.1 mg/mL of etoposide with D5W or NS. The diluted solution can be stored under 
refrigeration or at controlled room temperature for 24 hours. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
CANADIAN SITES 
Etoposide for Injection is available as 20 mg/mL solution. 
 
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites may 
purchase and import the USA commercial supply from Bristol Laboratories via an 
International Distributor (Pharma Exports LLC, phone: 1-412-885-3700, fax: 1-412-885-
8022, email: pharexp@aol.com) under the authority of the protocol’s No Objection Letter 
(NOL). Drug Accountability Record (DAL) must record Lot #’s and expiry dates of 
shipments received and doses dispensed.  Sites may use their own DAL as long as it 
complies with all elements of ICH GCP and Division 5 of the Food and Drugs Act.  Each 
site is responsible for the procurement (import +/- purchase) of Etoposide Phosphate 
(Etopophos). Sites may import and manage a single clinical trial supply for multiple 
protocols as long as each protocol has an NOL and the protocol the patient is registered on 
is recorded on the DAL.   
 
6.7 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ  
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®) NSC #614629  
 
 
 
 
          (11/15/16) 
 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by 
recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular 
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli 
bacteria into which has been inserted the human granulocyte colony stimulating factor 
gene. It differs from the natural protein in that the N- amino acid is methionine and the protein 

 
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is not glycosylated. G-CSF is a lineage specific colony-stimulating factor which regulates 
the production of neutrophils within the bone marrow and affects neutrophil progenitor 
proliferation, differentiation, and selected end-cell functional activation (including 
enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). Filgrastim exhibits nonlinear pharmacokinetics with 
clearance dependent on filgrastim concentration and neutrophil count. Filgrastim is cleared 
by the kidney. The elimination half-life is similar for subcutaneous and intravenous 
administration, approximately 3.5 hours. The time to peak concentration when administered 
subcutaneously is 2-8 hours 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 
children out of every 
100 
Rare 
Happens to <5 children out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more common with IV 
administration than subq):skin (rash, urticaria, 
facial edema), respiratory (wheezing, dyspnea) 
and cardiovascular (hypotension, tachycardia), 
low grade fever  
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic rupture, rash or 
exacerbation of pre-existing skin rashes, sickle 
cell crises in patients with SCD, excessive 
leukocytosis, Sweet’s syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
Cutaneous vasculitis, ARDS 
Late: 
Anytime after 
completion of 
treatment 
 
 
MDS or AML (confined to patients with severe 
chronic neutropenia and long term 
administration) 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting data exist in 
animal studies and filgrastim is known to pass the placental barrier. It is unknown whether the drug 
is excreted in breast milk. 
 
Formulation and Stability:  
Neupogen® is supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. 
Neupogen® vials are preservative free single use vials. Discard unused portions of open 
vials. 
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes 
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous 
administration. Store refrigerated at 2º-8ºC (36º-46ºF). Protect from light. Do not shake. 
Prior to injection, filgrastim and filgrastim-sndz may be allowed to reach room temperature 
for a maximum of 24 hours (infusion must be completed within 24 hours of preparation). 
TBO-filgrastim may be removed from 2°C-8°C (36°F-46°F) storage for a single period of 
up to 5 days between 23°C to 27°C (73°F to 81°F). Avoid freezing and temperatures 
> 30ºC.  
 

 
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For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W only to 
concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in D5W to 
concentrations between 5 mcg/mL and 15 mcg/mL. At concentrations below 15 mcg/mL, 
human serum albumin should be added to make a final albumin concentration of 0.2% 
(2 mg/mL) in order to minimize the adsorption of filgrastim to plastic infusion containers 
and equipment for all 3 products (communication on file from Teva Pharmaceuticals USA). 
Filgrastim or filgrastim-sndz dilutions of 5 mcg/mL or less are not recommended. Tbo-
filgrastim dilutions below 2 mcg/mL are not recommended. Diluted filgrastim biosimilar 
products should be stored at 2º-8ºC (36º-46ºF) and used within 24 hours. Do not shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
Guidelines for Administration:  
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
Filgrastim biosimilar products should not be administered within 24 hours of (before AND 
after) chemotherapy. 
 
  
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.8 
IFOSFAMIDE 
(Isophosphamide, Iphosphamide, Z4942, Ifex®) NSC #109724  
 (05/09/11) 
 
Source and Pharmacology:  
Ifosfamide is a structural analogue of cyclophosphamide. Ifosfamide requires hepatic 
microsomal activation (P450 3A isoenzymes) for the production of the reactive 4-
hydroxyoxazaphorine intermediate which serves as a carrier molecule for the ultimate 
intracellular liberation of acrolein and phosphoramide mustard which is an active 
bifunctional alkylating species. Acrolein is thought to be the cause of the hemorrhagic cystitis 
as seen with cyclophosphamide. Ifosfamide demonstrates dose-dependent pharmacokinetics 
whereby the terminal half-life ranges from 7 to 16 hours at doses of 1.6-2.4 g/m² to 3.8-5 
g/m², respectively. At 1.6-2.4 g/m²/d, 12 to 18% of the dose was excreted as unchanged drug 
in the urine, whereas at a 5 g/m² single-dose, 61% was excreted in the urine as the parent 
drug. Evidence also exists to suggest that ifosfamide metabolism is inducible, with more 
rapid clearance occurring in the second and later doses when a course of therapy is given as 
fractionated doses over 3 to 5 days. There is more chloroethyl side chain oxidation of 
ifosfamide (up to 50%) than of cyclophosphamide (< 10%), and the degree of such 
metabolism is more variable than with cyclophosphamide. Oxidation of the chloroethyl 
groups produces chloroacetaldehyde, which is thought to be responsible for the 
neurotoxicity and renal toxicity that have been seen with ifosfamide therapy. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 
100 
Occasional 
Happens to 5-20 children out 
of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea & vomiting 
(acute and delayed) 
CNS toxicity (somnolence, 
depressive psychosis and 
confusion) 
Anorexia, diarrhea, constipation, 
encephalopathy which may 
progress to coma (L), seizure, 
SIADH, phlebitis, hypokalemia 
Prompt: 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, anemia, 
cardiac toxicities (arrhythmia, 
↑ liver enzymes, ↑ bilirubin, 
hemorrhagic cystitis with 

 
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Within 2-3 weeks, 
prior to next 
course 
asymptomatic ECG changes), 
microscopic hematuria, 
metabolic acidosis 
macroscopic hematuria, dysuria, 
cystitis and urinary frequency 
(< 5% with mesna and vigorous 
hydration) (L), bladder fibrosis 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
 
Renal failure acute or chronic, 
renal tubular acidosis, 
Fanconi-like syndrome gonadal 
dysfunction, ovarian failure1 (L), 
CHF 
Late: 
Any time after 
completion of 
treatment 
Moderate nephrotoxicity 
(↓ in glomerular 
filtration rate, renal 
tubular threshold for 
phosphate, and serum 
bicarbonate) 
 
Secondary malignancy, 
hypophosphatemic rickets  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of ifosfamide have been noted in animals. Ifosfamide 
is excreted into breast milk.  
1 Dependent on dose, age, gender and degree of pubertal development at time of treatment 
 (L) Toxicity may also occur later. 
 
Formulation and Stability:  
Ifosfamide is available in 1 g and 3 g single dose vials of lyophilized white powder without 
preservatives and as a 50 mg/mL solution in 20 mL and 60 mL vials.  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
Reconstitute ifosfamide lyophilized powder with sterile water for injection or bacteriostatic 
water for injection(use 20 mL for the 1 g vial and 60 mL for the 3 g vial) to produce a final 
concentration of 50 mg/mL. Use sterile water for injection without benzyl alcohol for 
neonates and infants < 2 years of age or patients with hypersensitivity to benzyl alcohol. 
Although the reconstituted product is stable for 7 days at room temperature and up to 6 weeks 
under refrigeration, the manufacturer recommends refrigeration and use within 24 hours to 
reduce the possibility of microbial contamination. Store unreconstituted vials at room 
temperature 20°-25°C (68°-77°F). Protect from temperatures above 30°C (86° F). 
Ifosfamide may liquefy at temperatures > 35°C. 
 
Reconstituted solutions of ifosfamide or ifosfamide solution should be diluted further to 
concentrations of 0.6 to 20 mg/mL in dextrose or saline containing solutions. Such 
admixtures, when stored in large volume parenteral glass bottles, Viaflex bags or PAB 
bags, are physically and chemically stable for 1 week at 30°C (86°F) or 6 weeks at 5°C 
(41°F). The manufacturer recommends refrigeration and use within 24 hours to reduce the 
possibility of microbial contamination. 
 
Mesna must always be administered in conjunction with ifosfamide. Adequate hydration 
is required. Achieve urine specific gravity ≤ 1.010 prior to start of ifosfamide. Refer to the 
Chemotherapy Administration Guidelines for additional information. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further 
information. 
 

 
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6.9 
MESNA - INJECTION 
 
 
 
 
 
(10/13/17) 
(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex) NSC #113891 
 
Source and Pharmacology: 
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis 
induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide 
(dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly 
eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol 
compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites 
(acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the 
detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a 
nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein 
and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model 
studies, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or 
multiple courses) failed to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half lives for mesna and dimesna are 0.36 hours and 1.17 hours, 
respectively. Approximately 32% and 33% of the administered dose was eliminated in the 
urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered 
was eliminated within 4 hours.  
 
Toxicity1: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Nausea, vomiting, 
stomach pain, fatigue, 
headache 
Facial flushing, fever, pain in arms, legs, and 
joints, rash, transient hypotension, 
tachycardia, dizziness, anxiety, confusion, 
periorbital swelling, anaphylaxis, coughing 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Diarrhea 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 10 times the 
recommended human doses. There are however no adequate and well-controlled studies in 
pregnant women. It is not known if mesna or dimesna is excreted into human milk 
1All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has 
been associated with death in pre-term infants weighing less than 2500 g and receiving 99-
405 mg/kg/day. Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine 
in the liver, and excreted as hippuric acid. In pre-term infants, however, this metabolic pathway 
may not be well developed. Onset of toxic illness in these infants occurred between several days and 
a few weeks of age with a characteristic clinical picture that included metabolic acidosis 
progressing to respiratory distress and gasping respirations. Many infants also had central-
nervous-system dysfunction, including convulsions and intracranial hemorrhage; hypotension 
leading to cardiovascular collapse was a late finding usually preceding death. [For comparison in 
the ICE regimen of 3000 mg/m²/day of ifosfamide and a daily mesna dose of 60% of the ifosfamide 
dose = to 1800 mg/m²/day; a child would be expected to receive 18 mL/m²/day of mesna 
(concentration of 100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2 mg/m²/day of benzyl alcohol 
or 6.24 mg/kg/day.] 
 

 
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Formulation and Stability: 
Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 
0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection 
multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. Store product 
at controlled room temperature 15º-25C (68º-77ºF). Mesna is not light-sensitive, but is 
oxidized to dimesna when exposed to oxygen. Mesna as benzyl alcohol-preserved vials 
may be stored and used for 8 days. 
 
Guidelines for Administration: 
See Treatment, Dose Modifications, and Supportive Care sections of the protocol. 
 
For IV administration, dilute mesna to 20 mg/mL with dextrose or saline containing 
solutions. Mesna may be mixed with ifosfamide or cyclophosphamide. After dilution for 
administration, mesna is physically and chemically stable for 24 hours at 25ºC (77ºF). 
Mesna may cause false positive test for urinary ketones.  
 
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information. 
 
 
6.10 
MESNA - ORAL 
 
 
 
 
 
 
(11/27/17) 
(sodium 2-mercaptoethane sulfonate,UCB 3983, Mesnex) NSC #113891 
 
Source and Pharmacology: 
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis 
induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide 
(dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly 
eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol 
compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites 
(acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the 
detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a 
nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein 
and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model 
studies, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or 
multiple courses) failed to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half lives for mesna and dimesna are 0.36 hours and 1.17 hours, 
respectively. Approximately 32% and 33% of the administered dose was eliminated in the 
urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered 
was eliminated within 4 hours. Mesna tablets have an oral bioavailability of 45-79% and a 
urinary bioavailability which ranged from 45-79% of intravenously administered mesna. 
The oral bioavailability is unaffected by food. When compared to intravenously 
administered mesna, the intravenous plus oral dosing regimen increases systemic 
exposures (150%) and provides more sustained excretion of mesna in the urine over a 24-
hour period. 
 
 
 

 
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Toxicity1: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Bad taste with oral use 
Nausea, vomiting, stomach 
pain, fatigue, headache, 
Facial flushing, fever, pain in 
arms, legs, and joints, rash, 
transient hypotension, 
tachycardia, dizziness, anxiety, 
confusion, periorbital swelling, 
anaphylaxis, coughing 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Diarrhea 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 10 times the 
recommended human doses. There are however no adequate and well-controlled studies in 
pregnant women. It is not known if mesna or dimesna is excreted into human milk 
1All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has 
been associated with death in pre-term infants weighing less than 2500 g and receiving 99-
405 mg/kg/day. Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine 
in the liver, and excreted as hippuric acid .In pre-term infants, however, this metabolic pathway 
may not be well developed. Onset of toxic illness in these infants occurred between several days and 
a few weeks of age with a characteristic clinical picture that included metabolic acidosis 
progressing to respiratory distress and gasping respirations. Many infants also had central-
nervous-system dysfunction, including convulsions and intracranial hemorrhage; hypotension 
leading to cardiovascular collapse was a late finding usually preceding death. [For comparison in 
the ICE regimen of 3000 mg/m²/day of ifosfamide and a daily mesna dose of 60% of the ifosfamide 
dose = to 1800mg/m²/day; a child would be expected to receive 18 mL/m²/day of mesna 
(concentration of 100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2 mg/m²/day of benzyl alcohol 
or 6.24 mg/kg/day.] 
 
Formulation and Stability:  
Mesna is available as scored 400 mg oral tablets. Excipients include lactose, 
microcrystalline cellulose, calcium phosphate, cornstarch, povidone, magnesium stearate, 
hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, and simethicone. 
 
Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 
0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection 
multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. Store product 
at controlled room temperature, 15-25C (68-77ºF). Mesna is not light-sensitive, but is 
oxidized to dimesna when exposed to oxygen. Mesna as benzyl alcohol-preserved vials may 
be stored and used for 8 days. 
 
Guidelines for Administration: 
See Treatment, Dose Modifications and Supportive Care sections of the protocol. 
 
The oral dose of mesna is twice the IV dose. 
 
Oral tablets: 
Administer tablets or diluted parenteral solution. Mesna tablets are scored and doses can 
be rounded to half a tablet (200mg).  

 
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Injection for oral use: 
Dilute the mesna parental solution before oral administration to decrease the sulfur odor 
associated with the product. The solution can be diluted 1:1 to 1:10 in water, carbonated 
cola drinks, fruit juices (grape, apple, tomato and orange) or plain or chocolate milk. The 
most palatable is chilled grape juice. 
 
Mesna may cause false positive test for urinary ketones.  
 
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information. 
 
6.11 
PEGFILGRASTIM, PEGFILGRASTIM-JMDB, PEGFILGRASTIM-CBQV  
 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®, Fulphila®, Udenyca®) NSC 
#725961 
         (01/28/19) 
 
Source and Pharmacology: 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). 
Pegfilgrastim 
is 
produced 
by 
covalently 
binding 
a 
20-kilodalton 
(kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of 
filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage specific 
colony-stimulating factor which regulates the production of neutrophils within the bone 
marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-
cell functional activation (including enhanced phagocytic ability, priming of the cellular 
metabolism associated with respiratory burst, antibody dependent killing, and the increased 
expression of some functions associated with cell surface antigens). 
 
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 15 to 
80 hours and the time to peak concentration ranges from 24 to 72 hours. Serum levels are 
sustained in most patients during the neutropenic period postchemotherapy, and begin to 
decline after the start of neutrophil recovery, consistent with neutrophil-dependent 
elimination. After subcutaneous administration at 100 mcg/kg in 37 pediatric patients with 
sarcoma, the terminal elimination half-life was 30.1 (+/- 38.2) hours in patients 0 to 5 years-
old, 20.2 (+/- 11.3) hours in patients 6 to 11 years-old, and 21.2 (+/- 16) hours in children 
12 to 21 years-old. 
 
 
Toxicity: 
Incidence 
Toxicities 
Common 
(>20% of patients) 
• 
Bone pain 
Occasional 
(4-20% of patients) 
• 
Pain in extremity 
Rare 
(<3% of patients) 
• 
Acute respiratory distress syndrome (ARDS) 
• 
Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, 
urticaria, generalized erythema, and flushing  
• 
Antibody development 
• 
Capillary leak syndrome 
• 
Glomerulonephritis 

 
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• 
Injection site reaction 
• 
Leukocytosis 
• 
Sickle cell crisis 
• 
Splenic rupture, splenomegaly 
• 
Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous 
vasculitis  
• 
Aortitis 
Pregnancy & 
Lactation 
Fetal toxicities and teratogenic effects of pegfilgrastim in humans are unknown. 
Adverse events were observed in some animal reproduction studies. It is unknown 
whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
Pegfilgrastim (Neulasta®): Supplied as a preservative-free solution containing 6 mg 
(0.6 mL) of pegfilgrastim (10 mg/mL) in a single-dose syringe with 27 g, ½ inch needle 
with an UltraSafeTM Needle Guard. The needle cover of the prefilled syringe contains drug 
natural rubber (a derivative of latex).  
 
Pegfilgrastim-jmdb (Fulphila®): Supplied as 6 mg/0.6 mL sterile, clear, colorless 
preservative-free solution (pH 4.0) containing acetate (0.7 mg), D-sorbitol (30 mg), 
polysorbate 20 (0.024 mg) and sodium (0.01 mg) in Water for Injection, USP.  It is intended 
for subcutaneous use only and is supplied in a single-dose prefilled syringe with a 29 gauge, 
½ inch needle, with UltraSafe Passive Plus™ Needle Guard. The prefilled syringe does not 
bear graduation marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 
mL).  
 
Pegfilgrastim-cbqv (Udenyca®): Supplied as 6 mg/0.6 mL syringe in a sterile, clear, 
colorless, preservative- free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 
(0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP. It is 
supplied in 0.6 mL prefilled single-dose syringes with an UltraSafe Passive™ Needle 
Guard for manual subcutaneous injection. The prefilled syringe does not bear graduation 
marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 mL). The 
needle cap of the prefilled syringe is not made with natural rubber latex. 
 
Storage: 
Store refrigerated between 2° to 8°C (36° to 46°F) in the carton to protect from light. Do 
not shake. Discard Neulasta® and Udenyca® syringes if stored at room temperature for 
more than 48 hours. Fulphila™ syringes should be discarded if stored at room temperature 
for more than 72 hours. Avoid freezing; if frozen, thaw in the refrigerator before 
administration. Discard syringe if frozen more than once. 
 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol. 
 
Pegfilgrastim should not be administered in the period between 14 days before and 
24 hours after chemotherapy. Do not shake. The manufacturers do not recommend use of 
the 6-milligram (mg) fixed-dose formulation of pegfilgrastim in infants, children, or 
adolescents under 45 kilograms. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 

 
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6.12 
VINCRISTINE SULFATE 
 
(Oncovin®, VCR, LCR) NSC #67574  
 
 
 
(08/16/12) 
 
Source and Pharmacology:  
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to tubulin, 
disrupting microtubules and inducing metaphase arrest. Its serum decay pattern is triphasic. 
The initial, middle, and terminal half-lives are 5 minutes, 2.3 hours, and 85 hours 
respectively; however, the range of the terminal half-life in humans is from 19 to 155 hours. 
The liver is the major excretory organ in humans and animals; about 80% of an injected 
dose of vincristine sulfate appears in the feces and 10% to 20% can be found in the urine. 
The p450 cytochrome involved with vincristine metabolism is CYP3A4. Within 15 to 
30 minutes after injection, over 90% of the drug is distributed from the blood into tissue, 
where it remains tightly, but not irreversibly bound. It is excreted in the bile and feces. There 
is poor CSF penetration.  
 
Toxicity: 
 
Common 
Happens to 21-
100 children out 
of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
Jaw pain, headache 
Extravasation (rare) but if occurs = local 
ulceration, shortness of breath, and bronchospasm 
Prompt: 
Within 2-
3 weeks, prior 
to the next 
course 
Alopecia, 
constipation 
Weakness, abdominal pain, 
mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, anemia) 
Paralytic ileus, ptosis, diplopia, night blindness, 
hoarseness, vocal cord paralysis, SIADH, seizure, 
defective sweating 
Delayed: Any 
time later 
during therapy 
Loss of deep 
tendon reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, foot 
drop, abnormal gait  
Difficulty walking or inability to walk; sinusoidal 
obstruction syndrome (SOS, formerly VOD) (in 
combination); blindness, optic atrophy; urinary 
tract disorders (including bladder atony, dysuria, 
polyuria, nocturia, and urinary retention); 
autonomic neuropathy with postural hypotension; 
8th cranial nerve damage with dizziness, 
nystagmus, vertigo and hearing loss 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with other 
antineoplastic agents) have been noted in humans. The toxicities include: chromosome 
abnormalities, malformation, pancytopenia, and low birth weight. It is unknown whether the drug 
is excreted in breast milk. 
 
Formulation and Stability: 
Vincristine is supplied in 1 mL and 2 mL vials in which each mL contains vincristine 
sulfate 1 mg (1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate are 
added for pH control. The pH of vincristine sulfate injection, USP ranges from 3.5 to 5.5. 
This product is a sterile, preservative free solution. Store refrigerated at 2˚-8˚C or 36˚-46˚F. 
Protect from light and retain in carton until time of use. 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 

 
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Guidelines for Administration: See Treatment and Dose Modifications sections of 
protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United States) 
and the Safety and Quality Council (Australia) all support the use of minibag rather than 
syringe for the infusion of vincristine. The delivery of vincristine via either IV slow push 
or minibag is acceptable for COG protocols. Vincristine should NOT be delivered to the 
patient at the same time with any medications intended for central nervous system 
administration. Vincristine is fatal if given intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. 
Vincristine sulfate must be administered via an intact, free-flowing intravenous needle or 
catheter. Care should be taken to ensure that the needle or catheter is securely within the 
vein to avoid extravasation during administration. The solution may be injected either 
directly into a vein or into the tubing of a running intravenous infusion.  
 
Special precautions: FOR INTRAVENOUS USE ONLY.  
The container or the syringe containing vinCRIStine must be enclosed in an overwrap 
bearing the statement: “Do not remove covering until moment of injection. For intravenous 
use only - Fatal if given by other routes.” 
 
Supplier: Commercially available from various manufacturers. See package insert for 
more detailed information. 
 
 
 

 
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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 (except where explicitly prohibited within the protocol). 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations  
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.  
 
7.1.1 
Required and Optional Clinical, Laboratory and Disease Evaluations at Study 
Entry, during Induction and at the end of Induction 
STUDIES TO BE OBTAINED 
Baseline 
During 
Chemotherapy 
End of Induction / 
Pre-Local Control 
History and Physical Exam 
X 
X1 
X 
Height, Weight, BSA 
X 
X1 
 
CBC, differential, platelets 
X 
X1, 2 
X 
Urinalysis 
X 
X1 
 
Urine or serum pregnancy test 
X8 
 
 
Electrolytes including Ca++, PO4, Mg++ 
X 
X1 
 
Creatinine, SGPT (ALT), Total bilirubin 
X 
X1 
 
Albumin  
X 
 
 
EKG 
X 
 
 
Echocardiogram or MUGA 
X 
X4 
 
Plain film of primary tumor (Recommended at 
baseline for bone tumors only) 
X 
 
 
MRI or CT of primary tumor6 
X 
 
X 
Chest CT7  
X 
 
X 
FDG-PET scan, including primary tumor SUV  
X10 
 
X10, 13 
Anatomic imaging of bone and soft tissue 
metastases 
X10 
 
X10 
MRI or CT and FDG-PET scans submitted for 
imaging aims12 
X 
 
X 
Bilateral bone marrow aspirates and biopsies 
X 
X5 
  X5   
Serum for ganitumab pharmacokinetics 
(only for first 10 patients < 21 years of age in 
Regimen B) 
X11 
(prior to 
ganitumab) 
X11 
(Days 15, 29  
and 71) 
 
Submission of bone marrow aspirate (optional)9 
X 
X 
X 
Peripheral blood in red top tube (required)9 
X 
Prior to Week 5 
Chemotherapy 
 
Peripheral blood in Streck tube for ctDNA study 
(optional, patients enrolling with Amendment 
#1 and beyond)9 
X 
Prior to Week 
314 and Week 5 
Chemotherapy 
X14 
Unstained slides/block (required at study entry)9 
X 
      
 
Peripheral blood in EDTA tube (required at 
study entry)9 
X 
 
 
1 
Obtain prior to each cycle. 
2 
Obtain additional CBCs as needed for good patient care. Recommended guidelines for 
administering interval-compressed chemotherapy include checking CBC with differential on 

 
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Day 1 and 8 of each cycle and then every Monday, Wednesday and Friday (or 3 other 
nonconsecutive days per week) after Day 12, until the criteria for starting the next cycle are 
satisfied.  
4 
Determination of shortening fraction or ejection fraction is to be obtained prior to Week 9 
doxorubicin. Use the same test each time for consistency in evaluation. 
5 
For patients with clinical evidence of bone marrow metastatic disease at study entry, repeat 
bilateral bone marrow aspirates and biopsies after Cycle 3 of Induction chemotherapy. If still 
positive, repeat at time of other end-Induction disease evaluations. See Sections 10.3.4 and 10.4 
for definitions of marrow response. See Section 15.0 for recommended bone marrow aspirate 
submission.  
6 
MRI preferred for most primary tumor sites. 
7 
CT scan of the chest should use spiral technique (if available) with a single breathhold, for 
patients able to cooperate. If whole body PET/CT obtained with thin cuts through chest, this 
scan may substitute for required chest CT scan otherwise a dedicated chest CT is required.    
8 
Pregnancy test required prior to study enrollment for females of childbearing potential only. 
9 
See Section 15.0 and Appendix II for specimen submission for required and optional studies.  
10 Sites suspicious for bone or soft tissue metastasis by FDG-PET scan at study entry should be 
imaged further with MRI or CT (whole body CT as part of PET/CT is acceptable) at study entry 
and at end-Induction.  
11 Serum samples for ganitumab concentrations are required for the first 10 patients < 21 years of 
age in Regimen B. See Section 15.5 for specimen requirements. (Enrollment to this required 
cohort completed as of July 2015 and all induction samples have been collected for this cohort) 
12 See Section 16.3 for instructions on submitting CT or MRI and FDG-PET images for imaging 
correlative aims.  
13 If an FDG-PET is obtained prior to the scan required at end-Induction, data on SUV at the 
primary tumor site should also be submitted. 
14. This time point is for patients who consented to Amendment #3C and beyond.   
 
This table only includes evaluations necessary to answer the study aims. Obtain other 
studies as indicated for good clinical care.  
  
 

 
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7.1.2 
Required and Optional Clinical, Laboratory and Disease Evaluations during Local 
Control, Consolidation, and Metastatic Site Radiation 
STUDIES TO BE 
OBTAINED 
Prior to Resuming 
Consolidation 
Chemotherapy 
During 
Chemotherapy 
End of 
Consolidation / 
Pre-Metastatic 
Site Radiation 
Metastatic Site 
Radiation 
History and Physical Exam, 
including O2 saturation for 
patients receiving whole 
lung radiation 
X 
X1 
X 
Weekly and 
within 30 days of 
completion of 
whole lung 
radiation 
Height, Weight, BSA 
X 
X1 
 
 
CBC, differential, platelets 
X 
X1, 2 
X 
Weekly 
Urinalysis 
X 
X1 
X 
 
Electrolytes including Ca++, 
PO4, Mg++ 
X 
X1 
X 
 
Creatinine, SGPT (ALT), 
Total bilirubin 
X 
X1 
X 
 
Echocardiogram or MUGA 
X4 
X4 
X4 
 
Pulmonary Function Testing 
 
 
X8 
 
MRI or CT of primary 
tumor6 
 
Prior to Week 9 
X 
Any time for 
suspected 
relapse13 
Chest CT7  
 
Prior to Week 9 
X 
Any time for 
suspected 
relapse13 
FDG-PET scan  
 
Prior to Week 910 
X10 
Any time for 
suspected 
relapse13 
Anatomic imaging of bone 
and soft tissue metastases 
 
Prior to Week 910  
X10 
 
Bilateral bone marrow 
aspirates and biopsies 
 
X5 
X5 
Any time for 
suspected 
relapse13 
Peripheral blood in red top 
tube (required)9 
 
 
X12 
 
Submission of bone marrow 
aspirate (optional)9 
 
X 
X 
 
Unstained slides/block from 
patients undergoing surgical 
local control (optional)9 
X 
 
X 
 
Peripheral blood in Streck 
tube for ctDNA study 
(optional for patients 
enrolling with Amendment 
#1 and beyond)9 
 
Prior to Week 912 
X 
 
Percent tumor necrosis for 
patients undergoing surgical 
local control11 
X 
 
 
 
1 
Obtain prior to each cycle. 
2 
Obtain additional CBCs as needed for good patient care. Recommended guidelines for 
administering interval-compressed chemotherapy include checking CBC with 
differential on Day 1 and 8 of each cycle and then every Monday, Wednesday and 
Friday (or 3 other nonconsecutive days per week) after Day 12, until the criteria for 

 
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starting the next cycle are satisfied. 
4 
Echocardiogram or MUGA (radionuclide angiogram) is to be obtained prior to each 
doxorubicin-containing cycle of Consolidation, prior to Week 11 Consolidation and 
again at end-Consolidation (at time of disease re-staging studies that take place at end-
Consolidation). More frequent monitoring may be indicated as part of good clinical 
care. Use the same test each time for consistency in evaluation. 
5 
For patients with clinical evidence of bone marrow metastatic disease at end-Induction 
evaluation, repeat bilateral bone marrow aspirates and biopsies prior to Week 9. All 
patients with clinical evidence of bone marrow metastatic disease at study entry will 
undergo repeat bilateral bone marrow aspirates and biopsies at end-Consolidation. See 
Sections 10.3.4 and 10.4 for definitions of marrow response. See Section 15.0 for 
recommended bone marrow aspirate submission. 
6 
MRI preferred for most primary tumor sites. Note that MRI may not be interpretable 
if the patient has undergone resection of the primary bony site of disease with 
placement of a massive metallic prosthesis. Imaging of the primary site following such 
procedures may be limited to plain radiographs and/or CT scan with contrast.  
7 
CT scan of the chest should use spiral technique (if available) with a single breathhold, 
for patients able to cooperate. If whole body PET/CT obtained with thin cuts through 
chest, this scan may substitute for required chest CT scan otherwise a dedicated chest 
CT is required.   
8 
For all patients with lung metastases at study entry who receive whole lung 
radiotherapy during Metastatic Site Radiation.  
9 
See Section 15.0 for specimen submission for optional recommended biology studies. 
Submission of unstained slides is requested for patients undergoing surgical local 
control during Local Control phase or as part of a delayed resection of a residual 
primary tumor or metastatic deposit.  
10 Sites of bone or soft tissue metastasis identified at study entry and any new sites of 
concern for bone or soft tissue metastasis based on FDG-PET should be imaged further 
with MRI or CT (whole body CT as part of PET/CT is acceptable) at each time point. 
11 See Section 14.3.3. 
12 This time point is for patients who consented to Amendment #3C and beyond. 
13 Submission of 
imaging 
demonstrating the 
first 
episode of 
disease 
progression/suspected relapse is required for central review (see Section 16.3). For 
times other than suspected relapse, follow recommended disease evaluation schedule 
for all patients in Regimens A and B in Section 7.3 timed from end-Consolidation. 
This includes disease restaging 3 months and 6 months from end-Consolidation.  
 
