A Phase Ib Trial of Neoadjuvant AMG 232 (KRT-232) Concurrent With Preoperative Radiotherapy in Wild-Type P53 Soft Tissue Sarcoma (STS)
Phase: PHASE1
Conditions: Resectable Soft Tissue Sarcoma, Soft Tissue Sarcoma
Sponsor: National Cancer Institute (NCI)

i 
 
For Protocol Amendment 8 to: NRG-DT001, A Phase IB Trial Of Neoadjuvant AMG 232 
(KRT-232) Concurrent With Preoperative Radiotherapy In Wild-Type P53 Soft Tissue Sarcoma 
(STS) 
 
NCI/Local Protocol #: NRG-DT001 
 
NCI Protocol Version Date: December 01, 2021 
 
Section 
Change 
 
Global 
The protocol version date was updated in the document footer. 
Formatting and typographical errors were corrected as needed.  
 
Cover pages 
This amendment was added to the Document History table.  
 
5.1.1 
9.1 
x In response to a CTEP Notice to Investigators for studies using AMG 232 
(KRT 232), sections 5.1.1 and 9.1 were updated to include changes in the 
drug supply and pharmaceutical information.  
x The step 2 dosing time for AMG 232 (KRT) was revised to “30 minutes 
to 1 hour before RT” for clarification in section 5.1.1.  
 
10.5 
Appendix IX 
x References to the “ETCTN Biorepository” were changed to “EET 
Biobank” in 10.5 and Appendix IX.  
x An email contact was added in Appendix IX.  
 
     

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NRG ONCOLOGY 
 
              NRG-DT001 
                                     (ClinicalTrials.gov NCT # 03217266) 
 
A PHASE IB TRIAL OF NEOADJUVANT AMG 232 (KRT-232) CONCURRENT WITH 
PREOPERATIVE RADIOTHERAPY IN WILD-TYPE P53 SOFT TISSUE SARCOMA 
(STS) 
 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology. 
(9May2018) 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (22-FEB-2021) 
Principal Investigator/ Radiation 
Oncology 
Meng Xu Welliver, MD, PhD 
Department of Radiation Oncology 
The Ohio State University James Cancer 
Center  
460 W. 10th Avenue, D252P 
Columbus, OH 43210 
614-293-0216/FAX 614-293-4044 
Meng.welliver@osumc.edu 
Co-Principal Investigator/Radiation 
Oncology  
Dian Wang, MD, PhD 
Department of Radiation Oncology 
Rush University Medical Center 
500 S. Pauline Street 
Chicago, IL 60612 
312-942-5751/ FAX 312-942-2894 
Dian_Wang@rush.edu  
Translational Science Co-Chair 
David Kirsch, MD, PhD 
Department of Radiation Oncology 
Duke Cancer Center 
20 Duke Medicine Circle 
Durham, NC 27710 
919-668-7339/FAX 919-668-7345 
david.kirsch@duke.edu 
Translational Science Co-Chair 
Michelle Rudek, PharmD, PhD 
Sidney Kimmel Comprehensive Cancer Center 
at Johns Hopkins University 
1650 Orleans Street, CRB1 1M52 
Baltimore, MD 21231 
443-287-6476/410-502-0895 
mrudek2@jhmi.edu 
Pathology Co-Chair 
Paul E. Wakely, Jr. MD 
Department of Pathology 
The Ohio State University Wexner Medical 
Center 
129 Hamilton Hall 
1645 Neil Avenue 
Columbus, OH 43210 
614-293-9232/FAX 614-292-7072 
paul.wakely@osumc.edu 
Medical Oncology Co-Chair 
Gary Schwartz, MD 
Columbia University Medical Center, Division 
of Hematology and Oncology 
Herbert Irving Pavilion 9th Floor 
161 Fort Washington Ave 
New York, NY 10032 
212-305-2055 
schwartzg@columbia.edu 
 
Study Team continued on next page 

NRG-DT001 
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Study Team continued 
Medical Oncology Co-Chair 
Brian A. Van Tine, MD, PhD 
Department of Medicine 
Washington University Physicians 
Washington University School of Medicine  
Center for Advanced Medicine 
4921 Parkview Place 
St. Louis, MO 63110 
314-747-1171/FAX 314-362-7086 
bvantine@wustl.edu 
 
Surgery Co-Chair 
Raphael Pollock, MD, PhD 
Division of Surgical Oncology 
Department of Surgery 
The Ohio State University Wexner Medical 
Center 
614-688-7915/FAX (614) 293-3465 
Raphael.pollock@osumc.edu 
 
Surgery Co-Chair 
John Kane, MD 
Chairman, Department of Surgical Oncology 
Roswell Park Cancer Institute 
Elm and Carlton Streets 
Buffalo, NY 14263 
716-845-3284/FAX 716-845-2320 
johnkane@buffalo.edu 
Medical Physics Co-Chair 
Steve B. Jiang, Ph.D. 
Department of Radiation Oncology 
University of Texas Southwestern Medical 
Center 
5323 Harry Hines Boulevard 
Dallas, TX 75390 
214-645-8510 
Steve.Jiang@UTSouthwestern.edu   
Radiology Co-Chair 
Alan D. Rogers, MD 
Department of Radiology 
The Ohio State University Wexner Medical 
Center 
395 W. 12th Ave, 4th Floor 
Columbus, OH 43210 
614-293-8315/FAX 614-293-6935 
Alan.Rogers@osumc.edu 
 
Senior Statistician 
Pedro Torres-Saavedra, PhD 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-717-0851/FAX 215-928-0153 
torresp@nrgoncology.org    
 
 
 

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NRG Oncology Contact Information (22-FEB-2021) 
Data Management 
For questions concerning eligibility or 
data submission 
Data Managers  
Vanita Patel, MS 
Lisa Abate  
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102  
215-574-3170 (Patel) 
215-574-3178 (Abate) 
FAX: 215-940-8830 
PatelV@nrgoncology.org  
AbateL@nrgoncology.org  
RTQA:  
For questions concerning RT data 
submission 
 
Dosimetrist 
Marsha Radden, BS, R.T.(R)(T) 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3219 
mradden@acr.org     
RTQA:  
For questions concerning RT 
Credentialing 
 
http://irochouston.mdanderson.org 
OR 
IROC-Credentialing@mdanderson.org 
 
RTQA:   
For questions concerning data 
submission to TRIAD 
 
Triad-Support@acr.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Protocol Administrator 
Thien Nu Do 
NRG Oncology 
50 South 16th Street, Suite 2800 
Philadelphia, PA 19102 
215-574-3174 
dot@nrgoncology.org  
 
 
 

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Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
AMG 232 (KRT-
232) 
NCI/PMB 
789723 
 
 
DCTD 
 
 
Participating Sites (9May2018) 
 U.S. 
 Canada 
 Approved International Member Sites 
 
 
Document History 
 
Version Date 
Amendment 8 
December 01, 2021 
Amendment 7 
February 22, 2021 
Amendment 6 
January 28, 2020 
Amendment 5 
May 29, 2019 
Amendment 4 
October 9, 2018 
Amendment 3 
May 9, 2018 
Amendment 2 
December 19, 2017 
Amendment 1 
November 16, 2017 
Initial 
October 25, 2017 
 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 

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                                                   TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCHEMA .........................................................................................................................................9 
1. OBJECTIVES ............................................................................................................................10 
1.1 Primary Objectives.......................................................................................................10 
1.2 Secondary Objectives ...................................................................................................10 
1.3 Exploratory Objectives: ...............................................................................................10 

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2. BACKGROUND .......................................................................................................................10 
2.1 Soft Tissue Sarcoma (STS) ..........................................................................................10 
2.2  p53-MDM2 regulation in STS, radiotherapy, and MDM2 inhibitors .........................11 
2.3 AMG 232 (KRT-232) ( ................................................................................................13 
2.4 Pathologic Versus Radiographic Response Assessment ..............................................20 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA ..................................................................20 
3.1 Eligibility Criteria ........................................................................................................20 
3.2 Ineligibility Criteria ......................................................................................................22 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..................25 
5. TREATMENT PLAN/REGIMEN DESCRIPTION ..................................................................28 
5.1 AMG 232 (KRT-232) Therapy  ...................................................................................28 
5.2 Radiation Therapy ........................................................................................................30 
5.3 Imaging Requirement for Primary Tumor Site ............................................................42 
5.4 Surgery .........................................................................................................................43 
5.5 General Concomitant Medication and Supportive Care Guidelines ............................46 
5.6 Duration of Therapy .....................................................................................................46 
6. TREATMENT MODIFICATIONS/MANAGEMENT) ...........................................................47 
6.1 Hepatotoxicity Stopping and Re-challenge Rules .......................................................50 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................51 
7.1  Protocol Agents ...........................................................................................................51 
7.2 Adverse Events and Serious Adverse Events ..............................................................51 
7.3 Comprehensive Adverse Events and Potential Risks list (CAEPR) ............................52 
7.4 Expedited Reporting of Adverse Events ......................................................................54 
8. REGISTRATION AND STUDY ENTRY PROCEDURES .....................................................57 
8.1 Food and Drug Administration (FDA) Regulations and National Cancer 
Institute (NCI) Policy  ........................................................................................................57 
8.2 CTSU Registration Requirements................................................................................58 
8.3 RT-Specific Pre-Registration Requirements ................................................................61 
8.4 Patient Enrollment .......................................................................................................62 
9. 
DRUG INFORMATION ...................................................................................................64 
9.1 AMG 232 (KRT-232) (NSC 789723)...........................................................................64 
9.2 Supply ..........................................................................................................................66 
10. PATHOLOGY/BIOSPECIMEN .............................................................................................67 
10.1 Mandatory Submission of Specimens for NGS sequencing ......................................67 
10.2 Mandatory Submission of Specimens for Retrospective Central Pathology 
Review ...............................................................................................................................67 
10.3 Mandatory Submission of Specimens for AMG 232 (KRT-232) Plasma 
Pharmacokinetic Profile .....................................................................................................68 
10.4 Mandatory Submission of Specimens for Serum Macrophage Inhibitory 
Cytokine-1 (MIC-1)) ..........................................................................................................69 

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10.5 Biospecimen Submission Tables ...............................................................................69 
11. SPECIAL STUDIES (Non-Tissue)..........................................................................................74 
12. MODALITY REVIEWS .........................................................................................................74 
12.1 Radiation Therapy Quality Assurance Reviews ........................................................74 
12.2 Medical Oncology Modality Quality Assurance Reviews .........................................75 
12.3 Surgical Quality Assurance Reviews .........................................................................75 
12.4 Standard of Care Imaging Quality Assurance Reviews .............................................75 
13. DATA AND RECORDS .........................................................................................................75 
13.1 Data Management/Collection ....................................................................................75 
13.2 Summary of Data Submission ...................................................................................76 
13.3 Data Quality Portal ....................................................................................................77 
13.4 Rave-CTEP-AERS integration ..................................................................................78 
13.5 Global Reporting/Monitoring ....................................................................................79 
14. STATISTICAL CONSIDERATIONS ....................................................................................79 
14.1 Study Design ..............................................................................................................79 
14.2 Study Endpoints .........................................................................................................79 
14.3 Primary Objectives Study Design ..............................................................................79 
14.4 Study Monitoring of Primary Objectives ...................................................................80 
14.5 Accrual/Study Duration Considerations ....................................................................81 
14.6 Dose Level Guidelines ...............................................................................................82 
14.7 Secondary or Exploratory Endpoints   .......................................................................82 
14.8 Gender/Ethnicity/Race Distribution ...........................................................................83 
REFERENCES ..............................................................................................................................85 
Appendix I: Collaborative Agreements Language ........................................................................88 
Appendix II: PLASMA PHARMACOKINETICS ........................................................................90 
Appendix III: SERUM MACROPHAGE INHIBITORY CYTOKINE-1 (MIC-1) ......................93 
APPENDIX IV: Sample Combined PK/PD Blood Draw Schedules ............................................95 
APPENDIX V: Drug-Induced Liver Injury (DILI) Reporting & Additional Assessments 
Reporting............................................................................................................................97 
Appendix VI: CYP2C8 and CYP3A sensitive substrates* ............................................................99 
APPENDIX VII:  THE FNCLCC SARCOMA GRADING SYSTEM .......................................100 
Appendix VIII: World Health Organization Classification of Soft Tissue Tumours: Intermediate 
(Rarely Metastastizing) and Malignant Tumours, 2013 ..................................................101 
APPENDIX IX: NRG-DT001 Specimen transmittal clinical testing: TP53 Sequencing ...........104 

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NRG-DT001 
 
SCHEMA (16NOV2017) 
Cohort A: Extremity/body wall 
Cohort B: Abdomen/pelvis/retroperitoneum 
 
STEP 1  
 
Biopsy submission for TP53 NGS sequencing 
 
AMG 232 (KRT-232) administration (on week -1 only*) (see escalated dose level)  
 
NOTE: Tumor tissue must be received and NGS sequencing results must be completed before STEP 2 
registration can occur.  
 
*Patients can continue on AMG 232 (KRT-232) week 1 dose if there is a delay in NGS sequencing results. 
Ļ 
STEP 2  
 
 
 
p53 wild-type (data collection for MTD/RP2D)
 
 
Continue AMG 232 (KRT-232) week 1 to 5 at 
assigned dose level,   
 
and RT (Week 1-5), followed by surgery (5-8 weeks 
after RT completion)                        
                                                                                            
                                                                                            
       
 
                
 
p53 deleted/mutant                                          
 
Change to standard of care  (RT alone) 
(Week 1-5) followed by                                    
surgery (5-8 weeks after RT completion)          
 
Patients enrolled in Cohorts A and B will be given independently escalated AMG 232 (KRT-232) dose 
regimen as detailed in table below. 
 
AMG 232 (KRT-232) Dose Escalation/De-escalation Table for MTD/RP2D Determination* 
Dose Level 
Dose Frequency 
Dose (mg) 
-1 
2x/week 
120 mg 
1** 
3x/week 
120 mg 
2 
4x/week 
120 mg 
3 
5x/week 
120 mg 
* For detailed information on the process of dose escalation/de-escalation to determine 
MTD/RP2D as well as the DLT definition, please refer to section 14. 
** Dose level 1 is the starting dose level. 
 
 

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1. OBJECTIVES 
1.1 Primary Objectives  
1.1.1 To evaluate the safety and tolerability of AMG 232 (KRT-232) in combination with 
standard-dose radiotherapy in STS in two separate patient cohorts (A, extremity or body 
wall; B, abdomen/pelvis/retroperitoneum);  
1.1.2 To determine the maximum tolerated dose/recommended phase II dose (MTD/RP2D) of 
AMG 232 (KRT-232) in combination with radiotherapy.  
 
1.2 
Secondary Objectives 
1.2.1 To observe and record anti-tumor activity.  Although the clinical benefit of AMG 232 
(KRT-232) in combination with radiotherapy has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient 
will be carefully monitored for tumor response and symptom relief in addition to safety 
and tolerability. 
1.2.2 To determine % necrosis and pathologic complete response (pCR) in final surgical 
resection specimen;  
1.2.3 To determine % local failure (LF), disease free survival (DFS) and overall survival (OS) 
at 2 years; 
1.2.4 To determine pharmacodynamics (PD) effects of AMG 232 (KRT-232) when combined 
with radiotherapy by assessing serial serum Macrophage Inhibitory Cytokine (MIC)-1 
levels;  
1.2.5 To determine AMG 232 (KRT-232) exposure (pharmacokinetics)-response relationships 
(PD, toxicity, and efficacy). 
 
1.3 
Exploratory Objectives:  
1.3.1 To determine tumor volume changes determined by MRI or CT with and without contrast 
pre- and post-radiotherapy; 
1.3.2 To characterize clinical outcomes in patients treated with AMG 232 (KRT-232) by 
genomic biomarkers; 
1.3.3 To determine the correlation between mdm2/4 expression determined by NGS and the 
protein levels by IHC; 
1.3.4 To explore the possibility of identifying tumor genetic mutations in (1) cf ctDNA, (2) 
DNA/RNA isolated from exosomes, and determine the concordance of these results and 
that from NGS   
 
2. BACKGROUND  
2.1 Soft Tissue Sarcoma (STS)   
Soft tissue sarcomas (STSs) are uncommon, with an estimated 12,300 new cases and 5000 
deaths each year in the U.S. (Siegel 2016). Of these, 45-50% are located in the extremities, 
and 15% in the retroperitoneum. Seventy percent of retroperitoneal sarcomas present in 
abdomen, and 30% occur in the pelvis (Liles 2009). A majority of STS present as large 
masses, many greater than 5 cm in diameter before they are diagnosed since they could 
remain asymptomatic for a long time. This is especially true for STS located in the 
retroperitoneum, abdomen or pelvis. The large tumor size and complex anatomy of the 
tumor location represent a therapeutic challenge in the management of these tumors as 
negative surgical margins are difficult to achieve in many patients.  With the possible 

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exception of low-grade, well-differentiated liposarcoma, most studies of retroperitoneal 
sarcoma have shown the importance of complete macroscopic resection to improve local 
control and disease-specific survival (Lewis 1998; Stoeckle 2001; Jaques 1990; Hassan 
2004; Gronchi 2009; Bonvalot 2009). Recently, Keung (2014) reported median PFS, 
LRFS, DRFS, and OS were 21.1, 21.5, 45.8, and 59.0 months, respectively, and were 
significantly worse with R2 resection in 119 patients with retroperitoneal dedifferentiated 
liposarcoma. Since most patients with retroperitoneal sarcoma die of local recurrence, 
improving local control may translate into improved overall survival and patient quality of 
life, since surgical removal of recurrent tumors can be morbid and challenging.  In addition, 
even though STS located in the extremities and body wall have better local control rate, 
distant failure is still substantial, especially in high grade tumors. Rate of distant metastasis 
was reported to be in a range of 15% to 37% at 5 years (Lewis 1998; Gronchi 2009; 
Bonvalot 2009). For example, Bonvalot reported 1-, 3-, and 5-year metastasis rates were 
14% (95% CI, 0.11 to 0.19), 29% (95% CI, 0.24 to 0.34), and 34% (95% CI, 0.29 to 0.40), 
respectively, after curative treatment in his large institutional series (286 patients with 
retroperitoneal sarcoma). Thus, improving cure rate in STS represents an unmet clinical 
need, and better therapies conferring better local and distant control are needed. 
 
