Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or Minus Pazopanib (NSC# 737754)
Phase: PHASE2
Conditions: Alveolar Soft Part Sarcoma, Angiomatoid Fibrous Histiocytoma, Atypical Fibroxanthoma, Clear Cell Sarcoma of Soft Tissue, Epithelioid Malignant Peripheral Nerve Sheath Tumor, Epithelioid Sarcoma, Extraskeletal Myxoid Chondrosarcoma, Extraskeletal Osteosarcoma, Fibrohistiocytic Neoplasm, Fibrosarcoma, Inflammatory Myofibroblastic Tumor, Intimal Sarcoma, Leiomyosarcoma, Liposarcoma, Liver Embryonal Sarcoma, Low Grade Fibromyxoid Sarcoma, Low Grade Myofibroblastic Sarcoma, Malignant Peripheral Nerve Sheath Tumor, Malignant Skin Granular Cell Tumor, Malignant Triton Tumor, Mesenchymal Chondrosarcoma, Myxofibrosarcoma, Myxoid Chondrosarcoma, Myxoinflammatory Fibroblastic Sarcoma, Nerve Sheath Neoplasm, PEComa, Pericytic Neoplasm, Plexiform Fibrohistiocytic Tumor, Sclerosing Epithelioid Fibrosarcoma, Skin Glomus Tumor, Stage IB Soft Tissue Sarcoma AJCC v7, Stage IIB Soft Tissue Sarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Synovial Sarcoma, Undifferentiated High Grade Pleomorphic Sarcoma of Bone
Sponsor: National Cancer Institute (NCI)

                          
 
ARST1321 
 
 
Version date: 04/08/2019 
1 
 
Activated: 
07/07/14 
Version Date: 
04/08/2019 
Closed: 
      
Amendment: 
#7 
 
CHILDREN'S ONCOLOGY GROUP and 
NRG ONCOLOGY 
 
ARST1321 
 
Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS): A 
Phase II/III Randomized Trial of Preoperative Chemoradiation or Preoperative Radiation Plus or 
Minus Pazopanib (NSC# 737754) 
 
An Intergroup NCTN Phase II/III Study 
 
This trial is part of the national NCI Clinical Trials Network (NCTN) program which is sponsored by the 
National Cancer Institute (NCI). The trial will be conducted by the network of NCTN researchers, led by 
the COG and NRG Oncology 
 
NCI Supplied Agent: Pazopanib (NSC# 737754) 
IND sponsor for Pazopanib: 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. 
 
COG Co-Chair 
NRG Oncology Co-Chair 
Aaron Weiss, DO 
Yen-Lin Chen, MD 
Maine Children’s Cancer Program 
Massachusetts General Hospital 
Division of Pediatric Hematology/Oncology Division of Radiation Oncology 
100 Campus Drive, Suite 107 
50 Fruit Street 
Scarborough, ME 04074 
 
Boston, MA 02114 
Phone: (207) 396-7565 
 
Phone: (617) 643-7250 
Email: weissa2@mmc.org 
 
Email: ychen9@partners.org 
 
NRG Oncology Co-Chair 
Thomas Scharschmidt, MD 
The Ohio State University 
Division of Orthopedic Oncology 
Prior Hall, 376 W. 10th Street, Suite 725 
Columbus, OH 43210 
Phone: (614) 293-4420 
Email: Thomas.Scharschmidt@osumc.edu 
 

                          
 
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Version date: 04/08/2019 
2 
 
Participating Organizations 
 
COG / Children's Oncology Group 
NRG / NRG Oncology 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG 
Canadian Cancer Trials Group 
 
 
 
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_SYSTE
M/ 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. 

                          
 
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TABLE OF CONTENTS 
 
SECTION 
PAGE 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
7 
ABSTRACT 
11 
EXPERIMENTAL DESIGN SCHEMAS 
12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
15 
1.1 
Primary Objectives 
15 
1.2 
Secondary Objectives 
15 
1.3 
Exploratory Aims 
15 
2.0 
BACKGROUND 
16 
2.1 
Pediatric NRSTS 
16 
2.2 
Adult NRSTS 
17 
2.3 
Rationale for Inhibition of Angiogenesis in Soft Tissue Sarcomas 
17 
2.4 
Rationale for Tyrosine Kinase Inhibitors in Non-Rhabdomyosarcoma Soft Tissue 
Sarcomas 
18 
2.5 
Pazopanib in Adults with Soft Tissue Sarcomas 
18 
2.6 
Pazopanib use in Children 
19 
2.7 
Combination of TKIs and Cytotoxic Chemotherapy in Soft Tissue Sarcomas 
20 
2.8 
Combination of TKIs and Radiotherapy in Soft Tissue Sarcomas 
22 
2.9 
Response Assessment in NRSTS: Radiologic versus Pathologic 
22 
2.10 
ARST0332 Preliminary Data Regarding Pathologic Response in Pediatric NRSTS 
23 
2.11 
Chemotherapy-Resistant Pediatric NRSTS 
24 
2.12 
RTOG 95-14 Data Regarding Pathologic Response in Adult NRSTS 
24 
2.13 
Rationale for Chemotherapy and Non-Chemotherapy Cohorts 
25 
2.14 
Pazopanib and Radiotherapy 
27 
2.15 
Rationale for Concurrent Sequencing of Pazopanib and Preoperative Radiotherapy in  
the Non-Chemotherapy Cohort 
27 
2.16 
Wound Complications 
28 
2.17 
FDG PET in NRSTS 
28 
2.18 
Correlative Biology Studies 
29 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
31 
3.1 
Study Enrollment 
31 
3.2 
Patient Eligibility Criteria 
35 
4.0 
TREATMENT PROGRAM 
42 
4.1 
Overview of Treatment Plan 
42 
4.2 
Treatment Administration Schedule for Patients on Regimen A 
49 
4.3 
Treatment Administration Schedule for Patients on Regimen B 
55 
4.4 
Treatment Administration Schedule for Patients on Regimen C 
61 
4.5 
Treatment Administration Schedule for Patients on Regimen D 
62 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
63 
5.1 
Dose-Limiting Toxicity 
63 
5.2 
Pazopanib Dose Reductions Table 
64 
5.3 
Hematologic Toxicity 
64 
5.4 
Mucositis 
66 

                          
 
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5.5 
Nephrotoxicity 
66 
5.6 
Proteinuria 
68 
5.7 
Cardiotoxicity 
68 
5.8 
Hypertension 
69 
5.9 
Gastrointestinal Toxicity 
73 
5.10 
Radiation Toxicity 
75 
5.11 
Impaired Wound Healing and Wound Complications 
76 
5.12 
Rash 
78 
5.13 
Neurotoxicity 
79 
5.14 
Hematuria 
80 
5.15 
Electrolyte Abnormalities 
81 
6.0 
DRUG INFORMATION 
81 
6.1 
PAZOPANIB 
81 
6.2 
DEXRAZOXANE 
90 
6.3 
DOXORUBICIN 
92 
6.4 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
94 
6.5 
IFOSFAMIDE 
95 
6.6 
MESNA – ORAL and IV 
97 
6.7 
PEGFILGRASTIM 
99 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
101 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
101 
7.2 
Optional Studies 
107 
7.3 
Follow-up 
107 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
 
108 
8.1 
Criteria for Removal from Protocol Therapy 
108 
8.2 
Off Study Criteria 
108 
9.0 
STATISTICAL CONSIDERATIONS 
108 
9.1 
Sample Size and Study Duration 
108 
9.2 
Dose-Finding Phase for Pazopanib in Both Patient Cohorts 
109 
9.3 
Monitoring of Dose Limiting Toxicities Following the Dose Finding Phase 
111 
9.4 
Design and Statistical Considerations for the Phase II Study for Patients With 
Chemotherapy 
111 
9.5 
Design and Statistical Considerations for the Phase II/III Study for Patients Without 
Chemotherapy 
112 
9.6 
Statistical Considerations for Study Secondary Objectives 
113 
9.7 
Statistical Considerations for Exploratory Aims 
114 
9.8 
Gender and Minority Accrual Estimates 
116 
10.0 
EVALUATION CRITERIA 
116 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
116 
10.2 
Response Criteria for Patients with Solid Tumors 
116 
10.3 
Other Response Parameters 
125 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
125 
11.1 
Purpose 
125 
11.2 
Determination of Reporting Requirements 
125 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
126 
11.4 
Special Situations for Expedited Reporting 
126 
11.5 
Reporting Requirements for Specialized AEs 
128 

                          
 
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11.6 
Exceptions to Expedited Reporting 
129 
11.7 
Reporting Requirements - Investigator Responsibility 
130 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
130 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
132 
11.10 Protocol Specific Additional Instructions and Reporting Exceptions 
132 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
 
133 
11.12 Routine Adverse Event Reporting 
133 
12.0 
STUDY REPORTING AND MONITORING 
134 
12.1 
CDUS 
134 
12.2 
Data and Safety Monitoring Committee 
134 
12.3 
CRADA/CTA 
134 
13.0 
SURGICAL GUIDELINES 
136 
13.1 
Initial Biopsy for Diagnosis and Tissue Submission 
136 
13.2 
Surgery 
136 
13.3 
Definitive Surgical Procedure 
137 
13.4 
Principles of Surgery 
137 
13.5 
Surgical Management of Patients with Metastasis Prior to Study Enrollment 
138 
13.6 
Surgical Adverse Events 
139 
13.7 
Surgical Quality Assurance Reviews 
139 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
140 
14.1 
Aims of Retrospective Central Pathology Review 
140 
14.2 
Specimen Submission Requirements 
141 
14.3 
Central Pathology Review Guidelines 
142 
14.4 
Sample Labeling and Shipping 
143 
14.5 
Review Pathologists 
143 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS 
144 
15.1 
Analysis of Actionable Mutations and Whole Genome Sequencing 
144 
15.2 
Microvessel Density and Circulating Tumor DNA as Predictors of Tumor Response  
and Outcome (Optional) 
148 
15.3 
Doxorubicin Pharmacokinetics in Combination with Pazopanib (Optional) 
150 
16.0 
IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING 
152 
16.1 
Goals of Diagnostic Imaging 
152 
16.2 
Timing of Diagnostic Imaging 
152 
16.3 
Required Imaging Studies 
153 
16.4 
Recommendations for PET and Diffuse-Weighted MR Imaging Studies 
153 
16.5 
Central Review of Imaging Studies 
154 
16.6 
Submission of Imaging Studies for Central Review 
155 
16.7 
Diagnostic Imaging Guidelines 
157 
16.8 
Growth Plate Evaluation 
160 
17.0 
RADIATION THERAPY GUIDELINES 
161 
17.1 
General Guidelines 
161 
17.2 
Treatment Overview 
162 
17.3 
Timing of RT 
163 
17.4 
Radiation Treatment Planning and Delivery Techniques 
164 
17.5 
Radiation Treatment Targets 
167 
17.6 
Radiation Treatment Dose 
171 
17.7 
Treatment Technique 
175 

                          
 
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17.8 
Organs at Risk (OAR) 
176 
17.9 
Dose Calculation and Reporting 
179 
17.10 Quality Assurance and Documentation 
179 
17.11 Adverse Effects of Radiation and Management 
181 
APPENDIX I:  CTEP AND CTSU REGISTRATION PROCEDURES 
183 
APPENDIX II:  ANATOMIC SITE DEFINITIONS 
186 
APPENDIX III:  THE FNCLCC SARCOMA GRADING SYSTEM 
189 
APPENDIX IV:  WORLD HEALTH ORGANIZATION CLASSIFICATION OF SOFT TISSUE 
TUMOURS: INTERMEDIATE (RARELY METASTASIZING) AND MALIGNANT 
TUMOURS, 2013 
190 
APPENDIX VA:  90TH AND 95TH PERCENTILE BLOOD PRESSURE BY PERCENTILE  
HEIGHT IN GIRLS AGE 1-17 YEARS 
192 
APPENDIX VB:  90TH AND 95TH PERCENTILE BLOOD PRESSURE BY PERCENTILE  
HEIGHT IN BOYS AGE 1-17 YEARS 
193 
APPENDIX VC:  ORAL ANTIHYPERTENSIVE MEDICATIONS 
194 
APPENDIX VI:  CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
195 
APPENDIX VII:  MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
197 
APPENDIX VIII:  SUPPORTIVE CARE GUIDELINES 
198 
APPENDIX IX:  THERAPY DELIVERY MAPS FOR REGIMEN A 
203 
APPENDIX X:  THERAPY DELIVERY MAPS FOR REGIMEN B 
211 
APPENDIX XI:  THERAPY DELIVERY MAPS FOR REGIMEN C 
215 
APPENDIX XII:  URINE PROTEIN TO CREATININE (UPC) RATIO 
219 
APPENDIX XIII:  REFERENCE GUIDE FOR REQUIRED AND  RECOMMENDED  
CORRELATIVE STUDIES 
220 
APPENDIX XIV:  YOUTH INFORMATION SHEETS 
221 
APPENDIX XV:  SUBJECT’S MEDICATION DIARY - PAZOPANIB 
225 
APPENDIX XVI:  RADIATION TREATMENT TARGET VOLUME 
227 
APPENDIX XVII:  PEDIATRIC (< 18 YEARS OF AGE) DOSING TABLES FOR PAZOPANIB 
229 
REFERENCES 
231 
 
 

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ARST1321 
 
STUDY COMMITTEE 
COG Study Committee Members 
 
STUDY CHAIR 
Aaron Weiss, DO 
Hematology/Oncology 
Maine Children’s Cancer Program 
Pediatric Hematology/Oncology 
100 Campus Drive – Suite 107 
Scarborough, ME 04074 
Phone: (207) 396-7565 
Fax: 
(207) 396-7577 
E-mail: weissa2@mmc.org 
 
STUDY VICE CHAIR 
Sheri Spunt, MD 
Stanford University 
Lucile Packard Children's Hospital 
Pediatric Hematology/Oncology 
100 Welch Road 
Suite 300, MC 5798 
Palo Alto CA  94304 
Phone: (650) 723-5535 
E-mail: sspunt@stanford.edu 
 
STUDY STATISTICIAN 
Yueh-Yun Chi, PhD 
Biostatistics 
Children's Oncology Group - Data Center  
University of Florida 
6011 NW 1st Place 
Gainesville, FL 32607 
Phone: (352) 294-5917 
Fax: 
(352) 294-5931 
E-mail: ychi@cog.ufl.edu 
 
STUDY COMMITTEE MEMBERS 
Douglas Hawkins, MD 
Seattle Children’s Hospital 
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 
 
Mark Kayton, MD 
Surgery 
Palm Beach Children’s Hospital, St. Mary’s Medical 
Center/Florida Atlantic University 
927 45th Street, Suite 301 
West Palm Beach, FL 33407 
Phone: (561) 295-9100 
Fax: 
(561) 845-9295 
E-mail: kaytonm@fau.edu 
STUDY COMMITTEE MEMBERS 
Stephen Skapek, MD 
Hematology/Oncology 
University of Texas Southwestern Medical Center 
Pediatrics 
5323 Harry Hines Blvd 
Dallas, Texas 75390-9063 
Phone: (214) 648-3081 
Fax: 
(214) 648-3122 
E-mail: Stephen.skapek@UTSouthwestern.edu 
 
Barry Lynn Shulkin, MD 
Diagnostic Imaging 
St. Jude Children's Research Hospital 
Radiological Sciences 
262 Danny Thomas Place, MS 220 
Memphis, TN 38105-3678 
Phone: (901) 595-3347 
Fax: 
(901) 595-3981 
E-mail: barry.shulkin@stjude.org 
 
Simon Ching-Shun Kao, MD 
Diagnostic Imaging 
University of Iowa Hospitals and Clinics 
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 
 
Julie C. Fanburg-Smith, MD 
Pathology 
Penn State Children’s Hospital 
Anatomic Pathology, Orthopaedic Surgery 
500 University Drive 
Hershey, PA 17033 
Phone: (703) 623-7013 
E-mail: jcfsmd@gmail.com 
 
Jennifer Black, MD 
Pathology 
Children’s Hospital Colorado 
Pediatric Pathology 
13123 East 16th Avenue, Box 120 
Aurora, CO 80045 
Phone: (720) 777-1852 
Fax: 
(720) 777-7119 
E-mail: jennifer.black2@childrenscolorado.org 

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ARST1321 
STUDY COMMITTEE MEMBERS 
Stephanie Terezakis, MD 
Radiation Oncology 
University of Minnesota/Masonic Cancer Center 
Department of Radiation Oncology 
516 Harvard St. Southeast, PWB-1 
Minneapolis, MN 55455 
Phone: (612) 626-6710 
E-mail: sterezak@umn.edu 
 
Robin Arens, AAS 
Clinical Research Associate 
Connecticut Children’s Medical Center 
Clinical Trials Unit 
282 Washington Street 
Hartford, CT 06106 
Phone: (860) 545-9614 
Fax: 
(860) 545-8986 
Email: Rarens@connecticutchildrens.org 
 
Mary Schlapkohl, BSN 
Nursing 
University of Iowa/Holden Comprehensive Cancer 
Center 
Department of Pediatric Hematology and Oncology 
200 Hawkins Dr. 1300 BT 
Iowa City, IA 52242 
Phone: (319) 384-6002 
Fax:  
(319) 356-7659 
E-mail: mary-schlapkohl@uiowa.edu 
 
Andrew Ostrenga, PharmD  
Pharmacy 
University of Mississippi Medical Center 
Blair E. Batson Hospital for Children 
2500 North State Street 
Jackson, MS 39216 
Phone: (601) 815-8391 
Email: aostrenga@umc.edu 
 
Robert Lor Randall, MD FACS 
Surgery 
Primary Children's Hospital 
Dept. of Orthopaedic Surgery  
c/o Huntsman Cancer Institute 
200 Circle of Hope Drive Room 4262 
Salt Lake City UT 84112 
Phone: (801) 585-0300 
Fax: 
(801) 585-7084 
Email: r.lor.randall@hci.utah.edu 
 
 
STUDY COMMITTEE MEMBERS 
Joel I. Sorger, MD 
Surgery 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Ave, ML 2017 
Cincinnati, OH 45229 
Phone: (513) 636-7267 
E-mail: joel.sorger@cchmc.org 
 
Lynn Million, MD 
Radiation Oncology 
Lucile Packard Children's Hospital Stanford University 
Radiation Oncology 
875 Blake Wilbur Drive 
Stanford, CA 94305 
Phone: (650) 725-9903 
E-mail: lmillion@stanford.edu 
 
Ethan A. Smith, MD 
Diagnostic Imaging 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue, MLC 5031 
Cincinnati, OH 45229 
Phone: (513) 803-2209 
Email: ethan.smith@cchmc.org 
 
Donald Williams Parsons, MD PhD 
Hematology/Oncology 
Baylor College of Medicine/Dan L Duncan 
Comprehensive Cancer Center 
1102 Bates, Suite 1030.15 
Houston, TX 77030 
Phone: (832) 824-4643 
Email: dwparson@txch.org 
 
 
PROTOCOL COORDINATOR 
Christine Wang, PhD 
Children’s Oncology Group- Operations Center 
222 E. Huntington Drive, Suite 100 
Monrovia, CA 91016 
Phone: (626) 241-1626 
Fax: 
(626) 445-4334 
E-mail: cewang@childrensoncologygroup.org 
 
RESEARCH COORDINATOR 
Justin Davis 
Children’s Oncology Group- Operations Center 
Statistics and Data Center 
222 E. Huntington Drive, Suite 100 
Monrovia, CA  91016 
Phone: (626) 241-1509 
Fax: 
(626) 445-4334 
E-mail: jdavis@childrensoncologygroup.org 
 

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ARST1321 
AGENT  
NSC# 
 
IND# 
Dexrazoxane 
169780  
Exempt  
Doxorubicin 
123127   
Exempt  
Filgrastim 
614629  
Exempt 
Ifosfamide 
109724   
Exempt 
Mesna  
113891  
Exempt  
Pazopanib 
737754  
 
Pegfilgrastim 
725961  
Exempt 
 
IND sponsor for pazopanib; DCTD, NCI 
 
SEE SECTIONS 14 AND 15 FOR  
SPECIMEN SHIPPING ADDRESSES. 
 

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ARST1321 
NRG Oncology Study Committee Members 
 
STUDY CO-CHAIR/Radiation Oncology 
Yen-Lin Chen, MD 
Massachusetts General Hospital 
50 Fruit Street 
Boston, MA 02114 
Phone: (617) 643-7250 
Fax: 
(617) 724-9532 
E-mail: ychen9@partners.org 
 
STUDY CO-CHAIR/Orthopedic Oncology 
Thomas Scharschmidt, MD 
The Ohio State University 
376 W. 10th Street, Prior Hall, Suite 725 
Columbus, OH 43210 
Phone: (614) 293-4420 
Fax: 
(614) 293-3747 
E-mail: Thomas.Scharschmidt@osumc.edu 
 
Radiation Oncology Co-Chair 
Dian Wang, MD, PhD 
Rush University Medical Center 
500 S. Paulina, Suite 013 
Chicago, IL 60612 
Phone: (312) 942-7774 
Fax: 
(312) 942-2894 
E-mail: dian_wang@rush.edu 
 
Medical Oncology Co-Chair 
Edwin Choy, MD, PhD 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Phone: (617) 643-0230 
Fax: 
(617) 643-1915 
E-mail: echoy@partners.org 
 
Medical Oncology Co-Chair 
Scott H. Okuno, MD 
Mayo Clinic 
200 First Street, SW 
Rochester, MN 55905 
Phone: (507) 284-4849 
Fax: 
(507) 284-1803 
E-mail: okuno.scott@mayo.edu 
 
Translational Science Co-Chair 
Sam S. Yoon, MD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue, H1209 
New York, NY 10065 
Phone: (212) 639-7436 
Fax: 
(212) 639-7460 
E-mail: yoons@mskcc.org 
Pathology Co-Chair 
Eduardo Zambrano, MD, MS 
Presbyterian St. Luke/Rocky Mountain Hospital for 
Children 
1719 East 19th Avenue 
Denver, CO 80218 
Phone: (650) 498-1031 
Fax: 
(650) 724-6843 
E-mail: Eduardo.Zambrano@HealthONEcares.com 
 
Medical Physics Co-Chair 
Ning J. Yue, PhD 
Rutgers Univ./Cancer Institute of New Jersey 
195 Little Albany Street 
New Brunswick, NJ 08901 
Phone: (908) 239-4519 
Fax: 
(723) 253-3953 
E-mail: yuenj@cinj.rutgers.edu 
 
Radiologic Imaging Co-Chair 
Daniel Pryma, MD 
University of Pennsylvania 
3400 Spruce Street; 110-C Donner Bldg. 
Philadelphia, PA  Zip code 
Phone: (215) 349-5272 
Fax: 
(215) 349-5843 
E-mail: daniel.pryma@uphs.upenn.edu 
 
Senior Statistician 
Qiang Zhang, PhD 
Radiation Therapy Oncology Group/ACR 
1818 Market Street, Suite 1600 
Philadelphia, PA 19103 
Phone: (215) 574-3197 
Fax: 
(215) 928-0153 
E-mail: ezhang@acr.org 
 
Ruth Lim, MD 
Radiologic Associates, Mass General Hospital 
55 Fruit Street 
Boston, MA 02114-2696 
Phone: (617) 724-4207 
Email: rlim@partners.org 
 
Anthony M. Zelazny, MD 
Rush University Medical Center 
1653 W. Congress Parkway 
Chicago, IL 60612 
Phone: (312) 942-2749 
Email: Anthony_zelazny@rush.edu 
 
NRG Oncology Operations Center 
1600 JFK Blvd., Suite 1020 
Four Penn Center 
Philadelphia, PA 19103 

                
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The Children's Oncology Group has received a Certificate of Confidentiality from the federal government, which 
will help us protect the privacy of our research subjects. The Certificate protects against the involuntary release of 
information about your subjects collected during the course of our covered studies. The researchers involved in 
the studies cannot be forced to disclose the identity or any information collected in the study in any legal 
proceedings at the federal, state, or local level, regardless of whether they are criminal, administrative, or 
legislative proceedings. However, the subject or the researcher may choose to voluntarily disclose the protected 
information under certain circumstances. For example, if the subject or his/her guardian requests the release of 
information in writing, the Certificate does not protect against that voluntary disclosure. Furthermore, federal 
agencies may review our records under limited circumstances, such as a DHHS request for information for an 
audit or program evaluation or an FDA request under the Food, Drug and Cosmetics Act. 
The Certificate of Confidentiality will not protect against mandatory disclosure by the researchers of information 
on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others 
 
 
ABSTRACT 
The non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise 4% of all childhood malignancies and 
less than 1% of all adult malignancies. Intermediate- and high-risk NRSTS account for about 40% of the 
population. Despite multi-modality therapy, survival rates for these patients are approximately 50% and 
15%, respectively. The chemotherapy backbone of ifosfamide and doxorubicin (ID) is considered to be the 
most active and among the most commonly used regimens in NRSTS but radiographic response rates and 
outcomes remain poor for those with large, high-grade tumors and those with unresectable or metastatic 
disease. Further, the lack of homogeneous chemotherapy sensitivity across all subtypes suggests a more 
histologic-specific approach to NRSTS treatment may be needed. 
 
Certain tyrosine kinases have been found to be expressed and dysregulated in a range of NRSTS subtypes. 
Multi-targeted tyrosine kinase inhibitors (TKIs), such as pazopanib, have the ability to target multiple 
signaling pathways that may be disrupted in many NRSTS. The therapeutic approach for this study builds 
on ARST0332 and RTOG 0630 by adding pazopanib to standard chemotherapy and radiotherapy. This 
study will first determine the feasibility of adding a TKI in combination with radiation or chemoradiation 
in pediatric and adult patients newly diagnosed with unresected intermediate- and high-risk NRSTS. 
Subsequently, it will compare the rates of near complete pathologic response (> 90% necrosis) of 
(1) preoperative pazopanib plus chemoradiation versus preoperative chemoradiation alone for potentially 
resectable > 5 cm, Grade 2 or 3 intermediate to high risk chemotherapy-sensitive adult and pediatric 
NRSTS, and (2) pazopanib plus preoperative radiotherapy versus preoperative radiotherapy alone for 
potentially resectable intermediate to high risk adult and pediatric NRSTS. It has not been well established 
whether a significant change in the size of the tumor mass, as determined by RECIST, is a meaningful 
surrogate of patient outcome in NRSTS. Treatment-induced pathologic necrosis may be a more reliable 
surrogate of response and predictor of outcome, particularly with the use of targeted therapies, and will be 
the primary response endpoint used for this study.  
 
This joint study represents a unique and unprecedented opportunity to advance the treatment of both 
pediatric and adult NRSTS. The study will evaluate the feasibility of standardizing the use of preoperative 
radiotherapy, with high quality MRI image fusion, consensus clinical target volume definition, and accurate 
delivery using image guidance technology (IGRT) across both pediatric and adult NRSTS. The study will 
also benefit from a larger number of NRSTS patients available to explore a common biological targeted 
therapy in both pediatric and adult populations. The correlative studies will collect the largest sample of 
pediatric and adult NRSTS to understand the similarities and differences between pediatric and adult 
NRSTS and potentially identify other actionable targets for future development.  
 
 
 

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EXPERIMENTAL DESIGN SCHEMAS 
DOSE FINDING PHASE
During the dose-finding phase, patients will be non-randomly assigned to treatment with pazopanib.
Chemotherapy Cohort  
 
 
 
 
Non-Chemotherapy Cohort
(Regimen A) 
 
 
 
 
 
 
(Regimen C)
The 
Chemotherapy Cohort dose-
finding phase is closed and dose level 1 
has been found as the MTD, effective 
May 2015.
The Non-Chemotherapy Cohort 
dose-finding phase is closed and 
dose level 2 has been found as the 
MTD, effective with Amendment 
#3A.
Study Entry 
First 10 patients begin at Dose Level 1
Pazopanib#
2 cycles of ID
XRT begins Week 4
Week 6: Comparison and Measures of 
Feasibility
Dose level adjustments
Therapy to continue as outlined in the 
efficacy phase schema
I:   Ifosfamide, 2.5 grams/m2/dose IV on Days 1, 2, 3 (7.5 grams/m2/cycle)
D: Doxorubicin, 37.5 mg/m2/dose IV on Days 1, 2 (75 mg/ m2/cycle)
One cycle of ID is 21 days.
#Pazopanib (Tablet formulation, PO once daily)
Dose Level 
 
Pediatric Dose 
 
Adult Dose
        0 
 
 
   275 mg/m2
400 mg
        1 
 
 
   350 mg/m2
   600 mg
        2 
 
 
   450 mg/m2
   800 mg
Study Entry 
First 10 patients begin at Dose Level 1
Pazopanib#
XRT begins Week 1
Therapy to continue as outlined in the 
efficacy phase schema
Dose level adjustments
Week 6: Comparison and Measures of 
Feasibility

                
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EFFICACY PHASE- CHEMOTHERAPY COHORT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Pazopanib is to be held pre- and post-surgery. 
I = Ifosfamide; D = Doxorubicin. Each cycle lasts 21 days. 
** Postoperative boost radiotherapy is required for gross residual disease and is optional for positive margins. 
XRT begins Week 4 
 
Study Entry and Randomization 
INDUCTION 
Pazopanib* dose level 1 daily  
Weeks 1-12 
along with 2 cycles of ID and  
INDUCTION 
2 cycles of ID and  
2 cycles of I 
Evaluation 
(Week 13) 
Evaluation 
(Week 13) 
 
Primary Site Surgery 
 
Primary Site Surgery 
CONTINUATION 
Pazopanib* dose level 1 daily  
Weeks 16-25 
along with 2 cycles of ID and  
1 cycle of D 
CONTINUATION 
2 cycles of ID and  
1 cycle of D 
Postoperative Boost 
Radiotherapy at Week 16 for 
gross or microscopic residual 
tumor** after surgery 
End of Protocol Therapy 
Surgery/Radiotherapy to 
metastatic sites at completion 
of and recovery from assigned 
therapy 
 
Progressive Disease 
 
Off Protocol Therapy 
 
Regimen A 
 
Regimen B 

                
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EFFICACY PHASE- NON-CHEMOTHERAPY COHORT 
 
The Non-Chemotherapy Cohort is closed to further accrual, effective October 12, 2017. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Entry and Randomization 
INDUCTION 
Pazopanib dose level 2 daily 
Weeks 1-9 
INDUCTION 
Radiation Therapy Alone 
Evaluation 
(Week 10) 
Evaluation 
(Week 10) 
Primary Site Surgery 
Primary Site Surgery 
CONTINUATION 
Pazopanib dose level 2 daily Weeks 13-25 
+ Postoperative Boost Radiotherapy**  
 
End of Protocol Therapy 
 
Surgery/Radiotherapy to metastatic sites 
at completion of and recovery from 
assigned therapy 
* Pazopanib is to be held pre- and post-surgery. 
** Postoperative boost radiotherapy is required for gross residual disease and optional for positive margins. 
 
Progressive Disease 
 
Off Protocol Therapy 
CONTINUATION 
Postoperative Boost 
Radiotherapy**  
 
XRT begins Week 1 
 
Regimen C 
 
Regimen D 

                
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1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
1.1 
Primary Objectives 
1.1.1 
To identify the dose of pazopanib that is feasible when given in combination with 
radiation or chemoradiation in pediatric and adult patients newly diagnosed with 
unresected intermediate- and high-risk NRSTS. 
 
1.1.2 
To compare the rates of near complete pathologic response (> 90% necrosis) with 
the addition of pazopanib to preoperative chemoradiation versus preoperative 
chemoradiation alone for potentially resectable > 5 cm, Grade 2 or 3 intermediate 
to high risk chemotherapy-sensitive NRSTS in the Phase II portion of the study for 
this cohort. 
 
1.1.3 
To compare the rates of near complete pathologic response (> 90% necrosis) with 
the addition of pazopanib to preoperative radiotherapy versus preoperative 
radiotherapy alone for potentially resectable intermediate to high risk adult and 
pediatric NRSTS in the Phase II portion of the study for this cohort (using a 
Phase II decision rule to go onto the Phase III portion of the study). 
 
1.1.4 
To compare the rates of event-free survival (EFS) with the addition of pazopanib 
to preoperative radiotherapy versus preoperative radiotherapy alone for localized 
intermediate to high risk adult and pediatric NRSTS in the Phase III portion of the 
study for this cohort if the Phase II decision rule is passed. 
 
1.2 
Secondary Objectives 
1.2.1 
To estimate the rates of local failure, regional failure, distant metastasis free 
survival, disease-free survival, and overall survival with the addition of pazopanib 
to preoperative chemoradiation or preoperative radiation in intermediate to high 
risk adult and pediatric NRSTS. 
 
1.2.2 
To compare the pattern of recurrence (local, regional and distant) between 
preoperative chemoradiation or radiation with the addition of pazopanib for adult 
and pediatric NRSTS. 
 
1.2.3 
To define the toxicities of ifosfamide and doxorubicin chemotherapy and radiation 
when used in combination with pazopanib in intermediate to high risk adult and 
pediatric NRSTS. 
 
1.2.4 
To define the toxicities of preoperative radiotherapy when used in combination 
with pazopanib in intermediate to high risk adult and pediatric NRSTS. 
 
1.3 
Exploratory Aims 
1.3.1 
To gain insight into the disease biology of childhood and adult NRSTS through 
analysis of actionable mutations and whole genome sequencing.   
 
1.3.2 
To determine if microvessel density and circulating tumor DNA predict response 
to pazopanib and outcome. 
 
1.3.3 
To determine the effect of pazopanib on doxorubicin exposure in children and 
adults with NRSTS. 

                
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1.3.4 
To evaluate change in FDG PET maximum standard uptake value (SUVmax) from 
baseline to Week 10 or 13 in patients with unresected tumors and to correlate this 
change with pathologic response and EFS. 
 
1.3.5 
To compare the rate of response by standard imaging and pathologic assessment 
to determine which correlates better with local tumor control, distant tumor 
control, EFS, and overall survival. 
 
 
2.0 
BACKGROUND 
2.1 
Pediatric NRSTS 
NRSTS comprise 4% of all childhood malignancies affecting at least 500 children under 
the age of 20 years in the United States each year.1 Few prospective studies of pediatric 
NRSTS have been conducted.2-4 Low-risk patients, which account for about 60% of the 
population, have an excellent long-term survival.5,6 However, high doses of radiotherapy 
are required for certain subsets of these patients, which may lead to significant long-term 
complications.7,8 Survival rates for patients with intermediate- and high-risk disease, which 
account for about 40% of the population, are approximately 50% and 15%, respectively.5,6 
The largest prospective study to date is the recent Children’s Oncology Group (COG) study 
ARST0332, whose primary aim is to define a risk-based treatment strategy for pediatric 
patients with NRSTS using a combination of surgery with or without chemotherapy and 
radiation therapy. At the conclusion of ARST0332 in February 2012, approximately 600 
patients enrolled over a 5-year period, which will be adequate to satisfy the primary aim of 
the study. The chemotherapy backbone of ifosfamide and doxorubicin (ID) used in 
ARST0332 is considered to be the most active and among the most commonly used 
regimens in NRSTS.9 Although this chemotherapy combination is considered “standard of 
care”, the radiographic response rate to chemotherapy is only 35-40% and outcomes remain 
poor for those with large, high-grade tumors and those with unresectable or metastatic 
disease.2,3 
 
Given the limited efficacy of chemotherapy for NRSTS and the poor outcomes of a 
significant fraction of the patient population, novel therapeutic approaches are needed. As 
knowledge of the tumor biology among the various soft tissue subtypes begins to expand, 
more biologically-driven, targeted therapy study designs are beginning to emerge.10,11 In 
children and young adults with NRSTS the extreme biological heterogeneity across each 
of the histologic subtypes and involvement of multiple signaling pathways in 
tumorigenesis suggests that using single targeted agents would be suboptimal. Further, the 
limited number of patients with each histologic subtype makes single-histology studies 
impractical in this age group. An alternative approach, particularly for this patient 
population, is to inhibit more than one oncogenic pathway with a multi-targeted agent. 
Ideally, the drug targets should be found within the majority, if not all, of the NRSTS 
subtypes and their disruption should counter the malignant phenotype. Moreover, because 
single drug approaches have not traditionally had a great impact on outcome, combining 
the novel agent with traditional cytotoxic chemotherapy may maximize the benefit. 
 
The therapeutic approach for intermediate- and high-risk pediatric patients builds on 
ARST0332 by adding a multitargeted tyrosine kinase inhibitor (TKI) to standard 
chemotherapy. This approach takes advantage of the ability of this drug to target multiple 
signaling pathways that may be disrupted in many NRSTS. This study will determine the 

                
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feasibility of adding a TKI to standard chemotherapy and radiotherapy, and will determine 
if it produces a higher rate of pathologic tumor response in patients with unresected 
chemotherapy-sensitive tumors compared to those receiving standard chemotherapy alone. 
Additionally, the study will assess the tumor response in pediatric patients with historically 
chemotherapy-resistant histologic subtypes given a TKI in combination with radiotherapy. 
 
2.2 
Adult NRSTS 
In adults, NRSTS comprise < 1% of adult malignancies affecting nearly 10,000 adults in 
the United States each year (median age of 50). While local control rate is excellent for 
intermediate-to-high grade STS of extremity or trunk, the risk for metastasis remains 
significant. Forty percent of patients die of either loco-regional recurrence or distant 
metastases. Efforts are needed to improve distant control. It has been shown in some studies 
that complete or near-complete pathologic response (necrosis rate of > 90%) is a significant 
prognostic factor in patients with STS treated with neoadjuvant radiotherapy or 
neoadjuvant chemoradiotherapy. The rate of near-complete pathologic response (> 90%) 
after neoadjuvant radiotherapy alone is reported to be ~ 5-10% and is associated with more 
favorable disease outcomes.12 Neoadjuvant chemoradiotherapy has been shown to 
significantly improve the pathologic response rate compared to historical controls of 
neoadjuvant radiotherapy alone. Similarly, the rate of significant pathologic necrosis after 
neoadjuvant chemoradiotherapy has been shown to predict distant control.13,14 In RTOG 
95-14, a Phase II study of doxorubicin and ifosfamide based neoadjuvant 
chemoradiotherapy for high risk truncal and extremity sarcomas, the rate of complete 
pathologic response was 27% and rate of > 75% necrosis was 37%.15,16 However, the 
chemoradiotherapy regimen was associated with significant toxicities, which continue to 
make adoption of this neoadjuvant chemoradiotherapy regimen challenging and 
controversial. Efforts to improve outcomes with dose intensification or other cytotoxic 
chemotherapy combinations in adult NRSTS have failed or have proven to be too toxic.17,18 
Preoperative radiotherapy is now a widely accepted standard for the treatment of localized 
NRSTS. The radiation treatment on this protocol builds on RTOG 0630, a Phase II trial 
evaluating preoperative image guided radiotherapy (IGRT) in STS, which recently 
completed accrual. Thus far, it appears that IGRT was feasible with centralized review of 
target volume definition with acceptable toxicities (June 2012 RTOG Semi-Annual 
Meeting). Results presented at ASTRO 2013 showed that IGRT with smaller margins 
resulted in reduced lymphedema, fibrosis, and joint stiffness for adult NRSTS.19 
Furthermore, a consensus atlas was built on appropriate CT-based GTV and CTV to 
improve target volume consistency for preoperative radiotherapy for extremity STS.20 
Therefore, preoperative radiotherapy with IGRT will serve as the backbone for 
radiotherapy used for all patients on this study. 
 
2.3 
Rationale for Inhibition of Angiogenesis in Soft Tissue Sarcomas 
Targeted therapy has particular appeal in the treatment of STS. STS require angiogenesis. 
VEGF expression is upregulated in STS and elevated pre-treatment VEGF levels have been 
correlated with worse histologic grade survival.21-23 Anti-VEGF therapy has been shown in 
preclinical models as well as clinical trials in other solid tumors to normalize permeable 
and tortuous tumor blood vessels leading to improved delivery of oxygen and potentially 
augmentation of the effects of radiotherapy.24 Various studies have demonstrated that the 
combination of anti-angiogenic agent and radiotherapy can improve tumor response to 
treatment.25-27 
 

                
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A pilot study conducted at Massachusetts General Hospital demonstrated that neoadjuvant 
bevacizumab enhanced pathologic response to radiotherapy to levels nearly comparable to 
neoadjuvant doxorubicin based chemoradiotherapy.28 Forty-five percent of patients treated 
ZLWKEHYDFL]XPDEKDGQHFURVLVKDG! 90% necrosis, and 15% had complete 
pathologic response. The regimen was well tolerated with < 20% Grade 3 toxicities. High 
microvessel density and gene array profile correlated with high pathological responders.28 
 
2.4 
Rationale for Tyrosine Kinase Inhibitors in Non-Rhabdomyosarcoma Soft Tissue 
Sarcomas 
Tyrosine kinases (TKs) are critical regulators of cellular growth, proliferation, and 
survival. TK dysregulation is felt to be a major contributor to tumorigenesis in a variety of 
cancer types.29 Certain TKs have been found to be expressed in a range of NRSTS subtypes. 
Among these, vascular endothelial growth factor receptor (VEGFR), platelet-derived 
growth factor receptor (PDGFR), c-Kit, and epidermal growth factor receptor (EGFR) have 
been the most prevalent and dysregulated across histologic subtypes.30-33 Tumor growth 
and metastatic spread are critically dependent on tumor angiogenesis. VEGF and PDGFR 
are two of the main receptor proteins involved in this process.31-34 Further, their elevated 
expression has correlated with higher malignancy grade and worse outcome.35,36 Preclinical 
research demonstrates that the effect of simultaneous inhibition of VEGF and PDGFR on 
tumor angiogenesis and growth is additive suggesting that concurrent targeting of multiple 
signaling pathways may be more effective than targeting either pathway alone.37,38 The 
multi-targeted TKI pazopanib (GW786034) is a potent inhibitor of VEGFR, PDGFR and 
c-Kit.39 While VEGFR and PDGFR are critical regulators of tumor angiogenesis, c-Kit is 
associated with tumor progression.40 
 
2.5 
Pazopanib in Adults with Soft Tissue Sarcomas 
Pazopanib has undergone Phase I and II studies in adults with advanced, refractory 
sarcomas.41,42 As a single agent, pazopanib demonstrated antitumor activity in patients with 
leiomyosarcoma, synovial sarcoma, chondrosarcoma, and “other” sarcomas. A Phase I trial 
of pazopanib in 63 patients with advanced cancers demonstrated partial responses in 3 
SDWLHQWVDQGVWDEOHGLVHDVHPRQWKVLQ14 patients.41 Three of the 6 sarcoma patients 
enrolled were among those with prolonged stable disease, including a patient with 
leiomyosarcoma and 2 patients with chondrosarcoma. Pazopanib was evaluated in a Phase 
II study in patients with refractory advanced soft tissue sarcoma using PFS at 12 weeks as 
the primary endpoint.42 One hundred and forty-two patients were enrolled and placed into 
4 different strata: adipocytic STS, leiomyosarcoma, synovial sarcoma, and “other” 
sarcoma. The adipocytic stratum was closed early due to inadequate predetermined 
statistical response (5 (26%) of 19). In the leiomyosarcoma, synovial sarcoma, and “other” 
sarcoma cohorts, PFS was 44% (18 of 41), 49% (18 of 37), and 39% (16 of 41), 
respectively. Four of the 5 patients with synovial sarcoma were still progression free at last 
follow-up (range, 415 to 812 days after treatment start). Compared to historical controls, 
PFS and overall survival (OS) were prolonged in the collective group of the 3 active strata 
in which the primary endpoint was reached. 
 
Van der Graaf et al. conducted a multi-center, international, double-blind, placebo-
controlled Phase III trial of pazopanib in patients with metastatic soft tissue sarcoma.43 
Three hundred and sixty-nine patients were randomized in a 2:1 fashion (246 pazopanib, 
123 placebo). The primary endpoint of PFS was significantly prolonged with pazopanib 
versus placebo (median: 20 weeks versus 7 weeks; P<0.0001). The interim analysis for 
overall survival demonstrated a non-significant improvement of pazopanib versus placebo 

                
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(median: 11.9 months versus 10.4 months). Based upon these results, the FDA approved 
pazopanib for advanced soft tissue sarcoma in April 2012. 
 
The maximum tolerated dose (MTD) for pazopanib is 800 mg once daily.41 Pazopanib was 
generally well-tolerated and produced toxicities that were easily manageable in doses at or 
below the MTD. Common toxicities for pazopanib have included myelosuppression, 
hepatic enzyme elevation, proteinuria, hypertension, fatigue, hypopigmentation, hand-foot 
syndrome, rash, anorexia, diarrhea and nausea.41-43 The majority of drug-related adverse 
events have been Grade 1 or 2 and reversible on treatment dose reduction or 
discontinuation. Much of the severe toxicity with TKI use has been observed within 
2 weeks of the start of treatment.44 Moreover, hypertension has typically occurred early in 
treatment (within the first 4 weeks) and only a few have developed it beyond this time 
period.42 
 
2.6 
Pazopanib use in Children 
A COG Phase I study of pazopanib in children with relapsed or refractory solid tumors 
(ADVL0815) was recently conducted.45 Twenty-five patients were eligible for the dose 
escalation phase and 23 of the patients were evaluable for DLT. Observed Cycle 1 DLTs 
included lipase elevation (n=1, 275 mg/m2), proteinuria and Grade 3 hypertension (n=1, 
450 mg/m2), amylase elevation (n=1, 600 mg/m2), and Grade 3 hypertension (n=1, 
600 mg/m2). Cycle 1 non-hematologic toxicities observed in > 10% of patients included 
Grade 2 hypertension (n=6), left ventricular dysfunction (n=1), fatigue (n=3), rash (n=2), 
hypothyroidism (n=1), diarrhea (n=1), nausea (n=1), vomiting (n=1) amylase (n=1), lipase 
(n=2), proteinuria (n=1), abdominal pain (n=2) and headache (n=5), and reversible Grade 
3 hypophosphatemia (n=1). DLTs observed in later courses of therapy included diarrhea 
(n=1, 275 mg/m2, course 2), neutropenia (n=1, 275 mg/m2, course 12), hand-foot syndrome 
(n=1, 350 mg/m2, course 3), ALT (n=1, 450 mg/m2, course 7 and 13), myalgia (n=1, 600 
mg/m2, course 2 and 3), and mucositis (n=1, 600 mg/m2, course 2). The time to achieve 
maximal concentration was constant across dose levels with a median of 4 hours. Steady 
state concentrations were achieved by Day 15. The MTD for pazopanib in tablet form was 
determined to be 450 mg/m2 on a once daily continuous dosing schedule. This is 
comparable to the adult dose of 800 mg daily. A suspension dose escalation cohort began 
once the MTD from the tablet form was determined. The starting dose was 50% of the 
MTD determined in part 1 (225 mg/m2) due to preliminary data in adults which suggested 
a nearly 2-fold increase in mean systemic exposure to pazopanib. Two of the first 4 patients 
experienced reversible Grade 3 ALT elevation. The dose was lowered to 160 mg/m2 with 
only one of 6 patients experiencing a DLT (cerebral hemorrhage) establishing 160 mg/m2 
as the recommended Phase II dose for the suspension. Five NRSTS patients were included 
on study (3 synovial sarcoma, 2 ASPS). Three patients demonstrated a minor response and 
SDWLHQWVUHFHLYHGF\FOHVLQFOXGLQJDV\QRYLDOVDUFRPDSDWLHQWZKRKDVUHFHLYHG
cycles to date (Julia Glade-Bender, personal communication). No pazopanib Phase II 
studies in children have been completed to date. 
 
Another multi-targeted TKI, sorafenib, has been studied in adults and children with 
sarcoma.44,46-48 While the mechanism of action and toxicity profiles for pazopanib and 
sorafenib are similar, important differences have been noted. The dermatologic adverse 
events (rash/desquamation, hand-foot syndrome) have been more pronounced and frequent 
with the use of sorafenib often leading to dose reductions and/or discontinuations.41,42,44,47,49 
Among the more prevalent NRSTS histologic subtypes in children, such as synovial 
sarcoma and undifferentiated sarcomas, pazopanib has demonstrated greater efficacy.42,43 

                
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2.7 
Combination of TKIs and Cytotoxic Chemotherapy in Soft Tissue Sarcomas 
Preclinical studies have demonstrated a potential synergistic interaction between multi-
targeted TKIs and conventional cytotoxic chemotherapy, suggesting that these drug 
combinations may overcome chemoresistance.50-55 Pazopanib, when used in combination 
with cytotoxic agents, has demonstrated similar preclinical findings.56,57 
 
The potential for a synergistic relationship has been tested clinically in a variety of different 
tumor types. The majority of these studies have involved the use of the sorafenib, 
particularly in combination with doxorubicin.58-66 Most of these are Phase I or II designed, 
for which efficacy conclusions cannot be reliably drawn. The one randomized study 
suggested a synergistic efficacy relationship between the agents without overlapping 
toxicities.58 However, this study has been criticized because the role of doxorubicin for 
hepatocellular cancer appears to be modest at best.67,68  
 
There is a substantial body of data on the addition of VEGFR2 TKIs to chemotherapy. For 
example, a number of VEGFR2 TKIs have been evaluated with chemotherapy regimens in 
patients with advanced non-small-cell lung cancer (NSCLC). Morgensztern and Herbst69 
summarize results from 6 randomized Phase II or III clinical evaluations that included 
approximately 5000 adults with NSCLC. The overall conclusion from these trials is that 
the addition of a VEGFR2 TKI to chemotherapy generally resulted in less than 1 month 
improvement in PFS and OS for patients with NSCLC. Negative results with chemotherapy 
given with TKIs are not restricted to NSCLC, and have also been reported for cediranib for 
colorectal cancer70,71, for vatalanib with colorectal cancer72,73, for sunitinib for colorectal 
cancer74, and for sunitinib for breast cancer75. One recent positive study was for cediranib 
for patients with advanced platinum-sensitive ovarian cancer in which patients receiving 
chemotherapy with concurrent and maintenance cediranib had significantly longer PFS and 
OS compared to patients receiving chemotherapy alone.76 In this study, the effect of 
cediranib in prolonging PFS may be related to its extended single agent use during 
maintenance therapy.   
 
The above referenced studies have not included patients with STS. Further, none have 
involved the use of pazopanib. A limited number of early phase combination studies with 
the use of pazopanib and cytotoxic chemotherapy have been conducted. An abstract by 
Hamberg et al. presented at the 2012 ASCO annual meeting77 reported on a Phase I 
pharmacokinetic study of pazopanib in combination with 2 schedules of ifosfamide 
(9 mg/m2/cycle, continuously or bolus for 3 days) in patients with advanced solid tumors. 
MTDs and toxicities differed based on the treatment schedule but observed toxicities were 
generally predictable. Pharmacokinetic analysis demonstrated no effect of pazopanib on 
ifosfamide exposure. Differences in agent dosing and administration timing preclude direct 
comparison and toxicity predictions as it relates to this study.  
 
Preliminary results from an open-label, safety pharmacokinetic, and pharmacodynamic 
dose escalation Phase Ib study of pazopanib in combination with epirubicin or doxorubicin 
in subjects with advanced solid tumors have been reported (http://download.gsk-
clinicalstudyregister.com/files/d8007df9-87bf-4df3-8832-ff75c1cbd173). Three different 
dose schedules of pazopanib in combination with epirubicin were initially studied. Safety 
and tolerability assessments were used to determine the optimal pazopanib dose schedule 
to combine with doxorubicin. Information regarding tumor types was not provided. The 
combination was overall well tolerated with the 3 most common adverse events 

                
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experienced by subjects including neutropenia, nausea and diarrhea. The one arm of the 
study in which patients received continuous pazopanib (given Days 1-21 of a 21 day cycle) 
in combination with epirubicin did not progress to the second part of the study secondary 
to DLTs exceeding the protocol-defined MTD for the optimum tolerated regimen. The 
majority of DLTs involved neutropenia. The recommended dose and schedule for 
pazopanib with doxorubicin was established at pazopanib 800 mg oral daily dosing on 
Days 1-8 with doxorubicin 60 mg/m2 infusion on Day 3 of a 21 day cycle based on a 
preliminary analysis of the safety data demonstrating fewer overall Grade 3 or 4 adverse 
events, fewer serious adverse events, and lower percentage of adverse events leading to 
treatment discontinuation and withdrawal from the study compared to the other arms. Since 
a continuous pazopanib dosing schedule is what has demonstrated efficacy in clinical 
studies for STS, the difficulty in extrapolating pazopanib and epirubicin combination 
toxicity outcomes onto that of pazopanib and doxorubicin, and the general manageability 
of neutropenia as an adverse event, we feel our proposed study design remains justified for 
this specific patient population.  
 
Due to the anticipated tolerable safety profile, single agent activity of pazopanib, and 
potential synergistic interaction between multi-targeted TKIs and conventional cytotoxic 
chemotherapy in NRSTS, we aim to add pazopanib to the “standard” ifosfamide and 
doxorubicin backbone in our study.  
 
2.7.1 
Rationale for Pazopanib Dose in Chemotherapy Cohort 
The first 10 patients enrolled onto the chemotherapy cohort received pazopanib at 
dose level 1 (Pediatric: 350 mg/m2; Adult: 600 mg) during the dose-finding phase 
of the study. Criteria to determine feasibility were analyzed as outlined in Section 
9.2. There were 2 protocol-defined dose-limiting toxicities: one patient experienced 
a Grade 3 ALT and one patient was removed from protocol therapy as a result of 
“intolerable toxicity”. Eight of 10 patients received greater than 75% of the 
prescribed full pazopanib dosing. Based on the review outcome, the dose-finding 
phase for the chemotherapy cohort completed and dose level 1 was the dose of 
pazopanib established for the efficacy phase for the chemotherapy cohort. 
 
2.7.2 
Rationale for Pazopanib Dose in Non-Chemotherapy Cohort 
The first 11 patients enrolled onto the non-chemotherapy cohort received pazopanib 
at dose level 1 (Pediatric: 350 mg/m2; Adult: 600 mg) during the dose-finding phase 
of the study. Criteria to determine feasibility were analyzed as outlined in Section 
9.2. There were no reported protocol-defined targeted toxicities. Grade 3 fatigue 
resulted in the pazopanib being held for 1 week. Otherwise, no additional reported 
Week 1-6 toxicities appeared directly attributable to pazopanib. No patients 
received less than the 75% of full dose pazopanib. Two patients never received 
protocol therapy and were not evaluable. Based on these findings and our 
parameters outlined in Section 9.2, we escalated to pazopanib dose level 2. 
 
The next 10 patients enrolled onto the non-chemotherapy cohort received pazopanib 
at dose level 2 (Pediatric: 450 mg/m2; Adult: 800 mg) during the dose-finding phase 
of the study. Once again, criteria to determine feasibility were analyzed as outlined 
in Section 9.2. There were 2 protocol-defined dose-limiting toxicities: one patient 
experienced a Grade 3 dermatitis radiation and one patient was removed from 
protocol therapy as a result of “intolerable toxicity”. Grade 3 diarrhea resulted in 
the pazopanib being held for 1 week. Otherwise, no additional reported Week 1-6 

                
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toxicities appeared directly attributable to pazopanib. Nine of 10 patients received 
greater than 75% of the prescribed full pazopanib dosing. Based on these findings, 
the dose-finding phase for the non-chemotherapy cohort completed and dose level 2 
was the dose of pazopanib established for the efficacy phase for the non-
chemotherapy cohort. 
 
2.8 
Combination of TKIs and Radiotherapy in Soft Tissue Sarcomas  
Data regarding concomitant radiotherapy with TKIs in adults with solid tumors are limited. 
Reports of multi-targeted TKI use in combination with radiation in patients with advanced 
hepatocellular carcinoma have demonstrated clinical and radiologic benefit with 
manageable toxicities.78,79 Similar findings have been reported in patients with renal cell 
carcinoma.80,81   
 
Conversely, reports of enhanced toxicities have been noted in renal cell and hepatocellular 
carcinoma patients receiving TKIs and have included radiation recall dermatitis and bowel 
perforation.82-84 A larger, Phase I study of sorafenib and palliative radiation in adult patients 
with malignancies of the thorax, abdomen, or pelvis was reported at the American Society 
of Clinical Oncology 2011 meeting.85 Thirty-four patients were enrolled on study and 
received sorafenib at dose levels of 200 mg once daily (level 1), 200 mg BID (level 2), and 
400 mg BID (level 3) while receiving radiation (30 Gy in 10 daily fractions) in Weeks 2 
and 3. Two of the 3 anatomic cohorts reached dose level 3. Significant sorafenib dose 
modifications occurred in 6 of 10 patients on dose level 3 due to sorafenib systemic 
toxicities. DLTs were noted in each cohort (thorax dose level 2 – Grade 3 esophagitis; 
abdominal dose level 3 – Grade 3 ALT elevation; pelvis dose level 1 – Grade 5 bowel 
perforation). No other high grade, radiation-related toxicities were noted. Grade 2 radiation 
dermatitis was observed in 7 of 8 patients who completed continuous sorafenib at 200 or 
400 mg BID and planned radiation. The trial was terminated early once systemic toxicity 
of sorafenib resulted in drug dose reductions and discontinuations at 400 mg BID 
preventing proper evaluation of radiation-related toxicity combined with this dose of 
sorafenib.   
 
2.9 
Response Assessment in NRSTS: Radiologic versus Pathologic 
It has not been well established whether a significant change in the size of the tumor mass, 
as determined by RECIST, is a meaningful surrogate of patient outcome in NRSTS. 
Previous randomized studies comparing chemotherapy regimens for soft tissue sarcoma have 
shown significant differences in radiologic response rates but no difference in outcome.86,87 
While some studies have described a significant correlation between tumor response and 
improved survival88,89 others have found no such correlation.90-92 Likewise, after 
neoadjuvant radiotherapy or chemoradiation, radiographic response is highly variable. In 
one series, 4 of the 6 patients defined as having progressive disease by standard imaging after 
QHRDGMXYDQWWKHUDS\KDGQHFURVLVIROORZLQJVXUJLFDOexcision.91 In another series of 
50 patients undergoing neoajduvant RT, radiographic decrease in tumor volume was 0.5% 
(range -85% to 285%, P=0.15).93 When pathologic response was plotted versus radiographic 
response, imaging progression did not predict poor pathological response (range 0-100%, 
p=0.8).This suggests that the tumor was sensitive to the cytotoxic effects of the therapy and 
the increase in tumor size did not accurately reflect the actual disease response. Given the 
heterogeneous composition of soft tissue sarcomas, in which viable tumor is often admixed 
with areas of pre-existing necrosis, hemorrhage, and fibrosis, tumor size may not accurately 
reflect chemotherapeutic effect, and ultimately, outcome.90,94,95 Recent studies involving 

                
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multi-targeted TKIs have demonstrated similar discrepancies in response interpretation by 
noting individuals with cystic changes on imaging not associated with a RECIST response.42,44   
 
Treatment-induced tissue necrosis following neoadjuvant therapy has been established as 
a reliable predictor of outcome in bone sarcomas.96,97 Similar attempts have been made to 
study this relationship in soft tissue sarcomas. Although more limited representation in the 
literature compared to standard imaging assessments, the association of pathologic response 
and prognosis in soft tissue sarcomas is well-founded. In the largest study evaluating this 
association, 496 patients with intermediate to high-grade extremity soft tissue sarcomas 
underwent surgical resection following protocol neoadjuvant chemoradiotherapy.98 The 5 and 
\HDUORFDOUHFXUUHQFHUDWHVIRUSDWLHQWVZLWKSDWKRORJLFQHFURVLVZHUHsignificantly 
lower (6% and 11%, respectively) compared to those patients with < 95% pathologic necrosis 
(17% and 23%, respectively, p=0.002). The 5- and 10-year survival rates were also 
VLJQLILFDQWO\KLJKHUIRUSDWLHQWVZLWKSDWKRORJLFQHFURVLVDQGUHVSHFWLYHO\
than those with < 95% pathologic necrosis (62% and 55%, respectively, p=0.0001). When 
analyzed in a multivariate manner, pathologic necrosis was an independent predictor of 
survival.   
 
Another study involving 34 patients with locally advanced soft tissue sarcomas of the 
extremity received neoadjuvant chemoradiotherapy followed by surgical resection.13 Fifty 
percent of tumors demonstraWHG SDWKRORJLF QHFURVLVThe 5-year freedom from 
distant metastasis was superior if treatment-LQGXFHGWXPRUQHFURVLVZDVYV
20%, p=0.02). Further understanding of the relationship between radiographc and 
pathologic response after neoadjuvant therapy and ultimate patient outcome is necessary. 
 
2.10 
ARST0332 Preliminary Data Regarding Pathologic Response in Pediatric NRSTS 
The pathologic response rates in advanced soft tissue sarcomas appear to be consistent 
across multiple studies.13,14,98,99 Only 40-50% of STS patients achieve a good response 
 90% necrosis) with preoperative chemotherapy. With permission from the COG DSMC, 
we analyzed the distribution of pathologic response by histology in Arm D patients (neo-
adjuvant chemoradiotherapy) on ARST0332. Those histologies demonstrating an overall 
JRRG SDWKRORJLFUHVSRQVH QHFURVLVDW Week 13 included synovial sarcoma, 
unclassified sarcoma, and embryonal sarcoma of the liver, which were among the most 
common histologies seen on ARST0332. Good pathologic response was seen in a smaller 
number of ‘other’ histologies, including fibrosarcoma, mesenchymal chondrosarcoma and 
angiosarcoma. Taken together, these favorable subtypes represent 80% of all Arm D 
patients enrolled on ARST0332 and the majority of these patients underwent resection at 
Week 13.   
 
A review of the literature lends further support to the pathologic response findings achieved 
within these specific histologies on ARST0332. Chemotherapy-sensitive NRSTS tumor 
types have predominantly included synovial sarcoma,87,100 angiosarcoma,101,102 
undifferentiated sarcoma,103 mesenchymal chondrosarcoma,104 and embryonal sarcoma of 
the liver.105 Some subtypes, such as leiomyosarcoma and liposarcoma, demonstrate modest 
response to single agent chemotherapy but mixed response and outcome when used in 
combination.100,106 
 
Data from ARST0332 demonstrated pathologic necrosis rates at Week 13 similar to 
literature-based estimates. The consistency of this finding among such a heterogeneous 
group of diseases, compared to standard imaging, further strengthens its selection as an 

                
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appropriate primary response surrogate for our study population. Since pathologic response 
is associated with outcome and only about 40% of pediatric chemotherapy-sensitive 
NRSTS patients achieve a good pathologic response with ID + RT (radiotherapy), this 
study’s primary end point will be to determine whether the addition of pazopanib to ID + 
RT increases the rate of pathologic response.  
 
