A Phase II Randomized Trial of RAdium-223 and SABR Versus SABR for oligomEtastatic Prostate caNcerS (RAVENS)
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

 
COVER SHEET 
 
 
 
 
 
A phase II randomized trial of RAdium-223 and SABR Versus SABR for 
oligomEtastatic prostate caNcerS (RAVENS) 
 
NCT04037358 
 
Document Date:  February 7, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A phase II randomized trial of                                                      
RAdium-223 and SABR Versus SABR for oligomEtastatic prostate 
caNcerS (RAVENS) 
 
Protocol Number 
 
J18147 
IND Number  
 
EXEMPT for Xofigo 
 
 
 
 
 
 
 
Principal Investigator 
Ana P. Kiess, MD, PhD   
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
Weinberg Building 
401 N. Broadway, Suite 1442 
Baltimore, MD  21287 
Phone:  443-287-7528 
Fax:      410-502-1419 
Email:  akiess1@jhm.edu 
 
 
Co-Investigators 
  
Theodore DeWeese, M.D. 
Danny Song, M.D. 
Michael Carducci, M.D. 
Mark Markowski, M.D. 
Samuel Denmeade, M.D. 
Channing Paller, M.D. 
Kenneth Pienta, M.D. 
Martin Pomper, M.D., PhD 
Stephen Greco, M.D. 
Curtiland DeVille, M.D. 
Fariba Asrari, M.D. 
Michael Goldstein, M.D. 
 
Statisticians 
Hao Wang, PhD 
 
 
Suqi Ke 
 
 
 
 
Research Nurse 
Shirl Dipasquale 
 
Research Managers: 
Dana Kaplin 
 
 
 
Funding: 
 
 
Bayer Pharmaceuticals 
 
 
 
 
                                                 

                                                  Protocol Date: February 07, 2025 
 
 
 
 
CONTACT INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
PARTICIPATING SITE 
(address included) 
 
 
  
 
 
 
 
Name 
 
 
Contact Information 
(email address and phone) 
 
 
Lead Investigator 
 
 
 
 
 
 
 
 
Clinical Coordinator(s) 
 
 
 
Regulatory Specialist(s) 
 
 
 
Other roles (please specify) 
 
 

 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information contained 
herein will not be disclosed to others without written authorization from the lead site/sponsor, 
except to the extent necessary to initiate the study or conduct study‐related activities. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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Table of Contents 
 
SCHEMA ........................................................................................................................................................................ 8 
 
1. 
PROTOCOL SYNOPSIS ..................................................................................................................................... 9 
2. 
ABBREVIATIONS AND DEFINITIONS OF TERMS .......................................................................................... 11 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................................................................ 12 
3.1 STUDY DESIGN ................................................................................................................................. 12 
3.2 PRIMARY OBJECTIVE ........................................................................................................................ 12 
3.3 SECONDARY OBJECTIVES ................................................................................................................. 12 
3.4 CORRELATIVE OBJECTIVES ............................................................................................................... 13 
4. 
BACKGROUND ................................................................................................................................................. 13 
4.1 OLIGOMETASTATIC DISEASE ............................................................................................................. 13 
4.2 STEREOTACTIC BODY RADIATION THERAPY (SBRT) OR STEREOTACTIC ABLATIVE RADIATION THERAPY       
(SABR) ........................................................................................................................................... 14 
4.3 RATIONALE FOR USE OF SBRT/SABR IN OLIGOMETASTATIC DISEASE................................................ 15 
4.4 RATIONALE FOR RADIUM-223 FOR BONE METASTASES IN PROSTATE CANCER ..................................... 17 
4.5 RATIONALE FOR SBRT/SABR FOR BONE OLIGOMETASTASES IN PROSTATE CANCER ......................... 17 
4.6 RATIONALE FOR PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA) ................................................... 18 
4.7 RATIONALE FOR CORRELATIVE SCIENCE ............................................................................................ 20 
5. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ................................................................. 25 
5.1 INCLUSION CRITERIA ......................................................................................................................... 25 
5.2 EXCLUSION CRITERIA ....................................................................................................................... 27 
6. 
PATIENT REGISTRATION AND TREATMENT PLAN ...................................................................................... 27 
6.1 MULTI-CENTER 
REGISTRATION……………………………………………………………………………………………...27 
6.2    RANDOMIZATION ............................................................................................................................... 29 
6.3 DIAGNOSTIC PROCEDURES ............................................................................................................... 29 
6.4 THERAPEUTIC PROCEDURES ............................................................................................................. 29 
6.5 TREATMENT COMPLIANCE ................................................................................................................. 37 
6.6 DRUG ACCOUNTABILITY .................................................................................................................... 37 
6.7 FOLLOW-UP PROCEDURES ............................................................................................................... 37 
6.8 DURATION OF THERAPY .................................................................................................................... 39 
6.9 DURATION OF STUDY ACCRUAL ......................................................................................................... 40 
6.10 DURATION OF FOLLOW-UP ................................................................................................................ 40 
6.11 CRITERIA FOR PATIENT REMOVAL ..................................................................................................... 40 
6.12 ALTERNATIVES ................................................................................................................................. 40 
6.13 COSTS ............................................................................................................................................. 40 
6.14 COMPENSATION ............................................................................................................................... 41 
6.15 WITHDRAWAL FROM STUDY .............................................................................................................. 41 
7. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ............................................................. 41 
7.1 INVESTIGATIONAL AGENT – RADIUM-223 ........................................................................................... 41 
7.2 INVESTIGATIONAL AGENT – PSMA-PET/CT ...................................................................................... 41 
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
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8. 
STUDY CALENDARS ........................................................................................................................................ 41 
 
STUDY CALENDAR: SABR ARM ONLY............................................................................................................ 43 
          STUDY CALENDAR: SABR = RADIUM-223 ARM............................................................................................. 45 
9. 
MEASUREMENT OF EFFECT .......................................................................................................................... 47 
9.1 ANTITUMOR EFFECT – METASTATIC TUMORS ..................................................................................... 47 
9.2 DEFINITIONS..................................................................................................................................... 47 
9.3 DISEASE PARAMETERS ..................................................................................................................... 47 
9.4 METHODS FOR EVALUATION OF MEASURABLE DISEASE ...................................................................... 48 
9.5 RESPONSE CRITERIA ........................................................................................................................ 48 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS ........................................................................................ 50 
10.1 GENERAL ......................................................................................................................................... 50 
10.2 DEFINITIONS..................................................................................................................................... 51 
10.3 POTENTIAL ADVERSE EVENTS ........................................................................................................... 52 
10.4 STEREOTACTIC BODY RADIATION TREATMENT (SBRT) OR STEREOTACTIC ABLATIVE RADIATION 
TREATMENT (SABR) ........................................................................................................................ 52 
10.5 REPORTING PROCEDURES ................................................................................................................ 53 
11. 
DATA REPORTING AND REGULATORY REGULATIONS AND SAFETY MONITORING PLAN .................... 58 
12. 
DATA SAFETY MONITORING PLAN ............................................................................................................... 58 
12.1 DATA MANAGEMENT .......................................................................................................................... 58 
12.2 DATA SAFETY .................................................................................................................................... 59 
12.3 MULTICENTER GUIDELINES ................................................................................................................ 61 
12.4 BIOSPECIMEN MANAGEMENT ............................................................................................................. 63 
 
13. 
REGULATORY CONSIDERATIONS .................................................................................................................. 63 
13.1 PROTOCOL REVIEW AND AMENDMENTS ............................................................................................. 63 
13.2 INFORMED CONSENT ........................................................................................................................ 64 
13.3 ETHICS AND GCP ............................................................................................................................. 64 
14. 
STATISTICAL CONSIDERATIONS ................................................................................................................... 64 
14.1 ENDPOINTS ...................................................................................................................................... 64 
14.2 SAMPLE SIZE/ACCRUAL RATE/FOLLOW-UP......................................................................................... 65 
14.3 EARLY STOPPING GUIDELINES: ......................................................................................................... 65 
14.4 ANALYSIS OF PRIMARY OBJECTIVE .................................................................................................... 66 
14.5 ANALYSIS OF SECONDARY OBJECTIVES ............................................................................................. 66 
14.6 EVALUATION OF TOXICITY ................................................................................................................. 66 
14.7 CORRELATIVE SCIENCE .................................................................................................................... 67 
15. REFERENCES ...................................................................................................................................................... 68 
16. APPENDICES ........................................................................................................................................................ 70 
APPENDIX I: BRIEF PAIN INVENTORY FORM ................................................................................................. 70 
APPENDIX II: PERFORMANCE STATUS CRITERIA .......................................................................................... 72 
APPENDIX III: CAPP-SEQ SAMPLE COLLECTION & PROCESSING ................................................................... 73 
APPENDIX IV: EPIC-HD CTC SAMPLE COLLECTION & PROCESSING .............................................................. 74 
APPENDIX V: IMMUNOSEQ SAMPLE COLLECTION & PROCESSING ................................................................. 76 
APPENDIX VI: RECTAL SWAB COLLECTION FOR MICROBIOME ANALYSIS ...................................................... 78 
APPENDIX VII: ORDERING FROM INVITAE .................................................................................................... 79 
APPENDIX VIII: IMMUNOPHENOTYPING ........................................................................................................ 81 
APPENDIX IX: RAPID SPECT IMAGING SUB-CONTRACT STUDY ................................................................. 83 
APPENDIX X: XOFIGO PATIENT INFORMATION SHEET..................................................................................... 91 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
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APPENDIX XI: BAYER PATIENT RELEASE CARD.............................................................................................. 92 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Men with histologically confirmed oligometastatic (<3 mets on standard imaging or 
<5 on Axumin/Choline/18F-DCFPyL (“PyL”) -PET/CT;at least 1 bone met)  
hormone-sensitive prostate cancer and the following: 
PSADT <15 mos, tumors ≤ 5.0 cm or <250 cm3, Age >18 yrs & ECOG < 2 
Day 1 
PSA, LDH, CBC, Chemistry Panel (CMP), ctDNA (CAPP-seq), CTC-HD (Epic-HD), 
PBMCs (ImmunSEQ), Immunophenotyping, Rectal Swab & Invitae Test 
 
Month 3 
PSA, LDH, CBC, Chemistry Panel (CMP), UA, ctDNA (CAPP-seq), PBMCs 
(ImmunSEQ), Immunophenotyping & Rectal Swabs 
     Follow-Ups: Q6 Months 
              SOC labs (CBC, CMP, PSA, LDH), Bone Scan & CT-chest/abdomen/pelvis 
Total: 2 year f/u (4 visits) 
Day 1-30 (Both arms) 
SABR 
 
Randomize 1:1 
       
  
SABR (n=32)    versus     SABR + Radium-223 (n=32) 
Month 6 
PSA, LDH, CBC, Chemistry Panel (CMP), Testosterone, ctDNA (CAPP-seq), 
Immunophenotyping & CTC-HD (Epic-HD); and Bone scan & CT-
chest/abdomen/pelvis or Axumin/Choline PET 
Day 1-Month 6 (SABR + Radium-223 ONLY) 
Six Radium-223 monthly infusions  
     Month 12 
  
PSA, LDH, CBC, Chemistry Panel (CMP), Testosterone, Immunophenotyping& 
ctDNA (CAPP-seq); and Bone scan & CT-chest/abdomen/pelvis and/or 18F-DCFPyL 
(“PyL”) -PET/CT  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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1. PROTOCOL SYNOPSIS 
TITLE 
A phase II randomized trial of RAdium-
223 and SABR Versus SABR for 
oligomEtastatic prostate caNcerS 
(RAVENS)  
STUDY PHASE 
Phase II 
INDICATION 
Men with oligometastatic disease (<3 
mets) and at least one bone metastasis 
INVESTIGATIONAL PRODUCT 
Radium-223 (Xofigo®) is an alpha-
emitting radioisotope developed by Algeta 
ASA. Radium-223 is indicated for 
treatment of men with castrate-resistant 
prostate cancer (CRPC) with symptomatic 
bone metastases and no known visceral 
metastatic disease. The approved dose 
and schedule of radium-223 is 50 kBq (or 
1.35 microcurie) (55 kBq/kg (or 1.49 
microcurie)) after implementation of the 
NIST update) per kg body weight 
intravenous (IV) infused at 4 week interval 
for 6 injections  
PRIMARY OBJECTVES 
• To assess progression-free 
survival of men who have  
oligometastatic prostate cancer 
after randomization to stereotactic 
ablative radiation therapy (SABR) 
versus SABR and Radium-223  
SECONDARY OBJECTIVES 
• To assess the toxicity of SABR + 
Radium-223 in patients with 
oligometastatic disease 
• To determine local control at 12-
months after SABR versus SABR 
+ Radium-223 in patients with 
oligometastatic disease  
• To assess time to locoregional 
progression, time to distant 
progression, time to new 
metastasis and duration of 
response  
• To assess ADT-free survival after 
randomization to SABR versus 
SABR + Radium-223 
• To assess quality of life following 
SABR versus SABR + Radium-223  
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
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CORRELATIVE SCIENCE 
• To enumerate circulating tumor 
cells (CTC) using EPIC HD-CTC 
platforms at baseline, months 3, 6 
and 12 from randomization. 
• To enumerate circulating tumor 
DNA (ctDNA) using Cancer 
Personalized Profiling by deep 
sequencing (CAPP-Seq) at 
baseline, months 3, 6 and 12 from 
randomization for SABR versus 
SABR + Radium-223.  
• To quantitatively sequence T-cell 
receptor (TCR) repertoires using 
peripheral blood monocytes and 
the ImmunoSEQ platform at 
baseline, months 3, 6 and 12 from 
randomization. 
• To evaluate immunophenotypes by 
running PBMCs through a Cytek 
Aurora machine, which allows for 
simultaneous detection of up to 25 
markers; to evaluate metabolic 
fitness of the total PBMCs using 
the mitochondrial stress test on the 
Seahorse analyzer; and to 
determine the relative capacity of 
peripheral T cells to metabolically 
respond to T cell receptor 
stimulation through activation of 
CD3 and CD28 by running 
functional assays on PBMCs. 
• To determine frequency of 
germline DNA repair mutations in 
the oligometastatic state 
• Descriptive statistics will be 
performed to correlate the metrics 
above with clinical outcomes. 
HYPOTHESES 
SABR + Radium-223 will increase median 
progression-free survival from 10 months 
in the SABR arm to 20 months in the 
SABR + Radium-223 arm 
STUDY DESIGN 
Men with oligometastatic prostate cancer 
lesions will be randomized (1:1) to SABR 
versus SABR + Radium-223. The study 
will NOT be blinded. Within three weeks 
of the initial treatment planning, SABR(1-

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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5 fractions) will be administered for all 
men.  For the SABR + Radium-223 the 1st 
radium-223 infusion will be within four 
weeks from randomization.  
SAMPLE SIZE BY TREATMENT GROUP 64 patients total   
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
1.Metastatic bone or nodal sites ≤ 3 on 
standard imaging (or ≤ 5 on Axumin, 
Choline with at least one bone 
metastasis. 
2.PSADT <15 months 
3.Tumor ≤ 5.0 cm or <250 cm3. 
4.Age > 18 years. 
5.ECOG perfomance status ≤ 2. 
6.Histologic confirmation of malignancy 
(primary or metastatic tumor). 
CONTROL GROUP 
N/A 
PROCEDURES 
1. Physical exam 
2. CT/MRI and Bone scan and/or 18F-
DCFPyL (“PyL”) PET/CT of Involved Site 
3. Randomization 
4. Blood draws, Rectal Swab and Invitae 
Test 
5. SABR versus SABR + Radium-223 
6. CT/MRI Scan and Bone Scan or 
Axumin/Choline-PET of Involved Site at 6 
months 
8. 18F-DCFPyL (“PyL”) PET/CT at 360 
Days from first “PyL” 
 
 
 
2. ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
Activities of daily living 
AE 
Adverse event 
BID 
Twice daily 
BSA 
Body surface area 
CBC 
Complete blood count 
CI 
Confidence interval 
CMAX 
Maximum concentration of drug 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
CRPC 
Castration-Resistant Prostate Cancer 
CTC 
Circulating Tumor Cell 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field  
HTN 
Hypertensions 
IRB 
Institutional Review Board 
IV 
Intravenous 
LLN 
Lower limit of normal  
MTD 
Maximum tolerated dose 
OS 
Overall survival  
PLT 
Platelet 
PD 
Progressive diseased 
PFS 
Progression free survival  
PR 
Partial response 
PSADT 
PSA Doubling Time 
PSMA 
Prostate Specific Membrane Antigen 
QD 
Once daily 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SABR 
Stereotactic ablative radiation therapy 
SAE 
Serious adverse event 
SBRT 
Stereotactic body radiation therapy 
SD 
Stable disease 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
WBC 
White blood cell 
 
3. STUDY DESIGN AND OBJECTIVES 
3.1 Study Design 
Phase II non-blinded randomized, multi-center, study evaluating men with 
oligometastatic prostate cancer lesions randomized (1:1) to stereotactic ablative 
radiation therapy (SABR) versus SBAR + Radium-223.  
3.2 Primary Objective 
To determine the progression-free survival of men who have oligometastatic 
prostate cancer with at least one bone metastasis with stereotactic ablative 
radiation therapy (SABR) versus SABR + Radium-223. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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3.3 Secondary Objectives 
To assess the toxicity of SABR + Radium-223 in patients with oligometastatic 
disease. 
 
To determine local control at 12-months after SABR + Radium-223 in patients with 
oligometastatic disease. 
 
To assess time to locoregional progression, time to distant progression, time to 
new metastatsis and duration of response after randomization to SABR versus 
SABR + Radium-223. 
 
 
 
 
 
 
 
 
 
To assess ADT-free survival after randomization to SABR versus SABR + Radium-
223. 
 
To assess quality of life following completion of SABR + Radium-223. 
3.4 Correlative Objectives 
To enumerate circulating tumor cells (CTC) using EPIC HD-CTC platforms at 
baseline and 6 months from randomization. 
 
To enumerate circulating tumor DNA (ctDNA) using Cancer Personalized Profiling 
by deep sequencing (CAPP-Seq) at baseline, months 3, 6 and 12 from 
randomization for SABR versus SABR + Radium-223 arms. 
 
To quantitatively sequence T-cell receptor (TCR) repertoires using peripheral 
blood monocytes and the ImmunoSEQ platform at baseline and 3 months from 
randomization. 
 
To evaluate immunophenotypes by running PBMCs through a Cytek Aurora 
machine, which allows for simultaneous detection of up to 25 markers; to 
evaluate metabolic fitness of the total PBMCs using the mitochondrial stress test 
on the Seahorse analyzer; and to determine the relative capacity of peripheral T 
cells to metabolically respond to T cell receptor stimulation through activation of 
CD3 and CD28 by running functional assays on PBMCs. 
 
