A Phase 2 Trial of Radium Ra 223 Dichloride in Combination With Androgen Deprivation Therapy and Stereotactic Body Radiation Therapy for Patients With Oligometastatic Castration Sensitive Prostate Cancer
Phase: PHASE2
Conditions: Prostate Adenocarcinoma
Sponsor: City of Hope Medical Center

IRB 17085 
Packet: 13 
 
08/03/23 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
 
Dept. of Radiation Oncology 
 
TITLE:  
A Phase 2 Trial of Radium Ra 223 Dichloride in Combination with Androgen Deprivation 
Therapy and Stereotactic Body Radiation Therapy for Patients with Oligometastatic 
Castration-Sensitive Prostate Cancer (SHARP) 
 
CITY OF HOPE PROTOCOL NUMBER: 17085 
 
 
 
PROTOCOL DATE: 08/03/23 
 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Approval  
Protocol version: 12/04/2017 v00 
 
 
Version 00 
Amendment 01  
Protocol version: 12/12/2017 v01 
 
 
Version 01 
Amendment 02 
Protocol version: 05/03/2018 v02 
 
 
Version 02 
Amendment 03 
Protocol version: 08/16/2018 v03 
 
 
Version 03 
Amendment 04 
Protocol version: 01/21/2020 v04 
 
 
Version 04 
Amendment 05 
Protocol version: 07/15/2020 v05 
 
 
Version 05 
Amendment 06 
Protocol Dated:   07/23/2020  
 
 
Packet: 06 
Amendment 07 
Protocol Dated:   02/16/2021  
 
 
Packet: 07 
Amendment 08 
Protocol Dated:   06/21/2021  
 
 
Packet: 08 
Amendment 09 
Protocol Dated: 06/21/2021 (tp) 
 
 
Packet: 09 
Amendment 10 
Protocol Dated: 02/17/2022  
 
 
Packet 10 
Amendment 11 
Protocol Dated: 02/17/2022 (tp) 
 
 
Packet 11 
Amendment 12 
Protocol Dated: 08/03/2023 (v11) 
 
 
Packet 12 
Amendment 13 
Protocol Dated: 08/03/2023 (v11)TP  
 
Packet 13 
 
 
 
SPONSOR/IND NUMBER: 
City of Hope/ Exempt 
DISEASE SITE: 
Prostate Cancer 
STAGE (if applicable): 
 N/A 
MODALITY: 
    Hormone therapy and radiation therapy 
PHASE/TYPE: 
    Phase 2  
 
PRINCIPAL INVESTIGATOR: 
 
 
Savita Dandapani, M.D. 
Ph: (626)-256-4673 ext 82247 
Email: sdandapani@coh.org 
CO-INVESTIGATOR(S): 
 
 
Tanya Dorff, MD  
Kun Qing, PhD 
PARTICIPATING CLINICIANS: 
 
Jeffrey Wong, MD, Sagus Sampath, MD, Dave 
Yamauchi, MD,  Sumanta Pal, MD, Scott Glaser, MD, 
Julie Ressler, MD, Yi-Jen Chen, MD 
 
BIO-STATISTICIAN: 
Paul Frankel, Ph.D. 
 
 
PARTICIPATING SITES: 
City of Hope, Duarte, CA 
 

This document is confidential and for research purposes only. Do not copy, redistribute, 
disclose or use except as authorized. 
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
A Phase 2 Trial of Radium Ra 223 Dichloride in Combination with Androgen 
Deprivation Therapy and Stereotactic Body Radiation Therapy for Patients with 
Oligometastatic Castration Sensitive Prostate Cancer (SHARP) 
 
Version Date: August 03, 2023  
Protocol Version: 11 
City of Hope#: 17085 
Agents: Androgen deprivation therapy, radium 
Ra 223 dichloride, stereotactic body 
radiation therapy 
IND Number: IND Exempt 
Sponsor/IND Holder: City of Hope 
Funding Support/Industry Partner: Bayer 
NCT Number: NCT03361735 
 
Principal Investigator 
Savita Dandapani, MD., PhD. 
City of Hope National Medical Center 
Dept. of Radiation Oncology 
T:626-301-8247 x 82071 
Email:sdandapani@coh.org 
 
 

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PROTOCOL TEAM 
Biostatistician 
Paul Frankel, PhD 
Dept. of Information Sciences 
T: 626-256-4673, x65265 
Email:pfrankel@coh.org 
Co-Investigator 
Tanya Dorff, MD 
Dept. of Medical Oncology 
T:626-301-8247 x 89200 
Email:tdorff@coh.org 
 
 
 
 
 
 
 
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 
 
OR relugolix 

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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2 Trial of Radium Ra 223 Dichloride in Combination with Androgen Deprivation Therapy and 
Stereotactic Body Radiation Therapy for Patients with Oligometastatic Castration Sensitive Prostate Cancer 
(SHARP) 
Study Detail 
Population/Indication(s): 
Prostate adenocarcinoma 
Phase: 
Phase 2  
Sample Size: 
24 evaluable patients 
Estimated Accrual Duration: 
48 months 
Estimated Study Duration 
~8 years 
Participant Duration: 
68 months (~8 months of treatment + 60 months follow-up) 
Participating Sites: 
City of Hope Duarte, CA 
Study Agents: 
Androgen deprivation therapy, radium Ra 223 dichloride, stereotactic 
body radiation therapy 
Sponsor: 
City of Hope 
Industry Partner:  Bayer 
Industry Partner Protocol 
Number: 
IIR-US-2016-1801 
Rationale for this Study 
Carcinoma of the prostate remains a significant health problem in the United States, with 181,000 new cases 
and 26,120 deaths estimated in 2016[1]. Despite progress in early detection thanks to the widespread use of 
serum Prostate Specific Antigen (PSA) about 15 % of patients present with metastatic disease at diagnosis and 
30 % of patients suffer eventual relapse to regional lymph nodes or distant organs despite local therapy. 
Historically several hypotheses based on clinical evidence attempted to explain mechanisms of metastatic tumor 
cell spread. Halsted suggested that tumors spread in an orderly manner initially spreading to regional lymph 
nodes and then centrifugally to distant organs[2]. In contrast the “systemic hypothesis” most clearly articulated 
by Fisher proposed two principal types of cancer: those that cannot metastasize and those that have 
metastasized widely before clinical detection[3]. In an attempt to reconcile clinical and laboratory features in a 
unified hypothesis, the “spectrum” model has been proposed[4]. This theory accepts that some tumors spread 
widely before clinical detectability while others never metastasize, but for the majority of cancers, metastatic 
capacity evolves during the clinical phase of tumor growth.  
During the evolutionary process there may be a stage, termed “oligometastases”, when metastases are limited 
in number and location because metastatic capacity has not fully evolved[5].With a few exceptions such as testis 
cancer and some hematologic malignancies, the treatment of metastatic cancer by hormonal or cytotoxic agents 
is rarely curative and in many instances ineffective. In this context an important question is whether in the 
natural history of metastatic spread, there is a time when metastases are limited in number and/or in destination 
organs, and therefore treatment with systemic agents augmented by regional treatments may be effective. 
Examples of this include resection of lung metastases from sarcoma, liver metastases from colorectal cancer and 
isolated resection of breast metastases[6-8]. 
Despite its limitations hormone therapy and chemotherapy have been effective in eradicating subclinical 
deposits when used as an adjuvant to local therapy. But all too often the tumor recurs in a few locations, the 
likely consequence of the large number of tumor cells at these sites or limited drug availability at the site. These 
remaining oligometastases then may serve as a nidus for further dissemination. Metastatic prostate cancer is a 
heterogeneous disease and patients with ≤5 lesions have better survival than patients with > 5 metastatic 
lesions[9]. It is considered more likely that patients with limited number of metastases will benefit from local 
therapy to metastases and the patients with ≤ 4 metastases will be the focus of this proposed study. We have 

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previously reported results of a clinical trial in 29 patients with oligometastatic hormone sensitive prostate 
cancer treated at City of Hope with 36 weeks of androgen deprivation therapy and external beam radiation 
therapy (EBRT) up to 45 Gy to all (≤ 5) metastases[10]. We concluded that treatment with radiation therapy to 
oligometastases was feasible. 90% of patients treated with 36 weeks of ADT and EBRT to metastases achieved 
PSA nadir of <0.2 ng/mL that is known to be associated with good prognosis[11]. 4/8 patients with metastases 
limited to pelvic lymph nodes remained in remission off ADT after a median follow up of 25.7 months. We 
postulated that patients with oligometastases represent distinct subset of hormone sensitive prostate cancer 
that may serve as a focus for clinical trials evaluating novel local and systemic therapies in combination with 
ADT. 
We hypothesize that it is possible and safe to treat patients with oligometastatic prostate cancer with even more 
aggressive regimen including: ADT, radium Ra 223 dichloride and SBRT to all known oligometastatic sites and 
that aggressive treatment of oligometastases(and bone micrometastases with radium Ra 223 dichloride early in 
the course of disease when disease is still sensitive to hormone manipulation will improve treatment outcomes 
of these patients and potentially delay disease progression and development of castration resistant phenotype.  
It is well known that bone is the most common site of micro and macrometastatic disease in prostate cancer 
and metastatic bone recurrence is present in 90% of patients with advanced prostate cancer and represents a 
significant site of treatment failure and source of morbidity and mortality[12].Therefore aggressive focus on the 
treatment of presumed micrometastatic bone disease underlies the hypothesis of early application of bone 
targeting with radium Ra 223 dichloride in our study. The proposed clinical trial builds upon our previous 
experience and expands the concept by introducing in this setting but also providing consolidation SBRT to 
known metastatic sites that will allow to deliver fully therapeutic doses of RT (versus sometimes palliative doses 
in the previous study).  
Objectives 
Primary Objective 
 
To assess the time to treatment failure (TTF) in patients who initiated the protocol regimen of 
androgen deprivation therapy (ADT) with stereotactic body radiation therapy (SBRT) and radium Ra 
223 dichloride and received at least one dose with radium Ra 223 dichloride. 
Secondary Objective 
 
To assess the safety of adding radium Ra 223 dichloride to SBRT and ADT in patients with 
oligometastatic castration sensitive prostate cancer. 
 
To assess the Prostate-Specific Antigen (PSA) and overall response rate (ORR) after 6 cycles of radium 
Ra 223 dichloride (Cycle 8 Day 1). 
 
To assess the progression-free survival (PFS) in patients with oligometastatic castration sensitive 
prostate cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 223 dichloride 
and received at least one dose of radium Ra 223 dichloride.  
 
To assess time to bone specific PFS in patients with oligometastatic castration sensitive prostate 
cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 223 dichloride and 
received at least one dose of radium Ra 223 dichloride.  
 
To assess overall survival, complete response rate, duration of response, and duration of overall 
complete response and duration of stable disease in patients with oligometastatic castration sensitive 
prostate cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 223 dichloride. 
 
To assess long-term toxicities during 5-year follow-up in patients with oligometastatic castration 
sensitive prostate cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 223 
dichloride and received at least one dose of radium Ra 223 dichloride 
Exploratory Objective 

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 
To perform exploratory analysis of primary or metastatic tumor mutation patterns in this study 
population at baseline 
 
To identify immune system factors in the blood that change during the course of ADT-radiotherapy 
for metastatic prostate cancer 
 
To describe the rate of normalization of the total alkaline phosphatase level (defined as a return to a 
value within the normal range) at the end of protocol therapy in patients oligometastatic castration 
sensitive prostate cancer with total alkaline phosphatase values above the upper limit of the normal 
range at baseline 
 
To analyze the patients who were in consideration for the study and the reason for ineligibility, 
including radiographic review, PSA value, and treatment window. 
Study Design 
The SHARP study is a single-center open-label, Phase 2 clinical trial of stereotactic body radiation therapy 
(SBRT), hormone/androgen deprivation therapy (ADT) and radium Ra 223 dichloride for participants with 
metastatic castration sensitive prostate cancer. 
 
Participants will initiate ADT (LHRH agonist leuprolide or goserelin, or LHRH antagonist degarelix or relugolix) 
for 4 weeks and then receive 32 weeks of ADT on protocol for a total of 36 weeks. Concurrent with standard of 
care ADT on protocol participants will receive 1 cycle of SBRT followed by 6 cycles of radium Ra 223 dichloride. 
SBRT is limited to ≤4 metastatic lesions with at least 1 bone lesion. Treatment cycles will be 28 days. 
Participants will receive bisphosphonate or RANKL inhibitor bone health agents at the dose and schedule 
consistent with the treatment of bone metastases or prevention of osteoporosis, starting approximately when 
the protocol therapy is initiated and ending when the patient reaches testosterone recovery (>50 ng/dL) or at 
the discretion of the PI.   
 
Protocol therapy will last until completion of planned 8 cycles of therapy, unacceptable toxicity or progression, 
whichever comes first. If one agent is discontinued due to toxicity, then the participant may continue to 
receive the other protocol therapy agent(s). 
 
Participants who end protocol therapy will undergo follow-upfor 5 years.   
Evaluation Criteria and Endpoints 
Response and progression will be evaluated in this study using modified Prostate Cancer Working Group 2 
criteria. PSA levels will be a part of overall response assessment.   
Efficacy Endpoints: 
 
Time to treatment failure  
 
Objective response rate  
 
Complete response rate 
 
Progression-free survival  
 
Bone specific progression-free survival  
 
Duration of response  
 
Duration of overall complete response 
 
Duration of stable disease 
 
Overall Survival  
Toxicity 
Toxicity will be recorded using the NCI CTCAE v 5.0. 

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Alkaline phosphatase 
 
Levels of alkaline phosphatase from baseline to end of study treatments 
Statistical Considerations 
With 24 evaluable patients treated we will estimate median time to treatment failure (radiographic or PSA 
progression, death or cessation of treatment due to clinical progression or toxicity).  We seek to demonstrate a 
median TTF of at least 25 months, exceeding reports from all previous prior studies that examined only a two 
modality approach.   With 24 evaluable patients, accrued over 16 months and followed for 18 months, we will 
have greater than 80% power to detect an improvement in TTF from 16 months to 32 months with a one-sided 
type I error of 10%.  The critical value for a promising median TTF based on this design is 25 months, or an 
improvement of 9 months over our historical data.   
Other secondary analysis will include progression-free survival, overall survival, complete response rate, 
duration of response, and duration of overall complete response, duration of stable disease and analysis of 
alkaline phosphatase levels.Exploratory analysiswill include evaluation of the role of genomic mutations and 
immune biomarker studies on outcome and toxicity.  These outcomes will be reported to provide further 
support, combined with the activity, and tolerability to help guide additional studies.  
 
Eligibility Criteria 
Main Inclusion Criteria 
 
Adult patients with life expectancy > 12 months and ECOG ≤ 2 
 
Histologic diagnosis of prostate adenocarcinoma. 
 
Stage M1 
 
Up to 5 metastatic lesions: 
 
Must have at least 1 bone lesion AND each non-visceral lesion should be less than 5 cm 
 
Visceral lesions will be limited to one lung lesion (< 2cm) or one lymph node;  no liver lesions allowed. 
Lymph nodes allowed provided they are not in a field of prior radiation, and if amenable to SBRT (to 
be reviewed by PI). (note: locoregional recurrence is not considered a “visceral metastatic lesion”. 
This is discussed more below) 
 
Two lesions can be in close proximity (i.e. within 5cm of each other) if they meet radiation SBRT 
normal tissue toxicity requirements 
 
If have untreated primary prostate cancer: Must undergo debulking prostatectomy at discretion of 
treating urologist or definitive radiation therapy. Definitive radiation fields to include close proximity 
lymph nodes at discretion of treating radiation oncologist. Definitive radiation dose at discretion of 
treating radiation oncologist. 
 
If had prior treatment to the prostate primary (definitive radiation therapy or prostatectomy, and can 
include salvage radiation to the prostate bed +/- lymph nodes), no evidence of locally persistent or 
recurrent prostate cancer on digital rectal exam (DRE) OR imaging studies (CT or MRI). 
 
Note: patients with asymptomatic low volume locoregional recurrent disease will be allowed 
to enroll on this study after discussion with the PI. In the case where the low volume 
recurrence is amenable to SBRT, it will be included in the SBRT treatment. In the case where 
the low volume recurrence is not amenable to SBRT based on reirradiation risk, then we will 
follow these lesions with re-imaging scans and reassess at later time points for further local 
control. Additionally, if these patients  fail only at the untreated site (due to the untreated 
recurrence not being amenable to SBRT) they will be censored in the primary efficacy analysis 
at that time. 
 
Does not have castration resistant disease (i.e. testosterone >50 ng/dl) 

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 
PSA ≥0.2 prior to start of androgen deprivation treatment (ADT) 
 
Patients will be receiving approximately 36 weeks of ADT as part of this trial. The 36 weeks of ADT 
may start prior to consenting to this study. The patient may join the study at any point of the 36-week 
period of ADT treatment. . 
 
Patients must be willing to receive bisphosphonate or RANKL inhibitor bone health agents at the dose 
and schedule consistent with the treatment of bone metastases or prevention of osteoporosis, 
starting approximately from when the patient begins protocol therapy, until the patient’s 
testosterone reaches normal levels or at the discretion of the PI. Patients who are already on a bone 
health agent separate from the protocol may continue on this treatment regimen and will not be 
required to start treatment with an additional bone health agent. 
 
May have received prior hormonal therapy at the discretion of the PI. Patients may have received 
prior targeted therapy in the context of definitive treatment of a primary tumor.  
 
Must have refused standard of care treatment for metastatic disease 
Main Exclusion Criteria 
 
Prior Radium Ra 223 dichloride  
 
Prior or concomitant chemotherapy for metastatic or recurrent disease with the following exceptions: 
 
Prior chemotherapy for local primary disease is permitted. 
 
Prior radiation treatment for metastatic disease is allowed provided that it is controlled and the total 
number of metastatic lesions does not exceed 5. 
 
Concomitant radiation treatment to primary prostate site 
 
Bilateral orchiectomy. If unilateral orchiectomy, eligible if testosterone >50 ng/dl. 
 
Metastases that in the judgment of investigator-radiologist are not amenable to SBRT 
 

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Investigational Product Dosage and Administration 
 
Agent/Therapy and  
Route of Administration  
Dose 
Timing of administration and planned 
duration  
Stereotactic Body Radiation Therapy 
(SBRT) 
via  
External Beam Radiation via TrueBeam 
Stx 
9Gy x 3 
fractions (bone) 
5Gy x 5 
fractions 
(lymph node) 
10Gyx5 (lung) 
 
Cycle 1 
Day 1, then dosing administered minimum 
every 40 hours over 7 to 21 days during Cycle 1 
Radium Ra 223 dichloride 
via  
Slow IV over 1 minute 
55 kBq/kg 
Cycles 2-7 
Day 1 of each 28-day cycle 
Leuprolide OR goserelin OR degarelix OR 
relugolix 
Per package insert/ investigator 
discretion 
 
For a total of approximately 36 weeks. May 
start prior to consenting on study. 
 