This table only includes evaluations necessary to answer the study aims. Obtain 
other studies as indicated for good clinical care.  
  
 

 
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7.2 
Correlative Biology Studies  
The correlative biology studies include both required and strongly recommended samples 
for all patients in both Regimen A and Regimen B of the study. These studies are critical 
to improve our understanding of metastatic Ewing sarcoma and response to IGF-1R 
inhibition. Any time a tumor is resected or biopsied in a patient who has consented to 
optional tissue collection on this study, tumor material should be submitted to support 
correlative biology studies.  
 
In addition to the correlative biology studies embedded within this clinical trial, all patients 
should be offered co-enrollment on the COG Ewing sarcoma biology study, AEWS07B1 
or APEC14B1. 
 
See Section 15.0 for detailed specimen requirements and Appendix II for a summary. 
 
 

 
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7.3 
Follow-up  
General follow-up should occur as per local institutional standards and as appropriate for individual patient care and known long term 
toxicities of 
agents received. 
See 
COG Late 
Effects Guidelines for 
recommended 
post 
treatment follow-up at: 
http://www.survivorshipguidelines.org/.  
 
7.3.1 
Suggested Clinical, Laboratory and Disease Evaluations during Follow-up 
Note that evaluations are timed from the end of Consolidation therapy for patients in both Regimen A and in Regimen B. 
Observation 
3  
Months 
6  
Months 
9  
Months 
1 
Year 
1.25  
Years 
1.5  
Years 
1.75  
Years 
2 
Years 
2.25  
Years 
2.5  
Years 
2.75 Years 
3 
Years 
3.5  
Years 
4 
Years 
4.5 
Years 
5 
Years 
History and 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Oxygen 
Saturation by 
Pulse Oximetry1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT Chest2,5 
X 
X 
X 
X 
 
 
  If Relapse Suspected  
Chest 
Radiograph5 
 
 
 
 
X 
X 
X 
X 
 
 X 
 
X 
X 
X 
X 
X 
MRI or CT3,5 
(Primary Site) 
X 
X 
X 
X 
If Relapse Suspected  
Plain film 
primary site and 
sites of bone 
metastasis5 
 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
FDG-PET scan4,5 
X 
X 
X 
X 
 
 
  If Relapse Suspected 
Bilateral bone 
marrow aspirates 
and biopsies 
If Relapse Suspected 
Echocardiogram 
or MUGA 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
1 
For patients treated with whole lung radiation. 
2 
CT Scan of the chest should use spiral technique (if available) with a single breathhold, for patients able to cooperate. May be omitted if FDG-PET scan includes 
diagnostic quality chest CT otherwise a dedicated chest CT is required. If residual abnormalities on chest CT, ongoing chest CT should replace chest radiograph 
during year 2 following completion of Consdolidation chemotherapy.     
3 
MRI preferred for most primary tumor sites. Note that MRI may not be interpretable if the patient has undergone resection of the primary bony site of disease with 
placement of a massive metallic prosthesis. Imaging of the primary site following such procedures may be limited to plain radiographs and/or CT scan with contrast.   
4 
Sites of bone or soft tissue metastasis identified at study entry and any new sites of concern for bone or soft tissue metastasis based on FDG-PET should be imaged 
further with MRI or CT (whole body CT as part of PET/CT is acceptable) at each time point FDG-PET scan required. 

 
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5 
Submission of the imaging demonstrating the first episode of disease progression/suspected relapse is required for central review (see Section 16.3). 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) schedule. 

 
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7.3.2 
Evaluations at time of suspected relapse 
Biopsy confirmation of suspected recurrence is recommended in most cases when 
feasible. In case of local relapse, metastatic work-up is required for confirmation 
of extent of recurrence.  
 
See Section 15.0 for submission of follow-up bone marrow aspirate material and/or 
unstained slides/tissue block and/or blood sample in Streck tubes obtained at the 
time of relapse.  
 
See Section 16.3 for submission of scans obtained at the time of first episode of 
relapse or disease progression.   
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease according to Section 10.3.  
b) Biopsy positive residual bone marrow metastatic disease by routine morphology at 
end-Consolidation (Section 10.4.1). 
c) Biopsy positive viable tumor after completion of Metastatic Site Radiation 
(Section 10.4.3). 
d) Refusal of further protocol therapy by patient/parent/guardian. 
e) Completion of planned therapy. 
f) Physician determines it is in patient’s best interest. 
g) Development of a second malignant neoplasm. 
 
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 (e.g., at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Tenth anniversary of patient’s entry to the study. 
f) Patients initially enrolled and randomized with a diagnosis of Ewing sarcoma or PNET 
for whom the initial enrolling diagnosis is changed to a diagnosis other than Ewing 
sarcoma or PNET.   
  
 

 
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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Statistical Design 
 
9.1.1 
Randomization 
The purpose of this study is to evaluate the role of ganitumab in the treatment of 
newly-diagnosed metastatic Ewing sarcoma. All patients enrolled on AEWS1221 
will be randomized at the time of enrollment, after confirmation of eligibility.  
 
Randomization will be done in the ratio of 1:1 to the non-ganitumab containing 
therapy (‘comparator regimen’) v. the ganitumab containing therapy (‘experimental 
regimen’). Randomization will be stratified according to age at enrollment 
(< 21 years vs. ≥ 21 years) and extent of disease (lung only vs. any other metastatic 
site): (1) stratum 1 – patients < 21 years with metastatic disease in one or both lungs 
only; (2) stratum 2 – patients < 21 years with any extra-pulmonary metastases; 
(3) stratum 3 – patients ≥ 21 years with metastatic disease in one or both lungs only; 
and (4) stratum 4 – patients ≥ 21 years with any extra-pulmonary metastases. 
 
9.1.2 
Primary Endpoint and Hypothesis 
The primary outcome measured on each participant will be time to adverse analytic 
event (EFS), defined to be disease-related event, diagnosis of a second malignant 
neoplasm, or death. A disease-related event will be: (1) disease progression as defined 
in Section 10.1-10.3; (2) persistent disease in bone marrow at the end of 
Consolidation therapy as defined in Section 10.4.1; or (3) biopsy-proven viable tumor 
after radiation of metastatic disease is completed, as described in Section 10.4.2. 
 
The primary analysis will entail estimation of the relative risk of adverse analytic 
event for patients on the experimental therapy compared with that for the standard 
therapy. The primary statistical null hypothesis is H0: The relative risk of an EFS-
event associated with the ganitumab containing therapy is 1 and the statistical 
alternative hypothesis is H1: The relative risk of an EFS-event associated with the 
ganitumab containing therapy is 0.67. 
 
9.2 
Patient Accrual and Expected Duration of Trial 
Under the statistical null hypothesis we expect to observe 218 events in the study 
population at the time of analysis for the primary study goal (Table 2B). This will entail 
5 years enrollment plus 1.5 years of follow-up of 300 randomized patients. With one-sided 
test of size 0.025, we will achieve 81% power under the alternative hypothesis. 
 
Table 1A. Aggregate EFS from previous COG studies of newly diagnosed metastatic 
Ewing sarcoma. 
 
Time Since Start 
Treatment (Years) 
Estimated Proportion 
Event-Free 
95% Confidence Interval 
1 
0.66 
0.60-0.72 
2 
0.36 
0.30-0.42 
3 
0.24 
0.22-0.34 
4 
0.23 
0.19-0.30 
 

 
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Based on this historical result, we estimate the survivor function for EFS for patients 
randomized to the comparator arm as the piecewise exponential survivor function with the 
times since enrollment and probabilities of remaining event-free given in Table 1B: 
 
Table 1B: EFS from Enrollment Expected for Patients Enrolled to the Comparator Therapy 
 
Time in Months Since 
Enrollment 
Proportion Analytic Event Free 
6 
0.881 
12 
0.664 
18 
0.457 
24 
0.357 
30 
0.308 
36 
0.280 
42 
0.265 
48 
0.244 
54 
0.240 
60 
0.238 
66 
0.235 
72 
0.234 
78 
0.233 
 
The enrollment experience as of June 2016 to AEWS1221 indicates we can expect 
approximately 5 patients per month (60 per year) to be enrolled. The study design will 
require the enrollment of 300 eligible patients with 1.5 years of follow-up after the last 
enrollment. We will enroll up to 330 patients to account for ineligible patients. The study 
will be open for accrual for approximately 5 years if 300 patients are required. In summary, 
the study will require 6.5 years to obtain sufficient data to address the primary study goal 
(5 years of enrollment plus 1.5 years of follow-up after the last patient is enrolled). 
 
Design Summary 
The two regimens will be compared using the relative risk regression model with strata 
representing those used for randomization. Each patient’s outcome will be associated with 
that individual’s assigned regimen regardless of received therapy. A log-partial-likelihood 
one-sided test of size 0.025 will be used to compare the two regimens. This level of α-error 
is commonly utilized in superiority designs intended to collect substantive evidence for a 
new treatment, particularly in a rare indication in which multiple definitive trials are not 
feasible. A one-sided comparison is used because the experimental regimen will be 
identified as the preferred therapy only if it is judged to be superior to the comparator 
regimen according to the statistical criteria described above. If the statistical alternative 
hypothesis is true, the experimental regimen will be identified for further development with 
probability 0.81. This probability was calculated using the method of Barthel et al,107 as 
illustrated in the evaluations of the statistical properties of the proposed design presented 
below: 

 
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Table 2A: Characteristics of the Proposed Design If the Alternative Hypothesis is True  
 
ART - ANALYSIS OF RESOURCES FOR TRIALS       (version 1.1.0, 10 December 2013) 
------------------------------------------------------------------------------ 
A sample size program by Abdel G Babiker, Patrick Royston & Friederike 
Barthel,MRC Clinical Trials Unit at UCL, London WC2B 6NH, UK. 
------------------------------------------------------------------------------ 
Type of trial                            Superiority - time-to-event outcome 
Statistical test assumed                 Unweighted logrank test (local) 
Number of groups                         2 
Allocation ratio                         Equal group sizes 
 
Total number of periods                  13 
Length of each period                    6 months 
 
Survival probs per period (group 11)      0.881 0.664 0.457 0.357 0.308 0.280 
                                          0.265 0.244 0.240 0.238 0.235 0.234 
                                          0.233 
Survival probs per period (group 22)      0.919 0.761 0.593 0.503 0.456 0.428 
                                          0.413 0.390 0.386 0.384 0.381 0.380 
                                          0.379 
Number of recruitment periods            10 
Number of follow-up periods              3 
Method of accrual                        Uniform 
Recruitment period-weights               1 1 1 1 1 1 1 1 1 1 0 0 0 
 
Hazard ratios as entered (groups 1,2)    1, .666666666667 
Alpha                                    0.025 (one-sided) 
Power (calculated)                       0.809 
 
Total sample size (designed)             300 
Expected total number of events          196 
 
1 Group 1– Comparator Regimen (Regimen A): The median EFS occurs at 16.6 months 
2 Group 2– Experimental Regimen (Regimen B): The median EFS occurs at 24.4 months 
 
Table 2B: Projected Number of Events Observed at Various Time Points After the Start of 
Enrollment If the Null Hypothesis is True 
 
Number of Elapsed Six 
Month Periods Since 
Study Opening 
Expected Cumulative 
Number of Patients 
Enrolled 
Expected 
Cumulative Number 
of Events – 
Comparator 
Regimen 
Expected 
Cumulative Number 
of Events – 
Experimental 
Regimen 
1 
30 
1 
1 
2 
60 
5 
5 
3 
90 
12 
12 
4 
120 
21 
21 
5 
150 
31 
31 
6 
180 
41 
41 
7 
210 
52 
52 
8 
240 
63 
63 
9 
270 
75 
75 
10 
300 
86 
86 
11 
300 
97 
97 
12 
300 
105 
105 
13 
300 
109 
109 

 
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Table 2C: Projected Number of Events Observed at Various Time Points After the Start of 
Enrollment If the Alternative Hypothesis is True 
 
Number of Elapsed Six 
Month Periods Since 
Study Opening 
Expected Cumulative 
Number of Patients 
Enrolled 
Expected 
Cumulative Number 
of Events – 
Comparator 
Regimen 
Expected 
Cumulative Number 
of Events – 
Experimental 
Regimen 
1 
30 
1 
1 
2 
60 
5 
3 
3 
90 
12 
8 
4 
120 
21 
14 
5 
150 
31 
22 
6 
180 
41 
31 
7 
210 
52 
40 
8 
240 
63 
49 
9 
270 
75 
57 
10 
300 
86 
67 
11 
300 
97 
75 
12 
300 
105 
82 
13 
300 
109 
87 
 
We expect many of the instances of disease progression will be identified at the time of 
regularly scheduled follow-up visits. This can lead to underestimation of the true relative 
risk associated with experimental regimen when relapse times are treated as exact.108 
Various solutions have been proposed.108,109 To assess the effect of this possible bias we 
will use the methodology proposed by Whitehead.110 Briefly, if all recurrences are detected 
at a scheduled screening time at the end of a reporting or follow-up period, we will apply 
Method 2 proposed by Whitehead.110 That is, the data will be treated as a discrete time 
survival process with the effect of treatment acting multiplicatively on the conditional 
probability of relapse. If some recurrences are detected at times other than scheduled screen 
times, we will adopt Method 4 proposed by Whitehead.110 That is, we will fit a parametric 
model that treats disease progressions identified at routine visits as interval censored 
observations with the left censoring time as the date of the last screening prior to the 
identification of the relapse and other relapse times as being know exactly. Initially we will 
fit generalized Gamma model for the exact time of relapse and use the Weibull model if 
this provides adequate fit.  
 
Interim Monitoring of Primary Endpoint 
The study will be monitored for evidence of reduction in EFS-event risk associated with 
ganitumab at 3 times after the start of randomization and prior to the final analysis. The 
flexible α-spending function approach will be used with the function α(t)=αt2. Each of these 
analyses will occur at the first report preparation date where the information fraction 
identified in Table 3A has been met or exceeded. Given the model for the outcome for the 
comparator arm delineated in Table 2B above, the calendar timing of these analyses will 
be approximately 2.5 years, 3.5 years and 4.5 years after the study is opened. The 
boundaries for the test statistic that will result in identifying the study to the DSMC for 
possible closure are summarized in Table 3A.  
 

 
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The planned time for the final analysis is that time at which 218 EFS-events have been 
observed (Table 2B). If the enrollment rate and the EFS-event rate for the comparator arm 
are as predicted, and study enrollment is not terminated because of interim monitoring or 
futility monitoring, this will occur with 5 years of accrual and 1.5 years of follow-up after 
the last patient is enrolled. 
 
Table 3A. Summary of Interim Monitoring for Evidence of EFS-Risk Reduction 
 
Expected 
Number of 
Years of 
Enrollment 
of 
Randomized 
Patients 
Total 
Expected 
Number of 
EFS-
events 
Given the 
Null 
Hypothesis 
Expected 
Information 
Log-rank 
Test 
Statistic 
Boundary 
Typical Value 
of 
ˆe
* at the 
Cutoff Value 
Cumulative 
α 
2.5 
61 
28% 
-2.88 
0.481177 
0.00196 
3.5 
104 
48% 
-2.61 
0.613302 
0.00576 
4.5 
149 
68% 
-2.39 
0.676864 
0.0116 
5 + 1.5 
Years of 
Follow-up 
218 
100% 
-2.07 
0.755484 
0.025 
 
* ˆ is the estimate of the log-hazard ratio and 
ˆe
is the estimated relative hazard rate for 
the EFS-event rates of Experimental
Comparator
 regimens from the relative risk regression model. 
 
Assessing inefficacy of ganitumab will be done following the methodology of Freidlin et 
al.111 The table below provides a summary of the time point at which each evaluation is 
done, the statistic used for the comparison and the boundary where, if the statistic is greater 
than or equal to the boundary, the study will be identified to the COG DSMC for possible 
termination because of inefficacy of ganitumab. 
 
Table 3B: Monitoring for Inefficacy of the Experimental Regimen 
  
Expected 
Number of 
Years of 
Enrollment of 
Randomized 
Patients 
Total Expected 
Number of 
EFS-events 
Given the Null 
Hypothesis 
Expected 
Information 
Statistic 
Considered 
Boundary 
2.5 
61 
28% 
( )
ˆ
ˆ
. .
s d


+ 
1.96 
3.5 
104 
48% 
ˆe
 
1 
4.5 
149 
68% 
ˆe
 
0.97 
 

 
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+    ˆ is the estimate of the log-hazard ratio, 
ˆe
is the estimated relative hazard rate for 
the EFS-event rates of Experimental
Comparator
 regimens and 
( )
ˆ
. .
s d  is the estimated standard 
error of ˆ from the relative risk regression model. Ten thousand simulated experiments 
were conducted under the null and alternative hypotheses to assess the frequency properties 
of the statistical design rules. The data for the comparator arm were generated using the 
survival distribution based on Table 1B, identified as 
( )
C
S
t  subsequently. The survivor 
function for the experimental regimen is identified as 
( )
E
S
t . 
 
Null Hypothesis - 
( )
( )
E
C
S
t
S
t
=
  
 
Time Point in Proportion 
of Expected Information 
Recommendation 
Probability 
Recommendation Will be 
Made Assuming Null 
Hypothesis is True 
28% 
Experimental Arm 
Considered Superior 
0.0015 
Insufficient Efficacy of the 
Experimental Arm 
0.021 
48% 
Experimental Arm 
Considered Superior 
0.0039 
Insufficient Efficacy of the 
Experimental Arm 
0.4716 
68% 
Experimental Arm 
Considered Superior 
0.0058 
Insufficient Efficacy of the 
Experimental Arm 
0.1315 
100% 
Experimental Arm 
Considered Superior 
0.0108 
Experimental Arm is Not 
Considered Superior 
0.3539 
 
The estimated size of the testing procedure is 0.022 
 
 
 

 
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Alternative Hypothesis - 
( )
( )
(
)
2
3
E
C
S
t
S
t
=
  
 
Time Point in Proportion 
of Expected Information 
Recommendation 
Probability 
Recommendation Will be 
Made Assuming 
Alternative Hypothesis is 
True 
28% 
Experimental Arm 
Considered Superior 
0.0644 
Insufficient Efficacy of the 
Experimental Arm 
0.0007 
48% 
Experimental Arm 
Considered Superior 
0.1789 
Insufficient Efficacy of the 
Experimental Arm 
0.0029 
68% 
Experimental Arm 
Considered Superior 
0.2372 
Insufficient Efficacy of the 
Experimental Arm 
0.0059 
100% 
Experimental Arm 
Considered Superior 
0.2977 
Experimental Arm is Not 
Considered Superior 
0.1862 
 
The estimated power of the test procedure is 0.78. 
 
Overall Toxicity of the Addition of Ganitumab to VDC/IE Chemotherapy 
Patients who receive treatment during: (1) Induction; or (2) Consolidation phases will be 
considered in this analysis. Any of these phases in which a patient receives all planned 
chemotherapy, has an adverse experience that requires termination of protocol therapy or 
stops protocol therapy because of a disease related event will be considered in this analysis. 
A phase where a patient experiences a Grade 4 non-hematological toxicity, Grade 3 left 
ventricular systolic dysfunction, or terminates protocol therapy because of a CTC codeable 
adverse experience will be considered a phase with a toxicity-event. The frequency of 
toxicity-events for each of the two phases will be modeled according to the formula: 
 
(
)
1
1
0
Pr
|
;
1
:
k
o
ij ij
j
k
o
ij ij
j
x
i
x
i
i
e
Toxicity
event x
e
Where x are the reporting period characteristics
is the baseline toxicity
event coefficient
are the coefficients associated with the characteristics






=
=
+
+

−
=

+
−
 
 
The phase characteristics are indicator variables including the randomized regimen as well 
as the local control modalities used on the primary tumor site. The null hypothesis βrandomized 

 
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regimen = 0 will be tested using a one-sided test against the alternative that the experimental 
regimen has an increased frequency of toxicity-events for each of the phases each time the 
study progress report is prepared for this trial. If this is significant at the 0.05 level, the 
study committee will alert the COG DSMC and CTEP that the experimental regimen has 
an increased toxicity-event rate. The committee will consult with the DSMC and CTEP to 
determine whether the experimental regimen should be modified. No adjustment will be 
made for multiple testing, since this is the most conservative approach to monitoring. For 
the Induction phase, where we expect 150 patients on each regimen to contribute to the 
analysis, the method proposed will identify the experimental regimen as having increased 
toxicity-event rate with at least probability 0.80 when the experimental regimen’s toxicity-
event rate is 33.2% and the comparator regimen’s toxicity-event rate is 20%. At the time 
of the preparation of each study progress report, we will construct the 95% confidence 
interval for the toxicity-event rate for each phase noted above for patients enrolled on the 
comparator therapy. If this lower bound of this confidence interval exceeds 33.2%, the 
committee will consult with the DSMC and CTEP to determine whether the study 
treatments should be modified. This analysis will be presented only to the COG DSMC 
except when consultation as described above is required. 
 
Sinusoidal Obstructive Disease (SOS) Associated with the Addition of Ganitumab to 
VDC/IE  
Patients who receive treatment during: (1) Induction; or (2) Consolidation phases will be 
considered in this analysis. Any of these phases in which a patient receives all planned 
chemotherapy, has an adverse experience that requires termination of protocol therapy or 
stops protocol therapy because of a disease related event will be considered in this analysis.  
 
Each phase will be evaluated for the occurrence of SOS according to the definition in 
Section 5.7.1. 
  
A phase where a patient experiences any SOS will be considered a phase with an SOS 
toxicity-event. The relative frequency of toxicity-events for each of the two phases will be 
modeled according to the formula: 
 
Pr Toxicity - event | xi
(
)= e
bo+b1xi
1+e
bo+b1xi ;
Where : xi is 1if the patient is randomized to ganitumab; 0 otherwise
b0 is the baseline toxicity -event coefficient
b1 is the coefficient associated with the randomized regimen
 
 
The null hypothesis β1 = 0 will be tested using a one-sided test against the alternative that 
the experimental regimen has an increased frequency of SOS toxicity-events for each of 
the phases each time the study progress report is prepared for this trial. For this analysis, 
initially all patient-phases will be considered as independent analytic units. 
 
If the exact conditional test of the hypothesis β1 = 0 is significant at the 0.10 level (one-
sided), the study committee will alert the COG DSMC and CTEP that the experimental 
regimen has an increased SOS toxicity-event rate. The committee will consult with the 
DSMC and CTEP to determine whether the experimental regimen should be modified. No 
adjustment will be made for multiple testing, since this is the most conservative approach 

 
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to monitoring. At the time of the primary analysis, under the null hypothesis and given the 
historical EFS experience, we expect 286 patient-phases to be accumulated for each 
regimen. The method proposed will identify the experimental regimen as having increased 
toxicity-event rate with at least probability 0.80 when the experimental regimen’s SOS 
toxicity-event rate is 5.7% and the comparator regimen’s SOS toxicity-event rate is 2% 
during each of the Induction and Consolidation phases.  
 
We will explore the effect of possible correlations between analytic units that arises 
because some analytic units are contributed by the same individual. We will employ a 
random effects binomial model where a Normally distributed random effect with 0 mean 
and unknown variance σ2 is contributed by each unit in a pair of analytic units that arise 
from the same individual. The results with respect to estimated regimen coefficient and p-
value for the null hypothesis for the two analytic approaches (completely independent v. 
random effects) β1 = 0 will be compared. 
 
A separate rule will monitor risk of SOS during the Maintenance phase. Because the 
experimental therapy has a Maintenance component that is not present in the comparator 
regimen, monitoring the incidence of SOS during Maintenance will be restricted to patients 
who are randomized to the experimental therapy and start the Maintenance phase of the 
protocol. A Maintenance phase in which a patient receives all planned ganitumab as 
prescribed by the protocol, has an adverse experience that requires termination of protocol 
therapy or stops protocol therapy because of a disease related event will be considered in 
this analysis. Each phase considered in the analysis will be evaluated for the occurrence of 
SOS according to the definition in Section 5.7.1. A phase where a patient experiences any 
SOS will be considered a phase with an SOS toxicity-event. All evaluable Maintenance 
phases will be aggregated and the statistical hypothesis: 
 
(
)
0 :Pr SOS Toxicity-Event is observed during maintenance
0.02
H
=
 
will be tested using a one sided exact binomial test of size 0.10. Evaluation of COG 
experience with the treatment of newly-diagnosed metastatic Ewing sarcoma indicates at 
least 90% of patients will remain event-free through Induction and Consolidation. We 
expect, therefore, to have approximately 135 phases available for evaluation per regimen. 
If 5 or fewer patients experience SOS the treatment will be considered to have an 
acceptable rate of SOS during Maintenance. If the true probability of SOS during 
Maintenance is 2%, the probability of declaring that Maintenance is associated with an 
excessive SOS rate is 0.055. If the true SOS toxicity probability is 5.8%, the method 
proposed will identify the Maintenance phase SOS toxicity rate as elevated with probability 
0.80. If the number of phases available for analysis differs from 135, we will adjust the 
cutoff values for the binomial test to maintain a type I error rate of at most 10% and a type 
II error rate of at most 20%, if possible. 
 
The above-noted analyses will be presented only to the COG DSMC except when 
consultation as described above is required. Further, if an incident of severe SOS is 
identified, a report describing the incident will be prepared by the AEWS1221 study 
committee and presented to the COG DSMC within one month of the reporting of such an 
incident. 
 

 
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In an effort to capture and monitor for potentially undiagnosed cases of SOS, the study 
committee will tabulate all episodes of Grade > 3 AST, ALT, and bilirubin according to 
randomized regimen twice yearly for review by the sponsor and COG DSMC.   
 
Comparing Risk for Death 
The two randomized regimens will be compared with respect to risk of death.  The outcome 
measure for this secondary aim will be overall survival (OS) defined as the time from 
enrollment to death regardless of cause or last patient contact.  A patient who is alive at 
last contact will be censored at that time for the purposes of this analysis; otherwise the 
patient will be considered to have experienced an event for the analysis described below. 
 
Based on this historical result, we estimate the survivor function for OS for patients 
randomized to the comparator arm as the piecewise exponential survivor function with the 
times since enrollment and probabilities of remaining event-free given in Table 1B: 
 
Table 4A: OS from Enrollment Expected for Patients Enrolled to the Comparator Therapy 
 
Time in Months Since 
Enrollment 
Proportion Alive 
6 
0.975 
12 
0.853 
18 
0.696 
24 
0.578 
30 
0.503 
36 
0.464 
42 
0.436 
48 
0.417 
54 
0.380 
60 
0.368 
66 
0.340 
72 
0.333 
78 
0.333 
 
We will use a relative risk regression model with strata representing those used for 
randomization. Each patient’s outcome will be associated with that individual’s assigned 
regimen regardless of received therapy. A log-partial-likelihood one-sided test of size 0.05 
will be used to compare the two regimens for this secondary analysis.  A one-sided 
comparison is used because the experimental regimen will be identified as the preferred 
therapy only if it is judged to be superior to the comparator regimen according to the 
statistical criteria described above. One analysis will be conducted at the time the analysis 
utilizing the primary outcome measure (EFS) is done. The statistical alternative hypothesis 
for the OS endpoint is quantified as the hazard ratio for death for Regimen B relative to 
Regimen A is 0.67 or lower. If the statistical alternative hypothesis is true, the experimental 
regimen will be identified for further development with probability 0.796. This probability 
was calculated using the method of Barthel et al,107 as illustrated in the evaluations of the 
statistical properties of the proposed design presented below: 
 

 
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ART - ANALYSIS OF RESOURCES FOR TRIALS       (version 1.1.0, 10 December 2013) 
------------------------------------------------------------------------------ 
A sample size program by Abdel G Babiker, Patrick Royston & Friederike Barthel, 
MRC Clinical Trials Unit at UCL, London WC2B 6NH, UK. 
------------------------------------------------------------------------------ 
Type of trial                            Superiority - time-to-event outcome 
Statistical test assumed                 Unweighted logrank test (local) 
Number of groups                         2 
Allocation ratio                         Equal group sizes 
 
Total number of periods                  13 
Length of each period                    6 months 
 
Survival probs per period (group 1)1      0.975 0.853 0.696 0.578 0.503 0.464 
                                          0.436 0.417 0.380 0.368 0.340 0.333 
                                          0.333 
Survival probs per period (group 2)2      0.984 0.899 0.785 0.694 0.632 0.600 
                                          0.575 0.558 0.525 0.513 0.487 0.480 
                                          0.480 
Number of recruitment periods            10 
Number of follow-up periods              3 
Method of accrual                        Uniform 
Recruitment period-weights               1 1 1 1 1 1 1 1 1 1 0 0 0 
 
Hazard ratios as entered (groups 1,2)    1, .666666666667 
Alpha                                    0.050 (one-sided) 
Power (calculated)                       0.796 
 
Total sample size (designed)             300 
Expected total number of events          150 
------------------------------------------------------------------------------ 
 
1 Group 1 – Comparator Regimen (Regimen A): The median OS occurs at 30.4 
months 
2  Group 2 – Experimental Regimen (Regimen B): The median OS occurs at 63 
months 
 
Comparing Bone Marrow Response Rates 
All eligible randomized patients who are enrolled on the trial with clinical evidence of bone 
marrow metastatic disease and who receive at least one dose of protocol chemotherapy will 
be considered for the evaluation of this endpoint. Each bone marrow evaluable patient will 
be assessed for the presence or absence of bone marrow metastatic disease over the interval 
between enrollment and the time of first local control measure or the end of the Induction 
reporting period, whichever comes first. Only one evaluation of best response will be used 
to classify the patient as complete responder (no evidence of marrow disease) or incomplete 
responder (residual marrow disease or progression according to Sections 10.3.4 and 10.4). 
We will provide an estimate of the proportion of patients who achieve complete bone 
marrow response and an associated 95% confidence interval. 
 
We expect approximately 20% of the 300 randomized patients to have bone marrow 
disease detected at enrollment. Since the assignment to ganitumab is done through 
randomization, we expect approximately half of such patients will be assigned to the 
experimental regimen, providing approximately 30 patients for the evaluation of this 
endpoint for each treatment arm. The maximum expected confidence interval will occur if 
50% of patients achieve a bone marrow CR, and the expected interval is 0.31-0.69. 
 
