A Phase 2 Study of Radium-223 and Radiotherapy in Hormone-Naïve Men With Oligometastatic Prostate Cancer to Bone
Phase: PHASE2
Conditions: Prostate Cancer Metastatic to Bone
Sponsor: University of Utah

 
Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
 
A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with 
Oligometastatic Prostate Cancer to bone 
Trial ID HCI102312/ IRB#102312 
Bayer Study Number: IIR-US-2016-1635 
 
 
Principal Investigator 
Jonathan Tward, MD, PhD 
Huntsman Cancer Institute 
2000 Circle of Hope 
Salt Lake City, UT 84112 
jonathan.tward@hci.utah.edu  
 
               Medical Monitor 
Randa Tao, MD 
Drug Manufacturer  
Bayer 
 
Investigational agent 
Radium-223 
 
 
 
IND Number 
Exempt  
 
NCT Identifier 
NCT03304418 
 
 
 
Historical Protocol Versions 
Version 1: 29AUG2017 
Version 2: 09JUL2018 
Version 3: 19DEC2018 
Version 4: 11MAR2019 
Version 5: 25OCT2019 
Version 6: 27MAR2020 
Version 7: 27AUG2020 
Version 8: 08APR2021 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 2 of 73 
 
TABLE OF CONTENTS 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 
Protocol Signature Page….………………………….........................................................9 
Study Summary………………………………………………………...………………10 
1 
OBJECTIVES ........................................................................................................... 10 
1.1 
Primary Objectives and Endpoint ....................................................................10 
1.2 
Secondary Objectives and Endpoint ................................................................10 
1.3 
Exploratory Objectives ....................................................................................11 
2 
BACKGROUND ...................................................................................................... 11 
3 
DRUG AND RAdiation Therapy INFORMATION................................................. 13 
3.1 
Radium Ra-223 (Drug information for Radium-223 taken from the 
investigators brochure and Xofigo prescribing information. .........................................13 
3.2 
External beam radiation therapy ......................................................................19 
4 
STUDY DESIGN...................................................................................................... 20 
4.1 
Description.......................................................................................................20 
4.2 
Number of Patients ..........................................................................................20 
4.3 
Number of Study Centers ................................................................................20 
4.4 
Study Duration .................................................................................................20 
5 
ELIGIBILITY CRITERIA........................................................................................ 21 
5.1 
Inclusion Criteria .............................................................................................21 
5.2 
Exclusion Criteria ............................................................................................22 
6 
STRATIFICATION .................................................................................................. 24 
7 
TREATMENT GUIDELINE .................................................................................... 24 
7.1 
External Beam Radiation Administration Schedule ........................................24 
7.2 
Radium-223 .....................................................................................................28 
7.3 
Prohibited Concomitant Medications ..............................................................33 
7.4 
Duration of Therapy ........................................................................................33 
8 
TOXICITIES AND DOSEAGE MODIFICATION ................................................. 34 
8.1 
Dose Modifications..........................................................................................34 
8.2 
Supportive Care ...............................................................................................36 
9 
STUDY CALENDAR .............................................................................................. 37 
10 CRITERIA FOR EVALUATION AND ENDPOINT .............................................. 39 
Assessment of clinical outcomes: ..................................................................................39 
10.1 
Primary Endpoint – 15 month Hormone Free Survival ...................................39 
RECIST 1.1 and PCGW 2 Assessments: .......................................................................40 
10.2 
Myriad CCP Correlative studies. .....................................................................42 
10.3 
Safety ...............................................................................................................43 
10.4 
Stopping Rules .................................................................................................43 
11 STATISTICAL CONSIDERATIONS...................................................................... 43 
12 REGISTRATION GUIDELINES ............................................................................. 44 
13 DATA SUBMISSION SCHEDULE ........................................................................ 45 
14 SPECIAL INSTRUCTIONS .................................................................................... 46 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 3 of 73 
 
14.1 
Myriad CCP and HRD Analysis ......................................................................46 
15 ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 46 
15.1 
Informed consent .............................................................................................46 
15.2 
Institutional Review .........................................................................................46 
15.3 
Data and Safety Monitoring Plan ....................................................................46 
15.4 
Adverse Events / Serious Adverse Events .......................................................46 
15.5 
SAE Reporting Requirements .........................................................................49 
15.6 
Reporting of Pregnancy ...................................................................................50 
15.7 
Protocol Amendments .....................................................................................50 
15.8 
Protocol Deviations .........................................................................................51 
15.9 
FDA Annual Reporting ...................................................................................51 
15.10 
Clinical Trials Data Bank ................................................................................51 
15.11 
Record Keeping ...............................................................................................51 
16 BIBLIOGRAPHY ..................................................................................................... 52 
17 APPENDIX ............................................................................................................... 53 
17.1 
PROMIS-29 Questionnaire..............................................................................53 
 
55 
Appendix 17.2 EPIC Questionnaire ...............................................................................56 
Appendix 17.3 Bayer Radium Ordering ........................................................................68 
Appendix 17.4 Radium-223 Patient Handouts ..............................................................71 
Appendix 17.5 ECOG/KPS Conversion ........................................................................73 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 4 of 73 
 
LIST OF ABBREVIATIONS 
Abbreviation or 
Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 5 of 73 
 
Abbreviation or 
Term1 
Definition/Explanation 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional review board 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 6 of 73 
 
Abbreviation or 
Term1 
Definition/Explanation 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 7 of 73 
 
Abbreviation or 
Term1 
Definition/Explanation 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
All of these abbreviations may or may not be used in protocol.  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 8 of 73 
 
PROTOCOL SIGNATURE 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein 
and according to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practice, and the applicable laws 
and regulations of the federal government. I will promptly submit the protocol to the IRB 
for review and approval. Once the protocol has been approved by the IRB, I understand 
that any modifications made during the course of the study must first be approved by the 
IRB prior to implementation except when such modification is made to remove an 
immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study treatment, the conduct of 
the study, and the obligations of confidentiality. 
 
Note: This document is signed electronically through submission and approval by the 
Principal Investigator in the University of Utah IRB Electronic Research Integrity and 
Compliance Administration (ERICA) system. 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 9 of 73 
 
STUDY SUMMARY 
 
Title 
A Phase 2 study of Radium-223 and 
Radiotherapy in Hormone-Naïve Men with 
Oligometastatic Prostate Cancer to bone 
Short Title 
Radium-223 and Radiotherapy for 
Oligometastatic ProstatE cancer (RROPE) 
Protocol Number 
IRB #102312 
IND 
IND Exempt 
Phase 
Phase IIA 
Design 
Prospective, single arm, non-randomized, 
non-blinded open label study of Radium-
223 and radiotherapy in men with 
oligometastatic prostate cancer to bone 
Study Duration 
3-4 years (accrual at 2 patients per month. 
Study duration 6 months per patient. 2 year 
follow up.) 
Study Center(s) 
This is a single site study conducted at the 
Huntsman Cancer Institute 
Objectives 
Primary Objective: Freedom from 
Androgen Deprivation Therapy (ADT) or 
other antineoplastic systemic at 15 months. 
Secondary Objective: QOL assessments, 
Progression Free Survival, Overall 
Survival 
Number of Subjects 
20 
Diagnosis and Main Eligibility Criteria 
Men with Prostate Cancer and no more than 
5 sites of bony metastatic disease without 
visceral involvement. 
Study Product, Dose, Route, Regimen 
 Radium-223 55 kBq (1.49 
mCi)/kg (+/- 10% total dose) at 
study enrollment, and then 
every 4 weeks following 
definitive radiation therapy for a 
total of six Radium-223 
infusions. 
 Hypofractionated Radiotherapy 
to all oligometastatic sites 
Duration of administration 
6 months of therapy 
Reference therapy 
Institutional Care Standard (99% of subjects 
starting Androgen Deprivation Therapy by 
15 months) 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 10 of 73 
 
Statistical Methodology 
Assess the proportion of ADT naïve men 
who progress and require ADT at 15 
months. 
1 
OBJECTIVES 
We hypothesize that treatment with Radium-223 and focal radiotherapy to 5 
or fewer sites of clinically detectable bony metastases will delay the time to 
start systemic therapies (androgen deprivation therapies (ADT) or other 
antineoplastic systemic therapies). This hypothesis will be tested through the 
following aims. 
1.1 
Primary Objectives and Endpoint 
 Determine if 20% of ADT naïve men treated with concurrent EBRT 
and Radium-223 will not require ADT for progression by 15 months.  
Endpoint: Determine the time from start of study therapy to start of 
ADT. 
1.2 
Secondary Objectives and Endpoint 
 Determine the hormone-therapy free survival time for men treated with 
concurrent EBRT and Radium-223 and determine whether it is a 30% 
risk reduction over the SWOG intermittent ADT historic cohort 
Endpoint: Determine the time from start of study therapy to start of 
ADT. 
 Evaluate health-related quality of life (QOL) as scored by the 50-item 
Expanded Prostate Inventory Composite (EPIC) EPIC urinary, bowel, 
sexual, and hormonal domains. The PROMIS 29 will be used to assess 
general function and well-being 
Endpoint: The PROMIS 29 will be used to assess general function and 
well-being. 
 Evaluate time to first skeletal related event (SRE) 
Endpoint: Documentation of complications associated with bone 
metastases and may include (but not limited to) fractures, spinal cord 
compression, bone pain, and hypercalcemia. 
 Evaluate the PSA doubling time 
Endpoint: Time elapsed from baseline PSA to double in value. 
  
 Evaluate overall survival at 2 years relative to the SWOG intermittent 
ADT historic cohort. 
Endpoint: Patients will be followed for survival for two years after 
study enrollment 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 11 of 73 
 
 Evaluate CTCAE version 4.0 toxicities in the study population 
Endpoint: Patients will be monitored for adverse events related to 
Radium-223 and EBRT using CTCAE criteria. 
1.3 
Exploratory Objectives 
 Evaluate whether a commercially available cell-cycle progression gene 
assay (Myriad CCP) performed on the original prostate biopsy or 
surgical pathology specimen correlates with biochemical or clinical 
progression free survival in the study population. 
 Evaluate whether a commercially available homologous recombination 
DNA repair assay correlates with biochemical or clinical progression 
free survival in the study population (Myriad HRD). 
 
2 
BACKGROUND 
 
Background: Prostate cancer is the most commonly diagnosed cancer in the United States 
and second leading cause of cancer death. At diagnosis, approximately 10% of men will 
have bone metastases identified on technetium bone scan [1]. These bone metastases can 
result in skeletal related events (SREs) causing substantial morbidity [2]. Men with five 
or fewer prostate cancer bone metastases noted on initial bone scan have a 94% 2-year 
survival rate, and a significantly favorable overall survival when compared to those with 
more lesions [3]. The current standard of care for men with overt metastatic disease is 
immediate androgen deprivation therapy (ADT) [4]. Long term androgen deprivation 
therapy results in a significant decrement in quality of life[5] and a host of unfavorable 
side effects including but not limited to loss of libido, lack of energy, difficulty 
concentrating, hot flashes, decreased bone density, decreased muscle mass, and increased 
risk of heart attack and stroke. Although ADT will delay the appearance of tumor related 
symptoms in metastatic patients, there are no data that it prolongs overall survival[4]. 
Developing novel strategies to control metastatic prostate cancer with side effect profiles 
superior to that of ADT or other approved systemic agents is highly desirable. External 
beam radiation treatment is effective at controlling both primary and metastatic prostate 
cancers, and Radium-223 has demonstrated a survival benefit in castrate-resistant 
prostate cancers. Both forms of therapy have been shown to palliate painful bony lesions.  
 