Clinical Observations and Tests to be Performed 
 
Medical history and physical exam 
 
Safety assessments (CBCs and comprehensive chemistry panel) 
 
PSA, serum alkaline phosphatase, serum testosterone 
 
CT/ MRI scans  
 
Correlative tumor tissue and blood 
 
 
 

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TABLE OF CONTENTS 
SECTION ............................................................................................................................................................  
 
 ............................................................................................................................................................  
 
 ............................................................................................................................................................  PAGE 
Protocol Team ................................................................................................................................................. 2 
Experimental Design Schema .......................................................................................................................... 3 
Protocol Synopsis ............................................................................................................................................ 4 
Table of Contents .......................................................................................................................................... 10 
List of Tables and Figures .............................................................................................................................. 12 
Abbreviations ................................................................................................................................................ 13 
1.0 
Objectives ....................................................................................................................................... 14 
1.1 
Primary Objectives .................................................................................................................... 14 
1.2 
Secondary Objectives ................................................................................................................ 14 
1.3 
Exploratory Objectives .............................................................................................................. 14 
2.0 
Background ..................................................................................................................................... 15 
2.1 
Introduction/Rationale for Development ................................................................................. 15 
2.2 
Hormone Therapy ..................................................................................................................... 16 
2.3 
Radium Ra 223 Dichloride ......................................................................................................... 16 
2.4 
Stereotactic radiation therapy .................................................................................................. 17 
2.5 
Bone Health Agents ................................................................................................................... 18 
2.6 
Overview and Rationale of Study Design .................................................................................. 20 
3.0 
Eligibility Criteria ............................................................................................................................. 23 
3.1 
Inclusion Criteria ....................................................................................................................... 23 
3.2 
Exclusion Criteria ....................................................................................................................... 25 
4.0 
Participant Enrollment .................................................................................................................... 26 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures ................................................. 26 
4.2 
Participant Enrollment .............................................................................................................. 26 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment .................. 27 
5.0 
Treatment Program ........................................................................................................................ 28 
5.1 
Treatment Program Overview .................................................................................................. 28 
5.2 
Cycle Definition ......................................................................................................................... 29 
5.3 
Treatment Plan.......................................................................................................................... 29 
5.4 
Agent Administration ................................................................................................................ 29 
5.5 
Assessments and Special Monitoring ........................................................................................ 30 
5.6 
Criteria for Removal from Protocol Therapy ............................................................................. 31 
5.7 
Follow-Up .................................................................................................................................. 31 
5.8 
Duration of Study Participation ................................................................................................. 32 
5.9 
Supportive Care, Prohibited Medications and Concomitant Therapy ...................................... 32 
6.0 
Criteria For InitiatingSBRT and Radium Ra 223 Dichloride & Dose Delay Guidelines ..................... 34 
6.1 
Criteria to START SBRT (Cycle 1 Day 1) ...................................................................................... 34 
6.2 
Criteria to START Radium Ra 223 Dichloride (Cycle 2 Day 1) .................................................... 35 
6.3 
Dose Delay Guidelines ............................................................................................................... 36 
7.0 
Adverse Events List ......................................................................................................................... 38 
7.1 
Leuprolide ................................................................................................................................. 38 
7.2 
Goserelin ................................................................................................................................... 38 
7.3 
Degarelix ................................................................................................................................... 39 
7.4 
Relugolix .................................................................................................................................... 39 

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7.5 
Stereotactic body radiation therapy ......................................................................................... 40 
7.6 
Radium Ra 223 dichloride ......................................................................................................... 41 
8.0 
Data & Safety Monitoring, Adverse Event And Unanticipated Problem Reporting ........................ 42 
8.1 
COH Data and Safety Monitoring Plan ...................................................................................... 42 
8.2 
Exceptions to Expedited Reporting ........................................................................................... 44 
8.3 
Reporting to Bayer .................................................................................................................... 44 
9.0 
Agent Information .......................................................................................................................... 45 
9.1 
Radium Ra 223 dichloride ......................................................................................................... 45 
9.2 
Androgen Deprivation Therapy ................................................................................................. 49 
9.3 
Stereotactic Body Radiation Therapy ........................................................................................ 54 
10.0 
Correlative/ Special Studies ............................................................................................................ 55 
10.1 
Tumor Tissue Clinical Testing .................................................................................................... 55 
10.2 
Correlative Blood Studies .......................................................................................................... 56 
11.0 
Study Calendar ................................................................................................................................ 57 
12.0 
Endpoint Evaluation Criteria/Measurement of Effect .................................................................... 60 
12.1 
Efficacy Endpoints ..................................................................................................................... 60 
12.2 
Toxicity ...................................................................................................................................... 60 
12.3 
Alkaline phosphatase ................................................................................................................ 60 
13.0 
Statistical Considerations ................................................................................................................ 61 
13.1 
Study Design .............................................................................................................................. 61 
13.2 
Evaluable Participants ............................................................................................................... 61 
13.3 
Accrual and Expected Duration of Trial ..................................................................................... 61 
13.4 
Stopping Rules for Excessive Toxicity ........................................................................................ 61 
13.5 
Statistical Analysis Plan ............................................................................................................. 62 
14.0 
Data Handling, Data Management, Record Keeping ...................................................................... 64 
14.1 
Source Documents .................................................................................................................... 64 
14.2 
Data Capture Methods and Management ................................................................................ 64 
14.3 
Case Report Forms/Data Submission Schedule ........................................................................ 64 
14.4 
Regulatory Records ................................................................................................................... 64 
15.0 
Adherence to the Protocol ............................................................................................................. 65 
16.0 
Study Oversight, Quality Assurance, and Data & Safety Monitoring .............................................. 65 
16.1 
All Investigator Responsibilities ................................................................................................ 65 
16.2 
Study Principal Investigator Responsibilities............................................................................. 65 
16.3 
Protocol Management Team (PMT) .......................................................................................... 65 
16.4 
Auditing ..................................................................................................................................... 66 
16.5 
City of Hope Data and Safety Monitoring Committee .............................................................. 66 
17.0 
Ethical and Regulatory Considerations ........................................................................................... 67 
17.1 
Ethical Standard ........................................................................................................................ 67 
17.2 
Regulatory Compliance ............................................................................................................. 67 
17.3 
Institutional Review Board ........................................................................................................ 67 
17.4 
Informed Consent ..................................................................................................................... 68 
17.5 
Participant Withdrawal ............................................................................................................. 68 
17.6 
Special and Vulnerable Populations .......................................................................................... 68 
17.7 
Participant Confidentiality ........................................................................................................ 69 
17.8 
Conflict of Interest .................................................................................................................... 70 
17.9 
Financial Obligations, Compensation, and Reimbursement of Participants ............................. 70 
17.10 
Publication/Data Sharing .......................................................................................................... 70 
18.0 
References ...................................................................................................................................... 71 

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Appendix A: Performance Status .................................................................................................................. 74 
Appendix B: Staging Criteria .......................................................................................................................... 75 
Appendix C: Disease Parameters and Methods for Evaluation ..................................................................... 76 
Appendix D: Response Criteria ...................................................................................................................... 79 
LIST OF TABLES AND FIGURES 
Table 5.3 Treatment Regimen and Schedule........................................................................................... 29 
Table 6.1 Cycle 1 Day 1 SBRT Administration Criteria ............................................................................. 34 
Table 6.2 Cycle 2 Day 1 Radium Ra 223 Dichloride START Criteria ......................................................... 35 
Table 6.3 Dose Delay Guidelines ............................................................................................................. 36 
Table 10.1 Tumor tissue overview .......................................................................................................... 55 
Table 10.2 Peripheral blood studies overview ........................................................................................ 56 
Table 11.0 Study Activity Calendar .......................................................................................................... 57 
Table 12.1 Efficacy Endpoints .................................................................................................................. 60 
Table 14.3 Data Submission Schedule ..................................................................................................... 64 

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ABBREVIATIONS 
Abbreviation 
Meaning 
ADT 
AE 
ALT 
ANC 
AST 
CBC 
CFR 
CCP 
COH 
CR 
CRA/CRC 
CRF 
CSPC 
CT 
CTCAE 
CTEP 
DLT 
DNA 
DSMC 
ECG 
ECOG 
HER 
FDA 
FSH 
GCP 
HIPAA 
HIV 
IB 
IND 
IRB 
IV  
LH 
LHRH 
MRI 
MRN 
OCTAM 
OIDRA 
ORR 
PC 
PD 
PET-CT 
PFS 
PHI 
PI 
PMT 
PR 
PSA 
RR 
SAE 
SBRT 
SD 
TTF 
ULN 
UP 
Androgen deprivation therapy 
Adverse event 
Alanine aminotransferase 
Absolute neutrophil count 
Aspartate aminotransferase 
Complete Blood Count 
Code of Federal Regulation 
Comprehensive Chemistry Panel 
City of Hope 
Complete response 
Clinical Research Associate/Coordinator 
Case Report Form 
Castration Senstitive Prostate Cancer 
Computerized tomography 
Common Terminology Criteria for Adverse Events 
Cancer Therapy Evaluation Program 
Dose-limiting toxicity 
Deoxyribonucleic acid 
Data Safety Monitoring Committee 
Electrocardiography 
Eastern Cooperative Oncology Group 
Electronic Health Record 
Food and Drug Administration 
Follicle stimulating hormone 
Good Clinical Practice 
The Health Insurance Portability and Accountability Act 
Human immunedeficiency virus 
Investigator Brochure 
Investigational New Drug  
Institutional Review Board 
Intravenous  
Luteinizing hormone 
Luteinizing hormone-releasing hormone 
Magnetic resonance imaging 
Medical record number 
Office of Clinical Trials Auditing and Monitoring 
Office of IND Development and Regulatory Affairs 
Objective response rate 
Prostate Cancer 
Progressive Disease 
Positron emission tomography–computed tomography  
Progression-free survival 
Protected health information 
Principal Investigator 
Protocol Management Team 
Partial response 
Prostate specific antigen 
Response rate 
Serious Adverse Event 
Stereotactic Body Radiation Therapy 
Stable disease 
Time to treatment failure 
Upper limit of normal 
Unanticipated problem 

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1.0 OBJECTIVES 
1.1 Primary Objectives 
o To assess the time to treatment failure (TTF) in patients who initiated the protocol regimen of 
androgen deprivation therapy (ADT) with stereotactic body radiation therapy (SBRT) and radium 
Ra 223 dichloride and received at least one dose with radium Ra 223 dichloride. 
1.2 Secondary Objectives 
o To assess the safety of adding radium Ra 223 dichloride to SBRT and ADT in patients with 
oligometastatic castration sensitive prostate cancer. 
o To assess the Prostate-Specific Antigen (PSA) and overall response rate (ORR) after 6 cycles of 
radium Ra 223 dichloride (Cycle 8 Day 1)  
o To assess the progression-free survival (PFS) in patients with oligometastatic castration sensitive 
prostate cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 223 
dichloride and received at least one dose of radium Ra 223 dichloride.  
o To assess time to bone specific PFS in patients with oligometastatic castration sensitive prostate 
cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 223 dichloride and 
received at least one dose of radium Ra 223 dichloride.  
o To assess overall survival, complete response rate, duration of response, and duration of overall 
complete response and duration of stable disease in patients with oligometastatic castration 
sensitive prostate cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 
223 dichloride. 
o To assess long-term toxicities during 5-year follow-up in patients with oligometastatic castration 
sensitive prostate cancer who initiated the protocol regimen of ADT with SBRT and radium Ra 
223 dichloride and received at least one dose of radium Ra 223 dichloride 
1.3 Exploratory Objectives 
o To perform exploratory analysis of primary or metastatic tumor mutation patterns in this study 
population at baseline 
o To identify immune system factors in the blood that change during the course of ADT-
radiotherapy for metastatic prostate cancer 
o To describe the rate of normalization of the total alkaline phosphatase level (defined as a return 
to a value within the normal range) at the end of protocol therapy in patients oligometastatic 
castration sensitive prostate cancer with total alkaline phosphatase values above the upper limit 
of the normal range at baseline.  
o To analyze the patients who were in consideration for the study and the reason for ineligibility, 
including radiographic review, PSA value and treatment window.  
 

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2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
Carcinoma of the prostate remains a significant health problem in the United States, with 181,000 new 
cases and 26,120 deaths estimated in 2016[1]. Despite progress in early detection thanks to the 
widespread use of serum Prostate Specific Antigen (PSA) about 15 % of patients present with metastatic 
disease at diagnosis and 30 % of patients suffer eventual relapse to regional lymph nodes or distant organs 
despite local therapy. Historically several hypotheses based on clinical evidence attempted to explain 
mechanisms of metastatic tumor cell spread. Halsted suggested that tumors spread in an orderly manner 
initially spreading to regional lymph nodes and then centrifugally to distant organs[2]. In contrast the 
“systemic hypothesis” most clearly articulated by Fisher proposed two principal types of cancer: those 
that cannot metastasize and those that have metastasized widely before clinical detection[3]. In an 
attempt to reconcile clinical and laboratory features in a unified hypothesis, the “spectrum” model has 
been proposed[4]. This theory accepts that some tumors spread widely before clinical detectability while 
others never metastasize, but for the majority of cancers, metastatic capacity evolves during the clinical 
phase of tumor growth.  
During the evolutionary process there may be a stage, termed “oligometastases”, when metastases are 
limited in number and location because metastatic capacity has not fully evolved[5]. With a few exceptions 
such as testis cancer and some hematologic malignancies, the treatment of metastatic cancer by hormonal 
or cytotoxic agents is rarely curative and in many instances ineffective. In this context an important 
question is whether in the natural history of metastatic spread, there is a time when metastases are 
limited in number and/or in destination organs, and therefore treatment with systemic agents augmented 
by regional treatments may be effective. Examples of this include resection of lung metastases from 
sarcoma, liver metastases from colorectal cancer and isolated resection of breast metastases[6-8].  
Despite its limitations hormone therapy and chemotherapy have been effective in eradicating subclinical 
deposits when used as an adjuvant to local therapy. But all too often the tumor recurs in a few locations, 
the likely consequence of the large number of tumor cells at these sites or limited drug availability at the 
site. These remaining oligometastases then may serve as a nidus for further dissemination. Metastatic 
prostate cancer is a heterogeneous disease and patients with ≤5 lesions have better survival than patients 
with > 5 metastatic lesions[9]. It is considered more likely that patients with limited number of metastases 
will benefit from local therapy to metastases. 
 
We have previously reported results of a clinical trial in 29 patients with oligometastatic hormone sensitive 
prostate cancer treated at City of Hope with 36 weeks of androgen deprivation therapy (ADT) and external 
beam radiation therapy (EBRT) up to 45 Gy to all (≤ 5) metastases[10]. We concluded that treatment with 
radiation therapy to oligometastases was feasible. Ninety percent of patients treated with 36 weeks of 
ADT and EBRT to metastases achieved PSA nadir of <0.2 ng/mL that is known to be associated with good 
prognosis[11]. Four of 8 patients with metastases limited to pelvic lymph nodes remained in remission off 
ADT after a median follow up of 25.7 months. We postulated that patients with oligometastases represent 
distinct subset of hormone sensitive prostate cancer that may serve as a focus for clinical trials evaluating 
novel local and systemic therapies in combination with ADT. In our current trial we are now allowing 
patients with lower PSA (i.e. PSA >0.2) due to recent advances in imaging to detect oligometastatic disease 
at lower PSA levels.[13]Similar PSA levels were used as inclusion criteria in the recently published 
oligometastatic STOMP trial[14, 15]. 
 

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We hypothesize that it is possible and safe to treat patients with oligometastatic prostate cancer with 
even more aggressive regimen including: ADT, radium Ra 223 dichloride and SBRT to all known 
oligometastatic sites and that aggressive treatment of oligometastases(and bone micrometastases with 
radium Ra 223 dichloride) early in the course of disease when disease is still sensitive to hormone 
manipulation will improve treatment outcomes of these patients and potentially delay disease 
progression and development of castration resistant phenotype.  It is well known that bone is the most 
common site of micro and macrometastatic disease in prostate cancer and metastatic bone recurrence is 
present in 90% of patients with advanced prostate cancer and represents a significant site of treatment 
failure and source of morbidity and mortality[12]. Therefore, aggressive focus on the treatment of 
presumed macrometastatic bone disease underlies the hypothesis of early application of bone targeting 
with radium Ra 223 dichloride in our study.   The proposed clinical trial builds upon our previous 
experience, and expands the concept by introducing radium Ra 223 dichloride in this setting but also 
providing consolidation SBRT to known metastatic sites that will allow to deliver fully therapeutic doses 
of RT (versus sometimes palliative doses in the previous study)[10]. 
2.2 Hormone Therapy 
Since testosterone is the main growth and survival factor for prostate cancer most patients will respond 
initially to ablation of gonadal androgen production through surgical (bilateral orchiectomy) or medical 
(luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy [39]) approaches[16]. 
Unfortunately eventually all patients will develop progressive disease despite continued androgen 
suppression, with a median time to progression of 14 to 30 months[17].There are many mechanisms 
responsible for the development of resistance to androgen deprivation. They include amplification of 
androgen receptors, increased sensitivity of androgen receptors, mutations of androgen receptors that 
allow activation by non-androgenic ligands and activation of alternative survival pathways[18]. Recent 
data suggests that early application of docetaxel chemotherapy in addition to androgen suppression 
results in significant survival extension in patients with metastatic hormone sensitive prostate cancer, but 
this benefit appears to be particularly robust in patients with extensive metastatic disease and data for 
patients with oligometastatic disease (our study population) is not compelling[19].  
Unfortunately once resistance to hormone therapy occurs, prognosis is dismal. This so-called castration 
resistant prostate cancer (CRPC) is characterized by virulent biologic and clinical behavior with median 
survival of 18-35 months[20]. Multiple life –extending agents have been approved in the last 10 years for 
the treatment of CRPC including immunotherapy (Sipuleucel-T), second generation androgen-pathway 
inhibitors (abiraterone, enzalutamide), chemotherapy (docetaxel, cabazitaxel) and radioactive isotope 
Radium Ra 223 dichloride[20]; however no significant therapeutic progress has been made in patients 
with hormone sensitive disease outside  of subset with extensive metastases[19]. 
2.3 Radium Ra 223 Dichloride 
Radium Ra 223 dichloride is an α emitting, bone seeking calcium-mimetic that selectively targets and binds 
to increased areas of bone turnover in bone metastases. The drug is administered by intravenous injection 
at four week intervals for a total of six injections.  
2.3.1 
Clinical experience 
The ALSYMPCA trial was a randomized, double blind, Phase 3 study that compared six injections of radium 
Ra 223 dichloride against placebo in men with CRPC and bony metastases who had received, were not 
eligible to receive, or had declined docetaxel chemotherapy[21].Median overall survival was longer with 

