Stereotactic Body Radiotherapy (SBRT) for Pulmonary Metastases in Ewing Sarcoma, Rhabdomyosarcoma, and Wilms Tumors
Phase: PHASE1
Conditions: Ewing Sarcoma, Rhabdomyosarcoma, Wilms Tumor, Osteosarcoma, Non-Rhabdomyosarcoma Soft Tissue Sarcoma, Nos, Renal Tumor, Rhabdoid Tumor, Clear Cell Renal Cell Carcinoma, Sarcoma, Sarcoma, Ewing, Soft Tissue Sarcoma
Sponsor: Dana-Farber Cancer Institute

1 
DF/HCC Protocol #: Assigned by the Office for Human Research Studies (OHRS) after 
submission for SRC and IRB review. 
 
DF/HCC Radiation Protocol Template: June 30, 2014 
 
TITLE:  Phase I/II Study of Stereotactic Body Radiotherapy (SBRT) for Pulmonary Metastases 
in Ewing Sarcoma, Rhabdomyosarcoma, and Wilms Tumors 
 
*Principal Investigator (PI): 
  
 
 
 
 
 
 
 
Other Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biostatistician: 
 
     
 
     
 
     
 
     
 
     
 
     
 
     
  
 
Study Coordinator:  
 
 
 

 
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Responsible Research Nurse: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   
 
 
Original Protocol / Version Date: 23 February 2015 
 
 
 

 
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INDEX 
 
SCHEMA .........................................................................................................................................5 
1. 
Introduction ..........................................................................................................................6 
1.1 
Study Disease ...........................................................................................................6 
1.2 
Rationale ..................................................................................................................6 
2. 
OBJECTIVES ......................................................................................................................7 
2.1 
Study Design ............................................................................................................7 
2.2 
Primary Objectives...................................................................................................7 
2.3 
Secondary Objectives...............................................................................................7 
3. 
PARTICIPANT SELECTION .............................................................................................7 
3.1 
Eligibility Criteria ....................................................................................................7 
3.2 
Exclusion Criteria ....................................................................................................8 
3.3 
Inclusion of Women and Minorities ........................................................................8 
4. 
PRETREATMENT EVALUATIONS/MANAGEMENT ...................................................8 
5. 
REGISTRATION PROCEDURES .....................................................................................8 
5.1 
General Guidelines for DF/HCC and DF/PCC Institutions .....................................8 
5.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................9 
5.3 
General Guidelines for Other Participating Institutions .....................................9 
5.4 
Registration Process for Other Participating Institutions .......................................9 
5.5 
Stratification .............................................................................................................9 
6. 
RADIATION THERAPY ....................................................................................................9 
6.1 
Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT ..................9 
6.2 
Dose-limiting toxicities (DLTs) .............................................................................11 
6.3 
Toxicities and Adverse Events...............................................................................12 
7. 
OTHER THERAPIES ........................................................................................................17 
8. 
TISSUE/SPECIMEN SUBMISSION ................................................................................18 
9. 
PARTICIPANT ASSESSMENTS .....................................................................................18 
9.1 
Response Criteria ...................................................................................................18 
10. 
DATA COLLECTION ......................................................................................................21 
10.1  Study Documentation.............................................................................................21 
11     STATISTICAL CONSIDERATIONS..................................................................................22 
11.1  Study Design/Endpoints............................................................................................22 
11.2 Sample Size, Accrual Rate and Study Duration ........................................................22 
11.3 Analysis of Primary Endpoints ..................................................................................23 
11.4 Analysis of Secondary Endpoints ..............................................................................23 

 
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12     REGULATORY CONSIDERATIONS ................................................................................23 
12.1 Protocol Review and Amendments ............................................................................23 
12.2 Informed Consent.......................................................................................................24 
12.3 Study Monitoring .......................................................................................................24 
12.4 Ethics and Good Clinical Practice (GCP) ..................................................................24 
12.5 Records Retention ......................................................................................................25 
13     PUBLICATION PLAN ........................................................................................................25 
REFERENCES ..............................................................................................................................26 
APPENDIX A 
DOSE ESCALATION BY DISEASE .......................................................27 
APPENDIX B 
UTSW DOSE CONSTRAINTS ................................................................28 
 
 

 
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SCHEMA 
 
 
Register  → Simulation →  Radiation Treatment (dose escalation by disease in Appendix A) 
 
In each of the 2 cohorts: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Dose Levels (2 cohorts, 3 dose levels per cohort) 
 
1) Cohort 1 (Wilms/Renal tumor) 
- 
SBRT: begin at Dose level 1 
 
2) Cohort 2 (Ewing sarcoma or rhabdomyosarcoma)  
- 
SBRT: begin at Dose level 2 
 
 
Number 
of DLTs 
Treat cohort 
(3 participants) 
Start at dose 
level 1 
Recruit 3 more 
participants 
Further 
DLTs? 
Phase II 
Yes 
No 
1 
2 or 3 
0 
Current 
dose at 
Level 1?
Yes 
STOP 
No 
Dose de-
escalation 
Meet 
efficac
y
Yes 
No 
Study 
complete 
At highest 
dose or had 
de-
eescalation?
Yes 
No 
STOP 
Dose 
escalation 