Rationale for the combination of Radium-223 and External Beam Radiation: Radium-223 
is a calcium-mimetic radiopharmaceutical that accumulates in bones and emits alpha 
radiation from Radium-223 decay and releases relatively high energy with a narrow range 
(2 to 10 cells)[5]. Following promising results in a phase II trial, the phase III 
ALSYMPCA trial was conducted in mCRPC with symptomatic bone metastases who 
either had received or were ineligible for docetaxel [6, 7]. Patients received 6 doses of 
Radium-223 50 kBq/kg intravenously every 4 weeks. A pre-planned interim analysis 
showed a significant 2.8-month median OS benefit compared to the placebo arm (14 vs. 
11.2 months), which is anticipated to lead to regulatory approval [8]. An updated analysis 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 12 of 73 
 
showed a further improvement in overall survival to 3.6 months with a hazard ratio of 
0.695 (i.e., 30.5% reduction in risk of death) [9]. Moreover, the toxicity profile appeared 
excellent with grades 3-4 neutropenia in 1.8% and thrombocytopenia in 4% of patients. 
Reassuringly, long-term, 24-month outcomes in the previous randomized phase II trial 
showed no increase in hematologic toxicities [6, 7].  
 
Radiotherapy for Oligometastasis: In 1995, Hellman and Weichselbaum coined the term 
“oligometastases” to characterize a state of limited metastasis in which aggressive local 
control measures could be potentially curative [10, 11]. This led to the development of 
prospective clinical trials employing the use of Stereotactic Body Radiotherapy (SBRT) 
to ablate visible oligometastatic disease with curative intent [12]. This approach has been 
demonstrated to be safe and effective, with local control rates in the 80% range, and 
durable progression-free survival rates around 20%. In one of the only trials evaluating 
the role of SBRT exclusively in 40 patients with bone only metastatic prostate cancer, the 
actuarial 24-month local tumor control rate was 95.5% as measured by MRI and PET CT 
imaging and the median initial PSA before treatment was 5.4 ng/dl which dropped to 2.7 
ng/dl after 3 months [13]. We propose that the combination of external beam 
radiotherapy and Radium-223 will be an effective therapy at controlling oligometastatic 
prostate cancer in hormone-therapy naïve patients.  
 
Comparator Cohort:  
 
At the Huntsman Cancer Institute at the University of Utah, 100% of persons have been 
started on systemic therapies to treat their metastatic prostate cancer by 15 months of the 
identification of oligometastasis. The goal of the current study is to assess whether the 
Radium-223 and EBRT to oligometastatic sites will delay the need to initiate additional 
antineoplastic systemic therapies by 15 months. 
 
Other Comparators of interest that are not specified as the primary aim: 
 
In 2012 the SWOG cooperative group reported mature results of a randomized trial 
evaluating continuous versus intermittent androgen-deprivation therapy in men with 
hormone-naïve metastatic prostate cancer [14]. This trial was pivotal in cementing the 
care standard of immediate and continuous androgen deprivation in men with hormone-
naïve metastatic prostate cancer, as a median survival benefit was noted over the 
intermittent cohort despite the fact that, statistically speaking, inferiority of intermittent 
therapy was not proven nor disproven. Men on the intermittent therapy arm did have 
significant improvement in quality of life domains. Notably, 78% of persons on the 
“intermittent” androgen therapy arm had to resume ADT within the first 15 months. 
Additionally, the investigators of this study classified patients as having “minimal” 
versus “extensive” disease as an analysis stratification. Minimal disease was defined as 
disease confined to the spine, pelvic bones, or lymph nodes. Those with visceral 
metastasis or other bony sites were classified as extensive. At 2 years, subjects with 
“minimal disease” receiving intermittent androgen deprivation had an 85% overall 
survival. We propose using the intermittent ADT cohort of the SWOG trial as a historic 
comparator of efficacy to this study. 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 13 of 73 
 
Oligometastasis is a limited disease state that some have postulated may by curable. We 
will use best available ablative therapies to destroy gross tumor, and allow radium--223 
to obliterate occult sites of metastasis that cannot be resolved by available imaging 
modalities. This may lead to delay of initiation of ADT or other antineoplastic systemic 
therapies, improved QOL, survival benefit, and potential cure. 
Reference treatment is the standard of care use of immediate and continuous ADT as well 
as other reasonable standards of intermittent ADT, or other antineoplastic systemic 
therapies. Hypofractionated radiotherapy is not routinely used in asymptomatic lesions 
unless there is risk of impending pathologic injury. 
3 
DRUG AND RADIATION THERAPY INFORMATION  
3.1 Radium Ra-223 (Drug information for Radium-223 taken from the 
investigators brochure and Xofigo prescribing information. 
 Description 
 
Radium Ra-223 dichloride, an alpha particle-emitting pharmaceutical, is a 
radiotherapeutic drug. Radium Ra-223 dichloride is supplied as a clear, colorless, 
isotonic, and sterile solution to be administered intravenously with pH between 6 
and 8. Each milliliter of solution contains 1100 kBq Radium-223 dichloride (30 
microcurie), corresponding to 0.58 ng radium-- 223, at the reference date. Radium 
is present in the solution as a free divalent cation. Each vial contains 6 mL of 
solution (6,600 kBq (178 microcurie) Radium-223 dichloride at the reference 
date). The inactive ingredients are 6.3 mg/mL sodium chloride USP (tonicity 
agent), 7.2 mg/mL sodium citrate USP (for pH adjustment), 0.2 mg/mL 
hydrochloric acid USP (for pH adjustment), and water for injection USP. The 
molecular weight of Radium-223 dichloride, 223RaCl2, is 293.9 g/mol. Radium-
223 has a half-life of 11.4 days. The specific activity of Radium-223 is 1.9 MBq 
(51.4 microcurie)/ng. The six-stage-decay of Radium-223 to stable lead-207 
occurs via short-lived daughters, and is accompanied predominantly by alpha 
emissions. There are also beta and gamma emissions with different energies and 
emission probabilities. The fraction of energy emitted from Radium-223 and its 
daughters as alpha-particles is 95.3% (energy range of 5 - 7.5 MeV). The fraction 
emitted as beta-particles is 3.6% (average energies are 0.445 MeV and 0.492 
MeV), and the fraction emitted as gamma-radiation is 1.1% (energy range of 0.01 
- 1.27 MeV).  
 
NIST Standardization 
 
The quantification of Radium-223 radioactivity is based on the primary 
standardization performed by the US NIST. National Institute of Standards and 
Technology prepares the standard reference material (SRM) using an official dial 
setting (primary standardization) as published (as provided in the Investigator 
Brochure). The NIST SRM is used to calibrate the instruments in production and 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 14 of 73 
 
quality control for both the drug substance and drug product. Additionally, the 
NIST SRM is used to prepare the NIST traceable Ra-223 reference materials 
which are then sent to the end users (e.g., nuclear medicine laboratory physicians 
or technicians) for dial-setting of their dose calibrators, to allow verification of the 
patient dose. 
 
In 2014, NIST performed a re-assessment of the primary standardization based on 
preliminary information suggesting a potential discrepancy of approximately 8-
10% between the published NIST primary standardization (as provided in the 
Investigator Brochure) and results obtained by other national metrology institutes 
(United Kingdom, Germany, Japan). After completion of the re-assessment, NIST 
reported their findings (ss provided in the Investigator Brochure) and had issued a 
revised NIST SRM in 2015. The discrepancy in the NIST standardization was 
determined to be −9.5% between activity values obtained using the old reference 
standard relative to the new primary standardization. Consequently the current 
numerical values need to be corrected by approx. + 10.5%. 
 
The current NIST standard for Radium-223 dichloride remained in effect until 
4/25/16. As of that date the FDA approved the regulatory variation submitted for 
Radium-223. The change in the numerical description of the patient’s dose, 
product strength and labeled vial activity does not impact the safety or efficacy of 
Radium-223. The change in the NIST Radium-223 standard has no impact on 
subjects; dose subjects are receiving, and will continue to receive. Subjects will 
receive the same actual dose and volume that was studied in Study 15245 (BC1-
06 dosimetry study) and is associated with the proven safety and efficacy of 
Radium-223 dichloride, though the stated nominal radiation dose received is 
being updated to reflect the new standard. The current dose regimen of Radium-
223 is 55 kBq (1.49 microcurie) per kg body weight.  
 Mechanism of Action 
The active moiety of Radium Ra-223 dichloride is the alpha particle-emitting 
isotope Radium-223 (as radium Ra-223 dichloride), which mimics calcium and 
forms complexes with the bone mineral hydroxyapatite at areas of increased bone 
turnover, such as bone metastases. The high linear energy transfer of alpha 
emitters (80 keV/micrometer) leads to a high frequency of double-strand DNA 
breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The 
alpha particle range from Radium-223 dichloride is less than 100 micrometers 
(less than 10 cell diameters) which limits damage to the surrounding normal 
tissue. 
 Preclinical 
In single and repeated dose toxicity studies in rats, the main findings were 
reduced body weight gain, hematological changes, reduced serum alkaline 
phosphatase and microscopic findings in the bone marrow (depletion of 
hematopoietic cells, fibrosis), spleen (secondary extra-medullary hematopoiesis) 
and bone (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous lesions, 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 15 of 73 
 
disruption/disorganization of the physis/growth line). These findings were related 
to radiation-induced impairment of hematopoiesis and a reduction of osteogenesis 
and occurred beginning in the dose range of 20 (0.00056 mCi) – 80 kBq (0.0022 
mCi) per kg body weight, with the exception of body weight decreases. 
Dose-limiting myelotoxicity was seen in dogs after single administration of 450 
kBq (0.012 mCi) Radium Ra-223 dichloride per kg body weight (9 times the 
clinically recommended dose).  
Osteosarcomas, a known effect of bone-seeking radionuclides, were observed at 
clinically relevant doses in rats 7 to 12 months after start of treatment. 
Osteosarcomas were not observed in dog studies. The presence of neoplastic 
changes, other than osteosarcomas, was also reported in the longer term (12 to 15 
months) rat toxicity studies. Due to its mode of action, and as seen with 
conventional radiotherapy and other radiotherapeutics, Radium-223 dichloride 
may have the potential to induce secondary malignancies. No case of 
osteosarcoma has been reported in clinical studies with Radium Ra-223 
dichloride. The risk for patients to develop osteosarcomas with exposure to 
Radium Ra-223 dichloride is unknown at present.  
 
Studies on reproductive and developmental toxicity have not been performed. 
Since Radium Ra-223 dichloride binds to bone, the potential risk for toxic effects 
in the male gonads in cancer patients with castration-resistant prostate cancer is 
very low, but cannot be excluded. Studies on the mutagenic and carcinogenic 
potential of Radium Ra-223 dichloride have not been performed. 
 