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radium Ra 223 dichloride than placebo (14.9 v 11.3 months; hazard ratio 0.70, 0.58 to 0.83; P<0.001). 
Subsequent subgroup analysis showed a survival benefit with radium Ra 223 dichloride, irrespective of 
previous docetaxel use. In addition, a significant improvement in median time to first symptomatic skeletal 
event was seen for radium Ra 223 dichloride versus placebo (15.6 v 9.8 months; hazard ratio 0.66, 0.52 
to0.83; P<0.001). Radium Ra 223 dichloride was well tolerated and associated with fewer adverse events 
than placebo. Although the difference was not significant, a slightly higher rate of diarrhea (25% v 15%) 
was seen with radium than with placebo. Other known side effects include nausea, vomiting, peripheral 
edema, and hematologic abnormalities (anemia, leukopenia, thrombocytopenia, neutropenia). It is 
notable that hematologic toxicities of Radium 223 were modest even in this population of patients with 
very advanced, and heavily pretreated disease.  A meaningful improvement in quality of life was also noted 
for radium compared with placebo. The American Urological Association (AUA) guideline recommends 
radium Ra 223 dichloride for use in patients with CRPC with bony metastases, no known visceral 
metastases, and good performance status, irrespective of previous docetaxel use. Radium Ra 223 
dichloride has always been used in conjunction with ongoing ADT therefore safety data for that 
combination is established.   
2.4 Stereotactic radiation therapy 
Stereotactic body radiation treatment (SBRT) for oligometastatic disease has emerged as a treatment 
modality to improve local control of metastases and delay need for toxic systemic treatment. There are 
numerous studies utilizing SBRT for oligometastatic patients with various histologies. For prostate in 
particular there have been a few recent papers documenting safety and efficacy of treating 
oligometastatic prostate cancer patients.  
One such study from Philadelphia looked at the benefit of SBRT in patients heavily treated for metastatic 
prostate cancer[22]. 24 patients were treated and there was improved median survival (>3yrs vs. 11 
months) for patients with ≤ 4 oligometastases. The radiation dose for SBRT was 24 Gy (18-50Gy) in 3 to 5 
fractions (8Gy x 3). Most sites were bone and lymph nodes and toxicity was only reported in 2patients, 
one with grade 1 diarrhea and one with Grade 2 pelvic pain[22]. 
Another study from Belgium looked at benefit of SBRT for newly diagnosed oligometastatic patients[23]. 
Their dose was 50 Gy in 10 fractions (40-50Gy in 8-10 fractions, dose sculpted to respect normal tissue 
tolerances) for newly metastatic patients presenting with three synchronous oligometastases (bone and 
or lymph nodes). Berkovic et al.[23]demonstrated that SBRT was able to defer palliative androgen 
deprivation therapy for a median of 38 months and was safe with no Grade 3 toxicity observed.  
Of note there are two ongoing multi-institutional trials using androgen deprivation and SBRT radiation for 
the bulk of the metastatic prostate cancer already but none thus far combining with xofigo to eradicate 
micrometastatic disease NRG BR001 A Phase 1 Study of Stereotactic Body Radiotherapy (SBRT) for the 
Treatment of Multiple Metastases and STOMP surveillance or metastasis-directed therapy for 
oligometastatic prostate cancer recurrence[24].In the multi-institutional NRG BR001 Phase 1 study, 
oligometastatic breast, lung, or prostate patients are eligible to receive radiation to ≤ 4 metastatic sites. 
For prostate in particular the continuation of androgen deprivation is allowed. The radiation doses are in 
the range of 10-15Gy per fraction for 3 to 5 days as compared to palliative radiation given in doses of 3Gy 
per fractions for 10 days. The Phase 1 portion of this trial for bone has already met accrual and results are 
pending. 
In the STOMP trial, prostate patients with oligometastatic recurrence of prostate cancer are eligible to 
receive SBRT[24].The trial is limited to SBRT alone without concurrent systemic treatment. It is a 
randomized Phase 2 study to see if there is benefit of SBRT versus active surveillance of patients with 

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oligometastatic prostate cancer. The hypotheses is that patients treated with SBRT will have a longer ADT 
free survival and longer time to initiation of long term androgen deprivation use. The trial delineates 
radiation dose guidelines for lymph node and bone metastases. The dose is 10Gy x 3 fractions building 
from prior studies of this same groups utilizing this SBRT radiation dose with concomitant androgen 
deprivation therapy[24]. Toxicities from this SBRT regimen were mild and of 50 patients treated, only 10 
patients had either Grade 1 or 2 toxicities[24]. The 50 patients had 70 metastatic lesions treated and local 
control of 100%; lesions included mostly bone and lymph nodes with only 2% visceral metastases; from 
2005-2012 the dose was 50Gy in 10 fractions and from 2012-2014 the dose was 30Gy in 3 fractions. Our 
study is limiting to lymph node and bone metastases using similar radiation dose guidelines of both the 
STOMP trial and the NRG BR001 trial. The STOMP trial has now been published and demonstrated that 
SBRT to multiple metastatic sites (three or less) is safe and does delay metastatic progression and thus 
initiation of androgen deprivation therapy (ADT) (Ost et al 2018)[14]. The median ADT-free survival was 
13 months for the observation/active surveillance group and 21 months for the metastasis-directed 
therapy group (either surgery, radiation or a combination)[14]. 
A recent National Cancer Database (NCDB) analysis of metastatic prostate cancer patients demonstrated 
that patients who received radiation to prostate primary had improved overall survival on both univariate 
and multivariate analysis[25]. On univariate analysis 5 year OS improved from 25% to 49% and 8yr OS 
estimates improved from 13% to 33%). Radiation dose over 65Gy was associated with improved overall 
survival consistent with reports of men with localized prostate cancer. Cho et al. [26]also demonstrated 
improved overall survival in metastatic prostate patients who received radiation to prostate primary in 
addition to ADT (3 yr OS increased from 43% to 69%) [26]. A large phase III trial of over 2000 patients, 
STAMPEDE, also showed improved survival with definitive radiation to the prostate primary in the subset 
of patients with limited metastatic disease (low burden metastatic burden) [27]. 3 year OS  in this limited 
metastatic disease subset of STAMPEDE increased from 73% to 81% with HR of 0.68 (p value of .0098)[27]. 
In the STAMPEDE trial limited metastatic disease was defined as <4 bone metastases and no visceral 
metastases (i.e. lung, liver metastases) [27]. Lymph nodes were not included in the metastatic definition 
(i.e. visceral disease always recorded as nonnodal and in STAMPEDE over 60% had lymph nodes N+ 
disease) [27]. There has also been a recent abstract of adding definitive prostate radiation (74Gy to 
prostate, 60Gy to lymph nodes) concurrent with Ra-223 but no SBRT (ADRRAD trial); recent abstract shows 
this regimen to be safe and early promising results on whole body MRI [28]. Also in our predecessor trial 
IRB# 05190, approximately 50% of patients on the trial had definitive prostate radiation (+/- close 
proximity lymph nodes) [10, 29]. Due to the recent literature, recent change in NCCN and Via Oncology 
guidelines and that our predecessor trial allowed definitive prostate radiation we are now allowing 
definitive radiation to the prostate prior to cycle 1 of this trial. 
Other earlier papers also analyzing large databases have demonstrated benefit of radical prostatectomy 
in men with metastatic prostate cancer[30-33]. We have been allowing radical prostatectomy prior to 
cycle 1 of this trial as well and will continue to allow patient choice of treatment for untreated prostate 
primary similar to our predecessor trial IRB #05190 [10, 29]. 
2.5 Bone Health Agents 
To optimize treatment with androgen deprivation therapy, Ra-223 and SBRT, we must minimize risk of 
adverse events. In particular, non-pathologic fractures are an area of concern. Patients on this study are 
required to take bone health agents (BHAs) including bisphosphonates or RANKL inhibitors, from the start 
of protocol therapy (approximately) until the participant’s testosterone levels are within the normal range 
or at the discretion of the PI.  

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The present study is a phase II trial on the use of Ra-223 with ADT and SBRT for metastatic castrate 
sensitive prostate cancer (mCSPC) patients. Each treatment agent on this study independently increases 
fracture risk. Ra-223 alone was shown to increase fracture risk in the REASURE study, a prospective trial 
on fracture risk in patients receiving Ra-223 monotherapy. For the Ra-223 cohort (n=36), 74 new 
fractures were identified in 20 patients (56%) at a median follow-up of 16.3 months,  while for the 
reference cohort (n=36), 16 new fractures were identified in 12 patients (33%) at a median follow-up of 
24 months [34]. Radiation therapy is also associated with a high incidence of fractures. A meta-analysis 
of 21 studies and 3929 patients with gynecologic cancers who received external beam radiation therapy 
found that pelvic insufficiency fractures occurred in 14% of patients, with 73.6% of fractures developing 
in the sacral bone or joint. The median time to fracture was 7.1 to 19 months post-radiation therapy 
[35]. The effect of ADT on fracture risk was described in a nationwide cohort study (n=144,670) in Korea, 
which showed that in patients with prostate cancer, ADT significantly increases the risk of newly 
developed fractures (HR, 1.815; 95% CI, 1.703–1.935; p < 0.0001) and osteoporosis (HR, 1.381; 95% CI, 
1.305–1.461; p < 0.0001) compared to those not receiving ADT, and this is positively correlated with the 
duration of ADT [36].  
Patients receiving androgen deprivation therapy (ADT) and Radium-223 (Ra-223) in combination face a 
significantly increased risk of non-pathological fractures. The phase 3 ERA 223 study on metastatic 
castrate resistant prostate cancer (mCRPC) patients was unblinded prematurely after an unplanned ad-
hoc analysis revealed significantly increased fracture rates with the addition of Ra-223 to treatment with 
abiraterone acetate and prednisone or prednisolone. While fractures of any grade occurred in 11% of 
patients receiving a placebo instead of Ra-223, this increased to 29% of patients for the group receiving 
Ra-223 [37]. 78% of all fractures occurred at uninvolved sites, not metastatic sites.  
BHAs have been shown to reduce the occurrence of fractures in this setting. On the ERA 223 study, the 
use of bone health agents (BHAs) was only allowed for patients who were on BHAs at baseline, which 
was around 40% of the study population. No patients were permitted to initiate BHA use while on study. 
They reported that in both the Ra-223 and placebo groups, patients on BHAs from baseline were 
associated with a lower fracture rate. For the Ra-223 group, fractures occurred in 15% of patients using 
BHAs, compared to 37% of patients not using BHAs. For the placebo group, fractures occurred in 7% of 
patients using BHAs, compared to 15% of patients not using BHAs [38].  
After the ERA223 trial reported the increased risk of fractures with the addition of Ra-223, the 
EORTC1333/PEACE III trial was amended to mandate that all patients must start using a BHA. This trial 
compared enzalutamide and Ra-223 to enzalutamide alone for mCRPC patients, and reported that when 
Ra-223 is combined with enzalutamide treatment, the risk of fracture significantly increases from 13% to 
33%. They found that when BHAs are used a minimum of 6 weeks before the first administration of Ra-
223, this risk is almost abolished [39]. The results of these studies necessitate BHA use in our present 
study, as Ra-223, ADT and SBRT are used in a combined treatment regimen. The need for BHA use is 
clearly demonstrated for mCRPC patients treated with ADT and Ra-223. BHAs like bisphosphonates and 
RANKL inhibitors are also indicated for use in mCSPC patients on ADT to prevent treatment-induced 
bone loss and resulting fractures at a dosage of 60 mg denosumab every 6 months or 5 mg zoledronic 
acid once per year, respectively [40]. Patients on this study will be required to take bisphosphonates or 
RANKL inhibitors to reduce the risk of fracture associated with Ra-223, ADT and SBRT.  

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2.6 Overview and Rationale of Study Design 
The SHARP study is a single-center open-label, Phase 2 clinical trial of stereotactic body radiation 
therapy (SBRT), hormone/androgen deprivation therapy (ADT) and radium Ra 223 dichloride for 
participants with newly diagnosed oligometastatic castration sensitive prostate cancer. 
Eligibility 
Participants will be adults diagnosed with metastatic prostate adenocarcinoma who have undergone full 
treatment at the primary prostate site. Participants will be chemotherapy naïve to metastatic sites, unless 
exposure occurred during treatment for primary disease.   
Oligometastic burden will be limited to a maximum of four lesions, consistent with a summary analysis 
demonstrating improved prognosis for SBRT in prostate cancer for participants with four of fewer lesions 
[22]. In addition, participants must have at least one bone lesion to increase benefit over any risk from the 
bone specific radium Ra 223 dichloride regimen.   
Participants must have at least one bone lesion and each non-visceral lesion (bone and lymph node) should 
not exceed more than 5 cm. In addition, participants may have one lung lesion (< 2cm); no liver lesions 
are permitted. 
Treatment program 
The treatment program is comprised of SBRT, administered over the first cycle, radium Ra 223 dichloride 
administered over 6 cycles, and concurrent standard of care ADT (luteinizing hormone-releasing hormone 
agonist-either leuprolide or goserelin, or LHRH antagonist degarelix or relugolix). Each treatment cycle is 
28 days. 
Participants will be receiving ADT for approximately 36 weeks as part of this study (can be started prior to 
consent) to increase radiosensitivity [23, 41]. Metastatic prostate cancer patients often present at COH 
having initiated standard of care ADT. Therefore, there is no benefit derived from monitoring patients 
during their initial single-agent standard of care ADT.   
Typically standard of care ADT is continued indefinitely however it is associated with side effects of fatigue, 
hot flushes, erectile dysfunction, muscle loss, osteoporosis and sometime “drug holidays” are given. Thus, 
ADT will be discontinued after a total of 36 weeks and participants will be monitored carefully. We 
hypothesize that some patients may achieve long-term remission off ADT, however upon disease 
recurrence ADT (and other appropriate standard treatment) will be resumed.  
Around initiation of protocol therapy, participants will also be required to take bisphosphonate or RANKL 
inhibitor bone health agents at the dose and schedule consistent with the treatment of bone metastases 
or prevention of osteoporosis. Participants will continue this regimen until they have reached testosterone 
recovery, or at the discretion of the PI.  
SBRT 
SBRT (dosing administered minimum every 40 hours from Day 1 over 7-21 days during Cycle 1). The dose 
of SBRT will be 9Gy x 3 fractions to bone metastases and 5Gy x 5 factions to lymph node metastases 
respecting normal tissues tolerances. Dose constraints will be similar to previous radiation therapy 
oncology group trials and multiple papers detailing stereotactic body radiation therapy (SBRT). Normal 
tissue constraints based on previous published multi-institutional trials and on the national physics 
guidelines set forth by AAPM task group 101 [42]. Primarily our dose constraints will be based on NRG-
BR001 and previous published RTOG trials: RTOG 0236, 0813, 0915, 0438, 0613. These other RTOG trials 

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already looked at safe SBRT doses for lung, liver, spine and bone metastases. Per previous established 
SBRT protocols each separate oligometastatic site will have its own separate isocenter. Of note ongoing 
SBRT trial STOMP dose escalates to 10Gy x 3 fractions but does not allow for the concurrent use of ADT or 
include radium Ra 223 dichloride [24]. NRG BR001 also dose escalates based on tumor metastasis site 
from 10Gy x 3 fractions to 15Gy x 3 fractions or 10Gy x 5 fractions if central structures and allows 
concurrent use of ADT (NCT02206334). Other published studies have documented efficacy of 9Gy x 3 
fractions and this is Dose Level -1 for the ongoing SBRT trials and thus we have chosen this as the starting 
SBRT dose level for the bone metastases. 
Patients with asymptomatic low volume locoregional recurrent disease will be allowed to enroll on this study after 
discussion with the PI. In the case where the low volume recurrence is amenable to SBRT, it will be included in the 
SBRT treatment. In the case where the low volume recurrence is not amenable to SBRT based on reirradiation risk, 
then we will follow these lesions with re-imaging scans and reassess at later time points for further local control, 
which will be allowed on study. Additionally, if these patients fail only at the untreated site (due to the untreated 
recurrence/disease not being amenable to SBRT) they will be censored in the primary efficacy analysis at that time. 
Patients with high risk disease in which salvage radiation to the prostate bed is recommended in the absence of 
lesions noted on scans will be allowed to enroll after discussion with the PI. In these cases, salvage radiation to the 
prostate bed may occur at the same time as the SBRT. 
Radium Ra 223 dichloride will be administered during ADT therapy based on the knowledge of general 
synergy between ADT and radiation therapies in the treatment of prostate cancer. Radium Ra 223 
dichloride has been developed as a treatment given concurrently with ADT therefore safety of that 
combination has been established. The purpose of radium Ra 223 dichloride therapy is to enhance 
anticancer effect against known oligo bone metastases required for eligibility for this study, but also 
treatment of likely invisible bone micrometastases. Laboratory tests will be monitored every 4 weeks and 
general guidelines for administration of Radium 223 will be followed. These include: for the 1st dose of 
Radium 223 baseline laboratory test need to be: Hgb ≥ 9.0 g/dL, ANC ≥ 1,500 cells/mm3, platelets ≥ 
100,000 cells/ mm3.  For subsequent infusions (2-6) there is no Hgb requirement, ANC ≥ 1,000 cells/ mm3, 
platelets ≥ 50,000 cells/ mm3.  
Up to 7 cycles of protocol therapy are planned in the absence of unacceptable toxicity or disease 
progression, whichever comes first. If one agent is discontinued due to toxicity, then the participant may 
continue to receive the other protocol therapy agent(s).  
In addition to capturing efficacy endpoints, participants will undergo follow-up up to 5 years to capture 
long term toxicities (e.g. secondary malignancies) due SBRT and/or radium Ra 223 dichloride.  
Efficacy 
Prostate-specific antigen (PSA) assessments will occur every cycle during protocol therapy and then every 
3 months during Response Follow-up to mimic the ongoing STOM trial [24]. Tumor evaluation will occur 
pre-SBRT and then at the post Ra-223 visit (post-6 doses of radium Ra 223 dichloride), and during Response 
Follow-up (every 6 months and at PSA progression).   
This study will assess response via PSA levels alone and also use combined PSA and tumor evaluations per 
the modified Prostate Cancer Working Group 2 criteria [43]. Time to treatment failure will be a primary 
efficacy endpoint. 
Correlative Tumor Studies 
Genomic alterations in prostate cancer are being extensively studied although majority of data pertains 
to metastatic castration resistant prostate cancers (mCRPC) and primary tumors, with relative scarcity of 
information regarding metastatic hormone sensitive sites. Approximately 90% of mCRPC patients harbor 

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clinically actionable molecular alterations. Alterations in androgen receptor (AR) signaling pathways, ETS 
genes, TP53, and PTEN are reported in about 40-60% of patients. Other genomic alterations 
includePIK3CA/B, RSPO, RAF, APC, β-catenin, and ZBTB16. Germline and somatic alterations in DNA repair 
genes gathered significant attention because of potential implications for sensitivity to PARP inhibitors 
and platin chemotherapy. 23% of mCRPC patients harbor DNA repair pathway aberrations (BRCA2, BRCA1, 
ATM) and 8% harbor germline findings [44]. Exploratory biomarker analysis on baseline pre-SBRT archival 
and fresh tissue will be performed. A prostate cancer biomarker panel (e.g. Foundation One platform) will 
be utilized to analyze genomic alterations in metastatic prostate cancer prior to development of castration 
resistance.  
Correlative Blood Studies 
The purpose of the blood correlatives of the study is to assess in-vivo effects of radiation on expression of 
proteins related immune suppression in patients with metastatic prostate cancer. Circulating immune cell 
populations and plasma levels of cytokines, chemokines and growth factors will be assessed. From this 
data, we will be able to determine the feasibility of conducting future first-in-human studies involving 
pathway-specific and novel immunotherapeutic agents for this disease site. 
Alkaline Phosphatase Normalization Studies 
Alkaline phosphatase levels will be monitored during the study. Increased serum alkaline phosphatase is 
associated with progression of bone metastases and may predict disease progression and death [21]. The 
protocol regimen may suppress bone metastases and lead to normalization of alkaline phosphatase levels 
at the end of protocol therapy in participants with elevated levels of alkaline phosphatase at baseline. 

