Phase II Randomized Observation Versus Stereotactic Ablative RadiatIOn for OLigometastatic Prostate CancEr (ORIOLE) Trial
Phase: PHASE2
Conditions: Prostate Cancer, Oligometastases
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
J15180 - Version 5.4 July 11, 2017 
 
 
1 
 
Phase II Randomized Observation versus Stereotactic Ablative RadiatIon for OLigometastatic 
Prostate CancEr (ORIOLE) Trial 
 
Protocol Number 
 
J15180 
IND Number  
 
# 121,064 
 
Principal Investigator 
Phuoc T. Tran, M.D., PhD 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
Weinberg Building 
 
1550 Orleans St., CRB 2 Rm 406 
Baltimore, MD 21231 
Phone:  410-614-3880 
Fax:  410-502-1419 
Email: tranp@jhmi.edu 
 
 
Co-Investigators 
Theodore DeWeese, M.D. 
Danny Song, M.D. 
Mario Eisenberger, MD 
Ashley Ross, MD, PhD 
Michael Gorin, M.D. 
Michael Carducci, M.D. 
Emmanuel Antonarakis, M.D. 
Channing Paller, M.D. 
Kenneth Pienta, M.D. 
Lawrence Kleinberg, M.D. 
Kristin Redmond, M.D. 
Steve Rowe, M.D., PhD 
Martin Pomper, M.D., PhD 
Stephen Greco, M.D. 
Curtiland Deville, M.D. 
 
Statisticians 
Hao Wang, PhD 
 
 
Bruce Trock, PhD 
 
Research Nurse 
Shirl Dipasquale 
 
Research Managers: 
Helen Kim 
Terry Caldwell 
 
Study Coordinator:  
Noura Radwan, M.D. 
 
Funding: 
 
 
NCI 1U01CA183031-01A1 (Pomper/DeWeese) 
Movember-PCF Challenge Award (Tran/Ross/Dicker) 
 
 
 
 
NCT02680587

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
J15180 - Version 5.4 July 11, 2017 
 
 
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Table of Contents 
 
SCHEMA ........................................................................................................................................................................ 4 
 
1. 
PROTOCOL SYNOPSIS ...................................................................................................................................... 5 
2. 
ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................................................................. 7 
3. 
STUDY DESIGN AND OBJECTIVES ................................................................................................................... 8 
3.1  STUDY DESIGN ................................................................................................................................................ 8 
3.2  PRIMARY OBJECTIVE....................................................................................................................................... 8 
3.3  SECONDARY OBJECTIVES ............................................................................................................................... 8 
3.4  CORRELATIVE OBJECTIVES ............................................................................................................................ 8 
4. 
BACKGROUND .................................................................................................................................................... 9 
4.1  OLIGOMETASTATIC DISEASE ........................................................................................................................... 9 
4.2  STEREOTACTIC BODY RADIATION THERAPY (SBRT) OR STEREOTACTIC ABLATIVE RADIATION THERAPY       
(SABR) ........................................................................................................................................................... 9 
4.3  RATIONALE FOR USE OF SBRT/SABR IN OLIGOMETASTATIC DISEASE ..................................................... 10 
4.4  RATIONALE FOR SBRT/SABR FOR BONE OLIGOMETASTASES IN PROSTATE CANCER ............................. 10 
4.5  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 ......................................................................................................................................................... 11 
4.6  RATIONALE FOR CORRELATIVE SCIENCE ..................................................................................................... 14 
4.7  RATIONAL FOR COLOR GENOMICS ............................................................................................................... 17 
5. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES .................................................................. 18 
5.1  INCLUSION CRITERIA ..................................................................................................................................... 18 
5.2  EXCLUSION CRITERIA.................................................................................................................................... 19 
6. 
TREATMENT PLAN ........................................................................................................................................... 19 
6.1  RANDOMIZATION ........................................................................................................................................... 19 
6.2  DIAGNOSTIC PROCEDURES........................................................................................................................... 20 
6.3  THERAPEUTIC PROCEDURES ........................................................................................................................ 20 
6.4  FOLLOW-UP PROCEDURES ........................................................................................................................... 23 
6.5  DURATION OF THERAPY ................................................................................................................................ 25 
6.6  DURATION OF STUDY ACCRUAL ................................................................................................................... 25 
6.7  DURATION OF FOLLOW-UP ........................................................................................................................... 25 
6.8  CRITERIA FOR PATIENT REMOVAL ................................................................................................................ 25 
6.9  ALTERNATIVES .............................................................................................................................................. 25 
6.10  COSTS ........................................................................................................................................................... 25 
6.11  COMPENSATION ............................................................................................................................................ 25 
6.12  WITHDRAWAL FROM STUDY .......................................................................................................................... 26 
6.13  CROSS-OVER ................................................................................................................................................ 26 
7. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION .............................................................. 26 
7.1  INVESTIGATIONAL AGENT - DCFPYL ........................................................................................................... 26 
8. 
STUDY CALENDARS ........................................................................................................................................ 27 
 
STUDY CALENDAR: OBSERVATION ARM ONLY ........................................................................................... 27 
          STUDY CALENDAR: SBRT ARM ONLY ........................................................................................................... 28 
9. 
MEASUREMENT OF EFFECT ........................................................................................................................... 29 
9.1  ANTITUMOR EFFECT – METASTATIC TUMORS .............................................................................................. 29 

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
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9.2  DEFINITIONS .................................................................................................................................................. 29 
9.3  DISEASE PARAMETERS ................................................................................................................................. 29 
9.4  METHODS FOR EVALUATION OF MEASURABLE DISEASE ............................................................................. 30 
9.5  RESPONSE CRITERIA .................................................................................................................................... 31 
9.6  IMAGING REFERENCE STANDARD, AS APPLICABLE (I.E., “GOLD STANDARD”) ............................................ 31 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS ......................................................................................... 33 
10.1  GENERAL ....................................................................................................................................................... 33 
10.2  DEFINITIONS .................................................................................................................................................. 33 
10.3  POTENTIAL ADVERSE EVENTS ...................................................................................................................... 34 
10.4  STEREOTACTIC BODY RADIATION TREATMENT (SBRT) OR STEREOTACTIC ABLATIVE RADIATION 
TREATMENT (SABR) .................................................................................................................................... 35 
10.5  DCFPYL ........................................................................................................................................................ 35 
10.6  REPORTING PROCEDURES ........................................................................................................................... 39 
11. 
DATA AND SAFETY MONITORING PLAN ........................................................................................................ 41 
12. 
REGULATORY CONSIDERATIONS .................................................................................................................. 42 
12.1  PROTOCOL REVIEW AND AMENDMENTS ....................................................................................................... 42 
12.2  INFORMED CONSENT ..................................................................................................................................... 42 
12.3  ETHICS AND GCP ......................................................................................................................................... 42 
13. 
STATISTICAL CONSIDERATIONS .................................................................................................................... 43 
13.1  ENDPOINTS .................................................................................................................................................... 43 
13.2  SAMPLE SIZE/ACCRUAL RATE ...................................................................................................................... 44 
13.3  EARLY STOPPING GUIDELINES: .................................................................................................................... 44 
13.4  ANALYSIS OF PRIMARY OBJECTIVE .............................................................................................................. 45 
13.5  ANALYSIS OF SECONDARY OBJECTIVES....................................................................................................... 45 
13.6  EVALUATION OF TOXICITY ............................................................................................................................. 46 
13.7  CORRELATIVE SCIENCE ................................................................................................................................ 46 
14. REFERENCES ....................................................................................................................................................... 47 
15. APPENDICES ........................................................................................................................................................ 51 
APPENDIX I: BRIEF PAIN INVENTORY FORM ........................................................................................................... 52 
APPENDIX II: PERFORMANCE STATUS CRITERIA ................................................................................................... 54 
APPENDIX III: CAPP-SEQ SAMPLE COLLECTION & PROCESSING .......................................................................... 55 
APPENDIX IV: EPIC-HD CTC SAMPLE COLLECTION & PROCESSING ..................................................................... 56 
APPENDIX V: IMMUNOSEQ SAMPLE COLLECTION & PROCESSING ........................................................................ 58 
APPENDIX VI: RECTAL SWAB COLLECTION FOR MICROBIOME ANALYSIS ............................................................ 59 
APPENDIX VII: COLOR SALIVA KIT SAMPLE COLLECTION ...................................................................................... 60 
 