No histological changes were observed in organs involved in the excretion of 
Radium Ra-223 dichloride. No significant effects were seen on vital organ 
systems, i.e., cardiovascular (dog), respiratory or central nervous systems (rat), 
after single dose administration of 450 to 1000 kBq (0.012 to 0.027 mCi) per kg 
body weight (9 (dog) to 20 (rat) times the clinically recommended dose. 
 Clinical Experience Summary 
The clinical development of Radium Ra-223 dichloride includes phase I and 
phase II studies in prostate cancer patients with bone metastases. The results of 
these completed studies indicated that safety and tolerability of Radium Ra-223 
dichloride in CRPC/HRPC patients with bone metastases was well tolerated, and 
that there was evidence of dose related efficacy against bone markers and other 
markers of disease. In addition there was an effect on median overall survival in a 
Phase II (BC1-02) placebo-controlled study. These studies enabled the initiation 
of the Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) 
study. 
The clinical safety and efficacy of Radium Ra-223 dichloride have been evaluated 
in a double-blind, randomized, multiple dose, phase III multicenter study 
(ALSYMPCA) in castration-resistant prostate cancer patients with bone 
metastases. The primary efficacy endpoint was Overall Survival (OS).  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 16 of 73 
 
At the cut-off date of the pre-planned interim analysis, a total of 809 patients were 
randomized 2:1 to receive Radium Ra-223 dichloride 50 kBq (0.0014 mCi)/kg 
intravenously every 4 weeks for 6 cycles (N=541) plus best standard of care or 
matching placebo plus best standard of care (N=268). Best standard of care 
included e.g., local external beam radiotherapy, corticosteroids, antiandrogens, 
estrogens, estramustine, or ketoconazole.  
An updated descriptive analysis of safety and of OS was performed in 921 
randomized patients prior to implementing crossover (i.e., offering patients in the 
placebo group to receive Radium Ra-223 dichloride treatment). 
The results of both, interim and updated analysis, revealed that OS was 
significantly longer in patients treated with Radium Ra-223 dichloride plus best 
standard of care compared to patients treated with placebo plus best standard of 
care. For the updated analysis, an increase in median overall survival of 3.6 
months was seen with Radium Ra-223 dichloride plus best standard of care 
compared to placebo plus best standard of care (HR =0.695 (95% CI 
0.581/0.832), median OS 14.9 months versus 11.3 months, respectively). 
In the ALSYMPCA study, the results of the interim analysis and the updated 
analysis showed also a significant improvement in all main secondary endpoints 
in the Radium Ra-223 dichloride arm compared to the placebo arm: 
 Time to first SRE (defined as time to EBRT, time to first pathological bone 
fracture, time to spinal cord compression and time to surgical intervention) was 
statistically significantly longer in the Radium-223 chloride group compared to 
placebo (median number of months=15.6 for Radium-223 chloride versus 9.8 
months for placebo (HR=0.658, 95 CI 0.522–0.830, p= 0.00037). 
 Time to total ALP progression (defined as ≥ 25% increase compared to 
baseline/nadir) was statistically significantly longer in the Radium-223 chloride 
group 7.4 months compared to placebo 3.8 months  (HR = 0.167, 95% CI 0.129 – 
0.217; p= <0.00001). 
 Time to PSA progression (defined as a ≥ 25% increase and an increase in absolute 
value of ≥ 2 ng/mL compared to baseline/nadir ) was also significantly prolonged 
in patients receiving Radium Ra-223 dichloride compared to patients receiving 
placebo (HR = 0.643, 95% CI 0.539,0.768; p = <0.00001) 
 A total ALP response (defined as a confirmed ≥ 30% or ≥ 50% reduction 
compared to baseline) at week 12 was observed in higher proportions of subjects 
who were treated with Radium-223 chloride group (47%  and 3% respectively) 
compared to those in the placebo (3% and <1% respectively) group.  
 Subgroup survival analysis showed a consistent survival benefit for treatment 
with Radium Ra-223 dichloride, independent of total alkaline phosphatase (ALP), 
current use of bisphosphonates, prior use of docetaxel and baseline ECOG status. 
The results from the phase III ALSYMCA study regarding time to external beam 
radiation therapy (EBRT) for pain relief and fewer patients reporting bone pain as 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 17 of 73 
 
an adverse event in the Radium Ra-223 dichloride group indicate a positive effect 
on bone pain.  
The most common adverse reactions (≥ 10%) in patients receiving Radium Ra-
223 dichloride were nausea, diarrhea, vomiting, and peripheral edema (Table 2.1). 
Grade 3 and 4 adverse events were reported among 57% of Radium Ra-223 
dichloride-treated patients and 63% of placebo treated patients. The most 
common hematologic laboratory abnormalities in Radium Ra-223 dichloride-
treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, 
thrombocytopenia, and neutropenia (Table 2.2). Treatment discontinuations due 
to adverse events occurred in 17% of patients who received Radium Ra-223 
dichloride and 21% of patients who received placebo.  
The most common hematologic laboratory abnormalities leading to 
discontinuation for Radium Ra-223 dichloride were anemia (2%) and 
thrombocytopenia (2%). 
Table 2.1 shows adverse reactions occurring in ≥ 2% of patients and for which the 
incidence for Radium Ra-223 dichloride exceeds the incidence for placebo. 
Table 2.1: Adverse Reactions in the Randomized Trial 
Laboratory Abnormalities 
Table 2.2 shows hematologic laboratory abnormalities occurring in > 10% of 
patients and for which the incidence for Radium Ra-223 dichloride exceeds the 
incidence for placebo. 
 
 
System/Organ 
Class Preferred 
Term  
Radium Ra-223 dichloride 
(n=600)  
Placebo (n=301)  
Grades 1-4 %  
Grades 3-4 %  
Grades 1-4 %  
Grades 3-4 %  
Blood and lymphatic system disorders  
Pancytopenia  
2  
1  
0  
0  
Gastrointestinal disorders  
Nausea  
36  
2  
35  
2  
Diarrhea 
25  
2  
15  
2  
Vomiting  
19  
2  
14  
2  
General disorders and administration site conditions  
Peripheral 
edema  
13  
2  
10  
1  
Renal and urinary disorders  
Renal failure 
and impairment  
3  
1  
1  
1  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 18 of 73 
 
Table 2.2: Hematologic Laboratory Abnormalities 
Laboratory values were obtained at baseline and prior to each 4-week cycle. 
Hematologic  
Radium-223 (n=600)  
Placebo (n=301)  
Laboratory  
Grades 1-4  
Grades 3-4  
Grades 1-4  
Grades 3-4  
Abnormalities  
%  
%  
%  
%  
Anemia  
93  
6  
88  
6  
Lymphocytopenia  
72  
20  
53  
7  
Leukopenia  
35  
3  
10  
<1  
Thrombocytopenia  
31  
3  
22  
<1  
Neutropenia  
18  
2  
5  
<1  
As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of 
patients on Radium Ra-223 dichloride and in 2% of patients on placebo. Among 
patients who received Radium Ra-223 dichloride, the laboratory abnormality 
grade 3-4 thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% 
of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 
1% of docetaxel naïve patients and in 3% of patients who have received prior 
docetaxel. 
Fluid Status 
Dehydration occurred in 3% of patients on Radium Ra-223 dichloride and 1% of 
patients on placebo. Radium Ra-223 dichloride increases adverse reactions such 
as diarrhea, nausea, and vomiting which may result in dehydration.  
Injection Site Reactions 
Erythema, pain, and edema at the injection site were reported in 1% of patients on 
Radium Ra-223 dichloride. 
Secondary malignant neoplasms 
No cases of radiation-induced cancer have been reported in reported in clinical 
trials with Radium-223 dichloride in follow-up of up to three years. However, the 
radiation dose resulting from therapeutic exposure may result in higher incidence 
of cancer (e.g., sarcomas of the bone, or leukemia), mutations and a potential for 
development of hereditary defects. 
Bone Marrow Suppression 
In the randomized trial, 2% of patients on the Radium Ra-223 dichloride arm 
experienced bone marrow failure or ongoing pancytopenia compared to no 
patients treated with placebo. There were two deaths due to bone marrow failure 
and for 7 of 13 patients treated with Radium Ra-223 dichloride, bone marrow 
failure was ongoing at the time of death. Among the 13 patients who experienced 
bone marrow failure, 54% required blood transfusions. Four percent (4%) of 
patients on the Radium Ra-223 dichloride arm and 2% on the placebo arm 
permanently discontinued therapy due to bone marrow suppression. 
In the randomized trial, deaths related to vascular hemorrhage in association with 
myelosuppression were observed in 1% of Radium Ra-223 dichloride-treated 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 19 of 73 
 
patients compared to 0.3% of patients treated with placebo. The incidence of 
infection-related deaths (2%), serious infections (10%), and febrile neutropenia 
(<1%) were similar for patients treated with Radium Ra-223 dichloride and 
placebo. 
Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and 
leukopenia; has been reported in patients treated with Radium Ra-223 dichloride. 
In the randomized trial, complete blood counts (CBCs) were obtained every 4 
weeks prior to each dose and the nadir CBCs and times of recovery were not well 
characterized. In a separate single-dose phase 1 study of Radium Ra-223 
dichloride, neutrophil and platelet count nadirs occurred 2 to 3 weeks after 
Radium Ra-223 dichloride administration at doses that were up to 1 to 5 times the 
recommended dose, and most patients recovered approximately 6 to 8 weeks after 
administration. 
In the Radium-233 arm of the Phase 3 clinical trial reported in Parker et al. (2013) 
12.7% (76/600) of subjects had grade 3+ anemia, 6.5% (39/600) of subjects had 
grade 3+ thrombocytopenia, and 2.2% (13/600) of subjects had grade 3+ 
neutropenia. 
The safety and efficacy of concomitant chemotherapy with Radium Ra-223 
dichloride have not been established. Outside of a clinical trial, concomitant use 
with chemotherapy is not recommended due to the potential for additive 
myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody 
external radiotherapy are administered during the treatment period, Radium Ra-
223 dichloride should be discontinued. 
3.2 
External beam radiation therapy 
Radiation therapy will be performed on linear accelerators capable of 
delivering X-ray or electron therapy in the 4MeV to 18 MeV range with 
image guidance systems.  
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 20 of 73 
 
4 
STUDY DESIGN 
4.1 
Description 
This is a phase IIa, open-label, single-arm, and prospective study of hormone 
therapy-naïve men with oligometastatic prostate cancer to the bone. The study 
will test if treating the primary tumor sites and 5 or fewer sites of bone-only 
metastasis with external beam radiation with concomitant systemic Radium-
223 will reduce the utilization of androgen deprivation therapy, improve QOL 
and improve OS over the comparator cohort of SWOG intermittent ADT 
historic cohort. 
4.2 
Number of Patients 
 20 patients  
4.3 
Number of Study Centers  
 This study will be conducted at a single site, the Huntsman Cancer Institute 
4.4 
Study Duration  
 The estimated duration for the protocol (from start of screening to last subject 
processed and finishing the study) is 3 to 4 years (Accrual at 2 patients per 
month. Study duration will be 6 months per patient. Patient will be followed 
for approximately 2 years after study enrollment).  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 21 of 73 
 
5 
ELIGIBILITY CRITERIA 
 
This eligibility checklist is used to determine patient eligibility and filed with signature in 
the patient research chart.  
 