2.2  p53-MDM2 regulation in STS, radiotherapy, and MDM2 inhibitors (9May2018) 
Tumor suppressor gene p53 is one of the most commonly mutated genes in all human 
cancers; in tumors with WT p53, its activity is principally regulated by its high rate of 
turnover and degradation mediated by the E3 ubiquitin ligase, MDM2 (mouse double 
minute 2). MDM2 catalyzes p53 ubiquitination and subsequent degradation by proteasome. 
Activation of p53 in response to genotoxic stress leads to induction or repression of p53-
responsive genes at the transcriptional level, resulting in cell cycle arrest, senescence, or 
apoptosis. (Wasylishen 2016; Karni-Schmidt 2016)  In tumors with WT p53, high levels 
of MDM2 suppress p53 activity resulting in worse treatment outcome. Conversely, 
inhibition of MDM2 is an excellent strategy to treat WT p53 tumors. Since majority of STS 
contain WT p53, STS is an excellent target disease for MDM2 inhibition. (Tabubert 1998). 
More recent analyses showed that TP53 is altered (deleted or mutated) in 13.5 % soft tissue 
sarcoma cases (207 cases from MSKCC) (Barrentina 2010) and 44.76% soft tissue 
sarcomas cases from TCGA project (248 case). (Cancer Genome Atlas Research Network 
2017)  
MDM2 overexpression is also a good biomarker predictive for response to this class of 
inhibitors. An analysis of 4000 human tumors samples have previously found that MDM2 
is overexpressed in 7% of cancers and its overexpression is mutually exclusive from p53 
mutations. It has long been observed that 90% of well-differentiated (WD) and de-
differentiated (DD) LPS contain supernumerary rings and/or giant rod chromosomes that 
contain amplified segments of the 12q13-15 region.  Of the genes residing in this amplified 
chromosomal region, MDM2 (murine double minute) and CDK4 (cyclin-dependent kinase 
4) amplifications are used in pathology to help differentiate WD and DD LPS from other 
STS subtypes and lipoma. (Pollock 1997; Bartel 2001). Many current MDM2 inhibitors, 
including AMG 232 (KRT-232), function by inhibiting MDM2-p53 protein-protein 
interactions in order to re-activate p53 function.  MDM2/MDM4 accumulation has also 
been found to be the cause of developing resistance to this class of MDM2 inhibitors, 
causing tumor regrowth after drug withdrawal (Hoffman-Luca 2015; Aziz 2011). This 

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accumulation leading to resistance can be abrogated by the use of DNA damage agents, 
including ionizing radiation. Since RT is a part of standard therapy for STS, combining RT 
with MDM-2 inhibition to improve efficacy is a rational strategy.    
 
Multiple competitive inhibitors (e.g. nutlin, MI-219, RG7112. MK8242, AMG 232 (KRT-
232), RG7338) of the MDM2-p53 interaction have been developed to counter the effect of 
MDM2 and restore the activity of cellular p53.  These MDM2 antagonists seem to function 
only in the presence of tumors with wild-type p53.  Pre-clinical studies that evaluated these 
inhibitors in the treatment of osteosarcoma and LPS cell lines overexpressing MDM2 
demonstrated that these MDM2 antagonists were able to reactivate p53 activity, induce G2 
cell cycle arrest and apoptosis in vitro.  In a prior evaluation of RG7112 against pediatric 
cancer cell lines, and a variety of p53 wild-type xenografts in immune-deficient mice 
(Carol 2013), cell sensitivity in vitro differed based on p53 mutation status.  It was observed 
that p53-mutant cell lines were ~ 10-fold less sensitive to this MDM2 inhibitor than cells 
with wild-type p53. In contrast, RG7112 induced regressions in only 5 of 26 solid tumor 
models that had wild-type p53 by sequencing (Carol 2013). However, despite the relatively 
modest anti-tumor activity, RG7112 did induce p53 and downstream targets (p21, PUMA), 
hence clearly inhibited the MDM2:p53 interaction by stabilizing p53. In these “non-
responsive” tumors, the increase in p53 was inadequate to induce apoptosis, or cell cycle 
arrest, but the combination of an MDM2 inhibitor with DNA damage agents is potentially 
synergistic in stabilizing p53 and inducing cell death. This is the rationale for combining a 
second generation MDM2 inhibitor, RG7338, with ionizing radiation.  In vivo studies 
combining RG7338, using either daily or weekly schedules of administration, with daily 
fractionated radiation  (2Gy fractions) to a total of 10, 20 or 30Gy are completed using 
childhood sarcoma models transplanted into immune-deficient mice (Phelps  2015). 
Results of this study demonstrated that the MDM2 inhibitor RG7388 was well tolerated at 
80 mg/kg on the daily x 5 schedule (schedule 1) and once weekly x 2 at 200 mg/kg (given 
as split doses 12 hr apart; Schedule 2). RG7388 was administered 2 hr before XRT (2 Gy) 
daily for 5 days (Schedule 1) and a split dose given 12 hr and 2 hr pre-irradiation (Schedule 
2).  RG7388, as a single agent, had no significant effect on the growth of Rh18 xenografts 
administered on either schedule (P=0.8959 and P=0.5011 for Schedule 1 and 2, 
respectively). Skin toxicity was not significantly increased in the mice treated with 
radiation and RG7388 compared with radiation alone (Phelps 2015). RG7388, 
administered on both schedules, significantly enhanced the effect of daily fractionated 
radiation (figure 1). In a separate study, AMG 232 (KRT-232) was found to synergize with 
radiotherapy in a variety of cancer cell lines and xenograft models harboring WT p53 
(Werner 2015). 
 
In summary, strong preclinical evidence suggests that MDM-2 inhibitor AMG 232 (KRT-
232) and radiotherapy may have additive or synergistic anti-tumor activity in p53 WT STS. 
Since the majority of STS harbor WT p53 and radiotherapy is a standard treatment 
modality in STS, we believe this is a very feasible and promising study.    
 
 
 

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2.4 
Pathologic Versus Radiographic Response Assessment 
Even though imaging of the primary tumor before and after neoadjuvant therapy (MRI with and 
without contrast for extremity STS, CT with and without contrast for 
abdominal/pelvic/retroperitoneal tumors) have been standard imaging modalities for STS, it has 
not been established whether a significant change in the size of the tumor mass could serve as a 
meaningful surrogate marker for patient outcomes after neoadjuvant therapy.  While some 
randomized studies comparing chemotherapy regimens for soft tissue sarcoma have shown 
significant differences in radiologic response rates but no difference in outcome (Antman K 
1992, Edmonson 1993), others have described a significant correlation between tumor response 
and improved survival (Meric 2002, Pezzi 1990). Radiographic response after neoadjuvant 
radiotherapy or chemoradiotherapy has also been highly variable when only RECIST criteria was 
utilized.  
 
Treatment-induced tissue necrosis following neoadjuvant therapy has been established as a 
reliable predictor of outcome in bone sarcomas (Bacci 2005, Picci 1997). For STS, a large 
retrospective study of 496 patients with intermediate to high-grade extremity STS soft tissue 
sarcomas showed superior 5- and 10-year local recurrence (LR) rates for patients with 95% 
pathologic necrosis compared to those with <95% pathologic necrosis (Eilber 2001).  
 
Tumor volume change, and in particular, necrosis adjusted tumor volume, is known to be highly 
correlated with pathologic percent necrosis.  Percent necrosis on surgical pathology analysis 
following neo-adjuvant chemotherapy in sarcoma is a predictive biomarker of long term clinical 
outcomes.  The use of imaging, especially MRI, as a means to predict necrosis as a result of CRT 
would provide a less costly and less invasive means of assessing this predictive factor in sarcoma 
patients undergoing standard and experimental types of neoadjuvant CRT.  
 
 
3. ELIGIBILITY AND INELIGIBILITY CRITERIA (29-MAY-2019) 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (see protocol cover page). For radiation therapy-related eligibility 
questions, please contact RTQA (see protocol cover page).  
 
3.1 Eligibility Criteria (29-MAY-2019) 
 
A patient cannot be considered eligible for this study unless ALL of the following conditions 
are met. 
 
Prior to Step 1 Registration: 
3.1.1 Patients with pathologically proven diagnosis of grade 2-3 (intermediate or high grade) 
VRIWWLVVXHVDUFRPDZLWKVL]HFPDUHHOLJLEOHWRHQUROOLIWKHLQWHQWLRQWRWUHDWLV
curative. They must have sufficient tissue to submit to central laboratory for review as 
well as for NGS sequencing (see submission requirement). Biopsy should be obtained 
within 180 days prior to registration. 

NRG-DT001 
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Version Date: December 01, 2021 
Availability of tumor tissue is mandatory for study eligibility. The patient must have 
consented to provide archived formalin-fixed paraffin-embedded tumor tissue for future 
central pathology review, NGS sequencing and/or translational research. (Refer to 
Section 10 regarding tissue collection parameters). 
3.1.2 Appropriate stage for study entry based on the following diagnostic workup: 
x History/physical examination within 30 days prior to registration; 
x Imaging of the primary tumor by MRI and/or CT with or without contrast and/or 
PET/CT within 30 days prior to registration; 
x Staging workup evaluated by chest CT and/or PET/CT showing no distant metastasis 
within 30 days prior to registration  
3.1.3 There is a planned definitive surgical resection of the primary tumor;  
3.1.4 $JH 
3.1.5 ECOG or Zubrod performance status of 0-1 within 30 days prior to registration; 
3.1.6 Adequate hematologic function within 30 days prior to registration defined as follows: 
x $EVROXWHQHXWURSKLOFRXQWȝ/ 
x 3ODWHOHWFRXQWȝ/ 
x +HPRJORELQ10 g/dL (transfuse as necessary to raise levels; no transfusions 
within 7 days of start) 
3.1.7 Adequate renal and hepatic function within 30 days prior to registration defined as follows: 
x &DOFXODWHG&UHDWLQLQH&OHDUDQFHPOPLQE\&RFNURIW-Gault formula) within 
30 days prior to registration.  
x The patient has an adequate coagulation function as defined by International 
1RUPDOL]HG5DWLR,15[8/1RUSURWKURPELQWLPH37[8/1DQG
SDUWLDOWKURPERSODVWLQWLPH377RUD377[8/1WKRVHUHFHLYLQJ
anticoagulation therapy except low molecular weight heparin are excluded).  
x 7RWDOELOLUXELQ[XSSHUOLPLWRIQRUPDO8/1appropriate for age (except 
for patients with Gilbert’s Syndrome, who must have a total bilirubin <3 mg/dL) 
x SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) appropriate 
for age 
3.1.8 Females of child-bearing potential must have a negative serum pregnancy test within 7 days 
prior to registration.  
 
Exceptions: Females not of child-bearing potential due to surgical sterilization (at least 6 
weeks following tubal ligation, hysterectomy, or surgical bilateral oophorectomy with or 
without hysterectomy) confirmed by medical history; or female after menopause. 
x A “postmenopausal woman” is a woman meeting either of the following 
criteria: 
o spontaneous amenorrhea for at least 12 months, not induced by a 
medical condition such as anorexia nervosa and not taking medications 
during the amenorrhea that induced the amenorrhea (for example, oral 
contraceptives, hormones, gonadotropin releasing hormone, 
antiestrogens, selective estrogen receptor modulators [SERMs], or 
chemotherapy) 
o spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating 
hormone (FSH) level >40 mIU/mL 

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x Females of child-bearing potential and males must agree to use highly 
effective contraceptive precautions during the trial and up to 12 months 
following the last dose of study treatment. A highly effective method of birth 
control is defined as one that results in a low failure rate (that is, <1% per 
year) when used consistently and correctly, such as implants, injectables, 
combined oral contraceptives, some intrauterine contraceptive devices (IUDs), 
sexual abstinence, or a vasectomized partner. 
3.1.9 The patient or a legally authorized representative must provide study-specific informed 
consent prior to study entry. 
 
Prior to Step 2 registration 
3.1.10  TP53 sequencing by NGS performed by central pathology lab (Refer to section 10.1) 
 
 
3.2 
Ineligibility Criteria (22-FEB-2021) 
Patients with any of the following conditions are NOT eligible for this study. 
 
Prior to Step 1 Registration: 
3.2.1 Well-differentiated liposarcoma or other low grade STS; Kaposi sarcoma, bone sarcomas, 
cartilage sarcomas and GIST. See Appendix VIII. 
3.2.2 Definitive clinical or radiologic evidence of metastatic disease; indeterminate lung 
nodules less than 8mm are acceptable. 
3.2.3 The patient has history of another primary malignancy, with the exception of 
a) curatively treated non-melanomatous skin cancer; 
b) curatively treated cervical carcinoma in situ;  
c) non-metastatic prostate cancer;  
d) other primary non-hematologic malignancies or solid tumor treated with curative intent, 
no known active disease, and no treatment administered during the last 3 years prior to 
registration. 
3.2.4 The patient has a serious cardiac condition, such as congestive heart failure; New York 
Heart Association Class II/ III/IV heart disease; unstable angina pectoris, cardiac stenting 
within 6 months of enrollment; myocardial infarction within the last 3 months; 
valvulopathy that is severe, moderate, or deemed clinically significant; or arrhythmias that 
are symptomatic or require treatment. 
3.2.5 Females who are pregnant or breastfeeding. 
3.2.6 Prior systemic chemotherapy for the study cancer (sarcoma); note that prior chemotherapy 
for a different cancer is allowable. However, unresolved toxicities from prior anti-tumor 
therapy, defined as not having resolved to Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 grade 0 or 1, or to levels dictated in the eligibility criteria 
with the exception of alopecia (Grade 2 or 3 toxicities from prior antitumor therapy that 
are considered irreversible [defined as having been present and stable for > 6 months], such 
as ifosfamide-related proteinuria, may be allowed if they are not otherwise described in the 
exclusion criteria AND there is agreement to allow by both the investigator and sponsor). 
3.2.7 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation 
therapy fields. 

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o HIV testing is not required 
3.2.15 Treatment with medications known to cause QTc interval prolongation within 7 days of 
study day 1 is not permitted unless approved by the sponsor.  Use of ondansetron is 
permitted for treatment of nausea and vomiting. 
 
 

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4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP (29-
MAY-2019) 
 
PRE-TREATMENT ASSESSMENTS  
Assessments 
Prior to Step 1 
Registration 
(calendar days) 
 
 
Prior to Treatment 
(calendar days) 
 
Tumor tissue of primary tumor  
180 
 
Evaluable disease defined by 
RECIST 
30 
 
History/Physical Exam  
30 
 
Height/Weight 
30 
 
Concurrent Medications  
30 
 
Baseline Toxicity 
30 
 
MRI with/without contrast 
and/or CT with/without contrast 
and/or PET/CT of the primary tumor 
evaluation 
30 
 
Chest CT and/or PET/CT staging 
studies   
 
30 
 
ECOG or Zubrod status 
30 
 
No major surgery 
 
28 
ANC, platelet, hemoglobin 
30 
 
Calculated creatinine clearance, 
PT/INR, PTT or aPTT, total 
bilirubin, SGOT (AST)* or SGPT 
(ALT), Alk phos  
30 
 
 
 
SGOT (AST) 
 
 
Amylase, lipase  
 
 30 
Serum pregnancy test 
7  
72 hours 
Informed consent 
30 
 
Tissue for TP53 NGS sequencing 
Must be submitted within 7 days after Step 1 
registration 
PK/PD of AMG 232 (KRT-232) 
 
As scheduled in the PK/PD section  
(see Appendices II, III, and IV) 
* If SGOT (AST) is not done prior to Step 1 registration then it is required within 30 days prior 
to the first dose of AMG 232 (KRT-232). 
 
 
 
 
 
 

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ASSESSMENTS DURING TREATMENT 
 
Assessments 
Weekly During AMG 
232 (KRT-232) alone 
and AMG 232 (KRT-
232)/RT 
4 wks post AMG 232 
(KRT-232)/RT prior 
to surgery 
At time of surgery 
History and physical 
X 
X 
 
CBC, ANC, platelets 
X 
X 
 
ALT, AST, total 
bilirubin, alk phos, 
amylase, lipase  
X 
X 
 
Coagulation (PT, PTT, 
INR) 
 
X 
X 
 
Adverse Events 
X 
X 
 
 
Concurrent 
Medications 
X 
X 
 
PK/PD of AMG 232 
(KRT-232) 
 
As scheduled in the PK/PD section  
(see Appendices II, III, and IV) 
 
MRI and/or CT with 
contrast for primary 
tumor 
 
X 
 
CT chest for re-staging 
purpose 
 
X 
 
Research specimen 
collection – surgical 
tissue specimen  
 
 
X (As specified in 
Section 10) 
NOTE: Final surgical specimen will be collected and sent to Dr. Wakely for central pathology 
review.  
NOTE: If P53 status is wild type, the patient is eligible for final analysis. If p53 status is found to 
be deleted or mutated, the patient will be informed of the results and protocol treatments [AMG 
232 (KRT-232)] will be stopped. Standard of care treatments, however, including preoperative 
radiotherapy and subsequent surgical resection will remain in place. Clinical data will continue 
to be collected from these patients but collected data will not be used for primary and secondary 
end point. 
 
 
 
 
 
 
 
 
 
 

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ASSESSMENTS IN FOLLOW UP 
Assessments 
Time Point 
From end of RT: q3 mos. for 2 yrs. then final 
follow-up at 2.5 years from end of RT 
 
MRI or CT of primary tumor with/without 
contrast 
 
X 
 
Chest X-ray, chest CT or PET/CT  
X 
 
History and physical (including adverse event 
evaluation) 
X 
 
Adverse Events 
X 
Research specimen collection (optional) 
At time of recurrence/progression or of solid 
second neoplasm occurrence (as specified in 
Section 10) 
 
 
Measurement of Effect/Definition of Disease Assessments 
Although the clinical benefit of AMG 232 (KRT-232) has not yet been established, the intent of 
offering this treatment is to provide a possible therapeutic benefit, and thus the patient will be 
carefully monitored for tumor response and symptom relief in addition to safety and tolerability.  
Patients with measurable disease will be assessed by standard criteria per the assessment tables 
above.  
 