 
 
 

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
J15180 - Version 5.4 July 11, 2017 
 
 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Men with histologically confirmed oligometastatic (<3 mets)  
hormone‐sensitive prostate cancer and the following: 
PSADT <15 mos, tumors ≤ 5.0 cm or <250 cm3, Age >18 yrs & ECOG < 2 
Day 1  
OBS and SBRT Arm: DCFPyL‐PET/MRI or ‐PT/CT  
Day 1 
OBS & SBRT Arm: PSA, LDH, CBC, Chemistry Panel (CMP), ctDNA (CAPP‐seq), Rectal 
Swab, & Color Test** 
* SBRT Arm ONLY: + CTC (Epic‐HD) & PBMCs (ImmunoSEQ) *** Assays 
Patients that progress in the Observation (OBS) Arm can be crossed over off‐
protocol to receive SBRT.    
All other patients can continue with standard of care. 
* Additional Blood Correlative for SBRT Arm ONLY 
** One‐time Color Test will be provided for ALL enrolled patients 
***First 10 patients randomized to OBS Arm will have PBMCs (ImmunoSEQ)  
Day 90 
 OBS and SBRT Arm: PSA, LDH, CBC, CMP, Testosterone, ctDNA (CAPP‐seq),  
& Rectal Swab  
* SBRT Arm ONLY: + PBMCs (ImmunoSEQ)***
Day 1‐30 
Observation (OBS)     versus      SABR to 1‐3 mets 
Randomize 1:2 
        Observation (n=18)     versus     SBRT (n=36) 
     Day 180 
  
OBS and SBRT Arm: PSA, LDH, CBC, CMP, Testosterone, & ctDNA (CAPP‐seq) 
 
* SBRT Arm ONLY: +CTCs (Epic‐HD)  
Day 180 
OBS and SBRT Arm: Bone Scan & DCFPyL‐PET/MRI or ‐PT/CT   

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
J15180 - Version 5.4 July 11, 2017 
 
 
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1. PROTOCOL SYNOPSIS 
TITLE 
Phase II Randomized Observation versus 
Stereotactic Ablative RadiatIon for 
OLigometastatic Prostate CancEr 
(ORIOLE) Trial 
STUDY PHASE 
Phase II 
INDICATION 
Men with oligometastatic disease (<3 
mets) and PSADT <15 months 
PRIMARY OBJECTVES 
 Proportion of men who have 
progressed after 6 months from 
randomization to observation 
versus stereotactic body radiation 
therapy (SBRT) who have  
oligometastatic prostate cancer  
SECONDARY OBJECTIVES 
 To assess the toxicity of SBRT in 
patients with oligometastatic 
disease 
 To determine local control at 6-
months after SBRT in patients with 
oligometastatic disease  
 To assess progression free survival 
after randomization to observation 
versus SBRT 
 To assess ADT-free survival after 
randomization to observation 
versus SBRT 
 To assess quality of life following 
control versus SBRT arm 
 Estimate the proportion of 
metastatic lesions found on bone 
scan that are DCFPyL-PET/MRI or 
–PET/CT positive and vice versa. 
 Estimate the proportion of DCFPyL-
PET/MRI or –PET/CT positive sites 
that are positive for new or 
progressive metastatic disease by 
bone scan at 6-months from SBRT 
and vice versa 
CORRELATIVE SCIENCE 
 To enumerate circulating tumor 
cells (CTC) using EPIC HD-CTC 
platforms at baseline and day 180 
from randomization. 
 To enumerate circulating tumor 
DNA (ctDNA) using Cancer 

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
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Personalized Profiling by deep 
sequencing (CAPP-Seq) at 
baseline, day 90 and day 180 from 
randomization for control and SBRT 
arms.  
 To quantitatively sequence T-cell 
receptor (TCR) repertoires using 
peripheral blood monocytes and the 
ImmunoSEQ platform at baseline 
and day 90 from randomization. 
 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 
SBRT will reduce progression at 6-months 
from >80% in the control arm to <40% in 
the SBRT arm 
STUDY DESIGN 
Men with oligometastatic prostate cancer 
lesions will be randomized (1:2) to 
observation versus SBRT. The study will 
NOT be blinded. Within three weeks of the 
initial treatment planning, SBRT (1-5 
fractions) will be administered.  
SAMPLE SIZE BY TREATMENT GROUP 
54 patients total   
SUMMARY OF SUBJECT ELIGIBILITY 
CRITERIA 
1.Metastatic bone or nodal sites ≤ 3. 
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 scan of Involved Site 
3. Bone scan 
4. Randomization 
5. DCFPyL-PET/MRI or –PET/CT 
6. Blood draws and Rectal Swab 
7. Observation versus SBRT 
8. Blood draws and Color Test 
9. DCFPyL-PET/MRI or –PET/CTand bone 
scan of Involved Site 
 
 

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
J15180 - Version 5.4 July 11, 2017 
 
 
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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 
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 
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 
 

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
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3. STUDY DESIGN AND OBJECTIVES 
3.1 Study Design 
Phase II non-blinded randomized study evaluating men with oligometastatic 
prostate cancer lesions randomized (1:2) to observation versus stereotactic 
body radiation therapy (SBRT).  
3.2 Primary Objective 
To determine the proportion of men who have progressed after 6 months from 
randomization to observation versus SBRT who have oligometastatic prostate 
cancer. 
3.3 Secondary Objectives 
To assess the toxicity of SBRT in patients with oligometastatic disease. 
 
To determine local control at 6-months after SBRT in patients with 
oligometastatic disease. 
 
To assess progression free survival (PFS) after randomization to observation 
versus SBRT. 
 
To assess ADT-free survival after randomization to observation versus SBRT. 
 
To assess quality of life following completion of SBRT. 
 
Estimate the proportion of metastatic lesions found on bone scan/CT that are 
DCFPyL-PET/MRI positive and vice versa. 
 
Estimate the proportion of DCFPyL-PET/MRI or –PET/CT positive sites that are 
positive for new or progressive metastatic disease by bone scan/CT at 6-months 
following SBRT and vice versa. 
3.4 Correlative Objectives 
To enumerate circulating tumor cells (CTC) using EPIC HD-CTC platforms at 
baseline and day 180 from randomization. 
 
To enumerate circulating tumor DNA (ctDNA) using Cancer Personalized 
Profiling by deep sequencing (CAPP-Seq) at baseline, day 90 and day 180 from 
randomization for control and SBRT arms. 
 