Tolerability of Maintenance with Ganitumab 
Each patient who receives ganitumab Maintenance will be evaluated for toxicity-event as 
described above. At the time each study progress report is prepared, the toxicity-event rate 
will be calculated and the one-sided test of size 0.05 of the null hypothesis that the toxicity-

 
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event rate is 25% will be performed. No adjustment for multiple testing will be made. If 
the true toxicity-event rate is 35% and 135 patients are evaluable for Maintenance toxicity, 
the therapy will be identified as associated with an elevated toxicity-event rate with 
probability 0.80. 
 
Ganitumab Pharmacokinetics 
The first 10 patients < 21 years of age at enrollment (‘younger patients’) assigned to 
Regimen B will be considered in the evaluation of dosing adequacy for younger patients. 
These patients will be required to submit samples for pharmacokinetic (PK) testing in 
Induction as described in Section 15.5. The proportion of patients achieving a trough serum 
concentration ≥ 10 µg/mL prior to the second dose of ganitumab in Induction will be 
obtained. If 7 or more of these 10 patients achieve this trough concentration, then the dose 
of 18 mg/kg will be deemed adequate in younger patients and randomization will continue 
for this age group. If < 7 patients achieve this trough concentration, the study committee 
will discuss the PK results with CTEP in order to determine if protocol modification is 
required prior to continuing the randomization for younger patients. Randomization will 
continue without interruption while PK data from these first 10 patients are analyzed and 
reviewed, up to 3 months from Induction Day 29 of the 10th patient < 21 years of age at 
enrollment. If the true proportion of patients with trough levels that are ≥ 10 µg/mL is 0.45, 
the dose will be identified for modification with probability 0.90. If the true proportion of 
patients with trough levels that are ≥ 10 µg/mL is 0.81, the dose will be identified as 
providing sufficient trough levels with probability 0.90. Additional trough levels in 
Induction will allow for estimation of accumulation, half-life, and steady state clearance of 
ganitumab.  
 
The first 10 patients < 21 years of age assigned to Regimen B will be required to submit 
samples for PK testing in Maintenance as described in Section 15.5. Results of this PK 
testing will be reported descriptively, with an emphasis on the proportion of patients 
achieving a trough serum ganitumab concentration ≥ 10 µg/mL at a dose of 18 mg/kg IV 
every 3 weeks. Additional trough levels in Maintenance will allow for estimation of 
accumulation, half-life, and steady state clearance of ganitumab.     
 
Feasibility and Efficacy of SBRT for Bone Metastases 
Based on data obtained from INT-0091, we expect approximately 45% of patients with 
newly-diagnosed metastatic Ewing sarcoma to present with bone metastases as a 
component of their metastatic disease burden. We expect at least half of these patients will 
receive SBRT, acknowledging there may be selection bias with respect to which patients 
receive SBRT. Compliance with protocol recommendations for SBRT timing (during local 
control vs. after completion of chemotherapy), dose and fractionation, and sites treated will 
be assessed in collaboration with IROC Rhode Island (formerly QARC). A patient will be 
considered an SBRT-feasibility-success if that individual has SBRT planned for at least 
one site, starts the treatment of metastatic disease phase of the protocol and has at least 
85% of tumor sites planned to be treated with SBRT receive successful SBRT. Patients 
who are removed from protocol therapy prior to the planned start date of radiation to 
metastatic sites will not be considered in this evaluation. Successful treatment delivery is 
defined as a treatment plan that is acceptable or has only minor variation as assessed by 
IROC Rhode Island (formerly QARC) (see Section 17.14). In addition to this feasibility 
assessment, efficacy will be evaluated by comparing the failure rate at irradiated bone 
metastases with SBRT and EBRT, recognizing selection bias between patients treated with 
SBRT or EBRT. Failure at a radiated bone metastasis will be defined according to Section 

 
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10.3.3. The cumulative incidence of local failure as a function of time will be estimated 
using cumulative incidence methods as described by Kalbfleisch and Prentice.112 Finally, 
the rates and grades of soft tissue ulceration and compression/insufficiency fractures at 
sites of SBRT will be reported descriptively.    
 
Association between Serum IGF Pathway Components and Tissue Markers and Outcome  
We will conduct exploratory analyses of initial IGF-1 level as well as other serum IGF-1 
pathway components as well as tissue protein, DNA, and RNA markers. One of the 
analyses that will be conducted will be to segregate the population into groups according 
the median value of the particular biological characteristic. Given the current aggregate 
outcome, a plausible long-term EFS for one of the median groups is 35% and for the other 
is 21%; this corresponds to a 1.5-fold increase in risk. If such a difference is present, we 
will identify the median division in initial IGF-1 levels as prognostic for outcome with 
probability of greater than 86% when using a test of size 0.10 when 90% of patients submit 
evaluable samples.  
 
It is of interest to compare the effect of each of the biological markers across groups defined 
by randomized treatment assignment. This will be done using the proportional hazards 
regression model: 
 
(
)
( )
1
2
3
0
; ,
[9.2.1]
z
f
z f
t z f
t e





+
+

=
 
 
Where: 
 
z takes on the value 0 if the patient is enrolled on the comparator arm and 1 otherwise; and 
 
f takes on the value 0 if the patient’s biological characteristic is at the median or below and 
1 otherwise. A formal statistical of 
0
3
:
0
H
=
 will be conducted and a two-sided p-value 
of 0.20 or less will be considered suggestive of an interaction between the assigned 
treatment and the biological characteristic. 
 
Linear trend in EFS-risk will be investigated by segregating the marker level according to 
quartiles. For bone marrow response rate analyses, Fisher’s exact test will be used to 
compare the objective bone marrow response rate (complete response vs. incomplete 
response) at start of local control between patients with biomarker levels above and below 
the group median. In addition, exploratory analyses will be performed using marker 
divided according to quartile of IGF-1 level. These analyses will be repeated for other 
serum and tissue markers. 
 
Evaluation of Bone Marrow Micrometastatic Disease and Tumor Cell Surface IGF-1R 
Expression  
The percentage of patients with detectable bone marrow micrometastatic disease at 
baseline who clear their bone marrow micrometastatic disease after three and six cycles of 
study therapy will be reported descriptively according to treatment arm. Extent of tumor 
cell IGF-1R co-expression will also be reported. Moreover, the change in tumor cell IGF-
1R co-expression in patients treated with and without ganitumab will be reported 
descriptively.  
 

 
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Germline Polymorphisms in EGFR  
Patients will undergo genotyping for EGFR promoter polymorphism at -216. EFS will be 
compared between patients with and without the presence of the minor allele using the log 
rank test. We will use a two sided test of size 0.10 for this exploratory analysis. Power 
calculations are provided below for various participation rates for genotyping and allele 
frequency for the entire population:  
 
Proportion 
Participation 
Proportion with 
G/G Absent 
Long-Term EFS 
with G/G Absent 
Relative Risk for 
EFS-Event 
with 
G/G Absent 
Power 
1.0 
0.50 
0.35 
1.5 
0.89 
0.75 
0.50 
0.35 
1.5 
0.81 
0.50 
0.50 
0.35 
1.5 
0.66 
1.0 
0.25 
0.35 
1.5 
0.79 
0.75 
0.25 
0.35 
1.5 
0.69 
0.50 
0.25 
0.35 
1.5 
0.53 
 
The presence of the promoter polymorphism may have different prognostic implications 
depending on treatment assignment. We will fit the model specified by equation [9.2.1] 
and test for an interaction between polymorphism status and treatment regimen. A formal 
statistical of 
0
3
:
0
H
=
 will be conducted and a two-sided p-value of 0.20 or less will 
be considered suggestive of an interaction between the assigned treatment and 
polymorphism status. EFS also will be compared between patients with and without the 
presence of the minor allele using the log rank test within groups defined assigned 
treatment. 
 
Additional analyses will compare overall survival and objective bone marrow response rate 
prior to local control as clinical outcomes of interest. Association between the number of 
copies of the minor allele and these clinical endpoints will be evaluated. 
 
Aim 1.3.11: The institutional result of EWS tumor testing will be categorized as 
translocation detected (yes v. no) and the type of translocation detected will also be 
recorded. From previous experience, we expect translocation testing will be done for at 
least 80% of patients. The proportion of patients with a particular EWS translocation variant 
will be tabulated.   
 
Risk for EFS-event will be compared across groups defined by translocation positivity 
using the log rank test. The power associated with such comparisons, as a function of 
patients evaluated for translocations and frequency of translocation positivity, can be 
obtained from the table above for Germline Polymorphisms in EGFR. The prognostic 
significance of each particular type of translocation, and any modifying effect of treatment 
assignment, will be assessed using a proportional hazards regression with indicator 
variables for the presence of each particular type of translocation and an indicator variable 
for treatment assignment. Since this is an exploratory exercise, a two-sided p-value of 0.10 
or less will identify any particular coefficient as of interest for further exploration. 
 
Aim 1.3.12: The results of ctDNA testing will be used to provide planning data for future 
trials. We expect baseline plasma samples obtained from the required EDTA baseline 
sample will be available from at least 250 patients (those who consented to future research 
for leftover samples prior to Amendment #1 and those who consent to the ctDNA 

 
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correlative study with Amendment #1 and beyond). With Amendment #1, we will also 
collect serial samples and expect that serial testing will be accomplished in at least 75 
patients. The proportion of patients with detectable EWSR1 translocations and key somatic 
mutations such as STAG2 and TP53, along with the allelic frequency for these mutations 
will be reported along with the proportion of patients with these characteristics from 
samples done at later time points. For patients who are evaluated serially, we will report 
the proportion of patients that have a change in translocation result associated with ctDNA 
testing across time periods. 
 
Aim 1.3.13: The results of serial genomic profiling from cells identified by flow cytometry 
will be used to provide planning data for future trials. We expect such testing will be 
accomplished in at least 50 patients, though the proportion of patients with insufficient 
bone marrow tumor cells to support genomic testing will be described. The profiles will be 
presented graphically, and samples obtained from different sites of tumor within the same 
individual will also be presented. 
 
 
Statistical Considerations for Imaging Correlative Studies 
Aim 1.3.9: This analysis will be conducted using modeling via the proportional hazards 
regression model. The outcome measure for this aim will be the event-free survival post 
Induction therapy. Analytic events include disease progression, disease recurrence, 
diagnosis of a second malignant neoplasm or death. Any patient who completes Induction 
chemotherapy without an analytic event and has received a PET scan at both start of 
therapy and end of Induction will be considered in this analysis. The change in average 
SUV (ΔS) between start of therapy and end of Induction and randomized treatment 
assignment will be independent variables in this analysis. Below, the variable zi will be 
used to represent variously ΔS, including a categorical variable which takes on the value 0 
if ΔS is below the median ΔS and 1 otherwise; ΔS categorized in tertiles; Z, where Z is 1 
if all PET signal disappears and 0 otherwise; and actual ΔS. RECIST response is 
represented by the variable Ri below. 
 
The proportional hazards regression model: 
 
(
)
( )
1
2
0
; ,
i
i
z
R
i
i
t z t
t e




+
=
 
 
The partial likelihood ratio test of H0: β1 = 0 will be conducted with R present in the relative 
risk regression model. A significance level of 0.10 will be considered suggestive of an 
augmentation of the predictive value of RECIST response in this population. We expect 
approximately 70% of patients will have the initial PET scan and of these, approximately 
95% will complete Induction chemotherapy. Thus we expect 200 patients will be available 
for this analysis, fifty percent of whom will be randomized to ganitumab. The power for 
test noted above depends the correlation between Z, the characterization of ΔS and Ri, as 
seen in the following table for the variable Z which takes on the value 0 if ΔS is below the 
median ΔS and 1 otherwise: 
 
Relative Hazard Rate 
Associated with Z = 1 
Correlation between Z and R 
Probability the Variable Z 
will be Identified as Of 
Interest According to the 
Criteria Above 
2.2 
0 
0.80 
2.5 
0.5 
0.80 

 
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Aim 1.3.10: This analysis will be conducted using modeling via the proportional hazards 
regression model. The outcome measure for this aim will be the event-free survival post 
Induction therapy. Analytic events include disease progression, disease recurrence, 
diagnosis of a second malignant neoplasm or death. Any patient who completes Induction 
chemotherapy without an analytic event and has received a PET scan at both start of 
therapy and end of induction will be considered in this analysis. The change in average 
SUV (ΔS) between start of therapy and end of Induction and randomized treatment 
assignment will be independent variables in this analysis. Below, the variable ai will be 
used to represent variously ΔS, including a categorical variable which takes on the value 0 
if ΔS is below the median ΔS and 1 otherwise; ΔS categorized in tertiles: 1 if all PET signal 
disappears and 0 otherwise; and actual ΔS. The randomized treatment assignment, bi, will 
be included if there is evidence of a treatment effect. 
 
The proportional hazards regression model: 
 
(
)
( )
1
2
0
;
,
i
i
a
b
i
i
t a b
t e




+
=
 
 
will be fitted to the data at the time of analysis for the primary study analysis. We will test 
H0: β1 = 0, a measure of effect of ΔS. A p-value less than 0.15 will be indicative of a 
possible relationship in this exploratory analysis. Estimated relative risks and 85% 
confidence intervals associated with the various characterizations of ΔS will be constructed 
from the proportional hazards regression model with all significant (as defined above) 
terms included. We expect approximately 70% of patients will have the initial PET scan 
and of these, approximately 95% will complete Induction chemotherapy. Thus we expect 
200 patients will be available for this exploratory analysis. 
 
The correlation between ΔS and percent necrosis in the resection specimen from the 
primary site of disease will be estimated. The correlation will be estimated treating the data 
as arising from a bivariate normal distribution. Any patient who completes Induction 
chemotherapy without an analytic event, has ΔS calculated and has the primary tumor site 
resected prior to the administration of primary site radiation treatment will be considered 
for this analysis. Of the 200 patients we expected will be available for the exploratory PET 
analysis described in the first paragraph of this section, we expect at least 50% of these 
individuals will also have resection of the primary disease site. With 100 patients, a test of 
size 0.10 of the null hypothesis of zero correlation between the results will be rejected with 
probability 0.80 if the true correlation is 0.245 or greater. 
 
 

 
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9.3 
Gender and Minority Accrual Estimates 
 
If 330 patients are required to complete the study, 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 
15 
15 
30 
Not Hispanic or Latino 
137 
163 
300 
Ethnic Category: Total of all subjects 
152 
178 
330 
Racial Category 
 
American Indian or Alaskan Native 
3 
3 
6 
Asian 
3 
3 
6 
Black or African American 
3 
5 
8 
Native Hawaiian or other Pacific Islander 
3 
0 
3 
White 
140 
167 
307 
Racial Category: Total of all subjects 
152 
178 
330 
This distribution was derived from AEWS1031. 
 
 
 
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 
Disease Assessment Requirements and Definitions 
See Section 7.0 for required disease staging at study entry, after initiation of protocol 
therapy, and during follow-up.  
 
10.2.1 Definitions 
 
Evaluable for event-free survival: All eligible patients will be evaluable for the 
event-free survival primary endpoint from the time of randomization (intent-to-
treat analysis).  
 
Evaluable for overall survival: All eligible patients will be evaluable for the overall 
survival secondary endpoint from the time of randomization (intent-to-treat 
analysis). 

 
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Evaluable for bone marrow metastatic disease response: Patients with morphologic 
evidence of Ewing sarcoma bone marrow involvement based on H&E stains at 
study entry will be will be evaluable for the bone marrow response secondary 
endpoint. In the absence of morphologic evidence of marrow involvement on 
H&E, patients with bone marrow involvement detected ONLY by flow cytometry, 
RT-PCR, or immunohistochemistry will not be considered to have clinical bone 
marrow involvement for the purposes of this study.  
 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of 
their first treatment with protocol therapy. 
 
10.2.2 Event-free Survival 
The following will constitute an event for the purposes of the primary study 
endpoint: 
• Death from any cause; 
• Development of a second malignant neoplasm other than non-melanoma skin 
cancer (see Section 11 for reporting requirements); 
• Disease progression according to Section 10.3.  
 
10.3 
Disease Response Criteria 
Disease progression will be defined according to site of disease involvement and will be 
based upon local investigator assessment. Progression at any site of previous or existing 
disease involvement will constitute disease progression. Development of disease 
involvement at a previously uninvolved site by imaging and/or biopsy will also constitute 
disease progression. 
 
10.3.1 Disease Assessment of Primary Bone Tumors 
This study will use three-dimensional measurements of primary bone tumors (not 
metastatic bone lesions) rather than single dimension as used in RECIST. The 
value of 3D volume measurement has already been substantiated in several 
studies.113-115 Moreover, bone tumors are considered non-measurable according to 
RECIST guidelines.  
 
10.3.1.1 Magnetic resonance imaging (MRI) 
MRI is the preferred imaging modality for primary bone tumors. Axial 
images and at least one additional plane are acquired. At least two pulse 
sequences, such as T1, T2, and STIR images are obtained. Post-contrast 
images are obtained if appropriate. Measurements should be made using 
the same sequence best showing the tumor in follow up for comparisons. 
Only axial images will be used for measurement. The cranio-caudal 
diameter is represented by the distance between the most cranial and 
caudal slice positions plus one slice thickness (or [slice thickness + gap] x 
number of slices showing the tumor minus one gap distance).  
 

 
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10.3.1.2 Technical guidelines for cross-sectional imaging computed tomography 
(CT)  
  All CT scans should be done with technical factors using the lowest 
radiation exposure possible (ALARA principle). 
2. CT slice thickness should be 5 mm or less. 
3. The diameter of a "measurable" mass should be at least twice the 
reconstructed slice thickness. Smaller masses are considered 
detectable, but will be counted as "non-measurable." 
4. Edge-enhanced lung windows, liver, and bone windows should be 
photographed, if recorded in hard copies. Digital images are submitted 
either electronically or in CD using DICOM format. 
 
10.3.1.3 The primary tumor will be measured in the largest anterior-posterior, 
transverse and longitudinal dimensions. Reporting of these three 
dimensions will be required. These dimensions will be used for central 
estimation of tumor volume using the formula for a prolate ellipsoid: 
volume in mm3= π /6 (d1·d2·d3) = (AP x transverse x longitudinal) x 0.5. 
Measurements should be obtained as described in the figure below. 
 
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 plus one slice
thickness), or [b] the product of ([slice 
thickness + gap] and the number of slices 
showing the tumor) minus one gap distance
WHO criteria: TxW is used
RECIST: the larger of the two (T & W) is      
used (W in this example)
Elliptical model volume=0.5 LxWxT
The same modality and measurement method 
used in the initial imaging should be used in 
follow ups
X-Y
PLANE
L
 
 
10.3.1.4 Response of the Primary tumor 
 
Based on previously published data correlating tridimensional 
measurements to bi-directional and unidirectional measurements the 
following response criteria for the primary tumor will be used116: 
 

 
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Complete Response (CR): Complete disappearance of the tumor. 
 
Partial Response (PR): At least 64% decrease in volume compared to the 
baseline. 
 
Progressive Disease (PD): At least 40% increase in tumor volume 
compared to the smallest measurement obtained since the beginning of 
therapy. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as reference the smallest 
disease measurement since the treatment started. 
 
10.3.2 Disease Assessment of Soft Tissue Primary Tumors and Metastatic Lesions 
Assessment of soft tissue primary tumors and soft tissue metastatic lesions 
(including lung and node metastasis) will follow revised Response Evaluation 
Criteria in Solid Tumors (RECIST) guideline (version 1.1)117 Changes in the 
largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm 
by chest x-ray, as ≥ 10 mm with CT scan, or ≥ 10 mm with calipers by clinical 
exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might 
not be considered measurable.  
 
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small 
lesions (longest diameter < 10 mm or pathological lymph nodes with ≥ 10 to 
< 15 mm short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 

 
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Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline. Measurements of these lesions are 
not required, but the presence, absence, or in rare cases unequivocal progression 
of each should be noted throughout follow-up.  
 
10.3.2.1 Methods for Evaluation of Measurable Soft Tissue Disease 
All measurements should be taken and recorded in metric notation using 
a ruler or calipers. All baseline evaluations should be performed as 
closely as possible to the beginning of treatment and never more than 
4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used 
to characterize each identified and reported lesion at baseline and during 
follow-up. Imaging-based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (eg, skin nodules and palpable lymph nodes) 
and  10 mm diameter as assessed using calipers (eg, skin nodules). In 
the case of skin lesions, documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of 
lesions on CT scan based on the assumption that CT slice thickness is 
5 mm or less. If CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (eg, for body 
scans).  
 

 
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MRI is widely available, has excellent contrast, spatial, and temporal 
resolution and should be used as the modality of choice for staging of 
most primary tumors, except some chest wall tumors. MRI is also 
evolving as a radiation-free imaging modality for whole body staging. 
As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions 
should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse 
sequence parameters for all scanners, body parts, and diseases. Ideally, 
the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body 
scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET-CT: Modern PET/CT scanners allow one to obtain a diagnostic, low 
dose CT scan, which can be both used for diagnostic purposes and for 
attenuation correction of PET data. In addition to reconstructing the 
whole body CT data in a soft tissue algorithm, the chest CT scan should 
be reconstructed in the lung algorithm. Most sites would be expected to 
be able to obtain such a combined scan in order to avoid duplicate 
irradiation of the patient. If a diagnostic CT (with IV contrast) is acquired 
as part of a PET-CT, then the CT portion of the PET-CT can be used for 
evaluation of pulmonary nodules and RECIST measurements.  
 
However, some centers with older scanners may not be able to generate 
diagnostic CT quality for use with RECIST measurements and may have 
to obtain an additional, diagnostic CT scan on a separate CT scanner as 
a separate imaging procedure, and use this scan for RECIST 
measurements. This would be considered suboptimal based on ALARA 
guidelines.  
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. Ultrasound 
examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for 
objective tumor evaluation is not advised. However, such techniques 
may be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate 

 
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between partial responses (PR) and complete responses (CR) in rare 
cases (eg, residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met 
criteria for response or stable disease is mandatory to differentiate 
between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET: While FDG-PET response assessments need additional 
study, it is sometimes reasonable to incorporate the use of FDG-PET 
scanning to complement CT scanning in assessment of progression 
(particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at a site at baseline, with a positive FDG-PET 
at follow-up is concerning for progressive disease based on 
development of a new lesion. For the purposes of this study, 
confirmatory imaging with CT scan or MRI scan is required. 
Biopsy is strongly encouraged, but not required to confirm new 
site of bone metastasis. See Section 15.0 for submission of biopsy 
material at time of relapse in patients consenting to correlative 
biology studies. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, MRI or biopsy, this is progressive 
disease. If the positive FDG-PET at follow-up is not confirmed as 
a new site of disease on CT, MRI, or biopsy, additional follow-up 
CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan). If the positive FDG-PET at 
follow-up corresponds to a pre-existing site of disease on CT that 
is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner 
similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. The use of 
FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical 
literature for the indication. However, it must be acknowledged 
that both approaches may lead to false positive CR due to 
limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid 
with an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
 
10.3.2.2 
Evaluation of Target Soft Tissue Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any 

 
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pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD):At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
 
10.3.2.3 
Evaluation of Non-Target Soft Tissue Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions 
and normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
 
Note: If tumor markers are initially above the upper normal limit, they 
must normalize for a patient to be considered in complete clinical 
response. 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump target lesion status. 
It must be representative of overall disease status change, not a single 
lesion increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such 
circumstances, and the progression status should be confirmed at a later 
time by the review panel (or Principal Investigator). 
 
10.3.2.4 Evaluation of Best Overall Response for Soft Tissue Lesions 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the 
treatment started).  
 

 
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For Patients with Measurable Disease (ie, Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-
PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
For Patients with Non-Measurable Disease (ie, Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be 
measured is not advised 
 
10.3.3 Disease Assessment of Bone Metastases 
Radiographic assessment of bone metastasis can be difficult as remodeling bone 
may lead to residual abnormalities on bone scan, CT scan, and MRI scan. For the 
purposes of the current protocol, response at bone metastasis will be graded as 
follows: 
 
Complete response (CR) = FDG-PET negative at all previous sites of bone 
metastasis. 
 
Progressive disease (PD) = Any of the following will constitute PD: 
• Development of new bone metastasis at a previously uninvolved site. FDG-
PET imaging may NOT be the only study to document development of a new 
bone metastasis. Confirmatory imaging with bone scan, CT scan, or MRI scan 
is required. Biopsy is strongly encouraged, but not required to confirm new 
site of bone metastasis. See Section 15.0 for submission of biopsy material at 
time of relapse in patients consenting to correlative biology studies. 
 
• Development of a new soft tissue mass ≥ 1 cm in maximum axial dimension 
at a previous site of bone metastasis without a soft tissue component or with a 
soft tissue component < 1 cm in maximum axial dimension on previous 
evaluations. 

 
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• For bone metastasis with a soft tissue component ≥ 1 cm in maximum axial 
dimension on previous evaluations, an increase in the longest axial diameter 
of the soft tissue component by > 20%.  
 
• A previous bone metastasis that was positive on FDG-PET, became negative 
with protocol therapy, and then becomes positive again should prompt concern 
for progression at that site. Confirmatory testing is required to document 
progression at a previous site of bone metastasis. Together with return of FDG-
PET uptake, MRI scan with documentation of an enhancing bone lesion will 
constitute adequate evidence to support progression at that site. Biopsy is 
strongly encouraged, but not required to confirm progression at a previous site 
of bone metastasis. See Section 15.0 for submission of biopsy material at time 
of relapse in patients consenting to correlative biology studies.  
• Biopsy evidence of viable Ewing sarcoma at a previously radiated bone 
metastasis, at least 8 weeks after completion of treatment. 
 
Stable disease (SD) = Patients not meeting either CR or PD criteria. 
 
10.3.4 Disease Assessment of Bone Marrow Metastatic Disease  
Since disease involvement can be patchy, bilateral bone marrow aspirates and 
biopsies are recommended for assessing bone marrow metastatic involvement. 
Bone marrow metastatic status is based solely on standard morphologic review of 
H&E stained bone marrow aspirate and biopsy material. For the purposes of this 
study, flow cytometry, FISH, RT-PCR for EWSR1 fusion transcripts, and 
immunohistochemistry for CD99 are considered investigational for assessing bone 
marrow metastatic status.  
 
The suggested approach for patients with large pelvic tumors in which a posterior 
iliac crest bone marrow biopsy would track through the tumor is to instead undergo 
two marrow biopsies on the contralateral side (either two posterior biopsies or one 
posterior and one anterior biopsy). 
 
Bone marrow metastatic response will be graded as follows: 
 
Complete response (CR) = No morphologic evidence of Ewing sarcoma 
 
Progressive disease (PD) = Development of new marrow involvement in a patient 
without previous marrow involvement or in a patient who had previously achieved 
bone marrow CR. For patients in the latter category with < 10% bone marrow 
involvement, a confirmatory biopsy should be performed 2-4 weeks after initial 
biopsy showing recurrent marrow involvement. 
 
Stable disease (SD) = Patients not meeting either CR or PD criteria.  
 
10.4 
Demonstration of Residual Viable Tumor  
In addition to the above definitions of disease progression, the following criteria will 
constitute failure of protocol therapy to clear disease sufficiently at benchmark timepoints 
for the patient to continue on protocol therapy. Patients meeting these criteria will be 

 
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considered to have had an analytic event for the purposes of the primary study endpoint, 
even in the absence of disease progression as defined above. 
 
10.4.1 Residual bone marrow metastatic disease by end-Consolidation 
Patients who have not achieve a bone marrow CR as defined in Section 10.3.4 by 
the end of the Consolidation phase of therapy will constitute failure of protocol 
therapy to eradicate disease and patients will be removed from protocol therapy at 
that time. 
 
10.4.2 Biopsy-proven residual tumor at any site after completion of Metastatic Site 
Radiation Phase 
Patients with biopsy proven residual Ewing sarcoma following completion of the 
Metastatic Site Radiation phase of therapy and at least 8 weeks after completion 
of radiation treatment (if applicable) will constitute failure of protocol therapy to 
eradicate disease and patients will be removed from protocol therapy at that time. 
Biopsy is not mandated or recommended at this timepoint. Note that this criterion 
applies to patients in both Regimen A and Regimen B. This criterion also applies 
to radiated sites or non-radiated sites. This criterion applies to primary tumor sites 
and metastatic sites.  
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS  
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Certain adverse events must be 
reported in an expedited manner to allow for timelier monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the Phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Application (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply.  
• 
Concurrent administration: When an investigational agent is used in combination 

 
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with a commercial agent, the combination is considered to be investigational and 
expedited reporting of adverse events would follow the guidelines for 
investigational agents. 
• 
Sequential administration: When a study includes an investigational agent and a 
commercial agent on the same study arm, but the commercial agent is given for a 
period of time prior to starting the investigational agent, expedited reporting of 
adverse events which occur prior to starting the investigational agent would follow 
the guidelines for commercial agents. Once therapy with the investigational agent 
is initiated, all expedited reporting of adverse events follow the investigational 
agent reporting guidelines. 
 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting tables 
assigned to the protocol, using the NCI’s CTEP Adverse Event Reporting System (CTEP-
AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations which are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse drug experience when, 
based upon medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
11.4 
Special Situations for Expedited Reporting  
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol.  
 
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered to be serious AEs 
 

 
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11.4.3 Death 
 
Reportable Categories of Death  
 
• Death attributable to a CTCAE term.  
• Death Neonatal: Newborn death occurring during the first 28 days after birth.  
• Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5.  
• Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
• Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions”. Evidence that the death was a manifestation 
of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (eg, treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) 
must also be reported via the routine reporting mechanisms outlined in this 
protocol. 
 
11.4.5 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. 
 
 

 
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11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal 
loss”, 
the Pregnancy Information Form, available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 897-7404. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 
Pregnancy 
Patients who become pregnant on study risk intrauterine exposure 
of the fetus to agents which may be teratogenic. For this reason, 
pregnancy needs to be reported in an expedited manner via CTEP-
AERS as Grade 3 “Pregnancy, puerperium and perinatal 
conditions - Other (pregnancy)” under the “Pregnancy, 
puerperium and perinatal conditions” SOC. 
 
There is a possibility that the sperm of male patients treated on 
studies involving possible teratogenic agents may have been 
damaged. For this reason, pregnancy in partners of men on 
study needs be reported and followed in the same manner as 
a patient pregnancy. 
 
Pregnancy needs to be followed until the outcome is known. If 
the baby is born with a birth defect or anomaly, then a second 
CTEP-AERS report is required. 
 
11.4.6.2 
Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and 
perinatal conditions” SOC. Do NOT report a pregnancy loss as a 
Grade 5 event since CTEP-AERS recognizes any Grade 5 event 
as a patient death. 
 
11.4.6.3 
Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring 
during the first 28 days after birth”, should be reported 
expeditiously as Grade 4, “Death neonatal” under the “General 
disorders and administration” SOC, when the death is the 
result of a patient pregnancy or pregnancy in partners of men 
on study. Do NOT report a neonatal death resulting from a patient 
pregnancy or pregnancy in partners of men on study as a Grade 5 
event since CTEP-AERS recognizes any Grade 5 event as a 
patient death.  
 

