A Randomized Phase 3 Study of Vincristine, Dactinomycin, Cyclophosphamide (VAC) Alternating With Vincristine and Irinotecan (VI) Versus VAC/VI Plus Temsirolimus (TORI, Torisel, NSC# 683864) in Patients With Intermediate Risk (IR) Rhabdomyosarcoma (RMS)
Phase: PHASE3
Conditions: Alveolar Rhabdomyosarcoma, Botryoid-Type Embryonal Rhabdomyosarcoma, Embryonal Rhabdomyosarcoma, Rhabdomyosarcoma, Sclerosing Rhabdomyosarcoma, Spindle Cell Rhabdomyosarcoma
Sponsor: National Cancer Institute (NCI)

  
 
 
i 
 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Research 
Institute  
Mailstop: JMB 9 
1900 9th Avenue 
Seattle, WA 98101 
P 206 884 1107 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Chief Operating Officer 
Elizabeth O’Connor, MPH 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, MS 
crabtreed@email.chop.edu 
 
Group Administration Office 
Children’s Hospital of 
Philadelphia Research Institute 
Roberts Center for Pediatric  
Research 
2716 South Street 
14th Floor, RC#14251 
Philadelphia, PA 19146-2305 
P 215 590 6354 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
800 Royal Oaks Drive 
Suite 210 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
SDC Gainesville Office 
6011 NW 1st Place 
Suite 10 
Gainesville, FL 32607 
P 352 273 0566 
F 352 392 8162 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
November 16, 2020 
 
 
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, 
 
Enclosed please find Amendment #4B for protocol ARST1431, A Randomized Phase 3 
Study of Vincristine, Dactinomycin, Cyclophosphamide (VAC) Alternating with Vincristine 
and Irinotecan (VI) Versus VAC/VI Plus Temsirolimus (TORI, TORISEL, NSC# 683864) in 
Patients with Intermediate Risk (IR) Rhabdomyosarcoma (RMS), for CTEP review.  
 
This amendment will: 
x 
expand the permitted use of blood samples already being collected and stored at 
the Biopathology Center to include use of white blood cells for germline analysis 
x 
reflect the completion of central FOXO1 fusion status testing 
x 
clarify dose modification guidelines 
x 
modify surgical guidelines to reflect the most up-to-date information 
x 
and clarify use of filgrastim, pegfilgrastim, and their biosimilars. 
 
Revisions to the protocol and consent documents are detailed in the pages below. Minor 
administrative updates (such as the correction of typographical errors or updates to the 
numbers of referenced sections) are tracked but not specified below.  
 
Please contact me with any questions or concerns.  
 
 
Sincerely,  
 
Tiffany Liu, MS, MA, Protocol Coordinator (for) 
 
Abha Gupta, MD, ARST1431 Study Chair 
Rajkumar Venkatramani, MD, COG Soft Tissue Sarcoma Disease Chair 
Douglas Hawkins, 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 
Throughout 
Version date and amendment number have been updated. 
2. 
Table of 
Contents 
3-6 
The table of contents has been updated and repaginated. 
3. 
Study 
committee 
7-9 
The study committee has been updated to reflect the current roster and 
contact information. 
4. 
1.3.3 
13 
Expanded Exploratory Aim 1.3.3 to allow the study team to examine 
patterns of tumor heterogeneity and evolution in ctDNA from multiple 
timepoints:  
“To estimate the frequency of patients with circulating tumor DNA 
(ctDNA) at diagnosis and subsequent time-points, and explore 
whether tumor-specific somatic variants are detectable in the 
ctDNA.” 
5. 
3.1.2 
30-31 
IRB approval text was updated to match current CTSU template 
language. 
6. 
3.1.3 
3.1.4 
31 
32-33 
Reservation requirement and patient enrollment texts have been 
updated to match current CTSU template language. 
7. 
3.3.1 
14.2.1 
37 
163 
The test to determine the concordance rate between institutional and 
central FOXO1 fusion status has been completed. These sections have 
been modified to reflect this update.  
8. 
4.1.2.2 
42 
Clarified that temsirolimus should must be held for 1 week following any 
minor surgical procedures (insertion of central venous catheters, 
gastrostomy tubes, biopsies) and 2 weeks prior to any major surgical 
procedures (tumor resection either initially or at DPE). 
9. 
4.1.3 
43 
Clarified concomitant use of aprepitant and fosaprepitant.  
10. 
4.2.1 
4.2.4 
4.2.7 
4.3.1 
4.3.4a 
4.3.4b 
4.3.7 
4.5.1 
Appendix VII 
45 
50 
55 
60 
66 
67 
73 
83 
220 
Modified myeloid growth factor support guidelines to allow the use of 
pegfilgrastim biosimilars. 

 
 
 
iii  
# 
Section 
Page(s) 
Change 
11. 
4.2.1 
4.2.3.2 
4.2.4 
4.2.6.2 
4.2.7 
4.2.9.2 
4.3.1 
4.3.3.2 
4.3.4a 
4.3.4b 
4.3.6.2 
4.3.7 
4.3.9.2 
4.5.1 
4.5.3.2 
4.5.4 
4.5.6.2 
45 
48 
50 
53 
55 
58 
60 
63 
66 
67 
70 
73 
76 
83 
86 
87 
90 
 
Clarified that dactinomycin could be administered by either slow IV push 
over 1-5 minutes or IV infusion over 10-15 minutes.  
12. 
4.2.2 
4.2.5 
4.2.8 
4.3.2 
4.3.5 
4.3.8 
4.4.2 
4.5.2 
4.5.5 
46 
51 
56 
61 
68 
74 
80 
84 
88 
The total bilirubin observation in the required observations table was 
clarified for protocol consistency.  
13. 
4.3.1 
4.3.4a 
4.3.4b 
4.3.7 
Appendix VII 
60 
66 
67 
73 
220 
Clarified that the use of filgrastim and biosmiliar may be continued 
without regard to VCR or TORI. 
14. 4.4.3.2 
82 
x 
Provided site instructions for patients who vomit after or within 
20 minutes of a dose of cyclophosphamide (tablet, capsule, and oral 
suspension). 
x 
For Canadian sites, provided high-level guidance with a reference to 
Appendix XII for splitting tablets if liquid formulation is not available.  

 
 
 
iv  
# 
Section 
Page(s) 
Change 
15. 5.2 
92 
Clarified dose modification guidelines for temsirolimus during VAC/VI 
cycles:  
x 
“In the event of any Grade ≥ 3 non-hematological toxicity, the 
doses of temsirolimus will be adjusted according to the 
guidelines shown in the Dose Modifications tables below 
described in Section 5.1.” 
x 
“Dose levels will be as shown in the Dose Modifications tables 
below. No dose escalations are permitted after reductions for 
confirmed toxicity. If an AE is not covered in the relevant table, 
doses may be reduced or held at the discretion of the 
investigator for the patient’s safety. Dose modifications for 
hematological toxicity are based on the blood counts obtained 
on the day of treatment.” 
x 
“Patients with toxicities that are manageable with supportive 
therapy 
may 
not 
require 
dose 
reductions 
(e.g., 
hypertriglyceridemia or cholesterol high). Patients requiring 
more than 2 dose reductions of temsirolimus will discontinue 
temsirolimus and remain on study and receive VAC/VI alone. 
Patients requiring dose reductions will not have the dose 
re-escalated with subsequent treatments.” 
16. 5.4 
98 
Revised hematological dose modification guidelines to:  
x 
recommend the provision of myeloid support for prolonged 
neutropenia before a dose reduction of irinotecan  
x 
provide guidance if subsequent cycle is delayed. 
17. 6.1 
102-111 
Updated Temsirolimus Monograph. 
18. 6.5 
116-118 
Updated Filgrastim Monograph. 
19. 6.9 
123-124 
Updated Pegfilgrastim Monograph. 
20. 6.10 
125-127 
Updated Vincristine Sulfate Monograph. 
21. 11.4.3 
11.4.6 
146 
147 
Updated reporting guidelines for adverse events to match current 
template. 
22. 
13.3 
13.4.2 
13.4.4 
13.5.3 
13.5.4 
13.5.7 
155 
156-157 
158 
158 
159 
160-161 
Surgical guidelines were modified based on a review of data regarding 
nodal sampling in paratesticular RMS.  
23. 13.4 
13.4.4 
156 
157 
Provided guidance to sites that amputations and other radical 
procedures are to be avoided whenever possible. 
24. 14.2.2 
163 
x 
Rearranged information on materials to send for readability  
x 
Updated the contact information for study pathologist Dr. Michael 
Arnold. 

 
 
 
v  
# 
Section 
Page(s) 
Change 
25. 15.0 
164 
Moved the list detailing how diagnostic pretreatment tumor tissue will be 
prioritized from Section 15.1.1 to 15.0. List was also rearranged so the 
ctDNA correlative is higher on the list of prioritization for patients who 
consented.  
26. 15.1 
164-165 
x 
Removed panel for NOS-1 because it was not staining robustly:  
“Use of formalin-fixed, paraffin-embedded tissue sections for 
immunohistochemical staining including a panel for four 
3 antibodies (myogenin, AP2b, NOS-1, and HMGA2). This will 
identify tumors which may harbor a fusion protein that does not 
include the FOXO1 gene, which would not be detected by 
institutional FISH or other molecular techniques.” 
x 
Expanded the methodology to analyze variant gene fusion cases to 
include targeted sequencing panel: 
“Cases 
suspicious 
for 
variant 
gene 
fusions 
after 
immunohistochemical analysis, institutional FOXO1 results and 
PAX3/7 testing will be further analyzed by an indepth FISH 
and/or targeted sequencing panel to identify any of the 
currently 
known 
fusion 
variants 
implicated 
in 
RMS 
tumorigenesis.” 
27. 15.1.2 
165 
x 
Reduced the number of required unstained slides sent to 
Dr. Rudzinski to reflect the removal of the NOS-1 panel mentioned 
above: 
“For all cases enrolled, four (4) three (3) unstained slides will 
then be sent to Erin Rudzinski, MD at Seattle Children’s 
Hospital for immunohistochemical staining with antibodies to 
AP2b, NOS-1, HMGA2, and myogenin.” 
x 
Revised the number of unstained slides sites submit to the 
Biopathology Center for analysis of PAX3/7 by FISH to identify 
common fusion partners. All cases with an institutional diagnosis of 
ARMS confirmed FOXO1 fusion will be analyzed.  
x 
“For cases with a discrepancy between the immunohistochemical 
panel, FOXO1 fusion result or PAX3/7 fusion result, 6 additional 
unstained slides will be sent to Julia Bridge at the University of 
Nebraska Medical Center and/or the Translational Genomics 
Research Institute (TGen) for comprehensive FISH analysis of all 
fusion variants described in rhabdomyosarcoma.” 
28. 15.2.3 
167 
Clarified pre-treatment blood sample submission requirement.  
29. 15.2.4 
167 
Listed information that must be labeled on Streck tubes to increase 
readability. 

 
 
 
vi  
# 
Section 
Page(s) 
Change 
30. 15.2.5 
168 
x 
Expanded ctDNA correlative to the permit use of samples already 
collected for ctDNA analysis and are currently being stored at the 
BPC to include the use of white blood cells for germline analysis. 
x 
Expanded the methodology of the correlative to include the 
following: 
 “After the above aims have been completed, additional 
nucleic acids will then be subjected to deep next-
generation sequencing (including but not restricted to 
whole-exome sequencing) to determine whether detection 
of a greater number of somatic single-nucleotide variants is 
better able to detect the presence of ctDNA and whether we 
can detect patterns of tumor heterogeneity and evolution in 
ctDNA from multiple timepoints.” 
31. 16.2.1 
169-170 
x 
Clarified that the Week 42 imaging timepoint is at the end of VAC/VI 
therapy +/- temsirolimus for Regimens A and B for internal 
consistency.  
x 
Baseline radiology submission requirements have been expanded to 
include both scans and reports.  
32. 16.3 
170 
Clarified the pre-study image submission requirement for patients who 
were scanned with more than one imaging modality. 
33. 16.4.3 
Appendix XIII 
173-175 
234-237 
x 
Removed link to ACRIN PET Standard Operating Procedures 
because it is no longer active and maintained. An appendix has 
been added with pediatric FDG PET/CT guidelines. 
x 
Updated ACR link to reflect most up-to-date information. 
x 
Made two minor revisions to provide clarifications:  
o 
“Prior to and following [18F]FDG injection”, was added to the 
statement “the patient is kept at rest in a warm room until the 
time of imaging to minimize [18F]FDG uptake in activated brown 
adipose tissue or other physiologic [18F]FDG artifacts” to 
acknowledge that brown adipose tissue can be lessened by 
keeping the patient warm prior to injection. 
o 
The text “if needed to assist bladder emptying” was added to the 
statement “In patients with tumors in the pelvis, placement of a 
Foley catheter is recommended” as some patients may be able 
to empty their bladder sufficiently that a Foley catheter is not 
needed. 
34. 17.7.2 
186 
Clarified the prescribed radiation dose instructions to note that patients 
with positive lymph nodes at diagnosis that were only sampled by biopsy 
are Clinical Group III and will receive 50.4 Gy to the primary while 
those that are completely resected will receive 41.4 Gy to the primary. 
35. 17.12 
200 
Clarified the “End of Therapy VAC/VI +/- temsirolimus” image 
submission timepoint for the purposes of RT review.  
36. 17.12.3 
202 
Text has been updated to match current CTSU template language. 

 
 
 
vii  
# 
Section 
Page(s) 
Change 
37. Appendix I 
203-205 
Appendix was updated to match revised CTSU language. 
38. Appendix XI 
231 
Removed the following sentence because it was a duplicate:  
“*Patients exceeding a BSA of 3.00 m2 should have their 
cyclophosphamide doses calculated on actual BSA with no 
maximum dose.” 
39. Appendix XII 
232-233 
For Canadian sites, provided instructions for splitting tablets if liquid 
formulation is not available. 
 
 

 
 
Version date: 11/16/2020 
Page 1  
 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
 
ARST1431 
 
 
A Randomized Phase 3 Study of Vincristine, Dactinomycin, Cyclophosphamide (VAC) Alternating 
with Vincristine and Irinotecan (VI) Versus VAC/VI Plus Temsirolimus (TORI, Torisel,  
NSC# 683864) in Patients with Intermediate Risk (IR) Rhabdomyosarcoma (RMS) 
 
 
An Intergroup NCTN Phase 3 Study 
 
NCI Supplied Agents: Temsirolimus (NSC# 683864) 
 
IND sponsor for temsirolimus: 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 
 
Abha A. Gupta, MD, FRCPC  
Hospital for Sick Children 
555 University Avenue 
Toronto, ON M5G 1X8, CA 
Phone: (416) 813-7744 
Fax: 
(416) 813-5327 
E-mail: abha.gupta@sickkids.ca 
 
 
Activated: 
5/23/2016 
Version Date: 11/16/2020 
Closed: 
      
Amendment: #4B 

 
 
Version date: 11/16/2020 
Page 2  
 
 
Participating Organizations 
 
COG / Children's Oncology Group 
 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
 
NRG / NRG Oncology  
 
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_SYSTEM/ 
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. 
 
 

 
 
ARST1431 
 
Version date: 11/16/2020 
Page 3  
TABLE OF CONTENTS 
 
SECTION 
PAGE 
STUDY COMMITTEE 
7 
ABSTRACT 
10 
EXPERIMENTAL DESIGN SCHEMA: FEASIBILITY PHASE 
11 
EXPERIMENTAL DESIGN SCHEMA: EFFICACY PHASE 
12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
13 
1.1 
Primary Aims 
13 
1.2 
Secondary Aims 
13 
1.3 
Exploratory Aims 
13 
2.0 
BACKGROUND 
13 
2.1 
Introduction and Rationale for Development 
13 
2.2 
Rationale for Investigation of an mTOR inhibitor in Children with Newly Diagnosed 
RMS: Temsirolimus (Torisel®) 
15 
2.3 
Vincristine, Dactinomycin and Cyclophosphomide (VAC) with Vincristine and 
Irinotecan (VI) 
18 
2.4 
Initial Safety Phase Prior to Randomization 
20 
2.5 
Local Control Recommendations 
20 
2.6 
FDG-PET Definitions and Its Utility to Assess Outcome in RMS 
25 
2.7 
Fusion Status 
26 
2.8 
Maintenance Therapy (Implemented with Amendment #3) 
27 
2.9 
Biological Correlatives 
28 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
29 
3.1 
Study Enrollment 
29 
3.2 
Patient Eligibility Criteria 
34 
3.3 
FOXO1 Fusion Status 
36 
4.0 
TREATMENT PLAN 
38 
4.1 
Overview of Treatment Plan 
38 
4.2 
Regimen A (VAC/VI Only) 
45 
4.3 
Regimen B (VAC/VI Plus Temsirolimus) 
60 
4.4 
Regimens A & B – Maintenance 
79 
4.5 
Regimen C (VAC/VA Only) 
83 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
91 
5.1 
Dose Limiting Toxicity for Temsirolimus 
91 
5.2 
Dose Modifications for Temsirolimus on Regimen B during VAC/VI Cycles 
92 
5.3 
Non-Hematological Dose Modifications for VAC/VI Cycles 
97 
5.4 
Hematological Dose Modifications for VAC/VI Cycles – Regimen A 
98 
5.5 
Dose Modifications for Vincristine, Dactinomycin, and Irinotecan in Patients with 
Hyperbilirubinemia Secondary to Biliary Obstruction due to Tumor and Other Situations 
with Elevated Bilirubin 
98 
5.6 
Dose Modifications for Patients who Receive Liver Irradiation 
99 

 
 
ARST1431 
 
Version date: 11/16/2020 
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5.7 
Dose Modifications for Hepatopathy 
99 
5.8 
Neurotoxicity Secondary to Vincristine 
100 
5.9 
Dose Modifications for Maintenance Therapy – Regimens A & B 
100 
6.0 
DRUG INFORMATION 
102 
6.1 
TEMSIROLIMUS 
102 
6.2 
CYCLOPHOSPHAMIDE INJECTION 
112 
6.3 
CYCLOPHOSPHAMIDE - ORAL 
113 
6.4 
DACTINOMYCIN 
115 
6.5 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
116 
6.6 
IRINOTECAN 
118 
6.7 
MESNA – INJECTION 
120 
6.8 
MESNA – ORAL 
122 
6.9 
PEGFILGRASTIM, PEGFILGRASTIM-JMDB, PEGFILGRASTIM-CBQV 
123 
6.10 
VINCRISTINE SULFATE 
125 
6.11 
VINORELBINE TARTRATE 
127 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
129 
7.1 
Recommended End of Therapy & Follow-up 
129 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
131 
8.1 
Criteria for Removal from Protocol Therapy 
131 
8.2 
Off Study Criteria 
131 
9.0 
STATISTICAL CONSIDERATIONS 
132 
9.1 
Patient Accrual and Expected Duration of Trial 
132 
9.2 
Statistical Analysis Methods 
132 
9.3 
Gender and Minority Accrual Estimates 
135 
10.0 
EVALUATION CRITERIA 
136 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
136 
10.2 
Response Criteria 
136 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
144 
11.1 
Purpose 
144 
11.2 
Determination of reporting requirements 
144 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
145 
11.4 
Special Situations for Expedited Reporting 
145 
11.5 
Reporting Requirements for Specialized AEs 
147 
11.6 
Exceptions to Expedited Reporting 
148 
11.7 
Reporting Requirements - Investigator Responsibility 
149 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
149 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
150 
11.10 
Protocol Specific Additional Instructions 
151 
11.11 
Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway152 
11.12 
Routine Adverse Event Reporting 
152 
12.0 
RECORDS AND REPORTING 
153 

 
 
ARST1431 
 
Version date: 11/16/2020 
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12.1 
CDUS 
153 
12.2 
CRADA/CTA 
153 
13.0 
SURGICAL GUIDELINES 
155 
13.1 
Data Submission 
155 
13.2 
Pretreatment Clinical Staging 
155 
13.3 
Surgical-Pathologic (Clinical) Group 
155 
13.4 
Surgical Principles 
156 
13.5 
Specific Anatomic Sites 
158 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
162 
14.1 
Tissue Specimens/Pathology Review at Time of Diagnosis, Delayed Primary Excision, 
Relapse and Autopsy 
162 
14.2 
Pathology Review Requirements 
163 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
164 
15.1 
Identification of Fusion Partners and Variant Gene Fusions in RMS 
164 
15.2 
Circulating Tumor DNA (ctDNA) 
166 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
169 
16.1 
Goals of Diagnostic Imaging 
169 
16.2 
Timing of Diagnostic Imaging 
169 
16.3 
Required Imaging Studies 
170 
16.4 
Diagnostic Imaging Guidelines 
170 
17.0 
RADIATION THERAPY GUIDELINES 
177 
17.1 
General Guidelines 
177 
17.2 
Treatment of Metastatic Disease 
178 
17.3 
Timing 
179 
17.4 
Emergency Radiation Therapy 
179 
17.5 
Equipment and Methods of RT Delivery and Verification 
180 
17.6 
Target Volumes 
181 
17.7 
Target Dose 
186 
17.8 
Treatment Technique 
189 
17.9 
SBRT Guidelines 
192 
17.10 
Organs at Risk for Fractionated Targets (Not SBRT) 
198 
17.11 
Dose Calculations and Reporting 
199 
17.12 
Quality Assurance Documentation 
199 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
203 
APPENDIX II:  YOUTH INFORMATION SHEETS 
207 
APPENDIX III: TNM PRE-TREATMENT STAGING CLASSIFICATION 
210 
APPENDIX IV:  STS CLINICAL GROUPING CLASSIFICATION 
212 
APPENDIX V:  ANATOMIC DEFINITIONS OF PARAMENINGEAL, ORBIT AND OTHER 
HEAD AND NECK SITES FOR USE IN PRE-TREATMENT STAGING 
214 
APPENDIX VI: DESIGNATION OF THE PRIMARY SITE FOR USE IN PRE-TREATMENT 
STAGING (SELECTION OF “SITE CATEGORY” FOR PATIENT ENTRY) 
216 

 
 
ARST1431 
 
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APPENDIX VII: SUPPORTIVE CARE GUIDELINES 
219 
APPENDIX VIII: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
221 
APPENDIX IX: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
223 
POSSIBLE DRUG INTERACTIONS 
224 
APPENDIX X: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
229 
APPENDIX XI: CYCLOPHOSPHAMIDE DOSING GUIDELINES DURING MAINTENANCE 
231 
APPENDIX XII: INSTRUCTIONS FOR CYCLOPHOSPHAMIDE TABLETS 
PREPARATION, ADMINISTRATION AND SAFE HANDLING (CANADIAN SITES) 
232 
APPENDIX XIII: PEDIATRIC FDG PET/CT GUIDELINES FOR ARST1431 
234 
REFERENCES 
238 
 
 

  
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STUDY COMMITTEE 
 
STUDY CHAIR 
Abha A. Gupta, MD, FRCPC 
Hematology/Oncology 
Hospital for Sick Children 
555 University Avenue 
Toronto, ON M5G 1X8, CA 
Phone: (416) 813-7744  
Fax: 
(416) 813-5327 
E-mail: abha.gupta@sickkids.ca 
 
STUDY VICE CHAIR 
Douglas J. Harrison, MD 
Hematology/Oncology 
MD Anderson Cancer Center 
Division of Pediatrics, Unit 87 
1515 Holcombe Blvd 
Houston, TX 77030-4009 
Phone: (713) 792-6620 
E-mail: djharrison@mdanderson.org 
 
STUDY STATISTICIAN 
Wei Xue, PhD  
Statistics 
COG Data Center 
2004 Mowry Road 
Gainesville, FL 32611 
Phone: (352) 294-5919 
Email wxue@cog.ufl.edu 
 
STUDY COMMITTEE MEMBERS 
Douglas Hawkins, MD 
Seattle Children’s Hospital 
Pediatric Hematology/Oncology 
4800 Sand Point Way, Mail Stop MB.8.501 
Seattle, WA  98105 
Phone: (206) 987-3096 
Fax: 
(206) 987-3946 
E-mail: doug.hawkins@seattlechildrens.org 
 
Carola A. S. Arndt, MD 
Hematology/Oncology 
Mayo Clinic 
Pediatric Hem-Onc, E-9 
200 First Street SW, Mayo 16 
Rochester, MN 55905 
Phone: (507) 284-2695 
Fax: 
(507) 284-0727 
E-mail: carndt@mayo.edu 
STUDY COMMITTEE MEMBERS 
Michael A. Arnold, MD PhD 
Pathology 
Children's Hospital Colorado 
13123 East 16th Avenue 
Aurora, CO 80045 
Phone: (720) 777-6188  
E-mail: michael.arnold@childrenscolorado.org  
 
Christine E. Hill-Kayser, MD 
Radiation Oncology 
Children’s Hospital of Philadelphia 
3400 Spruce Street, 2 Donner 
Philadelphia, PA 19146 
Phone: (215) 850-7903 
Fax: 
(215) 349-5445 
E-mail: hill@uphs.upenn.edu 
 
Carol D. Morris, MD MS 
Surgery 
Johns Hopkins University/Sidney Kimmel Cancer Center 
Orthopedics 
601 N Caoline Street 
Baltimore, MD 21287 
Phone: (410) 955-2888 
E-mail: cmorri61@jhmi.edu 
 
Erin R. Rudzinski, MD 
Pathology 
Seattle Children’s Hospital 
Department of Laboratories, OC.8.720 
4800 Sandpoint Way NE 
Seattle, WA 98105 
Phone: (206) 987-0375  
Fax: 
(206) 987-3840 
E-mail: erin.rudzinski@seattlechildrens.org 
 
Suzanne L. Wolden, MD 
Radiation Oncology 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, Box 22 
New York, NY 10065 
Phone: (212) 639-5148 
Fax: 
(212) 639-2417 
Email: woldens@mskcc.org 
 
 
 

  
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STUDY COMMITTEE MEMBERS 
Simon Ching-Shun Kao, MD 
Diagnostic Imaging 
University of Iowa/Holden Comprehensive Cancer Center 
Department of Radiology 
Radiology 3885 JPP, 200 Hawkins Dr. 
Iowa City, IA 52242 
Phone: (319) 356-4447 
Fax:  
(319) 356-2220 
E-mail: simon-kao@uiowa.edu 
 
Barry Lynn Shulkin, MD 
Diagnostic Imaging 
St. Jude Children's Research Hospital 
262 Danny Thomas Place, MS 220 
Memphis, TN 38105-3678 
Phone: (901) 595-3347 
Fax: 
(901) 595 3981 
E-mail: barry.shulkin@stjude.org 
 
Aaron C. Spalding, MD PhD 
Radiation Oncology 
Norton Children’s Hospital 
676 S. Floyd Street 
Louisville, KY 40047 
Phone: (502) 629-4562 
Fax: 
(502) 629-4599 
Email: aaron.spalding@nortonhealthcare.org 
 
Lisa A. Teot, MD 
Pathology 
Dana-Farber/Harvard Cancer Center 
300 Longwood Ave, Bader 110 
Boston, MA 02115 
Phone: (857) 218-4962 
Fax: 
(617) 730-0207 
Email: lisa.teot@childrens.harvard.edu 
 
Tamara MacDonald, PharmD 
Pharmacy 
IWK Health Centre 
5850 University Avenue 
Halifax, NS B3J 3G9, CA 
Phone: (902) 470-6474 
Fax: 
(902) 470-6701 
Email: tamara.macdonald@iwk.nshealth.ca 
 
Marguerite T. Parisi, MD 
Diagnostic Imaging 
Seattle Children’s Hospital 
M/S MA.7.220, PO Box 5371 
Seattle, WA 98145 
Phone: (206) 987-2134 
Fax: 
(206) 987-2730 
Email: meg.parisi@seattlechildrens.org  
STUDY COMMITTEE MEMBERS 
Shari Feinberg, RN MSN CPNP CPON 
Nursing 
Maimonides Medical Center 
6300 Eighth Avenue, 2nd Floor 
Brooklyn, NY 11220 
Phone: (718) 765-2690  
Fax: 
(347) 955-2320 
E-mail: sfeinberg@maimonidesmed.org 
 
Alvin Ongoco, BS 
Clinical Research Associates 
Seattle Children's Hospital 
1900 9th Ave  
Seattle, WA 98101 
Phone: (206) 884-1214  
E-mail: alvinrussell.ongoco@seattlechildrens.org 
 
Jonathan Charles Routh, MD, MPH 
Surgery 
Duke University Medical Center 
DUMC 3831 
Durham, NC 27710 
Phone: (919) 684-6994 
Fax: 
(919) 681-5507 
Email: jonathan.routh@duke.edu 
 
Leo Mascarenhas, MD MS  
Hematology/Oncology 
Children's Hospital of Los Angeles 
USC Keck School of Medicine at CHLA 
4650 Sunset Blvd., MS 54 
Los Angeles, CA 90027 
Phone: (323) 361-2529 
Fax: 
(323) 361-8174 
Email: lmascarenhas@chla.usc.edu 
 
Abby Rachel Rosenberg, MD  
Hematology/Oncology 
Seattle Children's Hospital 
M/S MB.8.501, PO Box 5371 
Seattle, WA 98145 
Phone: (206) 987-2106 
Email: abby.rosenberg@seattlechildrens.org 
 
Roshni Dasgupta, MD 
Surgery 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue, ML 3018 
Cincinnati, OH 45229 
Phone: (513) 636-4576 
Fax: 
(513) 636-0345 
Email: roshni.dasgupta@cchmc.org 

  
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STUDY COMMITTEE MEMBERS 
Brian Crompton, MD 
Hematology/Oncology 
Dana-Farber/Harvard Cancer Center 
450 Brookline Avenue 
Boston, MA 02215 
Phone: (617) 582-8553 
Email: brian.crompton@childrens.harvard.edu 
 
David Anthony Rodeberg, MD 
Surgery 
East Carolina University 
600 Moye Blvd 
Greenville, NC 27834 
Phone: (252) 744-2832 
Email: rodebergd@ecu.edu  
 
Ruthann Pfau, PhD 
Laboratory Science 
Nationwide Biopathology Center 
700 Children's Drive, C0831 
Columbus, OH 43205 
Phone: (614) 722-0637 
Email: ruthann.pfau@nationwidechildrens.org 
 
 
 
 
 
Rajkumar Venkatramani, MD MS 
Hematology/Oncology 
Baylor College of Medicine/Dan L Duncan Comprehensive 
Cancer Center 
6621 Fannin Street 
Houston, TX 77030 
Phone: (832) 822-4511 
Email: rajkumar.venkatramani@bcm.edu 
 
PROTOCOL COORDINATOR 
Tiffany Liu, MS, MA 
Children’s Oncology Group - Operations Center 
Phone: (626) 241-1616 
Fax: 
(626) 445-4334 
E-mail: tliu@childrensoncologygroup.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AGENT 
NSC# 
IND# 
Temsirolimus 
# 683864 
 
Cyclophosphomide 
# 26271 
Commercial 
Dactinomycin 
# 3053 
Commercial 
Irinotecan 
# 616348 
Commercial 
Vincristine sulfate 
# 67574 
Commercial 
Vinorelbine tartrate 
# 608210  
Commercial 
 
IND sponsor: DCTD, NCI 
SEE SECTION 14.0 AND 15.0 FOR SPECIMEN SHIPPING ADDRESSES.

  
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal 
government, which will help us protect the privacy of our research subjects. The Certificate protects 
against the involuntary release of information about your subjects collected during the course of our 
covered studies. The researchers involved in the studies cannot be forced to disclose the identity or any 
information collected in the study in any legal proceedings at the federal, state, or local level, regardless 
of whether they are criminal, administrative, or legislative proceedings. However, the subject or the 
researcher may choose to voluntarily disclose the protected information under certain circumstances. For 
example, if the subject or his/her guardian requests the release of information in writing, the Certificate 
does not protect against that voluntary disclosure. Furthermore, federal agencies may review our records 
under limited circumstances, such as a DHHS request for information for an audit or program evaluation 
or an FDA request under the Food, Drug and Cosmetics Act.  
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of 
information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm 
to self or others. 
 
 
ABSTRACT 
 
Unfortunately about 25% of patients with intermediate-risk (IR) embryonal rhabdomyosarcoma (ERMS) 
and 50% of those with IR alveolar rhabdomyosarcoma (ARMS) will experience disease recurrence with a 
resulting long-term event-free survival (EFS) of 65%. The mTOR pathway is important in RMS biology, 
and temsirolimus, an mTOR inhibitor, has demonstrated clinical activity in patients with relapsed RMS. 
In an attempt to improve long-term survival for patients with IR RMS, ARST1431 will compare the EFS 
of patients with newly diagnosed IR RMS randomly assigned to standard vincristine, dactinomycin, and 
cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) versus VAC/VI plus 
temsirolimus. Radiotherapy (RT) is planned to start at Week 13 of therapy for all patients, with RT to 
metastatic sites at the end of VAC/VI therapy. Beginning with Amendment #3, all patients will also be 
receiving maintenance chemotherapy with low dose oral cyclophosphamide and IV vinorelbine following 
the completion of the initial 42 weeks of VAC/VI therapy. Correlative biology studies will be performed 
including a determination of the FOXO1 gene fusion status in the tumor, and measurement of cell free 
tumor DNA. 
 
 
 

  
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EXPERIMENTAL DESIGN SCHEMA: FEASIBILITY PHASE 
The feasibility phase is complete, effective with Amendment #1.  
During the feasibility (dose-finding) phase, patients will be non-randomly assigned to treatment with 
VAC/VI plus temsirolimus. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** All patients undergo institutional pathology review and FOXO1 fusion determination. FOXO1 status results must 
be available by Week 3 (Day 21) of therapy. Patients who are FOXO1 fusion positive with Group IV/Stage 4 
disease, will be removed from protocol therapy. Patients who are ARMS FOXO1 fusion negative and Stage 1, 
Group I/II, Stage 1, Group III (orbit) or Stage 2, Group I/II are eligible for Regimen C (as shown in the Feasibility 
schema above). Transfer to Regimen C prior to the start of Week 4 of therapy (see Section 3.1.8 for call back 
details). 
 
Drug 
Age 
Dose 
V 
VINCristine 
 0.6 m2 BSA 
BSA-based dosing, see dosing table (Section 4.2.3.2) 
t 0.6 m2 BSA 
1.5 mg/m2 IV Days 1, 8 & 15 (maximum dose 2 mg)  
A 
Dactinomycin 
< 14 kg 
Weight-based dosing, see dosing table (Section 4.2.3.2) 
≥ 14 kg 
0.05 mg/kg IV Day 1 (maximum dose 2.5 mg)  
C 
Cyclophosphamide 
 0.6 m2 BSA 
BSA-based dosing, see dosing table (Section 4.2.3.2) 
t 0.6 m2 BSA 
1200 mg/m2 IV Day 1 
I 
Irinotecan 
 0.6 m2 BSA 
BSA-based dosing, see dosing table (Section 4.2.3.2) 
t 0.6 m2 BSA 
50 mg/m2 IV Days 1-5 (maximum dose 100 mg) 
Study Entry  
First 10 patients < 21 years of age begin 
at Dose Level 1 
Temsirolimus# 
4 cycles of VAC/VI** 
 
Week 13: Feasibility assessment 
Dose level adjustments 
Therapy to continue as outlined in the 
efficacy phase schema 
#Temsirolimus  
 
Dose Level 
 
Temsirolimus Dose 
        1 
 
 
15 mg/m2 IV, Days 1, 8 and 15 of each cycle  
        0 
 
 
10 mg/m2 IV, Days 1, 8 and 15 of each cycle 
       -1  
 
10 mg/m2 IV, Days 1 and 8 of each cycle 

  
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EXPERIMENTAL DESIGN SCHEMA: EFFICACY PHASE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 0.5 mg/kg (for patients < 10 kg) or 15 mg/m2 (for patients 
≥ 10 kg) on Day 1 of each week. Note: Temsirolimus is to be 
held pre- and post-surgery. 
# All patients undergo institutional pathology review and 
FOXO1 fusion determination. FOXO1 status results must be 
available by Week 3 (Day 21) of therapy. Patients who are 
FOXO1 fusion positive with Group IV/Stage 4 disease, will be 
removed from protocol therapy. 
% Patients with Clinical Group I, FOXO1 negative tumors or 
Clinical Group I, FOXO1 indeterminate tumors will not 
receive radiotherapy. 
^ Metastatic sites should be treated with radiotherapy at the 
completion of VAC/VI chemotherapy. 
** Includes 1 cycle of VAC which will be given prior to 
enrollment on Regimen C; do not repeat Cycle 1 therapy that 
was given as part of Regimen A or B 
V = VinCRIStine; A = DACTINomycin; 
C = Cyclophosphamide (IV); I = Irinotecan;  
CPO = Cyclophosphamide (oral); VINO = Vinorelbine 
Each cycle of VAC, VI, or VA lasts 21 days (3 weeks). 
Each cycle of maintenance therapy lasts 28 days (4 weeks). 
 
Study Entry and Randomization 
2 cycles of VAC and 
1 cycle of VI#  
XRT% begins Week 13 
XRT% begins Week 13 
3 cycles of VAC and  
3 cycles of VI 
3 cycles of VAC and  
3 cycles of VI, plus 
TORI* Weeks 21-30 
Evaluation (Week 42) 
Progressive 
Disease 
 
Off Protocol 
Therapy 
 
Regimen A 
 
Regimen C 
2 cycles of VAC and  
2 cycles of VI, plus 
TORI* Weeks 31-42 
2 cycles of VAC and 
2 cycles of VI  
Evaluation 
(Week 30) 
Evaluation 
(Week 30) 
Progressive 
Disease 
 
Off Protocol 
Therapy 
3 cycles of VAC**  
End of Protocol Therapy 
Evaluation (Week 24) 
 
Regimen B 
XRT begins Week 13 
4 cycles of VA 
Evaluation 
(Week 9) 
1 cycle of VAC  
Evaluation 
(Week 9) 
Evaluation 
(Week 9) 
2 cycles of VAC and  
1 cycle of VI, plus 
Temsirolimus (TORI)* Weeks 1-9# 
1 cycle of VI  
1 cycle of VI, plus 
TORI* Weeks 10-12 
ARMS FOXO1 fusion negative: 
Stage 1, Group I/II, Stage 1, Group 
III (orbit) or Stage 2, Group I/II 
Transfer to Regimen C prior to the 
start of Week 4 of therapy. 
Maintenance (Weeks 43-66)^ 
6 cycles of CPO/VINO 
End of Protocol Therapy 

  
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
1.1.1 
To compare the event-free survival (EFS) of patients with IR RMS treated with 
surgery, radiotherapy, and VAC alternating with VI (VAC/VI) with maintenance 
to that of patients treated with surgery, radiotherapy and VAC/VI plus 
temsirolimus with maintenance. 
 
1.2 
Secondary Aims 
1.2.1 
To compare the overall survival (OS) of patients with IR RMS treated with 
surgery, radiotherapy, and VAC alternating with VI with maintenance to that of 
patients treated with surgery, radiotherapy and VAC/VI plus temsirolimus with 
maintenance. 
 
1.3 
Exploratory Aims 
1.3.1 
To compare the outcome of patients based on their FOXO1 fusion gene partner, 
by evaluating PAX3 vs. PAX7 in all patients found to be FOXO1 fusion positive. 
1.3.2 
To compare the outcome of patients based on their [F18]-fluorodeoxy-D-glucose-
positron emission tomography (FDG-PET) response at Week 9 (positive or 
negative), as assessed by Deauville Criteria (5-point). 
1.3.3 
To estimate the frequency of patients with circulating tumor DNA (ctDNA) at 
diagnosis and subsequent time-points, and explore whether tumor-specific 
somatic variants are detectable in the ctDNA. 
1.3.4 
To compare the outcome of patients (VAC/VI with or without temsirolimus) who 
have received maintenance therapy on ARST1431 to those who received 
VAC/VI on ARST0531. 
 
 
2.0 
BACKGROUND 
2.1 
Introduction and Rationale for Development 
The three most recent COG IR RMS studies (IRS-IV, D9803, and ARST0531) each 
tested the addition of one or more traditional cytotoxic chemotherapeutic agents to VAC 
and failed to improve outcome compared to VAC.1-3 As an alternative strategy, the 
current study will explore the addition of a biologically targeted agent, temsirolimus to a 
backbone of VAC alternating with VI in a randomized, phase 3 design, with a primary 
goal of comparing EFS and secondary objective of comparing OS between the two arms.  
 
2.1.1 
Intermediate Risk Rhabdomyosarcoma 
Rhabdomyosarcoma is the most common soft tissue sarcoma in children and 
adolescents with approximately 350 new diagnoses annually in the United 
States.4 Despite cooperative group trial efforts, about 25% of patients with IR 
ERMS tumors and 50% of those with IR ARMS tumors will experience disease 
recurrence5,6 and only a small fraction of the patients who relapse can be cured.7  
Patients with an estimated 3-yr EFS of 50-75% are considered to be IR and 
comprise almost 50% of all patients with RMS.3 Historically, this group was 
comprised of patients with unresected, non-metastatic ARMS at all primary sites 

  
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and ERMS arising in unfavorable sites and unresected.3,8 However, recent COG 
low-risk (ARST0331) and high-risk (ARST0431) RMS clinical trials support 
shifting some RMS populations into IR. First, patients < 10 years of age with 
metastatic ERMS have previously been treated on both high risk (ARST0431) 
and IR (D9803) protocols. In this trial these patients will be classified as IR as 
they had a 60% 3-yr EFS (n=20) with intensive, interval compressed seven-drug 
chemotherapy on COG ARST04319 and a 60% 4-yr EFS (n=47) with VAC (with 
or without topotecan) on COG D9803.3 In addition, patients with ERMS who 
were either Stage 1 (favorable site); Group III (unresected); non-orbit or Stage 3 
(unfavorable site); or Group I/II (resected) on ARST0331, who were considered 
as low-risk subset had a 3-yr EFS of only 64% after a 4.8 g/m2 cumulative dose 
of cyclophosphamide.10 When these patients were treated with 28 g/m2 of 
cyclophosphamide on D9602, 5-yr EFS was 85%.11 Thus, this latter group of 
patients will also be re-classified as “intermediate” risk in the current trial which 
will give a moderate cumulative dose of cyclophosphamide (8.4 g/m2) to all 
enrolled subjects.   
 
2.1.2 
Age of Eligibility: Adolescents and Young Adults 
To address the problem of trial accrual among young adults and encourage 
uniform treatment of adults with ‘pediatric-type’ RMS, previous RMS studies 
permitted enrolment up to age 50 years. However, two subsequent analyses have 
demonstrated that adolescents and young adults experience greater neurotoxicity 
and nausea compared to younger children.12,13 Despite the increased age of 
eligibility, accrual of adults was poor on ARST0531. In the current study, we will 
still hope to accrue young adults, but will limit accrual to below age 40 years, 
which coincides with the NCI definition of a young adult. Moreover, adults with 
RMS older than age 40 years are much more likely to have the pleomorphic 
subtype of the disease which is biologically and clinically distinct from, and 
unresponsive to chemotherapy compared with, ARMS and ERMS.14 
 
2.1.3 
Defining RMS Using Fusion Status Rather than Histology  
Patients who are newly diagnosed with biopsy proven RMS of any histologic 
type except adult-type pleomorphic (based upon institutional histology) will be 
eligible for enrollment. ARST1431 will use FOXO1 fusion status rather than 
histology for study eligibility because it is more predictive of outcome as 
demonstrated by two independent analyses.15,16 FOXO1 fusion status will be 
performed within the first 3 weeks of study enrollment. Patients with ERMS who 
have distant metastases and are found to be FOXO1 positive will be deemed 
ineligible and removed from study.  
 
2.1.4 
Translocation Negative ARMS: ‘Low Risk’ Patients to Receive Only VAC/VA 
Approximately 20% of histologically defined ARMS are negative for FOXO1 
fusion (nARMS). These patients will be considered IR, and continue on protocol 
therapy as randomized unless they are Stage 1/2, Group I-II (completely 
resected) or orbital primary site (Group I-III). This molecularly defined low risk 
population will receive 24 weeks of VAC/VA therapy as per ARST0331 instead 
of the randomized arm of therapy. On D9803, these low risk nARMS patients 
had 100% EFS but at the cost of a high cumulative cyclophosphamide dose 
(30.8 g/m2).15 Although the rarity of low risk nARMS will limit the ability to 

  
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draw strong statistical conclusions, ARST1431 will be the only opportunity to 
estimate the success of reduced intensity therapy for low risk nARMS.  
 
2.1.5  Reduced Staging Investigations for Patients with Translocation Negative Disease 
In an effort to simplify the staging evaluations in patients with RMS, a recent 
analysis of ERMS and ARMS patients demonstrated that patients with ERMS 
who have tumors that are less than 5 cm and non-invasive (T1), without nodal 
disease, had a 0% chance of having bone or bone marrow metastases.17 Based on 
the staging algorithm proposed in this analysis, patients in ARST1431 who have 
ERMS without nodal or lung metastases, will not require bone scans or bone 
marrow evaluations. 
 
2.2 
Rationale for Investigation of an mTOR inhibitor in Children with Newly 
Diagnosed RMS: Temsirolimus (Torisel®) 
Results of COG ARST0921, a randomized phase 2 selection design study in relapsed 
RMS that compared bevacizumab (BEV) to temsirolimus, both administered in 
combination with cyclophosphamide and vinorelbine, showed that the temsirolimus arm 
had a superior 6-month EFS (65%, 95% CI: 44%, 79%) compared to the bevacizumab 
arm (50%, 95% CI: 32%, 66%, p = 0.0031).18 There was also a higher proportion of 
partial responses on the temsirolimus arm (33%) versus the BEV arm (18%). 
Furthermore, the complete response (CR) + partial response (PR) rate for the 
temsirolimus arm was 47% compared with 28% for the BEV arm. Based upon this 
clinical evidence of activity in heavily pre-treated patients with RMS, temsirolimus is a 
high priority agent to evaluate in a large phase 3 study. 
 
2.2.1 
Mammalian Target of Rapamycin 
Mammalian target of rapamycin (mTOR) is a 289-kDa serine/threonine kinase 
that exists in the cytoplasm and plays a role in several tumor-promoting 
intracellular signaling pathways. Regulation of the mTOR pathway is highly 
complex and is mediated through a series of interactions linking growth factor 
receptor signaling and other cell stimuli as well as phosphatidylinositol 3-kinase 
and the Akt/protein kinase B pathway activation. This process leads to 
production of hypoxia inducible factor–1α that regulates transcription of genes 
that stimulate cell growth and angiogenesis including vascular endothelial growth 
factor (VEGF). Other effects of mTOR activation include stimulation of 
increased mRNA translation that encodes cell cycle regulators such as c-myc, 
cyclin D1, and ornithine decarboxylase resulting in increased cell division and 
survival.19 Thus, targeting the mTOR pathway is a relevant strategy to inhibit 
cancer. 
 
2.2.2 
Preclinical Data for mTOR in RMS 
Temsirolimus is a soluble ester prodrug of sirolimus, which is a natural product 
initially developed as an antifungal drug and then as an immunosuppressive 
agent and forms a complex with FK506-binding protein and prohibits the 
activation of mTOR.19 ARMS cell lines are highly sensitive to the growth-
inhibitory effects of sirolimus, and RMS cell line sensitivity was likely due to 
sirolimus inhibition of insulin-like growth factor 1 receptor-mediated signaling.20 
Temsirolimus has been shown to inhibit the growth of RMS xenografts.21 The 
Pediatric Preclinical Testing Program (PPTP) reported on single agent activity of 

  
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sirolimus against its models.22 Six RMS xenografts were tested. Two (Rh18 and 
Rh10) had partial responses to sirolimus. Of the remaining four tested, two had 
their times to event more than doubled by sirolimus compared to controls. These 
data suggest that mTOR inhibition by sirolimus has an in vivo effect on RMS 
xenografts.  
 
2.2.3 
Rationale for combining mTOR inhibitor with VAC/VI 
PPTP xenograft experiments also demonstrate a synergistic effect of mTOR 
inhibition in combination with cyclophosphamide, vincristine or irinotecan. 
Xenografts 
demonstrated 
the 
combination 
of 
sirolimus 
with 
either 
cyclophosphamide (Rh30) or vincristine (Rh18) was significantly more effective 
than the respective standard agents used alone at their maximum tolerated 
doses.23 Vincristine was found to be supra-additive and cyclophosphamide 
additive in combination with sirolimus. Similar results were seen with irinotecan 
in combination with sirolimus (unpublished observation, Peter Houghton). 
 
 
 
 
 
A synergistic anti-tumor effect was observed in Rh30 xenograft mice following 
treatment with vincristine or cyclophosphamide ± rapamycin 
 
RAPAMYCIN + VINCRISTINE 
RAPAMYCIN + CYCLOPHOSPHAMIDE 

  
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Synergistic activity was also observed with irinotecan plus sirolimus in the Rh30 
mouse xenograft model 
 
2.2.4 
Experience with Temsirolimus Alone and in Combination with Irinotecan in 
Patients with Solid Tumors 
A summary of relevant clinical experience with temsirolimus is provided in a 
table below. A pediatric phase 1 study of temsirolimus (n = 19) demonstrated 
dose limiting toxicities (DLTs) at 150 mg/m2 including thrombocytopenia, 
anorexia, anemia, neutropenia and transaminitis. The recommended phase 2 dose 
(RP2D) was 75 mg/m2 weekly IV, although in vivo Akt inhibition was 
demonstrated by decreases in pAKT, pS6, and p4EBP1 in peripheral blood 
mononuclear cells at all dose levels, including 10 and 25 mg/m2 IV weekly.24 As 
a single agent, Grade 1 hematological toxicity was seen at a temsirolimus dose of 
10 or 25 mg/m2 (see table below).  
 
A pediatric phase 1 trial of temsirolimus plus oral irinotecan and temozolomide 
investigated many different dose combinations.25 The RP2D was temsirolimus 
35 mg/m2 IV weekly, with oral irinotecan 90 mg/m2 (Days 1-5) and oral 
temozolomide 125 mg/m2 orally on (Days 1–5). With this dose of temsirolimus, 
there were frequent Grade 1 and 2 non-hematologic toxicities and frequent 
≥ Grade 3 hematological toxicity. 
 
ARST0921, a phase 2 study of temsirolimus plus vinorelbine (25 mg/m2) and 
cyclophosphamide (1.2 g/m2) in relapsed RMS confirmed the feasibility of 
adding temsirolimus to cyclophosphamide (1.2 g/m2) and a vinca alkaloid.18 
Temsirolimus was administered at a dose of 15 mg/m2 weekly, which was 
associated with frequent episodes of febrile neutropenia (FN) in this heavily pre-
treated cohort as demonstrated by an incidence of 26% in the first 6 weeks 
(reporting period 1 of therapy). In comparison, the rate of FN on ARST0531 with 
VAC/VI was 10.5% in the first 15 weeks of therapy. 
 

  
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Phase 1 
temsirolimus in 
children24 
Phase 1 
temsirolimus plus 
oral Irino plus 
Temodal25 
Phase 2 
temsirolimus plus 
VC18 
Phase 1 
temsirolimus plus 
Irino  
(adult sarcoma)26 
Phase 2 
temsirolimus 
plus Irino (adult 
colon CA)27 
Dose 
temsirolimus 25 
mg/m2 d1,8,15 q21d 
temsirolimus 35 
mg/m2 d 1,8,15 q21d 
Oral Irinotecan 
90 mg/m2 d 1-5 
Oral Temodal 
125 mg/m2 
temsirolimus 15 
mg/m2 d 1,8,15 q21d 
Vinorelbine 24 mg/m2 
d1,8 
Cyclophosphamide 
1.2 g/m2 d1 
temsirolimus 20 mg 
IV d1,8,15 q28d 
Irinotecan 80 mg/m2 
IV d1,8,15  
temsirolimus 25 mg 
IV weekly 
Irinotecan 180 
mg/m2 IV q2 weeks 
Selected Toxicities  
Grade 
1/2 
Grade 
3/4 
Grade 
1/2 
Grade 
3/4 
Grade 
1/2 
Grade 
3/4* 
Grade 
1/2 
Grade 
3/4 
Grade 
1/2 
Grade 
3/4 
Anemia 
0 
0 
6/6 
0 
NR 
0 
3/8 
0 
NR 
NR 
Neutropenia 
2/5 
2 
2/6 
4 
NR 
3/42 
1/8 
1 
6/64 
2 
Thrombocytopenia 
2/5 
0 
2/6 
4 
NR 
1/42 
2/8 
0 
17/64 
5 
Diarrhea 
1/5 
0 
3/6 
0 
NR 
0 
3/8 
0 
29/64 
3 
Nausea 
1/5 
0 
5/6 
0 
NR 
0/42 
2/8 
0 
25/64 
2 
Vomiting 
1/5 
0 
4/6 
2 
NR 
0 
1/8 
0 
NR 
NR 
Elevated LFTs 
2/4 
2/5 
0 
3/6 
1 
NR 
2/42 
1/8 
0 
NR 
NR 
Mucositis 
1/5 
0 
2/6 
0 
NR 
5/42 
0 
0 
33/64 
1 
Fatigue 
NR 
NR 
2/6 
0 
NR 
1/42 
1/8 
0 
NR 
NR 
Hyperglycemia 
3/5 
0 
5/6 
0 
NR 
0 
0 
0 
15/64 
5 
Hyperlipidemia 
3/5 
0 
4/6 
0 
NR 
4/42 
NR 
NR 
35/64 
4 
Hypercholesterolemia 
2/5 
0 
3/6 
0 
NR 
1/42 
NR 
NR 
NR 
NR 
Fever 
NR 
NR 
0 
0 
NR 
11/42 
0 
0 
18/64 
5 
NR: not reported; *denotes only reporting period 1 
 
2.3 
Vincristine, Dactinomycin and Cyclophosphomide (VAC) with Vincristine and 
Irinotecan (VI) 
Irinotecan was discovered to have substantial activity in preclinical models of RMS.28 
Subsequently, various schedules were explored in children with RMS, as summarized 
below. Due to a favorable toxicity profile and convenient schedule, irinotecan 
50 mg/m2 IV Days 1-5 in combination with vincristine every 21 days was selected for 
further study.  
 