To determine frequency of germline DNA repair mutations in the oligometastatic 
state. 
 
Descriptive statistics will be performed to correlate the metrics above with clinical 
outcomes. 
4. BACKGROUND 
4.1 Oligometastatic Disease 
Cancer is the second leading cause of death in the United States, chiefly from an 
inability to control metastatic disease. Systemic therapy alone is not curative for 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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patients with most metastatic solid tumors (1).  The metastatic capacity of cancers 
behaves along a spectrum of disease progression, such that some tumors have 
spread widely before clinical detectability and others never metastasize.  
Contained within this spectrum, is an oligometastatic state where metastases are 
limited in number and location.  The presence of an oligometastatic state was 
originally proposed by Hellman who suggested that these oligometastatic patients 
would benefit from effective local therapy in addition to systemic therapy (1).  In 
agreement with this hypothesis, surgery and chemotherapy for isolated pulmonary 
metastases can result in long term disease-free periods (2). Additionally, some 
25% of patients following resection and chemotherapy for colorectal cancer and 
isolated liver metastases can similarly have long-term disease free survival 
(3)(4)(5). 
 
4.2 
Stereotactic Body Radiation Therapy (SBRT) or Stereotactic Ablative 
 
Radiation Therapy (SABR) 
Conventional moderate dose radiation for metastatic disease is given primarily for 
palliation.  Recent advancements in radiation delivery now make it possible to 
image and treat precisely within any anatomical region of the body (6, 7).  As a 
result, the capacity to deliver tumor killing radiation doses in a single or few (1-5) 
outpatient radiation treatments is now possible (8-12).  In addition, by minimizing 
the irradiation of surrounding healthy tissue, it should also be possible to decrease 
the rate of complications. Intracranial stereotactic body radiation therapy (SBRT) 
[also known has stereotactic ablative radiation therapy (SABR)] has been shown 
to be a highly effective treatment for brain metastases (13).  Data suggests that 
selective small extracranial tumors (either primary or metastatic tumors) may be 
effectively controlled by similar focal high-dose SBRT/SABR. There is an 
increasing experience with extracranial SBRT as effective local therapy for 
metastatic lesions.  Local control in excess of 75% has been reported for 
metastatic tumors of the spine, lung and liver, which is significantly higher than 
standard conventional moderate dose radiation (9, 11, 12, 14)(15-27).  Toxicity 
has been minimal in multiple U.S., European and Japanese trials of extracranial 
stereotactic radiotherapy to the lung, liver, spine, pelvis and abdomen despite the 
use of very high biological equivalent doses for patients with both organ confined 
and metastatic cancer.   
4.3 Rationale for Use of SBRT/SABR in Oligometastatic Disease 
Historically, aggressive local therapy of metastases has not been fruitful secondary 
to further progression from microscopic metastatic deposits. Chemotherapy and 
even molecular-targeted agents rarely eradicate macroscopic metastases 
permanently. However, as systemic treatments for microscopic metastatic disease 
have improved the importance of local therapy in metastatic disease has been re-
examined.  It is now recognized that some patients with “oligo,” or few sites of 
metastases, may have isolated sites of metastases that can be potentially 
eradicated with aggressive local therapy. The term “oligometastases” was coined 
to refer to this stage of distant metastases.  Typically, the entire burden of disease 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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can be recognized as a finite number of discrete lesions. Although there is no strict 
definition of oligometastases, it is commonly interpreted to be no more than 5-10 
metastatic sites. 
 
Although there have been a number of retrospective patient series showing a 
putative benefit of MDT to oligometastatic patients (5, 9, 15, 28-32), there are 
recent encouraging randomized prospective data for total consolidation of 
macroscopic metastases in aggressive histologies such as non-small cell lung 
cancer (NSCLC).  Two recent randomized phase II trials in non-small cell lung 
cancer (NSCLC) patients with up to 3-5 metastases recently showed approximate 
tripling of progression-free survival (PFS) with the addition of metastasis-directed 
therapy (MDT) to maintenance treatment as compared to maintenance treatment 
alone, possibly due to ablation of systemic therapy resistant subpopulations that 
may have otherwise led to subsequent dissemination of treatment-refractory 
disease.  In-line with this hypothesis, Gomez et. al. demonstrated that local 
consolidation of macroscopic metastases delayed time to development of new 
metastases. 
 
4.4 Rationale for Radium-223 for Bone Metastases in Prostate Cancer 
Radium-223 is an alpha-emitting radioisotope which is a bone-seeking calcium 
mimetic. It selectively targets the area with increased bone turnover, especially 
within the microenvironment of osteoblastic or sclerotic metastases. It has been 
approved by FDA for the treatment of metastatic castrate-resistant prostate 
cancer (mCRPC) with symptomatic bone metastases and without known 
visceral disease based on its ability to extend overall survival as shown its 
pivotal phase III trial. Unlike beta particle emitting radiopharmaceuticals, radium-
223 emits high-energy alpha particles of short range (<100 μm) thus saving the 
surrounding healthy tissues and significantly reducing unwanted myelotoxicity. 
 
Radium-223 was approved by the US FDA on May 15, 2013 based on the 
interim results from a Phase III randomized trial, the ALSYMPCA study 
(Alpharadin in the treatment of patients with symptomatic bone metastases in 
castration-resistant prostate cancer). In this trial, 921 patients who had received, 
were not eligible to receive, or declined docetaxel were randomly assigned in a 
2:1 ratio to receive six injections of radium-223 (at a dose of 50 kBq per 
kilogram of body weight intravenously (55 kBq/kg after implementation of NIST 
standard update) every 4 weeks or matching placebo. At the interim analysis, 
which involved 809 patients, radium-223, as compared with placebo, 
significantly improved overall survival (median, 14.0 months vs. 11.2 months; 
HR=0.70; 95% CI, 0.55 to 0.88; two-sided P=0.002). The updated analysis 
involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 
months vs. 11.3 months; HR=0.70; 95% CI, 0.58 to 0.83; P<0.001). The rate of 
AEs was consistently lower in the radium-223 group than in the placebo group 
for all AEs (93% vs. 96%), grade 3 or 4 AEs (56% vs. 62%), and serious AEs 
(47% vs. 60%). There were no clinically meaningful differences in the frequency 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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of grade 3 and 4 hematologic AEs. Only one patient developed grade 3 febrile 
neutropenia in the radium-223 group. For serious AEs that occurred in at least 
5% of patients in the radium-223 group or the placebo group, the respective 
frequencies were as follows: disease progression (11% and 12%), bone pain 
(10% and 16%), anemia (8% and 9%), and spinal cord compression (4% and 
5%). Also a significantly higher percentage of patients who received radium-223 
had a meaningful improvement in the quality of life according to the Functional 
Assessment of Cancer Therapy-Prostate (FACT-P) total score during the period 
of study-drug administration (25% vs. 16%, P=0.02). 
4.5 Rationale for SBRT/SABR for Bone Oligometastases in Prostate Cancer 
With advances in detection and primary treatment, both with radical 
prostatectomy and definitive radiotherapy, the 92% of men diagnosed with 
prostate cancer in the local or regional stage can expect to live for decades with 
appropriate intervention. The long disease-specific and overall survival observed 
with treated hormone sensitive prostate cancer, particularly in the localized 
setting, are due not solely to primary treatment modalities, but also the ever-
evolving armamentarium of treatment approaches for men who recur, either 
locally or distantly, after definitive treatment. The management of locoregional 
recurrent prostate cancer comprises local salvage approaches including external 
beam radiotherapy (EBRT), brachytherapy, prostatectomy, or cryotherapy, along 
with re-staging to assess for nodal or distant metastases.   
 
Metachronous or oligorecurrent (oligoprogressive) prostate cancer comprises a 
large number of men, possibly the majority of men following failed primary 
therapy.  Assuming that these patients are possibly in a curable state before 
castration-resistance develops, we need additional treatment strategies for this 
potentially large number of men.   
 
For patients with metastatic prostate cancer disease recurrence, the established 
approach is to offer androgen deprivation therapy (ADT) which improves survival 
but inevitably leads to castration resistance, and can be associated with 
significant adverse effects. Many men can remain on ADT treatment for years 
before progression or failure of ADT.  However, similar to chemotherapy for other 
metastatic malignancies, ADT and even newer androgen receptor signaling 
inhibitory agents rarely eradicate metastatic disease permanently.  In addition, 
ADT has been shown conclusively to adversely affect patient quality of life.  
Thus, even the ability to defer ADT initiation in men with oligometastatic prostate 
cancer represents a considerable clinical advance. 
 
Major advancements in radiation treatment planning and delivery have resulted 
in resurgence in the use of radiation therapy (RT) as a treatment for bone 
metastases. SBRT/SABR is defined as highly focused, stereotactic localized, 
high-dose RT delivered in a hypofractionated course.  In selected patients, very 
high local control rates have been observed, with minimal toxicity.  Bone 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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metastases represent the major metastatic site (>90%) in men with rising PSA 
following primary treatment for their prostate cancer. 
 
The prospective randomized phase II STOMP trial reported the ability of 
metastasis-directed therapies (MDT), primarily SABR, to forestall initiation of 
ADT in men with hormone-sensitive metastatic prostate cancer with three or 
fewer detectable metastases.  STOMP showed ADT-free survival was 
lengthened in men randomized to MDT versus observation.  The authors 
reported median ADT-free survival of 21 vs 13 months for the MDT and 
surveillance arms, respectively.  All patients for whom ADT was initiated due 
purely to local (n = 6) or symptomatic (n = 3) progression were from the 
surveillance arm, underlining the high efficacy of MDT for local control of 
individual metastatic lesions.  Nearly equal numbers of men in the MDT (n = 19) 
and surveillance (n = 16) arms received ADT due to polymetastatic progression, 
suggesting there may have been distinct subpopulations within this oligorecurrent 
STOMP cohort, i.e. those who had oligometastatic disease and where MDT 
impacted future macroscopic metastatic colonization versus those who had so-
called “OligoVisible” polymetastatic disease already beyond the practical reach of 
MDT alone.   
 
Our own prospective randomized phase II ORIOLE trial is similar to STOMP and 
nearly completed.  Although preliminary, our data show a significant ability of 
SABR to delay progression in men with oligorecurrent prostate cancer.  In 
addition, these combined preliminary data suggest that progression at 
microscopic metastatic sites is the predominant mode of progression in men with 
oligorecurrent prostate cancer treted with SABR. 
 
Forestalling systemic therapy is attractive in order to shield patients from adverse 
effects, but the combination of MDT with systemic therapy also warrants 
additional investigation.  In patients not receiving MDT, immediate initiation of 
ADT can improve survival over delayed therapy and patients with low-volume 
disease appear to have improved overall survival on ADT and gain more benefit 
from ADT than those with greater disease burden.  An overall survival benefit 
from single-modality chemotherapy as management for oligometastatic prostate 
cancer  has not been appreciated in large studies to date, but such a benefit may 
exist in patients prone to castrate-resistance.  The combination of hormonal 
agents, chemotherapy or radiopharmaceutical agents such as Radium-223 with 
MDT is clinically relevant for the treatment of oligorecurrent prostate cancer 
patients.  On the basis of this clinical evidence and because SABR and radium-
223 separately are known to be safe, we propose a phase II study of SABR + 
Radium-223 in patients with oligometastatic prostate cancer.   
 
In general metastatic disease carries an extremely high mortality rate.  Current 
therapies provide only partial palliation of symptoms and mild to moderate 
prolongation of survival.  Patients are rarely cured of this disease; consequently, 
better treatment is clearly needed.  The proposed treatment represents a logical 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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extension of the current state-of-the-art radiation therapy.  It has the potential to 
translate into more effective palliation and longer patient survival free of intiation 
of ADT systemic treatment. 
 
4.6 Rationale for Prostate specific membrane antigen (PSMA) Functional 
Imaging to Help Refine Selection of Bone Lesions to Target with 
SBRT/SABR in Oligometastatic Prostate Cancer 
 
Conventional imaging modalities, i.e., bone scintigraphy, CT and MR imaging, 
are currently used to detect metastatic prostate cancer for staging (4).  Positron 
emission tomography (PET) imaging, particularly [18F]fluorodeoxyglucose 
positron emission tomography ([18F]-FDG PET), has gained an important role in 
the clinical management of cancer patients, more notably for staging and 
assessment of response to therapy (32, 33).  However, studies employing [18F]-
FDG PET have demonstrated low uptake in prostate cancer except for advanced 
metastatic disease (34-37).  A number of novel PET radiotracer are being 
investigated for use in prostate cancer but have yielded mixed results and have 
yet to gain widespread clinical use (38, 39).  [11C]Choline is the most widely 
studied PET radiotracer for prostate cancer detection and has demonstrated the 
ability to detect lymph node and bone metastases (40-42).  [11C]Acetate is 
another emerging radiotracer, which has been evaluated in a limited number of 
studies and appears to demonstrates comparable uptake in comparison to 
[11C]Choline for detection of prostate tumor and metastases (43).  One limitation 
of these radiotracers include nonspecific uptake at sites of inflammation.  18F-
Fluoride-PET (NaF-PET) for identifying bone metastases has proven very 
sensitive but is unable to differentiate between viable metastatic prostate tumor 
from chronic reactive bone changes (44, 45).  Other promising 
radiopharmaceuticals for prostate cancer include anti-1-amino-3-18F-
fluorocyclobutane-1-carboxylic acid (18F-FACBC) and 18F-
fluorodihydrotestosterone (18F-FDHT), which are also actively undergoing 
clinical evaluation in a variety of settings (46-48).  Further work needs to be done 
to compare the merits of [11C]Choline and other emerging PET radiotracers in 
the detection and management of prostate cancer (49).   
 
Prostate specific membrane antigen (PSMA) is a promising well-characterized 
biomarker specific for prostate cancer which has also been associated with 
prostate tumor aggressiveness.  Histologic studies have associated high PSMA 
expression with metastatic spread (50-52), androgen independence (53), and 
expression levels have be found to be predictive of prostate cancer progression 
(54, 55).  However, previous attempts to image PSMA by single-photon-emission 
computed tomography (SPECT) (ProstacintTM) demonstrated poor performance 
due to inherent limited antibody and imaging characteristics (poor tumor 
penetration, slow blood pool clearance, low SPECT resolution) (56, 57).   
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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[18F]DCFBC 
(N-[N-[(S)-1,3-Dicarboxypropyl]Carbamoyl]-4-[18F]Fluorobenzyl-L-
Cysteine) (DCFBC) is a promising clinically practical small molecule PET imaging 
agent specific for prostate cancer with superior pharmacodynamic and 
pharmacokinetic characteristics than existing prostate cancer imaging agents.  
This is a small molecule urea-based analog inhibitor of PSMA radiolabeled with a 
PET radiotracer fluorine-18 which was rationally designed based on knowledge of 
the crystal structure of PSMA (58, 59).   DCFBC is a high affinity inhibitory ligand 
for the prostate specific membrane antigen (PSMA). The relative affinity of DCFBC 
for PSMA was determined by evaluating ability of DCFBC to inhibit the N-
acetylaspartylglutamate (NAAG) peptidase activity of PSMA using a previously 
developed NAAG peptidase assay. The IC50 value for the inhibitory capacity of 
DCFBC for PSMA was 13.9 nM, as determined by a NAAG peptidase inhibition 
assay, in keeping with other compounds of this class.   
 
2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-
pentanedioic acid, DCFPyL, is a second generation compound that includes the 
pyridine moiety intended to improve pharmacokinetics through altered lipophilicity 
and potential pH dependent intra-tumoral sequestration. Extensive study of both 
DCFBC and DCFPyL in pre-clinical models has been performed and published, 
attesting to their suitability for clinical translation – including with respect to 
dosimetry. While the first generation compound (DCFBC) provided isogenic 
PSMA+ human PC3 PIP tumor to PSMA- PC3 flu tumor ratios of 20:1 at 3 h post-
injection, DCFPyL demonstrated ratios on the order of 400:1. Neither compound 
demonstrates appreciable de-fluorination in vivo and PSMA+ PIP to bone ratios 
are sufficient to enable imaging of bone metastases, as demonstrated below for 
DCFBC. After synthesis of ~100 compounds, including those with several new 
scaffolds designed to target PSMA, DCFPyL emerged as the best in vivo (63).  In 
our recently published ORIOLE trial, we have also shown that men with 
oligometastatic hormone-sensitive prostate cancer that have all their DCFPyL 
PET-CT lesions ablated with SABR have a significant improvement in median 
PFS (11.8 mos versus not reached, HR = 0.26, p =0.006).  On the basis of this 
promising clinical evidence with DCFPyL PET-CT, we propose incorporating this 
a better means to identify metastatic lesions for SBRT treatment in 
oligometastatic prostate cancer. 
 
4.7 Rationale for Correlative Science 
Novel Models of Metastasis and Circulating Tumor Cell (CTCs).  Older 
models of metastasis portray the unidirectional flow of circulating tumor cells 
(CTCs) leaving the primary tumor and seeding a metastasis at a distant site 
(64).  However, recent preclinical data using diverse experimental models of 
breast cancer, colon cancer and melanoma suggest metastasis is a 
multidirectional process where CTCs seed both distant sites as well as the 
original primary tumor – a process termed “self-seeding”(65, 66).  Proponents of 
self-seeding have posited that CTC self-seeding of established macroscopic 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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tumor sites likely requires less or no adaptation of CTCs to the recipient 
microenvironment in comparison to the colonization of CTCs to a distant and 
foreign site.  In addition, self-seeding CTCs have already undergone selection 
for movement into and out of the circulation as well as resistance to anoiksis.  
Pre-clinical data have shown that self-seeding CTCs home back and 
extravasate into the primary in reaction to signals from the recipient primary 
tumors cells and tumor stroma.  These self-seeding CTCs appear to be the most 
aggressive fraction of the CTC population (65).  This feed forward loop of 
increasingly more aggressive cancer cells interacting with the tumor stroma 
results in the release of signals that foster tumor growth, angiogenesis, immune 
evasion, and ultimately macroscopic metastases. 
 