Patient No. ______________________ 
Patient’s Initials: (L, F, M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
 _____ Asymptomatic or symptomatic hormone naïve men with 
testosterone levels ≥100 ng/dL with previously treated localized 
prostate cancer who now have rising PSAs and five or fewer bone 
metastases.  
 ____ Subjects who have been previously treated with definitive and/or 
adjuvant/salvage radiotherapy to the primary site and/or regional lymph 
nodes with concurrent ADT are allowed if the last hormone therapy 
delivered > 6 months prior. Subjects who have had more than 30 days 
and fewer than 45 days of bicalutamide monotherapy for any reason 
within the 6 months prior to enrollment are eligible for the study, 
providing they have been off of the drug for at least 30 days prior to 
enrollment. Subjects who have had fewer than 30 days of bicalutamide 
are eligible for the study, as long as they discontinue the drug at least 5 
days prior to the first study treatment. 
 _____ Histologic confirmation of Prostate Adenocarcinoma diagnosis.  
 _____ Age ≥ 18 years.  
 _____ Life expectancy of at least 2 years.  
 _____ Acceptable hematology and serum biochemistry screening 
values:  
 
o White Blood Cell Count (WBC) ≥ 3,000/mm3  
o Absolute Neutrophil Count (ANC) ≥ 1,500/mm3  
o Platelet (PLT) count ≥ 100,000/mm3  
o Hemoglobin (HGB) ≥ 10 g/dl  
o Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN)  
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 
2.5 x ULN   
o Creatinine ≤ 1.5 x ULN  
o Albumin > 2.5 mg/dL  
 _____ Willing and able to comply with the protocol, including follow-
up visits and examinations. 
 _____ Karnofsky Performance Score >60 or ECOG equivalent. 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 22 of 73 
 
 _____ Radiographic confirmation of oligometastatic diagnosis via Bone 
Scan validated by either CT scan, or MRI or PET/CT with Fluciclovine 
within the past 90 days.  
 _____ Subjects who have not had surgical removal of their prostate and 
have a partner of child bearing potential must agree to use condoms 
beginning at the signing of the ICF until at least 6 months after the last 
dose of study drug. Because of the potential side effect on 
spermatogenesis associated with radiation, female partners of 
childbearing potential must agree to use a highly effective contraceptive 
method during and for 6 months after completing treatment. 
 _____ Able to provide informed consent and willing to sign an 
approved consent form that conforms to federal and institutional 
guidelines. 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
 _____ Men with known brain or visceral metastases (except regional 
lymph nodes as defined by section 5.2.5) defined by CT or MRI 
Imaging of the abdomen or pelvis.  
 _____ Men who have had LHRH agonist or antagonist hormone 
therapy in the prior six months. 
 _____ Men with >5 validated bony metastases.  
 _____ Men with baseline serum Testosterone <100 ng/dL. 
 _____ Men with new or progressing lymphadenopathy clearly 
consistent with prostate metastasis on imaging or proven by pathologic 
biopsy at any time three months or later following their initial definitive 
therapy.  
 _____ Prior or concurrent invasive malignancy (except non-
melanomatous skin cancer) or lymphomatous/hematogenous 
malignancy unless continually disease free for a minimum of 3 years. 
All patients with in situ carcinoma are eligible for this study (for 
example, carcinoma in situ of the oral cavity is eligible) except patients 
with carcinoma of the bladder (including in situ bladder cancer or 
superficial bladder cancer). 
 _____ Use of finasteride within 30 days prior to therapy PSA should 
not be obtained prior to 30 days after stopping finasteride. 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 23 of 73 
 
 _____ Use of dutasteride within 90 days prior to therapy. PSA should 
not be obtained prior to 90 days after stopping dutasteride. 
 _____ Previous or concurrent cytotoxic chemotherapy for prostate 
cancer. 
 _____ Received systemic therapy with radionuclides (e.g., strontium-
89, samarium-153, rhenium-186, or rhenium-188, or Radium Ra-223 
dichloride) for the treatment of bony metastases.  
 ______ Men who will receive radical prostatectomy to the primary site.  
 _____ Imminent spinal cord compression based on clinical findings 
and/or magnetic resonance imaging (MRI). Spinal Cord compression 
will be defined as 360-degree circumferential obliteration of T2 
cerebrospinal fluid signal around the spinal cord. Treatment should be 
completed for spinal cord compression. 
 _____ Severe, active co-morbidity, defined as follows: 
 
 Unstable angina and/or congestive heart failure requiring 
hospitalization within the last 6 months 
 Transmural myocardial infarction within the last 6 months 
 Acute bacterial or fungal infection requiring intravenous antibiotics 
at the time of registration 
 Chronic obstructive pulmonary disease exacerbation or other 
respiratory illness requiring hospitalization or precluding study 
therapy at the time of registration 
 Hepatic insufficiency resulting in clinical jaundice and/or 
coagulation defects; note, however, that laboratory tests for liver 
function and coagulation parameters are not required for entry into 
this protocol. (Patients on Coumadin or other blood thinning agents 
are eligible for this study.) 
 Acquired Immune Deficiency Syndrome (AIDS) based upon 
current CDC definition; note, however, that HIV testing is not 
required for entry into this protocol. The need to exclude patients 
with AIDS from this protocol is necessary because the treatments 
involved in this protocol may be significantly immunosuppressive. 
 _____ Cardiac failure New York Heart Association (NYHA) III or IV 
Crohn’s disease or ulcerative colitis. 
 _____ Bone marrow dysplasia. 
 _____ Fecal incontinence. 
 _____ Any condition which, in the investigator’s opinion, makes the 
subject unsuitable for trial participation.  
 
I certify that this patient meets all inclusion and exclusion criteria for 
enrollment onto this study.  
 
______________________________ 
 
_________ 
_______ 
Investigator Signature  
 
 
 
Date  
Time 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 24 of 73 
 
6 
STRATIFICATION  
Not Applicable: This study will consist of subjects initially diagnosed 
with M0 prostate cancer at presentation who have completed definitive 
treatment to the prostate, seminal vesicles, and regional lymph nodes (if 
applicable), who then later developed oligometastatic disease. 
7 
TREATMENT GUIDELINE 
7.1 
External Beam Radiation Administration Schedule 
 All external beam radiations oligometastatic sites will commence after 
cycle one of Radium-223 but prior to cycle two of Radium-223.  
7.1.1.1 
All lesions seen on bone scan and corroborated by the 
validating scans will be treated. If there are additional 
suspicious bone lesions seen on Bone scan, CT, MRI, 
PET/CT, or treatment-planning simulation scans, but not 
corroborated by a second scan, they can be targeted at 
the treating physician’s discretion as long as no more 
than 5 lesions total are targeted with external beam 
radiation. 
 External Beam radiation for Oligometastasis 
7.1.2.1 Dose Specification 
 
All subjects will receive Stereotactic body or hypofractionated radiation to 
sites of bone disease seen on imaging studies using any one of the 
isoequivalent radiation regimens (based on the linear quadratic model with 
EQD2=60gy and an alpha/beta ration for prostate cancer= 2). EQD2 
(equivalent radiobiological dose if converted to 2Gy daily fractions) is being 
utilized to allow the radiation oncologist the flexibility to give an ablative 
dose to tumor but allow for differing regimens to spare critical normal tissues 
depending on tumor location.  
Any of the following regimens are considered ablative, acceptable, and are 
biologically equivalent to 60Gy EQD2: 
o Single fraction: 16 Gy total at 16 Gy per fraction (SBRT) 
o Three fractions: 24 Gy total at 8 Gy per fraction (SBRT) 
o Five fractions: 30 Gy total at 6 Gy per fraction (SBRT). When using 
five fractions, can reduce to 25 Gy total at 5 Gy per fraction (SBRT) or 
to a minimum of 20 Gy total at 4 Gy per fraction (SBRT), per treating 
investigator. 
o Six fractions: 32.4 Gy total at 5.4Gy per fraction (Hypofractionated) 
If any of the fractions need to be further reduced, this can be done in 
consultation with the medical monitor.  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 25 of 73 
 
7.1.2.2 Target Localization 
 
This study requires the use of IGRT. NRG Oncology defines IGRT as a 
computer-assisted process that uses imaging devices that generate a series of 
coordinates for shifting the patient support system in three orthogonal 
directions (sometimes including rotational changes) to position the treatment 
beams relative to target regions. The allowed technologies are as follows: 
cone-beam CT (CBCT) using either a specially mounted kV imaging head or 
the MV treatment beam with an opposed electronic imaging panel, dual 
fixed-position in-room kV imaging systems that are orthogonal or near 
orthogonal, an in-room standard diagnostic CT scanner that is geometrically 
linked to the treatment unit, and the tomotherapy approach. 
Simple portal imaging approaches that do not use computer assistance are not 
considered to be suitable for this study. 
When the treatment equipment is not equipped with any device that allows 
direct visualization of anatomical structures using the treatment beam, the 
recommendations of AAPM Task Group Report 142 for testing the 
coincidence of the imaging and treatment reference points must be 
implemented. For example, verification of treatment and imaging isocenter 
coincidence must be performed routinely for the CyberKnife, Tomotherapy 
units as well as any BrainLab equipment that does not include an electronic 
portal imaging device (EPID) that intercepts the treatment beam. 
7.1.2.3 Target Volume Definition 
Non-Spinal Osseous Sites: GTV= gross tumor apparent on CT or MRI, or 
PET/CT imaging. CTV= GTV. PTV will be uniform expansion of 3 to 5 mm. 
Spinal Osseous Sites: GTV= gross tumor apparent on CT or MRI, or PET/CT 
imaging. The GTV will include 1 of the following: 
(a) The vertebral body only OR 
(b) The vertebral body and pedicle OR 
(c) Posterior elements only 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 26 of 73 
 
CTV= GTV. PTV will be as per RTOG 0631.  
 
7.1.2.4 Planning Techniques  
General Considerations: A variety of planning techniques can be used to 
deliver SBRT for each metastasis. General guidelines include the following: 
 Multiple coplanar or non-coplanar beam arrangements are acceptable. 
 Typically 7 to 13 static radiation beams with equal weighting are 
used. It is recommended that at least 10 beams be used when 
possible. 
 A minimum field dimension of 3 cm should be observed treating small 
metastases. 
 Dynamic conformal arcs are acceptable. It is recommended that 
arcs span at least 340 degrees. 
 For non-IMRT or dose painting techniques, the conformal field 
aperture size and shape should correspond nearly identically to the 
projection of the PTV along a beam’s eye view (i.e., no additional 
“margin” for dose buildup at the edges of the blocks or MLC jaws 
beyond the PTV). The only exception will be when observing the 
minimum field dimension of 3 cm when treating small lesions. 
 The prescription isodose line covering 95% the PTV will generally 
be 80-90% but may range from 60-90% where the maximum dose is 
100%. As a result, a “hotspot” will exist within the PTV that is 
equal to the prescription dose divided by the prescription isodose 
line (i.e., 45Gy/0.6 = 75Gy when 45Gy is prescribed to the 60% 
isodose). 
 Doses higher than the prescription isodose (i.e., hotspots) should 
be manipulated to occur within the target. 
 
