Clinical trial NCT02278055
Conditions: Metastatic Prostate Cancer Pain
Keywords: Radium-223 14-098 Prostate Cancer Clinical Trials Consortium
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-10-08; Completion date: 2022-02-02
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if Radium-223 is effective in reducing cancer pain within 12 weeks of treatment. In order to see if Radium-223 is effective, the patient's level of pain will be followed throughout the study.

Detailed description:

Arms: arm 1: Radium Ra 223 dichloride will be administered as a bolus intravenous (IV) injection (up to 1 minute) at intervals of every 4 weeks for up to 6 cycles. The dosage of Radium Ra 223 dichloride after implementation of the new 2015 NIST standard is 55kBq/kg body weight.
Interventions: intervention 1: Radium-223
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
1 of 75 
 
 
Phase II open, non-randomized trial assessing pain efficacy with Radium- 
223 in symptomatic metastatic castration-resistant prostate cancer 
Prostate Cancer Clinical Trials Consortium, LLC (PCCTC) 
PCCTC LOI #: c13-124 
Lead Site/Sponsor: Memorial Sloan Kettering Cancer Center 
 
Principal Investigator 
Statistician 
Michael J. Morris, MD 
Glenn Heller, PhD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
email: morrism@mskcc.org 
email: hellerg@mskcc.org 
Co-investigators 
Project Manager 
Joseph Osborne, MD 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Prostate Cancer Clinical Trials Consortium 
55 Fifth Avenue, 13th Floor 
New York, NY 10003 
email: pcctc@mskcc.org 
email:osbornej@mskcc.org 
 
 
Participating Site 
Lead Investigator 
Role 
University of North Carolina 
New York-Presbyterian 
Hospital Cornell Medical Center 
Matthew Milowsky, MD 
Scott Tagawa, MD 
Data Collection 
Data Collection 
 
Protocol Date: May 5, 2014 
Amended Version Date: March 28, 2016 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information contained 
herein will not be disclosed to others without written authorization from the lead site/sponsor, 
except to the extent necessary to initiate the study or conduct study-related activities. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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INVESTIGATOR’S APPROVAL OF PROTOCOL 
 
Title: Phase II open, non-randomized trial assessing pain efficacy with Radium-223 in symptomatic 
metastatic castration-resistant prostate cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Signature: 
_______________________________________________________ 
 
Principal Investigator Print: 
_______________________________________________________ 
 
Date: 
_______________________________________________________ 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
3 of 75 
 
 
 
SYNOPSIS 
Title 
Phase II open, non-randomized trial assessing pain efficacy with Radium-223 in 
symptomatic metastatic castration-resistant prostate cancer 
Lead site 
Memorial Sloan Kettering Cancer Center 
Sponsor 
Investigator-initiated 
Investigational 
agent 
Radium 223 administered intravenously every 4 weeks for 6 doses at 50 kBq/Kg ( 
55kBq/kg b.w. after implementation of the NIST update). 
Phase 
II 
Target 
population 
Men with symptomatic metastatic castration-resistant prostate cancer. 
Inclusion Criteria 
• 
Males aged 18 years of age and above 
• 
Histological or cytological proof of prostate adenocarcinoma 
• 
Castrate serum testosterone level: ≤50 ng/dL (≤1.7 nmol/L) 
• 
Patients who have experienced disease progression despite initial hormonal 
therapy, either by orchiectomy or by using a GnRH agonist in combination with 
an anti-androgen, must first progress through anti- androgen withdrawal prior 
to being eligible. The minimum time frame to document failure of anti- 
androgen withdrawal will be four weeks. Patients on second-line (or beyond) 
hormonal maneuvers, and patients who had no PSA decline on combined 
androgen blockade as first line therapy, need not progress through AAW in 
order to be eligible. 
• 
Known progressive castration-resistant disease, defined as: 
o Serum PSA progression defined as two consecutive increases in PSA 
over a previous reference value within 6 months of first treatment, 
each measurement at least one week apart. Serum PSA at screening ≥ 2 
ng/mL 
or 
o Documented appearance of new lesions by bone scintigraphy 
• 
ECOG Performance Status of 0-2 (Appendix A: Performance Status Criteria) 
• 
2 or more bone metastases demonstrated on bone scintigraphy 
• 
Pain at baseline as measured by a BPI worst pain score average of ≥ 3. The BPI 
worst pain score average will be based on the worst pain scores completed by 
the patient in the 7 consecutive pretreatment days. A minimum of 4 days of 
pain scores must be completed by the patient in the 7 day window in order to 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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calculate the average worst pain score. The investigator will optimize the 
subject’s  pain regimen prior to study entry. 
• 
Normal organ function with acceptable initial laboratory values: 
o WBC 
> 3 x 109 /L 
o ANC 
> 1.5 x 109 /L 
o Platelets 
> 100 x 109 /L 
o Hemoglobin > 9.0 g/dL 
o Creatinine  < 1.5 x institutional upper limit of normal (ULN) 
o Bilirubin 
≤ 1.5 x ULN 
o AST/ALT ≤ 2.5 x ULN 
o Albumin 
> 25 g/L 
• 
All acute toxicities as a result of any prior treatment must have resolved to 
NCI-CTCAE v4.0 Grade 1 or less at the time of signing the Informed Consent 
Form (ICF) [Note: Ongoing grade 2 neuropathy as a result of treatment with a 
cytotoxic chemotherapy regimen is permitted] 
• 
Life expectancy of at least 6 months 
• 
Willing and able to provide written informed consent and HIPAA authorization 
for the release of personal health information 
NOTE: HIPAA authorization may be either included in the informed 
consent or obtained separately 
• 
Willing and able to comply with the protocol, including follow-up visits, 
examinations as well as having the ability to self-report pain and fatigue using 
a Patient Reported Outcome (PRO) instrument 
• 
Willingness to use adequate methods of contraception beginning at the signing 
of the ICF until at least 30 days after the last dose of study drug 
Exclusion Criteria 
• 
Prior exposure to Radium-223 
• 
Received an investigational therapy within the 4 weeks prior to registration, or 
is scheduled to receive one during the treatment period 
• 
Received a new anti-cancer agent within 4 weeks prior to registration 
• 
Received external beam radiotherapy within 4 weeks prior to registration 
• 
Received systemic therapy with radionuclides (e.g. strontium-89, samarium- 
153, rhenium-186 or rhenium-188) for the treatment of bone metastases 
• 
Treatment with cytotoxic chemotherapy within 4 weeks prior to registration 
• 
Symptomatic nodal disease, i.e. scrotal, penile or leg edema. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
5 of 75 
 