Interestingly, genomic lineage tracing data of metastases from a rapid autopsy 
series of men who died of metastatic prostate cancer suggest macroscopic 
metastases represent communal sanctuaries that are composed of prostate 
cancer cells from many other metastatic sites throughout the body of patients 
(67).  These communal sanctuaries are favorable niches that allow prostate 
cancer cells the ability to gain competence for the development of future 
macroscopic metastases.  These human data are consistent with the preclinical 
concept of “self-seeding” or a multidirectional flow of CTCs.  If these provocative 
data hold true, then SBRT/SABR to all macroscopic metastases in 
oligometastatic patients may eliminate these sanctuaries and alter the natural 
history of metastatic patients.  Following change in CTC numbers and biology 
following SABR may allow us to interrogate this hypothesis. Interventions that 
effectively target these macroscopic metastatic sanctuaries, such as 
SBRT/SABR, in combination with immune mediated therapies appear poised to 
arrest self-seeding and subsequent maturation of macroscopic metastases. 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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EPIC High-Definition 
analysis of single 
CTCs. 
 
The 
High 
Definition-CTC 
(HD-
CTC) method can be 
used 
for 
the 
longitudinal 
CTC 
enumeration and to 
assess 
for 
AR 
expression (68). The 
assay employs as little 
as 1 mL of blood and 
is an unbiased protocol to distinguish CTCs among the surrounding leukocytes 
based on their cytokeratin positive (CK+) phenotype by using a high resolution 
immunofluorescence imaging.  All cells are captured, and AR- cells can be 
evaluated.  In addition, the HD-CTC technology preserves the cell morphology in 
such a way that enables the morphometric and the indirect quantification of AR 
and CK protein expression levels for all the CTCs identified in the blood sample 
(Fig. 1).  Recently, the HD-CTC 
method has been used to examine 
expression of immune checkpoint 
molecules relevant to our proposal 
such as programmed cell death-1 
(PD-1) on CTCs (data not shown).  
The HD-CTC assay was technically 
validated with cell line spiking 
experiments to reach an R2=0.9997 
on linearity testing as previously 
reported. These experiments were 
performed using SK-BR-3 cell lines 
and 0 to 3x102 cells per mL of 
normal donor control blood.  The 
coefficient of variation is 16% and 
inter-processor 
correlation 
is 
R2 = 0.979.  Sample preparation 
process 
adhered 
to 
standard 
operating procedures for patient 
samples through a bar coded system 
for 
all 
consumables 
and 
instrumentation.  All off-the-shelf 
instrumentation 
was 
calibrated 
according to analytical validation 
protocols established during commissioning. 
Cancer personalized profiling by deep sequencing (CAPP-Seq) to detect 
circulating tumor DNA.  Circulating tumor DNA (ctDNA) is a promising 
biomarker for non-invasive assessment of cancer burden, but existing ctDNA 
Fig. 1. The HD-CTC assay.  Red blood cells are lysed followed by plating of 
nucleated cells on custom made cell-adhesion glass slides.  Slides are stained 
for cytokeratin (CK), CD45 and DAPI, then CTCs are identified among 
leukocytes using computerized high resolution immunofluorescence imaging. 
Fig. 2. CAPP-Seq ctDNA detection. (A) Analysis of 
exome sequencing from many tumors is used to select 
mutated genomic regions for a custom library of 
biotinylated oligonucleotides that are used for hybrid 
capture selection of tumor and germline genomic DNA and 
ctDNA.  (B) Dilution series analysis of expected versus 
observed frequencies of mutant alleles, assessed by 
spiking fragmented HCC78 DNA into control cell free DNA. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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detection methods have either insufficient sensitivity and/or lack broad clinical 
applicability.  Dr. Max Diehn’s laboratory recently published Cancer Personalized 
Profiling by deep sequencing (CAPP-Seq) (69), an economical and ultrasensitive 
method for quantifying ctDNA. CAPP-Seq was initially implemented for lung 
cancer with a design covering multiple classes of somatic alterations that 
identified mutations in >95% of tumors.  We detected ctDNA in 100% of patients 
with stage II–IV lung cancer and in 50% of patients with stage I, with 96% 
specificity for mutant allele fractions down to ~0.02%.  Levels of ctDNA were 
highly correlated with tumor volume and distinguished between residual disease 
and treatment-related imaging changes, and measurement of ctDNA levels 
allowed for earlier response assessment than radiographic approaches from 1.5 
mL of blood (Fig. 2).  We have designed a prostate cancer-specific CAPP-Seq 
selector that identifies at least 1 mutation in >95% of prostate tumors with a 
median of ~4 mutations per tumor.  We will apply CAPP-Seq to detect and monitor 
prostate cancer response to SBRT/SABR. 
 
ImmunoSEQ allows Unprecedented Profiling of the Anti-Tumor Immune 
Response. There are now an established body of pre-clinical and emerging 
clinical literature demonstrating that SABR can profoundly modify anti-tumor 
immune responses.  Radiation induced activation of antigen presenting cells has 
been demonstrated in animal models to enhance tumor antigen cross-
presentation in the draining lymph node and result in activation and proliferation 
of tumor specific cytotoxic T-cells (78). The cellular adaptive immune system 
generates a remarkable breadth of diversity in antigen-specific TCRs by 
combinatorial recombination of gene segments in lymphocytes. The TCR is 
composed of two peptide chains, encoded by the TCRA and TCRB or TCRG 
and TCRD genes, respectively.  There are thus two types of T-cell receptors, αβ 
and γδ, that differ by the TCR heterodimer type and immune function. The 
antigenic specificity of T-lymphocytes is in large part determined by the amino 
acid sequence in the hypervariable complementarity-determining region 3 
(CDR3) regions of the T-cell receptors.  Because of the potential diversity of 
receptors (a healthy adult has approximately 10 million different TCRB chains 
contained within their 1012 circulating T-cells (70)) it is highly improbable to 
randomly converge on the same TCRB nucleotide CDR3 sequence, effectively 
making each CDR3 sequence a unique tag for a T-cell clone. Adaptive 
Biotechnologies’ ImmunoSEQ assay, a multiplex PCR-based method that 
amplifies rearranged TCR CDR3 sequences and exploits the capacity of high 
throughout sequencing technology characterizes tens of thousands of TCRB 
CDR3 chains simultaneously.  Thus, the assay captures the full TCR repertoire 
including specific individual clones. The ImmunoSEQ assay provides a novel 
method to identify and track the presence and frequency of common and rare 
clones, in the context of the total adaptive immune system.  Recently, 
ImmunoSEQ showed profound evolution and diversification of the TCR 
repertoire of men with mCRPC treated with the immune stimulatory agent 
ipilimumab (71).  Improved clinical outcomes were associated with less T-cell 
clonotype loss, consistent with the maintenance of high-frequency TCR 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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clonotypes during treatment reported by ImmunoSEQ. These clones may have 
represented the presence of preexisting high-avidity T cells that may be relevant 
in the antitumor response. 
 
Rational for Invitae.  The evolution of human genome sequencing has enabled 
the assessment of genetic anomalies in routine clinical practice. According to a 
recent multicenter study in the New England Journal of Medicine, it was reported 
that inherited mutations in DNA-repair genes were much higher than expected in 
men with lethal metastatic castrate resistant prostate cancer (79). The study 
isolated germline DNA of 692 men with metastatic prostate cancer (unselected 
for family history of cancer or age at diagnosis), and identified 84 deleterious 
germline DNA-repair gene mutations in 82 of those men (79).  This was 
substantially higher than in men with non-metastatic hormone sensitive localized 
disease. The prevalence of germline DNA-repair mutations in the oligometastatic 
hormone sensitive or castrate-resistant state is unknown. 
 
In the Invitae’s Multi-Cancer Panel genetic test, Invitae uses a sequencing 
platform to analyze the risk of developing hereditary cancer due to inheritance of 
a pathogenic mutation in 84 cancer predisposition genes (81). The Invitae panel, 
covers 12 of 16 genes (BRCA1, BRCA2, MSH2, MSH6, PMS2, CHECK2, ATM, 
NBN, BRIP1, RAD51C, and RAD51D) that account for 92% of the germline 
mutations reported in Pritchard et al NEJM. Thus, inherited prostate cancer 
genomic data provided by Invitae can further allow investigators to personalize 
screening and target specified effective therapies for each patient disease (80). 
 
  
 
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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5. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
All patients will be eligible to receive systemic therapy alone at the time of clinical or 
radiographic disease progression.    
 
5.1 Inclusion Criteria   
5.1.1 Patient must have at least one and up to three asypmtomatic metastatic 
tumor(s) of the bone or soft tissue (with at least one bone metastasis)  within 
the past 3-months that are ≤ 5.0 cm or <250 cm3 as seen on either CT/MRI 
scan and/or bone scan. Up to five lesions are allowed on advanced funcitonal 
imaging such as fluciclovine (Axumin), choline or 18F-DCFPyL (“PyL”) PET-
CT scan within the past 6-months. (PET-CT scan is reasonable for study 
entry imaging as an alternative to CT/MRI scan and/or bone scan) 
5.1.2 Patient must have had their primary tumor treated with surgery and/or 
radiation. 
5.1.3 Histologic confirmation of malignancy (primary or metastatic tumor). 
5.1.4 PSADT <15 months. PSA doubling time (PSADT) will be calculated using as 
many PSA values that are available from time of relapse (PSA > 0.2). To 
calculate PSADT, the Memorial Sloan Kettering Cancer Center Prostate 
Cancer Prediction Tool will be used. It can be found at the following web site: 
https://www.mskcc.org/nomograms/prostate/psa-doubling-time. 
5.1.5 Patient may have had prior systemic therapy and/or ADT associated with 
treatment of their primary prostate cancer.  Patient may have had ADT 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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associated with salvage radiation therapy (to the primary prostate cancer or 
pelvis is allowed). 
5.1.6 PSA > 0.5  but <50. 
5.1.7 Any testosterone lab within the past 6 months > 50ng/dL. 
5.1.8 Patient must be ≥ 18 years of age. 
5.1.9 Patient must have a life expectancy ≥ 12 months.  
5.1.10 Patient must have an ECOG performance status ≤ 2.  
5.1.11 Patient must have normal organ and marrow function as defined as: 
Before the first administration of Xofigo, the absolute neutrophil count (ANC) 
should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 
10 g/dL.  
5.1.12 Patient must have the ability to understand and the willingness to sign a 
written informed consent document. 
5.1.13 LDH lab performed within 6 months of enrollment. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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5.2 Exclusion Criteria 
5.2.1 No more than 3 years of ADT is allowed, with the most recent ADT treatment 
having occurred greater than 6 months prior to enrollment.  
5.2.2 Castration-resistant prostate cancer (CRPC). 
5.2.3 Spinal cord compression or impending spinal cord compression. 
5.2.4 Suspected pulmonary and/or liver metastases (greater >10 mm in largest 
axis). 
5.2.5 Patient receiving any other investigational agents. 
5.2.6 Patient receiving abiraterone and prednisone. 
5.2.7 Patient is participating in a concurrent treatment protocol.  
5.2.8 Serum creatinine > 3 times the upper limit of normal.  
5.2.9 Total bilirubin > 3 times the upper limit of normal.  
5.2.10  Liver Transaminases > 5-times the upper limit of normal.  
5.2.11  Unable to lie flat during or tolerate PET/MRI, PET/CT or SBRT.  
5.2.12  Prior salvage treatment to the primary prostate cancer or pelvis is allowed.  
5.2.13  Refusal to sign informed consent. 
 
6. PATIENT REGISTRATION AND TREATMENT PLAN 
6.1 Multicenter/Participating Site Registration 
Central registration for this study will take place at SKCCC, Johns Hopkins 
University. 
Patient registration at each study site/institution will be conducted according to 
the institution’s established policies. Before registration, patients will be asked 
to sign and date an Institutional Review Board (IRB)‐approved consent form and 
a research authorization/HIPAA form. Patients must be registered with their 
local site/institution and also with the sponsor or Lead Site before beginning any 
treatment. 
 
6.1.1 General Guidelines  
Eligible patients will be entered on study centrally at the Sidney Kimmel 
Comprehensive Cancer Center at the Johns Hopkins University by the Lead 
Study Coordinator, Noura Radwan. All sites should call/email the coordinating 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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center at nradwan1@jh.edu for registration. The Eligibility Worksheet will be 
supplied to each participating site.  
 
Subjects who sign a consent form, but do not initiate protocol treatment for any 
reason (e.g., subjects who are screen failures), will be replaced and will not count 
towards our accrual goal. The Coordinating Center should be notified as soon as 
possible.  
 
6.1.2 Registration Process  
To register a patient, the following documents should be completed (and 
redacted from any PMI if being completed by a site outside of SKCCC) by the 
Research Nurse or Study Coordinator and emailed to nradwan1@jhmi.edu, the 
lead RAVENS Study Coordinator:  
 
• Signed Patient Informed Consent Form  
• Elgibility Screening Checklist 
• Copies of the following documents: 
• Diagnostic pathology and surgical reports 
• Baseline CT, Bone, MRI, and/or PET/CT scan report (scans that 
are applicable for enrollment) 
• Laboratory Reports:  
▪ Complete blood count (CBC) with differential (including 
absolute lymphocyte count) and direct platelet count 
▪ Chemistry (CMP): Albumin, SGOT (AST), SGPT (ALT), 
Bilirubin (total) (Direct only if clinically indicated), Calcium, 
Creatinine, Glucose, Total protein, Urea nitrogen, (Uric Acid 
only if clinically indicated), Electrolytes (including sodium, 
potassium, chloride and bicarbonate). 
▪ PSA 
▪ LDH 
▪ TESTOSTERONE 
• Treating physician’s medical note mentioning/indicating all 
inclusion/exclusion criteria, Full Physical Examination, ECOG 
(performance status), Past Medical/Surgical History 
• Other documents, if requested. 
 
Study treatment cannot begin until the patient is registered.  
 
The Research Nurse or Study Coordinator at the participating site will then e-mail 
the lead RAVENS Study Coordinator at nradwan1@jhmi.edu at the Coordinating 
Center to verify eligibility. To complete the registration process, the Coordinating 
Center will:  
• Assign a patient study number  
• Register the patient on the treatment portion/randomization of the 
study with the Sidney Kimmel Comprehensive Cancer Center’s 
Clinical Research Office  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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• Email the patient study number to the participating site 
6.2 Randomization 
Eligibility work-up will include a complete blood count, serum chemistries, PSA, 
and radiographic studies (of involved sites) and bone scan (unless PET 
indicated).  Once a signed informed consent has been obtained and after 
confirming patient eligibility, the lead data coordinator will assign a unique Study 
ID Number. 
 
Treatment must not commence until the patient has received his 
identification number. 
 
Stratification: 
Subjects who meet eligibility criteria and qualify for enrollment will be stratified 
according to the following:  
1) Instiution 
2) Initial treatment with surgery vs. radiation therapy  
2)  Prior hormonal therapy vs. no prior hormonal therapy 
3)  PSADT <6 months vs. 6-14.9 months 
 
Process for Randomization: 
The research team will utilize an interactive web response system (IWRS) to 
obtain the patient’s randomization assignment.  The lead coordinator will enter 
demographic and baseline characteristics in IWRS. The lead coordinator will 
obtain the patient’s randomization assignment from the IWRS and appropriately 
notify the study site. Randomization will be 1:1 for SABR: SABR + Radium-223 
arms and be stratified as above.  Minimization approach will be applied to ensure 
balanced assignment to each treatment arm. The ON STUDY date for protocol 
entry will be the day that the study subject is randomized. Within 30 days from 
the date of randomization, is considered DAY 1 of SABR and/or SABR + 
Radium-223 Arm.  
 
All institutions should allow 48 hours for patients to be randomized from the time 
they provide all elgibility documentation.  
 
6.3 Diagnostic Procedures 
A bone scan and CT (and/or MRI of questionable sites) must be available or will 
be obtained within 3-months of randomization for confirmation of 
oligometastatses.  And/or DCFPyL, Axumin- or Choline-PET/CT scan must be 
made available and obtained within 3-months of randomization A CT- and/or 
MRI-simulation scan will be performed for tumor localization and radiation 
planning using rigid immobilization appropriate for stereotactic treatment. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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6.4 Therapeutic Procedures 
Upon confirmation of eligibility and enrollment in the study, the following will be 
confirmed or completed: 
1) Demographics review, medical history and clinical exam 
2) Review of concurrent medications 
3) Vital signs, height and weight 
4) PSA, Testosterone, CBC, Chemistry Panel, LDH, CAPP-seq, EPIC HD-CTC 
and ImmunoSEQ. Immunophenotyping will only occur at Coordinating 
Center. Research Labs are voluntary and based on site participation. 
5) CT and/or MRI scan of the involved site(s) (if not previously conducted within 3 
month of enrollment). CT/MRI/Bone Scan can be supplemented if PET-CT 
is completed. 
6) Bone scan (if not previously conducted within 3 month of enrollment). 
7) Invitae Test 
 
    8) 18F-DCFPyL (“PyL”) PET/CT Diagnostic Imaging Protocol. Only for   
 
 
 participating sites. 
The subjects accrued at the outside insitutions may be scanned on a different 
scanner than that used at Johns Hopkins. This therapeutic procedure is only 
applicable for participating sites. 
 
• There are no dietary or food restrictions for this research study.  
• Fasting is not required prior to 18F-DCFPyL (PyL) dosing and PET/CT 
imaging. Increased fluid intake should occur before and after image 
acquisition to maintain proper hydration throughout the study period, 
decrease radiation exposure to the urinary bladder and improve image 
quality. 
• Subjects should be encouraged to void as frequent as possible. At a 
minimum void post study drug injection, immediately before imaging, 
and after imaging. 
• A single administration of 18F-DCFPyL Injection will be administered 
prior to PET/CT imaging 
• 
18F-DCFPyL Study Drug Administration:  
o Place an IV catheter in an antecubital vein or an equivalent 
venous access. 
o Ensure patency of the line with a saline flush. 
o Inject a bolus of the prescribed dose of 18F-DCFPyL (9 mCi or 
333 MBq) of into the IV line or equivalent venous access by slow 
push from the appropriately shielded syringe according to normal 
local practices. 
o Administer an intravenous flush (e.g., 5-10 ml sterile Sodium 
Chloride Injection, 0.9%), to ensure full delivery of the dose. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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• 
18F-DCFPyL PET/CT imaging will be performed using local PET/CT 
scanners with low dose CT for attenuation correction and anatomic 
localization. 
• Subjects will be asked to void prior to imaging. After voiding, a whole-
body CT and PET scan will be acquired starting from the mid-thigh 
through the skull. Whole body PET/CT scans must be obtained within 
60-120 minutes following the 18F-DCFPyL dosing. 
The study PI, co-I’s or study coordinator will contact the patient around 7 days 
(3 - 10 days) after the PET/CT study to inquire about delayed side effects.  If 
there are suspected problems the patient will be asked to return for a clinic 
visit for a follow-up clinic visit. 
 