Dose calculations: All dose distributions shall include corrections for tissue 
heterogeneities. Normalization: The treatment plan should be initially 
normalized such that 100% corresponds to the maximum dose within the PTV 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 27 of 73 
 
(MAXPTV). While this point will typically correspond to the PTV center of mass, 
it can be located elsewhere within the PTV. 
1. 
Prescription Isodose Surface Coverage: The prescription isodose surface 
will be chosen such that 95% of the target volume (PTV) is conformally covered 
by the prescription isodose surface. Doses less than 95% of the prescription dose 
are restricted to the outside edges of the PTV. The prescription isodose surface 
selected MUST be ≥ 60% and ≤90% of the dose maximum within the PTV 
(MAXPTV). The MAXPTV corresponds to the normalization point (100%) of 
the plan as noted above. 
2. 
Target Dose Heterogeneity: Rather than prioritizing target dose 
homogeneity, SBRT treatment planning prioritizes adequate minimum target 
coverage and rapid dose fall-off gradients outside of the target. Hot spots 
within targets are generally accepted without consequence since targets are 
mostly tumor. The only exception is when the hotspot within the PTV also 
intersects an OAR. 
3. Critical Organ Doses: Respect all critical organ dose volume limits as 
described by either: The report of AAPM Task Group 101, the NRG BR-001 
protocol, or the RTOG 0631 treatment protocol.  
4. High-Dose Spillage: 
a. Location: Any dose > 105% of the prescription dose should occur within the 
PTV and not within the normal tissues outside the PTV.  
b. Volume: Acceptable isodose distributions should be as conformal as 
possible. To this end the ratio of prescription isodose volume to PTV should 
be as small as possible. 
i. 
The ratio of the prescription isodose volume to the PTV volume should be < 
1.2. Acceptable variations include a ratio of 1.2 to 1.5. Ratios above 1.5 will 
be considered unacceptable variations. The prescription line for each lesion 
will be contoured for calculation of this ratio. The prescription line will be 
labelled as V_5000 with the 5000 changing to reflect the prescription dose in 
cGy.  
ii. Guidelines for the ratio of the 50% prescription isodose volume to the PTV 
volume (R50%) and for the maximum dose at 2cm (D2cm) from the PTV 
are given in Table 7.1.2.4. Because it may become more difficult to restrict 
the 50% isodose volume when dose is summed from treatment of multiple 
metastases, this ratio should be evaluated for dose calculated for a single 
metastasis (i.e., not for composite dose). This is acceptable as long as 
normal tissue constraints are met. 
iii. Elliptically shaped metastases as well as extremity metastases may not meet 
these guidelines. This is acceptable as long as normal tissue constraints are 
respected. 
iv. These criteria will not be required in treating very small tumors (<2.5 cm 
axial GTV dimension or < 1.5 cm craniocaudal GTV dimension) in which 
the required minimum field size of 3 cm results in the inability to meet a 
conformity ratio of 1.5. 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 28 of 73 
 
Table 7.1.2.4 
PTV Volume (cc) 
Ratio of 50% Prescription 
Isodose Volume to PTV 
Volume, R50% 
Maximum Dose at 2cm (D2cm) 
from PTV in any direction as % 
of Prescribed Dose 
1.8 
< 7.5 
<57.0 
3.8 
< 6.5 
<57.0 
7.4 
< 6.0 
<58.0 
13.2 
< 5.8 
<58.0 
22.0 
< 5.5 
<63.0 
34.0 
< 5.3 
<68.0 
50.0 
< 5.0 
<77.0 
70.0 
< 4.8 
<86.0 
95.0 
< 4.4 
<89.0 
126.0 
< 4.0 
<91.0 
163.0 
< 3.7 
<94.0 
NOTE: For values of PTV dimension or volume not specified, linear 
interpolation between table entries is required. 
NOTE: For tumors within 2 cm of the skin, it may be difficult to meet 
the values for D2cm and R50%. In these cases, these criteria will not be 
used. 
7.2 
Radium-223 
 
Radium Ra-223 dichloride will be delivered intravenously at 55 kBq (1.49 mCi)/kg (+/- 
10% total dose) for a total of six cycles. 1 cycle= 28 days. The first cycle will commence 
at study enrollment, then cycles 2 through 6 will commence after the completion of 
radiotherapies at 4-week intervals. 
 How Supplied, Stored, Packaged, and Labeled 
The alpha-pharmaceutical 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 is intended for a single use only. Radium-223 ordering 
documents are located in Appendix 17.3 Clinical Supply Agreement. Instructions 
for Huntsman Cancer Institute may be performed using the HCI Ordering and 
Scheduling Process for Radium.  
 
Radium Ra-223 dichloride is an alpha particle emitter with a physical half-life of 
11.4 days. The product is isotonic and has a pH of 6.0 to 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 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 29 of 73 
 
reference day, the volume should be corrected according to the physical decay 
table accompanying each shipment. 
 
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. 
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. 
 
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.  
 General warning RA-223 
 
Radium-223 dichloride should be received, used, and administered only by 
authorized persons in designated clinical settings. The receipt, storage, use, 
transfer, and disposal Radium-223 dichloride are subject to the regulations and/or 
appropriate licenses of the competent official organization. Radium-223 
dichloride should be handled by the user in a manner that satisfies both radiation 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 30 of 73 
 
safety and pharmaceutical quality requirements. Appropriate aseptic precautions 
should be taken. 
 Radiation protection RA-223 
 
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. 
 
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. 
 
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-223 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-223 and its daughters allows for the radioactivity 
measurement of Radium Ra-223 dichloride and the detection of contamination 
with standard instruments. 
 
Dose calibration 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 31 of 73 
 
Radium Ra-223 dichloride can be measured in a normal dose calibrator 
instrument. 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) the amount of Radium Ra-223 dichloride in the vial 
will be stated on the label. Instructions for the dial setting, including the 
calibration log form, will be enclosed with the dispatch of the calibration sample. 
 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-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 4.00 MBq (0.109 mCi) ((55kBq (.0015 ciper 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).  
The hematological adverse drug reactions observed in the clinical studies with 
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.  
 Dose handling 
 
The Radium Ra-223 dichloride vials must be stored inside their lead container in 
a secure facility. 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 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 32 of 73 
 
of Radium Ra-223 dichloride. All administrations of Radium Ra-223 dichloride 
are based on the certified activity of Radium Ra-223 dichloride at the calibration 
date. 
 Dose calculation 
 
The dosage of Radium Ra-223 dichloride is 55 kBq (1.49 mCi)/kg body weight 
(as documented in the written directive) (+/- 10% total dose). The patient dose is 
calculated based on date of injection, a decay correction (DK) factor specific to 
number of days from reference date applied to correct for physical decay of 
Radium-223, and patient weight. A table with DK values according to physical 
decay of the study medication will be provided with every shipment of Radium 
Ra-223 dichloride. Radium-223 is an alpha particle emitter with a physical t1/2 of 
11.4 days.  
 
For example: If the radioactive concentration at the reference date is 11,100 
kBq/mL then the volume to be administered for the current dose is calculated as 
follows: 
 
Body weight (kg) X dose (55kBQ/kg body weight) 
DK factor X 1100kBq (0.0297 Ci)/mL 
 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 into 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. 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 33 of 73 
 
 
Dose administration 
 
Before administration of study drug, the patient must be well hydrated; the patient 
should be instructed to drink ad libitum. Aseptic technique should be used in the 
administration of Radium Ra-223 dichloride. The syringe should be handed over to 
the individual who will perform the injection. The study medication will be 
administered by intravenous (IV) injection over 1 minute). 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.  
 
7.3 
Prohibited Concomitant Medications 
 
 Concurrent anti-cancer therapy (chemotherapy, androgen deprivation therapy, 
immunotherapy, biologic therapy, or tumor embolization) other than Ra-223 
dichloride and external beam radiation as specified in this protocol. 
 
 Prior use of Radium-223 dichloride. 
 
 Concurrent use of another investigational cytotoxic drug or cytotoxic device 
therapy (i.e., outside of study treatment) during, or within 4 weeks of trial entry 
(signing of the informed consent form). However, concomitant use of FDA 
approved nuclear medicine imaging agents (e.g., Fluciclovine, Choline C-11) 
used in an investigational imaging context will not be considered a 
contraindication to enrolling or continuing participation in the study. 
 
 Major surgery within 30 days prior to start of study drug.  
7.4 
Duration of Therapy 
Subjects must be withdrawn from the study treatment for the following reasons:  
 
Patients are expected to receive one neo-adjuvant dose of Radium-223 followed by 
EBRT for 2 to 6 weeks followed by 5 additional cycles of Radium-223. The treatment 
phase of the study should be completed in approximately 6 months pending dose delay 
or discontinuation 
 
    Subject withdraws consent from the study treatment and/or study procedures. 
A subject must be removed from the trial at his/her own request or at the request 
of his/her legally acceptable representative. At any time during the trial and 
without giving reasons, a subject may decline to participate further. The subject 
will not suffer any disadvantage as a result. 
    Subject is lost to follow-up. 
    Death. 
    Disease progression as defined in section 10 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 34 of 73 
 
o In the event of disease progression, the subject will no longer receive 
study treatment, but will remain on the study for all follow-up 
evaluations, which include indicated imaging studies, lab draws, and all 
questionnaires. 
 
Subjects may be withdrawn from the study for the following reasons:  
 The subject is non-compliant with study drug, trial procedures, or both; 
including the use of anti-cancer therapy not prescribed by the study protocol. 
 If, in the investigator's opinion, continuation of the trial would be harmful to 
the subject's well-being. 
 The development of a second cancer.  
 Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, significantly affect assessments of clinical status 
and trial endpoints. 
 Deterioration of ECOG performance status to 4. 
8 
TOXICITIES AND DOSEAGE MODIFICATION 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 4.0 for adverse event and serious adverse event reporting. A copy of the 
CTCAE Version 4.0 can be downloaded: (http://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx). 
8.1 
Dose Modifications 
 Dose Modification  
Every effort should be made to administer the full dosing regimen of Radium Ra-223 
dichloride. Adjustment of dose level is not permitted.  
Study visits for administration of Radium-223 during the treatment period should occur at 
28 day intervals (within a window of 0 and +14 days). Radium-223 cannot be 
administered earlier than 28 days from the previous administration. Dosing delays may 
be instituted under the following circumstances: 
 
Disease progression: 
The Investigator should delay cytotoxic chemotherapy, other systemic radioisotope, 
hemibody external radiotherapy or other investigational drug until the follow-up period. 
If such treatments have to be given during the treatment period, further study drug 
administrations must be discontinued.   
 