2.11 
Chemotherapy-Resistant Pediatric NRSTS 
Although encompassing an extremely heterogeneous population of histologic subtypes, 
therapeutic trial designs in adults with NRSTS have historically been all inclusive and have 
delivered uniform chemotherapy to all patients. Counter to this approach, it has been 
demonstrated that chemotherapy sensitivity is oftentimes histology-dependent. Subtypes 
generally considered chemotherapy-resistant include alveolar soft part sarcoma,107 
epitheloid sarcoma,2,108,109 clear cell sarcoma,110,111 malignant fibrous histiocytoma,112 
hemangiopericytoma,113 solitary 
fibrous tumor,114 and 
extraskeletal myxoid 
chondrosarcoma.115,116 Chemotherapy responsiveness in malignant peripheral nerve sheath 
tumor is somewhat variable but largely has been reported as resistant.117 
 
An analysis of preliminary data from ARST0332 (with permission from the DSMC) was 
undertaken to examine the distribution of pathologic response by histology in Arm D 
patients historically considered chemotherapy-resistant. Reassuringly, the most 
represented histologies with < 90% pathologic response included malignant peripheral 
QHUYHVKHDWKWXPRURQO\RI03167SDWLHQWVKDGSDWKRORJLFUHVSRQVHDQG
alveRODUVRIWSDUWVDUFRPDQRQHKDGSDWKRORJLFUHVSRQVH6LPLODUSRRUHUUHVSRQVH
rates were seen in a few ‘other’ subtypes such as malignant fibrous histiocytoma. 
Collectively, these histologies represent nearly 20% of all Arm D patients and 
demonstrated a good pathologic response rate of only 15%. 
 
The anticipated outcomes of these intermediate- and high-risk patients with chemotherapy-
resistant tumors are poor. Those with intermediate-risk features have an approximately 
50% survival, and those with high-risk features have an approximately 15% survival. Thus, 
novel therapies are needed for these rare soft tissue sarcomas. The combination of 
supportive literature and analysis of data from ARST0332 provide justification for 
treatment of these patients with pazopanib in a single-arm study. Observing responses in 
patients on this non-randomized arm, even in exceedingly rare histologies, would generate 
important information for patients with these rare sarcomas. 
 
2.12 
RTOG 95-14 Data Regarding Pathologic Response in Adult NRSTS 
Based on data on histology specific response provided by RTOG statisticians from RTOG 
95-14 (neoadjuvant chemoradiation trial for high risk adult soft tissue sarcomas  8 cm and 
Grade 3), we identified histologies with more than 50% of cases showing significant 
pathologic response (which in that trial was defined as having 0% viable cells or only 0-
25% viable cells) as potentially chemotherapy-sensitive. These included fibrosarcoma 
(60% of cases had 0% viable cells or 0-25% viable cells), pleomorphic sarcoma (72%), 
leiomyosarcoma (80%), liposarcoma (100%), and undifferentiated/NOS (100%). 
Conversely, those histologies in RTOG 95-14 showing poor response included MPNST 
(0% of cases had 0% viable cells or 0-25% viable cells), epithelioid sarcoma (0%), and 
myxofibrosarcoma (33%). 
 

                
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2.13 
Rationale for Chemotherapy and Non-Chemotherapy Cohorts 
The objectives of this trial are to determine the additional benefit (rate of near total 
pathological necrosis for the Phase II endpoint, and event free survival for the Phase III 
endpoint) of adding pazopanib to 2 currently accepted approaches to treating intermediate 
to high risk sarcomas in clinical practice: (1) preoperative chemoradiation and 
(2) preoperative radiation alone.    
 
The 2 treatment arms have been named “Chemotherapy” and “Non-Chemotherapy” 
cohorts instead of “Chemosensitive” and “Chemoresistant” cohorts, recognizing that 
histological subtype and chemosensitivity are 2 important factors but insufficient to 
determine whether a subject should be receiving chemotherapy as the backbone of the 
preoperative therapy for the unresected sarcoma. Currently, tumor size and tumor grade 
are routinely used to assess a patient’s risk of distant metastasis to determine whether 
chemotherapy should be considered. However, because chemotherapy is very toxic and its 
survival benefits marginal in most NRSTS, the role of chemotherapy is less clear. Because 
the benefits of chemotherapy are limited and the potential toxicity high, it is considered 
within the standard of care for patients to choose whether or not to receive chemotherapy. 
It is also routine for clinicians to avoid chemotherapy in older patients and those with 
comorbidities that would make chemotherapy more risky, given the marginal benefits that 
chemotherapy provides. 
 
Neoadjuvant ifosfamide/doxorubicin-based chemotherapy combined with preoperative 
radiotherapy has been utilized to treat certain “chemosensitive” types of adult NRSTS with 
large size (> 5 cm) and high-to-intermediate grade in some institutions. However, 
randomized comparison of preoperative chemoradiation versus preoperative radiation 
alone is not available. It is also important to note that neoadjuvant chemotherapy alone 
failed to show survival benefits for large (>8 cm) high-to-intermediate grade NRSTS in 
adult patients (EORTC STBSG 62871 Phase IIR study).118 Furthermore, the high toxicity 
of chemotherapy in adults (RTOG 95-14) makes it difficult to recommend preoperative 
chemoradiation in all adult NRSTS, even for the chemosensitive histologies.   
 
For the remaining patients, including patients with chemoresistant histologies, 
chemosensitive histologies but of smaller size (< 5 cm) and low grade, and even high risk 
patients unwilling or unable to receive chemotherapy, preoperative radiation before 
resecting the primary sarcoma is a widely accepted standard. Based on the accrual pattern 
to RTOG 0630 which contained both a Chemotherapy and a Non-Chemotherapy Cohort, 
more adult NRSTS are treated with preoperative radiation than preoperative 
chemoradiation. 
 
Based on the literature and data obtained from the recent COG and RTOG studies 
(ASRT0332 and RTOG 94-15), we have identified 3 histologies that have most 
consistently and significantly demonstrated sensitivity to chemotherapy. These include: 
unclassified (including undifferentiated and NOS) soft tissue sarcomas in patients 
< 30 years of age, synovial sarcoma, and embryonal sarcoma of the liver. As such, patients 
with these histologies meeting the grade and size criteria (Grade 2 or 3, > 5 cm) associated 
with high risk of metastatic disease, may ONLY enroll on the Chemotherapy Cohort (see 
Section 3.2.2.1). For all the other histologies with some evidence of chemosensitivity, we 
feel that allowing for enrollment on either cohort reflects the current pattern of care. 
Allowing these patients on the Non-Chemotherapy Cohort can still help answer the 

                
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question of whether pazopanib improves near total pathologic necrosis rate and event free 
survival over preoperative radiation alone.  
 
Lastly, allowing “chemosensitive histologies” in the Non-Chemotherapy cohort will not 
dilute the primary objective of this study. Patients with “chemosensitive histologies” will 
be randomized to both treatment arms in each cohort. Therefore, sensitivity to 
chemotherapy should not influence the study outcomes. In addition, whether 
chemosensitive or chemoresistant, preoperative radiation alone results in a low rate of near 
total pathologic necrosis across all NRSTS histologies of only 8-10%. Radiation sensitivity 
and chemotherapy sensitivity is not the same. Pazopanib sensitivity and chemotherapy is 
also not the same. Therefore, we will receive important information about pathologic 
necrosis and patterns of failure of preoperative radiotherapy +/- neoadjuvant pazopanib in 
patients with both chemo-sensitive histologies and chemo-resistant histologies who do not 
receive neoadjuvant chemotherapy.  
 
We believe that this study design best reflects the accepted standards for NRSTS treatment 
in both adult and pediatrics: a risk adapted approach that takes into account tumor size, 
grade, patient age, chemosensitivity, and ability to tolerate chemotherapy. For the patients 
with highest risk for metastatic disease from chemotherapy sensitive NRSTS histologies 
who are able to tolerate and accept chemotherapy, the study seeks to answer the question, 
what does pazopanib add to preoperative chemoradiation. For other patients, the study will 
answer the question, what benefits does pazopanib add to preoperative radiation. Both will 
advance our current approaches to NRSTS. This design will also maximize accrual since 
many practitioners feel strongly about the decision to offer or not offer chemotherapy to 
patients with NRSTS. 
 
2.13.1 Rationale for the FNCLCC Grading System and Inclusion of FNCLCC Grade 2 or 
3 Tumors in the Chemotherapy Cohort 
On the predecessor study, ARST0332, one of the secondary study aims included a 
comparison of the Pediatric Oncology Group (POG) and Fédération Nationale des 
Centres de Lutte Contre le Cancer (FNCLCC) pathologic grading systems to 
determine which better correlates with clinical outcomes. While awaiting the 
results of this analysis, we chose the FNCLCC grading system for our study largely 
due its more generalizable acceptance and familiarity among adult sarcoma 
providers. However, a retrospective study from Khoury et al. found that while that 
both systems provided adequate prognostic measures of outcome, a fairly 
significant subset of cases were graded differently by the two systems in patients 
with NRSTS.119 This discrepancy appeared to have largely resulted from the value 
assigned to the mitotic index. Further, the mitotic index demonstrated a highly 
significant correlation with EFS as a prognostic factor when assessed using 
univariate analysis (p<0.001). While both grading systems incorporate the mitotic 
index, each utilizes different cutoff points. The POG system has a lower cutoff 
compared to the FNCLCC system which resulted in upward assignment of 
FNCLCC Grade 2 cases to POG Grade 3 in this retrospective study. None of the 
FNCLCC Grade 3 tumors received lower grades with the POG system. 
Conversely, 44 POG Grade 3 tumors met criteria for FNCLCC Grade 1 (n=3) or 
2 (n=41). The study found the 44 patients whose tumors were graded discrepantly 
(FNCLCC Grade 1 or 2 and POG Grade 3, 48% EFS) had a prognosis that was 
intermediate between those whose tumors were graded in concordance (FNCLCC 
Grade 1 or 2 and POG Grade 1 or 2, 68% EFS; FNCLCC Grade 3 and POG Grade 

                
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3, 26% EFS; p=0018). Moreover, a mitotic count using a cutoff of 10 mitotic 
figures per 10 high power fields was found to be a significant EFS outcome 
discriminator in this subset of patients (p=0.0055). A mitotic count of 
 10 contributes a mitotic count score of 2 to the cumulative grade score in the 
FNCLCC system and a mitotiFFRXQWRILVGHVLJQDWHGD*rade 3 in the POG 
system. 
 
Other recent, large adult studies using chemotherapy in high-risk soft tissue 
sarcomas (STS) have defined FNCLCC Grade 2 or 3 as high-grade.120-123 Based 
upon historical pediatric data and inclusion parameters on more recent, large adult 
high-risk STS studies, patients with FNCLCC Grade 2 OR 3 tumors are eligible 
for the chemotherapy cohort assuming size and histologic criteria are met. 
 
2.14 
Pazopanib and Radiotherapy 
While preclinical data on pazopanib and radiotherapy specifically in NRSTS is not 
available, there is pre-clinical data showing synergistic effect with the combination of 
pazopanib and radiation in a number of in vivo tumor models.124 In addition, other TKIs 
have been safely combined with RT with beneficial effects in patients with advanced 
hepatocellular carcinoma and renal cell carcinoma.125,126 
 
Currently, NRG Oncology has an active study (RTOG 0912) of combined IMRT, 
paclitaxel, and pazopanib in the treatment of anaplastic thyroid cancer, with no major 
adverse events reported thus far. We will continue to assess the safety and tolerability 
profile of pazopanib given in combination with preoperative radiation in the proposed 
study. Furthermore, there also is emerging data that the combination of pazopanib and 
radiation is 
safe in 
the Phase I 
portion of an ongoing investigator-
initiated/GlaxoSmithKline-supported Phase 1/2I trial using pazopanib and radiation 
therapy in sarcomas by Hass and colleagues, the Netherlands Cancer Institute– Antoni van 
Leeuwenhoek Hospital (personal communications, July 2012).   
 
2.15 
Rationale for Concurrent Sequencing of Pazopanib and Preoperative Radiotherapy 
in the Non-Chemotherapy Cohort 
Based on the experience with the MGH bevacizumab and radiotherapy pilot study, this 
proposed trial is designed without a lead-in period of pazopanib alone prior to radiation 
therapy. The use of VEGF-inhibitors has been shown to potentially increase the metastatic 
potential of malignancies in other sites (colon and preclinical) if the tumor is not responsive 
to the agent. The effect of VEGF inhibition on intra-tumoral hypoxia and HIF-ĮDFWLYLW\
may vary between different tumors. Tumor blood vessels are immature, dilated, tortuous, 
and highly permeable with erratic flow127,128 and many of these abnormalities can be 
attributed to the overexpression of VEGF-A.129 These characteristics lead to areas of 
hypoxia in tumors. Administration of anti-VEGF agents can result in reduced vessel 
irregularity, diameter, and permeability, and transiently improve the delivery of oxygen.24 
However, sustained anti-VEGF therapy can ultimately lead to loss of tumor vessels and 
increased hypoxia.130 Recently, there has been significant controversy regarding the effects 
of VEGF inhibition on primary tumor invasiveness and metastatic potential.131 Casanovas 
and colleagues132 found that VEGF receptor 2 (VEGFR-2) inhibition of RIP1-Tag2 mouse 
pancreatic endocrine tumors led to increased intra-tumoral hypoxia along with increased 
tumor invasiveness and liver metastases.133 Similarly, Ebos et al.134 found that sunitinib 
(which targets VEGF and other pathways) increased liver and lung metastases for both 
experimental and spontaneous metastases. The effects of VEGF inhibition in primary 

                
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sarcomas on hypoxia, HIF-Į DFWLYLW\ DQG +,)-related phenotypes such as tumor 
progression, metastasis, and radiation response are currently unknown. Cooke et al.135 
found that PDGF inhibition in mouse models of primary breast cancer lead to loss of 
pericytes, increased hypoxia, and increased metastasis.  
 
It is important to note that the vast majority of cancer patients treated with VEGF and 
PDGF inhibitors prior to this proposal have established metastatic disease and relatively 
few studies have examined the use of these inhibitors in patients with primary tumors and 
no clinically evident metastases. For anti-angiogenic agents to be more broadly used in the 
neoadjuvant setting with radiation or chemoradiation, it is vital to determine under what 
circumstances these inhibitors may increase the invasiveness and metastatic potential of 
primary tumors. Clinical concern for increased invasiveness or metastasis following anti-
VEGF-A therapy has focused on glioblastoma, where the phenomenon of increased 
invasiveness following anti-angiogenic therapy is commonly observed.136 Since we do not 
know the responsiveness of soft tissue sarcomas, we do not feel it prudent to treat with 
single agent pazopanib at this time, and that is the rationale for starting pazopanib 
concurrently with radiation in the proposed study. 
 
2.16 
Wound Complications 
The care of soft tissue sarcomas is complex and multidisciplinary in nature. Even without 
radiation or chemotherapy wound complications are common after surgical resection of 
soft tissue sarcomas with a reported incidence of 6-42%.137 The known 30% incidence of 
wound complications with the approach of pre-operative radiation ± chemotherapy 
followed by surgical resection has been well documented and accepted in the 
literature.91,137-142 More relevant to this study, Yoon et al conducted a trial evaluating the 
neoadjuvant use of a VEGF receptor inhibitor (bevacizumab) in combination with radiation 
followed by resection in patients with soft tissue sarcomas. Major post-operative wound 
complications occurred in 25% of patients.28 Our current rate of major wound 
complications (14%), even with a small sample size, is within what would be expected 
based upon the above detailed literature review. 
 
The study design of ARST1321 provides us a unique ability to gain a clearer understanding 
of how pazopanib, and other tyrosine kinase inhibitors, may impact wound complication 
rates in this clinical setting. Since pazopanib will be the only variable on both the 
chemotherapy and non-chemotherapy arms, direct toxicity comparisons can be made 
within each treatment cohort in the randomized portion of the study. In addition to detailed 
protocol therapy management of wound complications within the dose modification 
section and the real time review of reported wound complication adverse events, expanded 
wound complication data collection is planned on the study reporting period and surgery 
central review case report forms (wound complication grading adapted from Dindo et al. 
2004 and characterization of the wound complication adapted from O’Sullivan et al. 
2013)143,144 as well as the required submission of any wound-related institutional procedure 
or operative reports. 
 
2.17 
FDG PET in NRSTS 
Tumor response to neoadjuvant therapy in NRSTS has been historically based upon 
standard anatomical imaging and histopathologic review. More recently, FDG PET has 
emerged as a surrogate predictor of early response in soft tissue sarcomas.145,146 
Additionally, there is a suggestion of improved accuracy in assessing pathologic response 
to neoadjuvant therapy using FDG PET compared to standard sized-base criteria in NRSTS 

                
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patients.147 Based on studies demonstrating a positive correlation between histopathologic 
response to neoadjuvant chemotherapy and outcome in soft tissue sarcoma patients,13,98 
incorporation of FDG PET into early treatment decisions could be beneficial. Studies 
evaluating FDG PET in children and adults with NRSTS is limited. To determine its 
predictive significance in these patients and its potential role in therapy-related decisions, 
as an exploratory aim of the study, we will attempt to correlate Week 10 or 13 response 
assessed by FDG PET maximum standard uptake value (SUVmax) with pathologic 
response and EFS. 
 
2.18 
Correlative Biology Studies 
2.18.1 Analysis of Actionable Mutations and Whole Genome Sequencing in NRSTS 
Given the rarity of the various subtypes of NRSTS, it is highly unlikely that 
development of drugs targeted to these particular tumors will be feasible. Thus, 
improvements in outcome depend on the optimal use of drugs developed for other 
diseases. It has already been shown that drugs developed for other indications may 
target signaling pathways important in specific subtypes of NRSTS. The best 
example of this is imatinib, which was developed for chronic myeloid leukemia 
but is effective in gastrointestinal stromal tumors (GIST) and dermatofibrosarcoma 
protuberans because of targeting of shared pathways. In an effort to better 
understand the biologic abnormalities in NRSTS that may be targeted by existing 
drugs, one of the exploratory aims of this clinical trial will be to identify actionable 
mutations in children, adolescents, and adults with NRSTS.   
 
Genetic abnormalities (eg, single nucleotide polymorphisms (SNPs), single 
nucleotide variants (SNVs), and small deletions/insertions) that can be targeted, 
often referred to as “actionable” mutations, are being identified in a growing 
number of adult cancers including NRSTS.148-150 MacConaill et al found actionable 
mutations in up to ~75% of carcinoma cases, depending on the specific cancer.148 
Another study revealed actionable mutations in RAS and KIT using MassARRAY 
in adult sarcomas.150 Additional smaller mutational analysis reports among 
individual NRSTS subtypes demonstrate that actionable mutations have been 
identified.32,151-153 
 
We expect the experiments proposed in this component of the exploratory aim to 
reveal the proportion of NRSTS cases with the tested potentially actionable 
mutations. Further, we will define the frequency with which individual genes are 
mutated and whether individual mutations are found across multiple histological 
subtypes. Finding that some mutations are independent of NRSTS histology will 
support the notion that functional classification of NRSTS based on molecular 
defects may more accurately guide the use of personalized anti-cancer therapy. 
 
Comprehensive genomics studies to identify mutations, structural abnormalities 
and copy number variation across the genome will provide insight into NRSTS 
disease biology that can be leveraged to achieve better risk stratification and more 
rational therapeutic approaches. To accomplish this task and as a final component 
to this exploratory aim, we plan to conduct whole genome sequencing in children 
and adults with NRSTS.   
 

                
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2.18.2 Microvessel Density and Circulating Tumor DNA as Predictors of Tumor 
Response and Outcome 
Numerous correlative science studies were performed as part of the MGH Phase II 
clinical trial of neoadjuvant bevacizumab and radiation therapy for resectable 
sarcomas.28 Twenty patients with intermediate-or high-grade sarcomas, > 5 cm in 
size, received bevacizumab for 2 weeks followed by 6 weeks of bevacizumab and 
radiation therapy (50 Gy). Tumor tissue samples were obtained before treatment 
and 10 days after the start of bevacizumab. Bevacizumab and radiation resulted in 
>80% pathologic necrosis in 9 of 20 tumors (45%), which is over double the 
historical rate with radiation alone. High initial microvessel density (MVD) 
(tau=0.53, p=0.0031) and decrease in MVD after bevacizumab alone (tau=0.43, 
p=0.0154) significantly correlated with  80% histologic necrosis. This suggests 
tumors with bevacizumab-responsive vasculature were more likely to have a good 
response to combination therapy with bevacizumab plus radiation.  
 
The bevacizumab and preop RT pilot study also included extensive analysis of 
(1) circulating factors and cells in blood, (2) gene and protein expression in tumors, 
and (3) tumor vasculature using perfusion CT scans to identify biomarkers for 
response to therapy. They found that gene expression signatures and tumor 
microvessel density were the most reliable biomarkers of treatment response. They 
also found that high expression of HIF-ĮDQGGRZQVWUHDPWDUJHWVRI+,)-Į
predicted a poor response to therapy. One goal of the correlative studies in the 
current proposal is to confirm that initial microvessel density is a biomarker of 
response to treatment.  
 
Another goal of the correlative science studies is to identify a circulating biomarker 
that may serve as a biomarker for response. In RTOG’s previous study, they 
analyzed 9 circulating angiogenic and growth factors and 3 types of circulating 
cells during the course of therapy, and a few correlations were made to treatment 
response. None of these correlations were reliable enough to base clinical decisions 
upon. In search of a more reliable circulating biomarker, we will attempt in this 
study to replicate the “personalized analysis of rearranged ends (PARE)" strategy 
proposed by Leary et al. at Johns Hopkins Medical Institutions (JHMI).154 In this 
strategy, first a patient’s tumor and normal tissue are whole genome sequenced to 
identify chromosomal translocations. Second, PCR primers are designed and 
tested that span the breakpoint. Third, circulating DNA is isolated from patient 
plasma, and sensitive quantitative PCR techniques (eg, digital PCR or BEAMing) 
are used to determine the amount of circulating tumor DNA. In one JHMI study, 
4 colon cancer and 2 breast cancers were tested and found to have between 7 and 
21 chromosomal rearrangements, and levels of circulating tumor DNA allowed 
investigators to monitor response to therapy.154 In a larger JHMI study of 
18 colorectal cancer patients, circulating tumor DNA was detected in all patients 
prior to surgical resection of the tumor.155 Following 20 surgical resections, 
circulating tumor DNA was detected in 16 of 20 patients. Recurrence occurred in 
15 of the 16 patients with persistent circulating tumor DNA and 0 of 4 patients 
without persistent circulating DNA.   
 
The application of the PARE strategy to STS is intuitively reasonable given about 
one-third of STS subtypes (synovial sarcoma, myxoid/round cell liposarcoma, 
clear cell sarcoma, extraskeletal myxoid chondrosarcoma) have known 

                
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chromosomal translocations that occur at high frequency. For example, over 90% 
of synovial sarcomas have translocation t(X;18)(p11.2;q11,.2) which fuses the 
SYT gene to either the SSX1 or SSX1 gene and over 75% of myxoid-round cell 
liposarcomas have translocation t(12;16)(q13;p111) which fuses the TLS(FUS) 
gene to the CHOP gene.156 The first step of the JHMI strategy (eg, whole genome 
sequencing) is currently quite costly, and thus the PARE strategy will be attempted 
in patients in our study who have a STS subtype with a high frequency of known 
translocations such as synovial sarcoma. Translocations will be identified using 
published PCR primers, and the PARE strategy will only be applied to patients 
whose tumors have an identified translocation.  
 
As a preliminary proof of principal experiment in a single myxoid liposarcoma 
patient with a t(12;16)(q13;p111) translocation, DNA was isolated from the tumor 
as well as the mononuclear cells contained in the buffy coat of the patient. The 
presence of the t(12;16)(q13;p111) translocation was found in tumor DNA but not 
in mononuclear cell DNA by PCR.155 When plasma samples obtained from the 
patient before and during treatment were examined for ctDNA, we were able to 
identify ctDNA, and levels of ctDNA decreased with therapy.  
 
2.18.3 Doxorubicin Pharmacokinetics in Combination with Pazopanib  
TKIs are known to modulate cellular ATP binding cassette (ABC) membrane 
transporters which can affect the efflux and intracellular accumulation of 
anticancer agents.157,158 The newer, multi-targeted TKIs appear to inhibit the 
activity of ABC transporters, increasing the bioavailability of co-administered 
drugs and potentially reversing multi-drug resistance.159,160 Doxorubicin is a 
known substrate for drug efflux pumps (ABC transporters);161 thus, its exposure 
may be altered by the concomitant use of pazopanib. In addition, pazopanib is a 
potent inhibitor of the liver uptake transporter organic anion-transporting 
polypeptide 1B1 (OATP1B1),162 and this may represent another pathway for a 
potential drug interaction with doxorubicin.163 We aim to collect doxorubicin 
pharmacokinetic data in hopes of gaining an enhanced understanding of the 
relationship among this novel drug combination. It is anticipated the results will 
continue to facilitate our ability to design future effective and safe drug 
combination therapies for children and adults with NRSTS. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
3.1 
Study Enrollment 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 

                
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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 to each patient as part of the 
registration process. Each patient will be assigned only one BPC number per COG 
Patient ID. For additional information about the labeling of specimens please refer to 
the Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix I for detailed CTEP Registration Procedures for Investigators 
and Associates, and CTSU Registration Procedures including: how to download site 
registration documents; requirement s for site registration, submission of regulatory 
documents and how to check your site’s registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll patients. 
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
x 
An active Federal Wide Assurance (FWA) number 
x 
An active roster affiliation with the Lead Network or a participating 
organization 
x 
A valid IRB approval 
x 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
x 
Active registration status 
x 
The IRB number of the site IRB of record listed on their Form FDA 1572 
x 
An active status on a participating roster at the registering site. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix I. 
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally. The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 

                
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Office. In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. Other site registration 
requirements (e.g., 
laboratory certifications, protocol-specific training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Reservation Requirements 
Patient enrollment for this study will be facilitated using the Slot-Reservation 
System in conjunction with the Registration system in the Oncology Patient 
Enrollment Network (OPEN). Prior to discussing protocol entry with the patient, 
site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot 
on the protocol is available for the patient. Once a slot-reservation confirmation is 
obtained, site staff may then proceed to enroll the patient to this study.  
 
If the study is active, a reservation can be made by following the steps below: 
 
1) Log in to https://open.ctsu.org/open/ using your CTEP IAM user name and 
password.  
2) In order to make a reservation, the patient must have an OPEN patient number. 
Click on the ‘Slot Reservation’ tab to create an OPEN patient number, under 
‘Patients’. 
3) Using the OPEN patient number ‘RESERVE’ a slot for that patient.  
4) On the ‘Create Slot Reservation’ page, select the Protocol Number, enter the 
COG Patient ID, and choose the required stratum (if applicable) in order to 
obtain a reservation. 
 
Refer to the ‘SITE – Slot Reservation Quick Reference’ guide posted under 
the ‘Help’ tab in OPEN for detailed instructions:  
https://www.ctsu.org/readfile.aspx?fname=OPEN/OPEN_SlotReservation_Q
uickReference_SiteUserGuide_102612.pdf&ftype=PDF  
 
Prior to obtaining informed consent and enrolling a patient, a reservation must be 
made following the steps above. Reservations may be obtained 24 hours a day 
through the OPEN system.  
 
3.1.4 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 
protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type. If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 

                
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crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
x 
All eligibility criteria have been met within the protocol stated timeframes.  
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. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.5 
Timing 
Patients must be enrolled before protocol therapy begins. The date protocol therapy 
is projected to start must be no later than fourteen (14) calendar days after the date 
of study enrollment. Patients who start protocol therapy prior to study 
enrollment will be ineligible.  
 
All clinical and laboratory studies to determine eligibility must be performed 
within 7 days prior to enrollment unless otherwise indicated in the eligibility 
section below. 
 
3.1.6 
Note for Baseline Imaging 
x 
Primary Tumor 
o 
If a subtotal resection of the primary tumor was performed prior 
to enrollment, the baseline study should be done after this 
operation.   
 
Note: Eligibility for this study depends on the pre-subtotal resection tumor size 
(see Section 3.2.2.1 and Section 3.2.2.2 for eligibility size criteria). 
 
x 
Lymph Node Bed  
o 
It is required that the baseline imaging also include imaging of the 
regional lymph node bed for clear cell sarcoma and epithelioid 
sarcoma only. If a subtotal resection of the lymph node bed was 
done, the baseline study (CT or MRI) should be done after this 
operation (unless proven to be biopsy negative). 
 
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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3.2 
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. 
The investigator is responsible for ensuring that all eligibility criteria are met. 
 
All clinical and laboratory studies to determine eligibility must be performed within 
7 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than seven (7) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within seven (7) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 7 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside 
the limits of eligibility, the patient may not receive protocol therapy and will be 
considered off protocol therapy. Imaging studies, including those used to determine 
eligibility, must be obtained within 4 weeks prior to enrollment (repeat imaging if 
necessary). Cardiac and pulmonary function studies, including those used to 
determine eligibility, must be obtained within 3 weeks prior to enrollment. 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
3.2.1 
Age 
Patients must be  2 years at the time of the biopsy that established the diagnosis of 
NRSTS will be eligible. 
Note: Eligible patients must have a Body Surface Area  0.5 m2 AND be able to 
swallow whole tablets (see Section 3.2.9.17 and Section 3.2.9.18). 
 
3.2.2 
Diagnosis  
Newly diagnosed and histopathologically confirmed, potentially resectable 
NRSTS of the extremity and trunk will be eligible for the chemotherapy or non-
chemotherapy cohort based on: 
x 
Evidence of chemotherapy sensitivity of the histologic sarcoma subtype 
based on existing evidence from prior clinical trials  
x 
Sufficient risk of metastatic disease to warrant chemotherapy based on size 
and grade and  
x 
Medically deemed able or unable to undergo chemotherapy. 
 
Notes: 
An incisional biopsy or core biopsy is preferred. Fine needle aspiration biopsy is 
not acceptable to establish the diagnosis. 
 
ELIGIBLE SITES: Please refer to Appendix II.   
o Extremities: upper (including shoulder) and lower (including hip) 
o Trunk: body wall 

                
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INELIGIBLE SITES: Head and neck, visceral organs (with the exception of 
embryonal sarcoma of the liver), retroperitoneum, peritoneum, pelvis within the 
confines of the bony pelvis.   
 
3.2.2.1 Eligibility for chemotherapy cohort: 
x 
Stage T2a/b (> 5 cm) and Grade 2 or 3 (see Appendix III)  
AND 
x 
One of the following chemosensitive histologies as defined in the 
WHO Classification of Soft Tissue Tumours (with some evidence of 
good response to chemoradiation and of sufficient high risk of 
metastases, or clear evidence of metastases) (Appendix IV): 
o Unclassified soft tissue sarcomas that are too undifferentiated to 
be placed in a specific pathologic category in the WHO 
classification (often called “undifferentiated soft tissue sarcoma” 
or “soft tissue sarcoma NOS”)  
o Synovial sarcoma 
o Angiosarcoma of soft tissue 
o Adult fibrosarcoma 
o Mesenchymal (extraskeletal) chondrosarcoma 
o Leiomyosarcoma 
o Liposarcoma (excluding myxoid liposarcoma) 
o Undifferentiated pleomorphic sarcoma  
o Embryonal sarcoma of the liver 
 
3.2.2.1.1 Patients meeting the above criteria (histology, size, and grade) 
with the EXCEPTION of histologies noted in 3.2.2.1.2 may 
enroll on the chemotherapy cohort or the non-chemotherapy 
cohort at the discretion of the enrolling investigator. Patients 
meeting these criteria with the EXCEPTION of histologies 
noted in 3.2.2.1.2 but medically deemed unable to receive 
chemotherapy or who elect not to receive chemotherapy are 
eligible for the non-chemotherapy cohort. 
 
3.2.2.1.2 Patients with the following histologies are only eligible for the 
chemotherapy cohort and cannot enroll on the non-
chemotherapy cohort: 
o Unclassified soft tissue sarcomas that are too 
undifferentiated to be placed in a specific pathologic 
category in the WHO classification (often called 
“undifferentiated soft tissue sarcoma” or “soft tissue 
sarcoma NOS”) in patients < 30 years of age  
o Synovial sarcoma 
o Embryonal sarcoma of the liver 
 
3.2.2.2 Eligibility for non-chemotherapy cohort: 
Note: The Non-Chemotherapy Cohort is closed to further accrual, 
effective October 12, 2017. 
x 
Patients with any size of Grade 2 or 3 of the following “Intermediate 
(rarely metastasizing)” or “malignant” tumors, as defined in the WHO 
Classification of Soft Tissue Tumours (see Appendices II and III) for 

                
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which we have consensus data of chemotherapy-resistance are eligible 
only for the non-chemotherapy cohort: 
o So-called fibrohistiocytic tumors – plexiform fibrohistiocytic 
tumor, giant cell tumor of soft tissues 
o Fibroblastic/myofibroblastic tumors – solitary fibrous tumor, 
malignant solitary fibrous tumor, inflammatory myofibroblastic 
tumor, low grade myofibroblastic sarcoma, myxoinflammatory 
fibroblastic sarcoma, atypical myxoinflammatory fibroblastic 
tumor, myxofibrosarcoma, low grade fibromyxoid sarcoma, 
sclerosing epithelioid fibrosarcoma  
o Tumors of uncertain differentiation – epithelioid sarcoma, 
alveolar soft part sarcoma, clear cell sarcoma of soft tissue, 
angiomatoid fibrous histiocytoma, ossifying fibromyxoid tumour, 
myoepithelioma, myoepithelial carcinoma, extraskeletal myxoid 
chondrosarcoma, neoplasms with perivascular epithelioid cell 
differentiation 
(PEComa), 
intimal 
sarcoma, 
atypical 
fibroxanthoma, mixed tumor NOS, phosphaturic mesenchymal 
tumor, malignant ossifying fibromyxoid tumor, malignant mixed 
tumor, malignant phosphaturic mesenchymal tumor 
o Chondro-osseous tumors – extraskeletal osteosarcoma 
o Pericytic (perivascular) tumors – malignant glomus tumor 
o Nerve sheath tumors - malignant peripheral nerve sheath tumor, 
malignant granular cell tumor, epithelioid malignant peripheral 
nerve sheath tumor, malignant Triton tumor 
o Undifferentiated sarcomas (with a specific pathologic category in 
the WHO classification) - undifferentiated round cell sarcoma, 
undifferentiated epithelioid sarcoma, undifferentiated spindle cell 
sarcoma  
 
3.2.2.2.1 Patients meeting the criteria (histology, size, and grade) in 
Section 3.2.2.1 with the EXCEPTION of histologies noted in 
3.2.2.1.2 may enroll on the non-chemotherapy cohort at the 
discretion of the enrolling investigator. Patients meeting these 
criteria with the EXCEPTION of histologies noted in 3.2.2.1.2 
but medically deemed unable to receive chemotherapy or who 
elect not to receive chemotherapy are eligible for the non-
chemotherapy cohort. 
 
Note that tumors arising in bone are NOT eligible for this study.  
 
3.2.3 
Extent of Disease 
a) Patients with non-metastatic and metastatic disease are eligible.  
 
b) Initially unresectable patients, with or without metastatic disease, are eligible as 
long as there is a commitment at enrollment to resect the primary tumor. 
 
3.2.4 
Specimen Submission 
Sufficient tissue and blood must be available to submit for required biology studies 
(see Section 15.1.1). 
 

                
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3.2.5 
Performance Level 
/DQVN\SHUIRUPDQFHVWDWXVVFRUH70 IRUSDWLHQWV\HDUVRIDJH 
Karnofsky SHUIRUPDQFHVWDWXVVFRUH70 for patients >16 years of age. 
 
3.2.6 
Organ Function Requirements 
 
3.2.6.1 Adequate bone marrow function defined as: 
- 
Absolute neutrophil count t 1500/μL 
- 
Platelet count t 100,000/μL 
- 
Hemoglobin: 
 
JG/IRUSDWLHQWV\HDUVRIDJH 
 
JG/IRUSDWLHQts > 16 years of age 
 
Note: No transfusions are permitted 7 days prior to laboratory studies to 
determine eligibility. 
 
3.2.6.2 Adequate renal function defined as: 
- 
Creatinine clearance or radioisotope GFR t 70 mL/min/1.73 m2 
or 
- 
A normal serum creatinine based on age/gender as follows: 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
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 
\HDUV 
1.5 
1.4 
The threshold creatinine values in this Table were derived from the 
Schwartz formula for estimating GFR164 utilizing child length and 
stature data published by the CDC. 
 
3.2.6.3 Adequate liver function defined as: 
- 
7RWDOELOLUXELQ 1.5 x upper limit of normal (ULN) for age 
- 
SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) 
for age 
 
3.2.6.4 Adequate cardiac function defined as: 
- 
Shortening fraction of t 27% by echocardiogram OR 
Ejection fraction of t 50% by radionuclide angiogram. 
- 
QTc < 480 msec 
 
3.2.6.5 Adequate pulmonary function defined as: 
- 
No evidence of dyspnea at rest, no exercise intolerance, and a resting 
pulse oximetry reading > 94% on room air if there is clinical 
indication for determination. 
 

                
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3.2.7 
Anticoagulation 
Patients on low molecular weight heparin or coumadin (with a stable INR) are 
eligible. 
 
 
3.2.8 
Life Expectancy 
Patient must have a life expectancy of at least 3 months with appropriate therapy. 
 
3.2.9 
Exclusion Criteria 
 
3.2.9.1 Patients with Grade 1 NRSTS tumors of any size are not eligible. 
 
3.2.9.2 Patients with known CNS metastases are not eligible.  
 
Note: Brain imaging is not an eligibility requirement. 
 
3.2.9.3 Bleeding Diathesis  
Patients with evidence of active bleeding or bleeding diathesis will be 
excluded (Note: Patients aged > 17 years with excess of 2.5 mL of 
hemoptysis are not eligible). 
 
3.2.9.4 Tumor Resection 
Patients with gross total resection of the primary tumor prior to enrollment 
on ARST1321 are NOT eligible. Patients who have experienced tumor 
recurrence after a gross total tumor resection are NOT eligible. 
 
3.2.9.5 Uncontrolled hypertension 
Patients with uncontrolled hypertension are ineligible. Uncontrolled 
hypertension is defined as follows: 
x 
3DWLHQWVDJHG \HDUVJUHDWHUWKDQWKpercentile systolic and 
diastolic blood pressure based on age and height (see Appendix V) 
which is not controlled by one anti-hypertensive medication. 
x 
3DWLHQWVDJHG!\HDUVV\VWROLFEORRGSUHVVXUH140 mmHg and/or 
GLDVWROLFEORRGSUHVVXUH 90 mmHg that is not controlled by one 
anti-hypertensive medication. 
 
3.2.9.6 Prior Therapy 
 
3.2.9.6.1 Patients must have had no prior anthracycline (eg, doxorubicin, 
daunorubicin) or ifosfamide chemotherapy.  
 
3.2.9.6.2 Patients must have had no prior use of pazopanib or similar multi-
targeted TKI.  
 
3.2.9.6.3 Patients must have had no prior radiotherapy to tumor-involved 
sites.  
 
Note: Patients previously treated for a non-NRSTS cancer are eligible 
provided they meet the prior therapy requirements and the criterion in 
Section 3.2.9.7 is not applicable. Patients who have had chemotherapy or 
radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) 

                
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prior to entering the study or those who have not recovered from adverse 
events due to agents administered more than 4 weeks earlier are excluded. 
 
3.2.9.7 Other types of invasive malignancy that are not disease free within 3 years 
except for non-melanoma skin cancer, lentigo maligna, any carcinoma-in-
situ or prostate cancer with low risk factors. 
 
3.2.9.8 CYP3A4 Substrates WITH Narrow Therapeutic Indices: Patients 
chronically receiving medications known to be metabolized by CYP3A4 
and with narrow therapeutic indices within 7 days prior to study 
enrollment, including but not limited to pimozide, aripiprazole, triazolam, 
ergotamine and halofantrine are not eligible. Note: the use of fentanyl is 
permitted. 
 
3.2.9.9 CYP3A4 Inhibitors: Patients chronically receiving drugs that are known 
potent CYP3A4 inhibitors within 7 days prior to study enrollment, 
including but not limited to itraconazole, clarithromycin, erythromycin, 
many NNRTIs, diltiazem, verapamil, and grapefruit juice are not eligible. 
See Appendix VI. 
 
3.2.9.10 CYP3A4 Inducers: Patients chronically receiving drugs that are known 
potent CYP3A4 inducers within 14 days prior to study enrollment, 
including but not limited to carbamazepine, phenobarbital, phenytoin, 
rifampin, and St. John’s wort are not eligible (with the exception of 
Glucocorticoids). See Appendix VI. 
 
3.2.9.11 Certain medications that are associated with a risk for QTc prolongation 
and/or Torsades de Pointes, although not prohibited, should be avoided 
or replaced with medications that do not carry these risks, if possible. 
Comprehensive lists of agents that that are associated with a risk for QTc 
prolongation and/or Torsades de Pointes can be found in Appendix VII. 
 
3.2.9.12 Subjects with any condition that may impair the ability to swallow or 
absorb oral medications/investigational product including: 
x 
any lesion, whether induced by tumor, radiation or other conditions, 
which makes it difficult to swallow capsules or pills  
x 
prior surgical procedures affecting absorption including, but not 
limited to major resection of stomach or small bowel 
x 
active peptic ulcer disease 
x 
malabsorption syndrome 
 
3.2.9.13 Subjects with any condition that may increase the risk of gastrointestinal 
bleeding or gastrointestinal perforation, including 
x 
active peptic ulcer disease 
x 
known intraluminal metastatic lesions 
x 
inflammatory bowel disease (eg, ulcerative colitis, Crohn’s disease) 
or other gastrointestinal conditions which increase the risk of 
perforation 
x 
history of abdominal fistula, gastrointestinal perforation or intra-
abdominal abscess within 28 days prior to beginning study treatment 

                
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3.2.9.14 Subjects with any of the following cardiovascular conditions within the 
past 6 months 
x 
cerebrovascular accident (CVA) or transient ischemic attack (TIA)  
x 
cardiac arrhythmia 
x 
admission for unstable angina 
x 
cardiac angioplasty or stenting  
x 
coronary artery bypass graft surgery  
x 
pulmonary embolism, untreated deep venous thrombosis (DVT) or 
DVT which has been treated with therapeutic anticoagulation for 
less than 6 weeks 
x 
arterial thrombosis  
x 
symptomatic peripheral vascular disease. 
x 
Class III or IV heart failure as defined by the NYHA functional 
classification system. A subject who has a history of Class II heart 
failure and is asymptomatic on treatment may be considered 
eligible. 
 
3.2.9.15 History of serious or non-healing wound, ulcer, or bone fracture. 
 
3.2.9.16 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.2.9.17 Patients who are unable to swallow whole tablets are not eligible. 
 
3.2.9.18 Patients with a Body Surface Area < 0.5 m2 are not eligible. 
 
3.2.9.19 HIV-positive subjects on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with pazopanib. 
In addition, these subjects are at increased risk of lethal infections when 
treated with marrow-suppressive therapy.  
  
3.2.9.20 Patients who are receiving any other investigational agent(s). 
 
3.2.9.21 Pregnancy and Breast Feeding 
3.2.9.21.1 Female patients who are pregnant are ineligible due to risks 
of fetal and teratogenic adverse events as seen in 
animal/human studies. 
 
3.2.9.21.2 Lactating females are not eligible unless they have agreed not 
to breastfeed their infants during treatment and for a period of 
1 month following completion of treatment. 
 
3.2.9.21.3 Female patients of childbearing potential are not eligible 
unless a negative pregnancy test result has been obtained. 
 

                
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3.2.9.22 Unwillingness to use an effective contraceptive method for the duration 
of their study participation and for at least 1 month after treatment is 
completed if sexually active with reproductive potential. 
 
3.2.10 Regulatory 
3.2.10.1 All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.10.2 All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
 
4.0 
TREATMENT PROGRAM 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the protocol). 
 
4.1 
Overview of Treatment Plan 
This study is designed with 2 independent clinical trials for patients with unresected 
NRSTS of extremities or trunk. Separate trials will be conducted for patients eligible for 
the chemotherapy cohort (randomized Phase II study of chemotherapy/RT with or without 
pazopanib) and non-chemotherapy cohort (randomized Phase II/III study of RT with or 
without pazopanib). 
 
The study includes a dose-finding and an efficacy phase for therapy with pazopanib. The 
dose finding phase of the study will assess for dose-limiting toxicities (DLTs) and define 
the MTD of pazopanib when used in combination with ifosfamide and doxorubicin (ID). 
The second phase will determine efficacy. Upon successful completion of the dose-finding 
phase, the protocol will be amended and during the efficacy phase patients will receive the 
dose of pazopanib defined as the MTD. Patients who received the MTD in the dose-finding 
phase will not be included in the efficacy phase. The dose-finding phase for the 
Chemotherapy Cohort has been completed and dose level 1 has been identified as the 
MTD, effective May 2015. The dose-finding phase for the Non-Chemotherapy Cohort 
has been completed and dose level 2 has been identified as the MTD, effective with 
Amendment #3A. The Non-Chemotherapy Cohort has been closed to further accrual, 
effective October 12, 2017. 
 
4.1.1 
Regimens 
Patients on this study will be eligible for enrollment either in the chemotherapy 
cohort or non-chemotherapy cohort based on the criteria as described in 
Section 3.2. All tumors must be potentially resectable.  
 
Chemotherapy Cohort 
Patients eligible for the chemotherapy cohort will be randomized to neoadjuvant 
combined modality therapy with ID + 45 Gy RT with or without pazopanib: 
 
 
 
Regimen A: ID + 45 Gy RT + pazopanib; or  

                
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Regimen B: ID + 45 Gy RT 
 
All patients in this cohort will receive radiotherapy (total dose 45 Gy) at Week 4 
and will have definitive surgery at Week 13. Week 4 radiotherapy should be started 
at least 24 hours after completion of the Week 4 doxorubicin. For patients 
randomized to Regimen A, pazopanib will be held pre- and post-surgery. Post-
operatively, patients will proceed with completion of their assigned treatment 
regimens. 
 
**For gross residual disease, postoperative boost radiotherapy with a dose of 
21.6 Gy at 1.8 Gy per fraction is required. For positive microscopic margins, 
postoperative boost with a dose of 16.2 Gy in 1.8 Gy per fraction is highly 
recommended but optional based on the discretion of the treating physician. No 
boost is to be given for negative margins. Negative margin is defined as the 
microscopic absence of tumor on the inked margins following resection regardless 
of the proximity of tumor cells to the margin. Week 16 radiotherapy, if required, 
should start at least 24 hours after completion of the Week 16 doxorubicin. Delay 
of the postoperative radiotherapy boost should be documented. Omission of the 
optional postoperative radiotherapy boost (positive microscopic margins) should 
be documented. Delay or omission documentation should be submitted with the 
RT QA materials (see Section 17.10).  
 
Patients with metastatic disease will undergo surgical resection of metastases at 
the completion of the assigned regimen therapy, with additional radiotherapy for 
incompletely resectable lesions.  
 
Non-Chemotherapy Cohort 
Note: The Non-Chemotherapy Cohort is closed to further accrual, effective 
October 12, 2017. 
 
Patients enrolled in the non-chemotherapy cohort will be randomized to 
neoadjuvant 50 Gy RT with or without pazopanib: 
 
 
 
Regimen C: 50 Gy RT + pazopanib; or 
 
 
Regimen D: 50 Gy RT 
 
All patients in this cohort will begin RT at Week 1 and will have definitive surgery 
at Week 10. Patients randomized to Regimen C will begin pazopanib concurrently 
with RT at Week 1 and will resume pazopanib post-operatively. Pazopanib will be 
held pre- and post-surgery. 
 
**For gross residual disease, postoperative boost radiotherapy with a dose of 
20 Gy at 2 Gy per fraction is required. For positive microscopic margins, 
postoperative boost with a dose of 16 Gy in 2 Gy per fraction is highly 
recommended but optional based on the discretion of the treating physician. Delay 
of the postoperative radiotherapy boost should be documented. Omission of the 
optional postoperative radiotherapy boost (positive microscopic margins) should 
be documented. Delay or omission documentation should be submitted with the 
RT QA materials (see Section 17.10). No boost is to be given for negative margins. 
Negative margin is defined as the microscopic absence of tumor on the inked 

                
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margins following resection regardless of the proximity of tumor cells to the 
margin. 
 
Patients with metastatic disease will undergo surgical resection of metastases at 
the completion of the assigned regimen therapy, with additional radiotherapy for 
incompletely resectable lesions.  
 
4.1.2 
Dose-Finding Phase 
The dose-finding phase for the Chemotherapy Cohort has been completed 
and dose level 1 has been identified as the MTD, effective May 2015. The dose-
finding phase for the Non-Chemotherapy Cohort has been completed and 
dose level 2 has been identified as the MTD, effective with Amendment #3A. 
 
The feasibility of combining pazopanib with ID and radiotherapy will be assessed 
during a carefully designed dose-finding phase. The dose-finding phase will be 
similar for both treatment cohorts. Initially, 10 patients (minimum of 3 patients 
< 18 \HDUVRIDJHDQGSDWLHQWV\HDUVRIDJH eligible for the chemotherapy 
cohort) will non-randomly be assigned to Regimen A and 10 patients (minimum of 
3 patients < 18 years of age and 3 SDWLHQWV\HDUVRIDJH eligible for the non-
chemotherapy cohort) will non-randomly receive Regimen C to assess feasibility 
(pazopanib pediatric starting dose 350 mg/m2; adult starting dose 600 mg). The 
following measures of feasibility will be used: dose-limiting toxicity frequency, total 
doses of pazopanib delivered, and overall adverse event profile when historically 
comparing ID to ID + pazopanib or RT alone to RT + pazopanib. Feasibility will be 
assessed in the first 6 weeks of therapy, during which time patients will have received 
2 cycles of ID and/or started RT, to determine pazopanib dose escalations and de-
escalations (see table below and Statistical Section).  
 
Pazopanib (Tablet formulation, PO once daily) 
 
Dose Level 
Pediatric Dose 
Adult Dose  
0 
275 mg/m2 
400 mg 
1 
350 mg/m2 
600 mg 
2 
450 mg/m2 
800 mg 
* Pediatric dosing is for subjects <18 years old and the total daily dose should not 
exceed the adult dose at the assigned dose level. 
 
4.1.3 
Radiation 
Radiation is built on the backbone of RTOG 0630 using image guidance. All 
conformal CT-based techniques including 3D-CRT or IMRT will be permitted. If 
a 5 mm planning target volume (PTV) is to be used for set-up uncertainty, then 
daily imaged guided radiotherapy (IGRT) will be required, as in RTOG 0630. For 
gross residual disease, postoperative boost radiotherapy is required. For positive 
microscopic margins, postoperative boost radiotherapy is highly recommended but 
optional based on the discretion of the treating physician. Delay of the 
postoperative radiotherapy boost should be documented. Omission of the optional 
postoperative radiotherapy boost (positive microscopic margins) should be 
documented. Delay or omission documentation should be submitted with the RT 
QA materials (see Section 17.10). No boost is to be given for negative margins. 
Negative margin is defined as the microscopic absence of tumor on the inked 

                
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margins following resection regardless of the proximity of tumor cells to the 
margin. 
 
Clinical target volume will be based on the RTOG Consensus Sarcoma Target 
Volume Definition20 using MRI image fusion to encompass areas of T2 edema 
beyond the T1 post-gadolinium gross tumor or at the minimum using an age 
specific margin definition (for patients > 18 years, Grade 2 or 3 > 5 cm tumors will 
be covered using 3 cm CTV margin in the longitudinal directions including 
suspicious MRI T2 edema and a radial CTV margin of 1.5 cm around portions of 
the tumor not confined by an intact fascial barrier or bone or skin surface; all other 
tumors will be covered using a 2 cm CTV margin encompassing suspicious MRI 
T2 edema and a 1 cm radial CTV margin around portions of the tumor not confined 
by an intact fascial barrier or bone or skin surface). For skeletally immature 
patients age  18, the CTV is based upon ARST0332 and is defined as GTV + 1.5 
cm (but not extending outside of the patient). 
See Section 17 for complete details of radiation therapy. 
 
4.1.4 
Treatment Plan 
The chemotherapy regimen to be utilized for the Chemotherapy Cohort 
(Regimen A) will be similar to that used on ARST0332 as described in the table 
below: 
 
Drug 
Dose 
Route 
Schedule 
I: Ifosfamide 
2500 mg/m2/dose 
(7500 mg/m2/cycle) 
IV 
 
Days 1, 2 and 3 
with mesna 
starting on Day 1 
Hour 0  
(see Section 4.2) 
 
D: DOXOrubicin 
 
37.5 mg/m2/dose 
(75 mg/m2/cycle) 
 
If BSA > 2 m2, 
maximum dose is 
75 mg/day and total 
dose is 150 mg over 
2 days. 
IV 
 
Days 1 and 2 with 
dexrazoxane for 
all doses 
 
P: Pazopanib 
(Only in Regimen A) 
 
350 mg/m2 (pediatric) 
600 mg (adult) 
Oral 
Daily in Weeks 1 - 
25 except around 
the time of surgery 
(see Section 4.2) 
 
For those patients in the Non-Chemotherapy Cohort randomized to receive 
pazopanib (Regimen C), the drug will be administered orally, daily in Weeks 1-25 
except around the time of surgery (see Section 4.4). The dose is 450 mg/m2 
(pediatric) and 800 mg (adult).  
 

                
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Note: Patients with progressive disease by imaging at Week 10 or 13 who do not 
have surgery and those with recurrent disease will go off protocol therapy 
(see Section 10.2.4 for the definition of progressive disease).   
 
 
4.1.4.1 Treatment Schema for Chemotherapy Cohort 
 
Regimen A: Neoadjuvant Chemotherapy and Radiotherapy with Pazopanib 
 
 
 
 
 
 
 
* For patients with liver primary tumors who do not receive neoadjuvant radiotherapy, Weeks 16 
and 19 DOXOrubicin doses may be administered at Weeks 7 and 10. 
^ Week 16 DOXOrubicin may be omitted and administered instead at Week 25 if necessary in 
patients receiving intraoperative RT or brachytherapy following Week 13 surgery. 
@ Week 19 DOXOrubicin may be omitted and administered instead at Week 25 if necessary in 
patients receiving external beam radiotherapy following Week 13 surgery. 
# Pazopanib is administered daily but will be held at least 7 days prior to surgery. For pediatric 
patients (< 18 years of age) please use dosing tables for pazopanib provided in Appendix 
XVII. Week 16 pazopanib therapy (and radiotherapy, if required) may be started up to 7 days 
early if wound healing is adequate, but should not begin fewer than 14 days after Week 13 
surgery. 
† See Section 17 for complete radiotherapy guidelines.   
- 
Omit radiotherapy at Week 4 for patients with hepatic primary tumors. Radiotherapy may 
be given at Week 16 for patients with hepatic primary tumors. 
- 
Postoperative boost radiotherapy dose at Week 16 depends on the extent of Week 13 
surgery and the microscopic margin status (see Section 17.6.1). 
- 
Radiotherapy to metastatic sites occurs at the completion of and recovery from all 
chemotherapy and pazopanib therapy, and after maximal resection of metastases. 
 
Regimen B: Neoadjuvant Chemotherapy and Radiotherapy 
 
 
 
 
 
 
* 
For patients with liver primary tumors who do not receive neoadjuvant radiotherapy, Weeks 16 and 19 
DOXOrubicin doses may be administered at Weeks 7 and 10. 
^ 
Week 16 DOXOrubicin may be omitted and administered instead at Week 25 if necessary in patients 
receiving intraoperative RT or brachytherapy following Week 13 surgery. 
@ Week 19 DOXOrubicin may be omitted and administered instead at Week 25 if necessary in patients 
receiving external beam radiotherapy following Week 13 surgery. 
† 
See Section 17 for complete radiotherapy guidelines.   
- 
Omit radiotherapy at Week 4 for patients with hepatic primary tumors. Radiotherapy may be given 
at Week 16 for patients with hepatic primary tumors. 
- 
Postoperative boost radiotherapy dose at Week 16 depends on the extent of Week 13 surgery and 
the microscopic margin status (see Section 17.6.1). 
- 
Radiotherapy to metastatic sites occurs at the completion of and recovery from all chemotherapy 
and after maximal resection of metastases. 
 
Regimen A 
Induction Phase 
Surgery  
Continuation Phase 
Week 1 
Week 4 
Week 7 
Week 10 
Week 13 
Week 16 
Week 19 
Week 22 
Weeks 23-25 
I 
I 
I 
I 
 
Surgery 
I 
I 
 
 
D 
D 
 
 
  D*^ 
    D*@ 
D 
 
Pazopanib# Weeks 1-12 
Pazopanib# Weeks 16-25 
 
Radiotherapy† 
Radiotherapy† 
 
 
Regimen B 
Induction Phase 
Surgery  
Continuation Phase 
Week 1 
Week 4 
Week 7 
Week 10 
Week 13 
Week 16 
Week 19 
Week 22 
I 
I 
I 
I 
 
Surgery 
I 
I 
 
D 
D 
 
 
   D*^ 
     D*@ 
D 
 
Radiotherapy† 
Radiotherapy† 
 

                
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4.1.4.2 Treatment Schema for Non-Chemotherapy Cohort 
Note: The Non-Chemotherapy Cohort is closed to further accrual, 
effective October 12, 2017. 
 
Regimen C: Neoadjuvant Radiotherapy and Pazopanib 
Regimen C 
Induction Phase 
Surgery  
Continuation Phase 
Week 1 
Week 4 
Week 7 
Week 10 
Surgery 
Week 13 
Week 16 
Week 19 
Weeks 22- 25 
Pazopanib # Weeks 1-9 
Pazopanib # 13-25 
Radiotherapy†
 
 
Radiotherapy† 
 
# Pazopanib is administered daily but will be held at least 7 days prior to surgery. For pediatric patients (< 18 years 
of age), please use dosing tables for pazopanib provided in Appendix XVII. Week 13 pazopanib therapy (and 
radiotherapy, if required) may be started up to 7 days early if wound healing is adequate, but should not begin 
fewer than 14 days after Week 10 surgery. 
† See Section 17 for complete radiotherapy guidelines.   
- 
Omit radiotherapy at Week 1 for patients with hepatic primary tumors. Radiotherapy may be given at 
Week 13 for patients with hepatic primary tumors. 
- 
Postoperative boost radiotherapy dose at Week 13 depends on the extent of Week 10 surgery and the 
microscopic margin status (see Section 17.6.1). 
- 
Radiotherapy to metastatic sites occurs at the completion of and recovery from all pazopanib therapy and 
after maximal resection of metastases. 
 
Regimen D: Neoadjuvant Radiotherapy 
Regimen D 
Induction Phase 
Surgery  
Continuation Phase 
Week 1 
Week 4 
Week 7 
Week 10 
Surgery 
Week 13 
Week 16 
Weeks 19-25 
Radiotherapy†
 
 
Radiotherapy† 
 
† See Section 17 for complete radiotherapy guidelines.   
- 
Omit radiotherapy at Week 1 for patients with hepatic primary tumors. Radiotherapy may be given at 
Week 13 for patients with hepatic primary tumors. 
- 
Postoperative boost radiotherapy dose at Week 13 depends on the extent of Week 10 surgery and the 
microscopic margin status (see Section 17.6.1). 
- 
Radiotherapy to metastatic sites occurs at the completion of and recovery from all other protocol-specified 
radiotherapy and after maximal resection of metastases. 
 
 
4.1.5 
Response Assessment 
During the efficacy phase, response to therapy will be assessed at Week 10 or 13 
by histopathologic review (pathologic response), standard imaging (CT or MRI, as 
appropriate), and FDG PET imaging. Patients with progressive disease by imaging 
at Week 10 or 13 will go off protocol therapy (see Section 10.2.4 for the definition 
of progressive disease). 
 
4.1.6 
Concomitant Therapy 
Pazopanib in vitro studies showed that pazopanib is a potent inhibitor of UGT1A1 
and OAT1B1 with IC50 of 1.2 and 0.79 μM respectively. Pazopanib may increase 
concentrations of drugs primarily eliminated through UGTA1A1 and OATP1B1. 
The active metabolite of irinotecan, SN-38, is a substrate for OATB1 and several 
UGT enzymes, including UGT1A1. Co-administration of pazopanib and 

                
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irinotecan increase the systemic exposure to both the parent drug and the active 
metabolite SN-38. Avoid, as much as possible, drugs primarily eliminated through 
UGTA1A1 and OATP1B1. 
 
Concomitant use of pazopanib and simvastin increases the incidence of ALT 
elevations. If a patient receiving concomitant simvastin develops ALT elevations, 
discontinue simvastin. 
 
Co-administration of pazopanib with medicines that increase gastric pH should be 
avoided. If concomitant administration of an H2 receptor antagonist is medically 
necessary, pazopanib should be taken without food at least 2 hours before or at 
least 10 hours after a dose of an H2-receptor antagonist. Pazopanib should be 
administered at least 1 hour before and 2 hours after administration of short-acting 
antacids.   
 
Concomitant medications that have narrow therapeutic windows and are substrates 
of CYP3A4, CYP2D6 or CYP2C8 should be used with caution.  
 
The table below provides examples of agents which should be avoided; note that 
this is not an exhaustive list. 
 
Class 
Drug examples 
Rationale 
Action 
Strong 
CYP3A4 
inhibitors  
See Appendix VI 
Ketaconazole 
Itraconazole 
Voriconazole 
Clarithomycin 
May increase pazopanib 
concentrations 
Avoid concomitant 
administration with 
pazopanib 
Neurokinin 
Antagonist 
Aprepritant 
Aprepitant can inhibit and induce 
CYP3A4 depending on the duration 
of therapy and may alter 
concentrations of medications 
metabolized by CYP3A4 
Do NOT give with 
ifosfamide or 
doxorubicin; avoid use 
with pazopanib 
CYP3A4 
inducers 
Rifampin 
May decrease pazopanib 
concentrations 
Select an alternative 
concomitant medication 
Simvastatin 
 
Concomitant use with pazopanib 
increases the risk of ALT elevation 
Avoid use if possible. 
Monitor closely if given 
concomitantly 
Medications 
eliminated 
through 
UGT1A1 
and 
OATP1B1 
A list of medications may be 
found at: 
http://www.pharmacologyweekly.
com/content/pages/online-drug-
therapy-tables 
 
http://www.fda.gov/Drugs/Develo
pmentApprovalProcess/Developm
entResources/DrugInteractionsLa
beling/ucm080499.htm 
 
Pazopanib may increase 
concentrations of drugs primarily 
eliminated by UGT1A1 and 
OATP1B1 
Avoid concomitant use 
with these medications. 
See Section 5.7.2 for 
recommendations for 
adjustments for isolated 
ALT elevations 

                
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Proton 
pump 
inhibitors  
Dexlansoprazole 
Esomeprazole 
Lansoprazole 
Omeprazole 
Pantoprazole 
Rabeprazole 
Pazopanib concentrations may be 
reduced by agents that increase 
gastric pH 
Pazopanib should be 
taken without food once 
daily in the evening with 
the PPI. 
H2-receptor 
antagonists 
Cimetidine 
Famotidine 
Nizatidine 
Ranitidine 
Pazopanib concentrations may be 
reduced by agents that increase 
gastric pH 
Take pazopanib in the 
a.m. and the H2-receptor 
antagonist in p.m.; if bid 
H2-receptor antagonist 
then take pazopanib 
without food 2 hours 
before or 10 hours after 
the H2-receptor 
antagonist dose 
Short-acting 
antacids 
Aluminum hydroxide 
Calcium carbonate 
Magnesium hydroxide 
Pazopanib concentrations may be 
reduced by agents that increase 
gastric pH 
Administer pazopanib 1 
hour before or 2 hours 
after the antacid 
Agents with 
potential to 
increase 
QTc 
See Appendix VII 
Chlorpromazine 
Clarithromycin 
Erythromycin 
Haloperidol 
Methadone 
Pentamidine 
Risk of QTc prolongation &/or 
Torsades de pointes 
Agents “generally 
accepted” to cause risk 
of Torsades de pointes 
are prohibited.  
Agents “associated” with 
a risk of Torsades de 
pointes should be 
discontinued or replaced 
with agents that don’t 
carry these risks, if 
possible. Ondansetron or 
granisetreon may be 
used if QTc prolongation 
is not seen on an EKG 
during the first week of 
co-administration. For 
other agents with an 
“associated” risk, close 
monitoring and 
additional EKGs should 
be performed at 
investigator discretion if 
medications continued.  
Avoid the use of 
pentamidine 
 
 
4.1.7 
Supportive Care Guidelines  
Please see Appendix VIII for protocol–specific supportive care guidelines. In 
addition, for COG Supportive Care Guidelines see:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-guidelines. 
 