 
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11.5 
Reporting Requirements for Specialized AEs  
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (eg, elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must reassess 
the event to determine if an expedited report is required. 
b. If the AE resolves and then recurs, the investigator must re-assess the event to 
determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles/courses.  
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent course. If the grade becomes more severe 
the AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent course. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.6 
Exceptions to Expedited Reporting 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
 

 
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11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.  
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted electronically to NCI via CTEP-AERS at:  
https://eapps-ctep.nci.nih.gov/ctepaers  
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site.  
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect, 
or is an IME, which based upon the medical judgment of the investigator may 
jeopardize the patient and require intervention to prevent a serious AE, must be 
reported via CTEP-AERS if the event occurs following investigational agent 
administration.  
 
 

 
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• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 24 
hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE 
requires expedited reporting within 24 hours.  
CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (eg, H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: (301) 897-7404.  
 
Also: Fax or email supporting documentation to COG for all IND studies (Fax # (310) 640-
9193; email: COGAERS@childrensoncologygroup.org; Attention: COG 
AERS 
Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided 
during trial registration on all reports. 
  
 

 
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11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR 
Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse 
Events, whether or not they are considered related to the investigational agent(s)/intervention 
(21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours. This  
does not include hospitalizations which are part of routine medical 
practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may  
be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may  require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported 
to the NCI via CTEP-AERS within the timeframes detailed in the table below.  
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour 
Notification 
5 Calendar 
Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found 
in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Additional Special Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days of 
the initial 24-hour notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 
calendar days of learning of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as 
follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  

 
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11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
• 
CTEP-AERS 24-hour Notification is required for any degree of clinical 
sinusoidal obstruction syndrome (SOS), from mild to severe (see protocol 
Section 5.7.1). 
 
• 
CTEP-AERS 24-hour Notification is required for ≥ Grade 1 pneumonitis. 
 
• 
CTEP-AERS 24-hour Notification is required for ≥ Grade 2 decreased 
ejection fraction. 
 
The following adverse events do NOT require expedited CTEP-AERS reporting 
for this protocol: 
• 
Grades 1- 4 myelosuppression do not require expedited reporting.  
• 
Hospital admission/prolongation of hospitalization for Grade 3 febrile 
neutropenia does not require expedited reporting unless unexpected. 
• 
Hospital admission/prolongation of hospitalization for Grade 3 infection does 
not require expedited reporting unless unexpected. 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy With a Commercial Agent or Within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent, regardless of attribution.  Any death that occurs more than 30 days 
after the last dose of treatment with a commercial agent which can be attributed 
(possibly, probably, or definitely) to the agent and is not due to cancer recurrence 
must be reported via CTEP-AERS. 
 

 
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Additional Instructions for CTEP-AERS Expedited Reporting Requirements for 
Commercial Agents: 
 
• 
CTEP-AERS 24-hour Notification is required for any degree of clinical 
sinusoidal obstruction syndrome (SOS), from mild to severe (see protocol 
Section 5.7.1). 
 
• 
CTEP-AERS 24-hour Notification is required for ≥ Grade 1 pneumonitis. 
 
• 
CTEP-AERS 24-hour Notification is required for ≥ Grade 2 decreased 
ejection fraction. 
 
11.12 Routine Adverse Event Reporting 
 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For all patients in this study, routine reporting requirements 
differ depending upon phase of therapy in which the adverse event occurs:  
• 
During Induction and Consolidation, routine reporting will include all toxicities 
reported via CTEP-AERS expedited reporting system, all Grade 3 and higher non-
hematologic Adverse Events, all Grade 4 and higher hematologic Adverse Events, 
and any toxicity that requires termination of protocol therapy.  
• 
During Metastatic Site Radiation, routine reporting will include all toxicities 
reported via CTEP-AERS expedited reporting system, all Grade 3 and higher 
Adverse Events (hematologic and non-hematologic), and any toxicity that requires 
termination of protocol therapy. 
• 
During Maintenance, routine reporting for patients who started Maintenance prior 
to activation of Amendment #3C will include all toxicities reported via CTEP-
AERS expedited reporting system, all Grade 3 and higher Adverse Events 
(hematologic and non-hematologic), and any toxicity that requires termination of 
protocol therapy. Routine reporting for patients who started Maintenance after 
activation of Amendment #3C will include all grade adverse events.   
 
In addition, any patient who receives radiation to a bone metastasis (SBRT or standard 
external beam radiation) will have Grade 2 or higher skin ulceration or Grade 2 or higher 
fracture at the site of bone radiation reported. Please specify on the AE form the type of 
radiation received. 
 
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. 

 
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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. 
 
 
12.3 
CRADA/CTA 
 
NCI/DCTD Standard Language to Be Incorporated into All Protocols Involving 
Agent(s) Covered by a Clinical Trials Agreement (CTA), a Cooperative Research and 
Development Agreement (CRADA) or a Clinical Supply Agreement, hereinafter referred 
to as Collaborative Agreement: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 

 
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a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design 
of the proposed combination protocol, and the existence of any obligations that 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its own 
Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data 
solely 
for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent 
to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication. Collaborator(s) will have 30 
days from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
 

 
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The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
 
 
13.0 
SURGICAL GUIDELINES 
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 (except where explicitly prohibited within the protocol). 
 
COG member institutions are encouraged to enroll patients on a specimen collection study (such as 
AEWS07B1 or APEC14B1). In addition, patients are encouraged to participate in the embedded 
correlative biology studies in this trial (see Section 15.0). Submission of material from initial tumor 
biopsy is required for participation in this study and this requirement should be considered when 
planning the initial biopsy. Surgeons, treating team and pathologists should review specimen 
requirements for tissue collection and handling for these studies prior to biopsy and definitive surgery. 
 
13.1 
Surgical Guidelines for Biopsy 
 
13.1.1 Technique 
Open, incisional biopsy of the primary is recommended to allow procurement of 
enough tissue for all biologic studies. Consultation with a surgical and/or 
orthopedic oncologist prior to open or needle biopsy is strongly recommended as 
the approach used for the initial biopsy may impact the future surgical approach.   
A move to performing open biopsy may be against the current practice in many 
institutions where a needle biopsy provides adequate tissue for diagnosis. Biologic 
studies are becoming increasingly important and may lead to changes in 
therapeutic approach. Multiple passes with a needle may not provide enough 
aggregate tissue for all of the studies currently done. A minimum of 1 cubic 
centimeter of tissue is required for special studies. An additional amount of fresh 
tissue must be obtained for diagnostic studies. Most children require a general 
anesthetic for needle biopsy, and often a venous access device can be inserted at 
the time of biopsy. Changing the practice to doing open biopsies therefore should 
not result in increased morbidity for the patients.  
 
In most instances the diagnosis can be made from the surrounding involved soft 
tissues avoiding the need for obtaining bone. Creation of a bone defect during 
biopsy significantly weakens the bone thus increasing the risk of pathologic 
fracture. This risk is markedly increased if radiotherapy is later given as the 
definitive local therapy. A bone biopsy will also preclude the possibility of 
performing a frozen section to determine the adequacy of material for diagnosis. 
 
13.1.2 Specimen Quality 
Biopsy material should be sent to pathology in a fresh state in normal saline or 
tissue culture medium. Ewing sarcomas are often necrotic, therefore intra-
operative frozen section or touch preparations should be done to be certain that the 
tissue obtained is adequate and sufficient for diagnosis. It is strongly recommended 

 
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that adequate tissue be obtained for biologic studies (AEWS07B1 and Section 15.0 
of the current trial). The specimen should be handled in an expeditious manner and 
not left on the back table for more than a few minutes as substantial degradation 
begins immediately ex vivo.118  
 
13.1.3 Specimen Quantity and Handling 
Proper handling of biopsy tissue requires knowledge of the objectives to be 
studied. A minimum of 3-5 grams of fresh, viable, non-necrotic tumor tissue 
should be sent immediately to the Pathology Department. Material must be 
obtained for multiple analyses (routine histopathology, cytology, touch 
preparations, electron microscopy, tissue culture, flow cytometry, cytogenetics, 
etc.) to permit full evaluation for diagnosis and cancer biology studies. 
 
13.1.4 Therapeutic Considerations 
Future surgical excision and radiation therapy must be borne in mind during the 
biopsy. Imaging, in particular MRI, should be obtained prior to biopsy. Principles 
of biopsy should be followed. These include: longitudinal incisions; the ability to 
remove the biopsy tract with the lesion at the time of surgical excision; avoidance 
of neurovascular structures; and a direct route to the tumor through muscles rather 
than retracting them. If appropriate management of the tumor requires a 
compartmental resection, one should be able to proceed after biopsy and 
neoadjuvant chemotherapy without significantly extending the margins beyond 
those previously planned. If one is unfamiliar with the suspected extension of the 
lesion and the three dimensional compartmental anatomy of the extremity, a simple 
error on incision orientation and placement or injudicious exposure of a major 
neurovascular structure could result in the need for amputation. Postoperative 
hematoma formation can render a previously resectable lesion unresectable. 
Techniques that will diminish the likelihood of hematoma formation and dissection 
could include the use of a tourniquet (after gravity exsanguination), thrombogenic 
agents (activated thrombin, Oxygel, Avitene), and a hemostatic subarticular 
closure. The tourniquet if used at all should be deflated prior to closure in order to 
assure absolute hemostasis. Anatomic structures and planes dissected by 
hematoma should be considered contaminated and may have to be included in the 
subsequent definitive surgical margins. If a drain is left in place, it should exit in 
line with the longitudinal biopsy incision and close to the margin of the incision. 
 
13.1.5 Regional Lymph Node Evaluation 
Soft tissue Ewing sarcoma has higher rates of regional lymph node involvement 
compared to bone Ewing sarcoma.  For patients with soft tissue primary tumors, 
clinical and imaging evaluation of regional lymph nodes must be performed before 
therapy begins. Pathologic evaluation of clinically suspicious nodes in patients 
with bone or soft tissue primary tumors should be performed. Regional node 
debulking or resection is not recommended. Open biopsy of the involved node is 
recommended, but needle biopsy or fine needle aspiration may be appropriate 
based on the surgeon’s judgment and pathologist’s recommendations. Sentinel 
node techniques may be used if lymph node sampling is planned. 
 
13.2 
Surgical Guidelines for Consideration of Amputation at Diagnosis 
While the role of amputation in the management of the extremity primary in Ewing 
sarcoma is controversial, in certain clinical situations amputation may be the best 

 
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alternative. In compliance with the objectives of the study, if necessary, amputation should 
be done after the completion of neo-adjuvant chemotherapy. In the case of pathologic 
fracture, in most instances it is preferable to attempt to splint, cast or brace the extremity 
for the Induction neo-adjuvant phase of chemotherapy before resorting to amputation. 
Large destructive lower extremity lesions in children less than the age of 10, where 
considerable limb length inequality will be anticipated, may be the best managed by 
amputation though definitive radiotherapy remains a viable option, particularly in this 
high-risk patient population. Consultation with an experienced orthopedic or surgical 
oncologist is encouraged, because newer methods of limb length equalization, the use of 
growth plate sparing operations (especially for diaphyseal lesions) and “expandable” 
prosthesis may make amputation unnecessary.  
 
13.3 
Surgical Guidelines for Primary Bone Lesions 
Tumors arising in the extremities are usually situated in recognized anatomical 
compartments.119,120 Utilizing standard radiographic techniques (e.g., plain films, bone 
scan, MRI and at times CT or CT angiography), the precise anatomic location of the lesion 
should be defined prior to biopsy and the studies repeated prior to resection. Furthermore, 
the extent of the lesions is usually dramatically reduced following Induction chemotherapy, 
rendering lesions that are huge at diagnosis smaller and more “resectable” after 
chemotherapy. A surgical staging system for extremity musculoskeletal sarcomas which 
incorporates histopathological grading has been extensively tested and devised, whereby 
the histologic grade (high or low) and the extent of the disease (compartments involved, 
presence or absence of metastases) can be linked to the type of surgical procedure. 121,122 
The procedures are defined based upon the margins they achieve relative to the tumor and 
its pseudocapsule. In the setting of pre-operative chemotherapy the aim of surgery should 
generally be to achieve a wide (R0) surgical margin of normal tissue around the lesion. The 
second surgical margin that may be acceptable is a marginal (R1) excision. In this surgery 
there are microscopically positive cells at the cut surface of the tumor which remain in the 
patient and must be treated by radiotherapy. The histologic response of the tumor to 
chemotherapy is also important but there is no means of making this assessment prior to 
resection.  
 
For the purpose of this study, viable tumor at the cut surface of the specimen is considered 
a positive margin and requires radiotherapy. The plane of dissection should be through 
non-inflamed, non-edematous tissue to avoid leaving tumor cells in this tumor reactive 
zone.  
 
Pre-resection consultation with a radiation oncologist is recommended, even if it seems 
likely a wide excision with a clear margin will be achieved. If a lesion is considered 
inoperable, that is, gross residual tumor would be left behind (an intralesional R2 excision), 
surgery should not be attempted. A partially removed tumor leaves the patient with a worse 
situation since full dose radiotherapy will be needed. The field size will be considerably 
larger since all of the surgical wound would have to be irradiated rather than the original 
tumor volume with a small margin. The post surgery tumor bed will be more anoxic 
rendering radiation less effective.  
 
13.3.1 Eligibility for Local Control 
Following Induction chemotherapy, patients will undergo disease restaging according 
to Section 7.0. It is recommended that all patients with a good clinical/radiologic 
response be considered for surgical resection with negative margins (i.e., “de-

 
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bulking” R2 excision is not an acceptable term or procedure). If initial surgical 
excision is elected, using the criteria defined below, the procedure should be 
performed following recovery from Week 11 Induction chemotherapy and prior to 
Consolidation therapy.  
 
13.4 
Anatomic Guidelines for Resectability 
The choice of local treatment will be left to the treating physicians, and may include: 
radiation alone, radiation followed by resection, resection followed by radiation, or surgical 
resection alone. The trend for local management of Ewing sarcoma has changed recently 
toward surgical resection whenever possible for non-metastatic disease. The guidelines for 
determining “resectability” and “adequate margins” are still being defined and require 
considerable judgement on the part of the entire treatment team. In general, the goal should 
be to remove the entire tumor and involved bone with a cuff of normal tissue around the 
tumor (a wide excision). Since the response of Ewing sarcoma to preoperative 
chemotherapy is often dramatic, the soft tissue extent of the tumor is frequently much less 
than at diagnosis. The exact thickness of the “cuff” of normal tissue oncologically "safe" 
(with respect to local recurrence) is not known, and probably depends upon the type of 
tissue forming the cuff. Fascia, periosteum and intermuscular septae are good barriers to 
tumor spread. On the other hand, fat and muscle are relatively poor barriers and require a 
thicker cuff. If margins are deemed "positive" after review of the treatment team (see 
Section 4.3.1.2), or if there is intra-operative tumor spill or cut through, then post-operative 
radiotherapy is indicated. Otherwise wide surgical resection alone is the goal when 
feasible. 
 
The decision about whether a given patient is "resectable" should be made by the treatment 
team which should include an experienced orthopedic/surgical oncologist, radiation 
oncologist and oncologist. Consideration must be given at each site to the neurovascular 
structures, uninvolved muscles, the adjacent joint(s) and the growth centers. Not every 
tumor is resectable, nor should this necessarily be a goal. Experience and wisdom are 
needed to make this decision for an individual patient. Some specific guidelines by site are 
as follows: 
 
13.4.1 Tibia 
Proximal tibial lesions must be evaluated for the status of the adjacent knee joint. If it 
is free of tumor involvement, an intra-articular resection may be employed, followed 
by reconstruction in using osteo-articular allografts or metallic prostheses. An 
estimation of growth remaining should be made and plans for limb length 
equalization considered. Lesions with joint involvement will require an extra-articular 
resection and reconstruction with an arthrodesis or metallic prosthesis or 
rotationplasty. 
 
Tibial lesions of the diaphysis may be treated by resection and diaphyseal 
reconstruction using allograft bone, autografts or metallic spacers. If it is possible 
to preserve the joint and growth plates at either end, near normal function can be 
expected. The posterior neurovascular bundle is often protected by the deep 
posterior compartment muscles. 
 
Distal tibial lesions (supramalleolar) are probably best managed by definitive 
radiation. Rarely are lesions suitable for resection and intercalary reconstruction 
or ankle arthrodesis. 

 
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13.4.2 Femur 
Proximal femoral lesions may be resected if there has been a good response to 
Induction chemotherapy. At times it is possible to preserve the femoral head and 
neck and perform an intercalary reconstruction. If an intra-articular resection is 
necessary, reconstruction with a metallic prosthesis, or allograft-prosthesis 
composite is indicated. Extra-articular resections can be achieved if the joint is 
involved and reconstruction carried out by means of an arthrodesis using allograft 
and/or autograft bone, or at times a modified total hip replacement or 
rotationplasty. 
 
Diaphyseal lesions are frequently resectable using the vastus intermedius as a 
muscle cuff around the tumor. Intercalary reconstructions with allograft, autografts 
or - metallic spacers are possible with good functional results if the adjacent joints 
and growth plates are possible to preserve. As in the tibia, if a growth plate must 
be sacrificed to achieve an adequate margin, plans should be considered for limb 
length equalization after the completion of the drug protocol. 
 
Distal femoral lesions may be resected either as an intra-articular procedure or an 
extra-articular procedure (depending upon the analysis of the staging studies with 
regard to joint involvement) if the neurovascular bundle is free. Intra-articular 
resections can be reconstructed with osteoarticular allograft or metallic prostheses, 
whereas extra-articular resections will require arthrodesis, metallic prostheses or 
allograft prosthesis composites. In skeletally immature patients less than age of 10, 
or in those with strong athletic inclinations, a rotationplasty may be considered. 
 
13.4.3 Bones of the Hands and Feet 
Lesions involving the digits, metacarpals, and metatarsals may be managed by ray 
amputation or resection, depending upon the degree of soft tissue and joint 
involvement following Induction chemotherapy. If surgically managed, the aim 
should be for complete resection with negative margins. Selected lesions may be 
managed by radiotherapy. Large destructive lesions of the hind portion of the foot 
may not be suited for either radiation or resection (due to the degree of destruction 
and lack of reconstruction options). Below-knee amputation is frequently the 
treatment of choice for these sites. 
 
13.4.4 Fibula 
The proximal fibula can be resected if the response to Induction chemotherapy is 
good. Soft tissue involvement noted at operation may be more extensive than that 
anticipated by pre-operative staging studies, therefore one should plan to take a 
wide cuff of tissue around the lesion. Extra-articular excision of the proximal tibial 
fibular joint can be done if there is epiphyseal involvement. MRI is the best 
imaging study from which to judge the extent of bony and soft tissue involvement. 
Reconstruction is not necessary as long as the distal 6-8 cm of fibula near the ankle 
can be preserved. The peroneal nerve may need to be sacrificed, but a posterior 
tibial tendon transfer or ankle foot orthosis compensates for its loss reasonably 
well. In some cases the soft tissue extent mandates that the toe and foot extensor 
muscles be removed with the tumor. Attention to varys instability should also be 
assessed. If present, the surgeon should consider lateral collateral ligament 
reconstruction.  
 

 
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Lesions involving the distal fibula may also be resected. Ideally, the lateral 
malleolus should be preserved, but if it is resected, adequate ankle function can be 
achieved by soft tissue reconstruction long term, bracing or, at times, an ankle 
arthrodesis. Occasionally a reconstruction is done with the uninvolved proximal 
fibular moved distally. 
 
13.4.5 Ankle Region 
For lesions located in the distal tibia, calcaneus and hindfoot a below knee 
amputation at the classical level is usually the best alternative (radiotherapy may 
be an alternative). Very small lesions might be managed by resection, but these are 
extremely unusual. 
 
13.4.6 Pelvis 
The pelvis is one of the most difficult areas for surgical resection. All pelvic lesions 
should be carefully studied by MRI with or without CT (and, at times CT or MR 
angiography) at the completion of Induction chemotherapy to decide if a resection 
is possible. Smaller lesions limited to the iliac wing, ischium or pubis, with good 
response, should be resected. Surgical complication rates are high particularly 
when they follow high dose radiotherapy. In this patient population, surgical 
resection is generally not indicated after a patient has received definitive radiation. 
Delays in resumption of chemotherapy may contribute to the poor prognosis of 
pelvic Ewing tumors.  
 
Lesions confined exclusively to the iliac wing (Zone I) are generally resectable 
without imparting significant morbidity. The surgeon should reconstruct the 
abductor mechanism as best as possible. 
 
Lesions in the periacetabular area (Zone II) require careful consideration. There 
are no good reconstruction options for a resection at this site. The decision will be 
individualized and require consultation with an experienced Orthopedic oncologist 
and radiotherapist, and full discussion of the local management options with the 
patient and his or her family. Possible reconstruction options include allografts 
(with or without hip joint prostheses), metallic implants, or arthrodesis (ilio-
femoral or ischio-femoral). Definitive radiation may be the best option in this 
population with metastatic disease. For pubo-ischial lesions (Zone III), the 
difficulty of resection depends on the extent of interior pubic-ischial involvement. 
Reconstruction is generally not necessary. 
 
Pelvic lesions which cross the sacroiliac joint (Zone IV) to reach the sacrum also 
require careful consideration. Most of these lesions will be managed by radiation 
alone. The ability to perform a resection will depend upon the extent of the lesion 
within the sacrum and the expected neurologic deficits (including possible loss of 
bowel and bladder function) which would remain following a resection. A 
combined radiotherapy/surgical approach may be appropriate if the improvement 
in disease control outweighs the functional loss.  
 
The role of complete hemipelvectomy (Zone I-III +/-IV) for large "unresectable" 
lesions of the pelvis is unclear. In most instances it is to be avoided in favor of 
definitive radiotherapy. 
 

 
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13.4.7 Spine 
Patients with symptoms of spinal cord compression should be considered for 
emergency radiotherapy (see Section 17.3.2). In many cases chemotherapy will 
relieve the cord compression and destabilizing laminectomies should be avoided. 
Surgical resection of primary lesions arising in the vertebrae may be indicated 
when there has been a good response to Induction chemotherapy. There are a 
variety of spine implants and bone grafts that are available for reconstruction 
following wide excision. Consultation could be made with a local orthopaedic 
spine surgeon. Radiation dose is limited at this site due to the sensitivity of the 
spinal cord. Special techniques can be used such as proton therapy (see Section 
17.0), for protection of spinal cord and adjacent structures. The final decision 
regarding local management is ideally made after the response to Induction 
chemotherapy is assessed. It is expected that patients with vertebral and/or 
paraspinal tumors will most likely require radiation therapy. Before attempting 
local control with surgery only, the plan should be discussed with the treatment 
team. 
 
13.4.8 Ribs 
Initial resection is strongly discouraged. Patients should receive Induction 
chemotherapy prior to resection. Defining the extent of the rib involvement is 
difficult due to the curvature of the chest wall. MRI is the best modality for 
documenting extent around the curvature of the chest. Consideration can be made 
to marking the extent of involvement by a metallic marker inserted at the margins 
with pre-operative CT. The rib with a cuff of surrounding normal tissue should be 
resected en bloc. Generally the resection has included one normal rib above and 
one below the lesion. The depth of the resection should include at least the full 
thickness of the musculoskeletal chest wall with pleura, and wide resection of any 
areas of attachment to underlying lung parenchyma, pericardium or diaphragm. 
More conservative procedures may also yield good oncologic results and eliminate 
a need of chest wall reconstruction. Half of the circumference of the uninvolved 
rib above and below can be excised with all of the soft tissues on the adjacent upper 
and lower ribs. Limiting factors for effective resection are lesions encroaching on 
vertebrae, great vessels, and brachial plexus. Resection of posterior rib lesions may 
necessitate consultation with a surgeon with expertise in spine / paraspinal surgery.   
 
Primary radiotherapy is an alternative to resection if resection is unreasonable, and 
post-operative radiotherapy is indicated if the margins are microscopic. If gross 
residual tumor is the expected outcome, surgery should not be attempted.  
 
13.4.9 Scapula 
Lesions presenting in the body of the scapula which do not invade the chest wall 
or glenoid can be resected without significant impairment of shoulder function. 
Primary lesions which involve the glenoid are possible to resect but reconstruction 
options are limited and there will be some loss of function (shoulder abduction 
active rotation strength). If the arm and brachial plexus can be preserved, resection 
may be attempted, even if it requires total scapulectomy. Reconstruction options 
include soft tissue repairs and fascial or artificial ligament slings to stabilize the 
proximal humerus to the chest wall. Metallic prostheses for the scapula and 
allografts have been attempted, but the functional results are as yet not well 
established. 

 
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13.4.10 Sternum and Medial One-fifth of Clavicle 
Most lesions of this site are resectable if there is a reasonable response to pre-
operative chemotherapy, but there is risk to the underlying normal structures in 
this area. Great care must be exercised regarding the heart, great vessels, trachea, 
esophagus, pleura and nerves. No reconstruction is necessary. 
 
13.4.11 Clavicle (Lateral four-fifths) 
A surgical resection should be considered unless this is precluded by the extent of 
the soft tissue involvement. The clavicle can be readily resected without 
appreciable loss of function. 
 
13.4.12 Humerus 
The proximal one third of the humerus may be resected in either an intra or extra-
articular fashion, along with surrounding soft tissues (deltoid). A reduction in 
abduction arc and power is almost a certainty. Reconstructions employing 
allografts or vascularized fibula grafts for arthrodeses (extra-articular resections 
including the deltoid and rotator cuff) or as osteoarticular implants (if the rotator 
cuff can be preserved at time of an intra-articular resection), or employing metallic 
implants are possible. Clavicula pro humero is also an attractive and viable option. 
 
The diaphyseal region of the humerus frequently lends itself to resection if the 
adjacent shoulder and elbow joint can be preserved and the neurovascular 
structures are free. Reconstruction of the intercalary defect with allograft or VFG 
autograft bone, or metallic implants is possible and offer excellent functional 
results. 
 
The distal humerus (elbow) is a rare site of occurrence, and decisions relative to 
resection will depend on the size of the lesion and its relationship to the adjacent 
neurovascular structures. Reconstructions at this site are not commonly performed 
and require innovation depending upon the exact clinical situation. Radiotherapy 
may be a superior option at this site. 
13.4.13 Radius and Ulna 
Small lesions localized to one of the two bones may be considered for resection if 
there has been a good response to chemotherapy. Lesions which lend themselves 
to intercalary resections of one of the bones are ideal, as are lesions of the distal 
ulna which can be sacrificed without reconstruction. The distal radius can be 
resected as well, and reconstructed with auto- or allografts to re-create the 
radiocarpal joint or to establish an arthrodesis. Radiotherapy is an alternative.  
 
 
13.4.14 Wrist 
Fortunately, tumors arising in the small bones of the carpus are rare. Small well-
localized lesions may be managed by radiation or resection; however, a below 
elbow amputation may be required. 
 
13.4.15 Skull and Mandible 
Tumors in these locations are beyond the scope of these guidelines. Consultation 
with a surgical oncologist or neurosurgeon experienced in tumors of these sites 
should be made. Resections are sometimes feasible, again with the aim of complete 
tumor excision with negative margins, but radiotherapy is usually required alone 
or as an adjunct for tumors in these locations. 

 
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13.4.16 Soft Tissue Ewing/PNET 
In general, soft tissue lesions should be staged and treated along the same 
guidelines as those for bone tumors. At the completion of Induction chemotherapy, 
the site of the primary tumor should be re-imaged, usually with MRI scan.  
 
In most cases, an enbloc resection of the lesion, the biopsy tract and a cuff of 
normal tissue surrounding the lesion en bloc should be attempted. If the lesion is 
adjacent to a major neurovascular structure or bone, definitive radiotherapy may 
be the best option. It is not necessary to resect the entire muscle compartment of 
involvement if the staging studies indicate lesser involvement, but in all cases the 
goal should be to achieve a wide or marginal excision as defined by Enneking.121,122 
Once transected a muscle is non-functional so generous margins of the muscle can 
be removed with the tumor. 
 
If the adjacent bone is clearly involved by tumor, treatment principles for bone 
tumors should be employed. In most cases, lesions adjacent to bone with no 
recognizable involvement by CT or MRI can be resected without removing the 
bone; periosteum should be taken as a margin in these cases. When postoperative 
radiation therapy is required, the denuded bone is more susceptible to late 
pathologic fracture. 
 
Major nerves should be preserved when feasible. If they are directly involved by 
tumor, a combined radiotherapy and surgical approach or radiation alone may be 
necessary. Similar guidelines apply to major vascular structures, but resection with 
vascular reconstruction is an alternative for involved vessels. 
 
Most major muscle groups can be sacrificed without much loss in function. Local 
muscle transfers to restore function, achieve soft tissue coverage or to prevent dead 
space are sometimes necessary either at the time of resection or at completion of 
therapy. Some surgeons recommend tendon transfers at the time of resection. 
 
13.5 
Resection of Residual Lung Metastases 
The role of resection of residual lung metastasis remains unclear in Ewing sarcoma. In 
general, lung metastases resolve completely during the course of chemotherapy. Resection 
of lung metastases remaining at the completion of Consolidation therapy is allowable. If 
performed, resection should take place prior to planned whole lung radiotherapy. See 
Section 15.0 for submission of resection specimens for correlative biology studies.   
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
Central pathology review will not be done. Submission of specimens for required and optional 
correlative biology studies is detailed in Section 15.0. Submission of tumor material from initial biopsy 
is required for study participation and this requirement should be considered in planning biopsy and 
tissue triage. 
 
COG member institutions are also encouraged to enroll patients on a Ewing sarcoma specimen 
collection study, such as AEWS07B1 or APEC14B1. Please see the specimen collection study for 
directions for specimen preparation and shipment. 

 
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14.1 
Biopsy Specimen 
Gross 
Surgeons and interventional radiologists should be encouraged to send fresh tissue from all 
biopsy procedures. 
 
Every effort should be made to obtain viable, undistorted tissue for study. Fixation and 
processing in a manner with which the laboratory routinely obtains good results (e.g., 10% 
neutral buffered formalin) is satisfactory. Whenever the amount of tissue is sufficient, fresh 
and frozen tissue should be obtained for cytogenetics and diagnostic biologic studies. A 1 mm 
slice from the cut surface of the tumor should be placed in buffered glutaraldehyde or other 
electron microscopy (EM) fixative and saved or processed for electron microscopy, if 
sufficient tissue is present. Touch preparations should be made for cytologic screening. 
Institutions are strongly encouraged to perform cytogenetics on fresh specimens when 
sufficient tissue is available and when this service is available. 
 
Microscopy 
The tumor must have a light microscopic appearance [by hematoxylin and eosin (H&E) 
staining] consistent with a Ewing family tumor [Ewing sarcoma/peripheral primitive 
neuroectodermal tumor (PNET)] of bone or soft tissue. In addition, there should be no 
immunohistochemical or ultrastructural evidence suggesting lymphoma or another 
sarcoma such as rhabdomyosarcoma.  
 