 
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1. INTRODUCTION 
 
1.1 
Study Disease 
 
The most common site of metastatic disease in Ewing sarcoma is the lung.  The standard 
management of pulmonary metastases continues to include whole-lung radiotherapy.  
Although there are reports advocating the use of whole-lung radiotherapy, this approach has 
not been shown in randomized trials to improve survival [1, 2.]  Localized Ewing sarcoma is 
curable with radiotherapy doses of 54-60 Gy, however whole-lung doses are limited because 
of lung toxicity.   Patients who relapse after whole-lung radiotherapy also have few curative 
options. An alternative to whole-lung radiotherapy is stereotactic body radiotherapy 
(SBRT). SBRT can provide sustained control of tumor in the lung by delivering a 
tumoricidal dose while limiting dose to the normal lung.  Similarly, the most common site 
of metastatic disease for Wilms and other primary pediatric renal tumors is the lung.  Whole 
lung radiotherapy is used in some children with metastatic renal tumors.  However, for those 
who had non-metastatic disease but relapse in the lung following completion of therapy, the 
efficacy of whole lung radiotherapy is unproven.  
 
1.2 
Rationale 
 
SBRT is a well studied and commonly used method of conforming the radiation dose to the 
target volume in order to spare normal surrounding tissues. By doing so, doses to the target 
can be increased without causing excessive toxicity to surrounding tissues.  SBRT is being 
used to treat adults with small inoperable lung cancers [3-5].  SBRT has been shown to be 
effective and well-tolerated.    
Several regimens have been used and are summarized in the table below along with results 
of local control, follow-up and risk of grade 3 or greater toxicity.  The table below was used 
at the American Association of Medical Dosimetrists (AAMD) annual meeting in 
Minneapolis in June 2010. 
 
 
 
SBRT has not routinely been used in the treatment of pulmonary metastases from Ewing 
sarcoma or from other malignancies in children, though there have been many studies 
published on its use in pulmonary metastases from adult cancers.  Stereotactic radiotherapy 
to the brain has been used since 1992 to treat pediatric brain tumors and there is increasing 
interest in using this highly conformal technology in children [6]. 

 
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2. OBJECTIVES 
 
2.1 
Study Design 
 
This is a Phase I/II study.   The purpose of this study is to find the lowest dose level with an 
acceptable safety profile and efficacy in this population. Therefore, the phase I and phase II 
designs will be run sequentially. Dose escalation in phase I does not go all the way to the 
MTD before moving to the phase II portion. If the dose being tested is found to be effective 
dose escalation will not continue.  There are two cohorts that will use the same study design. 
One cohort will include patients with Wilms tumors or other primary renal tumors, and the 
other will include patients with Ewing sarcoma or rhabdomyosarcoma. Different dose levels 
will be used in the two cohorts, with non-renal tumor patients beginning at dose level 2 and 
renal tumor patients beginning at dose level 1. The two cohorts will be enrolling patients 
independently and simultaneously. 
 
2.2 
Primary Objectives 
 
2.2.1 The primary aim of the Phase I portion is to determine the tolerability and safety of 
stereotactic body radiotherapy for pulmonary metastases in pediatric patients with Ewing 
sarcoma, rhabdomyosarcoma or Wilms tumor and other primary renal tumors. (See 11.1 for 
definitions.) 
 
2.2.2 The primary objective of the Phase II portion is to evaluate disease response at 6 weeks 
post SBRT in this patient population. Response will be defined according to RECIST criteria. 
 
2.3 
Secondary Objectives 
 
1. To determine the feasibility of SBRT in the pediatric population (including 
tolerability)  
2. To document the safety of the treatment  
3. To determine rate of relapse elsewhere in the lung 
4. Best overall response  
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria  
 
1. Diagnosis of Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, non-
rhabdomyosarcoma soft tissue sarcoma, Wilms tumor or other primary renal tumor 
(including clear cell and rhabdoid) 
2. Age ≤21years 
3. Must be capable of treatment without general anesthesia 
4. Lesion size 4 mm - 3 cm  
 
 

 
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5. Subjects who have lesions within 2 cm of central structures*, will be eligible on a 
case-by-case basis  
*Tumor within or touching the zone of the proximal bronchial tree, defined as 
a volume 2 cm in all directions around the proximal bronchial tree (carina, 
right and left main bronchi, right and left upper lobe bronchi, intermedius 
bronchus, right middle lobe bronchus, lingular bronchus, right and left lower 
lobe bronchi). 
6. Pulmonary metastases found at relapse (does not have to be first relapse); no more 
than 3 lesions per hemi-thorax will be treated but other lesions in the lung may be 
present 
7. Greater than 5 weeks from doxorubicin at the time of consent, with radiation to be 
initiated no less than 6 weeks from doxorubicin 
8. Informed consent/assent   
9. Life expectancy > 3 months 
10. Pulmonary function FEV1 ≥ 50% of predicted 
11. Concurrent immunotherapy is allowed 
 
3.2 
 
Exclusion Criteria 
 
1. Prior whole-lung or hemi-thorax irradiation of greater than 12 Gy received less than 6 
months prior to consent (focal radiotherapy to the thorax is not an exclusion)  
2. Lesion larger than 3 cm in diameter 
3. Patients for whom surgery would be deemed appropriate rather than radiotherapy. 
 