4.2 
Treatment Administration Schedule for Patients on Regimen A 
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 the infusion. As 

                
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applicable, also see the CAG for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
4.2.1 
Induction Phase for Regimen A (Weeks 1-12) 
Induction therapy consists of 12 weeks of chemotherapy plus pazopanib along with 
radiation therapy (see Section 17 for RT details). Week 4 radiotherapy should be 
started at least 24 hours after completion of the Week 4 doxorubicin. 
Note: omit radiotherapy at Week 4 for patients with hepatic primary tumors. 
For patients with liver primary tumors who do not receive neoadjuvant 
radiotherapy, Weeks 16 and 19 DOXOrubicin doses may be administered at 
Weeks 7 and 10 (scheduling of ifosfamide should remain the same). 
 
Therapy is presented as four 21-day cycles in the therapy delivery map. 
 
Criteria to start each F\FOH$1&/DQGSODWHOHWFRXQW 75,000/μL post 
nadir (without transfusion). The ANC often falls after discontinuing myeloid 
growth factor support. If the ANC has risen to  750/μL after the nadir but then 
falls the next cycle should be given despite ANC < 750/μL. 
 
Dexrazoxane: Slow IV push/infusion over 5-15 minutes given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1 and 4 
Dose: 375 mg/m2/dose (eg, 10 mg of dexrazoxane for every mg of DOXOrubicin).  
 
Note: Administer DOXOrubicin after completing the infusion of dexrazoxane. 
The administration of dexrazoxane plus doxorubicin should be completed within 
a total of 30 minutes.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes.  
Days: 1 and 2 of Weeks 1 and 4 
Dose: 37.5 mg/m2/dose (75 mg/m2/cycle). If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. 
 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing solution of 
D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a liposomal 
formulation. Use conventional DOXOrubicin only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Ifosfamide: IV, infuse the diluted solution over 2-4 hours 
Days: 1, 2 and 3 of Weeks 1, 4, 7 and 10 
Dose: 2500 mg/m2/dose (7500 mg/m2/cycle) 
 
Mesna must be administered in conjunction with ifosfamide (see below). Hydrate 
per institutional guidelines or according to recommendations below.  
 
Suggested 
hydration 
for 
ifosfamide: 
Administer 
3,000 mL/m²/day 
(125 mL/m²/hour) using fluid containing D5W/0.45% NaCl or 0.9% NaCl. 

                
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$FKLHYHXULQHVSHFLILFJUDYLW\ 1.010 prior to start of ifosfamide. May use 
diuretics (eg, furosemide) to increase urine output. Consider adding potassium and 
magnesium to prevent electrolyte deficiencies.  
 
Mesna with Ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-3 of Weeks 1, 4, 7 and 
10 
Total IV Dose: 2500 mg/m2/day.  
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 
100% of the daily ifosfamide dose. Mesna can be administered in 5 divided doses 
by short infusion over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the ifosfamide dose; 
subsequent doses are given 3, 6, 9, and 12 hours after the start of ifosfamide.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; 200 mg of mesna will be given 15 minutes before or with the 
ifosfamide dose (Hour 0) and 4 boluses of 200 mg each will be given at Hours 3, 
6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. 
The continuous infusion should be started 15-30 minutes before or at the same time 
as ifosfamide and finished no sooner than 12 hours after the end of the ifosfamide 
infusion.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; the 1,000 mg mesna continuous infusion will start 15-30 minutes 
before or at the same time as the ifosfamide and be completed no sooner than 
12 hours after the end of the ifosfamide infusion. If ifosfamide is administered 
over 2 hour and mesna is started 30 minutes before the ifosfamide infusion, the 
total mesna infusion will last at least 14 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna 
may receive the last FOUR bolus doses (originally at Hours 3, 6, 9, and 12) orally 
at 40% of the ifosfamide dose. The oral doses will be administered at Hours 1, 4, 
7, and 10. 
For example: if the ifosfamide dose is 1,000 mg, then the first 200 mg dose of 
mesna will be given IV 15 minutes before or with the ifosfamide dose (Hour 0) 
and FOUR oral doses of 400 mg each will be given at Hours 1, 4, 7, and 10. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute 
mesna parenteral solution before oral administration. The solution can be diluted 
1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, apple, tomato and 
orange) or plain or chocolate milk. The most palatable is chilled grape juice. 
Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be 
rounded up to nearest 200 mg. Administer doses on a schedule as determined by 
timing of ifosfamide administration. If a dose is missed, administer dose 
immediately. Give the next scheduled dose according to the original dosing 
schedule. Do not deviate from the original schedule. Notify provider if a dose is 
delayed or missed. 
 

                
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ARST1321 
Pazopanib: PO 
Days: Daily from Weeks 1-12. To be held at least 7 days PRIOR to surgery. 
This may mean stopping pazopanib before the end of Week 12 and will depend 
upon the timing of surgery. 
Dose: Dose level 1: 350 mg/m2 (pediatric), 600 mg (adult). For pediatric patients 
(< 18 years of age), please use dosing tables for pazopanib provided in 
Appendix XVII. Pediatric dosing is for subjects < 18 years old and the total daily 
dose should not exceed the adult dose at the assigned dose level. 
 
Subjects should be instructed to swallow tablets once a day (preferably in the 
morning) on an empty stomach, either 1 hour before or 2 hours after food with 
about 1 cup (240 mL.) water. Tablets should be swallowed whole; they must not 
be chewed, broken, or crushed. 
 
NOTE: If a dose is missed, do not take or “make up” the dose unless there is at 
least 12 hours until the next scheduled dose. If the patient vomits within 30 minutes 
of taking the dose, the dose may be repeated. If more than 30 minutes have elapsed, 
do not repeat the dose.  
 
Growth Factor Support  
Administration of growth factor is required after all chemotherapy cycles except 
when doxorubicin is administered alone. Use of growth factor after doxorubicin 
alone is optional. Begin myeloid growth factor support (filgrastim or pegfilgrastim 
according to institutional standards) at least 24-36 hours after the last dose of 
myelosuppressive chemotherapy. If given daily then continue a minimum of 
7 GD\VDQGXQWLO$1&2000/μL post nadir (continue without regard to pazopanib 
administration) and discontinue at least 24 hours prior to next cycle of 
chemotherapy.  
 
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Induction are provided in Appendix IX. 
 
Following the Induction phase, surgery (see Section 13 for details) will be done at 
Week 13. See Section 7.1.1 for observations prior to Local Control. The 
Continuation phase of therapy (detailed below) will follow Local Control. 
 
4.2.2 
Continuation Phase for Regimen A (Weeks 16-25) 
Continuation therapy consists of 10 weeks of chemotherapy plus pazopanib along 
with radiation therapy. Therapy is presented as three 21-day cycles plus one extra 
week of pazopanib in the therapy delivery map. 
 
Criteria to start each F\FOH$1&/DQGSODWHOHWFRXQW 75,000/μL post 
nadir (without transfusion). The ANC often falls after discontinuing myeloid 
growth factor support. If the ANC has risen to  750/μL after the nadir but then 
falls the next cycle should be given despite ANC < 750/μL. 
 

                
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ARST1321 
Week 16 chemotherapy (and radiotherapy, if required) may be started up to 7 days 
early if wound healing is adequate, but should not begin fewer than 14 days after 
Week 13 surgery. Also, Week 16 radiotherapy, if required, should start at least 24 
hours after administration of DOXOrubicin. 
 
Initiation of postoperative chemotherapy (and radiotherapy, if required or 
indicated by residual disease or positive margin) should begin within 6 weeks of 
the date of Week 13 surgery. If wound complications preclude initiating 
postoperative chemotherapy within 6 weeks of the date of surgery, this should be 
documented on the appropriate case report form (CRF). Documentation of the 
delay to postoperative boost radiotherapy should be submitted with the RT QA 
materials (see Section 17.10). 
 
PLEASE NOTE: 
x 
Week 16 DOXOrubicin may be omitted and administered instead at 
Week 25 if necessary in patients receiving intraoperative RT or 
brachytherapy following Week 13 surgery. 
x 
Week 19 DOXOrubicin may be omitted and administered instead at 
Week 25 if necessary in patients receiving external beam radiotherapy 
following Week 13 surgery. 
x 
See Section 17 for complete radiotherapy guidelines, these include: 
 Postoperative boost radiotherapy dose at Week 16 depends on the extent 
of Week 13 surgery and the microscopic margin status. 
 Week 16 radiotherapy is optional for patients with hepatic primary tumors. 
 Radiotherapy to metastatic sites occurs at the completion of and recovery 
from all chemotherapy and pazopanib therapy, and after maximal 
resection of metastases. 
 
Dexrazoxane: Slow IV push/infusion over 5-15 minutes given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 16, 19 and 22 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of DOXOrubicin).  
 
Note: Administer DOXOrubicin after completing the infusion of dexrazoxane. 
The administration of dexrazoxane plus doxorubicin should be completed within 
a total of 30 minutes.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes.  
Days: 1 and 2 of Weeks 16, 19 and 22 
Dose: 37.5 mg/m2/dose (75 mg/m2/cycle). If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. 
 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing solution of 
D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a liposomal 
formulation. Use conventional DOXOrubicin only; the conventional and 
liposomal formulations are NOT interchangeable. 
 

                
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ARST1321 
Ifosfamide: IV, infuse the diluted solution over 2-4 hours 
Days: 1-3 of Weeks 16 and 19 
Dose: 2500 mg/m2/dose (7500 mg/m2/cycle) 
 
Mesna must be administered in conjunction with ifosfamide (see below). Hydrate 
per institutional guidelines or according to recommendations below.  
 
Suggested 
hydration 
for 
ifosfamide: 
Administer 
3,000 mL/m²/day 
(125 mL/m²/hour) using fluid containing D5W/0.45% NaCl or 0.9% NaCl. 
$FKLHYHXULQHVSHFLILFJUDYLW\ 1.010 prior to start of ifosfamide. May use 
diuretics (eg, furosemide) to increase urine output. Consider adding potassium and 
magnesium to prevent electrolyte deficiencies.  
 
Mesna with Ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-3 of Weeks 16 and 19 
Total IV Dose: 2,500 mg/m2/day.  
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 
100% of the daily ifosfamide dose. Mesna can be administered in 5 divided doses 
by short infusion over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the ifosfamide dose; 
subsequent doses are given 3, 6, 9, and 12 hours after the start of ifosfamide.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; 200 mg of mesna will be given 15 minutes before or with the 
ifosfamide dose (Hour 0) and 4 boluses of 200 mg each will be given at Hours 3, 
6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. 
The continuous infusion should be started 15-30 minutes before or at the same time 
as ifosfamide and finished no sooner than 12 hours after the end of the ifosfamide 
infusion.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; the 1,000 mg mesna continuous infusion will start 15-30 minutes 
before or at the same time as the ifosfamide and be completed no sooner than 
12 hours after the end of the ifosfamide infusion. If ifosfamide is administered 
over 2 hour and mesna is started 30 minutes before the ifosfamide infusion, the 
total mesna infusion will last at least 14 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna 
may receive the last FOUR bolus doses (originally at Hours 3, 6, 9, and 12) orally 
at 40% of the ifosfamide dose. The oral doses will be administered at Hours 1, 4, 
7, and 10. 
For example: if the ifosfamide dose is 1,000 mg, then the first 200 mg dose of 
mesna will be given IV 15 minutes before or with the ifosfamide dose (Hour 0) 
and FOUR oral doses of 400 mg each will be given at Hours 1, 4, 7, and 10. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute 
mesna parenteral solution before oral administration. The solution can be diluted 
1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, apple, tomato and 

                
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Version date: 04/08/2019 
55 
ARST1321 
orange) or plain or chocolate milk. The most palatable is chilled grape juice. 
Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be 
rounded up to nearest 200 mg. Administer doses on a schedule as determined by 
timing of cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to the 
original dosing schedule. Do not deviate from the original schedule. Notify 
provider if a dose is delayed or missed. 
 
Pazopanib: PO 
Days: Daily from Weeks 16-25 (resume no sooner than 14 days FOLLOWING 
primary surgery; discontinue at least 7 days PRIOR to any surgery planned 
at the completion of Continuation therapy). 
Dose: Dose level 1: 350 mg/m2 (pediatric), 600 mg (adult). For pediatric patients 
(< 18 years of age), please use dosing tables for pazopanib provided in 
Appendix XVII. Pediatric dosing is for subjects < 18 years old and the total daily 
dose should not exceed the adult dose at the assigned dose level. 
 
Subjects should be instructed to swallow tablets once a day (preferably in the 
morning) on an empty stomach, either 1 hour before or 2 hours after food with 
about 1 cup (240 mL.) water. Tablets should be swallowed whole; they must not 
be chewed, broken, or crushed. 
 
NOTE: If a dose is missed, do not take or “make up” the dose unless there is at 
least 12 hours until the next scheduled dose. If the patient vomits within 30 minutes 
of taking the dose, the dose may be repeated. If more than 30 minutes have elapsed, 
do not repeat the dose.  
 
Growth Factor Support  
Administration of growth factor is required after all chemotherapy cycles except 
when doxorubicin is administered alone. Use of growth factor after doxorubicin 
alone is optional. Begin myeloid growth factor support (filgrastim or pegfilgrastim 
according to institutional standards) at least 24-36 hours after the last dose of 
chemotherapy. If given daily then continue a minimum of 7 GD\VDQGXQWLO$1&
2000/μL post nadir and discontinue at least 24 hours prior to next cycle of 
chemotherapy.  
 
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Regimen A Continuation therapy are provided in 
Appendix IX. 
 
4.3 
Treatment Administration Schedule for Patients on Regimen B 
 
4.3.1 
Induction Phase for Regimen B (Weeks 1-12) 
Induction therapy consists of 12 weeks of chemotherapy along with radiation 
therapy (see Section 17 for RT details). Note: omit radiotherapy at Week 4 for 
patients with hepatic primary tumors. For patients with liver primary tumors 
who do not receive neoadjuvant radiotherapy, Weeks 16 and 19 

                
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ARST1321 
DOXOrubicin doses may be administered at Weeks 7 and 10. (scheduling of 
ifosfamide should remain the same). 
 
Therapy is presented as four 21-day cycles in the therapy delivery map. 
 
Criteria to start each cycle$1&/DQGSODWHOHWFRXQW 75,000/μL post 
nadir (without transfusion). The ANC often falls after discontinuing myeloid 
growth factor support. If the ANC has risen to  750/μL after the nadir but then 
falls the next cycle should be given despite ANC < 750/μL. 
 
Dexrazoxane: Slow IV push/infusion over 5-15 minutes given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 1 and 4 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of DOXOrubicin). 
 
Note: Administer DOXOrubicin after completing the infusion of dexrazoxane. 
The administration of dexrazoxane plus doxorubicin should be completed within 
a total of 30 minutes.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes.  
Days: 1 and 2 of Weeks 1 and 4 
Dose: 37.5 mg/m2/dose (75 mg/m2/cycle). If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. 
 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing solution of 
D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a liposomal 
formulation. Use conventional DOXOrubicin only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Ifosfamide: IV, infuse the diluted solution over 2-4 hours 
Days: 1-3 of Weeks 1, 4, 7, and 10 
Dose: 2500 mg/m2/dose (7500 mg/m2/cycle) 
 
Mesna must be administered in conjunction with ifosfamide (see below). Hydrate 
per institutional guidelines or according to recommendations below.  
 
Suggested 
hydration 
for 
ifosfamide: 
Administer 
3,000 mL/m²/day 
(125 mL/m²/hour) using fluid containing D5W/0.45% NaCl or 0.9% NaCl. 
$FKLHYHXULQHVSHFLILFJUDYLW\ 1.010 prior to start of ifosfamide. May use 
diuretics (eg, furosemide) to increase urine output. Consider adding potassium and 
magnesium to prevent electrolyte deficiencies.  
 
Mesna with Ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-3 of Weeks 1, 4, 7, and 
10. 
Total IV Dose: 2500 mg/m2/day.  
 

                
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ARST1321 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 
100% of the daily ifosfamide dose. Mesna can be administered in 5 divided doses 
by short infusion over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the ifosfamide dose; 
subsequent doses are given 3, 6, 9, and 12 hours after the start of ifosfamide.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; 200 mg of mesna will be given 15 minutes before or with the 
ifosfamide dose (Hour 0) and 4 boluses of 200 mg each will be given at Hours 3, 
6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. 
The continuous infusion should be started 15-30 minutes before or at the same time 
as ifosfamide and finished no sooner than 12 hours after the end of the ifosfamide 
infusion.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; the 1,000 mg mesna continuous infusion will start 15-30 minutes 
before or at the same time as the ifosfamide and be completed no sooner than 
12 hours after the end of the ifosfamide infusion. If ifosfamide is administered 
over 2 hour and mesna is started 30 minutes before the ifosfamide infusion, the 
total mesna infusion will last at least 14 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna 
may receive the last FOUR bolus doses (originally at Hours 3, 6, 9, and 12) orally 
at 40% of the ifosfamide dose. The oral doses will be administered at Hours 1, 4, 
7, and 10. 
For example: if the ifosfamide dose is 1,000 mg, then the first 200 mg dose of 
mesna will be given IV 15 minutes before or with the ifosfamide dose (Hour 0) 
and FOUR oral doses of 400 mg each will be given at Hours 1, 4, 7, and 10. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute 
mesna parenteral solution before oral administration. The solution can be diluted 
1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, apple, tomato and 
orange) or plain or chocolate milk. The most palatable is chilled grape juice. 
Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be 
rounded up to nearest 200 mg. Administer doses on a schedule as determined by 
timing of cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to the 
original dosing schedule. Do not deviate from the original schedule. Notify 
provider if a dose is delayed or missed. 
 
Growth Factor Support  
Administration of growth factor is required after all chemotherapy cycles except 
when doxorubicin is administered alone. Use of growth factor after doxorubicin 
alone is optional. Begin myeloid growth factor support (filgrastim or pegfilgrastim 
according to institutional standards) at least 24-36 hours after the last dose of 
chemotherapy. If given daily then continue a minimum of 7 GD\VDQGXQWLO$1&
2000/μL post nadir and discontinue at least 24 hours prior to next cycle of 
chemotherapy.  
 

                
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ARST1321 
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Regimen B Induction are provided in Appendix X. 
 
Following the Induction phase, surgery (see Section 13 for details) will be done at 
Week 13. See Section 7.1.2 for observations prior to surgery. The Continuation 
phase of therapy (detailed below) will follow Local Control. 
 
4.3.2 
Continuation Phase for Regimen B (Weeks 16-24) 
Continuation consists of 9 weeks of chemotherapy along with radiation therapy. 
Therapy is presented as three 21-day cycles in the therapy delivery map. 
 
Criteria to start each F\FOH$1&/DQGSODWHOHWFRXQW 75,000/μL post 
nadir (without transfusion). The ANC often falls after discontinuing myeloid 
growth factor support. If the ANC has risen to  750/μL after the nadir but then 
falls the next cycle should be given despite ANC < 750/μL. 
 
Week 16 chemotherapy (and radiotherapy, if required) may be started up to 7 days 
early if wound healing is adequate, but should not begin fewer than 14 days after 
Week 13 surgery. Also, Week 16 radiotherapy, if required, should start at least 24 
hours after administration of DOXOrubicin. 
 
Initiation of postoperative chemotherapy (and radiotherapy, if required or 
indicated by residual disease or positive margin) should begin within 6 weeks of 
the date of Week 13 surgery. If wound complications preclude initiating 
postoperative chemotherapy within 6 weeks of the date of surgery, this should be 
documented on the appropriate case report form (CRF). Documentation of the 
delay to postoperative boost radiotherapy should be submitted with the RT QA 
materials (see Section 17.10). 
 
PLEASE NOTE: 
x 
Week 16 DOXOrubicin may be omitted and administered instead at 
Week 25 if necessary in patients receiving intraoperative RT or 
brachytherapy following Week 13 surgery. 
x 
Week 19 DOXOrubicin may be omitted and administered instead at 
Week 25 if necessary in patients receiving external beam radiotherapy 
following Week 13 surgery. 
x 
See Section 17 for complete radiotherapy guidelines, these include: 
 Postoperative boost radiotherapy dose at Week 16 depends on the extent 
of Week 13 surgery and the microscopic margin status. 
 Week 16 radiotherapy is optional for patients with hepatic primary tumors. 
 Radiotherapy to metastatic sites occurs at the completion of and recovery 
from all chemotherapy, and after maximal resection of metastases. 
 
Dexrazoxane: Slow IV push/infusion over 5-15 minutes given immediately 
prior to DOXOrubicin 
Days: 1 and 2 of Weeks 16, 19 and 22 
Dose: 375 mg/m2/dose (ie, 10 mg of dexrazoxane for every mg of DOXOrubicin).  

                
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ARST1321 
 
Note: Administer DOXOrubicin after completing the infusion of dexrazoxane. 
The administration of dexrazoxane plus doxorubicin should be completed within 
a total of 30 minutes.  
 
DOXOrubicin: IV push/infusion over 1-15 minutes.  
Days: 1 and 2 of Weeks 16, 19 and 22 
Dose: 37.5 mg/m2/dose (75 mg/m2/cycle). If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. 
 
Administer at a concentration not to exceed 2 mg/mL. It is suggested that 
DOXOrubicin be administered through the tubing of rapidly infusing solution of 
D5W or 0.9% NaCl and that it is infused into a large vein. 
 
Special precautions: Medication errors have occurred due to confusion between 
DAUNOrubicin and DOXOrubicin. DOXOrubicin is available in a liposomal 
formulation. Use conventional DOXOrubicin only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
Ifosfamide: IV, infuse the diluted solution over 2-4 hours 
Days: 1-3 of Weeks 16 and 19 
Dose: 2500 mg/m2/dose (7.5 grams/m2/cycle) 
 
Mesna must be administered in conjunction with ifosfamide (see below). Hydrate 
per institutional guidelines or according to recommendations below.  
 
Suggested 
hydration 
for 
ifosfamide: 
Administer 
3,000 mL/m²/day 
(125 mL/m²/hour) using fluid containing D5W/0.45% NaCl or 0.9% NaCl. 
$FKLHYHXULQHVSHFLILFJUDYLW\ 1.010 prior to start of ifosfamide. May use 
diuretics (eg, furosemide) to increase urine output. Consider adding potassium and 
magnesium to prevent electrolyte deficiencies.  
 
Mesna with Ifosfamide 
Administer MESNA by IV infusion or IV/PO on Days 1-3 of Weeks 16 and 19 
Total IV Dose: 2500 mg/m2/day. 
 
Mesna IV short or continuous infusion:  
For prophylaxis of hemorrhagic cystitis, the total daily mesna dose is equal to 
100% of the daily ifosfamide dose. Mesna can be administered in 5 divided doses 
by short infusion over 15 to 30 minutes. The initial bolus dose of mesna may be 
administered 15 minutes before or at the same time as the ifosfamide dose; 
subsequent doses are given 3, 6, 9, and 12 hours after the start of ifosfamide.  
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; 200 mg of mesna will be given 15 minutes before or with the 
ifosfamide dose (Hour 0) and 4 boluses of 200 mg each will be given at Hours 3, 
6, 9 and 12. 
 
This total daily dose of mesna can also be administered as IV continuous infusion. 
The continuous infusion should be started 15-30 minutes before or at the same time 
as ifosfamide and finished no sooner than 12 hours after the end of the ifosfamide 
infusion.  

                
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60 
ARST1321 
For example: if the ifosfamide dose is 1,000 mg, then the total daily mesna dose 
is 1,000 mg; the 1,000 mg mesna continuous infusion will start 15-30 minutes 
before or at the same time as the ifosfamide and be completed no sooner than 
12 hours after the end of the ifosfamide infusion. If ifosfamide is administered 
over 2 hour and mesna is started 30 minutes before the ifosfamide infusion, the 
total mesna infusion will last at least 14 hours and 30 minutes. 
 
Use of oral mesna:  
The oral dose of mesna is twice the IV dose. Patients able to tolerate oral mesna 
may receive the last FOUR bolus doses (originally at Hours 3, 6, 9, and 12) orally 
at 40% of the ifosfamide dose. The oral doses will be administered at Hours 1, 4, 
7, and 10. 
For example: if the ifosfamide dose is 1,000 mg, then the first 200 mg dose of 
mesna will be given IV 15 minutes before or with the ifosfamide dose (Hour 0) 
and FOUR oral doses of 400 mg each will be given at Hours 1, 4, 7, and 10. 
 
Administer tablets or diluted parenteral solution. To decrease sulfur odor, dilute 
mesna parenteral solution before oral administration. The solution can be diluted 
1:1 to 1:10 in water, carbonated cola drinks, fruit juices (grape, apple, tomato and 
orange) or plain or chocolate milk. The most palatable is chilled grape juice. 
Tablets are 400 mg and can be divided into 200 mg/0.5 tabs so dosing can be 
rounded up to nearest 200 mg. Administer doses on a schedule as determined by 
timing of cyclophosphamide/ifosfamide administration. If a dose is missed, 
administer dose immediately. Give the next scheduled dose according to the 
original dosing schedule. Do not deviate from the original schedule. Notify 
provider if a dose is delayed or missed. 
 
Growth Factor Support  
Administration of growth factor is required after all chemotherapy cycles except 
when doxorubicin is administered alone. Use of growth factor after doxorubicin 
alone is optional. Begin myeloid growth factor support (filgrastim or pegfilgrastim 
according to institutional standards) at least 24-36 hours after the last dose of 
chemotherapy. If given daily then continue a minimum of 7 GD\VDQGXQWLO$1&
2000/μL post nadir and discontinue at least 24 hours prior to next cycle of 
chemotherapy.  
 
Note: Use of GM-CSF (sargramostim) is not permitted. 
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Regimen B Continuation are provided in 
Appendix X. 
 

                
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61 
ARST1321 
4.4 
Treatment Administration Schedule for Patients on Regimen C 
Note: The Non-Chemotherapy Cohort is closed to further accrual, effective 
October 12, 2017. 
 
4.4.1 
Induction Phase for Regimen C (Weeks 1-9) 
Induction therapy consists of 9 weeks of pazopanib therapy along with radiation 
therapy (see Section 17 for RT details). Note: omit radiotherapy at Week 1 for 
patients with hepatic primary tumors. 
 
Therapy is presented as three 21-day cycles in the therapy delivery map. 
 
Pazopanib: PO 
Days: Daily from Weeks 1-9. To be held at least 7 days PRIOR to surgery. This 
may mean stopping pazopanib before the end of Week 9 and will depend upon the 
timing of surgery. 
Dose: Dose level 2: 450 mg/m2 (pediatric), 800 mg (adult). For pediatric patients 
(< 18 years of age), please use dosing tables for pazopanib provided in 
Appendix XVII. Pediatric dosing is for subjects < 18 years old and the total daily 
dose should not exceed the adult dose at the assigned dose level. 
 
Subjects should be instructed to swallow tablets once a day (preferably in the 
morning) on an empty stomach, either 1 hour before or 2 hours after food with about 
1 cup (240 mL.) water. Tablets should be swallowed whole; they must not be 
chewed, broken, or crushed. 
 
NOTE: If a dose is missed, do not take or “make up” the dose unless there is at 
least 12 hours until the next scheduled dose. If the patient vomits within 30 minutes 
of taking the dose, the dose may be repeated. If more than 30 minutes have elapsed, 
do not repeat the dose.  
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Induction are provided in Appendix XI. Following 
Induction phase, surgery (see Section 13 for details) and will be done at Week 10. 
See Section 7.1.3 for observations prior to Surgery. The Continuation phase of 
therapy (detailed below) will follow Local Control. 
 
4.4.2 
Continuation Phase for Regimen C (Weeks 13-25) 
Continuation therapy consists of 13 weeks of pazopanib therapy along with 
radiation therapy. Therapy is presented as four 21-day cycles plus one extra week 
of pazopanib in the therapy delivery map. 
 
Initiation of postoperative therapy (and radiotherapy, if required or indicated by 
residual disease or positive margin) should begin within 6 weeks of the date of 
Week 10 surgery. If wound complications preclude initiating postoperative 
pazopanib within 6 weeks of the date of surgery, this should be documented on the 
appropriate case report form (CRF). Documentation of the delay to postoperative 
boost radiotherapy should be submitted with the RT QA materials (see 
Section 17.10). 
 

                
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PLEASE NOTE: 
x 
See Section 17 for complete radiotherapy guidelines, these include: 
 Postoperative boost radiotherapy dose at Week 13 depends on the extent 
of Week 10 surgery and the microscopic margin status. 
 Week 13 radiotherapy is optional for patients with hepatic primary tumors. 
 Radiotherapy to metastatic sites occurs at the completion of and recovery 
from all pazopanib therapy, and after maximal resection of metastases. 
 
Pazopanib: PO 
Days: Daily from Weeks 13-25 
Dose: Dose level 2: 450 mg/m2 (pediatric), 800 mg (adult). For pediatric patients 
(<18 years old), please use dosing tables for pazopanib provided in Appendix 
XVII. Pediatric dosing is for subjects < 18 years old and the total daily dose should 
not exceed the adult dose at the assigned dose level. 
 
Subjects should be instructed to swallow tablets once a day (preferably in the 
morning) on an empty stomach, either 1 hour before or 2 hours after food with 
about 1 cup (240 mL.) water. Tablets should be swallowed whole; they must not 
be chewed, broken, or crushed. 
 
NOTE: If a dose is missed, do not take or “make up” the dose unless there is at 
least 12 hours until the next scheduled dose. If the patient vomits within 30 minutes 
of taking the dose, the dose may be repeated. If more than 30 minutes have elapsed, 
do not repeat the dose.  
 
Week 13 pazopanib therapy (and radiotherapy, if required) may be started 
up to 7 days early if wound healing is adequate, but should not begin fewer 
than 14 days after Week 10 surgery.  
Discontinue pazopanib at least 7 days PRIOR to any surgery planned at the 
completion of Continuation therapy.  
 
See Section 5.0 for Dose Modifications based on toxicities. 
 
The therapy delivery maps for Continuation phase are provided in Appendix XI. 
See Section 7.1.3 for observations required at the end of therapy.  
 
4.5 
Treatment Administration Schedule for Patients on Regimen D 
Note: The Non-Chemotherapy Cohort is closed to further accrual, effective 
October 12, 2017. 
 
Patients on Regimen D will receive radiotherapy as described in Section 17 and surgery as 
described in Section 13. 
 
PLEASE NOTE: 
x 
See Section 17 for complete radiotherapy guidelines, these include: 
 Omit radiotherapy at Week 1 for patients with hepatic primary tumors. 
 Postoperative boost radiotherapy dose at Week 13 depends on the extent 
of Week 10 surgery and the microscopic margin status. 
 Initiation of postoperative radiotherapy, if required or indicated by 
residual disease or positive margin should begin within 6 weeks of the date 

                
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of Week 10 surgery. If wound complications preclude initiating 
postoperative boost radiotherapy within 6 weeks of the date of surgery, 
documentation of the delay to postoperative boost radiotherapy should be 
submitted with the RT QA materials (see Section 17.10). 
 Week 13 radiotherapy is optional for patients with hepatic primary tumors. 
 Radiotherapy to metastatic sites occurs at the completion of and recovery 
from all other protocol-specified radiotherapy, and after maximal 
resection of metastases. 
 
Therapy delivery maps for radiotherapy administration are not provided in this protocol. 
 
 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
5.1 
Dose-Limiting Toxicity 
The following TKI-associated adverse events will be defined as dose-limiting toxicities 
(DLTs): 
 
Dose-limiting hypertension: 
x 
Grade 3 hypertension not controlled after a week on 2 anti-hypertensive 
medications  
x 
Grade 4 hypertension 
 
Dose-limiting cardiotoxicity 
x 
Grade 3+ left ventricular systolic dysfunction 
 
Dose-limiting dermatitis 
x 
Grade 3+ hand-foot skin reaction (palmar-plantar erythrodysesthesia 
syndrome) 
x 
Grade 3+ dermatitis radiation 
 
Dose-limiting gastrointestinal toxicity: 
x 
Grade 3+ ALT 
x 
Grade 3+ bilirubin 
x 
Grade 4 amylase 
x 
Grade 4 lipase 
x 
Grade 4 mucositis 
 
Dose-limiting nephrotoxicity: 
x 
Grade 3+ proteinuria 
 
In addition, any death as a first event not attributable to disease will be counted as a dose-
limiting toxicity event, as will any withdrawal from protocol treatment as a result of 
“intolerable toxicity”. 
 
 

                
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5.2 
Pazopanib Dose Reductions Table 
 
 
Chemotherapy Cohort 
Non-Chemotherapy Cohort 
Starting Dose 
Pediatric Dose* 
350 mg/m2 
Adult Dose 
600 mg 
Pediatric Dose* 
450 mg/m2 
Adult Dose 
800 mg 
Dose Reduction 
Level 1 
Decrease weekly 
dosing by 25% 
from the starting 
dose 
400 mg 
Decrease weekly 
dosing by 25% 
from the starting 
dose 
600 mg 
Dose Reduction 
Level 2 
Decrease weekly 
dosing by 50% 
from the starting 
dose 
200 mg 
Decrease weekly 
dosing by 50% 
from the starting 
dose 
400 mg 
Dose Reduction 
Level 3 
Decrease weekly 
dosing by 75% 
from the starting 
dose 
off protocol 
Decrease weekly 
dosing by 75% 
from the starting 
dose 
200 mg 
* Refer to Appendix XVII.  Pediatric dosing for patients < 18 years of age. 
 
5.3 
Hematologic Toxicity 
5.3.1 
Prolonged Neutropenia and Thrombocytopenia 
If a chemotherapy cycle is delayed for > 7 days (ie, beyond Day 28 of the prior 
cycle), reduce the dose of doxorubicin/ifosfamide (and pazopanib for Regimen A) 
as outlined below. Consider holding trimethoprim-sulfamethoxazole prophylaxis 
in the event of prolonged neutropenia (Grade 4 for > 7 days), and utilizing a 
different type of Pneumocystis (carinii) jirovecii prophylaxis (see Appendix VIII). 
 
5.3.1.1 Patients randomized to Ifosfamide/Doxorubicin WITHOUT Pazopanib 
 
Delay prior to Ifosfamide AND Doxorubicin WITHOUT Pazopanib Cycle 
Hematologic 
Parameters 
Delay 
Occurrence 
with this 
Combination 
Dose Modifications* 
ANC  
< 750/μL 
OR 
Platelets  
< 75,000/μL 
 
First 
x Ifosfamide: Reduce dose to 2000 mg/m2/day x 3 days (6000 mg/m2/cycle) 
x Doxorubicin: No change 
Second 
x Ifosfamide: Reduce dose to 1500 mg/m2/day x 3 days (4500 mg/m2/cycle) 
x Doxorubicin: No change 
Third 
x Ifosfamide: Continue dose of 1500 mg/m2/day x 3 days  
x Doxorubicin: Reduce dose to 30 mg/m2/day x 2 days (60 mg/m2/cycle) 
* 
Delay therapy until counts are met. Any cycle delay >3 weeks (ie, beyond Day 42 of the prior cycle) due to 
neutropenia or thrombocytopenia will result in the patient being removed from protocol therapy.  
 
,IFRXQWVDUHPHW$1&/DQG3ODWHOHWV/by the time of the next scheduled chemotherapy cycle 
following the dose reduction(s), subsequent cycles of therapy should be at the same reduced dose unless the 
apparent cause of delayed recovery is no longer present. 
 
Dose reductions will be made for neutropenia only during chemotherapy cycles that include both ifosfamide and 
doxorubicin. If single-agent therapy with either ifosfamide or doxorubicin is due, there will be no dose reduction. 
 

                
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5.3.1.2 Patients randomized to Ifosfamide/Doxorubicin WITH Pazopanib 
 
Delay prior to Ifosfamide AND Doxorubicin WITH Pazopanib Cycle 
Hematologic 
Parameters 
Delay 
Occurrence 
with this 
Combination 
Dose Modifications* 
ANC  
< 750/μL  
OR 
Platelets  
< 75,000/μL 
 
First 
x Ifosfamide: Reduce dose to 2000 mg/m2/day x 3 days (6000 mg/m2/cycle) 
x Doxorubicin: No change 
x Pazopanib: No change 
Second 
x Ifosfamide: Reduce dose to 1500 mg/m2/day x 3 days (4500 mg/m2/cycle) 
x Doxorubicin: No change 
x Pazopanib: No change 
Third 
x Ifosfamide: Continue dose of 1500 mg/m2/day x 3 days 
x Doxorubicin: Reduce dose to 30 mg/m2/day x 2 days (60 mg/m2/cycle) 
x Pazopanib: No change 
Fourth 
x Ifosfamide: Continue dose of 1500 mg/m2/day x 3 days 
x Doxorubicin: Continue dose of 30 mg/m2/day x 2 days (60 mg/m2/cycle) 
x Pazopanib: Reduce to Dose Reduction Level 1 (see the table in Section 
5.2) 
* 
Delay therapy until counts are met. Any cycle delay >3 weeks (ie, beyond Day 42 of the prior cycle) due to 
neutropenia or thrombocytopenia will result in the patient being removed from protocol therapy.  
 
,IFRXQWVDUHPHW$1&/DQG3ODWHOHWV/by the time of the next scheduled chemotherapy cycle 
following the dose reduction(s), subsequent cycles of therapy should be at the same reduced dose unless the 
apparent cause of delayed recovery is no longer present. 
 
,IKHPDWRORJLFSDUDPHWHUV$1&ȝ/RUSODWHOHWȝ/DUHQRWPHt within 7 days of a scheduled 
subsequent cycle, the dose of pazopanib should be held until count recovery. The patient may resume pazopanib 
at the same dose level for the subsequent cycle unless criteria for the above dose modification toxicities are met. 
 
5.3.1.2.1 
Delay prior to Pazopanib and Ifosfamide Cycle 
 
Delay prior to Pazopanib AND Ifosfamide Cycle 
Hematologic 
Parameters 
Delay 
Occurrence 
with this 
Combination 
Dose Modifications* 
 
ANC  
< 750/μL 
 OR 
Platelets  
< 75,000/μL 
 
First 
x Ifosfamide: No change 
x Pazopanib: No change 
Second 
x Ifosfamide: Reduce dose to 2000 mg/m2/day x 3 days (6000 mg/m2/cycle) 
x Pazopanib: No change 
Third 
x Ifosfamide: Reduce dose to 1500 mg/m2/day x 3 days (4500 mg/m2/cycle) 
x Pazopanib: No change 
* 
Delay therapy until counts are met. Any cycle delay >3 weeks (ie, beyond Day 42 of the prior cycle) due to 
neutropenia or thrombocytopenia will result in the patient being removed from protocol therapy.  
 
,IFRXQWVDUHPHW$1&/DQG3ODWHOHWV/by the time of the next scheduled chemotherapy cycle 
following the dose reduction, subsequent cycles of therapy should be at the same reduced dose unless the apparent 
cause of delayed recovery is no longer present. 
 
,IKHPDWRORJLFSDUDPHWHUV$1&ȝ/RUSODWHOHWȝ/DUHQRWPHt within 7 days of a scheduled 
subsequent cycle, the dose of pazopanib should be held until count recovery. The patient may resume pazopanib 
at the same dose level for the subsequent cycle unless criteria for the above dose modification toxicities are met. 
 

                
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5.3.1.2.2 
Delay prior to Pazopanib and Doxorubicin Cycle 
 
Delay prior to Pazopanib AND Doxorubicin Cycle 
Hematologic 
Parameters 
Delay 
Occurrence 
with this 
Combination 
Dose Modifications* 
 
ANC  
< 750/μL  
OR 
Platelets  
< 75,000/μL 
 
First 
x Doxorubicin: No change 
x Pazopanib: No change 
Second 
x Doxorubicin: Reduce dose to 30 mg/m2/day x 2 days (60 mg/m2/cycle) 
x Pazopanib: No change 
Third 
x Doxorubicin: Reduce dose to 30 mg/m2/day x 2 days (60 mg/m2/cycle) 
x Pazopanib: Reduce to Dose Reduction Level 1 (see the table in Section 5.2) 
* 
Delay therapy until counts are met. Any cycle delay >3 weeks (ie, beyond Day 42 of the prior cycle) due to 
neutropenia or thrombocytopenia will result in the patient being removed from protocol therapy.  
 
,IFRXQWVDUHPHW$1&/DQG3ODWHOHWV/by the time of the next scheduled chemotherapy cycle 
following the dose reduction, subsequent cycles of therapy should be at the same reduced dose unless the apparent 
cause of delayed recovery is no longer present. 
 
,IKHPDWRORJLFSDUDPHWHUV$1&ȝ/RUSODWHOHWȝ/DUHQRWPHt within 7 days of a scheduled 
subsequent cycle, the dose of pazopanib should be held until count recovery. The patient may resume pazopanib 
at the same dose level for the subsequent cycle unless criteria for the above dose modification toxicities are met. 
 
5.4 
Mucositis 
If Grade 3 mucositis develops for the first time following a doxorubicin-containing 
chemotherapy cycle, the same dose of doxorubicin should be given in the next cycle. If a 
second episode of Grade 3 mucositis develops, the dose of doxorubicin in the next 
doxorubicin-containing cycle should be decreased to 60 mg/m2 (30 mg/m2/dose) and 
continued at the reduced dose for all subsequent doxorubicin-containing cycles. If Grade 3 
mucositis develops following the dose-reduction of doxorubicin, the pazopanib dose 
should be reduced to Dose Reduction Level 1 (see the table in Section 5.2 for dosage) when 
administered in any subsequent doxorubicin-containing cycles.  
 
If Grade 4 mucositis develops following a doxorubicin-containing chemotherapy cycle, the 
dose of doxorubicin in the next doxorubicin-containing cycle should be decreased to 
60 mg/m2 (30 mg/m2/dose) and the dose of pazopanib should be reduced to Dose Reduction 
Level 1 (see the table in Section 5.2 for dosage). The reduced doxorubicin and pazopanib 
doses should be administered in any subsequent doxorubicin-containing cycles.  
 
See Appendix VIII and also see https://childrensoncologygroup.org/index.php/cog-
supportive-care-guidelines for supportive care recommendations for mucositis. 
 
5.5 
Nephrotoxicity 
Renal impairment is the primary, long-term dose-limiting side effect of ifosfamide. 
Available information indicates that the renal injury produced by ifosfamide is permanent, 
and in some cases progressive. Renal irradiation, young age (< 3 years of age), and absence 
of one kidney are risk factors for severe renal toxicity. All patients must be carefully 
monitored for declining renal function and Fanconi syndrome. 
 
If the estimated or measured creatinine clearance/GFR (see Section 3.2.6.2) drops below 
the abnormal range for age and the patient is well-hydrated, defer ifosfamide-containing 
chemotherapy for 1 week. The ifosfamide should then be dose reduced from 

                
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7500 mg/m2/cycle to 6000 mg/m2/cycle. A timed, 24-hour urine collection for creatinine 
clearance or radionuclide GFR measurement should be considered to confirm renal 
dysfunction. If an abnormal creatinine clearance/GFR for age is still present after a 1-week 
delay in ifosfamide-containing chemotherapy (in a well-hydrated patient), replace 
ifosfamide in all subsequent cycles with cyclophosphamide 700 mg/m2/dose IV over 
1 hour on Days 1, 2, and 3 and decrease the mesna dose to 140 mg/m2/dose IV over 
15 minutes prior to and at 3, 6, and 9 hours after the start of the cyclophosphamide dose.  
 
Cyclophosphamide also should be substituted for ifosfamide in an identical manner if 
Fanconi syndrome develops (see definition below). 
 
For patients receiving cyclophosphamide, the dose of cyclophosphamide should be 
reduced to 525 mg/m2/dose and the mesna dose should be reduced to 105 mg/m2/dose if 
the estimated creatinine clearance is < 10 mL/min/1.73 m2. A 24-hour urine collection for 
creatinine clearance or a radionuclide GFR should be obtained prior to cyclophosphamide 
dose reduction, making certain that the patient is well-hydrated before this evaluation. 
 
Fanconi Syndrome 
Elements of Fanconi syndrome include: 
x 
Renal phosphorus wasting with hypophosphatemia 
x 
Renal bicarbonate wasting with acidosis 
x 
Renal potassium wasting with hypokalemia (< 3.0 mEq/L) 
x 
1+ or greater glycosuria with serum glucose < 150 mg/dL 
x 
Proteinuria: A ratio of urine protein:urine creatinine > 0.2 occurring in the absence 
of significant malnutrition and acidosis due to sepsis/infection 
x 
Decreased GFR 
 
Incomplete Fanconi syndrome, with only one or a few of these elements, is common. Over 
time, these abnormalities may resolve, remain static, or progress. Any patient who has any 
2 of the metabolic abnormalities listed above other than (or in addition to) glycosuria 
should have the following studies done within 2 weeks after the onset of the abnormalities: 
x 
Measurement of GFR by Tc100 DTPA clearance or 24 hour urine collection 
x 
Measurement of non-fasting serum phosphorus (off supplementation, in the 
absence of malnutrition) on 2 consecutive days. 
x 
Measurement of serum bicarbonate (off supplementation), on 2 consecutive days. 
 
For the purposes of this study, Fanconi syndrome is defined as either: 
x 
GFR < 50 mL/min/1.73 m2 in a well-hydrated patient, that is associated with 
mineral/electrolyte wasting and is not due to other causes such as aminoglycoside 
toxicity, amphotericin B, etc. 
OR 
x 
Any GFR, with evidence of persistent renal tubular acidosis AND phosphorous 
wasting defined as: 
o Serum bicarbonate < 14 mmol/L  
AND 
o Serum phosphorous < 2 mg/dL (pre-pubertal) or < 1.5 mg/dL (post-pubertal) 
 
IF FANCONI SYNDROME OCCURS, REPORT IMMEDIATELY AS AN ADVERSE 
DRUG REACTION AND NOTIFY THE STUDY CHAIR. Future cycles of chemotherapy 
should include cyclophosphamide rather than ifosfamide. 

                
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5.6 
Proteinuria 
Proteinuria is a pazopanib-targeted toxicity. Management of pazopanib-induced 
proteinuria will proceed as follows: 
 
x 
,IXULQDO\VLVVKRZVSURWHLQWKHQREWDLQDXULQHSURWHLQFUHDWLQLQHUDWLR83& 
x 
If UPC is > 2, then obtain a 24-hour urine collection for protein estimation. 
x 
If the urine protein is < 3.5 grams/24 hours continue pazopanib at current dosing. 
,IWKHXULQHSURWHLQLV 3.5 grams/24 hours then hold pazopanib treatment and re-
assess weekly. 
x 
If pazopanib is held for > 21 days then remove from protocol therapy. If the urine 
protein decreases to < 3.5 grams/24 hours in  21 days then resume pazopanib at 
Dose Reduction Level 1 (see the table in Section 5.2 for dosage). 
x 
Monitor the 24 hour urine protein weekly for 2 consecutive weeks once pazopanib 
resumes. 
o If the urine protein again exceeds 3.5 grams/24 hours and occurs within 
the first 12 weeks of therapy, then remove from protocol therapy. 
o If the urine protein again exceeds 3.5 grams/24 hours and occurs beyond 
the first 12 weeks of therapy, then hold pazopanib treatment and re-assess 
weekly. 
x 
If pazopanib is held for > 21 days then remove from protocol 
therapy. If the urine protein decreases to < 3.5 grams/24 hours 
in  21 days then resume pazopanib at Dose Reduction 
Level 1 (see the table in Section 5.2). 
 
Urinary Tract Obstruction by Tumor 
Unobstructed urine flow (via a catheter or percutaneous, endoscopic, or open 
decompression) should be established prior to administering either ifosfamide or 
cyclophosphamide to prevent nephrotoxicity (ifosfamide) and hemorrhagic cystitis (both 
ifosfamide and cyclophosphamide). 
 
5.7 
Cardiotoxicity 
 
5.7.1 
Left Ventricular Systolic Dysfunction 
Dexrazoxane will be given for all doxorubicin containing cycles.  
 
If left ventricular systolic dysfunction (ejection fraction < 50% or shortening 
fraction < 27%) develops: 
 
x 
Hold pazopanib 
x 
Postpone the doxorubicin-containing chemotherapy cycle 
x 
Correct any malnutrition present 
x 
Repeat the echocardiogram/MUGA in 7 days 
o If the abnormalities persist, patient will be taken off protocol therapy 
and should be referred to a cardiologist.  
o If repeat echocardiogram/MUGA shows resolution of the 
abnormalities, patient may start next cycle of therapy on schedule with 
repeat echocardiogram/MUGA 14 days after start of next cycle. The 
pazopanib should be resumed at Dose Reduction Level 1 (see the table 
in Section 5.2). 

                
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No changes in therapy are recommended for an asymptomatic decrease in cardiac 
ejection or shortening fraction provided they remain at or above 50% and 27% 
respectively.  
 
If patient develops Grade 3 left ventricular systolic dysfunction, patient will be 
taken off protocol therapy. 
 
5.7.2 
QTc Prolongation 
Guidelines for the management of prolonged QTc interval are as follows: 
x 
Measure the QT interval (from the start of the Q wave to the end of the T wave) 
and the preceding RR interval. The QTc interval will be calculated as the QT 
interval (msec) divided by the square root of the RR interval (msec). 
x 
QTc interval < 500 msec: No specific therapy needed. Continue pazopanib. 
Serum K+, Ca++, Mg++ and Phos should be monitored and repleted only if 
low. 
x 
47FLQWHUYDOPVHF or an increase in the QTc by at least 60 msec from 
baseline: Hold pazopanib, review concomitant medications, and replete serum 
K+, Ca++, Mg++ and Phos as needed. The EKG should be repeated within 7 
GD\VDQGLIWKH47FLQWHUYDOUHPDLQVPVHF or an increase in the QTc by 
at least 60 msec from baseline persists, the patient should be removed from 
protocol therapy. 
 
Please see Section 4.1.6 for guidance on concomitant medications that are associated with 
a risk of QTc prolongation and/or Torsades de pointes 
 
5.8 
Hypertension 
Hypertension is a pazopanib-targeted toxicity. Hypertension typically occurs early in the 
course of pazopanib treatment (approximately 40% of cases occur by Day 9 and 90% occur 
in the first 18 weeks).  
 
5.8.1 
Dose Modification for Hypertension in Patients < 18 Years 
Age- and gender-adjusted norms will be used to determine whether the blood pressure is 
elevated.165 The upper limit of normal (ULN) is defined as a BP equal to the 95th percentile 
for age, height, and gender for patients < 18 years (see Appendix VA and VB). A 
previously described algorithm (adapted from Fox et al.166 and used within ADVL0815: A 
Phase I Study of Pazopanib as a Single Agent for Children with Refractory Solid Tumors) 
will be used to manage TKI-related hypertension for pediatric patients < 18 years of age. 
Management of pazopanib-induced hypertension will proceed as follows: 
 
 

                
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Elevations in BP are based on systolic or diastolic pressures. 
 
1 Elevated blood pressure (BP) measurements should be repeated on the same day to confirm the 
elevation. Patients with elevated BP at any time should have BP measurements performed at least 
twice weekly until BP within the ULN (Upper Limit of Normal). 
2 ULN is a BP equal to the 95th percentile for age, height, and gender-appropriate normal values 
(see Appendix VA and VB). 
3 If BP > 25 mm Hg above ULN for age (verified) or Grade 4 HTN at any time, hold drug. Study 
GUXJVKRXOGDOVREHKHOGIRU%3PP+JDERYHWKH8/1DJHIRU!GD\VRUPP+JDERYH
baseline for > 14 days. Antihypertensive agents can be used to control hypertension as clinically 
indicated after study drug is held. 
4 Anti-hypertensive therapy should be prescribed as clinically indicated, including the use of 
multiple anti-hypertensive agents. 
 
Arm 1 of algorithm: 
x 
,IEORRGSUHVVXUH%3IRUDJHKHLJKWDQGJHQGHUFRQWLQXHSD]RSDQLEDWWKHVDPH
dose. 
 
Arm 2 of algorithm: 
x 
,I%3PP+JDERYHWKH8/1IRUDJHKHLJKWDQGJHQGHUFRQWLQXHSD]RSDQLEDWWKH
same dose and recheck the BP within 72 h. 
x 
,IWKH%3LV8/1RQUHFKHFNFRQWLQXHSD]RSDQLEDWWKHVDPHGRVH 
x 
If the BP remains above the ULN on recheck, then start antihypertensive therapy and 
follow Arm 3 of the algorithm from the point that anti-hypertensive therapy is started. 

                
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Arm 3 of algorithm: 
x 
,I %3 LV  WR PP +J DERYHWKH IRUDJH KHLJKWDQGJHQGHURQ   RI
PHDVXUHPHQWVRU !  PP+JDERYHEDVHOLQHRQ  RIPHDVXUHPHQWVVWDUWDQWL-
hypertensive therapy, continue pazopanib at the same dose, and monitor BP at least twice 
weekly. 
x 
,IWKH%3 UHWXUQVWR8/1ZLWKLQGD\VFRQWLQXHSD]RSDQLEDWWKHVDPHGRVHDQG
continue anti-hypertensive therapy. 
x 
,IWKH%3UHPDLQVHOHYDWHGPP+JDERYHWKHfor more than 14 days or > 35 mm 
Hg above baseline for more than 14 days after the institution of anti-hypertensive therapy, 
hold pazopanib, monitor BP at least every 3 days, and follow Arm 4 of the algorithm from 
the point that pazopanib is held. The antihypertensive therapy should be continued until 
the BP is less than the ULN. 
o ,IWKH%3UHWXUQVWR8/1ZLWKLQGD\VUHVWDUWSD]RSDQLEDWDose Reduction 
Level 1 (see the table in Section 5.2). 
o If the BP remains > ULN for more than 14 days, patient should be removed 
from protocol therapy. 
x 
If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive therapy, hold 
pazopanib, but continue the anti-hypertensive agent(s). Monitor the BP as clinically 
indicated and follow Arm 4 of the algorithm from the point that pazopanib is held. 
o ,IWKH%3 LV  8/1 ZLWKLQGD\VSD]RSDQLEPD\EHUHVWDUWHGDW Dose 
Reduction Level 1 (See the table in Section 5.2). 
o If the BP is > ULN for > 14 days, the patient should be removed from protocol 
therapy. 
 
Arm 4 of algorithm: 
x 
If BP is >25 mm Hg above the 95% for age, height, and gender, hold pazopanib, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. If the BP returns to 
 ULN within 14 days, pazopanib may be restarted at Dose Reduction Level 1 (see the 
table in Section 5.2). 
x 
If the BP is > ULN for >14 days, the patient should be removed from protocol therapy. 
 
Arm 5 of algorithm: 
x 
If the participant develops Grade 4 hypertension (CTCAE v.5), discontinue pazopanib, 
monitor BP and administer anti-hypertensive therapy as clinically indicated. The patient 
should be removed from protocol therapy. 
 
5.8.2 
Dose Modification for Hypertension in 3DWLHQWV<HDUV 
Please refer to Appendix VC for a list of suggested oral antihypertensive 
medications.  
 
Recommended Hypertension Monitoring and Management 
(BP in mmHg) 
Grade 
(CTCAE v5) 
Antihypertensive 
Therapy 
Blood Pressure 
Monitoring 
Pazopanib 
Dose Modification 
Persistent Grade 1 
Pre-hypertension 
Systolic 120-139 
Diastolic 80-89 
 
Standard 
 
No Change 

                
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Persistent Grade 2- 
Moderate 
Systolic 140-159  
Diastolic 90-99  
   
Protocol-specific guidance 
supersedes any other 
management guidelines, 
including CTCAE v5 
Step 1) Initiate BB treatment 
and if needed, after 24-48 hr 
Rx, increase dose in stepwise 
fashion every 24-48 hours until 
BP is controlled or at max dose 
of Rx 
 
Step 2) If BP still not 
controlled, add another anti-
hypertensive Rx, a LA DHP 
CCB, ACE1, ARB, or ABB; 
increase dose of this drug as 
described in step 1   
 
Step 3) If BP still not 
controlled, add 3rd drug from 
the list of antihypertensives in 
step 2; increase dose of this 
drug as described in step 1 
 
Step 4) If BP still not 
controlled, consider either 1 
dose reduction of pazopanib or 
stopping pazopanib  
 
NOTE: Stopping or reducing 
the dose of pazopanib is 
expected to cause a decrease 
in BP. The treating physician 
should monitor the subject for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
BP should be monitored 
as recommended by the 
treating physician  
No change except as 
described in step 4 
Persistent Grade 3 
Severe  
6\VWROLF 
'LDVWROLF 
 
Protocol-specific guidance 
supersedes any other 
management guidelines, 
including CTCAE v5 
HOLD pazopanib until systolic 
%3and GLDVWROLF%3  
 
BP management is identical to 
that for Grade 2 (see steps 1-4 
above) with 2 major 
exceptions:  
1) If systolic BP >180 or 
diastolic BP >110 and the 
subject is symptomatic:  
optimal management with 
intensive IV support in ICU; 
STOP pazopanib and notify 
hospital staff that stopping 
pazopanib may result in a 
decrease in BP 
 and  
2) If systolic BP >180 or 
diastolic BP >110 and the 
subject is asymptomatic, 
2 new antihypertensives must 
be given together in step 1 
BP should be monitored 
as recommended by the 
treating physician 
unless the subject is 
symptomatic with  
systolic BP >180 or 
diastolic BP >110 in 
which case, 
monitoring should be 
intensive. 
 
 
HOLD pazopanib until 
V\VWROLF%3and 
GLDVWROLF%3 After this, 
pazopanib may be re-
administered. If BP is still 
grade 2, manage as 
described above for Grade 2 
hypertenison.  
 
In most circumstances, if 
BP cannot be controlled 
after an optimal trial of 
antihypertensive 
medications, consider either 
1 dose reduction of 
pazopanib when systolic BP 
and GLDVWROLF%3
or stopping pazopanib. 
 
HOWEVER, 
If the subject requires 
hospitalization for 

                
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(and dose escalated 
appropriately as in step 1). 
 
NOTE: Stopping or reducing 
the dose of pazopanib is 
expected to cause a decrease 
in BP. The treating physician 
should monitor the subject for 
hypotension and adjust the 
number and dose of 
antihypertensive 
medication(s) accordingly 
management of 
symptomatic systolic BP 
>180 or diastolic BP >110, 
permanently discontinue 
pazopanib or if BP is 
controlled to systolic BP 
and GLDVWROLF%3
consider re-starting 
pazopanib at 1 lower dose 
level after consultation with 
the study Principal 
Investigator 
Grade 4 
Life-threatening 
consequences of 
hypertension 
 
Optimal management with 
intensive IV support in ICU; 
STOP pazopanib and notify 
hospital staff that stopping 
pazopanib may result in a 
decrease in BP 
Intensive 
Permanently discontinue 
pazopanib or if systolic BP 
and GLDVWROLF%399, 
consider re-starting 
pazopanib at 1 lower dose 
level after consultation with 
the study Principal 
Investigator 
Abbreviations: Dihydropyridine calcium-channel blockers (DHP-CCB), selective beta blockers (BB), Angiotensin Converting 
Enzyme Inhibitors (ACEI), Angiotensin II Receptor Blockers (ARB), alpha beta blocker (ABB) 
x *See table below for suggested antihypertensive medications by class 
x If subjects require a delay of >2 weeks for management of hypertension, discontinue protocol therapy 
x If subjects require >2 dose reductions, discontinue protocol therapy 
x Subjects may have up to 2 drugs for management of hypertension prior to any dose reduction in pazopanib 
x 24-48 hours should elapse between modifications of antihypertensive therapy 
x Hypertension should be graded using CTCAE v5 
 
5.9 
Gastrointestinal Toxicity 
5.9.1 
Hyperbilirubinemia 
Patients with an elevated total bilirubin without elevation of direct (conjugated) 
bilirubin do not require chemotherapy dose modifications. However, patients with 
direct (conjugated) hyperbilirubinemia (direct bilirubin > 35% of total bilirubin) 
do require modification of pazopanib and doxorubicin as follows: 
 
Total bilirubin < 1.2 mg/dL 
Full doses of pazopanib and doxorubicin 
Total bilirubin 1.2 – 3.0 mg/dL 
Reduce dose of pazopanib to Dose 
Reduction Level 2* 
Reduce dose of doxorubicin by 25%  
Total bilirubin 3.1 – 5.0 mg/dL 
Reduce dose of pazopanib to Dose 
Reduction Level 3* 
Reduce dose of doxorubicin by 50% 
Total bilirubin > 5.0 mg/dL 
Withhold pazopanib and doxorubicin 
*See table in Section 5.2. 
 
If the bilirubin falls prior to subsequent chemotherapy cycles, increase the dose of 
doxorubicin as indicated above. Pazopanib can be resumed as soon as toxicity 
resolves at a dose indicated above. Do not make up missed doses. 
 

                
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Ifosfamide doses are not adjusted for hepatic dysfunction. 
 
5.9.2 
Hypertransaminasemia 
Elevations in alanine transaminase (ALT) can be seen with the use of pazopanib. 
Dose modifications should be made as follows: 
 
ALT < 3 x Upper Limit of Normal (ULN) Full dose of pazopanib 
 
Isolated ALT 3-8 x ULN 
Continue full dose pazopanib, but 
monitor weekly until ALT returns to 
 2.5 X ULN or baseline 
ALT 3-8 x ULN and total bilirubin 
< 2 mg/dL (with elevation in direct 
bilirubin as defined in Hyperbilirubinemia 
section) 
Reduce dose of pazopanib to Dose 
Reduction Level 2*  
Reduce doxorubicin as outlined above 
(see Hyperbilirubinemia section) 
ALT > 3 x ULN and total bilirubin 
 2 mg/dL (with elevation in direct 
bilirubin as defined in Hyperbilirubinemia 
section) 
Withhold pazopanib 
Reduce doxorubicin as outlined above 
(see Hyperbilirubinemia section) 
ALT > 8 x ULN 
Withhold pazopanib and doxorubicin 
Monitor weekly until ALT returns to 
baseline then reduce dose of 
pazopanib to Dose Reduction Level 
2* and reduce doxorubicin as outlined 
above (see Hyperbilirubinemia 
section) 
*See table in Section 5.2. 
 
If the ALT falls prior to subsequent chemotherapy cycles, increase the doses of 
pazopanib and doxorubicin as indicated above. Note exception: for ALT > 8 x 
ULN, maintain pazopanib at Dose Reduction Level 2 (see table in Section 5.2) 
without further escalation when ALT returns to baseline. 
 