All tumor recurrences including local recurrence, regional recurrence, distant metastasis, and 
second primary tumor must be recorded in this study. All tumor recurrences should be 
documented on cross-sectional imaging (CT or MRI with and without contrast). Pathological 
confirmation of recurrence is strongly recommended. 
 
Local tumor recurrence: Any tumor recurrence inside the clinical target volume (CTV) is 
defined as “in-field recurrence”; any tumor recurrence beyond the CTV to within 3 cm distance 
from the edge of the CTV is defined as “marginal recurrence”; this marginal recurrence is 
considered “geographic miss”. Any other local recurrence is defined as “outside-field 
recurrence”. 
Local tumor progression: At least a 20% increase in the maximal dimension of the primary 
tumor taking as reference the smallest maximal dimension recorded since treatment 
started; 
Regional tumor recurrence: Any nodal metastasis adjacent to the primary soft tissue 
sarcoma; 
Distant tumor metastasis: Any tumor that develops distantly from the primary site of 
sarcoma; 
Second primary tumor: Any different histology of sarcoma or any other type of malignancy 
within or outside the radiation field 
 

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5. TREATMENT PLAN/REGIMEN DESCRIPTION 
 
5.1 
AMG 232 (KRT-232) Therapy (01-DEC-2021) 
 
x Step 1:  All eligible patients will be registered in Step 1 and will provide tissue to the 
central lab for sequencing.   Patients will also start AMG 232 (KRT-232) lead-in 
treatment on week -1 at the assigned dose level and frequency from the dose escalation 
table.  Week (-1) is defined as one week before starting RT treatment. Protocol 
treatment must begin as soon as possible but within 21 days after Step 1 registration. 
 
x Step 2:   Based on the sequencing results, those with p53 WT will continue to receive 
combination treatment of AMG 232 (KRT-232) and RT for a total of 5 weeks.  Those 
who have p53 deletion/mutations will stop taking AMG 232 (KRT-232) but will continue 
daily radiotherapy, followed by subsequent surgery. Patients can continue on AMG 232 
(KRT-232) week 1 dose if there is a delay in NGS sequencing results. 
 
x All data will be collected, but only data from p53 WT will be used for primary and 
secondary endpoint analysis. 
 
5.1.1 Agent Administration  
AMG 232 (KRT-232) is to be given alone during week -1 in the lead-in (Step 1) and for a total 
of 5 weeks in Step 2 treatment. In step 2, AMG 232 (KRT-232) is to be given with RT starting 
on day 2 (or per the assigned dose level from the dose escalation table) and approximately 30 
minutes to 1 hour before RT. 
 
AMG 232 (KRT-232) is to be taken with a full glass of water with or without food.  AMG 232 
(KRT-232) should not be crushed, chewed, or dissolved in water. Patients should not be re-dosed 
with AMG 232 (KRT-232) after vomited doses.  
 
If a dose of AMG 232 (KRT-232) is missed due to reasons other than toxicity and the next dose 
is in less than 12 hours, take the next dose at the normal time.  Do not make up the missed dose.  
If a dose is missed and the next dose is in 12 hours or more, take the missed dose as soon as 
possible.  Take the next dose at normal time. 
 
Patients will keep a drug diary log book and return the drug diary at each clinic visit. 
 
Radiotherapy will start on week 1 to week 5 to receive a daily dose, day 1-5 for a total of 25 
treatments.  If RT is held on a day when the drug should be taken, the drug should be held, and 
the dose will be taken with RT on the following treatment day. Make up doses can occur outside 
of the 5-week treatment period if RT is to be given in this time frame due to missed or delayed 
RT treatments. 

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molecular weight heparin and prophylactic low-dose warfarin are permitted. PT/PTT 
must meet the inclusion criteria.  Subjects taking warfarin must have their INR 
followed closely. 
x Clinically significant bleeding within 4 weeks of screening, current use of warfarin, 
factor Xa inhibitors, and direct thrombin inhibitors unless these medications can be 
safely discontinued 14 days prior to receiving the first dose of AMG 232 (KRT-232) 
or surgical resection. Note: Low molecular weight heparin. PT/PTT must meet the 
inclusion criteria.  Subjects taking warfarin must have their INR followed closely. 
 
 
5.2 
Radiation Therapy (22-FEB-2021) 
 
IGRT IS MANDATORY FOR THIS STUDY (Section 5.2.1) 
 
Note: Pre-treatment reviews will be mandatory for Cohort B only - the first case from each 
institution will require a pre-treatment review. The patient cannot begin treatment until complete 
data from the first case is received, reviewed and approved.    Sites need to allow 3 business 
days for the pre-treatment review, and if necessary, 3 additional business days if a revision 
and re-plan is requested by the Reviewer (See Section 5.2.11).    
 
Protocol treatment must begin within 21 calendar days after Step 1 registration 
 
5.2.1 Treatment Technology 
Treatment Modalities 
This protocol focuses on the pre-operative external beam radiotherapy. All endpoints will be 
tracked till week 4 after the pre-operative radiotherapy (prior to surgery). Post-surgery boost 
treatment is not allowed in this protocol. Radiation therapy using megavoltage photons (4-18 
MV) and Co-60 energy (MRIdian only) are permitted in this study. For tumors adjacent or 
included in lung tissue, beam energy should be <10 MV. Proton therapy is not allowed for this 
protocol.  
 
For cohort A (Extremity and Body Wall), advanced delivery techniques including intensity 
modulated radiation therapy (IMRT), volumetric modulated radiation therapy (VMAT), 
MRIdian, CyberKnife, Vero, and Tomotherapy are recommended. However, 3D- conformal 
radiation therapy (3DCRT) is also permitted. For cohort B (Abdomen/Pelvis/Peritoneal cavity), 
advanced delivery technique is mandatory. 3DCRT is not permitted for cohort B. 
 
Image Guidance Devices 
Treatment machine with image-guided radiation therapy (IGRT) capability is mandatory for this 
protocol. IGRT is defined as the use of computer-assisted system that provides detailed 
information on shifts of the patient support system based on image registration software.  
 
Image guidance may be achieved using any one or more of the following techniques: 
x Orthogonal kilovoltage (KV) and/or MV electronic images, e.g., ExacTrac; 
x Linear-accelerator mounted kV and MV cone beam CT images (CBCT); 
x Linear-accelerator mounted MV CT images (e.g., Tomotherapy); 

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x Other mechanism, (ex. optical surface tracking and electromagnetic localization) after 
discussion with the Medical Physics Co-chair. 
 
5.2.2 Localization, Immobilization and Simulation 
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 devises may be utilized, including Vacbag, Alpha Cradle and thermoplastic 
casts.  
 
Adjustments of patient position should be made accordingly, if needed prior to treatment. 
Pretreatment images may include 2D or 3D imaging acquired using the techniques described in 
Section 5.2.1.  
 
Motion Management Technique 
Motion management is highly recommended for this protocol especially for tumors located in 
upper abdomen. Three categories of motion management are allowed on this protocol: 
(1) Motion encompass approach: 4DCT and free breathing treatment  
(2) Motion control approach: breath hold and abdominal compression  
(3) Active motion management approach: gated delivery or motion tracking delivery  
 
Simulation Imaging  
Simulation imaging must encompass the entire body part where tumor is located and the adjacent 
critical structures. Appropriate pre-treatment diagnostic imaging studies, such as the MRI (T1 
post contrast and T2 sequences), PET/CT or CT, when possible, must be fused with simulation 
CT to aid target delineation. Radiotherapy treatment plans will be generated after immobilization 
and computerized tomography (CT) simulation. Typically contrast is not required for sarcoma 
simulation but it can be considered if deemed necessary by the treating radiation oncologist. In 
case the contrast agent is employed, the density of contrast should be overridden to a 
representative background electron density or a set of non-contrast free-breathing scan can be 
acquired to prevent the dose calculation uncertainty caused by contrast agent. 
 
Simulation imaging for cohort A: Extremity and Body Wall 
Free-EUHDWKLQJ&7ZLWKVOLFHWKLFNQHVVPPLVPDQGDWRU\DVSULPDU\GDWDVHWIRUVLPXODWLRQ
and dose calculation. For extremity cases, CT scan should encompass the tumor and the adjacent 
joints (if applicable). For trunk/chest wall cases, CT scan should encompass the tumor, starting 
from cricoid cartilage and extending inferiorly to the bottom of ribcage.  
 
Simulation imaging for cohort B: Abdomen/Pelvis/Peritoneal cavity 
4DCT is recommended for primary tumors located in the upper abdomen. Free-breathing CT, 
averaged CT (if 4DCT is employed), or BH-CT (if breath-hold treatment is intended) with slice 
WKLFNQHVVPPLVPDQGDWRU\DVSULPDU\GDWDVHWIRUVLPXODWLRQDQGGRVHFalculation. It is 
desired to cover the tumor and the critical structures from liver to the bottom of pubic symphysis. 
However, the scanning range can be adjusted and determined by the physician.    
 
 
 

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5.2.3 Imaging for Structure Definition, Image Registration/Fusion and Follow-up 
Pre-treatment diagnostic imaging studies including MRI with and without contrast and/or CT 
with and without contrast and/or FDG-PET/CT will be required as part of staging and/or to assist 
in volume delineation in all eligible patients.  In order to standardize target volume definition 
using better tumor and soft tissue definition an MRI of primary site is highly preferred unless 
patient has contraindications to MRI (e.g., implanted pacemaker, neurostimulator, aneurysm 
clips, metallic foreign objects, or other contra-indications).  
 
Diagnostic MRI, CT, PET/CT images, when possible, must be fused to the planning CT (free-
breathing CT, averaged 4DCT, or BH-CT). Image fusion should be checked by physician prior 
to contouring. All targets and critical structure should be delineated on the planning CT. When 
the motion management is utilized for treatment, the motion of target should be properly 
accounted in the target definition. Site-specific guidance is provided in sections 5.2.4 and 5.2.5.        
 
Note: Diagnostic imaging that is fused with planning CT will be required for submission via 
TRIAD. Refer to protocol specific page on the NRG website for data submission and section 
13.2 in the protocol text.    
 
5.2.4 Definition of Target Volumes and Margins 
Note: All structures must be named for digital RT data submission as listed in the respective 
table below.  The structures marked as “Required” in the table must be contoured and submitted 
with the treatment plan. Structures marked as “Required when applicable” must be contoured 
and submitted when applicable. 
 
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
Target Definition for cohort A: Extremity and Body Wall 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
GTV_5000 
GTV to receive 50 Gy 
Required 
CTV_5000 
CTV to receive 50 Gy 
Required 
PTV_5000 
PTV to receive 50 Gy 
 
 
Required 

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PTV_Eval_5000  
 
PTV minus OARs 
Required when applicable 
 
Detailed Specifications  
The definition of volumes will be in accordance with the ICRU Report #62: Prescribing, 
recording and Reporting Photon Beam Therapy (supplement to ICRU Report #50). 
 
Gross Target Volume (GTV 5000): Gross tumor defined by MRI T1 plus contrast 
images (MRI with contrast is required unless contraindicated). Fusion of MRI and CT 
is recommended to delineate the GTV for radiotherapy planning, but this is optional. 
 
Clinical Target Volume (CTV_5000) for Intermediate-to-+LJK*UDGH7XPRUVFP: 
Include gross tumor and clinical microscopic margins. Typically CTV = GTV and 
suspicious edema (defined by MRI T1 post contrast images unless contraindicated) 
plus 3 cm margins in the longitudinal (proximal and distal) directions. CTV should 
also include areas with any suspicious MRI T2 signals. If this causes the field to 
extend beyond the 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: Include gross tumor and clinical microscopic margins. 
Typically CTV = GTV and suspicious edema (defined by MRI T1 post contrast 
images) plus 2 cm margins in the longitudinal (proximal and distal) directions. CTV 
should also include areas with any suspicious MRI T2 signals. If this causes the field 
to extend beyond the compartment, the field can be shortened to include the end of 
compartment. 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. 
 
Planning Target Volume (PTV_5000): Include CTV and error of setup and organ 
motion. Typically PTV includes CTV plus 5 mm (with daily IGRT). Skin surfaces 
should not be contoured in CTV or 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 oncologist. Use of 
bolus on the skin surfaces is not encouraged when IMRT is used. 
 
Planning Target Volume for Evaluation (PTV_Eval_5000): PTV volume minus 
impinging high priority OARs created for dosimetric evaluation. In cases where the 
PTV_5000 overlaps with critical organs, such as the spinal cord, the PTV_Eval_5000 
should be created to limit dose to the OARs. Care should be taken to ensure that the 
cold spots within the PTV_Eval_5000 do not exist within the GTV. 
 
 
 
 
 

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Target Definitive for cohort B: Abdomen/Pelvis/peritoneal cavity 
 
Standard Name 
 
Description 
 
Validation 
Required/Required when 
applicable/Optional 
GTV_5000 
GTV to receive 50 Gy 
Required 
IGTV_5000 
Volume enveloping GTV 
motion over the course of 
a respiratory cycle 
 
Required when applicable 
*CTV_4500 
(target in 
abdomen/pelvis/retro
peritoneal cavity) 
CTV to receive a 
minimum of 45 Gy (while 
GTV receives 50 Gy) 
Required 
*PTV_4500 
(target in 
abdomen/pelvis/retro
peritoneal cavity) 
PTV to receive a 
minimum of 45 Gy (while 
GTV receives 50 Gy) 
 
 
Required 
PTV_Eval_4500 
PTV minus OARs 
Required when applicable 
* Cohort B only: Prescription dose to CTV and PTV will be 45 Gy while dose to GTV (and 
IGTV if applicable) will be 50 Gy with simultaneous integrated boost (SIB) technique.  
 
Detailed Specifications 
 
The definition of volumes will be in accordance with the ICRU Report #62: Prescribing, 
recording and Reporting Photon Beam Therapy (supplement to ICRU Report #50). 
 
Internal margin (IM) definition  
For patients scanned with 4DCT, no IM is needed when IGTV is delineated based on individual 
phase CTs, maximum intensity projection (MIP) of the tumor. Otherwise, proper IM need to be 
applied to account for the internal motion.  
 
Setup margin (SM) definition: 5 mm as daily IGRT is mandatory for cohort B.  
 
Gross Target Volume (GTV_5000): gross tumor defined by CT or MRI T1 plus 
contrast images. Fusion of MRI and CT is recommended to delineate the GTV for 
radiotherapy planning, but this is optional. Dose to GTV (and IGTV if applicable) 
will be 50 Gy with simultaneous integrated boost (SIB) technique. 
 

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Clinical Target Volume (CTV 4500): typically CTV = GTV plus 10 mm margin, 
however, the CTV field should not be extended beyond other organ structures, or 
compartment or intact fascia or bone.  
 
For the retroperitoneal sarcoma extending to thigh through inguinal canal, the inferior 
margin in the thigh is typically 3 cm below the GTV and radial margin in thigh must 
be 1.5 cm, but should not beyond the compartment or intact fascia or bone.  
 
Planning Target Volume (PTV_4500): typically includes CTV_4500 +  IM + SM. In case the 
PTV expansion extends outside the skin, toward the spinal cord or into the spinal canal, it can be 
assumed that tumor motion will not occur in this direction and the PTV margin can be limited up 
to 5 mm in this direction.   
 
Planning Target Volume (PTV_Eval_4500): PTV volume minus impinging high priority OARs 
created for dosimetric evaluation. In cases where the PTV_4500 overlaps with critical organs, 
such as the spinal cord, the PTV_Eval_4500 should be created to limit the dose to the OARs. 
Care should be taken to ensure that the cold spots within the PTV_Eval_4500 do not exist within 
the GTV. 
 
5.2.5 
Definition of Critical Structures and Margins 
Note: All structures must be named for digital RT data submission as listed in the table below.  
The structures marked as “Required” in the table must be contoured and submitted with the 
treatment plan. Structures marked as “Required when applicable” must be contoured and 
submitted when applicable.   
Resubmission of data may be required if labeling of structures does not conform to the standard 
DICOM name listed.  Capital letters, spacing and use of underscores must be applied exactly as 
indicated. 
 
Critical Structure Definition for cohort A: Extremity and Body Wall 
 
1. Organs at Risk for Primary Tumors at Extremities 
Structure Name Description 
Validation 
Required/Required when 
applicable/Optional 
Femur_R(L) 
Right (or left) femur 
within field 
Required when applicable 
Joint_R(L) 
Right (or left) joint 
Required when applicable 
Skin 
Skin contoured as a 3 
mm thick rind 
 
Required 
SoftTissue_Sub 
A strip of subcutaneous 
soft tissue; at the 
discretion of treating 
physician 
Required 
 
 

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1. Organs at Risk for Primary Tumors at Body Wall (Trunk/chest wall) 
Structure Name 
Description 
Validation 
Required/Required when 
applicable/Optional 
BrachialPlex_R(L) Right (or left) 
brachial plexus 
Required  
Esophagus 
Esophagus  
Required  
Heart 
Heart 
Required 
Lungs 
Lungs 
Required 
SpinalCord 
Spinal cord 
Required 
 
Critical Structure Definition for cohort B: Abdomen/Pelvis/peritoneal cavity 
 
Structure Name 
Description 
Validation 
Required/Required when 
applicable/Optional 
Liver 
Liver 
Required when applicable 
Kidney_R(L) 
Right (or left) kidney  Required when applicable 
Spc_Bowel 
Bowel space 
Required when applicable 
Stomach 
Stomach 
Required when applicable 
Anus 
Anus 
Required when applicable 
Bladder 
Bladder 
Required when applicable 
Rectum 
Rectum 
Required when applicable 
Vulva 
Vulva 
Required when applicable 
Testis_R (L) 
Right (or left) Testis;  
Testes should be 
defined if fertility 
preservation desired 
Required when applicable 
Ovary_R (L)  
Right (or left) Ovary;  
Ovaries should be 
defined if fertility 
preservation desired 
Required when applicable 
SpinalCord 
Spinal cord 
Required when applicable 
 
5.2.6 Dose Prescription 
Note: The information provided in this section can be used for adjusting the dose constraints for 
treatment planning purposes.  This table together with the planning priority table should be used 
during dose optimization.  It is important to remember that ideal plans might not be achievable in 
all cases.  Thus, the Compliance Criteria table could be different than the information given here.  
Cases will be scored using the Compliance Criteria table. 
 