Regimen 
RMS Patient 
Population 
n 
Response Rate 
Reference 
Irinotecan [(dx5)2] 
Relapsed 
4 
75% 
29
 
Irinotecan q 3 
weeks 
Relapsed/refractory  
34 
11.4% 
30
 
Irinotecan (dx5) 
Relapsed  
18 
5.5% 
31
 
Irinotecan [(dx5)2] 
Untreated metastatic   
19 
42% 
32
 
Vincristine and 
Irinotecan [(dx5)2] 
Untreated metastatic 
50 
70% 
Vincristine and 
Irinotecan (dx5) 
Refractory/initial relapse  
47 
36% 
33
 
Vincristine and 
Irinotecan [(dx5)2] 
Refractory/initial relapse 
42 
26% 
 

  
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The recently completed study ARST0531 randomized patients with IR RMS to VAC 
versus VAC alternating with VI. For the current study VAC alternating with VI was 
selected as the standard backbone rather than VAC. The reasons for choosing VAC/VI 
are: 1) VAC and VAC/VI had similar outcomes on ARST0531; 2) VAC/VI had 
significantly less hematologic toxicity and less Grade 3 or 4 febrile neutropenia1; and 
3) VAC/VI has the potential for less infertility in both males and females due to lower 
cumulative cyclophosphamide dose (8.4 g/m2 versus 16.8 g/m2).1  
 
2.3.1 
Previous Experience with VAC/VI 
Due to the results from ARST0531, VAC/VI has now been selected as the new 
standard chemotherapy for IR RMS. In previous sequential studies from IRS-III 
to IRS-IV to D9803, the cumulative dose of cyclophosphamide had increased 
significantly.2,34,35 The dose per course of cyclophosphamide was increased from 
approximately 0.9 g/m2 during IRS-III to 2.2 g/m2 during IRS-IV in order to 
achieve equivalent hematologic toxicity with the ifosfamide-containing arms, 
VAI and VIE.2 The same cyclophosphamide dose per course was maintained 
during D9803. However, there was no improvement in outcome for either IR 
ERMS (3 year EFS on IRS-III, 74% versus IRS-IV, 75%, p = 0.47) or IR ARMS 
(3 year EFS on IRS-III, 70% versus IRS-IV, 64%, p=0.35), despite the escalation 
of cyclophosphamide cumulative dose.2,35 The IRS-IV/D9803 dose of 
cyclophosphamide contributed to acute and chronic toxicity, especially infertility. 
For these reasons, the control VAC arm was changed to 1.2 g/m2, which 
represents an intermediate dose intensity of cyclophosphamide between IRS-III 
and IRS-IV/D9803. This is the dose that has been used on the most recent RMS 
studies examining patients with low (ARST0331), intermediate (ARST0531), 
high (ARST0431) or relapsed (ARST08P1) disease.   
 
ARST0531 randomized patients with IR RMS to receive either VAC alone or 
VAC alternating with VI. The outcome was similar between the 2 arms, with no 
difference among patients with either ERMS or ARMS.1   
 
 
4-year EFS (95% CI) 
4-year OS (95% CI) 
Patient Category 
VAC 
VAC/VI 
P 
VAC 
VAC/VI 
P 
All patients 
(n = 448) 
63% (55-70%) 
59% (51-66%) 
0.51* 
73% (66-79%) 
72% (65-79%) 
0.80* 
ARMS only 
(n = 196) 
58% (48-69%) 
51% (39-62%) 
0.25 
68% (58-78%) 
66% (55-77%) 
0.59 
ERMS/NOS/other 
(n = 252) 
66% (57-76%) 
64% (54-73%) 
0.85 
77% (69-86%) 
76% (68-84%) 
0.96 
* Adjusted p-value after including randomization stratum (on the basis of central reviewed data, with 
24 patients excluded for not belonging to any of the 3 strata) as a covariate in a Cox regression model. 
Eight and 16 of the 24 patients were categorized by the enrolling institution as having ARMS, stage II/III 
and group 2/3, and ERMS, stage II/III and group 3, respectively. 
 
Myelosuppression was substantially lower in the VAC/VI arm (see table below). 
Additionally, we hypothesize that the overall cost of VAC/VI will be lower due 
to fewer admissions for FN and blood product transfusion, and that there is a 
potential for a decreased risk of infertility given the total lower cumulative dose 
of cyclophosphamide (8.4 g/m2 versus 16.8 g/m2). 
 

  
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Grade 3 or 4 
Toxicity 
Week 1-15 
Week 16-30 
Week 31-43 
VAC 
VAC/VI 
VAC 
VAC/VI 
VAC 
VAC/VI 
Diarrhea 
4.8% 
15.7% 
2.5% 
11.1% 
0.5% 
2.2% 
Oral mucositis 
10.1% 
18.3% 
2.0% 
2.5% 
0.5% 
1.1% 
Febrile neutropenia 
13.6% 
10.5% 
17.8% 
8.1% 
8.6% 
4.4% 
Anemia 
24.1% 
18.3% 
27.2% 
8.1% 
26.2% 
9.3% 
Thrombocytopenia 
11.4% 
5.2% 
31.7% 
12.1% 
29.9% 
6.6% 
 
2.4 
Initial Safety Phase Prior to Randomization 
A short safety phase in the first 10 subjects who enrolled was conducted. This phase was 
limited to patients < 21 years of age. These subjects received temsirolimus, 15 mg/m2 IV 
weekly, along with VAC/VI. Accrual was suspended until this cohort of patients 
completed the first 12 weeks of treatment. If fewer than 4 patients had dose limiting 
toxicity (DLT – see Section 5.1), and the median time to complete the first 12 weeks of 
prescribed therapy was < 16 weeks, the study would proceed to the randomization 
component of the trial (VAC/VI ± temsirolimus, 15 mg/m2). If 4 or more experienced a 
DLT or the median time to complete the first 12 weeks of prescribed therapy was 
≥ 16 weeks, a second cohort of 10 patients would be enrolled to receive 10 mg/m2 
temsirolimus. Again, accrual would be suspended until patients completed 12 weeks of 
prescribed therapy. If fewer than 4 patients experienced DLT and time to complete 
12 weeks of planned therapy was < 16 weeks, this would be the temsirolimus dose for 
patients randomized to receive VAC/VI + temsirolimus. If this dose was also intolerable, 
patients would be offered 10 mg/m2 temsirolimus on Days 1 and 8 only. If greater than 
4 patients experienced DLT or time to complete 12 weeks of planned therapy was greater 
than or equal to 16 weeks, the study would be closed.  
 
The first 10 eligible patients (excluding 1 low-risk Regimen C transfer) enrolled in the 
feasibility phase received VAC/VI with temsirolimus at 15 mg/m2 on Days 1, 8 and 15 of 
each cycle. Criteria to determine feasibility as outlined in Section 4.1.1 “Proceed to 
Efficacy Phase if < than 4/10 subjects experience a non-hematological DLT, and the 
median duration of the first 12 weeks of therapy is < 16 weeks, otherwise, proceed to 
dose level 0” were evaluated. Two patients experienced protocol-defined non-
hematological DLTs: one patient experienced oral mucositis and subsequently was 
removed from the protocol therapy due to physician determination that it was in the 
patient’s best interest, and one patient experienced oral mucositis and lung infection. The 
median duration of the first 12 weeks of therapy was 12 weeks. Based on the review of 
toxicities and treatment duration, the feasibility phase has been completed and Dose 
Level 1 (15 mg/m2) is the dose of temsirolimus established for the efficacy phase. 
 
2.5 
Local Control Recommendations  
2.5.1 
Improving Local Control: Rationale for Delayed Primary Excision and 
Increasing Boost Dose to Residual 
Local control of RMS may be attained through surgery, definitive RT, 
individually or in combination. A combined modality approach may optimize 
local control yet minimize the potential morbidity associated with each individual 

  
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modality. RT can be associated with significant late effects, particularly in young 
children.36-40 Surgery also can be associated with significant late effects, 
particularly if organs are sacrificed.41 In an effort to minimize RT toxicity, many 
European RMS trials have utilized RT selectively.42,43 In D9803, the RT dose 
was adjusted by the amount of residual tumor present following 12 weeks of 
induction chemotherapy: no evidence of disease (NED) 36 Gy, microscopic 
residual (MR) 41.4 Gy, and gross residual disease (GRD) 50.4 Gy. With this 
local control strategy for patients with Group III disease, the overall failure rate 
was 30%, with 19% including a component of local failure with the first 
progression. The rate of local failure did not vary by histology or regional nodal 
status and was similar to historical studies. 
 
Local Failure Pattern Among Patients with Group III Disease 
Patient subsets 
IRS-III 
IRS-IV 
D9803 
All patients 
19% 
13% 
19% 
Embryonal RMS 
19% 
 
20% 
Alveolar RMS (and 
undifferentiated 
sarcoma for IRS-III) 
17% 
 
17% 
Parameningeal 
19% 
16% 
19% 
Extremity 
17% 
7% 
15% 
Bladder/prostate 
14% 
19% 
14% 
N0 
16% 
 
19% 
N1 
32% 
 
17% 
≤ 5 cm 
16% 
 
 10%* 
> 5 cm 
21% 
 
 25%* 
*p=0.0004 
 
The only significant predictor of local failure was initial tumor size > 5 cm 
(25% vs 10%).44 Therefore, in the current study, we will explore two strategies to 
reduce the rate of local failure and also potentially minimize long term toxicity. 
These include: 1) delayed primary excision (DPE) and 2) increasing the boost 
dose of XRT to patients with tumors > 5 cm (at diagnosis) and residual disease.  
 
2.5.2 
Delayed Primary Excision 
To minimize RT toxicity, local tumor control may be achieved with reduced dose 
RT in conjunction with DPE following Week 9 evaluation in select patients. This 
local control paradigm may have potential benefit to the patient since patients 
who have DPE may be able to receive decreased RT dosing, although this 
strategy has not been shown to improve outcome. Patients may be considered for 
DPE for select non-parameningeal (PM) primary sites when gross total resection 

  
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(GTR) can be easily performed with minimal morbidity or loss of function and 
with minimal disruption to the overall treatment scheme. Adequate margins of 
uninvolved tissue are required unless this involves sacrifice of normal tissue that 
would result in an unacceptable loss of function, form or is not technically 
feasible. Debulking operations are absolutely discouraged as they may cause 
harm, and will not result in reduction of RT dose. Heroic attempted R0 
resections are also discouraged, as all patients will undergo planned RT; delay in 
the initiation of RT is associated with increased risk of local recurrence. 
 
In D9803, reduction of RT dose based upon the completeness of surgical 
resection of the primary tumor prior to chemotherapy did not compromise nor did 
it improve local control, failure free survival (FFS), or OS compared to historical 
controls.45 A total of 161 Group III patients were evaluated (24 bladder dome, 
63 extremity, and 74 trunk). Seventy-three patients (45%) underwent DPE which 
achieved removal of all gross disease in 61 (84%) who were then eligible for 
reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 
5-year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) 
was similar to IRS-IV, which did not encourage DPE and did not allow for DPE 
adapted RT dose reduction.  
 
In the current protocol, we will allow the paradigm of DPE and modulated RT 
dose for those patients who have easily resectable masses after 9 weeks of 
prescribed chemotherapy with a plan for GTR (not debulking) if such can be 
achieved without loss of form/function or a significant delay in overall protocol 
treatment. A similar strategy was used on CWS-81,46 resulting in a local failure 
rate of 18% for Stage 2-3 patients. 
 
2.5.3 
Increasing RT Dose to Tumors > 5 cm 
The analysis shown in the table above (in Section 2.5.1) demonstrates that a 
tumor size > 5 cm was a significant predictor of increased local failure. Thus, in 
ARST1431, we propose to increase the total dose of RT following induction 
chemotherapy to 59.4 Gy for primary sites > 5 cm at diagnosis for those patients 
who will not be undergoing DPE or those who have imaging evidence of gross 
residual disease after DPE, a situation we hope to avoid. We do not anticipate a 
greater risk of radiation toxicity because of significant advances in imaging and 
radiation delivery. ARST1431 will use smaller margins for uncertainty based on 
current standards of improved immobilization, planning and daily on-treatment 
imaging. All patients will undergo 3-dimensional conformal RT and the vast 
majority will receive intensity modulated radiation or proton radiotherapy. The 
original tumor at the time of diagnosis will be treated to 36 Gy, with the extra 
dose being given to residual tumor volume based on imaging done at Week 9. 
For patients undergoing DPE, an additional CT or MRI scan will be necessary 
post-operatively to confirm GTR or to indicate any gross residual disease 
requiring a boost to 50.4 Gy or 59.4 Gy depending upon the initial tumor size. 
 
Previously, IRS-IV randomized patients to conventional RT of 50.4 Gy or to 
hyperfractionated RT of 59.4 Gy. While the results of that study showed no 
statistically significant difference with respect to EFS, OS, and local control 
between the 2 groups, the cumulative local control at 5 years was 85-88%, the 
highest achieved on any IRS studies. Thus, we are hopeful that the current 

  
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proposed RT dose escalation will result in improved local control for several 
reasons. First, IRS-IV used small fraction sizes of 1.1 Gy BID to give 59.4 Gy. 
This is a lower biologically effective dose than 59.4 Gy in 1.8 Gy fractions as 
proposed in this study. Also, in IRS-IV, all patients were randomized which 
could have potentially diluted a benefit to those with higher risk tumors, such as 
those of large size, who fail to achieve a CR to induction chemotherapy. In 
ARST1431, only those with tumors at highest risk of local failure (> 5 cm at 
diagnosis with a PR following 9 weeks of induction chemotherapy) will receive 
the higher radiation dose. 
 
Patients who have large tumors (> 5 cm at diagnosis) who achieve a CR will not 
require higher dose RT. The definition of a CR that will warrant avoidance of a 
higher dose RT will include a radiological CR by cross sectional imaging (no 
visible tumor) AND any one of the following: 1) negative PET; or 2) biopsy that 
shows NO residual tumor, including rhabdomyoblasts. Furthermore, patients who 
achieve GTR with DPE (imaging to confirm no visible tumor left by surgeon and 
a pathology report with no more than microscopic residual tumor) will also not 
require higher dose RT. These definitions are applicable to the local control 
guidelines and are separate from the RECIST response definitions in 
Section 10.2. 
 
2.5.4 
Timing of Radiotherapy  
Loco-regional failure remains the most common pattern of initial disease 
progression in RMS. On D9803, the 4-yr local, regional, and distant failure rates 
were 17.5%, 4.6%, and 12.3%, respectively.3 Moreover, > 50% of IR RMS 
patients have a PM primary site, which was associated with a local failure rate of 
19% on D9803. The timing of RT differed in three sequential completed RMS 
studies: IRS-IV (Week 10), D9803 (Week 13), ARST0531 (Week 4). 
Furthermore, in IRS-IV, PM RMS patients with high-risk features were irradiated 
as close after study enrollment as possible. There was no difference in local 
failure rate among PM RMS patients with or without high risk features on IRS-
IV (19%) or D9803 (19%).47 We have therefore chosen to return RT delivery to 
Week 13. This strategy will permit the feasibility evaluation of temsirolimus with 
VAC/VI prior to introducing RT, provide sufficient time for complex RT 
planning, and will allow DPE in selected patients for which DPE is feasible after 
initial response to chemotherapy. RT should be initiated as soon as possible, once 
there is evidence of adequate wound healing. 
 
Occasionally patients present with function-limiting disease such as spinal cord 
compression or cranial nerve palsies. Chemotherapy may be as effective as RT to 
reduce tumor-related symptoms;48 thus, emergency RT may not be necessary. 
Patients for whom emergency RT (prior to Week 13) is planned should not enroll 
on ARST1431. The use of steroids in this regard is permissible. 
 
2.5.5 
Nodal Disease Assessment at Diagnosis 
To reduce loco-regional failure, systematic lymph node sampling (preferably 
using the sentinel node approach) is recommended. Until now, surgical lymph 
node staging has only been required for study eligibility for patients with 
extremity tumors or males > 10 years with paratesticular RMS; ARST0531 also 
recommended biopsy of clinically enlarged nodes. A recent analysis of the 

  
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Surveillance, Epidemiology, and End Results database demonstrated the survival 
benefit with the use of lymph node dissection in paratesticular RMS, although the 
benefit was restricted to those > 10 years old (86% 5 year survival rate with 
dissection versus 64% without, p < 0.009),49 further supporting the importance of 
adequate evaluation of regional lymph nodes in selected patients. On IRS-IV, 
23% of patients had regional lymph node disease (N1), which was an 
independent prognostic factor in patients with ARMS but not in ERMS.50 N1 
status was more common in older patients, those with ARMS, large tumors, and 
tumors at certain anatomic sites (including perineum, retroperitoneum, extremity, 
bladder/prostate, PM, and paratesticular). These data illustrate the importance of 
nodal disease in ARMS. Furthermore, in certain sites such as extremity and body 
wall, clinical positivity of nodal disease underestimated pathological nodal 
involvement. Thus, more attention to nodal disease is warranted. 
 
[F18]-fluorodeoxy-D-glucose-positron emission tomography (FDG-PET) imaging 
could provide a non-invasive alternative to surgical lymph node sampling, 
although the sensitivity of FDG-PET imaging compared to surgical lymph node 
sampling is unknown. ARST1431 will collect FDG-PET assessment of regional 
lymph nodes and pathologic data from surgical lymph node sampling to define 
FDG-PET false negative rate and for refinement of study guidelines in the future. 
Therefore, in addition to the previous requirements and recommendations for 
regional lymph node evaluation, pathological evaluation of clinically uninvolved 
nodes for all patients with ARMS and for all those with clinically involved nodes 
(regardless of histology) is recommended. The definition of “clinically involved” 
nodes is those including the following features: 1) > 1 cm on CT or MRI; OR 
2) FDG avid. Imaging of all potential sites of nodal disease, either by FDG-PET 
or cross sectional imaging, is strongly encouraged since RT is mandatory for 
nodal disease. If nodes are clinically involved, we strongly encourage biopsy in 
order to be confident that RT in fact is warranted. If nodes are clinically involved 
and not biopsied, RT will be delivered to those areas. 
 
For non-paratesticular primary sites, the preferred method of sampling would be 
to use the sentinel technique in order to identify the most likely drainage basin 
for the tumor. If this is not available, random regional nodal sampling should be 
performed. Nodes should either be sampled using excisional biopsy or core 
needle biopsy. Fine needle aspirates are discouraged due to the potential for false 
negatives. 
 
In the current study, the following algorithm will be followed. Note: Nodal 
sampling is MANDATORY for patients with paratesticular disease (if 
age ≥ 10 years) and for patients of any age with extremity tumors, regardless 
of histology. 
 

  
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2.6 
FDG-PET Definitions and Its Utility to Assess Outcome in RMS 
Defining positive versus negative scans remains a challenge, however, assessing interim 
PET using the Deauville criteria (5 point scale)51 have gained validity in adults with 
Hodgkin lymphoma.52,53 In ARST1431, the Deauville criteria will be used to define a 
‘positive’ scan using the primary site of disease. The limitations of using FDG-PET to 
identify at-risk lymph nodes are well appreciated, nonetheless, the more data available to 
help determine whether nodal disease should be biopsied is important for this study. 
Notably, institutional review will be used for decision making as central imaging review 
for decision making will not be performed on ARST1431. 
 
Response to therapy of the primary tumor as defined by change in tumor size, does not 
predict outcome in RMS.54,55 After 8-12 weeks of chemotherapy (with or without RT), 
15-23% of patients with Group III RMS have no response (stable disease). Surprisingly, 
patients with no response after initial therapy have a similar outcome as those with 
complete or partial response. Response at the completion of therapy also fails to predict 
outcome.56 As an alternative to anatomic imaging to define response, changes in 
metabolic activity could be more predictive of outcome. FDG-PET response predicts 
failure-free survival in non-RMS soft tissue sarcoma,57 Ewing sarcoma,58 and 
osteosarcoma.59 Memorial Sloan-Kettering Cancer Center (MSKCC) studied 94 patients 
with RMS who received varying chemotherapy protocols. RT was delivered at a median 
of 15 weeks after initiation of chemotherapy. With 3-year median follow-up, local 
relapse-free survival was improved among post-radiation PET-negative vs PET-positive 
patients: 94% vs 75%, p=0.02.60 A follow up analysis from MSKCC confirmed these 
findings in a larger cohort of RMS patients showing that metabolic response by 18F-FDG 
PET/CT accurately predicted EFS, overall survival, and local control with statistical 
significance.61 However, these results are limited by the relatively small study population, 
heterogeneous treatment, and inclusion of localized and metastatic patients. ARST1431 
 
ERMS –  
Observe 
 
PET Available 
 
No 
 
Yes 
 
N0 
 
N1 
 
PET negative 
 
PET positive 
 
ARMS – 
Encourage biopsy 
 
Encourage 
biopsy 
 
Encourage 
biopsy 

  
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will determine whether response of the primary tumor at Week 9 on FDG-PET correlates 
with EFS within the context of uniform therapy, risk grouping, and a larger prospective 
study.  
 
In ARST0531, FDG-PET was encouraged but not required prior to chemotherapy, 
Week 4, and Week 15 (following RT). Only 25 patients had FDG-PET performed at 
Week 4, precluding a statistical analysis. There was no association with PET response at 
Week 15 and outcome. However, all Week 15 PET evaluations were after RT, and it is 
possible that PET has limited utility following RT. In ARST1431, we will assess PET 
response at Week 9 following chemotherapy but prior to RT, with the potential for better 
correlation with outcome. 
 
2.7 
Fusion Status  
2.7.1 
Fusion Status to Confirm Eligibility 
Patients who are newly diagnosed with biopsy proven RMS of any histologic 
type, except adult-type pleomorphic, are eligible for enrollment on ARST1431. 
ARST1431 will use FOXO1 fusion status rather than histology for study 
eligibility because it is more predictive of outcome as demonstrated by 
two independent analyses.15,16 FOXO1 fusion status must be performed at local 
institutions within the first 3 weeks of study enrollment to confirm eligibility and 
for patients to remain on study. To confirm the anticipated high concordance rate 
between institutional and central FOXO1 fusion status, the first 150 patients 
enrolled on ARST1431 will have FOXO1 fusion status determined by FISH at 
the Biopathology Center (BPC). Patients with ERMS who have distant 
metastases and are found to be FOXO1 positive will be deemed inevaluable and 
removed from study.  
 
Patients with ARMS without distant metastases are eligible if FOXO1 fusion 
positivity is confirmed. Approximately 20% of histologically defined ARMS are 
negative for FOXO1 fusion (nARMS). These patients will continue on protocol 
therapy as randomized unless they are Stage 1/2, Group I-II (completely 
resected) or orbital primary site (Group I-III). This molecularly defined low risk 
population will receive 24 weeks of VAC/VA therapy as per ARST0331 instead 
of the randomized arm of therapy (see Appendix III). On D9803, these low risk 
nARMS patients had 100% EFS but at the cost of a high cumulative 
cyclophosphamide dose (30.8 g/m2).15 Although the rarity of low risk nARMS 
will limit the ability to draw strong statistical conclusions, ARST1431 will be the 
only opportunity to estimate the success of reduced intensity therapy for low risk 
nARMS.  
 
If institutions are not able to comply with local fusion testing, the patient will be 
removed from protocol therapy (but remain on study) for failure to comply with 
protocol requirement. If fusion study is performed but is an indeterminant result, 
the patient will remain on therapy. Finally, if an ARMS patient turns out to be 
FOXO1 fusion negative and low-risk, he/she will be transferred to VAC/VA arm 
(and stop temsirolimus if previously on arm B); we anticipate that 50% of the 
VAC/VA patients will have received 1-3 doses of temsirolimus. 
 
In FISH testing of 417 COG ARMS cases, 315 were translocated or positive 
(79% of 398 evaluable cases), 82 were negative (21% of evaluable cases), 4 were 

  
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equivocal (1% of all cases), and 15 failed hybridization (3.6% of all cases).62 The 
accuracy and reportable ranges were established by comparison to RT-PCR 
results. Of 109 cases deemed positive by RT-PCR, 105 (96%) were also positive 
by FISH and the others were equivocal by FISH (4%). Of 63 cases called 
negative by RT-PCR, 59 (94%) were negative by FISH, 3 (5%) were equivocal 
by FISH, and 1 case was positive by FISH (likely due to a variant translocation 
partner). 
 
2.8 
Maintenance Therapy (Implemented with Amendment #3) 
The duration of therapy has been of interest in the treatment of children with RMS. 
Recently, the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) completed 
a randomized phase 3 trial, with an objective to determine whether the addition of 
maintenance therapy following standard induction therapy and local control improves 
outcome. In EpSSG RMS 2005, patients with disease profiles that are similar to how 
COG defines IR RMS (including patients with non-metastatic alveolar and locally 
advanced embryonal disease) who achieved complete remission following induction 
chemotherapy (with ifosfamide, actinomycin, vincristine, doxorubicin) were randomized 
to receive an additional 6 months of maintenance therapy (n=185) versus no maintenance 
(n = 186).63 Maintenance therapy consisted of continuous daily low dose oral 
cyclophosphamide (CPM) plus weekly IV vinorelbine (on Days 1, 8, and 15 of each 
28-day cycle). The results as presented at ASCO 2018 are described in the table below. 
Addition of maintenance therapy was associated with a statistically significant 
improvement in overall survival. 
 
 
No Maintenance 
Maintenance 
p 
3-year EFS 
(95% CI) 
72.3% 
(65.0-78.3%) 
78.4% 
(71.5-83.8%) 
0.061 
3-year OS 
(95% CI) 
77.4% 
(70.1-83.1%) 
87.3% 
(81.2-91.6%) 
0.011 
 
 
Although there are differences between the EpSSG and COG approaches to RMS 
including differences in backbone therapy and in the precise definitions of ‘IR RMS,’ the 
overall conclusions are important and relevant for all patients with RMS. Additionally, 
the specific question of benefit of maintenance therapy will not be again tested in a 
randomized study. 
 
Furthermore, a recent comparison of similar cohorts of patients showed a lower EFS on 
ARST0531 (CPM = 1.2 g/m2/dose; total cumulative dose = 8.4 g/m2 on VAC/VI therapy) 
compared to D9803 (CPM = 2.2 g/m2/dose; total cumulative dose = 30.8 g/m2 on VAC 
therapy). The reason for the inferior outcome on ARST0531 compared to D9803 is 
uncertain, but may be related to lower cumulative CPM dose.1 A summary of the EFS/OS 
outcome comparison by clinical risk groups is presented below: 
 

  
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Clinical stratum 
4 year EFS 
Log 
rank 
p-value 
4 year OS 
Log 
rank 
p-value 
ARST0531 
D9803 
ARST0531 
D9803 
ERMS, 
Stage 2/3, Group 
III 
65% (55-72%) 
73% (67-78%) 
0.028 
77% (71-83%) 
79% (74-84%) 
0.21 
ARMS, Stage 1 
or Group I 
69% (55-84%) 
76% (65-87%) 
0.51 
85% (74-97%) 
90% (82-97%) 
0.77 
ARMS, Stage 2/3 
and Group II/III 
51% (42-60%) 
58% (50-66%) 
0.14 
62% (53-71%) 
71% (63-78%) 
0.13 
 
The COG STS Committee has given serious consideration to these two observations. 
There is substantive limitation to the retrospective non-randomized comparison of D9803 
to ARST0531, and it remains uncertain whether the difference in outcomes seen on 
D9803 and ARST0531 is indeed due solely to the higher cumulative CPM dose. 
Moreover, increased frequency of events on ARST0531 is predominantly local 
recurrence and is most pronounced in patients with tumors > 5 cm at diagnosis.  
  
The STS Committee has taken into consideration the following: 1) the role of 
temsirolimus in intermediate risk RMS remains an important question to answer; 
2) patients with tumors > 5 cm will receive a higher dose of radiation on ARST1431 
compared to ARST0531 (59.4 vs 50.4 Gy); 3) there is significantly increased acute and 
long-term toxicities associated with higher dose CPM (as used in D9803); and 
4) maintenance chemotherapy as used by EpSSG offers a more modest increase in 
cumulative CPM exposure (4.2 g/m2) and has been shown to improve overall survival in 
a similar population of patients with RMS. 
  
Taking all the above into account, ARST1431 will incorporate maintenance 
chemotherapy as a strategy to improve outcome without exposing all intermediate risk 
patients to a substantially higher cumulative CPM dose. Patients who receive either 
VAC/VI alone or VAC/VI plus temsirolimus will continue to receive an additional 
6 months of maintenance therapy beginning with Amendment #3. 
 
The toxicity observed in EpSSG RMS 2005 with maintenance therapy was minimal and 
treatment was delivered in an ambulatory setting. 
 
Patients on Regimen C will not receive maintenance therapy. 
 
2.9 
Biological Correlatives 
2.9.1 
Comparing Outcome Among Patients with Translocation Positive Disease: PAX3 
vs. PAX7 
The vast majority of ARMS cases are PAX3-FOXO1 or PAX7-FOXO1 
translocation positive.16,64 Previous reports suggest that for patients with 
metastatic disease, presence of a PAX7-FOXO1 fusion transcript may confer a 
more favorable prognosis than a PAX3-FOXO1 transcript. Conflicting reports 
exist, however, and there is currently insufficient data to base risk stratification 
on specific fusion type. We will compare the outcome of patients based on their 

  
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FOXO1 partner, by evaluating PAX3 vs. PAX7 in all submitted tumor specimens 
found to be FOXO1 fusion positive. 
 
Rare cases of fusion positive ARMS involve variant gene partners, ie. 
PAX3-NCOA1, PAX3-NCOA2, PAX3-FOXO4 (AFX), and FGFR1-FOXO1. 
Fusion negative ARMS will be further examined for the presence of one of these 
variant gene fusions using a combination of IHC and in depth fluorescence in situ 
hybridization (FISH) analysis. Of note, if a patient with fusion negative ARMS is 
found to have one of these uncommon translocations, that patient will be 
considered a fusion negative case since the results will not be available in real-
time. 
 
2.9.2 
Assessing Circulating Tumor DNA in Patients with Intermediate Risk RMS 
Radiographic response to therapy is unable to predict outcome in RMS, and so, 
alternative approaches to performing response-based stratification are needed. 
One appealing alternative includes minimal residual disease testing by detection, 
quantification, and serial tracking of circulating tumor DNA (ctDNA), also 
known as liquid biopsy, obtained from peripheral blood draws. ctDNA 
technologies have demonstrated superior rates of detection and quantification 
compared to assays for circulating tumor cells.65 Furthermore, ctDNA can be 
reliably extracted from plasma using commercially available kits.  
 
ctDNA from patients with solid tumors has been used to assess disease burden, 
track disease response to therapy, identify clonal evolution, and predict relapse 
after remission.65,66 However, the application of ctDNA technologies has yet to 
be applied prospectively in pediatric RMS. In ARST1431, we will collect serial 
plasma samples from patients to quantify ctDNA at diagnosis and during therapy. 
No prior data regarding frequency of ctDNA in patients with RMS at diagnosis is 
available. Further, no prior information on change in ctDNA is available from 
prior studies to assess response to therapy, and the timecourse of decline in 
ctDNA in response to therapy is unknown.   
 
Since FOXO1 translocations are never present in the germline, detection of any 
FOXO1 in plasma guarantees that it represents tumor DNA. FOXO1 negative 
RMS, in contrast, are driven by oncogenic single-nucleotide variants in a number 
of genes participating in tyrosine kinase signaling cascades.67 Approaches to 
developing a liquid biopsy assay for FOXO1 fusion negative RMS require the 
survey of several proto-oncogenes, distinguishing somatic from germline 
variants, and/or detecting somatic copy number changes that are frequent in these 
tumors.67 In this study, multiple approaches will be applied to detect ctDNA from 
blood samples of patients with FOXO1 translocated tumors as well as patients 
with FOXO1 fusion negative disease. 
 
 
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 

  
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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 
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 Cancer Trials Support Unit (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. For CTEP and Division of Cancer Prevention (DCP) studies open 
to the National Clinical Trials Network (NCTN) and NCI Community Oncology 
Research Program (NCORP) Research Bases after March 1, 2019, all U.S.-based 
sites must be members of the NCI Central Institutional Review Board (NCI 
CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will 
continue to be accepted for studies that are not reviewed by the CIRB, or if the 
study was previously open at the site under the local IRB. International sites 
should continue to submit Research Ethics Board (REB) approval to the CTSU 
Regulatory Office following country-specific regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent 
to open the study locally. The NCI CIRB’s approval of the SSW is automatically 
communicated to the CTSU Regulatory Office, but sites are required to contact 
the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. 
Site preferences can be set at the network or protocol level. Questions about 
establishing site preferences can be addressed to the CTSU Regulatory Office by 
email or calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 

  
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Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
x 
Local IRB documentation; 
x 
IRB-signed CTSU IRB Certification Form; and/or 
x 
Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on 
the IRB/REB approval) must meet the following criteria in order for the 
processing of the IRB/REB approval record to be completed: 
x 
Holds an active CTEP status; 
x 
Rostered at the site on the IRB/REB approval (applies to US and 
Canadian sites only) and on at least one participating roster; 
x 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
x 
Includes the IRB number of the IRB providing approval in the Form 
FDA 1572 in the RCR profile; and 
x 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or 
a Participating Organization (PO); and 
x 
Compliance with all protocol-specific requirements (PSRs). 
 
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. 
 
3.1.3 
Reservation Requirements 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps below. Reservations may be obtained 24 hours a day 
through the Oncology Patient Enrollment Network (OPEN) system.  
 
Patient enrollment for this study will be facilitated using the Slot Reservation 
System in conjunction with the registration system in OPEN. Prior to discussing 
protocol entry with the patient, all site staff must use the CTSU OPEN Slot 
Reservation System to ensure that a slot on the protocol is available to the 
patient. Once a slot reservation confirmation is obtained, site staff may then 
proceed to enroll the patient to this study.  

  
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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’. 
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 ‘Slot Reservation Site User Guide’ posted under the ‘Help’ tab 
in OPEN for detailed instructions:  
https://www.ctsu.org/open/Site_Resources/Training/Users_Manual/CTSU-
OPEN-SlotReservationSiteUserGuide.pdf 
 
3.1.4 
Patient Enrollment 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration 
system available on a 24/7 basis. OPEN is integrated with CTSU regulatory and 
roster data and with the LPOs registration/randomization systems or the 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient 
enrollment data in NCI’s clinical data management system, Medidata Rave. 
 
Requirements for OPEN access:   
x 
A valid CTEP-IAM account; 
x 
To perform enrollments or request slot reservations: Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 
with the role of Registrar. Registrars must hold a minimum of an 
Associate Plus (AP) registration type; 
x 
If a Delegation of Tasks Log (DTL) is required for the study, the 
registrars must hold the OPEN Registrar task on the DTL for the site; 
and 
x 
Have an approved site registration for the protocol prior to patient 
enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the 
treating, crediting, consenting, drug shipment (IVR only), or receiving 
investigator for a patient transfer in OPEN, the IVR or NPIVR must list the IRB 
number used on the site’s IRB approval on their Form FDA 1572 in RCR. If a 
DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
 

  
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Prior to accessing OPEN, site staff should verify the following: 
x 
Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
x 
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. You may print this confirmation for your 
records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU 
members’ website. Further instructional information is in the OPEN section of 
the CTSU website at https://www.ctsu.org or https://open.ctsu.org. For any 
additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
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 must start protocol therapy within 42 days from the date of collection of 
the material that establishes the diagnosis of RMS. Patients who fail to begin 
therapy within 42 days of the procedure which establishes diagnosis will be 
removed from protocol therapy per Section 8.1. 
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
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 by ground 
transportation. Shipping will take 3-5 business days.  
 
The Kit Management System can be accessed via the following link: 
https://ricapps.nationwidechildrens.org/KitManagement/Auth/Login. 
You must select ARST1431 as the protocol when ordering Streck tubes for 
ARST1431 patients.  
 
3.1.6 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study.  
 
3.1.7 
Randomization 
Randomization will take place at the time a patient is enrolled via OPEN. The 
treatment will be randomly assigned based on the statistical design of the trial.  
 

  
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3.1.8 
Callback 
Following randomization, if a patient is found to be eligible for Regimen C (see 
Section 3.3.2) they will require consent and callback. Callback, performed in 
OPEN as a Step 2 Registration, should be submitted for eligible subjects who 
consent to a new treatment regimen after initial randomization. 
 
3.1.9 
Emergent RT Therapy 
Patients for whom emergency RT (prior to Week 13) is planned should not enroll 
on ARST1431. The use of steroids in this regard is permissible. 
 
3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived. 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 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC 
with differential, bilirubin 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 studies, if applicable, must be obtained within 4 weeks 
prior to start of protocol therapy (repeat the tumor imaging if necessary). 
 
See Section 4.0 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Age 
Feasibility Phase: Patients must be < 21 years of age at the time of enrollment. 
Please note: the feasibility phase is complete, effective with Amendment #1.  
 
Efficacy Phase: 
Patients must be ≤ 40 years of age at the time of enrollment. 
 
3.2.2 
Diagnosis 
Patients with newly diagnosed RMS of any subtype, except adult-type 
pleomorphic, based upon institutional histopathologic classification, are eligible 
to enroll on the study based upon Stage, Group, and age, as below.  
 
RMS types included under ERMS include those classified in the 
1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS 
(classic, spindle cell, and botryoid variants), which are reclassified in the 
2013 WHO Classification as ERMS (classic, dense and botryoid variants) and 
spindle cell / sclerosing RMS (encompassing the historical spindle cell ERMS 
variant and the newly recognized sclerosing RMS variant). Classification of 

  
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ARMS in the 2013 WHO Classification is the same as in the ICR and includes 
classic and solid variants. 
 
x
ERMS 
x
Stage 1, Group III (non-orbit) 
x
Stage 3, Group I/II 
x
Stage 2/3, Group III 
x
Stage 4, Group IV, < 10 years old 
 
x
ARMS: Stages 1-3, Groups I-III 
 
3.2.3 
Specimen Submission 
Patients must have sufficient tissue available for the required biology study (see 
Section 15.0). 
 
3.2.4 
Performance Level 
Lansky performance status score ≥ 50 for patients ≤ 16 years of age.  
Karnofsky performance status score ≥ 50 for patients >16 years of age. 
 
3.2.5 
Organ Function Requirements 
3.2.5.1 
Adequate bone marrow function defined as:  
- 
Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- 
Platelet count ≥ 75,000/μL  
 
3.2.5.2 
Adequate renal function defined as: 
- 
Creatinine clearance or radioisotope GFR t 70 mL/min/1.73 m2 or 
- 
A serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
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 GFR68 utilizing child length and stature 
data published by the CDC. 
 
Patients with an elevated serum creatinine due to obstructive 
hydronephrosis secondary to tumor are still eligible. However, patients 
with urinary tract obstruction by tumor must have unimpeded urinary 
flow established via diversion (ie. percutaneous nephrostomies or ureteric 
stents) of the urinary tract. 
 

  
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3.2.5.3 
Adequate liver function defined as: 
- 
Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
3.2.6 
Exclusion Criteria 
3.2.6.1 
Patients who have previously received temsirolimus, another mTOR 
inhibitor, or any other investigational agent. 
 
3.2.6.2 
Patients who have received any chemotherapy (excluding steroids) 
and/or RT prior to this enrollment. 
 
3.2.6.3 
Patients with uncontrolled hyperglycemia  
 
3.2.6.4 
Patients with uncontrolled hyperlipidemia. 
 
3.2.6.5 
Sexually active patients of reproductive potential who have not agreed 
to use an effective contraceptive method for the duration of their study 
participation and for at least 3 months after treatment is completed.  
 
3.2.6.6 
Female patients who are pregnant are not eligible since fetal toxicities 
or teratogenic effects have been noted for several of the study drugs. 
Note: A pregnancy test is required for female patients of childbearing 
potential prior to study entry. 
 
3.2.6.7 
Lactating females who plan to breastfeed their infants are not eligible. 
 
Please see Section 4.1.3 for the concomitant therapy restrictions for patients 
during treatment. 
 
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. 
 
3.3 
FOXO1 Fusion Status 
3.3.1 
All patients will undergo institutional pathology review and FOXO1 fusion 
determination regardless of histology. If institutions are not able to comply with 
local fusion testing, the patient will be removed from protocol therapy (but 
remain on study) for failure to comply with protocol requirement. If fusion study 
is performed but the result is indeterminant, the patient will remain on therapy. 
 
FOXO1 status results must be available by Week 3 (Day 21) of therapy. 
Every effort should be made to SUBMIT FOXO1 results as an upload to RAVE 
soon as they are available. 
 
Patients will be eligible to remain on protocol therapy based upon Stage, Group, 
and age: (See Appendix III and Appendix IV for Stage and Grouping) 

  
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x
FOXO1 fusion negative:  
x
Stage 1, Group III (non-orbit) 
x
Stage 3, Group I/II  
x
Stage 2/3, Group III 
x
Stage 4, Group IV, < 10 years old 
x
FOXO1 fusion positive: Stage 1-3, Group I-III 
 
Note:  FOXO1 fusion status must be performed at local institutions. To confirm the 
anticipated high concordance rate between institutional and central FOXO1 fusion 
status, the first 150 patients enrolled on ARST1431 were to have FOXO1 fusion 
status determined by FISH at the Biopathology Center. Centrally determined FOXO1 
fusion status results will not be returned to the institution. 
 
As of August 24, 2019, 92 evaluable specimens have been analyzed at the 
Biopathology Center (BPC), of which 91 had concordant FOXO1 fusion status 
determined by FISH with local institutions, for an overall concordance rate of 98.9%. 
We will no longer be evaluating FOXO1 fusion status at the BPC as of 
Amendment #4. PAX3 and PAX7 evaluations will continue.  
 
3.3.2 
Patients with institutional histologic classification of ARMS but FOXO1 fusion 
negative with the following Stage and Group can remain on study but will 
receive VAC/VA therapy on Regimen C instead of the previously assigned 
treatment regimen. Patient consent is required to transfer to Regimen C. See 
Section 3.1.8 for callback details: 
x
Stage 1, Group I/II 
x
Stage 1, Group III (orbit) 
x
Stage 2, Group I/II 
 

  
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4.0 
TREATMENT PLAN 
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 
Prior to randomization, a feasibility phase will be conducted where all patients will be 
non-randomly assigned to receive VAC/VI plus temsirolimus. Once the appropriate dose 
is selected, the study will be amended and all subsequent patients will be randomized at 
study entry to receive either VAC/VI alone (Regimen A) or VAC/VI plus temsirolimus 
(Regimen B). Patients who had received the appropriate dose selected in the feasibility 
phase will be included in the analysis of the efficacy phase. The feasibility phase is 
complete, effective with Amendment #1A. Dose Level 1 (temsirolimus 15 mg/m2/day 
on Days 1, 8, 15) was found to be the safe dose. 
 
NOTE: REGIMEN C: Patients with an institutional histopathologic classification of 
ARMS that is FOXO1 fusion negative with the following Stage and Group as 
outlined below will receive VAC/VA therapy on Regimen C instead of the 
previously assigned treatment arm. If an eligible patient refuses treatment on 
Regimen C they will be removed from protocol therapy. 
• 
Stage 1, Group I/II 
• 
Stage 1, Group III (orbit) 
• 
Stage 2, Group I/II 
 
Transfer to Regimen C requires consent and callback (see Section 3.1.8). 
Eligible patients should be transferred as soon as the FOXO1 fusion result is 
obtained and prior to the start of Week 4 of therapy (see Section 4.5 for 
Regimen C treatment details).  
 
Prior to Amendment #3, the treatment duration was 42 weeks (VAC/VI with or without 
temsirolimus) for both Regimens A and B, with RT delivered at Week 13. Beginning 
with Amendment #3, the treatment duration will be extended to 66 weeks for both 
Regimens A and B (42 weeks of VAC/VI with or without temsirolimus, and 24 weeks of 
maintenance), with RT delivered at Week 13. The treatment duration for Regimen C will 
not change. 
 
For patients on Regimen B, temsirolimus will be held during and for 2 weeks 
following RT. A higher dose of boost RT will be given to patients with a large tumor at 
diagnosis (> 5 cm) who are not in CR at Week 9. Delayed primary excision (DPE) will be 
permitted in selected non-parameningeal patients with the potential to achieve gross total 
resection with minimal morbidity and without loss of function. In order to permit enough 
time for local control decision making, imaging assessment of CR will be made at 
Week 9. 
 

  
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Note: Multi-disciplinary consultation and discussion with radiation and surgical 
oncology is required for all patients prior to initiating any chemotherapy and again 
following Week 9 evaluations. 
 
FOXO1 Fusion Status 
All patients will undergo institutional pathology review and FOXO1 fusion 
determination. FOXO1 status results must be available by Week 3 (Day 21) of 
therapy. Failure to obtain FOXO1 status by Day 21 of therapy will result in removal 
from protocol therapy. Patients with FOXO1 fusion positive and Group IV/Stage 4 
disease will be removed from protocol therapy. Institutional PAX3 vs. PAX7 
determination is not required.  
 
Special Note for Patients ≤ 24 Months Old 
The long-term morbidity of RT or aggressive surgery for very young (≤ 24 months old) 
children makes appropriate local control challenging. Many clinicians are unwilling to 
follow standard local control guidelines for very young children. We strongly encourage 
adherence to standard local control guidelines for children ≤ 24 months old but 
administered dose is at the discretion of the local radiation oncologist. Documentation of 
rationale for dose and field of RT must be documented if different than protocol 
guidelines.  
 
Week 9 Evaluation: Assessment of CR 
TWO methods of defining CR are required to confirm CR at Week 9 that will warrant a 
dose reduction in RT. At Week 9, CR must be present on cross sectional imaging (CT or 
MRI) that has NO measurable tumor, AND the patient must have one of the following: 1) 
negative FDG-PET or 2) biopsy of residual disease to confirm no viable tumor. FDG-
PET is strongly encouraged, but not mandatory, prior to starting therapy and at Week 9 
and will be utilized for assessing nodal involvement, response to induction chemotherapy 
and determination of RT fields. (See Section 17.0 for details.) For those in whom FDG-
PET is not performed at diagnosis and Week 9, a BIOPSY of residual disease/tumor 
bed is required to confirm CR at Week 9. Central imaging review will not be 
conducted. 
 
Please note: Lymph node (LN) sampling is required for all patients with extremity 
primaries (preferably using the sentinel node technique) and males ≥ 10 years of age with 
paratesticular primaries, irrespective of whether the nodes are clinically involved or not 
and regardless of histology/FOXO1 status. Note that tumors arising in the shoulder and 
hip girdle are considered to be extremity tumors and are required to have LN sampling. 
LN sampling is also strongly encouraged in all patients with ARMS and in those with 
ERMS and clinically suspicious nodes on imaging. 
 
Delayed Primary Excision (DPE) 
Following the first evaluation at Week 9, patients may be considered for DPE for select 
non-PM primary sites when GTR can be easily performed with minimal morbidity or loss 
of function and with minimal disruption to the overall treatment scheme. If DPE is being 
considered, discussions with radiation and surgical oncology should be started 
immediately following Week 9 evaluation. Adequate margins of uninvolved tissue are 
required unless this involves sacrifice of normal tissue that would result in an 
unacceptable loss of function, form, or is not technically feasible. Debulking operations 
are absolutely discouraged as they may cause harm, and will not result in reduction 
of RT dose. Additional CT or MRI imaging will be necessary as soon as possible 

  
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following DPE to confirm GTR or to indicate residual disease that would require a full 
dose radiotherapy boost to 50.4 Gy or 59.4 Gy based on initial tumor size. For patients 
who do achieve GTR and are in CR, the dose of RT will be reduced. (See Section 17.0 
for details.) 
 
DPE should be planned as soon as possible following Week 9 evaluation to avoid 
potential delays to RT. For those considering DPE, hold chemotherapy and resume where 
you left off. If doses of specific agents (ie. temsirolimus) need to be held in the best 
interest of the patient, they will be omitted, and not made up at later dates. For those 
enrolled on Regimen B, temsirolimus must be held 2 weeks prior to and 1 week 
following DPE. 
 
Sperm Banking and Fertility Consult 
Sperm cryopreservation discussions with all post-pubertal boys receiving RMS therapy 
are strongly encouraged as per the ASCO guidelines.69 
 
4.1.1 
Feasibility Phase 
The feasibility phase is complete, effective with Amendment #1A. Dose 
Level 1 (temsirolimus 15 mg/m2/day on Days 1, 8, 15) was found to be the safe 
dose. The feasibility of combining temsirolimus with VAC/VI will be assessed 
prior to expanding to the efficacy phase. Initially, 10 eligible patients < 21 years 
of age will be non-randomly assigned to receive VAC/VI plus temsirolimus. 
Feasibility will be assessed during treatment Weeks 1-12. Accrual will be 
suspended during the assessment to determine feasibility (see table below and 
Section 9.0). 
 
Dose Level 
Temsirolimus Dose 
and Schedule 
 
 
Dose 1 
15 mg/m2 IV  
Days 1,8,15  
of each cycle 
Enroll 10 patients to 
complete Weeks 1-12. 
Suspend accrual until all 10 
patients evaluated. 
Proceed to Efficacy Phase if < than 4/10 subjects 
experience a non-hematological DLT, and the median 
duration of the first 12 weeks of therapy is < 16 weeks, 
otherwise, proceed to dose level 0 
Dose 0 
10 mg/m2 IV  
Days 1,8,15 
of each cycle 
Enroll 10 patients to 
complete Weeks 1-12. 
Suspend accrual until all 
10 patients evaluated. 
Proceed to Efficacy Phase if < than 4/10 subjects 
experience a non-hematological DLT, and the median 
duration of the first 12 weeks of therapy is < 16 weeks, 
otherwise, proceed to dose level -1 
Dose -1 
10 mg/m2 IV  
Days 1, 8 
of each cycle 
Enroll 10 patients to 
complete Weeks 1-12. 
Suspend accrual until all 
10 patients evaluated. 
Proceed to Efficacy Phase if < than 4/10 subjects 
experience a non-hematological DLT, and the median 
duration of the first 12 weeks of therapy is < 16 weeks, 
otherwise the study is not feasible.  
Note: See Section 5.1 for DLT definition. 
 
4.1.2 
Efficacy Phase 
Patients will be randomly assigned to Regimen A or B in which the only 
difference is the addition of temsirolimus. With Amendment #3, following 
completion of 42 weeks of therapy, all patients in Regimen A or B will receive 
24 weeks of maintenance therapy. See Section 4.1 regarding Regimen C. 

  
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4.1.2.1 Regimen A 
Patients will receive VAC/VI only for a total of 42 weeks, with primary 
site RT at Week 13, followed by 24 weeks of maintenance therapy. 
Metastatic site RT will occur at Week 43. 
 
Cycle 
1 
2 
3 
4 
Week 
1% 
2 
3 
4% 
5 
6 
7% 
8 
9** 
10 
11 
12& 
 
VAC 
V 
V 
VI 
V 
V 
VAC 
V 
V 
Eval. 
VI 
V 
V 
 
Cycle 
5 
6 
7 
8 
9 
10 
Week 
13 
14 
15 
16 
17 
18 
19% 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
 
VAC 
 
 
VI 
V 
 
VI 
V 
 
VAC 
V 
V 
VI 
V 
 
VAC 
 
Eval. 
 
Radiation Therapy*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 
11 
12 
13 
14 
Week 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42% 
 
VI 
V 
V 
VAC 
 
 
VI 
V 
 
VAC 
 
Eval. 
 
Cycle 
M1 
M2 
M3 
Week 
43^ 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
Eval. 
 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
 
Cycle 
M4 
M5 
M6 
 
Week 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67% 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
 
End of 
therapy eval. 
 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
 
 
% ctDNA sample, see Section 15.2  
**Consideration of DPE, if applicable 
& For patients who undergo DPE, post-operative CT or MRI is required prior to RT  
***See Section 17.0 for RT guidelines. Patients with Clinical Group I, FOXO1 negative tumors or Clinical 
Group I, FOXO1 indeterminate tumors will not receive radiotherapy. 
^ Metastatic sites should be treated with radiotherapy at the completion of VAC/VI chemotherapy. See 
Section 17.0. 
 