 
 
3.3 
Inclusion of Women and Minorities 
 
Females, minorities and other underrepresented populations are at risk to develop Ewing 
sarcoma and the other included malignancies and we will enroll any eligible patient in such 
groups.  There is no reason to suspect any differential effect of this treatment.  The 
eligibility criteria will not differentially affect the enrollment of these populations. 
 
4. PRETREATMENT EVALUATIONS/MANAGEMENT 
 
Eligible patients will be registered with the DF/HCC Office of Data Quality (ODQ).  
Registration must occur prior to initiation of therapy.  Any participant not registered to the 
protocol before treatment begins will be deemed ineligible and registration denied.  A 
member of the study team will confirm eligibility. 
 
5. REGISTRATION PROCEDURES 
 
5.1 General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System 
(CTMS) OnCore. Registrations must occur prior to the initiation of protocol therapy. 

 
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Any participant not registered to the protocol before protocol therapy begins will be 
considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator 
(PI). If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must be canceled. Registration cancellations 
must be made in OnCore as soon as possible.  
 
5.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
5.3 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Stereotactic Body 
Radiotherapy (SBRT) for Pulmonary Metastases in Ewing Sarcoma, Rhabdomyosarcoma, and Wilms 
Tumors (SOP #: REGIST-101) must be followed. General Guidelines for Other Participating 
Institutions 
 
N/A 
 
 
5.4 
Registration Process for Other Participating Institutions 
 
N/A 
 
5.5 
Stratification 
 
Patients will be stratified into two groups by diagnosis: Wilms/Renal tumors are Cohort 1, 
Ewing sarcoma /rhabdomyosarcoma are Cohort 2 
 
 
6. RADIATION THERAPY 
 
6.1 
Dose Specifications: 3D Conformal Radiotherapy (3DCRT) or IMRT 
 
6.1.1 Treatment simulation:  The patient will undergo simulation (treatment planning) in a 
standard stereotactic immobilization device.  The simulation will be done using 4DCT to 
account for respiratory motion.  A free-breathing CT scan will also be performed using 2.5-
mm slices.  Abdominal compression will be used if the tumor moves more than 1 cm with 
respiratory motion.  This approach is the standard protocol for SBRT at our institution.   
 
6.1.2 Contours:  The tumor nodule or nodules will be contoured  
 
6.1.2.1 Internal tumor volume (ITV): gross tumor plus margin for internal motion.  
 
6.1.2.2 Planning target volume (PTV):  will be ITV plus 5 mm  

 
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6.1.2.3 Organs at risk will be defined by the physician and/or the treatment 
planner: 
• Total lung: total lung volume-ITV 
• Heart: Defined from apex to first slice of great vessels 
• Spinal cord 
• Chest wall 
• Skin 
• Ribs abutting tumor 
• Esophagus: defined 5 cm above and below PTV 
• Proximal bronchial tree:  defined from inferior 2 cm of trachea 
to lobar bronchi, to point of bifurcation into segments 
• Brachial plexus 
 
6.1.2.4 Dose Level 1 will be the starting dose for patients with Wilms/Renal 
tumor.  Dose Level 2 will be the starting dose for patients with Ewing 
sarcoma/Rhabdomyosarcoma (non-renal).  SEE APPENDIX: A.  
 
Treatment will be delivered over 1- 2 weeks. Delivery of hypofractionated 
radiotherapy (i.e., using a small number of fractions) makes it challenging to 
determine normal-tissue dose constraints.  However, we will use very 
conservative critical-structure dose limits based on those used in published 
experience in SBRT in adults. See Appendix B for UTSW Dose Constraints.  
 
6.1.2.5 Dose Levels for each target lesion are as follows: 
Dose level 1 – 8 Gy x 3 
Dose level 2 –  10 Gy x 3 
Dose level 3 – 12 Gy x 3 
 
Non-renal tumor dose escalation scheme: Three participants with non-renal 
tumors will be treated starting at dose level 2. If no dose-limiting toxicities 
(DLTs, see definitions in 6.2) are seen, that cohort will move on to the phase II 
portion of the study. If one DLT occurs at the initial dose level, then 3 more 
patients will be accrued to that cohort. If no further DLTs occur in those 3 patients 
treated at the initial dose level, then that cohort will move on to the phase II 
portion of the study. In the phase II portion, if the efficacy criteria are not met, 
three more patients will be enrolled at the next dose level.   Dose will be escalated 
to the next dose level (3) for the next three patients. If one DLT, an additional 
three patients will be enrolled at that current dose level. If two or three DLTs, no 
dose escalation will occur; if this is at the starting dose level 2, dose will be de-
escalated to the next lower dose level for the next three patients, down to a 
minimum of dose level 1. If three patients are treated at dose level 2, three more at 
dose level 3, and there are still no DLTs, the dose will be held at level 3 for all 
additional non-renal tumor patients. 
 