Ifosfamide doses are not adjusted for hepatic dysfunction. 
 
 

                
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5.9.3 
Hyperamylasemia and/or Hyperlipasemia: 
Elevations in amylase and lipase can be seen with the use of pazopanib. Dose 
modifications should be made as follows: 
 
Grade 1 
Full dose of pazopanib 
Grade 2 
Full dose of pazopanib 
Grade 3 (Asymptomatic) 
Decrease pazopanib to Dose Reduction Level 
2* until improvement to Grade  1 then resume 
pazopanib at full dose 
Grade 3 (Symptomatic) 
Withhold pazopanib until improvement to 
Grade  1 then resume pazopanib at full dose 
Grade 4 (Asymptomatic) 
Withhold pazopanib until improvement to 
Grade  1 then resume pazopanib at full dose 
Grade 4 (Symptomatic) 
Withhold pazopanib until improvement to 
Grade  1 then resume pazopanib Dose 
Reduction Level 2* 
 
 
*See table in Section 5.2. 
 
Discontinue pazopanib and remove patient from protocol therapy for any 
recurrence of symptomatic Grade 3 or Grade 4 toxicity.  
 
Doxorubicin and ifosfamide doses are not adjusted for elevations in amylase or 
lipase. 
 
5.10 
Radiation Toxicity 
Radiation toxicity can be seen with the concomitant administration of radiotherapy and 
doxorubicin. Similar toxicities have been reported with the use of TKIs.82-85,167 The most 
common adverse effect is acute radiation dermatitis and post radiation recall dermatitis. 
 
5.10.1 Radiation Dermatitis 
If radiation dermatitis develops, dose modifications to pazopanib during radiation 
will be made as follows: 
 
Toxicity 
Dose modification 
Grade 1 
Full dose of pazopanib 
Grade 2 
Full dose of pazopanib 
Grade 3 
Discontinue pazopanib until improvement to Grade  2 then 
resume pazopanib at Dose Reduction Level 2* 
Grade 4 
Discontinue pazopanib and remove patient from protocol 
therapy 
*See table in Section 5.2. 
 
Pazopanib can be increased to full dose at the completion of radiation once 
Grade  2 toxicity is achieved. 
 
Ifosfamide doses are not adjusted for radiation dermatitis.  
 
5.10.2 Radiation Recall Reaction 
If a radiation recall reaction develops, dose modifications to pazopanib will be 

                
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made as follows: 
 
Toxicity 
Appearance 
Dose modification  
Grade 1 
Any 
Full dose of pazopanib 
Grade 2 
First 
Appearance 
Discontinue pazopanib until improvement to 
Grade  1 then resume pazopanib at full dose 
Second 
Appearance 
Discontinue pazopanib until improvement to 
Grade  1 then resume pazopanib at Dose Reduction 
Level 2* 
Third 
Appearance 
Discontinue pazopanib until improvement to 
Grade  1 then resume pazopanib at Dose Reduction 
Level 2* 
Fourth 
Appearance  
Discontinue pazopanib and remove patient from 
protocol therapy 
Grade 3 
First 
Appearance 
Discontinue pazopanib until improvement to 
Grade  1 then resume pazopanib at Dose Reduction 
Level 2* 
Second 
Appearance 
Discontinue pazopanib until improvement to 
Grade  1 then resume pazopanib at Dose Reduction 
Level 2* 
Third 
Appearance 
Discontinue pazopanib and remove patient from 
protocol therapy 
Grade 4 
Any 
Discontinue pazopanib and remove patient from 
protocol therapy 
*See table in Section 5.2. 
 
Doxorubicin and ifosfamide doses are not adjusted for a radiation recall reaction. 
 
5.11 
Impaired Wound Healing and Wound Complications 
5.11.1 Impaired Wound Healing 
Delays in wound healing have been reported with the use of TKIs.168,169 The most 
significant complications have been associated with the use of anti-VEGF 
monoclonal antibody bevacizumab which has a half-life of 20 days.170,171 Based 
upon the half-life of pazopanib (31-35 hours) significant peri-surgical 
complications are not expected. To minimize the risk of complications in patients 
undergoing surgery, pazopanib will be held for 7 days prior to and 14 days 
following surgery. Central venous catheter placement is considered a minor 
surgery that does not require a delay in therapy start. Pazopanib should be held for 
delayed wound healing and resumed once appropriate healing has occurred. 
 
For patients on the chemotherapy cohort (Regimen A or B), initiation of 
postoperative chemotherapy with or without pazopanib (and radiotherapy, if 
indicated by positive margin or residual disease) should begin within 6 weeks of 
the date of Week 13 surgery. If impaired wound healing precludes initiating 
postoperative therapy within 6 weeks of the date of surgery, this should be 
documented on the appropriate case report form (CRF). Week 16 chemotherapy 
should be postponed until radiotherapy (if needed) begins. If impaired wound 
healing precludes initiating postoperative therapy within 8 weeks of the date of 
surgery, the patient should be removed from protocol therapy effective the date 
8 weeks after Week 13 surgery.   

                
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For patients on the non-chemotherapy cohort (Regimen C or D), initiation of 
postoperative pazopanib (and radiotherapy, if indicated by positive margin or 
residual disease) should begin within 6 weeks of the date of Week 10 surgery. If 
impaired wound healing precludes initiating postoperative therapy within 6 weeks 
of the date of surgery, this should be documented on the appropriate case report 
form (CRF). If impaired wound healing precludes initiating postoperative therapy 
within 8 weeks of the date of surgery, the patient should be removed from protocol 
therapy effective the date 8 weeks after Week 10 surgery. 
 
If the criteria for a CTCAE v5.0 wound complication is met at any time during the 
wound healing process, refer to Section 5.11.2 below. 
 
5.11.2 Wound Complications 
Please refer to the table below for pazopanib therapy modifications for wound 
complications that occur anytime during therapy: 
 
CTCAE v5.0 
Toxicity 
Grade 
Therapy Modifications 
Wound 
Infection 
1-3 
x 
Hold pazopanib and resume at full dose when toxicity is brought to a 
satisfactory resolution 
x 
During Induction or Continuation Phases of therapy: if therapy delayed 
> 8 weeks, patient should be removed from protocol therapy 
x 
During Surgery Phase of therapy: if the start of the Continuation Phase is 
delayed > 8 weeks from date of surgery, patient should be removed from 
protocol therapy 
4 
x 
Patient should be removed from protocol therapy 
Wound 
Dehiscence 
1-3 
x 
Hold pazopanib and resume at full dose when toxicity is brought to a 
satisfactory resolution 
x 
During Induction or Continuation Phases of therapy: if therapy delayed 
> 8 weeks, patient should be removed from protocol therapy 
x 
During Surgery Phase of therapy: if the start of the Continuation Phase is 
delayed > 8 weeks from date of surgery, patient should be removed from 
protocol therapy  
x 
If recurrence of Grade 3 toxicity, patient should be removed from protocol 
therapy 
4 
x 
Patient should be removed from protocol therapy 
Wound 
Complication 
1-3 
x 
Hold pazopanib and resume at full dose when toxicity is brought to a 
satisfactory resolution 
x 
During Induction or Continuation Phases of therapy: if therapy delayed 
> 8 weeks, patient should be removed from protocol therapy 
x 
During Surgery Phase of therapy: if the start of the Continuation Phase is 
delayed  > 8 weeks from date of surgery, patient should be removed from 
protocol therapy  
x 
If recurrence of Grade 3 toxicity, patient should be removed from protocol 
therapy 
4 
x 
Patient should be removed from protocol therapy 
 

                
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For patients on the chemotherapy cohort (Regimen A or B), initiation of postoperative 
chemotherapy (and radiotherapy, if indicated by positive margin or residual disease) should 
begin within 6 weeks of the date of Week 13 surgery. If a wound complication precludes 
initiating postoperative chemotherapy ± radiotherapy within 6 weeks of the date of surgery, 
this should be documented on the appropriate case report form (CRF). Week 16 
chemotherapy should be postponed until radiotherapy (if needed) begins. If a wound 
complication precludes initiating postoperative chemotherapy ± radiotherapy within 8 
weeks of the date of surgery, the patient should be removed from protocol therapy effective 
the date 8 weeks after Week 13 surgery.   
 
For patients on the non-chemotherapy cohort (Regimen C or D), initiation of radiotherapy, 
if indicated by positive margin or residual disease, should begin within 6 weeks of the date 
of Week 10 surgery. If a wound complication precludes initiating postoperative 
radiotherapy within 6 weeks of the date of surgery, this should be documented on the 
appropriate CRF. If a wound complication precludes initiating postoperative radiotherapy 
within 8 weeks of the date of surgery, the patient should be removed from protocol therapy 
effective the date 8 weeks after Week 10 surgery. 
 
Any wound complication, regardless of attribution, should be recorded on the CRF for the 
reporting period in which the complication occurred. Additionally, any wound-related 
institutional procedure or operative reports (procedure reports would include 
radiologically-guided procedures such as drainage of collections) should be submitted. 
 
5.12 
Rash 
A variety of rashes have been demonstrated with the use of TKIs including hand-foot 
syndrome (palmar-plantar erythrodysesthesia syndrome), erythema, pruritis, follicular 
rash, xerosis and skin dryness. Hand-foot syndrome is the most prevalent.  
 
5.12.1 Hand-Foot (Palmar-Plantar Erythrodysesthesia) Syndrome 
Initiate vitamin B6 (pyridoxine) as outlined in the supportive care guidelines 
(Appendix VIII). 
 
x 
Grade 1 toxicity: Start immediately with prevention/supporting measures and 
continue treatment. 
x 
Grade 2 toxicity: 
o First appearance: 
 
Immediately start with prevention/supporting measures and 
dose reduce pazopanib to Dose Reduction Level 2 (see the 
table in Section 5.2 for dosage) for 21 days.  
 
If after pazopanib dose reduction toxicity decreases to 
Grade  1, return to full dose.  
 
If after pazopanib dose reduction toxicity does not revert to 
Grade  1, discontinue treatment for a minimum of 7 days 
until toxicity decreases to Grade  
 
If after discontinuation toxicity reverts to GUDGH 1, start 
treatment again at Dose Reduction Level 2 (see the table 
in Section 5.2 for dosage) for 21 days. 
 
 If at the reduced dose *UDGH 1 toxicity continues, 
return to full dose after 21 days. 
 
If after discontinuation toxicity does not revert to 

                
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Grade  1 within 21 days, patient is to be taken off 
protocol therapy. 
o Second/Third appearance: 
 
As for the first appearance, but start treatment again 
permanently at Dose Reduction Level 2 (see the table in 
Section 5.2 for dosage). 
o Fourth appearance: 
 
Discontinue pazopanib and the patient is to be taken off 
protocol therapy. 
x 
Grade 3 toxicity: 
o First appearance: 
 
Start immediately with prevention/supporting measures and 
discontinue treatment for at least 7 days. 
 
If after pazopanib dose discontinuation toxicity decreases to 
Grade  1, start treatment again at Dose Reduction Level 2 
(see the table in Section 5.2 for dosage) for 21 days. 
 
If at the reduced dose GUDGH 1 toxicity continues, return 
to full dose after 21 days. 
 
,IDIWHUGLVFRQWLQXDWLRQWR[LFLW\GRHVQRWUHYHUWWR*UDGH 1 
within 21 days, patient is to be taken off protocol therapy. 
o Second appearance: 
 
As for the 1st appearance, but start treatment again 
permanently at Dose Reduction Level 2 (see the table in 
Section 5.2 for dosage). 
o Third appearance: 
 
Discontinue pazopanib and the patient is to be taken off 
protocol therapy. 
x 
Grade 4 toxicity: 
 
Discontinue pazopanib and the patient is to be taken off 
protocol therapy. 
 
Dose modifications for radiation recall reaction and dermatitis radiation are provided in Section 5.8. 
 
Refer to Appendix VIII for additional supportive care measures. 
 
5.13 
Neurotoxicity 
Ifosfamide-induced neurotoxicity is a syndrome characterized by altered mentation 
ranging from mild confusion and disorientation to ataxia, myoclonus, seizures, and coma. 
The precise cause of this syndrome is unknown, but the metabolite chloroacetaldehyde 
appears to be a principal neurotoxin. Impaired renal function and low serum albumin may 
enhance the neurotoxicity of ifosfamide. Symptoms are usually but not always reversible, 
and may or may not recur with subsequent doses.  
 
After ruling out other causes of the neurologic abnormalities, acute neurotoxicity following 
ifosfamide administration should be treated with 1 mg/kg (max dose 50 mg) IV methylene 
blue.172 The dose may be repeated every 6 hours until symptoms resolve. Patients who 
experience acute ifosfamide-induced neurotoxicity should receive methylene blue 1 mg/kg 
(max dose 50 mg) IV daily prior to each subsequent dose of ifosfamide to prevent 
recurrence of the neurotoxicity. Note: methylene blue should not be used in patients who 
are G6PD deficient. 

                
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5.14 
Hematuria 
5.14.1 Microscopic Hematuria 
No modification of ifosfamide, cyclophosphamide, or mesna administration will 
be made for microscopic hematuria (defined as > 50 RBC/hpf) that is transient 
(occurring on no more than two separate days during a 21-day cycle of 
chemotherapy). For persistent microscopic hematuria (3 or more abnormal 
urinalyses on different days), increase IV hydration to 3500-4000 mL/m2/day and 
administer mesna equal to 100% of the daily ifosfamide or cyclophosphamide dose 
by IV continuous infusion over 24 hours during the next chemotherapy cycle. The 
continuous infusion should be started 15-30 minutes before or at the same time as 
the ifosfamide/cyclophosphamide infusion.  
 
5.14.2 Gross Hematuria 
All episodes of gross hematuria should be evaluated by urine culture and 
cystoscopy should be considered. If cystoscopy reveals a cause other than 
hemorrhagic cystitis for the gross hematuria, therapy may proceed without 
modification. If the gross hematuria is due (or possibly due) to hemorrhagic 
cystitis, management depends on the timing and duration of the episode: 
x 
Single < 24 hour long episode of gross hematuria that clears to microscopic 
hematuria during or following a cycle of therapy: 
o Increase IV hydration to 3500-4000 mL/m2/day and administer mesna 
equal to 100% of the daily ifosfamide/cyclophosphamide dose by IV 
continuous infusion over 24 hours for all subsequent ifosfamide doses, as 
described in Section 4. The continuous infusion should be started 15-
30 minutes before or at the same time as the ifosfamide/cyclophosphamide 
infusion. 
x 
Gross hematuria that persists for > 24 hours during or after an ifosfamide-
containing chemotherapy cycle: 
o Withhold further ifosfamide until the next cycle of therapy and use 
hydration and continuous infusion mesna as described in Section 4 for all 
subsequent ifosfamide doses. 
x 
Gross hematuria present at the time of scheduled ifosfamide-containing 
chemotherapy: 
o Withhold chemotherapy for up to 7 days to allow the gross hematuria to 
clear to microscopic levels. 
o Use hydration and continuous infusion mesna as described in Section 4 for 
all subsequent ifosfamide doses. 
x 
Recurrent gross hematuria or persistent microscopic hematuria following use 
of continuous infusion mesna: 
o Omit all further ifosfamide doses. Doxorubicin should be continued 
according to protocol guidelines. 
 
 

                
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5.15 
Electrolyte Abnormalities 
Management of Grade 2 or higher hypokalemia and hyperkalemia, management of Grade 
3 or higher hypomagnesemia and hypermagnesemia, Grade 3 or higher hypophosphatemia, 
and Grade 3 or higher hypocalcemia and hypercalcemia.   
 
Management of Abnormal Laboratory Assessments 
+\SRNDOHPLDRUK\SHUNDOHPLD Grade 2, 
 
+\SRFDOFHPLDRUK\SHUFDOFHPLD Grade 3, 
 
+\SRSKRVSKDWHPLD Grade 3, or 
 
+\SRPDJQHVHPLDRUK\SHUPDJQHVHPLD Grade 3 
x 
EKG must be performed. 
x 
Laboratory values should be corrected as soon as 
possible in a manner consistent with good medical 
judgment.   
x 
Hold pazopanib until:  
 
hypokalemia or hyperkalemia is Grade 1 or 
within institutional limits 
 
K\SRFDOFHPLDRUK\SHUFDOFHPLDLV Grade 2 
 
K\SRSKRVSKDWHPLDLV Grade 2 
 
K\SRPDJQHVHPLDRUK\SHUPDJQHVHPLDLV 
Grade 2   
 
 
6.0 
DRUG INFORMATION  
6.1 
PAZOPANIB  
(VotrientTM, GW786034, Pazopanib HCl, GW786034B (monohydrochloride salt)) 
NSC#737754  
 
 
 
 
(04/05/19) 
 
Source and Pharmacology:  
The chemical name for pazopanib is 5-[[4-[(2,3-Dimethyl-2H-indazol-6-yl) methylamino]-
2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. The molecular 
formula is C21H23N7O2S-HCl. The molecular weight is 474.0 (monohydrochloride salt) and 
437.5 (free base). The monohydrochloride salt is very slightly soluble in 0.1 M HCl (0.65 
mg/mL), practically insoluble in pH 7.0 phosphate buffer (0.00005 mg/mL), and practically 
insoluble in pH 11 piperidine buffer (0.0002 mg/mL). 
 
Pazopanib is a multi-targeted inhibitor of vascular endothelial growth factor (VEGF) receptor 
tyrosine kinases (VEGFR1, VEGFR2, and VEGFR3), platelet-derived growth factor 
receptor kinases (PDGFR-ĮDQG–ȕILEUREODVWJURZWKIDFWRUUHFHSWRU-1 and -3, cytokine 
receptor (Kit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific 
protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-
Fms). In vitro, pazopanib inhibited ligand-induced autophosphorylation of VEGFR-2, Kit 
and PDGFR-ȕ UHFHSWRUV ,Q YLYR SD]RSDQLE LQKLELWHG 9(*)-induced VEGFR-2 
phosphorylation in mouse lungs, angiogenesis in a mouse model, and the growth of some 
human tumor xenografts in mice. 
 
In adults, pazopanib is orally absorbed with median time to peak concentration of 2 to 
4 hours after the dose. Also in adults, the administration of a single, crushed pazopanib 
400 mg tablet increased AUC(0-72) by 46%, increased Cmax by approximately 2 fold, and 
decreased Tmax by approximately 2 hours compared to administration of the whole tablet. 
Due to this potential for increased exposure (increased bioavailability, increased rate of 
absorption), tablets of pazopanib should not be crushed. Systemic exposure is increased 
when pazopanib is administered with food. Administration with a high-fat or low-fat meal 
results in an approximately 2-fold increase in AUC and Cmax. Therefore, pazopanib 

                
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should be administered at least 1 hour before or 2 hours after a meal. Pazopanib is more 
than 99% bound to human plasma protein in vivo.  
 
In adults, pazopanib has a mean half-life of 30.9 hours after administration of the 
recommended dose of 800 mg. Elimination is primarily via feces with renal elimination 
accounting for <4% of the administered dose. To date there are no data on patients with 
mild or severe hepatic impairment. However, data in adult patients with cancer indicate 
that moderate hepatic impairment decreased the clearance of pazopanib is by 50%.  
 
Pazopanib may cause prolongation of the QT interval and torsades de pointes. Refer to 
Appendix VII for agents to avoid during administration of pazopanib.  
 
Toxicity: 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Pazopanib (GW786034, NSC 737754) 
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 2383 patients. Below is the CAEPR for Pazopanib 
(GW786034). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents 
and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 
 
Version 2.8, January 31, 20191 
 
 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 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) 
 
 
Hemolytic uremic syndrome2  
 
 
Thrombotic 
thrombocytopenic purpura 
  
CARDIAC DISORDERS 
  
 
 
Cardiac disorders - Other 
(Torsades de Pointes) 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
 
Myocardial infarction 
  
 
Sinus bradycardia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
  

                
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
EYE DISORDERS 
  
 
 
Eye disorders - Other (eye 
hemorrhage, retinal 
hemorrhage) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dyspepsia 
 
  
 
 
Gastrointestinal fistula3 
 Gastrointestinal fistula3 (Gr 2) 
 
 
Gastrointestinal hemorrhage4  
 
 
Gastrointestinal perforation5  Gastrointestinal perforation5 (Gr 
2) 
 
Mucositis oral 
 
  
Nausea 
 
 
 Nausea (Gr 3) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
  
HEPATOBILIARY DISORDERS 
  
 
 
Hepatic failure 
  
INFECTIONS AND INFESTATIONS 
  
 
 
Infection6 
  
INVESTIGATIONS 
  
 
Activated partial thromboplastin 
time prolonged 
 
  
Alanine aminotransferase 
increased 
 
 
 Alanine aminotransferase 
increased (Gr 4) 
 
Alkaline phosphatase increased 
 Alkaline phosphatase increased 
(Gr 3) 
Aspartate aminotransferase 
increased 
 
 
 Aspartate aminotransferase 
increased (Gr 3) 
Blood bilirubin increased 
 
 
 Blood bilirubin increased 
(Gr 3) 
 
Creatinine increased 
 
 Creatinine increased (Gr 2) 
 
 
Ejection fraction decreased   
 
 
Electrocardiogram QT 
corrected interval prolonged 
  
Lymphocyte count decreased 
 
 
 Lymphocyte count decreased 
(Gr 4) 
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 
4) 
Platelet count decreased 
 
 
 Platelet count decreased  
(Gr 4) 
 
Weight loss 
 
 Weight loss (Gr 2) 
White blood cell decreased 
 
 
 White blood cell decreased (Gr 
3) 
METABOLISM AND NUTRITION DISORDERS 
  

                
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypercalcemia 
 
  
Hyperglycemia 
 
 
 Hyperglycemia (Gr 2) 
 
Hyperkalemia 
 
 Hyperkalemia (Gr 2) 
 
Hypermagnesemia 
 
  
 
Hypernatremia 
 
  
 
Hypoalbuminemia 
 
 Hypoalbuminemia (Gr 2) 
 
Hypocalcemia 
 
 Hypocalcemia (Gr 3) 
 
Hypoglycemia 
 
 Hypoglycemia (Gr 2) 
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
Hyponatremia 
 
 
 Hyponatremia (Gr 3) 
 
Hypophosphatemia 
 
 Hypophosphatemia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) 
  
 
Tumor pain 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Dysgeusia 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
 
 
Intracranial hemorrhage 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
 
Acute kidney injury 
  
 
 
Hematuria 
  
 
Proteinuria 
 
 Proteinuria (Gr 2) 
 
 
Urinary fistula 
 Urinary fistula (Gr 2) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
  
 
 
Reproductive system and 
breast disorders - Other 
(female genital tract fistula) 
 Reproductive system and 
breast disorders - Other (female 
genital tract fistula) (Gr 2) 
 
 
Uterine fistula 
 Uterine fistula (Gr 2) 
 
 
Vaginal fistula 
 Vaginal fistula (Gr 2) 
 
 
Vaginal hemorrhage 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
Respiratory hemorrhage7 
 
 Respiratory hemorrhage7 (Gr 2) 

                
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 Adverse Events with Possible  
 Relationship to Pazopanib (GW786034) 
 (CTCAE 5.0 Term) 
[n= 2383] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(interstitial lung disease)8  
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
Hair color changes 
 
 
 Hair color changes (Gr 2) 
 
Palmar-plantar 
erythrodysesthesia syndrome 
 
  
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
Skin hypopigmentation 
 
 Skin hypopigmentation (Gr 2) 
VASCULAR DISORDERS 
  
 
 
Arterial thromboembolism9   
Hypertension 
 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event9 
  
 
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.  
 
2Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and 
Thrombotic thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034. 
 
3Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical fistula, 
Esophageal 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 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.  
 
5Gastrointestinal 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.  
 
6Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
7Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, 
THORACIC AND MEDIASTINAL DISORDERS SOC.  
 
8Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary fibrosis, 
Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress syndrome), Respiratory, 
thoracic and mediastinal disorders - Other (Aveolitis), Respiratory, thoracic and mediastinal disorders - 
Other (Bronchiolitis obliterans), Respiratory, thoracic and mediastinal disorders - Other (Interstitial fibrosis), 

                
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Respiratory, thoracic and mediastinal disorders - Other (Interstitial pneumonia), Respiratory, thoracic and 
mediastinal disorders - Other (Interstitial pneumonitis), Respiratory, thoracic and mediastinal disorders - 
Other (Organizing pneumonia), Respiratory, thoracic and mediastinal disorders - Other (Pulmonary 
infiltrates), Respiratory, thoracic and mediastinal disorders - Other (Toxic pneumonitis). 
 
9These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications. 
 
 
Adverse events reported on pazopanib (GW786034) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that pazopanib (GW786034) caused the 
adverse event:  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Febrile neutropenia; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac disorders - Other (sinus arrest); Cardiac disorders - 
Other (supraventricular extrasystoles); Cardiac disorders - Other (Takotsubo [Broken Heart Syndrome]); 
Chest pain - cardiac; Pericardial effusion; Supraventricular tachycardia 
ENDOCRINE DISORDERS - Adrenal insufficiency 
EYE DISORDERS - Blurred vision; Dry eye; Eye disorders - Other (asthenopia); Eye disorders - Other 
(foreign body sensation in eyes); Eye pain; Floaters; Glaucoma; Photophobia; Retinal tear 
GASTROINTESTINAL 
DISORDERS - Abdominal distension; Dry mouth; Duodenal obstruction; 
Dysphagia; Esophagitis; Flatulence; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(hyperactive bowel); Gastrointestinal disorders - Other (pneumatosis intestinalis); Gastrointestinal pain; 
Oral pain; Pancreatitis; Periodontal disease; Proctitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Edema face; Malaise; Non-
cardiac chest pain; Pain 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood lactate dehydrogenase increased; Cardiac troponin T increased; Cholesterol 
high; GGT increased; INR increased; Investigations - Other (blood TSH increased); Lipase increased; 
Serum amylase increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Hypertriglyceridemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Chest wall pain; 
Generalized muscle weakness; Head soft tissue necrosis; Muscle cramp; Muscle weakness lower limb; 
Muscle weakness upper limb; Neck pain 
NERVOUS SYSTEM DISORDERS - Extrapyramidal disorder; Ischemia cerebrovascular; Memory 
impairment; Paresthesia; Peripheral sensory neuropathy; Stroke; Syncope; Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; Insomnia; Suicide attempt 
RENAL AND URINARY DISORDERS - Urinary frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive system 
and breast disorders - Other (vaginal necrosis); Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Laryngeal edema; Oropharyngeal pain; 
Pharyngolaryngeal pain; Pleural effusion; Pleuritic pain; Pneumothorax; Postnasal drip; Sore throat; Voice 
alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Pruritus; Purpura; Skin 
hyperpigmentation; Skin ulceration 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Vasculitis 
 
 
Note: Pazopanib (GW786034) 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. 
 
Pregnancy and lactation:  
Pazopanib can cause fetal harm when administered to a pregnant woman. Based on its 
mechanism of action, pazopanib is expected to result in adverse reproductive effects. In 
pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, 

                
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and abortifacient. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, 
embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats 
GXULQJRUJDQRJHQHVLVDWDGRVHOHYHORI 3 mg/kg/day (approximately 0.1 times the human 
clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular 
malformations (retroesophageal subclavian artery, missing innominate artery, changes in 
the aortic arch) and incomplete or absent ossification. In addition, there was reduced fetal 
body weight, and pre- and post-implantation embryolethality in rats administered 
SD]RSDQLEDWGRVHV mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, 
increased post-implantation loss, and abortion) was observeGDWGRVHV 30 mg/kg/day 
(approximately 0.007 times the human clinical exposure). In addition, severe maternal 
ERG\ZHLJKWORVVDQGOLWWHUORVVZHUHREVHUYHGDWGRVHV 100 mg/kg/day (0.02 times 
the human clinical exposure), while fetal weight was reGXFHGDWGRVHV 3 mg/kg/day (AUC 
not calculated). 
 
There are no adequate and well-controlled studies of pazopanib in pregnant women. If this 
drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, 
the patient should be apprised of the potential hazard to the fetus. Women of childbearing 
potential should be advised to avoid becoming pregnant while taking pazopanib. 
 
Excretion in breast milk unknown and breast-feeding while on pazopanib is not 
recommended. 
 
Formulation and Stability: 
Novartis supplies and the PMB, DCTD, NCI distributes commercially-labeled 200 mg 
pazopanib tablets (as free base). Gray, film-coated tablets are debossed with “GS JT” on 
one side and packaged in bottles of 120 tablets. 
Tablet excipients include microcrystalline cellulose, povidone, sodium starch glycolate, and 
magnesium stearate. The film-coat consists of titanium dioxide, hypromellose, iron oxide 
black, macrogol/polyethylene glycol 400 and polysorbate 80. 
 
Store tablets at room temperature (20° C to 25° C or 68° F to 77° F); excursions permitted to 
15° C to 30° C (59 F° to 86° F) [USP controlled room temperature]. 
 
If a storage temperature excursion is identified, promptly return pazopanib to controlled room 
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. 
 
Stability: Refer to package label for expiration date of commercially-labeled supplies. 
 
Repackaging is not allowed and tablets must be dispensed in the original container. If exact 
quantity must be dispensed, then extra tablets should be removed, documented as waste 
and destroyed immediately. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
Pazopanib should be taken on an empty stomach at least 1 hour before or 2 hours after a meal. 
The tablets should be swallowed whole and cannot be crushed or broken.  
 

                
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If a dose is missed, do not take or “make up” the dose unless there is at least 12 hours until 
the next scheduled dose. If the patient vomits within 30 minutes of taking the dose, the 
dose may be repeated. If more than 30 minutes have elapsed, do not repeat the dose.  
 
Potential Drug Interactions: In vitro data indicate that pazopanib is primarily metabolized 
by CYP3A4 isoenzyme with minor contributions from CYP 1A2 and 2C8. Potent CYP3A4 
inducers and inhibitors are prohibited on pazopanib trials. Refer to Appendix VI for agents 
that should be avoided. Pazopanib is also a substrate for p-glycoprotein and breast cancer 
resistance protein (BCRP) transporters and concomitant administration of inhibitors such as 
lapatinib will result in increased plasma pazopanib concentrations. 
 
Clinical studies indicate that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and 
CYP2D6. Use caution when combining pazopanib with CYP3A4, CYP2C8, and CYP2D6 
substrates known to have a narrow therapeutic window.   
 
In vitro studies also showed that pazopanib is a potent inhibitor of UGT1A1 and OATP1B1. 
Pazopanib may increase concentrations of drugs primarily eliminated through these systems.  
 
Avoid co-administration of pazopanib with medicines that increase gastric pH. If the 
concomitant use of a proton pump inhibitor (PPI) is medically necessary, pazopanib should 
be taken without food once daily in the evening with the PPI. If the concomitant 
administration of an H2-receptor antagonist is medically necessary, pazopanib should be 
taken without food at least 2 hours before or at least 10 hours after a dose of an H2-receptor 
antagonist. Administer pazopanib at least 1 hour before or 2 hours after administration of 
short-acting antacids.  
 
Avoid co-administration of pazopanib with simvastatin. Concomitant use of pazopanib and 
simvastatin increases the risk of ALT elevation. Data are not sufficient to assess the risk of 
concomitant administration of other statins and pazopanib.  
 
Precautions: Pazopanib should be used with caution in patients with a history of QT interval 
prolongation, in patients taking antiarrhythmics or other medications that may prolong QT 
interval, and those with relevant pre-existing cardiac disease. Monitor EKGs and serum 
electrolytes (e.g., calcium, magnesium, potassium) at baseline and periodically and maintain 
within the normal range.   
 
Refer to Appendix VII for agents to avoid during administration of pazopanib. 
 
For patients who develop hepatic impairment, refer to Section 5 for appropriate dose 
modification or dose delay. 
 
Supplier:  
Pazopanib is supplied by Novartis and distributed by the Division of Cancer Treatment and 
Diagnosis (DCTD), NCI. Do not use commercial supply. 
 
Obtaining the Agent 
Agent Ordering:  
NCI supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution. The CTEP assigned protocol number 
must be used for ordering all CTEP supplied investigational agents. The responsible 
investigator at each participating institution must be registered with CTEP, DCTD through 

                
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an annual submission of FDA form 1572 (Statement of Investigator), NIH Biosketch, 
Agent Shipment Form, and Financial Disclosure Form (FDF). If there are several 
participating investigators at one institution, CTEP supplied investigational agents for the 
study should be ordered under the name of one lead participating investigator at that 
institution. 
 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status, and a 
“current” password, and active person registration status. For questions about drug orders, 
transfers, returns, or accountability, call or email PMB any time. Refer to the PMB’s 
website for specific policies and guidelines related to agent management. 
 
Agent Accountability 
Agent Inventory Records: 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the receipt, dispensing and final disposition of all agents received from 
PMB using the appropriate NCI Investigational Agent (Drug) Accountability Record 
(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 PMB-supplied 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 Identity and Access 
Management (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 IBcoordinator@mail.nih.gov    
 
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 
DEXRAZOXANE 
(ICRF-187, ADR-529, ZINECARD£, Totect£) NSC #169780  
(11/17/17) 
 
Source and Pharmacology:  
Dexrazoxane is a synthetic chemical, a cyclic derivative of EDTA that readily penetrates 
cell membranes. Results of laboratory studies suggest that dexrazoxane is converted 
intracellularly to a ring opened chelating agent that interferes with iron mediated free 
radical generation thought to be responsible, in part, for anthracycline-induced 
cardiomyopathy. The disposition kinetics of dexrazoxane are dose-dependent with 
administered doses from 60 to 900 mg/m2. The plasma half-life is 2 to 2.5 hours. 
Qualitative metabolism studies have confirmed the presence of unchanged drug, a diacid-
diamide cleavage product, and two monoacid-monoamide ring products in the urine of 
animals and man. Metabolite levels were not measured in the pharmacokinetics studies. 
Urinary excretion plays an important role in the elimination of dexrazoxane: 42% of the 
drug (500 mg/m2) was excreted in the urine. In vitro studies have shown that dexrazoxane 
is not bound to plasma proteins. The pharmacokinetics of dexrazoxane have not been 
evaluated in patients with hepatic or renal insufficiency. There was no significant effect of 
dexrazoxane on the pharmacokinetics of doxorubicin (50 mg/m2) or its predominant 
metabolite, doxorubicinol, in a crossover study in cancer patients. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Pain on injection, phlebitis, transient 
increases in triglycerides and 
amylase, increase in SGPT (ALT)/ 
SGOT (AST) and bilirubin, mild 
nausea, vomiting, diarrhea, increase 
in serum iron, decrease in serum 
zinc and calcium  
Anorexia, malaise, 
extravasation (rare) but if occurs 
may = ulceration 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Myelosuppression  
 
Prolongation of PT/PTT  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancies 
(have been reported with oral 
razoxane; the racemic mixture, of 
which dexrazoxane is the S(+)-
enantiomer) 
Unknown 
Frequency and 
Timing:  
Fetal toxicities and teratogenic effects have been noted in animals. Dexrazoxane was maternotoxic, 
embryotoxic, and teratogenic when given to pregnant rats and rabbits during the period of 
organogenesis. It is not known whether dexrazoxane is excreted in human milk. 
 
Formulation and Stability:  
Three products are available: 
1. Dexrazoxane for Injection (generic)  
a. Available as a sterile, pyrogen-free lyophilized powder in the following strengths: 
250 mg single dose vial packaged with a 25 mL vial of 0.167 Molar (M/6) Sodium 
Lactate Injection, USP, and 500 mg single dose vial packaged with a 50 mL vial 
of 0.167 Molar (M/6) Sodium Lactate Injection, USP.  

                
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b. Store protected from light at 25°C (77°F); excursions permitted to 15°-30°C (59°-
86°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Available in as a sterile, pyrogen-free lyophilized powder in 250 mg and 500 mg 
single use vials. Hydrochloric Acid, NF is added to the vials for pH adjustment. 
b. Intact vials should be stored at 25°C (77°F); excursions are permitted to 15° to 
30°C (59° to 86°F). 
 
3. Totect® (dexrazoxane for anthracycline extravasation only)  
a. Totect is packaged as an emergency treatment carton for single patient use. Each 
carton contains 10 vials of Totect (dexrazoxane for injection) 500 mg and 10 vials 
of 50 mL diluent, which provides a complete three day treatment. 
 
Reconstitution and dilution requirements and expiration dating vary based on the 
product used. Refer to package insert for additional details.  
 
1. Dexrazoxane (generic) 
a. Dexrazoxane (250 mg or 500 mg vials) must be reconstituted with a sufficient 
quantity of 0.167 Molar (M/6) Sodium Lactate Injection, USP, to a concentration 
of 10 mg dexrazoxane for each mL of sodium lactate.  
b. Further dilute solution in either D5W or NS to a final concentration of 1.3 to 5 
mg/mL.  
c. The final solution is stable for up to 6 hours at room temperature, 15°C to 30°C 
(59°F to 86°F), or under refrigeration, 2°C to 8°C (36°F to 46°F). 
 
2. Dexrazoxane (Zinecard®, Pfizer brand) 
a. Reconstitute with Sterile Water for Injection, USP as follows:  
x 
For 250 mg vials, reconstitute with 25 mL.  
x 
For 500 mg vials, reconstitute with 50 mL.  
x 
The resultant reconstituted solutions will have a concentration of 10 mg/mL.  
b. Following initial reconstitution, ZINECARD is stable for 30 minutes at room 
temperature or up to 3 hours when stored under refrigeration, 2° to 8°C (36° to 
46°F).  
c. The pH of the resultant solution is 1.0 to 3.0. Further dilution with Lactated 
Ringer’s Injection, USP is required to achieve a final concentration range of 1.3 to 
3 mg/mL in intravenous infusion bags. The infusion solution has a pH of 3.5 to 
5.5.  
d. The infusion solution is stable for one (1) hour at room temperature or if storage is 
necessary, up to 4 hours when stored under refrigeration, 2° to 8°C (36° to 46°F). 
 
3. Totect® (dexrazoxane for anthracycline extravasation only)  
a. Totect® must be reconstituted with supplied diluent to provide a final concentration 
of 10 mg/mL. The patient’s dose of Totect® (based on body surface area) should 
be injected into a 1000 mL bag of NS for infusion.  
b. This solution is stable for 4 hours (begin infusion within 2 hours of preparation) 
when stored at temperatures <25°C (<77°F). 
c. Stability studies indicate that Totect® is chemically and physically stable after 
reconstitution with sterile water for injection and dilution in Lactated Ringer’s 
Injection when stored in refrigerated conditions (2-8°C) for no more than 8 hours 
(email communication Cumberland Pharma). 

                
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Guidelines for Administration:  See Treatment and Dose Modifications sections of the 
protocol. 
 
For the prevention of anthracycline-induced cardiomyopathy, administer IV immediately 
prior to anthracycline dose. Administer the anthracycline after completing the infusion of 
dexrazoxane but within 30 minutes of beginning of the dexrazoxane infusion.  
 
The first infusion of Totect® should be administered as soon as possible and within the 
first 6 hours following the extravasation. 
 
Supplier:  Commercially available. See package insert for further information. 
 
CANADIAN SITES 
In Canada, Pfizer brand of Zinecard® is the only product commercially available and now 
has the same reconstitution, dilution, and expiration dating as the USA Pfizer Zinecard® 
above.  
 
6.3 
DOXORUBICIN  
(Adriamycin®) NSC #123127  
 
 
 
 
(05/09/11) 
 
Source and Pharmacology:  
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The 
cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various organs 
are thought to be related to nucleotide base intercalation and cell membrane lipid binding 
activities of doxorubicin. Intercalation inhibits nucleotide replication and action of DNA 
and RNA polymerases. The interaction of doxorubicin with topoisomerase II to form DNA-
cleavable complexes appears to be an important mechanism of doxorubicin cytocidal 
activity. Doxorubicin cellular membrane binding may affect a variety of cellular functions. 
Enzymatic electron reduction of doxorubicin by a variety of oxidases, reductases, and 
dehydrogenases generate highly reactive species including the hydroxyl free radical (OH•). 
Free radical formation has been implicated in doxorubicin cardiotoxicity by means of Cu 
(II) and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been 
shown to manifest the characteristic morphologic changes associated with apoptosis or 
programmed cell death. Doxorubicin-induced apoptosis may be an integral component of 
the cellular mechanism of action relating to therapeutic effects, toxicities, or both. 
 
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is approximately 
5 minutes suggesting rapid tissue uptake of doxorubicin. The terminal t½ of 20 to 48 hours 
reflects a slow elimination from tissues. Steady-state distribution volumes exceed 20 to 30 
L/kg and are indicative of extensive drug uptake into tissues. Plasma clearance is in the 
range of 8 to 20 mL/min/kg and is predominately by metabolism and biliary excretion. The 
P450 cytochromes which appear to be involved with doxorubicin metabolism are CYP2D6 
and CYP3A4. Approximately 40% of the dose appears in the bile in 5 days, while only 5 
to 12% of the drug and its metabolites appear in the urine during the same time period. 
Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins is about 
74 to 76% and is independent of plasma concentration of doxorubicin. 
 

                
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Nausea, vomiting, pink or 
red color to urine, sweat, 
tears, and saliva 
Hyperuricemia, facial 
flushing, sclerosis of the 
vein 
Diarrhea, anorexia, erythematous 
streaking of the vein (flare 
reaction), extravasation (rare) but 
if occurs = local ulceration, 
anaphylaxis, fever, chills, 
urticaria, acute arrhythmias 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
Any time later 
during therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses 
 450 mg/m²) (L) 
 
Cardiomyopathy1 (CHF occurs in 
< 5% at cumulative doses 
 400 mg/m²) (L), ulceration and 
necrosis of colon, 
hyper-pigmentation of nail bed 
and dermal crease, onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac 
dysfunction 
CHF (on long term 
follow up in pediatric 
patients) 
Secondary malignancy (in 
combination regimens) 
Unknown 
Frequency and 
Timing:   
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin have 
been noted in animal models. Doxorubicin is excreted into breast milk in humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
(L) Toxicity may also occur later. 
 
Formulation and Stability:  
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 20 mg¹, 
50 mg¹vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 50 mg¹, 200 mg² 
vials. 
¹:  Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin RDF (rapid 
dissolution formula) also contains methylparaben, 1 mg per each 10 mg of doxorubicin, to 
enhance dissolution. 
²   Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 
 
Aqueous Solution: Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain in 
carton until contents are used. 
 
Powder for Injection: Store unreconstituted vial at room temperature, 15°-30°C (59°-86°F). 
Retain in carton until contents are used. Reconstitute with preservative-free NS to a final 
concentration of 2 mg/mL. After adding the diluent, the vial should be shaken and the 
contents allowed to dissolve. The reconstituted solution is stable for 7 days at room 
temperature and 15 days under refrigeration, 2°-8°C (36°-46°F) when protected from light. 
Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is stable for up to 48 hours at 
room temperature (25°C) when protected from light. 
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol.  
 

                
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Administer IV through the tubing of rapidly infusing solution of D5W or 0.9% NaCl 
preferably into a large vein. Protect the diluted solution from sunlight. To avoid 
extravasation, the use of a central line is suggested. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information. 
 
6.4 
FILGRASTIM, TBO-FILGRASTIM, FILGRASTIM-SNDZ 
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®) NSC#614629  
 
 
 
 
 
      (11/15/16) 
 
Source and Pharmacology:  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by 
recombinant DNA technology. Filgrastim is a 175 amino acid protein with a molecular 
weight of 18,800 daltons manufactured by recombinant DNA technology utilizing E coli 
bacteria into which has been inserted the human granulocyte colony stimulating factor 
gene. It differs from the natural protein in that the N- amino acid is methionine and the protein 
is not glycosylated. G-CSF is a lineage specific colony-stimulating factor which regulates 
the production of neutrophils within the bone marrow and affects neutrophil progenitor 
proliferation, differentiation, and selected end-cell functional activation (including 
enhanced phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). Filgrastim exhibits nonlinear pharmacokinetics with 
clearance dependent on filgrastim concentration and neutrophil count. Filgrastim is cleared 
by the kidney. The elimination half-life is similar for subcutaneous and intravenous 
administration, approximately 3.5 hours. The time to peak concentration when administered 
subcutaneously is 2-8 hours 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children out of 
every 100 
Rare 
Happens to <5 children out of every 
100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the injection site, 
headache 
Allergic reactions (more common 
with IV administration than 
subq):skin (rash, urticaria, facial 
edema), respiratory (wheezing, 
dyspnea) and cardiovascular 
(hypotension, tachycardia), low grade 
fever  
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Mild to moderate 
medullary bone pain 
Increased: alkaline phosphatase, 
lactate dehydrogenase and uric acid, 
thrombocytopenia 
Splenomegaly, splenic rupture, rash 
or exacerbation of pre-existing skin 
rashes, sickle cell crises in patients 
with SCD, excessive leukocytosis, 
Sweet’s syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
Cutaneous vasculitis, ARDS 
Late: 
Anytime after 
completion of 
treatment 
 
 
MDS or AML (confined to patients 
with severe chronic neutropenia and 
long term administration) 

                
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Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting data exist 
in animal studies and filgrastim is known to pass the placental barrier. It is unknown whether the 
drug is excreted in breast milk. 
 
Formulation and Stability:  
Neupogen® is supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. 
Neupogen® vials are preservative free single use vials. Discard unused portions of open 
vials. 
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes 
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous 
administration. Store refrigerated at 2º-8ºC (36º-46ºF). Protect from light. Do not shake. 
Prior to injection, filgrastim and filgrastim-sndz may be allowed to reach room temperature 
for a maximum of 24 hours (infusion must be completed within 24 hours of preparation). 
TBO-filgrastim may be removed from 2°C-8°C (36°F-46°F) storage for a single period of 
up to 5 days between 23°C to 27°C (73°F to 81°F). Avoid freezing and temperatures 
> 30ºC.  
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W only to 
concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in D5W to 
concentrations between 5 mcg/mL and 15 mcg/mL. At concentrations below 15 mcg/mL, 
human serum albumin should be added to make a final albumin concentration of 0.2% 
(2 mg/mL) in order to minimize the adsorption of filgrastim to plastic infusion containers 
and equipment for all 3 products (communication on file from Teva Pharmaceuticals USA). 
Filgrastim or filgrastim-sndz dilutions of 5 mcg/mL or less are not recommended. Tbo-
filgrastim dilutions below 2 mcg/mL are not recommended. Diluted filgrastim biosimilar 
products should be stored at 2º-8ºC (36º-46ºF) and used within 24 hours. Do not shake. 
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
 
Guidelines for Administration:  
See Treatment, Dose Modification and Supportive Care sections of the protocol. 
 
Filgrastim biosimilar products should not be administered within 24 hours of (before 
AND after) chemotherapy. 
 
Supplier: Commercially available from various manufacturers. See package insert for 
further information  
 
6.5 
IFOSFAMIDE   
(Isophosphamide, Iphosphamide, Z4942, Ifex®) NSC #109724 
(05/09/11) 
 
Source and Pharmacology: 
Ifosfamide is a structural analogue of cyclophosphamide. Ifosfamide requires hepatic 
microsomal activation (P450 3A isoenzymes) for the production of the reactive 4-
hydroxyoxazaphorine intermediate which serves as a carrier molecule for the ultimate 
intracellular liberation of acrolein and phosphoramide mustard which is an active 
bifunctional alkylating species. Acrolein is thought to be the cause of the hemorrhagic cystitis 
as seen with cyclophosphamide. Ifosfamide demonstrates dose-dependent pharmacokinetics 
whereby the terminal half-life ranges from 7 to 16 hours at doses of 1.6-2.4 g/m² to 3.8-5 
g/m², respectively. At 1.6-2.4 g/m²/d, 12 to 18% of the dose was excreted as unchanged drug 

                
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in the urine, whereas at a 5 g/m² single-dose, 61% was excreted in the urine as the parent 
drug. Evidence also exists to suggest that ifosfamide metabolism is inducible, with more 
rapid clearance occurring in the second and later doses when a course of therapy is given as 
fractionated doses over 3 to 5 days. There is more chloroethyl side chain oxidation of 
ifosfamide (up to 50%) than of cyclophosphamide (< 10%), and the degree of such 
metabolism is more variable than with cyclophosphamide. Oxidation of the chloroethyl 
groups produces chloroacetaldehyde, which is thought to be responsible for the 
neurotoxicity and renal toxicity that have been seen with ifosfamide therapy. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea & vomiting 
(acute and delayed) 
CNS toxicity (somnolence, 
depressive psychosis and 
confusion) 
Anorexia, diarrhea, 
constipation, encephalopathy 
which may progress to coma 
(L), seizure, SIADH, 
phlebitis, hypokalemia 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Leukopenia, alopecia, 
immune suppression 
Thrombocytopenia, 
anemia, cardiac toxicities 
(arrhythmia, asymptomatic 
ECG changes), 
microscopic hematuria, 
metabolic acidosis 
ĹOLYHUHQ]\PHVĹELOLUXELQ 
hemorrhagic cystitis with 
macroscopic hematuria, 
dysuria, cystitis and urinary 
frequency (< 5% with mesna 
and vigorous hydration) (L), 
bladder fibrosis 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or 
oligospermia (prolonged 
or permanent)1 (L) 
 
Renal failure acute or 
chronic, renal tubular 
acidosis, Fanconi-like 
syndrome gonadal 
dysfunction, ovarian failure1 
(L), CHF 
Late: 
Any time after 
completion of 
treatment 
Moderate nephrotoxicity 
ĻLQglomerular filtration 
rate, renal tubular 
threshold for phosphate, 
and serum bicarbonate) 
 
Secondary malignancy, 
hypophosphatemic rickets  
Unknown 
Frequency 
and 
Timing: 
Fetal toxicities and teratogenic effects of ifosfamide have been noted in animals. 
Ifosfamide is excreted into breast milk.   
1 Dependent on dose, age, gender and degree of pubertal development at time of treatment 
 (L) Toxicity may also occur later. 
 
 
Formulation and Stability:  
Ifosfamide is available in 1 g and 3 g single dose vials of lyophilized white powder without 
preservatives and as a 50 mg/mL solution in 20 mL and 60 mL vials.  
 
Guidelines for Administration: See Treatment and Dose Modification sections of the 
protocol. 
 
Reconstitute ifosfamide lyophilized powder with sterile water for injection or bacteriostatic 
water for injection(use 20 mL for the 1 g vial and 60 mL for the 3 g vial) to produce a final 
concentration of 50 mg/mL. Use sterile water for injection without benzyl alcohol for 
neonates and infants < 2 years of age or patients with hypersensitivity to benzyl alcohol. 
Although the reconstituted product is stable for 7 days at room temperature and up to 6 weeks 

                
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under refrigeration, the manufacturer recommends refrigeration and use within 24 hours to 
reduce the possibility of microbial contamination. Store unreconstituted vials at room 
temperature 20°-25°C (68°-77°F). Protect from temperatures above 30°C (86° F). 
Ifosfamide may liquefy at temperatures > 35°C. 
 
Reconstituted solutions of ifosfamide or ifosfamide solution should be diluted further to 
concentrations of 0.6 to 20 mg/mL in dextrose or saline containing solutions. Such 
admixtures, when stored in large volume parenteral glass bottles, Viaflex bags or PAB 
bags, are physically and chemically stable for 1 week at 30°C (86°F) or 6 weeks at 5°C 
(41°F). The manufacturer recommends refrigeration and use within 24 hours to reduce the 
possibility of microbial contamination. 
 
Mesna must always be administered in conjunction with ifosfamide. Adequate hydration 
LVUHTXLUHG$FKLHYHXULQHVSHFLILFJUDYLW\ 1.010 prior to start of ifosfamide. Refer to the 
Chemotherapy Administration Guidelines for additional information. 
 
Supplier:  
Commercially available from various manufacturers. See package insert for further 
information 
 
6.6 
MESNA – ORAL and IV 
(sodium 2-mercaptoethane sulfonate, UCB 3983, Mesnex) NSC #113891(05/11/18) 
 
Source and Pharmacology:  
Mesna was developed as a prophylactic agent to reduce the risk of hemorrhagic cystitis 
induced by ifosfamide. Mesna is rapidly oxidized to its major metabolite, mesna disulfide 
(dimesna). Mesna disulfide remains in the intravascular compartment and is rapidly 
eliminated by the kidneys. In the kidney, the mesna disulfide is reduced to the free thiol 
compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites 
(acrolein and 4-hydroxy-ifosfamide) resulting in their detoxification. The first step in the 
detoxification process is the binding of mesna to 4-hydroxy-ifosfamide forming a 
nonurotoxic 4-sulfoethylthioifosfamide. Mesna also binds to the double bonds of acrolein 
and to other urotoxic metabolites. In multiple human xenograft or rodent tumor model 
studies, mesna in combination with ifosfamide (at dose ratios of up to 20-fold as single or 
multiple courses) failed to demonstrate interference with antitumor efficacy. 
 
After an 800 mg dose the half lives for mesna and dimesna are 0.36 hours and 1.17 hours, 
respectively. Approximately 32% and 33% of the administered dose was eliminated in the 
urine in 24 hours as mesna and dimesna, respectively. The majority of the dose recovered 
was eliminated within 4 hours. Mesna tablets have an oral bioavailability of 45-79% and a 
urinary bioavailability which ranged from 45-79% of intravenously administered mesna. 
The oral bioavailability is unaffected by food. When compared to intravenously 
administered mesna, the intravenous plus oral dosing regimen increases systemic 
exposures (150%) and provides more sustained excretion of mesna in the urine over a 24-
hour period. 
 
 

                
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Toxicity1: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to <5 children out 
of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Bad taste with oral use 
Nausea, vomiting, 
stomach pain, fatigue, 
headache 
Facial flushing, fever, pain 
in arms, legs, and joints, 
rash, transient hypotension, 
tachycardia, dizziness, 
anxiety, confusion, 
periorbital swelling, 
anaphylaxis, coughing 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
 
Diarrhea 
 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of mesna have not been noted in animals fed 
10 times the recommended human doses. There are however no adequate and well-
controlled studies in pregnant women. It is not known if mesna or dimesna is excreted 
into human milk 
1All currently available products in the U.S. are preserved with benzyl alcohol. Benzyl Alcohol has 
been associated with death in pre-term infants weighing less than 2500 g and receiving 99-
405 mg/kg/day. Benzyl alcohol is normally oxidized rapidly to benzoic acid, conjugated with glycine 
in the liver, and excreted as hippuric acid. In pre-term infants, however, this metabolic pathway may 
not be well developed. Onset of toxic illness in these infants occurred between several days and a few 
weeks of age with a characteristic clinical picture that included metabolic acidosis progressing to 
respiratory distress and gasping respirations. Many infants also had central-nervous-system 
dysfunction, including convulsions and intracranial hemorrhage; hypotension leading to 
cardiovascular collapse was a late finding usually preceding death. [For comparison in the ICE 
regimen of 3000 mg/m²/day of ifosfamide and a daily mesna dose of 60% of the ifosfamide dose = to 
1800mg/m²/day; a child would be expected to receive 18 mL/m²/day of mesna (concentration of 
100 mg/mL and 10.4 mg/mL of benzyl alcohol) 187.2 mg/m²/day of benzyl alcohol or 6.24 mg/kg/day.]   
 
Formulation and Stability:  
Mesna is available as scored 400 mg oral tablets. Excipients include lactose, 
microcrystalline cellulose, calcium phosphate, cornstarch, povidone, magnesium stearate, 
hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide, and simethicone. 
 
Mesna for injection is available as 100 mg/mL in 10 mL multidose vials which contain 
0.25 mg/mL edetate disodium and sodium hydroxide for pH adjustment. Mesna Injection 
multidose vials also contain 10.4 mg/mL of benzyl alcohol as a preservative. Store product 
at controlled room temperature, 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. 
 
For IV administration, dilute mesna to 20 mg/mL with dextrose or saline containing 
solutions. Mesna may be mixed with ifosfamide or cyclophosphamide. After dilution for 
administration, mesna is physically and chemically stable for 24 hours at 25ºC (77ºF). 
Carefully expel air in syringes prepacked for use to avoid oxidation to dimesna.  

                
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For oral administration, administer as tablets or diluted parenteral solution.  
 
Oral tablets: 
Mesna tablets are scored and doses can be rounded to half a tablet (200 mg).  
 
Injection for oral use: 
Dilute the mesna parenteral 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. 
 
6.7 
PEGFILGRASTIM 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®) NSC #725961         (02/10/16) 
 
Source and Pharmacology: 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF (filgrastim). 
Pegfilgrastim 
is 
produced 
by 
covalently 
binding 
a 
20-kilodalton 
(kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of 
filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage specific 
colony-stimulating factor which regulates the production of neutrophils within the bone 
marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-
cell functional activation (including enhanced phagocytic ability, priming of the cellular 
metabolism associated with respiratory burst, antibody dependent killing, and the increased 
expression of some functions associated with cell surface antigens). 
 
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 15 to 
80 hours and the time to peak concentration ranges from 24 to 72 hours. Serum levels are 
sustained in most patients during the neutropenic period postchemotherapy, and begin to 
decline after the start of neutrophil recovery, consistent with neutrophil-dependent 
elimination. After subcutaneous administration at 100 mcg/kg in 37 pediatric patients with 
sarcoma, the terminal elimination half-life was 30.1 (+/- 38.2) hours in patients 0 to 5 years-
old, 20.2 (+/- 11.3) hours in patients 6 to 11 years-old, and 21.2 (+/- 16) hours in children 
12 to 21 years-old. 
 
 
 

                
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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 
(pain, induration, and local 
erythema), headache 
Low grade fever, allergic 
reactions (anaphylaxis, 
angioedema, or urticaria), 
generalized erythema and 
flushing,  
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, 
sickle cell crises in patients with 
sickle cell disease (SCD), 
excessive leukocytosis, Sweet's 
syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
ARDS 
Unknown 
frequency and 
timing: 
Fetal toxicities and teratogenic effects of pegfilgrastim in humans are unknown. Conflicting data 
exist in animal studies. It is unknown whether the drug is excreted in breast milk. 
 
Formulation and Stability: 
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). Store refrigerated at 2º-8ºC (36º-46ºF) and in the carton to protect from light. 
Prior to injection, pegfilgrastim may be allowed to reach room temperature protected from 
light for a maximum of 48 hours. Avoid freezing. 
 
Guidelines for Administration: See Treatment and Dose Modifications sections of the 
protocol. 
 
Pegfilgrastim should not be administered in the period between 2 weeks 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. See package insert for further information. 
 
 
 

                
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7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the protocol). 
 
7.1 
Required Clinical, Laboratory and Disease Evaluations  
All baseline studies must be performed prior to starting protocol therapy unless otherwise 
indicated below. Obtain other studies prior to start of phase unless otherwise 
indicated.   
 
These tables only include evaluations necessary to answer the primary and secondary 
aims. Obtain other studies as indicated for good clinical care.  
 
7.1.1 
Required and Optional Clinical, Laboratory and Disease Evaluations for Patients 
Randomized to Regimen A 
 
Regimen A: CHEMORADIOTHERAPY + Pazopanib 
Observation 
Baseline Prior 
to Treatment 
Initiation 
During 
Induction 
Therapy 
Prior to 
Week 13 
Surgery 
During 
Continuation 
Therapy 
End of 
TherapyA 
History, Physical Exam, Ht, Wt, BSA, Vital 
Signs  
X 
XB 
X 
XB 
X 
Blood PressureC 
X 
WeeklyB 
X 
XB 
X 
CBC with differential and platelets  
X 
WeeklyB 
X 
WeeklyB 
X 
Electrolytes including Ca, Mg, PO4 
X 
WeeklyB 
X 
XB 
X 
Creatinine, ALT, Total bilirubin 
XD 
WeeklyB,D 
X D 
  X B,D 
XD 
Amylase and lipaseT 
X 
XB 
 
XB 
 
Urinalysis +/- UPCE 
X 
XB 
X 
XB 
X 
Pregnancy test (females of childbearing 
potential) 
X 
 
 
 
 
Sperm banking (optional) 
X 
 
 
 
 
EKG and Echocardiogram or MUGA 
X 
XF 
 
XF 
X 
Pulmonary function tests 
XG 
 
 
 
XG 
MRI or CT scan of primary site 
XH 
 
XH 
 
XH 
CT chest 
X 
 
X 
 
X 
Growth plate evaluationS 
X 
 
 
 
X 
18FDG PET scan (optional, see Sec 16.4) 
X 
 
X 
 
 
Metastatic site imagingI 
X 
 
X 
 
X 
Central imaging reviewJ 
XJ 
 
XJ 
 
 
Operative notes & pathology reports 
XK 
XL 
XL 
XL 
XL 
Central pathology review 
XM 
 
XM 
 
 
Central radiotherapy review 
XN 
XO 
 
XO 
 
Medication Reconciliation 
 
XP 
 
XP 
 
Required biology studiesQ 
X 
 
 
 
 
Optional biology studiesR 
X 
X 
X 
 
 
Patient diary 
 
 
X 
 
X 
 
A = 
 
End of therapy is defined as 21 days after the first day of the last cycle of chemotherapy. The end of therapy date in patients 
who undergo surgery or radiotherapy for metastases after the completion of chemotherapy should be the date of the last 

                
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operation or the date of the last dose of radiotherapy, whichever is later. The specified evaluations can occur ± 7 days from 
these end of therapy dates. 
B = 
Within 4 days prior to the start of each chemotherapy cycle. Laboratory studies can be obtained off-site but norms for off site 
lab must be available at time of audit. 
C = 
Blood pressure will be measured with an appropriate sized cuff at rest. Blood pressure measurement will be repeated within 
the same day if the blood pressure (BP) is elevated (see Appendix V and Section 5.6). If both BP measurements are elevated, 
follow the guidelines in Section 5.6. Patients with elevated BP at any time should have BP measurements performed at least 
twice weekly until BP is within an acceptable range. 
D = 
Obtain direct bilirubin if total bilirubin is abnormally elevated. 
E = 
,IXULQDO\VLVVKRZVSURWHLQWKHQREWDLQXULQHSURWHLQFUHDWLQLQH UDWLR83&VHHAppendix XII). If UPC is > 2, then obtain 
a 24-hour urine collection for protein estimation (see Section 5.4). 
F = 
Obtain prior to Cycle 3 (Week 7) then prior to every doxorubicin-containing chemotherapy cycle once cumulative doxorubicin dose 
> 225 mg/m2 (Weeks 19 and 22). EKGs are to be obtained pre-dose prior to chemotherapy on Weeks 7, 19 and 22. 
G = 
Required only for patients whose radiotherapy field encompasses a portion of the lungs and who are of adequate age to 
successfully complete the tests. 
H = 
Baseline MRI of the primary site is preferred, or CT if the patient has a contraindication to MRI. It is recommended that the 
baseline study should also include imaging of regional lymph node bed for clear cell sarcoma and epithelioid sarcoma only. If 
a subtotal resection was done, the baseline study of the lymph node bed should be done after this operation. Use the same 
imaging modality for all disease evaluations (see Section 10.2.1 and Section 16). 
I = 
Metastases should be imaged by the most appropriate modality. 
J = 
Submit imaging of the primary and metastatic sites for central review as the scans are acquired (see Section 16 for guidelines). 
Imaging also must be submitted for central review for patients with either progressive/recurrent disease while on study and 
within 4 weeks of completing therapy. Note: imaging for suspected tumor progression/recurrence more than 4 weeks after 
completing therapy or a second malignant neoplasm should be submitted for future review. 
K =  Operative notes & pathology reports for EVERY surgical procedure (including biopsies) performed on the primary tumor and 
metastatic sites prior to study enrollment must be submitted. For pathology reports, include baseline or original reports (if the 
diagnosis was obtained on pathology from elsewhere) and any referral/consultation reports or reports containing ancillary 
information about the patient’s tumor, including but not limited to additional tumor testing such as molecular studies, 
conventional cytogenetic studies or electron microscopy.  
L = 
Submit operative notes & pathology reports for all procedures performed on primary and metastatic sites during treatment as 
well as any wound-related institutional procedure or operative reports (procedure reports would include radiologically-guided 
procedures such as drainage of collections). 
M = 
The pathologic specimen obtained at the time of diagnosis and definitive surgery at Week 13 will be centrally reviewed to 
assess response to treatment (see Section 14.2). Material is also to be submitted for central review at the time of tumor 
progression/recurrence and at the development of a second malignant neoplasm. 
N = 
Consultation with a Radiation Oncologist should occur at the time of study entry to facilitate timely initiation of RT at Week 4. 
O = 
Materials must be submitted for central radiotherapy quality assurance review and approval 1 week prior to the start of radiation 
therapy for the primary site and additional data at the completion of treatment per Section 17.10. 
P = 
Record total number doses of pazopanib omitted on case report form for each reporting period.   
Q = 
Collect required peripheral blood in a PAXgene RNA tube (2.5 mL) and in an EDTA tube (5 mL). See Section 15.1 for details. 
R = 
Slides, snap frozen tissue and blood are requested at diagnosis/pre-treatment. Blood is requested on Days 1-3 of Cycle 2. Snap 
frozen tissue and blood are requested at the time of surgery. Full details are provided in Sections 15.1, 15.2 and 15.3. A summary 
is provided in Appendix XIII. 
S = 
Only required for patients aged < 18 years. If patient is found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained at the end of therapy (see Section 16.8). 
T = 
Amylase and lipase should both be performed at centers where both tests are available. For sites where either amylase or lipase 
are not available (certain Canadian provences), at least 1 of the tests must be performed and will meet the protocol requirement 
for testing.  
 