 
Drug 
Dosing Parameter 
Dose 
VAC/VI 
V 
VinCRIStine 
 0.6 m2 BSA 
BSA-based dosing, see dosing table 
t 0.6 m2 BSA 
1.5 mg/m2 IV (maximum dose 2 mg) See TDMs for 
days given 
A 
DACTINomycin 
< 14 kg 
Weight-based dosing, see dosing table 
≥ 14 kg 
0.05 mg/kg IV Day 1 (maximum dose 2.5 mg)  
C 
Cyclophosphamide 
(IV) 
 0.6 m2 BSA 
BSA-based dosing, see dosing table  
t 0.6 m2 BSA 
1200 mg/m2 IV Day 1 
I 
Irinotecan 
 0.6 m2 BSA 
BSA-based dosing, see dosing table  
t 0.6 m2 BSA 
50 mg/m2 IV Days 1-5 (maximum dose 100 mg) 
Maintenance (implemented with Amendment #3) 
VINO 
Vinorelbine 
 0.6 m2 BSA 
BSA-based dosing, see dosing table  
t 0.6 m2 BSA 
25 mg/m2 IV Days 1, 8, 15 

  
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CPO 
Cyclophosphamide 
(oral) 
 
25 mg/m2 PO once daily Days 1-28 
Mesna and fluids will be used with IV Cyclophosphamide 
Neutrophil growth factor will be used with VAC. See Appendix VII (Supportive Care) for specific directions. 
If there is an age change during treatment, use the new appropriate age dosing in the next cycle 
 
4.1.2.2 Regimen B 
Patients will receive VAC/VI plus temsirolimus for a total of 42 weeks, 
with primary site RT at Week 13, followed by 24 weeks of maintenance 
therapy. Metastatic site RT will occur at Week 43. Temsirolimus will be 
held during RT and restarted 2 weeks following completion of RT and 
once mucositis has resolved to ≤ Grade 1. The dose of RT will be the 
same in Regimen A and Regimen B. 
 
Temsirolimus must be held for 1 week following any minor surgical 
procedures (insertion of central venous catheters, gastrostomy tubes, 
biopsies) and 2 weeks prior to any major surgical procedures (tumor 
resection either initially or at DPE). Temsirolimus should be held for a 
minimum of 1 week following major surgery and may be reinitiated after 
a surgical procedure at the discretion of the treating physician/surgeon 
(all wound and surgical complications should not be greater than Grade 1 
according to CTCAE version 5.0). 
 
Cycle 
1 
2 
3 
4 
Week 
1% 
2 
3 
4% 
5 
6 
7% 
8 
9** 
10 
11 
12& 
 
VAC 
V 
V 
VI 
V 
V 
VAC 
V 
V 
Eval 
VI 
V 
V 
 
T 
T 
T 
T 
T 
T 
T 
T 
T 
 
T 
T 
T 
 
Cycle 
5 
6 
7 
8 
9 
10 
Week 
13 
14 
15 
16 
17 
18 
19% 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
 
VAC 
 
 
VI 
V 
 
VI 
V 
 
VAC 
V 
V 
VI 
V 
 
VAC 
 
Eval. 
 
 
 
 
 
 
 
 
 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
 
Radiation Therapy*** 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 
11 
12 
13 
14 
Week 
31 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42% 
 
VI 
V 
V 
VAC 
 
 
VI 
V 
 
VAC 
 
Eval. 
 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
T 
 
Cycle 
M1 
M2 
M3 
Week 
43^ 
44 
45 
46 
47 
48 
49 
50 
51 
52 
53 
54 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
Eval. 
 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
 
Cycle 
M4 
M5 
M6 
 
Week 
55 
56 
57 
58 
59 
60 
61 
62 
63 
64 
65 
66 
67% 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
 
VINO 
VINO 
VINO 
 
End of 
therapy eval. 
 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
CPO 
 
 
%ctDNA sample, see Section 15.2 
**Consideration of DPE, if applicable 

  
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& For patients who undergo DPE, post-operative CT or MRI is required prior to RT  
***See Section 17.0 for RT guidelines. Patients with Clinical Group I, FOXO1 negative tumors or Clinical 
Group I, FOXO1 indeterminate tumors will not receive radiotherapy. 
^ Metastatic sites should be treated with radiotherapy at the completion of VAC/VI chemotherapy. See 
Section 17.0. 
 
Please note: The schema above represents temsirolimus Dose Levels 1 and 0 only, Dose Level -1 is 
administered on Days 1 and 8 only, not on Day 15 (see Section 5.2).  
 
 
Drug 
Dosing Parameters 
Dose 
VAC/VI 
V 
VinCRIStine 
 0.6 m2 BSA 
BSA-based dosing, see dosing table 
t 0.6 m2 BSA 
1.5 mg/m2 IV (maximum dose 2 mg), see TDMs for 
days given 
A 
DACTINomycin 
< 14 kg 
Weight-based dosing, see dosing table 
≥ 14 kg 
0.05 mg/kg IV Day 1 (maximum dose 2.5 mg)  
C 
Cyclophosphamide 
(IV) 
 0.6 m2 BSA 
BSA-based dosing, see dosing table  
t 0.6 m2 BSA 
1200 mg/m2 IV Day 1 
I 
Irinotecan 
 0.6 m2 BSA 
BSA-based dosing, see dosing table  
t 0.6 m2 BSA 
50 mg/m2 IV Days 1-5 (maximum dose 100 mg) 
T 
Temsirolimus 
< 10 kg 
0.5 mg/kg IV Day 1 of each week during Weeks 1-12 
and Weeks 21-42 
No temsirolimus is administered during RT and for 
2 weeks after (see Section 4.1.2.2) 
≥ 10 kg 
15 mg/m2 IV (maximum dose 25 mg) Day 1 of each 
week during Weeks 1-12 and Weeks 21-42 
No temsirolimus is administered during RT and for 
2 weeks after (see Section 4.1.2.2) 
Maintenance (implemented with Amendment #3) 
VINO 
Vinorelbine 
 0.6 m2 BSA 
BSA-based dosing, see dosing table  
t 0.6 m2 BSA 
25 mg/m2 IV Days 1, 8, 15 
CPO 
Cyclophosphamide 
(oral) 
 
25 mg/m2 PO once daily Days 1-28 
Mesna and fluids will be used with IV Cyclophosphamide 
Neutrophil growth factor will be used with VAC. See Appendix VII for specific directions. 
If there is an age change during treatment, use the new appropriate age dosing in the next cycle 
 
4.1.3 
Concomitant Therapy  
Temsirolimus, vinCRIStine, vinorelbine, and irinotecan are sensitive substrates 
of CYP450 3A4 isozyme. The use of moderate to strong CYP3A4 inhibitors and 
inducers should be avoided within 7 days of study initiation and for the duration 
of the study (see Appendix VIII for more information on CYP3A4 inducers and 
inihibitors; please consult frequently updated medical references for a full list of 
CYP3A4 inducers and inhibitors). The use of systemic corticosteroids (eg., 
dexamethasone) is allowed on this study. Single aprepitant or fosaprepitant doses 
do not substantially inhibit CYP3A4 and are permitted on this study. Longer 
multi-day apprepitant regimens may cause moderate CYP3A4 inhibition and 
should be avoided. 
 
In addition, temsirolimus and irinotecan are substrates for P-glycoprotein (p-gp). 
The use of p-gp inhibitors (eg, amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, 

  
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quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, verapamil) or 
inducers (eg, carbamazepine, rifampin, saquinavir, tipranavir) should be avoided 
for the duration of the study.  
 
Concomitant use of temsirolimus and angiotensin-converting enzyme inhibitors 
(ACEIs) and/or calcium channel blockers (eg. amlodipine) may increase the risk 
of angioedema. Concurrent therapy with ACEIs and calcium channel blockers 
should be avoided in patients receiving temsirolimus.  
 
4.1.4 
Supportive Care Guidelines 
Please see Appendix VII for protocol-specific supportive care guidelines. In 
addition, for COG Supportive Care Guidelines see: 
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
Note: See the Parenteral Chemotherapy Administration Guidelines (CAG) for children on 
the 
COG 
website 
at: 
https://www.cogmembers.org/_files/disc/Pharmacy/
ChemoAdminGuidelines.pdf for special precautions and suggestions for patient 
monitoring during therapy. As applicable, also see the CAG for suggestions on hydration, 
or hydrate according to institutional guidelines. 

  
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Regimen A (VAC/VI Only) Cycles 1-4   
4.2 
Regimen A (VAC/VI Only) 
4.2.1 
ARST1431 Regimen A Cycles 1-4 
This therapy delivery map (TDM) relates to Cycles 1-4 of therapy (Weeks 1-12). Each 
cycle lasts 21 days (3 weeks).  
____________________________  
________________________ 
Patient COG ID number  
 
 
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This course 
lasts 84 days and the TDM is described on two pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of each week. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg.  
Administer before Irinotecan on days when both drugs are given 
DACTINomycin (DACT) 
Slow IV Push over 1-5 minutes 
or IV infusion over 
10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing 
table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 1 and 7. 
Maximum dose: 2.5 mg 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
 IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 1 and 7. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 50 mg/m2/dose 
Days 1 through 5 of 
Weeks 4 and 10. 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for 
patients < 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be continued 
without regard to VCR. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care 
Guidelines. 
 
Cycle 1 (Week 1): Ht_________cm 
Wt________kg 
BSA_________m2  
 
Cycle 2 (Week 4): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Cycle 3 (Week 7): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 4 (Week 10): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
1 
1 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-p 
 
 
 
2 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
 
3 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
2 
4 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c, p 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
5 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
 
6 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
3 
7 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c, p 
 
 
 
8 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
 
9 
1 
_____mg 
 
 
 
 
 
 
a, b, f-i 
 
 
4 
10 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
11 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
 
12 
1 
_____mg 
 
 
 
 
 
 
b, f 
 
 
 
 
 
Continue to Cycle 5 (Week 13) therapy if all criteria to start the next cycle have been met.  
 
Page 1 of 2 

  
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Regimen A (VAC/VI Only) Cycles 1-4   
4.2.2 
Required Observations Prior to and During Cycles 1-4 
NOTE: All patients will undergo institutional pathology review and FOXO1 fusion determination. 
FOXO1 status results must be available by Week 3 (Day 21) of therapy and submitted as an 
upload to RAVE as soon as possible. If patients FOXO1 status is FOXO1 fusion positive with 
Group IV/Stage 4 disease, they will be removed from protocol therapy (for example, a patient 
greater than 10 years of age with metastatic disease who is found to be FOXO1 fusion positive). 
Patients eligible to transfer to Regimen C must do so prior to the start of Week 4 of therapy (see 
Section 4.1). 
All baseline radiology reports should be submitted to IROC Rhode Island at the time of 
study enrollment (see Section 16.2.1). 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets 
c. 
Total bilirubin, ALT, creatinine. 
d. Bilateral bone marrow biopsy (not required for patients with ERMS and clinically uninvolved nodes, 
and no lung or bone metastases). Repeat bone marrow examinations are only required in patients who 
had positive bone marrow disease at diagnosis. 
e. 
Cerebrospinal fluid cytology for parameningeal tumors, including orbital site with parameningeal 
extension and paraspinal tumors with dural involvement. 
f. 
MR primary site and regional nodal basin, CT may be considered for intra-abdominal primary. See 
Section 16.0. CT may be used for regional nodes. Post-operative imaging is required at Week 12 
(prior to RT) only for patients who undergo DPE. 
g. CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. May be omitted for 
patients with ERMS and clinically uninvolved nodes. Repeat staging CT chest is required at Week 9 
only for those patients who had lung metastases at diagnosis. See Section 16.0. 
h. FDG-PET with diagnostic quality CT. For patients who consented to the FDG-PET part of the study. 
See Section 16.0. 
i. 
Bone scan. May be omitted if PET-CT is performed. May be omitted for patients with ERMS and 
clinically uninvolved nodes and no lung metastases. Only needs to be repeated at Week 9 in those 
patients who had bone metastases at diagnosis. See Section 16.0. 
j. 
CT or MRI of regional nodal basin. Week 9. May omit if PET-CT is done. Perform in those patients 
who had clinically involved nodes at diagnosis and in all patients with extremity tumors and those with 
paratesticular tumors who are ≥ 10 years of age. See Section 16.0. 
k. Lymph node biopsy. See Section 13.4.2 for details. Mandatory for extremity tumors, paratesticular 
tumors in patients ≥ 10 years of age regardless of histology; strongly recommended in all patients 
with alveolar histology (particularly if FOXO1 fusion positive) and in those with clinically involved 
nodes regardless of histology or fusion status).  
l. 
Performance status. Use the Lansky performance score if < 16 years of age and the Karnofsky 
performance scale if ≥ 16 years of age. 
m. Tissue submission for biology studies. Identification of fusion partners and variant gene fusions in 
RMS (Required). See Section 15.0. 
n. 
Sperm banking. Recommended for post-pubertal males. 
o. 
Fertility consult. Recommended for patients with abdominal/pelvic disease. 
p. 
Circulating tumor DNA. Patient Consent required. Samples must be drawn within 7 days prior to starting 
therapy (Day 1); Week 4 and 7 (prior to chemotherapy on that day). See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
 
 
 
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ARST1431 
 
Version date: 11/16/2020 
Page 47  
Regimen A (VAC/VI Only) Cycles 1-4   
 
4.2.3 
Regimen A (VAC/VI Only) Administration Details for Cycles 1-4 
Each VAC/VI cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. 
This course will take a minimum of 12 weeks (84 days). For those considering 
DPE, hold chemotherapy and resume where you left off. If doses of specific 
agents (ie. temsirolimus) need to be held in the best interest of the patient, they 
will be omitted, and not made up at later dates. 
 
All patients will undergo institutional pathology review and FOXO1 fusion 
determination. FOXO1 status results must be available by Week 3 (Day 21) of 
therapy and submitted as soon as possible. If patients FOXO1 status is 
FOXO1 fusion positive with Group IV/Stage 4 disease, they will be removed 
from protocol therapy (for example, a patient greater than 10 years of age with 
metastatic disease who is found to be FOXO1 fusion positive). Patients eligible 
to transfer to Regimen C must do so prior to the start of Week 4 of therapy (see 
Section 4.1). 
 
4.2.3.1 Criteria to Start Each Cycle 
4.2.3.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL 
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to >750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.2.3.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.2.3.2 Treatment 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 

  
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Page 48  
Regimen A (VAC/VI Only) Cycles 1-4   
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 1 through Week 12.  
Dose: BSA-based dosing: 
VINCRISTINE  
BSA (m2) 
Dose 
0.25-0.29 
0.24 mg 
0.3-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.4-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.5-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
NOTE: Give before Irinotecan on days when both drugs are to be 
given. 
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 1 and 7. 
Dose: Weight-based dosing: 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10 – 11.2 
0.4 mg 
11.3 –12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 
Cyclophosphamide: IV over 60 minutes 
Day: 1 of Weeks 1 and 7. 
Dose: BSA-based dosing: 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 

  
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Page 49  
Regimen A (VAC/VI Only) Cycles 1-4   
Irinotecan: IV over 90 minutes daily 
Days: 1 through 5 of Weeks 4 and 10. 
Dose: BSA-based dosing 
IRINOTECAN  
BSA (m2) 
Dose  
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
≥ 0.6 
50 mg/m2 (maximum 100 mg) 
 
4.2.3.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna, myeloid growth factor 
support during VAC cycles, and antibiotics for prevention of irinotecan-
induced diarrhea. 
 
Please see Appendix X for loperamide dosing in the treatment of 
irinotecan-induced diarrhea. In addition, for COG Supportive Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of this course, the next course starts on Day 1 of Week 13 
or when starting criteria are met, whichever occurs later. 
 
 

  
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ARST1431 
 
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Page 50  
Regimen A (VAC/VI Only) Cycles 5-10   
4.2.4 
ARST1431 Regimen A Cycles 5-10 
This therapy delivery map (TDM) relates to Cycles 5-10 of therapy (Weeks 13-30). Each cycle lasts 21 days (3 
weeks).  
_______________________ 
________________ 
 
Patient COG ID number  
 
 DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This 
course lasts 84 days and the TDM is described on two pages. See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 13, 16, 17, 19, 20, 
22-26 and 28. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg. Administer before Irinotecan on 
days when both drugs are given. 
DACTINomycin (DACT) 
Slow IV Push over 
1-5 minutes or IV infusion 
over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing 
table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 13, 22 and 28. 
Maximum dose: 2.5 mg. Give the Week 13 dose of DACT 
before beginning radiation therapy. 
For patients receiving liver irradiation, see Section 4.2.6.2. 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 13, 22 and 28. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 50 mg/m2/dose 
Days 1 through 5 of Weeks 16, 19 
and 25. 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for patients 
< 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be continued without 
regard to VCR. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. 
Cycle 5 (Week 13): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 6 (Week 16): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 7 (Week 19): Ht_____cm  Wt_____kg BSA_____m2 
Cycle 8 (Week 22): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 9 (Week 25): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 10 (Week 28): Ht_____cm  Wt_____kg BSA_____m2 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
5 
13 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
6 
16 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
17 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
7 
19 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c, h 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
20 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
8 
22 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
23 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
 
24 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
9 
25 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
26 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
10 
28 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
30 
 
 
 
 
 
 
 
 
b, d-g 
 
 
 
 
 
Continue to Cycle 11 (Week 31) therapy if all criteria to start the next cycle have been met.  
 
Page 1 of 2 

  
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Page 51  
Regimen A (VAC/VI Only) Cycles 5-10   
 
4.2.5 
Required Observations Prior to and During Cycles 5-10 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets 
c. 
Total bilirubin, ALT, creatinine. 
d. MR primary site and regional nodal basin, CT may be considered for intra-
abdominal primary. See Section 16.0. 
e. 
CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. 
May be omitted for patients with ERMS and clinically uninvolved nodes. Repeat CT 
chest is required only for those patients who had lung metastases at diagnosis. See 
Section 16.0. 
f. 
Bone scan or PET-CT. Only needs to be repeated in those patients who had bone 
metastases at diagnosis. See Section 16.0. 
g. CT or MRI of regional nodal basin. May omit if PET-CT is done. Perform in those 
patients who had clinical involved nodes at diagnosis and in all patients with extremity 
tumors and those with paratesticular tumors who are ≥ 10 years of age. See Section 
16.0. 
h. Circulating tumor DNA. Patient Consent required. Sample must be drawn at Week 19. 
See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Version date: 11/16/2020 
Page 52  
Regimen A (VAC/VI Only) Cycles 5-10   
 
4.2.6 
Regimen A (VAC/VI Only) Administration Details for Cycles 5-10 
Each VAC/VI cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. 
This course will take a minimum of 18 weeks (126 days). 
 
4.2.6.1 Criteria to Start Each Cycle 
4.2.6.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL  
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to > 750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.2.6.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.2.6.2 Treatment 
Radiotherapy 
RT begins at Cycle 5 (Week 13) and may last up to 6.5 weeks for all 
patients. See Section 17.0 for radiotherapy guidelines. 
 
Give the Week 13 dose of dactinomycin before beginning RT.  
 
Note: For patients receiving liver irradiation, reduce the dactinomycin 
dose by 50% for the next cycle (for example, if the full dactinomycin 
dose is 1.5 mg, then administer 0.7-0.8 mg for a 50% dose reduction) 
and increase by 25% (for example, if the 50% dose is 0.7-0.8 mg, then 
administer 0.9-1 mg to increase the dosage by 25%), if tolerated, up to 
full dose for subsequent cycles. No reductions of vincristine or 
cyclophosphamide are needed unless total bilirubin is elevated (see 
Section 5.3.1). 
 
Chemotherapy 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 

  
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Page 53  
Regimen A (VAC/VI Only) Cycles 5-10   
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy)  
Day: 1 of Week 13, 16, 17, 19, 20, 22-26, and 28.  
Dose: BSA-based dosing: 
VINCRISTINE  
BSA (m2) 
Dose  
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
NOTE: Administer before Irinotecan on days when both drugs are to be 
given. 
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 13, 22 and 28. 
Dose: Weight-based dosing 
DACTINOMYCIN 
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 
Cyclophosphamide: IV over 60 minutes  
Day: 1 of Weeks 13, 22, and 28. 
Dose: BSA-based dosing 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 

  
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Regimen A (VAC/VI Only) Cycles 5-10   
Irinotecan: IV over 90 minutes  
Days: 1 through 5 of Weeks: 16, 19, and 25. 
Dose: BSA-based dosing 
IRINOTECAN  
BSA (m2) 
Dose 
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
≥ 0.6 
50 mg/m2 (maximum 100 mg) 
 
4.2.6.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna, myeloid growth factor 
support during VAC cycles, and antibiotics for prevention of irinotecan-
induced diarrhea.  
 
Please see Appendix X for loperamide dosing in the treatment of 
irinotecan-induced diarrhea. In addition, for COG Supportive Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
See Section 16.0 for Week 30 evaluations. 
 
Following completion of this course, the next course starts on Day 1 of Week 31 
or when start criteria are met, whichever occurs later. 
 
 

  
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Page 55  
Regimen A (VAC/VI Only) Cycles11-14   
4.2.7 
ARST1431 Regimen A Cycles 11-14 
This therapy delivery map (TDM) relates to Cycles 11-14 of therapy (Weeks 31-42). Each 
cycle lasts 21 days (3 weeks).  
____________________________ 
 
________________________ 
Patient COG ID number  
 
 
DOB 
 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of 
normal (ULN) for age. This course lasts 84 days and the TDM is described on two pages. 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 31-34, 37, 38 
and 40. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg. Administer before Irinotecan 
on days when both drugs are given. 
DACTINomycin (DACT) 
Slow IV Push 
over 1-5 minutes or IV 
infusion over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 34 and 40. 
Maximum dose: 2.5 mg 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 34 and 40. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 50 mg/m2/dose 
Days 1 through 5 of Weeks 31 
and 37. 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for 
patients < 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be 
continued without regard to VCR. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive 
Care Guidelines. 
 
Cycle 11 (Week 31): Ht_________cm 
Wt________kg 
BSA_________m2  
 
Cycle 12 (Week 34): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Cycle 13 (Week 37): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 14 (Week 40): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
11 
31 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
32 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
 
33 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
12 
34 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
13 
37 
1 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
_____mg 
 
 
 
 
 
 
 
38 
1 
_____mg 
 
 
 
 
 
 
b 
 
 
14 
40 
1 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
42 
 
 
 
 
 
 
 
 
d-h 
 
 
 
43 
 
Continue to Cycle 1 of Maintenance (Week 43) if all criteria to start have been met (see Section 4.4). 
 
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Page 56  
Regimen A (VAC/VI Only) Cycles 11-14   
 
4.2.8 
Required Observations Prior to and During Cycles 11-14 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets 
c. 
Total bilirubin, ALT, creatinine. 
d. MR primary site and regional nodal basin, CT may be considered for intra-
abdominal primary. See Section 16.0. 
e. 
CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. 
May be omitted for patients with ERMS and clinically uninvolved nodes. Repeat CT 
chest is required only for those patients who had lung metastases at diagnosis. See 
Section 16.0. 
f. 
Bone scan or PET-CT. Only needs to be repeated in those patients who had bone 
metastases at diagnosis. See Section 16.0. 
g. CT or MRI of regional nodal basin. May omit if PET-CT is done. Perform in those 
patients who had clinical involved nodes at diagnosis and in all patients with extremity 
tumors and those with paratesticular tumors who are ≥ 10 years of age. See 
Section 16.0. 
h. Circulating tumor DNA. Patient Consent required. Sample must be drawn at Week 42. 
See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 

  
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Version date: 11/16/2020 
Page 57  
Regimen A (VAC/VI Only) Cycles 11-14   
 
4.2.9 
Regimen A (VAC/VI Only) Administration Details for Cycles 11-14 
Each VAC/VI cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. 
This course will take a minimum of 12 weeks (84 days). 
 
4.2.9.1 Criteria to Start Each Cycle 
4.2.9.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL  
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to > 750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.2.9.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.2.9.2 Treatment 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 31-34, 37, 38, and 40.  
Dose: BSA-based dosing 
VINCRISTINE  
BSA (m2) 
Dose  
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
NOTE: Administer before Irinotecan on days when both drugs are to be 
given. 

  
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Regimen A (VAC/VI Only) Cycles 11-14   
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 34 and 40. 
Dose: Weight-based dosing 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 
Cyclophosphamide: IV over 60 minutes  
Day: 1 of Weeks 34 and 40. 
Dose: BSA-based dosing 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 
Irinotecan: IV over 90 minutes daily 
Days: 1 through 5 of Weeks: 31 and 37. 
Dose: BSA-based dosing 
IRINOTECAN  
BSA (m2) 
Dose (mg) 
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
≥ 0.6 
50 mg/m2 (maximum 100 mg) 
 
4.2.9.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna, myeloid growth factor 

  
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Regimen A (VAC/VI Only) Cycles 11-14   
support during VAC cycles, and antibiotics for prevention of irinotecan-
induced diarrhea.  
 
Please see Appendix X for loperamide dosing in the treatment of 
irinotecan-induced diarrhea. In addition, for COG Supportive Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of this course, Maintenance starts on Day 1 of Week 43 or 
when starting criteria are met, whichever occurs later (see Section 4.4). 
 
In patients with metastatic disease, relevant metastatic sites should be treated 
with RT at the completion of VAC/VI chemotherapy. See Section 17.0. 
 
 

  
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Page 60  
Regimen B (VAC/VI Plus TORI) Cycles 1-4  
4.3 
Regimen B (VAC/VI Plus Temsirolimus)  
4.3.1 
ARST1431 Regimen B Cycles 1-4 
This therapy delivery map (TDM) relates to Cycles 1-4 of therapy (Weeks 1-12). Each cycle lasts 21 days (3 weeks).  
_____________________ 
_________ 
Patient COG ID number  
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This course 
lasts 84 days and the TDM is described on two pages. Please review Mucositis Management Guidelines in Appendix VII.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temsirolimus (TORI)* 
Do not use commercial 
supply -  
IV over 30-60 minutes 
15 mg/m2/dose 
OR  
0.5 mg/kg/dose for pt < 10 kg  
Day 1 of each week. 
Maximum dose: 25 mg.  
*Premedicate with diphenhydramine IV approx. 30 min prior to 
TORI. See Section 4.3.3.2 for administration guidelines.  
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of each week. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg. Administer before Irinotecan on days 
when both drugs are given. 
DACTINomycin (DACT) 
Slow IV Push 
over 1-5 minutes or IV 
infusion over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing 
table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 1 and 7. 
Maximum dose: 2.5 mg 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 1 and 7. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2:50 mg/m2/dose 
Days 1 through 5 of 
Weeks 4 and 10. 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for patients 
< 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be continued without 
regard to VCR or TORI. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines. 
Cycle 1 (Week 1): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 2 (Week 4): Ht_________cm 
Wt________kg 
BSA_________m2 
Cycle 3 (Week 7): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 4 (Week 10): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
TORI 
______mg 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
1 
1 
1 
_____mg 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-p 
 
 
 
2 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
3 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
2 
4 
1 
_____mg 
_____mg 
 
 
_____mg 
 
 
 
a-c, p 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
5 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
6 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
3 
7 
1 
_____mg 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c, p 
 
 
 
8 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
9 
1 
_____mg 
_____mg 
 
 
 
 
 
 
a, b, f-j 
 
 
4 
10 
1 
_____mg 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
11 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
12 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b, f 
 
 
 
 
 
Continue to Cycle 5 (Week 13) therapy if all criteria to start the next cycle have been met.  
 
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Regimen B (VAC/VI Plus TORI) Cycles 1-4  
4.3.2 
Required Observations Prior to and During Cycles 1-4 
NOTE: All patients will undergo institutional pathology review and FOXO1 fusion determination. 
FOXO1 status results must be available by Week 3 (Day 21) of therapy and submitted as an 
upload to RAVE as soon as possible. If patients FOXO1 status is FOXO1 fusion positive with 
Group IV/Stage 4 disease, they will be removed from protocol therapy (for example, a patient 
greater than 10 years of age with metastatic disease who is found to be FOXO1 fusion positive). 
Patients eligible to transfer to Regimen C must do so prior to the start of Week 4 of therapy (see 
Section 4.1). 
All baseline radiology reports should be submitted to IROC Rhode Island at the time of 
study enrollment (see Section 16.2.1). 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets. 
c. 
Total bilirubin, ALT, creatinine, calcium, phosphorus, triglycerides, cholesterol, urinalysis. If 
triglycerides or cholesterol levels are elevated, repeat with fasting. 
d. Bilateral bone marrow biopsy (not required for patients with ERMS and clinically uninvolved nodes, 
and no lung or bone metastases). Repeat bone marrow examinations are only required in patients who 
had positive bone marrow disease at diagnosis. 
e. 
Cerebrospinal fluid cytology for parameningeal tumors, including orbital site with parameningeal 
extension and paraspinal tumors with dural involvement. 
f. 
MR primary site and regional nodal basin, CT may be considered for intra-abdominal primary. See 
Section 16.0. Post-operative imaging is required at Week 12 (prior to RT) only for patients who 
undergo DPE. 
g. CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. May be omitted for 
patients with ERMS and clinically uninvolved nodes. Repeat CT chest is required at Week 9 only for 
those patients who had lung metastases at diagnosis. See Section 16.0. 
h. FDG-PET with diagnostic quality CT. Patients must have consented to the FDG-PET part of the 
study. Week 9. PET scans must be performed no sooner than 4 days following temsirolimus 
infusion. See Section 16.0. 
i. 
Bone scan. May be omitted if PET-CT is performed. May be omitted for patients with ERMS and 
clinically uninvolved nodes and no lung metastases. Only needs to be repeated at Week 9 in those 
patients who had bone metastases at diagnosis. See Section 16.0. 
j. 
CT or MRI of regional nodal basin. Week 9. May omit if PET-CT is done. Perform in those patients 
who had clinically involved nodes at diagnosis and in all patients with extremity tumors and those with 
paratesticular tumors who are ≥ 10 years of age. See Section 16.0. 
k. Lymph node biopsy. See Section 13.4.2 for details. Mandatory for extremity tumors, paratesticular 
tumors in patients ≥ 10 years of age regardless of histology; strongly recommended in all patients 
with alveolar histology (particularly if FOXO1 fusion positive) and in those with clinically involved 
nodes regardless of histology or fusion status).  
l. 
Performance status. Use the Lansky performance score if < 16 years of age and the Karnofsky 
performance scale if ≥ 16 years of age. 
m. Tissue submission for biology studies. Identification of fusion partners and variant gene fusions in 
RMS (Required). See Section 15.0. 
n. 
Sperm banking. Recommended for post-pubertal males. 
o. 
Fertility consult. Recommended for patients with abdominal/pelvic disease. 
p. 
Circulating tumor DNA. Patient Consent required. Samples must be drawn within 7 days prior to starting 
therapy (Day 1) and Weeks 4 and 7 prior to chemotherapy. See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
 
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Regimen B (VAC/VI Plus TORI) Cycles 1-4  
 
 
4.3.3 
Regimen B (VAC/VI Plus Temsirolimus) Administration Details for Cycles 1-4 
Each VAC/VI cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. 
This course will take a minimum of 12 weeks (84 days). For those considering 
DPE, hold chemotherapy and resume where you left off. If doses of specific 
agents (ie. temsirolimus) need to be held in the best interest of the patient, they 
will be omitted, and not made up at later dates. In those considering DPE, 
temsirolimus must be held 2 weeks prior to and 1 week following DPE. 
 
All patients will undergo institutional pathology review and FOXO1 fusion 
determination. FOXO1 status results must be available by Week 3 (Day 21) of 
therapy and submitted as soon as possible. If patients FOXO1 status is 
FOXO1 fusion positive with Group IV/Stage 4 disease, they will be removed 
from protocol therapy (for example, a patient greater than 10 years of age with 
metastatic disease who is found to be FOXO1 fusion positive). Patients eligible 
to transfer to Regimen C must do so prior to the start of Week 4 of therapy (see 
Section 4.1). 
 
4.3.3.1 Criteria to Start Each Cycle 
4.3.3.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL  
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to >750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.3.3.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.3.3.2 Treatment 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
 
Temsirolimus (Dose Level 1): IV over 30-60 minutes once weekly 
Day: 1 of Week 1 through Week 12. 
Dose: For patients < 10 kg, the dose is 0.5 mg/kg/dose. 
For patients ≥ 10 kg, the dose is 15 mg/m2/dose (maximum 
dose: 25 mg).  
 
Because of idiosyncratic infusion-related reactions, all patients 
receiving temsirolimus will be pre-medicated with diphenhydramine 
(0.5-1 mg/kg; maximum dose: 50 mg), approximately 30 minutes 
before the start of each temsirolimus infusion. If the patient begins to 
develop a reaction despite pretreatment with diphenhydramine, the 

  
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Regimen B (VAC/VI Plus TORI) Cycles 1-4  
infusion should be stopped for at least 30-60 minutes, depending upon 
the severity of the reaction. The infusion may be resumed by 
administering a histamine H2-receptor antagonist (ie, ranitidine or 
famotidine) 
approximately 
30 
minutes 
before 
restarting 
the 
temsirolimus. The rate of temsirolimus infusion may also be slowed 
(decreased by 50% or slower). All patients should be monitored while 
receiving temsirolimus and health care personnel must be readily 
available to respond to infusion-related reactions. Infusion-related 
reactions are not considered dose limiting, see Section 5.2.2 for detailed 
instructions. 
 
Temsirolimus is distributed by NCI. Do not use commercial supply. 
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 1 through Week 12.  
Dose: BSA-based dosing: 
VINCRISTINE  
BSA (m2) 
Dose  
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
NOTE: Administer before Irinotecan on days when both drugs are to be 
given. 
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 1 and 7. 
Dose: Weight-based dosing 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles 1-4  
 
Cyclophosphamide: IV over 60 minutes 
Day: 1 of Weeks 1and 7. 
Dose: BSA-based dosing 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 
Irinotecan: IV over 90 minutes daily 
Days: 1 through 5 of Weeks 4 and 10. 
Dose: BSA-based dosing 
IRINOTECAN  
BSA (m2) 
Dose  
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
≥ 0.6 
50 mg/m2 (maximum 100 mg) 
 
4.3.3.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna, myeloid growth factor 
support during VAC cycles, and antibiotics for prevention of irinotecan-
induced diarrhea. 
 
Please see Appendix X for loperamide dosing in the treatment of 
irinotecan-induced diarrhea. In addition, for COG Supportive Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines. 
 
4.3.3.4 Concomitant Therapy Restrictions  
The use of moderate to strong CYP3A4 and p-gp inducers and 
inhibitors should be discontinued prior to initiation of protocol therapy 
and should be avoided during protocol therapy, if reasonable 
alternatives exist. See Appendix VIII for a list of CYP3A4 inducers and 
inhibitors. See Section 4.1.3 for examples of p-gp inducers/inhibitors. 
Corticosteroids are permitted.  
 

  
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Regimen B (VAC/VI Plus TORI) Cycles 1-4  
St. John’s Wort may decrease temsirolimus plasma concentrations 
unpredictably and should be avoided. Grapefruit juice may increase 
plasma concentrations of sirolimus and should be avoided as well.  
 
The combination of temsirolimus and angiotensin converting enzyme 
inhibitors (ACEIs) or calcium channel blockers (eg. amlodipine) has 
resulted in angioedema-type reactions (including delayed reactions 
occurring up to 2 months after initiation of therapy). During 
temsirolimus treatment, the coadministration of ACEIs or calcium 
channel blockers is not permitted.  
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of this course, the next course starts on Day 1 of Week 13 
or when starting criteria are met, whichever occurs later. 
 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
 
4.3.4a ARST1431 Regimen B Cycles 5-10 
This therapy delivery map (TDM) relates to Cycles 5-10 of therapy (Weeks 13-30). Each cycle 
lasts 21 days (3 weeks).  
TEMSIROLIMUS TO BE HELD DURING AND FOR 2 WEEKS FOLLOWING RT. 
____________________________  
________________________ 
Patient COG ID number  
 
 
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This course 
lasts 84 days and the TDM is described on three pages. Please review Mucositis Management Guidelines in Appendix VII. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temsirolimus (TORI)* 
Do not use commercial 
suppy -  
IV over 30-60 minutes 
15 mg/m2/dose OR  
0.5 mg/kg/dose for pt < 10 kg 
Day 1 of Weeks 21-30. 
Maximum dose: 25 mg.  
*Premedicate with diphenhydramine IV approx 30 min prior 
to TORI. See Section 4.3.6.2 for administration guidelines.  
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 13, 16, 17, 
19, 20, 22-26 and 28. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg. Administer before Irinotecan on days 
when both drugs are given. 
DACTINomycin (DACT) 
Slow IV Push 
over 1-5 minutes or IV infusion 
over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing 
table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 13, 22 and 
28. 
Maximum dose: 2.5 mg. Give the Week 13 dose of DACT 
before beginning radiation therapy. 
For patients receiving liver irradiation, see Section 4.3.6.2. 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 13, 22 and 
28. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 50 mg/m2/dose 
Days 1 through 5 of Weeks 
16, 19 and 25. 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for patients 
< 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be continued without 
regard to VCR or TORI. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. 
 
Cycle 5 (Week 13): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 6 (Week 16): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 7 (Week 19): Ht_____cm  Wt_____kg BSA_____m2 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
TORI 
______mg 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
5 
13 
1 
 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
14 
 
 
 
 
 
 
 
 
 
b 
 
 
 
15 
 
 
 
 
 
 
 
 
 
b 
 
 
6 
16 
1 
 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
17 
1 
 
_____mg 
 
 
 
 
 
 
b 
 
 
 
18 
 
 
 
 
 
 
 
 
 
b 
 
 
7 
19 
1 
 
_____mg 
 
 
_____mg 
 
 
 
a-c, h 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
20 
1 
 
_____mg 
 
 
 
 
 
 
a, b 
 
 
 
21 
1 
_____mg 
 
 
 
 
 
 
 
b 
 
 
 
 
 
The therapy delivery map for Cycles 5-10 continues on the next page. 
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines.
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
 
 
4.3.4b ARST1431 Regimen B Cycles 5-10 
This therapy delivery map (TDM) relates to Cycles 5-10 of therapy (Weeks 13-30). Each cycle 
lasts 21 days (3 weeks).  
____________________________  
________________________ 
Patient COG ID number  
 
 
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This course 
lasts 84 days and the TDM is described on three pages. Please review Mucositis Management Guidelines in Appendix VII. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temsirolimus (TORI)* 
Do not use commercial 
supply -  
IV over 30-60 minutes 
15 mg/m2/dose OR  
0.5 mg/kg/dose for pt < 10 kg 
Day 1 of Weeks 22-30. 
Maximum dose: 25 mg.  
*Premedicate with diphenhydramine IV approx 30 min prior 
to TORI. See Section 4.3.6.2 for administration guidelines.  
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 13, 16, 17, 19, 
20, 22-26 and 28. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg. Administer before Irinotecan on days 
when both drugs are given. 
DACTINomycin 
(DACT) 
Slow IV Push 
over 1-5 minutes or IV 
infusion over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 13, 22 and 28. 
Maximum dose: 2.5 mg 
For patients receiving liver irradiation, see Section 4.3.6.2. 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 13, 22 and 28. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 50 mg/m2/dose 
Days 1 through 5 of Weeks 16, 
19 and 25. 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for patients 
< 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be continued without 
regard to VCR or TORI. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. 
 
Cycle 8 (Week 22): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 9 (Week 25): Ht_____cm  Wt_____kg  BSA_____m2 
Cycle 10 (Week 28): Ht_____cm  Wt_____kg BSA_____m2 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
TORI 
______mg 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
8 
22 
1 
_____mg 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
23 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
24 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
9 
25 
1 
_____mg 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
26 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
27 
1 
_____mg 
 
 
 
 
 
 
 
b 
 
 
10 
28 
1 
_____mg 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
29 
1 
_____mg 
 
 
 
 
 
 
 
b 
 
 
 
30 
1 
_____mg 
 
 
 
 
 
 
 
b, d-g 
 
 
 
 
 
Continue to Cycle 11 (Week 31) therapy if all criteria to start the next cycle have been met.  
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines. 
Page 2 of 3 

  
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
 
4.3.5 
Required Observations Prior to and During Cycles 5-10 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets. 
c. 
Total bilirubin, ALT, creatinine, calcium, phosphorus, triglycerides, cholesterol, 
urinalysis. If triglycerides or cholesterol levels are elevated, repeat with fasting. 
d. MR primary site and regional nodal basin, CT may be considered for intra-
abdominal primary. See Section 16.0. 
e. 
CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. 
May be omitted for patients with ERMS and clinically uninvolved nodes. Repeat CT 
chest is required only for those patients who had lung metastases at diagnosis. See 
Section 16.0. 
f. 
Bone scan or PET-CT. Only needs to be repeated in those patients who had bone 
metastases at diagnosis. See Section 16.0. 
g. CT or MRI of regional nodal basin. May omit if PET-CT is done. Perform in those 
patients who had clinical involved nodes at diagnosis and in all patients with extremity 
tumors and those with paratesticular tumors who are ≥ 10 years of age. See 
Section 16.0. 
h. Circulating tumor DNA. Patient Consent required. Sample must be drawn prior to 
chemotherapy at Week 19. See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
 
 
4.3.6 
Regimen B (VAC/VI Plus Temsirolimus) Administration Details for Cycles 5-10 
Each VAC/VI cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. 
This course will take a minimum of 18 weeks (126 days). 
 
4.3.6.1 Criteria to Start Each Cycle 
4.3.6.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL  
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to >750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.3.6.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.3.6.2 Treatment 
Radiotherapy 
RT begins at Cycle 5 (Week 13) and may last up to 6.5 weeks. See 
Section 17.0 for radiotherapy guidelines. 
 
Give the Week 13 dose of dactinomycin before beginning RT.  
 
Note: For patients receiving liver irradiation, reduce the dactinomycin 
dose by 50% for the next cycle (for example, if the full dactinomycin 
dose is 1.5 mg, then administer 0.7-0.8 mg for a 50% dose reduction) 
and increase by 25% (for example, if the 50% dose is 0.7-0.8 mg, then 
administer 0.9-1 mg to increase the dosage by 25%), if tolerated, up to 
full dose for subsequent cycles. No reductions of vincristine or 
cyclophosphamide are needed unless total bilirubin is elevated (see 
Section 5.3.1). 
 
Chemotherapy 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
Temsirolimus (Dose Level 1): IV over 30-60 minutes once weekly 
Day: 1 of Week 21-30. 
Dose: For patients < 10 kg, the dose is 0.5 mg/kg/dose. 
For patients ≥ 10 kg, the dose is 15 mg/m2/dose (maximum 
dose: 25 mg).  
 
Temsirolimus will be held during RT and restarted 2 weeks following 
completion of RT and once mucositis has resolved to ≤ Grade 1. 
Because of idiosyncratic infusion-related reactions, all patients 

  
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
receiving temsirolimus will be pre-medicated with diphenhydramine, 
(0.5-1 mg/kg; maximum dose: 50 mg) approximately 30 minutes 
before the start of each temsirolimus infusion. If the patient begins to 
develop an infusion-related reaction despite pretreatment with 
diphenhydramine, the infusion should be stopped for at least 
30-60 minutes, depending upon the severity of the reaction. The 
infusion may be resumed by administering a histamine H2-receptor 
antagonist (ie, ranitidine or famotidine) approximately 30 minutes 
before restarting the temsirolimus. The rate of temsirolimus infusion 
may also be slowed (decreased by 50% or slower). All patients should 
be monitored while receiving temsirolimus and health care personnel 
must be readily available to respond to infusion-related reactions. 
Infusion-related reactions are not considered dose limiting, see 
Section 5.2.2 for detailed instructions. 
 
Temsirolimus is distributed by NCI. Do not use commercial supply. 
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 13, 16, 17, 19, 20, 22-26, and 28.  
Dose: BSA-based dosing: 
VINCRISTINE  
BSA (m2) 
Dose  
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
NOTE: Administer before Irinotecan on days when both drugs are to be 
given. 
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 13, 22 and 28. 
Dose: Weight-based dosing 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
Cyclophosphamide: IV over 60 minutes  
Day: 1 of Weeks 13, 22, and 28. 
Dose: BSA-based dosing 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 
Irinotecan: IV over 90 minutes daily 
Days: 1 through 5 of Weeks: 16, 19, and 25. 
Dose: BSA-based dosing 
IRINOTECAN  
BSA (m2) 
Dose  
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
≥ 0.6 
50 mg/m2 (maximum 100 mg) 
 
4.3.6.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna, myeloid growth factor 
support during VAC cycles, and antibiotics for prevention of irinotecan-
induced diarrhea. 
 
Please see Appendix X for loperamide dosing in the treatment of 
irinotecan-induced diarrhea. In addition, for COG Supportive Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines. 
 
4.3.6.4 Concomitant Therapy Restrictions  
The use of moderate to strong CYP3A4 and p-gp inducers and 
inhibitors should be discontinued prior to initiation of protocol therapy 
and should be avoided during protocol therapy, if reasonable 
alternatives exist. See Appendix VIII for a list of CYP3A4 inducers and 
inhibitors. See Section 4.1.3 for examples of p-gp inducers/inhibitors. 
Corticosteroids are permitted. 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles 5-10  
St. John’s Wort may decrease temsirolimus plasma concentrations 
unpredictably and should be avoided. Grapefruit juice may increase 
plasma concentrations of sirolimus and should be avoided as well.  
 
The combination of temsirolimus and angiotensin converting enzyme 
inhibitors (ACEIs) or calcium channel blockers (eg. amlodipine) has 
resulted in angioedema-type reactions (including delayed reactions 
occurring up to 2 months after initiation of therapy). During 
temsirolimus treatment, the coadministration of ACEIs or calcium 
channel blockers is not permitted. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
See Section 16.0 for Week 30 evaluations. 
 
Following completion of this course, the next course starts on Day 1 of Week 31 
or when start criteria are met, whichever occurs later. 
 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles11-14  
 
4.3.7 
ARST1431 Regimen B Cycles 11-14 
This therapy delivery map (TDM) relates to Cycles 11-14 of therapy (Weeks 31-42). Each cycle lasts 21 days (3 weeks).  
_________________ 
_________ 
Patient COG ID number  
 
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. 
This course lasts 84 days and the TDM is described on two pages. Please review Mucositis Management Guidelines in Appendix VII. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Temsirolimus (TORI)* 
Do not use commercial 
supply -  
IV over 30-60 minutes 
15 mg/m2/dose OR  
0.5 mg/kg/dose for pt < 10 kg 
Day 1 of each week. 
Maximum dose: 25 mg.  
*Premedicate with diphenhydramine IV approx 30 min prior to 
TORI. See Section 4.3.9.2 for administration guidelines.  
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 31-34, 37, 
38 and 40. 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg. Administer before Irinotecan on days 
when both drugs are given. 
DACTINomycin (DACT) 
Slow IV Push 
over 1-5 minutes or IV 
infusion over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 34 and 40. 
Maximum dose: 2.5 mg 
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 34 and 40. 
 
Irinotecan (IRIN) 
IV over 90 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2:50 mg/m2/dose 
Days 1 through 5 of Weeks 
31 and 37 
Maximum dose: 100 mg/day 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 0.1 mg/kg/dose (for patients 
< 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles only). Filgrastim or biosimilar may be continued without 
regard to VCR or TORI. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle. See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines. 
Cycle 11 (Week 31): Ht_________cm 
Wt________kg 
BSA_________m2  
 
Cycle 12 (Week 34): Ht_________cm 
Wt________kg 
BSA_________m2 
Cycle 13 (Week 37): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 14 (Week 40): Ht_________cm 
Wt________kg 
BSA_________m2 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
TORI 
______mg 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
IRIN 
_______mg 
MESNA 
_______mg 
Myeloid growth factor used: _______ 
 
Calc. dose___________mcg 
Studies 
 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
11 
31 
1 
_____mg 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
32 
1 
_____mg 
_____mg 
 
 
 
 
 
 
B 
 
 
 
33 
1 
_____mg 
_____mg 
 
 
 
 
 
 
B 
 
 
12 
34 
1 
_____mg 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
35 
1 
_____mg 
 
 
 
 
 
 
 
B 
 
 
 
36 
1 
_____mg 
 
 
 
 
 
 
 
B 
 
 
13 
37 
1 
_____mg 
_____mg 
 
 
_____mg 
 
 
 
a-c 
 
 
 
 
2 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
3 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
4 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
 
5 
 
 
 
 
_____mg 
 
 
 
 
 
 
 
38 
1 
_____mg 
_____mg 
 
 
 
 
 
 
b 
 
 
 
39 
1 
_____mg 
 
 
 
 
 
 
 
b 
 
 
14 
40 
1 
_____mg 
_____mg 
_____mg 
_____mg 
 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
41 
1 
_____mg 
 
 
 
 
 
 
 
b 
 
 
 
42 
1 
_____mg 
 
 
 
 
 
 
 
b, d-h 
 
 
 
43 
 
Continue to Cycle 1 of Maintenance (Week 43) if all criteria to start have been met (see Section 4.4). 
 
Page 1 of 2 

  
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Regimen B (VAC/VI Plus TORI) Cycles11-14  
 
4.3.8 
Required Observations Prior to and During Cycles 11-14 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets. 
c. 
Total bilirubin, ALT, creatinine, calcium, phosphorus, triglycerides, cholesterol, 
urinalysis. If triglycerides or cholesterol levels are elevated, repeat with fasting. 
d. MR primary site and regional nodal basin, CT may be considered for intra-
abdominal primary. See Section 16.0. 
e. 
CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. 
May be omitted for patients with ERMS and clinically uninvolved nodes. Repeat CT 
chest is required only for those patients who had lung metastases at diagnosis. See 
Section 16.0. 
f. 
Bone scan or PET-CT. Only needs to be repeated in those patients who had bone 
metastases at diagnosis. See Section 16.0. 
g. CT or MRI of regional nodal basin. May omit if PET-CT is done. Perform in those 
patients who had clinical involved nodes at diagnosis and in all patients with extremity 
tumors and those with paratesticular tumors who are ≥ 10 years of age. See 
Section 16.0. 
h. Circulating tumor DNA. Patient Consent required. Sample must be drawn at Week 42. 
See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 2 of 2 

  
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Regimen B (VAC/VI Plus TORI) Cycles11-14  
 
4.3.9 
Regimen B (VAC/VI Plus Temsirolimus) Administration Details for Cycles 11-
14 
Each VAC/VI cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. 
This course will take a minimum of 12 weeks (84 days). 
 
4.3.9.1 Criteria to Start Each Cycle 
4.3.9.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL  
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to > 750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.3.9.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.3.9.2 Treatment 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
 
Temsirolimus (Dose Level 1): IV over 30-60 minutes weekly 
Day: 1 of Week 31-42. 
Dose: For patients < 10 kg, the dose is 0.5 mg/kg/dose. 
For patients ≥ 10 kg, the dose is 15 mg/m2/dose (maximum 
dose: 25 mg).  
 
Because of idiosyncratic infusion-related reactions, all patients 
receiving temsirolimus will be pre-medicated with diphenhydramine, 
(0.5-1 mg/kg; maximum dose: 50 mg) approximately 30 minutes 
before the start of each temsirolimus infusion. If the patient begins to 
develop an infusion-related reaction despite pretreatment with 
diphenhydramine, the infusion should be stopped for at least 
30-60 minutes, depending upon the severity of the reaction. The 
infusion may be resumed by administering a histamine H2-receptor 
antagonist (ie, ranitidine or famotidine) approximately 30 minutes 
before restarting the temsirolimus. The rate of temsirolimus infusion 
may also be slowed (decreased by 50% or slower). All patients should 
be monitored while receiving temsirolimus and health care personnel 
must be readily available to respond to infusion-related reactions. 
Infusion-related reactions are not considered dose limiting, see 
Section 5.2.2 for detailed instructions. 
 
Temsirolimus is distributed by NCI. Do not use commercial supply.  

  
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Regimen B (VAC/VI Plus TORI) Cycles11-14  
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 31-34, 37, 38, and 40.  
Dose: BSA-based dosing 
VINCRISTINE  
BSA (m2) 
Dose  
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
NOTE: Administer before Irinotecan on days when both drugs are to be 
given. 
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 34 and 40. 
Dose: Weight-based dosing 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 
Cyclophosphamide: IV over 60 minutes  
Day: 1 of Weeks 34 and 40. 
Dose: BSA-based dosing 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles11-14  
Irinotecan: IV over 90 minutes daily 
Days: 1 through 5 of Weeks: 31 and 37. 
Dose: BSA-based dosing  
IRINOTECAN  
BSA (m2) 
Dose  
0.25-0.29 
8 mg 
0.3-0.34 
12 mg 
0.35-0.39 
15 mg 
0.4-0.44 
18 mg 
0.45-0.49 
22 mg 
0.5-0.54 
24 mg 
0.55-0.59 
28 mg 
≥ 0.6 
50 mg/m2 (maximum 100 mg) 
 
4.3.9.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna, myeloid growth factor 
support during VAC cycles, and antibiotics for prevention of irinotecan-
induced diarrhea.  
 
Please see Appendix X for loperamide dosing in the treatment of 
irinotecan-induced diarrhea. In addition, for COG Supportive Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines. 
 
4.3.9.4 Concomitant Therapy Restrictions  
The use of moderate to strong CYP3A4 and p-gp inducers and 
inhibitors should be discontinued prior to initiation of protocol therapy 
and should be avoided during protocol therapy, if reasonable 
alternatives exist. See Appendix VIII for a list of CYP3A4 inducers and 
inhibitors. See Section 4.1.3 for examples of p-gp inducers/inhibitors. 
Corticosteroids are permitted.  
 
St. John’s Wort may decrease temsirolimus plasma concentrations 
unpredictably and should be avoided. Grapefruit juice may increase 
plasma concentrations of sirolimus and should be avoided as well.  
 
The combination of temsirolimus and angiotensin converting enzyme 
inhibitors (ACEIs) or calcium channel blockers (eg. amlodipine) has 
resulted in angioedema-type reactions (including delayed reactions 
occurring up to 2 months after initiation of therapy). During 
temsirolimus treatment, the coadministration of ACEIs or calcium 
channel blockers are not permitted. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following completion of this course, Maintenance starts on Day 1 of Week 43 or 
when starting criteria are met, whichever occurs later (see Section 4.4). 
 

  
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Regimen B (VAC/VI Plus TORI) Cycles11-14  
In patients with metastatic disease, relevant metastatic sites should be treated 
with RT at the completion of VAC/VI chemotherapy. See Section 17.0. 
 