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3.0 ELIGIBILITY CRITERIA 
Patient MRN  
Patient Initials (F, M, L): 
Participants must meet all of the following criteria on screening examination to be eligible to participate in the study: 
3.1 Inclusion Criteria 
Informed Consent and Willingness to Participate 
__1. Documented informed consent of participant and/or Legally Authorized Representative. 
__2. Agreement to provide archival primary or metastatic tumor tissue if available 
Age Criteria, Performance Status, and Life Expectancy 
__3. Age: ≥ 18 years 
__4. ECOG ≤ 2 (Appendix A) 
__5. Life expectancy > 12 months 
Nature of Illness and Treatment History 
__6. Histologic diagnosis of prostate adenocarcinoma.  
Pure small cell carcinoma will be excluded, however component of neuroendocrine /small 
cell differentiation will be allowed provided that adenocarcinoma constitutes majority of 
the tissue specimen. 
__7. Stage M1. See Appendix B. 
Metastatic disease can be documented by bone scan or computed tomography (CT) scan 
or MRI or PET/CT or the combination of these tests.  
__8. Up to 5 metastatic lesions: 
Must have at least 1 bone lesion, AND each non-visceral lesion should be less than 5 cm 
Visceral lesions will be limited to one lung lesion (< 2cm) or one lymph node; no liver lesions allowed. 
Lymph nodes allowed provided they are not in a field of prior radiation, and if amenable to SBRT (to 
be reviewed by PI). (note: locoregional recurrence is not considered a “visceral metastatic lesion”. 
This is discussed more below in #11) 
 
__9. Two lesions can be in close proximity (i.e. within 5cm of each other) if they meet radiation 
SBRT normal tissue toxicity requirements. 
__10. If have untreated primary prostate cancer: Must undergo debulking prostatectomy at 
discretion of treating urologist or definitive radiation therapy. Definitive radiation fields to include 
close proximity lymph nodes at discretion of treating radiation oncologist. Definitive radiation dose 
at discretion of treating radiation oncologist (see #14 below: for patients presenting with untreated 
prostate primary along with oligomets, ADT may begin concurrently with the definitive radiation, 
for a total of approximately 36 weeks duration) 
 
 

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Patient MRN  
Patient Initials (F, M, L): 
 
__11. If had prior treatment to the prostate primary (definitive radiation therapy or prostatectomy, 
and can include salvage radiation to the prostate bed +/- lymph nodes), no evidence of locally 
persistent or recurrent prostate cancer on digital rectal exam (DRE) OR imaging studies (CT or 
MRI). 
• Note: patients with asymptomatic low volume locoregional recurrent disease will be allowed to 
enroll on this study after discussion with the PI. In the case where the low volume recurrence is 
amenable to SBRT, it will be included in the SBRT treatment. In the case where the low volume 
recurrence is not amenable to SBRT based on reirradiation risk, then we will follow these lesions 
with re-imaging scans and reassess at later time points for further local control. Additionally, if 
these patients fail only at the untreated site (due to the untreated recurrence/disease not being 
amenable to SBRT) they will be censored in the primary efficacy analysis at that time. 
 
__12. Does not have castration resistant disease  
 
Castration resistance defined as progression of disease despite serum testosterone level 
of <50 ng/dL 
__13. PSA≥0.2 prior to start of androgen deprivation treatment 
PSA value:  
Date: 
__14. Patients will be receiving approximately 36 weeks of ADT as part of this trial. The 36 weeks of 
ADT may start prior to consenting to this study. The patient may join the study at any point of the 
36-week period of ADT treatment.  
 
Only Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist treatment is 
considered ADT; bicalutamide or other antiandrogens used alone do not count. 

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Patient MRN  
Patient Initials (F, M, L): 
__15. Patients must be willing to receive bisphosphonate or RANKL inhibitor bone health agents at 
the dose and schedule consistent with the treatment of bone metastases or prevention of 
osteoporosis, starting approximately from when the patient begins protocol therapy, until the 
patient’s testosterone reaches normal levels or at the discretion of the PI. Patients who are 
already on a bone health agent separate from the protocol may continue on this treatment 
regimen and will not be required to start treatment with an additional bone health agent. 
__16. Patients may have received prior hormone therapy at the discretion of the PI. Patients may 
have received prior targeted therapy in the context of definitive therapy.  
__17. Patients may have had one prior systemic non-chemotherapeutic treatment (i.e. 
immunotherapy, receptor tyrosine kinase inhibitor, antiangiogenic agent, differentiating agent) 
for recurrent or metastatic disease.  
__18. Must have refused standard of care treatment for metastatic disease 
__19. Recovered from all acute side-effects (except alopecia) related to previous systemic therapy 
Clinical Laboratory Criteria (To be performed within 14 days prior to Day 1 of protocol therapy) 
__20. ANC ≥ 1,500/mm3 
NOTE: Growth factor support is not permitted to normalize 
baseline ANC parameters, however subsequent growth factor 
administration is permitted as standard supportive care. 
ANC: 
Date: 
__21. Platelets ≥ 100,000/mm3 
NOTE: Transfusion of blood products are not allowed to normalize 
baseline blood parameters, however subsequent transfusions are 
allowed per standard supportive care guidelines. 
Plts: 
 
Date: 
__22. Hemoglobin (HgB) ≥9.0 g/dL 
NOTE: Transfusion of blood products are not allowed to normalize 
baseline blood parameters, however subsequent transfusions are 
allowed per standard supportive care guidelines 
HgB: 
Date: 
__23. Total serum bilirubin ≤ 2 x ULN 
ULN: 
Bil: 
Date: 
__24. AST ≤ 2.5 x ULN 
ULN: 
AST: 
Date: 
__25. ALT ≤ 2.5 x ULN 
ULN: 
ALT: 
Date: 
__26. Creatinine ≤2.5 mg/dL 
Serum Cr: 
Date: 
3.2 Exclusion Criteria 
Prior and/or concomitant therapies 
__1.  Prior Radium Ra 223 dichloride 
__2.  Prior or concomitant chemotherapy for metastatic or recurrent disease with the 
following exceptions: 
 
Prior chemotherapy for local primary disease is permitted. 

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__3.  Prior radiation to prior metastatic sites is allowed provided that it is controlled and the 
total number of metastatic lesions does not exceed 5. 
__4.  Concomitant radiation treatment to primary prostate site 
 
__5.  Bilateral orchiectomy. If unilateral orchiectomy, eligible if testosterone >50 ng/ml. 
Other illnesses or conditions 
__6.  Unstable medical comorbidities (i.e. uncontrolled cardiac comorbidities) 
__7.  Metastases that in the judgment of investigator-radiologist are not amenable to SBRT 
__8.  History of brain metastases or who currently have treated or untreated brain metastases 
__9.  Uncontrolled HIV infection 
__10.  Any other condition that would, in the Investigator’s judgment, contraindicate the 
patient’s participation in the clinical study due to safety concerns with clinical study 
procedures. 
Noncompliance 
__11.  Prospective participants who, in the opinion of the investigator, may not be able to 
comply with all study procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
4.0 PARTICIPANT ENROLLMENT 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values and/or to determine pre-
eligibility, even if the studies were done before informed consent was obtained. The informed consent 
process is to be fully documented (see Section 17.4), and the prospective participant must receive a copy 
of the signed informed consent document.  All screening procedures and their respective windows are 
detailed in Section 11.0, Study Activity Calendar. 
4.2 Participant Enrollment 
4.2.1 
COH DCC Availability and Contact Information 
Eligible subjects will be registered on the study centrally by the Data Coordinating Center (DCC) at City of 
Hope.   
Patient MRN  
Patient Initials (F, M, L): 

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DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday (except 
holidays). DCC contact information is as follows:  
o Phone: (626) 256-4673 ext. 83968 
o E-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
Designated study staff should call the DCC to verify current dose level (See Table 5.2), slot availability, and 
to reserve a slot for a specific prospective subject.  Slots can only be held for a limited time.   
Eligible subjects must be registered prior to start of protocol therapy. Issues that would cause treatment 
delays should be discussed with the Principal Investigator. If a subject does not receive protocol therapy 
following registration, the subject’s registration on the study may be canceled after discussion with the PI. 
The Data Coordinating Center should be notified of cancellations as soon as possible. 
4.2.3 
Registration Process  
To register a participant the subsequent procedure is to be followed: 
1. The study team should contact the DCC via telephone or email to provide notification regarding 
the pending registration and communicate desired timeline of the registration, especially if it must 
be completed promptly to meet the registration window. 
2. The protocol nurse or CRC will email a copy of the following documents to the DCC: 
o Completed eligibility checklist (printed from Section 3.0 of the protocol) 
o Signed Informed Consent  
o Signed subject’s bill of Rights  
o Signed HIPAA authorization form and  
o Provide copies of source documentation only if not readily available as a finalized record 
in the COH Electronic Medical Record (EMR).  
3. After having received all transferred documentation, the DCC will complete the review the 
documents to verify eligibility, working with the study team as needed to resolve any missing 
required source elements. A participant failing to meet all protocol eligibility requirements will 
not be registered. 
4. Once eligibility has been confirmed, DCC staff will register the participant by: assigning a subject 
accession number, register the subject on study centrally into a COH clinical trials management 
system (e.g. MIDAS), and enter the subject into the eCRF system, Medidata RAVE. 
5. Once registration has been completed, DCC staff will send a Confirmation of Registration Form 
within 24 hours, including the participant study number and cohort assignment (dose level or 
expansion cohort) to:  
o The site study team: Principal Investigator, treating physician, protocol statistician, 
protocol nurse, CRC and COH IDS Pharmacy. 
o the COH sponsor team designees 
4.3 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
The DCC is to be notified of all participants who sign consent but do not meet eligibility criteria or do not 
initiate protocol therapy.  

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5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
This is a single-center open-label, Phase 2 clinical trial of radium Ra 223 dichloride in combination with 
standard of care androgen deprivation therapy (ADT) and stereotactic body radiation therapy (SBRT) for 
participants with metastatic castration sensitive prostate cancer (Section 5.3). 
 
Treatment will be administered in an outpatient basis. 
SBRT and radium Ra 223 dichloride will be administered in 28 day treatment cycles (Section 5.2). Up to 7 
cycles of protocol therapy is planned in the absence of unacceptable toxicity or disease progression, 
whichever comes first. If one agent is discontinued due to toxicity, then the participant may continue to 
receive the other protocol therapy agent(s). 
While the participant is on protocol therapy, they will receive bisphosphonate or RANKL inhibitor bone 
health agents at the dose and schedule consistent with the treatment of bone metastases or prevention 
of osteoporosis, until their testosterone levels are within the normal range (>50 ng/dL) or at the discretion 
of the PI.  
OR relugolix 

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Participants who end protocol therapy will undergo follow-up (Section 5.9).  Windows for all assessments 
and treatments are detailed in Section 11.0. 
5.2 Cycle Definition 
In the absence of delay due to toxicity, each treatment cycle lasts 28 days. 
Cycle 1 Day 1 is defined by the administration of SBRT. 
Cycles 2-7 Day 1 is defined by the administration of radium Ra 223 dichloride. 
Post Ra-223 is defined as approximately 28 days post-last dose of radium Ra 223 dichloride. 
 
5.3 Treatment Plan 
The treatment plan is as follows (Table 5.3). Participants must already have received at least 28 days of 
ADT (leuprolide OR goserelin OR degarelix OR relugolix) prior to initiating Cycle 1 Day 1 SBRT. While on 
protocol therapy, participants must also receive bisphosphonate or RANKL inhibitor bone health agents 
at the dose and schedule consistent with the treatment of bone metastases or prevention of osteoporosis, 
until their testosterone levels reach the normal range or at the discretion of the PI.  
Stopping rules may be implemented if there is unacceptable toxicity. For further details see Section 13.0 
Table 5.3 Treatment Regimen and Schedule 
Agent/Therapy and  
Route of Administration  
Dose 
Timing of administration and 
planned duration  
Stereotactic Body Radiation Therapy (SBRT) 
via  
External Beam Radiation via TrueBeam Stx 
9Gy x 3 fractions (bone) 
5Gy x 5 fractions (lymph node) 
10Gyx5 (lung) 
 
Cycle 1 
Day 1,  then  dosing administered 
minimum every 40 hours over 7 to 21 
days during Cycle 1 
Radium Ra 223 dichloride 
via  
Slow IV over 1 minute 
55 kBq/kg 
Cycles 2-7 
Day 1 of each 28-day cycle 
Leuprolide OR goserelin OR degarelix OR 
relugolix 
Per package insert/ investigator discretion 
 
Starting at least 4 weeks prior to 
SBRT and continuing for a total of 36 
weeks as part of regimen on protocol 
5.4 Agent Administration 
5.4.1 
Androgen deprivation therapy 
Luteinizing hormone-releasing hormone (LHRH) agonists consisting of either leuprolide OR goserelin OR 
LHRH antagonist degarelix OR relugolix will be administered per package insert and investigator discretion.   
Participants will receive in total 36 weeks of therapy with a LHRH agonist/antagonist; starting at least 28 
days prior to initiating Cycle 1 Day 1 stereotactic body radiation therapy.  
There is no requirement that the same LHRH agonist/antagonist (whether leuprolide or goserelin or 
degarelix or relugolix) be administered for the duration of the study. 
Dose delay guidelines are described in Section 6.3. 

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5.4.2 
Stereotactic body radiation therapy (SBRT) 
Participants must meet criteria in Section 6.1 to initiate SBRT on Cycle 1 Day 1. 
SBRT will be administered by a trained radiation oncologist. Radiation therapy will initiate at least 28 days 
following initiation of leuprolide OR goserelin OR degarelix OR relugolix. Participant dosing is described in 
Table 5.3. 
Participants will receive 3 or 5 fractions as determined by the location of the metastases to be irradiated 
during Cycle 1. There should be a minimum of 40 hours between treatments for an individual metastasis.  
For supportive care guidelines refer to Section 5.9. 
For administration details refer to Section 9.3. For dose modification refer to Section 6.3. 
5.4.3 
Radium Ra 223 dichloride 
Participants will receive 6 cycles of Radium Ra 223 dichloride following completion of SBRT.  
Participants must meet criteria in Section 6.2 to receive the first dose of radium Ra 223 dichloride.  
Radium Ra 223 dichloride will be administered as a slow bolus intravenous injection over 1 minute by a 
trained physician.  
The volume of radium Ra 223 dichloride to be administered to a given participant should be calculated 
using the: 
o Participant’s body weight (kg)- calculated within 30 days of the dosing day 
o Dosage level 55kBq/kg body weight 
o Radioactivity concentration of the product (1,100 kBq/mL; 30 microcurie/mL) at reference date 
o Decay correction factor to correct for physical decay of Radium Ra 223 dichloride 
 Radium-223 is an alpha particle emitter with a physical t½ of 11.4 days. 
 
Before administration of radium Ra 223 dichloride, the participant must be well hydrated; the 
participant should be instructed to drink ad libitum.  
For additional information regarding administration and preparation refer to Section 9.1.  
Prophylactic treatment for nausea and vomiting is not recommended. For supportive care guidelines 
refer to Section 5.9. 
For dose delays due to treatment-related toxicity refer to Section 6.2. 
5.5 Assessments and Special Monitoring 
For a detailed list of all study procedures including timing and windows, see Section 11.0. 
Note: Protocol therapy should be administered on Day 1 of each cycle after all procedures/safety 
assessments have been completed. 
It may be necessary to perform study procedures at unscheduled time points if deemed clinically 
necessary by the investigator. 

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5.5.1 
Special Monitoring 
Gastrointestinal AEs 
 Radium Ra 223 dichloride increases AEs such as diarrhea, nausea, and vomiting, which 
may result in dehydration. Constipation has also been reported in participants receiving 
radium Ra 223 dichloride. 
 Participants should be educated to report signs of dehydration, hypovolemia, urinary 
retention or renal insufficiency/failure. 
Secondary Malignant Neoplasms 
 Treatment with radium-223 dichloride contributes to a patient’s overall long-term 
cumulative radiation exposure.  
 Long-term cumulative radiation exposure may be associated with an increased risk of 
cancer and hereditary defects. 
 Monitor for incidence of osteosarcoma or other secondary neoplasms. 
5.6 Criteria for Removal from Protocol Therapy 
Participants will receive protocol therapy until one of the following criteria are met: 
o Disease progression despite castration levels of testosterone < 50 ng/dL 
o Completion of 7 cycles of protocol therapy 
o Participant is deemed intolerant to protocol therapy because of toxicity, despite dose 
modification/ delay  
 Note: Participants may continue to receive ADT as clinically indicated and per investigator 
discretion if the other study agents are discontinued. 
o Withdrawal of consent for future protocol therapy (See Section 17.5) 
o General or specific changes in the participant's condition that render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
Once participants meet criteria for removal from protocol therapy, the participant should then proceed 
to End of Treatment assessments. 
Documentation of the reason for discontinuing protocol therapy and the date effective should be made 
in the Electronic Health Record (EHR) and appropriate eCRF. 
5.7 Follow-Up 
After End of Treatment assessments, all participants will enter follow-up for a maximum of 5 years. This is 
comprised of: 
o Response Follow-up- for those who have yet progress 
o Long-term Follow-up- for all participants who have progressed OR completed Response Follow-
Up for survival and long-term toxicities. This follow-up will be performed typically via medical 
record review. 
Assessment time points and windows are detailed in Section 11.0. 