 
• 
Visceral metastases (including cerebral metastases) from CRPC (>2 lung 
and/or liver metastases [size ≥2cm]; Lymphadenopathy exceeding 6 cm in 
short-axis diameter or any size pelvic lymphadenopathy if it is thought to be a 
contributor to concurrent hydronephrosis), as assessed by CT, MRI or chest X- 
ray within the 8 weeks prior to registration. 
• 
Concurrent chemotherapy. Patients may be on other non-chemotherapy anti- 
cancer treatments, per FDA labeling of Radium-223, provided that these are 
not changed during the primary pain assessment period 
• 
Major surgery within 30 days prior to registration. 
• 
Imminent spinal cord compression based on clinical findings and/or magnetic 
resonance imaging (MRI). Treatment should be completed for spinal cord 
compression. 
• 
Patients with a, “currently active,” second malignancy other than non- 
melanoma skin cancers or non-invasive bladder cancers or other in-situ or 
non-invasive malignancies. Patients who have completed therapy for a prior 
malignancy and are free of disease for ≥3 years are eligible. 
• 
Any other serious illness or medical condition, such as but not limited to: 
o Any infection ≥ National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 4.03 Grade 2 
o Cardiac failure New York Heart Association (NYHA) III or IV 
o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia 
o Fecal incontinence 
• 
Any other condition which, in the opinion of the Investigator, would make the 
subject unsuitable for trial participation 
Study centers 
3 sites in the United States 
Start 
date/Duration 
First patients are expected to be enrolled in January 2015. Accrual is estimated to last 
1 year with up to 6 months of follow-up after the last patient has been entered. 
Expected 
enrollment 
63 patients 
Rationale 
The dose selected for this agent is (50 kBq (0.00135 mCi) (55kBq (.0015 after NIST 
update)  administered every 4 weeks for 6 doses. This was selected based on prior 
studies, including the dose used in the randomized, phase III study that demonstrated 
a 31% reduction in the risk of death in comparison to placebo. 
Objectives 
Primary 
The primary objective of this study is to determine the effects of pain palliation with 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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Radium-223. 
 
Secondary 
The secondary objectives of this study are: 
• 
To assess the impact of treatment on markers of bone turnover 
• 
To assess the impact of treatment on PSA 
• 
To assess the impact of treatment on time to radiographic progression 
• 
To assess the impact of treatment on quantifiable imaging biomarkers assessing 
bone metabolism 
• 
To assess the impact of treatment on tiredness 
• 
To assess the toxicity of treatment 
• 
To assess the impact of treatment on pain interference specifically evaluating its 
affect on general activity and sleep as measured by the BPI 
• 
To assess the impact of treatment on time to pain progression 
• 
To assess the impact of treatment on change in analgesic use 
 
Study design 
This is an open, single arm phase II study. 
 
The study will open in three sites in the U.S. Prostate Cancer Clinical Trials Consortium 
(PCCTC). 
 
This is a two-phase design such that in the first phase, 27 patients will be accrued. If 6 
or more patients achieve a pain response (defined as a 30% decline in the BPI worse 
pain item from baseline to week 8, with a confirmed reduction at week 12 without an 
escalation of the subjects pain regimen from Step 1 to Step 2 or Step 2 to Step 3 of the 
WHO analgesic ladder.), then an additional 36 patients will be enrolled. If fewer than 6 
patients achieve a pain palliation response, the study will be terminated. 
 
Treatment period: From first intravenous administration of study drug to 4 weeks 
after the last administration of study drug. 
 
Safety Follow-up Visit: Patients will be evaluated 1 month (±7 days) after they have 
completed treatment with 6 doses or the patient is prematurely discontinued from 
treatment. 
 
Follow-up period: Patients will be evaluated every 3 months (± 1 week) until 6 months 
after the safety follow-up visit for a total of 2 visits. 
 
End of study: Last follow-up visit for the last patient on study. 
A schema for study treatment appears below: 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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Baseline Daily Reporting 
BPI assessment (PRO Instrument) + 
Pain medications Diary 
= Pain assessment 
Follow-up Daily Reporting x 7d 
Pain assessment using the PRO instrument 
 
 
 
 
7d 
5wk 
* 
* 
9wk 
13wk 
 
17wk 
 
21wk 
25wk** 
(Run in period) 
R 
R 
R 
R 
R 
R 
 
 
 
 
*Primary endpoint: Pain response at 8wk confirmed at 12wk 
**Pain measured every 12 weeks thereafter 
R=Radium-223 50kBq/kg 
PRO Instrument 
 
Criteria for 
evaluation 
Primary 
Proportion of patients with pain palliation (pain response) at week 8, confirmed at 
week 12 without an escalation of the subjects pain regimen from Step 1 to Step 2 or 
Step 2 to Step 3 of the WHO analgesic ladder. 
 
Secondary 
• 
Changes in Bone-ALP 
O Percentage of change from baseline to 12 weeks (or earlier for those who 
discontinue study therapy) 
O Maximum change (rise or fall) in bone-ALP during the treatment period 
reported for each patient as a waterfall plot 
• 
Changes in other bone markers: 
O Serum C-telopeptide (sCTX-1) 
O N-terminal propeptide of procollagen type 1 (PINP) 
O Changes in total-ALP will be defined as for bone-ALP above 
• 
Changes in PSA 
O Using Prostate Cancer Working Group 2 (PCWG2) guidelines 1, the 
percentage of change in PSA from baseline to 12 weeks, as well as the 
maximum decline in PSA will be reported for each patient using a waterfall 
plot. 
O Progression, for those patients showing an initial decline in PSA from 
baseline, is defined as an increase in PSA that is ≥25% and ≥2 ng/mL above 
the nadir, and which is confirmed by a second value 3 or more weeks later 
(i.e., a confirmed rising trend). 
O Progression, for those patients with no decline in PSA from baseline, is 
defined as an increase in PSA that is ≥25% and ≥2 ng/mL after 12 weeks.  
Note: PSA progression as such will not lead to study discontinuation 
• 
Time to First Radiographic or Clinical Progression (TTFROCP) based on RECIST 
version 1.12 and PCWG2 definitions1 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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• 
Radiographic response will also be determined using FDG PET/CT to assess for 
treatment effect in bone. Section 10.1.2 discusses how response will be assessed. 
• 
Time to pain progression, defined as time until a >2 point increase in pain 
compared to baseline confirmed at least 2 weeks later. 
• 
Change in analgesic use assessed by the WHO analgesic ladder 
• 
Changes in measure of tiredness measured by the worst fatigue item (item #3) 
from the Brief Fatigue Inventory. (see Appendix E) 
• 
Changes in measures of pain interference as assessed on Brief Pain Inventory. (see 
Appendix F) 
• 
Evaluate the short and long term toxicity to treatment 
Statistical 
method 
Primary Analysis 
The primary objective of this phase II study is to determine the effect of Radium-223 
on pain improvement for patients with symptomatic metastatic castration-resistant 
disease. The primary endpoint of the study is a 30% decline in the BPI worst pain item 
from baseline to week 8, with a confirmed reduction at week 12, without an escalation 
of the subject's pain regimen from Step 1 to Step 2 or Step 2 to Step 3 of the WHO 
analgesic ladder. We define this event as a response and propose declaring the 
treatment effective if the probability of a response in the population exceeds 0.20. 
A maximum of 63 patients will be entered onto the study. A two-stage design that 
differentiates between response rates of 0.20 and 0.35 will be used to assess treatment 
efficacy. In the first stage of the study 27 patients will be enrolled. If at most 5 patients 
respond, accrual will be terminated. If at least 6 patients respond, an additional 36 
patients will be entered onto the study. At the conclusion of this second stage, if at least 
17/63 patients respond, the treatment will be declared effective. The probability          
of declaring the treatment effective is 0.10 when the response rate in the population is 
0.20 and increases to 0.90 when the response rate is 0.35. 
Secondary Analysis 
Descriptive statistics will be used to report the proportion of patients with various 
changes in fatigue scores compared to baseline according to the worst fatigue item 
(Item #3) of the Brief Fatigue Inventory, at weeks 8 and 12. Descriptive statistics will 
also be used to report the proportion of patients with changes in pain interference 
scores compared to baseline based on the interference with activities item of the BPI, 
at weeks 8 and 12. 
The time to radiographic progression will be summarized using the cumulative 
incidence function. 
The percent change in PSA and bone turnover markers from baseline to 12 weeks will 
be summarized with descriptive statistics. 
Metabolic response will also be determined using FDG PET/CT to assess for treatment 
effect in bone. 
Safety analysis 
Standard safety summaries will be provided for treatment exposure, patient 
disposition, adverse events leading to discontinuation, serious adverse events, and all  
 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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events resulting in death, including those up to 4 weeks after treatment 
discontinuation. The incidence of adverse events will be tabulated and reviewed for 
potential significance and clinical importance. 
 