 

  
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Regimens A & B – Maintenance 
4.4 
Regimens A & B – Maintenance  
4.4.1 
ARST1431 Regimens A & B – Maintenance Cycles 1-6 
This therapy delivery map (TDM) relates to Cycles 1-6 of maintenance therapy (Weeks 43-66). Each cycle lasts 
28 days (4 weeks). Use a copy of this page once for each cycle. Please note cycle number below. 
 
_____________________ 
Patient COG ID number 
_____________ 
DOB 
Criteria to start each cycle of therapy: Maintenance chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after 
nadir. This TDM is described on two pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
Vinorelbine 
(VINO) 
IV push over 
6-10 minutes 
BSA < 0.6 m2: BSA-based dosing, 
see dosing table 
BSA ≥ 0.6 m2: 25 mg/m2 
Days 1, 8, 15. 
Flush vinorelbine injection site with 
75-125 mL of a compatible IV fluid 
for 15-60 minutes after administration 
to prevent burning at the injection 
site. 
Cyclophosphamide 
(CPM) 
PO 
25 mg/m2 once daily 
Days 1-28. 
See Section 4.4.3 for dose rounding 
and administration details. 
Enter Cycle #: _____ 
 
Ht_________cm 
Wt________kg 
BSA_________m2 
 
Date 
Due 
Date 
Given 
Day 
VINO 
______mg 
CPM 
______mg 
Studies 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
1 
_____mg 
_____mg 
a-c 
 
 
2 
 
_____mg 
 
 
 
3 
 
_____mg 
 
 
 
4 
 
_____mg 
 
 
 
5 
 
_____mg 
 
 
 
6 
 
_____mg 
 
 
 
7 
 
_____mg 
 
 
 
8 
_____mg 
_____mg 
B 
 
 
9 
 
_____mg 
 
 
 
10 
 
_____mg 
 
 
 
11 
 
_____mg 
 
 
 
12 
 
_____mg 
 
 
 
13 
 
_____mg 
 
 
 
14 
 
_____mg 
 
 
 
15 
_____mg 
_____mg 
b 
 
 
16 
 
_____mg 
 
 
 
17 
 
_____mg 
 
 
 
18 
 
_____mg 
 
 
 
19 
 
_____mg 
 
 
 
20 
 
_____mg 
 
 
 
21 
 
_____mg 
 
 
 
22 
 
_____mg 
 
 
 
23 
 
_____mg 
 
 
 
24 
 
_____mg 
 
 
 
25 
 
_____mg 
 
 
 
26 
 
_____mg 
 
 
 
27 
 
_____mg 
 
 
 
28 
 
_____mg 
 
 
 
29 
Continue to next maintenance cycle if all criteria to start the next cycle have been met. 
See Section 7.0 for end of therapy evaluations. 
(d-g)*, h^ 
* at end of Cycle 3 and end of protocol therapy 
^ at end of protocol therapy 
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Regimens A & B – Maintenance 
4.4.2 
Required Observations Prior to and During Maintenance Cycles 1-6 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets. 
c.  Total bilirubin. 
d. MR primary site and regional nodal basin, CT may be considered for intra-
abdominal primary. See Section 16.0. 
e. 
CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. 
May be omitted for patients with ERMS and clinically uninvolved nodes. Repeat CT 
chest is required only for those patients who had lung metastases at diagnosis. See 
Section 16.0. 
f. 
Bone scan or PET-CT. Only needs to be repeated in those patients who had bone 
metastases at diagnosis. See Section 16.0. 
g. CT or MRI of regional nodal basin. May omit if PET-CT is done. Perform in those 
patients who had clinical involved nodes at diagnosis and in all patients with extremity 
tumors and those with paratesticular tumors who are ≥ 10 years of age. See 
Section 16.0. 
h. 
Circulating tumor DNA. Patient Consent required. Sample must be drawn at end of 
protocol therapy. See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Regimens A & B – Maintenance 
 
4.4.3 
Regimens A & B Maintenance Administration Details for Cycles 1-6 
Maintenance therapy has been implemented with Amendment #3. Each cycle 
of maintenance lasts 4 weeks (28 days). Maintenance consists of 6 cycles and 
will take a total of 24 weeks. One cycle of maintenance is described below. 
 
In patients with metastatic disease, relevant metastatic sites should be treated 
with RT at the completion of VAC/VI chemotherapy (Week 43). See 
Section 17.0. 
 
4.4.3.1 Criteria to Start Each Cycle 
4.3.3.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL  
 
4.4.3.2 Treatment 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
 
Vinorelbine: IV push over 6-10 minutes 
Days: 1, 8, and 15. 
Dose: BSA-based dosing 
VINORELBINE 
25 mg/m2/dose  
BSA (m2) 
Dose  
0.25-0.29 
4 mg 
0.30-0.34 
6 mg 
0.35-0.39 
7.5 mg 
0.40-0.44 
9 mg 
0.45-0.49 
11 mg 
0.50-0.54 
12 mg 
0.55-0.59 
14 mg 
≥ 0.6 
25 mg/m2 
 
Infuse the diluted solution into the side port of a rapidly infusing 
solution of D5W or 0.9% NaCl. Consider flushing the vinorelbine 
injection site with 75-125 mL of a compatible IV fluid for 
15-60 minutes after administration to prevent burning at the injection 
site.   
 
Special precautions: FATAL IF GIVEN INTRATHECALLY.   
The container or the syringe containing vinORELBine should be labeled 
with the following statement: “WARNING - FOR IV USE ONLY. 
FATAL IF GIVEN INTRATHECALLY.” 
 
Cyclophosphamide: PO 
Days: 1-28. 
Dose: 25 mg/m2/dose once daily 
 

  
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Regimens A & B – Maintenance 
It is advised to administer cyclophosphamide early in the morning to 
decrease the amount of drug remaining in the bladder overnight. During 
the treatment, an adequate fluid intake (e.g., 1 L/m2) is recommended. 
 
If a patient vomits within 20 minutes after a cyclophosphamide tablet or 
capsule is administered, the dose can be repeated once. Otherwise the 
dose should be skipped. The next dose should be administered at the 
regularly scheduled time. 
 
Dose Rounding Recommendations: 
US sites: Doses should be rounded to the nearest 25 mg capsule [see 
dosing table in Appendix XI].  
Canadian sites: Dose should be rounded to the nearest 12.5 mg 
(1/2 tablet) [see dosing table in Appendix XI]. If liquid is unavailable 
and splitting a tablet is necessary follow institutional recommendations 
for safe handling of cytotoxic agents. Please refer to Appendix XII for 
safe 
handling, 
preparation, 
administration 
and 
disposal 
of 
cyclophosphamide tablets information for patients and families. 
AU/NZ sites: Doses should be rounded to the nearest 50 mg tablet [see 
dosing table in Appendix XI]. 
 
Cyclophosphamide oral solution can be prepared using IV formulation 
(see Section 6.3). When using cyclophosphamide oral solution, doses 
should be rounded to the nearest 1 mg if using 10 mg/mL solution or 
2 mg if using 20 mg/mL solution. If a patient vomits after taking 
cyclophosphamide oral solution, an additional dose should not be taken. 
The next prescribed dose should be taken at the usual time. 
 
4.4.3.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines. 
 
For 
COG 
Supportive 
Care 
Guidelines 
see: 
https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines. 
 
4.4.3.4 Concomitant Therapy Restrictions  
The use of moderate to strong CYP3A4 inducers and inhibitors should 
be avoided during maintenance therapy, if reasonable alternatives exist. 
See Appendix VIII for a list of CYP3A4 inducers and inhibitors. 
Corticosteroids are permitted.  
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
The next cycle of maintenance starts on Day 29 or when starting criteria are met, 
whichever occurs later. 
 
See Section 7.0 for end of therapy evaluations. 
 
 

  
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Regimen C (VAC/VA Only) Cycles 1-4   
4.5 
Regimen C (VAC/VA Only) 
4.5.1 
ARST1431 Regimen C Cycles 1-4 (VAC) 
This therapy delivery map (TDM) relates to Cycles 1-4 of therapy (Weeks 1-12). Each 
cycle lasts 21 days (3 weeks).  
Weeks 1-3 may have been given on Regimen A or B. DO NOT REPEAT Week 1-3 
therapy if already given on Regimen A or B. 
____________________________  
________________________ 
Patient COG ID number  
 
 
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This course 
lasts 84 days and the TDM is described on two pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 1-10 
* Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg.  
DACTINomycin (DACT) 
Slow IV Push 
over 1-5 minutes or IV 
infusion over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 1, 4, 7 and 10. 
Maximum dose: 2.5 mg.  
**Mesna and fluids will be used with CPM. See Appendix VII for specific directions. 
Cyclophosphamide 
(CPM)** 
IV over 60 minutes 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1200 mg/m2/dose 
Day 1 of Weeks 1, 4, 7 and 10. 
 
Start myeloid growth factor support (for example, filgrastim or biosimilar 5 mcg/kg/dose SubQ daily until the ANC is ≥ 2000/μL after the expected nadir or pegfilgrastim or biosimilar 
0.1 mg/kg/dose (for patients < 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards) 24 hours after myelosuppressive chemotherapy (VAC cycles 
only). Filgrastim or biosimilar may be continued without regard to VCR. Discontinue filgrastim or biosimilar at least 24 hours before the start of the next cycle.  
 
Cycle 1 (Week 1): Ht_________cm 
Wt________kg 
BSA_________m2  
 
Cycle 2 (Week 4): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Cycle 3 (Week 7): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 4 (Week 10): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Date 
Due 
Date 
Given 
Cycle 
Week 
Day 
VCR 
______mg 
DACT 
______mg 
CPM 
______mg 
MESNA 
_______mg 
Myeloid growth factor used:_____________ 
 
Calc. dose_______mcg 
Studies 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
Start date 
Stop date 
 
 
 
1 
1 
1 
_____mg 
_____mg 
_____mg 
_____mg_____mg_____mg 
 
 
a-p 
 
 
 
2 
1 
_____mg 
 
 
 
 
 
b 
 
 
 
3 
1 
_____mg 
 
 
 
 
 
b 
 
 
2 
4 
1 
_____mg 
_____mg 
_____mg 
_____mg_____mg_____mg 
 
 
a-c, p 
 
 
 
5 
1 
_____mg 
 
 
 
 
 
b 
 
 
 
6 
1 
_____mg 
 
 
 
 
 
b 
 
 
3 
7 
1 
_____mg 
_____mg 
_____mg 
_____mg_____mg_____mg 
 
 
a-c, p 
 
 
 
8 
1 
_____mg 
 
 
 
 
 
b 
 
 
 
9 
1 
_____mg 
 
 
 
 
 
a, b, f-j 
 
 
4 
10 
1 
_____mg 
_____mg 
_____mg 
_____mg_____mg_____mg 
 
 
a-c 
 
 
 
11 
 
 
 
 
 
 
 
b 
 
 
 
12 
 
 
 
 
 
 
 
b, f 
 
 
 
 
 
Continue to Cycle 5 (Week 13) therapy if all criteria to start the next cycle have been met. 
 
See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines. 
 
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Regimen C (VAC/VA Only) Cycles 1-4   
4.5.2 
Required Observations Prior to and During Cycles 1-4 
NOTE: All baseline radiology reports should be submitted to IROC Rhode Island at the time of 
study enrollment (see Section 16.2.1). 
 
a. 
Physical exam/weight /height. 
b. CBC/diff/platelets 
c. 
Total bilirubin, ALT, creatinine. 
d. Bilateral bone marrow biopsy (not required for patients with ERMS and clinically uninvolved nodes, 
and no lung or bone metastases). Repeat bone marrow examinations are only required in patients who 
had positive bone marrow disease at diagnosis. 
e. 
Cerebrospinal fluid cytology for parameningeal tumors, including orbital site with parameningeal 
extension and paraspinal tumors with dural involvement. 
f. 
MR primary site and regional nodal basin, CT may be considered for intra-abdominal primary. See 
Section 16.0. CT may be used for regional nodes. Post-operative imaging is required at Week 12 
(prior to RT) only for patients who undergo DPE. 
g. CT chest. May be omitted if FDG-PET is performed with diagnostic quality CT. May be omitted for 
patients with ERMS and clinically uninvolved nodes. Repeat CT chest is required only for those 
patients who had lung metastases at diagnosis. See Section 16.0. 
h. FDG-PET with diagnostic quality CT. Patients must have consented to the FDG-PET part of the 
study. See Section 16.0. 
i. 
Bone scan. May be omitted if PET-CT is performed. May be omitted for patients with ERMS and 
clinically uninvolved nodes and no lung metastases. Only needs to be repeated at Week 9 in those 
patients who had bone metastases at diagnosis. See Section 16.0. 
j. 
CT or MRI of regional nodal basin. Week 9. May omit if PET-CT is done. Perform in those patients 
who had clinically involved nodes at diagnosis and in all patients with extremity tumors and those with 
paratesticular tumors who are ≥ 10 years of age. See Section 16.0. 
k. Lymph node biopsy. See Section 13.4.2 for details. Mandatory for extremity tumors, paratesticular 
tumors in patients ≥ 10 years of age regardless of histology; strongly recommended in all patients 
with alveolar histology (particularly if FOXO1 fusion positive) and in those with clinically involved 
nodes regardless of histology or fusion status).  
l. 
Performance status. Use the Lansky performance score if < 16 years of age and the Karnofsky 
performance scale if ≥ 16 years of age. 
m. Tissue submission for biology studies. Identification of fusion partners and variant gene fusions in 
RMS (Required). See Section 15.0. 
n. 
Sperm banking. Recommended for post-pubertal males. 
o. 
Fertility consult. Recommended for patients with abdominal/pelvic disease. 
p. 
Circulating tumor DNA. Patient Consent required. Samples must be drawn within 7 days prior to starting 
therapy (Day 1), Week 4, and 7 prior to chemotherapy on that day. See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and secondary aims. 
OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
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Regimen C (VAC/VA Only) Cycles 1-4   
 
4.5.3 
Regimen C (VAC/VA Only) Administration Details for Cycles 1-4 
ARMS FOXO1 fusion negative patients with the following Stage and Group are 
eligible to receive VAC/VA therapy on Regimen C instead of the previously 
assigned treatment regimen: 
x 
Stage 1, Group I/II 
x 
Stage 1, Group III (orbit) 
x 
Stage 2, Group I/II 
 
Patient consent is required to transfer to Regimen C and transfer must occur prior 
to Week 4 of protocol therapy. 
 
Each cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. This 
course will take a minimum of 12 weeks (84 days). 
 
4.5.3.1 Criteria to Start Each Cycle 
4.5.3.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL 
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to > 750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.5.3.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.5.3.2 Treatment 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
 
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 1 through Week 10.  
Dose: BSA-based dosing 
VINCRISTINE  
BSA (m2) 
Dose 
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg  
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 

  
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Regimen C (VAC/VA Only) Cycles 1-4   
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 1, 4, 7 and 10. 
Dose: Weight-based dosing 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 
Cyclophosphamide: IV over 60 minutes 
Day: 1 of Weeks 1, 4, 7 and 10. 
Dose: BSA-based dosing 
CYCLOPHOSPHAMIDE  
BSA (m2) 
 Dose  
0.25-0.29 
220 mg 
0.3-0.34 
280 mg 
0.35-0.39 
360 mg 
0.4-0.44 
440 mg 
0.45-0.49 
520 mg 
0.5-0.54 
600 mg 
0.55-0.59 
660 mg 
≥ 0.6 
1200 mg/m2  
Note: Mesna and fluids will be used with cyclophosphamide. See 
Appendix VII for specific directions. 
 
4.5.3.3 Supportive Care 
Please see Appendix VII for protocol-specific supportive care 
guidelines, including administration of mesna and myeloid growth 
factor support during VAC cycles. In addition, for COG Supportive 
Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines. 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
Following the Week 9 evaluations and the completion of Cycle 4, select patients 
may be considered for delayed primary excision for non-PM primary sites when 
GTR can be easily performed with minimal morbidity or loss of function and 
with minimal disruption to the overall treatment scheme. Surgical intervention 
where gross tumor is left behind is absolutely discouraged. For patients who 
achieve GTR confirmed by postoperative CT or MRI scan, the dose of RT will 
be reduced (see Section 17.0 for details). 
 

  
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Regimen C (VAC/VA Only) Cycles 5-8   
 
4.5.4 
ARST1431 Regimen C Cycles 5-8 (VA) 
This therapy delivery map (TDM) relates to Cycles 5-8 of therapy (Weeks 13-24). Each 
cycle lasts 21 days (3 weeks).  
____________________________  
________________________ 
Patient COG ID number  
 
 
DOB 
Criteria to start each cycle of therapy: Chemotherapy cycles may begin when the ANC ≥ 750/μL and platelets ≥ 75,000/μL after nadir. Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age. This course 
lasts 84 days and the TDM is described on two pages. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
VinCRIStine (VCR) 
IV Push over 1 minute* 
BSA < 0.6 m2: BSA-based dosing, see dosing table 
BSA ≥ 0.6 m2: 1.5 mg/m2/dose 
Day 1 of Weeks 13-22 
*Or infusion via minibag as per institutional policy 
Maximum dose: 2 mg.  
DACTINomycin 
(DACT) 
Slow IV Push 
over 1-5 minutes or IV 
infusion over 10-15 minutes 
Weight < 14 kg: Weight-based dosing, see dosing table 
Weight ≥ 14 kg: 0.05 mg/kg/dose 
Day 1 of Weeks 13, 16, 19 and 22. 
Maximum dose: 2.5 mg. Give the Week 13 dose of DACT 
before beginning radiation therapy. Omit Week 16 DACT 
during radiation therapy. Omit Week 19 DACT only if 
radiation therapy continues into Week 19. 
For patients receiving liver irradiation, see Section 4.7.3.2. 
 
Cycle 5 (Week 13): Ht_________cm 
Wt________kg 
BSA_________m2  
 
Cycle 6 (Week 16): Ht_________cm 
Wt________kg 
BSA_________m2 
 
Cycle 7 (Week 19): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
Cycle 8 (Week 22): Ht_________cm 
Wt________kg 
BSA_________m2 
 
 
 
Date Due 
Date Given 
Cycle 
Week 
Day 
VCR 
______mg 
DACT 
______mg 
Studies 
 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
5 
13 
1 
_____mg 
_____mg 
a-c 
 
 
 
14 
1 
_____mg 
 
b 
 
 
 
15 
1 
_____mg 
 
b 
 
 
6 
16 
1 
_____mg 
_____mg 
a-c 
 
 
 
17 
1 
_____mg 
 
b 
 
 
 
18 
1 
_____mg 
 
b 
 
 
7 
19 
1 
_____mg 
_____mg 
a-c, g 
 
 
 
20 
1 
_____mg 
 
a, b 
 
 
 
21 
1 
_____mg 
 
b 
 
 
8 
22 
1 
_____mg 
_____mg 
a-c 
 
 
 
24 
 
 
 
a, b, d-g 
See Section 5.0 for Dose Modifications for Toxicities and Appendix VII for Supportive Care Guidelines. 
 
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Regimen C (VAC/VA Only) Cycles 5-8   
4.5.5 
Required Observations Prior to and During Cycles 5-8 
 
a. Physical exam/weight /height. 
b. CBC/diff/platelets. 
c. Total bilirubin, ALT & creatinine. 
d. MR primary site and regional nodal basin, CT may be considered for intra-
abdominal primary. See Section 16.0. 
e. CT chest. May be omitted if FDG-PET is performed with diagnostic quality 
CT. May be omitted for patients with ERMS and clinically uninvolved 
nodes. See Section 16.0. 
f. CT or MRI of regional nodal basin. May omit if PET-CT is done. Perform in 
those patients who had clinical involved nodes at diagnosis and in all patients 
with extremity tumors and those with paratesticular tumors who are ≥ 10 years 
of age. See Section 16.0. 
g. Circulating tumor DNA. Patient Consent required. Sample must be drawn at 
Week 19 and end of protocol therapy. See Section 15.2. 
 
This listing only includes evaluations necessary to answer the primary and 
secondary aims. OBTAIN OTHER STUDIES AS REQUIRED FOR GOOD 
CLINICAL CARE.  
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Regimen C (VAC/VA Only) Cycles 5-8   
 
4.5.6 
Regimen C (VAC/VA Only) Administration Details for Cycles 5-8 
Each cycle in ARST1431 is a minimum of 3 weeks (21 days) duration. This 
course will take a minimum of 12 weeks (84 days). 
 
4.5.6.1 Criteria to Start Each Cycle 
4.5.6.1.1 Adequate bone marrow function defined as:  
- Peripheral absolute neutrophil count (ANC) ≥ 750/μL  
- Platelet count ≥ 75,000/μL 
 
NOTE: 
The ANC frequently falls after discontinuing myeloid 
growth factor support (secondary neutrophil nadir). If the 
ANC recovers to > 750/μL after nadir but then falls to 
< 750/μL after the myeloid growth factor is stopped, the next 
cycle of therapy can be given despite ANC < 750/μL if all 
other criteria for the next cycle of chemotherapy are met. No 
dose 
modification 
should 
be 
made 
under 
these 
circumstances. 
 
4.5.6.1.2 Adequate liver function defined as: 
- Total bilirubin d 1.5 x upper limit of normal (ULN) for age 
 
4.5.6.2 Treatment 
Radiotherapy (RT) 
RT begins at Cycle 5 (Week 13) and may last up to 6.5 weeks for all 
patients. See Section 17.0 for RT guidelines. 
 
Give the Week 13 dose of dactinomycin before beginning RT. Omit 
Week 16 dactinomycin during RT. Omit Week 19 dactinomycin only if 
RT continues into Week 19. 
 
Note: For patients receiving liver RT, reduce the dactinomycin dose by 
50% for the next cycle (for example, if the full dactinomycin dose is 
1.5 mg, then administer 0.7-0.8 mg for a 50% dose reduction) and 
increase by 25% (for example, if the 50% dose is 0.7-0.8 mg, then 
administer 0.9-1 mg to increase the dosage by 25%), if tolerated, up to 
full dose for subsequent cycles. No reductions of vincristine or 
cyclophosphamide are needed unless total bilirubin is elevated (see 
Section 5.3.1). 
 
Chemotherapy 
The dose should be calculated on Day 1 of each cycle and not adjusted 
solely for weight during the cycle. 
 

  
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Regimen C (VAC/VA Only) Cycles 5-8   
VinCRIStine: IV Push over 1 minute (or infusion via minibag as per 
institutional policy) weekly 
Day: 1 of Week 13 through Week 22.  
Dose: BSA-based dosing 
VINCRISTINE  
BSA (m2) 
Dose  
0.25-0.29 
0.24 mg 
0.30-0.34 
0.34 mg 
0.35-0.39 
0.44 mg 
0.40-0.44 
0.55 mg 
0.45-0.49 
0.65 mg 
0.50-0.54 
0.74 mg 
0.55-0.59 
0.8 mg 
≥ 0.6 
1.5 mg/m2 (maximum 2 mg) 
 
DACTINomycin: Slow IV Push over 1-5 minutes or IV infusion over 
10-15 minutes 
Day: 1 of Weeks 13, 16, 19 and 22. 
Dose: Weight-based dosing 
DACTINOMYCIN  
Weight (kg) 
Dose  
3 – 4.5 
0.09 mg 
4.6 – 6 
0.14 mg 
6.1 – 7.3 
0.21 mg 
7.4 – 8.6 
0.26 mg 
8.7 – 9.9 
0.33 mg 
10- 11.2 
0.4 mg 
11.3 -12.5 
0.5 mg 
12.6 – 13.9 
0.6 mg 
≥ 14  
0.05 mg/kg (maximum 2.5 mg) 
 
4.5.6.3 Supportive Care 
For COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines. 
 
 
See Section 5.0 for Dose Modifications based on Toxicities.  
 
 

  
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5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
5.1 
Dose Limiting Toxicity for Temsirolimus 
The following will be considered non-hematological dose limiting toxicities (DLTs) and 
will be monitored in real time via AERS reporting: 
 
x
Grade ≥ 3 mucositis  
x
Grade ≥ 3 pulmonary events 
x
Grade 3 hyperglycemia (requiring hospitalization for control) 
x
Grade ≥ 4 hyperglycemia 
x
Grade ≥ 4 cholesterol high (hypercholesterolemia) or hypertriglyceridemia that does 
not return to ≤ Grade 2 levels with appropriate medical management within 35 days 
x
Grade ≥ 3 proteinuria 
 
Patients who experience pulmonary events, hyperglycemia, or proteinuria as described 
above will be dose-modified as follows: 
x 
If toxicity resolves to baseline or Grade 1 before the next cycle of therapy, then 
temsirolimus will resume at 100% (full) dose in subsequent cycles unless 
otherwise specified. 
x 
Patients who are receiving temsirolimus on Days 1, 8, and 15 who experience the 
same non-hematological DLT for a second time will reduce the dose by one dose 
level (see Section 5.2). Patients who experience the same DLT again (3rd time) 
will change the temsirolimus schedule to Days 1 and 8 only (see Section 5.2) and 
maintain this new schedule for all subsequent therapy. Patients who experience 
the same DLT again (4th time) will remain on study but will discontinue 
temsirolimus and receive VAC/VI only. 
x 
If toxicity does not resolve by the next cycle, then the temsirolimus dose should 
also be reduced to the next dose level (see Section 5.2). 
 
In all cases, temsirolimus will be held until toxicity resolves to baseline or Grade 1, but 
the rest of chemotherapy (VAC or VI or V) will continue as planned. The dose of 
temsirolimus to restart is as described above. 
 
See Section 5.2.4 below for dose modifications for mucositis and Section 5.2.6 below for 
dose modifications for hypercholesterolemia and hypertriglyceridemia. 
 
All other non-hematological toxicities attributable to temsirolimus must resolve to 
≤ Grade 1 or baseline to resume temsirolimus. Dose modifications for temsirolimus are as 
per the guidelines above. 
 
5.1.1 
Additional Important Dose Limiting Toxicities for Temsirolimus 
In subjects that are receiving temsirolimus, the following adverse events (AEs) 
will also be considered dose-limiting irrespective of their attribution to 
temsirolimus and will be monitored in real time via AERS reporting. If any of 
these AEs occur, temsirolimus will be discontinued and VAC/VI chemotherapy 
will resume when the patient is clinically well enough to start and counts have 
recovered as outlined under criteria to start each cycle in the relevant treatment 
section. 

  
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x
Any visceral perforation including fistula or leak (gastrointestinal or any 
other organ) 
x
Any intra-abdominal abscess/infection 
x
Grade ≥ 2 wound dehiscence 
x
Grade ≥ 3 wound infection - requiring IV antibiotics 
 
5.2 
Dose Modifications for Temsirolimus on Regimen B during VAC/VI Cycles 
The anticipated toxic effects of temsirolimus include: pancytopenia, hypertension, 
hypotension, fatigue, fever, rash/desquamation, pruritis, acne/acne-like rash, urticaria, 
nail disorder, anorexia, nausea, diarrhea, stomatitis/pharyngitis, vomiting, dysgeusia, 
infection 
without 
neutropenia, 
hypercholesterolemia, 
hyperglycemia, 
hypertriglyceridemia, hypophosphatemia, conjunctivitis, chest pain (non-cardiac, non-
pleuritic), headache, abdominal pain, back pain, pneumonitis, pulmonary infiltrates, 
cough, alveolitis, dyspnea, and respiratory failure. 
 
In the event of any Grade ≥ 3 non-hematological toxicity, the doses of temsirolimus will 
be adjusted according to the guidelines described in Section 5.1.  
 
Dose levels will be as shown in the table below. No dose escalations are permitted after 
reductions for confirmed toxicity. Dose modifications for hematological toxicity are 
based on the blood counts obtained on the day of treatment. 
 
Patients with toxicities that are manageable with supportive therapy may not require dose 
reductions (e.g., hypertriglyceridemia or cholesterol high). Patients requiring dose 
reductions will not have the dose re-escalated with subsequent treatments. 
 
Dose reductions will be made based on the following schema: 
 
 
5.2.1 
Hematological Toxicity – Regimen B 
Day 1 only 
Recovery of ANC to ≥ 750/μL and platelets ≥ 75,000/μL is required at the start 
of each cycle (VAC or VI). If a cycle is delayed more than 14 days*, HOLD 
temsirolimus for 1 cycle and resume temsirolimus at Dose Level 0. If a 
subsequent cycle is delayed more than 14 days*, discontinue temsirolimus. 
Patient will remain on study and receive VAC/VI alone. 
 
Patients < 10 kg: 
Dose Level 
 
Temsirolimus Dose 
        1 
 
 
0.5 mg/kg IV, Days 1, 8 and 15 of each cycle  
        0 
 
 
0.33 mg/kg IV, Days 1, 8 and 15 of each cycle 
       -1  
 
0.33 mg/kg IV, Days 1 and 8 of each cycle 
 
Patients ≥ 10 kg: 
Dose Level 
 
Temsirolimus Dose 
        1 
 
 
15 mg/m2 IV, Days 1, 8 and 15 of each cycle  
        0 
 
 
10 mg/m2 IV, Days 1, 8 and 15 of each cycle 
       -1  
 
10 mg/m2 IV, Days 1 and 8 of each cycle 

  
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*Note: The rule of 14 days applies only to hematological toxicity. For non-
hematological toxicity, please refer to the guidelines in Section 5.1. 
 
Days 8, 15 
Give temsirolimus regardless of ANC or platelet count. 
 
5.2.2 
Idiosyncratic Infusion-Related Reactions 
Reactions to temsirolimus that begin shortly after the start of the infusion and end 
after stopping the infusion have been reported but are NOT considered dose 
limiting. Signs and symptoms include flushing of the face and neck (sometimes 
also the extremities and trunk); descriptions of feeling hot, uncomfortable, and/or 
anxious; chest pain/tightness; shortness of breath; decrease in oxygen saturation 
and cyanosis; hypotension; lightheadedness; periorbital puffiness; descriptions of 
feeling like the head is swelling; nausea; back pain; numbness and tingling of 
hands/feet/face; and difficulty speaking.  
 
Because 
of 
these 
idiosyncratic 
reactions, 
patients 
will 
receive 
diphenhydramine IV approximately 30 minutes before the start of the 
temsirolimus infusion.  
 
Patients who experience Grade 1 or 2 infusion-related reaction to temsirolimus, 
may resume drug as deemed safe by treating physician. Patients who experience 
≥ Grade 3 or life-threatening infusion-related reaction should discontinue 
temsirolimus and will remain on study and receive VAC/VI alone. Infusion-
related reactions of any grade are not considered a DLT and dose of temsirolimus 
will not be reduced. 
 
Grade of Infusional 
Reaction 
Action 
Grade 1 Mild transient 
reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
or  
 
Grade 2 Therapy or 
infusion interruption 
indicated but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs 
If a patient develops an infusion-related reaction despite diphenhydramine 
pretreatment, stop infusion, wait 30-60 minutes (depending upon the reaction 
severity). At physician’s discretion, it may be possible to resume treatment by 
administering an H2 blocker approximately 30 minutes before restarting the 
infusion. Suggest: famotidine 0.5 mg/kg IV (max. 20 mg). If famotidine 
unavailable, administer ranitidine 1-2 mg/kg IV (max. 50 mg).  
 
Re-attempt infusion at a slower rate, possibly over 60 minutes. If Grade 1-2 
infusion reactions recur with subsequent dose, add dexamethasone 0.2 mg/kg 
(max 10 mg) IV or equivalent to premedications above.  
(Only dose interruption/discontinuation, but not dose reduction, is required for 
allergic/infusional reactions) 

  
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Grade 3 Prolonged (e.g., 
not rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for clinical sequelae 
Stop infusion immediately. Administer dexamethasone 0.2 mg/kg (max 10 mg) 
IV (or equivalent), bronchodilators for bronchospasms, and other medications as 
medically indicated.  
 
Patient should discontinue temsirolimus. Patient should stay on study and receive 
VAC/VI alone. 
Grade 4 Life-threatening 
consequences; urgent 
intervention indicated 
Stop infusion immediately. Administer dexamethasone 0.2 mg/kg (max 10 mg) 
IV (or equivalent), and other anaphylaxis medications as indicated. Epinephrine 
or bronchodilators should be administered as indicated.  
 
Patient should discontinue temsirolimus. Patient should stay on study and receive 
VAC/VI alone. 
 
5.2.3 
Pneumonitis/Pulmonary Infiltrates on Temsirolimus 
Pneumonitis/pulmonary infiltrates and alveolitis have been reported among 
cancer patients receiving temsirolimus. Some patients have been asymptomatic 
with pneumonitis detected incidentally on CT scan or chest x-ray, while others 
have had symptoms of dyspnea, cough, and fever. In this situation, temsirolimus 
is discontinued and patients are treated with steroids and/or antibiotics. If a 
patient experiences these symptoms, temsirolimus will be discontinued, and the 
patient will remain on study and receive VAC/VI alone.  
 
5.2.4 
Mucositis 
The development of mucositis in patients receiving temsirolimus plus VAC/VI is 
of greatest concern. Special attention is required to prevent mucositis and treat it 
aggressively when it occurs in order to avoid treatment delays, dose reduction, 
and morbidity. (See Appendix VII for mucositis management guidelines.) 
 
Grade 
Action 
Grade 1 – mild, 
asymptomatic 
Continue full dose temsirolimus. 
Use conservative measures such as non-alcoholic mouth wash or salt water (0.9%) 
mouth wash several times a day until resolution. 
Grade 2 - Moderate pain 
or ulcer that does not 
interfere with oral intake; 
modified diet indicated 
Continue full dose temsirolimus. 
Topical analgesic mouth treatments (i.e., local anesthetics such as benzocaine, 
butyl aminobenzoate tetracaine hydrochloride, menthol, or phenol) may be used 
with or without topical corticosteroids, such as triamcinolone oral paste 0.1% 
(Kenalog in Orabase®). Agents containing hydrogen peroxide, iodine, and thyme 
derivatives may worsen mouth ulcers and should not be used. Ensure good 
nutritional support. 
Grade 3/4 - Severe pain; 
interfering with oral 
intake 
Hold temsirolimus until resolves to < Grade 1. 
Restart temsirolimus at next lower dose. 
If Grade 3/4 mucositis recurs at lower dose, discontinue temsirolimus. 
 
Please note the following: 
x
If fungal or viral infections are suspected, appropriate mouth swabs should 
be obtained. Empiric treatment of these infections with systemic agents 
should be avoided unless infection is documented. 

  
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x
Systemic 
imidazole 
antifungal 
agents 
(ketoconoazole, 
fluconazole, 
itraconazole, etc.) should be avoided due to their strong inhibition of 
temsirolimus metabolism, therefore leading to higher temsirolimus exposure. 
Echinocandins are preferred if an infection is diagnosed.70  
x
Acyclovir can be added if HSV or CMV is confirmed.  
 
5.2.5 
Hyperglycemia 
Grade of Hyperglycemia 
Action 
Grade 2  
Change in daily management from baseline 
for a diabetic; oral antiglycemic agent 
initiated; workup for diabetes 
Initiate oral antiglycemic agent.* 
Grade 3 
Insulin therapy initiated; hospitalization 
indicated 
Initiate insulin therapy. Hold temsirolimus until ≤ Grade 1 
and the patient is judged to be suitable for retreatment. 
Resume temsirolimus at same dose IF patient is 
asymptomatic, AND fasting serum glucose is ≤ Grade 1 and 
recovery takes ≤ 7 days.  
 
The patient may continue to receive concomitant insulin or 
an oral diabetic agent for the management of hyperglycemia 
while receiving temsirolimus.  
 
If Grade 3/4 hyperglycemia recurs, then patient will 
discontinue temsirolimus and remain on study and receive 
VAC/VI alone. 
Grade 4  
Life-threatening consequences; urgent 
intervention indicated 
Discontinue temsirolimus. 
*Recommended guidelines for use of oral diabetic agents: 
x
Initiation of treatment for hyperglycemia should occur under the guidance of a pediatric 
endocrinologist. Metformin may be used per local endocrinologist’s recommendations. 
x
Other oral anti-hyperglycemic agents may be used.  
x
Insulin therapy should be directed by specialists in pediatric diabetes with the goal of normal 
fasting blood sugars < 126 mg/dL and HgbA1C < 8%. 
 
5.2.6 
Cholesterol High and Hypertriglyceridemia 
Cholesterol high 
Grade 
Action 
Grade 1 
cholesterol high 
> ULN - 300 mg/dL;  
> ULN - 7.75 mmol/L 
No change. 
Grade 2  
cholesterol high 
> 300 - 400 mg/dL;  
> 7.75 - 10.34 mmol/L 
Continue temsirolimus; consider treatment with a cholesterol lowering 
agent depending upon recommendations of institutional consultants. 
Grade 3 
cholesterol high 
> 400 - 500 mg/dL;  
> 10.34 - 12.92 mmol/L 
Continue temsirolimus; A cholesterol lowering agent should be started, 
and dosages adjusted based upon recommendations of institutional 
consultants. It is expected that optimal effects of the lipid lowering 
medication will be observed 2-4 weeks after its initiation. Treatment with 
temsirolimus 
can 
continue 
during 
this 
time 
provided 
that 
hypercholesterolemia remains ≤ Grade 3. 

  
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Grade 4 
cholesterol high 
> 500 mg/dL; 
> 12.92 mmol/L 
Hold temsirolimus; 
A cholesterol lowering agent should be started, and dosages should be 
adjusted based upon recommendations from institutional consultants. It is 
expected that optimal effect of the lipid lowering medication will be 
observed 2-4 weeks after initiation. Temsirolimus is to be resumed at the 
same dose when recovery to ≤ Grade 3 fasting cholesterol is observed. 
Upon retreatment with temsirolimus concurrent with a lipid lowering 
agent if Grade 4 elevations recurs, temsirolimus should be held until 
recovery to ≤ Grade 3. Further lipid lowering medication options should 
be discussed with institutional consultants. Upon recovery to ≤ Grade 3 
fasting cholesterol, temsirolimus should be resumed at next lower dose 
level. 
If the toxicity recurs, hold temsirolimus while continuing cholesterol 
lowering agent until fasting cholesterol is < Grade 3 and then resume 
temsirolimus at next lower dose level. 
If Grade 4 hypercholesterolemia recurs following this dose adjustment, 
discontinue temsirolimus and patient will remain on study to receive 
VAC/VI only.  
Hypertriglyceridemia 
Grade 
Action 
Grade 2  
hypertriglyceridemia 
> 300 mg/dL – 500 mg/dL;  
> 3.42 mmol/L - 5.7 mmol/L 
Continue temsirolimus; consider treatment with a triglyceride lowering 
agent depending upon recommendations of institutional consultants.  
Grade 3 
hypertriglyceridemia 
> 500 mg/dL – 1000 mg/dL; 
> 5.7 mmol/L - 11.4 mmol/L 
 
OR 
 
Grade 4 
hypertriglyceridemia 
> 1000 mg/dL;  
> 11.4 mmol/L;  
life-threatening consequences 
Hold temsirolimus until recovery to ≤ Grade 2; 
A triglyceride lowering agent should be started, and dosages should be 
adjusted based upon recommendations from institutional consultants. 
Upon retreatment at the same dose level, if Grade 3 or 4 toxicity recurs, 
lipid lowering medication should be adjusted in consultation with 
institutional consultants. Temsirolimus should be held until recovery to 
≤ Grade 2 and resumed at next lower dose level. 
 
Upon retreatment with temsirolimus concurrent with a triglyceride 
lowering agent if Grade 3 or 4 elevations recur, temsirolimus should be 
held until recovery to ≤ Grade 2 and the triglyceride lowering agents 
continued. 
Upon recovery to ≤ Grade 2, temsirolimus should be resumed at next 
lower dose level. If Grade 3 or 4 hypertriglyceridemia recurs, discontinue 
temsirolimus and patient will remain on study to receive VAC/VI only. 
 
5.2.7 
Wound Dehiscence 
mTOR inhibitors directly inhibit wound healing,71 and thus if a patient 
experiences wound dehiscence (≥ Grade 2), there is little likelihood that the 
wound will close while still receiving the drug. Therefore, in patients with 
≥ Grade 2 wound dehiscence, temsirolimus should be held until the wound is 
completely closed and healed. Temsirolimus can be restarted at the same dose 
once the wound is healed. If wound re-opens (≥ Grade 1), discontinue 
temsirolimus and continue VAC/VI alone.  
 
5.2.8 
Wound Infection 
If a superficial wound infection occurs (Grade 2), hold temsirolimus until 
resolves, then restart at full dose. If infection recurs, hold until it resolves and 

  
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resume at next lower dose level. If infection again recurs, patient will discontinue 
temsirolimus, and remain on study to receive VAC/VI alone.  
 
5.2.9 
Hyperbilirubinemia 
In patients with mild hepatic impairment (total bilirubin > 1 to 1.5 x ULN) 
decrease temsirolimus dose by 40% (e.g., 9 mg/m2/dose up to a max of 
15 mg/dose for Dose Level 1).  
 
If total bilirubin is > 1.5 × ULN prior to chemotherapy, omit temsirolimus dose. 
If temsirolimus dose is omitted because of hyperbilirubinemia, subsequent doses 
should be based on above criteria, i.e., if bilirubin returns to normal the full dose 
of temsirolimus is to be given.  
 
5.2.10 Interstitial Lung Disease 
Consider withholding temsirolimus for clinically significant respiratory 
symptoms until after recovery of symptoms or radiographic improvement. 
 
5.3 
Non-Hematological Dose Modifications for VAC/VI Cycles  
Toxicity 
Dose Modification 
Hematuria  
Transient microscopic hematuria (≥ 50 rbc/hpf 1 or 2 times): double rate of 
post-hydration; give mesna as continuous infusion at 60% of the 
cyclophosphamide dose over 8 hours. 
 
Persistent microscopic hematuria: (≥ 50 rbc/hpf ≥ 3 times): double rate of 
post-hydration, continue for 24 h, and give mesna as 100% of the 
cyclophosphamide dose over 24 h. 
 
Transient gross hematuria: as per persistent microscopic hematuria. 
 
Persistent gross hematuria: discontinue cyclophosphamide until urine clears 
to microscopic hematuria; resume at 50% of full dose with post-hydration 
and mesna as for persistent microscopic hematuria; escalate dose to 75% and 
100% of full dose as tolerated. Consider urology consultation. 
 
Consider continuous infusion of mesna for subsequent cycles (see Appendix 
VII). 
Neurotoxicity 
See Section 5.8 for vincristine dose modifications. 
No dose reduction for dactinomycin, irinotecan. 
Jaw Pain 
No dose reduction; offer analgesia. 
Grade ≥ 3 Mucositis 
Hold dactinomycin and cyclophosphamide until resolves to < Grade 1. 
No dose reduction for vincristine, irinotecan. 
Review mucositis guidelines in Appendix VII. 
Creatinine clearance 
< 10 mL/min/1.73 m2 
Reduce cyclophosphamide by 25%. 
No dose reduction for vincristine, dactinomycin, irinotecan. 
Grade ≥ 3 diarrhea related to 
irinotecan despite antibiotic 
prophylaxis 
Reduce dose of irinotecan by 30% 
 

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5.4
Hematological Dose Modifications for VAC/VI Cycles – Regimen A
Note: recovery of ANC to ≥ 750/μL and platelets ≥ 75,000/μL is required at the start of 
each cycle (VAC or VI). 
Day 1 ANC < 750/uL
Delay chemotherapy by 1 week. If recovered, proceed at full dose.
If ANC recovery is delayed by > 1 week following VAC cycle, reduce the 
dose of dactinomycin and cyclophosphamide by 25% during next cycle of 
VAC. If If ANC recovery is delayed by > 1 week following VI cycle, add 
myeloid growth factor support (filgrastim, pegfilgrastim or biosimilars)
prior to subsequent VI cycles. Do not reduce dose of irinotecan.
If subsequent cycle is also delayed, reduce dose of chemotherapy (except 
vincristine) by 30% for next cycle. For example, if preceding cycle is VAC, 
dose reduce cyclophosphamide and dactiomycin by an additional 30% each 
in the next VAC cycle. If preceding cycle was VI, reduce irinotecan by 
30% for next VI. 
Day 1 Platelets < 75,000/μL
Delay chemotherapy by 1 week. If recovered, proceed at full dose. 
If 
platelets 
not 
recovered, 
reduce 
dose 
of 
dactinomycin 
and 
cyclophosphamide by 25% or irinotecan by 30% for next cycle for which 
the same drug is due. ie. if preceding cycle is VAC, dose reduce next VAC. 
If preceding cycle was VI, reduce irinotecan for next VI. .
Please note the following:
Weekly vincristine doses should be given regardless of blood counts.
The ANC frequently falls after discontinuing myeloid growth factor support
(secondary neutrophil nadir). If the ANC recovers to ≥750/μL after nadir but then 
falls to < 750/μL after the myeloid growth factor is stopped, the next cycle of therapy 
can be given despite ANC < 750/μL if all other criteria for the next cycle of 
chemotherapy are met. No dose modification should be made under these
circumstances.
See Section 17.7.10 for guidelines for radiation treatment modifications due to low 
blood counts.
5.5
Dose Modifications for Vincristine, Dactinomycin, and Irinotecan in Patients with 
Hyperbilirubinemia Secondary to Biliary Obstruction due to Tumor and Other 
Situations with Elevated Bilirubin
Please note: Cyclophosphamide dose is not adjusted for hepatic dysfunction.
Direct bilirubin 
[mg/dL]
Direct bilirubin
[micromole/L]
Dose to give
< 3.0
< 53
Full dose
3.1 – 5.0
54-85
50% of calculated dose
5.1 – 6.0
86-102
25% of calculated dose
> 6.0
> 102
Omit dose
Note: If bilirubin falls prior to subsequent cycles, increase the dose as indicated above in 
next cycle.

  
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5.6 
Dose Modifications for Patients who Receive Liver Irradiation 
After completion of liver irradiation, reduce the dactinomycin dose by 50% for the next 
cycle (for example, if the full dactinomycin dose is 1.5 mg, then administer 0.7-0.8 mg 
for a 50% dose reduction) and increase by 25% (for example, if the 50% dose is 
0.7-0.8 mg, then administer 0.9-1 mg to increase the dosage by 25%), if tolerated, up to 
full dose for subsequent cycles. No reductions of vincristine or cyclophosphamide are 
needed unless total bilirubin is elevated (see Section 5.5). 
 
5.7 
Dose Modifications for Hepatopathy 
It appears that hepatopathy is closely related to the administration of VAC. Patients of 
young age appear to be at increased risk. A prior persistent or slow recovery of 
thrombocytopenia may be an indicator of hepatopathy. 
 
5.7.1 
Criteria for Diagnosis of Hepatopathy 
Pathologic confirmation by liver biopsy OR 
Reversal of portal venous flow by ultrasound OR 
Two or more of the following: 
1. Bilirubin > 1.4 mg/dL. 
2. Unexplained weight gain greater than 10% of baseline weight or ascites. 
3. Hepatomegaly or RUQ pain without other explanation. 
 
5.7.2 
Grading Criteria for Hepatopathy 
 
Mild Hepatopathy 
Total bilirubin < 6 mg/dL 
Weight gain of < 5% of baseline of non-cardiac origin 
Reversible hepatic dysfunction 
 
Moderate Hepatopathy 
Total bilirubin > 6 mg/dL and < 20 mg/dL 
Weight gain > 5% of baseline of non-cardiac origin 
Clinical or image documented ascites 
Reversible hepatic dysfunction 
 
Severe Hepatopathy 
Total bilirubin > 20 mg/dL and/or 
Ascites compromising respiratory function and/or 
Renal deterioration and/or 
Hepatic encephalopathy which may or may not be 
reversible 
 
5.7.3 
Therapy Modification for Hepatopathy 
Since hepatopathy most likely results from a combination of factors including 
dactinomycin, cyclophosphamide and vincristine, the following therapy 
modifications should be taken in the presence of this complication. 
 
 
 
Mild Hepatopathy 
Half drug dose of dactinomycin and cyclophosphamide 
(age adjusted per Section 4.2.3.2) for the next course (for 
example, if the full dactinomycin dose is 1.5 mg, then 
administer 0.8 mg for a half-dose; and if the full 
cyclophosphamide dose is 1200 mg, then administer 
600 mg for a half-dose) and then resume full doses per 
course if tolerated.  
 
Moderate Hepatopathy 
Discontinue VAC. Patient will be removed from protocol 
therapy.  
 
Severe Hepatopathy 
Discontinue VAC. Patient will be removed from protocol 
therapy.  

  
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5.8 
Neurotoxicity Secondary to Vincristine 
5.8.1 
Neuropathy: (see grading scale below) 
x 
Grade 2 motor or sensory neuropathies (see neuropathy grading scale 
below): give 50% of full dose; increase to 75% of full dose when signs and 
symptoms improve to Grade 1 or resolve; increase dose to 100% after 
2 additional doses of vincristine if signs and symptoms remain at Grade 1 or 
resolve. Hold the dose if symptoms worsen. 
x 
Grade 3 neuropathies (see neuropathy grading scale below): omit doses until 
signs and symptoms improve to Grade 2, then resume at 50% of full dose 
and manage as above. 
x 
Constipation: Give 50% dose if stimulant laxatives (e.g. senna) do not 
preserve bowel motility; omit dose if manual disimpaction is required or if 
ileus occurs. 
x 
Jaw pain: Avoid dose modifications; try chewing gum, gabapentin, and/or 
pain medication instead. 
 
5.8.2 
Neuropathy grading: 
Motor neuropathy: 
x 
Grade 1: Subjective weakness, but no deficits on neurological exam 
x 
Grade 2: Weakness that alters fine motor skills (buttoning shirt, writing or 
drawing, using eating utensils) or gait without abrogating ability to perform 
these tasks. 
x 
Grade 3: Unable to perform fine motor tasks (buttoning shirt, writing or 
drawing, using eating utensils) or unable to ambulate without assistance. 
x 
Grade 4: Paralysis 
Sensory neuropathy: 
x 
Grade 1: Paresthesias, pain, or numbness that do not require treatment or 
interfere with extremity function. 
x 
Grade 2: Paresthesias, pain, or numbness that is controlled by non-
narcotic medications, or alter (without causing loss of function) fine motor 
skills (buttoning shirt, writing or drawing, using eating utensils) or gait, 
without abrogating ability to perform these tasks. 
x 
Grade 3: Paresthesias or pain that is controlled by narcotics, or interfere 
with extremity function (gait, fine motor skills as outlined above), or quality 
of life (loss of sleep, ability to perform normal activities severely impaired). 
x 
Grade 4: Complete loss of sensation or pain that is not controlled by 
narcotics 
 
5.9 
Dose Modifications for Maintenance Therapy – Regimens A & B 
5.9.1 
Hematological Toxicity 
CBC needs to be checked weekly during maintenance therapy. Hold oral 
cyclophosphamide 
if 
ANC < 750/μL 
or 
platelets < 75,000/μL. 
Resume 
cyclophosphamide once counts have recovered. 

  
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If cyclophosphamide is held for > 7 consecutive days during any cycle, hold 3rd 
dose of vinorelbine (Day 15) for next cycle only. 
 
If vinorelbine dose was held during a prior cycle and needs to be held a second 
time, reduce the dose of vinorelbine to 75% of calculated dose for all subsequent 
cycles and omit 3rd dose of vinorelbine (Day 15) for all subsequent cycles. 
 
5.9.2 
Dose Modifications for Vinorelbine in Patients with Hyperbilirubinemia 
Secondary to Biliary Obstruction due to Tumor and Other Situations with 
Elevated Bilirubin 
Please note: Cyclophosphamide dose is not adjusted for hepatic dysfunction. 
 
Direct bilirubin 
[mg/dL] 
Direct bilirubin 
[micromole/L] 
Dose to give 
≤ 3.0 
< 53 
Full dose 
3.1 – 5.0 
54-85 
50% of calculated dose 
5.1 – 6.0 
86-102 
25% of calculated dose 
> 6.0 
> 102 
Omit dose 
Note: If bilirubin falls prior to subsequent cycles, increase the dose as indicated 
above in next cycle. 
 
5.9.3 
Neurotoxicity Secondary to Vinorelbine 
See neuropathy grading in Section 5.8.2. Vinorelbine should be dose modified 
only for incapacitating peripheral neurotoxicity (e.g. ≥ Grade 3 neurological 
toxicity [interferes with activities of daily living] or ≥ Grade 3 constipation), as 
follows: 
x 
Grade 3 or higher neurological toxicity: Hold vinorelbine; resume at 75% of 
full dose when the symptoms have improved to Grade 1 toxicity or 
completely resolved. If ≥ Grade 3 toxicity recurs, no further vinorelbine will 
be given. 
x 
Grade 3 or higher constipation: Hold vinorelbine; resume at 75% of full dose 
when the symptoms have improved to Grade 1 toxicity or completely 
resolved. Omit dose if manual disimpaction is required or if ileus occurs. 
 

  
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6.0 
DRUG INFORMATION  
6.1 
TEMSIROLIMUS   
 
 
 
 
 
 
(02/07/20) 
(Torisel®, CCI-779, rapamycin analog, WAY-130779) NSC# 683864 
 
Source and Pharmacology: Temsirolimus is an ester of the immunosuppressive compound 
sirolimus 
(rapamicin). 
Its 
chemical 
name 
is 
rapamycin 
42-[2,2-
bis(hydroxymethyl)propionate]. Temsirolimus is a specific inhibitor of the mammalian 
target of rapamycin (mTOR), an enzyme that regulates cell growth and proliferation. 
Temsirolimus binds to an intracellular protein FK506 binding protein (FKBP) 12 and the 
protein-drug complex inhibits the activity of mTOR and controls cell division. Inhibition of 
mTOR prevents progression from G1 to S phase of the cell cycle. In vitro studies show that 
inhibition of the activity of mTOR resulted in reduced levels of the hypoxia-inducible 
factors HIF-1 and HIF-2 alpha and VEGF.  
 