To quantitatively sequence T-cell receptor (TCR) repertoires using peripheral 
blood monocytes and the ImmunoSEQ platform at baseline and day 90 from 
randomization. 
 
Descriptive statistics will be performed to correlate the metrics above with clinical 
outcomes. 

SBRT for Oligometastatic Prostate Cancer 
 
Protocol Chair:  Phuoc T. Tran, M.D., PhD  
J15180 - Version 5.4 July 11, 2017 
 
 
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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 
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). 
 
The treatment of metastases depends on multiple factors including 1) the 
location of the primary tumor, 2) the presence or absence of other metastatic 
foci, 3) the size, number and location of metastases, 4) the effectiveness of 
various forms of therapy (such as surgery, radiation and chemotherapy), and 5) 
patient’s functional status.  Extracranial metastatic tumors most often referred for 
local therapy in the form of resection include colon cancer, sarcomas, germ cell 
tumors, and melanoma metastatic to the lung. For the more common primary 
tumors such as those of breast and prostate, metastases are rarely referred for 
resection as chemotherapy (or hormonal manipulation) is generally considered to 
be the primary mode of treatment. 
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, 

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Protocol Chair:  Phuoc T. Tran, M.D., PhD  
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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 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 or 6 metastatic sites. 
 
Milano et al. (9) from the University of Rochester have also shown that the net 
tumor burden for patients with 5 or fewer sites of macrometastatic disease, 
treated on 2 prospective SBRT protocols, was an independent predictor of 
overall outcome.  Whether SBRT, as an adjunct to systemic therapy, to selected 
macroscopic metastases can influence overall survival by keeping the burden of 
disease below such a “lethal threshold” is being investigated. 
 
Colorectal carcinoma metastatic to the liver, selected modern resection series 
have yielded 5-year survival rates of approximately 50% showing that improved 
systemic treatments and local therapy has the potential to cure “oligo” or isolated 
liver metastases (5, 9, 28-31).  The benefit of local therapy in non-colorectal liver 
metastases is less clearly defined, but long-term survival has been reported after 
the resection of liver metastases from sarcoma, breast cancer, and other tumor 
sites (32). 
  
Goodman et al. (15) reported a phase I dose-escalation single-fraction trial for 
patients with liver metastases or intrahepatic cholangiocarcinoma. Doses were 
escalated in 4-Gy cohorts from 18 Gy up to 30 Gy in 1 fraction. Twenty-six 
patients with 40 lesions were treated. There was no dose-limiting toxicity. The 
median follow-up was 17 months, and this corresponded to a 12-month local 
control rate of 77%. The 2-year actuarial survival rate was 50.4%.  
 
4.4 Rationale for SBRT/SABR for Bone Oligometastases in Prostate Cancer 
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, 

SBRT for Oligometastatic Prostate Cancer 
 
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J15180 - Version 5.4 July 11, 2017 
 
 
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high-dose RT delivered in a hypofractionated course.  In selected patients, very 
high local control rates have been observed, with minimal toxicity.  Bone 
metastases represent the major metastatic site (>90%) in men with rising PSA 
following primary treatment for their prostate cancer. 
 
The primary management of metastatic prostate cancer is systemic therapy in 
the form of androgen deprivation therapy (ADT).  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. 
 
On the basis of this emerging clinical evidence and because SBRT for bone 
metastases is known to be safe, we propose a phase II study of SBRT in patients 
with oligometastatic prostate cancer.  Abundant experience with SBRT for bone 
metastases provides useful safety information for our trial.  We are also building 
off of our Phase II SBRT trial in diverse histologies here at Johns Hopkins - 
J12137.  This trial has almost completed accural to the target of 42 patients, but 
we have already finished accuring the 20 prostate cancer patient limit.  Although 
very preliminary we have seen only low G1-G2 toxicites and no local failures to 
date in our prostate cancer patients.  Thus the proposed study  represents an 
informed estimate based on current knowledge of SBRT doses and those 
administered in currently approved image-guided protocols including our own 
JHU protocol (brain, base of skull, cervico-thoracic spine, pancreas and liver).   
 
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 
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 systemic treatment. 
 
4.5 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]-

SBRT for Oligometastatic Prostate Cancer 
 
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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).   
 
[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.  Our proposed work is 
innovative because DCFBC PET imaging will optimize functional PSMA prostate 
cancer imaging by improving the following factors: (1) as a small molecule it 
allows for higher tumor penetration and rapid blood clearance allowing for 

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increased tumor to background ratio, (2) it targets the more accessible external 
binding domain of PSMA, and (3) PET imaging allows for quantitative high 
resolution images, and (4) clinically practical labeling with 18F, with a 2-hour half-
life.  PSMA-specific uptake of this radiotracer have been validated in PET 
imaging of pre-clinical human prostate cancer xenograft models which verify high 
selective uptake in PSMA expressing prostate tumors but no uptake in prostate 
tumors not expressing PSMA (60, 61).  Small animal PET imaging of DCFBC in 
subcutaneous prostate cancer bearing mice demonstrated specific uptake in 
PSMA expressing PC-3 PIP tumors, achieving a maximum target to background 
(muscle) ratio of 20:1 at 120 min after injection. The time-activity curve 
demonstrates that DCFBC has achieved equilibrium by 120 minutes and has 
begun to decrease in concentration at the target site, with washout from target 
sites slower than non-target sites. 
 
Preliminary results of a recently completed Phase I first-in-man biodistribution 
and dosimetry study of DCFBC in five patients with advanced metastatic disease 
demonstrated high radiotracer uptake in both nodal and bone metastatic sites, 
minimal radiotracer metabolism, and favorable biodistribution (62).  Of 32 total 
sites of DCFBC uptake, 21 were concordant with prostate cancer metastases as 
determined by conventional imaging modalities (CIM) (CT, bone scan) at 21 sites 
and the other 11 sites of DCFBC uptake not detected by CIM were unconfirmed 
but considered suspicious for metastases. Seven bone findings thought to be 
benign fracture or stable changes on bone scan were negative for DCFBC 
uptake.  Radiotracer administration was found to be safe with no severe adverse 
events. Tumor-to-background ratio for metastatic detection was highest at 2 
hours post-radiotracer injection.  A 2-hour post-injection DCFBC PET/CT with 
anterior MIP image demonstrating multiple pelvic bone metastases and sagittal 
PET, CT, and fused PET/CT images demonstrating T12 and L4 bone metastases 
(SUVmax 4.7 and 3.4, respectively).  A 2-hour post-injection DCFBC transaxial 
PET/CT in another patient with prominent high level DCFBC uptake in a large 
right external iliac (SUVmax 11.6) and smaller left common iliac (SUVmax 5.3) 
pelvic nodal metastases.  Dosimetry studies demonstrates the highest mean 
absorbed dose per unit administered activity (µGy/MBq) was to the bladder wall 
(32.4) and the mean effective dose (ED ± StdDev) was 19.9 ± 1.34 µSv/MBq, 
with dose estimates for our DCFPyL PET radiopharmaceutical that are 
comparable to those of other PET radiopharmaceuticals such as 
18F-
fluorodeoxyglucose.  Although further studies are needed for validation, our 
findings demonstrate the potential of DCFBC-PET imaging as a new positron-
emitting imaging agent for detection of metastatic prostate cancer. 
 
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 

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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).  
On the basis of this promising clinical evidence with DCFBC-PET and the 
superiority of DCFPyL pre-clinically and because bone scintigraphy and NaF-
PET are non-specific, we propose as a secondary objective evaluating the 
performance of DCFPyL-PET versus the conventional bone scan as a means to 
identify bone lesions for SBRT treatment in oligometastatic prostate cancer. 
 