9) SBRT/SABR treatment planning 
CT- and/or MRI-simulation will then be performed with fabrication of a radiation 
therapy immobilization device (such as the Alpha Cradle) which will be custom 
made for each patient. The treating radiation oncologist will identify the location 
of the tumor.  Gross tumor volume (GTV) delineation will be performed with a 
diagnostic radiologist on sequential axial computed tomography images. A 
radiosurgical treatment plan will be developed based on tumor geometry and 
location.  The clinical tumor volume (CTV) will equal the GTV.  The dose will be 
prescribed to the minimal isodose line that completely covers the planning target 
volume (PTV) PTV (=CTV plus a 3-5 mm margin).  Adjacent normal structures 
including but not limited to the heart, esophagus, aorta, spinal cord, kidneys, 
rectum, bowel, liver, and stomach within 5 cm of the CTV will be identified for 
the purpose of limiting incidental radiation to these structures. 
 
In addition, prior to treatment delivery, a four-dimensional cone beam CT study 
will be performed on individual patients to assess respiration in these patients 
and to determine tumor targeting accuracy for those tumors that may be subject 
to respiratory motion such as those in the bones of the thorax. If tumor motion 
is greater than 5 mm, PTV will be expanded to account for respiration. 
 
SBRT/SABR will be delivered in 1 to 5 fractions, and the dose and fractionation 
schedule will depend on the size and location of the lesion and the surrounding 
normal tissue constraints in accordance with AAPM Task Group 101 
recommendations. Typical doses include 16 – 24 Gy in 1 fraction, 48 – 50 Gy in 
4 fractions, and 50 – 60 Gy in 5 fractions. For example, isolated osseous lesions 
will be treated in a single fraction, lesions close to the lung and liver lesions will 
be treated in 3 to 5 fractions depending on their size (5 fractions for ≥ 3 cm or 
central tumors in close proximity to the mediastinum), and bone lesions will be 
treated in 5 fractions if small-bowel constrains fewer doses. 
 
Within three weeks of the initial treatment planning imaging study, SBRT/SABR 
will be administered using image-guidance. An Alpha Cradle (or equivalent 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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immobilization device) will be used to minimize movement of the chest, spine, 
and abdomen during treatment. During treatment, real time cone beam CT 
images of the patient’s body site of interest will be obtained. Cone beam CT 
scan will be obtained immediately prior to treatment and will be repeated until 
the treatment shift, required to align the CT planning scan and the cone beam 
CT scan performed on the day of treatment cone beam CT, is within tolerance 
for the body site.   
 
 
Patients will be evaluated for adverse events/toxicities during their treatment. 
The dose limits for surrounding critical structures are as follows: 
Spinal Cord: maximal allowable dose should be = 800 cGy in 1 fraction  
Lung: 2/3 of the lung volume should be kept under 500 cGy. 
Heart: 50 % of the heart volume should be kept under 1000 cGy. 
Esophagus: 50 % of the esophagus volume should be kept under 1000 cGy 
and no single point dose in the esophagus should exceed 2000 cGy. 
Brachial Plexus: maximal allowable point dose = 1000 cGy 
Liver: One third of the uninvolved liver or approximately 700 cc <15 Gy.  
Kidneys: 75% of volume of each kidney <5 Gy. 
Small Bowel: <5% of bowel limited to <20 Gy. 
 
9) Radium-223 
 
 
Dosage Forms and Strength: 
Radium-223 is available in single-use vials containing 6 mL of solution at a 
concentration of 1,000 kBq/mL (27 microcurie/mL) (1,100 kBq/mL (29.7 
microcurie/mL)after implementation of the NIST update) at the reference date 
with a total radioactivity of 6,000kBq/vial (162 microcurie/vial) (6,600 kBq/vial 
(178 microcurie/vial) after implementation of the NIST update) at the 
reference date. 
 
Preparation: 
Radium-223 is a ready-to-use solution and should not be diluted or mixed 
with any solutions.  Each vial is for single use only. Parenteral drug products 
should be inspected visually forparticulate matter and discoloration prior to 
administration, whenever solution and container permit. 
 
Before the first administration of Xofigo, the absolute neutrophil count (ANC) 
should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 
10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 
x 109/L and the platelet count ≥ 50 x 109/L. If ANC is not within normal limit 
prior to protocol window, then CBC can be drawn, per treating physician 
advisement. All doses 6 doses should still be administered regardless of 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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treatment delay due to ANC. Unless, there is no recovery to these values 
within 6 to 8 weeks after the last administration of Xofigo, despite receiving 
supportive care, then further treatment with Xofigo should be discontinued. 
Patients with evidence of compromised bone marrow reserve should be 
monitored closely and provided with supportive care measures when clinically 
indicated. Discontinue Xofigo in patients who experience life-threatening 
complications despite supportive care for bone marrow failure. 
 
 
Dosage: 
The dose regimen of radium-223 is 50 kBq (1.35 microcurie) (55 kBq/kg 
(1.49 microcurie/kg) after implementation of the NIST update) per kg body 
weight, given at 4 week intervals for 6 injections. 
 
The volume to be administered to a given patient should be calculated using 
the: 
– Patient’s body weight (kg) 
– Dosage level 50 kBq/kg body weight (55 kBq/kg after implementation of 
the NIST update) or 1.35 microcurie/kg body weight (1.49 microcurie after 
implementation of the NIST update) 
– Radioactivity concentration of the product (1,000 kBq/mL; 27 
microcurie/mL (1,100 kBq/mL after implementation of the NIST 
update;29.7 microcurie/mL) at the reference date 
– Decay correction factor to correct for physical decay of radium-223. 
 
The total amount (volume to be drawn into the syringe) to be administered to 
a patient should be calculated as follows: 
 
 
Volume to be administered (mL) =  
 
Body weight (kg) x dose (50 kBq/kg b.w)a/ 
 
DK factor x 1,000 kBq (0.027 mCi)/mLb 
 
 
a 55 kBq/kg after implantation of the NIST update 
 
b 1,100 kBq (29.7 microcuriei)/mL after implantation of the NIST update 
 
 
Decay Correction Factor Table 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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The Decay Correction Factor Table is corrected to 12 noon Central Standard 
Time (CST). To determine the decay correction factor, count the number of 
days before or after the reference date. The Decay Correction Factor Table 
includes a correction to account for the 7 hour time difference between 12 
noon Central European Time (CET) at the site of manufacture and 12 noon 
US CST, which is 7 hours earlier than CET. 
 
Immediately before and after administration, the net patient dose of 
administered radium-223 should be determined by measurement in an 
appropriate radioisotope dose calibrator that has been calibrated with a 
National Institute of Standards and Technology (NIST) traceable radium-223 
standard (a new reference vial will be sent to each center corresponding to 
the updated NIST reference material) and corrected for decay using the date 
and time of calibration. The dose calibrator must be calibrated with nationally 
recognized standards, carried out at the time of commissioning, after any 
maintenance procedure that could affect the dosimetry and at intervals not to 
exceed one year. 
 
Each center must perform the Radium Ra 223 dichloride dial setting on their 
relevant dose calibrator(s) (upon notification by Bayer each center is required 
to update the dial setting to correspond to the new NIST standard). The 
current dial settings are to remain in effect until Bayer obtains FULL approval 
from the FDA for implementation. In preparation for implementation of the 
NEW dial setting, the clinical study center will receive a sealed vial labeled 
NIST standard containing a Radium Ra 223 dichloride solution for calibration 
only. The vial is identical to the vials used for study treatment. The amount of 
Radium Ra 223 dichloride in the vial will be stated on the label. Instructions 
for the dial setting, including the calibration log form, will be enclosed with the 
dispatch of the calibration sample. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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NIST Standardization Update: 
The qualification of radium-223 radioactive in Xofigo (radium-223 dichloride; 
BAY 88-8223) is based on the primary standardization performed by the US 
NIST. National Institute of Standards and Technology prepares the standard 
reference material (SRM) using an official dial setting (primary 
standardization) as published [20]. The NIST SRM is used to calibrate the 
instruments in production and quality control for both the drug substance and 
drug product. Additionally, the NIST SRM is used to prepare the NIST 
traceable Ra-223 reference materials which are then sent to the end-users 
(e.g., nuclear medicine laboratory physicians or technicians) for dial-setting of 
their dose calibrators, to allow verification of the patient dose. 
 
In 2014, NIST performed a re-assessment of the primary standardization 
based on preliminary information suggesting a potential discrepancy of 
approximately 8-10% between the published NIST primary standardization 
[20] and results obtained by other national metrology institutes (United 
Kingdom, Germany, Japan). After completion of the re-assessment, NIST 
reported their findings [21] and had issued a revised NIST SRM in 2015. The 
discrepancy in the NIST standardization was determined to be -9.5% between 
activity values obtained using the old reference standard relative to the new 
primary standardization. Consequently, the current numerical values need to 
be corrected by approximately +10.5%. 
 
The current NIST standard for radium-223 dichloride will remain in effect until 
the FDA has fully approved the regulatory variation submitted for Xofigo and 
is anticipated in the 2nd quarter of 2016. All sites are expected to begin 
preparation for the updated NIST standardization and obtain all necessary 
IRB approvals. Bayer will continue to notify sites about the status of the 
regulatory approval and the date that the updated NIST standardization is to 
be implemented. Upon notification, and prior to the implementation, all sites 
are expected to add a new dial setting to their dose calibrators for the new 
NIST standardization for radium-223 dichloride, which should be documented 
on the appropriate study forms. 
 
The change in the numerical description of the patient’s dose, product 
strength and labeled vial activity does not impact the safety or efficacy of 
Xofigo. The change in the NIST radium-223 standard has no impact on 
subjects; dose subjects are receiving, and will continue to receive. Subjects 
will receive the same actual dose and volume that was studied in Study 
15245 (BCI-06 dosimetry study) and is associated with the proven safety and 
efficacy of radium-223 dichloride, though the stated nominal radiation dose 
received is being updated to reflect the new standard. The formula for the 
calculation of the volume to be administered has to be changed respectively. 
(see dose section) Subjects who are on-treatment at the time the new NIST 
reference standard goes into effect should be notified of this change and 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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should be required to sign a Patient Information Sheet to acknowledge that 
they have received information on the updated NIST standard calibration. All 
patients randomized after the new reference standard is in effect should sign 
a revised Informed Consent Form that contains the updated NIST 
standardization. 
 
 
Administration: 
Radium-223 should be administered by slow IV injection over 1 minute. The 
IV access line or cannula should be flushed with isotonic saline before and 
after injection of radium-223. 
 
 
Handling and Patient Protection: 
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy 
emitted as alphaparticles. The fraction emitted as beta-particles is 3.6%, and 
the fraction emitted as gammaradiation is 1.1%. The external radiation 
exposure associated with handling of patient doses is expected to be low, 
because the typical treatment activity will be below 8,000 kBq (216 
microcurie). (8,800 kBq (238 microcurie) after implementation of the NIST 
update) In keeping with the As Low As Reasonably Achievable (ALARA) 
principle for minimization of radiation exposure, it is recommended to 
minimize the time spent in radiation areas, to maximize the distance to 
radiation sources, and to use adequate shielding. Any unused product or 
materials used in connection with the preparation or administration are to be 
treated as radioactive waste and should be disposed of in accordance with 
local regulations. The gamma radiation associated with the decay of radium-
223 and its daughters allows for the radioactivity measurement of radium-223 
and the detection of contamination with standard instruments. 
 
 
General warning: 
Radium-223 should be received, used and administered only by authorized 
persons in designated clinical settings. The receipt, storage, use, transfer and 
disposal of radium-223 are subject to the regulations and/or appropriate 
licenses of the competent official organization. 
 
Radium-223 should be handled by the user in a manner which satisfies both 
radiation safety and pharmaceutical quality requirements. Appropriate aseptic 
precautions should be taken. 
 
 
Radiation protection: 
The administration of radium-223 is associated with potential risks to other 
persons (e.g., medical staff, caregivers and patient’s household members) 
from radiation or contamination from spills of bodily fluids such as urine, 
feces, or vomit. Therefore, radiation protection precautions must be taken in 
accordance with national and local regulations. 
 
 
For drug handling: 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Follow the normal working procedures for the handling of 
radiopharmaceuticals and use universal precautions for handling and 
administration such as gloves and barrier gowns when handling blood and 
bodily fluids to avoid contamination. In case of contact with skin or eyes, the 
affected area should be flushed immediately with water. In the event of 
spillage of radium-223, the local radiation safety officer should be contacted 
immediately to initiate the necessary measurements and required procedures 
to decontaminate the area. A complexing agent such as 0.01 M ethylene-
diaminetetraacetic acid (EDTA) solution is recommended to remove 
contamination. 
 
 
For patient care: 
Whenever possible, patients should use a toilet and the toilet should be 
flushed several times after each use. When handling bodily fluids, simply 
wearing gloves and hand washing will protect caregivers. Clothing soiled with 
radium-223 or patient fecal matter or urine should be washed promptly and 
separately from other clothing. 
 
6.5 Treatment Compliance 
Study drugs will be administered or dispensed only to eligible patients under the 
supervision of the investigator or identified sub-investigator(s). The appropriate 
study personnel will maintain records of study drug receipt and dispensing. 
 
6.6 Drug Accountability 
Study drugs should be kept in a secure place and must be administered only to 
patients in the trial. A log of study drug (received, administered to patients and 
destroyed) must be maintained and signed by the person responsible for drug 
handling at each center. Study site/institution personnel will record all study drug 
administered during this trial on the drug-dispensing log. Description of 
monitoring of the overall drug accountability will be detailed in study and site 
specific procedures. 
 
The nuclear medicine specialist or radiation oncologist at the center is 
responsible for drug accountability for radium-223. When the drug accountability 
has been monitored, the vials can be destroyed in accordance with hospital 
procedure for the handling of radioactive material, normally after storage for 4 
months from date of receipt (>10 half-lives) before disposal; they may then be 
disposed as non-radioactive waste. 
6.7 Follow-Up Procedures 
6.7.1 Blood Draws 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Subsequent to randomization, patients will be followed clinically and 
radiographically.  A detailed medical and physical examination with blood draws 
for PSA, LDH, CBC w/Diff, Serum Chemistry panel (CMP), ctDNA (CAPP-seq), 
immune cell profiling (ImmunoSEQ), CTCs (EPIC HD-CTC), immunophenotyping,   
and testosterone will be performed within the first month, months 3, 6 and 12 (from 
date of randomization) for all patients. Correlatives at outside sites are optional 
and not mandatory. In-clinic visits are not required otherwise, unless indicated by 
laboratory tests.  For men randomized to the SABR + Radium-223, they will also 
receive monthly CBCs as per standard of care for radium-223 infusions (within 7-
10 days of radium-223 injection).  Following 12-months patients will be followed by 
any physician as per standard of care which may include but not be limited to every 
3-6 month clinic visits, laboratory evaluations for PSA and imaging, if appropriate. 
Further labs and imaging is at the discretion of the treating physician. This 
information of two year followup will be collected by the clincal study team for all 
participating sites. 
 
Correlative science blood draws will be performed as above (details for these blood 
draws are contained within the APPENDIX III-V). 
Briefly:  
CAPP–Seq: 30-ml whole blood in purple top (EDTA) tubes (see APPENDIX III 
for details). The blood is stored in a freezer, then shipped in batches as per 
APPENDIX III. Baseline, months 3, 6 and 12 from randomization for both arms.  
EPIC HD-CTC: 4-10 ml Streck Cell-Free DNA BCT tubes (see APPENDIX IV 
for details).  Whole blood is shipped out the same day as it is drawn as per 
APPENDIX IV. Baseline and day 180 from all men.  
ImmunoSEQ: 10-ml whole blood in purple top (EDTA) tubes (see APPENDIX 
V for details).  The patient samples are stored in a 80 Degree Celsius freezer 
and shipped in batches as per APPENDIX V. Baseline and day 90 from all men.  
Immunophenotyping: 2-10-mL whole blood in green top (heparin) tubes (see 
APPENDIX VIII for details).  
 
Only participating sites that have the resources to do so, will participate in bloow draw 
collection and shipment. 
6.7.2 Imaging  
Bone scan and CT/MRI of metastatic site(s) will be at 6- and 12-months for all 
patients, unless indicated more frequently by clinical or laboratory findings.  
 
If applicable, bone scan and 18F-DCFPyL (“PyL”) -PET/CT of metastatic site(s) will 
be at 6 months for all patients, unless indicated more frequently by clinical or 
laboratory findings. The results of the 18F-DCFPyL (“PyL”) -PET/CT will be made 
available to the treating physicians prior to enrollment to determine treatment. 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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The CT portion of the 18F-DCFPyL (“PyL”) -PET/CT scans at 6 months will be used 
to determine radiographic response based on RECIST 1.1 criteria for soft tissue 
lesions. Similarly, the CT or MRI scans at 6- and 12-months will be used to 
determine radiographic response based on RECIST 1.1 criteria for soft tissue 
lesions. 
6.7.3 Rectal Swab  
The collected rectal swab (see APPENDIX VI for details) will provide researchers 
with a tool to analyze the gut microbiome of patients in an effort to investigate 
potential correlations between the gut microbiome and response to cancer 
therapies. Consented patients will be asked to self-collect two rectal swabs 
during an office visit by inserting a cotton tipped application approximately 3 cm 
(about 1 inch) into the anal canal and rotating it. The swab can then be returned 
to the provided tube. Rectal swabs (two per specified time-point) will be collected 
at enrollment within 1-mos of randomization but prior to SABR or radium-223 
infusion and at the 3-month time points. 
Only participating sites that have the resources to do so, will participate in rectal 
swab collection. 
6.7.4 Rectal Swab Processing  
The collected swabs will be immediately stored at 4° C to prevent bacteria growth 
before being moved to -20/-80° C. Collected swabs will be processed for DNA 
extraction and eventual next generation sequencing to provide a genomic profile 
of the bacteria present in the gut microbiome of patients.  
6.7.5 Invitae Genomic Testing  
Consented patients will be asked to provide a blood or saliva sample during an 
office visit or at home, via an Invitae collection kit (see APPENDIX VII for details). 
This collection will be performed on all enrolled patients, at any time point 
during study or after completion of study (F/U), regardless of their 
randomization arm. The Invitae collection kit will then be activated online and 
dropped in the mail. Invitae will then analyze the genes from the patient’s blood 
or saliva sample.  Once the patient’s results are ready, an email will be sent by 
Invitae prompting the PI to log into his established Invitae account and view the 
results. The patient will be allowed to make an appointment with one of the 
Invitae’s genetic counselors at no cost. Further, Invitae will also keep the patient 
updated if any information related to their results changes. 
 