Renal tumor dose escalation scheme: Three participants with renal tumors will 

 
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be treated starting at dose level 1. If no dose-limiting toxicities (DLTs, see 
definitions in 6.2) are seen, that cohort will move on to the phase II portion of the 
study. If one DLT occurs at the initial dose level, then 3 more patients will be 
accrued to that cohort. If no further DLTs occur in those 3 patients treated at the 
initial dose level, then that cohort will move on to the phase II portion of the 
study. In the phase II portion, if the efficacy criteria are not met, three more 
patients will be enrolled at the next dose level.   Dose will be escalated to the next 
dose level (2) for the next three patients. If one DLT, an additional three patients 
will be enrolled at that current dose level. If two or three DLTs, no dose 
escalation will occur; if this is at the starting dose level 1 (the lowest dose level), 
the study will be terminated. If three patients are treated at dose level 2, three 
more at dose level 3, and there are still no DLTs, the dose will be held at level 3. 
  
6.1.2.6 Dose-escalation (please refer to Dose Schema section 6.1.2.5): The Phase 
I and Phase II portions will be done sequentially.  If a dose level does not meet the 
safety criteria (none of three or no more than one out of six develops a DLT), and 
the next lower dose level does not meet the Phase II pre-specified criteria for 
efficacy, the study will be terminated.  If two or more DLTs are observed at the 
starting dose level, the SBRT dose will be de-escalated to the next lower dose 
level; if this happens at dose level 1 (the lowest dose level), the study will be 
terminated.     
 
The same Phase I/II design applies to both cohorts, Wilms and sarcoma patients, 
separately, except for the starting dose level in the Phase I portion.  There are 3 
dose levels (8, 10 and 12 Gy x 3) in this study.  Patients with Wilms tumor or 
other renal tumors will start at dose level 1 (8 Gy x 3) and dose escalation will 
stop for this cohort at dose level 3 (12 Gy x 3).   Ewing sarcoma and 
rhabdomyosarcoma patients will start at dose level 2 (10 Gy x 3). 
 
6.1.2.7 Stopping rules: If two or more DLTs are observed at the starting dose 
level, the SBRT dose will be de-escalated to ther next lower dose level; if this 
happens at dose 1 (the lowest dose level), the study will be terminated.  
 
6.2 
Dose-limiting toxicities (DLTs) 
 
DLTs are toxicities experienced between the start of the stereotactic radiotherapy and 6 
months after radiotherapy. DLTs will be graded according to the CTEP active version of the 
National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
The current version is CTCAE v4.0. 
 
For this study, DLTs are defined as follows: 
The following grade 2 or higher toxicities:  
 

 
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• Myelitis 
• Esophageal fistula, perforation, hemorrhage 
 
The following grade 3 or higher toxicities considered to be a direct result of therapy:  
 
 
• Pneumonitis  
• Pericarditis, pericardial effusion 
• Esophageal necrosis, stenosis, ulcer 
• Dyspnea 
 
The following grade 4 toxicities:  
 
 
• Esophagitis 
• Pericardial tamponade 
• Pulmonary toxicity excluding infectious pneumonia 
• Skin toxicity  
• Hemoptysis/pulmonary hemorrhage 
 
All grade 5 toxicities, including:  
 
• Pulmonary toxicity including pneumonitis 
• Excluding infectious pneumonia 
 
 
 
6.3 
Toxicities and Adverse Events 
 
6.3.1 Toxicities 
 
6.3.1.1 All patients will be seen weekly by their treating radiation oncologist or co-
investigators (pediatric oncologist) while undergoing therapy.  The following 
toxicities are expected and listed according to their likelihood and whether they are 
immediate or long term.  
 
Evaluation of toxicity.  All participants will be evaluable for toxicity from the time 
of their first treatment. Evaluation will be by the radiation oncology physician or by 
the patient’s pediatric oncologist by physical examination and testing as indicated in 
the study calendar. Patients will be seen by the radiation oncologist for each treatment 
to assess toxicities and adverse events. 
 
 
 
6.3.1.2 Immediate Toxicities 
 
 
Common (>20%) 
• Tiredness 

 
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• Hair loss in the treatment field 
• Skin redness in the treatment field 
 
Uncommon (10-20%) 
• Inflammation of the lung 
   
Rare (<10%) 
• Nausea 
 
      6.3.1.3 Late Toxicities 
          
Common (>20%)   
• Scarring of the lung not requiring treatment (permanent) 
     
Uncommon (10-20%) 
• Shortness of breath (permanent) 
• Skin dryness in the treatment field (permanent) 
• Inflammation of the heart (duration weeks) 
• Chest wall pain 
 
Rare (<10%) 
• Inflammation of the muscles of the chest wall (duration weeks) 
• Scarring of the lung requiring treatment (permanent) 
• Rib fracture 
• Tumors caused by radiotherapy (lifelong) 
 
Extremely rare (<5%)        
• Spinal cord injury (permanent) 
• Fatal inflammation of the lung 
 
6.3.1.4 Clinical discretion may be used in managing radiotherapy-related side effects. 
 
 
6.3.2 Adverse Event Reporting 
 
6.3.2.1 Definitions 
 
6.3.2.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical 
condition or experience that develops or worsens in severity after starting 
the first dose of study treatment or any procedure specified in the protocol, 
even if the event is not considered to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse 
events only if they induce clinical signs or symptoms or require treatment 

 
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or further diagnostic tests. 
 