 
 
 
 
 

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Dose Prescription for cohort A: Extremity and Body Wall 
 
Target 
Standard 
Name 
 
Dose 
(Gy) 
Fraction 
Size (Gy) 
# of 
Fractions 
Frequency 
Dose Specification 
Technique 
PTV_5000 
50 
2 
25 
Daily 
Covering >=95% PTV 
 
Dose Prescription for cohort B: Abdomen/Pelvis/peritoneal cavity 
 
Target 
Standard 
Name 
 
Dose 
(Gy) 
Fraction 
Size (Gy) 
# of 
Fractions 
Frequency 
Dose Specification 
Technique 
PTV_4500 
45 
1.8 
25 
Daily 
Covering >=95% PTV 
GTV_5000 
50 
2 
25 
Daily 
Covering >= 95% 
GTV 
 
5.2.7 Compliance criteria 
The compliance criteria listed here will be used to score each case.  Given the limitations 
inherent in the treatment planning process, the numbers given in this section can be different than 
the prescription table.  The Per Protocol and Variation Acceptable categories are both considered 
to be acceptable.  The Per Protocol cases can be viewed as ideal plans, and the Variation 
Acceptable category can include more challenging plans that do not fall at or near the ideal 
results.  A final category, called Deviation Unacceptable, results when cases do not meet the 
requirements for either Per Protocol or Variation Acceptable. Plans falling in this category are 
considered to be suboptimal and additional treatment planning optimization is recommended. 
 
Compliance Criteria for cohort A: Extremity and Body Wall 
 
Normalization of Dose: The plan is normalized such that 95% of the PTV_5000 volume 
receives prescription dose of 50 Gy. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met 
 
Target Volume Constraints:  
Name of 
Structure 
Dosimetric 
parameter* 
Per 
Protocol  
Variation 
Acceptable 
PTV_5000 or 
PTV_Eval_5000 
 
D95%[Gy] 
>=50 Gy 
>=49 Gy 
D99%[Gy] 
> =46.5 Gy 
> =45 Gy 
V55Gy[%] 
< =20% 
< =25% 

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Normal Structure Constraints for Primary Tumors at Extremities: 
Name of Structure 
Dosimetric 
parameter 
Per 
protocol  
Variation 
Acceptable 
Toxicity endpoint 
Femur 
V50Gy[%] 
<50% 
<=60% 
Fracture 
Joint 
V50Gy[%] 
<50% 
<=60% 
Joint Stiffness 
 
Skin 
V20Gy[%] 
<50% 
<=60% 
Poor wound 
healing/lymphedema 
 
Normal Structure Constraints for Primary Tumors at Body Wall (Trunk/Chest Wall): 
Name of 
Structure 
Required DVH 
metric 
Per protocol 
cumulative dose 
Variation 
Acceptable 
Toxicity 
endpoint 
BrachialPlexus 
D0.03cc[Gy] 
< =63 Gy 
<=65Gy 
Brachial 
Plexopathy 
Esophagus 
Mean[Gy] 
<30 Gy 
<=33 Gy 
Esophagitis 
 
D0.03cc[Gy] 
<70 Gy 
<=74 Gy 
Heart 
Mean[Gy] 
<26 Gy 
<=30 Gy 
Pericarditis 
V30Gy[%] 
<40% 
<=50% 
Lungs 
Mean[Gy] 
<7 Gy 
<=8 Gy 
Pneumonitis 
V5Gy[%] 
<60% 
<=65% 
V20[%] 
<30% 
<=35% 
SpinalCord 
D0.03cc[Gy] 
< =45 Gy 
<=48 Gy 
Myelopathy 
 
Delivery Compliance Criteria 
 
Per Protocol 
 Variation 
Acceptable 
RT Start Date 
Concurrent with AMG 
232 (KRT-232) 
chemotherapy 
0-1 week 
Overall Treatment Time 
< 37 days 
38-42 days 
Non-Medically Indicated 
Treatment Interruption  
0-2 days 
3-5 days  
 
 
Compliance Criteria for cohort B: Abdomen/Pelvis/Retroperitoneum 
Normalization of Dose: The plan is normalized such that 95% of the PTV_4500 volume 
receives prescription dose of 45 Gy. 
 
Note: Deviation Unacceptable occurs when dose limits for Variation Acceptable are not 
met 
 
 
 
 
 

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Target Volume Constraints:  
Name of 
Structure 
Dosimetric parameter* 
Per 
Protocol  
Variation 
Acceptable 
PTV_4500 or 
PTV_Eval_4500 
 
D95%[Gy] 
>=45 Gy 
>=44 Gy 
D99%[Gy] 
>=41.9 Gy >=40.5 Gy 
V55Gy[%] 
<=15% 
<=25% 
GTV_5000 
 
D95%[Gy] 
>=50 Gy 
>=49 Gy 
D99%[Gy] 
>=46.5 Gy >=45 Gy 
V55Gy[%] 
<=20% 
<=25% 
 
Normal Structure Constraints: 
Name of 
Structure 
Required DVH 
metric 
Per protocol 
cumulative dose 
Variation 
Acceptable 
Toxicity endpoint 
Liver 
Mean[Gy] 
<30 Gy 
<=33 Gy 
RILD in normal 
function liver 
R&L Kidneys 
Mean[Gy] 
<14.4 Gy 
<=16 Gy 
Renal Dysfunction 
 
V20Gy[%] 
<30% 
<=33 % 
Bowel Space 
V45 Gy[%] 
<20%  
 
<=30 %  
 
Grade 3+ toxicity 
Stomach 
D0.03cc[Gy] 
D2%[Gy] 
D25%[Gy] 
<52 Gy 
<=50 Gy 
<=45 Gy 
 
<=54 Gy 
<=54 Gy 
<=54 Gy 
Ulceration 
Anus 
V30Gy[%] 
<50% 
<= 60% 
Grade 3 toxicity 
V50Gy[%] 
<20% 
<= 25% 
Bladder 
V50Gy[%] 
<50% 
<= 60% 
Grade 3 toxicity 
V70Gy[%] 
<20% 
<= 25% 
Rectum 
V50Gy[%] 
<50% 
<= 60% 
Grade 3 toxicity 
V70Gy[%] 
<20% 
<= 25% 
Vulva 
V30Gy[%] 
<50% 
<= 60% 
Moist 
Desquamation 
Testes (if 
fertility 
preservation 
desired) 
V1Gy[%] 
<50% 
<= 60% 
Infertility 
Ovaries (if 
fertility 
preservation 
desired) 
V5Gy[%] 
<50% 
<= 60% 
Infertility 
Spinal Cord 
D0.03cc[Gy] 
45 Gy 
<=48 Gy 
Myelopathy 
 
 
 
 
 

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Delivery Compliance Criteria 
 
Per Protocol 
 Variation 
Acceptable 
RT Start Date 
Concurrent with AMG 
232 (KRT-232) 
chemotherapy 
0-1 week 
Overall Treatment Time 
<37 days 
38-42 days 
Non-Medically Indicated 
Treatment Interruptions  
0-2 days 
3-5 days 
 
 
5.2.8 Treatment Planning Priorities and Instructions 
Every attempt should be made to minimize dose to OAR without compromising coverage of the 
target coverage and to meet the planning goals listed in the above session. The priorities of 
structures are listed in the order of decreasing importance and to be used when conflict between 
tumor coverage and OAR dose presents in the optimization.   
   
Critical structure and target priority for cohort A: Extremity and Body Wall 
1. Spinal Cord 
2. PTV_Eval_5000 (if applicable)  
3. PTV_5000 
4. Esophagus 
5. Lung 
6. Other  
 
Critical structure and target priority for cohort B: Abdomen/Pelvis/Retroperitoneum 
1. Spinal Cord 
2. PTV_Eval_4500  (if applicable)  
3. PTV_4500 
4. Liver 
5. Rectum 
6. Other 
 
Dose calculation algorithm and dose reporting  
The tissue heterogeneity correction is mandatory for this protocol. Any algorithm used for this 
study must be credentialed by IROC Houston. Acceptable choices of algorithm are listed at 
http://rpc.mdanderson.org/RPC/Services/Anthropomorphic_%20Phantoms/TPS%20-
%20algorithm%20list%20updated.pdf 
 
For Convolution/Superposition type algorithms, dose should be reported as computed inherently 
by the given algorithm.   For Monte Carlo or Grid Based Boltzmann Solver algorithms, 
conversion of Dm (dose-to-medium) to Dw (dose-to-water) should be avoided.  Dm, computed 
inherently by these algorithms, should be reported. 
 
 
 

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Primary dataset 
Calculation must take into account tissue heterogeneity and should be performed with CT-based 
treatment planning. The primary dataset for dose calculation must be a contrast corrected or non-
contrasted free-breathing CT, averaged CT when 4D-CT, or breath-hold CT. Maximum Intensity 
Pixel (MIP) generated images from 4DCTs may not be used as the primary dose calculation 
dataset. The relative electron density (or the physical density for Monte Carlo) derived from the 
Hounsfield Units (HU) of CT images should be utilized for dose calculation.  
 
Dose matrix resolution 
'RVHJULGVL]HVKRXOGEHPPLQDOOGLUHFWLRQV 
 
5.2.9 Patient specific QA 
Independent patient specific dose/MU QA is mandatory for all plans. For 3D CRT, an 
independent secondary dose calculation can be used instead of measurement based QA. Point 
dose or MU difference between plan calculation and secondary dose calculation should be <5%.  
For IMRT and VMAT, the plan must be verified prior to first fraction of treatment. 
Measurements in a QA phantom can be sufficient for a check as long as patient’s plan can be 
directly applied to the phantom geometry. QA can also be done in calculation-based approach, 
which reconstruct the 3D patient dose via a machine recorded delivery parameter file (Dynalog 
file) or EPID measured images obtained from a dry run IMRT plan delivery. The recommended 
patient specific QA criteria is for > 90% of the comparison points to pass a 3%/3mm Gamma 
analysis.  
 
5.2.10 Daily Treatment Localization/IGRT 
Image-guided radiation therapy (IGRT) is radiation therapy using imaging to facilitate accuracy 
and precision throughout its entire process from target and normal tissue delineation, to radiation 
delivery, to adaptation of therapy to anatomic and biological changes over time in individual 
patients. In this section we use the terminology IGRT to focus on image-guidance at the time of 
radiation delivery to ensure its adherence to the planned treatment. 
 
Image Guidance Procedures 
The institution’s procedure to register treatment day imaging dataset with the reference dataset 
should comply with the following recommendations: 
x The allowed image modalities are listed in session 5.2.1 
x Region-of-Interest (ROI) or “clip box” for image registration should be set to encompass 
the high dose PTV and adjacent bony anatomy; 
x If the image registration software allows the user to create an irregular ROI 
(e.g.,ExacTrac), treatment room objects (e.g., patient support system structure) seen on 
in-room X-rays should be excluded from the registration; 
x Both manual (e.g., based on bony anatomy) and automatic (e.g., 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. 
x Institutions are encouraged to include joints in the imaging process in order to increase 
the information used in the image registration process.  
x When orthogonal kV imaging is employed for sites where respiratory motion is expected 
and not controlled via motion management techniques, care must be taken to ensure 

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accurate targeting of the ITV within the treatment 
x Daily pretreatment images for each case should be archived at each treating institution 
and made available for central review by NRG Oncology upon request.  
x IGRT requirements and tolerance 
Location 
No Fiducials 
With Fiducials** 
Tolerance Level 
Extremity 
Orthogonal 2D Orthogonal 2D 
Residual error after shift  
-$FFHSWDEOHPP 
-Minor variance: 3-5 mm 
-Unacceptable: > 5 mm 
Lung* 
Volumetric 3D Orthogonal 2D 
Liver* 
Volumetric 3D Orthogonal 2D 
Abdominal-pelvic* Volumetric 3D Orthogonal 2D 
*Registration using a soft tissue surrogate for the tumor is recommended. 
**Clearly visible anatomical markers are acceptable as fiducials, e.g. inserted radio-opaque 
markers or Lipiodol from prior TACE treatment. 
 
5.2.11 
Case Review  
The Principal Investigators, Meng Xu Welliver, MD, PhD, and Dian Wang, MD, PhD, will 
perform RT Quality Assurance Review after cases enrolled have been received at  IROC 
Philadelphia-RT. The scoring mechanism is: Per Protocol, Variation Acceptable, Deviation 
Unacceptable.   
 
Note: Pre-treatment reviews will be mandatory for Cohort B only -   the first case from each 
institution will require a pre-treatment review. The patient cannot begin treatment until complete 
data from the first case is received, reviewed and approved. Sites need to allow 3 business days 
for the pre-treatment review, and if necessary, 3 additional business days if a revision and 
re-plan is requested by the Reviewer. The goal of the review is to evaluate protocol 
compliance. 
 
5.3 
Imaging Requirement for Primary Tumor Site (28-JAN-2020) 
5.3.1 For STS located at extremities or body wall (cohort A), MRI with and without contrast or 
CT with and without contrast is required at baseline, 4 weeks after neoadjuvant AMG 
232 (KRT-232)/RT treatment prior to surgery and after surgery. 
x If possible, try to use the same imaging facility for the below 4 scans; 
x Slice thickness and matrix per institutional norms.  Recommend maximum slice thickness 
of 4 mm MRI sequences should include: (1) Axial (short axis) T1 and T2 (fat saturation 
encouraged) or STIR imaging; (2) Coronal (long axis) T1 and T2 fat saturated (or STIR) 
imaging; (3) Axial (short axis) post contrast T1 fat saturated and either coronal or sagittal 
T1 fat saturated imaging.  Fat saturation required; (4) if able axial diffusion imaging with 
b50 and b800 with ADC map; use same FOV and slice thickness and above axial scans if 
possible 
x Local extremity coils should be used for distal appendicular imaging (elbows through 
wrist/hand), knees through ankle/foot.  Shoulder coil for upper arm imaging encouraged 
if entire tumor can be encompassed.  Otherwise, torso array coil recommended. 
5.3.2  For STS located at abdomen/pelvis/retroperitoneum (cohort B), MRI with and without 
contrast or CT with and without contrast is required at baseline, 4 weeks after 
neoadjuvant AMG 232 (KRT-232)/RT treatment prior to surgery and after surgery 
x CT imaging should use slice thickness of 5 mm or less. 

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x T1 and T2 axial imaging should include slice thickness of 5mm.  Post gadolinium T1 
axial imaging should include fat saturation.  Remainder of MR imaging should be per 
local institutional norms based on anatomic region of the tumor.   
5.3.3  Tumor volume measurements: Primary tumor size should be included in the radiology 
report. Tumor volume should be estimated utilizing ellipsoid approximation (L * W * D 
* 0.52). This estimate will be made by site radiologists  and reviewed/audited by Dr. Alan 
Rogers.  
5.3.4 MRI or CT images for the primary tumor at baseline and 4 weeks after neoadjuvant 
treatment (prior to surgery) and at first local progression should be submitted for 
central review. Other imaging studies are not required for central review.   
 
 
5.4 
Surgery (9-OCT-2018) 
5.4.1 Planned surgical resection must occur within week 5-8 after completion of radiation 
therapy.  
5.4.2 
Initial Biopsy for Diagnosis and Tissue Submission.   
For extremity or truncal tumors (cohort A), core needle biopsy or an incisional biopsy 
are preferred. Fine needle aspiration (FNA) biopsy is not acceptable to establish the 
diagnosis. A minimum of 6-8 core needle biopsies are recommended. Care must be 
taken to prevent penetration of the needle through the tumor into unaffected soft 
tissues. If the grade and subtype of the tumor cannot be determined from the core 
biopsy, then an incisional biopsy is required. Either biopsy technique should be done 
in such a way as to permit excision of the biopsy site at the time of definitive wide 
resection. Based upon the staging imaging, the tumor should be sampled in a manner 
to allow for adequate pathologic assessment of heterogeneous areas. 
 
For retroperitoneal/pelvic/peritoneal tumors (cohort B), image guided core needle 
biopsy is the preferred technique. Fine needle aspiration biopsy is not acceptable to 
establish the diagnosis. Surgical incisional biopsy should be avoided unless 
absolutely necessary to make the diagnosis to reduce the risk for peritoneal 
seeding/sarcomatosis. In that situation, surgically guided core needle biopsies would 
be preferred. A minimum of 6-8 core needle biopsies are recommended. Based upon 
the staging imaging, the tumor should be sampled in a manner to allow for adequate 
pathologic assessment of heterogeneous areas. 
 