4.6 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 
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 

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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. 
 
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 
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.

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detect circulating tumor DNA.  Circulating tumor DNA (ctDNA) is a promising 
biomarker for non-invasive assessment of cancer burden, but existing ctDNA 
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 

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ipilimumab (71).  Improved clinical outcomes were associated with less T-cell 
clonotype loss, consistent with the maintenance of high-frequency TCR 
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. 
 
4.7 Rational for Color Genomics 
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 April 2015, Color launched a test with 19 genes in which germline mutations 
have been associated with an elevated risk of cancer. In the hereditary cancer 
genetic test, Color uses a sequencing platform to analyze the risk of developing 
hereditary cancer due to inheritance of a pathogenic mutation in 30 cancer 
predisposition genes (81). The Color Genomics 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 Color can further allow investigators to personalize screening and 
target specified effective therapies for each patient disease (80). 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 develop within the past 6-months that are ≤ 
5.0 cm or <250 cm3 
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 
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 Testosterone > 125 ng/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: 
Leukocytes 
>2,000/μL 
Absolute Neutrophil Count 
>1,000/μL 
Platelets  
>50,000/μL 
5.1.12 Patient must have the ability to understand and the willingness to sign a 
written informed consent document. 
 

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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 DCFPyL-PET/MRI or DCFPyL-PET/CT scan within the past 6 months with 
results that demonstrate more disease lesions than baseline CT/Bone Scan 
5.2.3 Castration-resistant prostate cancer (CRPC). 
5.2.4 Spinal cord compression or impending spinal cord compression. 
5.2.5 Suspected pulmonary and/or liver metastases (greater >10 mm in largest 
axis). 
5.2.6 Patient receiving any other investigational agents. 
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. TREATMENT PLAN 
6.1 Randomization 
Eligibility work-up will include a complete blood count, serum chemistries, PSA, 
and radiographic studies (of involved sites) and bone scan.  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) Initial treatment with surgery vs. radiation therapy  
2) Prior hormonal therapy vs. no prior hormonal therapy 

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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.  Randomization will be 1:2 for 
observation: SBRT 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 SBRT and/or Observation Arm.  
6.2 Diagnostic Procedures 
A bone scan and CT (and/or MRI of questionable sites) must be avilaible or will 
be obtained within 3-months of randomization for confirmation of 
oligometastatses and a separate DCFPyL-PET/MRI or -PET/CT scan will be 
performed for protocol purposes as below.  A CT- and/or MRI-simulation scan 
will be performed for tumor localization and radiation planning using rigid 
immobilization appropriate for stereotactic treatment. 
6.3 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, 
and 
ImmunoSEQ 
5) Additional correlative blood draws: Epic HD-CTC only for men 
randomized to the SBRT arm  
6) CT and/or MRI scan of the involved site(s) (if not previously conducted within 3 
month of enrollment). 
7) Bone scan (if not previously conducted within 3 month of enrollment). 
8) DCFPyL-PET/MR or -PET/CT Diagnostic Imaging Protocol. Our 
collaborating center at the NIH Clinical Center has a PET/MRI available and will 
proceed with these exams, while at the Johns Hopkins campus will be proceed 
with PET/CT.  The subjects accrued at the NIH will be scanned on a Siemens 
Biograph mMR PET/MR scanner, a simultaneous PET and MR imaging system. 
The system is operated by the radiology department of the National Institutes of 
Health clinical center located on the NIH campus in Bethesda MD.  The Johns 
Hopkins campus has Discovery DRX PET/CT scanner (GE Healthcare) imaging 
systems. 
 
 
 

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Patient Preparation. 
i. Patient has to be NPO for 4-6 hrs. 
ii. When the patient arrivals in the clinic they are explained the procedure by 
the Nuclear Medicine Staff and all questions are answered prior the start of the 
procedure. 
iii. IV access is obtained and verified that it is patent with a saline flush prior to 
giving the F-18 DCFPyL. 
iv. A dose of 9-10 mCi F-18 DCFPyL is injected through the IV and followed by 
at least 10 ml of saline to flush the IV line of the remaining dose. 
v. Intravenous fluid (5% dextrose + 0.45% normal saline) will be delivered at a 
low flow rate during the duration of the study (maximum 2 litters). 
vi. The patient is asked to void prior to the scan 15-20 minutes before the 
scan.  After the patient is finished voiding, they are positioned on the scanner 
bed with the head placed first and arms down to their side. 
vii. A CT or (MR) localizer scan is taken from the top of the head to mid-thigh 
to properly frame the subjects’ skull vertex through mid-thigh in the CT (or MR) 
scanner's field of view. It is expected to require 7 to 9 bed positions. 
viii.  At the 1-hour post injection time (50-70 minutes), the PET/CT or PET/MR 
imaging sequence begins. 
ix.  The PET system of the CT (or MR) scanner will collect data for each bed 
position required to scan the subject from the skull vertex to mid-thigh. The 
scan time for each bed position will be on the order of 7 to 8 minutes 
depending on the details setup of the MR imaging sequences. The PET 
images will be reconstructed using a 3D iterative reconstruction algorithm, with 
3 iterations and 24 subsets. Detector pair normalization, random scatter and 
attenuation corrections will be applied during the image reconstruction 
process. No image post filtering will be applied. 
x.   Simultaneous with the PET acquisition the following MR imaging 
sequences will be collected. 
a.  A  T1 weighted gradient echo TR=200ms, TE =2.3ms, slice 
thickness=5mm, matrix =376x116, FOV 47cm 
b.  DWI  TR=6000ms, TE=79ms, slice thickness=5mm, matrix=128x128, 
b=0,1000,2000,FOV 47cm 
c  STIR TR=12000, TE=110, TI=200ms, slice thickness=5mm, matrix 
=376x116, FOV 47cm 
 
The study PI, co-I’s or study coordinator will contact the patient around 7 days 
(3 - 10 days) after the PET/CT or PET/MRI 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. 
 
DCFPyL-PET/MRI or -PET/CT images will be evaluated and compared to bone 
scan. However, additional sites(s) of suspected metastatic disease detected by 
DCFPyL-PET/MRI or -PET/CT will not be considered for treatment by 
SBRT/SABR or undergo further required evaluation.  The results of the DCFPyL-

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PET/MRI or –PET/CT will not be made available to the treating physicians until 
after the trial is completed and these results will not be made available to the 
patient. 
 
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 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 
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. 
 
 

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6.3.1 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. 
6.4 Follow-Up Procedures 
6.4.1 Blood Draws 
 
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), 
and testosterone will be performed within the first month, month 3 and 6 (from 
date of randomization) for all patients. Immune cell profiling (ImmunoSEQ) will be 
performed within the first month and at 3 months from randomization for all men 
on the SBRT arm and the first 10 patients randomized to the observartion arm. 
The patients randomized to the SBRT arm will also have blood draws for CTCs 
(EPIC HD-CTC) correlative studies at the start and end of the study.  In clinic 
visits are not required otherwise, unless indicated by laboratory tests.   
 
Correlative science blood draws will be performed at Day 1 (within 30 days of 
randomization), Day 90 from randomization, and Day 180 from randomization.  
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, day 90 and day 180 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 randomization for SBRT arm only.  
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 
randomization for all men on the SBRT arm and the first 10 patients 
randomized to the observation arm.  