6.8 Duration of Therapy 
Within three weeks of the initial treatment planning imaging study, SABR will be 
administered in a 1-5 fractions to each treated site (within 60 days from 
randomization) of the study and coincides with delivery of fraction 1. 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Within four weeks of randomization to the SABR + Radium-223 arm, men will 
receive their 1st of 6 monhtly infusions of radium-223. 
6.9 Duration of Study Accrual 
A trial with a similar patient population took 2 years to screen 60-70 patients. Thus 
we anticipate this study will last 3 years.  
6.10 Duration of Follow-Up  
Patients will be followed for 2-years, after Day one. Importantly, this follow-up 
period will include the collection of all Skeletal Related events. 
6.11 Criteria for Patient Removal 
Diagnosis of >3 bone and/or soft tissue metastases on entry imaging studies 
before SBRT/SABR. PSA >50 ng/ml before SABR. Progression as defined in 
section 9.5.5. 
 
Radium-223 administration may be delayed by no more than four weeks for 
recovery of adverse events. In case of a treatment delay greater than four weeks, 
treatment should be discontinued. It is important to note that in general (unless 
otherwise agreed), in cases where study drug has been ordered, the time 
window is reduced to -3 days to + 3 days, due to decay. If administration has to 
be postponed more than 3 days after drug has been ordered, replacement of the 
drug order is required. Dose reduction for radium-223 will not be permitted and 
subjects with any toxicity requiring radium-223 dose reduction must discontinue 
radium-223 treatment. 
 
Any toxicity requiring radium-223 discontinuation will be recorded as an AE in the 
subject’s medical record and on the CRF. 
6.12 Alternatives 
The study has been designed to minimize potential risks to participants.  First, 
this population of asypmtomatic oligometastatic men is heavily pre-selected 
based on institutional data, STOMP and on-going ORIOLE phase II randomized 
data indicating that similar men will progress in 6-12-months (72-74).  Secondly, 
the level of clinical-radiographic interrogation will allow both arms to be safely 
transitioned to standard of care treatments that can be initiated within a typical 
interval between clinic visits (72-74).  Lastly, the SABR dose has been shown to 
be safe in previous trials.  Risks to confidentiality will be minimized by having 
access to study records avaialble only to the investigators with the exception of 
the standard clinical records (lab values, dictations, operative notes, etc). 
Standard therapies for metastatic prostate disease include radiotherapy, ADT or 
observation. Such treatment may or may not be applicable for patients enrolled in 
this study. Regardless, patients will be expected to forgo standard treatment until 
there is evidence of clinical, biochemical (PSA >50 ng/ml) or radiographic disease 
progression. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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6.13 Costs 
Every patient will be provided a copy of the Insurance and Research Participant 
Financial Responsibility Information Sheet.  This document outlines the financial 
responsibilities for each study test and procedure based on a standard of care 
versus research analysis. 
6.14 Compensation 
Patients will not be financially compensated if they join the study. 
6.15 Withdrawal from Study 
In accordance with the Declaration of Helsinki, patients have the right to withdraw 
from the study at any time for any reason, without prejudice to their medical care. 
The investigator also has the right to withdraw patients from the study for any of 
the following reasons: 
• 
Subject withdraws consent for follow-up. 
• 
Subject is lost to follow-up. 
• 
Study is terminated for any reason. 
• 
Occurrence of AEs, if discontinuation of study medication is considered 
necessary by the Investigator and/or patient. 
• 
Lack of patient compliance. 
• 
Protocol violation. 
• 
Progressive disease as defined in section 9.5.5. 
7. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
7.1 Investigational Agent – Radium-223 
This information is loaded into the IND application section of eIRB.  Additional 
radiopharmaceutical information not listed below is downloaded on the FDA IND 
application in the supporting documents section of eIRB and available there for 
review. 
7.2 Investigational Agent - 18F-DCFPyL (“PyL”) 
This information is loaded into the IND application section of eIRB.  Additional 
radiopharmaceutical information not listed below is downloaded on the FDA IND 
application in the supporting documents section of eIRB and available there for 
review. 
 
8. 
STUDY CALENDARS 
 
Study Calendars 
 
In order to minimize the need for research-only in-person visits, telemedicine visits 
may be substituted for in person clinical trial visits or portions of clinical trial visits 
where determined to be appropriate and where determined by the investigator not 
to increase the participants risks. Prior to initiating telemedicine for study visits the 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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study team will explain to the participant, what a telemedicine visit entails and 
confirm that the study participant is in agreement and able to proceed with this 
method. Telemedicine acknowledgement will be obtained in accordance with the 
Guidance for Use of Telemedicine in Research. In the event telemedicine is not 
deemed feasible, the study visit will proceed as an in-person visit. Telemedicine 
visits will be conducted using HIPAA compliant method approved by the Health 
System and within licensing restrictions. 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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STUDY CALENDAR: SBRT ARM ONLY    
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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STUDY CALENDAR: SBRT + Xofigo ARM  
  
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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9. 
MEASUREMENT OF EFFECT 
9.1 Antitumor Effect – Metastatic Tumors 
For the purposes of this study, patients should be re-evaluated for radiographic 
response 6- and 12-months after randomization.  Trial radiologists evaluating for 
treatment responses will be blinded to the treatment group and treatment specifics 
(lesions treated with SABR). 
 
Response and progression will be evaluated in three ways: 
1) Using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Committee 
definition.  Changes in only the largest diameter (uni-dimensional 
measurement) of the tumor lesions are used in the RECIST criteria.   
2) Lesions by bone scan will be evaluated as positive, negative or no change.  
MRI of the bone lesion can be used to clarify equivocal lesions. 
3) Serial PSA changes. 
9.2 Definitions 
Evaluable Population: will consist of all patients who have received SABR. 
Safety Population: Will consist of all subjects who were enrolled and have 
undergone at least one fraction of SABR. This will be used to assess the clinical 
safety and tolerability of the study. 
 
Evaluable for Objective Response:  Only those patients who have measurable 
disease present at baseline, have completed all fractions of SABR, and have had 
their disease re-evaluated will be considered evaluable for response.  These 
patients will have their response classified according to the definitions stated 
below.   
9.3 Disease Parameters 
Measurable Disease:  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) 
as >10 mm with diagnostic techniques (CT, or MRI). All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters).  Serial PSA 
measurements will also be analyzed. 
 
Non-Measurable Disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm with diagnostic techniques), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis, abdominal masses (not followed by CT 
or MRI), and cystic lesions are all non-measurable. 
 
Target Lesions:  Target lesions in this study will be considered oligometastatic 
sites up to a maximum of 3 lesions per patient. They should be recorded and 
measured at baseline. Target lesions should be equal to or larger than 10 mm in 
the smallest cross-sectional diameter on CT or MRI and/or any lesion that shows 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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increase uptake on bone scans.  A sum of the longest diameter (LD) for all target 
lesions will be calculated and reported as the baseline sum LD.  The baseline sum 
LD will be used as reference by which to characterize the objective tumor 
response. For bone scans we will also use a simple evaluation system composed 
of positive, negative or no change to lesions. 
 
Non-Target Lesions:  N/A 
9.4 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
Conventional CT, PET/CT, and MRI. These techniques should be performed with 
cuts of 10 mm or less in slice thickness contiguously.  Spiral CT should be 
performed using a 5 mm contiguous reconstruction algorithm.  This applies to 
tumors of the chest, abdomen, and pelvis.  Head and neck tumors and those of 
extremities usually require specific protocols. 
9.5 Response Criteria 
9.5.1 Evaluation of Target Lesions/PSA Response 
Complete Response (CR):  
 
Disappearance of all target lesions and PSA < pre 
SBRT PSA 
 
Partial Response (PR):  
 
 At least a 30% decrease in the sum of the longest 
diameter (LD) of target lesions, taking as reference 
the baseline sum LD.  Or a third of the lesions are 
negative or no change by bone scan and PSA < pre-
SBRT PSA. 
 
Progressive Disease (PD):  
 At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD 
recorded since the treatment started or the 
appearance of >1 new lesion(s).  Or >1 new lesion(s) 
appear by bone scan. Or PSA ≥25% increase in PSA 
from nadir or > 50 ng/ml. 
 
Stable Disease (SD):  
 
 Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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reference the smallest sum LD since the treatment 
started.  Or PSA > pre-SBRT PSA, but not ≥25% 
increase in PSA from nadir and <50 ng/ml. 
9.5.2 Evaluation of Non-Target Lesions 
N/A 
9.5.3 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).  Best overall response will be based on the overall response of the 
target lesions. 
9.5.4 Duration of Response 
Response will be defined as evidence of CR, PR, or stable disease. The 
duration of response will be measured from the start of treatment until the 
criteria for progression are met.   
 
Duration of CR or PR: The duration of CR or PR will be recorded from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until 
the first date that current or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
Duration of Stable Disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  
9.5.5 Clinical Response Parameters 
Progression is a composite endpoint defined from the Prostate Cancer 
Working Group 2 (PCWG2) criteria for metastatic castrate resistant prostate 
cancer (mCRPC) (75) and our previous trials in a population of men with 
biochemical failure without metastases (72-74).  Progression will be defined as 
either: 1) a ≥25% increase in PSA from nadir (and by ≥2 ng/mL), requiring 
confirmation ≥4 weeks later (PCWG2 criteria); and/or, 2) clinical/radiographic-
progression defined as symptomatic progression (worsening disease-related 
symptoms or new cancer-related complications), or radiologic progression (on 
CT scan: ≥20% enlargement in sum diameter of soft-tissue target lesions 
[RECIST 1.1 criteria]; on bone scan: ≥1 new bone lesions), initiation of ADT or 
death due to any cause, whichever occurs first. Death is considered a severe 
adverse event here. 
Progression Free Survival (PFS) is defined as the time from starting 
treatment to the time of progression as defined above.  Subjects who do not 
progress will be censored at the time of the last contact.  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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ADT Free Survival (ADT-FS) is defined as the time from starting treatment to 
the time of initiation of palliative ADT. ADT will typically be initiated on tumor 
progression and/or development of new metastases.  Subjects who do not start 
ADT will be censored at the time of the last contact.  
Time to Progression (TTP) is defined as the time from starting treatment to 
the time of first documented tumor progression or new lesions by CT and/or 
bone scan or initiation of ADT. Subjects who do not progress will be censored 
at the time of the last contact. In addition, death from any cause will also be 
censored.   
Time to New Metastasis (TNM) is defined as the time from starting treatment 
to the time of a new documented tumor metastasis by CT and/or bone scan. 
Subjects who do not progress will be censored at the time of the last contact.  
Overall Survival (OS) is defined as the time from starting treatment until death 
due to any cause. For subjects who do not die, time to death will be censored 
at the time of last contact. 
 
 Locoregional Control (LRC) is defined as the time from starting treatment 
until local and/or regional relapse is documented 
9.5.6 Response Review 
All responses will be reviewed by the study co-investigator radiologists. 
 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS 
10.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This 
study will use the descriptions and grading scales found in the NCI Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE v 4.0) that is 
available at http://ctep.cancer.gov/reporting//ctc.html.  
 
Information on all adverse events, whether reported by the participant, directly 
observed, or detected by physical examination, laboratory test or other means, will 
be collected, recorded, followed and reported as described in the following 
sections.  
 
Participants should be instructed to report any serious post-study event(s) that 
might reasonably be related to participation in this study. The investigator should 
notify the IRB and any other applicable regulatory agency of any unanticipated 
death or adverse event occurring after a participant has discontinued or terminated 
study participation that may reasonably be related to the study.  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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10.2 Definitions 
10.2.1 Adverse Event (AE) 
An adverse event 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 or 
further diagnostic tests.  
10.2.2 Serious adverse event (SAE) 
   A serious adverse event is an undesirable sign, symptom, or medical     
   condition which: 
 
• 
is fatal or life-threatening; 
• 
requires or prolongs inpatient hospitalization; 
• 
results in persistent or significant disability/incapacity; 
• 
constitutes a congenital anomaly or birth defect; or 
• 
jeopardizes the participant and requires 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 
10.2.3 Expectedness  
• 
Expected: Expected adverse events are those that have been previously 
identified as resulting from administration of the agent. For the purposes 
of this study, an adverse event is considered expected when it appears in 
the current adverse event list, the Investigator’s Brochure, the package 
insert or is included in the informed consent document as a potential risk. 
• 
Unexpected: An adverse event is considered unexpected when it varies 
in nature, intensity or frequency from information provided in the current 
adverse event list, the Investigator’s Brochure, the package insert or when 
it is not included in the informed consent document as a potential risk 
10.2.4 Attribution  
Attribution is the relationship between an adverse event or serious adverse 
event and the study treatment. Attribution will be assigned as follows: 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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• 
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 clearly NOT related to the study treatment. 
10.3 Potential Adverse Events 
Signs and symptoms of disease progression are not considered AEs.  The 
development of a new cancer should be regarded as an AE.  New cancers are 
those that are not the primary reason for administration of study treatment and 
have been identified after inclusion of the patient into the clinical study. 
 
Because patients are receiving standard treatments, which are not part of this 
study, their treating physician will be counseling them on the risk of their 
treatments, including the risk of surgery, radiation therapy, and/or chemotherapy, 
whichever is appropriate for the type and the stage of their cancer. The procedures 
related to the study are phlebotomy, SBRT, and Radium-223 administration. 
 
Phlebotomy can cause pain, bleeding, and rare needle site infection.  
 
Reporting: All patients will be seen during the required protocol and calendar 
time-points, by their radiation oncologist or study team membe, during the 
entirety of the trial. Any observations durig the entirety of the study (2 years) will 
be recorded and should include attention toward the following potential side 
effects: 
• Anal hemorrhage, colitis, constipation, diarrhea, fecal incontinence, 
hemorrhoids, nausea, proctitis, rectal hemorrhage, vomiting 
• Anorexia, anxiety, and/or insomia 
• Bladder spasms, hematuria, urinary frequence, irinary incontinence, 
urinarary retion, urinary tract pain, urinary urgency, erectile dysfunction 
• Dermatitis radiation 
• Fatigue and/or pain 
• Hot flashes 
• 
Bone Pain 
• Netrophil count decrease and/or platelet count decrease 
Any and ALL additional adverse events should be recorded, even if not 
listed in the above potential side effects. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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10.4 Stereotactic Body Radiation Treatment (SBRT)/Stereotactic Ablative 
Radiation Treatment (SABR) 
It is difficult at this time to predict with confidence the complication rate from the 
proposed SBRT/SABR; however, it is reasonable to extrapolate from the current 
experience with SBRT/SABR to the lung, prostate, spine, liver and pancreas.  One 
significant toxicity is radiation pneumonitis, which can be manifested as fever, 
increased excertional dypsnea, pleuritic chest pain, and peritumoral infiltrate on 
chest imaging.  It generally occurs between 1 to 3 months of completion of 
radiotherapy. The risk of grade 2-4 radiation pneumonitis is aproximately 10-15% 
in patients treated with standard fractionated large field radiotherapy and higher in 
patients treated with combined chemoradiotherapy.  It is highly dependent on the 
volume of the lung treated to high dose and the mean lung dose.  At this point, the 
incidence of RT pneumonitis from stereotactic radiosurgery for small pulmonary 
tumors is unknown.  However, if the treated tumor volume is kept ≤ 65 cc, the risk 
should be < 10-15% with the proposed dose level. 
 
Other toxicities commonly associated with such treatment includes dysphagia, 
odynophagia, nausea, vomiting, anorexia, and weight loss.  Some of these 
symptoms can also be due to tumor progression.  Clinical and radiographic 
assessments will be performed as indicated to identify all adverse effects, 
ascertain their etiology, and provide the most appropriate palliative measures.  
Complications orther than radiation pneumonitis, if any, will be graded according 
to the Common Toxicity Criteria, National Cancer Institute, version 4.0. 
 
10.5 Reporting Procedures 
10.5.1 General and Multi-Site Reporting 
         
        10.5.1.1 General 
Adverse events will be recorded at each visit.  If an adverse event requiring 
medical attention occurs between visits, this will be recorded as well.  The 
variables to be recorded for each adverse event include, but are not limited 
to, onset, resolution, intensity, action taken, outcome, causality rating and 
whether it constitutes an SAE or not.  The intensity of the adverse event 
should be captured using CTCAE criteria, version 4.0, when possible.  
Additionally, the collection of all skeletal related events will be collected for 2 
years.  
 
All Serious Adverse Events (SAEs) will be reported via the AdEERS (Adverse 
Event Expedited Reporting System) application accessed via the CTEP web 
site 
(https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup).   
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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In addition, any safety concerns, new information that might affect either the 
ethical and or scientific conduct of the trial, or protocol deviations will be 
immediately reported to the industry collaborator Bayer HealthCare 
Pharmaceutical Inc. When required, and according to local law and 
regulations, serious adverse events must be reported to the Ethics 
Committee and Regulatory Authorities. All serious adverse events should be 
reported to Bayer HealthCare Pharmaceutical Inc. within 24 hours. 
 
All adverse events will be captured on the appropriate study-specific case 
report forms (CRFs).  
 
       10.5.1.2 Reporting SAEs at Multi‐Site/Participating Institutions 
 
A subject’s AEs and SAEs will be recorded and reported from the signing 
of the ICF up to at least 30 days after completing salvage radiotherapy. 
The investigator must instruct the subject to report AEs and SAEs during 
this time period. 
 
Subjects with evidence of Xofigo related toxicity at the post‐treatment 
follow‐up visit will be followed via telephone contact or weekly visits until 
the drug‐ related toxicity has resolved. Additionally, the collection of all 
skeletal related events will be collected for 2 years. Adverse events 
should be based on the signs or symptoms detected during the 
physical examination and on clinical evaluation of  the subject. In 
addition to the information obtained from those sources, the subject 
should be asked the following nonspecific question: "How have you 
been feeling since your last visit?" Signs and symptoms should be 
recorded using standard medical terminology. Any unanticipated risks 
to the subjects must be reported promptly to the IRB/IEC. In the event 
of an adverse event the first concern will be for the safety of the subject. 
 
All AEs and SAEs must be recorded on source documents. All AEs and 
SAEs for subjects who meet inclusion and exclusion criteria will be 
recorded in the CRFs and submitted to the lead site. The investigator 
must follow up on all AEs and SAEs until the events have subsided, 
returned to baseline or, in case of permanent impairment, until the 
condition stabilizes. 
 
Additional reporting is required for SAEs as follows: 
● 
SAEs that are fatal and possibly protocol related should be reported 
by phone to the Protocol Chair immediately upon knowledge of the 
event. 
 
Each participating site is responsible for evaluating and completing any 
additional reporting to their local IRB according to local IRB guidelines. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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All SAEs, regardless of causality to study drug and/or administration 
device, will be reported promptly to the Coordinating Center (e-mail: 
crocc@jhmi.edu and nradwan1@jh.edu), within 24 hours of recognition of 
the event. If this falls on a weekend or holiday, an email notification is 
acceptable but must be followed by an SAE reporting form on the next 
business day.  
 