5.4.3 It is strongly recommended that any eligible patient is seen by the surgeon, 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 (if applicable for cohort A) after 
preoperative radiation. For cohort A,  every effort should be made to perform limb 
preservation surgery after preoperative radiation for extremity tumors 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.    
x Upon removal, the tumor specimen should be immediately submitted to the pathologist. It 
should not be bisected or cut into pieces prior to pathologic evaluation. If there will be 

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any delay in transferring the specimen to the pathologist, it should be transported in 
cytogenetics medium. The surgeon should document both the time of tumor removal 
from the patient as well as the time that the specimen was sent to pathology.   
x The resection should be done with the goal of trying to achieve negative pathologic 
margins. Quality assurance for surgical resection will be performed by both a review of 
the operative note and assessment of the specimen by surgical pathology. A negative 
margin (R0) resection will be defined as microscopic absence of tumor on the inked 
margins. 
5.4.4 For protocol purposes, the adequacy of surgical resection will be determined after an 
assessment of the formal operative note by one of the study surgical co-chairs and 
pathologic evaluation of the resected specimen. The definitions include:   
x Amputation: Margin status will still be assessed and categorized if a limb preservation 
approach was not possible after the preoperative radiation.    
x Limb sparing surgery with the following margin status:  
o R0: No residual tumor and microscopically negative margins;  
o R1: Microscopic positive margin(s) but no gross tumor;  
o R2: Macroscopic gross/residual tumor. It is strongly encouraged that any patient 
with an R2 margin status should be assessed for surgical re-excision, to try to 
achieve an R0 or R1 margin.   
5.4.5    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. Boost 
radiotherapy will not be allowed in this protocol. Therefore all patients who underwent an 
R2 resection should be encouraged to undergo re-resection to obtain R0/R1 margins.  
  
x For cohort A, any incisional biopsy site should be excised en bloc with the definitive 
surgical specimen. Core needle biopsy tracts should also be excised unless doing so 
would result in excessive morbidity.  
x 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 perform 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. 
x 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 tissues immediately 
adjacent to the structures are 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.   
x 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 adjacent 
lymph nodes.  
x 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 

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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.   
x Secondary to the preoperative radiation, closed suction drainage should be strongly 
considered for all postoperative dead spaces. The drains should exit the skin close to the 
edge of the surgical incision and ideally in line with the incision.  
x As all patients will have received 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.       
x It is strongly encouraged that the surgeon clearly state in the operative note what type of 
surgical resection was intended (R0, R1, or R2) and from where any frozen sections of 
the margins were taken, if applicable. The final margin status (R status) should be based 
on the permanent pathology assessment (not frozen section).  
x The surgeon may state in the operative note 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.   
x In general, the following principles should be followed in postoperative management of 
these patients: Maintain staples or skin sutures per surgeon preference, recognizing that 
all patients will have received preoperative radiation.   Leave drains in place until the 
drainage meets the surgeon’s criteria for removal. Begin rehabilitation per surgeon’s 
discretion. 
x If the postoperative pathologic evaluation reveals positive soft tissue margins other than 
bone (periosteum), nerve or major 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 boost will not be used in this protocol.  
5.4.6    Surgical Adverse Events    
x Wound Complications. Major wound complications (eg, secondary operations, re-
admissions, anastomotic dehiscence, 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.   
 
5.4.7 Surgical Quality Assurance Reviews. The Surgical Oncology Co-Chairs from NRG 
Oncology will perform a Quality Assurance Review on a rolling basis once data is 
received at the Statistics and Data Management Center (SDMC). 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 NRG SDMC, whichever occurs 
first.   
x 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 

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6. TREATMENT MODIFICATIONS/MANAGEMENT (29-MAY-2019) 
 
DLT includes all grade 4-5 toxicities attributable to AMG 232 (KRT-232) or combined AMG 
232 (KRT-232) with radiotherapy up to 4 weeks after the completion of AMG 232 (KRT-
232)+RT treatment. Any grade 3 AE at least possibly attributable to AMG 232 (KRT-232) or 
combined AMG 232 (KRT-232) with radiotherapy will also be considered DLT if any of the two 
following situations occur: a GHOD\RI!ZHHNVGXHWRWKHJUDGHWR[LFLW\RUWZRGRVH
reductions due to the grade 3 toxicity.  
 
For all toxicity management: 
x All toxicities are per NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. 
x Patients requiring a delay of >2 weeks must discontinue AMG 232 (KRT-232). 
x Patients requiring > two dose frequency reductions must discontinue AMG 232 (KRT-
232). 
x Toxicities include nausea, vomiting, diarrhea, febrile neutropenia, thrombocytopenia or 
anemia. 
 
Table 6A. AMG 232 (KRT-232) “Dose” Reduction by Changing Frequency 
AMG 232 (KRT-232) will be dose reduced per the toxicity tables detailed below 
  
Dose Level 
Dose (Weekly Total Dose 
mg) 
  
First Dose Frequency 
Reduction by 1 dose/week 
(Weekly Total Dose mg) 
  
  
Second Dose Frequency 
Reduction by 2 doses/ 
week (Weekly Total Dose 
mg) 
  
  
-1 
120 mg (240 mg) 
(Days 2 and 4 only) 
120 mg (120mg) 
(Day 2 only) 
Discontinue AMG 232 
(KRT-232) 
(Off study) 
1 
120 mg (360 mg) 
(Days 2, 3, and 4 only) 
120 mg (240 mg) 
(Days 2 and 4 only) 
120 mg (120mg) 
(Day 2 only) 
2 
120 mg (480 mg) 
(Days 2, 3, 4, and 5 only) 
120 mg (360 mg) 
(Days 2, 3, and 4 only) 
120 mg (240 mg) 
Days 2 and 4 only 
3 
120 mg (600 mg) 
(Days 1, 2, 3, 4 and 5 only) 
120 mg (480 mg) 
(Days 2, 3, 4, and 5 only) 
120 mg (360 mg) 
(Days 2, 3, and 4 only) 
 
 
Nausea 
Management/Next Dose for AMG 
232 (KRT-232) 
Management/Next Dose for 
Radiotherapy 
*UDGH 
No change in dose 
Continue treatment 
Grade 2 
No change in dose with appropriate 
antiemetics and best supportive care. 
Continue treatment   
Grade 3 
Hold* until  Grade 2.  Resume at next 
Hold* until  Grade 2.   

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Nausea 
Management/Next Dose for AMG 
232 (KRT-232) 
Management/Next Dose for 
Radiotherapy 
lower dose level according to table 6A 
above with appropriate antiemetics and 
best supportive care.  
Grade 4 
Off protocol therapy 
 
Recommended management: * antiemetics. 
 
 
 
Vomiting 
Management/Next Dose for 
AMG 232 (KRT-232) 
Management/Next Dose for 
Radiotherapy 
*UDGH 
No change in dose 
Continue treatment 
Grade 2 
No change in dose with appropriate 
antiemetics and best supportive 
care  
Continue treatment 
Grade 3 
Hold until  Grade 2.  Resume at 
next lower dose level according to 
table 6A above with appropriate 
antiemetics and best supportive 
care.  
Hold until  Grade 2.   
Grade 4 
Off protocol therapy 
Hold until  Grade 2.   
Recommended management:  antiemetics. 
 
 
Diarrhea 
Management/Next Dose for 
AMG 232 (KRT-232) 
Management/Next Dose for 
Radiotherapy 
*UDGH 
No change in dose 
Continue treatment 
Grade 2 
No change in dose with appropriate 
medical management below and 
best supportive care  
Continue treatment 
Grade 3 
Hold until < Grade 2.  Resume at 
next lower dose level according to 
table 6A above with appropriate 
medical management below and 
best supportive care. 
Hold until  Grade 2.   
Grade 4 
Off protocol therapy 
Hold until  Grade 2.   
Recommended management:  Loperamide antidiarrheal therapy 
Dosage schedule:   
at first onset, followed by  
 with each loose motion until diarrhea-
free for 12 hours (maximum dosage:  
 
 
Adjunct anti-diarrheal therapy is permitted and should be recorded when used. 

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Febrile Neutropenia 
Management/Next Dose for 
AMG 232 (KRT-232) 
Management/Next Dose for 
Radiotherapy 
*UDGH 
No change in dose 
Continue treatment 
Grade 2 
No change in dose 
Continue treatment 
Grade 3 
Hold until < Grade 3.  Resume at 
next lower dose level according to 
table 6A above.  
Hold until < Grade 3.   
Grade 4 
Off protocol therapy 
Hold until  < Grade 3 
 
 
Thrombocytopenia 
Management/Next Dose for 
AMG 232 (KRT-232) 
Management/Next Dose for 
Radiotherapy 
*UDGH 
No change in dose 
Continue treatment 
Grade 2 
+ROGXQWLO*UDGH5HVXPHDW
same dose level. 
Continue treatment 
Grade 3 
Hold until < Grade 3.  Resume at 
next lower dose level according to 
table 6A above with best 
supportive care. 
Hold until <Grade 3.   
Grade 4 
Off protocol therapy 
Hold until < Grade 3 
 
 
Anemia 
Management/Next Dose for AMG 232 (KRT-232) 
*UDGH 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold until  Grade 2.  Resume at next lower dose level according to 
table 6A above with best supportive care. 
Grade 4 
Off protocol therapy 
 
 
Other toxicities 
related to AMG 232 
(KRT-232) 
Management/Next Dose for AMG 232 (KRT-232) 
*UDGH 
No change in dose 
Grade 2 
No change in dose 
Grade 3 
Hold until  Grade 2.  Resume at next lower dose level according to 
table 6A above with best supportive care. 
Grade 4 
Off protocol therapy 
 

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6.1 Hepatotoxicity Stopping and Re-challenge Rules 
 
Subjects with abnormal hepatic laboratory values (e.g., ALP, AST, ALT, total bilirubin, or INR) 
or signs/symptoms of hepatitis may meet the criteria for withholding of investigational product.  
Withholding is either permanent or conditional depending upon the clinical circumstances 
discussed below (as specified in the Guidance for Industry Drug-Induced Liver Injury:  
Premarketing Clinical Evaluation, July 2009). 
 
6.1.1 Criteria for Permanent Withholding of AMG 232 (KRT-232) Due to Potential 
Hepatotoxicity 
 
AMG 232 (KRT-232) should be permanently withheld and the subject should be 
followed according to the recommendations in if ALL of the criteria below are met: 
 
x Increased AST or ALT from the relevant baseline value as specified below:  
 
o Baseline AST/ALT level is < 1 × ULN and AST/ALT is elevated > 3 × ULN 
AND 
o Total bilirubin level is > 2 × ULN or INR is > 1.5 
AND 
o No other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT 
and/or elevated total bilirubin values include, but are not limited to:  
 
¾ Hepatobiliary tract disease 
¾ Viral hepatitis (e.g., hepatitis A/B/C/D/E, Epstein-Barr virus (EBV), 
cytomegalovirus (CMV), herpes simplex virus (HSV), varicella, 
toxoplasmosis, and parvovirus) 
¾ Right sided heart failure, hypotension or any cause of hypoxia to the 
liver causing ischemia 
¾ Exposure to hepatotoxic agents/drugs including herbal and dietary 
supplements, plants, and mushrooms, 
¾ Heritable disorders causing impaired glucuronidation (e.g., Gilbert’s 
syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (e.g., indinavir and atazanavir) 
¾ Alpha-one antitrypsin deficiency 
¾ Alcoholic hepatitis 
¾ Autoimmune hepatitis 
¾ Wilson’s disease and hemochromatosis 
¾ Nonalcoholic steatohepatitis (NASH) or other “fatty liver disease” 
¾ Non-hepatic causes (e.g., rhabdomyolysis and hemolysis). 
 
 
 

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6.1.2 Criteria for Conditional Withholding of AMG 232 (KRT-232) due to Potential 
Hepatotoxicity 
 
For subjects who do not meet the criteria for permanent withholding of AMG 232 (KRT-
232) outlined above and with no underlying liver disease and eligibility criteria requiring 
normal transaminases and total bilirubin level at baseline or subjects with underlying 
liver disease and baseline abnormal transaminases, the following rules are recommended 
for conditional withholding of AMG 232 (KRT-232) and other protocol-required 
therapies: 
 
x Elevation of either AST/ALT according to the following schedule: 
 
o AST/ALT baseline value is any AND AST/ALT is elevated to any of the 
following values: 
¾ >8 × ULN at any time 
¾ !î8/1EXWî8/1IRU 2 weeks 
¾ >5 × ULN but < 8 × ULN and unable to adhere to enhanced 
monitoring schedule > 3 × ULN with clinical signs or symptoms that 
are consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice, rash, or 
eosinophilia (> 5%). 
OR 
o Total bilirubin is > 3 × ULN at any time 
OR 
o Alkaline phosphatase is > 8 × ULN at any time 
 
AMG 232 (KRT-232) should be withheld pending investigation into alternative causes of 
drug-induced liver injury.  If AMG 232 (KRT-232) is withheld, the subject should be 
followed according to recommendations for possible drug-induced liver injury in 
Appendix V.  Rechallenge may be considered if an alternative cause for impaired liver 
tests (i.e., ALT, AST, alkaline phosphatase) and/or elevated total bilirubin level is 
discovered and the laboratory abnormalities resolve to normal or baseline. 
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1  Protocol Agents 
 
 
Investigational Agent 
The investigational agent administered in NRG-DT001, AMG 232 (KRT-232), is 
being made available under an IND sponsored by CTEP.   
7.2 Adverse Events and Serious Adverse Events (9-OCT-2018) 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
 
 

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7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
For multi-modality trials, adverse event reporting encompasses all aspects of protocol 
treatment including radiation therapy, surgery, device, and drug. 
 
For AMG 232 (KRT-232) determination of whether an adverse event meets expedited 
reporting criteria, see the reporting table in section 7.4 of the protocol. 
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the 
pregnancy of a study participant must be reported via CTEP-AERS in an expedited 
manner. 
 
7.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
 KRT-232 (AMG 232, NSC 789723) (22-FEB-2021) 
 
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 247 patients. Below is the CAEPR for 
KRT-232 (AMG 232). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is required. 
 
 
 
 
 
 
 
 
 
 

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MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; Back pain; Bone pain; Joint 
range of motion decreased; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome; Tumor pain 
NERVOUS SYSTEM DISORDERS - Anosmia; Dizziness; Headache; Nervous system disorders - Other 
(hemorragic stroke); Somnolence; Syncope 
RENAL AND URINARY DISORDERS - Acute kidney injury; Dysuria; Proteinuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; Dyspnea; Epistaxis; Hypoxia; 
Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Hyperhidrosis; Pruritus 
VASCULAR DISORDERS - Flushing; Hypertension 
 
Note: KRT-232 (AMG 232) 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. 
 
7.4 
Expedited Reporting of Adverse Events (28-JAN-2020) 
All adverse events (AEs) are submitted for expedited reporting protocol-specific rules 
evaluation using the Medidata Rave data management system. All AEs will be evaluated 
by the Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) to determine whether expedited reporting is recommended based on a set of 
programmed expedited reporting rules. AEs identified as meeting the programmed 
expedited reporting requirements can then be submitted in CTEP-AERS. A deep link in 
Rave will take the user directly to CTEP-AERS where the expedited report may be 
completed and submitted via CTEP-AERS. 
 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the link in RAVE. CTEP-AERS is also accessed via the CTEP web 
site, but all expedited reports must be initiated in RAVE 
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613.  
 
See Section 13.3 for additional details.  
 
Submitting a report via CTEP-AERS satisfies NRG requirements for expedited adverse 
event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to CTEP by telephone at 301-897-8497 and to the NRG Oncology by phone at 1-
215-574-3191. An electronic report must be submitted immediately upon re-
establishment of the Internet connection. 
 
7.4.1 Expedited Reporting Methods 
x Per CTEP NCI Guidelines for Adverse Events Reporting, a CTEP-AERS 24-hour 
notification must be submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS 24-hour notification must be followed by a complete report within 5 
days.  
 

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Not resulting in 
Hospitalization  
KUV 
Not required 
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. 
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 AE, followed by a complete expedited report within 5 
calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
1Serious adverse events 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 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was 
last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
Additional Protocol-Specific Instructions or Exceptions to Expedited Reporting 
Requirements: 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases 
of concurrent AST or ALT and total bilirubin and/or INR elevation according to the 
criteria specified in Section 6.1 require a 24 hour notification/5 day report. See Appendix 
V for additional requirements. 
 
7.4.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
7.4.4 Secondary Malignancy  
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur during or subsequent to treatment 
with an agent under an NCI IND/IDE be reported via CTEP-AERS. In addition, 
secondary malignancies following radiation therapy must be reported via CTEP-AERS. 
Three options are available to describe the event: 

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x 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 
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 
AE reporting unless otherwise specified. 
 
8. REGISTRATION AND STUDY ENTRY PROCEDURES 
 
8.1   
Food and Drug Administration (FDA) Regulations and National Cancer Institute 
(NCI) Policy (22-FEB-2021) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and 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) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.   
RCR utilizes five person registration types. 
x IVR — MD, DO, or international equivalent; 
x NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
x AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications, such as the Roster Update Management System [RUMS], OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
x Associate (A) — other clinical site staff involved in the conduct of NCI-
sponsored trials; and 
x Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) 
with limited access to NCI-supported systems. 
 
 
 
 
 
 
 
 
 
 

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IRB review will continue to be accepted for studies that are not reviewed by the CIRB, or 
if the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations. 
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
x Local IRB documentation; 
x IRB-signed CTSU IRB Certification Form; and/or 
x Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
x Holds an active CTEP status; 
x Rostered at the site on the IRB/REB approval and on at least one participating 
roster; 
x If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
x Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
x Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements for Protocol NRG-DT001 Site Registration 
Additional requirements to obtain an approved site registration status include: 
x An active Federal Wide Assurance (FWA) number; 
x An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
x Compliance with all protocol-specific requirements (PSRs) 
x IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
to begin the modality credentialing process 

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x This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider. To manage provider associations or to add 
or remove associated providers, access the Provider Association page from the 
Regulatory section on the CTSU members’ website at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at 
least one Imaging and Radiation Oncology Core (IROC) credentialed provider to 
participate on trials with an RTI component. Enrolling sites are responsible for 
ensuring that the appropriate agreements and IRB approvals are in place with their 
RTI provider. An individual with a primary role on any roster is required to update 
provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, view the Person Roster 
Browser under the RUMS section on the CTSU website. 
To complete protocol-specific credentialing, the RTI provider or enrolling site should 
follow instructions in protocol section 8.3 to submit documentation or other materials 
to the designated IROC Quality Assurance (QA) center. Upon the IROC QA center 
approving the RTI provider for the study modality, IROC will notify your institution 
when all credentialing requirements have been met and the institution is credentialed 
to enter patients onto this study. The credentialing notification document (email) must 
be uploaded by the site to the CTSU Regulatory Submission Portal for RSS to be 
updated. 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to 
complete enrollments. The enrolling site will select their credentialed provider 
treating the subject in the OPEN credentialing screen and may need to answer 
additional questions related to treatment in the eligibility checklist.   
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory selection and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
 
Checking Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ website.  