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6.4.2 Imaging  
Bone scan and DCFPyL-PET/MRI or –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 DCFPyL-PET/MRI or –PET/CT will not be made 
available to the treating physicians until after the trial is completed and these 
results will not be made available to the patient. 
The CT portion of the DCFPyL-PET/MRI or –PET/CT scans at 6 months will be 
used to determine radiographic response based on RECIST 1.1 criteria for soft 
tissue lesions. 
6.4.3  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 the rectal swab 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 will be collected at enrollment within 1-mos of 
randomization but prior to SBRT and at the 90 day time point. 
6.4.4 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.  
6.4.5 Color Genomic Testing  
Consented patients will be asked to provide a saliva sample (tube collection) 
during an office visit or at home, via a Color 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 Color kit will then be activated online and dropped in 
the mail. Color will then analyze the genes from the patient salvia sample.  Once 
the patient’s results are ready, an email will be sent by Color prompting the PI to 
log into his established Color Provider Platform account and view the results. 
Color will also email the patients with instructions to create their own account, 
allowing them access to sign into Color’s website and view their results (once the 
PI has released the patient’s results). The patient will be allowed to make an 
appointment with one of the Color’s genetic counselors at no cost. Further, Color 
will also keep the patient updated if any information related to their results 
changes.   
 

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6.5 Duration of Therapy 
Within three weeks of the initial treatment planning imaging study, SBRT 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 for the SABR 
experimental arm and beginning of the observations period for me on the 
observation arm. 
6.6 Duration of Study Accrual 
A trial with a similar patient population took 2.5 years to screen 77 patients (72). 
Thus we anticipate this study will last 2-2.5 years.  
6.7 Duration of Follow-Up  
Patients will be followed for 180 days, after Day one.  
6.8 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 SBRT. Progression as defined in 
section 8.6.2. 
6.9 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 indicating that similar men without metastases will 
progress in 6-months based on rising serum PSAs (72-74).  Secondly, the level 
of clinical-radiographic interrogation will allow the control arm to be safely 
observed so that standard of care treatments can be initiated within a typical 
interval between clinic visits (72-74).  Lastly, the SBRT dose has been shown to 
be safe in previous SBRT 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. 
6.10 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. 
6.11 Compensation 
Patients will not be financially compensated if they join the study. 

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6.12 Withdrawal from Study 
The reasons for withdrawal from the study include: 
 
Subject withdraws consent for follow-up. 
 
Subject is lost to follow-up. 
 
Study is terminated for any reason. 
6.13 Cross-over 
The men on the control arm are allowed to cross over and be treated with SBRT 
following documented progression as defined in section 8.6.2. 
7. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
7.1 Investigational Agent - DCFPyL 
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.

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8. STUDY CALENDARS 
STUDY CALENDAR: OBSERVATION ARM ONLY 
 
Pre-Study
 
Day 1f 
 
Day 90 from 
randomization 
(+/- 7 days) 
Day 180 from 
randomization 
(+/- 7 days) 
 
Informed Consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical History & Review 
of Medication 
X 
 
X 
X 
Physical Exam 
X 
 
X 
X 
Vital Signs 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
 
 
 
Performance Status 
X 
 
X 
X 
CBC w/ Diffa 
Xe 
X 
X 
X 
LDH & Serum Chemistryb 
Xe 
X 
X 
X 
Testosterone 
Xe 
 
X 
X 
PSA 
Xh 
X 
X 
X 
CAPP-Seq 
 
X 
X 
X 
Immuno-SEQi 
 
Xi 
Xi 
 
Bone scan & CT/MRI of 
Involved Sitec 
X 
 
 
X 
DCFPyL- PET/CT or 
PET/MRIj 
 
X 
 
X 
Rectal Swab 
 
X 
X 
 
Color Test 
 
 Xg 
 
 
AE Evaluation and QoL - 
BPI 
 
X 
X 
X 
Randomization 

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STUDY CALENDAR: SBRT ARM ONLY 
 
Pre-Study 
 
Day 1i 
 
SBRT/SABR j
Day 90 from 
randomizatio
n 
(+/- 7 days) 
Day 180 from 
randomizatio
n 
(+/- 7 days) 
 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History & 
Review of Medication 
X 
 
Xf 
X 
X 
Physical Exam 
X 
 
Xf 
X 
X 
Vital Signs 
X 
 
 
 
 
Height 
X 
 
 
 
 
Weight 
X 
 
 
 
 
Performance Status 
X 
 
 
X 
X 
CBC w/ Diffa 
 Xh 
X 
 
X 
X 
LDH & Serum 
Chemistryb 
Xh 
X 
 
X 
X 
Testosterone 
Xh 
 
 
X 
X 
PSA 
Xm 
X 
 
X 
X 
CAPP-Seq  
 
Xd 
 
Xd 
Xd 
ImmunoSEQ 
 
Xd 
 
Xd 
 
Epic HD-CTC 
 
Xd 
 
 
Xd 
Bone scan & CT/MRI 
of Involved Sitec 
X 
 
 
 
Xg 
DCFPyL- PET/CT or 
PET/MRI 
 
Xl 
 
 
X 
Color Test 
 
 Xk 
 
 
 
Rectal Swab 
 
X 
 
X 
 
AE Evaluation 
 
X 
Xf 
X 
X 
QoL - BPI 
 
X 
Xf 
X 
X 
SBRT/SABR 
 
 
X 
X 
 
 
 
a. 
Including platelets. 
b. 
Albumin, Alkaline Phosphatase (AP), Total Bilirubin, Bicarbonate, BUN, Calcium, Chloride, Creatinine, Glucose, Potassium, Total Protein, 
SGOT [AST], SPGT [ALT], Sodium. 
 
a. 
Including platelets. 
b. 
Albumin, Alkaline Phosphatase (AP), Total Bilirubin, Bicarbonate, BUN, Calcium, Chloride, Creatinine, Glucose, Potassium, Total Protein, 
SGOT [AST], SPGT [ALT], Sodium. 
c. 
Enrollment bone scan and CT-imaging studies need to be within 3-months of enrollment. 
d. 
See APPENDIX III-VI for details regarding CAPP-Seq. (Correlative Blood draws are within 30 days from the date of randomization) 
e. 
CBC, Serum Chemistry, LDH, and Testosterone within 6 months prior to registration 
f. 
Day 1 denotes the start of Observation Arm. Day 1 must occur within 30 days of randomization. 
        g.     One-time saliva Color Kit collection performed at any point during the study or after (F/U) for ALL patients.        h.     PSA within 1 month 
prior to registration 
        i.      Only for first 10 patients randomized to the Observation Arm        j.      If you received a DCFPyL-PET/MRI or DCFPyL-PET/CT scan within 
the past 6 months with results and did not demonstrate more disease        
                more disease lesions than baseline CT/Bone scan, than that scan will be used for Day 1. 
 