Patients with a single PSA result that meets biochemical progression criteria may 
continue on treatment, at the investigator’s discretion, until a confirmatory PSA result is 
returned. Upon confirmed biochemical progression study treatment MUST be 
discontinued.  
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 35 of 73 
 
Patients who demonstrate radiographic or clinical progression must discontinue study 
treatment. 
 
Myelosuppression:   
Treatment-related changes in hematology parameters may occur. 
• If a patient experiences CTCAE v4.03 Grade 3 or 4 neutropenia, thrombocytopenia, or 
anemia the administration of study drug should be delayed until recovery to Grade 2 or 
better.  
• If a patient experiences CTCAE v4.03 Grade 3 or 4 neutropenia, thrombocytopenia, or 
anemia lasting > 14 days, further study drug administrations must be discontinued.  
• Blood transfusion is acceptable between study drug administrations but not prior to the 
start of the study. Use of biologic response modifiers, such as G-CSF or GM-CSF, is 
allowed in the management of acute toxicity. 
• Hematologic evaluation of patients must be performed at baseline and prior to every 
dose of Radium Ra-223 dichloride. Before the first administration of Radium Ra-223 
dichloride, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet 
count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of 
Radium Ra-223 dichloride, the ANC should be ≥ 1.0 x 109/L and the platelet count ≥ 50 
x 109/L and hemoglobin ≥ 9.0 g/dL. If there is no recovery to these values within 6 to 8 
weeks after the last administration of Radium Ra-223 dichloride, despite receiving 
supportive care, further treatment with Radium Ra-223 dichloride should be 
discontinued. Patients with evidence of compromised bone marrow reserve should be 
monitored closely and provided with supportive care measures when clinically indicated. 
Discontinue Radium Ra-223 dichloride in patients who experience life-threatening 
complications despite supportive care for bone marrow failure. 
 
Gastrointestinal events: 
Diarrhea should be treated as per local practice. A further dose of study medication 
should not be given before diarrhea is recovered to CTCAE v4.03 Grade 2 or baseline 
levels.  
Nausea or vomiting should be treated as per local practice. A further dose of study 
medication should not be given before nausea or vomiting is recovered to CTCAE v.4.03 
Grade 2 or baseline levels. 
 
Spinal Cord Compression: 
If the patient experiences spinal cord compression during the treatment period, the patient 
should be treated for the event, and may receive further study drug administration if 
adequately recovered.  
 
Surgical Intervention: 
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.  
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 36 of 73 
 
Non-pathological fractures: 
For traumatic fractures in weight-bearing bones during treatment phase, the study drug 
administration should be delayed for 2 to 4 weeks from the time of fracture.  
 
Pathological fractures: 
Pathological fractures may occur as the result of either progressive disease or increased 
physical activity associated with significant pain palliation. Pathologic fractures are to be 
treated in a manner that attempts to maintain the best functional status and quality of life. 
Study treatment may continue as planned. 
 
Any Other Toxicity:   
Local practice will apply. 
8.2 
Supportive Care 
 All supportive measures consistent with optimal patient care will be 
given throughout the study. 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. (RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 37 of 73 
 
9 
STUDY CALENDAR 
1 cycle = 28 days11 
 
Examination 
Screening1 
Neo-
adjuvant C1 
 
EBRT 
 
C27 
C3 
C4 
C5 
C6 
End of 
Treatment17 
Follow-up8 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical examination18 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Karnofsky Performance Status or ECOG 
Equivalent (Appendix 17.5)18 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Concomitant Medications18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology2, 13 
X 
X13 
 
X13 
X13 
X13 
X13 
X13 
X 
 
Chemistry3, 13 
X 
X13 
 
X13 
X13 
X13 
X13 
X13 
X 
 
ECG5  
X 
 
 
 
 
 
 
 
 
 
CT or MRI4 
X 
 
 
 
 
 
 
 
X 
 
Radium-22316 
 
X 
 
X 
X 
X 
X 
X 
 
 
EBRT 
 
 
X 
 
 
 
 
 
 
 
PSA and Testosterone9, 13 
X 
X 
X9 
X 
X 
X 
X 
X 
X 
X 
Bone scans6 
X 
 
 
X12 
X12 
X 
X12 
X12 
X 
X 
QOL questionnaires 
X 
 
X15 
 
 
X 
 
 
X 
X 
Myriad CCP10 
X 
 
 
 
 
 
 
 
 
 
Myriad HRD10 
X 
 
 
 
 
 
 
 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. (RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 38 of 73 
 
1 ALL Pre-study/Screening procedures should be completed within 4 weeks of study enrollment - with the exception of laboratory tests which need to be 
completed within 2 weeks prior to study enrollment, and imaging assessments which must be completed within 90 days of enrollment. Consent may be signed 
≤ 45 days prior to cycle one day one.  
2 Hematology includes CBC with differential and platelets.  
3 Chemistry includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen. 4 CT-based scans (either Fluciclovine PET/CT or diagnostic CT) or MRI that 
includes the chest, abdomen and pelvis. A similar imaging modality (MRI or CT-based) used at screening is preferred, but not required at follow up evaluation. 
Diagnostic CT at follow-up is sufficient if PET/CT was used at screening. Disease assessment to be conducted by PCWG2 and RECIST 1.1 section 10.1.1. 
5 ECG will be done only if medically indicated. 
6 Bone scans should be obtained between cycle 3 and 4 of the study dependent on any dose delays that may extend cycle time. Bone scans should be performed 
2-4 weeks after the final Radium-223 dose. Bone scans will also be performed at any sign of progression as defined in section 10.  
7 Cycle 2 may be delivered concurrently with external beam radiation to the primary site. Therefore, cycle 2 will NOT be delayed to allow completion of the 
external beam radiation. 
8 Follow-up visits will occur every 3 months (+90/-30 days) for an approximate duration of two years from the time patients are enrolled on the study. 
9 PSA and Testosterone within 24 hours prior to or after starting external beam radiation.  
10 Correlative studies are OPTIONAL; refer to section 14.1 for archival tissue instruction 
11 Cycles should occur at least 28 days after the previous cycle and no more than 42 days after the previous cycle (0 to +14 days). 
12 Bone scans are optional at the time points indicated by this superscript and will be performed if there is clinical suspicion of progression that falls outside the 
objective criteria of progression for this study.  
13 All post-screening laboratory tests should be drawn approximately 7 days, but no fewer than 3 business days, before radium dosing. Laboratory tests for CBC 
differential platelets must have results available prior to radium ordering. Laboratory safety assessments MUST be performed and resulted prior to radium 
dosing. 
14 The collection of all adverse events will begin after the first dose of study treatment and end 30 days after the last dose of study treatment. The collection of 
treatment related adverse events will continue until the last study visit (or until new cancer treatment is initiated, if sooner). 
15 QOL Questionnaires should be completed on the final day of EBRT ± 7days. 
16 If a patient meets biochemical progression, the patient may continue to receive treatment, at the Investigator’s discretion, until a validated PSA test has 
confirmed biochemical progression.  
17 End of treatment visit will occur 28 days (±7 days) after last treatment is administered.  
18 Physical exam, KPS or ECOG equivalent, and concomitant medications do not need to be repeated if they have been performed less than 7 days prior.  
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 39 of 73 
 
10 CRITERIA FOR EVALUATION AND ENDPOINT 
Assessment of clinical outcomes:   
 
Clinical outcomes will be assessed at various time points from the start of protocol 
treatment. Patients will be followed for a total of 2 years after enrollment. 
A study subject that completes Cycle 1 of Tadium-223, EBRT, and at least 3 cycles of 
Radium-223 will be considered evaluable.  
10.1 Primary Endpoint – 15 month Hormone Free Survival 
 
The primary objective is to determine the hormone-therapy-free survival time for men 
treated with sequential EBRT and Radium-223 and determine whether it is a 20% risk 
reduction over the institutional comparator of 100% use of systemic therapy by 15 
months. The primary outcome is 15 months hormone-free survival. Patients will remain 
on study treatment for the duration defined by the calendar or for disease progression. 
Patients will be followed up to determine the start of ADT which will be used to measure 
the primary end point.  
 
For the purposes of this study, progression will be measured after the completion of 
EBRT and the delivery of Cycle 2 of Radium-223 and defined as either:   
 
Biochemical Progression:  
 
 - For those subjects whose PSA is greater than 20ng/ml at baseline who do not have any 
PSA decrease after starting therapy: biochemical progression will be defined as a 10% 
rise over the baseline. 
 
- For those subjects whose PSA is greater than 20ng/ml at baseline, who demonstrate 
decrease in PSA after study treatment: if the PSA nadir remains > 20ng/ml, biochemical 
progression will be defined as a PSA rise greater than 10% of the PSA nadir. If the PSA 
nadir is < 20ng/ml, biochemical progression will be defined as a PSA rise greater than 
10% of the PSA nadir. 
 
-For those subjects whose PSA is less than 20ng/ml at baseline: biochemical progression 
will be defined as PSA >20ng/ml and 10%. 
 
*Any PSA test that would meet a failure definition has to be validated through Huntsman 
Cancer Institute or a Veterans Affairs Hospital with a repeat PSA test no sooner than 5 
days and no later than 14 days from the initial notification of the result demonstrating 
progression. 
 
OR 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 40 of 73 
 
Radiographic progression: Any new, progressing, or reappearing lesion on Bone Scan, 
CT/Scan, or MRI compared to the same scan performed previously. Radiographic 
Progression will be determined by Prostate Cancer Clinical Trials Working Group 
(PCWG2) and RECIST 1.1 as described below (section 10.1.1).   
 
* Of note: For a patient to meet radiographic progression criterion for appearance of new 
bone lesion only, the patient must demonstrate appearance of new bone disease, as 
confirmed by the treating radiation oncologist, and also meet the biochemical progression 
definition set out above. 
 
OR 
 
Clinical Progression: the development of any skeletal related event defined as: time to 
any EBRT not required as a study procedure, time to first pathological bone fracture, time 
to spinal cord compression, or time to surgical intervention. 
 
RECIST 1.1 and PCGW 2 Assessments: 
The following definitions and criteria for RECIST 1.1 and PCWG2 should be used for 
the baseline evaluations of existing disease and for the ongoing evaluation of tumor 
responses.  
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter (LD) ≥ 10 mm using CT, MRI, or caliper 
measurements or ≥20 mm with x-ray. 
Non-measurable lesions - all other lesions including small lesions (LD < 10 mm 
with CT, MRI, or caliper measurements or <20 mm with x-ray). 
 
Documentation of “Target” and “Non-Target” Lesions 
 All measurable lesions up to a maximum of two lesions per organ and five 
lesions in total, representative of all involved organs should be identified as 
target lesions and recorded and measured at baseline. 
 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 clinical assessments). 
 A sum of the LD for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as the reference by which 
to characterize the objective tumor response. 
 All other lesions (or sites of disease) 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. 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 41 of 73 
 
RECIST Response Criteria 
 
Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions  
(Must persist for a minimum of four weeks) 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD  
(Must persist for a minimum of four weeks) 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
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 
Stable Disease (SD) 
Persistence of one or more non-target lesion(s) 
Progressive Disease 
(PD) 
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
RECIST Evaluation of Overall Response 
The best overall response is the best response observed until progression/recurrence and 
is determined as indicated in the table below: 
Target Lesions 
Non-Target 
Lesions 
 
Evaluation of New 
Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Radionuclide Bone Scan Assessment 
 
Bone scan lesions should be enumerated at baseline. Questionable lesions, e.g., sites of 
previous fracture, may require confirmation by CT or MRI. 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
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Post-baseline Assessments and Definition of Progression of Bone Metastases  
 
Disease Based on Radionuclide Bone Scan 
 
Bone scan lesions should be assessed and enumerated at each follow-up assessment. 
 