Pharmacokinetic studies of a single IV dose of temsirolimus in adults showed that over a 
dose range of 1 mg to 25 mg, the drug exposure increased with increasing doses in a less 
than proportional fashion. After a single 25 mg IV dose, the volume of distribution was 
large (172 L) with preferential partitioning into blood, the mean clearance was 16.2 L/h, 
and the terminal half-life was 17.3 hours.  
 
The pharmacokinetics of temsirolimus was assessed in 19 pediatric subjects with relapsed 
or refractory advanced solid tumors. The typical subject was an 11-year-old male child, 
with a body weight of 44.4 kg and a body surface area of 1.38 m2. Subjects received 
doses of 10, 25, 75, and 150 mg/m2 once weekly. Comparisons of exposure with adult 
subjects show that temsirolimus Cmax and AUCsum (sum of temsirolimus and sirolimus 
area under the concentration vs time curve) in the pediatric subjects was comparable to 
adult subjects, while temsirolimus AUC was higher in the pediatric subjects. This greater 
exposure to parent drug in the pediatric population was balanced by the shorter half-lives 
of sirolimus metabolite and corresponding lower AUCs. 
 
The safety and pharmacokinetics of temsirolimus were evaluated in a dose escalation 
phase 1 study in 110 patients with normal or varying degrees of hepatic impairment. 
Patients with baseline bilirubin > 1.5 × upper limit of normal (ULN) experienced greater 
toxicity than patients with baseline bilirubin ≤ 1.5 × ULN when treated with 
temsirolimus. The overall frequency of ≥ Grade 3 adverse reactions and deaths, including 
deaths due to progressive disease, were greater in patients with baseline bilirubin 
> 1.5 × ULN due to increased risk of death. Caution should be used when treating 
patients with hepatic impairment. Concentrations of temsirolimus and its metabolite 
sirolimus were increased in patients with elevated AST or bilirubin levels. Temsirolimus 
is contraindicated in patients with bilirubin > 1.5 x ULN.  
 
Temsirolimus is metabolized extensively in the liver mainly by the isoenzyme cytochrome 
(CYP) P450 3A4. The main active metabolite is sirolimus and the other four metabolites 
account for less than 10% of the parent drug. The activity of temsirolimus is dictated both by 
the parent drug and by the equipotent metabolite sirolimus. Sirolimus half life is longer 
(54.6 hours) and after a single 25 mg IV dose its AUC is 2.7-fold that of temsirolimus AUC 
due to mainly the longer half-life of sirolimus. Temsirolimus elimination occurs primarily in 
the liver with only minor amounts of drug-related products eliminated in the urine. Multiple 
doses of 25 mg administered once weekly exhibited little or no substantial accumulation. 

  
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Since the primary oxidative metabolism of temsirolimus is via CYP3A4, inhibitors and 
inducers of the CYP3A4 enzyme system may alter the metabolism of temsirolimus; 
however, temsirolimus does not induce CYP3A4. Temsirolimus may inhibit the metabolic 
clearance of substrates of CYP3A4/5 or CYP2D6, but not CYP2C9 or CYP2C8. Caution 
should be used when administering strong CYP3A4 inhibitors or strong CYP3A4/5 inducers 
with temsirolimus IV. In phase 1 drug interaction studies, co-administration of IV 
temsirolimus with ketoconazole, a potent CYP3A4 inhibitor, had no significant effect on 
temsirolimus, but increased the major metabolite sirolimus exposure. Co-administration of 
temsirolimus with rifampin, a potent CYP3A4 inducer, had no significant effect on 
temsirolimus, but decreased sirolimus exposure.  
 
In vitro studies showed that temsirolimus is subject to P-gp-mediated efflux; additionally 
temsirolimus inhibited the transport of digoxin, a P-gp substrate. These results indicate 
that temsirolimus has the potential to alter the transport of agents that are P-gp substrates 
as well as to be altered by P-gp inhibitors. Clinical implications related to concomitant 
administration of P-gp substrates are unknown and dose modifications for co-
administration with P-gp substrates or inhibitors are not provided in the drug package 
insert. 
 
The combination of temsirolimus and angiotensin converting enzyme inhibitors (ACEIs) 
and/or calcium channel blockers (eg., amlodipine) resulted in angioedema-type reactions 
(including delayed reactions occurring up to 2 months after initiation of therapy). Co-
administration of sunitinib and temsirolimus resulted in increased toxicity. During 
temsirolimus treatment, the co-administration of sunitinib, ACEIs or calcium channel 
blockers should be avoided. Prothrombin time and INR should be monitored if warfarin 
is added or discontinued. 
 
Toxicity: 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Temsirolimus (CCI-779, NSC 683864) 
 
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 1927 patients. Below is the CAEPR for 
temsirolimus (CCI-779). 
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. 
 

  
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Version 2.6, August 19, 20181 
 
 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 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) 
 
Febrile neutropenia 
 
 Febrile neutropenia (Gr 3) 
ENDOCRINE DISORDERS 
  
 
Testosterone deficiency 
 
 Testosterone deficiency (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal distension 
 
 Abdominal distension (Gr 2) 
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Anal mucositis2 
 
 Anal mucositis2 (Gr 2) 
 
Constipation 
 
 Constipation (Gr 3) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
 
Gastrointestinal fistula3 
  
 
 
Gastrointestinal perforation4  Gastrointestinal perforation4 (Gr 4) 
Mucositis oral2 
 
 
 Mucositis oral2 (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Rectal mucositis2 
 
 Rectal mucositis2 (Gr 2) 
 
Small intestinal mucositis2 
 
 Small intestinal mucositis2 (Gr 2) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
 Edema face (Gr 2) 
 
Edema limbs 
 
 Edema limbs (Gr 3) 
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
 
Flu like symptoms 
 
 Flu like symptoms (Gr 2) 
 
Non-cardiac chest pain 
 
 Non-cardiac chest pain (Gr 2) 
 
Pain 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction5 
 
 Allergic reaction5 (Gr 2) 
INFECTIONS AND INFESTATIONS6 
  
 
Infection7 
 
 Infection7 (Gr 3) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
Wound dehiscence8 
 
 Wound dehiscence8 (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased  
(Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased 
(Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Cholesterol high9 
 
 
 Cholesterol high9 (Gr 4) 
 
Creatinine increased 
 
 Creatinine increased (Gr 3) 
 
Fibrinogen decreased 
 
 Fibrinogen decreased (Gr 2) 
 
GGT increased 
 
 GGT increased (Gr 2) 

  
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 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Lymphocyte count decreased 
 
 Lymphocyte count decreased  
(Gr 4) 
 
Neutrophil count decreased 
 
 Neutrophil count decreased (Gr 4) 
Platelet count decreased10  
 
 Platelet count decreased10 (Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 3) 
 
White blood cell decreased 
 
 White blood cell decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
  
 
Acidosis 
 
 Acidosis (Gr 2) 
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Glucose intolerance11 
 
 Glucose intolerance11 (Gr 2) 
 
Hyperglycemia11 
 
 Hyperglycemia11 (Gr 3) 
 
Hyperlipidemia9 
 
 Hyperlipidemia9 (Gr 4) 
 
Hypertriglyceridemia9 
 
 Hypertriglyceridemia9 (Gr 4) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypokalemia 
 
 Hypokalemia (Gr 4) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 4) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
 Back pain (Gr 2) 
 
Myalgia 
 
 Myalgia (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Depressed level of 
consciousness 
 
 Depressed level of consciousness 
(Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 3) 
 
 
Intracranial hemorrhage 
  
PSYCHIATRIC DISORDERS 
  
 
Depression 
 
 Depression (Gr 2) 
 
Insomnia 
 
 Insomnia (Gr 2) 
 
Libido decreased 
 
 Libido decreased (Gr 2) 
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury12 
  
 
 
Nephrotic syndrome 
  
 
 
Proteinuria 
  
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
Erectile dysfunction 
 
 Erectile dysfunction (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 3) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
Epistaxis 
 
 Epistaxis (Gr 2) 
 
Laryngeal mucositis2 
 
 Laryngeal mucositis2 (Gr 2) 
 
Pharyngeal mucositis2 
 
 Pharyngeal mucositis2 (Gr 2) 
 
Pleural effusion 
 
 Pleural effusion (Gr 3) 
 
Pneumonitis13 
 
 Pneumonitis13 (Gr 3) 
 
Sinus disorder 
 
 Sinus disorder (Gr 2) 
 
Tracheal mucositis2 
 
 Tracheal mucositis2 (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  

  
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 Adverse Events with Possible  
 Relationship to Temsirolimus (CCI-779) 
 (CTCAE 5.0 Term) 
[n= 1927] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes14 
 
 Nail changes14 (Gr 1) 
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash acneiform 
 
 Rash acneiform Gr 2) 
Rash maculo-papular 
 
 
 Rash maculo-papular (Gr 3) 
 
Urticaria 
 
 Urticaria (Gr 2) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
Hypotension 
 
 Hypotension (Gr 3) 
 
 
Thromboembolic event 
 Thromboembolic event (Gr 4) 
 
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. 
 
2Mucositis/stomatitis:  Gingivitis, mucositis/stomatitis, ulcers in mouth and throat, pharyngitis, and 
dysphagia have been reported in subjects receiving temsirolimus. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS 
SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC.  GI perforation (including fatal outcome) 
has been observed in subjects who received temsirolimus. 
 
5Hypersensitivity /infusion reactions (including some life threatening and rare fatal reactions), including 
and not limited to flushing, chest pain, dyspnea, hypotension, apnea, loss of consciousness, 
hypersensitivity, and anaphylaxis, have been associated with the administration of temsirolimus.  These 
reactions can occur very early in the first infusion but may also occur with subsequent infusions.  Patients 
should be monitored early during infusion and appropriate supportive care should be available.  
Temsirolimus infusion should be interrupted in all patients with severe infusion reactions and appropriate 
medical care administered.  A risk-benefit assessment should be done prior to the continuation of 
temsirolimus therapy in patients with severe life-threatening reactions. 
 
6Infections:  Bacterial and viral infections including opportunistic infections have been reported in 
subjects. Infections may originate in a variety of organ systems/body regions and may be associated with 
normal or grade 3-4 neutropenia. Bacterial and viral infections have included cellulitis, herpes zoster, 
herpes simplex, bronchitis, abscess, pharyngitis, urinary tract infection (including dysuria hematuria, 
cystitis, and urinary frequency), rhinitis folliculitis, pneumonia, and upper respiratory tract infection. 
 
7Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
8Wound Dehiscence:  The use of temsirolimus has been associated with abnormal wound healing. 
Therefore, caution should be exercised with the use of temsirolimus in the perisurgical period. 

  
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9Cholesterol High: The use of temsirolimus in subjects has been associated with increases in serum 
levels of triglycerides and cholesterol. This may require initiation of or increase in the dose of lipid-
lowering agents. 
 
10Thrombocytopenia and Neutropenia: Grades 3 and 4 thrombocytopenia and/or neutropenia have been 
observed at higher frequency in subjects with mantle cell lymphoma (MCL). 
 
11Hyperglycemia/Glucose Intolerance: The use of temsirolimus in subjects was associated with increases 
in serum glucose level. This may result in the need for an increase in the dose of, or initiation of, insulin 
and/or oral hypoglycemic agent therapy.  
 
12Acute Kidney Injury: Renal failure (including fatal outcome) has been observed in subjects receiving 
temsirolimus for advanced RCC and/or with pre-existing renal insufficiency. 
 
13Interstitial Lung Disease: There have been cases of nonspecific interstitial pneumonitis, including rare 
fatal reports. Some subjects were asymptomatic with pneumonitis detected on computed tomography 
scan or chest radiograph. Others presented with symptoms such as dyspnea, cough, and fever. Some 
subjects required discontinuation of temsirolimus or treatment with corticosteroids and/or antibiotics, while 
some subjects continued treatment without additional intervention. 
 
14Nail Changes includes Nail discoloration, Nail loss, and Nail ridging under the SKIN AND 
SUBCUTANEOUS TISSUE DISORDERS SOC. 
 
15Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, 
Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, 
Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower 
gastrointestinal 
hemorrhage, 
Oral 
hemorrhage, 
Pancreatic 
hemorrhage, 
Rectal 
hemorrhage, 
Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL 
DISORDERS SOC. 
 
 
 Adverse events reported on temsirolimus (CCI-779) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that temsirolimus (CCI-779) caused 
the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(coagulopathy); Hemolysis; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrial flutter; Cardiac arrest; Chest pain - cardiac; Heart failure; 
Left ventricular systolic dysfunction; Myocardial infarction; Pericardial effusion; Right ventricular 
dysfunction; Sinus tachycardia; Supraventricular tachycardia; Ventricular fibrillation; Ventricular 
tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (Cushing's syndrome); Endocrine disorders - 
Other (diabetes mellitus) 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Eye disorders - Other (diplopia); Eye pain; Flashing 
lights; Photophobia; Retinopathy 
GASTROINTESTINAL DISORDERS - Anal fissure; Anal pain; Anal ulcer; Ascites; Bloating; Colitis; 
Colonic obstruction; Colonic ulcer; Dry mouth; Duodenal ulcer; Dyspepsia; Dysphagia; Enterocolitis; 
Esophageal pain; Esophageal ulcer; Esophagitis; Flatulence; Gastritis; Gastrointestinal disorders - Other 
(gastroenteritis); Gastrointestinal hemorrhage15; Hemorrhoids; Ileus; Oral pain; Pancreatitis; Periodontal 
disease; Proctitis; Rectal pain; Small intestinal obstruction; Stomach pain; Typhlitis; Visceral arterial 
ischemia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema trunk; Facial pain; Gait 
disturbance; Injection site reaction; Localized edema; Malaise; Multi-organ failure; Sudden death NOS 

  
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HEPATOBILIARY DISORDERS - Hepatic failure 
IMMUNE SYSTEM DISORDERS - Anaphylaxis 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; Fracture; Postoperative 
hemorrhage; Vascular access complication; Wound complication 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood bilirubin increased; Blood 
lactate dehydrogenase increased; CD4 lymphocytes decreased; INR increased (potential interaction with 
Coumadin); Investigations - Other (BUN increased); Lipase increased; Lymphocyte count increased; 
Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypermagnesemia; Hypernatremia; Hyperuricemia; Hypoalbuminemia; Hypoglycemia; Hypomagnesemia; 
Hyponatremia; Metabolism and nutrition disorders - Other (albuminuria); Metabolism and nutrition 
disorders - Other (blood urea increased); Metabolism and nutrition disorders - Other (hypoproteinemia)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Avascular necrosis; Bone 
pain; Chest wall pain; Generalized muscle weakness; Joint effusion; Muscle cramp; Muscle weakness 
lower limb; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Leukemia 
secondary to oncology chemotherapy; Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (carcinoma of the lung); Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) - Other (lymphoma); Treatment related secondary malignancy 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dizziness; Dysesthesia; 
Hydrocephalus; Lethargy; Neuralgia; Paresthesia; Peripheral motor neuropathy; Peripheral sensory 
neuropathy; Reversible posterior leukoencephalopathy syndrome; Seizure; Somnolence; Spasticity; 
Stroke; Syncope 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Mania; Psychiatric disorders - Other (bipolar 
disorder); Psychosis 
RENAL 
AND 
URINARY 
DISORDERS 
- 
Bladder 
spasm; 
Cystitis 
noninfective; 
Hematuria; 
Hemoglobinuria; Renal hemorrhage; Urinary frequency; Urinary retention; Urinary tract pain; Urinary 
urgency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Hematosalpinx; Irregular menstruation; 
Menorrhagia; Ovarian hemorrhage; Prostatic hemorrhage; Reproductive system and breast disorders - 
Other (female genital tract fistula); Spermatic cord hemorrhage; Testicular disorder; Testicular 
hemorrhage; Testicular pain; Uterine hemorrhage; Vaginal discharge; Vaginal dryness; Vaginal fistula; 
Vaginal hemorrhage; Vaginal inflammation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Bronchopulmonary hemorrhage; Bronchospasm; Hiccups; Hypoxia; Nasal congestion; 
Pharyngolaryngeal pain; Pleuritic pain; Productive cough; Pulmonary edema; Pulmonary fibrosis; 
Pulmonary hypertension; Respiratory failure; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Erythema multiforme; Hyperhidrosis; 
Pain of skin; Palmar-plantar erythrodysesthesia syndrome; Photosensitivity; Skin and subcutaneous 
tissue disorders - Other (angioneurotic edema); Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Phlebitis; Superficial thrombophlebitis 
 
 
Note:  Intracerebral Bleeding: Subjects with central nervous system (CNS) tumors (primary CNS tumors 
or metastases) and/or receiving anticoagulation therapy may be at an increased risk of intracerebral 
bleeding (including fatal outcomes) while receiving therapy with temsirolimus (CCI-779). 
 
Note: Temsirolimus (CCI-779) 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. 
 
 
Effect in pregnancy: 
Temsirolimus can cause fetal harm. Female of childbearing potential should be advised 
to avoid becoming pregnant throughout treatment and for three months after temsirolimus 

  
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therapy has stopped. Male with partners of childbearing potential should use reliable 
contraception throughout treatment and are recommended to continue this for three 
months after the last dose of temsirolimus. 
 
Formulation and Stability: 
Temsirolimus (Torisel®) is supplied as the commercially labeled kit consisting of a 
concentration solution and a diluent. The kit components are: 
x 
Temsirolimus injection (25 mg/mL), 1.2 mL  
x 
DILUENT vial that includes a deliverable volume of 1.8 mL. 
 
Temsirolimus injection 25 mg/mL is a clear, colorless to light yellow, non-aqueous, 
ethanolic, sterile solution. The inactive ingredients include dehydrated alcohol (39.5% 
w/v), dl-alpha-tocopherol, propylene glycol, and anhydrous citric acid. The diluent is a 
sterile, non-aqueous solution that includes polysorbate 80 (40.0% w/v), polyethylene 
glycol 400 (42.8% w/v) and dehydrated alcohol (19.9% w/v). After the temsirolimus 
injection vial has been diluted with the provided diluent, the solution contains 35.2% 
alcohol. The two-vial kit must be stored at 2°-8°C (36°-46°F) protected from light. 
 
If a storage temperature excursion is identified, promptly return temsirolimus to 2° – 8° C 
temperature and quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
During handling and preparation of admixtures, temsirolimus should be protected from 
excessive room light and sunlight. In order to minimize the patient exposure to the 
plasticizer di-2-ethylhexyl phthalate (DEHP) which may be leached from polyvinyl 
chloride (PVC) infusion bags, the final temsirolimus dilution for infusion should be 
prepared in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin). 
The preparation of the solution for administration requires two-step dilution process in an 
aseptic manner. These mixing instructions apply to the commercial Torisel® kit that is 
provided for this study. 
 
Step 1: 
x 
The temsirolimus injection vial contains 30 mg temsirolimus in 1.2 mL 
(25 mg/mL).  
x 
Inject 1.8 mL of the provided diluent into the vial of temsirolimus injection 
(25 mg/mL). The resulting drug concentration is 10 mg/mL and the total volume 
is 3 mL.  
x 
Mix well by inversion of the vial. DO NOT SHAKE. Allow sufficient time for 
air bubbles to subside. The solution is clear to slightly turbid, colorless to yellow, 
and free from visual particulates.  
x 
The 10 mg/mL drug solution/diluent mixture is stable for up to 24 hours at 
controlled room temperature. This 10 mg/mL drug solution/diluent mixture must 
be further diluted as described in Step 2 below.  
 
Step 2: 
x
Withdraw the amount of temsirolimus required for the dose from the 10 mg/mL 
drug solution/diluent mixture prepared in Step 1.  
x
For doses less than 10 mg, filter the concentrate/diluents mixture using a syringe 
filter unit before measuring required volume. 

  
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x
Further dilute with 0.9% sodium chloride injection immediately in non-DEHP 
container (see above) to a final concentration between 0.04 mg/mL and 1 mg/mL.  
x
Mix by inversion of the bag or bottle. Avoid excessive shaking as this may cause 
foaming.  
x
The diluted solution for administration is stable at controlled room temperature 
for up to six hours from the time of the final dilution. Protect the bag/bottle from 
light. 
 
Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration.  
 
Route of Administration: Intravenous with an appropriate in-line filter (i.e. 0.2 to 
5 micron) for all temsirolimus doses equal to or greater than 10 mg. To avoid drug loss, 
prepare doses less than 10 mg by filtering the concentrate/diluent mixture as noted 
previously in the Formulation and Stability section Steps 1 and 2 using a syringe filter 
unit. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
To prevent hypersensitivity reaction, an H1 antihistamine (eg, diphenhydramine) should 
be administered before the start of the temsirolimus infusion. Administration of final 
diluted solution should be completed within 6 hours of preparation. 
 
Avoid contact of the diluted product with polyvinyl chloride (PVC) equipment or devices 
that are plasticized with di- (2-ethylhexyl)pthalate (DEHP) to prevent DEHP leaching. 
Store diluted temsirolimus solutions in bottles (glass) or plastic bags (polyolefin or 
polypropylene). Infusion sets containing polyvinyl chloride should not be used to 
administer temsirolimus to avoid leaching of plasticizer.  
 
The following are examples of in-line filters that are compatible with temsirolimus: 
• 
IV 6200 Disposable I.V. Filter 0.2 micron by EPS®, Inc  
• 
IV 6120 Disposable I.V. Filter 1.2 micron by EPS®, Inc  
• 
LV 5000 Large Volume 5 micron Conical Filter by B. Braun  
• 
Baxter Paclitaxel Set with 0.22 micron filter  
• 
Codan 5 micron monofilter 
 
Other polyethersulfone filters may be used.  
 
Supplier: Supplied by Pfizer and distributed by the NCI DTCD. Do not use 
commercially available drug. 
 
Agent Ordering 
NCI-supplied agents may be requested by eligible participating investigators (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), 
NCI Biosketch, Agent Shipment Form, and Financial Disclosure Form (FDF). If there are 
several participating investigators at one institution, CTEP-supplied investigational 

  
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agents for the study should be ordered under the name of one lead participating 
investigator at that institution. 
 
Subjects must be enrolled and assigned to the Regimen B treatment arm prior to 
submitting the agent request to PMB. 
 
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, 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. If 
expedited shipment is required, sites should provide an express courier account through 
the Online Agent Order Processing (OAOP) application. Provide the patient ID number 
in the comment box when submitting an order request. 
 
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 
the PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(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. 
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 
x 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
x 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
x 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
x 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP  
x 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
x 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov 
x 
PMB email:  PMBAfterHours@mail.nih.gov 
x 
IB Coordinator: IBCoordinator@mail.nih.gov  
x 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 

  
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6.2 
CYCLOPHOSPHAMIDE INJECTION 
 
 
 
(03/13/13) 
(Cytoxan) NSC #26271 
 
 
 
 
 
 
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.  
 
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). 

  
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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. 
 
6.3 
CYCLOPHOSPHAMIDE - ORAL 
 
 
 
 
(10/31/18) 
(Cytoxan) NSC #26271 
 
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. 
Cyclophosphamide is well absorbed orally with a bioavailability greater than 75%. The 
plasma half-life ranges from 4.1 to 16 hours after IV administration and 1.3 to 6.8 hours 
after oral administration. 
 
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 

  
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Delayed: 
Any time later 
during therapy, 
excluding the above 
conditions 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, 
ANLL, AML), bladder carcinoma 
(long term use > 2 years), bladder 
fibrosis  
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with 
other antineoplastic agents) have been noted in humans. Toxicities include: chromosomal 
abnormalities, multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is 
excreted into breast milk. Cyclophosphamide is contraindicated during breast feeding because 
of reported cases of neutropenia in breast fed infants and the potential for serious adverse 
effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment 
2 Risk increased with pulmonary chest irradiation and higher doses 
(L) Toxicity may also occur later 
 
Formulation and Stability: 
US: Available as 25 mg and 50 mg capsules. Inactive ingredients vary depending on 
manufacturer. 
Canada: Available as 25 mg and 50 mg tablets. Inactive ingredients vary depending on 
manufacturer.  
Australia/New Zealand: Available as 50 mg tablets. Inactive ingredients vary depending 
on manufacturer. 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
Cyclophosphamide injection for oral administration:  
1. The reconstituted cyclophosphamide injection (20 mg/mL) repackaged into 
polypropylene syringes is stable under refrigeration (4qC) for four weeks. (Kirk B, 
Melia CD, Wilson JV, et al. Chemical stability of cyclophosphamide injection. Br J 
Parenter Ther 1984;5:90 7).  
2. The reconstituted injection can also be used for the preparation of cyclophosphamide 
suspension. To prepare, reconstitute a vial of cyclophosphamide 2000 mg with 
100 mL of NS to a final concentration of 20 mg/mL. Measure 100 mL of Ora-Plus 
(or simple syrup) and pour into an 8 ounce or larger amber bottle. Add the 
reconstituted cyclophosphamide (100 mL of a 20 mg/mL solution) to achieve a final 
volume of 200 mL. Shake well to disperse evenly. The cyclophosphamide suspension 
concentration would be 10 mg/mL. Draw up individual doses into amber syringes for 
oral use. Store the syringes in the refrigerator (4ºC), protected from light. The 
suspension is stable in amber syringes in a dark, refrigerated environment, for up to 
56 days. (Kennedy R, Groepper D, Tagen M et al. Stability of cyclophosphamide in 
extemporaneous oral suspensions. Ann Pharmacother 2010;44:295-301). 
 
Supplier: 
Commercially available from various manufacturers. See package insert for further 
information. 
 

  
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6.4 
DACTINOMYCIN  
 
 
 
 
 
 
(05/09/11) 
(Actinomycin-D, Cosmegen®) NSC #3053 
 
 
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.  
 

  
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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. 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. 
 
6.5 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ, FILGRASTIM-AAFI 
 
 (05/13/19) 
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®, Grastofil®, Nivestym®) NSC #614629  
 
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 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. 

  
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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 
 
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®, Granix® and Nivestym® are supplied as a clear solution of 300 mcg/1 mL or 
480 mcg/1.6 mL preservative-free single use vials. Discard unused portions of open vials.  
 
Neupogen®, Granix®, Zarxio®, and Nivestym® 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, filgrastim-sndz, and filgrastim-aafi 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.  
 
For IV use, dilute filgrastim (Neupogen®), tbo-filgrastim (Granix®), and filgrastim-aafi 
(Nivestym®) in D5W only to concentrations > 15 mcg/mL. Filgrastim-sndz (Zarxio®) and 
filgrastim-aafi (Nivestym®) may be diluted in D5W to concentrations between 5 mcg/mL 
to 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 4 products 
(communication on file from Teva Pharmaceuticals USA). Filgrastim, filgrastim-sndz 
and filgrastim-aafi dilutions to a concentrations of 5 mcg/mL or less are not 
recommended. Tbo-filgrastim dilutions below 2 mcg/mL are not recommended. Diluted 

  
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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 or 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  
 
CANADIAN SITES: 
Grastofil® brand of filgrastim biosimilar is available in Canada. See package insert for 
further information. 
 
 
6.6 
IRINOTECAN  
 
 
 
 
 
 
(03/07/17) 
[CPT-11, Camptothecin-11,7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-
camptothecin), Camptosar®], NSC #616348 
 
 
 
 
 
Source and Pharmacology:  
Irinotecan is a semisynthetic water-soluble analog of camptothecin (a plant alkaloid 
isolated from Camptotheca acuminata). Irinotecan is a prodrug that requires conversion, 
by the carboxylesterase enzyme to the topoisomerase-I inhibitor, SN-38 in order to exert 
anti-tumor activity. SN-38 is approximately 1000 times more potent than irinotecan. 
Camptothecins interact specifically with the enzyme topoisomerase I, which relieves 
torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its 
active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent 
religation of these single-strand breaks. Current research suggests that the cytotoxicity of 
irinotecan is due to double-strand DNA damage produced during DNA synthesis when 
replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, 
and either irinotecan or SN-38. Renal excretion is a minor route of elimination of 
irinotecan. The majority of the drug is metabolized in the liver. SN-38 is conjugated to 
glucuronic acid and this metabolite has no anti-tumor activity. The extent of conversion 
of SN-38 to its glucuronide has been inversely correlated with the risk of severe diarrhea, 
because the other major route of SN-38 excretion is biliary excretion by canalicular 
multispecific organic anion transporter (cMOAT) which presumably leads to mucosal 
injury. In addition, APC and NPC are oxidative metabolites of irinotecan dependent on 
the CYP3A4 isoenzyme. After intravenous infusion of irinotecan in humans, irinotecan 
plasma concentrations decline in a multiexponential manner, with a mean terminal 
elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the 
active metabolite SN-38 is about 10 to 20 hours. Irinotecan is 30% to 68% bound to 
albumin and SN-38 is approximately 95% bound to albumin. 
 
 

  
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Toxicity: 
Incidence 
Toxicities 
Common 
(>20% of patients)  
x 
Anemia 
x 
Thrombocytopenia 
x 
Neutrophil count decreased 
x 
White blood cell count decreased 
x 
Nausea 
x 
Vomiting 
x 
Constipation 
x 
Anorexia 
x 
Fever 
x 
Asthenia 
x 
Cholinergic symptoms: (rhinitis, increased salivation, miosis, lacrimation, 
diaphoresis, flushing, and intestinal hyperperistalsis that can cause 
abdominal cramping and diarrhea) 
x 
Alopecia 
x 
Bilirubin increased 
x 
Mucositis 
x 
Dyspnea 
x 
Cough 
x 
Weight loss 
x 
Pain 
Occasional 
(4-20% of patients)  
x 
Abdominal fullness 
x 
Flatulence 
x 
Vasodilation 
x 
Hypotension 
x 
Dehydration 
x 
Edema 
x 
AST increased 
x 
Alkaline phosphatase increased 
x 
Ascites 
x 
Jaundice 
x 
Febrile neutropenia 
x 
Infection 
x 
Headache 
x 
Dizziness 
x 
Chills 
x 
Insomnia 
x 
Rash 
x 
Dyspepsia 
x 
Somnolence 
x 
Thromboembolic events 
x 
Pneumonia 
Rare 
(≤ 3% of patients)  
x 
Anaphylaxis 
x 
Bradycardia 
x 
Disorientation/confusion 
x 
Colitis 

  
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x 
Renal failure (secondary to severe dehydration) 
x 
Ileus 
x 
Pancreatitis 
x 
Pneumonitis (L) 
Pregnancy & 
Lactation 
Fetal toxicities and teratogenic effects of irinotecan have been noted in animals at 
doses similar or less than those used in humans. Toxicities include: decreased 
skeletal ossification, multiple anomalies, low birth weight and increased fetal 
mortality. It is not known if irinotecan is excreted into breast milk but it is 
excreted into rat milk. 
(L) Toxicity may also occur later. 
 
Formulation & Stability:  
Each mL of irinotecan injection contains 20 mg irinotecan (on the basis of the trihydrate 
salt), 45 mg sorbitol, and 0.9 mg lactic acid. When necessary, pH has been adjusted to 3.5 
(range, 3.0 to 3.8) with sodium hydroxide or hydrochloric acid. Irinotecan is available in 
single-dose amber glass vials in 40 mg (2 mL),100 mg (5 mL), 300 mg (15 mL), and 
500 mg (25 mL). Store at controlled room temperature 15°-30°C (59°-86°F). Protect 
from light. It is recommended that the vial (and backing/plastic blister) should remain in 
the carton until the time of use.  
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
IV administration: Irinotecan must be diluted prior to infusion. Irinotecan should be 
diluted in D5W, (preferred) or NS to a final concentration range of 0.12-2.8 mg/mL. The 
solution is physically and chemically stable for up to 24 hours at room temperature 
(approximately 25°C) and in ambient fluorescent lighting. Solutions diluted in D5W and 
stored at refrigerated temperatures (approximately 2°-8°C), and protected from light are 
physically and chemically stable for 48 hours. Refrigeration of admixtures using NS is 
not recommended due to a low and sporadic incidence of visible particulates. Care should 
be taken to avoid extravasation; the use of a central line is suggested. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for more detailed 
information. 
 
6.7 
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 

  
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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.]  
 
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-25qC (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 

  
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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. 
 
 
6.8 
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. 
 
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 

  
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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, 15q-25qC (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 (200 mg).  
 
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. 
 
6.9 
PEGFILGRASTIM, PEGFILGRASTIM-JMDB, PEGFILGRASTIM-CBQV 
 
 
 
 
 
 
(01/28/19) 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®, Fulphila®, Udenyca®) 
NSC #725961  
 
 
 
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 

  
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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) 
x 
Bone pain 
Occasional 
(4-20% of patients) 
x 
Pain in extremity 
Rare 
(İ 3% of patients) 
x 
Acute respiratory distress syndrome (ARDS) 
x 
Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, 
urticaria, generalized erythema, and flushing  
x 
Antibody development 
x 
Capillary leak syndrome 
x 
Glomerulonephritis 
x 
Injection site reaction 
x 
Leukocytosis 
x 
Sickle cell crisis 
x 
Splenic rupture, splenomegaly 
x 
Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous 
vasculitis  
x 
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 UltraSafe™ 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 

  
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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 2º to 8ºC (36º to 46ºF) 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 manufacturer does 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. 
 
 
6.10 
VINCRISTINE SULFATE  
 
 
 
 
 
(08/20/20) 
(Oncovin®, VCR, LCR) NSC #67574 
 
 
 
 
 
 
 
 
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.  
 

  
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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 
 
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. 
 
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 a minibag is 
preferred for COG protocols. Slow IV push vincristine administration is permissible. 
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 

  
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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. 
 
6.11 
VINORELBINE TARTRATE  
 
 
 
 
(05/10/11) 
(Navelbine®) NSC #608210 
 
Source and Pharmacology:  
Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca 
alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline 
and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of 
structural modification for vinorelbine. The antitumor activity of vinorelbine is thought to 
be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. 
Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic 
AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase 
activity, 3) cellular respiration. Vinorelbine may be selective to mitotic microtubules vs. 
axonal microtubules as compared to other vinca alkaloids. This selectivity possibly limits 
neurotoxicity compared to other vincas.  
 
Following IV administration, vinorelbine plasma concentration decays in a triphasic 
manner. The initial rapid decline primarily represents distribution of drug to peripheral 
compartments followed by metabolism and excretion of the drug during subsequent 
phases. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma 
clearance ranges from 0.97 to 1.26 L/hr/kg. Steady-state volume of distribution values 
range from 25.4 to 40.1 L/kg. Vinorelbine demonstrates high binding to human platelets 
and lymphocytes. Plasma binding ranged from 79.6% to 91.2%. Vinorelbine undergoes 
substantial hepatic elimination in humans, with large amounts recovered in feces after 
intravenous administration. 10-12% of vinorelbine is recovered unchanged in the urine. 
Two metabolites have been identified: vinorelbine N-oxide and deacetylvinorelbine. 
Deacetylvinorelbine is the primary metabolite of vinorelbine and has been shown to 
possess antitumor activity similar to vinorelbine. Metabolism of vinca alkaloids are 
mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. 
 

  
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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 
Injection site reactions 
(erythema, pain, vein 
discoloration), nausea, 
vomiting 
Muscle weakness, phlebitis, 
diarrhea 
Fever, hypersensitivity 
(anaphylaxis, SOB, bronchospasm, 
hypotension), hypertension, 
pulmonary edema, dyspnea, chest 
pain (usually with pre-existing 
cardiac or pulmonary disease), 
extravasation (rare) but if occurs = 
local ulceration  
Prompt: 
Within 2-3 weeks, 
prior to next course 
Granulocytopenia, 
leukopenia, anemia, 
fatigue, constipation, 
elevated SGOT (AST) 
Thrombocytopenia 
neuropathy (paresthesias, 
hypesthesia) (related to 
cumulative dose), anorexia, 
abdominal pain, stomatitis, 
elevated bilirubin, alopecia 
Rash, myocardial infarction , 
hepatoxicity, loss of deep tendon 
reflex, gait disturbances, myalgia, 
erythema and skin desquamation in 
palms & soles, auditory deficits, 
headache, jaw pain, hemorrhagic 
cystitis, pancreatitis, ARDS 
(interstitial pulmonary changes), 
thromboembolic events (pulmonary 
embolism, DVT, SCV thrombosis 
with IV catheters), paralytic ileus & 
intestinal obstruction with necrosis  
Delayed: 
Any time later 
during therapy 
 
 
SIADH, radiation recall (dermatitis, 
esophagitis) 
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities: Fetal toxicities and teratogenic effects of vinorelbine have 
been noted in animals at 1/3rd and 1/6th of the usual human dose. It is unknown whether the 
drug is excreted in breast milk. 
 
Formulation and Stability:  
Available as 10 mg/mL injection in 1 mL and 5 mL vials in SWFI. Contains no 
preservatives or other additives. Store vials under refrigeration at 2°-8°C (36°-46°F) in 
the carton. Unopened vials are stable at room temperature up to 25°C (77°F) for up to 
72 hours. Protect from light. Do not freeze. 
 
Guidelines for Administration: 
See Treatment and Dose Modifications sections of the protocol. 
 
Vinorelbine injection must be diluted in D5W or NS for bolus administration by syringe 
or short IV infusion. For syringe administration, dilute vinorelbine to a concentration of 
1.5 to 3 mg/mL. For infusion administration dilute to a concentration of 0.5 to 2 mg/mL. 
The diluted vinorelbine should be administered into the side port of a free-flowing IV 
closest to the IV bag followed by flushing with at least 75 to 125 mL of dextrose or 
saline containing solution. Care should be taken to avoid extravasation; the use of a 
central line is suggested. 
 
Syringes containing vinorelbine should be labeled: “WARNING - FOR IV USE ONLY. 
FATAL IF GIVEN INTRATHECALLY.” 
 
Vinorelbine may be used for up to 24 hours under normal room light when stored in 
polypropylene syringes or polyvinyl chloride bags at 5°-30°C (41°-86°F). 

  
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Supplier: 
Commercially available. See package insert for further information. 
 
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 
Recommended End of Therapy & Follow-up 
General Follow-Up, All Patients 
Years off therapy 
Evaluation 
First year  
-PE every 3 months 
-CBC, Platelets, creatinine as clinically indicated 
-CXR every 3 months 
-Imaging of primary site and nodal basin every 3 months 
-Other indicated imaging studies as clinically indicated every 3 to 6 months 
Second and third 
years  
-PE every 4 months  
-CXR every 4 months 
-Imaging of primary site and nodal basin every 4 months 
-Other indicated imaging studies as clinically indicated every 4 to 6 months 
Fourth year  
-PE every 6 months  
-CXR every 6 months 
-Imaging of primary site and nodal basin every 6 months 
Five to ten years  
-Annual visit for PE 
After ten years  
-Maintain annual visit or phone contact if possible. 
-Record any offspring.  
-Report any second malignancy. 
Additional General Follow-Up for Children 
Height and weight at 6 months to 1 year intervals. Any child showing a growth deceleration of 20-25 percentile 
units on standard growth charts from the pretreatment height, should be evaluated for thyroid and pituitary 
function. 
Annual Tanner Staging for girls and boys until maturity (Tanner Stage 5). If there is delayed appearance of 
secondary sexual maturation, the patient warrants evaluation of gonadal hormone values, i.e., at 10-12 years in 
girls (FSH, LH and estradiol) and 12-14 years in boys (FSH, LH and testosterone). Consider referral to pediatric 
endocrinologist. 
Males: Surveillance of testicular growth in boys at annual visits and initial screening of gonadal hormone values 
at 14 years of age (FSH, LH and testosterone). Adult values for these hormones are expected at 16-17 years of 
age. High FSH values suggest damage to the germinal epithelium. Semen analysis can be done in post-pubertal 
males if requested by the patient or if the patient is receptive to the suggestion by the physician. 
Record annual measurement of testicular size in boys using volume measured by Prader orchidometer if possible. 
All patients on this study will receive alkylating agents and may accrue damage to the germinal epithelium of the 
testis. 
Record the onset of menses in girls and regularity of periods. Because of local radiotherapy or alkylating agent 
therapy, acute ovarian failure may occur in some patients. In cases of delayed menses, referral to a pediatric 

  
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endocrinologist is warranted.  
History should include school performance and behavioral disturbances so that early intervention can be made for 
recognized problems. 
 
 
Additional follow-up for patients with: 
Head and Neck 
primaries 
1. Annual growth measurements plotted on standard growth curves for all patients  
2. Annual ophthalmologic exam by an ophthalmologist if eye was in radiotherapy field. 
3. Annual dental exam if maxillary/mandibular sites were in radiotherapy field. 
4. If radiotherapy was given to the primary site, get bone x-rays of the primary site every 
1-2 years until maturity. Include opposing normal side for comparison of degree of bone 
hypoplasia. 
5. Consider TSH, growth hormone, FSH, LH if clinically indicated 
Trunk primaries 
1. If radiotherapy was given to primary tumors of the chest take history for exercise 
intolerance or shortness of breath. 
2. Consider echocardiograms every 5 years for potential RT scatter to heart 
Abdominal/pelvic 
primaries 
1. Studies appropriate to investigate problems following abdominal/pelvic irradiation, which 
may include bowel obstruction, chronic diarrhea, inadequate absorption, rectal stenosis, 
and sphincter problems. 
2. Kidney function should be followed in patients receiving para-aortic node irradiation or 
other abdominal sites encroaching on the kidneys. Annual UA, creatinine, and imaging 
studies if indicated. 
3. If radiotherapy port included the upper femurs/hip joints, slipped capital femoral epiphyses 
or avascular necrosis may occur several years after therapy. Symptoms are limp or pain. 
Strongly consider referral to gynecologist/fertility specialist at age 18 years for ovarian 
function assessment in females who received abdominal/pelvic RT 
Genito-urinary 
primaries 
Ongoing follow-up with a pediatric urologist is recommended. 
1. Patients without a bladder and with various types of urinary diversion should have kidney 
function evaluated with imaging studies every 1-2 years for hydronephrosis, evidence of 
pyelonephritis and renal function. Contrast studies of ileal loops may be necessary to detect 
kinking, stenosis or reflux of the ureters. 
2. Females with uterine or vaginal tumors should be followed for sexual maturation and 
ovarian failure 
3. If radiotherapy was given to the bladder, the volume and function should be assessed by 
voiding cysto-urethrograms or other imaging studies if indicated. 
4. History in post pubescent males should include questions of normal ejaculatory function, 
particularly in patients with bladder/prostate of paratesticular primaries. 
5. Semen analysis 
Extremity 
primaries 
1. If radiotherapy was given, appropriate bilateral limb length measurements should be done 
annually. 
2. X-rays of primary sites for bone growth/abnormalities should be done as indicated. Get 
normal side for comparison. 
3. History should address limp, evidence of pain, and other dysfunction of the involved 
extremity. 
4. Pain in the primary site 5-10 years after therapy warrants investigation for the 
development of secondary bone tumors. This is applicable to all radiation sites. 

  
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Second Malignant Neoplasms – the development of a second malignant neoplasm, either leukemia, lymphoma, 
or solid tumor, should be reported immediately via the eRDE system and CTEP-AERS.  
x
Known risk familial factors for SMN in RMS include history of neurofibromatosis and Li-Fraumeni – 
germline p53 mutation. 
x
All tumors and leukemias should have chromosome analysis on fresh tissue performed at the local 
institution if possible. Please freeze fresh specimens for additional molecular biology studies. 
 
 
See COG Late Effects Guidelines for recommended post treatment follow-up:  
http://www.survivorshipguidelines.org/ 
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease or relapse. 
b) Unacceptable toxicity due to protocol therapy (see Section 5.0).  
c) Refusal of further protocol therapy by patient/parent/guardian. 
d) Completion of planned therapy. 
e) Physician determines it is in patient’s best interest. 
f) Development of a second malignancy. 
g) Repeat eligibility studies (if required) prior to the initiation of protocol therapy are 
outside the parameters required for eligibility (see Section 3.2). 
h) Pregnancy. 
i) 
FOXO1 fusion positive with Group IV/Stage 4 disease. 
j) Refusal to transfer to Regimen C for patients meeting eligibility requirements for 
Regimen C. 
k) FOXO1 fusion status not determined by the institution by Day 21.  
Note: FOXO1 fusion that yield indeterminate or equivocal results will not lead to 
removal from protocol therapy. 
l) Patient’s start date of protocol therapy is greater than 42 days from the date of the 
collection of the material that established the diagnosis of RMS.  
 
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 patient is taken off study.  
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Tenth anniversary of the date the patient was enrolled on this study. 
 
 

  
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9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Patient Accrual and Expected Duration of Trial 
Based on the prior enrollment experience of D9803 and ARST0531, we expect an annual 
accrual of about 100 patients (including the patients with metastatic FOXO1 fusion 
negative disease and < 10 years of age and the “low-risk”, subset 2 patients, who were 
previously treated on high- or low-risk studies, respectively). 
 
The sample size for ARST1431 is driven by the primary comparison of event-free 
survival (EFS: time from study enrollment to the first occurrence of progression, relapse, 
second malignant neoplasm, or death as a first event). The expected EFS outcome for 
patients randomized to VAC/VI is a 3-year EFS rate of 60% with a long-term EFS 
plateau at about 55%. The study is designed to have power of 0.84 (testing at a 1-sided 
0.05 Type I level; only improvement with the addition of temsirolimus is of interest) to 
detect an overall increase in the 3-year EFS from 60% to 74%, an absolute difference in 
the 3-year EFS of 14%, or a relative risk of failure of 0.59 for comparing VAC/VI with 
temsirolimus to VAC/VI only. A total of 282 patients and 101 observed events are 
required to attain the power of 0.84 to detect a relative risk of 0.59:1.00 assuming the 
property of proportional hazards holds. The sample size of 282 also allows detecting an 
increase in the overall survival (OS: time from study enrollment to death from any cause) 
by 10% at 3-year and an OS hazard ratio of 0.47. The power analysis was conducted 
using software STATA 15 with methods proposed by Lakatos.84 Prior to 
Amendment #3, we planned to enroll up to 307 patients to Regimens A and B (including 
10 initially non-randomly assigned to treatment with temsirolimus in the feasibility 
phase), to allow for the possibility of an ineligibility rate and the loss to follow-up prior 
to observing an event of interest of up to 5%. 
  
Patients with institutional histologic classification of ARMS but FOXO1 fusion negative 
with the following Stage and Group (Stage 1, Group I/II, OR Stage 1, Group III (orbit), 
OR Stage 2, Group I/II) will remain on study but will receive VAC/VA therapy as per 
ARST0331. Enrollment of about 5-10 such eligible patients per year is expected 
(approximately 30 patients in total). 
 
We anticipate that 60 randomized patients will be considered inevaluable because they 
have completed the 14 cycles of VAC/VI therapy with or without temsirolimus [Regimen 
A or B] before Amendment #3 to add maintenance therapy is approved. Thus total 
enrollment is expected to be up to 397 patients. We expect the enrollment will 
complete after about 6 years because the study has been temporarily closed for about 2 
years for feasibility evaluation and study amendments. Full information for the 
randomized comparison is expected to be available about 9 years after enrollment begins. 
 
9.2 
Statistical Analysis Methods  
Patient subset not eligible for randomization (feasibility phase): 
The first ten (10) evaluable patients will be non-randomly assigned to treatment with 
temsirolimus and enrollment then suspended while these subjects are monitored through 
protocol Week 12 for adverse events (AEs). The dose of temsirolimus will start at 
15 mg/m2 on Days 1, 8 and 15 of each cycle. The focus will be on evaluating AEs 
reasonably associated with the addition of temsirolimus. The study will be suspended 
until these feasibility phase patients have completed the first 12 weeks of treatment; their 
AE experience will be qualitatively assessed. Should it be determined that the AE 

  
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experience is acceptable, randomization will begin. Certain specific protocol defined 
temsirolimus-associated AEs (see Section 11.10.1) will be monitored in real time via 
AERs reporting. If the 10 mg/m2 temsirolimus dose is also found not to be feasible, we 
will consider discontinuous temsirolimus dosing (Day 1 and 8; omit Day 15) depending 
upon the observed toxicity profile. The feasibility phase is complete, effective with 
Amendment #1A. Dose Level 1 (temsirolimus 15 mg/m2/day on Days 1, 8, 15) was 
found to be the safe dose. 
 
Patient subset eligible for feasibility phase and randomization phase: 
Randomization on a 1:1 basis will be stratified by:  
1) ERMS Stage 3, Group I/II or Stage 1, Group III (non-orbit) 
2) ERMS Stage 2/3, Group III 
3) ARMS Stage 1-3, Group I-III  
4) ERMS Stage 4, Group IV < 10 years old 
 
The patient AE experience will continue to be monitored during the randomization phase. 
Study team conference calls will be held after the enrollment of approximately every 
50 patients to compare the AE experience of the experimental regimen to that of standard 
therapy. 
 
The EFS and OS distributions will be estimated using the Kaplan-Meier method and will 
be compared between the randomized treatment groups using the log-rank test. The 
primary analysis will be performed when 100% of the expected information 
(101 observed events) is observed. 
 
Interim efficacy monitoring of outcome for the randomized patients will begin after at 
least 50 protocol events (50% information) have been observed and then subsequently 
after 75 (75% information) events have been observed. Efficacy will be monitored using 
the O’Brien-Fleming-type cumulative error spending function.85 The table below lists the 
p-value boundaries for rejecting the null hypothesis (H0: no improvement in 3-year EFS 
with the addition of temsirolimus) when the one-sided Type I error rate is 0.05 and power 
is 0.84. The final analysis will be performed at the 0.0427 significance level.  
 
Efficacy 
Monitoring 
Cumulative 
Observed Events 
Information Content 
Significance Level 
1 
50 
50% 
0.00557 
3 
75 
75% 
0.0219 
 
Interim inefficacy monitoring of the primary EFS outcome for the randomized patients 
will begin when 50 protocol events (50% information) have been observed.82 Study 
termination or treatment modification will be considered if the observed log hazard ratio 
exceeds zero. 
 
The central pathology review diagnosis and FOXO1 fusion testing (when performed) will 
be used in all descriptive and outcome analyses in cases where there is discordance 
between institutional and central pathology review diagnosis. Patients may be excluded 
from the outcome analyses based upon the central pathology review. Possible scenarios 
include 1) histologic diagnosis other than RMS or 2) if patients received inappropriate 
therapy based on institutional FOXO1 testing – ie. Patients with stage 4 disease FOXO1 
negative by institution and positive by central review, and received therapy on 

  
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ARST1431. In either example, the patient will be excluded from the analytic dataset. 
Patients who completed the first 14 cycles of therapy before the maintenance therapy is 
made available will also be considered as inevaluable and will be excluded in the 
outcome analysis. 
 
Patient subset eligible for non-randomized treatment with VAC/VA therapy as per 
ARST0331: 
 
ARMS, FOXO1 fusion negative: 
1) Stage 1, Group I/II, III (orbit) 
2) Stage 2, Group I/II 
 
These patients are expected to have a long-term event-free survival (EFS) of about 85% 
(what is seen for patients with embryonal histology tumors with these characteristics). 
With 30 patients, a total of 4.5 failures are expected. The outcome for these patients will 
be monitored comparing the observed EFS to a fixed outcome which is that expected for 
similar patients with embryonal histology tumors, namely: 
 
S(t) = 0.85 + 0.15 * exp( -t) 
 
A one sample log-rank test will be used to assess the outcome for these patients. Testing 
at the 20% level of statistical significance, we will have power of 0.8 to detect a doubling 
of the risk of failure (long-term EFS 72%). We will perform an analysis when 4 events 
are observed. Under the null hypothesis, this would be expected to be observed after all 
patients have been enrolled and follow-up is about complete. Should the true long-term 
EFS be 72%, more than 8 events total would be expected and the analysis would be 
expected to be performed about half-way into the planned study. 
 
Exploratory aims 
The exploratory aims are primarily descriptive. The aims are: 
 
1. To estimate the frequency of circulating tumor DNA (ctDNA) at diagnosis and 
subsequent time-points for patients.  
We will determine the frequency with which of ctDNA is detected in patients 
with IR RMS at diagnosis and how these levels change over time with. In 
addition, the level of ctDNA as a percent of total cell-free DNA will be 
summarized by reporting the median and range. Since no prior data are available 
on the rate of positivity nor the change over time, the analysis will be purely 
descriptive. Changes over time will be plotted to visually determine and compare 
the trajectories of ctDNA during the early and late stages of therapy. 
 
2. To compare the outcome of patients based on their FOXO1 partner, by 
evaluating PAX3 vs. PAX7 in all patients found to be FOXO1 fusion positive. 
A total of 282 eligible patients are expected to be randomized. Approximately 
55% (n~155) are expected to be ERMS. The remaining 45% (n~127) will be 
ARMS. Ten percent (n~13) of these ARMS will not be evaluated for 
translocation status; of those remaining, about 85% (n~97) will be fusion 
positive. Based on Missiaglia 2012, we expect 75% of the fusion positive to be 
PAX3 (n~73) and 25% to be PAX7 (n~24).16 The power to detect a difference in 
3-year EFS of 20% (PAX3: 50%, PAX7: 70%, based on ARST0531) is 0.83 with 

  
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97 FOX01+ cases (~3:1, PAX3 (73) vs PAX7 (24)) and one-sided Type I error 
rate of 0.15. The power analysis was conducted using software PASS 2008 with 
methods proposed by Lakatos.84 
 
3. To compare the outcome of patients based on their [F18]-fluorodeoxy-D-
glucose-positron emission tomography (FDG-PET) response at Week 9 (positive 
or negative), as assessed by Deauville Criteria (5-point). 
Based on Casey 2014, we anticipate that approximately 40% of patients will have 
a negative PET at Week 9. We expect to compare the median EFS and EFS rates 
of the 186 FDG-PET responders and 124 non-responders.61  
 
4. To compare the outcome of patients (VAC/VI with or without temsirolimus) who 
have received maintenance therapy on ARST1431 to those who received VAC/VI 
on ARST0531. 
The two-sample log-rank test will be performed. 
 