Randomization 

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c. 
Enrollment bone scan and CT-imaging studies need to be within 3-months of randomization. 
d. 
See APPENDIX III-V for details regarding CAPP-Seq, EPIC HD-CTC & ImmunoSEQ. (Correlative Blood draws are within 30 days from the 
date of randomization) 
e. 
Only for CAPP-Seq 
f. 
Can be during SBRT on-treatment visit. 
g. 
Tumor measurements are to be calculated on CT scans at 6 months. 
h. 
CBC, Serum Chemistry, LDH, and Testosterone within 6 months prior to registration 
i. 
Day 1 denotes the start of SBRT Arm. Day 1 must occur within 30 days of randomization. 
j. 
SBRT/SABR should be completed within 60 days from randomization date.   
k. 
One-time saliva Color Kit collection performed at any point during the study or after (F/U) for ALL enrolled patients. 
l. 
If you received a DCFPyL-PET/MRI or DCFPyL-PET/CT scan within the past 6 months with results that did not demonstrate more disease 
lesions than baseline CT/Bone Scan, then that scan will be used for Day 1. 
m. 
PSA within 1 month prior to registration 
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 months after randomization.  Trial radiologists evaluating for 
treatment responses will be blinded to the treatment group and treatment 
specifics (lesions treated with SBRT). 
 
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 SBRT. 
Safety Population: Will consist of all subjects who were enrolled and have 
undergone at least one fraction of SBRT. 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 SBRT, 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. 
 

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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 
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. 
 
Secondary objectives for comparison of DCFPyL-PET/MRI or –PET/CT to bone 
scan at baseline and 1-year following SBRT/SABR.  We will estimate 1) the 
proportion of metastatic lesions found on bone scan that are DCFPyL-PET/MRI 
or –PET/CT positive and 2) the proportion of DCFPyL-PET/MRI or –PET/CT 
positive sites that are positive for metastatic disease by bone scan for prostate 
cancer. The results of the DCFPyL-PET/MRI or –PET/CT will not be made 
available to the treating physicians until after the trial is completed and these 
results will not be made available to the patient. 
 

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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 
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. 
9.6 Imaging Reference Standard, as Applicable (i.e., “Gold standard”) 
Reference standard will be determined by a truth panel consisting of a 
nuclear medicine physician, radiologist, and GU oncologist.  This panel will 
determine whether individual sites of suspected metastatic disease on initial 
baseline CIM (bone scan and chest/abdomen/pelvis CT) and DCFPyL-
PET/MRI or -PET/CT findings are truly positive based on following data: 
 
prior available imaging  
 
available follow-up imaging obtained as part of clinical care and/or 
investigational protocol and treatment history for up to 12 months from the 
time of DCFPyL-PET/MRI or –PET/CT scan. 

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 
The results of the DCFPyL-PET/MRI or –PET/CT will not be made 
available to the treating physicians until after the trial is completed and 
these results will not be made available to the patient. 
9.6.1 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.  
9.6.2 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.  
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.   

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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 
9.6.3 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.  
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: 
 

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 
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: 
 
 
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. 
 

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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, PET imaging, SBRT, and 
DCFPyL administration. 
 
Phlebotomy can cause pain, bleeding, and rare needle site infection. PET 
imaging results in low dose radiation exposure (see Investigator’s Brochure for 
details of dosimetry), which has an extremely small risk of causing a secondary 
cancer.  
10.4 Stereotactic Body Radiation Treatment (SBRT) or 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 DCFPyL 
10.5.1 [18F]DCFPyL is eluted with 1 mL of ethanol followed by 10 mL of 0.9% sodium 
chloride, via a sterilizing 0.22μ filter into a sterile vial containing 4 mL 0.9% 
sodium chloride.  Test radiopharmaceutical will be administered intravenously 
via slow I.V. push.  The maximum mass dose of the ligand corresponding to 
the 10 mCi dose of [18F]DCFPyL will be less than 4.02µg per administration, 
although the actual dose will be significantly less than depending on the 
specific activity achieved during each radiosynthesis run.  The lowest limit for 

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specific-activity (SA) we will use at the time of injection is 1000 mCi/µmole, 
although the validation and phase I study radiosynthesis SA was significantly 
higher than 1000 mCi/µmole. 
 
Preclinical Toxicology 
A toxicity report “Single Dose Toxicity Study of 19F- DCFBC (NSC-743104) in 
Rats” was prepared by Bridge GPS, Inc. (Study No. 1535-07015). The 
following summary is taken from that report.  
 
This study was designed to determine target organ toxicity of 19F- DCFBC 
(NSC-743104) and its reversibility in rats treated with a single intravenous 
dose. 
 
Sixty Fischer 344 rats (30/sex) were randomly assigned to one of three dose 
groups (10/sex/group) based on body weight and physical examination. Five 
rats/sex/group were designated to the main phase of the study, and five 
rats/sex/group were designated to the recovery phase of the study. All 
animals were dosed once on Study Day (SC) 1 via intravenous injection (tail 
vein) with either the control article (5% dextrose) or 19F- DCFBC (NSC-
743104) at nominal dose levels of 0.1 or 0.5 mg/kg. Terminal sacrifice 
necropsies were performed on SD 4; recovery sacrifice necropsies were 
performed on SD 15. Parameters evaluated during the study included 
mortality, clinical and cage side observations, body weights, body weight 
changes, clinical pathology parameters (clinical chemistry and hematology), 
gross pathology and histopathology. 
 
Mortality, clinical and cage-side observation, body weight and body weight 
changes, clinical pathology, gross pathology and histopathology were 
unaffected by treatment. 
 
Based on the results of this study, a single intravenous injection of 19F- 
DCFBC (NSC-743104) at doses up to 0.5 mg/kg to male and female Fischer 
344 rats was well tolerated. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 1: Tissue distribution of [18F] DCFBC (%ID/gm) 
 
          5 min
                      
           15 min         30 min            60 min         120min 
 
           n=5                n=4 
            n=4              n=4            n=3 
Blood 
11.34 
4.07 
2.26 
1.80 
0.36 
heart 
4.38 
2.01 
1.24 
0.77 
0.27 
lung 
7.03 
3.21 
1.78 
1.10 
0.36 
liver 
5.99 
4.07 
4.18 
5.12 
2.11 
stomach 
2.87 
1.35 
0.81 
0.46 
1.08 
pancreas 
2.17 
1.04 
0.99 
0.54 
0.18 
spleen 
8.76 
4.27 
1.94 
1.58 
0.44 
fat 
1.75 
1.56 
0.67 
1.05 
0.26 
kidney 
63.40 
62.94 
51.29 
41.55 
13.08 
bone 
2.88 
1.61 
1.72 
1.73 
2.46 
muscle 
2.21 
1.00 
0.45 
0.57 
0.24 
small intestine 
4.29 
2.31 
1.20 
0.66 
0.15 
large intestine 
2.82 
1.47 
0.78 
0.58 
0.27 
bladder 
55.41 
15.94 
15.18 
14.49 
2.57 
PC-3 PIP 
8.17 
6.03 
6.16 
8.16 
4.69 
PC-3 flu 
3.47 
1.72 
0.97 
0.77 
0.18 
cortex 
0.49 
0.25 
0.13 
0.10 
0.06 
cerebellum 
          0.58
          0.26 
           0.14 
         0.10 
0.04
PIP: flu 
         2.36
          3.51 
           6.35 
       10.57 
26.65
 
 
Similar toxicity was observed for our second generation compound DCFPyL 
and was awarded a physician sponsored FDA exploratory IND based in this 
acceptable pre-clinical data (IND#121,064) for 18F-DCFPyL as a PET 
radiopharmaceutical, which is held by the co-I, Dr. Martin Pomper. 
 