Progression on bone scan is defined as 2 or more new lesions on radionuclide bone scans. 
Should 2 or more new bone lesions be evident at the first assessment on treatment (end of 
cycle 3), 2 or more additional new lesions must be evident on a confirmatory assessment 
at least 6 weeks later (and no sooner than end of cycle 6). This confirmation is not 
required when 2 or more new lesions (compared to baseline or to the end of cycle 3 
assessment) first appear after the first follow-up assessment, i.e., at end of cycle 6 or 
thereafter. 
 
Should new bone lesions be documented at end of cycle 3 but not confirmed at end of 
cycle 6, then end of cycle 3 scan becomes the new baseline and 2 or more new lesions at 
subsequent assessments relative to end of cycle 3 defines bone scan progression. 
 
Stable disease (SD) on bone scan stable disease is defined as the absence of progression. 
Bone scan lesions are considered non-evaluable under RECIST, and thus there can be no 
partial response. Complete response is very rare. Thus, almost all bone scans will be rated 
as NE (no lesions present), SD, or PD. 
 
Overall Response Assessment 
 
The following table summarizes the overall response status calculation at each time point 
for patients who have either RECIST 1.1 evaluable soft tissue lesions and/or radionuclide 
bone scan lesions. Note that CR can only occur if there are RECIST 1.1-evaluable lesions 
and no bone lesions based on radionuclide bone scan. PR can occur if patients have CR 
or PR based on soft tissue evaluation and bone scan lesions that are stable. 
 
Overall Assessment Time Point Response 
 
PCWG2 Target/Nontarget 
soft tissue/RECIST 1.1 
Bone Scan (PCWG2) 
Overall 
CR 
No Metastases  (NE) 
CR 
CR,PR 
SD 
PR 
SD 
SD 
SD 
PD 
SD 
PD 
SD 
PD 
PD 
10.2 Myriad CCP Correlative studies.  
 
These studies are already FDA-approved, standard-of-care studies, and will not be 
required for participation on this clinical trial. For those patients consenting to these 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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correlative studies, existing banked biopsy tissues from the original prostate specimens 
will be used for the Myriad CCP testing. Procedures for testing these tissues will be per 
existing clinical protocols. 
10.3 Safety 
 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical 
laboratory test results. More frequent safety evaluations may be performed if clinically 
indicated or at the discretion of the investigator.  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a licensed 
physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
 
Vital signs include blood pressure, respiratory rate, pulse rate and temperature.  
 
Safety Laboratory Determinations 
 
Laboratory evaluations will be performed as noted in the Study Calendar.  
10.4 Stopping Rules 
 Toxicity: If 6 of the first 8 treated subjects develop 2 or more CTCAE 
grade 3 toxicities related to study drug, it will be reviewed by the 
DSMC to determine if the trial will continue. 
11 STATISTICAL CONSIDERATIONS 
The primary objective is to determine the hormone-therapy-free survival time for men 
treated with concurrent EBRT and Radium-223 and determine whether 20% of subjects 
do not meet the progression endpoint and require ADT at 15 months. The primary 
outcome is 15 months hormone- (or other systemic) therapy-free survival. The null 
hypothesis is that 99% of subjects will start systemic therapy within 15 months. The 
alternative hypothesis is that 80% of subjects will start systemic therapy within 15 
months. With 20 evaluable subjects there will be 93% power for this alternative 
hypothesis using an exact binomial test at the one-sided 0.05 significance level. The null 
hypothesis will be rejected if 2 or more out of 20 subjects are not placed on systemic 
therapy within one year.  
One of the secondary endpoints is to determine the hormone-therapy-free survival time 
for men treated with concurrent EBRT and Radium-223 and determine whether it is a 
30% risk reduction over the SWOG intermittent ADT historic cohort. This secondary 
hypothesis will be tested only if the primary null hypothesis is rejected. The outcome for 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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this secondary hypothesis is 15 month hormone- (or other systemic) therapy-free 
survival. In 2012 a SWOG cooperative group trial reported that 78% of subjects on 
intermittent androgen therapy had resumed ADT within 15 months, and this proportion 
will be used as a null hypothesis. With 20 evaluable subjects, and a null hypothesis that 
78% or more of patients will start systemic therapy within 15 months there will be 
80% power to detect an alternative hypothesis that 48% or fewer will start systemic 
therapy within 15 month using an exact binomial test at one-sided alpha =0.05 
significance level. 
Additional, secondary endpoints are time to first skeletal related event (SRE), overall 
survival, PSA doubling time, overall survival and toxicities. All secondary endpoints will 
be evaluated descriptively. Time to first SRE, OS, and PSA doubling time will be 
analyzed via Kaplan-Meier product limit methods and associated 95% confidence 
intervals. Toxicities will be tabulated using CTAE version 4.0. The number and 
proportion of subjects with toxicities will be reported.  
Exploratory endpoints are to evaluate if a commercially available cell-cycle progression 
gene assay (Myriad CCP) performed on the original prostate biopsy or surgical pathology 
specimen correlates with biochemical or clinical progression free survival in the study 
population.  
 
Correlations with survival endpoints will be performed using exploratory Cox 
proportional hazards regression analysis.  
Primary analysis and report planned at 15 months of follow up for all enrollees. 
 
Health-related Quality of Life as scored by EPIC urinary, bowel, sexual, and hormonal 
domains, as well as PROMIS-29 questionnaires. 
 
Medians, ranges, and quartiles will be computed for all health-related Quality of Life 
domains. Exploratory logrank tests will be used to relate domain scores to survival 
outcomes (hormone-free survival, time to first skeletal event, overall survival, and PSA 
doubling time).  
12 REGISTRATION GUIDELINES 
Patients must meet all of the eligibility requirements listed in Section 5 prior to 
registration.  
 
Study-related screening procedures can only begin once the patient has signed a 
consent form. Patients must not begin protocol treatment prior to registration. 
 
Treatment should start within 21 working days after registration. 
 
To register eligible patients on study, complete a Clinical Trials Office Patient Registration 
Form and submit to: CTORegistrations@hci.utah.edu.  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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13 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient 
that provides a record of the data generated according to the protocol. CRFs should be 
created prior to the study being initiated and updated (if applicable) when amendments to 
the protocol are IRB approved. Data capture should be restricted to endpoints and 
relevant patient information required for planned manuscripts. These forms will be 
completed on an on-going basis during the study. The medical records will be source of 
verification of the data. During the study, the CRFs will be monitored for completeness, 
accuracy, legibility, and attention to detail by a member of the Research Compliance 
Office. The CRFs will be completed by the Investigator or a member of the study team as 
listed on the Delegation of Duties Log. The data will be reviewed no less than annually 
by the Data and Safety Monitoring Committee. The Investigator will allow the Data and 
Safety Monitoring Committee or Research Compliance Office personnel access to the 
patient source documents, clinical supplies dispensing and storage area, and study 
documentation for the above-mentioned purpose. The Investigator further agrees to assist 
the site visitors in their activities. 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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14 SPECIAL INSTRUCTIONS  
14.1 Myriad CCP and HRD Analysis 
 
Either prostate biopsy tissue or radical prostatectomy specimens previously collected at 
the time of diagnosis and/or surgery will be used for the Myriad CCP and HRD assay. 
There will not be additional tissue collections for this clinical study. Samples from the 
respective pathology departments will be submitted to Myriad in accordance with the 
specimen handling requirements of the commercially available test.  
 
Details about CCP can be found at: https://prolaris.com/prolaris-for-physicians/for-
pathologists/sample-requirements/ 
 
Details about HRD can be found at: https://mychoicehrd.com/physicians/ 
15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 Informed consent  
Informed consent will be obtained from all research participants prior to performing 
any study procedures using the most recent IRB-approved version.  
15.2 Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
15.3  Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman 
Cancer Institute (HCI) and approved by the NCI to assure the well-being of patients 
enrolled on Investigator-Initiated Trials that do not have an outside monitoring 
review. Roles and responsibilities of the DSMC are set forth in the NCI-approved 
plan. The activities of this committee include a quarterly review of adverse events 
including SAEs, important medical events, significant revisions or amendments to the 
protocol, and approval of cohort/dose escalations. If the DSMC and/or the PI have 
concerns about unexpected safety issues, the study will be stopped and will not be 
resumed until the issues are resolved. The DSMC also reviews and approves audit 
reports generated by the Research Compliance Office.  
All phase II studies are reviewed by the full committee at each quarterly DSMC 
meeting. This includes a review of all serious adverse events (SAEs) occurring in 
patients treated at HCI or its affiliates as well as all grade 3 or greater toxicities for 
patients on treatment and within 30-day follow-up window (only if possibly, probably, 
or definitely related).  
15.4 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 4.0 for AE and SAE reporting. An electronic copy of the CTCAE 
Version 4.0 can be downloaded from:  
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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 Adverse Events (AE) 
 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or 
medical condition occurring after starting the study drug, even if the event is not 
considered to be related to study drug. For the purposes of this study, the terms toxicity 
and adverse event are used interchangeably. Medical conditions/diseases present before 
starting study drug are only considered adverse events if they worsen after starting study 
drug. Abnormal laboratory values or test results constitute adverse events only if they 
induce clinical signs or symptoms, are considered clinically significant, or require 
therapy. 
 
The collection of all adverse events will begin after the first dose of study treatment and 
end 30 days after the last dose of study treatment. The collection of treatment-related 
adverse events will continue until the last study visit (or until new cancer treatment is 
initiated, if sooner), 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, discovered by clinical research coordinator interview, or 
detected through physical examination, laboratory test or other means, will be collected 
and recorded and followed as appropriate. 
 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient at each visit or phone contact during the study. Adverse events also may be 
detected when they are volunteered by the patient during or between visits or through 
physical examination, laboratory test, or other assessments. As far as possible, each 
adverse event should be evaluated to determine: 
1. the severity grade based on CTCAE v.4 (grade 1-5) 
2. its relationship to Radium-223 or EBRT (definite, probable, possible, 
unlikely, not related).  
3. its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
5. whether it constitutes an SAE 
 
All adverse events will be treated appropriately. Such treatment may include changes in 
study drug treatment as listed in the dose modification section of this protocol (see 
section 8 for guidance). Once an adverse event is detected, it should be followed until its 
resolution or if patient’s participation on the study is terminated or otherwise 
discontinued, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
 
Information about common side effects already known about Radium-223 is described in 
the Drug Information (section 3) and the most recent Investigator Brochure. This 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
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Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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information will be included in the patient informed consent and will be discussed with 
the patient during the study as needed. 
 