 
 
 

                
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7.1.2 
Required and Optional Clinical, Laboratory and Disease Evaluations for Patients 
Randomized to Regimen B 
 
Regimen B: CHEMORADIOTHERAPY 
Observation 
Baseline Prior 
to Treatment 
Initiation 
During 
Induction 
Therapy 
Prior to 
Week 13 
Surgery 
During 
Continuation 
Therapy 
End of 
TherapyA 
History, Physical Exam, Ht, Wt, BSA, Vital 
Signs including Blood Pressure 
X 
XB 
X 
XB 
X 
CBC with differential and platelets 
X 
XB 
X 
XB 
X 
Electrolytes including Ca, Mg, PO4 
X 
XB 
X 
XB 
X 
Creatinine, ALT, Total bilirubin 
XC 
X B,C 
XC 
X B,C 
XC 
Urinalysis 
X 
XB 
X 
XB 
X 
Pregnancy test (females of childbearing 
potential) 
X 
 
 
 
 
Sperm banking (optional) 
X 
 
 
 
 
Echocardiogram or MUGA 
X 
XD 
 
XD 
X 
Pulmonary function tests 
XE 
 
 
 
XE 
MRI or CT scan of primary site 
XF 
 
XF 
 
XF 
CT chest 
X 
 
X 
 
X 
18FDG PET scan (optional, see Sec 16.4) 
X 
 
X 
 
 
Metastatic site imagingG 
X 
 
X 
 
X 
Central imaging reviewH 
XH 
 
XH 
 
 
Operative notes & pathology reports 
XI 
XJ 
XJ 
XJ 
XJ 
Central pathology review 
XK 
 
XK 
 
 
Central radiotherapy review 
XL 
XM 
 
XM 
 
Required biology studiesN 
X 
 
 
 
 
Optional biology studiesO 
X 
 
X 
 
 
 
A = 
 
End of therapy is defined as 21 days after the first day of the last cycle of chemotherapy. The end of therapy date in patients who 
undergo surgery or radiotherapy for metastases after the completion of chemotherapy should be the date of the last operation or 
the date of the last dose of radiotherapy, whichever is later. The specified evaluations can occur ± 7 days from these end of therapy 
dates. 
B = 
Within 4 days prior to the start of each chemotherapy cycle. Laboratory studies can be obtained off-site but norms for off site lab 
must be available at time of audit. 
C = 
Obtain direct bilirubin if total bilirubin is abnormally elevated. 
D = 
For patients < 21 years of age obtain prior to cycle 3 (Week 7) then prior to every doxorubicin-containing chemotherapy cycle once 
cumulative doxorubicin dose > 225 mg/m2 (Weeks 19 and 22))RUSDWLHQWV\HDUVRIDJHRQO\REWDLQRQWKHUDS\LIFOLQLFDOO\LQGLFDWHG 
E = 
Required only for patients whose radiotherapy field encompasses a portion of the lungs and who are of adequate age to successfully 
complete the tests. 
F = 
Baseline MRI of the primary site is preferred, or CT if the patient has a contraindication to MRI. It is recommended that the 
baseline study should also include imaging of regional lymph node bed for clear cell sarcoma and epithelioid sarcoma only. If a 
subtotal resection was done, the baseline study of the lymph node bed should be done after this operation. Use the same imaging 
modality for all disease evaluations (see Section 10.2.1 and Section 16). 
G = 
Metastases should be imaged by the most appropriate modality. 
H = 
Submit imaging of the primary and metastatic sites for central review as the scans are acquired (see Section 16 for guidelines). 
Imaging also must be submitted for central review for patients with either progressive/recurrent disease while on study and within 
4 weeks of completing therapy. Note: imaging for suspected tumor progression/recurrence more than 4 weeks after completing 
therapy or a second malignant neoplasm should be submitted for future review. 
I =  
Operative notes & pathology reports for EVERY surgical procedure (including biopsies) performed on the primary tumor and 
metastatic sites prior to study enrollment must be submitted. For pathology reports, include baseline or original reports (if the 
diagnosis was obtained on pathology from elsewhere) and any referral/consultation reports or reports containing ancillary 
information about the patient’s tumor, including but not limited to additional tumor testing such as molecular studies, conventional 
cytogenetic studies or electron microscopy. 
J = 
Submit operative notes & pathology reports for all procedures performed on primary and metastatic sites during treatment as well 
as any wound-related institutional procedure or operative reports (procedure reports would include radiologically-guided 
procedures such as drainage of collections). 

                
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K = 
The pathologic specimen obtained at the time of diagnosis and definitive surgery at Week 13 will be centrally reviewed to assess 
response to treatment (see Section 14.2). Material is also to be submitted for central review at the time of tumor progression/recurrence 
and at the development of a second malignant neoplasm. 
L = 
Consultation with a Radiation Oncologist should occur at the time of study entry to facilitate timely initiation of RT at Week 4. 
M = 
Materials must be submitted for central radiotherapy quality assurance review and approval 1 week prior to the start of radiation 
therapy for the primary site and additional data at the completion of treatment per Section 17.10. 
N = 
Collect required peripheral blood in a PAXgene RNA tube (2.5 mL) and in an EDTA tube (5 mL). See Section 15.1 for details. 
O =  Slides, snap frozen tissue and blood are requested at diagnosis/pre-treatment. Snap frozen tissue and blood are requested at the 
time of surgery. Full details are provided in Sections 15.1 and 15.2. A summary is provided in Appendix XIII. 
 
 
 
7.1.3 
Required and Optional Clinical, Laboratory and Disease Evaluations for Patients 
Randomized to Regimen C 
 
Regimen C: RADIOTHERAPY + Pazopanib 
Observation 
Baseline Prior 
to Treatment 
Initiation 
During 
Induction 
Therapy 
Prior to 
Week 10 
Surgery 
During 
Continuation 
Therapy 
End of 
TherapyA 
History, Physical Exam, Ht, Wt, BSA, Vital Signs 
X 
XB 
X 
XB 
X 
Blood PressureC 
X 
WeeklyB 
X 
XB 
X 
CBC with differential and platelets 
X 
WeeklyB 
X 
XB 
X 
Electrolytes including Ca, Mg, PO4 
X 
WeeklyB 
X 
XB 
X 
Creatinine, ALT, Total bilirubin 
XD 
Weekly B,D 
XC 
X B,D 
XD 
Amylase and lipaseT 
X 
XB 
 
XB 
 
Urinalysis +/- UPCE 
X 
XB 
X 
XB 
X 
Pregnancy test (females of childbearing potential) 
X 
 
 
 
 
Sperm banking (optional) 
X 
 
 
 
 
EKG and Echocardiogram or MUGA 
X 
 
XS 
XS 
X 
Pulmonary function tests 
XF 
 
 
 
XF 
MRI or CT scan of primary site 
XG 
 
XG 
 
XG 
CT chest 
X 
 
X 
 
X 
Growth plate evaluationR 
X 
 
 
 
X 
18FDG PET scan (optional, see Section 16.4) 
X 
 
X 
 
 
Metastatic site imagingH 
X 
 
X 
 
X 
Central imaging reviewI 
XI 
 
XI 
 
 
Operative notes & pathology reports 
XJ 
XK 
XK 
XK 
XK 
Central pathology review 
XL 
 
XL 
 
 
Central radiotherapy review 
XM,N 
 
 
 
 
Medication Reconciliation 
 
XO 
 
XO 
 
Required biology studiesP 
X 
 
 
 
 
Optional biology studiesQ 
X 
 
X 
 
 
Patient diary 
 
 
X 
 
X 
A = 
 
End of therapy is defined as the completion of Week 25. The end of therapy date in patients who undergo surgery or radiotherapy for 
metastases after the completion of chemotherapy should be the date of the last operation or the date of the last dose of radiotherapy, 
whichever is later. The specified evaluations can occur ± 7 days from these end of therapy dates. 
B = 
Within 4 days prior to the start of each chemotherapy cycle. Laboratory studies can be obtained off-site but norms for off site lab must 
be available at time of audit. 
C = 
Blood pressure will be measured with an appropriate sized cuff at rest. Blood pressure measurement will be repeated within the same 
day if the blood pressure (BP) is elevated (see Appendix V and Section 5.6). If both BP measurements are elevated, follow the 
guidelines in Section 5.6. Patients with elevated BP at any time should have BP measurements performed at least twice weekly until 
BP is within an acceptable range. 
D = 
Obtain direct bilirubin if total bilirubin is abnormally elevated. 
E = 
,IXULQDO\VLVVKRZVSURWHLQWKHQREWDLQXULQHSURWHLQFUHDWLQLQH UDWLR83&VHHAppendix XII). If UPC is > 2, then obtain a 24-
hour urine collection for protein estimation (see Section 5.4). 
F = 
Required only for patients whose radiotherapy field encompasses a portion of the lungs and who are of adequate age to successfully 
complete the tests. 
G = 
Baseline MRI of the primary site is preferred, or CT if the patient has a contraindication to MRI. It is recommended that the baseline 
study should also include imaging of regional lymph node bed for clear cell sarcoma and epithelioid sarcoma only. If a subtotal 

                
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ARST1321 
resection was done, the baseline study of the lymph node bed should be done after this operation. Use the same imaging modality for 
all disease evaluations (see Section 10.2.1 and Section 16). 
H = 
Metastases should be imaged by the most appropriate modality. 
I = 
Submit imaging of the primary and metastatic sites for central review as the scans are acquired (see Section 16 for guidelines). Imaging 
also must be submitted for central review for patients with either progressive/recurrent disease while on study and within 4 weeks of 
completing therapy. Note: imaging for suspected tumor progression/recurrence more than 4 weeks after completing therapy or a 
second malignant neoplasm should be submitted for future review. 
J = 
Operative notes & pathology reports for EVERY surgical procedure (including biopsies) performed on the primary tumor and 
metastatic sites prior to study enrollment must be submitted. For pathology reports, include baseline or original reports (if the diagnosis 
was obtained on pathology from elsewhere) and any referral/consultation reports or reports containing ancillary information about the 
patient’s tumor, including but not limited to additional tumor testing such as molecular studies, conventional cytogenetic studies or 
electron microscopy. 
K =  Submit operative notes & pathology reports for all procedures performed on primary and metastatic sites during treatment as well as 
any wound-related institutional procedure or operative reports (procedure reports would include radiologically-guided procedures 
such as drainage of collections). 
L = 
The pathologic specimen obtained at the time of diagnosis and definitive surgery at Week 10 will be centrally reviewed to assess 
response to treatment (see Section 14.2). Material is also to be submitted for central review at the time of tumor progression/recurrence 
and at the development of a second malignant neoplasm. 
M = 
Consultation with a Radiation Oncologist should occur at the time of study entry to facilitate timely initiation of RT at Week 1. 
N = 
Materials must be submitted for central radiotherapy quality assurance review and approval 1 week prior to the start of radiation 
therapy for the primary site and additional data at the completion of treatment per Section 17.10. 
O = 
Record total number doses of pazopanib omitted on case report form for each reporting period.  
P = 
Collect required peripheral blood in a PAXgene RNA tube (2.5 mL) and in an EDTA tube (5 mL). See Section 15.1 for details. 
Q = 
Slides, snap frozen tissue and blood are requested at diagnosis/pre-treatment. Snap frozen tissue and blood are requested at the time 
of surgery. Full details are provided in Sections 15.1 and 15.2. A summary is provided in Appendix XIII. 
R = 
Only required for patients aged < 18 years. If patient is found to have an open tibial growth plate, then repeat plain AP radiographs 
of the same tibial growth plate will be obtained at the end of therapy (see Section 16.8). 
S= 
Prior to Week 10 Surgery obtain EKG before stopping pazopanib prior to surgery (ECHO or MUGA can be obtained before or after 
stopping pazopanib but prior to surgery). During continuation therapy obtain EKG only (no ECHO or MUGA), 2-4 weeks after the 
start of the continuation phase. 
T = 
Amylase and lipase should both be performed at centers where both tests are available. For sites where either amylase or lipase are 
not available (certain Canadian provences), at least 1 of the tests must be performed and will meet the protocol requirement for testing. 
 
 
 

                
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7.1.4 
Required and Optional Clinical, Laboratory and Disease Evaluations for Patients 
Randomized to Regimen D 
 
Regimen D: RADIOTHERAPY 
Observation 
Baseline Prior to 
Treatment Initiation 
Prior to Week 10 
Surgery 
End of TherapyA 
History and Physical Exam 
X 
 
X 
CBC with differential and platelets 
X 
X 
X 
Electrolytes including Ca, Mg, PO4 
X 
X 
X 
Creatinine, ALT, Total bilirubin 
XB 
XB 
XB 
Urinalysis 
XC 
XC 
XC 
Pregnancy test (females of childbearing 
potential) 
X 
 
 
Sperm banking (optional) 
XD 
 
 
Echocardiogram or MUGA 
XE 
 
XE 
Pulmonary function tests 
XF 
 
XF 
MRI or CT scan of primary site 
XG 
XG 
XG 
CT chest 
X 
X 
X 
18FDG PET scan (optional, see Section 16.4) 
X 
X 
 
Metastatic site imagingH 
X 
X 
X 
Central imaging reviewI 
XI 
XI 
 
Operative notes & pathology reports 
XJ 
XK 
XK 
Central pathology review 
XL 
XL 
 
Central radiotherapy review 
XM,N 
 
 
Required biology studiesO 
X 
 
 
Optional biology studiesP 
X 
X 
 
 
A = 
 
End of treatment is defined as 30 days following the last dose of radiotherapy. The specified evaluations can occur ± 7 days 
from these end of therapy dates. 
B = 
Obtain direct bilirubin if total bilirubin is abnormally elevated. 
C = 
Only for patients whose kidneys, ureters, or bladder will be within the radiotherapy field. 
D = 
Recommended only if the testes are within the radiotherapy field. Surgical repositioning of the testes to the groin may be 
warranted to protect fertility if the testes will be in the radiotherapy field. 
E = 
Required only for patients whose radiotherapy field encompasses a portion of the heart. 
F = 
Required only for patients whose radiotherapy field encompasses a portion of the lungs and who are of adequate age to 
successfully complete the tests. 
G = 
Baseline MRI of the primary site is preferred, or CT if the patient has a contraindication to MRI. It is recommended that the 
baseline study should also include imaging of regional lymph node bed for clear cell sarcoma and epithelioid sarcoma only. 
If a subtotal resection was done, the baseline study of the lymph node bed should be done after this operation. Use the same 
imaging modality for all disease evaluations (see Section 10.2.1 and Section 16). 
H = 
Metastases should be imaged by the most appropriate modality. 
I = 
Submit imaging of the primary and metastatic sites for central review as the scans are acquired (see Section 16 for guidelines). 
Imaging also must be submitted for central review for patients with either progressive/recurrent disease while on study and 
within 4 weeks of completing therapy. Note: imaging for suspected tumor progression/recurrence more than 4 weeks after 
completing therapy or a second malignant neoplasm should be submitted for future review. 
J =  
Operative notes & pathology reports for EVERY surgical procedure (including biopsies) performed on the primary tumor and 
metastatic sites prior to study enrollment must be submitted. For pathology reports, include baseline or original reports (if the 
diagnosis was obtained on pathology from elsewhere) and any referral/consultation reports or reports containing ancillary 
information about the patient’s tumor, including but not limited to additional tumor testing such as molecular studies, 
conventional cytogenetic studies or electron microscopy. 
K = 
Submit operative notes & pathology reports for all procedures performed on primary and metastatic sites during treatment as 
well as any wound-related institutional procedure or operative reports (procedure reports would include radiologically-guided 
procedures such as drainage of collections). 
L = 
The pathologic specimen obtained at the time of diagnosis and definitive surgery at Week 10 will be centrally reviewed to 
assess response to treatment (see Section 14.2). Material is also to be submitted for central review at the time of tumor 
progression/recurrence and at the development of a second malignant neoplasm. 
M = 
Consultation with a Radiation Oncologist should occur at the time of study entry to facilitate timely initiation of RT at Week 1. 
N = 
Materials must be submitted for central radiotherapy quality assurance review and approval 1 week prior to the start of 
radiation therapy for the primary site and additional data at the completion of treatment per Section 17.10. 

                
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O = 
Collect required peripheral blood in a PAXgene RNA tube (2.5 mL) and in an EDTA tube (5 mL). See Section 15.1 for 
details. 
P = 
Slides, snap frozen tissue and blood are requested at diagnosis/pre-treatment. Snap frozen tissue and blood are requested at 
the time of surgery. Full details are provided in Sections 15.1 and 15.2. A summary is provided in Appendix XIII. 
 
7.2 
Optional Studies  
The correlative biology studies include both required and strongly recommended samples 
for all patients. These studies are very important to increase our understanding of pediatric 
and adult NRSTS. If a patient has consented to optional specimen collection on this study, 
tumor tissue and blood should be submitted to support correlative biology studies.  
 
See Section 15.0 for detailed specimen requirements and Appendix XIII for a summary. 
 
Use of specimens 
The tumor and blood samples collected in this study will be used for studies specified in 
the ARST1321 protocol and for studies to be conducted in the future related to the purposes 
of the ARST1321 study and not currently described in the protocol document. Detailed 
protocols for the genomics and proteomics work described in Section 15.0 of the protocol 
will be developed as separate protocols to include analytical and statistical methodologies 
and will be submitted for review and approval of these methodologies in accordance with 
the National Cancer Institute Clinical Trials Network. Studies conducted in the future 
related to the purposes of the ARST1321 study and not currently described in the protocol 
document will be submitted for review and approval in accordance with the National 
Cancer Institute Clinical Trials Network. 
 
The procured specimens, including DNA samples derived from them, will not be used 
for hereditary genetic studies involving genes conferring susceptibility to cancer or other 
diseases unless additional consent is obtained from the patient or parent or guardian or 
an anonymization process is used. Results of the correlative science studies will not be 
reported to the patient or their physician and will not have any bearing on their treatment. 
 
The results of the study will be communicated through publications, in peer reviewed 
scientific literature, and/or through presentations at scientific meetings. However, de-
identified or anonymized research data, including genome sequencing data, will be 
submitted to public research databases such as dbGaP for data sharing with scientific 
researchers outside of the COG/NRG Oncology. 
 
7.3 
Follow-up  
See Section 16.2.2 for recommended imaging post-treatment.  
 
Due to concerns of growth disturbances for patients with open growth plates at study entry, 
plain AP radiographs of the same tibial growth plate are required in follow-up for any 
patient aged < 18 years assigned to receive pazopanib (see Section 16.8). 
 
In addition, see COG Late Effects Guidelines for recommended post treatment follow-up 
for children: http://www.survivorshipguidelines.org/  
 
Note: Follow-up data must be submitted per the Case Report Forms (CRFs) schedule. 
 
 
 

                
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ARST1321 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease. 
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) are outside the parameters required for 
eligibility. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless consent was withdrawn. 
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (eg, at 
recurrence). 
d) Withdrawal of consent for any further data submission. 
e) The fifth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
This study is designed with 2 independent clinical trials for patients with unresected NRSTS of 
extremities or trunk. Separate trials will be conducted for patients eligible for the chemotherapy 
cohort (randomized Phase II study of chemo/RT with or without pazopanib) and non-chemotherapy 
cohort (randomized Phase II/III study of RT with or without pazopanib).  
 
9.1 
Sample Size and Study Duration 
Enrollment expected from COG: COG recently completed enrollment to enrollment to 
ARST0332 (Risk-Based Treatment for Pediatric NRSTS). Steady-state enrollment was 
about 125 patients annually. 
 
Only patients with unresected (ARST0332 Arm D) primary tumors of extremities or trunk 
will be eligible for this study. Enrollment of such patients was about 29 per year on 
ARST0332. 
 
Among these patients, 72% have tumors classified as “chemo-sensitive”.  
 
Thus, COG yearly enrollment is expected to be about 21 patients with chemo-sensitive 
tumors and 8 with chemo-resistant tumors. Of these, 15/21 and 5/8 are expected to have 
localized disease. 
 

                
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Enrollment expected from NRG Oncology: RTOG 0630, a recent study for the treatment 
of NRSTS accrued 98 patients in 2.5 years (12 to chemotherapy cohort; 86 to no 
chemotherapy cohort, all with localized disease). Thus, NRG Oncology would be expected 
to contribute 5 patients to the chemotherapy sensitive cohort and 35 patients to the 
chemotherapy resistant cohort annually. Additional patients with metastatic tumors are 
expected, but it is hard to estimate how many will be available. 
 
The table following provides the best estimate of the number of patients available for study 
annually. 
 
Enrollment is proposed to continue for about 4.5 years, with a total enrollment of up to 
340 patients (140 with chemo-sensitive disease and 200 with chemo-resistant disease).  
 
9.2 
Dose-Finding Phase for Pazopanib in Both Patient Cohorts 
Two of three dose levels of pazopanib (Pediatric patients: 275, 350, 450 mg/m2 PO once 
daily; Adult patients: 400, 600, 800 mg PO once daily) may be studied. Initially, up to 
10 patients (minimum of 3 patients DQG\HDUVRIDJHDQGSDWLHQWV\HDUVRI
age) eligible for each of the two study cohorts will be non-randomly assigned (to generate 
8 patients evaluable for toxicity) to receive treatment with pazopanib at dose level 1. The 
following TKI-associated adverse events will be defined as dose-limiting toxicities 
(DLTs): 
 
Dose-limiting hypertension: 
x 
Grade 3 hypertension not controlled after a week on 2 anti-hypertensive medications 
x 
Grade 4 hypertension 
 
Dose-limiting cardiotoxicity: 
x 
Grade 3+ left ventricular systolic dysfunction 
 
Dose-limiting dermatitis: 
x 
Grade 3+ hand-foot skin reaction  (palmar-plantar erythrodysesthesia syndrome) 
x 
Grade 3+ dermatitis radiation 
 
Dose-limiting gastrointestinal toxicity: 
x 
Grade 3+ ALT 
x 
Grade 3+ bilirubin 
x 
Grade 4 amylase 
x 
Grade 4 lipase 
x 
Grade 4 mucositis 
Patient subset 
COG annual 
enrollment 
NRG Oncology annual 
enrollment 
Total annual 
enrollment 
Chemo-sensitive, 
localized disease 
15 
5 
20 
Chemo-sensitive, 
metastatic disease 
6 
Unknown 
6+ 
Chemo-resistant, 
localized disease 
5 
35 
40 
Chemo-resistant, 
metastatic disease 
3 
Unknown 
3+ 

                
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Dose-limiting nephrotoxicity: 
x 
Grade 3+ proteinuria 
 
In addition, any death as a first event not attributable to disease will be counted as a dose-
limiting toxicity event, as will any withdrawal from protocol treatment as a result of 
“intolerable toxicity”. 
 
The pazopanib dose to be used in each treatment cohort will be determined using the 
following heuristic (with the DLT evaluation period defined as the first 6 protocol weeks 
of therapy):  
 
If 0-1 DLTs at dose level 1, escalate to dose level 2 and treat up to 10 more patients. 
If 2-3 DLTs at dose level 1, dose level 1 is the dose to be used in the study. 
If 4 or more DLTs at dose level 1, reduce to dose level 0 and treat up to 10 more 
patients. 
 
If 4 or more DLTs are observed at any dose level prior to enrollment of 8 pazopanib-treated 
patients, further enrollment will be stopped and further dose modification will be made as 
if 8 pazopanib-treated patients were enrolled. 
 
The DLTs defined above are rare when treatment does not include a TKI. 
 
The table below defines the probability of various actions following the treatment of the 
first 8 patients, for various true rates of DLT in the first 6 protocol weeks of therapy:  
 
 
True DLT rate for 
treatment in the first 
6 protocol weeks of 
therapy 
Prob (0-1 
DLTs), escalate 
to dose level 2 
Prob (2-3 DLTs), 
proceed with dose level 
1 for randomized phase 
Prob (4+ DLTs), 
de-escalate to dose 
level 0 
0.10 
0.81 
0.18 
0.005 
0.25 
0.37 
0.52 
0.11 
0.30 
0.26 
0.55 
0.19 
0.45 
0.06 
0.41 
0.52 
 
When the rate of DLT is near 10%, the most likely outcome is to escalate to dose level 2. 
For DLT rates in the range of 20-25%, the most likely outcome is to proceed with the 
formal evaluation of pazopanib at dose level 1. For a DLT rate of 45%, the most likely 
outcome is to de-escalate to dose level 0.  
 
Additional criteria for feasibility: The expected number of pazopanib doses a patient 
should receive during the first 6 weeks of therapy is 6 weeks x 7 doses/week = 42). The 
total number of full dose pazopanib doses a patient actually receives will be collected using 
a patient diary and recorded on the case report forms. Irrespective of the DLT rule above, 
if 3 or more patients out of 8 (> 25%) receive less than 75% of full dose pazopanib doses 
during the first 6 protocol weeks, a dose reduction (or dose non-escalation) will be 
considered. So, for instance, if 1 DLT was observed, but 5 patients received less than 75% 
of the protocol specified full dose pazopanib, the dose might remain at dose level 1 and the 
study proceed. Should 2-3 DLTs be observed and 3 or more patients receive less than 75% 

                
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of the protocol specified full dose pazopanib, the dose might be reduced to dose level 0 and 
up to 10 additional patients treated.  
 
If the dose is escalated or de-escalated after the enrollment of the first up to 10 patients, the 
heuristic will again be applied for the 8 evaluable patients treated at dose level 2 
(escalation) or 0 (de-escalation): 
 
At dose level 2, 0-3 DLTs would lead to that dose being used (provided no more than 
2 patients received less than 75% of the protocol specified full dose of pazopanib). 
4+ DLTs or 3+ patients receiving less than 75% of the protocol specified full dose of 
pazopanib might lead to dose level 1 being used. 
 
At dose level 0, 0-3 DLTs would lead to that dose being used (provided no more than 
2 patients received less than 75% of the protocol specified full dose of pazopanib). 
4+ DLTs or 3+ patients receiving less than 75% of the protocol specified full dose of 
pazopanib would likely lead to reconsideration of the randomized phase of the study. 
 
Applying the criteria: The criteria above are guidelines meant to inform the decision 
regarding the pazopanib dose to be used in the randomized phase of the study. Depending 
on the adverse events observed, de-escalation of the pazopanib dose may be required even 
if fewer than 4 DLTs are observed (for instance 3 cases of Grade 4 left ventricular systolic 
dysfunction). On the other hand, we may consider escalating the pazopanib dose after 
observing 4 DLTs (if, for instance they were all Grade 3 ALTs of short duration). 
 
9.3 
Monitoring of Dose Limiting Toxicities Following the Dose Finding Phase 
After at least 10 patients have been enrolled onto the chemo-radiotherapy plus pazopanib 
regimen or onto the radiotherapy plus pazopanib regimen, the rate of DLTs will be 
monitored as follows: 
 
Should the observed rate of DLTs on either of these treatment regimens at any of 
the scheduled interim analyses exceed 25% (e.g., > 5 out of 20 patients), study 
enrollment may be suspended so that the study committee may consider whether a 
change in the pazopanib dosing is necessary. 
 
The rates of other adverse events will be reported as part of each scheduled study progress 
report and CTEP-AERS-reportable events will be monitored and reviewed in real time. 
 
9.4 
Design and Statistical Considerations for the Phase II Study for Patients With 
Chemotherapy 
This study is designed as a randomized Phase II screening study where the primary 
endpoint is the protocol Week 13 pathologic response designed to assess the potential 
benefit for chemoradiotherapy plus pazopanib, compared to chemoradiotherapy alone. 
Patients randomized to pazopanib will continue to receive it subsequent to the Week 13 
evaluation if the patient does not have evidence of progressive disease. Before 
randomization, patients will be stratified by age (< 18 years versus 18+ years), localized 
versus metastatic disease and synovial sarcoma versus other sarcomas. 
 
Stage 1: Patients with high risk (> 5 cm, Grade 2 or 3) unresected chemotherapy-sensitive 
tumors with or without metastatic disease will be eligible for enrollment, provided 
resection of tumor is planned for the patients with metastatic disease at protocol Week 13. 

                
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The expected null (chemotherapy only) pathologic response rate (90%+ necrosis at Week 
13) is 40%. The significance level will be set at 20% (1-sided). Seventy (70) eligible 
patients with Week 13 pathologic response information will provide 80% power to detect 
a true response rate of 60% with pazopanib. The power calculations were performed 
assuming that the comparison of pathologic response rates will not be performed using a 
continuity correction. 
 
From the COG ARST0332 experience, up to 20% of patients may be lost due to 
ineligibility or off protocol therapy prior to the Week 13 surgical evaluation for reasons 
other than disease progression (patients off protocol therapy prior to protocol Week 13 for 
disease progression or non-response will be considered “Week 13” non-responders). We 
expect to have to randomize up to 100 patients total (50 per treatment) before we have the 
required 70 eligible patients evaluable for response.   
 
Interim monitoring for efficacy and futility will be performed, starting at about 43% of the 
expected information (Week 13 response known for 30 eligible patients) and again yearly. 
Interim monitoring for efficacy will use an O’Brien-Fleming boundary (truncated at 3 
standard deviations). For futility monitoring, we will repeatedly test the hypothesis that 
Prob{Response (ID + pazopanib)} – Prob{Response (ID)} =0.20 versus the alternative the 
difference is less than 0.20 at a p-value of 0.05. 
 
We will compute estimates of event-free survival (EFS: time to the first occurrence of 
progression, relapse after response, secondary cancer or death from any cause) for each 
randomized treatment group, although this will be descriptive only. The Phase II sample 
size will not be sufficient to provide adequate power to detect relative risks reductions that 
could be expected with the addition of pazopanib in this patient population.   
 
9.5 
Design and Statistical Considerations for the Phase II/III Study for Patients Without 
Chemotherapy 
The structure of this study is that of a two-stage Phase II/III study for patients with chemo-
resistant tumors or patients with chemo-sensitive tumors that meet the criteria in 
Section 3.2.2 and 3.2.3: a randomized Phase II screening study where the primary endpoint 
is the protocol Week 10 pathologic response; if Stage 1 suggests a potential benefit for 
radiotherapy plus pazopanib, the study will be extended to a Phase III study with event-
free survival as the primary endpoint. Pathologic response results (not EFS) from the Phase 
II study will be made available if the trial proceeds to the Phase III component. Before 
randomization, patients will be stratified by age (< 18 years versus 18+ years), grade 
(French criteria: 2 versus 3) and size of primary (< 5 cm versus 5+ cm).  
 
Stage 1: Patients with unresectable tumors with or without metastatic disease will be 
eligible for Stage 1 enrollment, provided resection of tumor is planned for the patients with 
metastatic disease at protocol Week 10. For chemo-resistant tumors, the expected null 
(radiation therapy only) pathologic response rate (90%+ necrosis at Week 10) is 10%. The 
significance level will be set at 20% (1-sided). Seventy (70) eligible patients with Week 10 
pathologic response information will provide 80% power to detect a response rate of 25%, 
of sufficient interest to complete the Phase III study (see details below). The power 
calculations were performed assuming that the comparison of pathologic response rates 
will not be performed using a continuity correction. 
 

                
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From the COG ARST0332 experience, up to 20% of patients may be lost due to 
ineligibility or off protocol therapy prior to the Week 10 surgical evaluation for reasons 
other than disease progression (patients off protocol therapy prior to protocol Week 10 for 
disease progression or non-response will be considered “Week 10” non-responders. We 
expect to have to randomize up to 100 patients total (50 per treatment) before we have the 
required 70 eligible patients evaluable for response.  
 
In the absence of adverse event concerns with radiotherapy + pazopanib, if Stage 1 
enrollment continues to 70 patients and is not stopped at interim monitoring, study 
enrollment will not be suspended while the final pathologic response data are 
assembled. The Week 10 response rates between the randomized treatments will be 
compared using a chi-square test for contingency tables.  
 
Interim monitoring for efficacy and futility will be performed, starting at about 50% of the 
expected information (Week 10 response known for 35 eligible patients) and again yearly. 
Interim monitoring for efficacy will use an O’Brien-Fleming boundary (truncated at 3 
standard deviations). For futility monitoring, we will repeatedly test the hypothesis that 
Prob{Response (RT + pazopanib)} – Prob{Response (RT)} =0.15 versus the alternative 
the difference is less than 0.15 at a p-value of 0. 05. 
 
Stage 2: Should Stage 1 indicate that the study can proceed to Stage 2, enrollment will 
then be restricted to patients with localized unresectable tumors (without metastatic 
disease). Patients with localized disease enrolled in Stage 1 will contribute to the Phase III 
study analysis. The primary endpoint for the Phase III study will be event-free survival, 
defined as the first occurrence of progression, relapse after response, a secondary cancer 
or death as a first event from any cause. 
 
The null (radiation therapy only) 5-year EFS for patients with localized unresectable 
chemo-resistant tumors is expected to be about 30%. Testing will be performed at the 5% 
level of statistical significance (1-sided; only an improvement with pazopanib is of 
interest). The study is designed to have 80% power to detect a 40% reduction is the event 
risk (0.6:1.0), equivalent to a 5-year EFS improvement to 49%); thus 95 total observed 
events are required. To assure that 95 events are observed, up to a total of 150 patients will 
be enrolled.  
 
Interim monitoring of the Phase III study will be performed. Interim monitoring will begin 
at about 33% of the expected information (which is expected to occur near the time Phase 
III enrollment begins and will be performed annually. Interim monitoring for efficacy will 
use an O’Brien-Fleming boundary (truncated at 3 standard deviations) and an alpha-
spending function approach to the monitoring. For futility monitoring, we will repeatedly 
test the hypothesis that the true event relative risk is 0.60 versus the alternative that the 
relative risk is greater than 0.60 at a p-value of 0.05. 
 
9.6 
Statistical Considerations for Study Secondary Objectives 
9.6.1 
Considerations for Aim 1.2.1 
Definitions of failure types: 
x 
Local failure: disease recurrence only at the primary site of disease at 
diagnosis 

                
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x 
Regional failure: disease recurrence at lymph nodes regional to the 
primary disease site, with or without local failure but without distant 
failure (see below) 
x 
Distant failure: disease recurrence at sites other than the primary site and 
diagnosis and nodes regional to that site (metastatic disease, whether or 
not present at diagnosis), with or without loco-regional failure.  
 
Failure types will be characterized into these mutually exclusive failure types and 
the cumulative incidence of these types of failure will be estimated, accounting for 
the fact that these are competing risks of failure (one type excluding the possibility 
of observing another type). 
 
9.6.2 
Considerations for Aim 1.2.2 
The relative risk of specific failure types will be estimated and compared 
descriptively using the Cox proportional hazard model. 
 
9.6.3 
Considerations for Aim 1.2.3 and Aim 1.2.4 
The adverse event profile of the treatments delivered (chemo-radiotherapy; 
radiotherapy) will be characterized using the current CTCAE version and adverse 
events defined in Section 11.10. 
 
9.7 
Statistical Considerations for Exploratory Aims 
9.7.1 
Statistical Analysis Plan for Actionable Mutations (Aim 1.3.1) 
Descriptive statistical analyses, conducted by Dr. Chi and colleagues at the COG 
Statistics and Data Center, will estimate the relative frequency of actionable 
mutations across the whole cohort and within more common histological subtypes, 
like synovial sarcoma and MPNST, as well as the frequency with which 
combinations of actionable mutations are observed in individual tumor types. 
 
9.7.2 
Statistical Analysis Plan for Whole Genome Sequencing (Aim 1.3.1) 
Descriptive and exploratory statistical analyses will be carried out as outlined 
above and will increase the precision with which the rates of actionable mutations 
are quantified in this population. 
 
9.7.3 
Statistical Analysis Plan for Microvessel Density and Circulating Tumor DNA 
Studies (Aim 1.3.2) 
Descriptive analyses will be performed. 
 
9.7.4 
Statistical Analysis Plan for Doxorubicin Pharmacokinetics in Combination with 
Pazopanib (Aim 1.3.3) 
Previous pharmacokinetic drug-drug interaction studies have indicated that 
decreases in the clearance of doxorubicin in adult patients with cancer of 30% are 
associated with significantly worsened side effects associated with the 
anthracycline182 including cardiotoxicity.183 The mean clearance for doxorubicin 
used in the power calculation was 25.6 L/h/m2, estimated from a group of 22 
pediatric cancer patients (median age, 15; range, 3.3-21.5 years) that had blood 
samples collected up to 48 hours after the end of infusion.184 In this group of 
patients, the observed SD of the doxorubicin clearance was estimated to be 
5.3 L/h/m2. The present trial is designed to allow detection of statistically 

                
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significant changes in the mean clearance of doxorubicin of at least 25% using a 
one-sample analysis, which concerns testing an observed experimental mean 
against the expected (historical) mean of 25.6 L/h/m2. Based on a double-sided 
analysis for a sample size of 10 for the prospective evaluation, with a significance 
level of 0.05 (5%), this provides a power of 0.93 (93%). The statistical analysis 
was 
performed 
in 
the 
SISA 
program 
(Available: 
http://www.quantitativeskills.com/sisa/; Accessed: November 2013). 
 
9.7.5 
Statistical Analysis Plan for FDG-PET Studies (Aim 1.3.4) 
FDG PET will be optional but encouraged for all enrolled patients. If done, FDG 
PET imaging should be performed prior to initiation of chemotherapy and at Week 
10 or 13 prior to tumor resection. Based upon ARST0332 and ARST0531, we 
anticipate 20-25% of patients will undergo FDG PET imaging. Due to the 
anticipated low percentage of study patients likely to have FDG PET scans 
performed, the FDG-PET images will be assessed as positive or negative at the 
primary site and PET response will be descriptively compared to the findings at 
Week 10 or 13 surgery. SUVmax will be determined. This data will provide pilot 
data regarding the relationship of FDG PET to therapy response. About 30 total 
events are expected among those patients with PET imaging at Week 10 or 13, too 
few to say anything definitive unless there is a very large difference in outcome 
between patients with PET+ and PET- disease, which is not expected. 
Nevertheless, we will estimate hazard ratios for the association between EFS and 
change in FDG PET SUVmax (or PET response at Week 10 or 13 based upon central 
review) and also estimate the association between pathologic response and PET 
response. 
 
9.7.6 
Statistical Analysis Plan for Exploratory Aim 1.3.5 
We will assess the relative risk of failure comparing CR to PR/NR based on both 
standard imaging and pathologic assessment using the log-rank test, to see if one 
response assessment method produces a larger difference in outcome between the 
response categories. 
 
We expect to observe few radiologic complete responses at the end of initial 
chemotherapy (the observed rate on ARST0332 was 1%), with a partial response 
rate of 20-30%, with most of the remaining patients classified as non-responders. 
We expect to show that imaging response is a poor predictor of subsequent event-
free survival, as was shown in rhabdomyosarcoma.185 
 
However, we expect to find that the EFS outcome for patients with good pathologic 
response (90+% necrosis) is better than that for those without a good pathologic 
response. As detailed in the statistical considerations, up to 20% of patients may 
not have evaluations of pathologic response at the Week 10 or 13 evaluation). We 
assume that (if the chemo resistant cohort continues to Phase III) about 250 patients 
will be available for assessing outcome from definitive surgery (excluding also 
those with progressive disease). If we restrict to patients with localized disease 
(N=175) we should expect to observe perhaps 85 events. Testing at the 5% level 
of statistical significance, we will have about 80% power to detect a relative risk 
difference of 0.55:1.00 (assuming an overall pathologic response rate of 50%. This 
corresponds to a long-term EFS of approximately 40% for non-responders and 
60% for responders.  

                
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9.8 
Gender and Minority Accrual Estimates  
The gender and minority distribution of the study population is expected to be: 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
27 
24 
51 
Not Hispanic or Latino 
153 
136 
289 
Ethnic Category: Total of all subjects 
180 
160 
340* 
Racial Category 
 
American Indian or Alaskan Native 
1 
3 
4 
Asian 
7 
4 
11 
Black or African American 
32 
26 
58 
Native Hawaiian or other Pacific Islander 
 
 
 
White 
140 
127 
267 
Racial Category: Total of all subjects 
180 
160 
340* 
 
 
 
 
* These totals must agree 
 
 
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 v5.0’ 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 Patients with Solid Tumors 
For the purposes of this study, patients should have imaging performed at baseline and be 
re-evaluated for response at Week 10 (treatment Regimens C and D) or Week 13 (treatment 
Regimens A and B). 
 
This study will use volumetric measurements of the primary tumor using an elliptical 
model (0.5 times the product of the three largest perpendicular diameters) to assess the 
diagnostic imaging response to neoadjuvant therapy. Response and progression of 
measurable metastases (including nodal metastases) will be evaluated using the largest 
unidimensional measurement. These measurements will be correlated with changes in the 
largest diameter in the (unidimensional measurement) of the primary tumor lesions and the 
shortest diameter in the case of malignant metastatic lymph nodes according to the new 

                
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international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1).186  
 
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.  
 
 
 
 
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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10.2.2 Disease Parameters 
10.2.2.1 Measurable disease: Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
UHFRUGHGDV 20 mm by chest x-UD\DV 10 mm with CT scan, or 
 10 mm with calipers by clinical exam. 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.  
 
10.2.2.2 Malignant lymph nodes: To be considered pathologically enlarged and 
PHDVXUDEOHDO\PSKQRGHPXVWEH 15 mm in short axis when assessed 
by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). At baseline and in follow-up, both the maximal long and short 
axis will be measured and followed. 
 
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 
TECHNICAL GUIDELINES FOR CROSS-SECTIONAL IMAGING
COMPUTED TOMOGRAPHY (CT)
All CT scans should be done with technical factors using the lowest radiation exposure possible (ALARA principle).
2. CT slice thickness should be 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).
RELATIONSHIP BETWEEN CHANGE IN SINGLE DIAMETER (RECIST), PRODUCT OF TWO 
DIAMETERS (WHO), AND THREE PERPENDICULAR DIAMETERS (“VOLUME”)
(Modified from Appendix II,Table 2, JNCI 92:213, 2000)
Diameter, 2R
Product, (2R)2
Volume, 4/3SR3
Response
Decrease
Decrease
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 ups. 

                
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ZLWK  10 to < 15 mm short axis), are considered non-measurable 
disease. 
Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis 
cutis/pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant lesions (neither 
measurable nor non-measurable) since they are, by definition, simple 
cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability 
described above. However, if non-cystic lesions are present in the same 
patient, these are preferred for selection as target lesions. 
 
10.2.2.4 Target lesions: All measurable lesions up to a maximum of 2 lesions per 
organ and 5 lesions in total, representative of all involved organs, should 
be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with 
the two longest perpendicular diameters), be representative of all 
involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can 
be measured reproducibly should be selected. A sum of the volumes and 
diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum 
volumes and diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
 
10.2.2.5 Non-target lesions: All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  
 
10.2.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations must be obtained within 3 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 preferred to evaluation by clinical examination unless 
the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
 
10.2.3.1 Clinical lesions: Clinical lesions will only be considered measurable 

                
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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 recommended.  
 
10.2.3.2 Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, 
CT is preferable and required. 
 
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. If DWI were 
acquired, they should be submitted with the rest of other MR sequences 
for central review (ref. Diffusion-weighted imaging (DWI) in 
musculoskeletal MRI: a critical review.187 
 
10.2.3.4 PET-CT: At present, the low dose or attenuation correction CT portion 
of a combined PET-CT is not always of optimal diagnostic CT quality 
for use with RECIST measurements. However, if the site can 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), then the CT 
portion of the PET-CT can be used for RECIST measurements and can 
be used interchangeably with conventional CT in accurately measuring 
cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
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 

                
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review at a later date and, because they are operator dependent, it cannot 
be guaranteed that the same technique and measurements will be taken 
from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
10.2.4 Response Criteria 
10.2.4.1 Evaluation of Target Lesions (Primary Tumor) 
 
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 64% decrease in volume compared 
to the measurement obtained at study 
enrollment. 
 
Progressive Disease (PD):At least 40% increase in tumor volume 
compared to the smallest volume obtained 
since the beginning of therapy. (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 disease 
volume since treatment started. 
 
10.2.4.2 Evaluation of Target Lesions (Metastatic Sites) 
 
 
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 
longest diameters of all target lesions, taking 
as reference the disease measurement done 
to confirm measurable disease at study 
enrollment   
 
Progressive Disease (PD):At least a 20% increase in the sum of the 
longest diameters of all target lesions, taking 
as 
reference 
the 
smallest 
disease 
measurement recorded since the start of 
treatment, or the appearance of one or more 
new lesions. 
 

                
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Stable Disease (SD): 
Neither sufficient shrinkage to qualify for 
PR nor sufficient increase to qualify for PD, 
taking as reference the smallest disease 
measurement since the treatment started. 
 
 
10.2.4.3 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. 
 
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 central imaging review 
panel (or Principal Investigator). 
 
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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For Non-Metastatic Patients with Measurable Disease (ie, Target 
Disease) 
 
Target 
Lesions 
(Primary 
Tumor) 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
 4 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
 
 4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at least once 
 4 wks. from baseline** 
PD 
Any 
Yes 
or 
No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes 
or 
No 
PD 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**Only for non-randomized trials with response as primary endpoint. 
***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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For Metastatic Patients with Measurable Disease (ie, Target Disease) 
Target 
Lesions 
(Primary 
Tumor) 
Target 
Lesions 
(Metastatic 
Sites) 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation 
is Required* 
CR 
CR 
CR 
No 
CR 
 4 wks. 
Confirmation** 
CR 
CR 
Non-
CR/Non-PD 
No 
PR 
 
 4 wks. 
Confirmation** 
CR 
PR 
Not evaluated 
No 
PR 
PR 
CR or PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
documented at 
least once 
 4 wks. from 
baseline** 
PD 
Any 
Any 
Yes 
or 
No 
PD 
 
no prior SD, PR 
or CR 
Any 
PD 
Any 
Yes 
or 
No 
PD 
Any 
Any 
PD*** 
Yes 
or 
No 
PD 
Any 
Any 
Any 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**Only for non-randomized trials with response as primary endpoint. 
***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 
 
 
10.2.5 Duration of Response 
10.2.5.1 Duration of overall response: The duration of overall response is 
measured from the time measurement criteria are met for CR or PR 
(whichever is first recorded) until the first date that recurrent or 
progressive disease is objectively documented (taking as reference for 

                
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progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is 
objectively documented. 
 
10.2.5.2 Duration of stable disease: Stable disease is measured from the start of 
the treatment until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the treatment started, including 
the baseline measurements.  
 
10.2.6 Progression-Free Survival 
Progression-free survival is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 
 
10.2.7 Response Review 
Central review of imaging studies will be performed in all patients (see 
Section 16). 
 
10.3 
Other Response Parameters 
Pathologic response will be assessed at Week 10 (treatment Regimen C and D) or Week 13 
(treatment Regimen A and B). Central pathology review will be performed in all patients 
(see Section 14). 
 
Surgical response will be assessed following the Week 10 (treatment Regimen C and D) 
or Week 13 (treatment Regimen A and B) definitive surgery (see Section 13). 
 
 
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.  
 

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

                
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possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol.  
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered to be serious AEs. 
 
11.4.3 Death 
Reportable Categories of Death  
 
x 
Death attributable to a CTCAE term.  
x 
Death Neonatal: A disorder characterized by cessation of life during the 
first 28 days of life.  
x 
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.  
x 
Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
x 
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions”. Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (eg, treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
x 
Leukemia secondary to oncology chemotherapy  
x 
Myelodysplastic syndrome  
x 
Treatment related secondary malignancy  

                
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Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified. 
 
11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to 301-230-0159. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents which may be teratogenic. For this reason, pregnancy 
needs to be reported in an expedited manner via CTEP-AERS as Grade 
3 “Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
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. 
 

                
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11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting Table A for this protocol. 
 
11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database.   
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A 
copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted electronically to NCI via CTEP-AERS at:  
https://eapps-ctep.nci.nih.gov/ctepaers. 
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to 
be made to the NCI for agents supplied under a CTEP IND by telephone call to 301-897-
7497.  
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site.   
 
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.  
 

                
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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.  
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: 301-230-0159 (back-up: 301-897-7404).  
Also: Fax or email to COG for all IND studies (fax # 626-303-1768; 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. 
 
 

                
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11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) $Q\$(WKDWUHVXOWVLQLQSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQIRU 24 hours. This 
 
does not include hospitalizations which are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may 
 
be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may 
 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 
 
312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below.   
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
KUV 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
KUV 
 
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 and Reporting Exceptions 
 
x 
Grades 1- 4 myelosuppression (anemia, neutropenia, thrombocytopenia) do not 

                
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require expedited reporting.  
 
x 
Grades 1-2 AST/ALT elevations do not require expedited reporting. 
 
x 
In addition to the defined CTCAE reporting of wound complication adverse 
events, there is expanded wound complication data submission requirements on 
the study reporting period and surgery central review case report forms (wound 
complication grading adapted from Dindo et al. 2004 and characterization of the 
wound complication adapted from O’Sullivan et al. 2013).143,144 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy With a Commercial Agent or Within 30 Days1 
 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent, regardless of attribution.  Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent which can be attributed (possibly, probably, 
or definitely) to the agent and is not due to cancer recurrence must be reported via CTEP-
AERS. 
 
 
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 4 and higher Adverse Events with the exception 
of the events listed in Section 11.10.  
 
 

                
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12.0 
STUDY REPORTING AND MONITORING  
The Case Report Forms and the submission schedule are posted on the COG web site with each 
protocol under “Data Collection/Specimens”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
Data and Safety Monitoring Committee 
To protect the interests of patients and the scientific integrity for all clinical trial research 
by the Children’s Oncology Group, the COG Data and Safety Monitoring Committee 
(DSMC) reviews reports of interim analyses of study toxicity and outcomes prepared by 
the study statistician, in conjunction with the study chair’s report. The DSMC may 
recommend the study be modified or terminated based on these analyses.  
 
Toxicity monitoring is also the responsibility of the study committee and any unexpected 
frequency of serious events on the trial are to be brought to the attention of the DSMC. The 
study statistician is responsible for the monitoring of the interim results and is expected to 
request DSMC review of any protocol issues s/he feels require special review. Any COG 
member may bring specific study concerns to the attention of the DSMC.  
 
The DSMC approves major study modifications proposed by the study committee prior to 
implementation (eg, termination, dropping an arm based on toxicity results or other trials 
reported, increasing target sample size, etc.). The DSMC determines whether and to whom 
outcome results may be released prior to the release of study results at the time specified 
in the protocol document. 
 
12.3 
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. 
 

                
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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 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: 

                
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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. 
 
 
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 
Initial Biopsy for Diagnosis and Tissue Submission  
An incisional biopsy or core biopsy is preferred. The biopsy should be done in such a way 
as to permit excision of the biopsy site at the time of formal resection. If the grade and 
subtype of the tumor cannot be determined from the core biopsy, then an incisional biopsy 
is required. Fine needle aspiration biopsy is not acceptable to establish the diagnosis. 
Sufficient tissue must be obtained by either method. The minimum recommended sampling 
is 8 core biopsies of 2 cm in length. The surgeon should sample heterogeneous areas as 
determined by prebiopsy imaging. Care must be taken to prevent penetration of the needle 
through the tumor into unaffected soft tissues.  
 
13.2 
Surgery 
 
13.2.1 
It is strongly recommended that any eligible patient is seen by the surgeon, 
pediatric/medical oncologist and radiation oncologist prior to instituting pre-operative 
therapy. The surgeon should determine and document a high possibility of both primary 
tumor resection and anticipation of a limb preservation approach after preoperative 
radiation to obtain local control. After radiation, every effort should be made to have limb 
preservation surgery unless there is documented evidence of tumor progression during or 
after the course of radiation that would require amputation for an appropriate negative 
margin resection. At the discretion of the treating physician(s), plastic and/or vascular 
surgeons may be consulted.  
 
Upon removal, the tumor specimen should be submitted immediately to the pathologist. It 
should not be bisected or cut into pieces prior to pathologic evaluation. The tissue should not 
be placed in formalin, as fresh and snap frozen tissue may be helpful in establishing the 
diagnosis and providing materials for biology studies and banking. If there will be any delay 
in transferring the specimen to the pathologist, it should be transported in cytogenetics 
medium. The surgeon should note the time of explantation to passing off of the specimen.  
 
13.2.2 
Resection of the sarcoma will occur following combined preoperative radiation and/or 
chemotherapy per study schema. The resection should be done with the goal of having 
negative pathologic margins. Quality assurance for surgical resection will be provided by 
both a review of the operative note and assessment of the specimen by surgical pathology. 
Microscopic absence of tumor on the inked margins will be accepted as a negative margin 

                
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resection (R0).  
 
13.2.3 
Definitions of operative procedures will be made after assessment of the operative note and 
pathologic evaluation of the resected specimen. The definitions include: 
 
13.2.3.1   
Amputation: Margin status will still be assessed and categorized if a limb 
preservation approach is not possible after the preoperative radiation.  
 
13.2.3.2   
Limb sparing surgery with the following margin status: R0: No residual tumor-
microscopically negative margins; R1: Microscopic residual tumor- microscopic 
positive margin(s) but no gross tumor; R2: Macroscopic residual tumor. It is strong 
encouraged that any patient with an R2 margin status following limb sparing 
surgery should be assessed for surgical re-excision, with a goal of achieving an RO 
or R1 margin. Any patient left with a R2 margin that is not reresected will be 
subject to central review. 
 
13.3 
Definitive Surgical Procedure
The surgical procedure necessary to resect the tumor with negative margins should be used. 
The definitions, as noted above, will be recorded in the surgical form. The goal of all 
surgery should also be limb preservation, if possible, within the realm of an appropriate 
oncologic resection.  
 
Because the presence or absence of residual tumor following definitive surgery determines 
whether or not postoperative primary-site radiotherapy is necessary, the goal of definitive 
tumor resection at Week 10 or 13 should be to achieve negative microscopic margins (R0), if 
possible. Patients with negative microscopic margins will not receive any postoperative 
primary-site radiotherapy. 
 
 
13.4 
Principles of Surgery  
13.4.1 
All lesions of the extremities and trunk should be treated with wide excision after 
preoperative radiation and/or chemotherapy. 
 
Any incisional biopsy site should be excised en bloc with the definitive surgical specimen. 
Needle biopsy tracks should only be excised if additional morbidity is not anticipated by 
doing so. Dissection should always be done through grossly normal tissue planes and 
ideally should be done beyond the fascial plane adjacent to the tumor. If the tumor is close 
to or displaces major vessels or nerves, these need not be removed if the adventitia or 
perineurium is removed and the underlying neurovascular structures are not involved with 
gross tumor. Dissection should include the periosteum if the tumor is adjacent to the bone 
but not invading. Radical excision or entire anatomic compartment resection is not 
recommended for patients on this study. 
 
To facilitate the assessment of surgical margins, the surgeon should take care to manipulate 
the specimen as little as possible to preserve anatomic relationships present at the time of 
resection; to mark and orient the margins for the pathologist; and to avoid bisecting, 
bivalving, or cutting the specimen into separate specimens. 

                
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If postoperative pathologic evaluation reveals positive soft tissue margins other than bone 
(periosteum), nerve or large blood vessels, surgical re-resection to obtain negative margins 
should strongly be considered if it will not have a major impact upon the patient’s 
functionality. If the margin on bone, major blood vessel or nerve is microscopically 
positive, additional radiation may be given as noted in the protocol. 
 
In general, lymph node dissection is not recommended, but primary tumors overlying 
major lymph node stations may be treated with surgical resection to include the associated 
lymph nodes. Surgical clips (titanium) should be placed to mark the periphery of the 
surgical field of resection and other relevant structures to help guide the radiation 
oncologist if postoperative radiation boost is necessary. Closed suction drainage may be 
used in all anatomic regions (Hemovac, JP, etc.). The drains should exit the skin close to 
the edge of the surgical incision and ideally in line with the incision distally. 
 
13.4.2 
It is strongly encouraged that the surgeon clearly state in the operative note what type of 
surgical procedure was intended (R0, R1, or R2) and from where the frozen sections of the 
margins were taken, if any. The final margin status (R status) should be based on the 
permanent pathology assessment (not frozen section). The surgeon may state that the intent 
of the procedure was wide resection to obtain a negative oncologic margin. However, the 
term “radical” should not be used to describe the procedure unless the intent of the surgery 
was truly to do a complete extracompartmental resection. 
 
13.4.3 
Because all patients will have had preoperative radiation, special attention must be given 
to the skin flaps. Use of muscle flaps, pedicled myocutaneous flaps, and even free flaps are 
encouraged to fill dead space and provide well-vascularized tissue. These flaps should be 
used if there is any concern regarding the viability of the skin flaps.  
 
13.4.4 
In general, the following principles should be followed in postoperative management of 
these patients: Maintain staples or skin sutures per surgeon preference. Leave drains in 
place until the drainage meets the surgeon’s criteria for removal. Begin rehabilitation per 
surgeon’s discretion.  
 
13.4.5 
Resectability will depend upon the judgment of the operating surgeon. The goal of all 
surgery for extremity tumors should be limb preservation, if possible within the realm of 
an appropriate oncologic resection. Every effort should be made to have limb preservation 
surgery. However, some extremity tumors may require amputation to obtain even grossly 
negative margins. Only amputation due to treatment complications (not primary intended 
surgical therapy) will be considered a surgical complication.  
 
13.5 
Surgical Management of Patients with Metastasis Prior to Study Enrollment 
All distant metastatic sites should be evaluated with appropriate imaging during the initial 
staging process. Biopsy should be performed whenever there is uncertainty as to the nature 
of an abnormal mass, particularly if all metastases are < 1 cm in maximal diameter. This 
may not be necessary in cases where a metastatic tumor growth is documented in a series of 
consecutive imaging studies including CT and/or MRI, which is highly suggestive of 

                
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metastatic disease by the institutional radiologist. The judgment should be made at the 
discretion of treating physician. These images should be submitted for central review upon 
request. The surgical approach for patients with metastatic disease should be individualized 
with the goal of accurately identifying involved sites and minimizing the number of 
surgical interventions required. If biopsy is required for tissue diagnosis of potential 
metastasis, the treating team may elect to resect the metastasis prior to study enrollment 
(for example, resecting pulmonary metastasis via thoracotomy or thoracoscopically). 
Clinical judgment should dictate the choice of surgical procedure and extent of resection. 
 
If not resected for tissue diagnosis, definitive resection to remove metastatic disease present 
at study entry should be performed at the completion of all protocol-required 
chemotherapy. Surgical resection of metastasis at Week 13 (chemotherapy cohort) or Week 
10 (non-chemotherapy cohort) (unless the metastasis can be removed via the same incision 
used for the primary tumor) or at any other time during therapy is prohibited unless there 
is strong clinical indication for doing so.  
 
13.5.1 Surgical Assessment of Lymph Nodes 
Lymph node sampling should be considered (but not required) in patients with 
epithelioid sarcoma and clear cell sarcoma because the incidence of nodal 
involvement in these tumors exceeds 15%. Lymph node sampling is recommended 
in patients with enlarged regional lymph nodes detected by physical exam or 
diagnostic imaging because this adenopathy may be reactive rather than neoplastic. 
This should be done prior to starting chemotherapy for staging purposes. 
 
When lymph node biopsy is to be done, the use of sentinel node mapping and 
biopsy techniques are encouraged (but not required) in cases of nonpalpable lymph 
nodes, as well as to supplement selective sampling among patients with clinically 
enlarged nodes. Sentinel node biopsy should be performed with technetium 99m 
sulfur colloid. The use of isosulfan blue 1% dye is an accepted adjunct to 
technetium, but is not required, particularly in younger pediatric patients, for 
whom effective yield of sentinel nodes has been demonstrated with technetium 
alone and in whom inadvertant tattooing of skin by the dye may be a consideration. 
 
Whether performed by selecting sampling or sentinel node technique, lymph node 
biopsies have a role in tumor staging and should therefore be done prior to the start 
of protocol therapy. If lymph node biopsies are positive for tumor (or the lymph 
nodes are classified as positive by the study radiologist), formal lymph node 
dissection may be considered at the time of Week 10 or Week 13 definitive surgery, 
or at completion of therapy when metastatic disease is resected. 
 
13.6 
Surgical Adverse Events  
 
13.6.1 Wound Complications 
Major wound complications (eg, secondary operations, re-admissions, and/or 
invasive procedures for wound complications: deep wound packing and prolonged 
dressing changes) will be reported using the relevant CTCAE version 5.0 criteria. 
 
13.7 
Surgical Quality Assurance Reviews 
The Surgical Oncology Co-Chairs from both COG and NRG Oncology will perform a 
Quality Assurance Review on a rolling basis once received at COG Statistics and Data 

                
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Center (SDC). The final cases will be reviewed within 3 months after this study has reached 
the target accrual or as soon as complete data for all cases enrolled has been received at 
COG SDC, whichever occurs first. 
 
Surgical quality assurance review will include examination of the formal operative report 
for the surgical resection, the treating institution’s final pathology report (including gross, 
frozen section, and microscopic pathologic descriptions), and the central pathology review. 
The reported resection (R) status from the operative note will be assessed and re-evaluated 
based upon the final pathology report and the central pathology review. The surgical 
quality assurance review will then assign an official protocol resection status based upon 
this information. From a clinical treatment and protocol standpoint, an R0 or R1 resection 
(especially following an attempt to preserve a major neurovascular or bony structure) 
would be considered an adequate surgical resection. For the purposes of this protocol, an 
R2 resection would not be considered adequate surgical therapy, even in the context of 
limb preservation. Any patient left with an R2 resection is subject to central review. 
 