6.3.2.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose 
and regardless of causality that: 
 
• Results in death 
 
• Is life-threatening. Life-threatening means that the person was at 
 immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction which hypothetically might have caused death had it 
occurred in a more severe form. 
 
• Requires or prolongs inpatient hospitalization (i.e., the event 
required at least a 24-hour hospitalization or prolonged a 
hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not 
considered SAEs if the illness or disease existed before the person 
was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier 
than planned). 
 
• Results in persistent or significant disability/incapacity. Disability 
is defined as a substantial disruption of a person’s ability to 
conduct normal life functions. 
 
• Is an important medical event when, based upon appropriate 
medical judgment, it may jeopardize the participant and require 
medical or surgical intervention to prevent one of the outcomes 
listed above. 
 
Events not considered to be serious adverse events are hospitalizations 
for: 
• routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition, or for elective 
procedures 
• elective or pre-planned treatment for a pre-existing condition that 
did not worsen 
• emergency outpatient treatment for an event not fulfilling the 
serious criteria outlined above and not resulting in inpatient 
admission 
• respite care 
 
6.3.2.1.3 Expectedness 

 
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Adverse events  
 
6.3.2.1.3.1 Expected adverse event (toxicities) 
 
Expected adverse events are those that have been previously identified as 
resulting from administration of stereotactic body radiotherapy. For the 
purposes of this study, an adverse event is considered expected when it 
appears in the current adverse event list or is included in the informed 
consent document as a potential risk. 
Please refer to Section 6.3.1 for a listing of expected toxicities. 
 
6.3.2.1.3.2 Unexpected adverse event 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information provided 
in the current adverse event list or when it is not included in the informed 
consent document as a potential risk. 
 
6.3.2.1.3.3 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse 
event and the study treatment. Attribution will be assigned as follows: 
 
 Definite – The AE is clearly related to the study treatment. 
 Probable – The AE is likely related to the study treatment. 
 Possible – The AE may be related to the study treatment. 
 Unlikely - The AE is doubtfully related to the study treatment 
 Unrelated – The AE is unrelated to the study treatment 
 
 
6.3.2.2 Procedures for AE and SAE Recording and Reporting 
 
During the study investigators will assess the occurrence of AEs and SAEs at all 
participant evaluation time points. AEs will be evaluated using the descriptions and 
grading scales found in the CTEP active version of the NCI TCAE located on the 
CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
The current version is CTCAE v4.0. 
 
All AEs and SAEs, whether reported by the participant, discovered during 
questioning, directly observed, or detected by physical examination, laboratory test or 
other means, will be recorded in the participant’s medical record and on the 
appropriate study specific case report forms. 
 

 
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Monitoring 
 
All adverse events, both serious and non-serious, and deaths that are encountered 
from initiation of study intervention, throughout the study, and within 6 months of the 
last study intervention should be followed to their resolution, until the investigator 
assess them as stable or determines the event to be irreversible, or the participant is 
lost to follow-up. The presence and resolution of AEs and SAEs (with dates) should 
be documented on the appropriate case report form and recorded in the participant’s 
medical record to facilitate source data verification. 
 
6.3.2.3 Reporting Requirements 
 
All investigators are required to abide by the reporting requirements set by the 
DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the principal investigator 
(PI). The PI will be notified of all AEs and SAEs. 
 
6.3.2.3.1 Reporting to Institutional Review Board (IRB) 
 
SAEs will be reported directly to the DFCI IRB via the DFCI Office for 
Human Research Studies (OHRS). Copies of all SAE report forms will be 
sent to the PI: 
Karen J Marcus, MD 
Email: kmarcus@partners.org 
Phone: 617-355-8399 
Fax: 617-730-0211 
 
 
6.3.2.3.2 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study 
treatment, during treatment, or within 6 months of the last dose of 
treatment must be reported to the DF/HCC Overall Principal Investigator 
and the DFCI IRB. SAEs include events meeting the criteria outlined in 
Section 6.3, as well as the following: 
 
 Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and 
at least possibly related/associated with the intervention. 
 All Grade 4 (life-threatening or disabling) events that are unexpected or 
not specifically listed in the protocol as not requiring reporting. 
 All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention. 
 
Note: If the participant is in long term follow up, report the death at the 
time of continuing review. 
 

 
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Investigators must report each serious adverse event to the PI within 24 
hours of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hours after 
learning of it and document the time of his or her first awareness of the 
adverse event. 
 