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x Click on Regulatory at the top of the screen; 
x Click on Site Registration; and 
x Enter the site’s 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with NCI or their affiliated networks. 
 
8.3 RT-Specific Pre-Registration Requirements (22-FEB-2021) 
For detailed information on the specific technology requirement required for this study, 
please refer to the table below and utilize the web link provided for detailed instructions. 
The check marks under the treatment modality columns indicate whether that specific 
credentialing requirement is required for this study. Specific credentialing components 
may require you to work with various QA centers; however, the IROC Houston QA center 
will notify your institution and NRG Headquarters when all credentialing requirements 
have been met and the institution is RT credentialed to enter patients onto this study.   
RT 
Credentialing 
Requirements 
 
Web 
Link 
for 
Procedures 
and 
Instructions:  
http://irochouston.mdanderson.org  
Treatment 
Modality 
Key Information 
 
Photons 
 
Facility 
Questionnaire 
9  
The IROC Houston electronic facility questionnaire (FQ) should 
be completed or updated with the most recent information about 
your institution. To access this FQ go to 
http://irochouston.mdanderson.org 
 
Credentialing 
Status Inquiry 
Form 
9  
Please complete a “Credentialing Status Inquiry Form” found 
under Credentialing on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org). 
Phantom 
Irradiation 
9  
An IROC Houston anthropomorphic phantom must be 
successfully completed (if the institution has not previously met 
this credentialing requirement) if the institution plans to deliver 
IMRT.  Flattening-filter-free (FFF) photon beam delivery, 
Tomotherapy, MRIdian, and Cyberknife treatment delivery 
modalities must be credentialed individually. Instructions for 
requesting and irradiating the phantom are available on the 
IROC Houston website under credentialing 

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8.4.1 Oncology Patient Enrollment Network (OPEN) 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management 
system, Medidata Rave. 
 
Requirements for OPEN access:   
x A valid CTEP-IAM account; 
x To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization (PO) roster with the 
role of Registrar. Registrars must hold a minimum of an Associate Plus (AP) 
registration type; 
x Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
Prior to accessing OPEN, site staff should verify the following: 
x Patient has met all eligibility criteria within the protocol stated timeframes; and  
x All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration: websupport@acr.org or call the NRG 
Registration Desk at (215)-574-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the registering 
individual’s e-mail address and/or return fax number. This information is required to assure 
that mechanisms usually triggered by the OPEN web registration system (e.g. drug 
shipment and confirmation of registration) will occur.  
 
8.4.2    Summary of Registration Procedures  
            This is a 2-step registration study.  
• 
 All eligibility criteria (except central p53 review) must be met prior to Step 1 
registration.  

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Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
 
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 IB Coordinator:  IBCoordinator@mail.nih.gov  
x PMB email:  PMBAfterHours@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) 
 
10. PATHOLOGY/BIOSPECIMEN   
10.1 Mandatory Submission of Specimens for NGS sequencing (See Section 10.5 for 
submission logistics) (9-OCT-2018) 
 
TP53 DNA sequencing will be an integral biomarker and only patients with wild-type (WT) 
p53 status will be evaluable for dose-escalation decisions, determination of the MTD/RP2D, 
and studied for other exploratory biomarkers.  
  
10.2 Mandatory Submission of Specimens for Retrospective Central Pathology Review (See 
Section 10.5 for submission logistics) 
10.2.1 Aims 
x To determine whether the addition of AMG 232 (KRT-232) to neoadjuvant 
radiotherapy improves pathologic response in STS.  
x To determine if pathologic response is predictive of outcome in STS. 
x To assess whether tumor response based on diagnostic imaging accurately reflects 
the pathologic response to neoadjuvant therapy in STS. 
o To confirm that only patients with STS with g2-3 are enrolled on this 
clinical trial.   
o All patients enrolled on this clinical trial will submit tumor tissue for 

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central pathology review. The diagnosis of STS and the histologic subtype 
will be confirmed during central pathology review of the percent 
pathologic necrosis rate. 
o To avoid delays, no rapid central review of the sarcoma histologic subtype 
will be required prior to enrollment or treatment initiation.   
 
10.2.2 Guidelines 
x 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 diagnosed based on the 2013 WHO sarcoma 
classification and be graded according to the guidelines of the FNCLCC 
grading systems (Appendix VIII). FNCLCC Grade 1, 2 and 3 will be 
considered low grade, intermediate grade and high grade, respectively.  Please 
see the 2013 WHO sarcoma classification and the FNCLCC grading in 
Appendix VII.       
x Final surgical resection specimen: The definitive resection specimen will be 
evaluated for pathologic response. This assessment will include a formal 
evaluation of percent necrosis according to the guidelines established for 
osteosarcoma. 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.   
x Tumor Progression/Recurrence Specimens (Optional): 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. 
x Second Malignant Neoplasm Specimens (Optional): 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.     
 
10.3 Mandatory Submission of Specimens for AMG 232 (KRT-232) Plasma 
Pharmacokinetic Profile (See Section 10.5 for submission logistics) 
10.3.1 Background: This assay will be utilized to determine AMG 232 (KRT-232) plasma 
concentrations and ultimately the drug exposure.  There was an exposure-response 
correlation observed between changes in serum MIC-1 levels and AMG 232 (KRT-232) 
plasma exposure (both maximal (Cmax) and total exposure (AUC) (Amgen Inc., 2015). 
10.3.2 Method: AMG 232 (KRT-232) blood levels will be measured by LC-MS/MS. The 
bioanalytical method for determining AMG 232 (KRT-232) in human plasma will be 
developed and validated utilizing liquid chromatography coupled with tandem mass 
spectrometry (LC-MS/MS) techniques.  The analytical method will be validated as 
recommended by the FDA Guidance for Industry: Bioanalytical Method Validation (FDA 
2013). 
10.3.3 Analysis: For AMG 232 (KRT-232), single dose PK parameters and steady-state trough 

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uncharged, air dried slides cut from 
one block.1,2,3,4 
x With prior permission from the chairs, 
submission of specimen in blocks is 
permitted, but please be aware results 
may be delayed.  
 
1       Include a copy of the corresponding anatomic pathology report with the shipment of tissue. 
2 
All slides must be cut sequentially from one block and numbered, starting with the H&E.  
3 
Include a copy of the Specimen Transmittal form for TP53 sequencing. 
4 
Prefer 20 slides, but minimal 10 slides. If testing of the sample fails due to insufficient 
amount of tissue submitted, additional tissue will be requested.   
 
Archival Formalin-Fixed Paraffin-Embedded (FFPE) Tumor Specimen  
 
The following criteria must be met for archival tissue: 
 
x Tissue must have been collected days prior to registration  
x Formalin-fixed paraffin-embedded tumor tissue slides must be submitted.  The 
optimal block used for sectioning is at least 70% tumor.  Specimen size requirement 
is as follows: 
o Surface area:  25 mm2 is optimal.  Minimum is 5 mm2. 
o Volume:  1 mm3 optimal.  Minimum volume is 0.2 mm3, however the success of 
DNA extraction decreases at suboptimal tissue volume. 
 
The following are mandatory and must be cut and numbered sequentially from one block: 
x One (1) H&E slide  
x Ten (10) to twenty (20) 10-μm unstained air-dried uncharged slides. Twenty slides 
are preferable, but a minimal of ten slides are required. If testing of the sample fails 
due to insufficient amount of tissue submitted, additional tissue will be requested.   
x With prior permission from the chairs, submission of specimen in blocks is permitted, 
but please be aware results may be delayed. 
x If a block is submitted, it will be forwarded to the NRGBB-SF for the mandatory 
central review after testing is complete. 
 
Specimen Labeling  
 
Tissue Specimen Labels 
 
Include the following on all tissue specimens or containers:  
x Protocol Number 
x Patient initials 
x Patient Study ID 
x Time point 
x Tissue type (P for primary or M for metastatic) 
x Collection date  

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x Surgical pathology ID (SPID) number from the corresponding pathology report  
x Block number from the corresponding pathology report  
 
Shipping Specimens from Clinical Site to the EET Biobank  
 
The Specimen Transmittal Form (see Appendix) and the corresponding anatomical 
clinical pathology report are required with specimen submission. The pathology report 
must state the disease diagnosis made by the reviewing pathologist. 
 
Specimen Shipping Instructions 
 
Slides may be shipped on Monday through Friday, but should not be shipped for 
Saturday delivery.   
 
Ship specimens via overnight courier to the address below. FedEx Priority Overnight is 
strongly recommended to prevent delays in package receipt. Include a cold pack during 
warm weather. 
 
Shipping Address 
 
Ship to the address below. Do not ship specimens the day before a holiday. 
 
EET Biobank 
The Research Institute at Nationwide Children's Hospital 
700 Children's Drive, WA1340 
Columbus, Ohio 43205 
PH: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 
FedEx Priority Overnight service is very strongly preferred.   
 
NOTE:  The EET Biobank FedEx Account will not be provided to submitting 
institutions. 
 
Contact Information for Assistance 
 
For all queries regarding shipping specimens to the EET Biobank, please use the contact 
information below: 
 
EET Biobank  
Toll-free Phone: (800) 347-2486 
E-mail:  BPCBank@nationwidechildrens.org 
 
 

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Mandatory Specimen Submission for Retrospective Central  Pathology Review 
From 10.2 above 
 
Forms: ST forms must be submitted with all submissions. Pathology reports must be submitted with all pathology 
submissions and must include study and case#, date of procedure and pathology accession number. Remaining 
PHI information must be fully redacted. 
Kits: Punch kits can be provided to sites when requested to NRGBB@ucsf.edu 
Shipping: Ship to NRGBB-SF. Sites are responsible for shipping costs for FFPE submissions 
 
Ship specimens by overnight courier to:  
NRG Oncology Biospecimen Bank – San Francisco 
UCSF Department of Radiation Oncology –Box 1800 
2340 Sutter Street- Room S341 
San Francisco, CA 94115 
415-476-7864/Fax 415-476-5271 
Email: NRGBB@ucsf.edu 
 
The NRG Biospecimen Bank will forward all material to Dr. Wakely for central pathology review at the end of the 
study. 
 
For questions about central pathology review, contact:  
Paul E. Wakely, Jr. MD; 614-292-2064; paul.wakely@osumc.edu 
 
Mandatory Specimen 
Types  
Collection Time Points 
 
Collection 
Information and 
Requirements/ 
Instructions for Site 
Shipping  
 
Representative formalin-
fixed paraffin blocks and 2 
corresponding H&E slides 
from each block. If blocks 
are unavailable, submit 2 
H&E section of all available 
blocks and one-two 3mm 
punches as an acceptable 
alternative to FFPE blocks.  
 
Pre-Treatment: Initial diagnostic 
specimen at time of Step 1 registration 
 
NOTE: For cases where there is only one 
tumor FFPE block and there is no tissue 
remaining in the block after sectioning for 
p53 analysis, please note this on the ST 
form. The H&E slides should still be 
submitted for central review. The H&E 
slide with final pathology report should be 
submitted for central review. 
Submit within 4 weeks 
of surgery date along 
with the final surgical 
resection specimen 
 
*If site is submitting 
punches instead of 
original block the 
punches should be from 
the same block and the 
H&E being submitted. 
Sites should embed the 
punches and create a 
new H&E to be 
submitted. 
Ship by overnight 
carrier to NRG BB – 
San Francisco 
(use cold packs 
during warm 
weather) 
Representative formalin-
fixed paraffin blocks and 2 
corresponding H&E slides 
from each block. If blocks 
are unavailable, submit 2 
H&E section of all available 
blocks and one-two 3mm 
punches as an acceptable 
alternative to FFPE blocks.   
Definitive Surgical Specimen - 
Mandatory 
Submit within 4 weeks 
of surgery date. If the 
patient undergoes more 
than one operation, 
specimens should be 
submitted from all 
procedures. (Mandatory) 
 
*If site is submitting 
punches instead of 
original block the 
punches should be from 
the same block and the 
H&E being submitted. 
Sites should embed the 
punches and create a 
Ship by overnight 
carrier to NRG BB – 
San Francisco 
(use cold packs 
during warm 
weather) 

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new H&E to be 
submitted. 
Representative formalin-
fixed paraffin blocks and 2 
corresponding H&E slides 
from each block. If blocks 
are unavailable, submit 2 
H&E section of all available 
blocks and one-two 3mm 
punches as an acceptable 
alternative to FFPE blocks. 
At the time of tumor 
progression/recurrence 
(optional, strongly encouraged) 
Only at the time of 
tumor progression or 
recurrence and when 
location for recurrence 
safe for biopsy.  
(optional) 
 
*If site is submitting 
punches instead of 
original block the 
punches should be from 
the same block and the 
H&E being submitted. 
Sites should embed the 
punches and create a 
new H&E to be 
submitted. 
Ship by overnight 
carrier to NRG BB – 
San Francisco 
(use cold packs 
during warm 
weather) 
Representative formalin-
fixed paraffin blocks and 2 
corresponding H&E slides 
from each block.  If blocks 
are unavailable, submit 2 
H&E section of all available 
blocks and one-two 3mm 
punches as an acceptable 
alternative to FFPE blocks.   
At the time of development of a solid 
second neoplasm (optional, strongly 
encouraged) 
Only when a secondary 
tumor was found near 
the treatment 
field.(optional) 
 
*If site is submitting 
punches instead of 
original block the 
punches should be from 
the same block and the 
H&E being submitted. 
Sites should embed the 
punches and create a 
new H&E to be 
submitted 
 
Ship by overnight 
carrier to NRG BB – 
San Francisco 
(use cold packs 
during warm 
weather) 
If sites are unable to embed the FFPE punches they can send the punches to the biospecimen 
bank in the punch tools. The NRGBB-SF will embed the punches. 
 
 
Mandatory Specimen Submission for Pharmacokinetics and Pharmacodynamics from 
Serum and Plasma Samples   
From 10.3 and 10.4 above 
 
Kits: The NRGBB-SF will provide kits that contain the following for these studies. All kit requests 
must be emailed to the lab at NRGBB@ucsf.edu. 
x 
100 cryovials and shipping materials for ONE dry ice batch shipment per case. 
x 
Note: Sites are responsible for providing all blood draw tubes 
x 
One Fed Ex priority overnight shipping label per case for one dry ice batch shipment per case 
from sites to the Baltimore lab. Sites unable to batch ship will be responsible for any additional 
shipping container and shipping costs. 
For any questions regarding the PK collections please contact: email onc-
pharmacology@lists.johnshopkins.edu here. 
 
Shipping:  
Analytical Pharmacology Core Laboratory* 
Attn: NRG-DT001 AMG 232 (KRT-232) Study Samples 

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1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000** 
Phone: 410-502-7192 or 410-955-1129 
Email: onc-pharmacology@lists.johnshopkins.edu  
 
**This zip code is for FedEx shipments.  If UPS will be utilized, please ship to the following zip code: 21287 
 
NOTE: Please notify the lab by email at onc-pharmacology@lists.johnshopkins.edu at least 24 hours prior 
to shipment. 
Mandatory Specimen Types  Collection Time Points 
 
Collection Information 
and Requirements/ 
Instructions for Site 
Shipping to 
Analytical 
Pharmacology Core 
Lab 
 
 
 
 
Please refer to Appendix II for Plasma Pharmacokinetics 
 
Please refer to Appendix III for Serum Macrophage Inhibitory Cytokine-1 (MIC-1) 
 
Please refer to Appendix IV Sample Combined PK/PD Blood Draw Schedules 
 
*All samples (but not 
all aliquots) should be 
batch shipped via 
overnight express 
courier in insulated 
containers with 
enough dry ice to 
maintain the samples 
in a frozen state.  
 
*Overnight shipments 
should occur on 
Monday through 
Wednesday (Tuesday 
is the preferred day) 
except when the 
following day is a 
holiday. 
 
 
 
11. SPECIAL STUDIES (NON-TISSUE) 
 
Not applicable  
 
12. MODALITY REVIEWS 
12.1 Radiation Therapy Quality Assurance Reviews 
The Radiation Oncology Co-Chairs, Meng Xu Welliver, MD, PhD, and Dian Wang, 
MD, PhD, will perform ongoing remote RT Quality Assurance Review after cases 
enrolled have been received at IROC-Philadelphia-RT. The scoring mechanism is: Per 
Protocol, Variation Acceptable, Deviation Unacceptable.   
 
Note: Pre-treatment reviews will be mandatory for Cohort B only - the first case 
from each institution will require a pre-treatment review. The patient cannot begin 
treatment until complete data from the first case is received, reviewed and approved.  

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Sites need to allow 3 business days for the pre-treatment review, and if 
necessary, 3 additional business days if a revision and re-plan is requested by the 
Reviewer. The goal of the review is to evaluate protocol compliance. 
 
12.2 Medical Oncology Modality Quality Assurance Reviews 
The Medical Oncology Co-Chairs, Gary Schwartz, MD, and Brian Van Tine, MD, will 
perform a AMG 232 (KRT-232) targeted therapy Assurance Review of all patients who 
receive or are to receive AMG 232 (KRT-232) targeted therapy in this trial.  The goal 
of the review is to evaluate protocol compliance. The review process is contingent on 
timely submission of chemotherapy treatment data as specified in Section 12.1. The 
scoring mechanism is: 1) Per Protocol, 2) Acceptable Variation, 3) Unacceptable 
Deviation, and 4) Not Evaluable.   
 
12.3 Surgical Quality Assurance Reviews 
The Surgical Oncology Co-Chairs, Dr. John Kane and Dr. Raphael Pollock, will 
perform a Quality Assurance Review after NRG Headquarters has received complete 
data for the first 20 cases enrolled.  
 