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5.8 Duration of Study Participation 
The reason(s) for discontinuing study participation should be documented and may include: 
o Completion of study activities (treatment and follow-up) 
o Withdrawal of consent (See Section 17.5) 
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative 
reasons 
The reason for study completion and associated date must be documented in the source documentation 
and the study-specific case report form (CRF). The participant’s status is to be modified in the COH CTMS 
once the participant completes the study.  
5.9 Supportive Care, Prohibited Medications and Concomitant Therapy 
If concomitant therapy must be added or changed, including over-the-counter medications or alternative 
therapies, the reason and name of the agent/therapy should be reported in the eCRF and recorded in the 
EHR. 
5.9.1 
Prohibited Therapy 
The following therapies are prohibited from Cycle 1 Day 1 until completion of End of Treatment visit 
procedures.  
o Other investigational therapy/agent 
o Other anticancer agents 
o Antiandrogen agents (bicalutamide, flutamide)   
o EXCEPTION: patients that enrolled on the study with asymptomatic low volume locoregional recurrent 
disease which was not amenable to SBRT at the time of enrollment will be followed with re-imaging scans. 
They will be reassessed at later time points during the study for further local control if needed.  
5.9.2 
Supportive Care 
With the exception of prohibited therapies (see Section 5.9.1), participants should receive prophylactic or 
supportive care as clinically indicated per institutional policies.  
Treatment /prevention of osteoporosis 
 Treatment with bisphosphonates or RANK Ligand inhibitors (e.g. denosumab) is required 
 Calcium supplementation, Vitamin D are also highly encouraged. 
 For the treatment /prevention of osteoporosis doses and schedule must be consistent 
with the treatment or prevention of osteoporosis.  
Non-pathological fractures 
 If in weight-bearing bones follow dose delay guidelines in Section 6.3.  
Pathological fractures 
 Pathological fractures may occur as the result of either progressive disease or increased 
physical activity associated with significant pain palliation.   
 Treat in a manner that attempts to maintain the best functional status and quality of life.  

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Erythropoietin-stimulating factors, granulocyte colony stimulating factors 
 Allowed 
Prophylactic treatment for gastrointestinal AEs 
 Prophylactic treatment for nausea and vomiting not recommended; however, anti-
emetic drugs may be used when needed. 
− 
Laxative can be continued as concomitant medication, but start of prophylactic 
treatments before radium Ra 223 dichloride injection is not recommended. Laxative 
may be used when needed. 
 No prophylactic treatment for diarrhea is recommended. 
Surgery 
 If surgery is required, the patient should continue with study treatment, if this is 
considered safe in the treating Investigator’s opinion.  The surgeon needs to be notified 
that the patient has been given radioactive drug, and needs to follow the guidelines for 
radioactive protection.   

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6.0 CRITERIA FOR INITIATINGSBRT AND RADIUM RA 223 DICHLORIDE & DOSE DELAY GUIDELINES 
6.1 Criteria to START SBRT (Cycle 1 Day 1) 
Table 6.1 details criteria participants must meet to initiate SBRT. 
Table 6.1 Cycle 1 Day 1 SBRT Administration Criteria 
Criteria to be met in order to START SBRT 
Action if criterion to the RIGHT is NOT met 
1. ANC ≥ 1,500/mm3 
NOTE:Growth factor supportis not permitted to normalize 
baseline ANC parameters, however subsequent growth 
factor administration is permitted as standard supportive 
care. 
Permanently discontinue protocol therapy if 
unable to initiate SBRT 28 (+ 7) days post-1st 
dose of ADT (time constraint exception is in 
patients who started ADT concurrent with 
radiation tx or surgery). 
ADT may continue as a non-protocol 
therapy if clinically indicated.  
2. Platelets ≥ 100,000/mm3 * 
3. Hgb ≥ 9.0 g/dL* 
*NOTE:Transfusion of blood products are not allowed to 
normalize baseline blood parameters, however 
subsequent transfusions are allowed per standard 
supportive care guidelines. 
4. Not experienced ≥ recurrent Grade 3 ADT-related AE 
Permanently discontinue protocol therapy. 
5. ADT related AEs ≤ Grade 2 
Permanently discontinue protocol therapy if 
unable to initiate SBRT 28 (+7) days post-1st 
dose of ADT (time constraint exception is in 
patients who started ADT concurrent with 
radiation tx or surgery). 
ADT may continue as non-protocol therapy 
if clinically indicated. 
6. Absence of toxicity not present at baseline that might 
adversely affect participation or results in a reasonable 
delay prior to initiating SBRT 
Permanently discontinue protocol therapy. 
ADT may continue as non-protocol therapy 
if clinically indicated. 

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6.2 Criteria to START Radium Ra 223 Dichloride (Cycle 2 Day 1) 
Table 6.2 details criteria participants must meet to initiate radium Ra 223 dichloride therapy. 
Table 6.2 Cycle 2 Day 1 Radium Ra 223 Dichloride START Criteria 
Criteria to be met in order to START 1st dose of radium Ra 223 
dichloride  
Action if criterion to the RIGHT is NOT met 
1. ANC ≥ 1,500/mm3 
NOTE:Growth factor supportis not permitted to normalize 
baseline ANC parameters, however subsequent growth 
factor administration is permitted as standard supportive 
care. 
Delay initiating radium Ra 223  dichloride 
until criterion is met. 
Permanently discontinue radium Ra 223  
dichloride if unable to initiate within 28 
days of planned dose. 
2. Platelets ≥ 100,000/mm3 * 
3. Hgb ≥ 9.0 g/dL* 
* NOTE:Transfusion of blood products are not allowed to 
normalize baseline blood parameters, however 
subsequent transfusions are allowed per standard 
supportive care guidelines 
4. Not experienced ≥ recurrent Grade 3 treatment-related 
AE 
Permanently discontinue protocol therapy. 
5. Treatment related AEs ≤ Grade 2 
Delay initiating radium Ra 223 
dichlorideuntil resolution of treatment-
related AE to ≤ Grade 2. 
Permanently discontinue radium Ra 223  
dichloride if unable to initiate within 28 
days of planned dose. 
6. Absence of unrelated toxicity not present at baseline that 
might adversely affect participation or results in a 
reasonable delay prior to initiating radium Ra 223 
dichloride 
Permanently discontinue radium Ra 223 
dichloride  
OR 
Delay initiating until criterion is met; 
permanenetly discontinue radium Ra 223  
dichloride if unable to initiate within 28 
days of planned dose. 

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6.3 Dose Delay Guidelines 
o Toxicities will be graded using the NCI CTCAE v 5.0. 
o Baseline values are from the last values obtained prior to treatment. 
o If one agent is permanently discontinued, then the participant may continue with the other 
agent(s).  
o SBRT 
 If there is concern of toxicity to critical normal structures the SBRT dose will be sculpted 
according to national guidelines to conform to limit risk of toxicities to normal structures to ≤ 
5%. 
 If a participant does not complete the SBRT segment as planned, then that participant may 
receive the other study agent(s)as clinically indicated. 
o Radium Ra 223 dichloride and ADT 
 Only dose delays are permitted  
 See Table 6.3 for dose delay guidelines 
 Participants may continue to receive ADT as clinically indicated and per investigator 
discretion if radium Ra 223 dichloride is discontinued. 
Table 6.3 Dose Delay Guidelines 
Toxicity 
Agent most likely 
attributed to 
toxicity 
Treatment Delay Guidelines 
Hematologic  
Neutropenia (ANC) Grade 3/4 
G3: 500- <1000/mm3 
G4: <500/mm3 
Radium Ra 223 
Dichloride 
First occurrence 
 
Hold the planned dose 
 
Resume when toxicity resolves to ≤ Grade 2 AND> 14 
days have passed from growth factor support 
discontinuation 
 
Permanently discontinue study agent if the planned 
dose is delayed > 28 days. 
Second occurrence 
 
Permanently discontinue study agent. 
Febrile neutropeniaGrade 3/4 
G3: ANC <1000/mm3 with a single 
temperature of >38.3 degrees 
C (101 degrees F) or a 
sustained temperature of 
>=38 degrees C (100.4 
degrees F) for more than one 
hour. 
 
G4: Life-
threateningconsequences; 
urgentintervention indicated 
Radium Ra 223 
Dichloride 
First occurrence 
 
Hold the planned dose  
 
Resume when ANC resolves to ≤ Grade 2 AND> 14 
days have passed from growth factor support 
discontinuation 
 
Permanently discontinue study agent if the planned 
dose is delayed > 28 days. 
Second occurrence 
 
Permanently discontinue study agent. 

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Toxicity 
Agent most likely 
attributed to 
toxicity 
Treatment Delay Guidelines 
Thrombocytopenia Grade 3/4 
G3: 25,000-<50,000/mm3 
G4: <25,000/mm3 
Radium Ra 223 
Dichloride 
First occurrence 
 
Hold the planned dose  
 
Resume when toxicity resolves to ≤ Grade 2 AND> 14 
days have passed from last platelet transfusion 
 
Permanently discontinue study agent if the planned 
dose is delayed >28 days. 
Second occurrence 
 
Permanently discontinue study agent. 
Other Non-hematological toxicities 
≥ Grade 3 
Leuprolide 
Goserelin 
Degarelix 
Relugolix 
First occurrence 
 
Hold next planned dose until toxicity resolves to ≤ 
Grade 2. 
 
Permanently discontinue ADT if the planned dose is 
delayed > 42 days. 
− 
Exception: if testosterone level remains in the 
castrated state (<50 ng/dL), then participantcan 
remain on the study following consultation with 
the Study PI or designee. 
Second occurrence 
 
Permanently discontinue protocol therapy. 
≥ Grade 3 
Radium Ra 223 
Dichloride 
First occurrence 
 
Hold next planned dose until toxicity resolves to ≤ 
Grade 2. 
 
Permanently discontinue study agent if the planned 
dose is delayed > 28 days. 
Second occurrence 
 
Permanently discontinue protocol therapy. 
Non-hematological toxicities- UNRELATED 
Any Grade 
UNRELATED 
 
Maintain treatment with study agent/ regimen. 
 
Interruption of protocol therapy is permitted if the 
investigator consults with the Study PI to determine 
that this is in the best interest of the participant. 
 

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7.0 ADVERSE EVENTS LIST 
7.1 Leuprolide 
The expected toxicities for leuprolide are as follows (*signifies ≥ 20%; no asterisk signifies 3-20%, and † 
signifies <3%): 
Cardiac 
Trachycardia, bradycardia, angina, palpitation, arrthythmia†, atrial 
fibrillation†, congestive heart failure†, syncope† 
Gastrointestinal  
Nausea*, vomiting*, altered bowel function, ulcer, intestinal obstruction, 
constipation, diarrhea, gastroenteritis/colitis, gastrointestinal hemonrrage† 
General Disorders and 
Administration Site 
Edema 
Immune system 
Flu-like syndrome, allergic reaction† 
Infections and infestations 
Infection 
Investigations (excluding 
hematological labs) 
BUN increase, creatinine increase, bicarbonate decrease, 
hyperphosphatemia, hyperuricemia, hypoalbuminemia, hypoproteinemia 
Metabolism and Nutrition 
Dehydration, hyperlipidemia, weight gain/loss 
Musculoskeletal and Connective 
Tissue  
Weakness, bone pain, joint disorder, myalgia, paresthesia 
Nervous system 
Headache*, pain*, insomnia*,nervousness, anxiety, confusion, fatigue, 
dizziness/vertigo, seizure† 
Psychiatric 
Depression* 
Renal and urinary  
Urinary disorders, bladder spasm, urinary retention 
Respiratory, Thoracic and 
Mediastinal 
Emphysema, epistaxis, pleural effusion, pulmonary edema, dyspnea, cough 
Skin and Subcutaneous Tissue  
Skin reaction, ache, alopecia, brusing, pruritus, rash 
Vascular 
Hyper/hypotension, deep thombophlebitis 
7.2 Goserelin 
The expected toxicities for goserelin are as follows (* signifies ≥ 20%; no asterisk signifies 3-20%, and † 
signifies <3%): 
Blood and lymphatic (including 
hematological labs) 
Anemia 
Cardiac 
Congestive heart failure, palpitation, trachycardia, cerebrovascular 
accident†, myocardial infarction† 
Eye 
Amblyopia, dry eyes 
Gastrointestinal  
Anorexia, appetite increase, nausea, abdominal pain, constipation, diarrhea, 
dyspepsia, flatualence, ulcer, vomiting, xerostomia 
General Disorders and 
Administration Site 
Sweating*, tumor flare*, injection site reaction, volice alteration, fever 

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Infections and infestations 
Infection, flu syndrome 
Investigations (excluding 
hematological labs) 
Weight gain/loss 
Metabolism and Nutrition 
Hyperglycemia 
Musculoskeletal and Connective 
Tissue  
Bone mineral density decrease*, weakness, arthralgia, back pain, 
hypertonia, bone/joint pain, leg cramps, myalgia, paresthesia 
Nervous system 
Headache*, dizziness, pain 
Psychiatric 
Anxiety, depression, insomnia, emotional lability 
Renal and urinary  
Urinary tract infection, urinary obstruction, urinary frequency 
Vascular 
Hypertension, vasodilation 
7.3 Degarelix 
The expected toxicities for degarelix are as follows (* signifies ≥ 20%; no asterisk signifies 3-20%, and † 
signifies <3%): 
Cardiac 
Hot flashes* 
Endocrine 
Gynecomastia†, testicular atrophy† 
Gastrointestinal  
Diarrhea†, nausea†, constipation 
General Disorders and 
Administration Site 
Injection site pain/erythema*, injection site swelling/induration/nodule, 
fatigue, chills, fever†, night sweats†, hyperhidrosis† 
Infections and infestations 
Urinary tract infection 
Investigations (excluding 
hematological labs) 
Elevation in transaminases/GGT 
Metabolism and Nutrition 
Weight gain 
Musculoskeletal and Connective 
Tissue  
Back pain, arthralgia 
Nervous system 
Asthenia†, dizziness†, headache†, insomnia† 
Urologic 
Erectile dysfunction† 
Vascular 
Hypertension 
7.4  Relugolix 
The expected toxicities for relugolix are as follows (* signifies ≥ 20%; no asterisk signifies 3-20%, and † 
signifies <3%): 
Vascular  
Hot flush*, stroke† 
Muscoloskeletal and Connective 
Tissue 
Musculoskeletal pain*, fracture† 
General 
Fatigue*  
 Gastrointestinal  
Diarrhea, constipation, abdominal pain† 

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Investigations (excluding 
hematological labs) 
Increased glucose*, increased triglycerides*, increased alanine 
aminotransferase*, increased aspartate aminotransferase, increased 
transaminases† 
Cardiac 
Myocardial infarction†, arrhythmia†, atrioventricular block†, cardiac 
failure† 
Blood and lymphatic 
Decreased hemoglobin*, hemmorrhage† 
Renal 
Urinary tract infection†, acute kidney injury† 
Respiratory 
Pneumonia† 
7.5 Stereotactic body radiation therapy 
Adverse events related to radiation therapy are depending on location of the tumor (i.e. spine metastases 
in thoracic spine has more risk to lung than spine metastases in pelvis or lumbar spine. As with any 
radiation there is a risk of secondary malignancies but usually reported 10+ years after the initial radiation 
treatment course. 
o Spine Metastases 
 Radiation Myelitis: paresthesia, sensory changes, motor weakness, permanent motor or 
sensory injury. Injury can be permanent and lead to loss of neurological function. 
 Compression fracture of treated spine metastases/vertebra 
 Radiation Esophagitis 
 Radiation Laryngitis/Pharyngitis 
 Tracheal Injury 
 Radiation Pneumonitis 
o Bone/osseous metastases 
 Common> 10%:  
− Skin and Subcutaneous Tissue: erythema, desquamation, alopecia 
 Less common 1-10%:  
− General Disorders and Administration Site: pain, edema,  
− Nervous System: neuralgia  
− Injury, poisoning and procedural complications: fracture  
o Abdominal/pelvic lymph node metastases 
 Common> 10*:  
− Blood and lymphatic: Change in blood counts 
− General Disorders and Administration Site: Fatigue 
− Skin and Subcutaneous Tissue: skin irritation, redness, itchiness,  
 Less common 1-10%:  
− Gastrointestinal: nausea, vomiting, diarrhea 
 Uncommon but serious< 1%:  
− Hepatic: liver failure 
− Gastrointestinal: bowel perforation requiring emergent surgery 

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7.6 Radium Ra 223 dichloride 
7.6.1 
Radiation exposure: 
In general, administration of radioactive drugs involves a potential risk for third parties because of 
radiation from the participant and possible contamination by spilling urine or feces. When radium Ra 223 
dichloride has been injected intravenously into a participant, the risk for external radiation exposure to 
third parties is extremely low, because of the short range of theα particles (<100 μm) and the low portion 
of β and γ radiation. For these reasons, the product can be administered on an out-patient basis.  
To minimize the risk of contamination, participants and his caregivers will receive oral and written 
instructions regarding hygiene precautions to abide by after receiving radium Ra 223 dichloride. 
7.6.2 
Side-effects: 
The expected toxicities for radium Ra 223 dichloride are as follows (no asterisk signifies ≥ 10%; * signifies 
1-10%, and † signifies <1%): 
Blood and lymphatic (including hematological labs) 
Anemia, lymphocytopenia, leukopenia, 
thrombocytopenia, neutropenia 
Gastrointestinal  
Nausea, diarrhea, vomiting  
General Disorders and Administration Site 
Peripheral edema, injection site reaction* 
Metabolism and Nutrition 
Dehydration* 
Neoplasms benign, malignant and unspecified (incl 
cysts and polyps) 
Treatment related secondary malignancy† 
Renal and urinary  
Renal failure and impairment* 
 

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8.0 DATA & SAFETY MONITORING, ADVERSE EVENT AND UNANTICIPATED PROBLEM REPORTING 
8.1 COH Data and Safety Monitoring Plan 
Definition of Risk Level 
This is a Risk Level 3 study as defined in the City of Hope Institutional Data and Safety Monitoring Plan. 
This determination was made because this study was deemed IND exempt by the FDA. 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) is responsible for monitoring the data and safety of this study.  
The PMT consists of the Principal Investigator (PI), Biostatistician, Research Protocol Nurse, and Clinical 
Research Coordinator.   
The PMT is required to submit periodic status reports (i.e., the PMT Report) according to the frequency 
prescribed in the City of Hope Institutional Data and Safety Monitoring Plan.  Important decisions made 
during PMT meetings (i.e., dose de-escalation, etc.) only need to be noted in the PMT Report submitted 
to the Data and Safety Monitoring Committee (DSMC). 
Adverse Events and Serious Adverse Events 
The PI or their designee will be responsible for determining the event name, assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events. 
Adverse Event (AE) - An adverse event is any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to be related to the 
protocol intervention.  
Reporting Non-serious Adverse Events – Adverse events will be collected after the patient is given the 
study treatment or any study related procedures.  Adverse events will be monitored by the PMT.  Adverse 
events that do not meet the criteria of serious OR are not unanticipated problems will be reported only in 
the PMT Report. 
Serious Adverse Event (SAE) [Modified from the definition of unexpected adverse drug experience in 21 
CFR 312.32] - defined as any expected or unexpected adverse events that result in any of the following 
outcomes: 
o Death 
o Is life-threatening experience (places the subject at immediate risk of death from the event as it 
occurred) 
o Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of existing 
hospitalization 
o A persistent or significant disability/incapacity 
o A congenital anomaly/birth defect 
o Secondary malignancy 
o Any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias of convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse). 