 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
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TABLE OF CONTENTS 
1. 
INTRODUCTION .......................................................................................................................... 12 
1.1 
Disease Background ........................................................................................................................................................... 12 
1.2 
Treatment Background ..................................................................................................................................................... 12 
1.3 
Rationale ................................................................................................................................................................................. 16 
2. 
OBJECTIVES .................................................................................................................................. 18 
2.1 
Primary Objective ............................................................................................................................................................... 18 
2.2 
Secondary Objectives ........................................................................................................................................................ 18 
3. 
PATIENT SELECTION ................................................................................................................. 19 
3.1 
Target Population ............................................................................................................................................................... 19 
3.2 
Inclusion Criteria ................................................................................................................................................................. 19 
3.3 
Exclusion Criteria ................................................................................................................................................................ 20 
4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN ...................................................... 21 
4.1 
Enrollment Plan ................................................................................................................................................................... 21 
4.2 
Registration Procedure .................................................................................................................................................... 21 
5. 
TREATMENT/INTERVENTION PLAN ................................................................................... 24 
5.1 
Screening/Pretreatment Assessment (Day -28 to Day -1) ............................................................................... 27 
5.2 
Treatment/Intervention Period (Week 1, Day 1 to Week 25, Day 169 (treatment visits have a 
window of ±3days)) ........................................................................................................................................................................ 28 
5.3 
Follow-Up ............................................................................................................................................................................... 29 
5.4 
Clinical and laboratory assessments ........................................................................................................................... 30 
5.5 
Dosing Delays and Dose Modifications for Toxicities .......................................................................................... 31 
5.6 
Removing Patients from the Protocol ........................................................................................................................ 33 
5.7 
Concomitant Medications ................................................................................................................................................ 34 
6. 
THERAPEUTIC AGENT .............................................................................................................. 35 
6.1 
Description of Treatments .............................................................................................................................................. 35 
6.2 
Dosage Selected, Preparation, and Schedule of Administration ..................................................................... 36 
6.3 
NIST Standardization ........................................................................................................................................................ 38 
7. 
ADVERSE EVENTS ...................................................................................................................... 38 
7.1 
Definitions .............................................................................................................................................................................. 38 
7.2 
Recording and Grading ..................................................................................................................................................... 40 
7.3 
Reporting Adverse Events ............................................................................................................................................... 41 
7.4 
Safety Reports ....................................................................................................................................................................... 43 
8. CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE ............................. 44 
8.1 
Primary endpoint ................................................................................................................................................................ 44 
8.2 
Secondary endpoints ......................................................................................................................................................... 44 
8.3 
Therapeutic Response ....................................................................................................................................................... 44 
8.4 
Response Criteria for Control/Relieve/Eliminate Endpoints .......................................................................... 47 
8.5 
Confirmatory Measures/Duration of Response ..................................................................................................... 48 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS .............................................. 50 
9.1 
Data Collection and Management ................................................................................................................................ 51 
9.2 
Study Monitoring and Quality Assurance ................................................................................................................ 51 
10. STATISTICAL CONSIDERATIONS ........................................................................................... 53 
10.1 Study Endpoints ................................................................................................................................................................... 53 
10.2 Analysis Populations ......................................................................................................................................................... 55 
10.3 Safety Analysis ..................................................................................................................................................................... 55 
11. REGULATORY AND PROTECTION OF HUMAN SUBJECTS .............................................. 56 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
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IRB#: 14-098 A (5) 
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11.1 Roles and Responsibilities ............................................................................................................................................... 56 
11.2 Ethical Considerations ...................................................................................................................................................... 57 
11.3 Regulatory Documentation ............................................................................................................................................. 57 
11.4 Protocol Amendments ...................................................................................................................................................... 58 
11.5 Additional IRB Correspondences ................................................................................................................................. 58 
11.6 Written Informed Consent .............................................................................................................................................. 59 
11.7 Protection of Privacy ......................................................................................................................................................... 60 
11.8 Terminating or Modifying the Study .......................................................................................................................... 60 
12. REFERENCES ................................................................................................................................ 61 
APPENDIX A: PERFORMANCE STATUS CRITERIA ..................................................................... 63 
APPENDIX B: PCCTC SERIOUS ADVERSE EVENT REPORT FORM ......................................... 64 
APPENDIX C: GLOSSARY OF ABBREVIATIONS AND ACRONYMS .......................................... 65 
APPENDIX D: DOSIMETRY ................................................................................................................ 69 
APPENDIX E: BRIEF FATIGUE INVENTORY ................................................................................. 70 
APPENDIX F: BRIEF PAIN INVENTORY ......................................................................................... 71 
APPENDIX G: RADIATION SAFETY PRECAUTIONS FOLLOWING RADIUM-223 
DICHLORIDE, INJECTION ................................................................................................................... 72 
APPENDIX H: PRO INSTRUMENT SCREENSHOT ........................................................................ 73 
APPENDIX I: PRO INSTRUMENT INSTRUCTIONS ...................................................................... 74 
APPENDIX J: RADIUM DOSE TRACKING SHEET (MSK SITE ONLY) ...................................... 75 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
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IRB#: 14-098 A (5) 
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1. 
INTRODUCTION 
1.1 
Disease Background 
Metastatic prostate cancer is characterized by a unique predilection for bone; 80-90% of 
patients with advanced disease have radiographically detectable osteoblastic metastases. 
With bone metastases comes significant clinical sequelae including bone pain, fractures, 
epidural disease and cord compression. Collectively these events can cause significant 
detriment to patient quality of life.  The prevalence of baseline bone pain in contemporary 
trials of patients with metastatic castration-resistant prostate cancer is estimated between 
2-54%3; however, there is variability in instruments used to assess pain, many of which 
have not been validated in this disease and the study populations have varied significantly. 
Despite the prevalence of bone pain, contemporary clinical trials have not addressed an 
agent’s ability to palliate pain in a fashion that could be used for regulatory approval for this 
indication. 
Establishing pain relief is a regulatory pathway for drug approval in oncology, although the 
last agent to do so was in 1996 with mitoxantrone/prednisone. Historically, the other 
agents that are FDA approved for use in palliating painful bone metastases are both beta- 
emitting bone seeking radiopharmaceuticals, Strontium-89 and Samarium-153 EDTMP. 
These agents however have been limited for concern for bone marrow toxicity. For this 
reason, the development of novel alpha emitting radiopharmaceuticals that offer less 
hematologic toxicity is an appealing strategy. 
 