Initial Phase I study Adverse Events 
An initial phase I study of the biodistribution and dosimetry of DCFBC was 
performed in five men with metastatic prostate cancer from 10/2010 through 
12/2010.  No serious adverse events (SAE) were observed.  One patient with 
history of hypertension experienced grade III hypertension after 
administration of DCFBC with no clinical symptoms.  Twenty-four hours later 
his blood pressure returned to baseline grade 2 hypertension and at 7 days’ 

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38 
 
post DCFBC administration, his blood pressure normalized to baseline levels.  
The attribution of this hypertension adverse event (AE) was listed as unlikely 
(the adverse event is doubtfully related to the investigational imaging tracer) 
given this patient had been previously controlled with a calcium-channel 
blocker medication but this was discontinued about two months prior to 
DCFBC administration and his blood pressure was more likely attributed to 
stress during the PET/CT scan and overall labile blood pressure of his 
calcium-channel blocker.  No other adverse events noted in all five patients 
over a 28-day follow-up post study radiopharmaceutical administration. 
 
Human Dosimetry 
In our biodistribution and dosimetry study, five patients with radiologic 
evidence of metastatic prostate cancer were studied after intravenous 
administration of 370 MBq (10 mCi) of DCFBC. Serial PET imaging was 
performed out to 2 hours after administration. Time-activity curves were 
generated for selected normal tissues and metastatic foci. Radiation dose 
estimates were calculated using OLINDA/EXM 1.1.  Most vascular organs 
demonstrated a slow decrease in activity concentration over time consistent 
with clearance from blood pool, with primarily urinary radiotracer excretion.  
The organ with the highest mean absorbed dose (μGy/MBq) is the urinary 
bladder wall (32.4), followed by the stomach wall (30.2), heart wall (29.2), and 
kidneys (28.4). The remaining GI tract organs (small intestines, SI; upper 
large intestines, ULI; lower large intestines, LLI), liver and lungs receive lower 
absorbed doses. The mean effective dose was 19.9 ± 1.34 μSv/MBq.  Dose 
estimates for 18F- DCFBC are comparable to those of other PET 
radiopharmaceuticals such as 18F-fluorodeoxyglucose (18F-FDG).  (Note: This 
study has been accepted for publication in the Journal of Nuclear Medicine in 
the fall of 2012 (35) and reported this dosimetry data to the FDA as part of a 
protocol revision for Protocol/IND 108,943 on 8/30/2011. 
 
    Table 2: Human Average Organ Absorbed Dose (mGy/MBq) and 
estimated effective dose (mSv/MBq) 
 
 
Average
Std Dev
COV 
 
 
 
 
Adrenals 
1.85E-02 2.83E-03 15.32% 
Brain 
4.21E-03 2.83E-04
6.73% 
Breasts 
8.51E-03 3.22E-04
3.78% 
GB Wall 
1.79E-02 1.95E-03 10.90% 
LLI Wall 
2.47E-02 3.69E-03 14.92% 
SI Wall 
2.36E-02 1.72E-03
7.31% 
Stomach Wall 
3.02E-02 3.24E-03 10.72% 
ULI Wall 
2.34E-02 2.20E-03
9.39% 

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Heart Wall 
2.92E-02 3.24E-03 11.12% 
Kidneys 
2.84E-02 3.81E-03 13.45% 
Liver 
2.46E-02 4.16E-03 16.88% 
Lungs 
2.45E-02 2.99E-03 12.22% 
Muscle 
9.69E-03 3.97E-04
4.10% 
Ovaries 
1.32E-02 5.26E-04
3.99% 
Pancreas 
1.92E-02 2.15E-03 11.19% 
Red Marrow 
1.70E-02 9.81E-04
5.79% 
Osteogenic Cells 1.82E-02 8.92E-04
4.90% 
Skin 
7.30E-03 3.50E-04
4.79% 
Spleen 
1.72E-02 1.05E-03
6.08% 
Testes 
1.54E-02 4.19E-03 27.23% 
Thymus 
1.10E-02 4.53E-04
4.12% 
Thyroid 
1.17E-02 6.87E-04
5.88% 
Bladder Wall 
3.24E-02 7.24E-03 22.35% 
Uterus 
1.34E-02 2.95E-04
2.20% 
Total Body 
1.09E-02 4.28E-04
3.91% 
ED 
1.99E-02 1.34E-03
6.73% 
 
 
10.6 Reporting Procedures 
10.6.1 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.   
 
 
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).   
 
All adverse events will be captured on the appropriate study-specific case 
report forms (CRFs).  
10.6.2 Expedited FDA Reporting Requirements for Unexpected and Related 
Serious Adverse Events (per 21CFR312.32) 
  

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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 DCFPyL 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 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. Martin Pomper) 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 DCFPyL within 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. 

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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, Abbott Laboratories, 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. 
 
Follow-up Reports 
 
All follow-up information concerning IND Safety Reports should be submitted 
to the FDA as soon as possible. 
 
10.6.3 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 AND SAFETY MONITORING PLAN  
 
This is a DSMP Level I study under the SKCCC Monitoring Plan (see Appendix VI). 
A Level I study requires both internal and external data monitoring. The Principal 
Investigator is responsible for internal monitoring for both safety and data quality. 
External data monitoring will be performed by the SKCCC at Johns Hopkins Clinical 
Research Office Quality Assurance Program (CRO QA).  
 
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. 
 
 

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12. 
REGULATORY CONSIDERATIONS 
12.1 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.  
12.2 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 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. 
12.3 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). 
 

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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.  
13. 
STATISTICAL CONSIDERATIONS  
13.1 Endpoints 
 
13.1.1 Primary Objective 
To determine the proportion of patients with oligometastatic hormone 
sensitive prostate cancer who have progressed after 6 months from 
randomization to observation versus stereotactic body radiation therapy 
(SBRT). 
 
13.1.2  Secondary Objectives 
o To describe the toxicity of SBRT/SABR delivered for the population 
enrolled using grading with CTCAE v. 4.0 
o To determine local control at 6-months after SBRT/SABR in patients with 
oligometastatic disease.  
o To assess progression free survival (PFS) of this patient population after 
randomization defined as the time interval between the day of 
randomization and progression.   
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 of the observation versus SBRT/SABR 
arms.  Brief Pain Inventory form which will be filled out by the patient at 
the treatment response intervals outlined above. 
o Secondary objectives for comparison of DCFPyL-PET/MRI or -PET/CT to 
bone scan at baseline and 1-year following SBRT/SABR.  We will estimate 
1) the proportion of metastatic lesions found on bone scan that are 
DCFPyL-PET/MRI or –PET/CT positive and 2) the proportion of DCFPyL-
PET/MRI or PET/CT positive sites that are positive for metastatic disease 
by bone scan for prostate cancer.  Each of these sites of metastatic 
disease will also be further characterized according to specific 
subcategories based on features of the lesion as follows for each modality 
and their specific features:   
 
· 
Bone scan 
 
Axial skeleton (spine, pelvis, sacrum, sternum, skull, ribs) 
 
Appendicular skeleton (arms, legs) 
 
Stable versus new or progressive metastatic site 
· 
CT scan 
 
Axial versus appendicular skeleton for bone lesions 
 
Size of soft tissue lesions (greatest transaxial and perpendicular 
diameters) 

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 
Location of soft tissue lesion 
· 
MRI scan 
 
Axial versus appendicular skeleton for bone lesions 
 
Size of soft tissue lesions (greatest transaxial and perpendicular 
diameters) 
 
Location of soft tissue lesion 
· 
PET 
 
Bone versus lymph node versus organ involvement 
 
PET-based SUV parameters (SUVpeak, SUVmax) 
 
13.2 Sample Size/Accrual Rate 
The primary endpoint will be rate of progression at 6-months. Historical data on 
this patient population indicate that >80% would show progression as defined 
above within a 6-month period without treatment, and thus this is the 
progression rate we expect in subjects in the control/observation arm (72-74). 
We hypothesize that SBRT will be able to reduce the progression at 6-months 
by 50% (76).  A sample size using a 1:2 randomization scheme of 18 patients 
in the control group and 36 in the SBRT arm will provide 85% power to detect a 
decrease relapse rate from 80% to 40% with a type I error = 0.05 using one-
sided Fisher’s exact test. Thus, we will have a total of 54 patients.  
 