12.4 Standard of Care Imaging Quality Assurance Reviews 
The Diagnostic Imaging Corelab staff of Imaging Analysts and Imaging 
Technologists will perform ongoing remote Image Quality Assurance reviews after 
cases enrolled have been received at IROC-Philadelphia-DI. IROC DI QA center staff 
will monitor for timeliness and completeness of imaging submissions form enrolling 
centers. QA of imaging submission would include assaying adherence to the 
recommended protocol requirements, and the overall image quality. Regular feedback 
to enrolling centers via RAVE will provide for rapid communication of 
incomplete/non-compliant submissions. 
 
13. DATA AND RECORDS 
13.1 Data Management/Collection (22-FEB-2021) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments.  
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, 
Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
x 
Rave role requirements: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as a Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
o Rave Read Only role must have at a minimum an Associates (A) 
registration type. 

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Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password, and click on the accept link in the upper right-corner of the iMedidata 
page. Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the link in the upper right pane 
of the iMedidata screen. If an eLearning is required and has not yet been taken, the link to 
the eLearning will appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been recorded, access to the 
study in Rave will be granted, and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com. 
 
13.2 Summary of Data Submission (29-MAY-2019) 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during the trial using Medidata Rave®. Additionally, certain 
adverse events must be reported in an expedited manner for more timely monitoring of 
patient safety and care. See Section 7.4 for information about expedited and routine 
reporting.   
 
Summary of Data Submission: Refer to the protocol-specific page on the NRG website. 
 
See Section 8.3.1 for TRIAD account access and installation instructions. 
 
           RT Digital Data Submission Requirements  
           Summary of Dosimetry Digital Data Submission  
 
 
DICOM 
DIGITAL 
DATA  
DICOM CT IMAGE SET 
TRIAD submission time point = 
          RT DIGITAL PLAN  
 
Due within 1 week of the start of 
DICOM RT STRUCTURE 
 

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DICOM RT DOSE  
RT 
 
 
Cohort B only – mandatory pre-
treatment review required for 
the first case from each 
institution; see section 5.2 and 
5.2.11 for details on time 
allotment for review. TRIAD 
submission time point = RT 
DIGITAL PLAN 
 
 
 
 
 
  
DICOM RT PLAN 
*DICOM PET (Required when 
Applicable) 
*DICOM PET/CT (Required when 
Applicable) 
*DICOM MRI (Required when 
Applicable) 
*All image data sets used for structure delineation 
must be submitted with RT data. (section 5.2.3) 
     
All required structures MUST be labeled per the tables 
in Section 5.2  
 
Upon submission of the Digital Data via TRIAD, 
complete an online Digital Data Submission 
Information Form (DDSI) 
https://www.irocqa.org/Resources/TRIAD-for-RT-QA  
 
NOTE: ALL SIMULATION AND PORTAL FILMS AND OR DIGITAL FILM IMAGES 
WILL BE KEPT BY THE INSTITUTION AND ONLY SUBMITTED IF REQUESTED. 
13.3 Data Quality Portal (28-JAN-2020) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   

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13.4 Rave-CTEP-AERS integration (22-FEB-2021) 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System 
(CTEP-AERS) Integration enables evaluation of post-baseline Adverse Events 
(AE) entered in Rave to determine whether they require expedited reporting, and 
facilitates entry in CTEP-AERS for those AEs requiring expedited reporting.    
All AEs that occur after baseline are collected in Medidata Rave using the 
Adverse Event form, which is available for entry at each treatment or reporting 
period and used to collect AEs that start during the period or persist from the 
previous reporting period. The CRA will enter AEs that occur prior to the start of 
treatment on a baseline form that is not included in the Rave-CTEP-AERS 
integration. AEs that occur prior to enrollment must begin and end on the baseline 
Adverse Events form and should not be included on the standard Adverse Events 
form that is available at treatment unless there has been an increase in grade. 
Prior to sending AEs through the rules evaluation process, site staff should verify 
the following on the Adverse Event form in Rave: 
x The reporting period (course/cycle) is correct; and 
x AEs are recorded and complete (no missing fields) and the form is query free. 
The CRA reports AEs in Rave at the time the Investigator learns of the event. If 
the CRA modifies an AE, it must be re-submitted for rules evaluation. 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for 
rules evaluation by completing the Expedited Reporting Evaluation form. Both 
NCI and protocol-specific reporting rules evaluate the AEs submitted for 
expedited reporting. A report is initiated in CTEP-AERS using information 
entered in Medidata Rave for AEs that meet reporting requirements. The CRA 
completes the report by accessing CTEP-AERS via a direct link on the Medidata 
Rave Expedited Reporting Evaluation form. 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to 
be made to CTEP by telephone at 301-897-7497. Once internet connectivity is 
restored, the 24-hour notification that was phoned in must be entered immediately 
into CTEP-AERS using the direct link from Medidata Rave. 
Additional information about the CTEP-AERS integration is available on the 
CTSU website: 
x Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides & Help Topics. 
NCI requirements for SAE reporting are available on the CTEP website:  
x NCI Guidelines for Investigators: Adverse Event Reporting Requirements is available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelin
es.pdf 
 

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13.5 Global Reporting/Monitoring (28-JAN-2020) 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
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 study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS 
reporting guidelines must be reported via the monitoring method identified above.   
 
14. STATISTICAL CONSIDERATIONS 
14.1 
Study Design  
 
This is a phase I study investigating the safety and tolerability of AMG 232 (KRT-
232) in combination with standard-dose radiotherapy in STS in two separate patient 
cohorts. Patients will be enrolled separately into two cohorts based on STS type 
(extremity or body wall vs. abdomen/pelvis/retroperitoneal cavity). Within each cohort 
patients will be assigned to the following dose escalation schedule:  increasing frequency 
with constant doses sequentially. The classic 3+3 design will be used to test the safety of 
each dose level, and testing will be started with dose level 1. All p53 wild type patients 
who receive at least one dose of AMG 232 (KRT-232) are considered evaluable for DLT, 
should a DLT occur. In the absence of DLT, patients must have received at least one 
fraction of radiation therapy and have completed the DLT observation period to be 
evaluable for DLT. Patients considered inevaluable will be replaced to ensure the 
minimum evaluable patients per arm.  The minimum sample size is 12 evaluable patients 
and the maximum sample size is 46 evaluable patients for the two cohorts combined.  
14.2 
Study Endpoints (9May2018) 
14.2.1 
Primary Endpoint 
MTD/RP2D at 4 weeks after treatment completion (AMG 232 (KRT-232) + 
radiotherapy). 
14.2.2 
Secondary Endpoints 
x Percent of necrosis and pCR in final surgical resection specimen; 
x Local failure (LF),  
x Disease free survival (DFS), and 
x Overall survival (OS) at 2 years; 
x Serial serum Macrophage Inhibitory Cytokine (MIC)-1 levels;  
x To correlate AMG 232 (KRT-232) exposure-response relationships (PD, toxicity, and 
efficacy). 
14.2.3 
Tertiary Endpoints 
Tumor volume changes by cohort and dose levels. 
Clinical outcomes by genomic biomarkers 
Correlation between mdm2/4 expression vs. protein levels. 
tumor genetic mutations in (1) cf ctDNA, (2) DNA/RNA isolated from exosomes  
 
14.3 
Primary Objectives Study Design 
14.3.1 Primary Hypothesis and Endpoints: Preoperative combined AMG 232 (KRT-232) and 
radiotherapy treatment is safe and well tolerated, and shows preliminary efficacy in STS 

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14.3.2  
There are two patient cohorts based on tumor locations therefore dose escalation is done 
separately with these two cohorts.    
 
DLT evaluation will occur 4 weeks after treatment completion prior to surgery, but 
toxicity data will be collected and monitored till surgery completion and during the 
follow up period.  
 
Patients must have sufficient tissue for NGS sequencing to be included on this trial. 
Patients with wild type p53 will continue on study drug.  
 
The rate of DLTs and 95%CI will be summarized using proportions for binary outcome 
per cohort. 
 
14.3.3 Sample Size and Power Calculations: Based on the dose escalation rule, for each of the 
two patient cohorts, the classic 3+3 design will be used to make the decision on dose 
escalation/de-escalation at each dose level, and dose level 1 will be tested first. See 
section 14.6.1 for the definition of DLTs. At dose level 1 for each cohort, among the first 
3 evaluable patients, if there is no DLT, then we escalate to next higher dose level; if one 
DLT is observed, 3 more patients will be accrued to the same dose level; if there is more 
than one DLT, we will then stop the accrual to this dose level and de-escalate the dose to 
dose level -1. Under the condition that there is one DLT among the first 3 patients and 6 
evaluable patients are accrued to this dose level still with one DLT observed among these 
6, we will escalate the dose to the next higher dose level, dose level 2; if there is one DLT 
among the first 3 patients and 6 evaluable patients are accrued to dose level 1 with more 
than one DLT observed among these 6, we will de-escalate the dose to dose level -1. If 
dose level 1 is proved to be not safe, dose level -1 will be tested based on the classic 3+3 
design. If dose level 1 is proved to be safe, dose level 2 will be tested similarly based on 
the classic 3+3 design. If dose level 2 is proved to be not safe, dose level 1 will be 
considered the MTD and dose escalation will be stopped: if dose level 2 is proved to be 
safe, dose level 3 will be tested using the classic 3+3 design. If dose level 3 is proved to 
be safe, this dose level will be considered the MTD; if not, dose level 2 will be 
considered the MTD. Five additional patients will be accrued to the MTD to ensure 
safety. The minimum sample size is 12 evaluable patients and the maximum sample size 
is 46 evaluable patients for the two cohorts combined. 
 
14.4 
Study Monitoring of Primary Objectives 
(Interim Analysis) 
Interim Analysis to Monitor Study Progress  
Interim reports will be prepared twice each year until the final analysis has been accepted for 
presentation or publication. In general, these reports will contain information about the 
accrual rate with projected completion date for the accrual phase, exclusion rates, 
pretreatment characteristics of patients accrued, and the frequency and severity of AEs. This 
study will be monitored by the Clinical Data Update System (CDUS), version 3.0. 
Cumulative CDUS data will be submitted quarterly by electronic means. 
 

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Evaluable patients (all patients started treatment) will be included in the final analysis. 
The usual components of this analysis are:  
• Tabulation of all cases entered, and any excluded from analysis with reasons for 
exclusion;  
• Patient accrual rate;  
• Distribution of important baseline prognostic variables;  
• Frequency and severity of adverse events;  
• Observed results with respect to the endpoints described above.  
 
After the start of the accrual, the study team, including the study chairs, study 
statisticians, data managers and protocol administrator, will hold regular conference calls 
to review the overall conduct of the study. Data on treatment dose delivery, adverse 
events reported, patient demographics and eligibility will be assembled and reviewed. 
When a decision on dose de-escalation/escalation must be made, the study team will hold 
a conference call to review information including the categorization and grading of 
reported adverse events, determination of the dose-limiting toxicities, etc. The decision to 
de-escalate or escalate is made by consensus of the study team in accordance with the 
decision rules outlined in the protocol. At each meeting, consideration is also given to the 
rate of accrual. Brief minutes of each meeting will be written by the study chairs to 
document the review of information and any decision made. The meeting minutes will be 
submitted to the NRG early phase protocol monitoring oversight committee for review. 
 
 
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next higher dose level. 
 out of 3 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).   
1 out of 3 
Enter 3 more patients at this dose level. 
x If 0 of these 3 patients experience DLT, proceed to 
the next higher dose level. 
x If 1 or more of this group suffer DLT, then dose 
escalation will be stopped, and this dose is declared 
the maximally administered dose.  
 
14.5     Accrual/Study Duration Considerations (9May2018) 
Based on prior studies (RTOG 9514, RTOG 0630 and ARST 1321) we project a monthly 
accrual rate of 1.5 patients. Minimal accrual is projected for the first 3 to 6 months after 
study activation. 
 

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14.6     Dose Level Guidelines: See Section 6 
 
(Escalation or de-escalation): 
14.6.1  Definition of Dose-Limiting Toxicity 
DLT includes all grade 4-5 toxicities attributable to AMG 232 (KRT-232) or 
combined AMG 232 (KRT-232) with radiotherapy up to 4 weeks after the 
completion of AMG 232 (KRT-232)+RT treatment. 
 
Any grade 3 AE at least possibly attributable to AMG 232 (KRT-232) or combined 
AMG 232 (KRT-232) with radiotherapy will also be considered DLT if any of the 
two following situations occur:  
x A delay of >2 weeks due to the grade 3 toxicity. 
x  two dose reductions due to the grade 3 toxicity. 
 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6. 
 
14.6.2  Dose Expansion Cohorts 
Once the RP2D is reached, an additional 5 evaluable patients will be treated at this dose.  
For the expansion cohort, patients will continue to be monitored for occurrence of DLT.  
If 2 of the -5 patients experience DLT, the Principal Investigator will discuss with all 
study investigators and with CTEP whether further addition of patients is needed to re-
assess the RP2D.   
 
14.7 
Secondary or Exploratory Endpoints (including correlative science aims) 
(9May2018) 
Descriptive statistics will be provided for selected demographic, safety, PK, and PD data 
by dose, p53 status and time as appropriate.   
 
Local failure: local recurrence or progression as defined in RTOG 0630 that occurs after 
surgery will be considered a local failure; local recurrence or progression prior to surgery 
will not be considered a local failure. Amputation for treatment complications or 
recurrence/progression will be considered a failure at the date of surgery; amputation due 
to any other reason will not be considered a local failure. Any patient that does not 
continue on to surgery will be considered to have local failure; failure time will be the 
minimum time to surgery as calculated from the patients that do continue on to surgery   
 
Disease-free survival (DFS) defined as local, regional, or distant failure, or death due to 
any cause, and overall survival (OS, Death due to any cause) will be described with 
Kaplan-Meier plots and local failure by cumulative incidence plots or descriptive 
statistics, as data allow. Percent of necrosis and pCR will be summarized using binomial 
proportions. Tumor volume changes will be summarized and described by cohort and by 
dose levels. Pearson’s correlation will be used to assess relationships between mdm2/4 
expression and protein levels.  
 
A full pharmacokinetic profile of AMG 232 (KRT-232) will be proposed in this LOI to 
assess exposure-response relationships with various PD endpoints (i.e., MIC-1 changes, 

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REFERENCES (9MAY2018) 
 
AMG 232 Investigators Brochure Date: February 26, 2018. 
 
Andreeff M, Kelly KR, Yee K, et al. Results of the Phase I Trial of RG7112, a Small-Molecule 
MDM2 Antagonist in Leukemia. Clin Cancer Res. 2016 Feb 15;22(4):868-76.  Epub 2015 Oct 
12.  
 
Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of 
doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and 
bone sarcomas. J Clin Oncol 11:1276-85, 1993. 
 
Aziz MH, Shen H, Maki CG. Acquisition Of P53 Mutations In Response To The Non-Genotoxic 
P53 Activator Nutlin-3. Oncogene. 2011 Nov 17;30(46):4678-86. Epub 2011 Jun 6. 
 
Bacci G, Mercuri M, Longhi A, et al: Grade of chemotherapy-induced necrosis as a predictor of 
local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities 
treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 41:2079-85, 2005. 
 
Barrentina J, Taylor B, Banerji S, et al: Subtype-specific genomic alterations define new targets 
for soft tissue sarcoma therapy. Nat Genet. 2010;42(8):715-721. 
 
Bartel F, Meye A, Würl P, et al. Amplification of the MDM2 gene, but not expression of splice 
variants of MDM2 MRNA, is associated with prognosis in soft tissue sarcoma Int J Cancer. 2001 
May 20;95(3):168-75. 
 
Bonvalot S, Rivoire M, Castaing M, Stoeckle E, Le Cesne A, Blay JY, Laplanche A. Primary 
retroperitoneal sarcomas: a multivariate analysis of surgical factors associated with local control. 
J Clin Oncol. 2009 Jan 1; 27(1):31-7. Epub 2008 Dec 1.  
 
Carol H, Reynolds CP, Kang MH, et al. Initial testing of the MDM2 inhibitor RG7112 by the 
Pediatric Preclinical Testing Program. Pediatr Blood Cancer 2013; 60 (4): 633-641.  
 
The Cancer Genome Atlas Research Network. Comprehensive and Integrated Genomic 
Characterizaiton of Adult Soft Tissue Sarcomas. 2017;171(4):950-965. 
 
Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus 
ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft 
tissue sarcomas. J Clin Oncol 11:1269-75, 1993. 
 
Eilber FC, Rosen G, Eckardt J, et al: treatment-induced pathologic necrosis: a predictor of local 
recurrence and survival in patients receiving neoadjuvant therapy for high- greade extremity 
STS, JCO 19: 3203-9, 2001. 
 
Guidance for Industry: Bioanalytical Method Validation. U.S. Department of Health and Human 
Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 

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Center for Veterinary Medicine (CVM). Draft Guidance, September 2013. U.S. Food and Drug 
Administration. 
 
Gronchi A, Lo Vullo S, Fiore M, et al. Aggressive surgical policies in a retrospectively reviewed 
single-institution case series of retroperitoneal soft tissue sarcoma patients. J Clin Oncol. 2009 
Jan 1; 27(1): 24-30. Epub 2008 Dec 1.  
  
Hassan I, Park SZ, Donohue JH, et al. Operative management of primary retroperitoneal 
sarcomas: A reappraisal of an institutional experience. Ann Surg. 2004; 239:244-250.  
  
Heslin MJ, Lewis JJ, Nadler E. Prognostic factors associated with long-term survival for 
retroperitoneal sarcoma: implications for management. J Clin Oncol. 1997; 15(8):2832-9.  
 
Hoffman-Luca, Yang CY, Lu J, et al. Significant Differences In The Development Of Acquired 
Resistance To The Mdm2 Inhibitor Sar405838 Between In Vitro And In Vivo Drug Treatment. 
PLoS One. 2015 Jun 12;10(6):e0128807. E-collection 2015.  
 
Jaques DP, Coit DG, Hajdu SI, et al. Management of primary and recurrent soft-tissue sarcoma 
of the retroperitoneum. Ann Surg.1990; 212:51-59.  
  
Keung EZ, Hornick JL, Bertagnolli MM, et al. Predictors of outcomes in patients with primary 
retroperitoneal dedifferentiated liposarcoma undergoing surgery Am Coll Surg. 2014 
Feb;218(2):206-17 Epub 2013 Oct 25.  
 