 
Immunohistochemistry 
In addition to routine H&E staining, it is recommended that institutional pathologists perform 
immunohistochemistry (IHC) using a panel of antibodies to aid in the diagnosis and exclude 
entities other than Ewing sarcoma/PNET. A suggested panel would include: CD99 (MIC2, 
12E7, O13) to support a diagnosis of Ewing sarcoma/PNET; myogenic markers (desmin, 
muscle-specific actin, myogenin and MyoD1) to rule out rhabdomyosarcoma; antibodies for 
detecting lymphoid antigens (CD45, TdT, and additional B and T cell markers); and other 
exclusionary antibodies as indicated by a particular case. While CD99 (MIC2; 12E7, O13) 
positivity suggests Ewing sarcoma/PNET, CD99 positivity alone is not sufficient for a 
diagnosis of Ewing sarcoma/PNET, as lymphomas, synovial sarcoma, and alveolar 
rhabdomyosarcoma, among other tumors, may express this antigen. 
 
14.2 
Molecular and Cytogenetic Studies for Initial Diagnosis 
 
Molecular studies 
The most common cytogenetic abnormalities in EWS/PNET include t(11;22) and t(21;22); 
other, less common translocations have also been described. It is strongly recommended that 
tissue be obtained for molecular biologic study of these and other abnormalities by reverse 
transcriptase polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization 
(FISH) using probes for the involved regions of chromosomes 11, 21, and 22. Evidence of an 
EWS rearrangement consistent with a Ewing family tumor may be used as supporting 
evidence for a Ewing sarcoma/PNET diagnosis. 
 
Cytogenetic Studies 

 
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If sufficient tumor is available after submission of tumor for molecular studies, it is suggested 
that tumor cytogenetics be done at the home institution, if available. Fresh, sterile, unfixed 
tumor tissue should be submitted as specified by the local institution's cytogenetics laboratory. 
 
14.3 
Specimen from Surgical Resection  
Gross 
Resection margins must be marked with India ink or other color indicator. Description of 
the specimen, including measurements, should be recorded. Gross assessment of the 
completeness of resection should be made. A specimen radiograph (when facilities are 
available) should be made prior to taking sections. A single slice through the largest axis 
of the tumor should be fixed, decalcified if necessary, and entirely submitted for 
processing, with the location of blocks clearly marked on a photograph or diagram of the 
gross specimen. These sections will then be used for assessment of histologic response to 
chemotherapy. Additional sections of primary tumor, extraosseous tumor, any grossly or 
radiographically abnormal areas and margins of bone and/or soft tissue should be obtained. 
If viable tumor is grossly recognizable, obtain tissue for cytogenetics, flow cytometry, 
biologic studies, and EM as described in Section 14.1. 
 
14.3.1 Surgical margins  
Completeness of resection and the status of the margins should be assessed. A positive 
margin will be any margin in which either viable tumor or tumor displaying 
coagulative necrosis is present at the inked surface. The presence of bland scar or 
loose fibrous tissue, in the absence of coagulative tumoral necrosis at the margin 
(where the cytoarchitecture of tumor cells is preserved) will not be considered as a 
positive margin, provided that there is 90% or greater overall tumor necrosis. In 
tumors with less than 90% overall necrosis, the presence of abnormal fibrosis or 
reactive inflammatory tissue at the margin (indicative of treated tumor bed) will be 
considered a positive margin. The distance of the tumor from the margins should be 
measured in millimeters, and positive margins should be described as going through 
a solid nodule of viable tumor, going through individual viable infiltrating tumor 
cells, or going through necrotic tumor.  
 
14.3.2 Histologic Response 
Following definitive surgery the tumor should be examined to determine “histologic 
response.” Since the effect of the preoperative chemotherapy may not be uniform 
throughout the tumor, adequate sampling as described in Section 14.3.3 is required to 
grade the histologic response accurately. The institutional pathologist should assess 
the tumor’s pathologic response using the method for quantitation of necrosis 
described in Section 14.3.3 and utilizing the grading system below as a guideline.  
 
Pathologic response 
Grade 
Percent Necrosis 
I 
Less than 50% necrosis 
II 
50%-89% necrosis 
III 
90%-99% necrosis 
IV 
100% necrosis 
 
14.3.3 Procedure for Quantitation of Necrosis 
Quantitation of necrosis is performed on the sections prepared from a single slice 
through the largest axis of the tumor. Only the areas representing tumor (viable 

 
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and necrotic) should be included in the quantitation. Areas representing normal 
tissue should not be included in the quantitation.  
 
In some cases, the amount of residual viable tumor is obvious (e.g., less than 50% 
necrosis or 100% necrosis). In these instances, one can assign response to the 
appropriate grade listed in Section 14.3. For problematic (non-obvious) cases, the 
total area occupied by tumor (both viable and necrotic) should be outlined using a 
marking pen on each glass slide containing tumor. Using a different color marking 
pen, the area occupied by viable tumor should be demarcated on the same slides. 
Lightly cross-hatching the demarcated viable areas may improve the ease of 
subsequent quantitation. Graph paper with 2 mm squares can be photocopied 
(actual size) on to acetate sheets for overhead projection. These sheets can then be 
cut into rectangles and fixed over the cover slip using transparent double-sided 
tape. The total area occupied by tumor (viable and necrotic) and the area occupied 
by viable tumor can thus be quantified, and the per cent necrosis can be quantified 
using the following formula: 
 
% Necrosis = 100 x [1 - (Area occupied by viable tumor/total area occupied by 
tumor)]. 
 
Quantitation of necrosis should not be performed by adding the estimated per cent 
necrosis on each slide and dividing by the number of slides containing tumor. This 
method does not take into account differences in the total area occupied by tumor 
on each slide and may result in inaccurate assessment of the amount of necrosis.  
 
Special attention to quantitation is essential, as one of the secondary aims is to 
compare the histologic response with the response as determined by MRI and FDG-
PET. 
 
14.4 
Pathology Specimen Requirements 
Submission of materials from the diagnostic biopsy and resection/amputation specimens 
for pathology central review is not required for this study, though biopsy material must be 
submitted for the biology studies in Section 15.0. Submission of specimens for the required 
and optional correlative biology studies is detailed in Section 15.0. Dr. Lisa Teot, MD, is 
the COG pathologist for AEWS1221 and can be contacted as listed below for questions 
regarding handling of either the biopsy or resection/amputation specimen. 
 
14.5 
Consultation 
If a consultation for a difficult case is desired this would be on a consultation basis only 
and a fee may be charged. If a consultation is desired, the institution should send pathology 
materials (all slides, a block or unstained slides, and surgical pathology report) to the 
consultant of their choice. Ship consultation materials using your own courier account. 
 
Study Pathologist: 
Lisa A. Teot, M.D. 
Boston Children's Hospital 
Department of Pathology 
Bader 110 
Boston, MA 02115 
Tel: 
(857) 218-4962 

 
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Fax: 
(617) 730-0207 
email: lisa.teot@childrens.harvard.edu 
 
Please note that materials sent to a reviewer for consultation are separate from a study 
submission 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
Any time a tumor is resected or biopsied in a patient who has consented to optional tissue collection 
on this study, tumor material should be submitted to support correlative biology studies.  
 
Submission of pretreatment blood, serum, and paraffin-embedded tumor material or unstained 
slides according to Sections 15.1, 15.2, and 15.3 is mandatory for enrollment and required of all 
patients. Submission of serum prior to Week 5 chemotherapy is also required.  
 
Submission of serum samples for ganitumab pharmacokinetic (PK) testing in Induction and 
Maintenance is also required from the first 10 patients < 21 years of age randomized to Regimen B 
(see Section 15.5). Enrollment to this cohort completed as of July 2015. 
 
Submission of bone marrow samples and all other follow-up samples from patients who provide 
additional consent is strongly encouraged of all patients (see Section 15.4).  
 
Submission of samples for plasma cell-free DNA analysis from patients who provide additional 
consent is strongly encouraged of all patients (see Section 15.6). Note that these samples are to be 
submitted in Streck Cell-Free DNA BCT tubes, which should be requested from the Biopathology 
Center (BPC) once a potential patient is identified for this study.   
 
See Appendix II for a reference guide to required and recommended correlative studies. 
 
In addition to the strongly recommended studies embedded within this clinical trial, all patients 
should be offered co-enrollment on AEWS07B1 or APEC14B1. Specimen requirements for 
AEWS1221 are independent of specimen requirements for AEWS07B1 or APEC14B1.  
 
Laboratories performing the correlative biology studies will be blinded to randomized treatment 
arm.  
 
15.1 
Serum Markers of IGF-1R Pathway 
 
15.1.1 Specimen Schedule and Requirements 
Collection of serum is mandatory at study entry (pretreatment), and just prior to 
the start of Week 5 Induction chemotherapy, and at the completion of 
Consolidation. Draw 10 mL of blood into a red top tube at each time point.  
For patients on Regimen B (ganitumab arm), who have consented to specimen 
banking, draw an additional 5 mL of blood (for a total of 15 mL) into a red top 
tube at each time point.  
 
15.1.2 Specimen Processing 
Allow the blood to clot at 4°C (or in a bucket with ice) for at least 30 minutes but 
no longer than 3 hours. Centrifuge the blood at 1000g for 15 minutes at 4ºC 
(preferred) or room temperature to separate the serum (top, straw-colored layer) 

 
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from the red blood cells (bottom, red layer). Dispense (aliquot) the serum into 
cryovials labeled according to the directions in 15.1.3. Aliquot serum into 0.5 – 
1 mL aliquots, with a minimum of 2 mL pretreatment serum required. Cap the vials 
securely. Immediately freeze the serum in an upright position in a -70oC to -
80oC freezer.  
 
15.1.3 Specimen Labeling and Shipment 
All tubes must be labeled with AEWS1221, the patient’s COG patient ID number, 
specimen type (serum), and collection date.  
 
The Biopathology Center (BPC) will provide a specimen procurement kit upon 
request. Kits are ordered via the BPC Kit Management system accessed  using the 
following link: https://ricapps.nationwidechildrens.org/KitManagement. 
 
All tubes should be sent to the COG BPC frozen on dry ice by FedEx Priority 
overnight. Ship to the COG BPC using a FedEx shipping label obtained through 
the BPC Kit Management system. See above for instructions. Serum may be 
shipped on Monday through Thursday for a Tuesday through Friday delivery. Do 
not ship frozen specimens to the BPC on a Friday or the day before a holiday. 
 
Samples may be batch shipped.  
 
 
Specimens must be accompanied by the completed AEWS1221 BPC specimen 
transmittal form printed out from the RAVE system and sent to the following 
address: 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol AEWS1221 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
 
*Be sure to include the room number. Packages received without the 
room number may be returned to the sender. 
 
For questions about this correlative study, please contact the study chair, Dr. 
DuBois. For questions about sample processing and shipping, please contact the 
BPC directly. 
 
15.1.4 Methodology 
Serum will be analyzed by a commercial laboratory, such as ARUP Laboratory, 
for a panel of IGF-related proteins, including but not limited to: IGF-1; IGF-2; 
growth hormone; IGFBP-3 and related proteins using clinically-validated assays. 
Additional serum from consenting patients on Regimen B (ganitumab arm) will be 
banked for future tests that may include pharmacokinetic testing, novel biomarker 
testing, and/or immunogenicity studies, depending upon needs determined at the 
conclusion of the trial.  
 

 
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15.2 
Tissue Markers  
 
15.2.1 Specimen Schedule and Requirements 
Pretreatment tumor material is mandatory for study entry for all patients. For 
patients who provide additional consent for follow-up samples, tumor material 
should also be submitted any time the patient undergoes resection or biopsy of 
tumor for any reason (including local control or confirmation of relapse/disease 
progression). If no viable tumor is seen from a follow-up sample, submission of 
that follow-up time point may be omitted.   
 
Either a paraffin-embedded tissue block (preferred) or unstained slides should be 
submitted. If unstained slides are submitted, a minimum of 10 slides are required 
and optimally, 25 unstained slides should be submitted at each time point. 
Unstained slides should be standard sections of 3 to 4 µM thickness. 
 
Submission of slides cut sequentially from the same block is strongly preferred. 
However, if the minimum 10 slides are not available from a single block, 
submission of slides from multiple blocks is acceptable.   
 
15.2.2 Specimen Processing 
No additional on-site processing is required.  
 
15.2.3 Specimen Labeling and Shipment 
All tumor material being shipped to the BPC must be labeled with the patient’s 
COG patient ID number, BPC Number, specimen type (primary or metastatic), 
collection date, surgical pathology ID and block number from the corresponding 
pathology report. 
 
For blocks and unstained standard slides, tumor material and associated pathology 
report(s) for that sample should be sent to the COG Biopathology Center (BPC) at 
room temperature by regular mail or by the submitting institution’s courier 
account. In addition to the pathology report, an AEWS1221 BPC specimen 
transmittal form must be completed in RAVE, printed and sent with the specimen 
to the following address: 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol AEWS1221 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax: 
(614) 722-2897 
 
*Be sure to include the room number. Packages received without the 
room number may be returned to the sender. 
 
 
For questions about this correlative study, please contact the study chair, Dr. 
DuBois. For questions about shipping the slides, please contact the BPC directly.  
 

 
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15.2.4 Methodology 
Immunohistochemistry: 
For all patients, tumor material will be used to quantify IGF-1R, AKT, EGFR, 
ERK, and related proteins using immunohistochemistry. 
 
Quantitative Proteomics Analysis (NantOmics): 
For patients who enroll with Amendment #3C and beyond, proteomic analysis of 
baseline samples by NantOmics will be performed for each patient with an 
available baseline tissue block. For patients who provide additional consent for 
follow-up samples, proteomic analysis of follow-up samples by NantOmics will 
also be performed. 
 
For patients who submit a tissue block, the BPC will cut an additional two (2) 10 
micron sections per time point to be placed onto DIRECTOR® slides (provided 
by NantOmics). Sections along with one (1) H+E slide will then be transferred to 
NantOmics. 
 
NantOmics will perform protein extraction and quanitification of IGF-1R pathway 
proteins using a mass spectrometry method.  Proteomic analysis will be performed 
in batches.  All efforts will be made to perform proteomic analysis should samples 
not meet the above specifications.     
 
Whole Genome DNA and RNA Sequencing (NantOmics):   
For patients who enroll with Amendment #3C and beyond, DNA and RNA 
sequencing of baseline samples by NantOmics will be mandatory. For patients who 
provide additional consent for follow-up samples, DNA and RNA sequencing of 
follow-up samples by NantOmics will also be performed. The BPC will perform 
co-extraction of tumor DNA and RNA using established methodology. The 
following materials (per sample time point) will be batch transferred by the BPC 
to NantOmics: 
• 
500 ng of tumor DNA at 5 ng/microliter (minimum acceptable: 50 ng at 1 
ng/microliter) 
• 
1 microgram of tumor RNA at 50 ng/microliter (minimum acceptable: 250 
ng at 25 ng/microliter) 
• 
500 ng of germline DNA at 5 ng/microliter (extracted by BPC as described 
in Section 15.3).  
 
NantOmics will perform whole genome DNA and RNA sequencing of tumor (and 
germline to enable designation of aberrations as somatic events) using next 
generation sequencing methods. Sequencing will be performed in batches. All 
efforts will be made to perform DNA and RNA sequencing should samples not 
meet the above specifications. 
 
15.3 
EGFR Promoter Polymorphisms 
 
15.3.1 Specimen Schedule and Requirements 
A single pretreatment sample is mandatory. A single 5-10 mL of peripheral blood 
in EDTA (purple top tube) could be collected any time prior to initiating systemic 
chemotherapy.  
 

 
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15.3.2 Specimen Processing 
Tubes should be gently inverted 3-4 times after sample collection. No other on-site 
processing is required. Sample should be kept in a refrigerator (4 C), until 
shipped.  
 
15.3.3 Specimen Labeling and Shipment 
Tubes must be labeled with the patient’s COG patient ID number, BPC Number, 
specimen type (blood), and collection date.  
 
Each sample should be sent on the day the sample was obtained. Do not collect 
and ship until after the patient is enrolled on AEWS1221. Sample should be 
shipped cold but not frozen by shipping along with a cold pack, taking care to keep 
the tube out of direct contact with the cold pack. (Do not use a cold pack when 
shipping during winter months or the specimen will freeze.) Ship to the COG 
Biopathology Center (BPC) using a Federal Express shipping label obtained 
through the BPC Kit Management application. See Section 15.1.3 for instructions 
on accessing the BPC Kit Management application. Blood may be shipped on 
Monday through Friday for a Tuesday through Saturday delivery.  
 
An AEWS1221 BPC specimen transmittal form must be completed in RAVE, 
printed and sent with the specimen to the following address: 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol AEWS1221 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
 
*Be sure to include the room number. Packages received without the 
room number may be returned to the sender. 
 
For questions about this correlative study, please contact Dr. E. Anders Kolb at 
eakolb@nemours.org or (302) 651-5567. For questions about sample processing 
and shipping, please contact the BPC directly.  
 
15.3.4 Methodology 
The BPC will process DNA from blood samples using standard methodology. 
Plasma will be frozen to support the study described in Section 15.6 for patients 
meeting criteria for inclusion in that study. A discrete 689 bp region of the EGFR 
gene containing the promoter and a portion of exon 1 will be amplified by 
polymerase chain reaction using primers CCATTATCCGACGCTGGCTCTA and 
GCATCGCTGCTCCCCGAAGA. PCR will be performed on a Stratagene 
Robocycler for 35 cycles (30 sec at 95C, 30 sec at 61C, and 1 min at 72C). PCR 
products will be purified with Qiaquick PCR Purification Kit (Qiagen). 
Sequencing reaction will be performed using the ABI BigDye Terminator Cycle 
Sequencing Ready Reaction kit v 3.1 in a 10 L reaction and cleaned with Edge 
Bio Performa DTR columns. Sequencing reactions will be analyzed on the 
ABI3130XL Genetic Analyzer. Paraffin-embedded tumor material collected as in 
Section 15.2 will also be used to quantify EGFR protein expression.  
 

 
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15.4 
Bone Marrow Micrometastatic Disease 
Since samples must arrive fresh in the laboratory, this correlative study applies only 
to sites in the United States and Canada.   
 
15.4.1 Specimen Schedule and Requirements 
For patients who provide additional consent, bone marrow aspirate material should 
be submitted anytime patients have a diagnostic bone marrow evaluation, 
including study entry. 
 
5-10 mL of aspirated marrow should be placed into an EDTA (purple top) tube 
and gently inverted several times to prevent clotting. Unilateral samples are 
adequate as are samples pooled from bilateral bone marrow aspiration. Samples 
should be kept at room temperature and shipped at room temperature. 
 
Material must arrive fresh in the laboratory. Marrow samples collected on 
Monday-Thursday are eligible for submission such that samples arrive in the 
laboratory Tuesday-Friday. For patients undergoing clinical biopsies on a Friday, 
do not submit marrow samples from that biopsy for this correlative study. The 
study chair and the TransLab at Dana-Farber/Boston Children’s must be notified 
prior 
to 
shipment 
by 
emailing: 
steven_dubois@dfci.harvard.edu and 
myriam.armant@childrens.harvard.edu. 
 
15.4.2 Specimen Processing 
No additional on-site processing is required.  
 
15.4.3 Specimen Labeling and Shipment 
Samples should be labeled with AEWS1221, COG patient ID number (NOT BPC 
number), Bone Marrow, and sample collection date. 
 
Samples must arrive fresh in the laboratory. Each sample should be sent on the day 
the sample was obtained (or within a maximum of 24 hours from sample 
acquisition). Sample should be shipped at room temperature. Tubes should be sent 
to the reference laboratory by Federal Express overnight to arrive the next 
morning. For these specimen shipments only, Federal Express account number: 
361615042 should be used. Be sure to also provide reference number 9618307.  
A bone marrow specimen transmittal form should be completed in RAVE, printed 
and sent with the specimen to the following address to arrive the next morning: 
 
ATTN: Myriam Armant, TransLab 
Boston Children’s Hospital 
61 Binney Street 
ENDERS Room 428 
Boston, MA 02115 
(617) 713-8085 
Email: myriam.armant@childrens.harvard.edu 
 
For questions about this correlative study, please contact the study chair Dr. 
DuBois 
or 
Myriam 
Armant 
in 
the 
reference 
laboratory 
at 
myriam.armant@childrens.harvard.edu or (617) 713-8085. 
 

 
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15.4.4 Methodology 
Bone marrow mononuclear cells will be isolated on a Ficoll gradient. One to five 
million bone marrow mononuclear cells will be prepared for staining using 
standard methods and then stained with commercially available flow cytometry 
monoclonal antibodies against CD99, CD45, and IGF-1R. Cells will then be 
washed and one to five million cells will be assayed and collected on a BD FACS 
Aria flow cytometer. The proportion of CD99+CD45- cells will be quantified. 
Among CD99+CD45- cells, the intensity of IGF-1R co-expression as well as the 
percentage of tumor cells co-expressing IGF-1R will be determined. Additional 
analytes may be assessed as new information emerges. 
 
Samples with sufficient CD99+CD45- cell burden will undergo fluorescent 
activated cell sorting to isolate CD99+CD45- cells to support Aim 1.3.13. DNA 
will be isolated from these cells followed by next-generation sequencing to identify 
primary oncogenic translocations, mutations in TP53 and STAG2, and extent of 
somatic heterogeneity in tumor cells. When available, primary tumor material will 
be tested to allow comparison between paired primary and metastatic tumors. 
 
15.5 
Ganitumab Pharmacokinetic Study 
The first 10 patients < 21 years of age assigned to Regimen B are required to provide 
serial blood samples for the assessment of ganitumab serum concentrations in Induction 
and Maintenance. Enrollment to this cohort completed as of July 2015. For patients 
previously assigned to this cohort, continue to collect samples as detailed in the following 
sections.   
 
15.5.1 Specimen Requirements 
Note: The samples for ganitumab pharmacokinetics can be drawn from a central 
line, including a central line used to administer ganitumab.  
 
Induction 
Serum samples are to be obtained: 
• 
Prior to first dose of ganitumab  
• 
Just prior to the second dose of ganitumab on Induction Day 15  
• 
Just prior to the third dose of ganitumab on Induction Day 29  
• 
Just prior to the sixth dose of ganitumab on Induction Day 71 
 
If the second dose of ganitumab is delayed due to toxicity, serum should still be 
obtained on Induction Day 15 even if the patient will not receive ganitumab that 
day. 
 
If the third and/or sixth dose of ganitumab is delayed beyond Induction Days 29 
and/or 71 due to toxicity, serum should be obtained 14 days after the second and/or 
fifth dose of ganitumab. 
 
At each time point, 2 mL of blood should be drawn into a serum separator tube 
without any added anticoagulant. After collection, the tubes should be gently 
inverted 5 times and held at room temperature for 30-60 minutes before processing 
according to Section 15.5.2. Samples should not sit for longer than 60 minutes 
before processing. 

 
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Maintenance  
Serum samples are to be obtained: 
• 
Prior to first Maintenance dose of ganitumab  
• 
Just prior to the third Maintenance dose of ganitumab at Week 7 
• 
Just prior to the fourth Maintenance dose of ganitumab at Week 10  
• 
Just prior to the sixth Maintenance dose of ganitumab at Week 16  
 
At each time point, 2 mL of blood should be drawn into a serum separator tube 
without any added anticoagulant.  After collection, the tubes should be gently 
inverted 5 times and held at room temperature for 30-60 minutes before processing 
according to Section 15.5.2. Samples should not sit for longer than 60 minutes 
before processing.  
 
15.5.2 Specimen Processing 
Centrifuge tubes 1500 x g for 15 minutes at room temperature (if you have a 
temperature controlled centrifuge, set it to 20°C).  With a pipette, remove serum 
from the top of the tube without disturbing the blood cells and transfer an equal 
volume (ideally 0.5 mL each) into labeled 2 mL cryovials (recommended vials: 
Sarstedt screw cap micro tube, self standing external thread, Catalog number 
72.694.005, 2.0 mL capacity). If there is an inadequate amount of serum for 0.5 mL 
per cryovial, then split the available serum volume equally into all cryovials. 
Immediately place the labeled 2 mL cryovials containing the serum sample in a -
70°C or colder freezer. If a -70°C freezer is unavailable, alternatively samples can 
be stored in a -20°C freezer for up to 3 months. If a -70°C or a -20°C freezer is 
unavailable, then freeze on dry ice and ship frozen to PPD on the day of collection. 
 
Each serum sample must be frozen within 2 hours of blood collection. 
 
15.5.3 Specimen Labeling and Shipment 
Each cryovial should be labeled with: 
• 
COG Patient ID number 
• 
“AEWS1221” 
• 
Date 
• 
Time 
 
Ship frozen cryovials on dry ice to PPD by overnight courier using the COG 
Federal 
Express 
account 
number 
provided 
in 
the 
link 
below: 
https://www.cogmembers.org/_files/reference/FEDEXmemo.pdf. Samples should 
be shipped Monday-Thursday for weekday first morning arrival at PPD. A study-
specific paper PK transmittal form (provided in the CRF packet on the protocol 
webpage) must be submitted with the samples to the following address: 
 
Sample Management 
PPD Bioanalytical Lab 
2246 Dabney Road 
Richmond, VA 23230 
Phone: (804) 977-8017 
Fax: (804) 977-8104 
 

 
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In addition, a copy of the completed PK transmittal form must be uploaded into 
RAVE. 
 
The first 3 Induction samples (prior to the first, second and third doses of 
ganitumab) should be batch shipped within 3 days of collection of the Day 29 
samples. Do not wait until the remaining samples are available for a patient before 
shipping the first 3 Induction samples. The remaining Induction and Maintenance 
samples can be batch shipped after the Week 16 Maintenance samples have been 
obtained.  
 
For questions about the pharmacokinetic study, please contact the study chair, Dr. 
DuBois.  For questions about shipping samples, please contact PPD directly.  
 
15.5.4 Methodology 
Serum will be used to quantify ganitumab concentrations as previously 
described.34 The primary data to be evaluated is trough concentrations. 
 
15.6 
Circulating Tumor DNA Analysis 
15.6.1 Streck Cell-Free DNA BCT Tube Ordering 
IMPORTANT: If the patient has consented to ctDNA study, tubes should be 
ordered via the BPC Kit Management system as soon as possible after patient 
enrollment to allow time for tubes to be shipped. When ordering  the first set 
of Streck tubes for a patient for AEWS1221, please select “Overnight” for 
FedEx Shipping Type. In “Shipping Comment” please document “Overnight 
Shipping Exception per AEWS1221 instructions” and include the patient 
registration number. All other shipments will be sent by ground 
transportation and shipping will take 3-5 business days. The Kit Management 
System 
can 
be 
accessed 
via 
the 
following 
link: 
https://ricapps.nationwidechildrens.org/KitManagement. 
You must select AEWS1221 as the protocol and Streck Cell-Free DNA Tube 
as the kit when ordering Streck tubes for AEWS1221 patients.  
 
15.6.2 Specimen Schedule and Requirements 
For patients who provide additional consent for this study of circulating tumor 
DNA (with Amendment #1 and beyond), 10 mL of blood in a Streck Cell-Free 
DNA BCT tube should be collected at the following time points: 
• 
Baseline (prior to initiation of protocol therapy) 
• 
Just prior to the start of Week 3 Induction 
• 
Just prior to the start of Week 5 Induction 
• 
End-Induction (at time of disease restaging) 
• 
Mid-Consolidation (at time of disease restaging prior to Week 9 
Consolidation) 
• 
End Consolidation (at time of disease restaging) 
• 
At time of relapse/progression. 
 
15.6.3 Specimen Processing 
Blood should be drawn directly into the Streck tubes. The tube should be 
completely inverted 8-10 times after sample collection. No other on-site processing 
is required. Sample should be kept at room temperature until shipped.  

 
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15.6.4 Specimen Labeling and Shipment 
The tube must be labeled with the patient’s COG patient ID number, BPC Number, 
specimen type (blood), and collection date.  
 
Each sample should be sent on the day the sample was obtained. Sample should 
be SHIPPED AT ROOM TEMPERATURE. Ship to the COG Biopathology 
Center (BPC) using a Federal Express shipping label obtained through the BPC 
Kit Management application. See Section 15.1.3 for instructions on accessing the 
BPC Kit Management application. Blood may be shipped on Monday through 
Friday for a Tuesday through Saturday delivery. Do not ship blood the day before 
a holiday. In cold months, add insulating material to keep the blood from freezing. 
 
A BPC specimen transmittal form should be completed in RAVE, printed and sent 
with the specimen to the following address: 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol AEWS1221 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
 
*Be sure to include the room number. Packages received without the 
room number may be returned to the sender. 
 
For questions about this correlative study, please contact the study chair, Dr. 
DuBois. For questions about sample processing and shipping, please contact the 
BPC directly. 
 
15.6.5 Methodology 
The cohort will include patients enrolled prior to Amendment #1 who consented 
to use of leftover material as well as patients who enrolled with Amendment #1 
and beyond who consent to serial sample collection to support this aim.   
 
A capture NGS sequencing approach will be used to detect relevant translocations 
and mutations from cell free DNA extracted from approximately 2 milliliters of 
plasma for each patient using a commercial kit. After extraction, capture 
sequencing of cell free DNA will be performed utilizing oligonucleotides 
complementary to the genomic regions of interest. Sequencing of the captured cell 
free DNA and data analysis will be preformed by the Center for Cancer Genome 
Discovery (CCGD) at Dana-Farber Cancer Institute to identify genomic 
rearrangements in the intronic regions of the EWSR1, FUS, CIC, and BCOR genes 
as well as the coding regions of the STAG2 and TP53. 
 
15.7 Additional correlative studies 
If the patient consented to banking of material for future research then blood, bone marrow, 
and paraffin-embedded material or unstained slides remaining after the studies detailed in 
Sections 15.1-15.4 have been completed may be used for future research exploring the 
biology of Ewing sarcoma or other diseases. Assays to be performed include sequencing 
(including whole exome or whole genome sequencing) and creation of cell lines. If used 

 
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for such additional biologic research, specimens would be de-identified prior to use. If 
biologic studies required linkage to treatment / outcome data (e.g., immunogenicity assays 
on banked serum) such linkage would be performed by an honest broker as is typical for 
this type of study.  
 
All material to be used for future research will be banked at the Biopathology Center. 
 
 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING  
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 (except where explicitly prohibited within the protocol). 
 
16.1 
Imaging Guidelines 
 
CT and MRI guidelines are available on the COG Member site at: 
https://www.cogmembers.org/_files/reference/RefMaterial/DiagnosticImagingGuidelines
_MRICT.pdf. 
 
For PET scan guidelines please refer to the NCI guidelines for the recommended set of 
procedures for the acquisition and analysis of 18F-FDG PET scans of patients participating 
in NCI-sponsored diagnostic and therapeutic clinical trials, which can be found in the 
consensus statement by Shankar and colleagues.123  
 
See also Section 10 for overview of response assessment and preferred imaging studies.  
 
For local staging, MRI scans are preferred in the vast majority of cases. CT is also useful 
in assessing cortical changes and for chest wall tumors. MRI for local staging should be 
performed at field strength of 1-3 Tesla, using dedicated surface coils for the anatomical 
area of interest, and should always include axial fat-saturated T2-weighted sequences and 
contrast-enhanced T1-weighted sequences in a second plane, among other site-specific 
sequences. Diffusion-weighted scans and ADC maps are desirable. Gadolinium-chelates 
may be used in patients with an eGFR of > 60. Tumor measurement in three dimensions 
will be requested (see separate data forms packet).  
 