All adverse events will be immediately recorded in the patient research chart.  
 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded in compliance 
with all institutional and government requirements. A serious adverse event is an 
undesirable sign, symptom, or medical condition that: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 is medically significant, i.e., defined as an event that jeopardizes the 
patient or may require medical or surgical intervention to prevent one of 
the outcomes listed above 
 causes congenital anomaly or birth defect 
 requires inpatient hospitalization or prolongation of existing 
hospitalization, unless hospitalization is for: 
o routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition (procedures such as 
central line placements, paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the 
start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling 
any of the definitions of a SAE given above and not resulting in 
hospital admission 
o social reasons and respite care in the absence of any deterioration in 
the patient’s general condition 
 
The collection of serious adverse events will begin after the first dose of study treatment 
and end 30 days after the last dose of study treatment. The collection of treatment-related 
serious adverse events will continue until the last study visit (or until new cancer 
treatment is initiated, if sooner). 
 
Any death from any cause while a patient is receiving treatment on this protocol or up to 
30 days after the last dose of protocol treatment, or any death which occurs more than 30 
days after protocol treatment has ended, but which is felt to be treatment related, must be 
reported. 
 
Toxicities that fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to treatment 
that do NOT fall within the definitions above must simply be documented as AEs in the 
patient research chart.  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
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15.5 SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, the IRB, and Bayer according to the 
requirements described below: 
 
A MedWatch 3500A form must be completed and submitted to 
compliance@hci.utah.edu  within 1 business day of first knowledge or notification of 
the event. 
 
DSMC Notifications: 
 An HCI Research Compliance Officer (RCO) will process and submit the 
MedWatch form to the proper DSMC member as necessary for each individual 
study.  
 The RCO will summarize and present all reported SAEs according to the Data 
and Safety Monitoring Plan at the quarterly DSMC meeting. 
FDA Notifications: 
 Adverse events occurring during the course of a clinical study that meet the 
following criteria will be promptly reported to the FDA: 
 
Serious 
 
Unexpected 
 
Definitely, Probably, or Possibly Related to the investigational drug 
 
Fatal or life-threatening events that meet the criteria above will be 
reported within 7 calendar days after first knowledge of the event by 
the investigator, followed by as complete a report as possible within 8 
additional calendar days. 
 All other events that meet the criteria above will be reported within 15 
calendar days after first knowledge of the event by the investigator. 
 The RCO will review the MedWatch report for completeness, accuracy, and 
applicability to the regulatory reporting requirements. 
 The RCO will ensure the complete, accurate, and timely reporting of the event 
to the FDA. 
 The Regulatory Coordinator will submit the report as an amendment to the 
IND application. 
 All other adverse events and safety information not requiring expedited 
reporting that occur or are collected during the course of the study will be 
summarized and reported to the FDA through the IND Annual Report. 
IRB Notification: 
 Events meeting the University of Utah IRB reporting requirements 
(http://www.research.utah.edu/irb/) will be submitted through the IRB’s 
electronic reporting system within 10 working days. 
 
Bayer Notifications: 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
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An ADEERS form (Adverse Event Expedited Reporting System) available at 
http://ctep.cancer.gov/reporting/adeers.html   
OR 
A MedWatch form  
All reports shall be sent electronically to:  
 
Electronic Mailbox:   
DrugSafety.GPV.US@bayer.com  
 
Facsimile:   
 
 
(973) 709-2185  
 
Address: 
 
 
Global Pharmacovigilance - USA  
Mail only: 
 
 
Bayer HealthCare  
P.O. Box 915Whippany, NJ 07981-0915 
 
Address:   
 
 
100 Bayer Blvd., Whippany, NJ 07981  
FDX or UPS only    
67 Whippany Road, Whippany, NJ 07981 for UPS  
 
Reports for all Bayer products can also be phoned in via our Clinical 
Communications Dept:  
 
Phone:  
 
 
1-888-842-2937 
 
*Medwatch 3500A form can be found at 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/uc
m082728.pdf 
15.6 Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject, 
including the pregnancy of a male subject’s female partner as an SAE. Pregnancies or 
lactation that occurs during the course of the trial or with 30 days of completing the 
trial or starting another new anticancer therapy, whichever is earlier, must be reported 
to the DSMC, IRB, FDA, and the sponsor as applicable. All subjects and female 
partners who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, fetal 
death, intrauterine death, miscarriage, and stillbirth must be reported as serious 
events.  
15.7 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the 
period, for which the IRB approval has already been given, will not be initiated 
without submission of an amendment for IRB review and approval.   
 
These requirements for approval will in no way prevent any immediate action 
from being taken by the investigator in the interests of preserving the safety of 
all patients included in the trial.  

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
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Any amendments to the protocol that significantly affect the safety of subjects, 
scope of the investigation, or the scientific quality of the study are required to 
submit the amendment for FDA review. 
15.8 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved 
by the IRB. Protocol deviations have the potential to place participants at risk and can 
also undermine the scientific integrity of the study thus jeopardizing the justification 
for the research. Protocol deviations are unplanned and unintentional events.  
 
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations 
which are: 
 
Exceptions to eligibility criteria. 
 
Intended to eliminate apparent immediate hazard to a research participant 
or  
 
Harmful (caused harm to participants or others, or place them at 
increased risk of harm - including physical, psychological, economic, or 
social harm), or  
 
Possible serious or continued noncompliance  
15.9 FDA Annual Reporting  
An annual progress report will be submitted to the FDA within 60 days of the 
anniversary of the date that the IND went into effect. (21 CFR 312.33).  
15.10 Clinical Trials Data Bank  
 
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical 
Trials Reporting Program) by the Clinical Trials Office. 
 
15.11 Record Keeping 
Per 21 CFR 312.57, Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or 
the application is not approved, until 2 years after the investigation is discontinued 
and the FDA is notified. 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
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16 BIBLIOGRAPHY 
 
1. 
Klatte, T., et al., [Radionuclide bone scan in patients with newly diagnosed 
prostate cancer. Clinical aspects and cost analysis]. Urologe A, 2006. 45(10): p. 
1293-4, 1296-9. 
2. 
Pelger, R.C., V. Soerdjbalie-Maikoe, and N.A. Hamdy, Strategies for 
management of prostate cancer-related bone pain. Drugs Aging, 2001. 18(12): p. 
899-911. 
3. 
Soloway, M.S., et al., Stratification of patients with metastatic prostate cancer 
based on extent of disease on initial bone scan. Cancer, 1988. 61(1): p. 195-202. 
4. 
NCCN Prostate Cancer Guidleine. 2017; Available from: https://www.nccn.org/. 
5. 
Bellmunt, J., Tackling the bone with alpha emitters in metastatic castration-
resistant prostate cancer patients. Eur Urol. 63(2): p. 198-200. 
6. 
Nilsson, S., et al., Two-Year Survival Follow-Up of the Randomized, Double-
Blind, Placebo-Controlled Phase II Study of Radium-223 Chloride in Patients 
With Castration-Resistant Prostate Cancer and Bone Metastases. Clin Genitourin 
Cancer. 
7. 
Nilsson, S., et al., Bone-targeted radium-223 in symptomatic, hormone-refractory 
prostate cancer: a randomised, multicentre, placebo-controlled phase II study. 
Lancet Oncol, 2007. 8(7): p. 587-94. 
8. 
Parker, C.C., et al., A randomized, double-blind, dose-finding, multicenter, phase 
2 study of radium chloride (Ra-223) in patients with bone metastases and 
castration-resistant prostate cancer. Eur Urol. 63(2): p. 189-97. 
9. 
Parker, C., et al., Updated analysis of the phase III, double-blind, randomized, 
multinational study of radium-223 chloride in castration-resistant prostate cancer 
(CRPC) patients with bone metastases (ALSYMPCA). 
10. 
Hellman, S. and R.R. Weichselbaum, Oligometastases. J Clin Oncol, 1995. 13(1): 
p. 8-10. 
11. 
Weichselbaum, R.R. and S. Hellman, Oligometastases revisited. Nat Rev Clin 
Oncol. 8(6): p. 378-82. 
12. 
Salama, J.K. and M.T. Milano, Radical irradiation of extracranial 
oligometastases. J Clin Oncol, 2014. 32(26): p. 2902-12. 
13. 
Singh, D., et al., Is there a favorable subset of patients with prostate cancer who 
develop oligometastases? Int J Radiat Oncol Biol Phys, 2004. 58(1): p. 3-10. 
14. 
Hussain , M., et al., Intermittent versus Continuous Androgen Deprivation in 
Prostate Cancer. New England Journal of Medicine, 2013. 368(14): p. 1314-
1325. 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
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Version Date: 08APR2021 
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17 APPENDIX  
17.1 PROMIS-29 Questionnaire 
 
 
 
 
 
 
RROPE 
 
PROMIS-29 Questionnaire 
 
Patient Study ID: 102312-01-____ ____ ____ 
 
Patient Initials: ____ ____ ____ 
 
Date of Completion: ____ / ____ / ______ 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
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Appendix 17.2 EPIC Questionnaire 
 

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Principal Investigator: Jonathan Tward, MD, PhD 
 
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Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 65 of 73 
 
 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 66 of 73 
 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 67 of 73 
 
 
 
 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 68 of 73 
 
Appendix 17.3 Bayer Radium Ordering 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 69 of 73 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 70 of 73 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 71 of 73 
 
Appendix 17.4 Radium-223 Patient Handouts 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 72 of 73 
 
 
 

Protocol: A Phase 2 study of Radium-223 and Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to bone. 
(RROPE) 
Version Date: 08APR2021 
Principal Investigator: Jonathan Tward, MD, PhD 
 
Page 73 of 73 
 
 
Appendix 17.5 ECOG/KPS Conversion 
 
ECOG PERFORMANCE STATUS 
KARNOFSKY PERFORMANCE STATUS 
0—Fully active, able to carry on all pre-disease 
performance without restriction 
100—Normal, no complaints; no evidence of 
disease  
 
90—Able to carry on normal activity; minor signs 
or symptoms of disease 
1—Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
80—Normal activity with effort, some signs or 
symptoms of disease  
 
70—Cares for self but unable to carry on normal 
activity or to do active work 
2—Ambulatory and capable of all selfcare but unable to 
carry out any work activities; up and about more than 50% 
of waking hours 
60—Requires occasional assistance but is able 
to care for most of personal needs  
 
50—Requires considerable assistance and 
frequent medical care 
3—Capable of only limited selfcare; confined to bed or 
chair more than 50% of waking hours 
40—Disabled; requires special care and 
assistance  
 
30—Severely disabled; hospitalization is 
indicated although death not imminent 
4—Completely disabled; cannot carry on any selfcare; 
totally confined to bed or chair 
20—Very ill; hospitalization and active 
supportive care necessary  
 
10—Moribund 
5—Dead 
0—Dead 
*Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, 
ed. Evaluation of Chemotherapeutic Agents. New York, NY: Columbia University Press; 1949:191–205. 
**Zubrod C, et al. Appraisal of methods for the study of chemotherapy in man: Comparative therapeutic 
trial of nitrogen mustard and thiophosphoramide. Journal of Chronic Diseases; 1960:11:7-33.