Within the following 24-48 hours, the participating investigator must 
provide follow-up information on the SAE. Follow-up information should 
describe whether the event has resolved or continues, if and how the event 
was treated, and whether the participant will continue or discontinue study 
participation. 
 
6.3.2.3.3 Non-Serious Adverse Event Reporting 
Non-serious adverse events will be reported to the PI on the toxicity case 
report forms. 
 
6.3.3 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
 
7. OTHER THERAPIES 
 
If systemic anti-cancer treatment is urgently required during the two weeks of study 
treatment, the subject will be removed from the study and replaced.  However, patients will 
be allowed to receive concurrent immunotherapy.  
 
During the Phase I portion, if clinically indicated, systemic therapy can be given and the 
subject will remain evaluable for the phase I (toxicity) portion. Surgery (other than to index 
lesions) will be allowed. These patients will be scored as unevaluable for response 
assessment. 
 
During the Phase II portion, if systemic therapy is needed prior to the 6 week post-treatment 
assessment time, that subject but will be scored as UNEVALUABLE for response 
assessment but will be followed for toxicity.  Surgery (other than to index lesions) is 
allowed if clinically indicated and the subject will remain evaluable. 
 
However, if the reason for non-protocol surgery or chemotherapy is disease worsening of 
the index lesions, those patients would be scored as disease progression  
 
Patients may receive Decadron orally prior to each fraction of radiotherapy per physician 
discretion. 
 

 
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8. TISSUE/SPECIMEN SUBMISSION 
 
Not applicable.  
 
 
9. PARTICIPANT ASSESSMENTS 
 
Evaluation of response.  All participants included in the study will be assessed for response 
to treatment, unless the subject received systemic therapy prior to the 6 week assessment.. 
Response in this study will be defined as disease control in the treated lesion at 6 weeks.  
We will continue to assess response and consider best overall response as a secondary 
objective. 
Each participant will be assigned one of the following categories: 1) complete response, 2) 
partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant 
disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown 
(not assessable, insufficient data). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database. 
 
Disease control at 6 weeks will include complete response (CR), partial response (PR) and 
stable disease (SD).   
 
Patients will be seen weekly during treatment for physical examination and assessment of 
acute side effects.  They will then be seen at one month from the end of study treatment for 
physical examination, A CT at will be done at 6 weeks post completion of SBRT  and then 
every three months  with physical examination and CT scan of the chest during the first 
year, followed by every 6 months for the next year and then annually until year 5, as is 
considered standard of care. (See: Study Calendar) 
  
The lesion or lesions treated will be measured as well as new lesions identified. 
Pulmonary function tests will be done at 3 months post treatment, then at 9 months. 
 
9.1 
Response Criteria 
 
9.1.1 Evaluation of Target Lesions (response will be measured using CT scans) 
 
Complete Response (CR)  
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.  
 
Partial Response (PR)  
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters  
 
 
Progressive Disease (PD)  
At least a 20% increase in the sum of the diameters of target lesions, taking as 

 
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reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
 
NOTE: The appearance of one or more new lesions will not be considered 
progression.   
 
Stable Disease (SD)  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study. (Note: a change of 
20% or more that does not increase the sum of the diameters by 5 mm or more is 
coded as stable disease).  To be assigned a status of stable disease, measurements 
must have met the stable disease criteria at least once after study entry at a minimum 
interval of 6 weeks.  
 
 
9.1.2 Evaluation of New Lesions  
 
The appearance of new lesions will not be considered Progressive Disease (PD). The 
goal of this study is to evaluate the safety and efficacy of stereotactic radiotherapy to 
individual lesions.  If subject develops new lesions, this would not impact the study 
results.  For example, a new lesion might be amenable to SBRT. However, on this 
protocol such new lesions will not be treated.   
 
 
 
9.1.4 Evaluation of Best Overall Response  
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient’s best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
 

 
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Target 
Lesions 
New 
Lesions 
Best Overall 
Response 
Remarks 
CR 
Yes or 
No 
CR 
 
PR 
Yes or 
No 
PR 
 
SD 
Yes or 
No 
SD 
Documented at 
least once >6 wks. 
from study entry 
PD 
Yes or 
No 
PD 
 
No prior SD, PR  
or CR 

 
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Study Calendar 
 
a PFTs (pulmonary function tests) will be performed only at 3 and 6 months (+/- 2 wks) after 
SBRT. 
b All serious adverse events that occur after the initial dose of study treatment, during treatment, 
or within 6 months of the last dose of treatment 
 
10.     DATA COLLECTION 
10.1  Study Documentation 
 
After a participant is enrolled on the study, we will collect information about their diagnosis, 
treatment, and any side effects of treatment as well as demographic data. Information 
regarding the tolerability of SBRT in the study population and any information about 
disease relapse if it should occur after study treatment. Study participants will be assigned a 
study number by the study team and all information will be de-identified when analyzed. 
This de-identified data will be stored electronically in the ODQ system and protected by 
multiple firewalls that exist within the Partners network. Any paper records including Case 
Report Forms will be stored in an office secured by a lock that only study team members 
have access to. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded data 
from automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  
 