Metastatic disease should be evaluated by FDG-PET scan and CT scan of the lungs. For 
FDG-PET scans, 18F-FDG should be injected intravenously 45–60 min prior to image 
acquisition, and patients should be asked to void their urine immediately before the scan. 
For centers with PET/CT capability, a diagnostic quality chest CT with slice thickness of 
5 mm or less is required of all patients. Diagnostic CT data will be reconstructed using soft 
tissue and lung algorithms. The same CT data can be used for attenuation correction of the 
PET emission data. PET and CT images will be merged and reconstructed in the transaxial, 
coronal and sagittal planes. 
 
Sites suspicious for bone or soft tissue metastasis should be imaged further with MRI or 
CT (whole body CT or MRI obtained as part of PET/CT or PET/MRI scan is acceptable) 

 
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at study entry. Confirmed sites of bone or soft tissue metastatic involvement at study entry 
should have repeat MRI or CT at each follow-up re-staging evaluation.  
  
For patients having a separate dedicated chest CT for metastatic staging, helical CT of the 
lungs should be obtained in low dose mode with a slice thickness of 5 mm or less. Contrast 
agent injection is optional and might be favored in case of a chest wall primary tumor 
and/or clinical suspicion for mediastinal or pleural disease.  
 
While some centers may utilize whole body MRI scans to evaluate for metastatic disease, 
these scans are optional and should not replace required imaging studies. Whole body MR 
images can be obtained using whole body surface coils and STIR and/or diffusion weighted 
sequences. Data sets obtained at different bed positions will be post-processed to generate 
“whole body” scans.  
 
The study radiologist is available for consultation for questions related to diagnostic 
imaging.  
 
16.2 
Correlative Imaging Aims 
As part of routine clinical care, patients will undergo MRI (less commonly CT) of the 
primary tumor as well as whole-body FDG-PET scans. Scans from study entry and end-
Induction will be submitted to IROC Rhode Island (formerly QARC) for batched central 
review and fusion of PET and MRI images by the study radiologist. MRI (or CT) data will 
be used to obtain the largest anterior-posterior, transverse and longitudinal dimensions. 
Reporting of these three dimensions will be required. These dimensions will be used for 
central estimation of tumor volume using the formula for a prolate ellipsoid: volume in 
mm3= π /6 · (d1·d2·d3) = (AP x transverse x longitudinal) x 0.5.  
 
Institutions will also report primary tumor FDG-PET standardized uptake value from the 
primary tumor at study entry and again at end-Induction.  
 
16.3 
Instructions for Submitting Imaging for Correlative Imaging Aims 
Anatomic imaging (MRI or CT) and FDG-PET scans from study entry, end-Induction, and 
first episode of disease progression / relapse will be submitted to IROC Rhode Island  as 
follows to support the correlative imaging aims 1.3.4, 1.3.9 and 1.3.10. If images already 
submitted to IROC Rhode Island as part of radiation oncology review, duplicate images do 
not need to be submitted to support these aims.  
 
The corresponding radiology reports will also be submitted to IROC Rhode Island. 
 
Submission of diagnostic imaging data in digital format is required. Digital files must be 
in DICOM format. These files can be submitted via sFTP. Information to obtain an sFTP 
account and submission instructions can be found at http://irocri.qarc.org/. Follow the link 
labeled digital data. Alternatively, if sFTP is not feasible, the imaging may be burned to a 
CD and mailed to IROC Rhode Island. Multiple studies for the same patient may be 
submitted on one CD; however, please submit only one patient per CD.  
 
Please submit to: 
IROC Rhode Island QA Center 
640 George Washington Highway, Building B, Suite 201 

 
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Lincoln, RI 02865-4207 
Phone: 401-753-7600 
Fax: 
401-753-7601 
 
 
17.0 
RADIATION THERAPY GUIDELINES 
Radiation Therapy for patients on COG protocols can only be delivered at approved COG RT 
facilities. 
 
 
 
 
 
 
 
 
 
17.1 
General Guidelines 
The radiation therapy guidelines for this study were developed specifically for patients with 
newly diagnosed, metastatic Ewing sarcoma. These guidelines apply to patients who 
require radiation therapy as a component of treatment of the primary tumor during the 
Local Control phase of therapy and also to patients who require radiation to metastatic sites 
during the Metastatic Site Radiation phase of therapy.  
 
17.1.1 Special Note for Very Young Children 
The long-term morbidity of RT or aggressive surgery for very young children 
makes appropriate local control challenging. Many clinicians are unwilling to 
follow standardized local control guidelines for very young children. This study 
encourages adherence to standardized local control guidelines for all children 
regardless of age. Consult with study surgeons and radiation oncologists as 
appropriate for a specific case. 
 
17.1.2 Credentialing 
• 
All therapy units used on this protocol must have their calibrations verified 
by IROC Houston (RPC). The table in Section 17.5 indicates allowable 
modes of treatment delivery. 
• 
IMRT: Institutions treating with IMRT and not previously credentialed for 
use of IMRT in COG trials must irradiate IROC Houston’s head and neck 
phantom. Contact IROC Houston (http://irochouston.mdanderson.org) for 
information about their phantoms. 
• 
Proton 
Therapy: 
The 
Proton 
Questionnaire 
(available 
at 
http://irochouston.mdanderson.org) must be completed. Each beam line 
used to treat patients on this study must be credentialed for clinical trial 
use by IROC Houston. See Section 17.1.4 below. 
• 
Motion Management: If patients are treated with IMRT and gating or 
tracking methods are used to compensate for respiratory motion, IROC 
Houston’s Thorax-Lung Phantom must be irradiated with its 
accompanying reciprocating platform to simulate motion. 
• 
SBRT: Use of SBRT is encouraged for treatment of bone metastases 
<5 cm (based upon maximal dimension at diagnosis), but credentialing is 
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 
(except where explicitly prohibited within the protocol). 

 
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required for its use. SBRT credentialing includes the following three 
components: (1) completion of the Motion Management Questionnaire 
(2), irradiation of IROC Houston’s Spine Phantom and (3) approval of the 
institution’s IGRT process. See http://irocri.qarc.org/for the Motion 
Management Questionnaire and a description of IGRT credentialing 
requirements. 
 
NOTE:  
• 
SBRT is not to be used for sites other than bone metastases. 
• 
COG will accept SBRT credentialing through NRG provided that 
the credentialing included irradiation of IROC Houston’s Spine 
Phantom (RTOG 0631). 
 
17.1.3 Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed 
for the use of IMRT in National Cancer Institute sponsored cooperative group 
trials. These guidelines are available through  http://irocri.qarc.org/. These 
guidelines require that the protocol explicitly state their requirements and methods 
for localization and immobilization; the use of volumetric imaging; target and 
organ motion management; nomenclature, definitions and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects 
of heterogeneity in tissues; and quality assurance. 
 
17.1.4 Guidelines and Requirements for the Use of Proton Beam Therapy 
Proton therapy may be used to deliver radiation therapy on this protocol.  The 
proton therapy method will be limited to scattering, uniform scanning and pencil 
beam scanning depending on institutional availability. Investigators using proton 
beam radiation must comply with current NCI proton therapy guidelines as 
outlined in the Guidelines for the Use of Proton Radiation Therapy in NCI 
Sponsored 
Cooperative 
Group 
Clinical 
Trials, 
available 
at 
http://rpc.mdanderson.org/RPC/home_page/Proton_guidelines.htm. 
 
17.1.5 Guidelines and Requirements for the Use of Brachytherapy or Intraoperative 
Radiation Therapy  
Brachytherapy, using either high dose rate or low dose rate radioactive sources 
may be used on this protocol. Typically, brachytherapy or intraoperative radiation 
therapy will be used to deliver focal RT to residual disease in the operative bed of 
the primary tumor for select patients.  
 
 
17.1.6 Institutional Requirements to Offer SBRT 
All sites treating with SBRT to sites of bone metastasis must be credentialed. 
COG will accept SBRT credentialing through NRG (see Section 17.1.2). As 
radiotherapy for metastatic sites is not performed until the completion of 
therapy, sites that are not credentialed at the initiation of therapy should have 
adequate time to obtain SBRT credentialing prior to its use. The pediatric 
radiation oncologist should be involved at the time of diagnosis to assess if 
imaging is adequate for local therapy and to ensure that all required 
credentialing tests for SBRT have been met.  
 

 
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17.2 
Indications for Radiation Therapy 
All patients should have all local and distant disease addressed with an appropriate local 
control modality. Definitive local therapy (surgery, SBRT, EBRT) is recommended to all 
metastatic sites documented at the time of diagnosis. SBRT is recommended to all bone 
metastatic sites < 5 cm in maximal dimension (based upon maximal dimension at 
diagnosis) if not treated surgically. Optimal local control will be determined by the treating 
institution and should involve input from pediatric oncology, surgery, and radiation 
oncology. The pediatric radiation oncologist should be involved at the time of 
diagnosis to assess if imaging is adequate for local therapy and to ensure that all 
required credentialing tests for SBRT have been met. It is expected that the majority of 
patients will receive radiotherapy to the often multiple sites of metastatic disease. Because 
of the option of SBRT for metastatic sites, RT guidelines follow for treatment of primary 
site and then separately for treatment of metastatic sites.  
 
Note: SBRT is not to be used for sites other than bone metastases. 
 
See Section 4.3 for a general discussion of local control. 
 
RT for Primary Site 
Definitive radiation therapy 
Unresected tumor 
Pre-operative radiation therapy 
Resectable tumor* 
Post-operative radiation therapy 
(1) Post-operative gross or microscopic residual tumor 
(2) Intra-operative spill 
Special presentations 
(1) Chest wall tumor with ipsilateral pleural-based 
secondary tumor nodules or positive pleural fluid cytology 
(2) Pathologically involved lymph nodes 
 
RT for Metastatic Sites 
Definitive radiation therapy 
Unresected tumor > 5cm 
Definitive SBRT 
Unresected/post-operative gross disease in bone mets that 
were <5 cm at diagnosis 
Post-operative radiation therapy 
(1) Post-operative gross or microscopic residual tumor 
(2) Intra-operative spill 
Special presentations 
(1) Pulmonary metastases 
(2) Pathologically involved lymph nodes 
 
*Pre-operative radiotherapy is generally not indicated in this patient population (see 
Section 4.3.1.3). 
 
Patients having microscopic or gross residual disease after planned pre-operative radiation 
therapy will receive additional radiation therapy (see table Section 17.7.2.1).  
 
Patients who have had a complete surgical excision of the involved area of bone and/or 
soft tissue mass with adequate surgical margins (see Sections 4.3.1, 14.3.1 and 17.7.2.1) 
will not receive postoperative radiation. 
 
Radiation is not indicated for the following conditions: bone marrow lesions with no 
evidence of bone involvement or sites not assessable clinically or by imaging and radiation 
that would exceed normal marrow tolerance.   
 

 
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17.3 
Timing of Radiotherapy 
 
17.3.1 Radiation Oncology Consultation 
All patients should be seen in consultation by a radiation oncologist as early as 
possible if RT may be indicated according to the protocol. The purpose of the 
consultation is to participate in staging and to review the adequacy of the initial 
diagnostic imaging studies that will be used for subsequent RT planning, as well 
as to discuss and plan for potential use of various radiation modalities (SBRT, 
proton therapy). 
 
Patients treated with radiation as the local control measure to the primary site, or 
preoperatively or postoperatively, will have radiotherapy delivered beginning 
concurrently with the beginning of Consolidation chemotherapy. If wound healing 
is incomplete, the possibility of a delay in initiation of radiation should be 
discussed with the protocol radiation oncologist. Ifosfamide and etoposide 
chemotherapy may be given concurrently with radiotherapy (See Section 4.1.1.1).  
 
If radiation is used for metastatic sites, radiotherapy should be given at the end of 
Consolidation chemotherapy during the Metastatic Site Radiation phase of 
therapy. An exception may be made for treatment of limited lesions immediately 
adjacent to the primary site which may be difficult to treat without overlap of 
radiation volumes if treated at a later date. These metastatic sites will be treated 
concurrently with the primary tumor site. See Section 4.1.1.2 for modifying order 
of Consolidation for patients who receive early whole lung radiation due to 
overlapping radiation fields with the primary tumor. 
 
17.3.2 Timing of Emergency/Urgent Radiation Therapy 
Patients who require emergency radiotherapy, such as patients with spinal cord 
compression, may receive radiotherapy to their emergency site on Day 1 if deemed 
necessary by the treating physician. This is expected to be a rare event, since most 
patients will respond quickly and dramatically to chemotherapy. In addition, early 
therapy intensity appears to be associated with improved outcomes in this disease. 
The entire course of the emergency radiotherapy should be administered starting 
Day 1, rather than splitting the treatment and concluding the course at the 
beginning of Consolidation.  
 
In cases requiring urgent or emergency radiotherapy, notify the study radiation 
oncologist. Note that doxorubicin courses must not be given during radiation with 
the exception of Consolidation Cycle 1 where concurrent start of chemotherapy 
and radiation is allowed. If emergency radiotherapy is required during Induction 
the order of the six planned chemotherapy cycles may be altered in order to avoid 
concurrent administration of doxorubicin with radiation (except Days 1 and 2 of 
doxorubicin in week 1 Induction, which may be given at the start of emergent 
radiation). Ifosfamide/etoposide courses may be given concurrently. Ganitumab 
must not be given concomitantly with radiation and therefore the schedule of 
ganitumab administration must also be altered while administering a total of 11 
doses of ganitumab across Induction and Consolidation for patients in Regimen B. 
 
 

 
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17.3.3 Mesna 
In the past, mesna was held during radiation therapy. There are no data to suggest 
that mesna is a radioprotector. Mesna will therefore not be held during radiation. 
 
17.4 
Emergency Radiation Therapy 
Radiation therapy may be delivered on an emergent basis to patients with spinal cord 
compression, loss of vision or other function-threatening conditions. The decision to 
irradiate emergently should be made by the treating physicians. If emergent radiation is 
initiated, the entire course of the radiotherapy for that site should be delivered using the 
protocol specified doses, rather than waiting until the protocol specified times for 
irradiation. Doxorubicin should be withheld if patients receive emergency radiation 
therapy (except Days 1 and 2 of doxorubicin in week 1 Induction, which may be given at 
the start of emergent radiation). Ifosfamide/etoposide courses may be given concurrently. 
Ganitumab must not be given concomitantly with radiation and therefore the schedule of 
ganitumab administration must also be altered while administering a total of 11 doses of 
ganitumab across Induction and Consolidation for patients in Regimen B. 
 
 
17.5 
Equipment and Methods of Delivery and Verification  
 
Equipment 
Photons** 
(any energy) 
Electrons 
(any energy) 
IMRT 
(4-10MV) Protons 
Brachytherapy* 
Linear Accelerator 
X 
X 
X 
 
 
Proton Beam  
 
 
 
X 
 
Intraoperative 
Radiation Therapy 
X 
X 
 
 
X 
Brachytherapy - 
high or low dose rate  
 
 
 
 
X 
* 
Permanent radioactive implants are not allowed on this protocol. 
** For tumors adjacent or included in lung tissue, photon beam energy should be < 10 MV. 
 
17.5.1 Treatment planning 
CT-treatment planning: All patients will undergo CT treatment planning for this 
protocol. Slices no more than 0.5cm thick (0.2-0.3cm is recommended) shall be 
taken throughout the extent of the irradiated volume. 
 
CT (volumetric) based planning is required to optimize dose to the target volumes 
while protecting normal tissues. Organs within the irradiated volume should be 
contoured including those required by treatment site (Section 17.10). A DVH is 
necessary to determine target coverage and evaluate dose to normal tissues. In the 
event that a patient must start radiation emergently with a non-volumetric 
treatment plan, a volumetric plan will be accomplished as soon as is reasonably 
possible and the previously utilized beams must be incorporated into the composite 
plan. 
 
 
17.5.2 In-room verification of spatial positioning  
Two-dimensional or volumetric imaging may be used to verify correct patient 
positioning. Portal imaging using EPIDs is the most common two-dimensional 
method, particularly when the target volume possesses a fixed spatial relationship 
with visualized bony anatomy. Film is discouraged but is acceptable. For IMRT 

 
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and 3-D CRT treatments, a pair of images (usually orthogonal AP and lateral) is 
required to verify that the isocenter is in correct alignment relative to the treatment 
plan; these may be MV or kV images. When proton radiation is employed, daily 
image guidance with either 2-D or volumetric imaging is required. 
 
Volumetric imaging for position verification may be in-room kV or MV cone beam 
or conventional CT imaging. For CT tomography where isocenters are not used, a 
printout of the isodoses overlaid on the fused CT images can be printed to 
demonstrate in room verification. 
 
17.6 
Target Volumes 
17.6.1 Standard tumor and target volume definitions 
International Commission on Radiation Units and Measurements (ICRU) Reports 
50, 62 and 78 (www.icru.org) define prescription methods and nomenclature that 
will be utilized for this study. Treatment planning will be based on the following 
definitions and applies only to the primary tumor site: 
 
Photons 
• 
Gross tumor volume (GTV) is the volume occupied at diagnosis by visible 
or palpable disease.  
 
• 
Clinical target volume (CTV) includes the GTV and sites with potential 
occult tumor involvement including lymph nodes adjacent to the GTV that 
may be clinically involved.  
 
• 
Planning target volume (PTV) is the CTV surrounded by a geometric 
margin to account for variability in set-up, breathing or motion during 
treatment. 
 
Protons 
• 
GTV is the same for protons and photons. 
 
• 
CTV is the same for protons and photons. 
 
• 
PTV will be uniquely defined for proton therapy. 
The planning target volume (PTV) for proton therapy will include a 
margin which is added to the CTV in 3-dimensions. The margin should be 
consistent with the motion control and setup accuracy for the particular 
type of treatment (scattered versus scanning) at the treating proton center.  
 
When proton therapy is used, the PTV will be used for dose reporting 
and not specifically for treatment planning. The goal of treatment 
planning will be CTV coverage at 100% with measures taken for each 
specific uncertainty. 
 
The PTV will vary with each individual field and will require additional 
adjustment including (1) the lateral margins, (2) smearing of compensator 
(if applicable), (3) range of beam (depth of penetration) and, (4) 
modulation (number of required Bragg peaks). Adjustments to any of the 
aforementioned parameters (usually 3-15 mm) will be based on the range 
uncertainty, CT number uncertainty, internal motion, and set up error 

 
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determined for the particular body site at the individual proton institution. 
The following parameters must be explicitly reported for each beam: 
range, modulation, smearing radius of the compensator, set-up margin 
(SM) and PTV margin. The specifics of dose reporting for the proton PTV 
and recommendations regarding the PTV margin are discussed in Section 
17.7.3.  
 
Brachytherapy 
• 
GTV is the same as for photons. 
 
• 
CTV is the same as for photons. 
 
• 
PTV is equal to CTV. 
 
 
17.6.2 Initial tumor and target volume definitions 
The definitions for GTV1, CTV1 and PTV1 apply to all definitive, preoperative 
and postoperative treatment scenarios for which radiation therapy is indicated. 
Treatment will be prescribed to the PTV, which will be derived from the GTV and 
CTV 
 
17.6.2.1 
GTV1 
GTV1 is defined as the visible and/or palpable disease defined by 
physical examination, computed tomography (CT), magnetic 
resonance imaging (MRI) or positron emission tomography (PET scan) 
prior to any surgical debulking or chemotherapy. It also includes 
enlarged but unresected, regional lymph nodes. For patients who 
undergo initial surgery, operative notes and pathology reports may be 
helpful. GTV1 may require modification for initial tumors that exhibit 
a “pushing margin” into body cavities (ie, thorax, abdomen). If the 
tumor has responded to chemotherapy and normal tissues have returned 
to their natural position, GTV1 excludes the pre-chemotherapy volume 
where that volume extends into the cavity. Examples include tumors 
that indent the lung, intestine or bladder that clearly return to a more 
normal anatomic position following chemotherapy. The modified 
GTV1 includes initially infiltrative disease which has responded to 
chemotherapy. 
 
17.6.2.2 
CTV1 
If there are no sites that warrant irradiation for potential occult tumor, 
then the CTV1 is defined as the GTV1 plus 1 cm (but not extending 
outside of the patient). It also includes regional lymph node chains for 
clinically or pathologically involved nodes. For tumors with no 
evidence of nodal involvement (N0), the draining regional lymph nodes 
are not irradiated. For some sites, the definition of CTV is modified to 
account for specific anatomic barriers to tumor spread. When lymph 
nodes are clinically or pathologically involved with tumor, the entire 
lymph node drainage chain should be included in the CTV.  
 
17.6.2.3 
PTV1 

 
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For external beam photon techniques, the PTV1 is defined as the CTV1 
plus an institutional specified margin to account for day-to-day setup 
variation related to the ability to immobilize the patient and physiologic 
motion of the CTV1. The minimum margin is 0.5 cm without daily 
image guidance but does not have to be uniform in all dimensions. 
Institutions with daily image-guidance may be able to reduce PTV 
based on institution-specific guidelines.  
 
For proton planning, beam specific PTV expansions will be required as 
described in Section 17.6.1.  
 
Motion of the target volume in three dimensions (cranial, caudal, 
anterior to posterior, and lateral) may be determined by 4-dimensional 
CT, respiratory gated CT, or other accepted techniques. An ITV 
(internal target volume) may be created to account for internal motion 
if average CT based planning is employed using the guidelines outlined 
in 17.8.6. 
 
17.6.3 Volume reduction tumor and target volume definitions 
The definitions for GTV2, CTV2, and PTV2 apply to all definitive, preoperative, 
and postoperative treatment scenarios for which radiation therapy is indicated.  
 
17.6.3.1 
GTV2 
GTV2 is defined as residual visible or palpable tumor as assessed by 
CT, MRI, PET scan or physical exam following Induction 
chemotherapy with or without surgery. For unresected tumors, GTV2 
includes the pre-treatment abnormalities in bone and the gross residual 
tumor in soft tissue after Induction chemotherapy. For partially 
resected tumors, GTV2 includes residual abnormalities in bone and the 
gross residual tumor in soft tissue and the tumor bed harboring 
microscopic residual tumor. For tumors with microscopic residual and 
>90% necrosis, this is the post-induction chemotherapy target volumes 
determined on pre-operative imaging. 
 
Special Considerations: In the case of extraosseous primaries with a 
complete response to chemotherapy or with intra-operative spill, there 
is only a single GTV (GTV1=GTV2). 
 
17.6.3.2 
CTV2 
CTV2 is defined as the GTV2 + 1 cm (but not extending outside the 
patient) and areas at risk for microscopic disease and modified to 
account for specific anatomic barriers to tumor spread. CTV2 includes 
lymph nodes adjacent to the GTV when appropriate. CTV2 should not 
extend outside of the patient. 
 
17.6.3.3 
PTV2 
PTV2 is defined as the CTV2 with an institution and modality specific 
margin (minimum: 0.5 cm) to account for day to day setup variation 
and physiologic motion of the CTV2. For proton planning, beam 

 
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specific PTV expansions will be required as described in Section 
17.6.1. 
 
Special Presentations:  
 
1) Chest Wall Tumors with Ipsilateral Pleural Nodules and/or Pleural 
Fluid Involvement (CTV3, PTV3) 
These patients will require irradiation of the ipsilateral hemithorax 
followed by irradiation to the primary site, and if applicable, pleural 
based nodules. Target volumes for ipsilateral hemithorax irradiation 
are designated CTV3, PTV3 and will be irradiated first. Irradiation of 
the primary site or pleural based disease will follow. The GTV1, CTV1, 
PTV1 and GTV2, CTV2, and PTV2 for the primary are defined and 
treated as outlined in previous sections after completion of hemithorax 
irradiation. If the primary has been resected with adequate margins, and 
irradiation of the primary site is not indicated, the primary will not be 
treated and radiation will be administered only to PTV3. For ipsilateral 
or bilateral lung irradiation, the lung and pleural cavity is defined as 
the CTV3. PTV3 is an expansion of CTV3 to account for organ motion 
during respiration as well as a 0.5-1 cm geometric expansion to account 
for day to day set-up uncertainty. Organ motion can be determined with 
a 4D simulation, fluoroscopy, or lateral chest radiograph at full 
inspiration to document diaphragmatic excursion. The GTV1 and 
GTV2 for the primary and for the pleural based metastases are defined 
and treated as outlined in previous sections, however, there will be no 
GTV2 assigned to pleural based metastases having complete response 
to chemotherapy. The CTV1 and CTV2 of the primary and the CTV1 
and CTV2 for the pleural based metastases respectively, may be 
combined if they can be treated in a single field based on the judgment 
of the radiation oncologist. Similarly a composite for the CTV3 
including the pleural surfaces of the entire hemithorax and including 
the primary site and the pleural based metastases may be created to 
simplify treatment planning as long as dose requirements to these 
regions are met. 
 
2) Pathologically Involved Lymph Nodes 
Nodal target volumes are included in the definitions of GTV1, CTV1, 
PTV1. Nodal target volumes are included in the definitions of GTV2, 
CTV2, and PTV2 with some modifications: 
 
In the case of a primary tumor which is resected with adequate margins, 
the nodal PTV should be drawn without the primary site and will be 
the only volume treated. The GTV for the primary site and GTV for the 
lymph nodes should initially be determined independently. If the 
volumes are contiguous the treating radiation oncologist should 
consider combining the volumes (especially after CTV and PTV 
expansions). The doses for the primary site and lymph nodes should be 
determined independently. 
 
GTV2 is only defined for unresected lymph nodes and includes 
the nodal volume after chemotherapy. GTV2 cannot be defined 

 
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for resected lymph nodes or when there has been a complete 
response to chemotherapy. 
 
CTV2 is only defined for unresected lymph nodes and its 
definition depends on the response to chemotherapy. CTV2 is 
defined as the original involved nodal region for unresected lymph 
nodes that have had a complete response to chemotherapy. CTV2 
is defined as the original involved nodal region with an additional 
margin of 1.0 cm surrounding GTV2 for unresected lymph nodes 
after a partial response to chemotherapy.  
 
PTV2 is only defined for unresected lymph nodes and includes an 
additional margin of 0.5-1.0 cm surrounding CTV2. When proton 
radiotherapy is employed, beam-specific PTV2 should be 
determined as described in Section 17.6.1. 
 
Vertebral Body Tumors 
The GTV1 and GTV2 are defined as outlined in previous sections. At 
a minimum, CTV1 is defined as the entire vertebral body. PTV1 is the 
CTV1 volume with an institution specific margin of approximately 0.5 
cm to account for day to day variation in set-up and physiologic 
motion. For the field-reduction boost, CTV2 is defined as GTV2 plus 
an additional 0.5-1.0 cm margin to account for sub-clinical areas of 
residual disease but confined by anatomic boundaries (e.g. does not 
enter the spinal canal if initial disease did not enter the canal). PTV2 is 
the CTV2 volume with an additional margin of approximately 0.5 cm 
to account for day to day variation in set-up and physiologic motion. 
Again, this may be further adjusted and beam-specific when protons 
are utilized. Institutions with daily image-guidance may be able to 
reduce PTV based on institution-specific guidelines. 
 
Extremity Tumors 
The CTV should be modified at the discretion of the radiation 
oncologist to avoid circumferential irradiation of extremity lymphatics 
and treatment across a joint unless absolutely necessary for tumor 
coverage. A strip of tissue must be provided for extremity tumors, so 
that lymphatic obstruction and unacceptable morbidity can be avoided. 
If any of the treatment margins necessitates irradiating the epiphysis of 
an adjacent bone and there is no extension across the joint space, a 
smaller margin may be considered so that the adjacent epiphysis can 
be excluded. If the patient has a diaphyseal lesion, every attempt should 
be made to exclude at least one epiphysis (or both) of the affected bone. 
The most active growing epiphyses are those about the knee in the 
lower extremity and those in the shoulder and wrist area of the upper 
extremity. The gross tumor volume (GTV) should be treated to the 
prescribed dose whenever possible. 
 
Head and Neck Tumors 
Many of these tumors may be considered unresectable due to close 
proximity to critical structures and surgical risks contributing to 

 
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functional or cosmetic deficits. Every attempt should be made to 
minimize dose to the brain, cochlea, optic chiasm and orbit including 
eye, lacrimal gland, and optic nerve. 
 
Orbital Tumors 
For orbit primaries, the CTV will not extend outside of the bony orbit, 
providing there is no bone erosion of the orbit. 
 
Chest Wall/Intrathoracic Tumors 
Tumors which have displaced a significant amount of lung parenchyma 
then returned to normal anatomic position following surgery or 
chemotherapy will have the GTV defined as the preoperative 
(prechemotherapy) tumor volume excluding the component of 
intrathoracic tumor which was removed by surgery or decreased in size 
by chemotherapy. All areas of pleural involvement will be included in 
the GTV regardless of whether the radiation is delivered pre or 
postoperatively. 
 
Intra-abdominal/Retroperitoneal/Pelvic Tumors 
Tumors which have displaced a significant amount of bowel then 
returned to normal anatomic position following surgery or 
chemotherapy will have the GTV defined as the preoperative 
(prechemotherapy) tumor volume excluding the component of intra-
abdominal or intra-pelvic tumor which was removed by surgery or 
decreased in size by chemotherapy. All areas of peritoneal or 
mesenteric involvement will be included in the GTV regardless of 
whether the radiation is delivered pre- or post-operatively. Whole 
abdomen RT is indicated for malignant ascites or diffuse peritoneal 
involvement. In such cases the entire peritoneal cavity is considered 
the CTV. 
 
Pulmonary Metastases and Pleural Effusions (CTV3, PTV3) 
These patients will require bilateral whole-lung radiation. Whole lung 
volume is designated CTV3. PTV3 is an expansion of CTV3 to account 
for organ motion during respiration as well as a 0.5-1 cm geometric 
expansion to account for day to day set-up uncertainty. Organ motion 
can be determined with a 4D simulation, fluoroscopy, or lateral chest 
radiograph at full inspiration to document diaphragmatic excursion. 
Note: IMRT is not allowed for whole lung radiation. 
 
Surgical management 
of 
residual 
pulmonary tumors 
after 
Consolidation chemotherapy is allowed. If the lung metastases are 
resected with adequate margins, boost irradiation is not indicated, and 
radiation will be administered only to PTV3. 
 
If metastatectomy of residual lung lesions is not performed, a field 
reduction boost will be administered based on a volume designated 
GTV2. As the post-chemotherapy volume (GTV2) is used, there will be 
no GTV1 in these patients. GTV2, CTV2, and PTV2 for the residual 

 
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lung lesions are defined and treated as outlined in previous sections and 
treated at the completion of whole lung irradiation.  
 
Non-Pulmonary Metastases Treated with Standard RT (not SBRT) 
The GTV2 for metastatic sites is the area of residual tumor defined on 
CT or MRI (post-chemotherapy/surgery) and involved bone. In cases 
where there is a discrepancy in volume between the scans, the larger 
volume will be irradiated. To minimize irradiated volume, no GTV1 
will be defined for metastatic sites. CTV2 is defined as GTV2 plus an 
additional 1.0 cm margin to account for sub-clinical areas of residual 
disease but confined by anatomic boundaries. PTV2 is the CTV2 
volume with an additional margin of approximately 0.5 cm. 
 