9.3 
Gender and Minority Accrual Estimates 
The gender and minority distribution of the study population is expected to be: 
 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ 
Alaska Native 
2 
2 
 
 
4 
Asian 
4 
11 
 
 
15 
Native Hawaiian or 
Other Pacific Islander 
 
 
 
 
 
Black or African 
American 
33 
26 
1 
1 
61 
White 
125 
149 
18 
25 
317 
More Than One Race 
 
 
 
 
 
Total 
164 
188 
19 
26 
397 
This distribution was derived from ARST0531. All gender and minority groups are included 
from enrollment, but some of the groups are unlikely to be represented based on the 
ARST0531 enrollment. 
 
 

  
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10.0 
EVALUATION CRITERIA  
10.1 
Common Terminology Criteria for Adverse Events (CTCAE)  
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) 
for toxicity and performance reporting. A copy of the CTCAE version 5.0 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 v5.0̓ is understood to represent the most current version of 
CTCAE v5.0 as referenced on the CTEP website (ie, v5.02 and all subsequent iterations 
prior to version 6.0). 
 
10.2 
Response Criteria  
For the purposes of this study, patients should have imaging performed at baseline and be 
re-evaluated for response at Week 9, Week 30*, Week 42*, Week 54*, and end of 
protocol therapy. (*for patients on Regimens A and B only)  
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).86 
10.2.1 Definitions 
The COG guideline (see diagram below) will be used for measurement of the 
primary tumor on cross-sectional imaging (either computed tomography [CT] or 
magnetic resonance imaging [MRI]). 
 
Evaluable for objective response: Only those patients who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for response. These 
patients will have their response classified according to the definitions stated 
below. (Note: Patients who exhibit objective disease progression prior to the end 
of the first response period will also be considered evaluable.) 
 
Evaluable non-target disease response: Patients who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, 
have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions. 
 
10.2.2 Disease Parameters 
10.2.2.1 Measurable disease: Measurable lesions are defined as those that are 
≥ 10 mm with CT or MRI. For masses that are smaller than 10 mm, a 
measurable mass has to be at least twice the slice thickness (< 5 mm) 
used. All tumor measurements must be recorded in millimeters or 
decimal fractions of centimeters. The 
maximal 
perpendicular 
diameters in all three planes are recorded. 
 

  
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10.2.2.2 Malignant lymph nodes: To be considered clinically 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) or MRI. At baseline and in follow-up, only the short 
axis will be measured and followed. (The long axis (craniocaudal) in 
lymph nodes may be >15 mm but not reflect clinical enlargement.) 
 
10.2.2.3 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, and 
pleural/pericardial effusions 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. 
 
10.2.2.4 Target lesions: Target lesion must include the primary site for all non 
Group I/II patients. Three dimensions must be recorded from cross 
sectional imaging (CT or MRI) in cm to 1 decimal place or mm.  
 
10.2.2.5 Non-target lesions: Non-target lesions should include lymph nodes for 
those who have nodal disease. All other lesions (or sites of disease) 
should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required in 
3 dimensions (in cm or mm).  
 
10.2.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler. 
All baseline evaluations must be obtained within 4 weeks prior to start of 
protocol therapy (repeat the tumor imaging if necessary). 
 
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 required. Evaluation by clinical examination for the 
purpose of reporting is not acceptable. 
 

  
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10.2.3.1 Clinical lesions: Clinical lesions will only be considered measurable 
when they are superficial (eg, skin nodules and palpable lymph nodes) 
and t 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 required if they represent the 
only site of measurable disease.  
 
10.2.3.2 Chest x-ray: Lesions seen on chest x-ray must be confirmed by CT.  
 
10.2.3.3 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).  
 
Use of MRI remains a complex issue. MRI has excellent contrast, 
spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. 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. 
The utility and potential of diffusion-weighted imaging (DWI) in soft 
tissue sarcoma diagnosis and therapy response is unknown. Its utility is 
encouraged. 
 
10.2.3.4 FDG-PET-CT: At present, the low dose or attenuation correction CT 
portion of a combined PET-CT is not of optimal diagnostic CT quality 
for use with RECIST measurements. Thus, the site must document that 
the CT performed as part of a PET-CT is of identical diagnostic quality 
to a diagnostic CT (with IV and oral contrast), in order to use the CT 
portion of the PET-CT for diagnostic staging and RECIST 
measurements and can be used interchangeably with conventional CT 
in accurately measuring cancer lesions over time.  
 
10.2.3.5 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 

  
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by ultrasound in the course of the study, confirmation by CT or MRI is 
required. 
 
10.2.3.6 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. 
 
10.2.4 Response Criteria 
10.2.4.1 Evaluation of Target Lesions  
 
Complete Response (CR): Disappearance of all target lesions. Any 
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 progressions). 
 
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. 
 
10.2.4.2 Evaluation of Non-Target 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. 
 

  
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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). 
 
10.2.4.3 Response Criteria Using [18F]-FDG-PET: 
FDG-PET scans will be evaluated locally using the 5-point Deauville 
criteria.51 The use of FDG-PET-MRI can be used instead of FDG-PET-
CT, when appropriate. 
Score 1 
No uptake 
Score 2 
Uptake ≤ mediastinum 
Score 3 
Uptake > mediastinum but ≤ liver 
Score 4 
Moderately increased uptake > liver 
Score 5 
Markedly increased uptake > liver and/or 
new lesions 
 
Response will be assessed by the table below: 
Baseline Score 
Week 9 Score 
Response 
1 or 2 
1 or 2 
SD 
1 or 2 
> 3 
PD 
3 
> 4 
PD 
3 
1 
CR 
3 
2 
PR 
4 
5 
PD 
> 3 
1 or 2 
CR 
4 
3 
PR 
5 
3 or 4 
PR 
 
Patients who have a PET-CT (or FDG PET-MRI) must also have a 
diagnostic quality CT/MRI with IV/oral contrast. Overall response 
must therefore suit both Deauville and RECIST criteria. 
 
10.2.4.4 Evaluation of Best Overall Response 
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). The patient's best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 

  
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Non-Metastatic Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesion 
(Primary 
Tumor) 
Non-Target 
Lesions 
New 
Lesions 
PET 
response 
(if done) 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
PR or CR 
CR 
 
CR 
Non- 
CR/Non-PD 
No 
PR 
PR 
 
CR 
Not evaluated 
No 
PR or CR 
PR 
PR 
Non- 
CR/Non- 
PD/not 
evaluated 
No 
PR or CR 
PR 
SD 
Non- 
CR/Non- 
PD/not 
evaluated 
No 
SD, PR, or 
CR 
SD 
 
PD 
Any 
Yes 
or 
No 
SD or PD 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes 
or 
No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document the objective progression even after discontinuation of 
treatment. 
 

  
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Metastatic Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesion 
(Primary 
Tumor) 
Target 
Lesion 
(Metastatic 
Site) 
Non-
Target 
Lesions 
New 
Lesions 
Pet 
Response 
(if done) 
Overall 
Response 
Best Overall 
Response when 
Confirmation 
is Required 
CR 
CR 
CR 
No 
PR or CR 
CR 
 
CR 
CR 
Non- 
CR/Non-
No 
PR or CR 
PR 
 
CR 
PR 
Not 
No 
PR or CR 
PR 
PR 
CR or PR 
Non- 
CR/No
n- 
PD/not 
No 
PR or CR 
PR 
SD 
SD 
Non- 
CR/No
n- 
PD/not 
No 
SD, PR, or 
CR 
SD 
 
PD 
Any 
Any 
Yes 
No 
or Any 
PD 
no prior SD, PR 
or CR 
Any 
PD 
Any 
Yes 
No 
or Any 
PD 
Any 
Any 
PD** 
Yes 
No 
or Any 
PD 
Any 
Any 
Any 
Yes 
Any 
PD 
 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**In exceptional circumstances, unequivocal progression in non-target lesions may 
be accepted as disease progression. 
 
Note: 
Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.” Every effort should be 
made to document the objective progression even after discontinuation of 
treatment. 
 
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 
 
 

  
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RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), PRODUCT OF 
TWO DIAMETERS (WHO), AND THREE PERPENDICULAR DIAMETERS (“VOLUME”) 
 
 
 
Response 
Diameter, 2R 
 
Decrease 
Product, (2R)2 
Decrease 
Volume, 4/3pR3 
Decrease 
 
30% 
50% 
65% 
 
50% 
75% 
87% 
Disease Progression 
Increase 
Increase 
Increase 
 
12% 
25% 
40% 
 
20% 
44% 
73% 
 
25% 
56% 
95% 
 
30% 
69% 
120% 
 
 
 
Target lesions at baseline must measure greater than 1 cm; if these target lesions decrease in size to below 
1 cm, care should be taken in measuring and inadvertently progressing a patient due to minimal changes 
in measurement from a nadir value below 1 cm, which may be within measurement error. When multiple 
primary or metastatic masses are present, all masses will be described. However, up to 5 target masses 
should be measured, using the same method in subsequent follow up 
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

  
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TECHNICAL GUIDELINES FOR CROSS-SECTIONAL IMAGING COMPUTED 
TOMOGRAPHY (CT) 
1. All CT scans should be done with technical factors using the lowest radiation exposure possible 
(ALARA principle). 
2. CT slice thickness should be 5mm 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. 
 
MAGNETIC RESONANCE IMAGING (MRI) 
1. Axial images and at least one additional plane are acquired. At least two pulse sequences, such as 
T1, T2, STIR, or FLAIR-weighted, or in-phase/out-of-phase 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. 
2. 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). 
 
 
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. 
x
Concurrent administration: When an investigational agent is used in 

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

  
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AERS if it occurs at any time following treatment with an agent under a NCI 
IND/IDE since these are considered to be serious AEs. 
 
11.4.3 Death 
Reportable Categories of Death  
o Death attributable to a CTCAE term.  
o Death Neonatal: Newborn death occurring during the first 28 days after 
birth.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “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 (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a 
secondary malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
x
Leukemia secondary to oncology chemotherapy  
x
Myelodysplastic syndrome  
x
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. 
 

  
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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. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy 
loss”, or “Death Neonatal”, 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 that may be teratogenic. For this reason, pregnancy 
needs to be reported in an expedited manner via CTEP-AERS as Grade 
3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the 
baby is born with a birth defect or anomaly, then a second CTEP-AERS 
report is required. 
 
11.4.6.2 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.  
 
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 

  
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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. 
 
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 

  
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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.   
 
x
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.  
 
x
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.  
 
x
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.  

  
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x
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).  
 
x
ALWAYS include the ticket number on all faxed documents. 
 
x
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 

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

  
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x 
Grade ≥ 4 cholesterol high (hypercholesterolemia) or hypertriglyceridemia 
that does not return to ≤ Grade 2 levels with appropriate medical 
management within 35 days 
x 
Grade ≥ 3 proteinuria 
x 
Any visceral perforation including fistula or leak (gastrointestinal or any 
other organ) 
x 
Any intra-abdominal abscess/infection 
x 
Grade ≥ 2 wound dehiscence 
x 
Grade ≥ 3 wound infection - requiring IV antibiotics 
 
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 that can be attributed 
(possibly, probably, or definitely) to the agent and is not due to cancer recurrence 
must be reported via CTEP-AERS. 
 
 
11.12 Routine Adverse Event Reporting 
 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, routine reporting will include all toxicities 
reported via CTEP-AERS and all Grade 2 and higher Adverse Events.  
 
 

  
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12.0 
RECORDS AND REPORTING 
See the Case Report Forms 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) Version 3.0. 
Cumulative protocol-and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application. 
Reports are due January 31, April 30, July 31 and October 31. Instructions for submitting 
data 
using 
the 
CDUS 
can 
be 
found 
on 
the 
CTEP 
website 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
12.2 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, 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”): 
 
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 

  
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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 
 
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. 
 
 

  
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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). 
 
13.1 
Data Submission 
The Surgical Committee of the STS Committee will evaluate the pretreatment stage 
assigned, the Clinical Group assignment, the anatomic site designation, and the adherence by 
the surgeon(s) to these surgical guidelines for quality assurance reporting. 
 
See Section 16.2.1 for instructions regarding the submission of baseline radiology reports to 
be used for central surgical review. Results from central review will not be returned to the 
originating institution. 
 
13.2 
Pretreatment Clinical Staging 
This is a modification of the UICC-TNM staging system and is based on site, size, clinical 
regional nodal status, and distant spread. The staging is CLINICAL and should be done BY 
THE RESPONSIBLE PHYSICIAN based on PREOPERATIVE imaging and physical 
findings. Intraoperative and/or pathologic results should not affect the stage (but will affect 
Clinical Group).  
 
Size should reflect actual physical examination or imaging measurements. Site 
designation alters stage and, therefore, treatment assignment. Careful evaluation of 
clinical and/or imaging findings should precede multidisciplinary site assignment. THE 
SURGEON IS GENERALLY BEST ABLE to designate site when choice is difficult. See 
Appendices III, IV, V and VI for Staging/Clinical Grouping Criteria and Site 
Classification. 
 
13.3 
Surgical-Pathologic (Clinical) Group 
Clinical Group assignment is based on intraoperative findings and post-operative 
pathologic status and must include final pathologic verification of margins, residual 
disease, node involvement, and cytological examination of pleural and peritoneal fluid, 
and CSF, when applicable. See Appendix IV for Clinical Grouping Criteria. 
 
*It is important to note that the Clinical Group designation is assigned prior to the 
initiation of chemotherapy and reflect best surgical outcome based on initial 
operative procedure and any other pre-treatment excision (PRE) but remains 
unchanged, regardless of any delayed primary excision that may be performed, 
after the initiation of chemotherapy. Upfront resection should only be considered 
when there is no loss of function or organ and is not recommended in certain sites 
including parameningeal tumors. 
 

  
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13.4 
Surgical Principles 
The basic principles of wide and complete resection of the primary tumor with a 
surrounding envelope of normal tissue should be followed at the initial and/or subsequent 
operations wherever possible and reasonable. Adequate margins of uninvolved tissue are 
required unless this involves sacrifice of normal tissue that would result in an 
unacceptable loss of function, form or is not technically feasible. IN OTHER WORDS 
THE INTENT OF EACH OPERATION SHOULD BE THE COMPLETE EXCISION 
OF DISEASE WITH NEGATIVE MARGINS UNLESS THIS WOULD RESULT IN 
UNACCEPTABLE LOSS OF FUNCTION OR FORM. Amputations and other radical 
procedures are to be avoided whenever possible. 
 
Debulking or partial resection of primary tumors have equivalent outcomes to patients 
that just have a biopsy and therefore should not be performed. When the neoplasm arises 
from a somatic muscle, excision of the entire muscle of origin or the entire compartment 
may not be necessary. However, adequate margins of normal tissue are preferable to 
leaving gross or microscopic tumor. Any tumor that is removed piecemeal is considered 
to have microscopic residual disease and should be classified as Clinical Group II. 
 
13.4.1 Margins 
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 sites such as in the head and neck. 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. The tumor should not be bisected or cut into separate 
specimens prior to this discussion. Any suspected microscopic or gross residual 
tumor should be marked in the tumor bed with small titanium clips to aid 
radiotherapy simulation. Again, any tumor that is removed piecemeal is 
considered to have microscopic residual disease and should be classified as 
Clinical Group II. 
 
13.4.2 Node Sampling or Node Dissection 
Clinical and/or imaging evaluation of regional lymph nodes should be performed 
pretreatment and preoperatively by the responsible surgeon and is an important 
part of pretreatment staging. In those patients with clinically/radiographically 
enlarged nodes, treatment with chemotherapy and RT is required. However, it is 
preferable to avoid the need for RT. Therefore, clinically or radiographically 
enlarged node(s) should be evaluated histologically; patients with no tumor in the 
node(s) will not require radiation of the regional nodal bed. Failure to obtain 
pathologic confirmation of nodal disease will necessitate nodal RT for clinically 
positive nodes. In general, prophylactic radical node dissection, as employed for 
some other malignancies, is not necessary in childhood RMS. Nodal evaluation 
by open biopsy is recommended, preferably using sentinel node technique, 
however core needle biopsy may be appropriate. Identification of the sentinel 
node by injection of methylene blue dye and technetium 99m at the site of the 
primary tumor is optimal for nodal evaluation and is strongly recommended as 
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available at your institution then random regional lymph node sampling is the 
next most appropriate method of surgical evaluation for most sites.  
 
Pathologic evaluation of clinically uninvolved regional nodes is site specific; it is 
required in extremity sites and in boys ≥ 10 years with paratesticular primaries. 
Radical bilateral regional node dissection, as employed for some other testicular 
malignancies, is not necessary nor appropriate in childhood paratesticular RMS. 
However, staging ipsilateral template nerve-sparing retroperitoneal lymph node 
dissection (SIRPLND) (see description Appendix IV) or ipsilateral infra-renal 
lymph node sampling of a minimum 7-12 nodes is required for all boys 10 years 
of age and older with paratesticular RMS and for patients < 10 yrs with positive 
nodes on CT exam. Data demonstrate that patients with FOXO1 fusion positive 
RMS and positive nodal disease have a worse prognosis. Therefore, pathologic 
nodal evaluation of clinically uninvolved nodes in FOXO1 fusion positive 
patients is strongly encouraged but is not required.45 
 
In summary, nodal evaluation is required for all patients with extremity 
primary tumors and patients with paratesticular primary tumors who are 
≥ 10 years of age, and is strongly encouraged for patients with ARMS or 
clinically involved lymph nodes (regardless of histology). The preferred 
method of nodal evaluation is sentinel node biopsy whenever available.  
 
13.4.3 Pretreatment Re-excision (PRE) 
The initial surgical procedure may have been performed prior to establishing the 
diagnosis and/or the involvement of the oncology team and may result in a 
situation in which there is: 1) gross residual tumor, 2) microscopically involved 
margins, or 3) uncertainty as to margins or residual. This applies even if the 
microscopic margin is thought to be clear, if the operation and pathologic study 
were not done as an oncologic procedure as described in Section 13.4.1. 
 
Under these circumstances the concept of Pretreatment Re-excision (PRE) is 
permissible and should be applied wherever feasible. This means wide re-
excision of the previous operative site, including an adequate "envelope" of 
normal tissue, with careful marking and examination of all margins. This 
approach is particularly applicable to extremity and trunk lesions although it 
should be applied wherever possible. In order for this to effect Clinical Group, 
and therefore prognosis this procedure must be done prior to administration of 
chemotherapy or RT. Clinical Group assignment will be determined on the basis 
of pathology from the definitive operation prior to the start of multimodal 
therapy. The prior procedure(s) will be considered as an excisional biopsy. The 
conclusion that PRE is not advisable or feasible must be reached by 
multidisciplinary discussion and the reasons are to be listed on the surgical check 
sheet. 
 
13.4.4 Delayed Primary Excision (DPE) 
Delayed primary excision (DPE) is the term used to describe resection of the 
primary tumor after the initiation of chemotherapy. In this protocol patients that 
were not resectable prior to the initiation of chemotherapy may be assessed to 
determine the feasibility of complete resection of the primary tumor at Week 9. 

  
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The same principles should be applied as previously described. The intent of 
each operation should be the complete excision of disease with negative margins 
unless this would result in unacceptable loss of function or form. Amputations 
and other radical procedures are to be avoided whenever possible. Debulking 
operations are absolutely discouraged as they may cause harm and will not result 
in reduction of RT dose. DPE may be utilized at any site provided this guideline 
is followed. The benefit of DPE is that it may allow a decreased dose of RT 
(36-41.4 Gy) to be administered depending on the completeness of disease 
resection. Recent data demonstrate that local control is equivalent using this 
paradigm of DPE and reduced dose RT compared to historical controls who 
received 50.4 Gy radiotherapy alone.45  
 
*It is important to note that the Clinical Group designation assigned at the 
time of enrollment on study remains unchanged regardless of any delayed 
primary excisions that may be performed. 
 
13.5 
Specific Anatomic Sites 
There are pathologic and biologic differences between tumors found in different sites that 
lead to differences in surgical management. 
 
13.5.1 Head and Neck (Superficial) 
Wide excision is appropriate, when feasible, but the possibility of achieving wide 
margins is generally restricted to those patients with relatively superficial lesions. 
Cosmetic and functional factors should always be considered. 
 
13.5.2 Orbit 
Rhabdomyosarcomas of this site are, in many respects, quite different from those 
arising in other head and neck sites. The prognosis is better, and non-excisional 
therapy has become standard. Biopsy generally is followed by chemotherapy and 
radiation as outlined elsewhere for Stage 1, Clinical Group III disease. 
 
13.5.3 Head and Neck (Parameningeal) 
Wide excision is appropriate when feasible, but the possibility of achieving wide 
margins is generally restricted to those patients with relatively superficial lesions. 
Cosmetic and functional factors should always be considered. 
 
Delayed primary excision is rarely applicable in these sites. However, 
craniofacial or skull base resection for anterior skull-base tumors of the nasal 
areas, paranasal sinuses, temporal fossa, and other such sites should be reserved 
to those surgical teams expert in its performance and to secondary procedures 
when tumor persists after initial chemo- and RT.  
Node management: See Section 13.4.2 
 
13.5.4 Extremity 
Children with extremity rhabdomyosarcoma have a relatively higher incidence of 
nodal and distant spread and a greater frequency of lesions with unfavorable 
histology, compared to those with head and neck sites. This observation should 

  
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encourage more extensive pretreatment assessment for regional, in-transit, and 
metastatic disease in these children. 
 
Local resection: Extremity tumors may be amenable to GTR while sparing the 
involved limb. Radical soft tissue or compartmental excision generally will 
provide a wide margin of resection that is sufficient for local tumor control. 
Excision of an entire muscle from origin to insertion or resection of the entire 
compartment may not be required, depending on the size and invasiveness of the 
specific tumor. 
 
The high rate of recurrence in extremity lesions is predominantly in the group of 
children with Group III disease. The definitive pre-treatment operation should be 
designed to remove all tumor. If there is suspicion or knowledge of residual 
tumor after the initial resection, PRE may be considered if can be performed with 
functional preservation; otherwise, DPE may be considered. 
 
Lymph Node Evaluation: Regional node evaluation is an integral part of the 
staging of patients with extremity RMS and should be performed in each patient 
(See Section 13.4.2). 
 
Clinically negative nodes: Sentinel node biopsy should be used whenever 
possible. Otherwise, random inguinal or axillary lymph node sampling is 
required even when there are no palpable involved nodes. Femoral triangle node 
sampling, rather than a formal node dissection, is recommended for lower 
extremity lesions. Lymph node mapping (See Section 13.4.2, above) should be 
done when feasible. 
 
NOTE: Removal of digits and distal portions of the hand or foot is regarded as a 
wide local excision, with the Clinical Group determined by the usual criteria. 
 
13.5.5 Chest Wall 
An initial biopsy should be performed on chest wall sites since many of these are 
sarcomas of the Ewing or PNET type and not rhabdomyosarcoma. The proper 
protocol is determined by histology. The biopsy should always be performed in 
the long axis of the tumor, i.e., parallel to the ribs. Once a diagnosis is established 
then definitive resection should be performed is possible. A wide excision should 
be accomplished, removing the full thickness of the chest wall, including the 
previous biopsy site, all involved chest wall muscles, and involved ribs. This may 
require wedge excision of underlying lung. Thoracoscopy is sometimes 
beneficial to determine the pleural extent of the tumor and the presence of 
attachments to the underlying lung. It is not necessary to remove the entire rib, 
but a wide margin should be accomplished, preferably 2 cm. It is not always 
necessary to remove the rib above and the rib below if a wide margin can be 
accomplished without so doing. Sometimes, removal of the periosteum of the rib 
above and the rib below will allow adequate margins while preserving the rib. If 
necessary, the rib above and rib below can be removed. Reconstruction can be 
accomplished with mesh. Sometimes, bone struts are necessary, using 
homografts, rib from the contralateral side, or titanium rib implants.  
 

  
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13.5.6 Genitourinary: Vulva/Vagina/Uterus/Cervix 
Complete gross removal of vaginal tumors prior to chemotherapy is frequently 
impossible when adhering to the surgical treatment paradigm outlined previously. 
However, the response of vaginal and vulvar tumors to primary chemotherapy is 
impressive and generally precludes the need for radical surgery, i.e., pelvic 
exenteration.  
 
Most vaginal tumors should be treated by chemotherapy and local control with 
RT utilizing brachytherapy whenever feasible. Primary uterine tumors may be 
less responsive to chemotherapy than those in vaginal sites. For uterine lesions 
the same surgical treatment guidelines and indications of primary resection, PRE, 
and DPE should be utilized. For uterine lesions treated by hysterectomy where 
fertility preservation is generally infeasible, preservation of the distal vagina and 
ovaries is usually possible. Some polypoid uterine tumors primary in the cervix 
may be removed without hysterectomy. Oophorectomy is not indicated unless 
there is gross ovarian involvement with tumor. 
 
Pelvic exenteration or total cystectomy is usually not required for patients with 
tumors in any of these sites but, if needed, anterior exenteration can usually 
encompass the tumor. 
 
13.5.7 Paratesticular 
Lesions adjacent to the testis or spermatic cord should be removed by 
orchidectomy and resection of the entire spermatic cord. This requires an 
inguinal incision and proximal spermatic cord control. Open biopsy or tumor 
spillage of any kind should be avoided since inguinal recurrence may follow. If 
biopsy is felt to be necessary prior to orchidectomy, the following should be 
performed: 1) atraumatic high spermatic cord control; 2) the mobilized testis and 
cord should be carefully isolated from the operative field with non-permeable 
drapes; 3) the biopsy site should be closed and the testis covered with a non-
permeable dressing (e.g. placed in a sterile baggy) awaiting frozen section report 
4) instruments used for the biopsy, gowns and gloves should be discarded from 
the field; 5) if the biopsy report is positive, the testis and the entire cord including 
the atraumatic clamp should be immediately removed without removing the 
protective dressing (baggy or the atraumatic clamp); 6) the field should be 
thoroughly irrigated. Any unprotected spillage should be considered Clinical 
Group IIa. Tumor invasion of the scrotum should be treated with 
hemiscrotectomy during resection of the primary tumor. However, previous 
transcrotal biopsy or resection does not require hemiscrotectomy. 
 
Nodal Management 
All patients with paratesticular primary tumors should have thin cut (< 10 yr. 
5 mm, ≥ 10 yr. 7 mm) abdominal and pelvic CT scans with double contrast to 
evaluate for evidence of nodal involvement. Regional lymph nodes are the 
ipsilateral iliac and retroperitoneal nodes up to the hilum of the ipsilateral kidney. 
 
For patients who are less than 10 years of age and whose CT scans show no 
evidence of lymph node enlargement, retroperitoneal node dissection is not 
necessary. Patients > 10 years old or with positive nodes on CT scan, regardless 

  
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of age, should have surgical assessment of retroperitoneal nodes; a minimum of 
7-12 nodes are required to adequately determine the presence or absence of nodal 
pathology. This number of nodes may be obtained either by nodal sampling of 
the ipsilateral infrarenal nodes, especially by the renal vein, or by a nerve sparing 
template dissection. The dissection recommended is an ipsilateral nerve sparing 
resection of the spermatic vessels and associated node-bearing tissue to the level 
of the renal vein using an abdominal or laparoscopic approach. Complete 
bilateral dissection has the disadvantage of the significant sequellae of bilateral 
sympathetic nerve resection and is not required. The "top" node of the dissection, 
i.e., at the level of the renal vein, should be marked for the pathologist. 
Alternatively, sentinel node resection to ensure removal of the sentinel node and 
then further sampling is acceptable. Any positive node(s) on CT scan not 
completely removed places the patient in Clinical Group III. 
 
These lesions rarely involve inguinal lymph nodes, except when there is scrotal 
invasion by the tumor. In this instance, i.e., with scrotal involvement, inguinal 
nodes should be biopsied. They are, however, not considered regional lymph 
nodes and the patient would be in Clinical Group IV, if they were positive. 
 
13.5.8 Genitourinary: Bladder/Prostate 
Tumors in these sites will be surgically managed as per the general principles 
outlined and receive subsequent therapy based on Stage and Clinical Group. 
Rarely, the tumor can (and should) be completely removed at presentation with 
preservation of bladder and urethral function. The initial operative procedure in 
most patients consists of a biopsy, which is usually performed endoscopically, 
perineally, or suprapubically, but may be by laparotomy. Pretreatment staging 
requires determination of the extent and size of the tumor by CT or MRI. If 
laparotomy is performed, iliac and paraaortic node sampling should be included, 
as well as biopsy of any other clinically involved nodes. Partial cystectomy, 
when applicable, has resulted in a similar survival rate and a higher rate of 
functional bladders when compared to other treatment options. This is usually 
applied to dome-of-bladder tumors but may occasionally be applicable to the 
more distal bladder and may require ureteral reimplantation or bladder 
augmentation. This technique should be used whenever appropriate and feasible, 
even in patients with distant spread. Timing can be either before chemotherapy 
(Clinical Group I or II) or as DPE. Bladder salvage is an important goal of 
therapy for tumors arising in this site and can be anticipated in 50-60% of 
patients. Complete response to non-operative therapy may not be rapid and, as 
long as there is partial response, radical resection procedures (e.g. pelvic 
exenteration) should be delayed. 
 
Urinary tract obstruction: Should obstructive uropathy occur prior to or during 
therapy, percutaneous, endoscopic or open decompression should not be delayed. 
 
Prostatectomy: Adequate but incomplete response of prostatic tumors to therapy 
may allow prostatectomy to be performed with complete gross and/or 
microscopic tumor removal and preservation of the urethra and bladder. This is 
rare. 
 

  
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13.5.9 Other sites 
Paraspinal/perineal/intrathoracic/retroperitoneum/abdominal wall: 
Rhabdomyosarcoma at these sites are usually large cannot be completely 
removed because of their close association with other vital structures. Regardless 
tumors at these sites follow the same principles of surgical intervention outlined 
previously. The intent of each operation (initial resection, PRE, DPE) should be 
the complete excision of disease with negative margins unless this would result 
in unacceptable loss of function or form. Debulking or partial resection of 
primary tumors have equivalent outcomes to patients that just have a biopsy and 
therefore are discouraged. 
 
Biliary tract:  
Tumors at this site respond relatively well with multimodal therapy without 
aggressive surgery. The primary role of surgery is for diagnosis and staging. 
Relief of biliary obstruction is likely to occur in response to chemotherapy: 
therefore attempts to establish bile drainage with aggressive surgery are 
unnecessary and are likely to result in an increase in morbidity. Likewise, 
external drainage of the biliary tract while the patient is immunosuppressed on 
chemotherapy appears to be associated with a high incidence of sepsis and should 
be avoided if possible. Most of these patients will have gross residual tumor. 
 
13.5.10 Tissue Handling 
The pathologist should be immediately notified and will deal with the specimen 
as defined in the Pathology Guidelines (See Section 14.0). 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
14.1 
Tissue Specimens/Pathology Review at Time of Diagnosis, Delayed Primary 
Excision, Relapse and Autopsy 
All patients enrolling on this protocol require institutional histological confirmation of 
RMS and institutional molecular confirmation of fusion status at the time of original 
diagnosis. Patients are required to submit tumor samples collected at original 
diagnosis and are encouraged to submit tumor samples at DPE, relapse, or autopsy.  
  
14.1.1 Suggested Minimal Histologic Sampling: 
a. Incisional biopsy material - If practical, all tissues should be processed. 
Needle biopsy specimens are the least desirable for classification of primary 
tumors. If needle biopsies are obtained, it is helpful to divide the tissue into 
multiple cassettes (one to two cores per cassette) for optimum conservation 
of tissue. 
 
b. Tumor excision – Representative tissue blocks are needed from various 
regions of the mass for tumor classification. Adequate sampling requires 
approximately 1 section per cm diameter of tumor. The narrowest tissue 
margins should be blocked to satisfy the examiner of complete or incomplete 
tumor excision. 
 

  
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14.2 
Pathology Review Requirements 
14.2.1 Retrospective Central Review of Diagnostic Samples  
All patients enrolling on this protocol will undergo a non-rapid, retrospective 
pathology review to confirm histologic classification.  
 
Note: As of Amendment #4, the test to determine the concordance rate 
between institutional and central FOXO1 fusion status has been completed. 
To confirm the anticipated high concordance rate between institutional and 
central FOXO1 fusion status, the first 150 patients enrolled on ARST1431 will 
have FOXO1 fusion status determined by FISH at the Biopathology Center. 
Centrally determined FOXO1 fusion status and results of the pathology review 
will NOT be returned to the referring institution.  
 
14.2.2 Retrospective Central Review at Time of DPE, Relapse, or Autopsy  
A pathology review will be performed on DPE, relapse, or autopsy specimens 
submitted for review. This is also a non-rapid, retrospective review and results 
will not be returned to the referring institution. 
 
Materials to send: 
Send at the time of study entry, DPE, 
relapse, or autopsy: 
 
Representative formalin-fixed paraffin 
blocks, and H&E stained slides:  
x 1 H&E section of all available blocks 
and  
x 1-2 representative FFPE block(s).  
 
If blocks absolutely cannot be sent, then 
submit 
20 
plus-charged 
(polarized) 
unstained 
sections 
(4 micron 
section 
thickness) from 1-2 representative blocks in 
addition to the H&E stained slides listed 
above. The unstained slides from each block 
must be cut sequentially and will be used for 
immunoperoxidase 
and 
other 
special 
studies.  
 
Paraffin blocks will only be returned upon 
request. 
 
Documentation including: 
Institutional Final Pathology Report  
Institutional Cytogenetics/Molecular Report 
Institutional Operative Report (even for 
biopsy only) 
COG Specimen Transmittal Form 
All reports must be labeled with the patient’s COG patient 
identification number. Blocks or slides for central review 
must be labeled with the COG patient identification 
number, surgical pathology ID, and block number from the 
corresponding 
pathology 
report 
and 
specimen 
type 
(primary or metastatic). 
 
Label the parcel, as applicable, with “Diagnostic Sample 
Review”, “Delayed Primary Excision Review”, “Relapse 
Review” or “Autopsy Review”.  
 
Please use the phone number listed below on all packages 
shipped to the Biopathology Center. 
 
Send all pathology central review materials via regular mail 
or using the institution’s courier account to: 
 
Biopathology Center 
Nationwide Children's Hospital 
700 Children’s Drive WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: 
(614) 722-2897 
Email:
 BPCParaffinTeam@nationwidechildrens.org 
 

  
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The study review pathologists are: 
Erin R. Rudzinski, MD 
Department of Laboratories, OC.8.720 
Seattle Children’s Hospital 
4800 Sandpoint Way NE 
Seattle, WA 98105 
Erin.rudzinski@seattlechildrens.org  
 
Lisa Teot, MD 
Boston Children's Hospital 
Department of Pathology, BCH3027 
300 Longwood Ave  
Boston, MA 02115 
Lisa.Teot@childrens.harvard.edu 
 
Michael Arnold, MD, PhD 
Department of Pathology 
Children’s Hopsital Colorado 
13123 East 16th Avenue 
Aurora, CO 80045 
michael.arnold@childrenscolorado.org 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
Use of diagnostic pretreatment tumor tissue will be prioritized in the following order: 
 
1) 
H&E stained slide for central pathology review  
2) 
Myogenin immunohistochemistry and additional immunohistochemical staining for 
fusion variants 
3) 
PAX3/7 fusion testing (in FOXO1 fusion positive cases) 
4) 
Correlation with circulating tumor DNA (if patient consented) 
5) 
Deeper analysis of fusion variants by FISH and /or targeted sequencing 
 
15.1 
Identification of Fusion Partners and Variant Gene Fusions in RMS  
We aim to identify fusion variant RMS cases to determine their clinicopathologic 
characteristics compared to traditional fusion negative and FOXO1 fusion positive 
tumors. There are four components to this correlative study: 
i) Central pathology review will confirm the pathologic diagnosis and identify 
histologic features unique to fusion type. 
ii) Use 
of 
formalin-fixed, 
paraffin-embedded 
tissue 
sections 
for 
immunohistochemical staining including a panel for 3 antibodies (myogenin, 
AP2b, and HMGA2). This will identify tumors which may harbor a fusion 
protein that does not include the FOXO1 gene, which would be detected by 
institutional FISH or other molecular techniques. 
iii) All FOXO1 fusion positive cases will undergo PAX3 and PAX7 testing by FISH 
to identify common fusion partners. 
iv) Cases suspicious for variant gene fusions after immunohistochemical analysis, 
institutional FOXO1 results and PAX3/7 testing will be further analyzed by an 

  
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indepth FISH and/or targeted sequencing panel to identify any of the currently 
known fusion variants implicated in RMS tumorigenesis. 
 
15.1.1 Sample Collection and Processing 
See Section 14.2 for required samples and shipping instructions.  
 
Note: The availability of adequate tumor tissue (pretreatment paraffin-embedded 
tumor material (block) or unstained slides) as defined in Section 14.2.2 is 
required for study entry.  
 
COG sites: if adequate representative blocks or stained and unstained slides have 
been submitted already on APEC14B1 (Project:EveryChild), additional tissue 
may not be required. If blocks or slides submitted via APEC14B1 are to be used 
for ARST1431 then you MUST communicate that to the BPC either through 
documentation on the APEC14B1 transmittal form or by email to 
bpcbank@nationwidechildrens.org. If the material submitted for APEC14B1 
does not meet the requirements for ARST1431, then the Biopathology Center 
will request additional material for ARST1431. 
 
15.1.2 Identification of Fusion Positive RMS 
The following workflow will be used: 
 
Prospective cases collected on ARST1431 will be processed, as material is 
received at the BPC, for fusion variants implicated in RMS tumorigenesis. 
 
Unstained slides will be processed at the BPC. 
For all cases enrolled, if an H&E slide is not submitted, one unstained slide will 
be stained with hematoxylin and eosin for routine histologic examination on 
subsequent central review. 
 
For all cases enrolled, three (3) unstained slides will be sent to Erin Rudzinski, 
MD at Seattle Children’s Hospital for immunohistochemical staining with 
antibodies to AP2b, HMGA2, and myogenin. Myogenin staining is essential for 
both central pathology review as well as an integral component of the 
immunohistochemical surrogate fusion panel. 
 
For all cases with confirmed FOXO1 fusion, two to four (2-4) unstained slides 
will be used by the Biopathology Center for analysis of PAX3/7 by FISH to 
identify common fusion partners.  
 
For cases with a discrepancy between the immunohistochemical panel, FOXO1 
fusion result or PAX3/7 fusion result, 6 additional unstained slides will be sent to 
Julia Bridge at the University of Nebraska Medical Center and/or the 
Translational Genomics Research Institute (TGen) for comprehensive analysis of 
all 
fusion 
variants 
described 
in 
rhabdomyosarcoma. 
For 
all 
cases, 
immunohistochemical and molecular data will be returned to the COG Statistics 
and Data Center (SDC). 
 

  
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15.1.3 Banking of Leftover Specimens 
If the patient consents, any specimens leftover after the required studies 
described above in Section 15.1 have been performed will be banked at the BPC 
for future research studies. 
 
15.2 
Circulating Tumor DNA (ctDNA) 
Patient consent is required for participation in this correlative study. 
 
15.2.1 Streck Cell-Free DNA BCT Tube Ordering 
IMPORTANT: Streck Cell-Free DNA BCT tubes can be ordered via the 
BPC Kit Management system. These tubes are provided to sites in North 
America who have patients who have consented to the ctDNA study. 
Funding for these tubes is specific to ARST1431, so they must be used only 
for patients enrolled on ARST1431. The Kit Management System can be 
accessed via the following link: 
https://ricapps.nationwidechildrens.org/KitManagement/Auth/Login. 
You must select ARST1431 as the protocol when ordering Streck tubes for 
ARST1431 patients. Tubes are shipped ground, so please allow 3-5 business 
days for receipt. 
 
15.2.2 Specimen Collection  
x 
2 of the unstained pretreatment tumor slides submitted as detailed in 
Section 14.2 will be used for this study.  
x 
Peripheral blood samples should be obtained as follows:  
- 
Blood should be collected in Streck Cell-Free DNA BCT tubes  
- 
For patients > 25 kg: Collect 20 mL (10 mL per tube x 2 tubes)  
- 
For patients > 2 kg but < 25 kg: Collect 10 mL (one tube)  
- 
For patients < 2 kg: Research samples will not be collected  
 
In all cases, blood draw volumes should strictly adhere to institutional 
limitations, taking other blood draws into consideration. However, if a reduction 
in volume is required, samples should be collected in 10 mL increments (ie. 0, 
10, or 20 mL should be collected such that each Streck Cell-Free DNA BCT is 
completely filled). After collection, blood samples in Streck tubes should be 
stored and shipped at room temperature, never on ice or refrigerated.  
 
15.2.3 Time Points for ctDNA Blood Sample Collection 
If patient consents for this biology study, peripheral blood will be required at the 
following time points: 
x 
Pre-Treatment (within 7 days prior to treatment start)* 
x 
Weeks 4, 7, and 19 prior to the delivery of chemotherapy on that day 
x 
Week 42 evaluation (within 1 week of CT/MRI evaluation; only for 
Regimens A and B) 
x 
End of protocol therapy evaluation (within 1 week of CT/MRI 
evaluation; for all patients including Regimen C) 
x 
At relapse/progression 
 

  
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*All patients should submit one pretreatment blood sample collected in a Streck 
tube.  
x 
If the patient also consented to Part A of APEC14B1, then the 
pretreatment sample must be submitted under APEC14B1 rather than 
ARST1431.  
x 
If the patient did not consent to Part A of APEC14B1, then the 
pretreatment sample is submitted through ARST1431. 
Only one pretreatment specimen should be collected per patient so if a 
pretreatment blood sample was already collected in a Streck tube and submitted 
under APEC14B1 prior to enrollment on ARST1431, then an additional 
pretreatment blood sample should not be collected. If the pretreatment blood 
sample is missed, samples should still be collected for all subsequent timepoints. 
 
Note: If treatment is delayed or held, please collect the blood on the day that 
treatment was scheduled to be given and not the day when treatment is actually 
delivered. 
 
Established institutional guideline should be followed for blood collection via 
vascular access devices. Heparin should be avoided in pre-collection flush 
procedures. In patients with heparinized central lines, we recommend collecting 
an EDTA tube as a waste tube prior to collection in the Streck Cell-Free DNA 
BCT. 
 
For patients who do not have indwelling catheters, blood should be collected via 
venipuncture. To guard against backflow, observe the following precautions: 
x 
Keep patient’s arm in the downward position during collection. 
x 
Hold tube with the stopper in the uppermost position so that tube 
contents do not touch the stopper or the end of the needle during sample 
collection. 
x 
Release tourniquet once blood starts to flow in tube, or within 2 minutes 
of application. 
x 
Fill tube completely. 
x 
Remove tube from adapter and immediately mix by gentle inversion 8 to 
10 times. Inadequate or delayed mixing may result in inaccurate test 
results.  
 
15.2.4 Specimen Labeling and Shipment 
Streck tubes must be labeled: 
x COG patient ID number 
x BPC number 
x Specimen type (blood) 
x Collection date.  
 
Streck tubes should be shipped by FedEx Priority Overnight at room temperature 
to the COG Biopathology Center for immediate separation, extraction, and 
storage of plasma and cellular DNA. Samples should be shipped from Monday 
through Friday for Tuesday through Saturday delivery. If blood is collected in the 
Streck tube over the weekend or on the day before a holiday, the sample can be 
stored at room temperature until shipped on the next business day.  

  
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North American sites will access the Kit Management application to print a 
FedEx shipping label for shipping blood in Streck tubes. A ctDNA Specimen 
Transmittal form must be included with each shipment. The time point listed on 
the transmittal form must be written on the transmittal form exactly as listed 
above. 
 
Ship specimens to the following address: 
 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol ARST1431 
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. Gupta. For questions about sample processing and shipping, please contact 
the BPC directly. 
 
15.2.5 Methodology 
Tumor tissue (consisting of a minimum of 2 unstained slides) or extracted nucleic 
acids, plasma and extracted germline DNA will be sent from the BPC to 
Dr. Crompton at Dana-Farber Cancer Institute. Extracted nucleic acids from 
these samples will be subjected to hybrid capture sequencing and low coverage 
whole-genome sequencing (WGS) to identify the patient-specific somatic 
variants in the tumors and detect the presence of circulating tumor DNA (ctDNA) 
in the plasma.87 For fusion positive or MYOD1 positive samples, data from 
paneled sequencing and the remaining nucleic acids from the tumor and plasma 
will be shared with Dr. Shukla at Memorial Sloan-Kettering Cancer Center 
(MSKCC) for the development of patient-specific digital PCR primers and 
detection of ctDNA. For fusion negative, MYOD1 negative samples, remaining 
tumor, plasma and germline nucleic acid material will be shared with Dr. Avanthi 
Shah at UCSF to identify somatic point mutations by CAPP-Seq to detect the 
presence of ctDNA in the plasma.88 
 
Sensitivity of each assay (hybrid capture sequencing, low-passage WGS, 
CAPP-Seq and ddPCR) will be determined for plasma samples obtained at 
diagnosis (prior to the initiation of therapy) and for samples serially collected 
during therapy. After the above aims have been completed, additional nucleic 
acids will then be subjected to deep next-generation sequencing (including but 
not restricted to whole-exome sequencing) to determine whether detection of a 
greater number of somatic single-nucleotide variants is better able to detect the 
presence of ctDNA and whether we can detect patterns of tumor heterogeneity 
and evolution in ctDNA from multiple timepoints. 
 

  
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15.2.6 Banking of Leftover Specimens 
If the patient consents, any specimens leftover after the research studies 
described above in Section 15.2 have been performed will be banked at the BPC 
for future research studies. 
 
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 
Goals of Diagnostic Imaging 
Routine diagnostic imaging will be performed at diagnosis, during treatment and 
follow-up, and at the time of suspected tumor progression/recurrence to detect and 
characterize sites of disease involvement.  
Full body FDG PET-CT (FDG PET-MRI) is optional (study consent is required). Central 
review of imaging studies will not be performed for decision making in this study.  
 
16.2 
Timing of Diagnostic Imaging 
16.2.1 Required Imaging Time Points 
x
Regimens A and B: 
x 
At study enrollment* 
x 
At Week 9 
x 
Immediately post-operatively (only in cases undergoing DPE) 
x 
At Week 30 
x 
At Week 42 (end of VAC/VI therapy +/- temsirolimus) 
x 
At Week 54 (end of maintenance Cycle 3) 
x 
At end of protocol therapy 
x 
At the time of suspected tumor progression/recurrence 
x 
At the time of diagnosis of a second malignant neoplasm 
 
x
Regimen C: 
x 
At study enrollment* 
x 
At Week 9 
x 
Immediately post-operatively (only in cases undergoing DPE) 
x 
At end of protocol therapy 
x 
At the time of suspected tumor progression/recurrence 
x 
At the time of diagnosis of a second malignant neoplasm 
 
Central review of diagnostic imaging studies will not be obtained at the above 
time points. 
 
*Note: All baseline radiology scans and reports should be submitted to IROC 
Rhode Island at the time of study enrollment. These scans and reports will be 
made available to the central surgical reviewers; results will not be returned to 

  
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the institution. Scans and reports can be uploaded via TRIAD, sFTP, or emailed 
to DataSubmission@qarc.org. Please label all materials with protocol & case #. 
 
16.2.2 Recommended Imaging Time Points Post-Treatment 
Please see Section 7.1 for required imaging following completion of therapy. 
 
16.3 
Required Imaging Studies 
x
Primary tumor – To be evaluated at the time points specified in using: 
o 
CT imaging or MR imaging or FDG-PET with diagnostic quality CT/MRI. 
 
NOTE: If more than one imaging modality was acquired, please submit all available 
pre-study images.  
 
In order to standardize target volume definition using better tumor and soft tissue 
definition, an MRI of the primary site is highly preferred unless a patient has 
contraindications to MRI (e.g., implanted pacemaker, neurostimulator, aneurysm 
clips, metallic foreign objects, or other contra-indications). 
 
x
Metastatic sites 
o CT or MR imaging of the draining lymph node bed. At study 
enrollment and at the time of suspected tumor progression/recurrence; 
repeat at each follow-up visit only if adenopathy identified on baseline 
study. 
o Chest CT - At the time points specified in Section 16.2.1 
o Other imaging studies - Any imaging studies in patients other than the 
above that identify sites of disease that were not detected on other scans 
should be repeated at the time points specified in Section 16.2.1. 
 
Note: the same imaging modality should be used at each evaluation. If possible, 
patients should be imaged on the same scanner for the baseline and follow-up studies. 
 
16.4 
Diagnostic Imaging Guidelines 
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 
(http://jnm.snmjournals.org/content/47/6/1059.long). 
 
Note: the guidelines below are recommendations only and are not intended to 
replace institutional guidelines. 
 
Assessment of the size and features of rhabdomyosarcoma requires cross-sectional 
imaging such as computed tomography (CT) and/or magnetic resonance (MR) imaging. 
The optimal imaging modality is selected based on the anatomic site of involvement, with 
the goal of evaluating the tumor volume and assessing tissue characteristics of the lesion 
[such as x-ray attenuation or density (CT) or signal intensity (MR)]. Usually, direct 

  
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axial (rarely coronal) images are obtained on CT imaging, and images are acquired in 
2 or more planes perpendicular to each other on MR imaging. 
 
In general, MR imaging is superior in evaluating tumors located in the soft tissues of the 
trunk and extremities, and may also be useful in retroperitoneal and pelvic sites. CT 
imaging is preferred for evaluation of pulmonary nodules and may be helpful for 
intraabdominal and pelvic tumors. The same modality should be used at study enrollment 
and at each follow up visit to allow fair comparisons to be made. [18F]FDG imaging is 
optional but is encouraged to allow an assessment of the value of this modality in 
identifying sites of disease and measuring tumor response. 
 
16.4.1 CT Imaging 
Breath-hold technique should be used in cooperative patients to reduce 
motion artifact and spatial misregistration from respiration. In patients 
incapable of immobilization, conscious sedation should be considered when 
clinically feasible to minimize image degradation from patient motion. 
 
Use of Contrast Medium 
Whether intravenous or enteral (oral and rectal) contrast medium is used is 
determined by the location and density of the lesion and the surrounding 
normal tissues. Vascular opacification helps to identify vascular encasement, 
displacement, and tumor margin. Tumor enhancement is absent in areas of 
necrosis or cystic degeneration before or after treatment. Enteral contrast 
helps to differentiate tumor from the surrounding opacified bowel. A dose of 
2 mL/kg of ionic or non-ionic contrast is usually given intravenously. The 
amount of enteral contrast varies with patient’s age and tolerance to oral (or 
nasogastric) or rectal administration. 
 
Technical Guidelines 
Technical parameters for CT scans should be chosen to achieve the best 
compromise between image quality, scan time, and patient radiation dose, and 
may vary based on the imaging equipment and expertise available at each 
institution. Image acquisition parameters include beam collimation, detector 
size configuration, table increment per detector rotation (pitch), gantry rotation 
time, reconstructed image thickness and spacing, contrast dose, contrast 
injection rate, image acquisition timing relative to contrast administration, and 
radiation exposure factors (kVp and tube current). Image display parameters 
include field-of-view, window width and level, and hardcopy or softcopy 
format (e.g., film or computer workstation monitors). Follow-up studies 
should be performed and interpreted with parameters as close as possible to 
the baseline study. For example, lesions should be measured at the same 
window width and level settings and reconstruction intervals. 
 
The selection of optimal slice thickness is influenced by the patient’s size. 
The use of thinner sections to increase spatial resolution may be valuable in 
certain settings, such as the evaluation of questionable small lesions, but 
incurs the expense of increased radiation dose and should be used judiciously. 
As a general guideline, radiation dose can be minimized and scan coverage 
maximized with helical/spiral CT by increasing pitch. For single detector CT 
(SDCT), pitch values in the range of 1.4 - 2.0 are usually optimal, with 

  
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degradation of longitudinal axis resolution limiting the use of higher values. 
For multiple detector CT (MDCT), a more complex relationship between 
pitch and radiation dose exists and the optimal value will vary with the type of 
scanner. Reconstruction intervals generally should be set to equal the slice 
thickness, although overlapping reconstructions with small interscan spacing 
may be used to increase lesion conspicuity in selected circumstances, such as in 
the evaluation of small lesions that would otherwise be obscured by volume 
averaging. The gantry 
rotation 
time 
of 
scanners 
can 
vary 
from 
0.42-1.0 second, and the more rapid rotation times should be chosen in 
pediatric patients to reduce scan time and motion artifact. Most pediatric body 
CT is performed with tube voltage in the range of 80-120 kVp. To keep radiation 
dose as low as reasonably achievable, the tube current (mA) and gantry 
rotation time should be set as low as possible while maintaining lesion 
conspicuity for diagnostic quality images. In general, the smaller and younger 
the patient, the lower the mAs should be set. The specific settings should be 
decided for the encountered range of patient sizes and ages at each institution 
based upon experience with the available CT scanning equipment and published 
recommendations. 
 