1.2 
Treatment Background 
Alpha Emitting Bone Seeking Radionuclide Radium-223 dichloride (Xofigotm) 
Radium-223, , is a first in class alpha-emitting radiopharmaceutical that offers substantially 
less marrow toxicity and has been developed for use in metastatic castration-resistant 
prostate cancer (mCRPC) patients with bone metastases. It is unique in that the alpha 
radiation range is limited to less than 100 micrometers and therefore highly localized with 
less damage to the surrounding marrow. This induces double strand breaks in DNA in 
contrast to beta-emitters that exert lower energy and induce single strand breaks that may 
be more amenable to cell repair. 
 
1.2.1 
Description 
 
Clinical studies 
Based on promising pre-clinical data, Radium-223 was introduced into clinical 
development in 2001 and has subsequently advanced through the stages of drug 
development, culminating in a recently completed, international randomized phase 
III trial (known as the ALSYMPCA trial) that demonstrated a 30% survival 
advantage in comparison to placebo. The drug is now FDA approved for men with 
symptomatic mCRPC with bone metastases.4 
Initial clinical trials (AT1-BC-1) studied 31 patients with bone metastases from 
breast or prostate cancer and evaluated escalating single doses of 46, 93, 163, 213 
and 250 kBq/kg b.w. corresponding to 51, 103, 180, 235, and 276 kBq/kg, 
respectively, after implementation of NIST update) as well as with multiple doses 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
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IRB#: 14-098 A (5) 
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(50 kBq/kg at 3 wk intervals x 5 corresponding to 55kBq/kg after implementation 
of the NIST) or 125 kBq/kg b.w. corresponding to 138kBq/kg after implementation 
of the NIST at 6 wk intervals x 2). Decreases in total alkaline phosphatase were 
observed as well as preliminary pain efficacy.5 
A second clinical trial of 64 patients treated with either 4 doses of 50 kBq/kq (to 
55kBq/kg after implementation of the NIST)q 4 weeks or placebo confirmed 
significant decline in alkaline phosphatase, as well as declines in PSA and an  
increase in survival from 46 to 65 weeks.6   In study BC1-03 of 100 patients that 
received single doses of 5, 25, 50 or 100 kBq/kg (corresponding to 6, 28, 55, and 
110 kBq/kg after implementation of NIST update] an ad-hoc analyses of pain 
palliative response was performed and found to demonstrate  pain relief at 8 weeks 
in 40%, 63%, 56%, and 71%, respectively.  There was suggestion that pain relief 
was improved at higher dose levels. However, the measures utilized to assess pain 
were not standard and therefore require prospective evaluation with a priori- 
preservation of statistical power.  Single dosing did not appear to induce PSA 
declines.7   Another trial (BC1-04) of 122 patients who received 3 doses of either 25, 
50, or 80 kBq/kg q 6 weeks (corresponding to 28, 55 and 88kBq/kg after 
implementation of the NIST update) did find that the lower dose group had fewer 
PSA responders and alkaline phosphatase responder.8 
Collectively, this data led to double-blind, randomized, multiple dose, phase III 
multicenter trial of Radium-223 50kBq/kg administered every 4 weeks for 6 doses 
compared to placebo in mCRPC (ALSYMPCA). The primary endpoint of this trial was 
overall survival, and a 2.8 mo survival advantage or 31% reduction in the risk of 
death was demonstrated.4 The results of both the interim and updated analysis, 
revealed that OS was significantly longer in patients treated with Radium-223 plus 
best standard of care compared to patients treated with placebo plus best standard 
of care. 
The ALYMPCA trial however did not address the effect of pain palliation in a 
rigorous manner or one in which this agent could be used for a pain label. 
Radiographic imaging was also not systematically addressed. These are two of the 
most compelling unanswered questions about this agent that can be addressed in 
the current trial. 
Initial prospective data about pain response is available from a prior phase 2, 
double-blind, randomized, multinational study that evaluated the pain relief of a 
single injection of Radium-223 at dose concentrations of 5, 25, 50, or 100 kBq/kg 
corresponding to 6, 28, 55 or 110 kBq/kg after implementation of the NIST update) 
for CRPC patients with painful bone metastasis.7 The primary endpoint was to 
measure the pain-relieving effect of a single dose of Radium-223 based on pain index 
composed of visual analogue scale (VAS) and analgesic use. The secondary  
endpoints included: change in BPI pain severity index (worst, least and average pain 
and pain experienced at current time) from baseline; BPI functional interference 
index (general activity, mood, walking ability, and work, relations with other people, 
sleep and enjoyment of life) and pain relief from medication; duration of pain relief, 
OS and safety.7 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
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Patients (n=100) with progressive CRPC with testosterone levels <50 ng/dL after 
orchiectomy or on androgen ablation therapy who have bone pain ≥2 on the BPI 
were assigned to 1 of 4 single-dose groups of 5 kBq/kg ( corresponding to 6kBq/kg 
after implementation of the NIST) (n=26), 25 kBq/kg  (corresponding to 28kBq/kg 
after implementation of the NIST) (n=25), 50 kBq/kg (corresponding to 55kBq/kg 
after implementation of the NIST) (n=25), or 100 kBq/kg (corresponding to 
110kBq/kg after implementation of the NIST) (n=24) of Radium 223 administered 
IV.7 Follow-up visits were conducted at 2, 4, 8, 12, and 16 weeks post-injection to 
access the palliative response. At Week 8, patients with no palliative response could 
be withdrawn from the study. Additionally, patients were evaluated annually for up 
to 2 years after dosing for long-term safety and survival. 
A statistically significant dose response occurred at Week 2 (P=0.035 [Jonckheere- 
Terpstra test]).6  At Week 8 there were 40%, 63%, 56%, and 71% pain responders 
(pain index ≤4) in the 5, 25, 50, and 100 kBq/kg groups  (corresponding to 6,28,55 
and 110kBq groups after implementation of the NIST) , respectively. Of the 
responders, 6/20 (30%), 8/19 (42%), 8/18 (44%), and 11/21 (52%) reached 
complete (pain index 1) or marked pain response (pain index 2), respectively. 
At Week 8, the mean daily diary pain decreased by 30 mm average in the responder 
group, remained unchanged in the stable group, and decreased 12 mm in the pain 
progression group.7 The pain progression group was allowed to increase analgesics. 
Up to week 8, fewer patients in the higher dose groups (50 and 100 kBq/kg) 
(corresponding to 55 and 110 kBQ/Kg after implementation of the NIST) required 
in increases in analgesia compared to lower dose groups. 
Mean pain relief duration of 44 days for higher-dose (50 and 100 kBq/kg) 
corresponding to 55 and 110 kBQ/kg after implementation of the NIST) groups, 28 
days for 5 kBq/kg (corresponding to 6kBq/kg after implementation of the NIST, and 
35 days for 25 kBq/kg (corresponding to 28kBq/kg after implementation of the 
NIST) dose groups.7 There was not a significant dose-response for pain relief 
duration. 
BPI data showed significant dose-dependent treatment effect at the 8-week point 
(P=0.040 [Jonckheere-Terpstra test]).7 For patients with a pain response, there was 
a significant decrease in BPI pain severity for all 4 dose groups (P=0.05, P=0.001, 
P=0.002, and P=0.0006 [Wilcoxon signed rank test]). 
Post-hoc analysis showed a significant dose-response among pain responders in 
mean daily pain at Week 8 (P=0.008, P=0.0005, P=0.002, and P<0.0001).7 Improved 
BPI functional interference index was also found for pain responders across all 
doses (P=0.04, P=0.01, P=0.002, and P=0.02 [Wilcoxon signed rank test]). 
AEs were reported for 97% of all participants, with approximately half reporting at 
least 1 serious AE.7 No trends were found with the increase of dose in the number, 
nature, or seriousness of AEs. Differences in AEs were not found across treatment 
groups. Disease progression was the most frequent AE with an outcome of death. 
Non-hematological AEs most frequently reported across all groups were nausea, 
fatigue, vomiting, diarrhea, bone pain, urinary tract infection, and peripheral edema. 