Radiation is recommended to all non-marrow metastatic sites. Bone 
marrow deposits of tumor must have bone disruption/erosion to qualify 
as bone disease. CT may be useful to determine bone involvement. 
However, feasibility of delivering metastatic site radiation diminishes 
as the number of metastatic sites increases and will be determined by 
the treating radiation oncologist. SBRT has been introduced to improve 
the feasibility of treating multiple metastatic sites. If the treating 
radiation oncologist does not feel treatment of all sites is feasible, 
radiation is recommended to those metastatic sites if there remains a 
concern about disease control at that site and the patient can tolerate 
further radiotherapy without undue morbidity. Re-evaluation imaging 
at the completion of therapy will help the radiation oncologist 
determine if the various remaining sites are in need of further treatment 
and will consider the following: (1) sub-optimal response to 
chemotherapy by clinical or imaging criteria, (2) sites which will be 
problematic in the event of disease progression (i.e., tumor in a weight 
bearing bone), and (3) sites that can be imaged with sufficient accuracy 
for treatment, and (4) expected tolerance and morbidity (i.e., bone 
marrow tolerance). Surgical resection of metastases can be considered 
if it can be done with reasonably low or acceptable morbidity.  
 
Bone Metastases Treated with SBRT 
The GTV2, CTV2 and PTV2 for metastatic sites is the area of residual 
tumor defined on MRI and/or CT (post-chemotherapy/surgery) and 
pre-treatment abnormalities in bone (see Section 17.6.3.1). In cases 
where there is a discrepancy in volume between the scans, the larger 
volume will be irradiated. To minimize irradiated volume, no GTV1 
will be defined for metastatic sites. 
 
For SBRT, modifications to CTV2 and PTV2 are as follows: 
CTV2=GTV2+1cm expansion for microscopic disease but limited by 
anatomic constraints such as bone cortex 
 
PTV2=CTV2+2mm expansion for setup error, but can be limited to 
avoid critical normal structures such as spinal canal 
 

 
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Definitive local therapy (surgery, SBRT, EBRT) is recommended to all 
bone metastatic sites documented at the time of diagnosis. SBRT is 
recommended to all bone metastatic sites < 5 cm in maximal dimension 
(based upon maximal dimension at diagnosis) if not treated surgically. 
Bone marrow deposits of tumor must have bone disruption/erosion to 
qualify as bone disease. CT may be useful to determine bone 
involvement. SBRT has been introduced to improve the feasibility of 
treating multiple metastatic sites. If the treating radiation oncologist 
does not feel treatment of all sites is feasible, radiation is recommended 
to those metastatic sites if there remains a concern about disease control 
at that site and the patient can tolerate further radiotherapy without 
undue morbidity. Re-evaluation imaging at the completion of therapy 
will help the radiation oncologist determine if the various remaining 
sites are in need of further treatment and will consider the following:  
(1) sub-optimal response to chemotherapy by clinical or imaging 
criteria, (2) sites which will be problematic in the event of disease 
progression (i.e., tumor in a weight bearing bone), and (3) sites that can 
be imaged with sufficient accuracy for treatment, and (4) expected 
tolerance and morbidity (i.e., bone marrow tolerance). 
 
17.7 
Target Dose 
Integrated boost radiotherapy plans are not permitted. 
 
17.7.1 Dose Definition  
Photon dose is to be specified in centigray (cGy)-to-muscle. For proton beams, the 
absorbed dose, ICRU 78’s DRBE, is specified in Gy(RBE), using a standard RBE 
of 1.1 with respect to Cobalt-60.  
 
17.7.2 Prescribed dose and fractionation 
Dose should be prescribed to an isodose surface that encompasses the PTV and 
allows the dose uniformity requirements to be satisfied. The protocol-specified 
dose per fraction is 180cGy. The treatment should be limited to one fraction per 
day. The dose per fractionation may be reduced from 180cGy to 150cGy when 
large volumes are treated (i.e., whole abdomen and pelvis) or when tolerance is 
poor (i.e., mucositis or diarrhea). Changes to the fractionation regimen should be 
noted in the treatment record and submitted information.  
 
17.7.2.1 
Radiation dose guidelines for all targeted volumes, excluding lymph 
nodes, and chest wall tumors with involved plueral fluid or nodules.  
All doses are described in Gy; however, equivalent doses should be 
prescribed in Gy (RBE)when proton therapy is utilized. 
Tumor Site and Presentation 
PTV1 
PTV2 
Definitive RT 
45 Gy 
10.8 Gy 
Definitive RT – vertebral bony lesion 
45 Gy 
5.4 Gy 
Definitive RT – extraosseous ESFT without bony involvement 
 
 
with CR to Chemotherapy 
50.4 Gy 
N/A 
Postop RT – microscopic positive margin and >90% necrosis 
N/A 
50.4 Gy 
Postop RT – microscopic positive margin and <90% necrosis 
50.4 Gy 
N/A 
Postop RT – gross residual 
45 Gy 
10.8 Gy 

 
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17.7.2.2 
Radiation dose guidelines for pathologically involved lymph nodes 
Involved Lymph Nodes Doses 
PTV1 
PTV2 
LN resected – separate from primary site 
50.4 Gy 
 
LN resected – contiguous with primary site 
50.4 Gy 
 
LN unresected - primary adequately resected 
45 Gy 
10.8 Gy 
LN unresected - primary inadequately resected (microscopic 
residual) 
45 Gy 
10.8 Gy 
Whole abdomen RT for malignant ascites or diffuse peritoneal 
involvement 
24 Gy* 
 
*Whole abdomen RT will be administered at 1.5 Gy per fraction 
 
17.7.2.3 
Radiation dose guidelines for chest wall tumors with pathologically 
involved pleural fluid 
 
Chest wall tumors with positive fluid cytology 
Age 
PTV1* 
PTV2* 
PTV3^ 
< 6 years 
32.4 Gy 
10.8 Gy 
12 Gy 
> 6 years 
30.6 Gy 
9 Gy 
15 Gy 
*PTV1 and PTV2 - 1.8 Gy per fraction 
^PTV3 - 1.5 Gy per fraction  
Note: Heterogeneity correction must be used for lung irradiation 
 
17.7.2.4 
Radiation dose guidelines for chest wall tumors with pleural nodules 
 
Chest wall tumor with secondary soft tissue only pleural nodules, radiographic PR 
Age 
PTV1* 
PTV2* 
PTV3^ 
< 6 years 
23.4 Gy 
19.8 Gy 
12 Gy 
> 6 years 
21.6 Gy 
19.8 Gy 
15 Gy 
Chest wall tumor with secondary soft tissue only pleural nodules, chest wall 
radiographic PR, pleural nodules radiographic CR 
Age 
PTV1*chestwall PTV2*chestwall 
PTV3^ 
< 6 years 
23.4 Gy 
19.8 Gy 
12 Gy 
> 6 years 
21.6 Gy 
19.8 Gy 
15 Gy 
Age 
PTV1*pleural 
nodules 
PTV2* 
PTV3^ 
< 6 years 
37.8 Gy 
 
12 Gy 
> 6 years 
36 Gy 
 
15 Gy 
 
 
 
 
 
 
 
 
Dose for soft tissue only (no bone involvement) chest wall primary and pleural 
nodules, chest wall radiographic PR and pleural nodules radiographic CR 
Age 
PTV1* 
PTV2* 
PTV3^ 
< 6 years 
37.8 Gy 
 
12 Gy 
> 6 years 
36 Gy 
 
15 Gy 
*PTV1 and PTV2 - 1.8 Gy per fraction 
^PTV3 - 1.5 Gy per fraction  
Note: Heterogeneity correction must be used for lung irradiation 
 
17.7.2.5 
Radiation dose guidelines for pulmonary metastases and pleural 
effusions without chest wall tumor 
Pulmonary metastasis or malignant pleural effusion (not chest wall tumor)^ 

 
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**PTV2 - 1.8 Gy per fraction 
^PTV3 - 1.5 Gy per fraction  
Note: Heterogeneity correction must be used for lung irradiation 
 
17.7.2.6 
Standard (non-SBRT) radiation dose guidelines for individual 
metastatic lesions requiring irradiation (all non-bone sites, all non-lung 
sites and bone sites >5cm). 
 
 
Dose (cGy) 
Total recommended dose for gross disease 
5580 
If resected with microscopic residual 
5040 
Non-osseous, complete response to chemotherapy 
5040 
If resected with no microscopic residual 
0 
 
17.7.2.7 
SBRT Dose Guidelines 
 
Dose/fraction (cGy) 
Dose (cGy) 
PTV2 =GTV2 
800 
4000 
PTV1= CTV2 + 2mm 
700 
3500 
After 15Gy whole lung 
 
 
PTV2 = GTV2 
700 
3500 
PTV1 = CTV2+2mm 
600 
3000 
 
17.7.3 Dose uniformity – Conventional fractionation  
At least 95% of the protocol-specified dose should encompass 100% of the 
PTV1/PTV2 and no more than 10% of PTV1 (PTV2 for patients with a volume 
reduction) should receive greater than 110% of the protocol dose as evaluated by 
DVH. The 100% isodose should be equal to the prescribed dose. Wedges, 
compensators and other methods of generating more uniform dose distributions 
are encouraged. 
 
Proton Specific Guidelines: For protons, the PTV concept differs from photon 
therapy. All uncertainties are taken into account explicitly to create a robust plan 
that provides full dose coverage of the CTV Proton plans should be evaluated for 
adequate PTV coverage from the summation of all beams. For scattered and 
uniform scanning beams, the aperture margin must include the appropriate beam 
penumbra for the selected beam energy, and setup and internal margins (SM and 
IM). These margins depend on the patient setup techniques used at the treating 
proton center. The aperture margin may be expanded further if a cold spot occurs 
near the edge of CTV due to insufficient lateral scatter. The smearing radius for 
the range compensator must be equal to the setup and internal margins (SM and 
Age 
PTV1* 
PTV2* 
PTV3 
< 6 years 
0 
36 Gy 
12 Gy 
> 6 years 
0 
34.2 Gy 
15 Gy 

 
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IM). The beam range should be equal to the maximum water equivalent depth of 
the CTV plus a range margin. Most proton centers use 3.5% of the maximum 
water-equivalent depth of the CTV to account for CT HU uncertainty and then add 
another 3 millimeters to account for uncertainties in beam range calibration and 
compensator fabrication. Additional range margin should be applied if internal 
motion could increase the water equivalent depth of the CTV. The modulation 
width should ensure proximal coverage of the target volume.   
 
A PTV should be created by a uniform expansion from CTV for reporting 
purposes. The expansion margin should be consistent with SM and IM and is 
typically 3 mm for a static target volume when daily imaging is performed. With 
the planning guidelines provided herein, no more than 10% of PTV should receive 
greater than 110% of the protocol dose as evaluated by DVH. In most cases, at 
least 95% of the protocol-specified dose should encompass 100% of the PTV. A 
potential exception is when the range margin is smaller than the PTV expansion 
(e.g., 3mm). As a result, the beam may not penetrate deep enough to sufficiently 
cover the distal portion of the PTV. This may occur for shallow target volumes 
where the maximum depth of the CTV is small and the range margin is small. This 
scenario is not expected for this protocol; however, such incomplete coverage of 
the PTV will not constitute a planning deviation because the plan should be 
sufficiently robust to cover the CTV with the protocol specified dose accounting 
for all uncertainties. 
 
17.7.4 Tissue heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed 
with CT-based treatment planning to generate dose distributions and treatment 
calculations from CT densities. When IMRT is used in lung, planning must be 
performed using an approved dose calculation algorithm. Approved algorithms 
include: convolution superposition, collapsed cone convolution, and Monte Carlo. 
When protons are used, tissue heterogeneity calculations should be performed with 
the CT-based treatment planning system to generate dose distributions from the 
proton relative stopping power. Proton therapy should be used with extreme 
caution when any of the treatment beams traverse normal lung parenchyma. Please 
see explicit planning guidelines for this situation in Section 17.9.1.1. 
 
17.7.5 Environment of care - Interruptions, delays and dose modifications 
There will be no planned rests or breaks from treatment. Once radiation therapy 
has been initiated, treatment will not be interrupted except for severe 
myelosuppression associated with complications which in the opinion of the 
treating physicians preclude administration of RT. Blood product support should 
be instituted according to institutional/protocol guidelines. Side effects that require 
treatment interruption include significant stomatitis or mucositis (> Grade 3). The 
reason for any interruptions greater than three treatment days should be recorded 
in the patient’s treatment chart and submitted with the QA documentation. When 
interruptions or delays occur, the total number of fractions or cumulative dose 
should not be modified. 
 
17.8 
Treatment Technique 
 

 
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17.8.1 Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Three-dimensional conformal 
therapy (coplanar or non-coplanar) IMRT or proton therapy are required to 
minimize dose to normal tissues.  
 
17.8.2 Selection of proton beam arrangements 
There are uncertainties (1-3 mm) in the distal range of the proton beam in which 
the RBE may be greater than 1.1; therefore, single proton beam plans which stop 
in a critical organ will not be allowed. Critical organs include, but are not limited 
to, spinal cord, brainstem, trachea, and mainstem bronchus. Individual proton 
beams which are a component of a multi-field proton beam, which stop within such 
an organ, will be allowed. 
 
17.8.3 Field Shaping  
Field shaping for photons will be done with either customized cerrobend blocking 
or multileaf collimation. The field shaping for protons will be done with either 
brass or cerrobend apertures or proton-specific multileaf collimation for scattered 
and uniform scanning beams. Pencil beam scanning does not require additional 
accessories for field shaping.  
 
17.8.4 Simulation including patient positioning and immobilization 
 
17.8.4.1 
Patient positioning  
Reproducible setups are critical and the use of immobilization devices 
is strongly encouraged. 
 
The patient may be treated in any appropriate, stable position. 
Consideration should be given to implications for inter and 
intrafraction motion when using non-standard position approaches. 
 
Immobilization devices 
Standard immobilization devices for the torso, extremities or head and 
neck are to be used. 
 
For IMRT and proton delivery approaches, the methods used for 
localization and immobilization of both patient and tumor are critical. 
The imaging studies should provide a clear assessment of the target 
volume with the patient in the treatment position.  
 
17.8.5 Special considerations  
Anesthesia or sedation may be required in certain patients, such as very young 
patients, to prevent movement during simulation and daily treatments.  
 
17.8.6 Motion Management and Margins to Account for Target Volume and Organ 
Motion 
Considering motion of normal tissues and target volumes is important. The internal 
target volume (ITV) is defined as the CTV surrounded by the internal motion (IM) 
component of the PTV and is meant to account for potential motion of the CTV. 
If adequate clinical data do not exist to define the IM component of the PTV 
margin, the following suggestions are provided: 

 
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• 
For a CTV susceptible to physiologic motion, a margin of at least 0.5cm 
should be added to the CTV prior to PTV margin expansion or a PTV 
margin of 1.0cm should be chosen. 
• 
For tumors of the thorax or abdomen, an assessment should be made to 
determine the extent of motion present. PTV margins should include this 
motion as a component.  
• 
IMRT may be used for tumors of the thorax only if the degree of tumor 
motion is assessed and can be limited to 0.5cm in any direction. If required 
to achieve this goal, techniques for managing or suppressing tumor motion 
shall be applied. 
• 
Protons may be used for tumors of the thorax only if the degree of tumor 
motion is assessed and can be limited to 0.5 cm in any direction. Motion 
should be accounted for in an ITV determined by 4-dimensional CT, 
respiratory gated CT, or other accepted techniques. 
• 
A description of the method used and evidence (i.e., observed motion 
during fluoroscopy, motion of surrogate markers using camera systems, or 
analysis of 4-D CT) of the remaining tumor motion should be submitted 
on the Motion Management Reporting Form with the Quality Assurance 
Documentation materials as noted in Section 17.11. 
NOTE: For patients treated with IMRT, use of gating or tracking methods 
to compensate for respiratory motion requires irradiation of IROC 
Houston’s Thorax-Lung Phantom with accompanying reciprocating 
platform 
to 
simulate 
motion. 
Contact 
IROC 
Houston 
(http://irochouston.mdanderson.org) 
for 
information 
about 
their 
phantoms. 
 
17.8.7 Brachytherapy 
 
Single Plane Implant 
It is expected that most patients will be treated by a single plane implant to the 
tumor bed after gross resection with microscopic residual disease or in the case of 
less than minimal margins. The target volume should include all sites of potential 
microscopic disease with at least 1.0 cm margin on all sides. A template, mesh or 
applicator can be used to keep the catheters parallel. If the area to be implanted is 
larger than 50cm2, external beam radiation therapy should be considered. Catheters 
should be parallel and positioned 1cm apart. To ensure sufficient coverage the 
catheters should be placed with the distal end of the catheter projecting 1-2cm 
beyond the target volume.  
 
Double or Multiple Plane Implant 
A double plane implant will be performed for unresectable tumors less than 2 cm 
thick. A larger tumor may require a volume (multiplane) implant. These techniques 
should not be used for patients with unresected boney disease. The target volume 
should include the entire palpable or post chemotherapy tumor volume with at least 
a 0.5cm margin on all sides. If the thickness of tissue to be implanted is larger than 
3 cm, external beam radiation therapy should be considered, but is not required. 
Catheters are to be implanted 1 cm apart throughout the tumor volume for these 
cases. The target volume is the entire palpable or post chemotherapy tumor with at 
least a 0.5 cm margin on all sides. 
 

 
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Brachytherapy Dosimetry 
CT planning shall be used for post-implant dosimetry. The GTV, CTV, and PTV 
shall be outlined on the CT. DVHs for the GTV, CTV, and PTV shall be calculated 
and submitted for review. 
 
Sources used shall have assay directly traceable to NIST. 
 
CT or MRI planning shall be used for postimplant dosimetry. The GTV and CTV 
shall be outlined on the CT or MRI. The PTV is identical to the CTV for purposes 
of brachytherapy planning. DVHs for the GTV, CTV, and PTV shall be calculated 
and submitted for review. 
 
Implants should be designed to meet the following dose uniformity criteria: 
CTVD100 ≥ 95% of the prescribed dose 
 
Dose homogeneity index 
80
.0
100
150
100

−
=
V
V
V
HI
CTV
CTV
CTV
 
 
Where CTVD100 is the dose received by 100% of the CTV, CTVV100 is the fraction of 
the CTV receiving the prescribed dose, and CTVV150 is the fraction of the CTV 
receiving 150% of the prescribed dose. 
 
It is recognized that the dose distribution from brachytherapy implants is inherently 
non-uniform and that for some implant geometries the above criteria for dose 
homogeneity index may be difficult to meet. 
 
When a brachytherapy implant is used, the isodose distribution shall be calculated 
in descriptive planes (3 perpendicular planes passing through the target center and 
in two transverse planes 2cm from the ends of the implant). CT-based planning 
shall be used. 
 
Total dose/fractionation and dose rate 
In the rare circumstance that postoperative brachytherapy is used instead of 
external beam radiation, then the following recommendations apply: 
 
LDR brachytherapy 
Total dose: 2600cGy  
Dose rate range: 40-100cGy/hour.  
 
HDR brachytherapy 
 
Total dose: 2100cGy  
 
Dose per fraction: 300cGy BID (separate fractions by ≥ 6 hours) 
 
Number of fractions: 7  
Brachytherapy should not begin until postoperative Day 5 to allow for wound 
healing.  
 
In the rare circumstance that brachytherapy is used instead of external beam 
radiation for an unresectable tumor, the following recommendations apply: 
 
LDR brachytherapy 
Total dose: 5000 cGy  
Dose rate range: 40-100cGy/hour.  

 
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17.8.8 SBRT Guidelines 
 
This study includes a secondary objective focused on evaluating the role of SBRT 
directed to sites of bone metastasis < 5 cm (based upon maximal dimension at 
diagnosis). For the purposes of this study, bone metastases are defined 
radiographically as lesions causing disruption of bone on anatomic imaging.   
 
All sites treating with SBRT to sites of bone metastasis must be credentialed. 
COG will accept SBRT credentialing through NRG. See Section 17.1.2 for full 
details of the credentialing process. 
 
Note: SBRT is not to be used for sites other than bone metastases. 
 
17.8.8.1 Localization 
Stereotactic radiation requires meticulous definition of the target, 
normal tissue structures, and visualization for localization during 
treatment delivery. Although CT is superior for evaluating bone 
changes due to tumor involvement, the extent of intramedullary 
involvement is difficult to determine on CT. Thus MRI within 4 weeks 
of treatment is required for planning for lesions treated with SBRT. 
This can either be in the form of treatment planning MRI or an MRI 
fused for treatment planning. A separate PET-CT is optional but can be 
used for treatment planning with fusion -- this study would be done 
identically if the patient were having standard fractionated radiation. 
These studies can assist with delineation of the target and visualization 
for stereotactic treatment.  
 
Patients will be positioned in a reproducible treatment position with an 
appropriate immobilization device custom-made for each patient and 
specific to treatment site. A variety of immobilization systems can be 
used on study such as stereotactic frames which surround the patient 
on three sides or large rigid pillows that reference to a stereotactic 
coordinate system. For cervical spine or cervicothoracic junctional 
areas, a rigid head and neck immobilization device should be used. 
Patient immobilization must be reliable enough to achieve the accuracy 
requirement of image-guidance.  
 
17.8.8.2 Simulation 
CT simulation will be performed. The simulation study must include 
the target and all organs at risk for treatment planning. Simulation scan 
length should be 5-10 cm superior and inferior to the target. All organs 
at risk within the scan length should be contoured for dose-volume 
histogram analysis. For stereotactic treatment, tomographic slice 
thickness of 1-3 mm through the target is recommended.  
 
Special consideration should be given to the analysis of internal organ 
motion if the target lesion is located in a site subject to motion such as 
the chest wall. Techniques to image moving targets such as active 
breath-hold techniques, accelerator gating with respiratory cycle, 
tumor tracking, 4D CT scan acquisition in conjunction with maximum 

 
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intensity projection (MIP), will be considered acceptable maneuvers to 
account for organ motion. All systems used to account for internal 
organ motion must be accredited by the Study Committee. If the target 
cannot be visualized or localized on the planning imaging modality as 
a result of motion or metal artifact, stereotactic treatment should not be 
used. 
 
The treating radiation oncologist will identify the location of the tumor. 
Gross tumor volume (GTV) delineation will be performed with a 
diagnostic radiologist on sequential axial computed tomography 
images. A radiosurgical treatment plan will be developed based on 
tumor geometry and location.  
 
Accurate contouring of normal structures is critical in SBRT (please 
see Table 17.10 for a list of normal tissue dose constraints to be used 
on protocol as well as constraints for high and low-dose spillage). OAR 
dose constraints are primary planning priority in SBRT treatment 
planning. Tumor coverage is secondary. Patients in whom optimal 
tumor coverage is not possible while meeting planning constraints 
should not receive SBRT and instead should be treated with standard 
fractionation EBRT. The following are examples of contouring 
requirements for bone lesions near these critical structures: 
 
Spinal Cord 
The spinal cord is the visualized spinal cord based on image fusion with 
T2-weighted MRI, T1-weighted MRI with contrast, or CT myelogram. 
Because of curvature in the spine that is dependent on position and 
immobilization, MRI in the treatment position is ideal but not required. 
The spinal cord should be drawn of every slice of simulation CT (ie not 
interpolated). Spinal cord volume will be defined as 5-6 mm above and 
below the radiosurgery target volume.  
 
Thecal Sac 
The spinal cord can move within the thecal sac. The thecal sac will be 
contoured based on T2 MRI or bony limit of spinal canal and will serve 
as a PRV (planning organ at risk volume) for the spinal cord. Thecal 
sac volume will be defined as 6 mm above and below the radiosurgery 
target volume. 
 
Skin 
The skin will be defined as the outer 0.5 cm of the body surface. The 
skin is essentially a rind of 0.5 cm enveloping the entire body in axial 
planes. The cranial and caudal surface of the superior and inferior limits 
of the planning CT should not be contoured as skin unless skin is 
actually present in these locations. Ribs within 5 cm of the PTV should 
be contoured by outlining bone and bone marrow. The intercostal 
spaces should not be included as part of the ribs.  
 
Esophagus 
The esophagus will be contoured using mediastinal windowing on CT 
to correspond to the mucosal, submucosa, and muscular layers. The 

 
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esophagus should be defined starting at least 10 cm above the superior 
extent of the target volume and continuing on every CT slice to at least 
10 cm below the inferior extent of the target volume. 
 
Larynx and Pharynx 
The larynx and pharynx will be contoured to the mucosa, submucosa, 
cartilages and airway channels associated with these structures. 
 
Trachea and Airway 
The trachea and airway adjacent to the spines will be contoured 
including the mucosa, submucosa, cartilage rings and airway channels. 
 
Lung 
Both the right and left lungs should be contoured using pulmonary 
windows. All inflated and collapsed lung should be contoured; 
however, paraspinal gross tumor, if any, should not be included in this 
structure. 
 
Kidney 
Both the right and left kidneys should be contoured. Paraspinal gross 
tumor as defined above should not be included in this structure. 
 
17.8.8.3 
Treatment Planning 
OAR dose constraints are primary planning priority in SBRT 
treatment planning.  Tumor coverage is secondary (See Section 17.14 
for assessment of deviations). Patients in whom optimal tumor 
coverage is not possible while meeting planning constraints should not 
receive SBRT and instead should be treated with standard fractionation 
EBRT.  The main criteria for dose prescription for tumors of or in 
proximity to the spine will be the achievement of the spinal cord dose 
constraint (see table below): 
 
 
For tumors distant from the spinal cord, the main criteria for dose 
prescription will be OAR as per table 17.10. 
 
Patients treated with SBRT will receive a prescribed dose of 40 Gy in 
5 fractions to cover at least 90% of the defined target volume. The 
minimum, mean, and maximum dose to the PTV will be reported. Only 
≤ 1 cc or ≤ 1-5% of unspecified tissue outside of the PTV can receive 
≥ 100-110% of the prescribed dose.  
 
17.8.8.4 
Treatment/Localization 
Within four weeks of the initial treatment planning imaging study, 
SBRT will be administered using image-guidance. This protocol 
allows conventional linear accelerators and specialized linear 
Normal 
Tissue 
Volume 
Volume 
Max 
(cGy) 
Max Point Dose 
(cGy) 
Endpoint 
(≥Grade 3) 
Spinal 
Cord 
<0.25 cc 
<1.2 cc 
20.2 Gy (4.05 Gy/fx) 
12.1 Gy (2.43 Gy/fx) 
27 Gy (5.4 Gy/fx) 
Myelitis 

 
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accelerators with image guidance (e.g. Novalis, Trilogy, Synergy, 
Artiste) capable of conformal dose delivery and IMRT. Specialized 
accelerators (e.g. Cyberknife or Tomotherapy) are also allowed 
provided that institutions have satisfied all credentialing requirements.  
 
SBRT is an image-guided procedure. In-room imaging technology 
allowing imaging of the target bone should be used. Coordinate 
systems between imaging system and delivery system should be 
aligned for SBRT. 
 
During treatment, real time cone beam CT images or orthogonal 
kilovoltage images of the patient’s body site of interest will be 
obtained. Cone beam CT scan or kilovoltage orthogonal images will be 
obtained immediately prior to treatment and will be repeated until the 
treatment shift, required to align the CT planning scan and the cone 
beam CT scan performed on the day of treatment, is within 2 mm. 
Imaging should be performed during and at the end of treatment to 
ensure maintenance of patient positioning throughout treatment.  
 
Anesthesia or sedation may be required in certain patients, such as very 
young patients, to prevent movement during simulation and daily 
treatments. Anesthesia will be delivered by a dedicated pediatric 
anesthesiologist. 
 
 
17.9 
Organs at Risk – Conventional Fractionation 
The organs at risk guidelines in this section are recommendations. If the recommended 
doses to the organs at risk are exceeded because of target volume coverage requirements 
or other conditions, an explanation should be included in the quality assurance 
documentation. Normal tissue dose recommendations are the same for photons and protons 
(proton dose measured in Gy(RBE)). 
 
17.9.1 Use of Proton Therapy in Treatment of Thoracic Tumors 
During treatment of thoracic tumors, or tumors in locations that require beams to 
traverse normal lung tissue, proton therapy should be used with extreme caution.  
The following specific constraints will apply in this situation: 
• 
When considering the total lung volume less the PTV: 
o The volume of lung receiving 20 Gy (V20) should be less than 
20% 
o The volume of lung receiving 5 Gy (V5) should be less than 60% 
o The mean lung dose should be less than 20 Gy 
• 
When considering the spinal cord: 
o The maximum dose should be 45 Gy 
o A structure called PAR-Cord should be created, and consist of the 
contoured spinal cord plus a 5 mm expansion. The maximum dose 
to the PAR-Cord structure should be 50 Gy. 
• 
Additionally, the distal end of the bragg peak of a single beam should not 
stop in a critical structure, such as the spinal cord, trachea, or mainstem 
bronchus due to uncertainty with regard to dose deposition at the distal end 

 
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of the beam. Individual proton beams which are a component of a multi-
field proton beam, which stop within such an organ, will be allowed. 
 
Table 17.9: Organs at risk dose recommendations for Conventional Fractionation 
 
Organ 
Volume (%) 
Dose (cGy) 
Single organs 
 
 
Bladder 
100% 
4500  
Esophagus 
50% 
4000 
Heart  
100% 
3000 
Liver  
100% 
2340 
 
50% 
3000 
Rectum  
100% 
4500 
Optic chiasm 
100% 
5400 
Small Bowel 
75% 
4500 
Spinal Cord# 
Any volume 
5040 
Paired organs  
 
 
Kidney (bilateral) 
50% 
2400 
Kidney (bilateral) 
100% 
1440 
Lung (bilateral)^ 
20% 
2000 
Lung (bilateral) ‡,$ 
35% 
2000 
Lung (bilateral)  
100% 
1500 
Optic nerve 
100% 
5400 
Eye 
100% 
4500 
Lens 
100% 
600 
Cochlea 
100% 
4000 
Paired organs - % refers to one of the paired organs unless specified as bilateral 
(kidney, lung) in which both of the paired organs are included in the %. 
 
^ V20 of 20% applies to patients not requiring hemithorax RT 
 
‡ V20 of 35% applies to patients who require hemithorax RT and boost treatment 
of the chest wall or pleura 
 
# Please see additional spinal cord constraints for patients receiving thoracic proton 
therapy (Section 17.9.1). 
 
$ Please see additional lung constraints for patients receiving thoracic proton 
therapy (Section 17.9.1). 
 