CRO Coordinating Center  
The CRO Coordinating Center is the central location for the collection and 
maintenance of documentation of adverse events and is responsible for 
submitting adverse event reports to the Protocol Chair promptly. The 
CROCC will maintain documentation of all adverse event reports for each 
participating site. Adverse event reports submitted to the CRO 
Coordinating Center must be signed and dated by the participating site’s 
Principal Investigator. The CRO Coordinating Center will provide 
appropriate forms to be used by all participating sites for reporting adverse 
events. Information to be provided must include:  
• Subject ID number, and initials  
• Date of the event  
• Description of the event  
• Description of site's response to the event  
• Assessment of the subject's condition  
• Subject's status on the study (on study, off study, etc.)  
• Attribution of event to study drug  
 
Participating Sites  
Participating sites are responsible for reporting adverse events to their IRB 
according to its specific requirements and to the CRO Coordinating Center 
as follows:  
Fatal Events whether anticipated or unanticipated, and whether or not 
related to the study must be reported to the CRO Coordinating Center 
within 24 hours of the participating site Principal Investigator's learning of 
the event.  
 
Serious and Unanticipated Adverse Events as defined above must be 
reported to the CRO Coordinating Center within 24 hours of the 
participating site Principal Investigator's learning of the event.  
 
Other Serious Adverse Events which may result in a change to the protocol, 
informed consent, or risk to subjects as specified in the protocol must be 
reported within three (3) working days of the participating site Principal 
Investigator's learning of the event. 
 
Adverse Events which result in no change to protocol, informed consent, or 
risk to subjects must be reported to the CRO Coordinating Center on a 
monthly basis.  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Adverse event reports are to be emailed (use fax as a back-up) to the CRO 
Coordinating Center at SKCCC. Follow-up reports are faxed, mailed, or sent 
electronically to the Coordinating Center as necessary.  
 
The investigator must also report follow-up information about SAEs within 
the same time frames.  
 
If a non-serious AE becomes serious, this and other relevant follow-up 
information must also be provided within the same time frames described 
above.  
 
All SAEs must be collected whether or not they are considered causally 
related to the investigational product. Investigators and other site 
personnel are responsible for reporting all casually related SAEs to their 
IRB and the Protocol Chair.  
 
 
The principal investigator will notify the appropriate regulatory agencies of 
any serious adverse event due to any cause during the course of this 
investigation. These include the Johns Hopkins Cancer Center Data and 
Safety Monitoring Committee, and the Johns Hopkins Medical Institutional 
Review Board (JHM-IRB) of The Johns Hopkins Medical Institutions. The 
required reporting time period is 3 days for fatal events, and 10 days for all 
other events. 
 
 
10.5.2 Expedited FDA Reporting Requirements for Unexpected and Related Serious 
Adverse Events (per 21CFR312.32) 
  
7 Calendar-Day Telephone or Fax IND Safety Report  
The Sponsor-Investigator is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the Sponsor-
Investigator to be possibly related to the use of Radium-223 within 7 calendar-
days of first learning of the event. An unexpected adverse event deemed 
possibly related to the use of an investigational study drug is defined as any 
adverse drug experience of which the specificity or severity is not consistent 
with the current investigator brochure, the general investigational plan, or 
elsewhere in the current application, as amended.  
 
Such reports are to be telephoned or faxed to the FDA within 7 calendar-days 
of first learning of the event. Each telephone call or fax transmission should 
be directed to the FDA new drug review division in the Center for Drug 
Evaluation and Research or in the product review division for the Center for 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Biologics Evaluation and Research, whichever department is responsible for 
the review of the IND. 
 
15 Calendar-Day Written IND Safety Report  
The Sponsor-Investigator (Dr. Ana Kiess) is required to notify the FDA, and 
all participating investigators (as applicable), in a written IND Safety Report, 
of any serious, unexpected adverse event considered by the Sponsor-
Investigator to be possibly related to the use of Radium-223within 15 calendar 
days of first learning of the event. If applicable, the Sponsor-Investigator must 
also notify the FDA, and all participating investigators (as applicable), of any 
finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or 
carcinogenicity within 15 calendar-days of first learning of the event.  
  
A serious, unexpected adverse event deemed possibly related to the use of an 
investigational study drug is any adverse drug experience of which the 
specificity or severity is not consistent with the current investigator brochure, 
the general investigational plan, or elsewhere in the current application, as 
amended, and results in any of the following outcomes:  
 
• 
Death (report first as a 7-day telephone/fax report); 
• 
life-threatening adverse drug experience (report first as a 7-day 
telephone/fax report); 
• 
inpatient hospitalization or prolongation of existing hospitalization; a 
persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect; or is an important medical event that may not result in death, be life-
threatening, or require hospitalization but is considered a serious adverse 
drug experience when, based upon appropriate medical judgment, it may 
jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
All written IND Safety Reports should include an Analysis of Similar Events in 
accordance with 21CFR312.32. All safety reports previously filed with the IND 
concerning similar events should be analyzed. The new report should contain 
comments on the significance of the new event in light of the previous, similar 
reports and be submitted to the FDA, Bayer Pharmaceuticals, and all 
participating investigators (as applicable), within 15 calendar-days of first 
learning of the event. The FDA prefers these reports be documented on a 
MedWatch 3500A Form, but alternative formats are acceptable (e.g., summary 
letter). This form is available at http://www.fda.gov/medwatch/report/hcp.htm. 
 
Summary: For studies conducted under an Investigator IND, such as this 
trial, any event that is both serious and unexpected must be reported to the 
Food and Drug Administration (FDA) as soon as possible and no later than 7 
days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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BMS will be provided with a simultaneous copy of all adverse events filed with 
the FDA.  
 
SAEs should be reported on MedWatch Form 3500A or similar form. It MUST 
include the institutional AND [Supporter Name] study ID [per study 
Agreement]  
 
MedWatch SAE forms should be sent to the FDA at:  
MEDWATCH  
5600 Fishers Lane  
Rockville, MD 20852-9787  
Fax: 1-800-FDA-0178 (1-800-332-0178) 
 
Follow-up Reports 
 
All follow-up information concerning IND Safety Reports should be submitted 
to the FDA as soon as possible. 
 
10.5.3 Institutional Review Board 
All adverse events and serious adverse events will be reported to the IRB per 
current institutional standards. If an adverse event requires modification of 
the informed consent, these modifications will be provided to the IRB with the 
report of the adverse event. If an adverse event requires modification to the 
study protocol, these modifications will be provided to the IRB as soon as is 
possible. 
 
 
11. 
DATA REPORTING AND REGULATORY REQUIREMENTS  
The SKCCC Lead Coordinating Center will monitor the conduct and progress of the 
clinical trial at all participating sites.  It will provide administrative, data management, 
regulatory, and organizational support in the conduct of this multi-center trial.  The 
Coordinating Center will also function as the central location for multi-center trial 
documents and patient registration.  For more information regarding reporting, regulatory 
requirements and guidelines, see Appendix D. 
 
 
11.1  Multicenter Guidelines 
 
 
11.1.1. The Protocol Chair 
 
The Protocol Chair, Ana P. Kiess, is responsible for performing the following 
tasks: 
 
• 
Taking responsibility for the overall conduct of the study at all 
participating institutions and for monitoring the progress of the study. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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• 
Coordinating, developing, submitting, and obtaining approval for the 
protocol as well as its subsequent amendments. 
• 
Assuring that all participating institutions are using the correct version 
of the protocol. 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs). 
• 
Reviewing data from all sites 
 
11.1.2. Lead Coordinating Center 
 
The Lead Center SKCCC, Johns Hopkins University is responsible for 
performing the following tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site 
prior to the first patient registration at that site. 
• 
Maintaining copies of IRB approvals from each site. 
• 
Implementing central patient registration 
• 
Prepare appropriate data as required for review by the Protocol Chair. 
• 
Establishing procedures for documentation, reporting and 
submitting of AE’s and SAE’s to the Protocol Chair and all other 
applicable parties. 
• 
Facilitating audits by securing selected source documents and 
research records from participating sites for audit, or by auditing at 
participating sites. 
 
12. 
DATA AND SAFETY MONITORING PLAN  
 
12.1 Data Management  
 
The Lead Coordinator, Noura Radwan (nradwan1@jh.edu) will manage the study 
activities at each of the participating sites. The responsibilities of the Lead 
Coordinator include project compliance, data collection, data entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and 
coordination of the activities of the protocol team.  
De-identified study data may potentially be combined with other data in future 
studies with the University of Maryland for other research purposes. A DUA and 
is in process (see Section 36 of the IRB application). 
Outside participating sites will share de-identified patient data/information, with   
our co-investigators/sponsors (Johns Hopkins University) including genetic  
           (somatic and germline) information that has been obtained for patient care  
and/or research purposes.  
 
Eligible patients will be entered on study centrally at the Sidney Kimmel 
Comprehensive Cancer Center at the Johns Hopkins University by the RAVENS 
Lead Study Coordinator. All sites should email the the Lead Study Coordinator 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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(Nradwan1@jh.edu). The Registration Form, and Eligibility Worksheet will be 
supplied to each participating site.  
 
At the time of registration:   
• Informed Consent Form (signed by the subject)  
• Eligibility Checklist  
• Source documents related to eligibility and randomization  
 
The Study Coordinator at the participating site will then e-mail the RAVENS Lead 
Study coordinator (nradwan1@jh.edu) to verify eligibility. To complete the 
registration process/randomization, the Coordinating Center will: 
• Assign a patient study number  
• Randomization Patient 
• Register the patient on the treatment portion of the study  
• E-mail the patient study number to the participating site  
• E-mail the research nurse or data manager or coordinator at the 
participating site 
 
If a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled. The Lead Coordinator at the 
Coordinating Center should be notified of cancellations as soon as possible.  
 
Within 4 weeks after randomization:  
• Baseline study case report forms  
• Pertinent source documents  
 
Within 18 weeks (4 months) after randomization:  
• Day 90 study case report forms  
• Xofigo 1, 2, 3 injections case report forms, if applicable 
• Pertinent source documents  
 
Within 24 weeks (6 months) after randomization:  
• Day 180 study case report forms  
• Xofigo 4, 5, 6 injections case report forms, if applicable 
• Pertinent source documents  
 
Within 2 weeks after Day 360 :  
• On study case report forms  
• Pertinent source documents  
 
Within 2 weeks after Month 18 F/U:  
• Follow-up case report forms  
• Pertinent source documents  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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12.2 Data Safety  
 
The SKCCC Lead Coordinating Center will monitor the conduct and progress of the 
clinical trial at all participating sites.  It will provide administrative, data management, 
regulatory, and organizational support in the conduct of this multi-center trial.  The 
Coordinating Center will also function as the central location for multi-center trial 
documents and patient registration.   
 
The SKCCC Compliance Monitoring Program will provide external monitoring for 
JHU-affiliated sites in accordance with SKCCC DSMP (Version 6.0, 
02/21/2019).  The SMC Subcommittee will determine the level of patient safety risk 
and level/frequency of monitoring. 
 
Data and safety monitoring oversight will be conducted by the SKCCC at Johns 
Hopkins Safety Monitoring Committee. Per the SKCCC at Johns Hopkins Safety 
Monitoring plan, the CRO AQ will forward summaries of all monitoring reports to the 
Safety Monitoring Committee for review. All reportable anticipated and unanticipated 
protocol events/problems and amendments that are submitted to the IRB will also be 
reviewed by the Safety Monitoring Committee Chair (or designee) and QA manager. 
 
Interim analysis of toxicity, outcome and ongoing scientific investigations will be 
performed at least annually by the Sidney Kimmel Comprehensive Cancer Center Data 
Safety Monitoring Board (SKCCC DSMB). The SKCCC DSMB Recommendation 
letter will state the timeline for the next required review. The 
SKCCC DSMB will review aspects of this trial that are outlined in the responsibilities 
section of the Data and Safety Monitoring Board (DSMB) Guidance. If the 
committee decides that amendments should be made to this trial, recommendations 
will be made in writing to the Study Principal Investigator. The study team will 
submit modifications to the IRB within 60 days of receipt from the DSMB. The 
Associate Director of Clinical Research, will arbitrate any disagreements between 
the DSMB and the study Principal Investigator. These changes may include 
early termination of accrual if deemed appropriate. 
12.3 Multicenter Guidelines 
 
Protocol Chair  
• The Protocol Chair is responsible for performing the following tasks:  
• Coordinating, developing, submitting, and obtaining approval for the protocol  
• as well as its subsequent amendments  
• Assuring that all participating institutions are using the correct version of the 
protocol. 
• Taking responsibility for the overall conduct of the study at all participating 
institutions and for monitoring the progress of the study.  
• Reviewing and ensuring reporting of Serious Adverse Events (SAE)  
• Reviewing data from all sites  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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De-identified study data may potentially be combined with other data in future 
studies with the University of Maryland for other research purposes. A DUA is in 
process with the JH Office of Research Administration (see also Section 36 of 
the IRB application). 
 
Outside participating sites will share de-identified patient data/information, with   
our co-investigators/sponsors (Johns Hopkins University) including genetic  
           (somatic and germline) information that has been obtained for patient care  
and/or research purposes.  
 
 
CRO Coordinating Center  
The CRO Coordinating Center and the Lead Study Coordinator are responsible 
for performing the following tasks:  
• Ensuring that IRB approval has been obtained at each participating site 
prior to the first patient registration at that site, and maintaining copies of 
IRB approvals from each site. 
• Managing central patient registration.  
• Collecting and compiling data from each site.  
• Establishing procedures for documentation, reporting, and submitting of 
AE’s and SAE’s to the Protocol Chair, and all applicable parties.  
• Facilitating audits by securing selected source documents and research 
records from participating sites for audit, or by auditing at participating 
sites.  
 
Participating Sites 
Participating sites are responsible for performing the following tasks:  
• Following the protocol as written, and the guidelines of Good Clinical 
Practice (GCP).  
• Submitting data to the Coordinating Center.  
• Registering all patients with the Coordinating Center by submitting patient 
registration form, and signed informed consent promptly.  
• Providing sufficient experienced clinical and administrative staff and 
adequate facilities and equipment to conduct a collaborative trial 
according to the protocol.  
• Maintaining regulatory binders on site and providing copies of all required 
documents to the Coordinating Center.  
• Collecting and submitting data according to the schedule specified by the 
protocol 
 
Principal Investigator Responsibilities  
The Protocol Chair is responsible for performing the following tasks:  
• Coordinating, developing, submitting, and obtaining approval for the 
protocol as well as its subsequent amendments.  
• Assuring that the correct version of the protocol is used.  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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• Taking responsibility for the overall conduct of the study and for monitoring 
the progress of the study.  
• Reviewing and ensuring reporting of Serious Adverse Events (SAE).  
• Reviewing data from all sites. 
 
 
Data Entry 
Data collected during this study will be entered into a secure database. Staff at 
the SKCCC coordinating center will be responsible for the initial study 
configuration and setup in the consortium database and for any future changes. 
 
Case report forms 
Case report forms will be generated by the coordinating center for the 
collection of all study data. Investigators will be responsible for ensuring that 
the CRFs are kept up-to-date.  
The schedule for completion and submission of Case Report Forms and all 
supporting documents to the Lead Coordinating Center is as follows: 
 
 
Form  
Submission Timeline 
Eligibility Checklist  
Complete prior to registration  
Baseline Assessment Form 
Within 14 days of registration  
On-Treatment Forms (including drug 
diary) 
Within 10 days of course completion  
Adverse Event Report Form 
Within 14 days of each visit date 
Follow-up Form 
Within 14 days of visit date 
Off Study Form 
Within 14 days of being taken off study for 
any reason  
Data should also be submitted within the Johns Hopkins OneDrive Folder or 
RedCap. 
 
Source documents 
Study personnel will record clinical data in each patient’s source 
documents (ie, the patient’s medical record). Source documentation will 
be made available to support the patient research record. Study monitors 
will review entries on the CRFs at regular intervals, comparing the content 
with source documents. 
 
Record retention 
The investigator will maintain adequate and accurate records to enable 
the conduct of the study to be fully documented and the study data to be 
subsequently verified. After study closure, the investigator will maintain all 
source documents, study-related documents, and the CRFs. Because the 
length of time required for retaining records depends upon a number of 
regulatory and legal factors, documents should be stored until the 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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investigator is notified that the documents may be destroyed. In this study, 
records are to be retained and securely stored for a minimum of 3 years 
after the completion of all study activities. 
12.4 Biospecimen Management 
Specimens will be received by JHU from other participating sites, per protocol 
calendar, and then stored at JHU.  Specimens will be sent to collaborating 
universities (Stanford University and Mayo Clinic) and vendors for analysis as 
per protocol appendices and materials transfer agreements. 
 
The rectal swab samples will be used for DNA sequencing of the microbiome. 
The fundamental DNA sequencing technology is common and available at most 
institutions, but the bioinformatic pipelines and expertise needed to ensure good 
data quality and analysis is niche. Dr. Michael Liss (UCSD) and Dr. Rob Knight 
(UCSD) are experts in this regard to help with end-to-end sample handling, 
sample preparation, sequencing, and data analysis. 
 
The role of Dr. Liss, Dr. Knight, and their team at UCSD will be to process the 
swab samples and perform DNA sequencing on the microbiota. The role of the 
JHU team in this collaboration will be to provide outcome data with no obvious 
PHI from the RAVENS trial to allow for clinical correlations to be made based on 
results of the DNA sequencing done at UCSD. No physical materials will be 
transferred back to Hopkins. The analysis will be performed at UCSD and the 
results will be shared with the JHU team once completed to facilitate writing of a 
manuscript. Dr. Liss' team will be leading the manuscript writing. 
 
The JHU Office of Research Administration is initiating a Material Transfer 
Agreement with UCSD regarding this data analysis.  
 
13. 
REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
 
Information regarding study conduct and progress will be reported to the 
Institutional Review Board (IRB) per the current institutional standards. 
 
Any changes to the protocol will be made in the form of an amendment and must 
be approved by the IRB prior to implementation.  
13.2 Informed Consent 
The investigator (or his/her designee) will explain to each subject the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential 
risks and benefits involved and any discomfort it may entail. Each subject will be 
informed that participation in the study is voluntary, that she may withdraw from 
the study at any time, and that withdrawal of consent will not affect her subsequent 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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medical treatment or relationship with the treating physician(s) or institution. The 
informed consent will be given by means of a standard written statement, written 
in non-technical language, which will be IRB approved. The subject should read 
and consider the statement before signing and dating it, and will be given a copy 
of the document. No subject will enter the study or have study-specific procedures 
done before his/her informed consent has been obtained. 
 