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Reporting Serious Adverse Events - begins after study treatment or any study related procedures.  All 
SAEs occurring during this study, whether observed by the physician, nurse, or reported by the patient, 
will be reported according to the approved City of Hope’s Institutional policy.  Serious Adverse Events that 
require expedited reporting will be submitted electronically using iRIS. 
Adverse Event Name and Severity 
The PI will determine the adverse event name and severity (grade) by using the most current CTCAE 
version 5.0. 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event, OR is an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
Unexpected Adverse Event [21 CFR 312.32 (a)] – An adverse event is unexpected if it is not listed in the 
investigator’s brochure and/or package insert; is not listed at the specificity or severity that has been 
observed; is not consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
Adverse Event Attribution 
The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
o Definite - The AE is clearly related to the investigational agent or study procedure and unrelated 
to any other cause. 
o Probable - The AE is likely related to the investigational agent or study procedure and unlikely 
related to other cause(s). 
o Possible -The AE may be related to the investigational agent or study procedure and may be 
related to another cause(s). 
o Unlikely -The AE is doubtfully related to the investigational agent or study procedure and likely 
related to another cause(s). 
o Unrelated -The AE is clearly not related to the investigational agent or study procedure and is 
attributable to another cause(s). 
Deviations and Unanticipated Problems 
Deviation - A deviation is a divergence from a specific element of a protocol that occurred without prior 
IRB approval.  Investigators may deviate from the protocol to eliminate immediate hazard(s) for the 
protection, safety, and well-being of the study subjects without prior IRB approval.  For any such deviation, 
the PI will notify the COH DSMC and IRB within 5 calendar days of its occurrence via iRIS in accordance 
with the Clinical Research Protocol Deviation policy. 
Single Subject Exception (SSE) 
An SSE is a planned deviation, meaning that it involves circumstances in which the specific procedures 
called for in a protocol are not in the best interests of a specific patient.  It is a deviation that is anticipated 
and receives prior approval by the PI and the IRB.  The SSE must be submitted as a “Single Subject 
Exception Amendment Request” via iRIS in accordance with IRB guidelines and the Clinical Research 
Protocol Deviation policy. An IRB approved SSE does not need to be submitted as a deviation to the DSMC. 

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Unanticipated Problem (UP) – Any incident, experience, or outcome that meets all three of the following 
criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given the following: a) the research 
procedures described in the protocol-related documents such as the IRB approved research 
protocol, informed consent document or Investigator Brochure (IB); and b) the characteristics of 
the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcomes may have been caused by the 
drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm) than previously known or recognized. 
Any UP that occurs during study conduct will be reported to the DSMC and IRB in accordance with the City 
of Hope’s Institutional policy using iRIS.   
8.2 Exceptions to Expedited Reporting 
The following AEs DO NOT require an expedited report UNLESS results in hospitalization (≥ 24 hours). 
However, they still must be reported through the routine mechanism in the eCRFs. 
CTCAE SOC  
List of Grade 1-2 Adverse Events  
Blood and lymphatic (including 
hematological labs) 
Leukopenia, neutropenia, anemia 
Eye 
Vision disorder 
Gastrointestinal  
Nausa, vomiting, diarrhea, constipation, dyspepsia, flatualence, 
General Disorders and 
Administration Site 
Fatigue, edema 
Metabolism and Nutrition 
Decreased appetite 
Nervous system 
Dizziness,  dysgeusia, fatigue, headache 
Investigations 
Blood testosterone decreased,  ALT/AST increase 
Skin and Subcutaneous Tissue  
Skin reaction, alopecia, bruising, pruritus, rash 
8.3 Reporting to Bayer 
The PI or designee will forward reports to Bayer in a timely fashion per below stated guidelines. 
1. Expedited reports that meet Unanticipated Problem (UP) criteria will be promptly forwarded to 
Bayer within 24 hours of being aware of the event via email: DrugSafety.GPV.US@bayer.com. 
2. Aggregate safety information will be reported to Bayer at time of COH DSMC report. 

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9.0 AGENT INFORMATION 
9.1 Radium Ra 223 dichloride 
Radium Ra 223 dichloride is indicated for treatment of patients with castration-resistant prostate cancer, 
symptomatic bone metastases and no known visceral metastatic disease. 
For additional details refer to the Investigator Brochure. 
9.1.1 
Other Name 
Xofigo® 
9.1.2 
Description 
Type of radiotherapeutid agent: 
Alpha particle-emitting pharmaceutical 
Formula: 
223RaCl2 
Molecular weight:  293.9 g/mol. 
9.1.3 
Mechanism of Action 
The divalent cation (223Ra2+) radium Ra 223 dichloride mimics calcium and selectively targets bone, 
specifically areas of bone metastases, by forming complexes with the bone mineral hydroxyapatite. The 
high linear energy transfer of alpha emitters (80 Kiloelectronvolt/micrometer) leads to a high frequency 
of double-strand DNA breaks in adjacent cells, resulting in a potent and localized anti-tumor effect. The 
alpha particle range from radium Ra 223 dichloride is less than 100 micrometers (less than 10 cell 
diameters) which limits damage to the surrounding normal tissue. 
9.1.4 
Pharmacokinetics 
Distribution 
15 minutes post injection, ~20% of the injected radioactivity remains in the blood. 
At 4 hours ~ 4% in the blood, by 24 hours <1% in blood. Observed in the bone 10 
minutes post-injection. At 4 hours post-injection ~ 61% in bone and 49% in 
intestine. 
Metabolism: 
N/A 
Elimination: 
~63% of radioactivity excreted within 7 days post-injection. Feces ~13%,  urine ~2% 
Half-life: 
11.4 days 
9.1.5 
Human Toxicity 
See Section 7.4. 
9.1.6 
Formulation 
Radium Ra 223 dichloride is a ready-to-use, sterile, non-pyrogenic, clear and colorless aqueous solution of 
Radium Ra 223 dichloride (223RaCl2) for IV administration. It should not be diluted or mixed with any 
solutions. Each vial for a single use only. 
The product is isotonic and has a pH of 6.0-8.0.  The radioactive concentration at the reference date is 
1,100 kBq/mL. The product has a pre-calibration of 14 days. When administered on a day other than the 
reference day, the volume should be corrected according to the physical decay table accompanying each 
shipment. 

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Radium Ra 223 dichloride, is manufactured by Bayer Healthcare LLC contract manufacturer Algeta’s 
Institute for Energy Technology, Isotope laboratories, Kjeller, Norway. The product is produced according 
to Good Manufacturing Practice (GMP). The product will be delivered in a glass vial, ready-to-use with a 
certified activity. Radium Ra 223 dichloride is shipped in a lead container and Type A radioactive package 
according to international transportation guidelines for radioactive materials.  
The volume per vial is 6 mL, corresponding to 6.6 MBq at the reference day.   
9.1.7 
Storage 
The Radium Ra 223 dichloride vials must be stored inside their lead container in a secure facility.  
Radium Ra 223 dichloride has a shelf life of 28 days from production day, when stored at ambient 
temperature. The shelf life has been demonstrated for temperatures from cold storage (2-8°C) up to 40°C. 
In addition, it has been shown that the product quality is not jeopardized upon freezing. 
9.1.8 
Handling and Dispensing 
All study drugs will be labeled according to the requirements of local law and legislation. For all study 
drugs, a system of numbering in accordance with all requirements of GMP will be used, ensuring that each 
dose of study drug can be traced back to the respective bulkware of the ingredients. 
Radium Ra 223 dichloride should be received, used and administered only by authorized persons in 
designated clinical settings. The receipt, storage, use, transfer and disposal Radium Ra 223 dichloride are 
subject to the regulations and/or appropriate licenses of the competent official organization. Radium Ra 
223 dichloride should be handled by the user in a manner which satisfies both radiation safety and 
pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. 
The study drug should be used within 28 days of production. Radium Ra 223 dichloride is an alpha-
pharmaceutical and should be handled by individuals who are qualified by training and experience in the 
safe handling of radionuclides. One dedicated person and a back-up designee will have responsibility as 
assigned from the Primary Investigator for handling and storage of radium Ra 223 dichloride.  
9.1.9 
Radiation Protection 
The administration of radium Ra 223 dichloride is associated with potential risks for other persons (e.g. 
medical staff, care givers and members of the patient’s family) from radiation or contamination from spills 
of body fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in 
accordance with national and local regulations. 
9.1.9.1 For drug handling 
Follow the normal working procedures for the handling of radiopharmaceuticals and use universal 
precautions for handling and administration such as gloves and barrier gowns when handling blood and 
bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be 
flushed immediately with water. In the event of spillage of Radium Ra 223 dichloride, the local radiation 
safety officer should be contacted immediately to initiate the necessary measurements and required 
procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diaminetetraacetic 
acid (EDTA) solution is recommended to remove contamination. 

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9.1.9.2 For patient care 
Whenever possible, patients should use a toilet and the toilet should be flushed several times after each 
use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing 
soiled with Radium Ra 223 dichloride or patient fecal matter or urine should be washed promptly and 
separately from other clothing. 
Radium Ra 223 dichloride is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-
particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 
1.1%. The external radiation exposure associated with handling of patient doses is considerably lower in 
comparison to other radiopharmaceuticals for therapeutic purposes as the administered radioactivity will 
usually be below 8.8MBq (0.238mCi). In keeping with the As Low As Reasonably Achievable (ALARA) 
principle, for minimization of radiation exposure, it is recommended to minimize the time spent in 
radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused 
product or materials used in connection with the preparation or administration are to be treated as 
radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation 
associated with the decay of radium Ra 223 dichloride and its daughters allows for the radioactivity 
measurement of radium Ra 223 dichloride and the detection of contamination with standard instruments. 
9.1.10 Dose Calibration 
Radium Ra 223 dichloride can be measured in a normal dose calibrator instrument. When written 
approvals for the use of radium Ra 223 dichloride from the Radiation Protection Agency for the specific 
center have been received by the sponsor, a vial of radium Ra 223 dichloride for technical use will be sent 
to the study center. 
Different clinical study centers possess dose calibrators from various suppliers; thus, the isotope 
calibration factor may differ from center to center. Consequently, each center must perform the Radium 
Ra 223 dichloride dial setting on their relevant dose calibrator(s). 
9.1.11 Dosimetry 
The absorbed radiation dose calculation was performed based on clinical biodistribution data. Calculations 
of 
absorbed 
doses 
were 
performed 
using 
OLINDA/EXM 
(Organ 
Level 
INternal 
Dose 
Assessment/EXponential Modeling), a software based on the Medical Internal Radiation Dose (MIRD) 
algorithm, which is widely used for established beta and gamma emitting radionuclides. For Radium Ra 
223, which is primarily an alpha emitter, additional assumptions were made for the intestine, red marrow 
and bone/osteogenic cells to provide the best possible absorbed dose calculations for Radium Ra 223 
dichloride, considering its observed biodistribution and specific characteristics. 
For an administered activity of 3.65 MBq (0.0987 mCi) (55kBq, 0.0015mCi) per kg body weight to a 73-kg 
adult, the calculated absorbed doses to the bone (osteogenic cells) is 4.2050 Gy (420.5 rad) and to the red 
marrow is 0.5066 Gy (50.66 rad). The calculated absorbed doses to the main excretory organs are 0.0265 
Gy (2.65 rad) for the small intestine wall, 0.1180 Gy (11.8 rad) for the upper large intestine wall and 0.1696 
Gy (16.96 rad) for the lower large intestine wall.  
The calculated absorbed doses to other organs are low, e.g. heart wall (0.0063 Gy, 0.63 rad), lung (0.0003 
Gy, 0.03 rad), liver (0.0109 Gy, 1.09 rad), kidneys (0.0117 Gy, 1.17 rad), urinary bladder wall (0.0147 Gy, 
1.47 rad), testes (0.0003 Gy, 0.03 rad), and spleen (0.0003 Gy, 0.03 rad).  

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The hematological adverse drug reactions observed in the clinical studies with radium Ra 223 are much 
lower in frequency and severity than what could be expected from the calculated absorbed doses to the 
red marrow. This may be related to spatial distribution of alpha particle radiation resulting in non-uniform 
radiation dose to the red marrow 
9.1.12 Dose Calculation 
The patient dose is calculated based on date of injection, a decay correction factor specific to number of 
days from reference date applied to correct for physical decay of radium-223, and patient weight 
(calculated within 30days of the dosing day).  
A table with decay correction values according to physical decay of the study medication will be provided 
with every shipment of radium Ra 223 dichloride. 
Refer to Section 5.4.3for the dose calculation formula. 
9.1.13 Dose Preparation 
Personnel should use appropriate protective clothing and equipment during syringe filling and application 
to prevent contamination with the radioactive solution (medical gloves/protective glasses).  
The individual responsible for study drug preparation will draw the correct volume of study drug into a 
syringe.  
The size of the syringe should be chosen according to the applied volume to reach the required dosing 
accuracy.  
Radium Ra 223 dichloride should not be diluted or mixed with any solutions. Do not store above 40°C 
(104°F).  
If the vials have been stored in a refrigerator, they should be left at room temperature for 1 hour prior to 
use, since cold material should not be injected in a patient. Store radium Ra 223 dichloride in the original 
container or equivalent radiation shielding. This preparation is approved for use by persons under license 
by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. 
9.1.14 Dose administration 
1. Aseptic technique should be used in the administration of radium Ra 223 dichloride.  
2. The syringe should be handed over to the individual who will perform the injection.  
3. The study medication will be administered as a bolus intravenous (IV) injection (up to 1 minute).  
4. After administration, the equipment used in connection with the preparation and administration 
of drug is to be treated as radioactive waste and should be disposed in accordance with local 
procedure for the handling of radioactive material. 
Refer to Section 5.4.3 for additional administration details. 
9.1.15 Supplier 
The investigational agent will be supplied free of charge by Bayer. 

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9.1.16 Ordering 
1. The Cardinal Product Request Form should be faxed to Cardinal Health Denver each time a dose 
is needed. Contact details can be found on the Cardinal Product Request Form. 
2. The order form must include the IIR Study number which is IIR-US-2016-1801. 
3. The patient’s weight should be calculated within 30days of the dosing day.   
4. The patient dose should be requested at least 3 business days prior to time of agent 
administration so that the volume of agent to be disbursed can be calculated.  
5. The form must be completed for each and every dose being ordered.   
6. Bulk supply will not be provided due to the short half-life of radium Ra 223 dichloride and possible 
changes inpatient weight. 
9.1.17 Accountability 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the investigational agent using a drug accountability log. 
9.1.18 Destruction and Return 
The investigator is responsible for keeping accurate records of the clinical supplies received from Bayer or 
designee, the amount dispensed to participants, and the amount remaining at the conclusion of the trial.  
Any unused agent at the end of the study, expired agent, and damaged agent will be destroyed according 
to applicable federal, state, local and institutional guidelines and procedures.  
Destruction will be documented in a drug accountability log.  
The certificate of destruction for radium Ra 223 dichloride should be sent to Bayer. 
9.2 Androgen Deprivation Therapy 
ADT therapy will consist of treatment with either LHRH agonist leuprolide (Section 9.2.1), goserelin 
(Section 9.2.2) or LHRH antagonist degarelix (Section 9.2.3) or relugolix (Section 9.2.4) per investigator 
discretion. 
9.2.1 
Leuprolide  
Leuprolide is indicated for:  
o Endometriosis 
o Advanced prostate cancer 
o Breast cancer 
o Infertilities 
o Paraphilia 
o Uterine fibroids 
Please refer to the package insert for additional details. 
9.2.1.1 Other Names 
Lupron Depot, leuprolide acetate 

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9.2.1.2 Description 
Structural formula: 
Empirical formula: 
C61H88N16O14 
Molecular weight:  1269.473 g/mol 
Chemical name: 
5-oxo-L-prolyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-Dleucyl- 
L-leucyl-L-arginyl-N-ethyl-L-prolinamide acetate 
9.2.1.3 Mechanism of Action 
Leuprolide binds to the gonadotropin releasing hormone receptor and acts as a potent inhibitor of 
gonadotropin secretion. 
9.2.1.4 Pharmacokinetics 
Elimination half-life: 
3 hours 
Tmax: 
IM: 4 hours, subQ~3-5 hours 
Protein binding: 
43-49% 
Metabolism: 
Hydolysis via peptidase enzyme 
Excretion: 
Renal (< 5% unchanged)  
9.2.1.5 Human Toxicity 
See Section 7.1 for details. 
9.2.1.6 Formulation 
Intramuscular or subcutaneous injection; monthly or every 3-months. 
9.2.1.7 Storage, Handling, Preparation 
Follow package insert instructions. 
9.2.1.8 Dose and Administration 
See Section 5.4.1for additional administration guidelines. Dosing will be per package insert and 
investigator discretion. 
9.2.1.9 Supplier 
Leuprolide is available commercially. 
9.2.2 
Goserelin  
Goserelin is indicated for:  
o Locally confined carcinoma of the prostate  
o Advanced carcinoma of the prostate  
o Breast cancer 
o Endometriosis 
 
Please refer to the package insert for additional details. 

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9.2.2.1 Other Names 
Zoladex®, goserelin acetate 
9.2.2.2 Description 
Structural formula: 
Empirical formula: 
C59H84N18O14 
Molecular weight:  1269.433 g/mol 
Chemical name: 
(2S)-1-[(2S)-2-[(2S)-2-[(2R)-3-(tert-butoxy)-2-[(2S)-2-[(2S)-3-hydroxy-2-[(2S)-2-[(2S)-3-
(1H-imidazol-5-yl)-2-[(2S)-5-oxopyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol-
3-yl)propanamido]propanamido]-3-(4 hydroxyphenyl)propanamido]propanamido]-4-
methylpentanamido]-5-[(diaminomethylidene)amino]pentanoyl]-N-
(carbamoylamino)pyrrolidine-2-carboxamide 
9.2.2.3 Mechanism of Action 
Goserelin is a synthetic decapeptide analogue of LHRH. Goserelin acts as a potent inhibitor of pituitary 
gonadotropin secretion when administered in the biodegradable formulation. The result is sustained 
suppression of LH and serum testosterone levels. 
9.2.2.4 Pharmacokinetics 
Elimination half-life: 
4.2 hours (male); 2.3 hours (female) 
Absorption: 
Rapid 
Protein binding: 
27% 
Metabolism: 
Liver hydolysis of the C-terminal amino acids 
Excretion: 
Renal 90% 
9.2.2.5 Human Toxicity 
See Section 7.2 for details. 
9.2.2.6 Formulation 
Subcutaneous injection; monthly or every 3-months. 
9.2.2.7 Storage, Handling, Preparation 
Follow package insert instructions. 
9.2.2.8 Dose and Administration 
See Section 5.4.1for additional administration guidelines. Dosing will be per package insert and 
investigator discretion. 