Karni-Schmidt O, Lokshin M, Prives C. The Roles of MDM2 and MDMX in Cancer. Annu Rev 
Pathol. 2016 May 23;11:617-44. 
 
Khaled YS, Elkord E, Ammori BJ. Macrophage inhibitory cytokine-1: a review of its pleiotropic 
actions in cancer. Cancer Biomark. 2012;11(5):183-90.  
 
Lewis JJ, Leung D, Woodruff JM, et al. Retroperitoneal soft-tissue sarcoma: analysis of 500 
patients treated and followed at a single institution. Ann Surg. 1998; 228:355-365.  
  
Liles JS, Tzeng CW, Short JJ, et al. Retroperitoneal and intra-abdominal sarcoma. Curr Probl 
Surg. 2009; 46(6): 445-503. 
 
Meric F, Hess KR, Varma DG, et al: Radiographic response to neoadjuvant chemotherapy is a 
predictor of local control and survival in soft tissue sarcomas. Cancer 95:1120-6, 2002. 
 
Patnaik A, Tolcher A, Beeram M, et al. Clinical pharmacology characterization of RG7112, an 
MDM2 antagonist, in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015 
Sep;76(3):587-95. Epub 2015 Jul 26.  
 
Pezzi CM, Pollock RE, Evans HL, et al: Preoperative chemotherapy for soft-tissue sarcomas of 
the extremities. Ann Surg 211:476-81, 1990 
 

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Phelps DA, Bondra K, Seum S,et al.  Inhibition of MDM2 by RG7388 confers hypersensitivity 
to X-radiation in xenograft models of childhood sarcoma. Pediatric Blood Cancer 2015; 
62(8):1345-1352.  
 
Picci P, Bohling T, Bacci G, et al: Chemotherapy-induced tumor necrosis as a prognostic factor 
in localized Ewing's sarcoma of the extremities. J Clin Oncol 15:1553-9, 1997 
 
Pollock RE, Lang A, El-Naggar AK, Radinsky R, Hung MC. Enhanced MDM2 Oncoprotein 
Expression in Soft Tissue Sarcoma: Several Possible Regulatory Mechanisms. Sarcoma. 
1997;1(1):23-9. 
 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66(1):7-30. 
Epub 2016 Jan 7. 
 
Stoeckle E, Coindre JM, Bonvalot S, et al. Prognostic factors in retroperitoneal sarcoma: a 
multivariate analysis of a series of 165 patients of the French Cancer Center Federation Sarcoma 
Group. Cancer. 2001; 92: 359-368.  
 
Taubert H, Meye A, Würl P. Soft tissue sarcomas and p53 mutations. Mol Med. 1998;4(6):365-
372. 
 
Wasylishen AR, Lozano G. Attenuating the p53 Pathway in Human Cancers: Many Means to the 
Same End. Cold Spring Harb Perspect Med. 2016 Aug 1;6(8).  
 
Werner LR, Huang S, Francis DM, et al.  Small Molecule Inhibition of MDM2-p53 Interaction 
Augments Radiation Response in Human Tumors, Mol Cancer Ther 2015 ; 14(9) : 994-2003.  
 
Ye Q, Jiang M, Huang WT, et al. Pharmacokinetics and metabolism of AMG 232, a novel orally 
bioavailable inhibitor of the MDM2-p53 interaction, in rats, dogs and monkeys: in vitro-in vivo 
correlation. Xenobiotica. 2015;45(8):681-92.  Epub 2015 Mar 23.  
 
Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT. Macrophage inhibitory cytokine-1: a 
novel biomarker for p53 pathway activation. Mol Cancer Ther. 2003 Oct;2(10):1023-9. 
 
 
 

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APPENDIX I: COLLABORATIVE AGREEMENTS LANGUAGE 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator”  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement.  A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the 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. 

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4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication.  Collaborator(s) will have 30 days from the 
date of receipt for review.  Collaborator shall have the right to request that publication be 
delayed for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected.  
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings.  Press 
releases and other media presentations must also be forwarded to CTEP prior to release.  
Copies of any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
 

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APPENDIX II: PLASMA PHARMACOKINETICS (29-MAY-2019) 
 
Collection of Specimen(s) 
Blood samples (~6 mL) will be taken into K2 EDTA tubes at designated time points, and 
immediately placed on ice. Please note that there is a window of ±5 mins from start to 8 hours 
and a window of ±1 hour for the 24 hour post dose. 
 
AMG 232 (KRT-232) through 4X/week: 
 
AMG 232 (KRT-232) alone (6 samples): Wk-1 first dose: predose, 1, 3, 5, 8, and 24 hours 
post dose 
 
AMG 232 (KRT-232) + RT (6 samples): Wk1D2, Wk3D2, and Wk5D2: predose and 24 
hours post dose  
 
 
AMG 232 (KRT-232) 5X/week: 
 
AMG 232 (KRT-232) alone (6 samples): Wk-1 first dose: predose, 1, 3, 5, 8, and 24 hours 
post dose 
 
AMG 232 (KRT-232) + RT (6 samples): Wk1D1, Wk3D1, and Wk5D1: predose and 24 
hours post dose  
 
*See Appendix IV for Sample Combined PK Blood Draw Schedule 
**If AMG 232 (KRT-232) is stopped because of p53 gene results or for any other reason PK 
blood draw will not be required 
 
Handling of Specimens(s)  
At each time point, ~6 mL of peripheral blood will be collected in a purple-top EDTA 
vacutainer (Becton Dickinson Catalog # 367863 or 367899, Franklin Lakes, NJ).  
 
- 
Obtain venous blood by standard phlebotomy technique from a peripheral access point.  
NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.   
- 
Fill-up the tubes as much as possible until blood flow stops. 
- 
GENTLY invert each tube several times (8-10 times) immediately after collection to 
avoid sample hemolysis. 
- 
Place samples immediately on ice after collection; samples must be processed within 30 
minutes. 
 
Processing instructions 
 
1. Invert sample 8-10 times immediately before processing.   
2. Centrifuge at ~1300 xg for 10 minutes in swinging bucket (SW) or 15 minutes in a 

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fixed angel (FA) rotor at 4ºC in a refrigerated centrifuge.  Make sure that the 
centrifuge reaches speed and is maintained throughout the entire spin. 
3. Carefully remove tube from centrifuge.  
4. Using a pipette, transfer equal aliquots of plasma into 2-3 labeled 2 mL cryovials 
(e.g., Corning #430659 external thread vial), not exceeding 1.5 mL per cryovial.   
5. Label samples as AMG 232 (KRT-232) PK, including protocol number (NRG-
DT001), unique patient ID assigned at registration, initials, date of collection, draw 
time, and time point.  
6. Store plasma samples at -70ºC or below until shipment or transfer to Johns Hopkins. 
 
Shipping of Specimen(s) 
Specimens should be stored through the duration of AMG 232 (KRT-232) correlative 
studies and shipped as a batch by participant (more than one participant/shipment is 
acceptable if the site has >1 participant on-study). A participant's samples should be 
shipped to the APC lab within 1 month of the last sample's collection date. (i.e., if sample 
is collected on 1/1/2017, all of that participant's samples should be at the APC lab by 
2/1/2017). The APC lab may contact the study team to request shipment off-schedule.  
The MIC-1 and AMG 232 (KRT-232) pharmacokinetic specimens can be shipped in the 
same shipment. 
Please ship 1-2 aliquots to the APC laboratory. Once receipt is confirmed, the back-
up aliquot may be shipped at that time or it can also be shipped later (e.g., with the 
next scheduled shipment). 
 
Preparing the shipment 
  
*Samples should be stored in cardboard boxes (5 1/8” x 5 1/8” x 2”, LxWxH).  
*Please organize the samples by Patient and Time point in the box.  
*Do not store in plastic bags (they break on dry-ice and labels will detach).  
*A copy of each of the pharmacokinetic sample collection forms for the respective 
patients or a sample list should be included with each shipment. To prevent problems 
with illegible writing on tubes, consider numbering them (in addition to sample label) 
and numbering samples on the sample sheet.  
*Note the study number, PI, and the drugs used/to be measured.  
*A name, phone number and email address should be included with samples so that 
receipt can be acknowledged.  
*Please notify the lab by email (onc-pharmacology@lists.johnshopkins.edu) at least 
24 hours prior to shipment.  
 
Shipping  
*All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state.  
*Overnight shipments should occur on Monday through Wednesday (Tuesday is the 
preferred day) except when the following day is a holiday. 
 
 

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Analytical Pharmacology Core Laboratory* 
Attn: NRG-DT001 AMG 232 (KRT-232) Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000** 
Phone: 410-502-7192 or 410-955-1129 
Email: onc-pharmacology@lists.johnshopkins.edu  
 
**This zip code is for FedEx shipments.  If UPS will be utilized, please ship to the 
following zip code: 21287 
 
NOTE: Please notify the lab by email (onc-pharmacology@lists.johnshopkins.edu) 
at least 24 hours prior to shipment. 
 
Site(s) Performing Correlative Study 
Dr. Michelle Rudek, The Analytical Pharmacology Core Laboratory at the Sidney 
Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCCC) 
 
 

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APPENDIX III: SERUM MACROPHAGE INHIBITORY CYTOKINE-1 (MIC-1)  
(29-MAY-2019) 
 
Collection of Specimen(s) 
Blood samples (~6 mL) will collected be in red-topped vacutainer tube at designated time 
points. Serum samples from the peripheral blood will be collected for MIC-1 assay on the 
following schedule: 
 
A baseline MIC-1 level will be determined by the average of two blood samples obtained 
at or between the time of step 1 registration and prior to the first AMG 232 (KRT-232) 
dose. 
 
Please note that there is a window of ±1 hour for the 24 hour post dose. 
 
 
AMG 232 (KRT-232) through 4X/week: 
 
AMG 232 (KRT-232) alone (3 samples): At or after Step 1 registration, and before 
Wk-1 first dose: predose (x2), and 24 hours post dose 
 
AMG 232 (KRT-232) + RT (6 samples): Wk1D2, Wk3D2, and Wk5D2: predose and 
24 hours post dose  
 
 
AMG 232 (KRT-232) 5X/week: 
AMG 232 (KRT-232) alone (3 samples): At or after Step 1 registration, and before 
Wk-1 first dose: predose (x2), and 24 hours  
post dose 
 
AMG 232 (KRT-232) + RT (6 samples): Wk1D1, Wk3D1, and Wk5D1: predose and 
24 hours post  
dose  
 
*See Appendix IV for Sample Combined PD Blood Draw Schedule 
**If AMG 232 (KRT-232) is stopped because of p53 gene results or for any other reason 
PD blood draw will not be required 
 
Handling of Specimens(s) 
At each time point, ~6 mL of peripheral blood will be collected in a red-topped 
vacutainer (Becton Dickinson Catalog #367815, Franklin Lakes, NJ).  
- 
Obtain venous blood by standard phlebotomy technique from a peripheral access point.  
NOTE:  Suggest using a minimum 18G needle to avoid sample hemolysis.   
- 
Fill-up the tubes as much as possible until blood flow stops. 
- 
GENTLY invert each tube several times (8-10 times) immediately after collection to 
avoid sample hemolysis. 

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- 
Transport the tube(s) as soon as possible to the laboratory. Allow the blood to clot in an 
upright position for at least 30 minutes but not longer than 1 hour before centrifugation.  
 
Processing instructions: 
1. Centrifuge at ~1200 xg for 15 minutes in swinging bucket (SW) or 15 minutes in 
a fixed angel (FA) rotor.  Make sure that the centrifuge reaches speed and is 
maintained throughout the entire spin. 
2. Carefully remove tube from centrifuge.  
3. Using a pipette, transfer equal aliquots of serum into ~4-6 labeled 2 mL cryovials 
(e.g., Corning #430659 external thread vial), with a minimum volume of 0.5 mL 
per cryovial.   
4. Label samples as MIC-1, including study number (NRG-DT001), unique patient 
ID assigned at registration, initials, date of collection, draw time, and time point. 
5. Store serum samples at -70ºC or below until shipment or transfer to Johns 
Hopkins. 
 
Shipping (Please refer to APPENDIX II for further details on the specifics of how to 
package and when to ship) 
 
*All samples should be shipped via overnight express courier in insulated containers 
with enough dry ice to maintain the samples in a frozen state.  
*Overnight shipments should occur on Monday through Wednesday (Tuesday is the 
preferred day) except when the following day is a holiday. 
 
Analytical Pharmacology Core Laboratory* 
Attn: NRG-DT001 AMG 232 (KRT-232) Study Samples 
1650 Orleans St. CRB1 Rm 184 
Baltimore, MD 21231-1000** 
Phone: 410-502-7192 or 410-955-1129 
Email: onc-pharmacology@lists.johnshopkins.edu  
 
**This zip code is for FedEx shipments.  If UPS will be utilized, please ship to the 
following zip code: 21287 
 
NOTE: Please notify the lab by email (onc-pharmacology@lists.johnshopkins.edu) 
at least 24 hours prior to shipment. 
 
Site(s) Performing Correlative Study 
Dr. Michelle Rudek, The Analytical Pharmacology Core Laboratory at the Sidney 
Kimmel Comprehensive Cancer Center at Johns Hopkins (SKCCC) 
 
 
 

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APPENDIX V: DRUG-INDUCED LIVER INJURY (DILI) REPORTING & 
ADDITIONAL ASSESSMENTS REPORTING 
 
To facilitate appropriate monitoring for signals of drug-induced liver injury (DILI), cases of 
concurrent AST or ALT and TBL and/or INR elevation according to the criteria specified in 
Section 6.1 require the following: 
 
x The event is to be reported to CTEP as a serious adverse event within 24 hours of 
discovery or notification of the event (i.e., before additional etiologic investigations 
have been concluded) 
x The appropriate CRF (e.g., Adverse Event CRF) that captures information necessary 
to facilitate the evaluation of treatment-emergent liver abnormalities is to be 
completed and sent to CTEP. 
x Other events of hepatotoxicity and potential DILI are to be reported as serious 
adverse events if they meet the criteria for a serious adverse event defined in Section 
7. 
 
Additional Clinical Assessments and Observation 
 
All subjects in whom investigational product(s) or protocol-required therapies is/are withheld 
(either permanently or conditionally) due to potential DILI as specified in Section 6.1 or who 
H[SHULHQFH$67RU$/7HOHYDWLRQVî8/1DUHWRXQGHUJRDSHULRG of “close observation” 
until abnormalities return to normal or to the subject’s baseline levels. Assessments that are to be 
performed during this period include: 
 
x Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 
x In cases of TBL > 2 × ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve. 
 
Testing frequency of the above laboratory tests may decrease if the abnormalities stabilize or the 
investigational product(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 
 
x Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL: 
o Obtain complete blood count (CBC) with differential to assess for eosinophilia 
o Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for 
autoimmune hepatitis 
o Obtain serum acetaminophen (paracetamol) levels 
o Obtain a more detailed history of: 
- Prior and/or concurrent diseases or illness 
- Exposure to environmental and/or industrial chemical agents 
- Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
- Prior and/or concurrent use of alcohol, recreational drugs and special diets 

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- Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
o Obtain viral serologies 
o Obtain CPK, haptoglobin, LDH, and peripheral blood smear 
o Perform appropriate liver imaging if clinically indicated 
x Obtain appropriate blood sampling for pharmacokinetic analysis if this has not already 
been collected 
x Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
x Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal. The “close observation period” is to continue 
for a minimum of 4 weeks after discontinuation of all investigational product(s) and 
protocol-required therapies. 
 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
 
 
 

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APPENDIX VII:  THE FNCLCC SARCOMA GRADING SYSTEM 
 
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: Sarcomas for which histologic typing is certain (eg, myxoid, 
liposarcoma, myxofibrosarcoma) 
x 
Score 3: Embryonal and undifferentiated sarcomas, synovial sarcomas, 
sarcomas of doubtful type, 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 
 
 
REFERENCE: 
 
Guillou L, Coindre JM, Bonichon F, et al: Comparative study of the National Cancer Institute 
and French Federation of Cancer Centers Sarcoma Group grading systems in a population of 410 
adult patients with soft tissue sarcoma. J Clin Oncol 15:350-62, 1997  
 
Trojani M, Contesso G, Coindre JM, et al: Soft-tissue sarcomas of adults; study of pathological 
prognostic variables and definition of a histopathological grading system. Int J Cancer 33:37-42, 
1984 
 
 

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APPENDIX VIII: WORLD HEALTH ORGANIZATION CLASSIFICATION OF SOFT 
TISSUE TUMOURS: INTERMEDIATE (RARELY METASTASTIZING) 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 
 
 
 
 
 
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* 
 
 
 
 
 
 
 
SMOOTH MUSCLE TUMORS 
 
Leiomyosarcoma 
 
PERICYTIC (PERIVASCULAR) 
TUMORS 
 
Malignant glomus tumour 
 
SKELETAL MUSCLE TUMORS 
 
Embryonal rhabdomyosarcoma* 
 
Alveolar rhabdomyosarcoma* 
 
Pleomorphic rhabdomyosarcoma* 
 
Spindle cell/sclerosing rhabdomyosarcoma* 
 
Botryoid rhabdomyosarcoma* 

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Mixed rhabdomyosarcoma* 
 
Rhabdomyosarcom**a, insufficient sample 
to categorize* 
VASCULAR TUMORS 
Retiform hemangioendothelioma* 
Epithelioid hemangioendothelioma* 
Papillary intralymphatic 
angioendothelioma* 
Angiosarcoma of soft tissue 
Composite hemangioendothelioma* 
 
Pseudomyogenic (epithelioid sarcoma-like) 
hemangioendothelioma* 
 
Kaposi sarcoma* 
 
 
 
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 

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Undifferentiated pleomorphic sarcoma 
 
Undifferentiated epithelioid sarcoma 
 
Undifferentiated spindle cell sarcoma 
 
Undifferentiated sarcoma NOS 
*These tumor types are NOT eligible for the NRG-DT001 protocol.