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The most common hematological AEs reported were anemia (11%) and hemoglobin 
decrease (15%), but neither was dose dependent. 
 
Clinical safety summary 
The pharmacokinetics, biodistribution, and dosimetry in humans have been 
established (Appendix D). When intravenously administered, this agent is 
eliminated from blood quickly and taken up by bone. It is excreted via the 
gastrointestinal tract with minimal exposure to the kidneys and bladder (less than 
1-5% at 48 hours). 
Most common hematologic adverse events all grades were anemia (31.2%), 
neutropenia (5%) and thrombocytopenia (11.5%). Most common non-hematologic 
all grades adverse events occurring in more than 15% of patients were: bone pain, 
diarrhea, nausea, vomiting and constipation. In the ALSYMPCA randomized trial, 2% 
of patients in the Xofigo arm experienced bone marrow failure or ongoing 
pancytopenia, compared to no patients treated with placebo. There were two deaths 
due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow 
failure was ongoing at the time of death. 
 
 
 
Table 1 
Adverse Reactions in the Phase III Randomized Trial shows adverse 
reactions occurring in ≥ 1% of patients and for which the rate for Ra-223 dichloride 
exceeds the rate for placebo. 
 
Table 1 Adverse Reactions in the Phase III Randomized Trial4 
System/Organ Class 
Preferred Term 
Radium-223 (n=600) 
Placebo (n=301) 
All Grades 
% 
Grades 3-4 
% 
All Grades 
% 
Grades 3-4 
% 
Blood and lymphatic system disorders 
Thrombocytopenia 
11.5 
6.3 
5.6 
2 
Anemia 
31 
13 
31 
13 
Neutropenia 
5 
2.2 
1 
0.7 
Leukopenia 
4.2 
1.3 
0.3 
0.3 
Pancytopenia 
2 
1.2 
0 
0 
Gastrointestinal disorders 
Diarrhea 
25 
1.5 (grade 3 
only) 
15 
1.7 (grade 3 
only) 


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Vomiting 
18.5 
1.7 (grade 3 
only) 
13.6 
2.3 (grade 3 
only) 
Nausea 
35.5 
1.7 (grade 3 
only) 
34.6 
1.7 (grade 3 
only) 
General disorders and administration site conditions 
Injection site 
reactions 
(including 
erythema, pain 
and swelling) 
1.2 
0 
0 
0 
Adverse reactions were identified using MedDRA version 14.1 and graded according to CTCAE version 3.0. 
 
An additional clinically important adverse reaction observed in less than 1% of 
treated patients and at a higher incidence than in placebo-treated patients was 
lymphopenia (0.8% vs. 0.3%). 
 
1.3 
Rationale 
 
1.3.1 
Rationale for conducting the study 
The prevalence of baseline bone pain in contemporary trials of patients with 
metastatic castration-resistant prostate cancer is estimated between 2-45%. Despite 
the prevalence of bone pain, contemporary clinical trials have not addressed an 
agent’s ability to palliate pain in a fashion that could be used for regulatory approval 
for this indication. The last agent to establish pain relief was in 1996 with 
mitoxantrone/prednisone.9 Other agents, such as Strontium-89 and Samarium-153 
EDTMP, are approved to palliate painful bone metastases. However, both agents are 
beta-emitting bone seeking radiopharmaceuticals and therefore have been limited 
for concern of bone marrow toxicity. The phase II trial would label Radium-223 FDA 
approved for use in palliating pain with minimum damage to surrounding bone and 
substantially less marrow toxicity, allowing better quality of life. 
 
Anticipated benefits of the treatment include the following: 
 
-Palliation of bone pain with associated improvement in QOL 
 
- Prolongation of overall survival, most definitively demonstrated in the 
randomized phase II trial 
 
-Anti-tumor efficacy as measured by chemical parameters of bone turnover 
 
- Minimal toxicity 
 
Anticipated risks attributed to Ra-223: 
 
- AEs: Gastrointestinal events (transient diarrhea, nausea and vomiting) 


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- Transient reduction in neutrophil count. Mild to moderate reversible 
myelosuppression may occur. 
 
- Ra-223 is a radioactive drug, and may, in the longer term (over several years), 
induce other primary cancers and bone marrow changes. From the data 
derived so far up to 2 years, there are no reports of long term toxicity. 
 
The risk profile attributed to Ra-223 is favorable compared with available products 
in prostate cancer. 
 
1.3.2 
Rationale for dosage selection 
The dose selected for this agent is (50 kBq (0.00135 mCi) (55kBq (.0015 after NIST 
update) administered every 4 weeks for 6 doses. This was selected based on prior 
studies, including the dose used in the randomized; phase III study that 
demonstrated a 31% reduction in the risk of death in comparison to placebo. This is 
the FDA-approved dose. 
 
1.3.3 
Rationale for correlative studies 
 
A. Imaging 
Routine imaging studies were not mandated by the ALSYMPCA trial. It is therefore 
not known what impact, if any, treatment with Radium-223 has on standard imaging 
studies, or the nature of the relationship between changes in standard imaging 
studies and cancer outcomes.  Post-treatment changes on standard bone 
scintigraphy and cross sectional imaging will be systematically examined in this 
study, using PCWG2 criteria. 1 
 
Unfortunately, bone scintigraphy does not demonstrate direct changes in metastatic 
disease, but rather on the surrounding bone. FDG has the capacity to demonstrate 
post-treatment changes in underlying tumor, even in bone, for patients with CRPC.10 
Recently, CMS has reviewed the evidence of using FDG as a post-treatment indicator 
of treatment effects in CRPC, concluded that it has utility as a post-treatment 
indicator of treatment effects, and that use of FDG PET results in significant changes 
in management.  Based on studies at MSKCC, CMS found that “FDG PET CT could be 
valuable even for assessing activity of bone metastases of prostate cancers in a large 
majority of patients”.11,12 
 
Consequently, CMS proposed that use of FDG PET/CT when used to guide 
subsequent anti-tumor treatment strategy for patients with cancer of the prostate is 
reasonable and necessary under § 1862(a)(1)(A).12 
 
Little is known about the anti-tumor effects of Ra- 223 in prostate cancer in regards 
to glucose metabolism evaluated by FDG PET/CT. However, twenty patients with 
metastatic breast cancer receiving Ra-223 were recently evaluated by FDG PET. 
Analysis revealed that a third of the target lesions defined as the standard uptake 
value (SUVmax)>twice normal liver uptake and a diameter >15mm on PET CT 
showed a significant metabolic decrease (>25% reduction in SUVmax from baseline 
or complete disappearance of lesions) after 2 treatment doses. 13 FDG PET/CT will 


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be performed on patients in centers where such imaging is feasible, and in patients 
who consent to such additional imaging. 
 