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9.2.2.9 Supplier 
Goserelin is available commercially. 
9.2.3 
Degarelix 
Degarelix is indicated for:  
o Advanced carcinoma of the prostate  
 
Please refer to the package insert for additional details. 
9.2.3.1 Other Names 
Firmagon® 
9.2.3.2 Description 
Structural formula: 
Empirical formula: 
C82H103N18O16Cl 
Molecular weight:  1632.3 Da 
Chemical name: 
(2S)-1-[(2S)-2-[(2S)-2-[(2R)-3-(tert-butoxy)-2-[(2S)-2-[(2S)-3-hydroxy-2-[(2S)-2-[(2S)-3-
(1H-imidazol-5-yl)-2-[(2S)-5-oxopyrrolidin-2-yl]formamido}propanamido]-3-(1H-indol- 
D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-chloro-Dphenylalanyl-3-(3-
pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-
4pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-
phenylalanyl-L leucyl-N6–(1methylethyl)-L-lysyl-L-prolyl 
9.2.3.3 Mechanism of Action 
Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, thereby 
reducing the release of gonadotropins and consequently testosterone. 
9.2.3.4 Pharmacokinetics 
Elimination half-life: 
Loading dose (subcut) ~53 days, maintenance dose (subcut) ~31 days 
Absorption: 
Rapid 
Protein binding: 
90% 
Metabolism: 
Peptide hydrolysis during passage of hepato-biliary system 
Excretion: 
Renal 20-30%, hepatobiliary 70-80% 
9.2.3.5 Human Toxicity 
See Section 7.2 for details. 
9.2.3.6 Formulation 
Subcutaneous injection; monthly. 

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9.2.3.7 Storage, Handling, Preparation 
Follow package insert instructions. 
9.2.3.8 Dose and Administration 
See Section 5.4.1for additional administration guidelines. Dosing will be per package insert and 
investigator discretion. 
9.2.3.9 Supplier 
Degarelix is available commercially. 
9.2.4 
Relugolix 
Relugolix is indicated for: 
o Advanced carcinoma of the prostate  
Please refer to the package insert for additional details. 
9.2.4.1 Other Names 
OrgovyxTM, Relumina, RGX, RVT-601, TAK-385 
9.2.4.2 Description 
Structural formula: 
Empirical formula: 
C29H27F2N7O5S 
Molecular weight:  623.6 Da 
Chemical name: 
1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-
methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea 
9.2.4.3 Mechanism of Action 
Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, 
thereby, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and 
consequently testosterone. 
9.2.4.4 Pharmacokinetics 
Elimination half-life: 
The mean effective half-life of relugolix is 25 hours and the mean (CV%) terminal 
elimination half-life is 60.8 (11%) hours. The mean (CV%) total clearance of relugolix 
is 29.4 (15%) L/h and the renal clearance is 8 L/h. 
Absorption: 
Relugolix is a substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of 
relugolix is approximately 12% (62%). The median (range) Tmax of relugolix is 2.25 
hours (0.5 to 5.0 hours).  
Protein binding: 
Plasma protein binding of relugolix is 68 to 71%, primarily to albumin and to a lesser 
extent to α1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. 
Metabolism: 
Relugolix is metabolized primarily by CYP3A and to a lesser extent by CYP2C8 in vitro 

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Excretion: 
After oral administration of a single 80-mg radiolabeled dose of relugolix, 
approximately 81% of the radioactivity was recovered in feces (4.2% as unchanged) 
and 4.1% in urine (2.2% as unchanged).  
9.2.4.5 Human Toxicity 
See Section 7.4 for details. 
9.2.4.6 Formulation 
Tablets, taken orally once daily 
9.2.4.7 Storage, Handling, Preparation 
Follow package insert instructions. 
9.2.4.8 Dose and Administration 
See Section 5.4.1 for additional administration guidelines. Dosing will be per package insert and 
investigator discretion. 
9.2.4.9 Supplier 
Relugolix is available commercially. 
9.3 Stereotactic Body Radiation Therapy 
9.3.1 
Description 
Stereotactic body radiation therapy will be performed on the True Beam Stx Machine utilizing 6MV 
photons using Rapid Arc (Varian, CA, USA).  
9.3.2 
Dosing and Administration 
Patients will be immobilized in a custom cushion and CT will be performed in treatment planning position. 
Respiratory management will be taken into account utilizing 4DCT.  
With radiology and consensus at multidisciplinary GU tumor board we will delineate the area of gross 
bone metastases and lymph node metastases and lung metastases. Contouring of metastases and organs 
at risk (OAR) in proximity to the metastatic tumor will be performed. The contouring of the metastases is 
the gross tumor volume (GTV). For SBRT there is no expansion of GTV to clinical target volume (CTV) to 
limit dose to normal tissue structures. For daily radiation setup error a 3-5mm margin with be applied to 
the GTV based on proximity to critical structures.  
. We will plan the radiation therapy according to guidelines per NRG BR001, prior published RTOG studies 
and AAPM task force 101 guidelines as well as the recently published STOMP trial which also references 
AAPM task force 101 guidelines [14, 42]. 
Local control of gross oligometastatic sites will be determined by subsequent standard of care reimaging 
studies including CT chest/abdomen/pelvis and bone scan. 
See Section 5.4.2for additional administration guidelines. 
9.3.2.1 Human Toxicity 
See Section 7.3 for details. 
 

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10.0 CORRELATIVE/ SPECIAL STUDIES 
10.1 Tumor Tissue Clinical Testing 
An overview of collection, processing, and analysis details are shown in Table 10.1. 
The collection, processing and testing will be considered as part of routine care. 
Table 10.1 Tumor tissue overview 
Tissue Type 
Primary (P) or 
Metastatic (M)? 
Timepoint 
of 
collection 
Receiving 
Laboratory 
Clinical 
Laboratory 
Performing 
Analysis 
Type of Downstream 
Research Analysis 
P 
M 
 
If available, archived 
formalin fixed paraffin 
embedded (FFPE) tissue 
X 
X 
Baseline 
COH 
Pathology 
Foundation 
Medicine 
Inc. 
 
Via the 
Foundation 
One assay 
platform 
 
Genomic 
alterations 
prior to 
developmen
t of 
castration 
resistance. 
 
Optional FFPE tissue from 
post-consent biopsy 
 
X 
 
o Baseline tissue:  
 FFPE: If available, archived primary or metastatic specimen should be submitted following 
enrollment for clinical testing. 
 Optional FFPE tissue from post-consent biopsy: If participant is willing and feasible, attempts 
should be made to take extra metastatic tissue for clinical testing at time of standard of care 
biopsy.  
10.1.1 Distribution to Foundation Medicine Inc. 
The COH Pathology core will distribute de-identified tissue to Foundation Medicine Inc.(see Table 10.1). 
Downstream genomic analysis will be considered research. NOTE: Participant agreement is required in 
order for this research analysis to be performed (see consent document). 

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10.2 Correlative Blood Studies 
Blood samples will be collected from an indwelling venous catheter or by venipuncture for the below 
stated analyses (see Table 10.2).  
Table 10.2 Peripheral blood studies overview 
Timepoint of collection 
Volume 
per 
Timepoint 
Tube Type 
Processing
/ 
Receiving 
Laborator
y 
Laboratory 
Performing 
the Analysis 
Type of Laboratory Analysis 
 Cycle 1 Day 1 (Baseline) 
 Pre-Cycle 2 (Post-SBRT) 
 End of Ra223/EOT 
20 mL 
Sodium 
Heparin 
green top 
Personnel 
in Dr. 
Marcin 
Kortylews
ki’s 
laboratory 
Dr. Marcin 
Kortylewski  
Plasma and peripheral blood 
mononuclear cells (PBMC) 
isolation to assess immune 
factors and immune cells 
 
10.2.1 Notification of Pending Collection, Blood Collection and Labeling  
Notification of Pending 
Collection to Kortylewski 
Laboratory 
Labeling and Collection Details 
Post-collection Instructions 
 Notify at least one day in 
advance) 
 Send calendar invite via e-
mail: Seok 
White(sewhite@coh.org) or 
designee and cc: Dr. Marcin 
Kortylewski 
(MKortylewski@coh.org) 
1. Label tubes with COH protocol #, subject 
ID, time of collection in 24-hour format, 
and timepoint of collection (e.g. D1C1 for 
Day1 of Cycle 1). 
2. Timepoints of collection are stated in 
Table 10.2. 
3. Invert tubes eight times after collection.  
4. Place the tubes on ice. 
 
 
 Promptly deliver the blood 
samples on ice to the Kortylewski 
Laboratory within 1-2 hours (± 
30 minutes). 
 
10.2.2 Processing of samples by Kortylewski laboratory 
Samples will be processed per Kortylewski laboratory protocols for PBMC and plasma. 
 

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11.0 STUDY CALENDAR 
All procedures may increase in frequency if clinically indicated. 
Table11.0 Study Activity Calendar 
Protocol Activities* 
Screening a 
Protocol Therapy c, d 
Follow-up 
(Max. 5 years) 
Cycle  
1 
Cycle  
2 
Cycle  
3-7 
Post 
Ra-
223/E
OT i 
Response j 
Long-termk 
Day 1e,f 
Day 1g,h 
Day 1g 
Informed Consentl 
X 
 
 
 
 
 
 
Medical Historym 
X 
 
 
 
 
 
 
Eligibility n 
X 
 
 
 
 
 
 
Registration o 
X 
 
 
 
 
 
 
Physical Examp and Vital Signsq 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
ECOG (Appx. A) 
X 
X 
X 
X 
X 
X 
 
Con-medicationsr 
X 
X 
X 
X 
X 
X 
 
AE assessments 
 
Xt 
Xt 
Xt 
Xt 
Xu 
Xu 
12-lead EKG 
Xv 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
 
Serum chemistryw 
X 
X 
X 
X 
X 
X 
 
Prostate-specific antigen (PSA) 
Xb 
X 
X 
X 
X 
X 
 
Serum testosterone 
Xb 
X 
X 
X 
X 
X 
 
Immune-biomarker studiesx 
 
X 
X 
 
X 
 
 
Archival tumor tissuey 
X 
 
 
 
 
 
 
Fresh tumor tissuez 
X 
 
 
 
 
 
 
Tumor Evaluation aa 
X 
 
 
 
X 
Xbb 
 
ADT: Leuprolide OR goserelinOR 
degarelix OR relugolix dd 
Dosing per package insert/ physician discretion for 36 
weeks starting at least 28 days prior to SBRT 
 
 
Criteria to initiate stereotactic 
body radiation therapy (SBRT) 
 
Xf 
 
 
 
 
 
SBRTf, cc 
 
X 
 
 
 
 
 
Criteria to initiate radium Ra 223 
dichloride 
 
 
Xh 
 
 
 
 
Radium Ra 223 dichlorideh, cc 
 
 
Day 1 of each 
cycle  
 
 
 
Survivalk 
 
 
 
 
 
 
X 
 
* Participants will receive bisphosphonate or RANKL inhibitor bone health agents at the dose and schedule consistent 
with the treatment of bone metastases or prevention of osteoporosis, starting approximately when protocol therapy 
begins until the participant’s testosterone reaches normal levels (>50 ng/dL) or at the discretion of the PI. 
a. Screening activities to occur within 56days prior to Cycle 1 Day 1 of protocol therapy except PSA and serum 
testosterone. 

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b. Screening PSA and serum testosterone should occur prior to 1st dose of androgen deprivation therapy (ADT). If not 
drawn prior to starting ADT, this will not constitute a protocol deviation as some patients will have started ADT prior 
to consenting on the trial   
c. 
Protocol therapy may last until completion of 7 cycles of therapy, unacceptable toxicity or disease progression, 
whichever occurs first (see Section 5.7 for more comprehensive list). 
d. In the absence of toxicity, each cycle lasts 28 ± 7 days. 
e. Cycle 1 Day 1:  With the exception of PSA, serum testosterone and blood counts other screening evaluations 
performed within 14 days prior to Cycle 1 Day 1 of protocol therapy may serve as Day 1 baseline evaluations. 
f. 
Participants must meet criteria in Section 6.1 to initiate SBRT on Cycle 1 Day 1. 
g. Assessments must be performed within 7 days prior to radium Ra 223 dichloride. Safety assessments must be 
reviewed within 7 days prior to initiating a new cycle.  
h. Cycle 2 Day 1 (1st dose of radium Ra 223 dichloride): Participants must meet criteria in Section 6.2. 
i. 
Post Ra-223/EOT visit to occur approx. 28 days +/- 7 days post-last dose of Ra 223 dichloride. 
j. 
Response follow-up assessments for participants yet to progress, will occur ~ every 3 months (± 4 wks) (except tumor 
evaluations) from the day of last response evaluation until progression or the initiation of a new therapy. 
k. Long-term follow-up assessments for participants who progressed or ended Response Follow-up to occur annually (± 
30 days) or as requested by the Study PI via medical record review, review of social security registry/ public records, 
and/or telephone call.  
l. 
Informed consent process to be fully documented (see Section 17.4). Informed consent must occur prior to any 
research only (non-SOC) screening procedures. 
m. Medical history to include a review of treatment history, any ongoing medical conditions and medical history 
pertaining to eligibility on study and involvement during study. 
n. Eligibility criteria are detailed in Section 3.0.  
o. Registration into a COH clinical trial management system (CTMS).  
p. Standard physical exam includes weight and skin analysis.  
q. Vital signs: heart rate, blood pressure, respiration rate, and temperature.   
r. 
Concurrent medications and reason for administration to be documented in the EHR and eCRF from within 56 days 
prior to protocol therapy up to EOT visit. See Section 5.11.1for concomitant medication restrictions and guidelines.  
s. 
Adverse event (AE) will be assessed using CTCAE v.5.0. 
t. 
Active AE reporting will start from start of treatment until the post RA-223 visit/EOT visit  NOTE: The highest AE 
grade per cycle will be reported in the eCRF from start of therapy until the EOT visit. Exceptions to expedited 
reporting are stated in Section 8.2 
u. Long-term toxicities -- secondary malignancy, thyroid dysfunction-- attributed to protocol therapy will be collected 
via medical record review and/or phone call during Response Follow-up, standard of care visits and Long-term 
Follow-up. NOTE: If the participant is no longer at COH, the study team will request relevant medical information 
from the external institution. 
v. 
If clinically indicated by history of cardiovascular disease. 
w. Serum chemistry panel to include: glucose, Blood Urea Nitrogen (BUN), creatinine, total protein, albumin, 
magnesium, bicarbonate, calcium, sodium, potassium, chloride, total bilirubin, alkaline phosphatase, ALT and AST. 
x. 
Immune biomarker studies: Collect 20 mL per timepoint in sodium heparin green-top tubes and store on ice until 
delivery to Dr. Kortylewski’s laboratory (See Section 10.2 for details). NOTE: Notification to the Kortylewski’s 
laboratory of pending sample collection must be made at least 1 day in advance (see Section 10.2.1 for details). 
y. Tumor tissue: If available, archival metastatic or primary tissue will be submitted for clinical testing. Refer to Section 
10.1for additional details. 

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z. 
Fresh metastatic tissue (optional): If the participant is willing attempts should be made to take extra metastatic 
tissue for clinical testing at the time of standard of care biopsy. See also Section 10.1. 
aa. Tumor Evaluation: Options include combination of: CT chest, abdomen, pelvis,  CXR,  targeted X-rays,  bone scan, 
Whole Body MRI, MRI of the TLS spine, MRI of the pelvis, PET/CT. All anatomical areas of the body need to be 
included (chest, abdomen, pelvis, skeleton) using combination of these tests. Follow up scans should at the 
minimum include the same scans utilized for screening. 
bb. Tumor evaluation to occur every 6 months (± 14 days) from last tumor evaluation, and at PSA progression (unless 
taken within the last 4 weeks). 
cc. Refer to Section 5.3 for the treatment plan. Refer to Section 6.3 for dose modification/ delay guidelines and Section 
5.9 for supportive care guidelines. 

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12.0 ENDPOINT EVALUATION CRITERIA/MEASUREMENT OF EFFECT 
12.1 Efficacy Endpoints 
Response and progression will be evaluated in this study using modified Prostate Cancer Working Group 
2 criteria [43] (see Appendix C and Appendix D). PSA levels will be a part of overall response assessment. 
Other clinical efficacy endpoints are described in Table 12.1. 
Table 12.1 Efficacy Endpoints 
Endpoint 
Definition 
Time to treatment failure 
(TTF) 
Time from the initiation of ADT for metastatic disease until PSA increase to > pre-
ADT level or PSA >10 (whichever is smaller) or radiographic or clinical progression 
or resumption of ADT by physician’s choice 
Objective response rate 
(ORR) 
Proportion of patients achieving CR or PR at Cycle 8 Day 1 (post-6 doses of radium 
Ra 223 dichloride) 
Complete response (CR) 
rate 
Proportion of patients achieving CR 
Progression-free survival 
(PFS) 
Time from the initiation of ADT for metastatic disease until PSA progression or 
radiographic progression or death 
Bone specific progression-
free survival (Bs-PFS) 
Time to progression of bone specific disease over baseline 
Duration of response 
(DOR) 
Time from documented response to recurrent or progressive disease is first met 
Duration of overall 
complete response 
Time from documented CR to recurrent/ progressive disease  
Duration of stable disease 
Time from start of treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
Overall Survival (OS) 
Date of initiation of protocol treatment to date of death from any cause 
12.2 Toxicity 
Toxicity will be graded according to the NCI CTCAE version 5.0.The highest AE grade per cycle will be 
reported in the eCRF from start of therapy until the end of treatment visit.  
12.3 Alkaline phosphatase 
Levels of alkaline phosphatase will be assessed at baseline and at the end of protocol therapy. The rate of 
normalization of the total alkaline phosphatase level (defined as a return to a value within the normal 
range) at the end of protocol therapy in patients with total alkaline phosphatase values above the upper 
limit of the normal range at baseline will be assessed. 