16.4.2 MR Imaging 
MR imaging allows a better evaluation of soft tissues than CT imaging by 
identifying differences in T1, T2, and proton density between normal tissues 
and tumor tissue. The signal amplitude detected is also affected by the 
presence of motion (such as flow), system noise, and pulse sequence used. The 
most commonly used pulse sequences in clinical MRI imaging include T1- and 
T2-weighted, and fat-suppressed short-tau inversion recovery (STIR) pulse 
sequences. Fat- suppressed T1-weighted pulse sequence is used in cases 
where the tumor is surrounded by fat (such as in subcutaneous tissues). The 
cellularity of a tumor, which may vary with the type of tumor and change in 
response to therapy, can be studied with diffusion-weighted imaging (optional). 
 
Breathhold techniques can be used for patients who are old enough to 
cooperate and this technique can reduce the scan time. In patients incapable 
of immobilization, conscious sedation should be considered when clinically 
feasible to minimize image degradation from patient motion. Initial and follow-
up studies should use the same pulse sequences, scanning plane, and IV 
contrast. 
 
Use of Contrast Medium 
The use of intravenous contrast agent (0.1 mmol/kg body weight gadolinium-
DTPA) may or may not enhance the differentiation of tumor from the 
surrounding normal tissues. However, IV contrast is required for MRI scans of the 
primary tumor obtained at study enrollment and at Weeks 13 and 43). IV contrast 
is required in these settings to enable an accurate assessment of tumor necrosis 
(and therefore tumor response). In this study, necrosis is defined as the absence of 
contrast enhancement. 
 

  
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16.4.3 Recommendations for FDG-PET and Diffuse-Weighted MR Imaging Studies 
[18F]–2-fluoro-2-deoxy-D-glucose ([18F]FDG) Positron Emission Tomography 
(FDG-PET) imaging is optional and requires consent but is encouraged. Please 
refer to Appendix XIII for pediatric FDG-PET/CT guidelines. 
 
The following generally accepted FDG-PET issues and items should be adhered 
to as much as possible in this clinical trial to allow for uniformity of inter- and 
intra-patient FDG-PET imaging and analysis needed for this study: 
 
Summary of Definite Requirements 
1) 
Patients should be fasted for at least 4 hours before [18F]FDG 
administration. 
2) 
PET imaging should begin at 60 ± 10 min after injection of [18F]FDG. 
3) 
Maximum recommended dose of [18F]FDG for children is 12 mCi and 
20 mCi for adults or as per institutional guidelines. 
4) 
For follow-up PET imaging of the same patient, all attempts should be 
made to image the patient on the same PET/CT (PET/MRI) scanner. 
5) 
The following PET parameters should be recorded for each imaging 
session: 
a. 
Patient’s weight and height 
b. 
[18F]FDG dose and time of administration 
c. 
Start time of PET imaging 
d. 
Serum glucose level (or verify that level is less than 200 mg/dL) 
e. 
Use of low-dose propranolol or fentanyl for pharmacologic 
suppression of activated brown adipose tissue 
f. 
Time (in days) from last infusion of temsirolimus for patients on 
Regimen B. 
6) 
Institutional radiologist or nuclear medicine physician assessment and 
report of the PET scan for qualitative visual classification (5-point 
Deauville criteria) and anatomical location of the primary tumor site only. 
a. 
This visual PET criteria are scored according to uptake in the 
primary tumor site: (1) no uptake, (2) uptake ≤ mediastinal blood 
pool, (3) > mediastinal blood pool but ≤ liver, (4) moderately 
increased uptake > liver, or (5) markedly increased uptake > liver 
and/or new lesions. Physiologic [18F]FDG liver uptake is used as a 
reference with score of 1 to 3 regarded as PET negative and 4 or 5 as 
positive. 
7) 
Temsirolimus is an inhibitor of GLUT1 and other glucose transporters into 
cells.81 An FDG-PET scan taken shortly after temsirolimus infusion could 
demonstrate decreased [18F]FDG uptake, as a pharmacodynamic effect of 
the mTOR inhibitor, separate from any anti-tumor activity. Since 
temsirolimus has a half-life of 17.3 hours, FDG-PET scans should not be 
performed within 4 days after infusion of the drug.  
 
Summary of Other Optional Recommendations 
1) 
State some type of annual scanner QC/QA. 
Recommend either: 
x 
American College of Radiology (ACR) - Nuclear Medicine/PET 
accreditation Program 

  
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(https://www.acraccreditation.org/Modalities/Nuclear-Medicine-and-
PET) or 
x 
Intersocietal Commission for the Accreditation of Nuclear Medicine 
Laboratories (ICANL) PET accreditation 
(http://www.icanl.org/icanl/index.htm) 
a) 
If either of these PET QC/QA are not used in your facility, please 
provide your PET scanner QC/QA accreditation. 
 
2) 
[18F]FDG dosing requirements 
a) Confirm dosing in recommended dosing is in the range of 
0.10-0.14 mCi/kg for children. 
b) Confirm dosing in recommended dosing is in the range of 5-20 mCi 
or per institutional guidelines for adults.  
c) If recommended dose range is not used, state institutional pediatric 
PET dosing formula or schema. 
 
3) 
Prior to and following [18F]FDG injection, the patient is kept at rest in a 
warm room until the time of imaging to minimize [18F]FDG uptake in 
activated brown adipose tissue or other physiologic [18F]FDG artifacts. 
 
Pregnancy 
All female patients ≥ 10 years of age should be asked about their pregnancy 
potential prior to [18F]FDG injection. Patients who are pregnant or breast feeding 
will only be injected if the FDG-PET scan is deemed necessary for clinical 
management by the patients’ primary physician and the patient agrees to the 
study. Patients who are sexually active and unsure of their pregnancy status 
should undergo a urine or serum pregnancy test prior to [18F]FDG injection. 
Pregnant guardians should not be allowed in the [18F]FDG uptake room. 
 
Recommended Technique 
Patients should be fasted for at least 4 hours before imaging, except for water and 
non calorie containing beverages. If the patient is going to receive sedation, then 
sedation/anesthesia guidelines may be more stringent. Total parenteral nutrition 
and intravenous fluids containing glucose should also be discontinued for at least 
4 hours before the study. The patient should be well hydrated (oral or intravenous 
fluid administration) before administration of [18F]FDG. Fluids administered for 
hydration should not contain glucose. 
 
It is suggested that the patient’s measured height and weight on the day of the 
FDG-PET scan be recorded for each imaging session. 
 
If intravenous access is not already in place, this should be obtained, typically in 
the antecubital fossa, for patient hydration (if needed), determination of serum 
glucose and [18F]FDG administration. Good hydration is required as the primary 
route of [18F]FDG excretion is renal. The patient should drink water or receive 
intravenous fluids after injection to promote urinary [18F]FDG excretion. 
 
Venous serum blood glucose will be measured and recorded just prior to 
injection of the [18F]FDG and should be ≤ 200 mg/dL.  
 

  
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Diabetic patients should be scheduled in the morning after an overnight fast 
before the first meal, and dose of insulin should be titrated appropriately in 
consultation with the patient’s referring physician to keep the serum glucose 
≤ 200 mg/dL at the time of scheduled [18F]FDG injection. If the serum glucose is 
significantly elevated (> 200 mg/dL) then the test should be rescheduled if at all 
possible with better glucose control or, if necessary, insulin can be used to 
achieve normoglycemia. After regular insulin the patient should wait 2-4 hours 
(with ultra short acting insulin 1-2 hours) prior to administration of [18F]FDG in 
order to minimize physiologic skeletal muscle and myocardial [18F]FDG uptake. 
 
In patients with tumors in the pelvis, placement of a Foley catheter is 
recommended if needed to assist bladder emptying. Patients in whom a Foley 
catheter is not placed should be asked to void immediately prior to imaging in 
order to minimize bladder activity and to reduce their radiation exposure. 
 
[18F]FDG Dosing and Injection 
Children: [18F]FDG is administered intravenously at a dose of 0.10-0.14 mCi/kg 
with a minimum dose of 1.0 mCi and maximum dose of 12 mCi.  
 
Adults: [18F]FDG is administered intravenously at a dose of 5 - 20 mCi or per 
institutional guidelines. 
 
After injection, the patient is kept at rest in a warm room until imaging. After 
voiding the bladder, whole-body imaging should begin at 60 ± 10 min after 
injection of [18F]FDG. For serial scans of the same patient it is important to start 
the PET scan with the same delay time after injection of the [18F]FDG 
radiotracer. Therefore, it is recommended that all subsequent PET scans have 
approximately the same delay time (± 10 min) as the baseline scan. The use of 
low-dose propranolol or fentanyl for pharmacologic suppression of [18F]FDG 
uptake in activated brown adipose tissue can be applied as per institutional 
protocol and recorded. 
 
The net injected [18F]FDG dose and time of injection should be recorded. The 
peripheral IV or central line injection site location should also be recorded. 
 
PET Scanning Protocol 
A whole body FDG-PET imaging protocol is utilized, covering the area from the 
base of skull/top of the ears to the proximal/mid-thigh, just below the pubis. If 
there is suspicion of involvement in the lower extremities, skull, or skull 
contents, the volume that is imaged may be expanded. The patient will be 
positioned supine, with arms comfortably positioned above the head if at all 
possible (to limit attenuation of the thorax), or at the side of the patient if 
necessary. Scans should proceed upward from the pelvis to diminish the effects 
of accumulation of [18F]FDG activity in the bladder.  
 
CT scanning matching the areas covered by the emission scan will need to be 
performed for attenuation correction of the emission scan. This will be done after 
injection of [18F]FDG. The CT can be performed either with or without 
intravenous contrast. It is recommended that the COG institution adjust the CT 
dose used for attenuation correction to limit the CT radiation dose to the patient 

  
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without significantly affecting PET quality or anatomic correlation to CT. Please 
refer to protocol recommendations from the Image Gently website 
(http://www.imagegently.org/Home.aspx). 
 
The 511 KeV-annihilation photons, produced by interaction of positrons with 
electrons, are imaged. Because of the short physical half-life of 18F of 1.8 hours 
and the high photon energy of 511 KeV, FDG-PET imaging may follow bone or 
gallium scintigraphy, or a MUGA study on the same day (that use lower energy 
photons) or FDG-PET imaging may be performed on the day preceding any of 
these other nuclear medicine studies. 
 
The following acquisition parameters should be recorded: start time of emission 
scan and type of transmission scan. 
 
The PET images should be reconstructed with and without attenuation correction. 
For serial scans of the same patient, image reconstruction techniques and 
parameters be consistent across all scans, including filters and application of the 
attenuation map. 
 
After Completion of the PET Scan 
The patient must empty his or her urinary bladder as soon as possible after 
imaging. Image reconstruction will depend on the scanner manufacturer. An 
iterative reconstruction method with parameters chosen to yield 6-8 mm 
resolution in the reconstructed images is standard. 
 
[18F]FDG Handling and Dose Documentation 
[18F]FDG is most often purchased from nuclear pharmacies licensed to sell 
[18F]FDG or, less commonly, synthesized by standard methods and tested for 
pyrogenicity and radiochemical purity on each production run. The 
radiochemical purity of the [18F]FDG should be > 90%.  
 
PET Imaging Quality Control Standards 
FDG-PET imaging will be performed using PET/CT. 
 
Daily and monthly steps will be taken to assure quantitative accuracy of FDG-
PET imaging studies and reliable imaging results at all performance sites, with 
recommended clinical standards described above under “Summary of Other 
Optional Requirements” under “State some type of annual scanner QC/QA”. 
 
The level of tumor uptake is assessed subjectively by visual inspection as 
described in the Evaluation Criteria (see Section 10). Semi-quantitative 
assessment of response by determination of standardized uptake values 
(SUV) is not utilized in this protocol response criteria, however SUV 
parameters can be provided as per routine clinical practice. Deauville score 
assessment should be performed utilizing coronal attenuation corrected FDG-
PET images rather than MIP or fused images. 
 
 

  
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17.0 
RADIATION THERAPY 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). 
 
Radiation therapy (RT) for patients on COG protocols can only be delivered at approved 
COG RT facilities.  
 
17.1 
General Guidelines 
The RT guidelines for this study were developed specifically for patients with newly 
diagnosed intermediate-risk RMS defined by protocol criteria. All patients should plan to 
receive radiotherapy to the primary tumor at Week 13. 
 
In select cases where delayed primary excision (DPE) is performed, post-operative CT or 
MRI imaging must be done to confirm gross total resection (GTR) or to define any gross 
residual disease requiring a boost. In these cases, post-operative RT should begin as soon as 
possible after allowing for post-operative imaging and adequate wound healing. 
 
For patients on Regimen B, temsirolimus will be held during RT. 
 
17.1.1 Special Note for Patients ≤ 24 Months Old  
The long-term morbidity of RT or aggressive surgery for very young 
(≤ 24 months old) children makes appropriate local control challenging. Many 
clinicians are unwilling to follow standard local control guidelines for very 
young children. ARST1431 encourages adherence to standard local control 
guidelines for children > 24 months old but permits deviations at the discretion of 
the treating clinicians only for children ≤ 24 months who are FOXO1 negative. 
Deviation from protocol-mandated radiotherapy must be included in the QA 
documentation submitted to IROC RI. For children ≤ 24 months of age with 
FOXO1 positive disease, deviations from standard local control guidelines 
will be considered a protocol violation. Only for patients ≤ 24 months with 
FOXO1 negative disease, deviations from the standard local control guidelines 
will not be considered protocol violations. 
 
17.1.2 Credentialing 
x 
All therapy units used on this protocol must have their calibrations verified 
by IROC Houston. The table in Section 17.5 indicates allowable modes of 
treatment delivery. 
x 
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. 
  

  
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x 
Proton Therapy: Each beam line used to treat patients on this study must be 
credentialed for clinical trial use by IROC Houston. See Section 17.1.3 
below. 
x 
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. 
x 
Stereotactic Body RT (SBRT): Use of SBRT is encouraged but not 
mandatory for treatment of bone metastases < 5 cm (based upon maximal 
dimension at diagnosis), but credentialing is 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:  
x 
SBRT is not to be used for sites other than bone metastases. 
x 
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 Proton Beam Therapy 
Proton therapy may be used to deliver RT 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. 
 
17.1.4 Guidelines and Requirements for the Use of Brachytherapy or Intraoperative 
Irradiation  
Brachytherapy, using either high dose rate or low dose rate radioactive sources may 
be used on this protocol. Typically, brachytherapy or intraoperative RT will be used 
for conformal RT of residual disease in the operative bed of the primary tumor for 
select patients. 
 
17.2 
Treatment of Metastatic Disease 
17.2.1 Metastatic Disease 
All patients should have all local and distant disease addressed with an appropriate 
local control modality after the completion of VAC/VI chemotherapy (Week 43). 
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 

  
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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 RT to the often multiple sites of 
metastatic disease. 
 
Because of the option of SBRT for bone 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.  
 
RT for Metastatic Sites  
Definitive RT  
Unresected tumor > 5 cm  
Definitive SBRT  
Unresected/post-operative gross disease in bone mets that 
were < 5 cm at diagnosis 
Post-operative RT  
(1) Post-operative gross or microscopic residual tumor  
(2) Intra-operative spill  
Special presentations  
(1) Pulmonary metastases  
(2) Pathologically involved lymph nodes  
 
RT 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. 
 
17.3 
Timing 
17.3.1 All patients should be seen in consultation by a radiation oncologist at the time of 
study enrollment. The purpose of the consultation is to participate in risk 
classification and to review the adequacy of the initial diagnostic imaging studies 
that will be used for subsequent RT planning. 
 
17.3.2 Patients will have RT delivered to the primary site and any involved regional lymph 
nodes with a goal to begin at Week 13. It is strongly recommended that the 
patient be evaluated by the radiation oncologist at the time of study entry 
(prior to any study therapy). This will allow adequate time for simulation and 
planning prior to Week 13. The radiation oncologist will review the adequacy of the 
initial diagnostic imaging studies for subsequent RT planning. In patients who are 
undergoing DPE, post-operative imaging must be obtained to assess completeness 
of resection. RT should be initiated as soon as possible once this imaging has been 
performed and there is evidence of adequate wound healing.  
 
Metastatic sites will be treated at the completion of VAC/VI chemotherapy 
(Week 43). 
 
17.3.3 Vincristine, cyclophosphamide, or irinotecan chemotherapy may be given 
concurrent with radiotherapy. Dactinomycin should be withheld during RT and re-
instituted after completion of RT. Dactinomycin can be given at Week 13 prior to 
starting RT. For those on Regimen B, Temsirolimus will be held during and for 
2 weeks following RT. 
 
17.4 
Emergency Radiation Therapy 
Patients for whom emergency RT is planned should not be enrolled on this study.  

  
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17.5 
Equipment and Methods of RT Delivery and Verification 
 
Equipment 
Photons (any 
energy) 
Electrons 
(any energy) 
IMRT 
(4-10MV) Protons Brachytherapy* 
Linear Accelerator** 
X 
X 
X 
 
 
Proton Beam 
 
 
 
X 
 
Intraoperative RT 
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 planning target 
volume (PTV) while protecting normal tissues. Organs within the irradiated volume 
should be contoured including those required by treatment site (see Table 17.10.1). 
A DVH is necessary to determine target coverage and evaluate dose to normal 
tissues. In the event that a patient must start 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 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. 
 

  
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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 
x
Gross tumor volume (GTV) is the volume occupied at diagnosis by visible 
disease.  
x
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.  
x
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 
x
GTV is the same for protons and photons. 
x
CTV is the same for protons and photons. 
x
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 
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 
x
GTV is the same as for photons. 
x
CTV is the same as for photons. 
x
PTV is equal to CTV. 
 

  
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17.6.2 Protocol Tumor and Target Volume Definition 
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. For patients who undergo initial surgery, 
operative notes and pathology reports may be helpful. For patients with 
initial tumors that extend into body cavities (i.e., thorax, abdomen) the 
GTV may require modification. If the tumor has been resected or 
responded to chemotherapy and the normal tissues have returned to their 
normal positions, the GTV excludes the volume which extends into the 
cavity. Examples include tumors which compress but not invade the lung, 
intestine or bladder that radiographically return to normal anatomic 
position following surgery or chemotherapy. The GTV must include all 
infiltrative disease detected at initial presentation. For select patients 
undergoing delayed primary excisions (DPE), GTV will also be defined 
by the initial extent of tumor and will encompass the post-operative 
surgical bed. 
 
17.6.2.2 CTV1 – RT to Nodal Disease 
If there are no sites that warrant irradiation for potential occult tumor, then 
the CTV1 is defined as GTV1 + 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. The definition of “clinically 
involved” nodes will be clarified as those including the following features: 
1) > 1 cm on CT or MRI; OR 2) FDG avid on PET-CT; OR 
3) pathologically confirmed to have microscopic disease. RT to the nodal 
basin will be required for clinically involved nodes, unless they are 
biopsied and deemed pathologically negative. 
 
17.6.2.3 PTV1 
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 0.3 cm but does not have to 
be uniform in all dimensions. For proton planning, beam specific PTV 
expansions will be required. 

  
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17.6.3 Target Dose 
On this study, patients with tumors > 5 cm at the time of diagnosis will receive 
an additional boost to a total of 59.4 Gy. For those patients who have a CR at 
Week 9 evaluation defined by CR on cross sectional imaging of tumor on 
CT/MRI AND 1) negative FDG-PET OR 2) radiological CR with biopsy 
confirmed no evidence of disease will receive a dose reduction regardless of the 
size at diagnosis. (See Section 17.7) If a patient undergoes DPE for a tumor that 
initially measured > 5 cm, any gross residual disease after DPE will be boosted to 
59.4 Gy. For this reason, we discourage DPE that cannot easily achieve a gross 
total resection in patients with initial tumors > 5 cm. 
 
17.6.4 Volume Reduction / Boost 
For patients whose total dose will be 36 Gy, the PTV1 should not be modified 
unless the normal tissue dose recommendations will be exceeded (Table 17.9.7). 
Volume reduction is permitted for patients whose total dose will be 41.4-59.4 Gy. In 
cases where there is a decrease in tumor size following chemotherapy, a cone-down 
should be performed after 36 Gy. This is encouraged for tumors with “pushing” 
rather than invasive margins when significant normal tissue sparing will result from 
a volume reduction. Examples include tumors that displace the lung, intestine, or 
bladder that show clear return to a more normal anatomic position. Volume 
reduction is not recommended for invasive tumors. If there is no measurable 
reduction in tumor size by Week 9, no volume reduction is required and the initial 
PTV1 may be maintained for the entire treatment. 
 
17.6.4.1 GTV2 
GTV2 is defined as residual visible or palpable tumor as assessed by CT, 
MRI, PET scan or physical exam following induction chemotherapy. If 
DPE is performed and gross residual disease is detected on mandatory 
postoperative imaging, that residual disease will represent GTV2. 
 
17.6.4.2 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. 
 
17.6.4.3 PTV2 
PTV2 is defined as the CTV2 with an institution and modality specific 
margin (minimum 0.3 cm) to account for day to day setup variation and 
physiologic motion of the CTV2. For proton planning, beam specific PTV 
expansions will be required. 
 
17.6.5 Site-Specific Modifications  
Extremity Tumors 
The CTV can be modified at the discretion of the Radiation Oncologist to avoid 
circumferential irradiation of extremity lymphatics and treatment across a joint.  
 
  

  
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Orbit 
For orbit primaries, the CTV will not extend outside of the bony orbit, providing 
there is no bone erosion of the orbit. The entire orbit does not need to be irradiated, 
only the tumor volume with margins (PTV). Every attempt should be made to shield 
the lens, cornea, and lacrimal gland appropriately (see Table 17.9.5). 
 
Head and Neck Tumors 
Many of these tumors may be considered unresectable due to close proximity to 
critical structures and surgical risks contributing to 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. 
 
Chest Wall/Intrathoracic Tumors 
Tumors which have displaced a significant amount of lung parenchyma which has 
subsequently returned to normal anatomic position following surgery or 
chemotherapy will have the GTV defined as the preoperative (pre-chemotherapy) 
tumor volume excluding the 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 which has 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 intrapelvic 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 postoperatively. In the event that whole abdomen radiotherapy is 
required (i.e., for malignant ascites or diffuse peritoneal involvement), the dose will 
be 24 Gy at 1.5 Gy per fraction with appropriate blocking of the kidneys and liver to 
keep them within normal tissue recommendations. 
 
Lymph Nodes 
For tumors with no evidence of nodal involvement (N0), the draining regional 
lymph nodes should not be irradiated. When lymph nodes are clinically or 
pathologically involved with tumor, the entire lymph node drainage chain should be 
included in the CTV. For example, the entire ipsilateral neck is treated for a jugular 
lymph node metastasis. Clinically enlarged nodes which are biopsied and do not 
contain tumor do not need to be irradiated. At the time of RT, any areas of potential 
microscopic nodal disease should receive 36 Gy while areas of residual gross nodal 
disease should be boosted to 50.4 Gy. 
 
Vaginal Tumors 
Brachytherapy is strongly encouraged for patients with vaginal primary tumors. 
 
Pulmonary Metastases and Malignant 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 

  
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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.  
IMRT is allowed for whole lung radiation.  
 
Non-Pulmonary Metastases  
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); (3) sites that can be imaged with sufficient accuracy for treatment; and 
(4) expected tolerance and morbidity (i.e., bone marrow tolerance).  
 
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.  
 
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 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. 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. 
 
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). 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 

  
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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 specified in Gray (Gy)-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 
The protocol-specified dose per fraction is 1.8 Gy. The treatment should be limited 
to one fraction per day. Five fractions should be given per week. There may be an 
exception if a department is closed on a major holiday but an effort should be made 
to minimize days missed. The dose per fractionation may be reduced from 1.8 Gy to 
1.5 Gy when large volumes are treated (i.e., whole abdomen and pelvis) or when 
tolerance is poor tolerance (i.e., mucositis or diarrhea). Changes to the fractionation 
regimen should be noted in the treatment record and submitted information. 
 
The primary site and any involved nodal regions should be treated concurrently 
though the total dose to the primary site and nodal region may differ depending 
upon the surgical status of each site. NOTE: Patients with positive lymph nodes at 
diagnosis that were only sampled by biopsy are Clinical Group III and will receive 
50.4 Gy to the primary while those that are completely resected will receive 41.4 Gy 
to the primary. 
 
17.7.3 Radiation dose according to FOXO1 fusion status, clinical group, and site. 
Patients with metastatic disease (Clinical Group IV) will have primary site 
radiotherapy according to the staging of the primary site. Patients with Clinical 
Group I, FOXO1 negative tumors or Clinical Group I, FOXO1 indeterminate 
tumors will not receive radiotherapy.  
 

  
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 Total Dose - Gy 
 
 post DPE - Dose Gy 
 
Clinical 
Group 
if no CR at 
Week 9** 
if CR at 
Week 9** 
if GTR post 
DPE with 
negative margin 
if GTR post DPE 
with microscopic 
margin 
if post DPE, gross 
residual disease 
I, FOXO1 neg 
0 
0 
N/A 
N/A 
N/A 
I, FOXO1 
indeterminate 
0 
0 
N/A 
N/A 
N/A 
I, FOXO1 + 
36 
36 
N/A 
N/A 
N/A 
II 
36 
36 
N/A 
N/A 
N/A 
III, ≤ 5 cm* 
50.4 
36 
36 
41.4 
50.4 
III, > 5 cm* 
59.4 
36 
36 
41.4 
59.4 
*Based on size at diagnosis 
**CR defined as Radiological CR by CT/MRI (no visible tumor) (see Section 10.2.4.3) and 1) CR by FDG-
PET; or 2) biopsy that shows no residual viable tumor. 
 
17.7.4 Radiation Dose Guidelines for Patients with Lung Metastases or Malignant 
Pleural Effusion  
All patients with any lung metastasis(es) or malignant pleural effusion should 
receive bilateral whole lung radiotherapy. The dose will be 15 Gy in 10 fractions of 
1.5 Gy. 
 
17.7.5 Standard (Non-SBRT) Radiation Dose Guidelines for Individual Metastatic 
Lesions (all non-bone sites, all non-lung sites and bone sites > 5 cm) 
 
Dose (Gy) 
Sites of initial metastases in CR 
40 in 20 fractions 
Lesions which are SD or PR 
50 in 25 fractions 
 
17.7.6 SBRT Dose Guidelines for Lesions that are SD or PR at Completion of VAC/VI 
Chemotherapy 
 
Dose/fraction (Gy) 
Dose (Gy) 
PTV2 = GTV2  
7.0 
35 
PTV1= CTV2 + 2mm  6.0 
30 
After 15Gy whole lung  
PTV2 = GTV2  
6.0 
30 
PTV1 = CTV2+2mm  
5.0 
25 
 
17.7.7 SBRT Dose Guidelines for Lesions that are CR at Completion of VAC/VI 
Chemotherapy 
PTV2 = GTV2  
6.0 
30 
PTV1= CTV2 + 2mm  5.0 
25 
After 15Gy whole lung  
PTV2 = GTV2  
5.0 
30 
PTV1 = CTV2+2mm  
4.0 
20 
 

  
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17.7.8 Dose Uniformity  
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 protocol-specified 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 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., 3 mm). 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. 
 
17.7.9 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 

  
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used with extreme caution when any of the treatment beams traverse normal lung 
parenchyma. 
 
17.7.10 Environment of Care – Interruptions, Delays and Dose Modifications 
There will be no planned rests or breaks from treatment, and once RT has been 
initiated, treatment will not be interrupted.  
 
The reason for any interruptions greater than 3 treatment days should be recorded in 
the patient’s treatment chart and submitted with the QA documentation. There 
should be no modifications in dose fractionation due to age or field size. If any area 
has been previously treated (emergently), care should be taken not to exceed normal 
tissue tolerance levels. In the unusual case of a prolonged interruption, patients will 
have their treatment regimen modified according to the schedule noted below. 
 
17.7.10.a Modifications in treatment regimen due to delays – Patients prescribed 36 Gy 
Timing 
Fx Size (Gy) 
# Fx 
Total Dose (Gy) 
Total Time 
Normal and/or up to 2 wk split 
1.8 
20 
36.0 
4 – 6 wks 
2-3 wk split 
1.8 
21 
37.8 
6 - 7 wks 
> 3 wk split 
1.8 
22 
39.6 
> 7 wks 
 
17.7.10.b Modifications in treatment regimen due to delays – Patients prescribed 41.4 Gy 
Timing 
Fx Size (Gy) 
# Fx 
Total Dose (Gy) 
Total Time 
Normal and/or up to 2 wk split 
 1.8 
23 
41.4 
4.6 – 6.5 wks 
2-3 wk split 
 1.8 
24 
43.2 
6.6 – 7.6 wks 
> 3 wk split 
 1.8 
25 
45.0 
> 7.6 wks 
 
17.7.10.c Modifications in treatment regimen due to delays – Patients prescribed 50.4 Gy 
Timing 
Fx Size (Gy) 
# Fx 
Total Dose (Gy) 
Total Time 
Normal and/or up to 2 wk split 
1.8 
28 
50.4 
5.4 - 7.3 wks 
2-3 wk split 
1.8 
29 
52.2 
7.4 - 8.4 wks 
> 3 wk split 
1.8 
30 
54.0 
>8.4 wks 
 
17.7.10.d Modifications in treatment regimen due to delays – Patients prescribed 59.4 Gy 
Timing 
Fx Size (Gy) 
# Fx 
Total Dose (Gy) 
Total Time 
Normal and/or up to 2 wk split 
1.8 
31 
59.4 
6.2-8.2 wks 
2-3 wk split 
1.8 
32 
57.6 
8.3-9.3 wks 
> 3 wk split 
1.8 
33 
59.4 
>9.3 wks 
 
17.8 
Treatment Technique 
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) or IMRT are required to minimize dose to normal tissue.  
 

  
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17.8.2 Selection of Proton Beam Arrangements 
There are uncertainties (0.1-0.3 cm) 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. 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.  
 
17.8.4.2 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 beam location 
relative to the target volume location 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 IM component of the 
PTV and is meant to account for potential motion of the CTV. The planning organ 
at risk volume (PRV) includes the organ at risk (OAR) surrounded by a margin to 
compensate for physiologic change in the target volume. If adequate clinical data do 
not exist to define the IM component of the PTV or the PRV margin, the following 
suggestions are provided: 
x
A margin of at least 0.5 cm should be added to any OAR to form the PRV. 
x
For a CTV susceptible to physiologic motion, a margin of at least 0.5 cm 
should be added to the CTV prior to PTV margin expansion or a PTV margin 
of 1 cm should be chosen. 
  
  

  
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x
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.  
x
A description of the method used and evidence (i.e., observed motion during 
fluoroscopy, motion of surrogate markers using camera systems, or analysis 
of 4D CT) of the remaining tumor motion should be submitted on the Motion 
Management Reporting Form as noted in Section 17.12. 
 
17.8.7 Brachytherapy 
Sources used shall have assay directly traceable to NIST. 
 
CT or MRI planning shall be used for post-implant 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. 
 
The following guidelines may be considered in planning the implant: 
A single plane implant is generally used for patients with microscopic residual 
disease. The target volume should include all sites of potential microscopic disease 
with at least 0.5-1 cm margin on all sides. If the area to be implanted is larger than 
50 cm2, external beam RT should be considered. Catheters should be parallel and 
positioned 1 cm apart. To ensure sufficient coverage the catheters should be placed 
with the distal end of the catheter projecting 1-2 cm beyond the target volume.  
 
Multi-plane implants are generally used for patients with gross disease. The target 
volume should include the entire palpable or post chemotherapy tumor volume with 
at least a 0.5 cm margin on all sides. If the thickness of tissue to be implanted is 
larger than 3 cm, external beam RT should be considered, but is not required. 
 
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
t

 
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 2 cm from the ends of the implant). CT based planning shall 
be used. 
 
  

  
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Total dose/fractionation and dose rate 
In the rare circumstance that post-operative brachytherapy is used instead of 
external beam radiation, then the following recommendations apply: 
LDR brachytherapy 
Total dose:  26 Gy Dose rate range:  0.40-1.00 Gy/hour.   
HDR brachytherapy 
Total dose:  21 Gy 
Dose per fraction:  3.00 Gy BID (separate 
fractions by ≥ 6 hours) 
Number of fractions: 7  
Brachytherapy should not begin until postoperative Day 5 to allow for wound 
healing. 
 
When brachytherapy is used for the treatment of gross disease, a dose and 
fractionation schedule should be determined that is biologically equivalent to the 
corresponding external beam dose of 50.4 Gy in 28 fractions (assuming tumor is 
< 5 cm). 
 
17.9 
SBRT Guidelines  
This study uses 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. 
 
SBRT is not to be used for sites other than bone metastases. 
  
17.9.1 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.  
 

  
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17.9.2 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 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. 
 
17.9.3 OAR Dose Constraints for SBRT 
Accurate contouring of normal structures is critical in SBRT (please see Tables 
17.9.4, 17.9.5, and 17.9.6 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. 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.  
 

  
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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 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. 
 
OAR dose constraints are primary planning priority in SBRT treatment 
planning. Tumor coverage is secondary (see Section 17.12 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). 
 
17.9.4 Spinal Cord DVH Parameters for Spinal Cord 
Normal Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
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  
For tumors distant from the spinal cord, the main criteria for dose prescription will be OAR as per 
Table 17.9.5. 
 

  
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17.9.5 Organs at Risk – SBRT 
Dose Constraints for Five Fractions – Based upon the AAPM Report TG 101 
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 
For patients with prior whole lung RT, Table 17.9.6 lists the OAR constraints to be used. 

  
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17.9.6 Organs at Risk – SBRT after Whole Lung RT  
Dose Constraints for Five Fractions – Based upon the AAPM Report TG 101 
reduced for prior chemotherapy and 15 Gy 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 
 
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. 
 
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 

  
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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.  
 
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. 
 
17.9.7 Conformality of Prescribed Dose for Calculations Based on Deposition of Photon 
Beam Energy in Heterogeneous Tissue 
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  
 
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 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. 
  

  
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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. 
 
17.10 Organs at Risk for Fractionated Targets (Not SBRT) 
The organs at risk (OAR) guidelines in this section are recommendations. If the 
recommended doses to the OAR are exceeded because of target volume coverage 
requirements or other conditions, an explanation should be included in the quality assurance 
documentation. In some cases, photon IMRT may be the preferred treatment method to meet 
these recommendations and the required target volume coverage guidelines. Normal tissue 
tolerance is the same for photons and protons (proton dose measured in CGE).  
 
17.10.1 Organs at Risk Dose Recommendations 
Organ 
Volume (%) 
Dose (Gy) 
Single organs 
 
 
Bladder 
100% 
45  
Heart 
100% 
30 
Liver 
100% 
23.4 
 
50% 
30 
Rectum 
100/% 
45 
Optic chiasm 
100% 
54 
Small Bowel 
50% 
45  
Spinal Cord 
Any volume 
45 
Paired organs 
 
 
Kidney (bilateral) 
50% 
24 
Kidney (bilateral) 
100% 
14.4 
Lung (bilateral) 
20% 
20 
Lung (bilateral) 
100% 
15 
Optic nerve 
100% 
54 
Lens 
100% 
14.4 
Lacrimal Gland/Cornea 
100% 
41.4 
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 %. 

  
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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 daily dose to the critical organs indicated should be calculated whenever any 
beam traverses the structure. The total dose shall be calculated and reported on the 
RT-2 Radiotherapy Total Dose Record form. The appropriate dose-volume 
histograms should 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. 
 
17.11.3 Required Normal Tissue DVH Data According to Primary Treatment Site(s)  
 
Treatment Area 
Required DVH 
Head 
Optic Nerve 
 
Optic Chiasm 
 
Pituitary 
 
Right and Left Cochlea 
Neck 
Thyroid 
Chest 
Lung 
 
Heart 
Abdomen 
Liver 
 
Right and Left Kidney 
Pelvis 
Bladder 
 
Rectum 
Spinal Cord 
Spinal Cord 
 
17.12 Quality Assurance Documentation 
Within three days of the start of RT, detailed treatment data for the primary site shall 
be submitted for on treatment review. Data for metastatic sites may be submitted at 
the end of treatment. 
 
Digital Submission: 
Submission of treatment plans in digital format as DICOM RT is required. Digital data must 
include CT scans, structures, plan, and dose files. Submission of these files by TRIAD is 
preferred. Instructions for TRIAD setup are in Section 17.12.3 below. Alternatively, sites 

  
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may use sFTP. Instructions for data submission via sFTP are on the IROC Rhode Island 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 TRIAD or 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  
x RT treatment plans including CT, structures, dose, and plan files. These items are 
included in the digital plan.  
x 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. 
x Digitally reconstructed radiographs (DRR) for each treatment field. DRR's are not 
required for IMRT. 
x Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest dose 
statistics. 
 
Supportive Data 
x All diagnostic imaging used to plan the target volume, including 
CT/MR/PET/Bone Scan images done at Pre-study and at Week 9 when applicable 
for planning volume reduction/boost volumes.  
x 
For metastatic sites, submit the End of VAC/VI +/- temsirolimus 
CT/MR images. For SBRT, include treatment planning MR images 
(within 4 weeks prior to start of RT). 
x 
For DPE patients, include the CT/MR done post-op prior to RT. Digital 
Imaging files can be submitted via TRIAD or sFTP with the DICOM 
RT submission. 
x Copies of all radiology reports corresponding to the diagnostic studies noted 
above. Copies of operative, pathology, and cytology reports. 
x If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by the IROC RI and the radiation oncology 
reviewers. 
x If emergency RT is administered, documentation should be provided in the form 
of the RT-2 Total Dose Record Form and the radiotherapy record (treatment 
chart). 
x If modifications are made for patients with age < 24 months, documentation 
should be provided. 
 
Forms 
x RT-1 Dosimetry Summary or Proton Reporting Form. 
x Motion Management Reporting Form (if applicable, see Section 17.8.6). 
x RT-2 Radiotherapy Total Dose Record Form. 
 

  
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Please submit the following additional information for brachytherapy: 
x Treatment planning CT used for post-implant dosimetry 
x Computer printouts of the isodose distribution and associated CT-based calculations. 
x Dose volume histograms for the GTV, CTV, and PTV. 
x A completed Brachytherapy Physics Reporting Form. 
x A copy of the written directive. 
 
Please submit the following additional information for intra-operative RT: 
x Radiotherapy record (treatment chart) including prescription and daily and cumulative 
doses to all required areas and organs at risk 
x 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: 
x Radiotherapy record (treatment chart) including prescription and daily and cumulative 
doses to all required areas and organs at risk. 
x RT-2 Radiotherapy Total Dose Record Form. 
 
These 
data 
can 
be 
submitted 
via 
TRIAD 
or 
sFTP, 
or 
e-mailed 
to 
DataSubmission@QARC.org. 
 
Questions regarding the dose calculations or documentation should be directed to: 
COG Protocol Dosimetrist 
IROC Rhode Island QA Center 
Email: physics@qarc.org 
Phone: (401) 753-7600 
 
17.12.1 Definition of Deviations  
 
Deviation 
 
Variation Acceptable 
Deviation Unacceptable 
Prescription Dose  
External beam 
Difference in prescribed or computed dose is 
6-10% of protocol-specified dose 
Difference in prescribed or computed dose 
is > 10% of protocol-specified dose 
Brachytherapy 
Difference in prescribed or computed dose is 
6-10% of protocol-specified dose 
Difference in prescribed or computed dose 
is > 10% of protocol-specified dose 
Dose Uniformity 
External beam 
10% PTV receives > 110% of 
protocol-specified 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 
Margins for CTV/PTV less than specified or 
excessively large 
A portion of the GTV or potentially 
tumor bearing area (CTV) is not included 
in the treated volume 
Organs at Risk 
Will be assessed at time of data review 
Will be assessed at time of data review 
 
  

  
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17.12.2 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. 
 
 
Deviation 
Dose 
Variation Acceptable 
Deviation Unacceptable 
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 Sections 17.9.4, 17.9.5, 17.9.6 
 
17.12.3 Digital Radiation Therapy Data Submission Using Transfer of Images and Data  
Transfer of Images and Data (TRIAD) is the American College of Radiology’s 
(ACR) image exchange application. TRIAD provides sites participating in 
clinical trials a secure method to transmit images. TRIAD anonymizes and 
validates the images as they are transferred. 
 
TRIAD Access Requirements: 
x 
A valid CTEP-IAM account.  
x 
Registration type of: Associate (A), Associate Plus (AP), Non-Physician 
Investigator (NPIVR), or Investigator (IVR). Refer to the CTEP 
Registration Procedures section for instructions on how to request a 
CTEP-IAM account and complete registration in RCR. 
x 
TRIAD Site User role on an NCTN or ETCTN roster. 
 
All individuals on the Imaging and Radiation Oncology Core provider roster 
have access to TRIAD and may submit images for credentialing purposes, or for 
enrollments to which the provider is linked in OPEN. 
 
TRIAD Installation: 
To submit images, the individual holding the TRIAD Site User role will need to 
install the TRIAD application on their workstation. TRIAD installation 
documentation is available at https://triadinstall.acr.org/triadclient/. 
 
This process can be done in parallel to obtaining your CTEP-IAM account and 
RCR registration. 
 
For questions, contact TRIAD Technical Support staff via email TRIAD-
Support@acr.org or 1-703-390-9858. 
 

  
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APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
 
INVESTIGATOR AND RESEARCH ASSOCIATE REGISTRATION WITH CTEP 
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 
at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr.    
 
RCR utilizes five person registration types. 
x 
IVR — MD, DO, or international equivalent; 
x 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
x 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the  Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
x 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
x 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
D 
D 
 
Financial Disclosure Form 
D 
D 
D 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
D 
D 
D 
 
HSP/GCP training 
D 
D 
D 
 
Agent Shipment Form (if 
applicable) 
D 
 
CV (optional) 
D 
D 
D 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 

  
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NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
x 
Addition to a site roster; 
x 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
x 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
x 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL must 
be rostered at the enrolling site with a participating organization.  
 
Additional information is located 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. 
 
 
CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted based on person and site roster assignment. To participate, the institution and its 
associated investigators and staff must be associated with the LPO or a Protocol Organization 
(PO) on the protocol. One way to search for a protocol is listed below.  
x 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
x 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select COG, and 
protocol number (*insert study number*). 
x 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load 
automatically to the CTSU.) 
   
Requirements for ARST1431 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 ) 
 
• 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must 
be aligned to an RTI provider. To manage provider associations or to add or remove 
associated providers, access the Provider Association page from the Regulatory section on the 
CTSU members’ website at https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must 
be linked to at least one Imaging and Radiation Oncology Core (IROC) provider to 
participate on trials with an RTI component. Enrolling sites are responsible for ensuring that 
the appropriate agreements and IRB approvals are in place with their RTI provider. An 
individual with a primary role on any roster is required to update provider associations, 

  
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though all individuals at a site may view provider associations. To find who holds primary 
roles at your site, view the Person Roster Browser under the RUMS section on the CTSU 
website. 
 
• 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston to 
verify credentialing status or to begin a new modality credentialing process.  
 
Submitting Regulatory Documents: 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive further 
instruction and support. 
 
Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  
x 
Click on Regulatory  at the top of the screen; 
x 
Click on Site Registration; and  
x 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
 
Data Submission / Data Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate 
Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) 
or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation e-mail 

  
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from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password and 
click on the accept link in the upper right-corner of the iMedidata page. Site staff 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. If an eLearning is required and has not 
yet been taken, the link to the eLearning will appear under the study name in iMedidata instead of 
the Rave EDC link; once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website in the 
Data Management section under the Rave resource materials (Medidata Account Activation and 
Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the 
CTSU members’ website in the Data Management > Rave section 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. 
 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. 
DQP Queries, DQP Delinquent Forms and the DQP Reports modules are available to access 
details and reports of unanswered queries, delinquent forms, and timeliness reports. Review the 
DQP modules on a regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead Protocol 
Organization for delinquent form details and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding questions about Rave Calendaring 
functionality.   
 
 

  
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APPENDIX II:  YOUTH INFORMATION SHEETS 
 (for children from 7 through 12 years of age) 
 
 
A study to compare 2 treatments for a type of cancer called Intermediate-Risk RMS 
 
1. We have been talking with you about rhabdomyosarcoma (RMS). RMS is a type of cancer that 
occurs in the soft tissues of the body like the muscles. After doing tests, we have found that you 
have RMS.  
 
2. We are asking you to take part in a research study because you have intermediate-risk (IR) RMS. 
A research study is when doctors work together to try out new ways to help people who are sick. 
In this study, we are trying to learn more about how to treat IR RMS. One standard treatment for 
IR RMS is a combination of 4 anti-cancer drugs called “VAC/VI” therapy. This study will 
compare VAC/VI therapy to VAC/VI plus a new drug called temsirolimus. This study will also 
look at giving treatment for longer than the standard treatment usually lasts. We do not know how 
well the study treatment will work in children. That is why we are doing this study. 
 
3. Children and teens who are part of this study will be randomly assigned to either Regimen A with 
VAC/VI or Regimen B with VAC/VI plus temsirolimus. A computer decides which treatment 
plan you will get and not your doctor. It is a lot like flipping a coin and this is done so that we 
have an equal number of patients in each regimen. You will also have surgery and/or receive 
radiation therapy. Radiation therapy is the use of high energy X-rays to kill cancer cells. After the 
treatment with VAC/VI or VAC/VI plus temsirolimus, you will get 6 additional months of 
treatment with 2 standard anti-cancer drugs. 
 
Your doctor is doing more tests on your tumor. Based on test results that may come back a few 
weeks after you start the study, your doctor may find that you have low-risk RMS. If you have 
low-risk RMS, you will get a different treatment called “VAC/VA” instead of the treatment you 
were assigned to. VAC/VA therapy is a combination of 3 standard anti-cancer drugs. You will 
also have surgery and/or receive radiation therapy. 
 
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 getting rid 
of the cancer but we don’t 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.” Being in this study may involve special risks, which your doctor will discuss 
with you. Other things may happen to you that we don’t yet know about. 
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional blood for special tests. These tests will help 
us better understand RMS. The blood draws would be taken when other standard blood tests are 
being performed. We would also like to save any leftover samples for other research tests in the 
future. You can still take part in this study even if you do not allow us to collect the extra blood 
samples or save the leftover samples for research.  

  
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YOUTH INFORMATION SHEETS  
(for teens from 13 through 17 years of age) 
 
A study to compare treatments with and without temsirolimus for Intermediate-Risk RMS 
 
1. We have been talking with you about rhabdomyosarcoma. Rhabdomyosarcoma (RMS) is a type of 
cancer that occurs in the soft tissues of the body like the muscles. After doing tests, we have found 
that you have intermediate-risk RMS. That means there is about a 1 in 3 chance that your tumor will 
come back after treatment. 
 
2. We are asking you to take part in a research study because you have intermediate-risk (IR) RMS. A 
research study is when doctors work together to try out new ways to help people who are sick. In this 
study, we are trying to learn more about how to treat IR RMS. We will do this by adding another drug 
to one of the standard treatments for IR RMS. A standard treatment for IR RMS is a combination of 
4 anti-cancer drugs called “VAC/VI” therapy. This study will compare VAC/VI therapy to VAC/VI 
plus a new drug called temsirolimus. This study will also look at extending the standard treatment to 
include a treatment phase called maintenance therapy. We do not know how well the study treatment 
will work in children. That is why we are doing this study. 
 
3. Children and teens who are part of this study will be randomly assigned to either Regimen A- 
VAC/VI chemotherapy (anti-cancer drugs) or Regimen B- VAC/VI plus temsirolimus. This is called 
randomization. This is a lot like flipping a coin. A computer decides which treatment plan you will 
get and not your doctor. You will also have surgery and/or receive radiation therapy. Radiation 
therapy is the use of high energy X-rays to kill cancer cells. You will also get 6 months of 
maintenance therapy after treatment with VAC/VI or VAC/VI plus temsirolimus. Maintenance 
therapy uses 2 standard anti-cancer drugs. 
 
Your doctor is doing additional testing on your tumor and the results may not be available until a few 
weeks after you join the study. Based on the test results, your doctor may find that you have a type of 
RMS that is low-risk. If you have low-risk RMS, you will stop getting the assigned treatment 
(VAC/VI or VAC/VI plus temsirolimus), and you will get a different treatment called “VAC/VA” 
therapy (a combination of 3 standard anti-cancer drugs). You will also have surgery and/or receive 
radiation therapy. You will not get maintenance therapy after VAC/VA therapy. 
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that the treatment 
you get will help make your health better. If you get temsirolimus, we hope it will be better at getting 
rid of the cancer, but, we don’t know this for sure. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things are 
called “risks.” Chemotherapy can cause side effects. For example, some types of chemotherapy cause 
changes in the blood cells. These changes can make a person feel tired or get an infection easier. Side 
effects can be increased when chemotherapy drugs are combined. If you receive temsirolimus, there 
is a chance that you will have more side effects. Being in this study may involve other special risks, 
which your doctor will discuss with you. Other things might happen to you that we don’t know about 
yet. 
 

  
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6. Your family can choose to be part of this study or not. Your family can also decide to stop being in 
this study at any time once you start. There may be other treatments for your illness that your doctor 
can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional blood for special tests. These tests will help us 
better understand RMS. The blood draws would be taken when other standard blood tests are being 
performed. We would also like to save any leftover samples for other research tests in the future. You 
can still take part in this study even if you do not allow us to collect the extra blood samples or save 
the leftover samples for research.  

  
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APPENDIX III: TNM PRE-TREATMENT STAGING CLASSIFICATION 
Staging prior to treatment requires thorough clinical examination, laboratory and imaging examinations. 
Biopsy is required to establish the histologic diagnosis. Pre-treatment size is determined by external 
measurement or MRI or CT depending on the anatomic location. For less accessible primary sites, CT 
will be employed as a means of lymph node assessment as well. Metastatic sites will require some form 
of imaging (but not histologic confirmation, except for bone marrow examination) confirmation. 
 
Stage  
Sites  
     T 
Size 
      N 
 
M 
1 
Orbit 
 
T1 or T2 
a or b 
N0 or N1 or Nx 
M0 
Head and neck  
(excluding parameningeal) 
GU – non-bladder/ 
non-prostate 
Biliary Tract/Liver 
 
2 
Bladder/Prostate 
T1 or T2 
a 
N0 or Nx 
 
M0 
Extremity, Cranial 
Parameningeal, Other 
(includes trunk, 
retroperitoneum, etc.) 
Except Biliary tract/Liver 
 
3 
Bladder/Prostate 
T1 or T2 
a 
N1 
 
M0 
  
Extremity Cranial 
 
b 
N0 or N1 or Nx 
M0 
Parameningeal, Other 
(includes trunk, 
retroperitoneum, etc.) 
Except Biliary tract/Liver 
 
4 
All  
 
T1 or T2 
a or b 
N0 or N1 
 
M1 
 
Definitions – See Appendix V for anatomic definitions of parameningeal, orbit and other head and neck 
sites 
 
Tumor – 
T(site)1 – confined to anatomic site of origin 
a. d 5 cm in diameter in size 
b. > 5 cm in diameter in size 
 
T(site)2 – extension and/or fixative to surrounding tissue 
a.  d 5 cm in diameter in size 
b. > 5 cm in diameter in size 
 
Regional Nodes – 
 N0 
regional nodes not clinically involved 
 N1 
regional nodes clinically involved by neoplasm defined as 
  
1) > 1 cm by CT or MRI OR 2) 18FDG avid  
 Nx 
clinical status of regional nodes unknown (especially sites that preclude lymph node evaluation 
 
  

  
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Metastasis –  
 M0 no distant metastasis 
 M1 distant metastasis present 
 
Note: The presence of positive cytology in pleural fluid, abdominal fluid, or CSF and the presence of 
implants on pleural or peritoneal are considered evidence of metastasis. 
 
 
 
 
 
 

  
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APPENDIX IV:  STS CLINICAL GROUPING CLASSIFICATION 
 
Clinical Group I: Localized disease, completely resected 
 
(Regional nodes not involved – lymph node biopsy or sampling is highly advised, except for head and 
neck lesions) 
 
a. 
Confined to muscle or organ of origin 
b. 
Contiguous involvement – infiltration outside the muscle or organ of origin, as through fascial planes. 
 
 
Notation: This includes both gross inspection and microscopic confirmation of complete 
resection. Any nodes that may be inadvertently taken with the specimen must be negative. If the 
latter should be involved microscopically, then the patient is placed in the Clinical Group IIb or 
IIc (See Below). 
 
Clinical Group II: Total gross resection with evidence of regional spread 
 
a. 
Grossly resected tumor with microscopic residual disease 
 
 
(Surgeon believes that he has removed all of the tumor, but the pathologist finds tumor at the 
margin of resection and additional resection to achieve clean margin is not reasonable). No 
evidence of gross residual tumor. No evidence of regional node involvement. Once radiotherapy 
and/or chemotherapy have been started, re-exploration and removal of the area of microscopic 
residual does not change the patient’s group. 
 
b. 
Regional disease with involved nodes, completely resected with no microscopic residual. 
 
 
Notation: Complete resection with microscopic confirmation of no residual disease makes this 
different from Clinical Groups IIa and IIc. Additionally, in contrast to Clinical Group IIa, 
regional nodes (which are completely resected, however) are involved, but the most distal node is 
histologically negative. 
 
c. 
Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual 
and/or histologic involvement of the most distal regional node (from the primary site) in the 
dissection. 
 
Clinical Group III: Incomplete resection with gross residual disease 
 
a. 
After biopsy only 
b. 
After gross major resection of the primary (>50%) 
 
Clinical Group IV: Distant Metastatic disease present at onset 
(Lung, liver, bones, bone marrow, brain, and distant muscle and nodes) 
 
Notation: The above excludes regional nodes and adjacent organ infiltration which places the 
patient in a more favorable grouping (as noted above under Group II). 
 