 

 
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17.10 Organs at Risk – SBRT 
 
Table 17.10a: Organs at Risk – SBRT  
Dose Constraints for Five Fractions – Based upon the AAPM Report TG 10132 reduced by 10% for 
prior systemic chemotherapy 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Endpoint (≥Grade 3) 
Optic Pathway 
<0.2 cc 
18 Gy (3.6 Gy/fx) 
22.5 Gy (4.5 Gy/fx) 
neuritis 
Cochlea 
 
 
24.7 Gy (4.95 Gy/fx) 
hearing loss 
Brainstem 
<1 cc 
23.4 Gy (4.68 Gy/fx) 
31 Gy (6.2 Gy/fx) 
cranial neuropathy 
Spinal Cord 
<0.25 cc 
<1.2 cc 
20.2 Gy (4.05 Gy/fx) 
12.1 Gy (2.43 Gy/fx) 
27 Gy (5.4 Gy/fx) 
myelitis 
Thecal Sac 
<2.5 cc 
<5 cc 
20.2 Gy (4.05 Gy/fx) 
15 Gy (3 Gy/fx) 
30 Gy (6 Gy/fx) 
myelitis 
Cauda Equina 
<5 cc 
27 Gy (5.4 Gy/fx) 
28.8 Gy (5.76 Gy/fx) 
neuritis 
Sacral Plexus 
<3 cc 
27 Gy (5.4 Gy/fx) 
28.8 Gy (5.76 Gy/fx) 
neuropathy 
Rib 
<1 cc 
31.5 Gy (6.3 Gy/fx) 
38.7 Gy (7.74 Gy/fx) 
Pain or fracture 
Esophagus* 
<5 cc 
24.7 Gy (4.95 Gy/fx) 
31.5 Gy (6.3 Gy/fx) 
stenosis/fistula 
Ipsilateral Brachial Plexus 
<3 cc 
27 Gy (5.4 Gy/fx) 
28.8 Gy (5.76 Gy/fx) 
neuropathy 
Heart/Pericardium 
<15 cc 
28.8 Gy (5.76 Gy/fx) 
34.2 Gy (6.84 Gy/fx) 
pericarditis 
Great vessels 
<10 cc 
42.3 Gy (8.46 Gy/fx) 
47.7 Gy (9.54 Gy/fx) 
aneurysm 
Trachea and Ipsilateral Bronchus* 
<4 cc 
16.2 Gy (3.24 Gy/fx) 
34.2 Gy (6.84 Gy/fx) 
stenosis/fistula 
Skin 
<10 cc 
27 Gy (5.4 Gy/fx) 
28.8 Gy (5.76 Gy/fx) 
ulceration 
Stomach 
<10 cc 
25.2 Gy (5.04 Gy/fx) 
28.8 Gy (5.76 Gy/fx) 
ulceration/fistula 
Duodenum* 
<5 cc 
16.2 Gy (3.24 Gy/fx) 
28.8 Gy (5.76 Gy/fx) 
ulceration 
Jejunum/Ileum* 
<5 cc 
17.5 Gy (3.51 Gy/fx) 
31.5 Gy (6.3 Gy/fx) 
enteritis/obstruction 
Colon* 
<20cc 
22.5 Gy (4.5 Gy/fx) 
34.2 Gy (6.84 Gy/fx) 
colitis/fistula 
Rectum* 
<20cc 
22.5 Gy (4.5 Gy/fx) 
34.2 Gy (6.84 Gy/fx) 
proctitis/fistula 
Bladder wall 
<15 cc 
16.4 Gy (3.28 Gy/fx) 
34.2 Gy (6.84 Gy/fx) 
cystitis/fistula 
Penile Bulb 
<3 cc 
27 Gy (5.4 Gy/fx) 
 45 Gy (9 Gy/fx) 
impotence 
Femoral Heads (Right & Left) 
<10 cc 
27 Gy (5.4 Gy/fx) 
 
necrosis 
Renal hilum/vascular trunk 
<2/3 
volume 
 20.7 Gy (4.14 Gy/fx) 
 
malignant hypertension 
Parallel Tissue 
Volume  
Critical Volume Dose  
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
1500 cc 
11.2 Gy (2.25 Gy/fx) 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
12.1 Gy (2.4 Gy/fx) 
 
Pneumonitis 
Liver 
700 cc 
18.9 Gy (3.78 Gy/fx) 
 
Basic Liver Function 
Renal cortex (Right & Left) 
200 cc 
15.7 Gy (3.15 Gy/fx) 
 
Basic renal function 
*Avoid circumferential irradiation 
 
 
 
 

 
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Table 17.10b: Organs at Risk – SBRT after Whole Lung RT 
Dose Constraints for Five Fractions – Based upon the AAPM Report TG 10132 reduced for 
prior chemotherapy and 15Gy whole lung RT 
 
 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Endpoint (≥Grade 3) 
Spinal Cord 
<0.25 cc 
<1.2 cc 
18.2 Gy (3.64 Gy/fx) 
10.9 Gy (2.18 Gy/fx) 
20.2 Gy (4.05 Gy/fx) 
 
myelitis 
Thecal Sac 
<2.5 cc 
<5 cc 
18.2 Gy (3.64 Gy/fx) 
13.5 Gy (2.7 Gy/fx) 
25 Gy (5 Gy/fx) 
myelitis 
Rib 
<1 cc 
26.5 Gy (5.3 Gy/fx) 
33.7 Gy (6.74 Gy/fx) 
Pain or fracture 
Esophagus* 
<5 cc 
19.7 Gy (3.94 Gy/fx) 
26.5 Gy (5.3 Gy/fx) 
stenosis/fistula 
Ipsilateral Brachial Plexus 
<3 cc 
22 Gy (4.4 Gy/fx) 
23.8 Gy (4.76 Gy/fx) 
neuropathy 
Heart/Pericardium 
<15 cc 
23.8 Gy (4.76 Gy/fx) 
29.2 Gy (5.84 Gy/fx) 
pericarditis 
Great vessels 
<10 cc 
37.3 Gy (7.46 Gy/fx) 
42.7 Gy (8.54 Gy/fx) 
aneurysm 
Trachea and Ipsilateral Bronchus* 
<4 cc 
11.2 Gy (2.24 Gy/fx) 
29.2 Gy (5.84 Gy/fx) 
stenosis/fistula 
Skin 
<10 cc 
22 Gy (4.4 Gy/fx) 
23.8 Gy (4.76 Gy/fx) 
ulceration 
Stomach 
<10 cc 
20.2 Gy (4.04 Gy/fx) 
23.8 Gy (4.76 Gy/fx) 
ulceration/fistula 
Duodenum* 
<5 cc 
11.2 Gy (2.24 Gy/fx) 
23.8 Gy (4.76 Gy/fx) 
ulceration 
Jejunum/Ileum* 
<5 cc 
12.5 Gy (2.51 Gy/fx) 
26.5 Gy (5.3 Gy/fx) 
enteritis/obstruction 
Colon* 
<20cc 
17.5 Gy (3.5 Gy/fx) 
29.2 Gy (5.84 Gy/fx) 
colitis/fistula 
Parallel Tissue 
Volume  
Critical Volume Dose  
 
Endpoint (≥Grade 3) 
Lung (Right & Left) 
500 cc 
11.2 Gy (2.25 Gy/fx) 
 
Basic Lung Function 
Lung (Right & Left) 
300 cc 
12.1 Gy (2.4 Gy/fx) 
 
Pneumonitis 
Lung (Right & Left)+ 
35% 
20 Gy 
 
Pneumonitis 
Liver 
200 cc 
18.9 Gy (3.78 Gy/fx) 
 
Basic Liver Function 
Liver+ 
50% 
30 Gy 
 
Basic Liver Function 
*Avoid circumferential irradiation 
+ Cumulative dose including 15 Gy whole lung RT  
 
Guidelines for Spillage  
 
High Dose Spillage: 
1. Any dose > 105% of the prescription dose should occur primarily within the PTV itself and 
not within the normal tissues outside the PTV. Therefore, the cumulative volume of all 
tissue outside the PTV receiving a dose > 105% of prescription dose should not be more 
than 15% of the PTV volume. 
2. Conformality of PTV coverage will be judged such that the ratio of the volume of the 
prescription isodose meeting criteria 1 through 4 to the volume of the PTV is ideally < 1.2 
(see table below). These criteria will not be required to be met in treating very small tumors 
(< 2.5 cm axial GTV dimension or < 1.5 cm craniocaudal GTV dimension) in which the 
required minimum field size of 3.5 cm results in the inability to meet a conformality ratio of 
1.2. 
  
 

 
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Low Dose Spillage 
1. The falloff gradient beyond the PTV extending into normal tissue structures must be rapid in 
all directions and meet the following criteria: 
a. The maximum total dose over all fractions in Gray (Gy) to any point 2 cm or greater away 
from the PTV in any direction must be no greater than D2cm where D2cm is given by the 
table below. 
2.  The ratio of the volume of 50% of the prescription dose isodose to the volume of the PTV 
must be no greater than R50% where R50% is given. See Table below. 
3. Respect all critical organ dose-volume limits listed above 
 
Table 17.10.1: Conformality of Prescribed Dose for Calculations Based on Deposition of 
Photon Beam Energy in Heterogeneous Tissue 
 
 
17.11 Dose Calculations and Reporting 
 
17.11.1 Prescribed Dose 
The prescribed dose for each target volume and/or phase of treatment shall be 
submitted using the RT-1 Dosimetry Summary Form or Proton Reporting Form. If 
IMRT or proton therapy is used, the monitor units generated by the IMRT/ proton 
therapy planning system must be independently checked prior to the patient’s first 
treatment. Measurements in a QA phantom can suffice for a check as long as the 
patient’s plan can be directly applied to a phantom geometry. The total dose 
delivered shall be calculated and reported on the RT-2 Radiotherapy Total Dose 
Record.  
 
17.11.2 Normal Tissue Dosimetry 
The dose to the critical organs indicated should be calculated whenever they are 
directly included in a radiation field. The dose shall be reported on the RT-2 
Radiotherapy Total Dose Record form and the appropriate dose-volume 
histograms shall be submitted. If IMRT is used a DVH must be submitted for a 
category of tissue called “unspecified tissue,” which is defined as tissue 
contained within the skin, but which is not otherwise identified by containment 
within any other structure. 
 
PTV 
Volume 
(cc) 
Ratio of Prescription 
Isodose Volume to the 
PTV volume 
 
Ratio 
of 
50% 
Prescription 
Isodose 
Volume to the PTV 
Volume, R50% 
Maximum dose (in% of 
dose prescribed) @ 2 
cm from PTV in Any 
Direction, D2cm (Gy) 
Percent of Lung Receiving 
20 Gy Total or More, V20 
(%) 
 
Goal 
Acceptable 
Goal 
Acceptable 
Goal 
Acceptable 
Goal 
Acceptable 
1.8 
<1.2 
<1.5 
<5.9 
<7.5 
<50.0 
<57.0 
<10 
<15 
3.8 
<1.2 
<1.5 
<5.5 
<6.5 
<50.0 
<57.0 
<10 
<15 
7.4 
<1.2 
<1.5 
<5.1 
<6.0 
<50.0 
<58.0 
<10 
<15 
13.2 
<1.2 
<1.5 
<4.7 
<5.8 
<50.0 
<58.0 
<10 
<15 
22.0 
<1.2 
<1.5 
<4.5 
<5.5 
<54.0 
<63.0 
<10 
<15 
34.0 
<1.2 
<1.5 
<4.3 
<5.3 
<58.0 
<68.0 
<10 
<15 
50.0 
<1.2 
<1.5 
<4.0 
<5.0 
<62.0 
<77.0 
<10 
<15 
70.0 
<1.2 
<1.5 
<3.5 
<4.8 
<66.0 
<86.0 
<10 
<15 
95.0 
<1.2 
<1.5 
<3.3 
<4.4 
<70.0 
<89.0 
<10 
<15 
126.0 
<1.2 
<1.5 
<3.1 
<4.0 
<73.0 
≤91.0 
<10 
<15 
163.0 
<1.2 
<1.5 
<2.9 
<3.7 
<77.0 
≤94.0 
<10 
<15 

 
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Table 17.11.2: Required normal tissue DVH data according to primary 
treatment site(s)  
 
Treatment Area 
Required DVH 
Head 
Brain  
 
Chiasm 
 
Cochlea  
 
Eyes (contour each separately) 
 
Lenses  
 
Optic nerves (contour each separately) 
Neck 
Esophagus 
 
Thyroid  
Chest 
Esophagus  
 
Heart  
 
Left Lung  
 
Right Lung  
Abdomen/Pelvis 
Bladder  
 
Left Kidney  
 
Liver 
 
Rectum  
 
Right Kidney  
 
Small Bowel (contour peritoneal cavity) 
 
Stomach 
All axial tumors 
Spinal Cord 
Proton therapy 
PAR-Cord (spinal cord expanded by 5 mm) 
 
17.12 Quality Assurance Documentation 
Key Points 
• 
Data for the primary site only must be submitted for on treatment review within 
3 days of the start of treatment (see checklist). Data for metastatic sites may be 
submitted at the end of treatment. 
Digital Submission: 
Submission of treatment plans in digital format DICOM RT is required. Digital data must 
include CT scans, structures, plan, and dose files. Submission may be by either sFTP or 
CD. Instructions for data submission are on the IROC Rhode Island (formerly QARC) web 
site at http://irocri.qarc.org/ under "Digital Data." Any items on the list below that are not 
part of the digital submission may be included with the transmission of the digital RT data 
via sFTP or submitted separately. Screen captures are preferred to hard copy for items that 
are not part of the digital plan. 
 
Please submit the following for All Radiated Sites: 
External Beam Treatment Planning System  
• 
RT treatment plans including CT, structures, dose, and plan files.  These 
items are included in the digital plan.  
• 
Dose volume histograms (DVH) for the composite treatment plan for all 
target volumes and required organs at risk. When using IMRT, a DVH shall 
be submitted for a category of tissue called “unspecified tissue.” This is 
defined as tissue contained within the skin, but which is not otherwise 
identified by containment within any other structure. DVHs are included in 
the digital plan. 

 
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• 
Digitally reconstructed radiographs (DRR) for each treatment field. DRR’s 
are not required for IMRT. 
• 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest 
dose statistics. 
 
Supportive Data 
• 
All diagnostic imaging used to plan the target volume. Digital format is 
preferred. Imaging scans previously submitted to IROC Rhode Island for 
secondary aims central review (Section 16.3) do not need to be resubmitted. 
• 
Copies of reports (radiology, operative, pathology, cytology) and any other 
information used in defining the target volumes. 
• 
If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by the IROC Rhode Island and the radiation 
oncology reviewers. 
• 
If modifications are made for patients with age < 24 months, documentation 
should be provided. 
• 
Documentation of any emergency RT administered prior to the protocol 
prescribed course of RT. Documentation should be provided in the form of 
the radiotherapy record (treatment chart). 
 
Forms 
• 
RT-1 Dosimetry Summary Form. 
• 
Proton Reporting Form (if applicable). 
• 
Motion Management Reporting Form (if applicable, see Section 17.8.6). 
 
Please submit the following additional primary site information for brachytherapy: 
• 
Treatment planning CT used for post-implant dosimetry 
• 
Computer printouts of the isodose distribution and associated CT-based 
calculations. 
• 
Dose volume histograms for each GTV, CTV, and PTV. 
• 
A completed Brachytherapy Physics Reporting Form. 
• 
A copy of the written directive. 
 
Please submit the following information for intra-operative radiation therapy: 
o Radiotherapy record (treatment chart) including prescription and daily 
and cumulative doses to all required areas and organs at risk 
o Physician’s note describing the procedure, dose calculation and 
description of the applicator along with any relevant dosimetric 
characteristics (i.e., percent depth dose for the prescribed energy) 
Within 1 week of the completion of radiotherapy submit the following items: 
• 
Radiotherapy record (treatment chart) including prescription and daily and 
cumulative doses to all required areas and organs at risk. 
• 
RT-2 Radiotherapy Total Dose Record Form. 
• 
If SBRT is used, setup images for the first fraction taken before and after 
treatment.  Depending on the IGRT system capabilities, submission may 
include cone beam CT and/or kV imaging in DICOM format, DICOM 
spatial registration file, screen capture of shifts needed for correct alignment, 
or screen captures showing the image registration. 

 
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These data should be forwarded to: 
IROC Rhode Island QA Center 
640 George Washington Highway, Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
Phone: (401) 753-7600 
Fax: 
(401) 753 7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
Imaging and Radiation Oncology Core, Rhode Island  
640 George Washington Highway, Building B, Suite 201 
Lincoln, Rhode Island 02865-4207 
physics@qarc.org 
 
17.13 Definition of Minor and Major Deviations  
 
Definitions of deviation in protocol performance will be applied to the treatment of the 
primary lesion only. 
 
 
 
 
 
DEVIATION 
 
Minor 
Major 
Prescription 
Dose 
 
External beam 
Prescription dose differs from protocol-
specified dose by  >5% but < 10% 
Prescription dose differs from 
protocol-specified dose by > 10% 
Brachytherapy 
Prescription dose differs from protocol-
specified dose by  >5% but < 10% 
Prescription dose differs from 
protocol-specified dose by > 10% 
Dose Uniformity 
External beam 
> 10% PTV receives > 110% of 
prescription dose 
or 
95% isodose covers < 90% of the PTV or 
< 100% but > 90% of the CTV 
95% isodose covers < 90% of 
CTV. 
Brachytherapy 
95% isodose covers <100% of CTV 
90% isodose covers < 100% of 
CTV. 
Volume 
CTV or PTV margins are smaller than 
specified in the protocol. 
The contoured GTV does not 
include imaging-visible residual 
tumor 
Organs at 
Risk 
Will be assessed at time of data review. 
Will be assessed at time of data 
review. 
 
17.14 Evaluation of SBRT Plans For Deviations 
Evaluation of SBRT plans will be performed for feasibility analysis. In the context of this 
feasibility study, deviations will be recorded and institutions will receive feedback but 
deviations will not affect institutional performance scores. 
 
 

 
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Treatment Delivery Compliance 
Setup images (obtained from the IGRT system) will be compared to corresponding 
reference images to identify any potential deviation. The institution’s IGRT systems must 
demonstrate < 2mm agreement between simulation/planning and treatment, as well as at 
the end of treatment. 
 
 
 
 
 
 
 
DEVIATION 
 
Minor 
Major 
Dose 
SBRT 
90% isodose covers < 90% 
but > 80% of the CTV 
  
90% isodose covers < 80% of CTV 
Volume 
CTV or PTV margins are smaller than 
specified in the protocol. 
The contoured GTV does not include 
imaging-visible residual tumor or bone 
abnormality 
Organs 
at Risk 
Will be assessed at time of data review. 
 
 
Exceeding max point dose for OAR as per 
Section 17.10 . 

 
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
 
CTEP REGISTRATION PROCEDURES 
 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their registration 
annually. To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) 
Identity and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, 
persons with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, or TRIAD or 
acting as a primary site contact) must complete their annual registration using CTEP’s web-based 
Registration and Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr). Documentation 
requirements per registration type are outlined in the table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP 
and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs 
must list all clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in 
RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
 

 
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements For AEWS1221 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider.  To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers.  Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component.   
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab 
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Delegation of Task Log (DTL)  
 
Each site must complete a protocol-specific DTL. The Clinical Investigator (CI) is required to 
review and electronically sign the DTL prior to the site receiving an Approved site registration 
status and enrolling patients to the study. The DTL application is located on the CTSU members’ 
website at www.ctsu.org. Any individual at the enrolling site on a participating roster may initiate 
the site DTL. Instructions on completing the DTL are embedded in the DTL application.  
 
Checking Your Site’s Registration Status: 
You can verify your site registration status on 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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Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 
 

 
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APPENDIX II: 
 
REFERENCE 
GUIDE 
FOR 
REQUIRED 
AND 
RECOMMENDED 
CORRELATIVE STUDIES 
 
Study Entry 
Induction 
Local Control Consolidation 
Maintenance 
Suspected 
Relapse 
Serum 
Markers 
(Section 15.1) 
10 mL blood 
(15 mL if 
Regimen B and 
consent for 
banking)** 
in RTT* 
10 mL blood  
(15 mL if Regimen 
B and consent for 
banking)** 
in RTT prior to 
start of  
Week 5* 
 
10 mL blood  
(15 mL if 
Regimen B and 
consent for 
banking)** 
in RTT at end 
Consolidation* 
 
 
Tissue 
Markers 
(Section 15.2) 
25 unstained 
slides or 
block*,$ 
 
25 unstained 
slides or 
block^,$ 
(if surgical 
local control) 
25 unstained slides or block^,$ 
(if delayed surgery or 
metastectomy) 
25 unstained 
slides or 
block^,$ 
(if biopsy to 
confirm 
relapse) 
EGFR Study 
(Section 15.3) 
5-10 mL blood 
in EDTA* 
 
 
 
 
 
Bone Marrow 
Studies 
(Section 15.4) 
5-10 mL 
marrow in 
EDTA^ 
5-10 mL marrow 
in EDTA^,& 
 
5-10 mL 
marrow in 
EDTA^,& 
5-10 mL marrow in EDTA^ 
(if relapse suspected) 
Ganitumab 
PK# 
(Section 15.5) 
 
Blood draws prior 
to   
Ganitumab on 
Days 1, 15, 29 and 
71 
 
 
Blood draws 
prior to 
Ganitumab 
in Weeks 1, 
7, 10 and 16 
 
ctDNA Study 
(Section 15.6) 
10 mL blood in 
Streck tube 
10 mL blood in 
Streck tube prior 
to start of Week 3, 
Week 5, and at 
end Induction 
 
10 mL blood 
in Streck tube 
prior to Week 
9 and at end 
Consolidation 
 
10 mL blood 
in Streck tube 
Imaging Aims 
(Section 16) 
1. Baseline 
SUV of primary 
tumor* 
 
2. Baseline PET 
and MRI/CT of 
primary tumor* 
1. End Induction 
SUV of primary 
tumor* 
 
2. End Induction 
PET and MRI/CT 
of primary tumor* 
Institutional 
report of 
primary tumor 
percent 
necrosis  
(if surgical 
local control) 
 
 
Imaging 
documenting 
first episode of 
relapse or 
progression 
* Required of all patients. 
** 10 mL required for all patients at both time points. For patients randomized to ganitumab arm (Arm B) 
and consented to specimen banking, obtain an additional 5 mL at each timepoint for a total of 15 mL. 
^ Recommended (option for participation embedded in main study consent). 
$ 25 unstained slides is optimal.  If limited tissue, a minimum of 10 unstained slides may be submitted. 
& Patients with documented marrow disease at study entry undergo repeat marrow evaluations after Cycle 3 
of Induction and at end of Consolidation. Additional marrows are to be obtained according to Section 

 
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7.0 if not clear after Cycle 3 of Induction. Submit marrows from consenting patients to Dana-Farber 
whenever obtained for clinical evaluation of bone marrow disease.  
# Required of the first 10 patients < 21 years old assigned to Regimen B. 
 
RTT = Red top tube 
 
 

 
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APPENDIX III:  YOUTH INFORMATION SHEETS 
 
 
INFORMATION SHEET REGARDING RESEARCH STUDY AEWS1221 
(for children from 7 through 12 years of age) 
 
A trial of a new drug, called ganitumab, to treat patients with EWS cancer that has spread 
 
1. We have been talking with you about your illness, Ewing Sarcoma (EWS). EWS is a type of cancer 
that grows in the bones. After doing tests, we have found that you have this type of cancer and it 
has spread into other areas of your body.  
 
2. We are asking you to take part in a research study because you have EWS that has spread to other 
areas of your body. A research study is when doctors work together to try out new ways to help 
people who are sick. We will do this by adding a new drug to the treatment often used for the type 
of cancer you have. This new drug is called ganitumab and it is an experimental drug.    
 
Some children in this study will get the new drug and some children will not. We do not know how 
well the new drug will work in children. That is why we are doing this study.  
 
3. All children who are part of this study will be treated with chemotherapy (anti-cancer drugs) on 1 
of 2 treatment plans. Children on one plan will get the drug ganitumab and children on the other 
plan will not get ganitumab. 
 
Children who are part of this study will be given either: 
▪ 
Chemotherapy or 
▪ 
Chemotherapy + ganitumab 
 
All children who are part of this study will also have surgery and/or receive radiation therapy. 
Radiation therapy is the use of high energy X-rays to kill cancer cells.  
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is a better chance of 
getting rid of the cancer for as long as possible. But we do not know for sure if there is any benefit 
to being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” One risk to you from this study is that the study treatment may not work as well 
as other therapies. Also, the study treatment may cause more side effects than other therapies. Your 
doctors will watch you for signs of any side effects. 
 
6. We want to see if there are ways to tell how the cancer will respond to treatment. To do this, we 
will collect extra blood and tumor samples from you for research tests. These samples would be 
taken when other standard blood draws or tumor surgery are being performed, so there would be 
no extra procedures. 
 
7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 

 
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8. We also would like your permission to collect extra bone marrow when you have standard bone 
marrow tests. We want to look for small amounts of cancer cells in your bone marrow. We will not 
perform an extra bone marrow test just to collect bone marrow for research. We would also like 
your permission to save any leftover samples. You can still take part in this study even if you don't 
allow us to collect the extra bone marrow for research or let us save any leftover samples. 
 
 
 
 

 
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INFORMATION SHEET REGARDING RESEARCH STUDY AEWS1221 
(for teens from 13 through 17 years of age) 
 
A trial of a new drug, called ganitumab, to treat patients with EWS cancer that has spread 
 
1. We have been talking with you about your illness, metastatic Ewing Sarcoma (EWS). EWS is a 
type of cancer that grows in the bones. Metastatic means the cancer has spread into other areas of 
your body. After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have metastatic EWS. A research 
study is when doctors work together to try out new ways to help people who are sick. We will do 
this by adding a new experimental drug called ganitumab to the treatment often used for metastatic 
EWS. Some people in this study will get ganitumab and some will not. We do not know how well 
ganitumab will work in children and teens with metastatic EWS. That is why we are doing this 
study.  
 
3. Children and teens who are part of this study will be treated with chemotherapy (anti-cancer drugs) 
on 1 of 2 treatment plans. People on one plan will get the experimental drug “ganitumab” and 
people on the other plan will not get ganitumab.  
 
A computer decides which treatment plan you will get and not your doctor. The reason for this is 
to make sure there is same number of people on both treatments. You have an equal chance of 
getting ganitumab or not getting ganitumab. 
 
Children and teens who are part of this study will be randomly assigned to receive either: 
 
Chemotherapy; or  
Chemotherapy + ganitumab  
 
All children and teens who are part of this study will also have surgery and/or receive radiation 
therapy. Radiation therapy is the use of high energy X-rays to kill cancer cells.  
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is a better chance of 
getting rid of the cancer for as long as possible. But we do not know for sure if there is any benefit 
of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” One risk to you from this study is that the study treatments may be less effective 
than other therapy options. If you receive ganitumab, there is a chance that you will have more side 
effects. Your doctors will monitor you closely for signs of any side effects. Other things may 
happen to you that we don’t yet know about. 
 
6. We want to see if there are ways to tell how the cancer will respond to treatment. To do this, we 
will collect extra blood and tumor samples from you for research tests. These samples would be 
taken when other standard blood draws or tumor surgery are being performed, so there would be 
no extra procedures. 
 

 
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7. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
8. We also would like your permission to collect extra bone marrow when you have standard bone 
marrow tests. We want to look for small amounts of cancer cells in your bone marrow. We will not 
perform an extra bone marrow test just to collect bone marrow for research. We would also like 
your permission to save any leftover samples. You can still take part in this study even if you don't 
allow us to collect the extra bone marrow for research or let us save any leftover samples. 
 
 

 
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APPENDIX IV:  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. Supplements may come in many forms, such as teas, drinks, juices, liquids, 
drops, capsules, pills, or dried herbs. All forms should be avoided. 
 
Some drugs, food, and supplements may interact with vincristine.  Examples include: 
Drugs that may interact with vincristine 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, 
voriconazole 
• 
Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine 
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir, 
tenofovir, tipranavir 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, carvedilol, diltiazem, dronedarone, proprafenone, quinidine, 
ranolazine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, fosnetupitant, ivacaftor, 
mifepristone, modafinil, natalizumab, nefazodone, netupitant 
 
Food and supplements that may interact with vincristine 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Some drugs, food, and supplements may interact with doxorubicin.  Examples include: 
Drugs that may interact with doxorubicin 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Clozapine, fluoxetine, fluvoxamine, nefazodone, paroxetine  
• 
Antibiotics and Antifungals  

 
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o Fluconazole, isavuconazole, itraconazole, ketoconazole, posaconazole, 
voriconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, Stribild®, telaprevir, tipranavir, zidovudine 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, diltiazem, dronedenarone, ranolazine, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
o Ado-trastuzumab emtansine, bevacizumab, idelalisib, trastuzumab, taxane 
derivatives 
• 
Many other drugs, including the following: 
o Aprepitant, cyclosporine, fosaprepitant, fosnetupitant, deferasirox, ivacaftor, 
mifepristone, natalizumab, netupitant 
 
Food and supplements that may interact with doxorubicin 
• 
Echinacea 
• 
Glucosamine  
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
Some drugs, food, and supplements may interact with cyclophosphamide.  Examples 
include: 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• 
Amiodarone 
• 
Carbamazepine 
• 
Cyclosporine 
• 
Digoxin  
• 
Efavirenz 
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Lumacaftor 
• 
Mifepristone 
• 
Pentostatin  
• 
Rifampin 
• 
Ritonavir 
• 
Warfarin  
 

 
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Food and supplements that may interact with cyclophosphamide 
• 
St. John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
 
 
Some drugs, food, and supplements may interact with dactinomycin.  Examples include: 
Drugs that may interact with dactinomycin 
• 
Clozapine, leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with dactinomycin 
• 
Echinacea 
 
 
Some drugs, food, and supplements may interact with ifosfamide.  Examples include: 
Drugs that may interact with ifosfamide 
• 
Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Clozapine, nefazodone 
• 
Antifungals  
o Fluconazole, isavuconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, diltiazem, dronedenarone, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Bosentan, aprepitant, lumacaftor, mifepristone, natalizumab, warfarin  
 
Food and supplements that may interact with ifosfamide 
• 
Echinacea 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Some drugs, food, and supplements may interact with etoposide.  Examples include: 
Drugs that may interact with etoposide 
• 
Antibiotics  

 
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o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
• 
Antidepressants and antipsychotics  
o Clozapine, nefazodone 
• 
Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• 
Arthritis medications  
o Leflunomide, tofacitinib 
• 
Anti-rejection medications 
o Cyclosporine 
• 
Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, telaprevir 
• 
Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
• 
Heart medications  
o Amiodarone, dronedarone, verapamil 
• 
Some chemotherapy (be sure to talk to your doctor about this) 
• 
Many other drugs, including the following: 
o Aprepitant, atovaquone, bosentan, deferasirox, ivacaftor, lomitapide, mifepristone, 
modafinil, natalizumab, pimozide 
 
Food and supplements that may interact with etoposide 
• 
Echinacea 
• 
Glucosamine 
• 
St. John’s Wort 
• 
Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Some drugs, food, and supplements may interact with dexrazoxane.  Examples include: 
Drugs that may interact with dexrazoxane 
• 
Clozapine 
• 
Deferiprone  
• 
Dimethyl sulfoxide (DMSO) 
 
Food and supplements that may interact with dexrazoxane 
• 
Unknown  
 
 
 
 

 
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APPENDIX V:  CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is 
important to regularly consult frequently updated medical references. 
CYP3A4 substrates  
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong Inducers 
Moderate 
Inducers 
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 
 
 

 
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ivacaftor 
ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib 
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1 Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2 Refer to Section 4.2.2 regarding use of corticosteroids.  
3 The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4 Narrow therapeutic range substrates 
5 Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 

 
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