In accordance with the Health Information Portability and Accountability Act 
(HIPAA), the written informed consent document (or a separate document to be 
given in conjunction with the consent document) will include a subject authorization 
to release medical information to the study sponsor and supporting agencies 
and/or allow these bodies, a regulatory authority, or Institutional Review Board 
access to subjects’ medical information that includes all hospital records relevant 
to the study, including subjects’ medical history. 
13.3 Ethics and GCP 
This study will be carried out in compliance with the protocol and Good Clinical 
Practice, as described in: 
 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 
50 and 56 concerning informed consent and IRB regulations). 
3. Declaration 
of 
Helsinki, 
concerning 
medical 
research 
in 
humans 
(Recommendations Guiding Physicians in Biomedical Research Involving 
Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong 
Kong 1989, Somerset West 1996). 
 
The investigator agrees to adhere to the instructions and procedures described in 
it and thereby to adhere to the principles of Good Clinical Practice that it conforms 
to.  
14. 
STATISTICAL CONSIDERATIONS  
14.1 Endpoints 
 
14.1.1 Primary Objective 
To determine progression-free survival in patients with oligometastatic (three 
metastases or less) hormone sensitive prostate cancer and at least one bone 
metastasis who have been are treated with SABR versus SABR + Radium-223. 
 
14.1.2  Secondary Objectives 
o To describe the toxicity of SABR and SABR + Radium-223 delivered for the 
population enrolled using grading with CTCAE v. 4.0 
o To determine local control at 12-months after SABR and SABR + Radium-
223 in patients with oligometastatic disease.  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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o To assess time to locoregional progression, time to distant progression, 
time to new metastasis and duration of response after randomization to 
SABR versus SABR + Radium-223. 
o To assess ADT-free survival (ADT-FS) of this patient population after 
randomization defined as the time interval between the day of 
randomization and the initiation of ADT.  ADT will typically be initiated on 
progression and/or development of new metastases. 
o To assess quality of life following SABR versus SABR + Radium-223 arms.  
Brief Pain Inventory form which will be filled out by the patient at the 
treatment response intervals outlined above. 
 
14.2 Sample Size/Accrual Rate/Follow-Up 
The primary endpoint will be progression-free survival (PFS). Data from STOMP 
and ORIOLE on this patient population indicate that >50-60% would show 
progression as defined above within a 12-month period from SABR, and a 
median PFS around 10 months. (72-74). We hypothesize that the addition of 
radium-223 will be able to reduce the risk of progression by 50%.  A sample size 
using a 1:1 randomization scheme of 30 patients per arm will provide 80% power 
to detect an increase of median PFS from 10 months to 20 month (corresponding 
to hazard ratio 0.5) with type I error = 0.1, using one-sided log-rank test. The 
calculation assumes 18 months of accrual time with an additional follow-up of 12 
months after the last patient is randomized. To account for 5% early drop out, we 
will randomize a total of 64 patients (32 per arm).   
 
There will be no interim analysis for futility, since the progression endpoint will 
not have been reached by a meaningful number of patients before full accrual. 
Follow-up (Every 3-6 months for 24 months or until death) 
Patients will be followed for 2 years after Day One of trial or until death. Patients 
withdrrawn from the study because of AEs will be followed until the adverse event 
has either resolved or stabilized. Reasons for premature withdrawl should be 
determined and noted.  
 
14.3 Stopping Guidelines 
 
This study will monitor site-specific grade 4/5 toxicity in the SABR + Radium-223 
arm. If it becomes evident that the proportion of grade 4/5 toxicity at specific sites 
convincingly exceeds 20%, the study will be halted for a safety consultation. 
Specifically, we will apply a Bayesian toxicity monitoring rule that suspends the 
enrollment if the posterior probability of toxicity being larger than 20% threshold 
is 75% or higher. The monitoring rule uses Beta (0.5, 5.5) as prior distribution. 
This means that our prior guess of the proportion of toxicity is 8.3%, and there is 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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90% chance that this proportion is 0.04%-30.6%.  The monitoring will start from 
the first patient, and the decision rule for safety stopping is as follows: 
 
Stop if: 
 
# grade 4/5 
toxicity >=  
3 
4 
5 
6 
7 
8 
9 
10 
Out of # 
patients 
3 - 5 6 - 10 11 - 14 15 - 18 19 - 23 24 - 27 28 - 32 33 - 36 
 
The operating characteristics of the stopping rule are shown below and are based on 5000 
simulations: 
True AE rate 
% simulated trials 
declaring unsafe 
Average sample size  
0.10 
2.4 
31.5 
0.2 
29.5 
26.8 
0.25 
52.6 
22.8 
0.3 
74.9 
18.4 
0.35 
89.2 
14.2 
14.4 Analysis of Primary Objective 
This is a randomized, Phase II trial of SABR versus SABR + Radium-223 in 
oligometastatic hormone sensitive prostate cancer patients. Minimization 
approach (77) will be applied to ensure balanced assignment to each treatment 
arm by stratification factors: 1) Institional; 2)Initial treatment with surgery vs. 
radiation therapy; 3) Prior hormonal therapy vs. no prior hormonal therapy; and 4) 
PSADT <6 mos vs. 6-14.9 mos. Baseline PSA level is defined as that measured 
Day 1 following randomization. Progression is defined as per section 9.6.2.  
 
The primary outcome of interest is PFS, defined as the time from the date of 
randomization to the date of disease progression or death, whichever happens 
earlier. For those who are alive and do not have progressive disease, PFS will be 
censored at the time of the last scan. Kapla-Meier method will be used to 
summarize PFS and log-rank test will be used to compare PFS between the two 
arms.  The analysis population includes all randomized subjects based on intent-
to-treat principle. 
 
14.5 Analysis of Secondary Objectives 
o For safety analysis, adverse events will be summarized by type and grade. 
o Kaplan-Meier (KM) estimates will be used to summarize ADT-free survival 
(ADT-FS), time to locoregional progression (TTLP), time to distant progression 
(TTDP), time to new metastasis (TNM) and duration of response over 
time.  The median PFS, ADT-FS, TTLP, TTDP TNM and duration of response 
will be reported.  
o The efficacy of SABR + Radium-223 in men with oligometastatic disease will 
also be determined by measuring local control of each lesion at 12-months. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Each metastatic lesion will be considered a target lesion and independently 
evaluated for response using RECIST 1.1 or bone scan evaluation criteria 
above. The lesion will be coded as being locally controlled if it is considered 
stable radiographic disease or if there is evidence of a partial or complete 
response. Local control assessment will start at three months following 
randomization and continuous assessment will be pursued during the follow-
up period.  The proportion of the lesions that have a stable or better response 
will be estimated using generalized estimating equation. 
o Quality of life will be assessed using the Brief Pain Inventory form.  An overall 
score will be calculated pre-treatment and at the time of the 2nd radiologic 
reassessment.  The change in score will be evaluated with a paired t-test.  
14.6 Evaluation of Toxicity 
All patients who receive at least one fraction of SABR and Radium-223 will be 
evaluable for toxicity from the time of their first treatment for SABR and Radium-
223. 
14.7 Correlative Science 
Descriptive statistics will be performed to correlate the temporal CTC, ctDNA, 
immunophenotyping and immune repertoire metric changes with clinical 
outcomes. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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PET with 2-deoxy-2-[F-18]fluoro-D-glucose. Radiology. Jun 1996;199(3):751-756. 
38. Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: a 
multidisciplinary perspective. Radiology. Apr 2007;243(1):28-53. 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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39. Lawrentschuk N, Davis ID, Bolton DM, Scott AM. Positron emission tomography and molecular 
imaging of the prostate: an update. BJU international. May 2006;97(5):923-931. 
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[11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: results 
confirmed by open pelvic-retroperitoneal lymphadenectomy. European urology. Aug 2007;52(2):423-
429. 
41. de Jong IJ, Pruim J, Elsinga PH, Vaalburg W, Mensink HJ. 11C-choline positron emission 
tomography for the evaluation after treatment of localized prostate cancer. European urology. Jul 
2003;44(1):32-38; discussion 38-39. 
42. Picchio M, Messa C, Landoni C, et al. Value of [11C]choline-positron emission tomography for re-
staging prostate cancer: a comparison with [18F]fluorodeoxyglucose-positron emission tomography. 
The Journal of urology. Apr 2003;169(4):1337-1340. 
43. Morris MJ, Scher HI. (11)C-acetate PET imaging in prostate cancer. European journal of nuclear 
medicine and molecular imaging. Feb 2007;34(2):181-184. 
44. Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone 
metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- 
and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. Feb 
2006;47(2):287-297. 
45. Even-Sapir E, Mishani E, Flusser G, Metser U. 18F-Fluoride positron emission tomography and 
positron emission tomography/computed tomography. Semin Nucl Med. Nov 2007;37(6):462-469. 
46. Beattie BJ, Smith-Jones PM, Jhanwar YS, et al. Pharmacokinetic assessment of the uptake of 
16beta-18F-fluoro-5alpha-dihydrotestosterone (FDHT) in prostate tumors as measured by PET. J 
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47. Schuster DM, Savir-Baruch B, Nieh PT, et al. Detection of recurrent prostate carcinoma with anti-
1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PET/CT and 111In-capromab pendetide 
SPECT/CT. Radiology. Jun 2011;259(3):852-861. 
48. Schuster DM, Votaw JR, Nieh PT, et al. Initial experience with the radiotracer anti-1-amino-3-18F-
fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med. Jan 
2007;48(1):56-63. 
49. Greco C, Cascini GL, Tamburrini O. Is there a role for positron emission tomography imaging in 
the early evaluation of prostate cancer relapse? Prostate cancer and prostatic diseases. 
2008;11(2):121-128. 
50. Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP. Prostate specific membrane antigen 
expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer. 
Jun 1 1998;82(11):2256-2261. 
51. Chang SS, Reuter VE, Heston WD, Gaudin PB. Comparison of anti-prostate-specific membrane 
antigen antibodies and other immunomarkers in metastatic prostate carcinoma. Urology. Jun 
2001;57(6):1179-1183. 
52. Sweat SD, Pacelli A, Murphy GP, Bostwick DG. Prostate-specific membrane antigen expression 
is greatest in prostate adenocarcinoma and lymph node metastases. Urology. Oct 1998;52(4):637-
640. 
53. Wright GL, Jr., Grob BM, Haley C, et al. Upregulation of prostate-specific membrane antigen after 
androgen-deprivation therapy. Urology. Aug 1996;48(2):326-334. 
54. Perner S, Hofer MD, Kim R, et al. Prostate-specific membrane antigen expression as a predictor 
of prostate cancer progression. Human pathology. May 2007;38(5):696-701. 
55. Ross JS, Sheehan CE, Fisher HA, et al. Correlation of primary tumor prostate-specific membrane 
antigen expression with disease recurrence in prostate cancer. Clin Cancer Res. Dec 15 
2003;9(17):6357-6362. 
56. Thomas CT, Bradshaw PT, Pollock BH, et al. Indium-111-capromab pendetide 
radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation 
therapy in men after failed prostatectomy. J Clin Oncol. May 1 2003;21(9):1715-1721. 
57. Wilkinson S, Chodak G. The role of 111indium-capromab pendetide imaging for assessing 
biochemical failure after radical prostatectomy. The Journal of urology. Jul 2004;172(1):133-136. 
58. Barinka C, Rovenska M, Mlcochova P, et al. Structural insight into the pharmacophore pocket of 
human glutamate carboxypeptidase II. Journal of medicinal chemistry. Jul 12 2007;50(14):3267-3273. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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59. Barinka C, Starkova J, Konvalinka J, Lubkowski J. A high-resolution structure of ligand-free 
human glutamate carboxypeptidase II. Acta crystallographica. Mar 1 2007;63(Pt 3):150-153. 
60. Foss CA, Mease RC, Fan H, et al. Radiolabeled small-molecule ligands for prostate-specific 
membrane antigen: in vivo imaging in experimental models of prostate cancer. Clin Cancer Res. Jun 
1 2005;11(11):4022-4028. 
61. Mease RC, Dusich CL, Foss CA, et al. N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-
[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: a new imaging probe for prostate cancer. Clin Cancer 
Res. May 15 2008;14(10):3036-3043. 
62. Cho SY, Gage KL, Mease RC, et al. Biodistribution, Tumor Detection and Radiation Dosimetry of 
N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-L-cysteine (18F-DCFBC), a Low 
Molecular Weight Inhibitor of PSMA, in Patients with Metastatic Prostate Cancer. J Nucl Med. 2012 
Dec;53(12):1883-91. 
63. Szabo Z, Mena E, Rowe SP, et al. Initial Evaluation of [(18)F]DCFPyL for Prostate-Specific 
Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer. Mol Imaging Biol. 2015 
Aug;17(4):565-74. 
64 Chiang, A. C. & Massague, J. Molecular basis of metastasis. N Engl J Med 359, 2814-2823, 
doi:10.1056/NEJMra0805239359/26/2814 [pii] (2008). 
65 Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315-1326, 
doi:10.1016/j.cell.2009.11.025S0092-8674(09)01437-8 [pii] (2009). 
66 Comen, E., Norton, L. & Massague, J. Clinical implications of cancer self-seeding. Nat Rev Clin 
Oncol 8, 369-377, doi:10.1038/nrclinonc.2011.64nrclinonc.2011.64 [pii] (2011). 
67 Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353-
357, doi:10.1038/nature14347nature14347 [pii] (2015). 
68 Marrinucci, D. et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast 
cancers. Phys Biol 9, 016003, doi:10.1088/1478-3975/9/1/016003S1478-3975(12)97631-6 [pii] 
(2012). 
69 Newman, A. M. et al. An ultrasensitive method for quantitating circulating tumor DNA with broad 
patient coverage. Nature medicine, doi:10.1038/nm.3519nm.3519 [pii] (2014). 
70 Robins, H. S. et al. Comprehensive assessment of T-cell receptor beta-chain diversity in 
alphabeta T cells. Blood 114, 4099-4107, doi:10.1182/blood-2009-04-217604blood-2009-04-217604 
[pii] (2009). 
71 Cha, E. et al. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in 
cancer patients. Sci Transl Med 6, 238ra270, doi:10.1126/scitranslmed.30082116/238/238ra70 [pii] 
(2014). 
72 Keizman D, Zahurak M, Sinibaldi V, et. al. Lenalidomide in nonmetastatic biochemically relapsed 
prostate cancer: results of a phase I/II double-blinded, randomized study.  Clin Cancer Res. 2010 Nov 
1;16(21):5269-76. 
73.  Pound C, Partin A, Eisenberger M, Chan DW, Pearson JD, Walsh PC. Natural history of 
progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–7. 
74.  Antonarakis ES, Trock BJ, Feng Z, et al. The natural history of metastatic progression in men 
with PSA-recurrent prostate cancer after radical prostatectomy: 25-year follow-up. J Clin Oncol 
2009;27: 15s, (suppl; abstr 5008. 
75.  Scher HI, Halabi S, Tannock I, et. al. Design and End Points of Clinical Trials for Patients With 
Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations of the Prostate 
Cancer Clinical Trials Working Group.  J Clin Oncol. 2008 Mar 1;26(7):1148-59. 
76.  Decaestecker K, De Meerleer G, Lambert B, et al. Repeated stereotactic body radiotherapy for 
oligometastatic prostate cancer recurrence. Radiat Oncol. 2014 Jun 12;9:135. 
 
77. Vickers AJ. How to randomize. J Soc Integr Oncol 2006;4:194-8. 
78.  Zeng, J., Harris, T. J., Lim, M., Drake, C. G. & Tran, P. T. Immune modulation and stereotactic 
radiation: improving local and abscopal responses. Biomed Res Int 2013, 658126, 
doi:10.1155/2013/658126 (2013). 
79. Pritchard CC, Mateo JM, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with 
Metastatic Prostate Cancer. N Engl J Med 2016; 375:443-453 
80. SEER Stat Fact Sheets: Colon and Rectum Cancer. Published November 2015. Updated April 
2016. Accessed August 7 2016. http://seer.cancer.gov/statfacts/html/colorect.html 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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81. Invitae Corporation. (2019). Invitae Multi-Cancer Panel.  [Test Catalog]. Retrieved from 
https://www.invitae.com/en/physician/tests/01101/  
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX I: Brief Pain Inventory Form 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX II: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX III: CAPP-Seq Sample Collection & Processing 
 
Diehn Lab Blood Processing Protocol (version 122314) 
❖ Materials (check to make sure you have all of it before you start) 
• Filtered P2000 pipette tips  
• P-2000 pipette 
• 2.0-mL Eppendorf tubes 
• Patient’s blood - usually 30 mL in 3 “purple top” tubes (EDTA) per time point. 
Blood should be kept on ice or in refrigerator after drawing and processed as 
soon as possible to minimize lysis of WBCs and release of cellular genomic DNA 
into plasma 
 
❖ Methods 
1. Spin samples in the clinical centrifuge using the settings: 3,500rpm, 10min, 4C 
2. While you wait, label tubes 
3. After spinning, carefully remove lavender top tubes from centrifuge. Do not 
disturb the separated plasma and cell-free whole blood 
i. Tip: It helps to put all the tubes into one holder and carefully carry 
the holder to the hood 
4. Using a filtered tip and p-2000 pipet aliquot ~1.8 mL clear plasma (not all the way 
to the top since tops of tubes tend to pop open upon freezing if filled all the way) 
into a 2.0 mL Eppendorf tube. Repeat until you have aliquoted the plasma from 
all the purple-top tubes into 2.0 mL Eppendorf tubes. With the tubes that have 
only the buffy coat and RBC remaining, mix the buffy coat and cell-free whole 
blood using a pipette tip and aliquot ~1.8 mL into a 2.0 mL Eppendorf tube. 
Repeat so you have a second 2.0 mL Eppendorf tube containing the buffy coat 
and RBC mixed together. 
5. Put Eppendorf tubes into -80C freezer. 
6. Write down # of plasma tubes stored, box number, date of blood draw, time 
of storage on the top of patients’ requisition forms.  
7. Enter the blood draw information into REDCap database. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX IV: EPIC-HD CTC Sample Collection & Processing 
 
  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX V: ImmunoSEQ Sample Collection & Processing 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX VI: RECTAL SWAB COLLECTION FOR MICROBIOME ANALYSIS  
 
OPTION 1: Flocked Swabs & Plastic Applicator - Reagents and Supplies Needed:  
Regular flocked swab, plastic applicator, sterile in dry tube (Copan, catalog #552C)  
Protocol:  
1. Remove swab from plastic tube. Hold the swab by the end of the plastic handle 
and take care not to touch the cotton tip of the swab to any surfaces or with 
fingers. 
2. Insert the swab through the rectal sphincter and approximately 3 cm into the anal 
canal. Rotate the swab and withdraw.   
3. Place the swab back into the plastic tube.  
 