Although every effort should be made to perform limb preservation surgery, some 
extremity tumors may require amputation to obtain negative margins if a limb preservation 
approach is not possible after preoperative radiation. In this scenario, amputation would 
still be considered adequate surgical therapy and margin status will be assessed or 
categorized based upon the R criteria for limb sparing surgery. 
 
 
14.0 
PATHOLOGY GUIDELINES AND SPECIMEN REQUIREMENTS 
 
14.1 
Aims of Retrospective Central Pathology Review 
The retrospective central pathology review has several goals: 
x 
To determine whether the addition of pazopanib to neoadjuvant 
chemoradiation or radiotherapy improves pathologic response in pediatric 
and adult NRSTS (study objectives 1.2.1 and 1.2.3). 
x 
To determine if pathologic response is predictive of outcome in pediatric and 
adult NRSTS (study objective 1.3.5). 
x 
To assess whether tumor response based on diagnostic imaging accurately 
reflects the pathologic response to neoadjuvant therapy in pediatric and adult 
NRSTS (study objective 1.3.5). 
x 
To confirm that only patients with NRSTS are enrolled on this clinical trial 
and that each patient was assigned to the appropriate treatment regimen 
based on the tumor histology and grade. 
 
All patients enrolled on this clinical trial will submit tumor tissue for central pathology 
review. The diagnosis of NRSTS and the histologic subtype will be confirmed during 
central pathology review of the percent pathologic necrosis rate. Due to high pathology 
concordance rates among individual enrolling institutions and central reviewers on 
ARST0332 and RTOG 0630 (information provided by COG and NRG Oncology), no rapid 
central review of the sarcoma histologic subtype will be required prior to enrollment or 
treatment initiation.  
 

                
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14.2 
Specimen Submission Requirements  
Please note: snap-frozen tissue is not required for study enrollment but should be collected 
whenever possible for correlative biology studies (see Section 15.1 and 15.2). 
COG sites: if a tissue block has been submitted already on APEC14B1, another block is 
not required for ARST1321. 
 
14.2.1 Pathology Specimens Must be Submitted at the Following Time Points: 
 
x 
Initial Pretreatment Specimen – The initial diagnostic specimen should be 
submitted for central review at the same time as the Week 10 or Week 13 
specimen.   
x 
Week 10 (treatment arms C and D) or Week 13 (treatment arms A and B) – 
After the surgical procedure is performed at Week 10 or Week 13, the resulting 
specimen must be submitted for central pathology review within 4 weeks of the 
surgery date. If the patient undergoes more than one operation at Week 10 or 
Week 13, specimens should be submitted from all procedures. 
x 
At the time of tumor progression/recurrence – The specimen obtained at the time 
of tumor progression/recurrence should be submitted for review to confirm the 
diagnosis. 
x 
At the time of development of a second malignant neoplasm – The biopsy or 
resection specimen obtained at the time of diagnosis of a solid second malignant 
neoplasm should be submitted for review to confirm the diagnosis. 
 
14.2.2 Samples to be Submitted on Study 
 
x 
Initial Pretreatment Specimen   
o Representative formalin-fixed paraffin blocks  
 
If blocks are unavailable, submit 1 H & E section of all available blocks and 
20 NRSTS plus-charged (polarized) unstained slides for immunoperoxidase 
studies from 1 or 2 representative blocks and 2 additional H & E slides from 
the same blocks. 
 
Note: If a block is not submitted for pathology review, then submission of 
10 scrolls of 15 micron thickness is strongly encouraged for biology studies 
(per Section 15.1.3) in addition to the submission of the materials for central 
pathology review. 
 
x 
Week 10 (treatment arms C and D) or Week 13 (treatment arms A and B) 
o Representative formalin-fixed paraffin blocks  
 
If blocks are unavailable, submit 1 H & E section of all available blocks and 
20 NRSTS plus-charged (polarized) unstained slides for immunoperoxidase 
studies from 1 or 2 representative blocks and 2 additional H & E slides from 
the same blocks. 
 
Note: in addition to these required samples, it is strongly recommended that the 
post treatment resections be handled similarly to treated osteosarcoma, and the 
following also be submitted: a cross section with a specimen map and the percent 
necrosis calculated accordingly. 

                
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x 
At the time of tumor progression/recurrence 
o Representative formalin-fixed paraffin blocks  
 
If blocks are unavailable, submit 1 H & E section of all available blocks and 
20 NRSTS plus-charged (polarized) unstained slides for immunoperoxidase 
studies from 1 or 2 representative blocks and 2 additional H & E slides from 
the same blocks. 
 
x 
At the time of development of a second malignant neoplasm  
o Representative formalin-fixed paraffin blocks  
 
If blocks are unavailable, submit 1 H & E section of all available blocks and 
20 tumor specimen plus-charged (polarized) unstained slides for 
immunoperoxidase studies from 1 or 2 representative blocks and 2 additional 
H & E slides from the same blocks. 
 
14.3 
Central Pathology Review Guidelines 
 
14.3.1 The Diagnostic Specimen 
No rapid central review of the sarcoma histologic subtype will be required prior to 
enrollment or treatment initiation. The original pretreatment specimen and the 
definitive surgical specimen will be reviewed together. The diagnostic specimen 
will be centrally reviewed by an expert panel of pathologists to determine the 
histologic subtype of soft tissue sarcoma. Each tumor also will be graded according 
to the guidelines of the FNCLCC grading systems (see Appendix III). FNCLCC 
Grade 1, 2 and 3 will be considered low grade, intermediate grade and high grade, 
respectively. In circumstances where more than one histology is present within a 
diagnostic specimen, the highest grade component determines the classification 
(i.e. chemotherapy or non-chemotherapy cohort).  
 
14.3.2 Week 10 or Week 13 Specimen 
The definitive resection specimen obtained at Week 10 (treatment arms C and D) 
or Week 13 (treatment arms A and B) patients will be evaluated for pathologic 
response. This assessment will include a formal evaluation of percent necrosis 
according to the guidelines established for osteosarcoma.188 The pathologic 
assessment of response (calculated percent necrosis) at Week 10 or Week 13 will 
be compared with the radiographic assessment of response to assess the degree of 
correlation between the two methods of measuring tumor response. The tumor 
response as assessed by central pathology review also will be evaluated to 
determine whether it predicts clinical outcomes such as local and distant disease 
control and survival. 
 
14.3.3 Tumor Progression/Recurrence Specimens 
The specimen obtained at the time of tumor progression/recurrence will be 
reviewed to confirm that the diagnosis is the same as at study entry and to 
document changes in pathologic appearance. 
 

                
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14.3.4 Second Malignant Neoplasm Specimens 
The specimen obtained at the time of diagnosis of a second malignant neoplasm 
will be examined to confirm the diagnosis and to ensure that the new diagnosis 
differs from the one assigned at the time of original diagnosis.   
 
14.4 
Sample Labeling and Shipping 
All tumor material must be labeled with the patient’s COG ID number and the surgical 
pathology ID number and block number from the corresponding pathology report. 
 
Please note that ANY tissue sample submission to the BPC for pathology review must 
include the following documentation:  
 
x 
Institutional pathology report 
x 
Pathology checklist 
x 
Institutional operative report (Can be provisional as long as final report is sent 
when available) 
x 
COG Specimen transmittal form  
 
All pathology review material should be sent to the COG Biopathology Center (BPC) at 
room temperature by regular mail or courier using the submitting institution’s courier 
account. Specimens must be accompanied by the Specimen Transmittal Form and sent to 
the following address:  
 
Biopathology Center  
Nationwide Children’s Hospital  
Protocol ARST1321 
700 Children’s Drive, WA1340*  
Columbus, OH 43205  
Phone: (614) 722-2865  
Fax: 
(614) 722-2897 
Email: BPCParaffinTeam@nationwidechildrens.org  
 
*Be sure to include the room number. Packages received without the room number may 
be returned to the sender.  
 
14.5 
Review Pathologists 
The central review pathologists for this study are listed below. DO NOT send specimens 
directly to the review pathologists. Send all materials to the Biopathology Center as 
directed in Section 14.4. 
 
Jennifer O. Black, MD 
Children’s Hospital Colorado 
Phone: (720) 777-1852 
Fax: 
(720) 777-7119 
E-mail: jennifer.black2@childrenscolorado.org  
 
Eduardo Zambrano, MD 
Presbyterian St. Luke/Rocky Mountain Hospital for Children 
Phone: (650) 498-1031 
Fax: 
(650) 724-6843 

                
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E-mail: Eduardo.Zambrano@HealthONEcares.com 
 
Julie C. Fanburg-Smith, MD 
Penn State Children’s Hospital 
Penn State Health/Milton S. Hershey Medical Center 
Phone: (703) 623-7013 
E-mail: jcfsmd@gmail.com 
 
 
15.0 
SPECIAL STUDIES SPECIMEN REQUIREMENTS  
 
15.1 
Analysis of Actionable Mutations and Whole Genome Sequencing  
 
15.1.1 Sample Collection and Processing 
Required samples: 
Submission of pretreatment paraffin-embedded tumor material (block) or 
unstained slides (per Section 14.2) is required of all patients. 
COG sites: if a block has been submitted already on APEC14B1, additional tissue 
is not required.  
 
If a block is not submitted for pathology review, then 10 scrolls of 15 micron 
thickness are strongly encouraged for the biology study. An H&E stained slide 
cut from the same block should also be submitted for quality control. 
 
The following peripheral blood samples are to be collected pre-treatment and 
shipped on the day of collection. 
 
x 
Peripheral blood (2.5 mL) in a PAXgene RNA tube  
x 
Peripheral blood (5 mL) in an EDTA-containing (purple top) tube 
 
Blood samples are to be processed as follows and shipped per Section 15.1.2 
below. 
 
When using the PAXgene RNA tube, blood is placed immediately into the tube, 
which is then inverted 8-10 times to mix. Blood should be maintained at room 
temperature if shipped on day of collection. If the tube cannot be shipped 
immediately then it should be maintained at room temperature for 2-24 hours and 
then placed in -20ºC (or colder) freezer until shipment. Please note that if tubes are 
to be kept at temperatures below -20ºC, they must first be stored at -20ºC before 
being transferred into a -80ºC freezer. Ship frozen tubes on dry ice. 
 
When using the EDTA-containing (purple top) tube, blood is collected in the tube 
and stored at room temperature until shipped. If specimen cannot be shipped on 
the day of collection, then it should be stored in a refrigerator until shipment on 
the next business day. 
 
Optional Samples (Patient Consent Required): 
Pre-treatment snap frozen tumor tissue from primary site and any metastatic 
site is requested. 

                
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Snap freeze tissue within 15 minutes after surgery for optimal preservation. Cut at 
least one specimen from the primary and metastatic areas (if present) into 
maximum 1 gram aliquots. Foil and zip lock bags are provided in the specimen 
procurement kit. Place a label inside each zip lock bag stating the tissue type (P for 
primary or M for metastatic), COG patient ID number and collection date. If 
available, please also include surgical pathology ID number. If tissue is frozen in 
a vial instead of foil, all labeling must be on the vial. 
 
Place tissue on a piece of foil and fold the foil around the tissue. Each type of tissue 
(primary, metastatic) is placed on a separate piece of foil. Snap freeze tissue on dry 
ice or in vapor phase liquid nitrogen (do not submerge the tissue in liquid nitrogen). 
Mark foils as P for primary or M for metastatic and place in separate zip lock bags 
if both are being submitted. Store snap frozen tissue at -80qC until shipment. 
 
15.1.2 Sample Labeling and Shipping 
 
Labeling 
Label biology specimens with the patient’s COG patient ID number, specimen type 
and collection date. Blocks, slides and scrolls must also be labeled with the surgical 
pathology ID and block number from the corresponding pathology report. 
 
Specimen Procurement Kit 
The BPC will provide a specimen procurement kit upon request. This kit is for the 
shipment of frozen and ambient specimens together in one shipment to the BPC. 
If you are shipping blood or other ambient specimens alone or shipping to a 
laboratory other than the BPC, then you must use your own shipping container and 
supplies. 
 
Kits are ordered via the BPC Kit Management system. To request a specimen 
procurement 
kit, 
access 
the 
Kit 
Management 
system 
(https://ricapps.nationwidechildrens.org/KitManagement/). 
 
The Biopathology Center provides Specimen Procurement Kits to institutions in 
the US and Canada. Institutions outside of the US and Canada are expected to 
provide their own supplies for submission of samples. 
 
Paperwork to Include 
Please note that ANY tissue sample submission to the BPC must include the 
following documentation: 
 
x 
Institutional pathology report 
x 
Institutional operative report (Can be provisional as long as final report is 
sent when available) 
x 
COG Specimen transmittal form 
 
In addition, any material submitted for pathology review must include the 
pathology checklist. 
 

                
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Packaging and Shipping Specimens 
 
The dual chamber specimen procurement kit is constructed to allow shipment of 
frozen (on dry ice) and ambient temperature tissues in the same container. Dry ice 
may be placed in either compartment of the kit, but should not be put in both. 
Include a specimen transmittal with every shipment and a pathology report, 
operative report and pathology checklist when appropriate (see above). 
 
1. Before specimens are placed into the dual chamber specimen procurement kit, 
they first need to be placed in three separate layers of packaging. Package the 
frozen specimens and the ambient specimens separately since they will be placed 
in separate compartments of the kit. Two sets of the biohazard and Tyvek 
diagnostic envelopes are provided in the kit for this purpose. 
a. Place the specimens in zip lock bags (one bag per specimen type/time 
point).  
b. Place the zip lock bags in a biohazard envelope with the absorbent 
material. Expel as much air as possible and seal the envelope. 
c. Place the biohazard envelope inside a Tyvek envelope. Expel as much 
air as possible and seal the envelope. 
2. Frozen specimens should be placed in one of the kit compartments filled with 
dry ice. Layer the bottom of the compartment with dry ice until it is 
approximately one-third full. Place the frozen specimens on top of the dry ice. 
Cover the specimens with the dry ice until the compartment is almost completely 
full. Place the foam lid on top to insulate the specimens during shipment. 
3. Ambient temperature specimens should be shipped in the other kit 
compartment at room temperature. Insulate ambient specimens with bubble 
wrap or similar material. 
4. Place the transmittal form(s) and pathology report inside the kit chamber with the 
ambient specimens. 
5. Place a foam cover on top of each kit chamber to insulate the specimens during 
shipment. 
6. Close the outer lid of the specimen procurement kit and secure with filament or 
other durable sealing tape. 
7. Print a shipping label via the BPC Kit Management application and attach to the 
top of the kit. 
8. Complete the dry ice label (UN 1845). Place the dry ice and Exempt Human 
Specimen labels on the side of the kit. 
9. Arrange for FedEx pickup per your usual institutional procedure or by calling 
1-800-238-5355. 
 
Shipping Address: 
Biopathology Center 
Nationwide Children’s Hospital 
Protocol ARST1321 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: 
(614) 722-2865 
Fax: 
(614) 722-2897 
Email: 
BPCBank@nationwidechildrens.org  
 

                
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*Be sure to include the room number. Packages received without the room 
number may be returned to the sender. 
 
Specimens should be shipped Monday through Thursday by FedEx Priority 
Overnight for delivery Tuesday through Friday. Blood in EDTA and PAXgene 
tubes (if not frozen) can also be shipped on Friday for Saturday delivery. Please 
do not ship any other specimens for Saturday Delivery.  
 
15.1.3 Methodology 
We aim to gain insight into the disease biology of childhood and adult NRSTS 
through analysis of actionable mutations and whole genome sequencing. There are 
two components to this correlative study:  
 
1) We will utilize formalin-fixed, paraffin-embedded (FFPE) material and blood 
(required) and next-generation sequencing (NGS) technology to assess the 
status of known or suspected pazopanib targets and a limited panel of other 
genes that may influence response to this molecularly targeted agent. 
 
2) Using snap-frozen tumor specimens (optional) paired with blood (see above), 
NGS approaches will be utilized for more comprehensive genomic studies 
including whole genome sequencing, with the goal to perform this work on 
~20 specimens representing major NRSTS categories, such as synovial 
sarcoma, fibrosarcoma, malignant peripheral nerve sheath tumor, and 
undifferentiated sarcoma 
 
We will utilize a workflow in which potentially-actionable mutations in patients 
treated with pazopanib are initially batched; as the project moves forward, we will 
move toward analysis in “real-time” to facilitate risk group-stratification and 
treatment assignment.  
 
15.1.3.1 
Determining the Prevalence of Actionable Mutations that can be 
Targeted by Currently Available Drugs Across All NRSTS Subtypes 
The following workflow will be used: 
 
Prospective cases collected on ARST1321 will be processed as 
material is received at the Biopathology Center (BPC)/Nationwide 
Children’s Hospital for research subjects enrolled in this trial. Blocks 
and pretreatment blood are required. 
 
a. FFPE tissue and blood will be processed in batches by the BPC 
for 1) diagnosis confirmation and tissue quality assessment, and 
2) DNA and RNA extraction with subsequent quality assessment 
and quantification.   
b. Tumor- and blood- derived nucleic acids will be shipped to the 
Skapek and/or Parsons laboratories for targeted gene panel and/or 
exome/transcriptome sequencing to evaluate key genes encoding 
VEGF receptors, PDGF receptors, c-KIT, p53, and N-, K-, and H-
RAS.22,30,32,33,151,189-193 This will be accomplished using Illumina 
HiSeq and MiSeq platforms and appropriate analysis tools with 
assistance from the CAP/CLIA-certified Pathology Laboratory at 

                
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Children’s Medical Center Dallas and the University of Texas 
Southwestern Medical Center DNA Sequencing Core and/or the 
Clinical Molecular Pathology Laboratory at Texas Children’s 
Hospital. 
c. Data will be stored at the COG Statistics and Data Center and 
correlated with relevant clinical and pathological features in each 
case. 
d. As the study progresses and potential targets are defined, efforts 
will be made to transition the analysis to one that can be performed 
in “real-time” within a CAP/CLIA-certified laboratory, such as at 
the COG Biopathology Center.  
 
15.1.3.2 
Conducting Whole Genome Sequencing in NRSTS in Children and 
Adults 
This aspect of the study is optional as it will be conducted using snap-
frozen material, which may not be available on every case. Available 
snap-frozen material will be paired with the blood collected for 
component 1 above. The requested snap frozen tumor tissue material 
is detailed in Section 15.1.3.  
 
a. Snap-frozen tissue and blood will be processed in batches by the 
BPC for 1) diagnosis confirmation and tissue quality assessment, 
and 2) DNA and RNA extraction with subsequent quality 
assessment and quantification.   
b. Tumor- and blood-derived nucleic acids will be shipped to the 
Skapek and/or Parsons laboratories for more comprehensive 
genomic studies including (in addition to the methods described 
in Section 15.1.3.1 above) whole genome sequencing. (Note that 
this experimental initiative is discovery-directed and will not be 
utilized for patient care decisions, nor will results for sequence 
analysis be provided to the research subject or enrolling 
institution.) 
c. Sequencing data will be stored on HIPAA-compliant database in 
the Skapek and/or Parsons laboratories and at the COG Statistics 
and Data Center; the data will be correlated with relevant clinical 
and pathological features in each case. 
 
15.2 
Microvessel Density and Circulating Tumor DNA as Predictors of Tumor Response 
and Outcome (Optional) 
 
15.2.1 Kit Ordering, Sample Collection and Processing 
 
Kits for this study can be requested from the NRG Oncology Biospecimen Bank 
in San Francisco by email at NRGBB@ucsf.edu.  
 
Kits will include instructions, specimen transmittal forms, supplies for FFPE, 
frozen tumor tissue and plasma processing. One shipping label will be included 
for batch shipping frozen specimens on dry ice to Dr. Yoon at MSK. Kits are 
shipped to sites by Fed Ex Ground from the San Francisco bank and can take 4-
6 business days to reach the sites. 

                
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The following material is requested from all consenting patients. There will be 
no banking of leftover material. 
 
i) 2 unstained FFPE slides from tumor tissue obtained at diagnosis or pre-
treatment.  
 
The slides can be stored for up to 2 months at room temperature. Slides will 
not be returned to sites. 
 
ii) Snap frozen tumor tissue from primary site obtained at the time of local control 
surgery (at Week 10 or Week 13). 
 
At least one specimen from the primary at least 1 cm by 1 cm should be cut 
into 2-3 mm slices and wrapped in foil and snap frozen in liquid nitrogen or 
cold isopentane. Store snap frozen tissue at -80qC until shipment. 
 
iii) A blood sample (10 mL) is requested at diagnosis/pre-treatment and at the time 
of local control surgery (at Week 10 or Week 13). Samples are to be processed 
as follows: 
 
x 
Collect 10 mL of peripheral blood in purple top (EDTA) tubes. 
(Blood draw tubes will not be provided in the kits, sites are 
responsible for providing this). 
x 
Centrifuge tubes at 820 g for 10 minutes. 
x 
Transfer plasma into 15 mL conical tube. 
x 
Store at -80°C. 
 
Blood samples can be stored indefinitely frozen at -80°C and may be batched 
for shipping. 
 
15.2.2 Sample Labeling and Shipping 
Label all specimens with ARST1321, the patient’s COG patient ID number, 
specimen type and collection date. 
 
Include a specimen transmittal form with all sample shipments. 
 
i) The slides can be batched and shipped by regular mail to arrive any day of 
the week. 
 
ii) Snap frozen tumor tissue and blood plasma samples are to be shipped 
frozen on dry ice for overnight delivery to arrive Tuesday through 
Thursday only. 
 
Please contact the lab prior to shipping. 
 
Lab person to contact with questions: 
 
Changhwan Yoon  

                
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Email: yoonc1@mskcc.org  
Phone: (212) 639-7436 
 
Shipping address: 
 
Sam Yoon Laboratory 
Zuckerman Building Z419-G 
Memorial Sloan Kettering Cancer Center 
408 East 69th Street, 
New York NY 10065 
 
15.2.3 Methodology 
There are two components to this correlative study:  
 
1) Microvessel Density Study: CD31 immunohistochemistry will be performed 
on pretreatment tumor tissue, and microvessel density (MVD) will be 
calculated as previously described.28 Following combined modality therapy, 
tumors will be resected and the degree of pathologic necrosis will be 
determined by an expert sarcoma pathologist. Initial MVD will be correlated 
to percent tumor necrosis using Kendall’s tau coefficients.  
 
2) Plasma levels of circulating tumor DNA: DNA will be collected from 
plasma using the QIAamp MinElute virus vacuum kit. The amount of total 
DNA will be quantified by measuring levels of the human long interspersed 
nuclear element-1 (hLINE-1) retroposon family member by PCR. 
Determination of chromosomal translocations in frozen tissue from resected 
STS specimens will be performed. Measurement of ctDNA in plasma will 
be performed as previously described.154,155 The levels of ctDNA will be 
correlated to the degree of pathologic necrosis in resected specimens.  
 
15.3 
Doxorubicin Pharmacokinetics in Combination with Pazopanib (Optional) 
Accrual to this correlative study ended upon completion of accrual to the dose finding 
phase of the chemotherapy cohort. 
 
Doxorubicin pharmacokinetics will be performed during the dose-finding phase of the 
study and in patients enrolled into the chemotherapy cohort only (ie, Regimen A). This is 
an optional study and patient consent is required. 
 
PK studies will be analyzed in up to 10 patients (minimum of 3 patients < 18 years of age 
DQG SDWLHQWV  \HDUVRIDJH QRQ-randomly assigned to receive ifosfamide and 
doxorubicin with pazopanib at dose level 1. An additional 10 patients may be added for 
analysis depending on the decision to escalate or de-escalate the pazopanib dose.   
 
Quantitation of doxorubinin and doxorubicinol concentrations will be performed. Using 
plasma samples, quantitative extraction is achieved by a simple solid phase extraction 
procedure after the addition of 0.1 M hydrochloric acid. Concentrations of doxorubicin and 
its metabolite doxorubicinol will be determined by UHPLC-MS/MS.194 
 
15.3.1 Sample Collection and Processing 
Blood samples will be obtained in Cycle 2 on Day 1-3 at the following 9 time 

                
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points related to doxorubicin dosing: 
x 
time 0 (predose)  
x 
5 minutes after dosing 
x 
30 minutes after dosing 
x 
60 minutes after dosing 
x 
2 hours after dosing 
x 
4 hours after dosing 
x 
8 hours after dosing 
x 
24 ± 3 hours after dosing 
x 
48 ± 3hours after dosing. 
 
Blood samples (3-5 mL) are to be drawn into tubes containing EDTA (purple top 
tubes) and immediately placed on ice. Within 30 minutes of collection, centrifuge 
for 5 min at 3000 g to yield plasma, divide into 2 aliquots and store frozen in 
polypropylene vials at or below -20°C until shipped.  
 
Samples may be batched and shipped following collection of all 9 samples. 
 
Note: It is strongly recommended the PK samples be collected from a site distant 
from the injection site. If possible, administer the doxorubicin through a central 
venous catheter and collect the PK samples from a peripheral i.v. inserted at a 
distant site. If a peripheral line is not possible, administration of drug and collection 
of the PK samples via central line may be done utilizing the flushing procedure as 
per individual institutional policy using normal saline to prevent sample 
contamination. 
 
15.3.2 Sample Labeling and Shipping 
Label all samples with “ARST1321”; patient ID#; date and time the sample was 
obtained. 
 
Samples are to be shipped overnight frozen on dry ice on Monday - Wednesday 
for delivery on Tuesday through Thursday only. Include a copy of the PK Data 
Collection Form with each shipment. 
 
Please contact the laboratory before shipping specimens: 
 
Aksana Vasilyeva or Daelynn Buelow 
Email: 
aksana.vasilyeva@stjude.org  
Email: 
daelynn.buelow@stjude.org 
Phone: (901) 595-4759 or (901) 595-5936 
Fax: 
(901) 595-3125 
 
Shipping address: 
 
Sharyn Baker, PharmD, PhD, c/o Aksana Vasilyeva 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place 
CCC Room 15503/15504, Mail Stop 313 
Memphis, TN 38105-3678 
 

                
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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. 
 
Central review of baseline and Week 10 (Non-chemotherapy cohort; treatment Regimens 
C and D) or Week 13 (Chemotherapy cohort; treatment Regimens A and B) imaging will 
be performed in all patients. This review has the following goals: 
x 
To evaluate change in FDG PET maximum standard uptake value (SUVmax) from 
baseline to Week 10 (treatment Regimens C and D) or Week 13 (treatment Regimens 
A and B) in patients with unresected tumors and to correlate this change with 
pathologic response and EFS. 
x 
To compare the rate of response by standard imaging and pathologic assessment to 
determine which correlates better with local tumor control, distant tumor control, 
EFS, and overall survival. 
 
Central review of imaging studies also will be performed in patients who experience tumor 
progression or recurrence while on study and within 4 weeks of completing therapy. In 
patients who develop a recurrence or progression more than 4 weeks after completing 
therapy or a second malignant neoplasm imaging studies will be stored for future review. 
This review will document the pattern of treatment failure (study objective 1.3.5). 
 
16.2 
Timing of Diagnostic Imaging 
16.2.1 Required Imaging Time Points 
x 
Treatment Arms A and B 
o At study enrollment# † 
o At Week 13† 
o At end of protocol therapy 
o At the time of suspected tumor progression/recurrence† 
o At the time of diagnosis of a second malignant neoplasm† 
 
x 
Treatment Arms C and D 
o At study enrollment# † 
o At Week 10† 
o At end of protocol therapy 
o At the time of suspected tumor progression/recurrence† 
o At the time of diagnosis of a second malignant neoplasm† 
 

                
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# Baseline imaging studies must be obtained within 4 weeks of study entry and before 
treatment starts. 
† Central review of diagnostic imaging studies will only occur at these time points. 
(Note: in patients who experience tumor progression or recurrence while on study and 
within 4 weeks of completing therapy, central review of imaging studies will be 
performed. Imaging for suspected tumor progression/recurrence more than 4 weeks 
after completing therapy or a second malignant neoplasm should be submitted for 
future review). Imaging studies done at other time points do not need to be submitted 
for central review. 
 
16.2.2 Recommended Imaging Time Points Post-Treatment 
The following imaging time points are recommended for all patients: 
 
x 
At 6, 12, 18, 24, 30, 36, 48, and 60 months from “end of therapy” date, 
defined as the last day of chemotherapy or radiotherapy, or the last date of 
protocol-required surgery, whichever is latest. 
 
The choice of whether to perform a chest CT or Chest x-ray in follow up is left to 
institutional preference. 
 
16.3 
Required Imaging Studies 
x 
Primary tumor – To be evaluated at the time points specified in Section 16.2.1 using: 
o CT imaging or 
o MR imaging. 
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 (eg, 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 for clear cell sarcoma and 
epithelioid sarcoma only. If a subtotal resection was done, the baseline study of the 
lymph node bed should be done after this operation. 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 
Week 10 (treatment arms C and D) or Week 13 (treatment arms A and B), at end 
of therapy, at the time of suspected tumor progression/recurrence, and at the time 
of diagnosis of a second malignant neoplasm. 
 
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 
Recommendations for PET and Diffuse-Weighted MR Imaging Studies 
[18F]–Fluorodeoxyglucose Positron Emission Tomography (FDG PET) imaging is optional 
and requires consent but is encouraged. 7KHSULPDU\OHVLRQPXVWEHFPon baseline 
anatomic imaging in order for a FDG PET scan to be performed. If done, FDG PET 
imaging should be performed at study enrollment and at Week 10 (Regimen C and D) or 
Week 13 (Regimen A and B) prior to definitive tumor resection. If insufficient FDG uptake 

                
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is seen at baseline, then the follow-up scan should not be performed. FDG PET imaging 
may also be helpful at the time of suspected tumor recurrence, particularly if a scan was 
performed at the time of study enrollment. Investigators are encouraged to submit FDG 
PET scans for central review to allow an assessment of the value of this modality in 
identifying areas involved by NRSTS and assessing tumor response to treatment. 
 
Diffuse-weighted MR imaging (DWI) is encouraged. If performed, investigators are 
encouraged to submit DWI (at b-values of 0-50, 400, and 1000 s/mm2) using spin-echo 
single shot EPI, parallel imaging factor of 2 slice thickness 5 mm) and ADC (apparent 
diffusion coefficient in μm2/s) maps for central review to allow an assessment of the value 
of this MR sequence in identifying areas involved by NRSTS and assessing tumor response 
to treatment. 
 
16.5 
Central Review of Imaging Studies 
For all patients enrolled, one to two central diagnostic imaging reviewers will 
independently assess the baseline tumor site, size (maximal tumor diameter and tumor 
volume), invasiveness [non-invasive, neurovascular invasion (touching), neurovascular 
invasion (surrounding), bone invasion (touching), bone invasion (destroying)], and depth 
(superficial or deep). Tumors that are located only in the skin or subcutaneous plane are 
defined as “superficial” and those involving tissues deep to the fascia or in internal organs 
are defined as “deep”. Just prior to definitive surgery at Week 10 (treatment Regimens C 
and D) or Week 13 (treatment Regimens A and B), tumor dimensions will be re-obtained 
according to the guidelines in Section 16.7.     
 
One to two central diagnostic imaging reviewers will independently assess the percent 
tumor necrosis on scans obtained at study enrollment and just prior to definitive surgery at 
Week 10 (treatment Regimens C and D) or Week 13 (treatment Regimens A and B). 
Necrosis will be defined as areas not showing contrast enhancement. If the tumor contains 
a fluid component whose margins are sharply defined, this will be interpreted as a cystic 
area and will not be included in the calculation of percent necrosis. Four (at 20%, 40%, 
60%, and 80% of the distance between the most superior and the most inferior images in 
the z plane) axial images representing the entirety of the tumor will be selected, and the 
percent tumor necrosis in each image will be estimated. An “overall percent necrosis” will 
be estimated based on these 4 images, bearing in mind that a smaller cross-sectional area 
in the narrower portions of the tumor will contribute proportionally less to the overall 
percentage in the calculation.   
 
The final calculated tumor dimensions and percent tumor necrosis at study enrollment and 
at Week 10 or Week 13 will be compared to the pathologic findings (see Section 14) to 
assess the degree of correlation between these two methods of measuring tumor response. 
The tumor response as assessed by central imaging review also will be evaluated to 
determine whether it predicts clinical outcomes such as local and distant disease control 
and survival.  
 
Note: these reviews will be performed retrospectively and the results will not be returned 
to the institution.  
 

                
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16.6 
Submission of Imaging Studies for Central Review 
 
16.6.1 Requirements for Patients on Treatment Regimen A and B 
Central review to assess baseline tumor characteristics and to assess tumor 
response by diagnostic imaging will be performed on all patients. Studies to be 
submitted for these patients include: 
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained prior to study enrollment. If multiple imaging studies were 
obtained prior to protocol enrollment, the imaging study showing the 
largest tumor diameter and the study performed closest to the time of 
enrollment should be submitted. Baseline scans must be obtained 
within 4 weeks of study entry and before initiation of therapy. 
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained at Week 13 prior to definitive tumor resection (required) 
x 
Patients with metastases: All imaging studies that identified 
metastases at study enrollment and the same scans obtained at 
Week 13 (required) 
x 
FDG PET scan obtained at study enrollment and at Week 13 prior to 
definitive tumor resection (optional) 
The same imaging modality (CT or MRI) must be used at both study entry and 
Week 13 so that a valid comparison can be made at the time of central imaging 
review. 
 
16.6.2 Requirements for Patients on Treatment Regimen C and D 
Central review to assess baseline tumor characteristics and to assess tumor 
response by diagnostic imaging will be performed on all patients. Studies to be 
submitted for these patients include: 
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained prior to study enrollment. If multiple imaging studies were 
obtained prior to protocol enrollment, the imaging study showing the 
largest tumor diameter and the study performed closest to the time of 
enrollment should be submitted. Baseline scans must be obtained 
within 4 weeks of study entry and before initiation of therapy. 
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained at Week 10 prior to definitive tumor resection (required) 
x 
Patients with metastases: All imaging studies that identified 
metastases at study enrollment and the same scans obtained at 
Week 10 (required) 
x 
FDG PET scan obtained at study enrollment and at Week 10 prior to 
definitive tumor resection (optional) 
The same imaging modality (CT or MRI) must be used at both study entry and 
Week 10 so that a valid comparison can be made at the time of central imaging 
review. 
 

                
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16.6.3 Radiotherapy Imaging Requirements 
The same imaging studies may be required for both central radiology review and 
radiotherapy quality assurance review. If submitted with RT QA documentation it 
is not necessary to resubmit the same scan for the imaging central review. Please 
see Section 17 for details of radiation planning and required RT studies. 
 
16.6.4 Requirements for Patients with Progressive/Recurrent Disease 
Central review of imaging at the time of tumor progression/recurrence, if it occurs 
while on study and within 4 weeks of completing therapy, is required in all patients 
who experience this complication. In patients who develop a recurrence or 
progression more than 4 weeks after completing therapy imaging studies should 
be submitted and will be stored for future review. At the time of 
progression/recurrence, submit all of the studies listed below that have not been 
submitted previously to IROC Rhode Island (formerly QARC): 
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained at study enrollment and prior to tumor resection.  
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained at the time of tumor recurrence/progression 
x 
All imaging studies that identified metastases at study enrollment and 
the same scans obtained at the time of tumor recurrence/progression 
x 
All imaging studies that identified metastases at the time of tumor 
recurrence/progression and the same scans obtained at the time of 
study enrollment 
 
16.6.5 Requirements for Patients Who Develop a Second Malignant Neoplasm 
For patients who develop a second solid tumor, studies should be submitted and 
will be stored for future review. At the time that a second solid tumor develops, 
submit the following studies to IROC Rhode Island (formerly QARC): 
x 
Primary site MRI including diffusion-weighted sequences (if 
acquired) or CT scan (if the patient has a contraindication to MRI) 
obtained at the time of diagnosis of the second malignant neoplasm 
x 
If the site of the primary tumor is unclear, submit all scans that 
demonstrate the sites of disease involvement 
 
16.6.6 Submission Guidelines 
All imaging studies should be submitted at the time they are acquired along with a 
copy of the institutional radiologist’s report. Submission of Diagnostic Imaging 
data in digital format is required. Digital files must be in DICOM format. These 
files can be submitted via sFTP. Information for obtaining an sFTP account and 
submission instructions can be found at www.QARC.org. Follow the link labeled 
digital data. Alternatively, if sFTP is not feasible, the imaging may be burned to a 
CD and mailed to IROC Rhode Island (formerly QARC) at the address below. 
Multiple studies for the same patient may be submitted on one CD; however, 
please submit only one patient per CD. Sites using Dicommunicator may submit 
imaging via that application. Contact IROC Rhode Island (formerly QARC) with 
questions or for additional information. 
 

                
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IROC Rhode Island QA Center 
640 George Washington Highway, Building B, Suite 201 
Lincoln, RI 02865-4207 
Phone: 
(401) 753-7600 
Fax: 
(401) 753-7601 
 
16.7 
Diagnostic Imaging Guidelines 
Note: the guidelines below are recommendations only and are not intended to replace 
institutional guidelines. 
 
Assessment of the size and features of NRSTS 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)]. 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. 
 
16.7.1 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 

                
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factors (kVp and tube current). Image display parameters include field-of-view, 
window width and level, and hardcopy or softcopy format (eg, 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. For 
single detector helical (SDCT) or conventional incremental CT, a slice thickness 
up to 7 - 10 mm is recommended for older children and adolescents, and a slice 
thickness as thin as 4 or 5 mm is recommended for infants and small children. 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 SDCT, pitch values in the range of 1.4 - 
2.0 are usually optimal, with degradation of longitudinal axis resolution limiting 
the use of higher values. For 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, 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 100-120 kVp. The use of 
dual-source and dual-energy CT are allowed and decrease in kVp to 70-100 is 
encouraged. 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. 
 
16.7.2 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 

                
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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 Week 10 (treatment arms C and D) or Week 13 (treatment 
arms A and B). IV contrast is required in these settings to enable an accurate 
assessment of tumor necrosis (and therefore tumor response) during central imaging 
review. In this study, necrosis is defined as the absence of contrast enhancement. 
 
Measurement of Tumor Volume  
For assessment of tumor volume, the 2 largest perpendicular diameters are obtained 
from the image that shows the largest tumor cross-section in an optimal plane. Since 
multiple planes are possible in MRI imaging, the third diameter is obtained by 
calculating the distance between the first and the last slices that show the tumor in the 
same optimal plane used to obtain the first 2 diameters. See Section 10.2.1. 
 
16.7.3 [18F]–Fluorodeoxyglucose Positron Emission Tomography (FDG PET) Imaging 
FDG PET imaging is optional, but is encouraged for all patients. If done, FDG 
PET imaging should be performed prior to initiation of chemotherapy and at 
Week 10 (treatment Regimens C and D) or at study enrollment and Week 13 
(treatment Regimens A and B) prior to tumor resection. Exceptional circumstances 
may require emergent therapy, and treatment should not be delayed in these cases 
to perform an FDG PET scan.  
 
Patient Guidelines 
The patient should fast for at least 4 hours prior to injection of FDG. FDG PET 
imaging may follow a MUGA study on the same day, or FDG PET imaging may 
be performed on the day preceding this study. Plasma glucose should be checked 
and, if the patient is hyperglycemic (plasma glucose > 250 mg/dL), appropriate 
treatment with small doses of insulin may be given to bring the plasma glucose 
into the normal range prior to FDG PET imaging. However, insulin administration 
may result in excessive muscle uptake of FDG and consequent tumor non-
visualization. If possible, the study should be postponed until the plasma glucose 
is under better control. 
 
Good hydration is required, as the primary route of FDG excretion is renal. The 
patient should drink water or receive intravenous fluids (not containing dextrose) 
after FDG injection to promote urinary excretion of the radioactive substrate. After 
injection, the patient must be kept in a resting state for 45-60 minutes prior to 
imaging. The patient should empty the bladder immediately prior to imaging. 
 
Imaging Technique 
The technique will vary by local institutional guidelines. In general, FDG is 
administered intravenously at a dose of 0.125-0.200 mCi/kg or by algorithms that 
adjust the dose by body surface area, within a minimum total dose of 1.0 mCi and 
maximum total dose of 20.0 mCi. The dose should not exceed 20.0 mCi.  
 

                
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The body should be imaged from the top of the ears to the bottom of the feet. If 
there is suspicion of involvement of the skull or skull contents, the volume that is 
imaged should be expanded.  
 
Imaging with a dedicated positron emission tomograph/computed tomography 
(PET/CT) camera is standard.   
 
The length of time needed to perform head to toe CT will depend on the patient’s 
height but will be approximately 45 seconds. Contiguous axial images should be 
obtained at 5 mm thickness using 90 mA and 120 Kv and adjusted for local 
institutional protocol. No oral or IV contrast is required but either or both are 
permissible and may be of benefit in cases where intraabdominal or pelvic 
pathology is a specific concern. With regard to patient positioning, the arms can 
be placed in a comfortable position at the patient’s sides as long as they fit into the 
field of view. If the patient is large it may be necessary to lay the arms across the 
abdomen and hold in position with a stabilizing device. 
 
FDG-PET done in combination with MRI is also an option (PET/MRI). For an 
individual patient, it is highly recommended that the same technology (either 
PET/CT or PET/MRI) be used for protocol studies. 
 
Study Processing 
The FDG PET study is processed for display by an iterative reconstruction 
algorithm. FDG activity should be corrected for attenuation, scatter, and 
radioactive decay. Attenuation correction is necessary, as apparent uptake will 
otherwise vary with depth of the lesion in the body and the nature of surrounding 
tissues. The procedure used for attenuation correction should be recorded. The 
level of tumor uptake is assessed subjectively by visual inspection and semi-
quantitatively by determination of standardized uptake values (SUV). Uptake time, 
glucose levels, and partial volume effects influence both methods. The SUV 
method is also dependent on body weight, and correction of SUV by normalizing 
for body surface area (BSA) reduces this dependency on body weight. SUVs 
should be calculated for lesions known to be 1.2 cm or larger in diameter. Smaller 
lesions may have underestimated SUVs due to partial volume averaging effects at 
typical scanner resolutions (0.6-1.2 cm). 
 
To calculate the SUV, a region of interest (ROI) should be carefully drawn around 
as much of the area of elevated FDG uptake as can be done. The SUV should be 
calculated as SUVBSA = ROI activity concentration (nCi/cc) x BSA / injected 
activity (nCi). SUVMAX is obtained by determining the activity of the pixel with 
the highest FDG uptake. 
 
The BSA is calculated from body mass (kg) and height (cm) using an appropriate 
algorithm. The SUVBSA for each measured lesion should be recorded and the 
technique for assessing SUVBSA should be consistent on follow-up studies. 
 
16.8 
Growth Plate Evaluation 
If patients are found to have a closed tibial growth plate, no further radiographs will be 
required. If patients are found to have an open tibial growth plate, then repeat plain AP 
radiographs of the same tibial growth plate will be obtained at the end of therapy and in 
post treatment follow-up as necessary. Consideration should be given towards obtaining 

                
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bilateral AP radiographs of the tibial growth plate during follow-up, only in patients with 
open growth plates, since end of therapy x-rays may not reflect recovery after pazopanib 
is stopped. These could be done at 6 months or a year off therapy, and perhaps repeated 
annually until normalization or complete fusion of the growth plates. The baseline 
radiograph will be compared with each radiograph performed during follow-up. 
 
 
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 pediatric patients on COG or NRG Oncology protocols can only 
be delivered at approved COG RT facilities or NRG Oncology RT facilities.  
 
17.1 
General Guidelines 
17.1.1 The radiation therapy guidelines for this study were developed specifically for 
patients with newly diagnosed, localized non-rhabdomyosarcoma soft-tissue 
sarcoma (NRSTS) or patients with limited metastatic NRSTS for whom resection 
of the primary is planned. This protocol is a successor study to RTOG 0630 and 
ARST0332 but only includes patients with an unresected primary site in the truncal 
and extremity sites with the exception of embryonal liver sarcoma for whom the 
protocol treatment will only consist of preop chemotherapy +/- pazopanib (without 
radiation).  
 
17.1.2 All primary NRSTS tumors must be deemed potentially resectable with limb-
preserving approach in discussion with surgical oncologist (see Section 13). The 
goal of combined modality preoperative therapy is to make surgery feasible and 
improve the extent of resection. 
 
17.1.3 All patients should be seen 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 RT planning. All treatment plans and supporting data for the primary 
site must be submitted to IROC Rhode Island (formerly QARC) for pre-
treatment review and approval prior to the start of radiotherapy. See 
Section 17.10 for submission instructions. 
 
17.1.4 This study requires credentialing dependent on the treatment techniques and/or 
treatment modalities to be used. See Section 17.4.3 for an outline of credentialing 
requirements. 
 

                
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17.2 
Treatment Overview 
17.2.1 Chemotherapy Cohort  
Patients eligible for the Chemotherapy Cohort will be randomized to neoadjuvant 
combined modality therapy with ifosfamide and doxorubicin (ID) and 45 Gy RT 
at 1.8 Gy per fraction starting at Week 4 plus or minus concurrent pazopanib. 
Definitive surgery will be done at Week 13, with postoperative completion of the 
assigned ID/pazopanib or ID regimen starting at Week 16. For patients with gross 
residual disease, a postoperative boost radiotherapy of 21.6 Gy at 1.8 Gy per 
fraction is required (cumulative dose 66.6 Gy). For patients with microscopic 
margins, postoperative boost radiotherapy to the tumor bed is highly recommended 
but optional based on the discretion of the treating physician. The recommended 
dose is 16.2 Gy at 1.8 Gy per fraction (cumulative dose 61.2 Gy). Equivalent boost 
with brachytherapy is allowed. Delay of the postoperative radiotherapy boost 
should be documented. Omission of the optional postoperative radiotherapy boost 
(positive microscopic margins) should be documented. Delay or omission 
documentation should be submitted with the RT QA materials (see Section 17.10). 
No boost is to be given for negative margins. Negative margin is defined as the 
microscopic absence of tumor on the inked margins following resection regardless 
of the proximity of tumor cells to the margin. Patients will receive postoperative 
chemotherapy plus or minus pazopanib based on the initial randomization. Patients 
randomized to the pazopanib regimen will resume pazopanib no sooner than 2 
weeks after surgery. If postoperative RT boost is given, doxorubicin will be held 
during the postoperative RT. Ifosfamide plus or minus pazopanib will be given 
concurrently with the postoperative RT and continued thereafter with doxorubicin 
for a total of 3 cycles. 
 
17.2.2 Non-Chemotherapy Cohort  
Patients enrolled in the Non-Chemotherapy cohort will be randomized to 
preoperative 50 Gy RT at 2 Gy per fraction with and without pazopanib. Those 
patients randomized to receive pazopanib will begin concurrently with RT at Week 
1. Preoperative radiation will be completed by the end of Week 5. Definitive 
surgery will be done at Week 10. For patients with gross residual disease, 
postoperative boost radiotherapy to a dose of 20 Gy at 2 Gy per fraction is required 
(cumulative dose 70 Gy). For patients with microscopic margins, postoperative 
boost radiotherapy to the tumor bed is highly recommended but optional based on 
the discretion of the treating physician. The recommended dose is 16 Gy at 2 Gy 
per fraction (cumulative dose 66 Gy). Equivalent boost with brachytherapy is 
allowed. Those patients randomized to receive pazopanib will resume the agent no 
sooner than 2 weeks after surgery; followed by radiation once wound has 
adequately healed (starting 3 weeks after surgery). Delay of the postoperative 
radiotherapy boost should be documented. Omission of the optional postoperative 
radiotherapy boost (positive microscopic margins) should be documented. Delay 
or omission documentation should be submitted with the RT QA materials (see 
Section 17.10). No boost is to be given for negative margins. Negative margin is 
defined as the microscopic absence of tumor on the inked margins following 
resection regardless of the proximity of tumor cells to the margin.   
 
17.2.3 Patients with Metastatic Disease in Either Cohort  
These patients will undergo surgical resection of metastases at the completion of 
therapy, with additional RT for incompletely resectable or unresectable lesions.  

                
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17.2.4 Special Considerations: 
Hepatic primary tumors: Patients with liver primaries will not receive pre-
operative RT. Postoperative radiotherapy is optional at Week 16 for the 
chemotherapy cohort or Week 13 for the non-chemotherapy cohort. 
 
 
17.3 
Timing of RT 
17.3.1 Timing for RT to Primary Site:  
 
17.3.1.1 Chemotherapy Cohort 
Patients in the chemotherapy cohort will receive preoperative RT to the 
primary site starting at Week 4. Week 4 radiotherapy should be started at 
least 24 hours after completion of the Week 4 doxorubicin. Doxorubicin 
should be withheld at Weeks 7 and 10 during radiation therapy. If needed, 
Week 16 radiotherapy should be started at least 24 hours after completion 
of the Week 16 doxorubicin. 
 
Postoperative boost radiotherapy for gross residual disease (required) or 
microscopic positive margins (optional) should begin at Week 16 
(3 weeks after surgery). If there is inadequate wound healing at Week 16, 
postoperative RT can be delayed until Week 19. If wound complications 
preclude initiating postoperative RT by Week 19 (6 weeks from surgery), 
the rationale for the delay should be documented by the treating physician. 
If radiotherapy for microscopic positive margins is omitted the rationale 
for omission should be documented. Delay or omission documentation 
should be submitted with the RT QA materials (see Section 17.10). 
 
17.3.1.1.1  Criteria to Start Radiation Therapy with Chemotherapy 
Radiation should not begin until the ANC  500/PL and platelets 
 75,000/PL for patients in the Chemotherapy Cohort.   
 
17.3.1.1.2  Interruptions, Delays and Dose Modifications 
There will be no planned rests or breaks from treatment, and once radiation 
therapy has been initiated, treatment will not be interrupted except for any 
life threatening infection. However, radiation therapy interruption should 
be strongly considered for ANC < 300/PL or platelets less than 20,000/PL 
until the counts have recovered above these levels. Blood product support 
should be instituted according to institutional/protocol guidelines. 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. If any area has been previously treated (emergently), care 
should be taken not to exceed normal tissue tolerance levels. 
 
17.3.1.2 Non-Chemotherapy Cohort 
Patients in the nonchemotherapy cohort will receive preoperative RT 
starting at Week 1. Resection takes place during Week 10.  
 
Postoperative boost radiotherapy for gross residual disease (required) or 
microscopic positive margins (optional) should begin at Week 13 
(3 weeks after surgery). If there is inadequate wound healing at Week 13, 

                
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postoperative RT can be delayed until Week 16. If wound complications 
preclude initiating postoperative RT by Week 16 (6 weeks from surgery), 
the rationale for the delay should be documented by the treating physician. 
If radiotherapy for microscopic positive margins is omitted the rationale 
for omission should be documented. Delay or omission documentation 
should be submitted with the RT QA materials (see Section 17.10). 
 
17.3.2 Metastatic Sites:   
For patients in the high risk group with metastatic sites of disease, radiation therapy 
will be delivered at the completion of all planned therapy and following surgical 
removal of resectable metastases.   
 
17.3.3 Emergency Radiation Therapy 
In the case of a neurologic compromise, uncontrolled tumor bleeding or life or 
function-threatening situations, RT may be administered early.   
 
17.4 
Radiation Treatment Planning and Delivery Techniques 
17.4.1 Simulation Including Patient Positioning and Immobilization  
 
17.4.1.1 Patient Positioning  
Patients should be immobilized in stable and comfortable positions to 
allow accurate repositioning from treatment to treatment and to prevent 
movement during treatments. A variety of immobilization devices may be 
utilized, including Alpha Cradle and thermoplastic casts. Consideration 
should be given to implications for inter and intrafraction motion when 
using non-standard position approaches. Positioning of the involved 
extremity to avoid variations in soft tissue distortion from day to day 
positioning is recommended. The contralateral limb should be positioned 
to avoid interference with optimal beam angles for the treatment limb. 
Whenever possible, skin folds should be minimized. 
 
17.4.1.2 Special Considerations for Immobilization and Simulation. 
Anesthesia or sedation may be required in certain patients, such as very 
young patients, to prevent movement during simulation and daily radiation 
therapy treatments.  
 
17.4.2 Equipment Allowed and Methods of RT Delivery/Verification  
Radiation therapy using photons, electrons or protons, 3D-conformal radiation 
therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) will be 
allowed in this study. Use of both LDR and HDR brachytherapy is allowed for 
boost treatment (see Section 17.6.1 for dose prescription). Intraoperative radiation 
therapy is allowed (see Section 17.6.1 for dose prescription).  
 
IMRT or protons may be used in the thoracic region or for treatment of tumors 
affected by respiratory motion when the degree of motion can be limited to 0.5 cm 
using breath hold or abdominal compression techniques. Use of IMRT in 
conjunction with gating or tracking techniques requires credentialing by the IROC 
Houston QA Center (RPC), see Section 17.4.3 below. The Motion Management 

                
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Reporting Form shall be submitted with the Quality Assurance Documentation 
materials whenever motion management techniques are used (see Section 17.10). 
 
Equipment 
Photons 
(4-15MV)** 
Electrons 
(4-20 MeV) 
IMRT 
(4-10MV) Protons Brachytherapy* 
Linear Accelerator 
X 
X 
X 
 
 
Proton Beam 
 
 
 
X 
 
Intraoperative 
Radiation 
Therapy*** 
X 
X 
 
 
 
Brachytherapy 
-
high or low dose 
rate 
 
 
 
 
X 
* Permanent radioactive implants are not allowed on this protocol. The dose prescription for 
brachytherapy is given in Section 17.6.1. 
** For tumors adjacent or included in lung tissue, beam energy should be < 10 MV. 
*** The dose prescription for intraoperative radiation therapy is given in Section 17.6.1. 
 
17.4.3 Credentialing Requirements 
x 
All therapy units used on this protocol must have their calibrations verified by 
the IROC Houston QA Center (RPC). The table above indicates allowable 
modes of treatment delivery. 
x 
IMRT: Those treating with IMRT and not previously credentialed for its use in 
clinical trials must update their Facility Questionnaire on the IROC Houston 
website and complete either the IMRT Benchmark (available at 
www.QARC.org) or IROC Houston’s head and neck phantom. Contact IROC 
Houston (http://rpc.mdanderson.org/rpc/) for information about their 
phantoms. 
x 
Proton 
Therapy: 
The 
Proton 
Questionnaire 
(available 
at 
http://rpc.mdanderson.org/rpc/) must be completed. Each beam line used to 
treat patients on this study must be credentialed for clinical trial use by IROC 
Houston. 
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 
IGRT: Standard PTV margins for this protocol are 1.0 cm. Reducing this 
margin to as little as 0.5 cm is possible with use of IGRT provided that IGRT 
credentialing has been completed. Prior credentialing for RTOG 0630 or other 
IGRT credentialing for soft tissue will be accepted. See www.QARC.org under 
“Benchmarks” for instructions on IGRT credentialing. Use of IGRT is not 
required if PTV margins of 1.0 cm are to be used. 
 
17.4.4 Guidelines and Requirements for the Use of IMRT 
Investigators using IMRT will be required to comply with the guidelines developed 
for the use of IMRT in National Cancer Institute sponsored cooperative group 
trials. These guidelines are available through www.qarc.org. These guidelines 

                
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require that the protocol explicitly state their requirements and methods for 
localization and immobilization; the use of volumetric imaging; target and organ 
motion management; nomenclature, definitions and rationale for targets and 
organs at risk; target volume coverage and normal tissue dose constraints; effects 
of heterogeneity in tissues; and quality assurance. 
 
17.4.5 Guidelines and Requirements for the Use of Proton Beam Therapy 
Investigators using proton beam therapy will be required to comply with current 
guidelines for the use of protons in National Cancer Institute sponsored 
cooperative group trials. These guidelines shall be available through 
www.qarc.org. These guidelines specify the following for the participating 
institution: dose reporting will be in Cobalt Gy equivalent (1 CGE = 1 proton Gy 
* 1.1) which is the same as ICRU 78 DRBE; radiation doses shall be prescribed to 
protocol specified definitions for gross (GTV) and clinical (CTV). For set-up 
uncertainties and target motion, additional margin, smearing, range of modulation 
will be added on a per beam basis. The proton institution is required to participate 
in on-site and remote review according to COG requirements. 
 
17.4.6 Guidelines and Requirements for the Use of Brachytherapy or Intraoperative 
Irradiation  
Brachytherapy or intraoperative radiation therapy may be used for conformal 
irradiation of residual disease in the operative bed. 
 
Brachytherapy, using either high dose rate or low dose rate radioactive sources 
may be used on this protocol as a boost to the positive tumor margin. 
Brachytherapy should not start until Day 5 after the surgery. Typically, 
brachytherapy catheters are placed at an interval of 0.5 -1.0 cm on the residual 
tumor bed (positive margin) plus a margin of 1 cm during surgery. Skin surface 
dose should be kept below 50% of the prescription dose unless positive margins 
occur in cutaneous or subcutaneous tissues. It is not necessary to include the entire 
surgical bed, drain sites and wound. The details of the dose prescription for 
brachytherapy are given in Section 17.6.1. 
 
Intraoperative radiation therapy may be used on this protocol. The details for the 
prescription for intraoperative radiation therapy are given in Section 17.6.1.  
 
17.4.7 Image Guidance Procedures (IGRT) 
IGRT is defined in this protocol as use of computer-assisted systems that provide 
detailed information on shifts of the patient support system based on image 
registration software. The institution’s procedure to register treatment day imaging 
datasets with a reference dataset should comply with the following 
recommendations: 
 
Imaging must be done each day if using reduced margins with IGRT. MV, KV and 
CBCT are all acceptable forms of daily image guidance. Sites treating young 
children should contact a Radiation Oncology member of the study committee if 
daily imaging cannot be performed. 
 
Region-of-Interest (ROI) or “clip box” for image registration should be set to 
encompass the high dose PTV and adjacent bony anatomy; If the image 

                
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registration software allows the user to create an irregular ROI (eg, ExacTrac), 
treatment room objects (eg, patient support system structure) seen on in room X-
rays should be excluded from the registration; Both manual (eg, based on bony 
anatomy) and automatic (eg, based on mutual information) types of registration 
can be used; the result of the image registration must be visually checked for the 
alignment of the bony anatomy. 
 
Institutions are encouraged to include closest joints in the imaging process in order 
to increase the information used in the image registration process for long bone 
image registration. 
 
The daily pretreatment images for each case should be archived at each 
treating institution and should be available for central review by NRG 
Oncology/COG upon request. 
 
17.4.7.1 Management of Radiation Dose to the Patient from IGRT 
The estimates of patient doses per imaging study for various imaging 
systems vary considerably. The doses are in the range of 0.1 cGy for 
Cyberknife’s and BrainLab’s ExacTrac planar kV-systems and can be 
considered negligible compared with doses from MV portal imaging and 
kV and MV CT. The doses from helical MV CT scan on a Tomotherapy 
unit were estimated to be in range from 1 to 3 cGy, similar to doses 
reported for kV cone beam CT on Elekta Synergy machine. The doses for 
MV cone beam CT vary from 1 cGy to 10 cGy depending on the field size. 
Thus, the doses for 3D imaging systems are in the range from 1 to 10 cGy 
for sarcoma imaging and can contribute from 0.5 to 5% to the daily dose 
of 2.0 Gy. As a technique of controlling patient dose, it is recommended 
that a QA procedure be established at each institution to verify the 
accuracy of the image registration software on a daily basis. The QA check 
should be performed by the therapists operating a particular treatment 
device and is aimed at reducing the use of repeat imaging by ensuring that 
the registration software functions properly when a shift in patient position 
is carried out. 
 
17.5 
Radiation Treatment Targets 
17.5.1 CT (Volumetric)-Based Planning 
CT (volumetric)-based planning is required to optimize dose to the PTV while 
protecting normal tissues. Organs within the irradiated volume should be 
contoured including those required by treatment site (see Section 17.8.2). A dose 
volume histogram (DVH) is necessary to determine target coverage and evaluate 
dose to normal tissues. 
 
17.5.2 MRI of the Affected Site 
MRI of the affected site is required unless a patient has contraindications for an 
MRI. When possible, direct fusion of the MRI with CT planning is recommended 
but is optional. For the best registration, MRI obtained in similar orientation as the 
planning CT is preferred. For example, for upper extremity lesions, same 
supination/pronation is preferable.  
 

                
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17.5.3 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: 
 
Photons 
Gross tumor volume (GTV) is the volume occupied at diagnosis by visible or 
palpable disease.  
 
Clinical target volume (CTV) includes the GTV and sites with potential occult 
tumor involvement including lymph nodes adjacent to the GTV that may be 
clinically involved.  
 
Planning target volume (PTV) is the CTV surrounded by a geometric margin to 
account for variability in set-up, breathing or motion during treatment.  
 
Protons 
GTV is the same for protons and photons. 
 
CTV is the same for protons and photons. 
 
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% directly with specific 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, (3) 
range of beam (depth of penetration) and, (4) modulation (number of required 
Bragg peaks). Adjustments to any of the aforementioned parameters (usually 2-
7 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 17.6.3. As 
stated above in Section 17.4.3 describing credentialing requirements, the use of 
IGRT with protons will allow a reduction of the setup margin from 1.0 cm to as 
low as 0.5 cm.  
 
Brachytherapy 
GTV is the same as for photons. 
 
CTV is the same as for photons. 

                
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PTV is equal to CTV 
 
17.5.4 GTV Definitions:  
 
GTV 
The GTV is defined as the visible and/or palpable disease defined by physical 
examination, computed tomography (CT), magnetic resonance imaging (MRI, 
usually the T1 post gadolinium sequence, highly preferred) or operative notes and 
pathology reports. The GTV must include all infiltrative disease detected at initial 
presentation. However, contouring GTV must respect anatomic boundary of tumor 
extension. Examples include truncal tumors which compress but not invade the 
lung, intestine or bladder that radiographically return to normal anatomic position 
following neoadjuvant chemotherapy plus/minus pazopanib. 
 
GTV boost postoperative radiation (external beam or brachytherapy [low-dose-
rate or high-dose-rate], or intraoperative radiation therapy) is required for gross 
residual tumor and highly recommended but optional for microscopic positive 
margin based on the discretion of the treating physician. Metallic clips or gold 
seeds are recommended to be placed during surgery to aid in defining the high-risk 
tumor bed (a positive margin or residual tumor). The GTV boost for postoperative 
RT will be the residual tumor bed and any residual gross tumor as defined by the 
surgical and pathological findings. If there is gross residual tumor, postoperative 
MRI is encouraged to visualize the residual tumor. It should be noted that the entire 
surgical bed, drain site, and wound are not required to be in the GTVboost for 
postoperative radiation because the patients will have received preoperative RT. 
 
17.5.5 CTV Definition: CTV is Defined Based on Skeletal Maturity.  
 
17.5.5.1 For > 18 year old Skeletally Mature Patients: Based on RTOG 0630 
 
CTV for Intermediate-to-+LJK*UDGH7XPRUVFP,QFOXGHJURVV tumor 
and clinical microscopic extension. CTV = GTV plus a 3 cm longitudinal 
margin. Using MRI (preferably with image fusion), the CTV will also 
include suspicious peritumoral edema as defined on T2 weighted MR 
sequences beyond the T1 post-gadolinium gross tumor. If this causes the 
field to extend beyond the involved anatomic compartment, the field can 
be shortened to include the end of a compartment. The radial margin from 
the lesion should be 1.5 cm including any portion of the tumor not 
confined by an intact fascial barrier or bone or skin surface.  
 