 
Pre-
study 
Week 
1 
Week  
2 
One 
month 
(+/- 2 
wks) post 
SBRT 
Every 3 months 
(+/- 2 wks) after 
first assessment 
done 6weeks after 
SBRT during first 
year 
Every 6 
months 
(+/- 6 wks) 
during 
second 
year  
Annually for 
the third, 
fourth, and 
fifth years 
SBRT 
 
x 
x 
 
 
 
  
Informed 
consent 
x 
 
 
 
 
 
  
History 
x 
 
 
x 
x 
x 
x 
Physical Exam 
x 
x 
x 
x 
x 
x 
x 
CT chest and 
tumor 
measurement 
x 
 
 
x (6 
weeks 
post 
SBRT) 
x 
x 
x 
PFTS 
x 
 
 
 
xa 
 
 
CBC 
x 
 
 
 
 
 
 
Adverse event 
reporting b 
 
x 
x 
x 
x 
x 
 

 
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11     STATISTICAL CONSIDERATIONS  
 
11.1 Study Design/Endpoints 
 
A 3+3 study design will be used in the Phase I portion and patients will enter the study in 
sets of three for each cohort.  For a given dose level, if none of three patients experiences a 
DLT, this dose level will move forward to the Phase II portion.  However, if one patient 
experiences a DLT among the first three patients at any dose level, three more patients will 
be treated at that dose level.  The dose level will enter the Phase II portion if no further DLT 
is observed following observation period of 6 months from treatment completion of third 
patient in the cohort.  If a DLT is observed in any of the three additional patients, this dose 
level will not move forward to the Phase II portion and the dose will be de-escalated to the 
next lower level.  If two or more patients experience a DLT among the first 3 patients, dose 
de-escalation will ensue, if applicable, without further testing of that dose level in the phase 
II portion.  The table below shows the probability of entering the phase II portion for a dose 
level under different true DLT rates. 
  
True DLT rate 
5% 
10% 
15% 
20% 
30% 
40% 
Probability of entering phase II 0.97 
0.91 
0.81 
0.71 
0.49 
0.31 
 
Once a dose level enters the Phase II portion, a two-stage design will be used to evaluate 
efficacy.  The first stage will accrue seven patients, including the patients enrolled at the 
same dose level in the Phase I portion.  If at least two responses are observed among the 
seven patients, additional eight patients will be entered.  If five or more responses are 
observed among the fifteen patients, there will be no further dose escalation and this dose 
level will be considered tolerable and effective for this patient population. With this design, 
the Phase II portion has 90% power to test the response rate of 50% vs. 20% based on a 0.14 
level one-sided exact binomial test.  The probability of stopping early is 0.58 if the true 
response rate is 20%; whereas if the true response rate is 50%, this probability is 0.06. 
 
If a dose level examined in the Phase II portion does not meet the pre-specified criteria for 
efficacy, the next higher dose level will start in the Phase I portion until a dose level that 
meets both Phase I and Phase II criteria for safety and efficacy is found.  If a dose level does 
not meet the safety criteria (none of three or no more than one out of six develops a DLT), 
and the next lower dose level does not meet the Phase II pre-specified criteria for efficacy, 
the study will be terminated.  If two or more DLTs are observed at the starting dose level, 
the SBRT dose will be de-escalated to the next lower dose level; if this happens at dose 
level 1 (the lowest dose level), the study will be terminated. The same Phase I/II design 
applies to both cohorts, renal tumor (cohort 1) and Ewing patients (cohort 2), separately, 
except for the starting dose level in the Phase I portion.   
 
11.2 Sample Size, Accrual Rate and Study Duration 
 
We expect to accrue 3 patients per year in the   renal tumor cohort (cohort 1) and 5 per year 
in the non-renal (Ewing/RMS) cohort (cohort 2).  The maximum total accrual for a given 
dose level for both cohorts combined is 30.  The accrual is expected to be completed in 5 

 
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years in the renal cohort and 2 years in the nonrenal cohort, for a dose level to be examined 
in both the Phase I portion and the Phase II portion. 
 
11.3 Analysis of Primary Endpoints 
 
This is a Phase I/II study to determine the lowest dose level of stereotactic body 
radiotherapy (SBRT) with an acceptable safety profile and efficacy in patients with relapsed 
Ewing sarcoma, rhabdomyosarcoma, soft tissue sarcoma or primary renal tumors (including 
Wilms tumor) who have limited pulmonary metastases.  The primary objective of the Phase 
I portion is to evaluate the toxicity profile of each dose level and determine whether a given 
dose level could move forward to the Phase II portion.  The primary endpoint of the Phase II 
portion is response to treatment (disease control at 6 weeks in the treatment field).  The 
response rate along with the 95% two-stage confidence interval will be reported by dose 
level for each cohort.  The Phase I and Phase II designs will be employed sequentially, i.e., a 
dose level will be examined in the Phase I portion for safety and then in the Phase II portion 
for efficacy if the Phase I safety criteria are met, to achieve the goal of balancing safety and 
efficacy in these rare tumor populations.  
  