B. Serum Biomarkers 
The primary serum biomarker that appears to be altered with Radium-223 are 
markers of bone turnover, more so than PSA. In study BC1-02 (33 patients received 
4 doses of 50 kBq (0.00135 mCi) corresponding to (55kBq (.0015 after NIST 
update) . at 4 week intervals, 31 patients received placebo), results showed a 
significant decline in serum bone markers i.e. bone-ALP (the study primary efficacy 
endpoint), PSA response and a delayed time to PSA progression. Overall survival 
was prolonged in the Ra-223 group, with an increase in median survival time from 
46 to 65 weeks (full analysis set). At 2 years, 10 of 33 of patients (30%) treated 
with Ra-223 were alive compared to 4 of 31 of placebo patients (13%).  The results 
obtained with the biochemical markers for bone-turnover (bone-ALP, CTX-1, 
Procollagen Type I N-Propeptide (PINP)) and tumour load (PSA) support the 
presence of a treatment effect during the treatment period and for one to two 
months after the end of treatment. These data suggest that increasing treatment to 
six injections at 4 week intervals may further delay disease progression. A 
beneficial trend in the survival data supported a treatment effect, although survival 
data in 64 patients should be interpreted with caution.6   However, the ALSYMPCA 
trail which was a randomized phase III placebo controlled trial did show a survival 
advantage or 31% reduction in the risk of death with Radium-223. 
 
C. Tiredness and Pain Interference 
Tiredness will be measured via the worst fatigue item (item #3) of the Brief Fatigue 
Inventory (BFI), which asks patients to “Please rate your fatigue (weariness, 
tiredness) by indicating the one number that best describes your WORST level of 
fatigue during the past 24 hours,” with rating via an 11-point numerical rating scale 
anchored by zero demarking “No fatigue” and 10 demarking fatigue “As bad as you 
can imagine.”  The BFI is a well-established and validated tool that has been used in 
myriad prior cancer trials.14 (See Appendix E for a copy of the Brief Fatigue 
Inventory, item #3) 
 
Interference with general activity and sleep related to pain will be assessed by the 
item from the Brief Pain Inventory that asks patients to “Circle the one number that 
describes how pain has interfered with your general activity (or sleep) ” using an 
11-point numerical rating scale anchored by zero demarking “Does not interfere” 
and 10 demarking “Interferes completely” (Appendix F). This item demonstrates 
strong psychometric properties in prior research.15 
 
2. 
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to determine the effects of pain palliation with 
Radium-223. 
 
2.2 
Secondary Objectives 
2.2.1 
To assess the impact of treatment on markers of bone turnover 


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2.2.2 
To assess the impact of treatment on PSA 
2.2.3 
To assess the impact of treatment on time to radiographic progression 
2.2.4 
To assess the impact of treatment on quantifiable imaging biomarkers assessing bone 
metabolism 
2.2.5 
To assess the impact of treatment on tiredness 
2.2.6 
To assess the toxicity of treatment 
2.2.7 
To assess the impact of treatment on pain interference specifically evaluating its affect on 
general activity and sleep as measured by the BPI 
2.2.8 
To assess the impact of treatment on time to pain progression 
2.2.9 
To assess the impact of treatment on change in analgesic use 
 
 
3. 
PATIENT SELECTION 
3.1 
Target Population 
Men with symptomatic metastatic castration-resistant prostate cancer. 
 
3.2 
Inclusion Criteria 
To be included in this study, patients should meet all of the following criteria: 
• 
Males  aged  18 years of age and above 
• 
Histological or cytological proof of prostate adenocarcinoma 
• 
Castrate serum testosterone level: ≤50 ng/dL (≤1.7 nmol/L) 
• 
Patients, who have experienced disease progression despite initial hormonal therapy, either 
by orchiectomy or by using a GnRH agonist in combination with an anti-androgen, must first 
progress through anti- androgen withdrawal prior to being eligible. The minimum 
timeframe to document failure of anti-androgen withdrawal will be four weeks. Patients on 
second-line (or beyond) hormonal maneuvers, and patients who had no PSA decline on 
combined androgen blockade as first line therapy, need not progress through AAW in order 
to be eligible. 
• 
Known progressive castration-resistant disease, defined as: 
• 
Serum PSA progression defined as two consecutive increases in PSA over a 
previous reference value within 6 months of first treatment, each measurement 
at least one week apart. Serum PSA at screening ≥ 2 ng/mL 
or 
 
• 
Documented appearance of new lesions by bone scintigraphy 
• 
ECOG Performance Status of 0-2 (Appendix A: Performance Status Criteria) 
• 
2 or more bone metastases demonstrated on bone scintigraphy 
• 
Pain at baseline as measured by a BPI worst pain score average of ≥ 3. The BPI worst pain 
score average will be based on the worst pain scores completed by the patient in the 7 
consecutive pretreatment days. A minimum of 4 days of pain scores must be completed by 
the patient in the 7 day window in order to calculate the average worst pain score. The 
investigator will optimize the subject’s pain regimen prior to study entry. 


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• 
Normal organ function with acceptable initial laboratory values: 
• 
WBC 
> 3 x 109 /L 
• 
ANC 
> 1.5 x 109 /L 
• 
Platelets 
> 100 x 109 /L 
• 
Hemoglobin > 9.0 g/dL 
• 
Creatinine  < 1.5 x institutional upper limit of normal (ULN) 
• 
Bilirubin 
≤ 1.5 x ULN 
• 
AST/ALT ≤ 2.5 x ULN 
• 
Albumin 
> 25 g/L 
• 
All acute toxicities as a result of any prior treatment must have resolved to NCI-CTCAE v4.0 
Grade 1 or less at the time of signing the Informed Consent Form (ICF) [Note: Ongoing 
grade 2 neuropathy as a result of treatment with a cytotoxic chemotherapy regimen is 
permitted] 
• 
Life expectancy of at least 6 months 
• 
Willing and able to provide written informed consent and HIPAA authorization for the 
release of personal health information 
NOTE: HIPAA authorization may be either included in the informed consent or 
obtained separately 
• 
Willing and able to comply with the protocol, including follow-up visits, examinations as 
well as having the ability to self-report pain and fatigue using a PRO instrument 
• 
Willingness to use adequate methods of contraception beginning at the signing of the ICF 
until at least 30 days after the last dose of study drug 
 
3.3 
Exclusion Criteria 
Patients that meet any of the criteria listed below will not be eligible for study entry: 
• 
Prior exposure to Radium-223 
• 
Received an investigational therapy within the 4 weeks prior to registration, or is scheduled 
to receive one during the treatment period 
• 
Received a new anti-cancer agent within 4 weeks prior to registration 
• 
Received external beam radiotherapy within 4 weeks prior to registration 
• 
Received systemic therapy with radionuclides (e.g. strontium-89, samarium-153, rhenium- 
186 or rhenium-188) for the treatment of bone metastases 
• 
Treatment with cytotoxic chemotherapy within 4 weeks prior to registration 
• 
Symptomatic nodal disease, i.e. scrotal, penile or leg edema. 
• 
Visceral metastases (including cerebral metastases) from CRPC (>2 lung and/or liver 
metastases [size ≥2cm]; Lymphadenopathy exceeding 6 cm in short-axis diameter or any 