Patients who drop out within one month of enrollment or prior to day 1 of SBRT 
or Observation will be replaced. We will accrue 54 evaluable patients and will 
update total accrual number for the study if necessary.  
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. 
13.3 Early Stopping Guidelines: 
This study will monitor site-specific grade 4/5 toxicity in the SBRT 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 
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
 

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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 
2.6 
35.3 
0.2 
31.5 
29.6 
0.25 
56.4 
24.6 
0.3 
78.4 
19.2 
0.35 
91.9 
14.7 
13.4 Analysis of Primary Objective 
This is a (1:2) randomized, Phase II trial of observation versus SBRT 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) Initial treatment with surgery vs. radiation 
therapy; 2) Prior hormonal therapy vs. no prior hormonal therapy; and 3) 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 the proportion of patients who have 
progressed after 6 months from randomization. For each arm, we will calculate 
the proportion of patients who have progressed and exact 95% confidence 
intervals. If a patient has withdrawn from the study before 6 months, they will be 
considered to have progressed when calculating the proportion of individuals 
who have progressed. We will compare the proportion of patients who have 
progressed in the observation and SBRT arms using Fisher’s exact test. The 
analysis population includes all randomized subjects based on intend-to-treat 
principle. 
 
13.5 Analysis of Secondary Objectives 
o For safety analysis, adverse events will be summarized by type and grade. 
o Hazard rate estimates and 95% confidence intervals as well as Kaplan-Meier 
(KM) estimates will be used to summarize progression free survival (PFS), 
ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time 
to distant progression (TTDP), duration of response functions over time.  The 
median PFS, ADT-FS, TTLP and TTDP will be reported.  
o The efficacy of SBRT/SABR with oligometastatic disease will also be 
determined by measuring local control of each lesion at 6-months. 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.  

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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.  
13.6 Evaluation of Toxicity 
All patients who receive at least one fraction of SBRT/SABR will be evaluable for 
toxicity from the time of their first treatment for SBRT. 
13.7 Correlative Science 
Descriptive statistics will be performed to correlate the temporal CTC, ctDNA and 
immune repertoire metric changes with clinical outcomes. 

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30. Christodouleas JP, Marks LB. Analysis of patients with oligometastases undergoing two or more 
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31. Kavanagh BD, McGarry RC, Timmerman RD. Extracranial radiosurgery (stereotactic body 
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33. Shankar LK, Hoffman JM, Bacharach S, et al. Consensus recommendations for the use of 18F-
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34. Turlakow A, Larson SM, Coakley F, et al. Local detection of prostate cancer by positron emission 
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35. Hofer C, Laubenbacher C, Block T, Breul J, Hartung R, Schwaiger M. Fluorine-18-
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36. Nunez R, Macapinlac HA, Yeung HW, et al. Combined 18F-FDG and 11C-methionine PET scans 
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38. Hricak H, Choyke PL, Eberhardt SC, Leibel SA, Scardino PT. Imaging prostate cancer: a 
multidisciplinary perspective. Radiology. Apr 2007;243(1):28-53. 
 
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. 
40. Scattoni V, Picchio M, Suardi N, et al. Detection of lymph-node metastases with integrated 
[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 
Nucl Med. Feb 2011;51(2):183-192. 
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. 
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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-
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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. 

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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. 
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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 
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64 Chiang, A. C. & Massague, J. Molecular basis of metastasis. N Engl J Med 359, 2814-2823, 
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65 Kim, M. Y. et al. Tumor self-seeding by circulating cancer cells. Cell 139, 1315-1326, 
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68 Marrinucci, D. et al. Fluid biopsy in patients with metastatic prostate, pancreatic and breast 
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72 Keizman D, Zahurak M, Sinibaldi V, et. al. Lenalidomide in nonmetastatic biochemically relapsed 
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73.  Pound C, Partin A, Eisenberger M, Chan DW, Pearson JD, Walsh PC. Natural history of 
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74.  Antonarakis ES, Trock BJ, Feng Z, et al. The natural history of metastatic progression in men 
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75.  Scher HI, Halabi S, Tannock I, et. al. Design and End Points of Clinical Trials for Patients With 
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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 
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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 

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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 
81. Color Genomics. (2016). Color Genomics Democratizes Access to Clinical-Grade Genetic Testing 
Worldwide.  [Press release]. Retrieved from http://www.prnewswire.com/news-releases/color-
genomics-democratizes-access-to-clinical-grade-genetic-testing-worldwide-300248913.html 
 
 

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APPENDIX I: Brief Pain Inventory Form 
 

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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. 

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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. 

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APPENDIX IV: EPIC-HD CTC Sample Collection & Processing 
 
  

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APPENDIX V: ImmunoSEQ Sample Collection & Processing 
 

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APPENDIX VI: RECTAL SWAB COLLECTION FOR MICROBIOME ANALYSIS  
 
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.   
 
The swab samples can be kept at 4°C or -20°C prior to transport to the Sfanos lab.  
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX VII: COLOR SALIVA KIT SAMPLE COLLECTION 
KIT INCLUDES:  
Saliva Tube, Detailed Instructions, and Blue Cap.  
Protocol:  
1. In order to not delay results or ruin sample, the patient must wait 30 minutes if he 
has: 
a. Had any food or drink 
b. Brushed his teeth 
c. Used mouthwash 
d. Smoked or chewed gum 
 
2. Remove tube from clear tray. Do not remove the plastic film from the lid attached 
to the funnel. It contains stabilizing liquid that will mix with the saliva later once 
you close the lid. 
 
3. Spit into the funnel until the amount of saliva reaches the “fill to” line. This might 
take a few minutes (thinking of candy or rubbing your cheeks can speed up the 
process). Remember saliva bubbles do not count. 
 
4. Once you have reached the “fill to” line, hold the tube upright with one hand, and 
close the funnel lid with the other hand by firming pushing until you hear a loud 
click. Do not be surprised when the fluid from the lid is released into the tube.  
Make sure it is closed tightly. 
 
5. Take the small blue cap out of the clear tray. Holding the tube upright, unscrew 
the funnel to remove it completely, then screw the small cap onto the tube tightly.  
 
6. Shake the tube for the 5 seconds, to mix the liquid and saliva together. This will 
preserve the sample across a wide range of temperatures. 
 
7. Visit www.getcolor.Com/activate to link sample to color account. You will need 
the bar code found on saliva tube.  
IT IS ABSOLUTELY NECESSARY THAT YOU ACTIVATE YOUR KIT OR 
COLOR WILL NOT BE ABLE TO ANALYZE THE SAMPLE. 
8. Place tube into the provided plastic bag, seal the bag, then place it back into the 
cardboard box. Seal the box and drop it off in any USPS mailbox. Postage has 
already been paid. Everything else can be thrown away, as long as you have 
activated your kit successfully. 
You will receive an email once the sample has been received by the lab and 
another email once results are ready.   

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