Given that the starting dose in the Phase I portion will be different for the patients with 
Wilms/renal tumor and the patients with relapsed Ewing sarcoma, rhabdomyosarcoma, soft 
tissue sarcoma, patients will be enrolled in two distinct cohorts, and escalate through the 
dose levels and enter the Phase II portion independently.   
 
11.4 Analysis of Secondary Endpoints 
 
Secondary endpoints include relapse elsewhere in the lung and toxicities, and these analyses 
will be performed by dose level.  The method of Kaplan and Meier will be used to 
characterize time to relapse elsewhere in the lung.  All patients who receive any part of the 
treatment will be monitored for toxicity, and the percent of patients with various toxicities 
will be tabulated for each dose level.  Assuming a total of 15 patients treated at a dose level, 
if the true probability of a rare toxicity is 5%, the probability of observing 1 or more rare 
toxicities is 54%.  A 90% confidence interval for any toxicity will be no wider than 46%. 
 
 
12     REGULATORY CONSIDERATIONS 
12.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will 
disseminate protocol amendment information to all participating investigators.  

 
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All decisions of the IRB concerning the conduct of the study must be made in writing. 
12.2 Informed Consent 
 
All participants and their parents must be provided a consent form describing this 
study and providing sufficient information for participants to make an informed 
decision about their participation in this study. The formal assent of a participant, 
using the IRB approved consent form, must be obtained before the participant is 
involved in any study-related procedure. The consent form must be signed and dated 
by the participant’s legally authorized representative, and by the person obtaining the 
consent if the participant is under the age of 10 years. If the participant is over the age of 
10 years, they may provide verbal assent to participate and form must be signed and 
dated by the person obtaining the assent. The participant must be given a copy of the 
signed and dated consent document. The original signed copy of the consent document 
must be retained in the medical record or research file.  
 
12.3 Study Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical 
specialists with experience in oncology and who have no direct relationship with the 
study. Information that raises any questions about participant safety will be addressed 
with the Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; any response information; audit 
results, and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request. Information that raises any questions 
about participant safety will be addressed with the Principal Investigator and study team.
 
 
12.4 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent 
good and sound research practice: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 

 
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o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx 02/21cfr56 02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
12.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
 
13     PUBLICATION PLAN 
 
We plan to publish this study and, if the results are favorable, we will develop a Phase II 
protocol to follow the present one.  The Principal Investigator will hold primary 
responsibility for publication of the study results.  
 
We expect to make the results public within 24 months of the end of data collection. We 
plan to publish a report in a peer-reviewed journal, however we may submit an abstract prior 
to that publication submission.  The abstract will meet the requirements of the International 
Committee of Medical Journal Editors. A full report of the outcomes will be made public no 
later than three (3) years after the end of data collection.  
 
 
 

 
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REFERENCES 
 
1. Paulusssen M, Aherns S, Burdach S, et al: Pulmonary metastatic (Stage IV) Ewing 
tumor: survival analysis of 171 patients from the EICESS studies.  European Intergroup 
Cooperative Ewing Sarcoma Studies. Ann Oncol 9 (3):275-281, 1998. 
 
2. Spunt SL, McCarville MB, Kun LE, et al: Selective use of whole-lung radiotherapy in 
Ewing sarcoma family of tumors and pulmonary metastases at the time of diagnosis. J 
PediatrHematolOncol 23(2):93-98, 2001.  
 
3. Uematsu M, Shioda A, Suda A, Fukui T, Ozeki Y, Hama Y, Wong JR, Kusnao S. 
Computed tomography-guided frameless stereotactic radiotherapy for stage I non-small 
cell lung cancer: a 5-year experience.Int J RadiatOncolBiolPhys 2001; 51:666-670. 
 
4. Onishi H, Shirato H, Nagata Y, Hiraoka M, Fujino M, Gomi K, Niibe Y, Karasawa K, 
Hayakawa K, Takai Y, Kimura T, Takeda A, Ouchi A, Hareyama M, Kokubo M, Hara R, 
Itami J, Yamada K, Araki T. Hypofractionated stereotactic radiotherapy (HypoFXSRT) 
for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-
institutional study.JThoracOncol.2007;2 (Suppl 3):S94-100. 
 
5. McGarryRC, Papiez L, Williams M, et al: Stereotactic body radiation therapy of early-
stage non-small-cell lung carcinoma: Phase I study. Int J RadiatOncolBiolPhys 63:1010-
1015, 2005. 
 
 

 
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APPENDIX A 
DOSE ESCALATION BY DISEASE 
 
 
 
Cohort 1: 
Wilms/Renal tumor 
 
Cohort 2: 
Ewing sarcoma, Sarcoma 
and 
Rhabdomyosarcoma 
Level 1      8 Gy x 3 
Starting dose level 
De-escalation dose level 
 
 
 
Level 2      10 Gy x 3 
Next dose level 
Starting dose level 
 
 
 
Level 3      12 Gy x 3 
Final dose level 
Final dose level 
 
 
 
 
 
 

 
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APPENDIX B 
UTSW DOSE CONSTRAINTS