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size pelvic lymphadenopathy if it is thought to be a contributor to concurrent 
hydronephrosis), as assessed by CT, MRI or chest X-ray within the 8 weeks prior to 
registration 
• 
Concurrent chemotherapy. Patients may be on other non-chemotherapy anti-cancer 
treatments, per FDA labeling of Radium-223, provided that these are not changed during 
the primary pain assessment period 
• 
Major surgery within 30 days prior to registration 
• 
Imminent spinal cord compression based on clinical findings and/or magnetic resonance 
imaging (MRI). Treatment should be completed for spinal cord compression. 
• 
Patients with a, “currently active,” second malignancy other than non-melanoma skin 
cancers or non-invasive bladder cancers or other in-situ or non-invasive malignancies. 
Patients who have completed therapy for a prior malignancy and are free of disease for ≥3 
years are eligible. 
• 
Any other serious illness or medical condition, such as but not limited to: 
• 
Any infection ≥ National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) version 4.0 Grade 2 
• 
Cardiac failure New York Heart Association (NYHA) III or IV 
• 
Crohn’s disease or ulcerative colitis 
• 
Bone marrow dysplasia 
• 
Fecal incontinence 
• 
Any other condition which, in the opinion of the Investigator, would make the subject 
unsuitable for trial participation 
 
4. 
PATIENT REGISTRATION AND ENROLLMENT PLAN 
4.1 
Enrollment Plan 
4.1.1 
Participating Study Centers 
This study is anticipated to be conducted at 3 sites. 
 
4.1.2 
Recruitment 
Potential research subjects will be identified by a member of the patient's treatment 
team, the protocol investigator, or research team at participating centers from 
Medical Oncology, Radiation Oncology and Urology offices. Investigators will screen 
the patient's medical records for suitable research study subjects and discuss the 
study and their potential for enrolling in the research study. 
 
4.2 
Registration Procedure 
After eligibility screening and confirmation that a patient is eligible, patients who are 
selected to participate will be registered with the PCCTC Caisis EDC, the PCCTC Clinical Data 
Management System (CDMS).  A record of patients who fail to meet eligibility criteria (i.e., 
screen failures) will be maintained. Patient registration must be complete before beginning 


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any treatment or study activities. A complete, signed study consent and HIPAA 
authorization are required for registration. 
 
4.2.1 
PCCTC Registration: 
 
 
Confirm eligibility as defined in Section 3 Patient Selection. 
Obtain informed consent, by following procedures in Section 11.4 Written Informed 
Consent 
Obtain completed or partially completed protocol specific Eligibility Checklist. 
All participants will be registered through PCCTC Caisis EDC, the PCCTC's CDMS. 
To complete registration and enroll a participant, the study staff at that site must 
contact the designated research staff at PCCTC to notify him/her of the participant 
registration. The site staff then needs to email registration/eligibility checklist and 
source documents to the PCCTC at PCCTC@mskcc.org. (Note: Source documentation 
of eligibility is not required for MSKCC participants.) 


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These documents must be sent for each enrollment within 24 hours of the informed 
consent form being signed. 
 
Upon receipt, the research staff at PCCTC will conduct an interim review of all 
documents for all non-MSKCC participants.  If the eligibility checklist or source 
documentation is missing, the patient will be registered pending enrollment and the 
site is responsible for sending the completed registration documents within 30 days 
of the consent. 
 
If the external registration submission is complete, the participating site IRB has 
granted approval for the protocol, and the site has been activated by MSKCC, PCCTC 
will register the non-MSKCC participants. MSKCC participants will be fully 
registered by MSKCC. 
Once the participant is registered, the participant will be assigned a PCCTC Caisis 
Subject ID. This number is unique to the participant and must be written on all data 
and correspondence for the participant. This PCCTC Caisis Subject ID will be 
relayed back to study staff at the registering site via e-mail and will serve as the 
enrollment confirmation. 
 
 
4.2.2 
Institutional Registration 
Patient registration at each study site/institution will be conducted according to the 
institution’s established policies. Patients must be registered with PCCTC, MSK and 
their local site/institution before beginning any treatment or study activities. 
At MSKCC, all participants must be pended with MSKCC's Protocol Participant 
Registration (PPR) Office prior to submitting registrations to PCCTC. 
PCCTC will register all non-MSKCC participants with MSKCC's Protocol Participant 
Registration Office (PPR) per MSKCC's guidelines. 
MSKCC will register all MSKCC participants with MSKCC's Protocol Participant 
Registration Office (PPR) per MSKCC's guidelines. 


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5. 
TREATMENT/INTERVENTION PLAN 
The following assessments and procedures will occur during the study. A schedule of assessments is shown below. 
 
Screening 
Period 
Treatment Period 
Follow up 
visit (visits 
occur every 
3 months 
+/- 1 
week)e,g 
Week -4a 
Wk1 (within 
5 days after 
the run-in 
period ends) 
Wk4 
Wk5 
Wk8 
Wk9 
Wk12 
Wk13 
Wk16 
Wk 
17 
Wk20 
Wk21 
Wk24 
Wk25/ 
Safety 
FU 
Run- 
in 
Perio 
d 
Ra-223 
X 
X 
X 
X 
X 
X 
Informed 
consent 
X 
Eligibility 
criteria/ 
Demographics 
/ Medical 
history 
X 
Testosterone 
level 
X 
Imaging 
assessmentsb 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinician 
reported 
X -------------------------------------------------------------------------------------------------- X 


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adverse 
events 
Concomitant 
meds 
X 
X -------------------------------------------------------------------------------------------------- X 
ECG 
X 
As clinically indicated 
Pain scale 
(BPI Short 
Form using a 
PRO 
instrument 
x7days) 
Xf 
X 
X 
X 
X 
X 
X 
X 
Fatigue scale 
(BFI item 
using a PRO 
instrument 
x7days) 
X 
X 
X 
X 
X 
X 
X 
X 
Analgesic 
diaryh 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum 
biochemistry d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone markers 
X 
X 
X 
Abbreviations: BFI=Brief Fatigue Inventory; BPI=Brief Pain Inventory; CT=computerized tomography; ECG=electrocardiogram; MRI=magnetic 
resonance imaging; PSA=prostate-specific antigen. 
a 
Informed consent must be obtained, and radiologic assessments will be obtained within 4 weeks of study start date. 
b 
Imaging assessments will be performed every 12 weeks ± 1 week.  Bone scan, FDG PET (FDG will be done in consenting patients and is 
considered optional) , CT scan or MRI of the abdomen and pelvis and CT scan of the chest or Chest X-ray 
c      Hematology: White blood cells count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), platelet count (UNVPLT), 
neutrophils (NEUTP), lymphocytes (LYMP), monocytes (MONP), eosinophils (EOSP), basophils (BASOP) 
 
d   Serum biochemistry: calcium (CA), albumin (ALB), total protein (TP), sodium (NA), potassium (K), chloride (CL), blood urea nitrogen (BUN), 
  
creatinine (CREAT), alkaline phosphatase (ALK), alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBILI), lactate  
 