The following are also considered evidence of metastatic disease and place the patient in Group 
IV:  
1. The presence of positive cytology in CSF,  

  
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2. Positive cytology in pleural or abdominal fluids  
3. The presence of implants on pleural or peritoneal surfaces  
 
NOTE: The presence of a pleural effusion or ascites without positive cytologic evaluation is not 
considered evidence of metastatic disease and the patient will not be considered to have Group IV 
disease.  
 
REGIONAL NODAL BASINS FOR RHABDOMYOSARCOMA 
 
Extremity 
Lower Extremity –inguinal, femoral, popliteal nodes (rarely involved) 
Upper extremity – axillary, brachial, epitrochlear, infraclavicular nodes (infraclavicular) 
 
Genitourinary 
Bladder/Prostate – pelvic, retroperitoneal nodes at renal artery level or below 
Cervix and Uterus– pelvic, retroperitoneal nodes at renal artery level or below 
Paratesticular – pelvic, retroperitoneal nodes at renal artery level or below 
Vagina – retroperitoneal, pelvic nodes at or below common iliacs inguinal nodes 
Vulva – inguinal nodes 
 
Head and Neck 
Head/Neck – ipsilateral cervical, jugular, preauricular, occipital, supraclavicular nodes for laterally placed 
tumors (excluding scalp); may have bilateral adenopathy with centrally placed tumors 
Orbit/Eyelid – ipsilateral jugular, preauricular, cervical nodes 
 
Intrathoracic 
Internal mammary, mediastinal nodes 
 
Retroperitoneum/Pelvis – 
Pelvic, retroperitoneal nodes 
 
Trunk 
Abdominal Wall – inguinal, femoral nodes 
Chest Wall – axillary, internal mammary, infraclavicular nodes 
 
OTHER 
Biliary/Liver – liver hilar nodes 
Perianal/Perineal – inguinal, pelvic nodes; may be bilateral 
 
NOTES  
Any tumor – involved node other than those listed above signifies distant metastasis (Stage 4/Group IV). 
Examples: perineal primary with nodes above the pelvis; thigh primary with iliac or periaortic nodes; 
intrathoracic primary with subdiaphragmatic nodes; paratestis primary with inguinal nodes with or 
without transscrotal biopsy or scrotal involvement. 

  
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APPENDIX V:  ANATOMIC DEFINITIONS OF PARAMENINGEAL, ORBIT AND OTHER 
HEAD AND NECK SITES FOR USE IN PRE-TREATMENT STAGING 
 
Introduction 
There are three groupings of sites in the head and neck: parameningeal; orbit; and all others (“head and 
neck”) 
 
PARAMENINGEAL 
1. 
Middle Ear 
This refers to a primary that begins medial to the tympanic membrane. This tumor is often 
advanced at presentation and because of extension laterally may present with a mass in front of or 
under the ear suggesting a parotid origin. It may also extend through the tympanic membrane and 
appear to be arising in the ear canal. When there is doubt about the site of origin, the “middle ear” 
designation should be picked as it implies the more aggressive therapy required. 
2. 
Nasal Cavity and Paranasal Sinuses 
The three paranasal sinuses are the maxillary sinuses, the ethmoid sinuses, and the sphenoid 
sinus. These surround the nasal cavity and primary in one will frequently extend to another. It can 
be difficult to determine the exact site of origin but the choice is academic as the randomization is 
not affected. The site designation will have a bearing on the design of radiotherapy portals. 
Tumor arising in the maxillary or the ethmoid sinuses may invade the orbit. This is much more 
likely than a primary in the orbit invading one of the sinuses. When the distinction between orbit 
and paranasal sinus is unclear, the site selected should be paranasal sinus as it is the more likely 
primary site and requires appropriately more aggressive therapy. A primary arising in the 
sphenoid sinus (rare) may extend inferiorly to involve the nasopharynx. Again the choice of site 
is academic as the therapy is not different. 
3. 
Nasopharynx 
This refers to the superior portion of the pharynx which is bounded anteriorly by the back of the 
nasal septum, superiorly by the sphenoid sinus, inferiorly by a level corresponding to the soft 
palate, and laterally and posteriorly by the pharyngeal walls. 
4. 
Infratemporal Fossa/Pterygopalatine and Parapharyngeal Area 
This refers to the tissues bounded laterally by the medial lobe of the parotid gland and medially 
by the pharynx. Large tumors in this region may extend through the parotid gland and present as a 
mass of the lateral face, sometimes extending even to the cheek. Where there is doubt as to the 
primary, the parameningeal designation should be chosen as it confers appropriately more 
aggressive treatment. The superior boundary of this tissue volume is the base of skull just under 
the temporal lobe, hence the term “infratemporal”. The distinction between this and the 
“parapharyngeal” area is academic. 
 
ORBIT 
1. 
Eyelid 
This site is sometimes erroneously designated as “eye”. Although there may occasionally be a 
case arising from the conjunctiva of the eye, the globe itself is not a primary site. The eyelid is 
much less frequent than the orbit itself.  
2. 
Orbit 
This refers to the bony cavity which contains the globe, nerve and vessels, and the extra ocular 
muscles. Tumor in this site will only rarely invade the bony walls and extend into the adjacent 
sinuses. This is why this tumor which is clearly adjacent to the skull base and it meninges is not 
by its natural history appropriate to include in the parameningeal sites unless there is invasion of 
the bone. 
 

  
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HEAD AND NECK 
1. 
Scalp 
This site includes primaries arising apparently in or just below the skin of all the tissues of the 
face and head that are not otherwise specified below. This usually means the scalp, external ear 
and pinna, the nose and forehead, but not the eyelids or cheek. 
2. 
Parotid Region 
The parotid gland lies just in front of and under the ear and may surround both sides of the 
posterior aspect of the ascending ramus of the mandible. Tumors in the parotid region may not 
arise in the parotid gland itself. As noted above, large primaries in the infratemporal fossa may 
erode through the parotid. A true parotid region primary should not, on radiographic studies, 
reveal a mass in the infratemporal fossa. 
3. 
Oral Cavity 
This includes the floor of the mouth, the buccal mucosa, the upper and lower gum, the hard 
palate, and the oral tongue (that portion of the tongue anterior to the circumvallate papillae). A 
primary arising in the buccal mucosa can be impossible to distinguish from one arising in the 
cheek but the distinction is academic. This would also include those lesions arising in and near 
the lips. 
4. 
Larynx 
This refers to the primaries arising in the subglottic, glottic, or supraglottic tissues. Tumors of the 
aryepiglottic folds can be difficult to distinguish from the hypopharynx but the distinction is 
academic. 
5. 
Oropharynx 
This includes tumors arising from the anterior tonsillar pillars, the soft palate, the base of the 
tongue, the tonsillar fossa, and oropharyngeal walls. Tumors arising in the parapharyngeal space 
may indent the oropharyngeal wall. In this circumstance, the primary should be considered 
parameningeal. If the mucosa of the oropharynx actually contains visible tumor as opposed to 
being bulged by it, the primary would be oropharynx. Primaries arising in the tongue base, soft 
palate, or tonsillar region may extend into the oral cavity. The oropharynx designation is 
preferred. 
6. 
Cheek 
This refers to the soft tissues of the face that surround the oral cavity. Tumors arising in the 
parotid may invade the cheek. As noted above, the distinction between this and the buccal 
mucosa is academic. 
7. 
Hypopharynx 
This refers to the pyriform sinus and may be difficult to distinguish from larynx although the 
designation is academic with regard to randomization. 
8. 
Thyroid and Parathyroid 
Primaries arising in these two sites are exceedingly rare, if they exist at all, and should those 
structures be involved, it would more likely be from a primary arising in an adjacent structure 
such as the trachea. 
9. 
Neck 
This refers to the soft tissues of the lateral neck between the mastoid tip and the clavicle. It does 
not include those medial structures such as hypopharynx and larynx noted above. Unfortunately 
this site overlaps with the designation “paraspinal” included under the site group “trunk”. 
Primaries arising in the neck can and frequently do behave as a paraspinal primary with direct 
invasion into the spinal extra dural space. 

  
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APPENDIX VI: DESIGNATION OF THE PRIMARY SITE FOR USE IN PRE-TREATMENT 
STAGING (SELECTION OF “SITE CATEGORY” FOR PATIENT ENTRY) 
 
NOTE: This will extend to other areas the guidelines prepared to aid in the identification of head and 
neck sites (Appendix V). Some of the distinctions made below are largely semantic. Although they do not 
change therapy they may be important in reviewing results for specific sites. Others are vital as they 
would make a change in stage and therapy. It is astonishing how frequently data forms on the same 
patient from the same institution list quite different primary sites. This can only be determined in 
retrospect, but it should make one cautious regarding accepting a confusing or illogical site designation at 
the time of registration. 
 
I. 
Comment on the Terms Used to Designate Primary Site for RMS 
 
The Dictated Operative Note 
If the patient has undergone an initial major operative procedure, the “post-operative diagnosis: 
listed on the operative note that should be dictated following the procedure will ordinarily include 
reference to site. In such cases, this is usually the most accurate source document for site 
designation. 
Larger Site Categories 
Most of the terms used follow common usage. As you are aware, we consider an “extremity” to 
include the total forequarter or total hindquarter. This extends the extremity area on the posterior, 
but not the anterior, aspect of the body. The muscles over the scapula are include in the upper 
extremity and the muscles making up the buttocks in the lower extremity. This confines the trunk 
area posteriorly to that which is paraspinal and chest wall; and anteriorly, chest wall and 
abdominal wall. The retroperitoneal and perineal sites are listed separately in the IRS. 
Primary Site vs. Areas of Extension 
Primary site rather than areas of extension ordinarily determines the site category. In the case of 
the parameningeal tumors, however, the primary site is incidental, and the approach to the 
meninges is the important factor in site determination in the IRS. 
Large Tumors Involving Multiple Organs and/or Structure 
Our aim in these cases is to attempt to select the most likely site of original involvement or origin. 
The terms “abdominal”, “thoracic” and “unknown” are the least helpful in analysis. 
“Bones” 
When the designated site on the institutional forms is a word indicating a bone, i.e. “tibia”, 
“scapula”, etc., try for something more accurate or at least make it an adjective. 
 
II. 
Specific Sites Within Major Categories 
The following is a glossary of site designations. They are almost entirely taken from IRS I-III 
forms reviewed by the Committee. Some of them should not be used and others would appear to 
need definition. In some cases we have simply provided an explanation of what a surgeon would 
ordinarily mean by a given term. Site designations in data collection sheets and even operative 
notes may be worded in terms that are not inaccurate but not appropriate for site designation in 
the IRS, where consistency is required. 
 
1. 
Abdominal Wall 
This refers to the anterior abdominal wall from the inferior costal margins superiorly to the 
inguinal ligaments and symphysis pubis, inferiorly, and extends laterally between the costal 
margin and iliac crests to the paraspinal region. From a practical point of view, this posterior 
extension is so narrow in a child that it is probably insignificant as a primary site. 

  
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2. 
Arm 
Refers to the area from the shoulder joint to the elbow joint. 
3. 
Biliary Tract/Liver 
Biliary tract tumors might also be called “choledochus” or “bile duct”. Tumors in the liver are 
believed to arise from intrahepatic bile ducts. Biliary tract represents the preferred primary site 
designation for these tumors. Localized biliary tract/liver tumors are considered Stage 1. 
4. 
Bladder 
Our criteria for identifying the bladder as a primary site has included the appearance of tumor 
within the bladder cavity, which can be biopsied through an endoscope or occasionally at 
laparotomy. We do not recognize as primary bladder tumors those that simply displace the 
bladder or distort its shape. The latter are ordinarily primary pelvic sites, unless otherwise 
specified. 
5. 
Bladder/Prostate 
In approximately 20% of males with bladder or prostatic tumors, the precise site cannot be 
determined even at autopsy. This histologic features are similar. Although it is desirable to have 
an indication of the “most probable: site from the institution, and one should strive to get this, it 
may not be possible. 
6. 
Buttocks - These are extremity lesions. 
7. 
Inguinal Canal 
See paratesticular 
8. 
Paraspinal 
 
When tumors are described as adjacent to the vertebral column, this designation is preferable to 
“truck” or “neck”. 
9. 
Paratesticular (testicular) 
Rhabdomyosarcomas rarely arise from testicular tissue. These tumors are almost always 
“paratesticular” arising either adjacent to the testes within the scrotum or in the inguinal canal, 
i.e., “groin” or lower abdominal wall. In either case they are classified in the G. U. major site 
category and called paratesticular. 
10. 
Pelvis 
This site must be distinguished from the previously designated “special pelvic” category used in 
prior IRS studies. It may be regarded as a tumor within the pelvis when no more specific site is 
appropriate. 
11. 
Perianal (often called “anus” or “rectum”) 
These sites are ordinarily “perirectal” or “perianal”. They are distinguished with difficulty from 
perineal and vulval sites; but the latter distinction is important. 
12. 
Perineum 
This should include the sites which appear anterior to the anus and posterior to the scrotum in 
males and posterior to the labia in females. It extends anteriorly to the base of the scrotum in 
males and to the introitus in females. It must be distinguished from labial and vaginal sites. 
13. 
Peritoneum 
This primary site is imprecise as it extends from the diaphragm to the pelvis. One should try for 
specific site. 
14. 
Prostate 
See Bladder/Prostate 
15. 
Retroperitoneal (often called “psoas muscle”) 
We reserve the term retroperitoneal for those posteriorly situated abdominal tumors in which 
there does not seem to be a more specific site. If the tumor arose in an abdominal viscus, such as 
the pancreas, etc., this would be a preferable site designation, to “retroperitoneal”. Tumors in a 
retroperitoneal site are in the posterior aspect of the abdomen and/or pelvis. The term “psoas” as a 

  
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site is not very specific, as this muscle extends through the posterior lower abdomen, pelvis, and 
into the leg. 
16. 
Shoulder 
The posterior aspect of the shoulder, i.e., the scapular area, is an extremity site. 
17. 
Testes 
See Paratesticular 
18. 
Uterus 
A tumor in this primary site may be difficult to differentiate from a primary vaginal site, because 
a tumor originating in the uterus may fill the vagina. After a therapeutic response the distinction 
is usually clear. In general there is wide separation of age ranges between these two groups with 
the vaginal cases occurring in infancy or early childhood and the uterine primaries in adolescents 
or young adults. One should be skeptical regarding a patient with a designated “vaginal” site who 
is over five years of age, or a patient with a designated uterine site in a patient who is under 
10 years of age. Fortunately, this is not a therapy-related distinction. 
19 
Vagina 
For the purpose of our study the patient with a primary vaginal lesion must have evidence of a 
visible tumor on the vaginal surface which can be biopsied through the vagina. Displacement or 
distortion of the vagina is not sufficient. 
20. 
Vulva 
Primary lesions in this site arise in the labial minor or majora, and these terms are often used, and 
are acceptable. 
  
  

  
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APPENDIX VII: SUPPORTIVE CARE GUIDELINES 
These supportive care guidelines are provided for institutional consideration but are not intended to 
supplant institutional practices. Investigator discretion should be used, and certain clinical situations and 
institutional guidelines may suggest other approaches. Investigators may wish to refer to Supportive Care 
of Children with Cancer, Arthur Ablin ed., 2004, for further recommendations. 
 
Sperm Banking and Fertility Consult 
The total dose of cyclophosphamide on both Regimen A and B is 8.4 g/m2. The effect of this dose on 
male fertility is unknown. Furthermore, the impact of mTOR inhibition on male fertility is unknown. We 
therefore strongly encourage sperm cryopreservation be discussed with all post-pubertal boys receiving 
RMS therapy. 
 
For males and females of all ages with primary disease in the abdomen/pelvis, RT to the gonads is almost 
a certainty. Due to the sterilizing effects of RT on both male and female gonads, disclosure regarding 
infertility is strongly encouraged, especially for children and adolescents with abdominal/pelvic disease. 
Egg cryopreservation is no longer considered experimental, and can be discussed with post-pubertal 
females who are planned to receive pelvic RT when appropriate. 
 
Mouthcare and Mucositis Management 
Temsirolimus is commonly associated with mucositis, which can be persistent and often result in 
treatment delay. In adults receiving mTOR inhibitors, mouth lesions can appear as discrete, ovoid, 
superficial, well demarcated ulcers with a grayish-white pseudomembrane.90 Alternative presentations 
include clustering of lesions (such as seen with herpetic lesions) and also larger ulcers similar in 
appearance to those observed in patients with major aphthous stomatitis. Lesions are often confined to the 
nonkeratinized, movable mucosa, such as the inner aspect of the lips, the ventral and lateral surfaces of 
the tongue, and the soft palate. An aggressive regimen is strongly recommended to help manage mucositis 
especially in patients receiving temsirolimus, but can be offered to all patients. 
x
Xyloxylin (1:1:1 ratio) (diphenhydramine, Maalox, lidocaine) 10 mL swish/swallow QID prn 
x
Caphosol (saliva substitute) 15 mL swish/spit Q 4 hours prn 
x
Biotene mouth wash Q 4 hours prn 
x
Sucralfate 1 Gm/10 mL 10 mL swish/swallow or spit QID prn 
 
Irinotecan-Induced Diarrhea Prophylaxis 
Cefixime or an available equivalent antibiotic is recommended as a diarrhea prophylaxis in Regimens A 
and B during VI or VI + temsirolimus cycles, respectively. Initiation of antibiotic treatment two days 
prior to the start of irinotecan is recommended, and should continue during, and for 3 days after the last 
dose of irinotecan for a total of 10 days. This antibiotic therapy will continue throughout protocol therapy. 
Cefixime will be dosed at 8 mg/kg PO once daily (max: 400 mg/day). If cefixime is not available, 
cefpodoxime can be used as an alternative at 5 mg/kg/dose PO twice daily (10 mg/kg/day in two divided 
doses; max: 200 mg/dose). In countries where cefiixime or cefpodoxime are not available, other 
equivalent antibiotics can be used instead. 
See Appendix X for loperamide dosing in the treatment of irinotecan-induced diarrhea.  
 
Central Venous Access 
Central venous access is recommended for all patients. 
 
Dental Consultation 
Dental consultation is recommended prior to initiation of therapy for patients with head/neck tumors. 
Removal of braces prior to initiation of therapy is recommended. 

  
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Supplemental Nutrition 
Supplemental parenteral nutrition should be considered for patients who have lost > 10% of their body 
weight or have persistent hypoalbuminemia of < 3 g/dl. Patients with nasopharyngeal primary tumors 
often experience significant mucosal reactions during radiation. Early placement of nasogastric or 
gastrostomy tube for supplemental feeding, prior to beginning irradiation, may be indicated. 
 
Pneumocystis Jirovecii Pneumonia Prophylaxis 
Trimethoprim (TMP)/sulfamethoxazole prophylaxis is not required but may be strongly considered as per 
treating physician, especially in children less than 5 years of age and in those on Regimen B. Suggest 
TMP 5 mg/kg/day divided bid, two-three consecutive days per week. If allergic or intolerant, use 
pentamidine or dapsone. 
 
Hemorrhagic cystitis prophylaxis 
Mesna and fluids will be used with Intravenous Cyclophosphamide  
x 
Recommended pre-hydration 0.9% NaCl, 750 mL/m2 IV over 1 hour. 
x 
Continuing hydration: 0.45% NaCl, 100 mL/m2/h IV until last mesna dose is finished. There is no 
need to measure urine specific gravity. 
x 
IV Mesna Dose: 20% of cyclophosphamide dose IV over 15-30 minutes immediately before (or 
mixed with) cyclophosphamide infusion, and again 4 and 8 hours after the start of cyclophosphamide 
infusion. 
x 
PO Mesna Dose: 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 
cyclophosphamide dose. The oral doses will be administered at Hours 2 and 6. 
x 
Alternative Mesna regimen (institutional choice): 60% of cyclophosphamide dose as 8-hour 
continuous infusion, beginning when cyclophosphamide infusion starts. 
 
Myeloid growth factor support: (for VAC cycles only) 
Filgrastim (G-CSF) or biosimilar 5 mcg/kg/day SubQ starting a minimum of 24 hours after the last dose 
of VAC chemotherapy. Continue until the ANC ≥ 2000/μL after the expected nadir. Myeloid growth 
factor support may be continued without regard to vinCRIStine or temsirolimus. Discontinue myeloid 
growth factor support a minimum of 24 hours prior to administration of the next chemotherapy cycle. 
Note: ANC ≥ 2000 prior to the nadir of a cycle is not sufficient for discontinuing growth factor support, 
as the ANC may rise before the nadir and then fall. Pegfilgrastim or biosimilar 0.1 mg/kg/dose (for 
patients < 45 kg) or 6 mg/dose (for patients ≥ 45 kg) SubQ x 1 dose or per institutional standards may 
be used starting 24 hours after the last dose of chemotherapy. 
 
Older patients can occasionally complain of bone pain associated with filgastrim. In this case, the drug 
can be discontinued early and will not be considered a protocol violation. 
 
 

  
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APPENDIX VIII: 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 a frequently updated medical reference. 
 
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 
ivacaftor 
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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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 4.1.3 regarding use of corticosteroids. The use of corticosteroids is permitted on the study. 
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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APPENDIX IX: PATIENT DRUG INFORMATION HANDOUT AND WALLET CARD 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
[Note to authors:  This appendix consists of an “information sheet” to be handed to the patient at the 
time of enrollment. Use or modify the text as appropriate for the study agent, so that the patient is aware 
of the risks and can communicate with their regular prescriber(s) and pharmacist. A convenient wallet-
sized information card is also included for the patient to clip out and retain at all times. If you choose to 
use them, please note that the information sheet and wallet card will require IRB approval before 
distribution to patients.] 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental study 
drug, temsirolimus.  This clinical trial is sponsored by the National Cancer Institute.  This form is 
addressed to the patient, but includes important information for others who care for this patient.  
 
These are the things that you as a healthcare provider need to know: 
 
Temsirolimus interacts with certain specific enzymes in your liver* and certain transport proteins that 
help move drugs in and out of cells**.  
 
x *The enzyme in question is CYP3A4 isoenzyme. Temsirolimus is broken down by this enzyme 
and may be affected by other drugs that inhibit or induce this enzyme.   
x **The protein in question is P-glycoprotein. Temsirolimus is moved in and out of cells/organs by 
this transport protein.  
 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
Temsirolimus may interact with other drugs which can cause side effects. For this reason, it is very 
important to tell your study doctors of any medicines you are taking before you enroll onto this clinical 
trial.  It is also very important to tell your doctors if you stop taking any regular medicines, or if you start 
taking a new medicine while you take part in this study.  When you talk about your current medications 
with your doctors, include medicine you buy without a prescription (over-the-counter remedy), or any 
herbal supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an updated 
medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, pharmacists) you are taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Temsirolimus must be used very carefully with other medicines that use certain liver enzymes or transport 
proteins to be effective or to be cleared from your system.  Before you enroll onto the clinical trial, your 
study doctor will work with your regular health care providers to review any medicines and herbal 
supplements that are considered moderate to strong inducers/inhibitors of CYP3A4 isoenzyme or P-
glycoprotein. 
 
x Please be very careful!  Over-the-counter drugs (including herbal supplements) may contain 

  
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ingredients that could interact with your study drug.  Speak to your doctors or pharmacist to 
determine if there could be any side effects.  
x Examples include certain heart and blood pressure medications (eg., amiodarone, dronedarone, 
propafenone, quinidine, ranolazine, carvedilol, verapamil), antibiotics (eg., clarithromycin, 
erythromycin, rifampin), antifungals (eg., itraconazole, voriconazole), anti-seizure medications 
(eg., carbamazepine, phenytoin, phenobarbital), antiretrovirals (eg., lapatinib, lopinavir, ritonavir, 
saquinavir, telaprevir, tipranavir), and herbal supplements (eg., St. John’s wart, grapefruit or 
grapefruit juice). 
x Your regular health care provider should check a frequently updated medical reference or call your 
study doctor before prescribing any new medicine or discontinuing any medicine.  Your study 
doctor’s 
name 
is 
_______________________ 
and 
he 
or 
she 
can 
be 
contacted 
at___________________________. 
                
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
You are enrolled on a clinical trial using the experimental study drug 
temsirolimus.  This clinical trial is sponsored by the NCI.  
Temsirolimus may interact with drugs that are processed by your 
liver, or use certain transport proteins in your body.  Because of 
this, it is very important to: 
¾ Tell your doctors if you stop taking any medicines or if you start 
taking any new medicines. 
¾ Tell all of your health care providers (doctors, physician assistants, 
nurse practitioners, or pharmacists) that you are taking part in a 
clinical trial. 
¾ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
 
 
 
Temsirolimus interacts with a specific liver enzyme called CYP3A4 
and a transport protein called P-glycoprotein, and must be used 
very carefully with other medicines that interact with this enzyme 
and/or transporter.  
¾ Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered moderate to 
strong inducers/inhibitors of CYP3A4, or P-glycoprotein. 
¾ Before prescribing new medicines, your regular health care 
providers should go to a frequently-updated medical reference for a 
list of drugs to avoid, or contact your study doctor.   
¾ Your study doctor’s name is _____________________________ 
and can be contacted at _________________________________.  

  
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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 temsirolimus. Examples 
include: 
Drugs that may interact with temsirolimus 
x Antibiotics  
o Clarithromycin, erythromycin, metronidazole, nafcillin, rifapentin, rifampin, 
telithromycin 
x Antidepressants and antipsychotics  
o Clozapine, desvenlafaxine, nefazodone 
x Antidiabetic agents 
x Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, 
voriconazole 
x Arthritis medications  
o Leflunomide, tofacitinib 
x Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
x Antiretrovirals and antivirals  
o Atazanavir, darunavir, delavirdine, efavirenz, etravirine, fosamprenavir, 
indinavir, lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 
telaprevir, tipranavir 
x Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
x Heart and blood pressure medications  
o Accupril, amiodarone, amlodipine, captopril, carvedilol, diltiazem, dronedarone, 
enalapril, felodipine, isradipine, lisinopril, nicardipine, nifedipine, nimodipine, 
propafenone, quinidine, ranolazine, ramipril, verapamil 
x Some chemotherapy (be sure to talk to your doctor about this) 
x Many other drugs, including the following: 
o Aprepitant, bosentan, conivaptan, cobicistat, deferasirox, ivacaftor, 
mifepristone, natalizumab, tocilizumab  
 
Food and supplements that may interact with temsirolimus 
x Echinacea 
x St. John’s Wort 
x Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 

  
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Some drugs, food, and supplements may interact with cyclophosphamide. Examples 
include: 
Drugs that may interact with cyclophosphamide 
x 
Allopurinol 
x 
Amiodarone 
x 
Carbamazepine 
x 
Cyclosporine 
x 
Digoxin  
x 
Efavirenz 
x 
Etanercept  
x 
Hydrochlorothiazide 
x 
Lumacaftor 
x 
Mifepristone 
x 
Pentostatin  
x 
Rifampin 
x 
Ritonavir 
x 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide 
x 
St. John’s Wort 
x 
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 
x 
Clozapine, leflunomide, natalizumab, tofacitinib 
 
Food and supplements that may interact with dactinomycin 
x 
Echinacea 
 
 
Some drugs, food, and supplements may interact with irinotecan. Examples include: 
Drugs that may interact with irinotecan 
x Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
x Antidepressants and antipsychotics  
o Clozapine, nefazodone 
x Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, 
voriconazole 
x Arthritis medications  
o Leflunomide, tofacitinib 

  
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x Anti-rejection medications 
o Cyclosporine 
x Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild®, 
telaprevir, tipranavir 
x Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
x Heart medications  
o Amiodarone, carvedilol, dronedenarone, diltiazem, propafenone, quinidine, 
ranolazine, verapamil 
x Some chemotherapy (be sure to talk to your doctor about this) 
x Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, conivaptan, ivacaftor, mifepristone, modafinil, 
natalizumab 
 
Food and supplements that may interact with irinotecan 
x Echinacea 
x St. John’s Wort 
x Grapefruit, grapefruit juice, Seville oranges, star fruit 
 
 
Some drugs, food, and supplements may interact with vincristine. Examples include: 
Drugs that may interact with vincristine 
x Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifapentin, rifampin, telithromycin 
x Antifungals  
o Fluconazole, itraconazole, isavuconazole, ketoconazole, posaconazole, 
voriconazole 
x Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
x Anti-rejection medications 
o Cyclosporine 
x Antiretrovirals and antivirals  
o Atazanavir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, 
indinavir, lapatinib, lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, 
Stribild®, telaprevir, tenofovir, tipranavir 
x Anti-seizure medications  
o Carbamazepine, fosphenytoin, phenobarbital, phenytoin, primidone 
x Heart medications  
o Amiodarone, carvedilol, diltiazem, dronedarone, propafenone, quinidine, 
ranolazine, verapamil 
x Some chemotherapy (be sure to talk to your doctor about this) 
x Many other drugs, including the following: 
o Aprepitant, bosentan, cobicistat, conivapatan, deferasirox, fosnetupitant, 
ivacaftor, mifepristone, modafinil, natalizumab, nefazodone, netupitant 

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

  
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APPENDIX X: PATIENT INSTRUCTIONS FOR TREATING DIARRHEA 
 
Guidelines for the Treatment of Diarrhea 
 
NOTE: Institutional practice may be used in place of these guidelines. 
 
You should purchase or will be given a prescription for loperamide to have available to begin treatment at 
the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent 
than normally expected for the patient. Patients will also be instructed to contact their physician if any 
diarrhea occurs. Patients will be given loperamide based on body weight.  
 
Early diarrhea 
Early onset diarrhea associated with irinotecan is usually preceded by sweating and abdominal cramping. 
Patients who have the onset of these symptoms followed by diarrhea within several hours after taking 
irinotecan should contact the treating physician immediately.  The treating physician may consider 
treatment with atropine. If symptoms do not improve with administration of atropine, treatment for late 
diarrhea (as outlined below) should be started. 
 
Late diarrhea (more than 24 hours after the administration of the first dose of irinotecan) 
Each family will be instructed to have antidiarrheal medication available and begin treatment at the first 
episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than 
normally expected for the patient.  
 
Be aware of your child's bowel movements. At the first sign they become softer than usual or if your child 
has any notable increase in the number of bowel movements over what is normal for him/her, begin 
taking loperamide (Imodium). If he/she does not start taking the loperamide right away, the diarrhea 
may become severe and last several days or require hospitalization. 
 
Please follow these directions carefully, using dosing guidelines below: 
x 
Take _____________ at the first sign of diarrhea. 
x Continue taking __________ every __ hours until the diarrhea slows or the normal pattern of 
bowel movements returns. Repeat the same doses and frequency if the diarrhea returns. 
x Do not exceed ___________ in a 24 hour period. 
x Please call your doctor if you have any questions about taking loperamide, if your child's diarrhea 
is not under control after two days, or if he/she is feeling extremely weak, lightheaded, or dizzy. 
x Make an extra effort to give your child lots of fluids (several glasses of pedialyte, fruit juices, 
soda, soup, etc.) while your child is participating in this study. 
x Side effects may include tiredness, drowsiness or dizziness. If your child experiences these side 
effects, or if your child is urinating less frequently than usual, please contact your child's 
physician. 
x 
Do not give your child any laxatives without consulting with his/her physician. 
 
 

  
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LOPERAMIDE DOSING RECOMMENDATIONS 
(NOTE: maximum dose of loperamide for adults is 16 mg/day) 
ALL patients: discontinue loperamide when the patient is no longer experiencing significant diarrhea. 
Weight (kg) 
ACTION 
<13 kg   
Take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral solution) after 
the first loose bowel movement, followed by 0.5 mg (2.5 mL [one-half 
teaspoonful] of the 1 mg/5 mL oral solution) every 3 hours.  During the night, the 
patient may take 0.5 mg (2.5 mL [one-half teaspoonful] of the 1 mg/5 mL oral 
solution) every 4 hours.  Do not exceed 4 mg (20 mL or 4 teaspoonfuls) per day. 
 
≥ 13 kg to < 20 kg 
Take 1 mg (5 mL [1 teaspoonful] of the 1 mg/5 mL oral solution or one-half tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] of 
the 1 mg/5 mL oral solution or one-half tablet) every 3 hours. During the night, the 
patient may take 1 mg (5 mL [one teaspoonful] of the 1 mg/5 mL oral solution or 
one-half tablet) every 4 hours.  Do not exceed 6 mg (30 mL or 6 teaspoonfuls) per 
day. 
 
≥ 20 kg to < 30 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] of 
the 1 mg/5 mL oral solution or one-half tablet) every 3 hours.  During the night, the 
patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 
1 tablet) every 4 hours. Do not exceed 8 mg (40 mL or 8 teaspoonfuls) per day. 
 
≥ 30 kg to < 43 kg 
Take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 tablet) 
after the first loose bowel movement, followed by 1 mg (5 mL [one teaspoonful] of 
the 1 mg/5 mL oral solution or one-half tablet) every 2 hours.  During the night, the 
patient may take 2 mg (10 mL [2 teaspoonfuls] of the 1 mg/5 mL oral solution or 
1 tablet) every 4 hours. Do not exceed 12 mg (60 mL or 12 teaspoonfuls) per day. 
 
Over 43 kg 
Take 4 mg (20 mL [4 teaspoonfuls] of the 1 mg/5 mL oral solution or 2 capsules or 
tablets) after the first loose bowel movement, followed by 2 mg (10 mL 
[2 teaspoonfuls] of the 1 mg/5 mL oral solution or 1 capsule or tablet) every 
2 hours.  During the night, the patient may take 4 mg (20 mL [4 teaspoonfuls] of 
the 1 mg/5 mL oral solution or 2 capsules or tablets) every 4 hours. Do not exceed 
16 mg (80 mL or 16 teaspoonfuls) per day. 
 
 
 

  
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APPENDIX XI: CYCLOPHOSPHAMIDE DOSING GUIDELINES DURING MAINTENANCE 
Cyclophosphamide 25 mg/m2 PO daily 
 
Body Surface 
Area (m2)* 
US sites 
Suggested Daily Dose (d) 
over 7 days 
 
(1 capsule = 25 mg) 
Canadian sites 
Suggested Daily Dose (d) 
over 7 days 
 
(1 tablet  = 25 mg) 
Cumulative 
Weekly Dose 
0.32-0.38  
use liquid formulation 
1/2 tab / d x 5  
62.5 mg/wk 
0.39-0.46  
use liquid formulation 
1/2 tab / d x 6  
75 mg/wk 
0.47-0.53   
use liquid formulation 
1/2 tab /d x 7  
87.5 mg/wk 
0.54-0.60 
use liquid formulation 
1 tab / d x 2; 1/2 tab / d x 4  100 mg/wk 
0.61-0.64   
use liquid formulation 
1 tab / d x 2; 1/2 tab / d x 5  112.5 mg/wk 
0.65 - 0.78  
1 cap / d x 5  
1 tab / d x 3; 1/2 tab / d x 4  125 mg/wk  
0.79 - 0.92  
1 cap / d x 6  
1 tab / d x 6  
150 mg/wk  
0.93 – 1.07  
1 cap / d x 7 
1 tab / d x 7 
175 mg/wk  
1.08 – 1.21  
2 cap / d x 1; 1 cap / d x 6 
2 tab / d x 1; 1 tab / d x 6 
200 mg/wk  
1.22 – 1.35  
2 cap / d x 2; 1 cap / d x 5 
2 tab / d x 2; 1 tab / d x 5 
225 mg/wk  
1.36 – 1.49  
2 cap / d x 3; 1 cap / d x 4 
2 tab / d x 3; 1 tab / d x 4 
250 mg/wk  
1.50 – 1.64  
2 cap / d x 4; 1 cap / d x 3 
2 tab / d x 4; 1 tab / d x 3 
275 mg/wk  
1.65 – 1.78  
2 cap / d x 5; 1 cap / d x 2 
2 tab / d x 5; 1 tab / d x 2 
300 mg/wk  
1.79 – 1.92  
2 cap / d x 6; 1 cap / d x 1 
2 tab / d x 6; 1 tab / d x 1 
325 mg/wk  
1.93 – 2.07  
2 cap / d x 7 
2 tab / d x 7 
350 mg/wk  
2.08 – 2.21  
3 cap / d x 1; 2 cap / d x 6 
3 tab / d x 1; 2 tab / d x 6 
375 mg/wk  
2.22 - 2.35  
3 cap / d x 2; 2 cap / d x 5 
3 tab / d x 2; 2 tab / d x 5 
400 mg/wk  
2.36 – 2.49  
3 cap / d x 3; 2 cap / d x 4 
3 tab / d x 3; 2 tab / d x 4 
425 mg/wk  
2.50 – 2.64  
3 cap / d x 4; 2 cap / d x 3 
3 tab / d x 4; 2 tab / d x 3 
450 mg/wk  
2.65 – 2.78  
3 cap / d x 5; 2 cap / d x 2 
3 tab / d x 5; 2 tab / d x 2 
475 mg/wk  
2.79 – 2.92  
3 cap / d x 6; 2 cap / d x 1 
3 tab / d x 6; 2 tab / d x 1 
500 mg/wk  
2.93 – 3.00*  
3 cap / d x 7 
3 tab / d x 7 
525 mg/wk  
 
Body Surface 
Area (m2)* 
Australia/New Zealand sites 
Suggested Daily Dose (d) 
over 7 days 
 
(1 tablet = 50 mg) 
Cumulative 
Weekly Dose 
< 1.3 
use liquid formulation 
 
1.3 – 1.57 
1 tab / d x 5 
250 mg/wk  
1.58 – 1.85 
1 tab / d x 6 
300 mg/wk  
1.86 – 2.14 
1 tab / d x 7 
350 mg/wk  
2.15 - 2.42 
2 tab / d x 1; 1 tab / d x 6 
400 mg/wk  
2.43 – 2.71 
2 tab / d x 2; 1 tab / d x 5 
450 mg/wk  
2.72 – 3* 
2 tab / d x 3; 1 tab / d x 4 
500 mg/wk  
 
*Patients exceeding a BSA of 3.00 m2 should have their cyclophosphamide doses calculated on actual BSA with no 
maximum dose.  
 

  
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APPENDIX XII: INSTRUCTIONS FOR CYCLOPHOSPHAMIDE TABLETS PREPARATION, 
ADMINISTRATION AND SAFE HANDLING (CANADIAN SITES)  
 
Patient Name: ___________________________        Cycle#: _____         Date Range: _______________ 
 
 
Cyclophosphamide is an oral medicine for the treatment of 
cancer. This information sheet will help you prepare, 
administer, store, and dispose of the medicine. Please read 
the information before preparing and giving the medicine. If 
you have any questions, please contact:_______________ 
 
 
WHAT DO I NEED?  
 
 
You should use the following number of tablets for each 
dose): 25 mg is a full tablet and 12.5 mg is half a tablet: 
___________________________________________ 
 
Give each dose by mouth on time each morning for the 
number of days per week that your doctor tells you to 
give cyclophosphamide to your child. 
You should give the cyclophosphamide on the following 
days of the week:______________________________ 
 
Supplies: 
Cyclophosphamide tablets as above 
Disposable pad or paper towels  
Disposable gloves and mask 
A pair of goggles (eye protection) 
Gown or designated shirt used for chemotherapy 
medication only 
Disposable medicine cup 
Tablet splitter used for chemotherapy medication only 
Tweezers used for chemotherapy medications only 
Oral syringe(s) with caps, if using liquid to dissolve drug 
Disposable clear plastic bag 
A container to collect waste (zip top plastic bag or medical 
waste bag or container) 
 
 
HOW DO I STORE THE MEDICINE AND WASTE?  
 
Store the medication in the original bottle away from food 
and out of the reach of children or pets. Store the waste 
container out of the reach of children or pets.  
 
 
 
WHAT SAFETY MEASURES SHOULD I TAKE? 
 
If the medicine gets into eyes, hold eyelids open while 
flushing with water for at least 15 minutes.  If you spilled the 
medicine on your skin, remove contaminated clothing.  Wash 
area with soap and large amount of water.  Seek medical 
attention if the skin becomes red, irritated, or if you are 
concerned.  Call your doctor or nurse immediately 
at:___________________________________________ 
 
 
HOW DO I PREPARE AND GIVE THE MEDICINE?  
 
 
CAUTION: If you are pregnant, could become pregnant, or are 
breast-feeding, DO NOT prepare or administer this medicine. 
 
1. Choose a quiet working space away from food, windows, 
fans or heat ducts. 
2. Clean the working space with damp paper towels. 
3. Wash your hands with soap and water; dry them well. 
4. Put on a gown. If you do not have a gown select a 
designated shirt to wear when preparing this medication 
and wash separately. 
5. Put on disposable mask, a pair of goggles or eye protection 
and then your disposable gloves. 
6. Place a disposable pad or paper towel on the clean working 
space and place all supplies on the pad or paper towel.  
7. Do not crush the tablets. 
8. If you need to split the tablets in half to obtain the correct 
dose for your child please do it immediately before your 
child’s dose is due.  
9. Use a pair of tweezers to place tablet in the splitter and to 
remove the split tablet piece. 
10.  Gently lower the lid of the splitter and ensure the tablet 
splits into two equal halves. 
11.  Discard any remaining piece of tablet in waste collection 
container. Do not put back in the medicine bottle/container. 
12.  If your child cannot swallow the tablet whole, dissolve the 
tablet in water as follows: 
a. 
Put water in a medicine cup. Do not use other drinks 
such as juice or a soft drink. 
b. 
Remove the plunger of the syringe. 
c. 
With tweezers, place the required number of tablets 
(including part tablets) into the barrel of the oral 
syringe. 
d. 
Replace the plunger and push in until it touches the 
tablets within. Cap the syringe. 
e. 
Hold the syringe so that the plunger will not move 
(thumb on plunger) and place in a clear plastic bag. 
Gently tap on the absorbent pad surface to break up 
the tablets. 
f. 
Place the medicine cup with water into a plastic bag 
and draw up 5 mL (one teaspoon) to 7.5 mL (one and 
1/2 teaspoons) of water. Cap the syringe. 
g. 
Gently rock syringe back and forth to mix. 
h. 
The dose should be given as soon as the tablet breaks 
apart (2 to 5 minutes). Note that you may see small 
particles floating in the water. It is fine to give the 
medicine like this to your child. 
i. 
After the dose has been given, draw up another 5 mL 
(one teaspoon) of water into the same syringe. Give 
this to your child to ensure there is no medicine left in 
the syringe. 

  
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ADDITIONAL INFORMATION ON HOW TO CARE FOR 
YOUR CHILD TAKING CYCLOPHOSPHAMIDE  
 
x 
Take/give an anti-nausea medicine 30-60 minutes 
before the cyclophosphamide only if instructed to do 
so by your doctor.  
x 
Take/give cyclophosphamide at around the same time 
each morning with or without food.  
x 
Have your child drink lots of fluid the day before and 
on the day he/she takes cyclophosphamide. Your 
doctor or nurse will tell you how much fluid your child 
should drink each day. 
x 
Try to get your child to empty their bladder every 2 
hours while awake and at bedtime. 
x 
If your child is able to swallow cyclophosphamide 
tablets whole and the dose is vomited within 20 
minutes, the dose can be repeated once. Otherwise 
the dose should be skipped. If the dose is vomited 
after taking cyclophosphamide liquid, do not repeat the 
dose. The next dose should be administered at the 
regularly scheduled time. 
x 
If your child is unable to take a dose, or a dose is 
accidentally missed, place the remaining medicine 
from this dose in the waste container, seal, and 
contact your doctor or nurse for instructions. 
 
 
HOW SHOULD I DISPOSE OF CHEMOTHERAPY-RELATED 
WASTE? 
 
x Remove disposable gloves without touching the outside 
where the residual medication may linger (turn inside out). 
If using reusable gloves, wash the outside with soap and 
water and dry with paper towel before removing. 
x Then remove your gown/shirt followed by your mask and 
goggles. Wash your hands with soap and water and dry 
thoroughly. 
x When you are finished, place all used disposable supplies 
in a plastic zip top bag or the waste container that was 
provided to you by your doctor, nurse, or pharmacist.  
x Wash and dry all non-disposable items thoroughly and 
separately from other items such as dishes. Store reusable 
supplies away from other similar items; a marked plastic 
container would be ideal. 
x Wash and dry preparation area well. 
x Ask your nurse where you should dispose of your 
chemotherapy related waste. 
 
 

  
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APPENDIX XIII: PEDIATRIC FDG PET/CT GUIDELINES FOR ARST1431 
 
FDG-PET/CT imaging is strongly recommended as part of staging and response evaluation in all 
eligible pediatric patients. Many institutions will have standard guidelines for acquisition of 
pediatric FDG-PET/CT. For the purposes of performing pediatric [18F]-FDG PET in ARST1431 
individual investigators must use this standard operating procedure as a minimum standard. An 
approach is outlined below which is designed to optimize acquisition.91-97  
 
Patient preparation 
The indication/appropriateness for PET CT exam and preparation required for the patient should 
be reviewed in advance. The height and weight of the patient should be measured and recorded 
within one week prior to the study.  
 
Patients should be fasting for 4-6 hours before [18F]-FDG injection to decrease serum glucose 
level and to maintain a low insulin level. Fasting should be continued during the uptake phase. If 
sedation is to be used the patient must be NPO for 4-6 hours. If the patient is not NPO in 
preparation for general anesthesia or sedation, then drinking only plain, unflavored water is 
permitted for example, 15 mL/kg during the 2 hours prior to injection and the patient is also 
encouraged to increase hydration and excretion of radiotracer. Patients must not drink liquids 
containing sugar. Glucose-containing IV fluids and parenteral nutrition must be discontinued and 
replaced by saline IV fluid at least 4 hours prior to injection. The serum glucose level should be 
measured before the radiotracer administration. The glucose level should be below 200 mg/dL 
(11.1 mmol/L). If the blood glucose level is found to be more than 200 mg/dL (11.1 mmol/L), 
the referring physician should be notified and the study should be rescheduled, if possible, when 
better glucose control is achieved. If anesthesia/sedation is needed for a high quality study, then 
NPO guidelines (minimum 4 hours) or per local regulations will apply. If clear liquids are 
permissible within 4 hours prior to injection, liquids must not contain glucose or other 
carbohydrates. Tests for pregnancy will be performed in females who have reached puberty per 
institutional protocol. If positive, the study will be deferred until the risks vs benefits of the scan 
are discussed with the referring physician and with the patient/legal guardian/parent. 
 
The patient should be sitting in a chair or lying on a bed in a quiet, dimly lit, warm room for 
[18F]-FDG injection and during the uptake phase. Patients should avoid exercising or chewing 
immediately before and after [18F]-FDG is administered. Vigorous exercise should be avoided 
for 24 hours before the examination to avoid increased muscle uptake. To minimize the patient’s 
distress and muscle tension, a peripheral IV access should be obtained in advance. Anesthetic 
cream or other distraction methods can be used to minimize pain. If a central line is used for 
tracer injection the line should be flushed with a sufficient amount of normal saline solution. 
 
To reduce brown fat uptake, the uptake room should be warm (minimum 25°C) both before and 
after injection. Pharmacologic methods to reduce brown fat uptake include, oral propranolol, oral 
diazepam, or intravenous fentanyl, and may be employed per institutional protocols.   
 
Recommended FDG-PET/CT Imaging Sequence and Details  
Intravenous administration of FDG 

  
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Dose: 
Please use 0.1 to 0.14 mCi/kg, minimum of 0.7 mCi, maximum of 12 mCi. This applies to 
pediatric patients from newborns to 21 years of age. The dose may be influenced by the 
characteristics of the PET CT scanner. Modern scanners have higher sensitivity than older 
scanners and require less activity for high quality images than do older scanners.   
 
The North American Guidelines for Pediatric Nuclear Medicine for high-quality images at low 
radiation dose can be found at “http://snmmi.files.cms-plus.com/docs/GoWithGuidelines_files/
ImageGentlyPoster_2017.pdf 
 
Uptake period: 
Patient should remain at rest in a warm, quiet, dimly light uptake room for the uptake period. 
Patients should empty their bladder immediately prior to imaging. Imaging must begin 
60 minutes +/- 10 minutes after FDG injection. Follow-up PET CT scans should match the 
technique of the baseline PET CT when possible (including same machine and software level 
when able). 
 
Imaging should include the base of skull through thighs at a minimum. Some trial protocols may 
require total body imaging on all patients. For children and short adolescents imaging of the 
entire body is preferred.  
 
Imaging typically begins with CT acquisition. CT parameters will vary depending on 
institutional protocols and the quality of CT desired. CT options available include, but are not 
limited to: 
1. C-CT (non-contrast enhanced CT) for CTAC (CT for attenuation correction and lesion 
localization) of the entire body is used at the majority of centers in the US in 2020. Arms 
may be placed by the patient’s side or raised. The side position may be more comfortable 
for longer duration PET CT scans and is preferred for head and neck tumors. Here, the 
CT is not intended for diagnostic purposes. Acquisition parameters will vary among 
institutions. In general, acquisition parameters for the low-dose CT scan for attenuation 
correction should be approximately as follows: kV = 80-120; effective mAs = 10-80 
(patient dependent, auto current modification acceptable); gantry rotation time < 0.5 sec; 
maximum reconstructed width = 3-5 mm without overlap; standard reconstruction 
algorithm, minimum reconstruction diameter = outer arm to outer arm; with or without 
iodinated contrast.   
2. Some centers will acquire a fully diagnostic C+CT (or contrast-enhanced CT in place of 
the non-contrast enhanced CTAC) with breath-hold, intravenous and/or oral contrast 
depending on the location of the primary tumor. The axial extent of the fully diagnostic 
CT vary and might be restricted to those regions of the body that require high anatomic 
detail, such as the lungs, or other areas of tumor location. Use of the diagnostic CT for 
attenuation correction may result in slightly lower overall radiation exposure compared to 
obtaining a PET/CT and diagnostic CT separately. 
 
The use of CT contrast during the time of PET may vary by institution protocol as this is 
not routinely performed in the US at this time (late 2020). If IV or iodine containing oral 

  
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contrast is used, please also follow institutional guidelines for consent and patient safety 
regarding possible contrast allergy and renal function guidelines.  
 
• 
The axial field of view of the CT scan for attenuation correction should match that 
of the PET acquisition and will likely range from the skull base to mid thighs at a 
minimum and in some cases will be full body, like the PET study - top of the head 
through the toes. Arm positioning will be the same as for the PET scan. 
• 
The CT scan will be performed during the patient’s normal breathing for a non-
diagnostic, C-CT attenuation correction only exam. Respiratory gating is not 
routine in this circumstance. After the CT scan, a PET scan covering the same 
axial field of view should be performed. Most often PET imaging will start at the 
head and proceed inferiorly. The number of bed positions and the acquisition time 
per bed position will be patient and scanner specific. Typical parameters are 6 bed 
positions and an acquisition of 2 to 5 minutes per bed position. 
• 
Additional diagnostic-quality CT of the neck or other areas should be performed 
with contrast if needed to fulfill requirements for anatomic post-treatment 
imaging.   
  
FDG-PET/CT Image Reconstruction   
The PET/CT data will be corrected for dead time, scatter, random coincidence events detected, 
and attenuation using standard algorithms provided by the scanner manufacturers. For the 
dedicated head and neck or other views, a post-filter with a full-width at half maximum (FWHM) 
in the range of 5 mm is recommended.   
 
Specific details of the CT and PET acquisitions will vary per machine and local customs. KvP, 
mA, kernel, slice thickness, rotation speed, patient feed (mm/sec), window and levels can all be 
varied at CT. For PET, various iterations, zooms, filters, colors can be applied per institution and 
manufacturer preferences. 
 
For output, please include: 
- 
PET MIP 
- 
Soft tissue (and where appropriate lung, bone, and/or brain windows) reconstructions in 
the axial, sagittal, and coronal planes for CT. Please also reconstruct PET in these same 
planes and also provide fused images in these planes.  
- 
Attenuation and non-attenuation corrected PET image sets should be provided in these 
planes 
- 
A final set of key images (with comparison to prior exams) is not required, although 
many find this helpful for final review and image sharing 
- 
Please include CTDI vol and DLP (for CT) whenever possible. This might be required in 
some locations, where reporting of these is required by law. 
 
Image analysis and interpretation: PET CT images should be relayed to a PACS (picture 
archiving and communication system) and/or nuclear medicine workstation for analysis and data 
storage. Report should include description of findings such as location, extent, and intensity of 
any abnormal [18F]-FDG activity, and relevant CT morphologic findings related to PET 
abnormalities on CT images. The intensity of [18F]-FDG activity can be described as mild, 

  
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moderate, or intense. It can alternatively or additionally be described semi-quantitatively as the 
SUV (usually SUVmax). The intensity of [18F]-FDG activity can be also compared with the blood 
pool and liver background activity. The Deauville score may be applicable in certain protocols, 
particularly lymphomas. As some protocols will also require SUV comparison to a normal 
appearing portion of the liver, please include this value in reports. Any incidental finding on 
either PET or CT should be reported. The findings should be compared with the previous 
relevant studies. The limitations, if any (e.g. previous G-CSF use and limited bone marrow 
evaluation, patient motion, altered biodistribution of radiotracer, etc.), and how they may affect 
the results of the study should be reported. Structured reports may be incorporated per 
institutional preference.  
 
PET/MRI may be used if available. The MRI serves as the basis for attenuation correction. MRI 
sequences should be obtained per local institutional preferences. At institutions where both 
PET/CT and PET/MRI are available, it is recommended that whichever technology is used 
initially be used for subsequent evaluations. 
 
 

  
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REFERENCES 
 
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