CTV for All Other Tumors (intermediate to high grade tumors < 5 cm): 
Include gross tumor and clinical microscopic extension. CTV = GTV plus 
at least a 2 cm longitudinal margin. Using MRI (preferably with image 
fusion), the CTV will also include suspicious peritumoral edema as 
defined on T2 weighted MR sequences beyond the T1 post-gadolinium 
gross tumor. The radial margin from the lesion should be 1 cm including 
any portion of the tumor not confined by an intact fascial barrier or bone 
or skin surface.  
 

                
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Special Considerations: Tumors located in subcutaneous tissues or in areas 
along the trunk and extremity where there are multiple potential high risk 
margins along different muscles/neurovascular bundles, the longitudinal 
margin should be expanded in all the planes that may be at high risk of 
spread. For example, CTV for subcutaneous sarcomas should include a 
PLQLPXPFPLQSDWLHQWVDQGFPLQSDWLHQWV!\HDUVROG
of the subcutaneous space in all planes except radially; radially it should 
include the fascia but not the muscles deep to the fascia. (see Appendix 
XVI) CTV also includes regional lymph node chains found to be involved. 
A treating physician is encouraged to discuss these special considerations 
with radiation oncology chairs in this protocol. 
 
17.5.5.2 For  18 year old Skeletally Immature Patients: Based on ARST0332 
 
CTV 
The CTV is defined as GTV + 1.5 cm (but not extending outside of the 
patient). Using MRI (preferably with image fusion), the CTV will also 
include suspicious peritumoral edema as defined on T2 weighted MR 
sequences beyond the T1 post-gadolinium gross tumor. CTV also includes 
regional lymph node chains that are known to harbor pathologically 
involved nodes. CTV is modified to account for specific anatomic barriers 
to tumor spread. Skin surfaces should not be contoured in CTV unless 
these are involved by gross tumor. If the incisional biopsy scar is small 
and will be resected at the time of surgery, it may not be contoured as CTV 
at the discretion of the treating radiation oncologist. Use of bolus on the 
skin surfaces is not encouraged when IMRT is used. A strip of normal 
tissue should be spared from high dose irradiation to avoid severe 
lymphedema if it is extremity sarcoma.  
 
For all patients: 
 
CTV boost for postoperative radiation if given (required for gross residual 
disease; optional for microscopic positive margins):  
 
The CTV boost is defined as GTV boost (as defined in Section 17.5.4) 
plus a 1 cm margin.  
 
PTV 
The PTV is defined as CTV with an additional standard margin of 1.0 cm. 
Smaller margins can be used after the institution is credentialed for the use 
of IGRT. If some portion or all of the standard margin is reduced from 1.0 
cm to a value that is no less than 0.5 cm, then daily image-guided 
radiotherapy (IGRT) will be required. In the absence of IGRT, the PTV 
margin must be 1.0 cm. The PTV margin does not need to be uniform in 
all dimensions, particularly if normal tissues are compromised. Beam 
specific PTV expansions may be required for proton planning, particularly 
in the axis of the beam. This treatment delivery technology can also take 
advantage of IGRT for margin reduction. Skin surfaces should not be 
contoured in PTV unless these are involved by gross tumor. If the 
incisional biopsy scar is small and will be resected at the time of surgery, 
it may not be contoured as CTV at the discretion of the treating radiation 

                
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oncologist. Use of bolus on the skin surfaces is not encouraged when 
IMRT is used. A strip of normal tissue should be spared from high dose 
irradiation to avoid severe lymphedema if it is extremity sarcoma. 
 
17.5.6 Site-Specific Modifications  
Nodal Radiation 
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 may be included in the 
CTV at the discretion of treating physician. 
 
Metastatic Sites 
Radiation is recommended to all metastatic sites when feasible at the completion 
of all protocol treatment. Feasibility diminishes as the number of metastatic sites 
increases and will be determined by the treating radiation oncologist. Surgical 
resection of metastases is encouraged prior to considering irradiation if it can be 
done with reasonably low or acceptable morbidity. Surgery and/or radiation should 
be used such that morbidity from treatment is minimized. Radiation therapy to a 
focal lung or liver metastases can be considered if surgery is not acceptable or 
possible. 
 
Targeting of Metastases 
The GTV for metastatic sites is the area of residual tumor defined on CT, PET, 
and/or MRI (post-chemotherapy/surgery). In cases where there is a discrepancy in 
volume between the scans, the larger volume will be irradiated. A CTV is not 
required for the treatment of metastatic lesions. The appropriate PTV should be the 
GTV with a geometric margin (approximately 1 cm at the discretion of treating 
physician). 
 
17.6 
Radiation Treatment Dose  
17.6.1 Prescribed Dose and Fractionation 
17.6.1.1 Preoperative Radiation:  
In the non-chemotherapy cohort, the total preoperative dose to the primary 
tumor on the non-chemotherapy regimen will be 50 Gy (PTV) in 2 Gy 
fractions.  
 
In the chemotherapy cohort, the total preoperative dose to the primary 
tumor will be 45 Gy (PTV) in 1.8 Gy fractions. This reflects a 10% 
reduction in radiation dose because of concurrent chemotherapy.  
 
 

                
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Table 17.6 
Prescribed RT doses and fractionation  
 
 
Target 
Dose 
(Gy) 
Dose per 
fraction 
(Gy) 
Cumulative 
Dose (Gy) 
Chemotherapy Regimen 
 
 
 
Preoperative RT  
Postoperative RT 
       Positive microscopic margins (optional) 
      Gross residual disease (required) 
45 
 
16.2 
21.6 
1.8 
 
1.8 
1.8 
45 
 
61.2 
66.6 
Non-Chemotherapy Regimen 
 
 
 
Preoperative RT  
Postoperative RT 
       Positive microscopic margins (optional) 
      Gross residual disease (required) 
50 
 
16 
20 
2 
 
2 
2 
50 
 
66 
70 
Metastases* 
 
 
 
* Metastases: Resection and/or irradiation is recommended at the discretion of the 
treating team. The radiation dose and fractionation for metastases will be at the 
discretion of treating physician.  
 
17.6.1.2 Postoperative Boost (if applicable) 
For patients with gross residual tumor after the resection, a boost is 
required. For patients with microscopic positive margin, postoperative 
radiation is controversial; it is highly recommended but optional. Delay of 
postoperative RT OR omission of postoperative RT for microscopic 
margin should be documented. Delay or omission documentation should 
be submitted with the RT QA materials (see Section 17.10). No boost is to 
be given for negative margins. Negative margin is defined as the 
microscopic absence of tumor on the inked margins following resection 
regardless of the proximity of tumor cells to the margin. Postoperative 
boost may be given with the following techniques: 
 
17.6.1.2.1 External Beam Radiotherapy  
In the Chemotherapy Cohort: 
For gross residual disease (required) the boost dose is 21.6 Gy in 
12 fractions for a cumulative dose of 66.6 Gy. For positive margins 
(optional), the recommended boost dose is 16.2 Gy in 9 fractions for a 
cumulative dose of 61.2 Gy. 
 
In the Non-Chemotherapy Cohort: 
For gross residual disease (required), the boost dose is 20 Gy in 
10 fractions once a day for a cumulative dose of 70 Gy. For positive 
margins (optional), the boost dose is 16 Gy in 8 fractions once a day for a 
cumulative dose of 66 Gy  
 
Postoperative external beam boost RT (required for gross residual and 
optional for microscopic positive margins) should begin 3 weeks 
following resection, if the healing of the surgical wound is satisfactory at 

                
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the discretion of the surgeon. If wound complications preclude initiating 
postoperative RT by 6 weeks from surgery, the reasons for a delay in boost 
treatment or omission of boost for microscopic margin should be 
documented and reported with the QA documentation (Section 17.10). 
Bolus should be avoided unless positive margins occur in cutaneous or 
subcutaneous tissues. Because preoperative radiation therapy has been 
delivered, it is not necessary to include the entire surgical bed, drain sites, 
and wound. Unless brachytherapy or intraoperative RT is to be used, 
postoperative RT should be consistent with the technique used for the 
patient’s preoperative RT, ie, if image-guided 3D-CRT was used for 
preoperative RT, it should be used for postoperative RT; if image-guided 
IMRT was used for preoperative RT, it should be used for postoperative 
RT.  
 
Brachytherapy 
Either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy as a 
boost to the positive tumor margin is acceptable as an alternative to 
external beam radiotherapy. Brachytherapy should not start until Day 5 
after the surgery (Day 0) and must be completed within 2 weeks following 
surgery. Typically, brachytherapy catheters are placed at an interval of 0.5 
-1.0 cm on the residual tumor bed (positive margin) plus a margin of 1 cm 
during surgery. Skin surface dose should be kept below 50% of the 
prescription dose unless positive margins occur in cutaneous or 
subcutaneous tissues. It is not necessary to include the entire surgical bed, 
drain sites and wound. For LDR brachytherapy, the dose is 16 Gy at no 
more than 80 cGy per hour. For HDR brachytherapy, 4 fractions of 3 to 
3.4 Gy are delivered in a b.i.d. fashion, with an interval of at least 6 hours 
between fractions. 
 
Intraoperative Radiotherapy Boost 
Intraoperative radiation therapy (electron therapy or high-dose-rate 
interstitial brachytherapy) in a single fraction is allowed. For 
chemotherapy cohort, a dose of 7.5-10 Gy to microscopic margin and a 
dose of 12.5 Gy to macroscopic disease (gross residual disease). For non-
chemotherapy cohort, a dose of 10-12.5 Gy to microscopic margin and a 
dose of 15 Gy to macroscopic disease (gross residual disease). Note: A 
frozen section diagnosis of positive margin must be obtained prior to 
intraoperative radiotherapy. Typically the dose is prescribed to 1 cm depth 
or 90% isodose line. However, prescription depth or isodose line coverage 
should be decided at the discretion of the treating radiation oncologist 
based on the consideration of boost target volume, surgical/pathological 
findings, and adjacent normal tissue structure tolerance. 
 
17.6.2 Dose Definition 
Photon dose is to be specified in Gray (Gy)-to-muscle. For proton beam, the 
absorbed dose is specified in Gy RBE, which is the same as ICRU 78 DRBE using 
a standard RBE of 1.10 with respect to Cobalt-60.  
 

                
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17.6.3 Dose Uniformity 
At least 95% of the PTV/PTVBoost and 100% of the CTV/CTVBoost should be 
encompassed by 95% of the protocol-specified dose. No more than 10% of the 
PTV (PTVBoost for patients with a volume reduction) should receive greater than 
110% of the protocol dose as evaluated by DVH. Wedges, compensators and other 
methods of generating more uniform dose distributions are encouraged. 
 
It is recognized that in some cases it may be difficult to achieve full coverage of 
the PTV. This may be the case, for example, in extremity sarcomas in young 
children where the PTV extends into the buildup region. Cases such as this will be 
considered per protocol if 95% of the protocol dose encompasses 100% of the 
CTV. 
 
Proton Specific Guidelines: For protons, treatment planning does not specifically 
use a traditionally defined PTV for treatment planning. All uncertainties are taken 
into account explicitly to create a robust plan that provides full dose coverage of 
the CTV, generally from each beam – proton plans should be evaluated for 
adequate coverage provided by each individual beam and for PTV coverage from 
the summation of all beams. For passive scattering and uniform scanning, 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. The 
main part of the range margin comes from uncertainty in CT accuracy and the 
conversion of the Hounsfield units to proton stopping power ratios. Most proton 
centers are expected to use 3.5% of the maximum water-equivalent depth of the 
CTV and then add another millimeter 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 be increased consistently to ensure proximal 
coverage of the target volume. The beam range may be adjusted at the discretion 
of the treating radiation oncologist based on normal tissue dose concerns. 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 (eg, 3mm). As a result, 
the beam may not penetrate deep enough to sufficiently cover the distal portion of 
the PTV. This may occur for shallow target volumes where the maximum depth of 
the CTV is small and the range margin is small. This scenario is not expected for 
this protocol; however, such incomplete coverage of the PTV will not constitute a 
planning deviation because the plan should be sufficiently robust to cover the CTV 
with the protocol specified dose accounting for all uncertainties. 
 

                
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17.6.4 Tissue Heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed 
with CT-based treatment planning to generate dose distributions and treatment 
calculations from CT densities. When treatment beams traverse 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, correlation between the institutional CT 
treatment planning system Hounsfield Units and “relative proton stopping power” 
must be established and documented. Proton therapy should be used with extreme 
caution when any of the treatment beams traverse normal lung parenchyma. Please 
see explicit planning guidelines for this situation in Section 17.8.3. 
 
17.7 
Treatment Technique 
17.7.1 Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without 
compromising coverage of the target volume. Three-dimensional conformal 
therapy (coplanar or non-coplanar), IMRT or proton therapy is required to 
minimize dose to normal tissues.  
 
17.7.2 Selection of Proton Beam Arrangements 
There are uncertainties (1-3 mm) in the distal range of the proton beam in which 
the RBE may be greater than 1.1; therefore, single proton beam plans which stop 
in a critical organ will not be allowed. Critical organs include, but are not limited 
to, spinal cord, trachea, and mainstem bronchus. Individual proton beams which 
are a component of a multi-field proton beam, which stop within such an organ, 
will be allowed. 
 
17.7.3 Field Shaping 
Field shaping for photons will be done with multileaf collimation. Use of 
customized cerrobend blocking is allowed when needed. Field shaping for protons 
will be done with either brass or cerrobend apertures or proton-specific multileaf 
collimation.  
 
17.7.4 Motion Management and Margins to Account for Target Volume and Organ 
Motion 
Considering motion of normal tissues and target volumes is important. The internal 
target volume (ITV) is defined as the CTV surrounded by the internal motion (IM) 
component of the PTV and is meant to account for potential motion of the CTV. 
If adequate clinical data do not exist to define the IM component of the PTV 
margin, the following suggestions are provided: 
 
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 1.0 cm should be chosen. 
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.  

                
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x 
IMRT may be used for tumors of the thorax only if the degree of tumor motion 
is assessed and can be limited to 0.5 cm in any direction. IMRT can also be 
used in combination with gating or tracking when appropriate credentialing is 
performed for this type of treatment. Techniques for managing or suppressing 
tumor motion shall be applied as needed. 
x 
Protons may be used for tumors of the thorax only if the degree of tumor 
motion is assessed and can be limited to 0.5 cm in any direction. Motion should 
be accounted for in an ITV. Motion of the target volume in three dimensions 
(cranial, caudal, anterior to posterior, and lateral) may be determined by 4-
dimensional CT, respiratory gated CT, or other accepted techniques. 
x 
A description of the method used and evidence (ie, observed motion during 
fluoroscopy, motion of surrogate markers using camera systems, or analysis 
of 4-D CT) of the remaining tumor motion should be submitted on the Motion 
Management Reporting Form with the Quality Assurance Documentation 
materials as noted in Section 17.10. 
 
NOTE: For patients treated with IMRT, use of gating or tracking methods to 
compensate for respiratory motion requires irradiation of IROC Houston’s 
Thorax-Lung Phantom with accompanying reciprocating platform to simulate 
motion. Contact IROC Houston’s (http://rpc.mdanderson.org/rpc/) for 
information about their phantoms. 
 
17.7.5 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 
Organs at Risk (OAR) 
17.8.1 General Principles  
Radiation dose to normal tissues should be kept within the accepted normal tissue 
tolerances when using standard 1.8 to 2 Gy fractionation schedules. All critical 
structures appropriate for each anatomic site must be contoured consistently and 
dose to normal structures should be strictly limited. Exceptions based on the site 
of the sarcoma should be documented to avoid a deviation. 
 
Every effort should be made to avoid treating the full circumference of an 
extremity. No more than 50% of a longitudinal stripe of skin and subcutaneous 
tissue of an extremity should receive 20 Gy. This stripe of normal tissue is 
contoured at the discretion of treating radiation oncologist. Full prescription dose 
to skin over areas commonly traumatized (eg, the elbow, knee, shin) should be 
avoided. Efforts should be made to avoid treating anus, vulva and scrotum, lung, 
spinal cord, femoral head/neck. 
 
If the tumor is close to the following structures, typically less than 50% volume of 
anus and vulva should receive 30 Gy, the testes should be kept to < 1 Gy and the 
ovaries to < 5 Gy, the V20 lungs should be <30%, and less than 5% of femoral 
head/neck should receive 60 Gy. Less than 50% of any joints (including shoulder, 
elbow and knee) should receive 50 Gy. Kidney dose > 20 Gy should be kept to 
< 30%. 

                
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For any other normal tissue structures, no radiation dose more than the established 
TD5/5 limit should be given. The above criteria must be met in the CT based plan. 
 
No more than 50% of normal weight-bearing bone within the radiation field 
(contoured for full length covered by PTV plus 2 cm to both ends) should receive 
50 Gy except when the tumor invades the bone or when there is circumferential 
involvement of the tumor more than a quarter of the bone or when the bone will 
be resected in a subsequent surgical resection after radiation with plans for 
plating/prosthetic/graft placement to strengthen the bone. 
 
We recommend that skin surface (5 mm thickness) including scar from incision 
biopsy is not included in CTV or PTV and is not bolused for IMRT, unless (1) the 
biopsy scar is not subsequently resected after radiotherapy (resection of the biopsy 
scar is highly recommended) (2) the tumor is subcutaneous and within 5 mm of 
the skin; or (3) the tumor infiltrates or ulcerates through the skin based on clinical 
exam and/or imaging. 
 
17.8.2 Organs at Risk (OAR) Dose Constraints 
OAR and planning organ at risk volumes (PRV) and dose guidelines are 
cumulative dose limits. These limits are adapted from Quantitative Analyses of 
Normal Tissue Effects in the Clinic QUANTEC195 and adjusted based on 
potential increased effect from concurrent therapy. OARs include additional 
structures specific to extremity sarcomas. Contouring of normal structures should 
be 
based 
on 
the 
atlas 
available 
on 
the 
RTOG 
web 
site. 
http://www.rtog.org/CoreLab/ContouringAtlases.aspx. 
 
Primary 
Tumor 
Site 
DVH required if 
structure is in 
path of or near 
any treatment 
beam 
Required 
DVH 
Metric 
Per Protocol 
Cumulative 
Dose 
Variation 
Acceptable  
Deviation 
Unacceptable  
Toxicity 
Endpoint 
Trunk/ 
Chest wall 
Brachial Plexus 
Max 
63 Gy 
<= 65 Gy 
> 65 Gy 
Brachial 
plexopathy 
 
Esophagus 
Mean  
Max 
<30 Gy 
< 70 Gy 
<= 33 Gy 
<= 74 Gy 
> 33 Gy 
Esophagitis 
 
Heart 
Mean 
V30 
<26 Gy 
<40% 
<= 30 Gy 
<= 50% 
> 30 Gy  
> 50% 
Pericarditis 
 
Lung 
Mean 
V5 
V20 
7 Gy 
< 60% 
< 30% 
<= 8 Gy 
<= 65% 
<= 35% 
> 8 Gy 
> 65% 
> 35% 
Symptomatic 
pneumonitis 
 
Spinal cord (if 
receiving any dose) 
Max 
45 Gy 
<=48 Gy 
> 48 Gy 
Myelopathy 
 
PAR-cord (see 
Section 17.8.3) 
Max 
50 Gy 
<=52 Gy 
> 52 Gy 
Myelopathy 
Abdominal 
wall 
Liver 
Mean 
<30 Gy 
<= 33 Gy 
> 33 Gy 
RILD in normal 
function liver 
 
R & L Kidneys 
Mean 
V20 
< 14.4 Gy 
< 30% 
<= 16 Gy 
<= 33% 
> 16 Gy 
> 33% 
Renal 
dysfunction 
 
Small bowel 
(peritoneal cavity) 
V45 
< 20%  
(or max volume 
195 cc) 
<= 30% 
 (or max 
volume 205 cc) 
> 30% 
(or max volume 
> 205 cc) 
Grade 3+ 
toxicity 
 
Stomach 
Max 
<45 Gy 
<= 47 Gy  
> 47 Gy 
Ulceration 

                
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* Exception allowed for tumor infiltrating the femur or joints. 
** Exception allowed for primarily subcutaneous tumors or tumor infiltrating the skin for which the subcutaneous 
fat/skin lymphatics is the high risk margin. 
 
17.8.3 Use of Proton Therapy in Treatment of Thoracic Tumors 
During treatment of truncal tumors that may require beams to traverse normal lung 
tissue, proton therapy should be used with extreme caution. The following specific 
constraints will apply in this situation: 
x 
When considering the total lung volume less the PTV: 
o The volume of lung receiving 20 Gy (V20) should be less than 
30% 
o The volume of lung receiving 5 Gy (V5) should be less than 60% 
o The mean lung dose should be less than 7 Gy 
x 
When considering the spinal cord: 
o The maximum dose should be 45 Gy 
o A structure called PAR-Cord should be created, and consist of 
the contoured spinal cord plus a 5 mm expansion. The maximum 
dose to the PAR-Cord structure should be 50 Gy. 
x 
Additionally, the distal end of the Bragg peak of a single beam should 
not stop in a critical structure, such as the spinal cord, trachea, or 
mainstem bronchus due to uncertainty with regard to dose deposition at 
the distal end of the beam. Individual proton beams which are a 
component of a multi-field proton beam, which stop within such an 
organ, will be allowed. 
 
Pelvis 
Anus 
V30 
V50 
<50% 
< 20% 
<= 60% 
<= 25% 
> 60% 
> 25% 
Grade 3+ 
toxicity 
 
Bladder 
V50 
V70 
<50% 
<20% 
<= 60% 
<= 25% 
> 60% 
> 25% 
Grade 3+ 
toxicity 
 
Rectum 
V50 
V70 
<50% 
<20% 
<= 60% 
<= 25% 
> 60% 
> 25% 
Grade 3+ 
toxicity 
 
Vulva** 
V30 
< 50% 
<= 60% 
> 60% 
Moist 
desquamation 
 
Testes (if fertility 
preservation 
desired) 
V1 
<50% 
<= 60% 
> 60% 
Infertility 
 
Ovaries (if fertility 
preservation 
desired) 
V5 
<50% 
<= 60% 
>60% 
Infertility 
Paraspinal 
Spinal Cord  
Max 
<45 Gy 
<=48 
>48 
Myelopathy 
 
PAR-Cord (see 
Section 17.8.3) 
Max 
50 Gy 
<= 52 Gy 
>52 Gy 
Myelopathy 
Extremity 
Femur within the 
field* 
V50 
<50% 
<= 60% 
>60% 
Fracture 
 
Joints* 
V50 
<50% 
<= 60% 
>60% 
Joint stiffness 
 
Total skin within 
field (5 mm 
thickness)** 
V20 
<50% 
<= 60% 
>60% 
Wound 
healing/lymph-
edema 

                
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17.9 
Dose Calculation and Reporting 
17.9.1 Prescribed Dose 
The monitor units required to deliver the prescribed dose shall be calculated and 
submitted using the RT-1 Dosimetry Summary Form or Proton Reporting Form. If 
IMRT is used, the monitor units generated by the IMRT 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 daily and total prescribed dose shall be calculated and 
reported on the RT-2 Radiotherapy Total Dose Record.  
 
17.9.2 Required Normal Tissue DVH Data According to Primary Tumor Site 
The dose to the critical organs indicated in Section 17.8.2 should be calculated 
whenever any beam traverses the structure. The dose shall be reported on the RT-
2 Radiotherapy Total Dose Record form and the appropriate dose-volume 
histograms shall be submitted. If IMRT is used, a DVH must be submitted for a 
category of tissue called “unspecified tissue,” which is defined as tissue contained 
within the skin, but which is not otherwise identified by containment within any 
other structure. 
 
17.10 Quality Assurance and Documentation 
Primary Site: One week prior to the start of radiation therapy, detailed treatment data shall 
be submitted for pre-treatment review and approval. 
 
Postoperative Boost (when done): Detailed treatment data shall be submitted at the end of 
treatment to the boost. 
 
Metastatic Site(s): Data may be submitted at the end of treatment. Only the RT-2 form and 
a copy of the radiotherapy record (treatment chart) are required. 
 
Digital Submission: 
Submission of treatment plans as DICOM RT is required. Digital data must include CT 
scans, structures, plan, and dose files. Submission may be by either sFTP or CD. 
Instructions for data submission are on the IROC Rhode Island (formerly QARC)  web site 
at www.qarc.org under "Digital Data." Any items on the list below that are not part of the 
digital submission may be included with the transmission of the digital RT data via sFTP 
or submitted separately. Screen captures are preferred to hard copy for items that are not 
part of the digital plan. 
 
Please submit the following for the Primary Site Target Volume (and postoperative 
boost, if applicable): 
 
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. 

                
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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. Digital format is 
preferred. This includes CT or MRI PRIOR to attempted surgical resection of 
the primary tumor. 
x 
Copies of reports (radiology, operative, pathology, cytology) and any other 
information used in defining the target volumes. 
x 
If the recommended doses to the organs at risk are exceeded, an explanation 
should be included for review by the IROC Rhode Island (formerly QARC) 
and the radiation oncology reviewers. 
x 
If modifications are made for patients with age < 24 months, documentation 
should be provided. 
x 
Documentation of any emergency RT administered prior to the protocol 
prescribed course of RT. Documentation should be provided in the form of 
the radiotherapy record (treatment chart). 
x 
Documentation of postoperative boost delay or omission of postoperative 
boost for positive margins. 
 
Forms 
x 
RT-1 Dosimetry Summary Form. 
x 
Proton Reporting Form (if applicable). 
x 
Motion Management Reporting Form (if applicable). 
 
Submit the following items within 1 week following the completion of each 
treatment phase 
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. 
 
Please submit the following for Metastatic Sites 
Forms 
x 
RT-2 Radiotherapy Total Dose Record Form. 
x 
Radiotherapy record (treatment chart) including prescription and daily and 
cumulative doses to all required areas and organs at risk. 
 
Please submit the following additional information for brachytherapy, if used: 
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. 
 

                
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Please submit the following additional information for intra-operative radiation 
therapy, if used: 
x Radiotherapy record (treatment chart) including prescription 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 (ie, percent 
depth dose for the prescribed energy) 
x Documentation of approval by a Radiation Oncology Study Committee 
Member. 
 
These data should be forwarded to IROC Rhode Island (formerly QARC). 
 
Questions regarding the dose calculations or documentation should be directed to: 
Protocol Dosimetrist 
IROC Rhode Island QA Center 
640 George Washington Highway 
Building B, Suite 201 
Lincoln, RI 02865-4207 
Tel: 
(401) 753-7600 
Fax: 
(401) 753-7601 
Email: physics@qarc.org  
 
Definitions of Deviation in Protocol Performance  
 
The Per Protocol definition of the dose prescription is given in Sections 17.6.1 and 17.6.3. 
 
 
Variation Acceptable 
Deviation Unacceptable 
Dose 
External beam 
10% PTV receives > 110% of protocol dose 
EXW 
or 
< EXWRIWKHSURWRFROGRVH
covers 95% of PTV or 100% of CTV* 
10% PTV receives > 115% of protocol 
dose 
or 
< 90% of the protocol dose covers 95% 
of PTV or 100% of CTV* 
Brachytherapy 
< EXW 90% of the protocol dose 
covers 100% of CTV 
< 90% of the protocol dose 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 
Dose to any required OAR exceeds the goal 
stated in Section 17.8.2 
Dose to any required OAR exceeds the 
variation acceptable limit in 
Section 17.8.2 
* See Section 17.6.3 for handling targets near the skin surface. 
 
17.11 Adverse Effects of Radiation and Management 
17.11.1Radiotherapy related treatment effects are both location- and time-dependent and 
clearly related to the dose delivered to specific organs or structures. Effects are 
divided into acute reactions, early delayed reactions and late reactions divided by 
arbitrary time periods indicated below. 

                
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17.11.2Acute reactions (during radiotherapy): Fatigue, regional alopecia, skin erythema, 
desquamation, reduction in blood counts, cough, shortness of breath, nausea, 
diarrhea, swelling of the limb dependent on location of the tumor in the trunk or 
extremity.  
 
17.11.3Subacute reactions (6 weeks to 3 months after irradiation): Soft tissue edema, 
wound healing complications.   
 
17.11.4Late reactions (more than 3 months after irradiation): Fibrosis of soft tissues 
including muscle, injury to muscle or bone, including changes in bone growth, and 
changes in tissue vascularity, lymphedema, joint stiffness, bowel injury, 
osteoradionecrosis, bone fracture, and radiation associated second malignancy. 
  
 

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

                
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CTSU REGISTRATION PROCEDURES 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the ARST1321 protocol page located on the CTSU 
members’ website. 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. 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the COG link to expand, then select trial protocol #ARST1321 
Click on LPO Documents, select the Site Registration documents link, and download and 
complete the forms provided. 
 
Requirements for ARST1321 Site Registration: 
 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form 
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must 
be aligned to a RTI provider. To manage provider associations access the Provider Association 
tab on the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or 
remove associated providers. Sites must be linked to at least one IROC credentialed provider 
to participate on trials with an RT component. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered 
and tracked in the CTSU RSS. 
 
Regulatory Submission Portal: www.ctsu.org (members’ area) Æ Regulatory Tab 
ÆRegulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory 
Office immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: 
Sites will not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 

                
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and password 
 
Click on the Regulatory tab at the top of your screen 
 
Click on the Site Registration tab 
 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. It does not reflect 
compliance with protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data 
management system. Access to the trial in Rave is granted through the iMedidata application to all 
persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave 
via iMedidata, the site user must have an active CTEP-IAM account (check at 
https://ctepcore.nci.nih.gov/iam) and the appropriate Rave role (Rave CRA, Read-Only, CRA (Lab 
Admin, SLA or Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. To the hold Rave CRA role or CRA Lab Admin role, the user must hold a minimum 
of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered 
as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study has a DTL, 
individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the 
DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on 
the appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right-corner of the 
iMedidata page. Please note, site users will not be able to access the study in Rave until all required 
Medidata and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the 
iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata to 
activate their account. Account activation instructions are located on the CTSU website, Rave tab 
under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 

                
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APPENDIX II:  ANATOMIC SITE DEFINITIONS 
The determination of the anatomic site of the primary tumor should be based on the location of the epicenter 
of the tumor as defined by muscle and/or bony landmarks. Tumors that arise in subcutaneous tissues should 
be considered to belong to the closest anatomic site. 
 
Head and Neck Sites (NOT eligible for this study) 
Head – Tumors arising in the facial and sub-mandibular structures, the mouth and pharynx, and in all sites 
superior to the skull base. This site is excluded in this study. 
 
Neck – Tumors that arise above the level of the inferior aspect of cervical vertebra 7 and below the skull 
base, but not arising from the face, sub-mandibular structures, mouth, or pharynx. Tumors arising within 
the trapezius above the level of the clavicle are also included. Tumors within the paraspinal muscle complex 
in the neck should be classified as paraspinal. Tumors arising within the spinal canal should be categorized 
as intraspinal.  
 
Body Wall Sites (Eligible for this Study) 
Anterior chest wall – Tumors arising within intercostal muscles in proximity to the anterior ribs, and tumors 
arising superficial to the pectoralis muscles that do not involve the breast. This site is bordered superiorly 
by the top of the first rib and sternal notch, inferiorly by the cartilage and bone forming the rib cage, and 
laterally by the mid-axillary line. Tumors that arise within the pleural space and those with an associated 
pleural effusion should be classified as intrathoracic. Tumors arising within the pectoralis muscle and all 
axillary tumors except those originating in the intercostal muscles of the chest wall should be classified as 
shoulder. Tumors arising within the fibroglandular tissue of the breast should be classified as breast.  
 
Breast - Tumors arising anterior to the pectoralis muscles and within the fibroglandular tissue of the breast. 
Tumors superficial to the pectoralis muscles that do not involve either the breast tissue or the pectoralis 
muscles themselves should be classified as anterior chest wall. 
 
Posterior chest wall – Tumors arising within the intercostal muscles in proximity to the posterior ribs. This 
site is bordered superiorly by the top of the first rib, inferiorly by the 12th rib, and laterally by the mid-
axillary line and includes only sites deep to the scapular musculature. Tumors arising within the 
musculature of the scapula should be categorized as shoulder. All axillary tumors except those originating 
in the intercostal muscles of the chest wall also should be classified as shoulder.  
Note that tumors that arise within the pleural space and those with an associated pleural effusion should be 
classified as intrathoracic.  
 
Paraspinal – Tumors located within the paraspinal muscle complex (transversospinalis muscle group and 
the erector spinae muscles) that arise superior to the upper aspect of the sacrum and outside of the spinal 
canal. The erector spinae muscles occupy the vertebrocostal groove of the back and lie just deep to the 
thoracolumbar fascia. This muscle group is composed of three longitudinally oriented groups of fasicles 
extending from a common tendinous origin from the sacrum to variable attachments on the ribs and spinous 
processes. The transversospinalis muscle group is deep to the erector spinae muscles and consists of the 
multifidus and rotatores muscles which extend obliquely upward two to four levels and one to two levels, 
respectively, from the transverse processes to the spinous processes of the vertebrae. Tumors arising within 
the musculature of the scapula should be categorized as shoulder. Tumors that arise within the pleural space 
and those with an associated pleural effusion or ascites should be classified as intrathoracic or 
intraperitoneal, as appropriate. Tumors with their epicenter at or below the upper aspect of the sacrum should 
be classified as hip. Tumors arising within the spinal canal should be categorized as intraspinal. 
 

                
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Intraspinal – Tumors with their epicenter within the spinal canal and between the skull base and the upper 
aspect of the sacrum. Tumors extending intraspinally but with their epicenter within the paraspinal muscle 
complex should be classified as paraspinal. Tumors with their epicenter at or below the upper aspect of the 
sacrum should be classified as hip. 
 
Abdominal wall – Tumors within extraperitoneal soft tissues bordered superiorly by the cartilage and bone 
forming the rib cage, posteriorly by the lateral edge of the paraspinal muscle complex, and inferiorly by a 
line running anteriorly from the lateral margin of the paraspinal muscle complex along the iliac crests and 
the inguinal ligaments to the superior pubic rami. Tumors arising more inferiorly should be classified as 
hip. Tumors with their epicenter within the peritoneal space or that are associated with ascites should be 
classified as intraperitoneal or pelvis, as appropriate.  
 
Visceral Sites (NOT eligible for this study)) 
Intrathoracic – Tumors with their epicenter in the area between the apical lung pleura/superior 
mediastinum and the diaphragms. All contents of the pleural space and mediastinum are included. Tumors 
of the diaphragms are included. 
 
Intraperitoneal – Tumors with their epicenter within the peritoneal cavity between the dome of the 
diaphragms and a plane defined by the superior aspect of the iliac crests and the sacrum. Tumors of the 
diaphragms should be classified as intrathoracic. Intra-abdominal tumors with their epicenter inferior to 
the uppermost aspect of the iliac crests and sacrum should be classified as pelvis. Tumors arising in 
retroperitoneal structures (as defined below) should be classified as retroperitoneal. Retroperitoneal tumors 
that invade the peritoneal space as defined above should be classified as intraperitoneal. 
 
Retroperitoneal – Tumors with their epicenter in the space bounded superiorly by the diaphragm, inferiorly 
by a plane defined by the superior aspect of the iliac crests and the sacrum, anteriorly by the posterior layer 
of the peritoneum, and posteriorly by the muscles of the back. This space includes the intra-abdominal aorta 
and inferior vena cava, psoas muscle, pancreas, kidneys, ureters, perirenal space, and adrenal glands. 
Tumors of the diapharagms should be classified as intrathoracic. Tumors with their epicenter inferior to 
the uppermost aspect of the iliac crests should be classified as pelvis. Tumors within the muscles of the 
back should be classified as paraspinal or abdominal wall. Note that retroperitoneal tumors that invade the 
peritoneal space should instead be classified as intraperitoneal or pelvic, as appropriate (tumors that invade the 
peritoneal space in both locations should be classified as intraperitoneal).  
 
Pelvis – Tumors within the confines of the bony pelvis and internal to the sciatic notch with their epicenter 
below the plane defined by the superior aspect of the sacrum and iliac crests and extending inferiorly to the 
urogenital diaphragm. Tumors arising within muscles that course through the pelvis (iliopsoas complex, 
piriformis) are included if the epicenter falls within the anatomic confines noted above. Tumors arising in 
an extraperitoneal location in the anterior abdominal wall should be classified as abdominal wall. Tumors 
with their epicenter superior to the iliac crests should be classified as either intraperitoneal or 
retroperitoneal. Retroperitoneal tumors that invade the peritoneal space within the anatomic confines of 
the pelvis as defined above should be classified as pelvis. Tumors arising inferior to the urogenital 
diaphragm should be classified as perineum (tumors of the prostate should be classified as pelvis). Tumors 
arising external to the sciatic notch and those external to the bony pelvis should be classified as hip. 
Paratesticular sarcomas involving the scrotum or spermatic cord are not eligible for this study as 
postoperative radiotherapy may be preferable due to the difficulty of wound healing in this region with 
preoperative radiotherapy. 
 
Perineum – Tumors with their epicenter in the space below the urogenital diaphragm bounded anteriorly 
by the pubic symphysis, laterally by the inferior pubic rami and ischial tuberosities, and posteriorly by the 

                
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coccyx. This space includes the urethra (in males, only the portion inferior to the prostate), levator ani 
muscles, ischiorectal fossa, and other periurethral and perianal structures. Tumors arising immediately 
outside of this space should be classified as either pelvis or hip, as appropriate. 
 
Upper Extremity Sites (Eligible for this Study) 
Shoulder – Tumors arising in or around the periscapular musculature (rhomboids, teres major/minor, 
supraspinatus, infraspinatus, subscapularis), deltoid, and pectoralis major/minor. This region also includes 
tumors arising in or around the following muscles above the insertion of the deltoid: biceps, triceps, 
corachobrachialis. All axillary sites except sites originating in the intercostal muscles of the chest wall are 
also included. Note that the superior boundary of the axilla is T1; sites above T1 should be considered to 
be neck sites. Tumors arising within the trapezius muscle are included if the epicenter is inferior to level of 
the clavicles (tumors of the trapezius muscle whose epicenter is superior to the level of the clavicles are 
included in the neck site). 
 
Upper arm – Tumors that arise in or around the following muscles below the deltoid insertion: biceps, 
triceps, corachobrachialis, brachialis (including their insertion points about the elbow). Tumors arising in 
the elbow joint proper are classified in this group. 
 
Lower arm – Tumors with their epicenter in or around the forearm musculature from the elbow to the level 
of the radiocarpal joints. Tumors arising in the elbow joint proper should be classified as upper arm. Tumors 
that arise in tendons that pass through the wrist into the hand are considered hand tumors when the epicenter 
is distal to the radiocarpal joint. 
 
Hand – Tumors arising within or around the intrinsic muscles of the hand and tumors with their epicenter 
in the forearm tendons distal to the radiocarpal joint. Tumors arising around the carpus proper are classified 
in this group. Tumors of the fingers are included. 
 
Lower Extremity Sites (Eligible for this Study) 
Hip – Tumors arising external to the bony pelvis inferior to a line running from the upper aspect of the 
sacrum along the iliac crests and the inguinal ligaments to the superior pubic rami and external to the sciatic 
notch, above the level of the lesser trochanter of the femur. This site includes the neurovascular and related 
structures in the inguinal canal and muscles that originate, insert, or course through this anatomic region 
(gluteus maximus/medius/minimus, piriformis, superior/inferior gemelli, obturator internus/externus, 
iliopsoas, tensor fascia latae, adductor brevis/longus/magnus, gracilis, sartorius, quadriceps femoris, rectus 
femoris, biceps femoris, semimembranosus, and semitendinosus). Tumors arising in the perineal space or 
pelvis (as defined in this appendix) are excluded. 
 
Thigh – Tumors arising within or around the following muscles (adductor brevis/longus/magnus, gracilis, 
sartorius, quadriceps femoris, rectus femoris, biceps femoris, semimembranosus, and semitendinosus) below 
the level of the lesser trochanter. Tumors arising from the knee joint proper are classified in this group. 
 
Leg – Tumors arising within or around the gastrocnemius, soleus, popliteus, and plantaris muscles, and 
tumors arising at or above the malleoli in or around the following muscles: tibialis posterior, flexor digitorum 
longus, flexor hallucis longus, tibialis anterior, extensor digitorum longus, extensor hallucis longus, and 
peroneus longus/brevis. Tumors arising from the ankle joint proper are classified in this group. 
 
Foot – Tumors arising within or around the extensor digitorum brevis and the instrinsic muscles of the foot, 
and tumors arising in or around tendons of the following muscles below the malleoli: tibialis posterior, 
flexor digitorum longus, flexor hallucis longus, tibialis anterior, extensor digitorum longus, extensor 
hallucis longus, peroneus longus/brevis. Tumors of the toes are included. 
 
 

                
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APPENDIX III:  THE FNCLCC SARCOMA GRADING SYSTEM196,197  
 
Tumour differentiation 
x 
Score 1: Sarcomas closely resembling normal adult mesenchymal tissue and 
 
potentially difficult to distinguish from the counterpart benign tumor (eg, 
 
well-differentiated liposarcoma, well-differentiated leiomyosarcoma) 
x 
Score 2: Intermediate recognition known histologic type, myxoid (eg, myxoid 
liposarcoma, myxofibrosarcoma) 
x 
Score 3: Embryonal and undifferentiated sarcomas, synovial sarcomas, sarcomas of 
 
doubtful phenotype, synovial sarcomas  
Mitotic count (established on 10 high-power field – HPF; a HPF measures 0.1734 mm²) 
x 
Score 1: 0 to 9 mitoses per 10 HPF 
x 
Score 2: 10 to 19 mitoses per 10 HPF 
x 
Score 3:  mitoses per 10 HPF 
Tumour necrosis 
x 
Score 0: no necrosis 
x 
Score 1: < 50% of tumour necrosis 
x 
Score 2: 50% of tumour necrosis  
Histologic grade 
x 
Grade 1: total score 2, 3  
x 
Grade 2: total score 4, 5 
x 
Grade 3: total score 6, 7, 8 
  
 

                
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APPENDIX IV:  WORLD HEALTH ORGANIZATION CLASSIFICATION OF SOFT TISSUE 
TUMOURS: INTERMEDIATE (RARELY METASTASIZING) AND MALIGNANT 
TUMOURS, 2013 
Adapted from Fletcher CD, et al. World Health Organization Classification of Tumours, Pathology, and 
Genetics. Tumours of Soft Tissue and Bone. IARC Press, Lyon, 2013 
 
Intermediate (Rarely Metastasizing) 
Malignant 
ADIPOCYTIC TUMORS 
Atypical lipomatous tumour / Well 
differentiated liposarcoma 
 
 
Dedifferentiated liposarcoma 
 
Myxoid liposarcoma* 
 
Pleomorphic liposarcoma 
 
Liposarcoma, not otherwise specified 
FIBROBLASTIC/MYOFIBROBLASTIC TUMORS 
 
Adult fibrosarcoma 
Solitary fibrous tumour  
Malignant solitary fibrous tumour  
Inflammatory myofibroblastic tumour 
Myxofibrosarcoma 
Dermatofibrosarcoma protuberans* 
Low grade fibromyxoid sarcoma 
Fibrosarcomatous dermatofibrosarcoma 
protuberans* 
 
Pigmented dermatofibrosarcoma protuberans*  
Low grade myofibroblastic sarcoma  
Sclerosing epithelioid fibrosarcoma 
Myxoinflammatory fibroblastic sarcoma 
 
Atypical myxoinflammatory fibroblastic 
tumour 
 
Infantile fibrosarcoma* 
 
SO-CALLED FIBROHISTIOCYTIC TUMORS 
Plexiform fibrohistiocytic tumour  
 
Giant cell tumour of soft tissues 
 
SMOOTH MUSCLE TUMORS 
 
Leiomyosarcoma 
PERICYTIC (PERIVASCULAR) TUMORS 
 
Malignant glomus tumour 
SKELETAL MUSCLE TUMORS 
 
Embryonal rhabdomyosarcoma* 
 
Alveolar rhabdomyosarcoma* 
 
Pleomorphic rhabdomyosarcoma* 
 
Spindle cell/sclerosing rhabdomyosarcoma* 
VASCULAR TUMORS 
Retiform hemangioendothelioma* 
Epithelioid hemangioendothelioma* 
Papillary intralymphatic angioendothelioma* Angiosarcoma of soft tissue 
Composite hemangioendothelioma* 
 
Pseudomyogenic (epithelioid sarcoma-like) 
hemangioendothelioma* 
 
Kaposi sarcoma* 
 
 
(con’t) 
 

                
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Intermediate (Rarely Metastasizing) 
Malignant 
CHONDRO-OSSEOUS TUMORS 
 
Mesenchymal chondrosarcoma 
 
Extraskeletal osteosarcoma  
NERVE SHEATH TUMORS 
 
Malignant peripheral nerve sheath tumor 
 
Epithelioid malignant peripheral nerve sheath 
tumour 
 
Malignant Triton tumour 
 
Malignant granular cell tumor 
 
Ectomesenchymoma* 
TUMORS OF UNCERTAIN DIFFERENTIATION 
Atypical fibroxanthoma 
 
Angiomatoid fibrous histiocytoma 
Synovial sarcoma  
Ossifying fibromyxoid tumor 
Malignant ossifying fibromyxoid tumour 
 
Epithelioid sarcoma 
Mixed Tumour NOS 
Malignant mixed tumour 
Myoepithelioma 
Myoepithelial carcinoma 
Phosphaturic mesenchymal tumour 
Malignant phosphaturic mesenchymal tumour 
 
Alveolar soft part sarcoma 
 
Clear cell sarcoma of soft tissue 
 
Extraskeletal myxoid chondrosarcoma 
 
Extraskeletal Ewing sarcoma* 
 
Desmoplastic small round cell tumor* 
 
Extra-renal rhabdoid tumor* 
 
Neoplasms with perivascular epithelioid cell 
differentiation (PEComa) 
 
Intimal sarcoma 
VISCERAL TUMORS 
 
Embryonal sarcoma (undifferentiated sarcoma) 
of the liver 
UNDIFFERENTIATED SARCOMAS 
 
Undifferentiated round cell sarcoma 
 
Undifferentiated pleomorphic sarcoma 
 
Undifferentiated epithelioid sarcoma 
 
Undifferentiated spindle cell sarcoma 
 
Undifferentiated sarcoma NOS 
 
*These tumor types are NOT eligible for ARST1321, but may be eligible for other COG or NRG Oncology 
studies sponsored by the Soft Tissue Sarcoma, Bone Tumors, Renal Tumors, and Rare Tumors committees. 
 
  
 

                
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APPENDIX VA:  90th and 95th PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT 
IN GIRLS AGE 1-17 YEARS 
 
Age  
BP  
 
Systolic BP (mmHg) 
 
 
Diastolic BP (mmHg) 
(Year) 
Percentile 
 
Percentile of Height 
 
 
 
Percentile of Height 
 
 
p 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
90th 
95th 
97  
100  
97  
101 
98 
102  
 100 
104  
101 
105  
102 
106  
103  
107   
52  
56  
53  
57  
53  
57  
54  
58  
55 
59  
55  
59  
56  
60  
2 
90th 
95th 
98  
102  
99 
103  
100 
104  
 101 
105  
103  
107  
104  
108  
105 
109  
 57  
61  
58  
62  
58  
62  
59 
63  
60 
64  
61  
65  
61  
65  
3 
90th 
95th 
 
100  
104  
100  
104  
102  
105  
103  
107  
104  
108  
106  
109  
106  
110  
 61  
65  
62  
66  
62  
66  
63  
67  
64  
68  
64  
68  
65  
69  
4 
90th 
95th 
101  
105  
102  
106  
103  
107  
104  
 108  
106 
 110  
107 
 111  
108 
 112 
64 
 68  
64 
68  
65 
69  
66  
70  
67 
71  
67  
71  
68  
72  
5 
90th 
95th 
103 
107  
103  
107 
105 
 108 
 106 
 110  
107 
111 
109 
 112 
109  
 113  
66  
 70 
67 
 71 
67 
 71  
68  
 72  
69  
 73  
69  
73   
70  
74  
6 
90th 
95th 
104 
108  
105 
109 
106 
 110 
108  
 111 
109  
 113  
110 
114 
111 
 115  
68 
 72 
68  
 72  
69  
 73 
70  
 74 
70 
 74   
71  
75  
72  
76  
7 
90th 
95th 
106 
110  
 107  
111  
108 
112 
109  
 113 
111  
 115 
112  
 116 
113 
 116  
 69 
 73  
70  
74 
70  
 74  
71 
75  
72  
76   
72  
76   
73  
77  
8 
90th 
95th 
108 
112  
109  
112  
110  
 114  
111  
115  
113 
 116  
114 
 118  
114  
 118   
71  
75  
71  
75  
71  
 75   
72  
76  
73 
77  
74  
78  
74  
78  
9 
90th 
95th 
110 
114  
 110 
 114  
 112 
 115  
 113 
 117  
 114 
 118  
 116 
 119  
 116 
 120  
 72 
 76 
 72 
 76  
 72 
 76 
 73 
 77  
 74 
 78 
 75 
 79 
 75  
 79  
10 
90th 
95th 
112 
 116  
 112 
116  
114 
 117  
115 
 119 
116 
 120 
118 
 121  
 118 
 122  
 73 
 77 
 73 
 77 
 73 
 77  
 74 
 78 
 75 
 79  
 76 
 80 
 76  
 80   
11  
90th 
95th 
114  
118  
114 
118 
116 
119 
117 
121  
118 
122  
119  
123  
120  
124 
74 
 78   
74 
78  
74  
78  
75  
79  
76 
80  
77  
81   
77  
81  
12 
90th 
95th 
116  
119  
116  
120  
117 
121 
119  
123  
120  
124  
121  
125  
122  
126  
75  
79  
75  
79  
75  
79  
76  
80  
77  
81 
78  
 82  
78  
82  
13  
90th 
95th 
117  
121  
118 
122  
119 
123 
121  
124  
122  
126  
123  
127  
124  
128  
76  
80  
76  
80  
76  
80 
77 
81 
 78  
 82  
79  
83   
79  
83  
14  
90th 
95th 
119  
123 
120  
123 
121  
125  
122 
126 
124  
127  
125  
129  
125  
129  
77  
81  
77  
81 
77  
 81  
78 
82   
 79  
83   
80  
84   
80  
84  
15  
90th 
95th 
120  
124  
121 
125  
122 
126 
123 
127  
125  
129 
126  
130  
127 
131 
 78  
 82  
78  
 82  
78  
82  
 79  
83   
80  
84 
81  
 85  
81  
85  
16  
90th 
95th 
121 
125  
122  
126  
123  
127  
124 
128 
126  
130  
127 
131 
 128 
 132 
 78  
 82  
78  
 82  
79  
83  
 80  
 84  
81  
85  
81  
85  
82  
86  
17  
90th 
95th 
122 
125 
122  
126 
123  
127 
125 
129 
126  
130  
127 
131  
 128  
132  
 78  
82 
79 
 83  
  79  
 83  
80 
 84 
 81  
 85   
81  
85  
82  
86  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents; NIH Publication No. 05-5267. 
 
 

                
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APPENDIX VB:  90th and 95th PERCENTILE BLOOD PRESSURE BY PERCENTILE HEIGHT 
IN BOYS AGE 1-17 YEARS 
Age  
BP  
 
Systolic BP (mmHg) 
 
 
Diastolic BP (mmHg) 
(Year) 
Percentile 
 
Percentile of Height 
 
 
 
Percentile of Height 
 
 
p 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
5th 
10th 
25th 
50th 
75th 
90th 
95th 
1 
90th 
95th 
94 
98 
95 
99 
97 
101 
99 
103 
100 
104 
102 
106 
103 
106 
49 
54 
50 
54 
51 
55 
52 
56 
53 
57 
53 
58 
54 
58 
2 
90th 
95th 
97 
101 
99 
102 
100 
104 
102 
106 
104 
108 
105 
109 
106 
110 
54 
59 
55 
59 
56 
60 
57 
61 
58 
62 
 58 
63 
59 
63 
3 
90th 
95th 
100 
104 
101 
105 
103 
107 
105 
109 
107 
110 
108 
112 
109 
113 
59 
63 
59 
63 
60 
64 
61 
65 
62 
66 
63 
67 
63 
67 
4 
90th 
95th 
102 
106 
103 
107 
105 
109 
107 
111 
109 
112 
110 
114 
111 
115 
62 
66 
63 
67 
64 
68 
65 
69 
66 
70 
66 
71 
67 
71 
5 
90th 
95th 
104 
108 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
112 
116 
65 
69 
66 
70 
67 
71 
68 
72 
69 
73 
69 
74 
70 
74 
6 
90th 
95th 
105 
109 
106 
110 
108 
112 
110 
114 
111 
115 
113 
117 
113 
117 
68 
72 
68 
72 
69 
73 
70 
74 
 71 
75 
72 
76 
72 
76 
7 
90th 
95th 
106 
110 
107 
111 
109 
113 
111 
115 
113 
117 
114 
118 
115 
119 
70 
74 
70 
74 
71 
75 
72 
76 
73 
77 
74 
78 
74 
78 
8 
90th 
95th 
107 
111 
109 
112 
110 
114 
112 
116 
114 
118 
115 
119 
116 
120 
71 
75 
72 
76 
72 
77 
73 
78 
74 
79 
75 
79 
76 
80 
9 
90th 
95th 
109 
113 
110 
114 
112 
116 
114 
118 
115 
119 
117 
121 
118 
121 
72 
76 
73 
77 
74 
78 
75 
79 
76 
80 
76 
81 
77 
81 
10 
90th 
95th 
111 
115 
 112 
 116 
114 
117 
115 
119 
117 
121 
119 
122 
119 
123 
73 
77 
73 
78 
74 
79 
75 
80 
76 
81 
77 
81 
78 
82 
11 
90th 
95th 
113 
117 
114  
118 
115 
 119  
117 
121  
119 
123 
 120 
 124  
 121 
125  
74  
78  
74 
78 
75 
 79  
76  
 80  
77  
81   
78  
82  
78  
82  
12 
90th 
95th 
115 
119  
116  
120 
118  
 122 
120  
 123  
121 
125 
 123 
 127 
123  
 127  
74  
78 
75  
 79  
75  
80 
76 
 81 
77  
 82   
78  
82   
79  
83  
13 
90th 
95th 
117  
121 
118  
 122  
120 
124  
 122  
126  
124 
128  
125  
129 
126  
 130  
75  
79  
75 
79  
76 
80  
77 
81  
78  
82  
79  
83  
79  
83  
14 
90th 
95th 
120  
124 
121  
 125 
123 
 127 
125 
 128  
126  
 130  
128  
 132 
128  
 132 
75 
80  
76 
80   
 77 
81   
78  
82  
79  
83  
79  
84  
80  
84  
15 
90th 
95th 
122  
126  
124  
127  
125  
129  
127  
131  
129  
133  
130  
134  
131  
135  
76  
81   
77  
81   
78  
82  
79  
83  
80  
84   
80  
85  
81  
85  
16 
90th 
95th 
125  
129  
126  
130  
128 
132   
130  
134  
131  
135  
133 
137  
134  
137  
78  
82 
78  
 83  
79 
83  
80  
 84  
81 
85  
82  
86  
82  
87  
17 
90th 
95th 
127  
131  
 128  
132  
130  
134  
132 
136 
134  
 138  
135 
139  
  136  
140  
 80 
84  
  80 
85  
 81 
86   
82  
87 
83  
 87  
84  
88  
84  
89  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: Adapted from: The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents; NIH Publication No. 05-5267. 
  
 

                
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APPENDIX VC:  ORAL ANTIHYPERTENSIVE MEDICATIONS 
Agents in bold characters are suggested as optimal choices to avoid or minimize potential drug-interactions 
with pazopanib through CYP450. 
 
Agent 
class 
 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-
pyridine 
Calcium-
Channel 
Blockers 
(DHP CCB) 
nifedipine XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 substrate 
and inhibitor 
Selective 
E Blockers 
(BB) 
metoprolol 
25 mg 
twice daily 
50 mg 
twice daily 
100 mg 
twice daily 
CYP 2D6 substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg 
twice daily 
200-300 mg twice 
daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x daily 
25 mg 3x daily 
50 mg 3x daily 
CYP 2D6 substrate 
enalapril 
5 mg daily 
10-20 mg daily 
40 mg daily 
CYP 3A4 substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 
40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
 
4 mg daily 
 
none 
 
8 mg daily 
 
Yes, but not CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not CYP450 
D and E 
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice daily 
400 mg twice 
daily 
CYP 2D6 substrate 
and inhibitor 
 
 

                
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APPENDIX VI:  CYP3A4 SUBSTRATES, INDUCERS, AND INHIBITORS 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. 
 
CYP3A4 substrates  
Strong 
Inhibitors1 
Moderate 
Inhibitors 
Strong Inducers 
Moderate 
Inducers 
acalabrutinib5 
alfentanil4,5 
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib 
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan 
isavuconazole5 
itraconazole 
ivacaftor 
ketoconazole 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
graperfruit3 
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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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 4.1.6 regarding use of corticosteroids. 
3 The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4 Narrow therapeutic range substrates 
5 Sensitive substrates GUXJVWKDWGHPRQVWUDWHDQLQFUHDVHLQ$8&RI 5-fold with strong inhibitors) 
  
 

                
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APPENDIX VII:  MEDICATIONS ASSOCIATED WITH PROLONGED QTC 
The use of the following medications should be avoided during protocol therapy if reasonable alternatives 
exist. This is not an inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. For the most current list of medications, please 
refer to the following reference: 
Woosley, RL and Romero, KA, www.Crediblemeds.org, QTdrugs List, Accession Date December 2nd, 
2016, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ  85755 
 
 
Medications that prolong QTc 
Amiodarone 
Flecainide 
Anagrelide 
Fluconazole 
Arsenic trioxide 
Haloperidol 
Azithromycin 
Ibutilide 
Chloroquine 
Methadone 
Chlorpromazine 
Moxifloxacin 
Ciprofloxacin 
Ondansetron 
Citalopram 
Pentamidine 
Clarithromycin 
Pimozide 
Disopyramide 
Procainamide 
Dofetilide 
Propofol 
Domperidone 
Quinidine  
Droperidol 
Sevoflurane 
Dronedarone 
Sotalol 
Erythromycin 
Thioridazine  
Escitalopram 
Vandetanib  
 
 
Medications that MAY prolong QTc 
Aripiprazole 
Lapatinib 
Bortezomib 
Lenvatinib 
Bosutinib 
Leuprolide 
Ceritinib 
Mirtazapine 
Clomipramine 
Nicardipine 
Crizotinib 
Nilotinib 
Dabrafenib 
Olanzapine 
Dasatinib 
Osimertinib 
Degarelix 
Pazopanib 
Desipramine 
Promethazine 
Dolasetron 
Risperidone 
Eribulin mesylate 
Sorafenib 
Famotidine 
Sunitinib 
Foscarnet 
Tacrolimus 
Gemifloxacin 
Vemurafenib 
Granisetron 
Venlafaxine 
Isradipine 
Vorinostat 
 
 
 

                
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APPENDIX VIII:  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.   
 
Central Venous Access 
Placement of a central venous catheter is recommended for patients receiving chemotherapy to facilitate 
simultaneous administration of doxorubicin and ifosfamide/mesna. Selected patients receiving radiotherapy 
also may be candidates for a central venous access device if daily intravenous sedation is required for 
radiotherapy.   
 
Dental Evaluation 
A baseline dental examination is recommended prior to initiation of chemotherapy and/or radiotherapy to 
document dental development at baseline and identify potential foci of infection. Significant caries or other 
problems that pose an infectious risk should be treated prior to initiation of antineoplastic therapy, if possible. 
All patients and their families should be educated about dental hygiene and mouth care during treatment. 
 
Since chemotherapy is associated with abnormal dental development and a greater risk for tooth loss and decay, 
patients receiving chemotherapy (particularly young children) should be seen for regular follow-up to identify 
problems and reinforce dental hygiene. Regular post-treatment dental follow-up is important for patients 
receiving radiotherapy that involves the jaw, as these patients are at risk for abnormal dental development, 
severe caries, and oral infections.   
 
Anti-Emetics 
Routine use of anti-emetics is recommended for patients receiving chemotherapy and those receiving 
radiotherapy to a field that includes abdominal/pelvic contents. Due to the highly emetogenic nature of the 
chemotherapy regimen, a serotonin antagonist (eg, ondansetron, granisetron) may be considered for all 
patients receiving chemotherapy. Other medications may be helpful in combination with the seratonin 
antagonists. Dexamethasone may be warranted for patients who remain symptomatic despite combinations 
of other anti-emetics. Aprepitant interacts with CYP3A4 and may not be given during either ifosfamide or 
doxorubicin chemotherapy and should be avoided with the use of pazopanib. 
 
Fever and Neutropenia  
All patients should be evaluated promptly for fever of 38°C (oral) three times in a 24-hour period or a single 
temperature of 38.5°C. If the ANC is < 500/μL, appropriate cultures should be obtained to rule out an occult 
invasive bacterial or fungal infection and broad spectrum antibiotics should be administered. 
 
Specific infections identified should be managed according to institutional guidelines. Even in the absence 
of an identified infection, broad spectrum antibiotics should be continued until the patient is afebrile for 
more than 24 hours and has an ANC > 200/μL. If fever without an obvious source persists for more than 5 
days or recurs after defervescence while on broad-spectrum antibiotics, systemic antifungal coverage 
should be considered. 
 
Mucositis 
Mucositis following doxorubicin-containing chemotherapy is common, and may be exacerbated by herpes 
simplex infection. Pazopanib may result in mucositis as well. Consideration should be given to herpes 
simplex prophylaxis in patients with a history of herpetic stomatitis. Patients with significant mucositis 
during chemotherapy should have a viral culture of the oral lesions performed, and anti-viral therapy should 

                
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be started if herpes simplex virus is identified. Patients with documented herpes simplex infection during 
therapy should receive antiviral prophylaxis throughout the remainder of chemotherapy. 
 
Oral swish-and-swallow glutamine suspension at a dose of 2 g/m² BID has been shown to reduce the 
severity and duration of mucositis associated with chemotherapy and radiotherapy in a randomized 
controlled clinical trial.198 Sucralfate swish-and-swallow may reduce the symptoms or severity of 
chemotherapy- and radiotherapy-induced mucositis.199 Sucralfate blocks the oral absorption of many 
medications. Pazopanib should be given at least 2 hours before or 4 hours after a dose of sucralfate. 
 
Cardiotoxicity 
Dexrazoxane is required for all doxorubicin-containing cycles. Dexrazoxane has been shown to provide 
short- and medium-term protection from cardiotoxicity induced by anthracyclines in children and adults 
with sarcomas.200,201 Although recommended that dexrazoxane be considered in adults receiving more than 
300 mg/m2 doxorubicin-based therapy,202 no such recommendations exist for pediatric patients. Due to the 
concern of added cardiac toxicity of pazopanib and doxorubicin, the use of dexrazoxane is required. To 
facilitate direct comparison of the randomization arms and to limit cardiotoxicity, all patients in the 
chemotherapy cohort will receive dexrazoxane for all doxorubicin-containing cycles. Hypertension may 
result with the use of pazopanib. Anti-hypertensive management is detailed in Section 5.6. 
 