  
OPTION 2: Peel-Pouch Swabs - Reagents and Supplies Needed: 
 
• Regular flocked swab, plastic applicator, sterile in peel pouch (Copan, catalog 
#519CS01) 
• Sterile 15mL conical tube  
• Pair of purple nitrile powder free exam gloves  
• Biohazard collection bag 
Protocol: 
1. Put on purple nitrile gloves. 
2. Remove swab from peel pouch. Hold the swab by the end of the plastic 
applicator and take care not to touch the cotton tip of the swab to any surfaces or 
with fingers. 
3. Insert the swab directly into the rectum and approximately 3 cm into the anal 
canal. Rotate the swab and withdraw. If fecal matter is on the swab, it has 
been done correctly.  
4. Place the swab into the 15mL conical tube and snap off at the red break-off point. 
Discard gloves as to not get any material on the outside of the tube. 
5.  Screw cap back onto tube securely and place tube into biohazard bag. 
 
ALL OPTIONS: The swab samples can be kept at 4°C or -20°C prior to transport to the 
Sfanos lab.  
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX VII: Ordering from Invitae 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX VIII: Immunophenotyping 
Peripheral blood will be collected into two heparin tubes (green top tubes) according to 
the study calendar. Following collection, Elizabeth Thompson from the Powell lab will be 
notified for collection (see contact information below).  Peripheral blood mononuclear 
cells (PBMCs) will be isolated using standard protocols of Ficoll isolation and 
cryopreserved in freezing media (FBS, 10%DMSO).  Cells will be stored long-term in 
liquid nitrogen until thawed for batch analysis.  Upon thawing, cells will be 
immunophenotyped using multiparameter flow cytometry to evaluate the immunologic 
and metabolic phenotype of the following cell subsets: CD4 and CD8 T cells, FOXP3+ 
Tregs, B cells, NK cells, monocytes, dendritic cells, and myeloid derived suppressor 
cells (Table 1).  Samples will be run on a Cytek Aurora machine, which allows for the 
simultaneous detection of up to 25 markers.  Additionally, the metabolic fitness of the 
total PBMCs will be evaluated using the mitochondrial stress test on the Seahorse 
analyzer.  Functional assays will be run on PBMCs to determine the relative capacity of 
peripheral T cells to metabolically respond to T cell receptor stimulation through 
activation of CD3 and CD28. Additional vials will be stored for RNA-sequencing of 
relevant populations identified in initial immunophenotyping.  
 
Contact information 
Primary point of contact 
Elizabeth Thompson 
Ethomp58@jhmi.edu 
410-814-1261 
 
Secondary point of contact 
Jiayu Wen 
Jwen1@jhmi.edu 
410-502-7444 
 
 
Table 1. Immuno- and metabolic phenotyping of PBMCs 
Marker 
Purpose 
Live Dead 
Dead cell exclusion 
H3K27me3  
Histone Methylation 
CTLA4  
Immune phenotype-Co-inhibitory 
PD1  
Immune phenotype-Co-inhibitory 
41BB  
Immune phenotype-Co-stimulatory 
CCR7  
Immune phenotype-Memory  
CD45RA  
Immune phenotype-Memory  
Ki67  
Immune phenotype-Proliferation 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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CD19 
Immune subset-B cell 
CD15  
Immune subset-MDSC 
CD33  
Immune subset-MDSC 
HLA-DR  
Immune subset-Monocyte/DCs 
CD14  
Immune subset-Monocyte/MDSC 
CD56 
Immune subset-NK cell 
CD3 
Immune subset-T cell 
CD4 
Immune subset-T cell 
CD8  
Immune subset-T cell 
FOXP3  
Immune subset-Treg 
CPT1a 
Metabolic phenotype-Fatty acid 
oxidation 
GLUT1  
Metabolic phenotype-Glycolysis 
Hexokinase II 
Metabolic phenotype-Glycolysis 
LDHA  
Metabolic phenotype-Glycolysis 
pS6  
Metabolic phenotype-mTOR activity 
TOMM20  
Metabolic phenotype-OXPHOS 
VDAC1 
Metabolic phenotype-OXPHOS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX IX: RAPID SPECT Imaging Sub-Contract Study 
Purpose: To measure radiation exposure to specific metastases by performing SPECT scans at 2-
4 hours, 24 hours (+/- 4 hours), and 48 hours (+/- 4 hours) following Xofigo infusions #1 and #6 
to calculate the total radiation exposure to the specific metastases. 
 
All patients participating in Hopkins Xofigo/XRT (RAVENS) trial will be eligible for 
participation in the Rapid SBIR-contract supported CXαRPT (companion) trial. 
 
Patient treatment will not change. A data collection effort for retrospective evaluation of results 
will be conducted by Hopkins via a companion protocol that patients participating in the parent 
trial may sign on to. The target population is 20 out of the 30-34 patients that will be enrolled in 
the SABR + Xofigo arm of the RAVENS trial. The expected accrual is 10 patients in year 1 and 
10 patients in year 2.  
 
Patients will be compensated with a $100 gift card for the 3 223Ra SPECT/CT scans following 
Xofigo infusion #1, and a $100 gift card for the 3 223Ra SPECT/CT scans following Xofigo 
infusion #6. gift cards and scans will be paid for by the research budget from the NIH sub-
contract. 
 
Hypothesis: The 223Ra dosimetry calculations performed will demonstrate, retrospectively, that > 
30% of the patients would have required an adjustment in the XRT treatment plan, to meet the 
following criteria: 
 
1. Tumor absorbed dose (to at least 5 lesions) ≥ 80 EQD2 -Gy (BED=96 Gy; α/β=10 Gy),  
2. Normal organ doses within tolerance limits. 
 
Data/Workflow:  
● For patients participating in the RAVENS protocol, Hopkins will collect 223Ra 
SPECT/CT at 2-4 hours, 24 hours (+/- 4 hours), 48 hours (+/- 4 hours) after first and last 
Xofigo infusion. 
● Rapid receives anonymized SPECT projection data, performs quantitative recon, 3D-RD 
dosimetry, and provides combined RPT-XRT (CXRPT) dose map to Hopkins. 
● Hopkins compares XRT dose map w/ and w/o αRPT dosimetry and determines if a 
change would have been merited. 
● Rapid receives Hopkins assessments. 
 
 
 
 
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Standard Operating Procedure 
Quantitative Imaging and Dosimetry of Radium-223 
V2.2; July 8, 2019  
 
Characteristics of 
Ra-223 
Radium-223 is primarily an alpha emitter (95.3% abundance). The 
fractions emitted as beta and gamma particles are 3.6% and 1.1%. The 
gamma component allows for the in-vivo imaging. 
Purpose of 
imaging 
procedure 
Exploratory – to evaluate variability in Ra-223 uptake across patients and 
how the proposed combination agents impact this, also how tumor burden 
impacts distribution and dosimetry. 
Dosage level1 
As per Xofigo package insert 
Radiation dose to 
main organs1  
(Gy/MBq) 
Adrenals 
0.00012 
Brain 
0.00010 
Breasts 
0.00005 
Gallbladder wall 
0.00023 
Lower large intestine wall 
0.04645 
Small intestine wall 
0.00726 
Stomach wall 
0.00014 
Upper large intestine wall 
0.03232 
Heart wall 
0.00173 
Kidneys 
0.00320 
Liver 
0.00298 
Lungs 
0.00007 
Muscle 
0.00012 
Ovaries 
0.00049 
Pancreas 
0.00011 
Red marrow 
0.13879 
Osteogenic cells 
1.15206 
Skin 
0.00007 
Spleen 
0.00009 
Testes 
0.00008 
Thymus 
0.00006 
Thyroid 
0.00007 
Urinary bladder wall 
0.00403 
Uterus 
0.00026 
Whole body 
0.02311 
Patient 
preparation 
Nothing beyond what is already specified in the protocol 
SPECT imaging 
length 
~30 mins per FOV 
FOVs taken 
Chest & Abdomen, if there are relevant lesions outside these two fields of 
view then additional views could be collected as needed. After first field 
is collected, to extent possible, patient should remain on couch for 
subsequent FOV collection. 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Imaging Time 
points (post-
injection) 
2-4 hours, 24 hours  4 hours, 48 hours  4 hours 
SPECT 
Acquisition 
parameters for 
SPECT/CT 
Collimator 
MEGP 
Matrix 
128 x 128 
Time / view 
30 seconds/view 
# of projection views 
120 
Angle range 
360 
Energy Window Setting 
(KeV) 
71.4 
96.6 
 (30% at 84) 
138.5 168.5  (20% at 154) 
249.7 290.2  (15% at 270) 
CT acquisition 
parameters for 
SPECT/CT 
The CT portion of the first SPECT/CT scan for each patient should be in 
high res (i.e., diagnostic mode); attenuation mode (low-dose) may be used 
for subsequent scans. Standard vendor settings for high 
resolution/diagnostic vs low-dose or attenuation acquisition may be 
applied. 
Quality control 
required 
Standard camera quality control (QC) as specified by the vendor should 
be up to date on all cameras that will be used for this study. Typical QCs 
include uniformity, linearity/spatial resolution, and center of rotation 
alignment. 
Dose calibrator QCs should also be routinely performed and documented 
(accuracy, consistency, linearity, and geometry). 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Additional 
requirement  
Sensitivity needs to be measured prior to or immediately after the patient 
scan. Suspend a calibration source (with known amount of Ra-223 – 
2MBq) between the two camera heads (by taping it to a yard stick and 
supporting the stick on the bed). The source should be such that there are 
no attenuating materials between, including the bed or meter stick, 
between the source and collimator. Position the source so it is 15 ± 0.5 cm 
from the face of each collimator and collect a 5 min dual head single view 
scan (256x256 matrix, same collimator/energy windows as above).   
 
Recommended 
phantom 
calibration scan 
There is a recommended phantom calibration scan with either a NEMA 
PET IEC Body Phantom or an ACR Phantom to be collected for each 
camera that may be used for Ra-223 patient imaging. This scan is 
collected once prior to camera’s use for Ra-223 patient imaging. The 
body of the phantom should be filled with water at room temperature 
removing as much of the air as possible. All spheres must be removed 
except the largest one. The activity and measurement time of the 
syringe prepared earlier should be recorded. All the activity (~2 MBq) 
contained in the syringe should be injected into the largest sphere (a 
long needle might be needed). Both, activity and measurement time 
after the injection (with needle on) must be recorded. The rest of the 
large sphere can be completely filled with water, using a new syringe 
and needle.  
The image technician must make sure that the largest sphere is in place 
before putting the lid on the phantom and hand-tighten the screws.  
The phantom should be placed flat-side down on the bed (pad can be 
removed, if necessary) and in the middle of the camera field of view. 
SPECT and CT images should be acquired using pre-defined patient 
imaging protocol(s) and parameters used should be recorded. 
Reporting 
requirements 
None, a table of results will be provided for each patient to the institution 
or to the PI of the protocol with the expectation that this will lead to a 
publication. 
Interpretation for 
dosimetry (or any 
other) purpose 
N/A; Results will be analyzed and used for publication to evaluate patient 
to patient variability and impact of tumor burden.  Study will also provide 
accurate SPECT-imaging based dosimetry. 
Camera
Camera
Bed
Meter stick
Syringe
15 cm
15 cm

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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Step by step 
imaging 
procedure 
Routine SPECT/CT imaging procedure in clinical practices should be 
used with the parameters specified above. 
Data to send 
SPECT projections, attenuation map, and all CT slices (in DICOM 
format). 
Image 
quantification 
procedure 
SPECT projections will be reconstructed using previously published 
iterative quantitative reconstruction methods established by Rapid2-5. 
Volume of interest (VOIs) will be drawn around the major organs and 
lesions of interest at each time points. Total counts in the VOIs at each 
time point will be calculated and converted to activity by measured 
sensitivity. The time integrated activity coefficients (TIACs), 
mathematically equivalent to the number of decays per unit injected 
activity, will be calculated from single or double exponential fits for the 
main source organs and the lesions. The TIACs in the red marrow 
(TIACRM) will be derived from contours drawn around lumbar vertebrae 
L3-L5, the TIACRM will be divided by the marrow mass in this region to 
give TIACRM concentration. Total TIACRM will be obtained as the 
product of this concentration and the estimated patient RM mass. 
Dosimetry 
analysis 
procedure 
The absorbed dose values for target organs will be derived by using whole 
organ S-value based method and MC-calculation using images and 3D-
RD approach (RBE =5 for alphas). Importantly, Rapid follows SNMMI 
MIRD Committee recommendations as published in its series of 
pamphlets and will update calculation accordingly if necessary. Mean 
absorbed dose (mAD) and mean (mBED) will be obtained using the 
software package 3D-RD6-10. The methodology used in 3D-RD is briefly 
summarized below:  
1. Using the Electron Gamma Shower (EGS) Monte Carlo (MC) software, 
one million events will be run for the beta- and photon components of the 
isotope decay spectra, for each time point.  
2. The energy deposition distribution from the contributing components 
from MC will be weighted for probability and unit activity then converted 
to absorbed dose rate for each VOI (spectra probability distributions 
obtained from LBL/Lund web site11). 
3. The dose rates for the each VOI will be fitted using the simulation 
Analysis and Modeling II (SAAM II) software package (The Epsilon 
Group, Charlottesville VA), and the area under the curve calculated as the 
absorbed dose mAD.  
4. The mBED will be calculated using the linear-quadratic (LQ) BED 
methodology described in reference12. 
References 
1. Xofigo (radium Ra 223 dichloride) Prescribing Information. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203971lbl.pdf 
2. Frey EC, Tsui BMW. A new method for modeling the spatially-variant, object 
shape dependent scatter response function in SPECT. IEEE Nuclear Science 
Symp Conference Record. 1996:1082-1086.  

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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3. Frey EC, Tsui BMW. A PRACTICAL METHOD FOR INCORPORATING SCATTER 
IN A PROJECTOR-BACKPROJECTOR FOR ACCURATE SCATTER 
COMPENSATION IN SPECT, 1993.  
4. Frey EC, Tsui BMW, Gullberg GT. Improved estimation of the detector 
response function for converging beam collimators. Physics in Medicine and 
Biology. 1998;43:941-950.  
5. He B, Du Y, Segars WP, et al. Evaluation of quantitative imaging methods for 
organ activity and residence time estimation using a population of 
phantoms having realistic variations in anatomy and uptake. Med Phys. 
2009;36:612-619. 
6. Hobbs RF, Wahl RL, Lodge MA, et al. I-124 PET-Based 3D-RD Dosimetry for a 
Pediatric Thyroid Cancer Patient: Real-Time Treatment Planning and 
Methodologic Comparison. Journal of Nuclear Medicine. 2009;50:1844-1847.  
7. Kolbert KS, Sgouros G, Scott AM, et al. Implementation and evaluation of 
patient-specific three-dimensional internal dosimetry. J Nucl Med. 
1997;38:301-308.  
8. Sgouros G, Hobbs RF, Atkins FB, Van Nostrand D, Ladenson PW, Wahl RL. 
Three-dimensional radiobiological dosimetry (3D-RD) with 124I PET for 131I 
therapy of thyroid cancer. Eur J Nucl Med Mol Imaging. 2011;38 Suppl 1:S41-
47.  
9. Sgouros G, Kolbert KS, Sheikh A, et al. Patient-specific dosimetry for 131I 
thyroid cancer therapy using 124I PET and 3-dimensional-internal dosimetry 
(3D-ID) software. J Nucl Med. 2004;45:1366-1372.  
10. Prideaux AR, Song H, Hobbs RF, et al. Three-Dimensional Radiobiologic 
Dosimetry: Application of Radiobiologic Modeling to Patient-Specific 3-
Dimensional Imaging-Based Internal Dosimetry. J Nucl Med. 2007;48:1008-
1016. 
11. Ekström 
L, 
Firestone 
R. 
WWW 
Table 
of 
Radioactive 
Isotopes. 
http://ie.lbl.gov/toi/index.htm.  
12. Hobbs RF, Sgouros G. Calculation of the biological effective dose for piecewise 
defined dose-rate fits. Med Phys. 2009;36:904-907. 
 
 
- approval signatures page. This will be have to be signed off at each imaging site. 
 
 
Responsibility for: 
- 
Data transfer, receiving / accepting images at Rapid: 
o Bin He (bhe@rapiddosimetry.com) 
- 
Assurance of de-identification of patient data: 
o  TRIAD 
- 
Storing images (and for how long), and interpreting these images 
o Images and data related to dosimetry will be transferred back to TRIAD 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX X: XOFIGO PATIENT INFORMATION SHEET 
  Johns Hopkins Hospital 
Department of Radiation Oncology and Molecular Radiation Sciences 
 
 
Patient Information – Radium-223 (Xofigo) Therapy 
 
• Prior to all injections of Radium-223 it is important that you obtain required labs. 
• Report any signs of bleeding or infection. 
• Shut the lid and double flush the toilet after each urination/stool for the next 7 
days (for 7 days after each and every treatment). 
• If urine/feces/blood soils your clothing, you should wash the clothing separately 
and promptly.   
• If you wear an undergarment (Depends, pad, etc.), you should double bag it and 
discard it in the regular trash.   
• Caregivers should use gloves and gowns when handling bodily fluids and wash 
hands well.  
• You may return to work or school the day of treatment. 
• You may have sexual contact immediately but use a condom during the 6 
months of treatment and 6 months after treatments are completed.  Female 
partners with reproductive potential should use effective birth control.  
• There are no restrictions regarding contact with other people after receiving 
Radium-223.   
 
 
Any concerns regarding Radium-223 (Xofigo) may be addressed by calling  
410-955-6980 during normal business hours (Monday-Friday, 8AM – 4:30PM). 
 
 
For concerns after hours, please call 410-955-4331 and ask for the Radiation Oncology 
doctor on-call.   
  
 
 
 
 
 
 
___________________________ 
 
___________________________ 
Patient Signature 
 
      Date 
 
Provider Signature  
 
 
 
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
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APPENDIX XI: BAYER PATIENT RELEASE CARD  
 
 
Please print and fill out the card for all patient’s randomized to the SABR + 
XOFIGO Arm. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SABR +/- Radium-223 for Oligometastatic Prostate Cancer                                                                         Version 2.6 
Protocol Chair:  Ana P. Kiess, M.D., PhD  
J18147 – February 07, 2025 
 
 
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