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13.0 STATISTICAL CONSIDERATIONS 
13.1 Study Design 
This multimodality Phase2study is designed to test the preliminary efficacy and to determine if androgen 
deprivation therapy (ADT), stereotactic body radiation therapy (SBRT) and radium Ra 223 dichloride, all 
delivered at the standard doses are well-tolerated in patients with oligometastatic hormone sensitive 
prostate cancer.  The motivation behind using the standard doses for each as the starting dose is due to 
the limited sites of SBRT permitted in this study (≤4 metastatic lesion) and the prior data of radium Ra 223 
dichloride when combined with ADT in a more advanced disease setting which suggest that the standard 
dosing should be safe and appropriate[21].   
Correlative tissue studies are also incorporated into this protocol to explore the prevalence of genomic 
alterations in this population. Additionally, changes in immune biomarkers over the course of ADT-
radiotherapy will be analyzed in an exploratory manner. 
13.2 Evaluable Participants 
o Evaluable for toxicity  
 Patients who received at least 1 SBRT dose will be evaluable for toxicity. 
 Patients who have received at least 1 dose of SBRT and at least 1 dose of Radium 223 will be 
evaluable for assessment of toxicity and efficacy. 
o Evaluable for response 
 Only those patients who have evaluable disease present at baseline, have received at least 
one dose of SBRT and at least 1 dose of radium Ra 223 dichloride, will be considered 
evaluable for response.   
13.3 Accrual and Expected Duration of Trial 
The sample size is 24 evaluable patients (as of July 2023 we had 1 inevaluable patient, therefore we will 
need to accrue a total of 25 patients to get 24 evaluable patients). Accrual is expected to be completed in 
66 months.  
Participant duration is planned for 68 months which includes protocol therapy (~ 8 months) and follow-
up (5 years).  
The estimated total study duration will be 134 months (~ 11 years), with 66 months of accrual and 
approximately 68 months of protocol therapy and follow-up for the last patient. 
13.4 Stopping Rules for Excessive Toxicity 
The stopping rules for safety/toxicity will be assessed for each patient after the first 2 cycles of radium 
dichloride 223. The expected rate of unacceptable toxicity should not be ≥33%. 
A patient will be deemed to have experienced an Unacceptable Toxicity (UT) if any of the following occur 
during the first 2 cycles of radium Ra 223 dichloride (Cycles 2 and 3) and are attributed as possibly, 
probably, or definitely related to protocol therapy: 
o Hematological 
 Any ≥ Grade 3 hematological toxicity that delays the next planned dose of radium Ra 223 
dichloride by > 28 days 

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o Non-hematological 
 Any >Grade 2 fracture 
 Any ≥ Grade 3 non-hematological toxicity that does not resolve to ≤ Grade 2 with adequate 
supportive care and delays the next planned dose of radium Ra 223 dichloride by> 28 days 
 Any recurrent  ≥ Grade 3 toxicity 
The following table will be consulted as relevant toxicities defined above are encountered. 
When a stopping rule is triggered, the study PMT will review and assess the safety of the trial and submit 
a report to the COH DSMC.  The COH DSMC will review for approval any decision to continue accrual, 
amendment the protocol, or permanently suspend accrual to the trial. 
 
# of patients 
treatedthat 
determines 
early stopping 
# of patients with 
unacceptable 
toxicity  
Given the following toxicity rates, 
cumulative probability of early stopping: 
10% 
25% 
35% 
<=6 
2 
0.11 
0.47 
0.68 
<=10 
3 
0.14 
0.56 
0.80 
<=12 
4 
0.14 
0.58 
0.81 
<=15 
5 
0.14 
0.59 
0.83 
<=18 
6 
0.14 
0.60 
0.85 
<=21 
7 
0.14 
0.61 
0.86 
<24 
8 
0.14 
0.61 
0.86 
13.5 Statistical Analysis Plan 
With 24 evaluable patients treated we will estimate median time to treatment failure (radiographic or PSA 
progression, death or cessation of treatment due to clinical progression or toxicity).  Our historical data 
suggest a 16 month median time to TTF [10].  Other studies varied in results and endpoints used, ranging 
from a median time to failure of 11 months [45], median distant progression free survival of 21 months 
[46], and median time to clinical progression of 18 months[23]. Even when permitting a lower PSA entry 
criteria (PSA>0.2) the median time to progression was 21 months[14].  (Note: This observation has allowed 
us to amend this study to permit that lower PSA entry criteria to help with accrual). We seek to 
demonstrate a median TTF of at least 25 months, exceeding reports from all previous prior studies that 
examined only a two modality approach.   With 24 evaluable patients, accrued over 16 months and 
followed for 18 months, we will have greater than 80% power to detect an improvement in TTF from 16 
months to 32 months with a one-sided type I error of 10%.  The critical value for a promising median TTF 
based on this design is 25 months, or an improvement of 9 months over our historical data.  If patients 
experience treatment failure at ONLY an untreated asymptomatic low volume locoregional recurrence 
(allowed per amendment 6 based on PI discretion), TTF will be censored at that time for that patient.   
Other secondary analysis will include progression-free survival, overall survival, complete response rate, 
duration of response, and duration of overall complete response, bone specific progression-free survival 
and duration of stable disease.  
Exploratory analysis will include describing the rate of normalization of the total alkaline phosphatase level 
at the end of protocol therapy and evaluation of the role of genomic mutations and immune biomarker 

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studies on outcome and toxicity.  These outcomes will be reported to provide further support, combined 
with the activity, and tolerability to help guide additional studies.  

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14.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
14.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial.  
The investigator or their designee will prepare and maintain adequate and accurate source documents.  
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial.  Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
14.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system that is compliant with 21 
CFR Part 11.  
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF).   
14.3 Case Report Forms/Data Submission Schedule 
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that visit is 
available.  
The investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the investigator. All case report forms must be completed by designated study personnel.  The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 14.2, and will be 
submitted according to the timelines indicated in Table 14.3. 
Table 14.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 10 calendar days of treatment administration 
Adverse Event Report Forms 
Within 7 calendar days of AE assessment/notification  
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms (concomitant 
medications) 
Within 10 calendar days of the assessment 
Off Treatment/Off Study Forms 
Within 10 calendar days of end of treatment/study 
Follow up/Survival Forms 
Within 14 calendar days of the follow up activity 
14.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 

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15.0 ADHERENCE TO THE PROTOCOL 
It is understood that deviations from the protocol should be avoided, except when necessary to eliminate 
an immediate hazard to a research participant. Protocol deviations may be on the part of the subject, the 
investigator, or study staff.   
All deviations from the protocol must be documented in study subject source documents and promptly 
reported.  The Study PI will report the deviation according to City of Hope’s deviation policy for reporting 
deviations (See Section 8.0). 
16.0 STUDY OVERSIGHT, QUALITY ASSURANCE, AND DATA & SAFETY MONITORING 
16.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
All investigators agree to: 
o Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when necessary to protect the safety, rights or welfare of 
subjects.  
o Personally conduct or supervise the study (or investigation).  
o Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56.  
o Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance 
with §21 CFR 312.64.  
o Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments.  
o Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee).  
o Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible 
for initial and continuing review and approval of the clinical study.  
o Promptly report to the IRB and the Sponsor all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND 
safety reports).  
o Seek IRB and Sponsor approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the patients/subjects.  
o Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
16.2 Study Principal Investigator Responsibilities 
The Study Principal Investigator is responsible for the conduct of the clinical trial, including overseeing that 
sponsor responsibilities as defined in § 21 CFR 312.  
16.3 Protocol Management Team (PMT) 
Refer to Section 8.0.  

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16.4 Auditing 
Clinical site auditing is conducted to ensure that the rights of human subjects are protected, that the study 
is implemented in accordance with the protocol and regulatory requirements, and that the quality and 
integrity of study data and data collection methods are maintained. Auditing for this study will be 
performed by the City of Hope Office of Clinical Trials Auditing and Monitoring (OCTAM). 
Documentation of audit activities and findings by OCTAM will be provided to the study team, the PI, and 
the COH DSMC. 
16.5 City of Hope Data and Safety Monitoring Committee 
The DSMC is a multidisciplinary committee charged with overseeing the monitoring of safety of 
participants in clinical trials, and the conduct, progress, validity, and integrity of the data for all clinical 
trials that are sponsored by City of Hope. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. The committee reviews the progress and 
safety of all active research protocols that are not monitored by another safety and data monitoring 
committee or board. 
The COH Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and accrual data 
from this trial. Information that raises any questions about participant safety will be addressed with the 
Principal Investigator, statistician and study team. Refer to Section 8.0 for details. 

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17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 
the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 Title 21 Part 11 – Electronic Records; Electronic Signatures  
 Title 21 Part 50 – Protection of Human Subjects  
 Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 Title 21 Part 56 – Institutional Review Boards  
 Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 Title 21 Part 312 – Investigational New Drug Application  
 Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 Health Insurance Portability and Accountability Act of 1996  
 Section 801 of the Food and Drug Administration Amendments Act   
o State of California Health and Safety Code, Title 17 
o Institutional policies and procedures 
17.3 Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the federal 
regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 17,  must 
review and approve this protocol and the informed consent form prior to initiation of the study.  All 
institutional, NCI, Federal, and State of California regulations must be fulfilled. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol amendments, 
Investigator’s Brochure, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The IRB’s written 
unconditional approval of the study protocol and the informed consent document will be in the possession 
of the investigator before the study is initiated. 
The IRB will be informed of revisions to other documents originally submitted for review; serious 
unexpected or unanticipated adverse experiences occurring during the study, and any additional adverse 
experiences in accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; an annual 
update and/or request for re-approval; and when the study has been completed. 
Any amendment to the protocol document and accompanying informed consent document/template, as 
developed and provided by the PI, will require review and approval by the COH IRB before the changes 
are implemented in the study. 

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17.4 Informed Consent 
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Prospective participants will be informed that they may withdraw 
from the study at any time and for any reason without prejudice, including as applicable, their current or 
future care or employment at City of Hope or any relationship they have with City of Hope.  Prospective 
participants will be afforded sufficient time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
Before implementing any study procedure, informed consent shall be documented by the use of a written 
consent form approved by the IRB and signed and dated by the prospective participant or his/her legally 
authorized representative at the time of consent.  A copy of the signed informed consent will be given to 
the participant or his/her legally authorized representative. The original signed consent must be 
maintained by the investigator and available for inspection sponsor designated representatives, or 
regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation 
17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures 
(safety visit) and chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review 
and survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
17.6 Special and Vulnerable Populations 
17.6.1 Inclusion of Women and Minorities 
Women are excluded from participation because prostate cancer is a disease of men. The study is open 
to any male regardless of ethnicity. If differences in outcome that correlate to racial or ethnic identity are 
noted, accrual may be expanded or additional studies may be performed to investigate those differences 
more fully. 
17.6.2 Exclusion of Pediatric Patients 
Pediatric recipients (children <18 years old of age) are excluded from this study because prostate cancer 
is not present in this population. 

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17.6.3 HIV Positive Individuals 
Patients with controlled HIV will be included because those with well-controlled disease should not be at 
increased risk of developing neutropenia compared to other patients.   
17.6.4 Vulnerable Populations 
45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, or economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose additional 
risks for adults lacking capacity than for the general population.  In such instances, informed consent will 
be sought and documented from the prospective participant’s legally authorized representative in 
agreement with institutional policies and local IRB approval. 
17.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants. 
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA). HIPAA regulations require a signed participant authorization informing 
the participant of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, ant the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a participant revokes authorization to collect or use 
PHI, the investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of participant authorization.  For participants that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the participant 
is alive) at the end of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used. 
Medical records of participants will be securely maintained in the strictest confidence, according to 
current legal requirements. Data will be entered, analyzed and stored in encrypted, password protected, 
secure computers that meet all HIPAA requirements. All data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned patient number.  
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities. The access may consist of trial-
related monitoring/auditing, IRB reviews, and FDA/regulatory authority inspections. The participant’s 
confidentiality will be maintained and will not be made publicly available to the extent permitted by the 
applicable laws and regulations. 

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17.8 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
17.9 Financial Obligations, Compensation, and Reimbursement of Participants 
Radium Ra 223 dichloride will be provided free of charge to participants.  
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
The standard of care drug(s) and standard of care procedures provided will be the responsibility of the 
research participant and/or the insurance carrier.  The research participant will be responsible for all 
copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by the 
insurance carrier.  The research participant and/or the insurance carrier will be billed for the costs of 
treatment and diagnostic procedures in the same way as if the research participant were not in a research 
study.   
In the event of physical injury to a research participant, resulting from research procedures, appropriate 
medical treatment will be available at the City of Hope to the injured research participant, however, 
financial compensation will not be available. 
The research participant will not be paid for taking part in this study. 
17.10 Publication/Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of Study PI. Any investigator involved with this 
study is obligated to provide City of Hope with complete test results and all data derived from the study. 
The preparation and submittal for publication of manuscripts containing the study results shall be in 
accordance with a process determined by mutual written agreement between City of Hope and Bayer. 
The publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov and results will be 
reported on ClinicalTrials.gov within 12 months of the estimated or actual completion date of the trial, 
whichever date is earlier.  

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O'Sullivan, J.M., et al., Radium-223 Within the Evolving Treatment Options for Metastatic 
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Tombal, B.F., et al., Decreased fracture rate by mandating bone-protecting agents in the EORTC 
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Dal Pra, A., F.L. Cury, and L. Souhami, Combining radiation therapy and androgen deprivation for 
localized prostate cancer—a critical review. Current Oncology, 2010. 17(5): p. 28-38. 
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Benedict, S.H., et al., Stereotactic body radiation therapy: the report of AAPM Task Group 101. 
Med Phys, 2010. 37(8): p. 4078-101. 
43. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive prostate 
cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials 
Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
44. 
Robinson, D., et al., Integrative clinical genomics of advanced prostate cancer. Cell, 2015. 161(5): 
p. 1215-28. 
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James, N.D., et al., Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel 
Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). 
Eur Urol, 2015. 67(6): p. 1028-38. 
46. 
Ost, P., et al., Progression-free Survival Following Stereotactic Body Radiotherapy for 
Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis. Eur 
Urol, 2016. 69(1): p. 9-12. 
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Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am 
J Clin Oncol, 1982. 5(6): p. 649-55. 
 
 

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APPENDIX A: PERFORMANCE STATUS 
 
ECOG Performance Scale[47] 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-
disease performance without restriction. 
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). 
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. 
3 
In bed >50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on 
any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 

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APPENDIX B: STAGING CRITERIA 
 
 
Stage 
Sub-stage 
Definition 
Metastasis  
   
   
   
   
   
Systemic spread  
M0  
No distant metastasis  
M1a  
Non-regional lymph node metastasis  
M1b  
Bone metastasis 
     1) Axial skeleton only 
     2) Extending also to peripheral skeleton   
M1c  
Metastasis at other sites  
 
 
 
 

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APPENDIX C: DISEASE PARAMETERS AND METHODS FOR EVALUATION 
Response and progression will be evaluated in this study using modified Prostate Cancer Working Group 
2 criteria [43].  
Disease Parameters 
o Measurable disease:   
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10mm with conventional techniques (CT, 
MRI, or caliper measurement) and as >20mm by chest X-ray (if clearly defined and 
surrounded by aerated lung.) Lymph nodes greater than 15mm on short axis are considered 
measureable as well. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
o Non-measurable disease:   
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm by 
chest X-ray or <10 mm using CT, MRI or caliper measurement), are considered non-
measurable disease.  Organomegaly, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI are all non-measurable. 
o Target lesions:   
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Lymph nodes less than 15mm in the short axis cannot be used as target 
lesions.  Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  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. 
o Non-target lesions:   
All other lesions (or sites of disease) including any measurable lesions over and above the 10 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up.  
 

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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 30 days 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 
o Clinical lesions: 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
o Chest x-ray: 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable. 
o Conventional 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 
o Ultrasound (US):  
 When the primary endpoint of the study is objective response evaluation, US should not be 
used to measure tumor lesions.  It is, however, a possible alternative to clinical measurements 
of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US might 
also be useful to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination 
o Endoscopy, Laparoscopy:   
The utilization of these techniques for objective tumor evaluation has not yet been fully and 
widely validated.  Their uses in this specific context require sophisticated equipment and a 
high level of expertise that may only be available in some centers.  Therefore, the utilization 
of such techniques for objective tumor response should be restricted to validation purposes 
in reference centers. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained. 
o Tumor markers: 
Baseline PSA is defined as the last known PSA prior to the onset of ADT (anti-androgen or 
LHRH agonist/antagonist).PSA response criteria will be a part of overall response assessment 
and will also be recorded as a separate PSA response criteria. They are follows: 
− 
PSA CR - PSA <0.04 confirmed at least 3 weeks later  
− 
PSA PR - PSA decline by >50 % from baseline, confirmed at least 3 weeks later 
− 
PSA SD - PSA not meeting criteria for CR, PR or PD 

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− 
PSA PD - PSA increase by ≥ 25 % over baseline and to at least PSA >2 ng/mL 
confirmed at least 3 weeks later 
o Cytology, Histology: 
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, 
where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
 
 

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APPENDIX D: RESPONSE CRITERIA 
Response and progression will be evaluated in this study using modified Prostate Cancer Working Group 
2 criteria [43].  
Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions. Lymph node CR is when the 
lymph node has decreased to less than 10mm in the short axis. 
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. 
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 (including the baseline scan if that is the 
smallest), and at least a 5mm increase or the appearance of new 
lesions. 
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. 
 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
Disappearance of all non-target lesions and  PSA level  <0.04 
(undetectable)   
Incomplete Response/Stable 
Disease (SD) 
Persistence of one or more non-target lesion(s) and/or  of PSA 
≥0.04 but no increase ≥ 25 % over baseline and to at least PSA >2 
ng/mL 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. . PSA increase by ≥ 25 % 
over baseline and to at least PSA >2 ng/mL . However, unequivocal 
progression should not normally trump target disease status.  It 
must be representative of overall disease status change, not a 
single lesion increase 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
measurement criteria, but confirmation is not necessary. 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
PSA 
Overall 
Response 
CR 
CR 
No 
<0.04 
CR 
CR 
Non-
CR/Non-PD 
No 
Decline by >50% from baseline –pre ADT 
PR 
PR 
Non-PD 
No 
Decline by >50% from baseline –pre ADT 
PR 
SD 
Non-PD 
No 
No increase by 25 % over baseline  and to a value of >2 
ng/dL 
SD 

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Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
PSA 
Overall 
Response 
PD 
Any 
Yes or 
No 
Any 
PD 
Any 
PD* 
Yes or 
No 
Any 
PD 
Any 
Any 
Yes 
Any 
PD 
Any 
Any 
Any 
increase by 25 % over baseline  and to a value of >2 
ng/dL 
PD 
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as “symptomatic deterioration”.  Every effort should be made to 
document the objective progression even after discontinuation of treatment.