Blood Product Support 
Indications 
There are no standardized guidelines for blood product support, and decisions should be based on the 
patient’s symptoms, examination findings, medical history, and the clinical setting.   
 
Depending on the particular setting, red blood cell transfusions may be appropriate in the following 
situations: 
x 
Hgb < 8 gm/dL and an expectation that a rise in Hgb is not imminent 
x 
Symptoms of anemia present and Hgb < 10 g/dL 
x 
Hgb < 10 gm/dL in a patient receiving radiotherapy (theoretical considerations suggest that 
radiotherapy may be more efficacious in patients with adequate tissue oxygenation) 
x 
Acute blood loss estimated at > 10% of blood volume 
x 
Hgb < 12 gm/dL in a patient with respiratory insufficiency not corrected by supplemental oxygen 
or ventilatory support 
 
Platelet transfusions may be indicated in the following settings, depending on the particular situation: 
Platelet count < 10,000/μL 
x 
Active bleeding in a patient with a normal PT/PTT/fibrinogen and a platelet count < 50,000/μL or 
dysfunctional platelets 
x 
Platelet count < 50,000/μL in a patient who requires a surgical procedure 
 
Leukocyte Depletion 
Leukocyte depleted blood products are recommended to decrease the likelihood of alloimmunization and 
prevent febrile, non-hemolytic transfusion reactions. Leukocyte depletion may be accomplished via 
leukocyte depletion filters or blood product washing. 
 
Irradiation 
All blood products should be irradiated as per institutional and national guidelines. 
 

                
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Platelet Products 
Platelet apheresis products should be used, if available. If single-donor products are not available, random-
donor pooled platelets are acceptable. 
 
Growth Factor Administration 
Administration of growth factor is required after all chemotherapy cycles except when doxorubicin is 
administered alone. Use of growth factor after doxorubicin alone is optional. Selection of growth factor is 
based on patient body weight and physician preference: 
x 
Filgrastim (G-CSF): 5 mcg/kg subcutaneous daily (max 480 mcg) starting on the day after the last 
dose of chemotherapy until ANC > 2,000/μL after the nadir. Use of intravenous filgrastim is 
permitted, but discouraged. Filgrastim should not be administered within 24 hours of 
chemotherapy. 
x 
Pegfilgrastim (NeulastaTM3DWLHQWV 45 kg: 100 mcg/kg subcutaneous x 1 dose on the day after 
the last dose of chemotherapy.203 Patients > 45 kg: 6 mg subcutaneous x 1 dose on the day after the 
last dose of chemotherapy. Pegfilgrastim should not be administered in the period between 2 weeks 
before and 24 hours after chemotherapy. 
x 
The use of exogenous erythropoietin (ie, epoetin, darbepoetin) is at the investigator’s discretion. 
 
Pneumocystis (carinii) jirovecii Prophylaxis 
Consideration should be given for all patients receiving chemotherapy to receive prophylaxis against 
Pneumocystis (carinii) jirovecii infection. If used, treatment should begin with the initiation of chemotherapy 
and continue for 12 weeks after chemotherapy finishes. Co-trimoxazole [trimethoprim (TMP) and 
sulfamethoxazole (SMX)] 1:5 drug combination at 75 mg/m2/dose of TMP twice daily on 3 consecutive days 
each week is recommended. An alternate form of prophylaxis also should be used for patients who experience 
excessive myelosuppression during chemotherapy administration, as TMP/SMX can enhance bone marrow 
suppression. 
 
Patients who are allergic to or intolerant of TMP/SMX should receive an alternate form of prophylaxis: 
x 
Dapsone 2 mg/kg daily (max 100 mg) OR 
x 
Atovaquone 
o Patients 12 - 24 months old: 45 mg/kg once daily with food 
o Patients > 24 months old: 30 mg/kg once daily with food  
o $GROHVFHQWV 13 years and adults: 1500 mg once daily with food 
 
Pentamidine should be avoided due to the risk of QT prolongation and should only be used if the patient is 
intolerant to or has failed all other agents.  
 
Nutritional Support 
Adequate nutritional status is critical for wound healing and tolerance of therapy. Supplemental enteral or 
parenteral nutrition should be considered for patients who have lost 10% or more of body weight before or 
during therapy and for those who have persistent hypoalbuminemia (albumin < 3 g/dL). Parenteral support also 
should be considered for patients receiving abdominal and/or pelvic radiotherapy who experience significant 
gastrointestinal toxicity. 
 
Issues for Postmenarchal Females 
Postmenarchal females receiving chemotherapy are at risk for excessive menstrual bleeding. Thus, 
consideration should be given to suppressing menses with hormonal interventions in these patients. In addition, 
sexually active females should be counseled to avoid sexual intercourse during periods of 
neutropenia/thrombocytopenia. All postmenarchal females receiving chemotherapy or radiotherapy should be 
counseled about the risks of fetal exposure and the need for contraception. 

                
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Sperm Banking  
Adolescent males receiving chemotherapy or radiotherapy to a field involving the testes should be provided 
with information regarding sperm banking prior to initiation of treatment.  
 
Recommendations for Specific Anatomic Sites of Tumor 
Chest Wall/Intrathoracic Sites 
Baseline evaluations that may be useful, depending on the specific anatomic sites of tumor involvement, 
include: 
x 
Echocardiogram with doppler and/or MUGA (multiple gated acquisition) scan 
x 
Pulmonary function tests 
x 
Upper airway endoscopy/bronchoscopy 
x 
Barium esophagram 
x 
Esophagoscopy 
 
Abdominal/Retroperitoneal/Pelvic Sites 
Depending on the particular anatomic sites of tumor involvement, the following evaluations may be useful: 
x 
Endoscopic examination of the bowel 
x 
Female pelvic examination 
x 
Cystoscopy/vaginoscopy/proctoscopy with examination under anesthesia 
x 
Ultrasound examination of the urinary or biliary tract to assess need for decompression 
 
Oophoropexy to move the ovaries out of the radiotherapy field may be considered in female patients with pelvic 
tumors who will receive radiotherapy. 
 
Extremity Sites 
A baseline rehabilitation evaluation is recommended for identifying functional limitations and initiating 
rehabilitation. 
 
Rash 
Suggested products for the treatment of skin reactions for patients on pazopanib have been adapted from 
Bracarda et al.204 and includes:  
x 
Non foaming cleansing cream containing taurate and sarcosinate detergents 
x 
Polydecene based highly emollient ointment 
x 
Glycolic salicylic peeling cream 
x 
Zinc oxide and magnesium silicate lenitive cream without vaseline 
x 
Benzalkonium chloride 0.2% aqueous solution 
x 
Cicatrizing PEG and allantoin ointment 
x 
Potassium permanganate (tablet 250 mg) 
o To prepare, dissolve a 250 mg tablet in 2L of boiling water, cool and keep in a dark glass 
bottle 
x 
Sulfosalicylic cream without vaseline 
 
All products for external use compress ONLY 
 
Hand-Foot Syndrome  
Oral administration of vitamin B6 (pyridoxine) should be administered for patients on pazopanib who 
develop hand-foot syndrome:  
x 
BSA < 0.5 m2: 50 mg per day 

                
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x 
BSA 0.5-1.0 m2: 100 mg per day 
x 
BSA 1.1-1.5 m2: 200 mg per day 
x 
BSA > 1.5 m2: 300 mg per day 
 
 
 

                
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APPENDIX IX:  THERAPY DELIVERY MAPS FOR REGIMEN A 
 
Regimen A: Neoadjuvant Chemotherapy and Radiotherapy with Pazopanib 
 
 
 
 
 
 
 
 
 
 
See Section 4.2 and Section 17 for complete details of protocol therapy. 
 
The therapy delivery maps relating to Induction and Continuation therapy for patients on Regimen A are 
provided in the following 7 pages. 
 
 
 
 
Regimen A 
Induction Phase 
 
Surgery  
Continuation Phase 
 
Week 1 
Week 4 
Week 7 
Week 10 
Week 13 
Week 16 
Week 19 
Week 22 
Weeks 23-25 
I 
I 
I 
I 
 
Surgery 
I 
I 
 
 
D 
D 
 
 
D 
D 
D 
 
Pazopanib Weeks 1-12 
Pazopanib Weeks 16-25 
 
Radiotherapy 
Radiotherapy 
 
 

                
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Regimen A 
Induction (Weeks 1-12): This therapy delivery map relates to Cycle 1 of therapy, Weeks 1-3 
Induction consists of 12 weeks of therapy (84 days in total) made up of four 21-day cycles. 
This therapy delivery map presents Induction therapy on 4 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
 
&ULWHULD WRVWDUWHDFK F\FOH$1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXWWUDQVIXVLRQ,IWKH$1&KDVULsen to  750/μL after the nadir but then falls the 
next cycle should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV 
push/infusion over  
5-15 mins 
375 mg/m2/dose  
1 and 2 of 
Week 1 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
VKRXOGEH 30 min. See Section 4.2.1. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
g. EKG and ECHO or MUGA 
h. Pulmonary function tests** 
i. Imaging studies** 
j. Pregnancy test 
k. Optional sperm banking 
l. Required & optional biology studies 
 
**See Section 7.1.1 for full details.  
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 of 
Week 1 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose 
is 75 mg/day and total dose is 150 mg over 
2 days. See Section 4.2.1 for details. 
Ifosfamide (IFOS) IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of Wk 1 
See Section 4.2.1 for details. 
Mesna (MESNA)  IV or IV/PO 
Total IV Dose: 2500 mg/m2/day 
1-3 of Wk 1 
Administer with IFOS, see Section 4.2.1 
Pazopanib  
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of  
Wk 1-3 
For pediatric patients (<18 years of age) use dosing 
tables for pazopanib provided in Appendix XVII. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of myelosuppressive chemotherapy. If given 
daily then continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLU(continue without regard to pazopanib administration) and discontinue 
at least 24 hours prior to next cycle of chemotherapy. 
 
Ht__________cm  
Wt__________kg  
BSA__________m2  
 
 
 
Date 
Due 
Date 
Given 
Week Day 
DXRZ  
____mg 
DOXO 
____mg 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Pazopanib 
________mg 
Studies 
Comments 
(Include 
any held 
doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
Growth factor used:______________________    
End date:_____________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
________mg 
 
 
 
 
 
 
 
 
 
________mg 
(a-d, e$, f)#, g-k, lĮ 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4 
Start growth factor. Record type and end date. 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
2 
1 
 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
 
 
 
 
3 
1 
 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
 
 
The therapy delivery map for Induction continues on the next page. 
% Enter total daily mesna dose as mg/day by CI or intermittent infusion. 
# Obtain within 4 days prior to the start of each cycle. 
  
 
 
 
 
 
 
 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
  
 
 
 
 
 
 
 
Į Blood is required; slides, tumor tissue and blood are requested (see Sections 15.1 & 15.2). 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
 
Page 1 of 4 

                
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Regimen A 
Induction Continued: Cycle 2 of therapy, Weeks 4-6 
Induction consists of 12 weeks of therapy (84 days in total) made up of four 21-day cycles.  
This therapy delivery map presents Induction therapy on 4 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
&ULWHULD WRVWDUW HDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXW WUDQVIXVLRQ,IWKH $1&KDVULsen to  750/μL after the nadir but then falls the next cycle 
should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV 
push/infusion over  
5-15 mins 
375 mg/m2/dose  
1 and 2 of 
Week 4 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
VKRXOGEH 30 min. See Section 4.2.1. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
g. Optional biology study (DOXO PK) 
**See Section 7.1.1 for full details. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 of 
Week 4 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose 
is 75 mg/day and total dose is 150 mg over 
2 days. See Section 4.2.1 for details. 
Ifosfamide (IFOS) IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of Wk 4 
See Section 4.2.1 for details. 
Mesna (MESNA)  IV or IV/PO 
Total IV Dose: 2500 mg/m2/day 
1-3 of Wk 4 
Administer with IFOS, see Section 4.2.1 
Pazopanib  
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of Wk 4-6 For pediatric patients (<18 years of age) use dosing 
tables for pazopanib provided in Appendix XVII. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of myelosuppressive chemotherapy. If given 
daily then continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLU(continue without regard to pazopanib administration) and discontinue 
at least 24 hours prior to next cycle of chemotherapy. 
 
Ht__________cm Wt__________kg  
BSA__________m2  
 
 
 
Date 
Due 
Date 
Given 
Week Day 
DXRZ  
____mg 
DOXO 
____mg 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Pazopanib 
________mg 
Studies 
Comments 
(Include 
any 
held 
doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
Growth factor used:______________________    
End date:_____________ 
 
 
4† 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
________mg 
(a, b, c, d, e$, f)#, g ȕ 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
g ȕ 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
g ȕ 
 
 
 
4 
Start growth factor. Record type and end date. 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
5 
1 
 
 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
 
 
 
 
 
6 
1 
 
 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
 
________mg 
 
The therapy delivery map for Induction continues on the next page. 
 
% Enter total daily mesna dose as mg/day by CI or intermittent infusion.  
 
# Obtain within 4 days prior to the start of each cycle. 
† Begin RT. Note: omit RT at Week 4 for patients with hepatic primary tumors (see Sec. 17). 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated.  
 
  
 
ȕ%ORRGLVUHTXHVWHG VHHSection 15.3 for a list of time points. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
Page 2 of 4 

                
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206 
ARST1321 
Regimen A 
Induction Continued Cycle 3 of therapy, Weeks 7-9 
Induction consists of 12 weeks of therapy (84 days in total) made up of four 21-day cycles.  
This therapy delivery map presents Induction therapy on 4 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
 
&ULWHULD WRVWDUW HDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXW WUDQVIXVLRQ,IWKH $1&KDVULsen to  750/μL after the nadir but then falls the next cycle 
should be given despite ANC < 750/μL.  
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of  
Week 7 
See Section 4.2.1 for details. 
 
a. 
History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
g. EKG and ECHO or MUGA 
 
**See Section 7.1.1 for full details. 
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
 
Mesna (MESNA)  IV or IV/PO 
Total IV Dose: 2500 mg/m2/day  1-3 of  
Week 7 
Administer with IFOS, see Section 4.2.1. 
Pazopanib 
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of  
Wk 7-9 
For pediatric patients (<18 years of age) use 
dosing tables for pazopanib provided in 
Appendix XVII. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of myelosuppressive 
chemotherapy. If given daily then continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLU(continue without regard to 
pazopanib administration) and discontinue at least 24 hours prior to next cycle of chemotherapy. 
 
Ht__________cm Wt__________kg  
BSA__________m2  
 
 
 
Date Due 
Date Given 
Week 
Day 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Pazopanib 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
Growth factor used:______________________    
End date:_____________ 
 
 
7 
1 
_____mg 
________mg/day% 
_____mg 
(a, b, c, d, e$, f)#, g 
 
 
 
2 
_____mg 
________mg/day% 
 
 
 
 
 
3 
_____mg 
________mg/day% 
 
 
 
 
 
4 
Start growth factor. Record type and end date. 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
1 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
 
 
 
9 
1 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
_____mg 
 
The therapy delivery map for Induction continues on the next page. 
 
% Enter total daily mesna dose as mg/day by CI or intermittent infusion.  
# Obtain within 4 days prior to the start of each cycle. 
 
 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
 
 
Page 3 of 4 

                
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Version date: 04/08/2019 
207 
ARST1321 
Regimen A 
Induction Continued, Cycle 4 of therapy, Weeks 10-12 
Induction consists of 12 weeks of therapy (84 days in total) made up of four 21-day cycles.  
This therapy delivery map presents Induction therapy on 4 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
 
&ULWHULD WRVWDUW HDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXW WUDQVIXVLRQ,IWKH $1&KDVULsen to  750/μL after the nadir but then falls the next cycle 
should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of  
Week 10 
See Section 4.2.1 for details. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
**See Section 7.1.1 for full details. 
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
Mesna (MESNA)  
IV or IV/PO 
Total IV Dose: 2500 mg/m2/day  1-3 of  
Week 10 
Administer with IFOS, see Section 4.2.1 
Pazopanib 
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of  
Wk 10-12 
For pediatric patients (<18 years of age) use 
dosing tables for pazopanib provided in 
Appendix XVII. Pazopanib will be held pre- and 
post-surgery. See Section 4.2.1 for details. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of myelosuppressive chemotherapy. 
If given daily then continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLU(continue without regard to pazopanib administration) 
and discontinue at least 24 hours prior to next cycle of chemotherapy. Note: Use of GM-CSF (sargramostim) is not permitted. 
 
 
Ht__________cm Wt__________kg  
BSA__________m2  
 
 
 
Date Due 
Date Given 
Week 
Day 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Pazopanib 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered 
below 
 
Growth factor used:______________________ 
End date of growth factor:_____________ 
 
End date of pazopanib:_____________ 
 
 
10 
1 
_____mg 
________mg/day% 
_____mg 
(a, b, c, d, e$, f)# 
 
 
 
2 
_____mg 
________mg/day% 
 
 
 
 
 
3 
_____mg 
________mg/day% 
 
 
 
 
 
4 
Start growth factor. Record type and end date. 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
11 
1 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
 
 
 
12^ 
1 
 
 
 
b, c, d, e$ 
 
 
 
2-7 
 
 
_____mg 
 
 
 
 
 
Surgery will follow Induction during Week 13; see Section 13 for details.  
See Section 7.1.1 for observations required prior to surgery. 
 
% Enter total daily mesna dose as mg/day by CI or intermittent infusion.  
 
^ Pazopanib is to be held at least 7 days prior to surgery. This may mean stopping pazopanib before the end of Week 12 and will depend upon the timing of surgery. 
 
# Obtain within 4 days prior to the start of each cycle.  
 
 
 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
 
Page 4 of 4 

                
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Version date: 04/08/2019 
208 
ARST1321 
Regimen A 
Continuation (Weeks 16-25): This therapy delivery map relates to Cycle 1, Weeks 16-18 
Continuation phase consists of 10 weeks of therapy (70 days in total) made up of three 21-day cycles plus one further week of 
pazopanib. The therapy delivery map presents Continuation phase on 3 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
 
&ULWHULD WRVWDUW HDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXW WUDQVIXVLRQ,IWKH $1&KDVULsen to  750/μL after the nadir but then falls the next cycle 
should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV 
push/infusion over  
5-15 mins 
375 mg/m2/dose  
1 and 2 
of Week 16@ 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO should be 
 30 min. See Section 4.2.2. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- 
UPC** 
 
**See Section 7.1.1 for full details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 
of Week 16@ 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. See 
Section 4.2.2 for details. 
Ifosfamide (IFOS) IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of Wk 16 
See Section 4.2.2 for details. 
Mesna (MESNA)  IV or IV/PO 
Total IV Dose: 2500 mg/m2/day 1-3 of Wk 16 
Administer with IFOS, see Section 4.2.2. 
Pazopanib 
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of  
Wk 16-18 
For pediatric patients (<18 years of age) use dosing tables for 
pazopanib provided in Appendix XVII. Pazopanib will be 
held at least 14 days post-surgery prior to starting 
Continuation (see Section 4.2.2). 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of myelosuppressive chemotherapy. If given daily 
then continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLU(continue without regard to pazopanib administration) and discontinue at least 
24 hours prior to next cycle of chemotherapy. Note: Use of GM-CSF (sargramostim) is not permitted. 
 
Ht__________cm Wt__________kg  
BSA__________m2  
 
 
 
Date 
Due 
Date 
Given 
Week Day 
DXRZ  
____mg 
DOXO 
____mg 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Pazopanib 
________mg 
Studies 
Comments 
(Include 
any 
held 
doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
Growth factor used:______________________    
End date:_____________ 
 
 
 
16@ 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
________mg 
 
(a, b, c, d, e$, f)# 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4 
Start growth factor. Record type and end date. 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
17 
1 
 
 
 
 
c 
 
 
 
2-7 
 
 
 
 
 
 
 
18 
1 
 
 
 
 
c 
 
 
 
2-7 
 
 
 
 
________mg 
 
The therapy delivery map for Continuation continues on the next page.  
% Enter total daily mesna dose as mg/day by CI or intermittent infusion. 
@ Begin RT, if postoperative RT given (see Section 17.2). This may delay DOXO administration (see Section 4.2.2). 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
  
# Obtain within 4 days prior to the start of each cycle.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
 
Page 1 of 3 

                
                                 THIS PRO TOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
   
Version date: 04/08/2019 
209 
ARST1321 
Regimen A 
Continuation Continued: Cycle 2 of therapy, Weeks 19-21 
Continuation phase consists of 10 weeks of therapy (70 days in total) made up of three 21-day cycles plus one further week of pazopanib. 
The therapy delivery map presents Continuation phase on 3 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
&ULWHULD WRVWDUW HDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXW WUDQVIXVLRQ,IWKH $1&KDVULsen to  750/μL after the nadir but then falls the next cycle 
should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV 
push/infusion over  
5-15 mins 
375 mg/m2/dose  
1 and 2  
of Week 19@ 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
VKRXOGEH 30 min. See Section 4.2.2. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
g. EKG and ECHO or MUGA 
**See Section 7.1.1 for full details. 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 
of Week 19@ 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose 
is 75 mg/day and total dose is 150 mg over 
2 days. See Section 4.2.2 for details. 
Ifosfamide (IFOS) IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of Wk 19 
See Section 4.2.2 for details. 
Mesna (MESNA)  IV or IV/PO 
Total IV Dose: 2500 mg/m2/day 
1-3 of Wk 19 
Administer with IFOS, see Section 4.2.2. 
Pazopanib 
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of  
Wk 19-21 
For pediatric patients (<18 years of age) use dosing 
tables for pazopanib provided in Appendix XVII. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of myelosuppressive chemotherapy. If given 
daily then continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLU(continue without regard to pazopanib administration) and discontinue 
at least 24 hours prior to next cycle of chemotherapy. Note: Use of GM-CSF (sargramostim) is not permitted. 
 
Ht__________cm Wt__________kg  
BSA__________m2  
 
 
 
Date 
Due 
Date 
Given 
Week Day 
DXRZ  
____mg 
DOXO 
____mg 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Pazopanib 
________mg 
Studies 
Comments 
(Include 
any 
held 
doses, or dose 
modifications) 
 
 
 
 
Enter calculated dose above and actual dose administered below 
 
Growth factor used:______________________    
End date:_____________ 
 
 
 
19@ 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
________mg 
(a, b, c, d, e$, f)#, g 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4 
Start growth factor. Record type and end date. 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
20 
1 
 
 
 
 
c 
 
 
 
2-7 
 
 
 
 
 
 
 
21 
1 
 
 
 
 
c 
 
 
 
2-7 
 
 
 
 
________mg 
 
The therapy delivery map for Continuation continues on the next page. 
% Enter total daily mesna dose as mg/day by CI or intermittent infusion. 
# Obtain within 4 days prior to the start of each cycle. 
@ RT administration may delay DOXO administration (see Sec 4.2.2).   
$ Obtain direct bilirubin if total bilirubin is abnormally elevated.  
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
  
 
Page 2 of 3 

                
                                 THIS PRO TOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
   
Version date: 04/08/2019 
210 
ARST1321 
Regimen A 
Continuation Continued: Cycle 3 of therapy + 1 week of pazopanib alone, Weeks 22-25 
Continuation phase consists of 10 weeks of therapy (70 days in total) made up of three 21-day cycles plus one further week of pazopanib 
alone. The therapy delivery map presents Continuation phase on 3 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
&ULWHULD WRVWDUW HDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXW WUDQVIXVLRQ,IWKH $1&KDVULsen to  750/μL after the nadir but then falls the next cycle 
should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV 
push/infusion over  
5-15 mins 
375 mg/m2/dose  
1 and 2 
of Week 22 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO should be 
 30 min. See Section 4.2.2. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- 
UPC** 
g. EKG and ECHO or MUGA 
 
**See Section 7.1.1 for full details. 
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 
of Week 22 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. See 
Section 4.2.2 for details. 
Pazopanib 
 
PO 
350 mg/m2 (pediatric) 
600 mg (adult) 
1-7 of 
Wk 22-25 
For pediatric patients (<18 years of age) use dosing tables for 
pazopanib provided in Appendix XVII.  Pazopanib is to be 
held at least 7 days prior to any surgery planned at the end of 
Continuation therapy. See Section 4.2.2 for details. 
The use of growth factor support is optional for this cycle, see Section 4.2.2. 
 
Ht__________cm Wt__________kg  
BSA__________m2  
 
 
Date Due 
Date Given 
Week 
Day 
DXRZ 
_____mg 
DOXO  
_________mg 
Pazopanib 
________mg 
Studies 
Comments (Include any held doses, or dose 
modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
End date of pazopanib:_____________ 
 
 
22 
1 
_____mg 
________mg 
_____mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
_____mg 
(a, b, c, d, e$, f)#, g 
 
 
 
2 
_____mg 
________mg 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
23 
1 
 
 
c 
 
 
 
2-7 
 
 
 
 
 
24 
1 
 
 
c 
 
 
 
2-7 
 
 
 
 
 
25% 
1 
 
 
c 
 
 
 
2-7 
 
 
 
 
 
 
 
See Section 7.1.1 for observations required at the end of protocol therapy. 
 
# Obtain within 4 days prior to the start of each cycle. 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated.  
 
% Dexrazoxane/Doxorubicin should be given at week 25 if omitted in weeks 16 or 19.   
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
Page 3 of 3 

                
                                 THIS PRO TOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
   
Version date: 04/08/2019 
211 
ARST1321 
 
APPENDIX X:  THERAPY DELIVERY MAPS FOR REGIMEN B 
 
Regimen B: Neoadjuvant Chemotherapy and Radiotherapy 
 
 
 
 
 
 
 
 
 
See Section 4.3 and Section 17 for complete details of protocol therapy. 
 
The therapy delivery maps relating to Induction and Continuation therapy for patients on Regimen B are 
provided in the following 3 pages. 
 
 
 
Regimen B 
Induction Phase 
Surgery  
Continuation Phase 
Week 1 
Week 4 
Week 7 
Week 10 
Week 13 
Week 16 
Week 19 
Week 22 
I 
I 
I 
I 
 
Surgery 
I 
I 
 
D 
D 
 
 
D 
D 
D 
 
Radiotherapy 
Radiotherapy 
 

                
                                 THIS PRO TOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
   
Version date: 04/08/2019 
212 
ARST1321 
 
Regimen B 
Induction (Weeks 1-12): This therapy delivery map relates to Cycles 1 and 2 of therapy, Weeks 1-6. 
Induction consists of 12 weeks of therapy (84 days in total) made up of four 21-day cycles.  
The therapy delivery map presents Induction therapy on 2 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
&ULWHULD WRVWDUWHDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXWWUDQVIXVLRQ,IWKH$1&KDVULsen to  750/μL after the nadir but then falls the 
next cycle should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV 
push/infusion over  
5-15 mins 
375 mg/m2/dose  
1 and 2 of 
Weeks 1 and 4 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
VKRXOGEH 30 min. See Section 4.3.1. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Urinalysis 
g. ECHO or MUGA 
h. Pulmonary function tests** 
i. Imaging studies** 
j. Pregnancy test 
k. Optional sperm banking 
l. Required & optional biology studies 
 
**See Section 7.1.2 for full details.  
 
OBTAIN OTHER STUDIES AS REQUIRED 
FOR GOOD PATIENT CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over 
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 of 
Weeks 1 and 4 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose 
is 75 mg/day and total dose is 150 mg over 
2 days. See Section 4.3.1 for details. 
Ifosfamide (IFOS) IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of 
Weeks 1 and 4 
See Section 4.3.1 for details. 
Mesna (MESNA)  IV or IV/PO 
Total IV Dose: 2500 mg/m2/day 
1-3 of 
Weeks 1 and 4 
Administer with IFOS, see Section 4.3.1 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of chemotherapy. If given daily then 
continue a minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLUDQGGLVFRQWLQXH DWOHDVW hours prior to next cycle of chemotherapy. Note: Use 
of GM-CSF (sargramostim) is not permitted. 
 
 
 Cycle 1: Ht__________cm 
Wt__________kg  
BSA__________m2  
Cycle 2: Ht__________cm Wt__________kg BSA__________m2 
 
 
Date 
Due 
Date 
Given 
Week Day 
DXRZ  
____mg 
DOXO 
____mg 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
Cycle 1, Growth factor used:____________________ 
End date:_____________ 
 
Cycle 2, Growth factor used:____________________ 
End date:_____________ 
 
 
1 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
(a-d, e$, f)#, g-k, lĮ 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4-7 
Start growth factor. Record type and end date. 
 
 
 
2 
1-7 
 
 
 
 
 
 
 
3 
1-7 
 
 
 
 
 
 
 
4† 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
(a-d, e$, f)# 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4-7 
Start growth factor. Record type and end date. 
 
 
 
5 
1-7 
 
 
 
 
 
 
 
6 
1-7 
 
 
 
 
 
The therapy delivery map for Induction continues on the next page. 
% Enter total daily dose as mg/day by CI or intermittent infusion.  
 
 
# Obtain within 4 days prior to the start of each cycle. 
† Begin RT. Note: omit RT at Week 4 for patients with hepatic primary tumors (see Sec. 17). 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated.  
Į Blood is required; slides, tumor tissue and blood are requested (see Sections 15.1 & 15.2) 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII SUPPORTIVE CARE 
  
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Regimen B 
Induction Continued: Cycles 3 and 4 of therapy, Weeks 7-12. 
Induction consists of 12 weeks of therapy (84 days in total) made up of four 21-day cycles.  
The therapy delivery map presents Induction therapy on 2 pages. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
  
&ULWHULD WRVWDUWHDFKF\FOH $1&/DQGSODWHOHW FRXQW/SRVWQDGLUZLWKRXWWUDQVIXVLRQ,IWKH$1&KDVULsen to  750/μL after the nadir but then falls the 
next cycle should be given despite ANC < 750/μL.  
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Ifosfamide 
(IFOS) 
IV over 2-4 hours 
2500  mg/m2/dose  
1-3 of 
Weeks 7 and 10 
See Section 4.3.1 for details. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Urinalysis  
g. ECHO or MUGA** 
 
**See Section 7.1.2 for full details. 
 
OBTAIN 
OTHER 
STUDIES 
AS 
REQUIRED FOR GOOD PATIENT 
CARE 
Mesna 
(MESNA)  
IV or IV/PO 
Total IV Dose: 2500 mg/m2/day  
1-3 of 
Weeks 7 and 10 
Administer with IFOS, see Section 4.3.1. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of chemotherapy. If given daily then continue a 
minimum of 7 GD\VDQGXQWLO$1&/SRVWQDGLUDQGGLVFRQWLQXHDWOHDVW hours prior to next cycle of chemotherapy. Note: Use of GM-CSF 
(sargramostim) is not permitted. 
 
Cycle 3: Ht__________cm Wt__________kg  
BSA__________m2  
Cycle 4: Ht__________cm Wt__________kg  
BSA__________m2 
 
Date Due 
Date Given 
Week 
Day 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
Cycle 3, Growth factor used:____________________ 
End date:_____________ 
 
Cycle 4, Growth factor used:____________________ 
End date:_____________ 
 
 
7 
1 
_____mg 
________mg/day% 
(a-d, e$, f)#, g^ 
 
 
 
2 
_____mg 
________mg/day% 
 
 
 
 
3 
_____mg 
________mg/day% 
 
 
 
 
4-7 
Start growth factor. Record type and end date. 
 
 
 
8 
1-7 
 
 
 
 
 
9 
1-7 
 
 
 
 
 
10 
1 
_____mg 
________mg/day% 
(a-d, e$, f)# 
 
 
 
2 
_____mg 
________mg/day% 
 
 
 
 
3 
_____mg 
________mg/day% 
 
 
 
 
4-7 
Start growth factor. Record type and end date. 
 
 
 
11 
1-7 
 
 
 
 
 
 
 
 
 
 
 
 
12 
1-7 
 
 
 
Surgery will follow Induction at Week 13; see Section 13 for details. See Section 7.1.2 for observations required prior to surgery. 
 
% Enter total daily dose as mg/day by CI or intermittent infusion. 
# Obtain within 4 days prior to the start of each cycle. 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated.  
^ Obtain for patients < 21 years)RUSDWLHQWV\HDUVREWDLQRQO\LIFOLQLFDOO\LQGLFDWHG 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
 
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ARST1321 
Regimen B 
Continuation, Weeks 16-24 
Continuation phase consists of 9 weeks of therapy (63 days in total) made up of three 21-day cycles. 
The therapy delivery map presents Continuation phase on 1 page. 
 
____________________                             _____________________ 
Patient ID                                                     DOB 
 
&ULWHULDWRVWDUWHDFKF\FOH$1&/DQGSODWHOHWFRXQW/SRVWQDGLUZLWKRXWWUDQVIXVLRQ,IWKH$1&KDVULsen to  750/μL after the nadir but then falls the next cycle should be 
given despite ANC < 750/μL.  
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Dexrazoxane 
(DXRZ) 
Slow IV push/infusion 
over 5-15 mins 
375 mg/m2/dose  
1 and 2 of 
Weeks 16, 19@ and 22 
Give immediately prior to DOXOrubicin. 
The combined infusion time for DXRZ + DOXO 
VKRXOGEH 30 min. See Section 4.3.2. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. 
Urinalysis 
g. ECHO or MUGA** 
 
**See Section 7.1.2 for full details.  
 
OBTAIN OTHER STUDIES AS 
REQUIRED FOR GOOD PATIENT 
CARE 
DOXOrubicin 
(DOXO) 
IV push/infusion over  
1-15 mins 
37.5 mg/m2/dose*  
1 and 2 of 
Weeks 16, 19@ and 22 
*75 mg/m2/cycle. If BSA > 2 m2, maximum dose is 
75 mg/day and total dose is 150 mg over 2 days. See 
Section 4.3.2 for details. 
Ifosfamide (IFOS) 
IV over 2-4 hours 
2500 mg/m2/dose  
1-3 of 
Weeks 16 and 19  
See Section 4.3.2 for details. 
Mesna (MESNA)  
IV or IV/PO 
Total IV Dose: 2500 mg/m2/day 
1-3 of 
Weeks 16 and 19  
Administer with IFOS, see Section 4.3.2. 
Begin myeloid growth factor support (filgrastim or pegfilgrastim) at least 24-36 hours after the last dose of chemotherapy. If given daily then continue a minimum 
of 7 GD\VDQGXQWLO$1&/SRVWQDGLUDQGGLVFRQWLQXHDWOHDVW hours prior to next cycle of chemotherapy. Note: Use of GM-CSF (sargramostim) is not 
permitted. The use of growth factor after doxorubicin alone is optional. 
 
Cycle 1: Ht__________cm 
Wt__________kg  
BSA__________m2  
Cycle 2: Ht__________cm 
Wt__________kg BSA__________m2 
 
Cycle 3: Ht__________cm 
Wt__________kg  
BSA__________m2 
 
 
Date Due Date 
Given 
Week Day 
DXRZ  
____mg 
DOXO 
____mg 
IFOS 
_____mg 
MESNA (with IFOS)  
_________mg/day% 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
Enter calculated dose above and actual dose administered below 
 
Cycle 1, Growth factor used:____________________ 
End date:_____________ 
Cycle 2, Growth factor used:____________________ 
End date:_____________ 
 
 
16@ 
1 
_____mg 
____mg 
_ ____mg 
__                  mg/day% 
(a-d, e$, f)# 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4-7 
Start growth factor. Record type and end date. 
 
 
 
17 
1-7 
 
 
 
 
 
 
 
18 
1-7 
 
 
 
 
 
 
 
19@ 
1 
_____mg 
____mg 
_____mg 
_________mg/day% 
(a-d, e$, f)#, g 
 
 
 
2 
_____mg 
____mg 
_____mg 
_________mg/day% 
 
 
 
 
3 
 
 
_____mg 
_________mg/day% 
 
 
 
 
4-7 
Start growth factor. Record type and end date. 
 
 
 
20 
1-7 
 
 
 
 
 
 
 
21 
1-7 
 
 
 
 
 
 
 
22 
1 
_____mg 
____mg 
 
 
(a-d, e$, f)#, g 
 
 
 
2 
_____mg 
____mg 
 
 
 
 
 
 
3-7 
 
 
 
 
 
 
 
23 
1-7 
 
 
 
 
 
 
 
24 
1-7 
 
 
 
 
 
 
 
25^ 
 
 
 
 
 
 
See Section 7.1.2 for observations required at the end of protocol therapy. 
% Enter total daily mesna dose as mg/day by CI or intermittent infusion.  # Obtain within 4 days prior to the start of each cycle. @ Begin RT, if postoperative RT given (see Section 17.2). RT 
may delay DOXO administration (see Sec 4.3.2) 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. ^ Dexrazoxane/Doxorubicin should be given at week 25 
if omitted in weeks 16 or 19.        SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
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APPENDIX XI:  THERAPY DELIVERY MAPS FOR REGIMEN C 
 
Note: The Non-Chemotherapy Cohort is closed to further accrual, effective October 12, 2017. 
 
 
Regimen C: Neoadjuvant Radiotherapy and Pazopanib 
 
Regimen C 
Induction Phase 
Surgery  
Continuation Phase 
Week 1 
Week 4 
Week 7 
Week 10  
Surgery 
 
Week 13 
Week 16 
Week 19 
Weeks 22- 25 
Pazopanib Weeks 1-9 
Pazopanib Weeks 13-25 
Radiotherapy
 
 
Radiotherapy 
 
 
See Section 4.4 and Section 17 for complete details of protocol therapy. 
 
The therapy delivery maps relating to Induction and Continuation therapy for patients on Regimen C are 
provided in the following 3 pages. 
 
 

                
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Regimen C 
Induction, Weeks 1-9 
Induction consists of three 21-day cycles of daily pazopanib therapy (63 days in total). 
This therapy delivery map presents Induction phase on 1 page.  
Repeat this TDM for each cycle of pazopanib therapy.  
 
_____________                      ________________ 
Patient ID                                                     DOB 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Pazopanib 
 
PO 
450 mg/m2 (pediatric) 
800 mg (adult) 
1-7 of Weeks 1-9 
 
For pediatric patients (<18 years of age) use 
dosing tables for pazopanib provided in 
Appendix XVII.  
 
Pazopanib will be held pre- and post-surgery.  
 
See Section 4.4.1 for further details. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
g. EKG and ECHO or MUGA 
h. Pulmonary function tests** 
i. Imaging studies** 
j. Pregnancy test 
k. Optional sperm banking 
l. Required & optional biology studies 
 
**See Section 7.1.3 for full details.  
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
 
Cycle: _________ 
 Ht__________cm 
 
Wt__________kg 
 
BSA__________m2 
 
Date Due 
Date Given Week 
Day 
Pazopanib   ________mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
 
 
Enter calculated dose above and actual 
dose administered below 
 
End date of pazopanib:_____________ 
 
 
1@/4/7 1 
________mg 
 
 
 
 
 
________mg 
(a-d, e$, f)#, (g-k)&, l Į 
 
 
 
2-7 
 
 
 
2/5/8 
1 
b, c, d, e$ 
 
 
 
2-7 
 
 
 
3/6/9^ 1 
b, c, d, e$, g% 
 
 
 
2-7 
 
Surgery will follow Induction at Week 10; see Section 13 for details.  
See Section 7.1.3 for observations required prior to surgery. 
# Obtain within 4 days prior to the start of each cycle. 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
& Prior to Cycle 1 only. 
Į Blood is required; slides, tumor tissue and blood are requested (see Sections 15.1 & 15.2). 
% Obtain EKG before stopping pazopanib prior to surgery (see Section 7.1.3). 
@ Begin RT. Note: omit at Week 1 for patients with hepatic primary tumors (see Section 17). 
^ Pazopanib is to be held at least 7 days prior to surgery. This may mean stopping pazopanib before the end of Week 9 and will depend upon the timing of surgery. 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
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Regimen C 
Continuation Phase (Weeks 13-25): This therapy delivery map relates to Cycles 1 and 2, Weeks 13-18. 
Continuation phase consists of 13 weeks of therapy (91 days in total) made up of four 21-day cycles plus one extra week of 
pazopanib therapy. This therapy delivery map presents the Continuation phase on 2 pages.  
 
____________________                ______________ 
Patient ID                                                     DOB 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Pazopanib 
 
PO 
450 mg/m2 (pediatric) 
800 mg (adult) 
1-7 of Weeks 13-18 
 
For pediatric patients (<18 years of age) use 
dosing tables for pazopanib provided in 
Appendix XVII.  
 
Pazopanib will be held at least 14 days post-
surgery prior to starting Continuation.  
 
See Section 4.4.2 for further details. 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
g. EKG 
 
**See Section 7.1.3 for full details.  
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
 
Cycle 1:  Ht__________cm 
Wt__________kg BSA__________m2 
Cycle 2:  Ht__________cm  
Wt__________kg  
BSA__________m2 
 
Date Due 
Date Given Week 
Day 
Pazopanib   ________mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
Enter calculated dose above and actual dose administered below 
 
 
 
 
13@ 
1 
________mg 
 
(a-d, e$, f)# 
 
 
 
2-7 
 
 
 
14 
1 
 
 
 
 
2-7 
 
 
 
15 
1 
g% 
 
 
 
2-7 
 
 
 
16 
1 
________mg 
(a-d, e$, f)# 
 
 
 
2-7 
 
 
 
 
 
 
________mg 
 
 
 
17 
1 
 
 
 
 
2-7 
 
 
 
18 
1 
 
 
 
 
2-7 
 
The therapy delivery map for Continuation continues on the next page. 
# Obtain within 4 days prior to the start of each cycle. 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
@ Begin RT, if postoperative RT given (see Section 17.2). 
%Obtain EKG 2-4 weeks after the start of the Continuation phase (see Section 7.1.3). 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
  
 
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Regimen C 
Continuation Phase Continued Weeks 19-25: Cycles 3 and 4 plus 1 week of pazopanib 
Continuation phase consists of 13 weeks of therapy (91 days in total) made up of four 21-day cycles plus one extra week of 
pazopanib therapy. This therapy delivery map presents the Continuation phase on 2 pages.  
 
____________________                ______________ 
Patient ID                                                     DOB 
 
 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Pazopanib 
 
PO 
450 mg/m2 (pediatric) 
800 mg (adult) 
1-7 of Weeks 19-25 
 
For pediatric patients (<18 years of age) use 
dosing tables for pazopanib provided in 
Appendix XVII.  
 
Pazopanib is to be held at least 7 days 
prior to any surgery planned at the end of 
Continuation therapy.  
 
See Section 4.4.2 for further details. 
 
 
a. History, PE with VS, Ht, Wt, BSA 
b. Blood Pressure** 
c. CBC, differential, platelets 
d. Electrolytes, including Ca, Mg, PO4 
e. Creatinine, ALT, Total bilirubin 
f. Amylase**, Lipase**, Urinalysis +/- UPC** 
 
**See Section 7.1.3 for full details.  
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE 
 
Cycle 3:  Ht__________cm 
Wt__________kg BSA__________m2 
Cycle 4:  Ht__________cm  
Wt__________kg  
BSA__________m2 
 
Date Due 
Date Given Week 
Day 
Pazopanib   ________mg 
Studies 
Comments (Include any held doses, or dose modifications) 
 
 
Enter calculated dose above and actual dose administered below 
 
End date of pazopanib:_____________ 
 
 
19 
1 
________mg 
(a-d, e$, f)# 
 
 
 
2-7 
 
 
 
20 
1-7 
 
 
 
21 
1-7 
 
 
 
22 
1 
________mg 
(a-d, e$, f)# 
 
 
 
2-7 
 
 
 
________mg 
 
 
 
23 
1-7 
 
 
 
24 
1-7 
 
 
 
25 
1-7 
 
See Section 7.1.3 for observations required at the end of protocol therapy. 
# Obtain within 4 days prior to the start of each cycle. 
$ Obtain direct bilirubin if total bilirubin is abnormally elevated. 
 
SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE APPENDIX VIII FOR SUPPORTIVE CARE 
 
 
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ARST1321 
 
 
APPENDIX XII:  URINE PROTEIN TO CREATININE (UPC) RATIO 
 
Clinical Meaning of UPC 
There is a good correlation between the ratio of urine protein to creatinine concentrations (UPC) in a random 
urine sample and the amount of protein excreted in a 24-hour urine collection period.205 Thus the UPC 
allows for an estimation of the 24-hour urine protein excretion from a random sample. The creatinine 
excretion is fairly constant throughout the day regardless of changes in urine flow rate: 
x 
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day 
x 
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day 
Normal protein excretion is <100 mg to 150 mg per 24 hours. 
x 
The UPC ratio is roughly equal to the 24 hour urine protein excretion in g/day 
 
 
Calculating UPC Ratio 
UPC ratio = (Urine protein [mg/dL]) / (urine creatinine [mg/dL]) = numerically equivalent to grams (g) 
protein excreted in urine over 24 hours.  
 
Example:  If a subject has a urine protein of 90 mg/dL and urine creatinine of 30 mg/dL,   
then UPC ratio =  
90 (mg/dL)  = 3 
30 (mg/dL) 
Result UPC is 3 correlating to roughly 3g of protein excretion in a 24-hour period. 
 
 
Units for UPC ratio 
UPC is a calculated ratio. The guidelines in the protocol are based on having urine protein and urine 
creatinine measured in the same units (eg, mg/dL). The SI units for urine protein and urine creatinine are 
not the same, so these must be converted to mg/dL before calculating the ratio. For reference, the conversion 
factors for commonly used units for protein and creatinine are provided below. 
 
Starting units 
Conversion to mg/dL 
Protein (g/L) 
Multiply by 100 
Creatinine (Pmol/L) 
Divide by 88.4 
Creatinine (mmol/L) 
Multiply by 11.3 
 
  
 

                
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APPENDIX XIII:  REFERENCE GUIDE FOR REQUIRED AND  RECOMMENDED 
CORRELATIVE STUDIES 
 
Note: in addition to the specimens below, this study includes a retrospective central pathology review with 
additional specimen requirements (see Section 14.0). 
 
 
At Diagnosis/Pre-
treatment 
Induction Cycle 2,  
Day 1-3 
Local Control 
Surgery (Week 
10 or Week 13) 
Suspected 
Tumor 
Recurrence 
Lab 
Receiving 
Specimens 
Analysis of 
actionable 
mutations* 
(Section 15.1) 
x Peripheral blood 
(2.5 mL) in a 
PAXgene RNA 
tube 
x Peripheral blood 
(5 mL) in purple 
top (EDTA) tube 
 
 
 
BPC 
Whole genome 
sequencing^ 
(Section 15.1) 
Snap frozen tumor 
tissue from 
primary site and 
any metastatic site  
 
 
 
BPC 
Microvessel density 
and circulating 
tumor DNA^ 
(Section 15.2) 
x 2 unstained 
slides from 
tumor tissue 
x Peripheral blood 
(10 mL) in 
purple top 
(EDTA) tubes 
 
x Snap frozen 
tumor tissue 
from primary 
site 
x Peripheral blood 
(10 mL) in 
purple top 
(EDTA) tubes 
 
Yoon 
Doxorubicin 
pharmacokinetics^ 
(Section 15.3) 
 
NOTE: Accrual to 
this correlative study 
ended upon 
completion of 
accrual to the dose 
finding phase of the 
chemotherapy cohort 
 
Blood (3-5 mL) in tubes 
containing sodium citrate 
at the following 9 time 
points pre- and post-
doxorubicin: 
x time 0 (predose)  
x 5 min after dosing 
x 30 min after dosing 
x 60 min after dosing 
x 2 hours after dosing 
x 4 hours after dosing 
x 8 hours after dosing 
x 24 ± 3 hours after 
dosing 
x 48 ± 3 hours after 
dosing. 
 
 
Baker 
Imaging Aims^ 
(Section 16) 
FDG PET 
 
FDG PET  
(pre-surgery) 
FDG PET 
IROC RI 
 
* 
Required of all patients. 
^ Recommended (option for participation embedded in main study consent). 
  
 

                
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ARST1321 
APPENDIX XIV:  YOUTH INFORMATION SHEETS 
 
INFORMATION SHEET REGARDING RESEARCH STUDY ARST1321 
(for children from 7 through 12 years of age) 
 
A study to compare treatments for a type of cancer called Soft Tissue Sarcoma (STS)  
 
1. We have been talking with you about your Soft Tissue Sarcoma (STS). STS is a type of cancer 
that grows in the soft tissues of the body like the muscles. It can grow in many places in the body. 
After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have STS. A research study is 
when doctors work together to try out new ways to help people who are sick.  
The usual treatment for STS includes surgery, radiation therapy and chemotherapy.  
- 
Radiation therapy is like using high energy x-rays.  
- 
Chemotherapy is a name for drugs that fight cancer. 
Not all STS tumors are alike; some do respond to chemotherapy and some do not. 
 
We want to see if giving pazopanib along with the usual therapy is safe without bad side effects. 
We also want to see how well each of the study treatments works against the type of cancer that 
you have. 
 
In this study, we will test whether adding a drug called pazopanib to the usual therapy will improve 
the treatment for the type of cancer that you have.  
 
3. Children who are part of this study will be treated in one of 2 ways. 
 
If you have a type of STS that we think will respond to chemotherapy, you will be treated with 
 
x 
Chemotherapy + Radiation therapy + Surgery + pazopanib 
or 
x 
Chemotherapy + Radiation therapy + Surgery 
 
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 you 
get rid of the cancer for a long time. 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.” The risks to you from this study are that the study treatment may not work as 
well as other therapies. Also, the study treatment may cause more side effects than other 
therapies. 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 use leftover tumor tissue and to collect additional blood. We 
want to see if there are ways to tell how the cancer will respond to treatment. These samples 

                
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would be taken when surgery or standard blood tests are being performed, so there would be no 
extra procedures. You can still take part in this study even if you don't allow us to collect the 
extra blood samples and use tumor tissue for research.  
 
8. Also, if you are to be treated with pazopanib, we may ask your permission to collect extra blood 
for biology research tests. These samples would be taken when you would not usually have blood 
drawn. These samples are likely to be taken from your central line and should not cause pain. 
You can still take part in this study even if you don't allow us to collect the extra blood samples 
for this research. 
 
 
 
 

                
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INFORMATION SHEET REGARDING RESEARCH STUDY 
(for teens from 13 through 17 years of age) 
 
A study to compare treatments with and without pazopanib for soft tissue sarcoma (STS)  
 
1. We have been talking with you about your Soft Tissue Sarcoma (STS). STS is a type of cancer 
that grows in the soft tissues of the body like the muscles. It can occur in many places in the 
body. After doing tests, we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have STS. A research study is 
when doctors work together to try out new ways to help people who are sick.   
 
The usual treatment for STS includes surgery, radiation therapy (high energy x-rays), and 
chemotherapy (anti-cancer drugs). Not all STS tumors are alike; some do respond to 
chemotherapy and some do not. 
 
We want to see if giving pazopanib along with the usual therapy is safe without bad side effects. 
We also want to see how well each of the combinations works against the type of cancer that you 
have. 
 
In this study, we will test whether adding an experimental drug, called pazopanib, to the usual 
therapy will improve the treatment for the type of cancer that you have.  
 
3. Children and teens who are part of this study will be treated in one of 2 ways. 
 
If you have a type of STS that is sensitive to chemotherapy, you will be treated with 
 
x 
Chemotherapy + Radiation therapy + Surgery + pazopanib 
or 
x 
Chemotherapy + Radiation therapy + Surgery 
 
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 you 
get rid of the cancer for a long time. 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.” The risks to you from this study are that the study treatment may not work as 
well as other therapies. Also, the study treatment may cause more side effects than other 
therapies. 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. This study includes required biology research tests. We want to see if there are ways to tell how 
the cancer will respond to treatment. For this test we will use some of the tumor tissue that was 
removed to make the diagnosis of NRSTS. You will not have an extra procedure to collect tumor 
tissue for this test. In addition, we will collect about 1½ teaspoons of blood for these tests. This 

                
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blood will be taken when other standard blood tests are being performed, so there would be no 
extra procedures. 
 
8. This study also includes optional biology research tests. We are asking your permission to use 
leftover tumor tissue and to collect additional blood. We want to see if there are ways to tell how 
the cancer will respond to treatment. These samples would be taken when surgery or standard 
blood tests are being performed, so there would be no extra procedures. You can still take part in 
this study even if you don't allow us to collect the extra blood samples and use tumor tissue for 
research.  
 
9. Also, if you are to be treated with pazopanib, we may ask your permission to collect additional 
blood. We want to examine the effect pazopanib might have on one of the standard chemotherapy 
drugs. These samples would be taken when you would not usually have blood drawn. These 
samples are likely to be taken from your central line and should not cause pain. You can still be 
treated on this study even if you don't allow us to collect the extra blood samples for research. 
 
  
 

                
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APPENDIX XV:  SUBJECT’S MEDICATION DIARY - PAZOPANIB 
 
Today’s date: _______________________________ 
Agent:  Pazopanib 
 
Subject Name: ________________________ (initials acceptable)Subject Study ID: ______________ 
 
 
INSTRUCTIONS TO THE SUBJECT: 
1. 
Complete one form for each 21 day cycle. 
2. 
Take your dose of pazopanib each day in the morning either 1 hour before or 2 hours after you eat with 
about 1 cup (240 mL) of water. You will take the tablets as instructed by your provider. You should 
swallow the tablets whole. Do not chew, crush, or break the tablets. 
3. 
If a dose is missed, do not take or “make up” the dose unless there is at least 12 hours until the next 
scheduled dose. If you vomit within 30 minutes of taking the dose, the dose may be repeated. If more 
than 30 minutes have elapsed, do not repeat the dose.  
4. 
Record the date, the number of tablets you took, and when you took them.   
5. 
If you have any comments or notice any side effects, please record them in the Comments column.   
6. 
Please return the forms to your provider when you go for your next appointment. 
 
 
Starting Week: ____    BSA: ____m2    Weekly Dose: ____mg/m2 
 
 
Day 
 
Date 
What time was 
dose taken? 
Number of 200 mg 
tablets taken 
Comments 
1 
 
 
# prescribed: ___ 
# taken: ___ 
 
2 
 
 
# prescribed: ___ 
# taken: ___ 
 
3 
 
 
# prescribed: ___ 
# taken: ___ 
 
4 
 
 
# prescribed: ___ 
# taken: ___ 
 
5 
 
 
# prescribed: ___ 
# taken: ___ 
 
6 
 
 
# prescribed: ___ 
# taken: ___ 
 
7 
 
 
# prescribed: ___ 
# taken: ___ 
 
8 
 
 
# prescribed: ___ 
# taken: ___ 
 
9 
 
 
# prescribed: ___ 
# taken: ___ 
 
10 
 
 
# prescribed: ___ 
# taken: ___ 
 
11 
 
 
# prescribed: ___ 
# taken: ___ 
 
12 
 
 
# prescribed: ___ 
# taken: ___ 
 
13 
 
 
# prescribed: ___ 
# taken: ___ 
 
14 
 
 
# prescribed: ___ 
# taken: ___ 
 
15 
 
 
# prescribed: ___ 
# taken: ___ 
 

                
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16 
 
 
# prescribed: ___ 
# taken: ___ 
 
17 
 
 
# prescribed: ___ 
# taken: ___ 
 
18 
 
 
# prescribed: ___ 
# taken: ___ 
 
19 
 
 
# prescribed: ___ 
# taken: ___ 
 
20 
 
 
# prescribed: ___ 
# taken: ___ 
 
21 
 
 
# prescribed: ___ 
# taken: ___ 
 
 
Physician’s Office will complete this section: 
1.      Date subject started protocol treatment_________________________________________________ 
2.      Date subject was removed from study  _________________________________________________ 
3.      Subject’s planned total daily dose  ____________________________________________________ 
4.     Total number of pills taken this month  _________________________________________________ 
5.     Physician/Nurse/Data Manager’s Signature  _____________________________________________ 
 
 
Subject’s signature: _____________________________________________________ 
 
 
 

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APPENDIX XVI:  RADIATION TREATMENT TARGET VOLUME
Example 1:
From RTOG Lower Extremity Sarcoma Atlas (https://www.rtog.org/LinkClick.aspx?fileticket
=AThtvc6dabE%3d&tabid=356DFFHVVHG&79IRULQWHUPHGLDWHWRKLJKJUDGHWXPRUVFP
should include 3 cm longitudinal margin and 1.5 cm radial margin, confined by anatomic barriers. Note the 
trimming of the CTV at the cortex of the abutting femur and deep fascia rather than extend to the skin. 

                
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Example 2:  
Grade 3 sarcoma along chest wall involving latissimus dorsi. The thickened red volume is the GTV and the 
thickened purple line indicates the correct expansion for the involved muscle. The thin orange volume 
shows overexpansion into the subcutaneous space and extension to skin. The thin light blue volume is a 
strict 1.5 cm radial expansion of the GTV along the X-Y axis, which would be inadequate for the 
longitudinal spread along the involved muscle along the chest wall. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

                
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APPENDIX XVII:  PEDIATRIC (< 18 YEARS OF AGE) DOSING TABLES FOR PAZOPANIB 
 
Chemotherapy Cohort 
Pazopanib 350 mg/m2  
 
Body Surface Area (m2) 
Daily dose (d) for 7 days 
(1 tablet = 200 mg) 
Cumulative Weekly Dose 
0.3 – 0.36 
1 tab / d QOD x 4 
800 mg/wk 
0.37 – 0.44 
1 tab / d x 5 
1000 mg/wk 
0.45– 0.53 
1 tab / d x 6 
1200 mg/wk 
0.54 – 0.61 
1 tab / d x 7 
1400 mg/wk 
0.62 – 0.69 
1 tab / d x 6; 2 tab / d x 1 
1600 mg/wk 
0.7 – 0.77 
1 tab / d x 5; 2 tab / d x 2 
1800 mg/wk 
0.78 – 0.85 
1 tab / d x 4; 2 tab / d x 3 
2000 mg/wk 
0.86 – 0.93 
2 tab / d x 4; 1 tab / d x 3  
2200 mg/wk 
0.94 – 1.02 
2 tab / d x 5; 1 tab / d x 2  
2400 mg/wk 
1.03 – 1.1 
2 tab / d x 6; 1 tab / d x 1  
2600 mg/wk 
1.11 – 1.18 
2 tab / d x 7 
2800 mg/wk 
1.19 – 1.26 
2 tab / d x 6; 3 tab / d x 1 
3000 mg/wk 
1.27 – 1.34 
2 tab / d x 5; 3 tab / d x 2 
3200 mg/wk 
1.35 – 1.42 
2 tab / d x 4; 3 tab / d x 3 
3400 mg/wk 
1.43 – 1.51 
3 tab / d x 4; 2 tab / d x 3 
3600 mg/wk 
1.52 – 1.59 
3 tab / d x 5; 2 tab / d x 2 
3800 mg/wk 
1.6 – 1.67 
3 tab / d x 6; 2 tab / d x 1 
4000 mg/wk 
1.68 and greater 
3 tab / d x 7 
4200 mg/wk 
 
For dose modifications to the chemotherapy cohort (350 mg/m2), please see Section 5.2. 
 
 
 

                
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Note: The Non-Chemotherapy Cohort is closed to further accrual, effective October 12, 2017. 
 
Non-Chemotherapy Cohort 
Pazopanib 450 mg/m2  
 
Body Surface Area (m2) 
Daily dose (d) for 7 days 
(1 tablet = 200 mg) 
Cumulative Weekly Dose 
0.3 – 0.34 
1 tab / d x 5 
1000 mg/wk 
0.35– 0.41 
1 tab / d x 6 
1200 mg/wk 
0.42 – 0.47 
1 tab / d x 7 
1400 mg/wk 
0.48 – 0.53 
1 tab / d x 6; 2 tab / d x 1 
1600 mg/wk 
0.54 – 0.6 
1 tab / d x 5; 2 tab / d x 2 
1800 mg/wk 
0.61 – 0.66 
1 tab / d x 4; 2 tab / d x 3 
2000 mg/wk 
0.67 – 0.73 
2 tab / d x 4; 1 tab / d x 3  
2200 mg/wk 
0.74 – 0.79 
2 tab / d x 5; 1tab / d x 2 
2400 mg/wk 
0.8 – 0.85 
2 tab / d x 6; 1 tab / d x 1 
2600 mg/wk 
0.86 – 0.92 
2 tab / d x 7 
2800 mg/wk 
0.93 – 0.98 
2 tab / d x 6; 3 tab / d x 1 
3000 mg/wk 
0.99 – 1.04 
2 tab / d x 5; 3 tab / d x 2 
3200 mg/wk 
1.05 – 1.11 
2 tab / d x 4; 3 tab / d x 3 
3400 mg/wk 
1.12 – 1.17 
3 tab / d x 4; 2 tab / d x 3 
3600 mg/wk 
1.18 – 1.23 
3 tab / d x 5; 2 tab / d x 2 
3800 mg/wk 
1.24 – 1.3 
3 tab / d x 6; 2 tab / d x 1 
4000 mg/wk 
1.31 – 1.36 
3 tab / d x 7 
4200 mg/wk 
1.37 – 1.42 
3 tab / d x 6; 4 tab / d x 1 
4400 mg/wk 
1.43 – 1.49 
3 tab / d x 5; 4 tab / d x 2 
4600 mg/wk 
1.5 – 1.55 
3 tab / d x 4; 4 tab / d x 3 
4800 mg/wk 
1.56 – 1.61 
4 tab / d x 4; 3 tab / d x 3 
5000 mg/wk 
1.62 – 1.68 
4 tab / d x 5; 3 tab / d x 2 
5200 mg/wk 
1.69 – 1.74 
4 tab / d x 6; 3 tab / d x 1 
5400 mg/wk 
1.75 and greater 
4 tab / d x 7 
5600 mg/wk 
 
For dose modifications to the non-chemotherapy cohort (450 mg/m2), please see Section 5.2. 
 
 
 

                
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This 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.,  
174. 
Thrombotic microangiopathy (TMA) which includes both Hemolytic uremic syndrome (HUS) and 
Thrombotic thrombocytopenic purpura (TTP) has been reported in clinical trials of GW786034.,  

                
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175. 
Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Enterovesical 
fistula, Esophageal 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. ,  
176. 
Gastrointestinal 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. ,  
177. 
Gastrointestinal 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. ,  
178. 
Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC. ,  
179. 
Interstitial lung disease may include, Adult respiratory distress syndrome, Pneumonitis, Pulmonary 
fibrosis, Respiratory, thoracic and mediastinal disorders - Other (Acute respiratory distress 
syndrome), Respiratory, thoracic and mediastinal disorders - Other (Aveolitis), Respiratory, 
thoracic and mediastinal disorders - Other (Bronchiolitis obliterans), Respiratory, thoracic and 
mediastinal disorders - Other (Interstitial fibrosis), Respiratory, thoracic and mediastinal disorders 
- Other (Interstitial pneumonia), Respiratory, thoracic and mediastinal disorders - Other (Interstitial 
pneumonitis), Respiratory, thoracic and mediastinal disorders - Other (Organizing pneumonia), 
Respiratory, thoracic and mediastinal disorders - Other (Pulmonary infiltrates), Respiratory, 
thoracic and mediastinal disorders - Other (Toxic pneumonitis).  
180. 
These events can result in life-threatening pulmonary, cardiac, cerebral, and other complications. ,  
181. 
Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC.,  
182. 
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