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dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), phosphate (PHOS), magnesium (MG), glucose (GLU), carbon dioxide (CO2) 
 
 
e 
Subjects should be followed up every 3 months following the safetly follow-up visit for a total of 2 visits or until initation of another therapy 
and be assessed for any potential long term toxicity as well as key efficacy parameters 
f 
Subjects will indicate their daily pain score for 7 days during the 28 day screening period to establish that their average baseline pain score is 
>3 as measued for 4 of 7 days. 
g    During the follow-up period, subjects will answer questions on the BPI and BFI as well as enter information on their analgesic dairy for at least 
4 of 7 days prior to their scheduled follow up visit 
h      Subjects will update their analgesic dairy daily during the run-in period and daily during the pain assessment periods throughout the trial 
 


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5.1 
Screening/Pretreatment Assessment (Day -28 to Day -1) 
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, patients should be asked to 
sign and date a research authorization/HIPAA form and an IRB-approved statement of 
informed consent that meets the requirements of the Code of Federal Regulations (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50. 
The screening visit will determine patient eligibility according to the inclusion and 
exclusion criteria. The following assessments will be performed at this visit: 
• 
Obtain informed consent and research authorization 
• 
Record demographics (including age) and medical history (including prior treatment for 
prostate carcinoma) 
• 
Physical exam 
• 
ECOG performance status 
• 
Vital signs [body temperature, blood pressure, pulse, respiratory rate, weight, height] 
• 
Obtain histologic and radiologic confirmation of disease 
• 
Confirm eligibility according to the inclusion/exclusion criteria 
• 
Perform laboratory tests [hematology, serum biochemistry, PSA, testosterone level, 
bone markers] 
• 
ECG 
• 
Baseline imaging assessments: Bone scan, FDG PET (in consenting patients at centers 
that agree to perform FDG PET scans), CT scan or MRI of the abdomen and pelvis and CT 
scan of the chest or Chest X-ray] 
Relevant information should be documented. The institutional registration should be 
finalized, and appropriate documents (i.e., signed informed consent, research 
authorization/HIPAA form, and supporting source documentation for eligibility questions) 
emailed to the lead site/sponsor. 
Information for patients who do not meet the eligibility criteria to participate in this study 
(i.e., screening failures) should be captured in consortium database at the pretreatment 
assessment. 
5.1.1 
Run-In Period (Day -7 to Day -1 +/- 5 days) 
During the Run-In Period, subjects will self-report pain and fatigue using a PRO 
instrument daily for 7 days and record analgesic medication information on a paper 
pain medication diary to establish that their BPI average baseline pain score is >3 as 
measured for a minimum of 4 of the 7 days (See Appendix I for instructions). This 
data will be used to confirm eligibility based on pain experience.  Upon confirmation 
of eligibility, the subject’s registration will be completed and the subject must start 
treatment within 5 days of registration. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
28 of 75 
 
 
If run-in requirements are not met with respect to pain score, subjects may be 
eligible to rescreen at a later time. 
 
5.2 
Treatment/Intervention Period (Week 1, Day 1 to Week 25, Day 169 (treatment visits 
have a window of ±3days)) 
Unless otherwise specified, all visit procedures are to be performed prior to Radium-223 
administration on the day of the visit. Radium -223 will be administered every 4 weeks for 6 
doses at a dose of (50 kBq (0.00135 mCi) (55kBq (.0015 after NIST update)  Because 
ALSYMPCAa did not assess radiographic assessments during treatment, neither 
radiographic progression nor PSA progression should be used to discontinue treatment. 
However, patients are permitted, per FDA labeling, to be maintained on other anti-cancer 
therapies in addition to Radium-223 provided that these are not changed in the midst of 
pain assessments. Other-cancer therapies must be initiated 4 weeks prior to the run-in 
period. Patients with an increase in pain of 2 points on their BPI worst pain item compared 
to baseline and confirmed at least 2 weeks later will be considered to be treatment failures 
and will be taken off trial. In the absence of clinical progression, patients will continue to 
receive all six treatments, and will continue treatment until clinical progression, 
unacceptable toxicity, or any criteria in Section 5.6 Removing Patients from the Protocol. 
Patients will return to the clinic every 4 weeks for the following assessments: 
• 
Physical exam 
• 
ECOG performance status 
• 
Vital signs [body temperature, blood pressure, pulse, respiratory rate, weight] 
• 
ECG (as clinically indicated – not required at every visit) 
• 
Lab tests [hematology, serum biochemistry, PSA, bone markers (to be done at the Wk 9 
and Wk 13 visit)] 
• 
Clinician reported adverse events and concomitant medications will be monitored 
continuously throughout the study 
• 
Imaging assessments will be performed every 12 weeks ± 1 week during treatment 
period (Week 13, Week 25 [Safety Follow-Up Visit]): Bone scan, FDG PET (in consenting 
patients at participating centers), CT scan or MRI of the abdomen and pelvis and CT scan 
of the chest or Chest X-ray] 
• 
During the treatment period, as outlined in the table above, subjects will self-report 
information on pain, fatigue and health-related quality of life via a PRO instrument (See 
Appendix I for instructions). Data will be entered by the subject daily during the 7 day 
reporting period according to the scheduled outline in the above table. Subjects will also 
update their analgesic dairy during this 7 day period as well.  All PRO entries should be 
done at home prior to visits to the clinic for either regularly scheduled visits or imaging 
appointments. If for any reason PRO entries are done while the subject is at the clinic, 
the staff should not provide any input or assistance other than technical help on using 
the system. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
29 of 75 
 
 
5.2.1 
Safety Follow-Up Visit (Week 25±7 days) 
Once a patient has completed treatment with 6 doses of Radium-223, or the patient 
is prematurely discontinued from treatment for any reason specified in Section 5.6 
Removing Patients from the Protocol, the patient will complete a safety follow-up 
visit including the following assessments: 
 
• 
Physical exam 
• 
ECOG performance status 
• 
Vital signs [body temperature, blood pressure, pulse, respiratory rate, weight] 
• 
ECG (as clinically indicated – not required at every visit) 
• 
Pain scale (BPI Short Form using a PRO instrument) 
• 
Fatigue scale (BFI item using a PRO instrument) 
• 
Analgesic diary 
• 
Lab tests [hematology, serum biochemistry, PSA] 
• 
Adverse events and concomitant medications will be monitored continuously 
throughout the study 
For the pain and fatigue scale, data will be entered by the subject daily during the 7 day 
reporting period prior to their safety visit. Subjects will also update their analgesic dairy 
during this 7 day period as well. 
 
5.3 
Follow-Up 
• 
Patients will be evaluated every 3 months (+/- 1 week) until 6 months after the safety 
follow-up visit for a total of 2 visits or until initation of another therapy. The following 
assessments will be performed at these visits: 
• 
ECOG Performance Status 
• 
Pain scale (BPI Short Form using a PRO instrument) 
• 
Fatigue scale (BFI item using a PRO instrument) 
• 
Analgesic diary 
• 
Lab tests [hematology, serum biochemistry, PSA] 
• 
Imaging Assessments: Bone scan, FDG PET (FDG will be done in consenting patients and 
is considered optional) , CT scan or MRI of the abdomen and pelvis and CT scan of the 
chest or Chest X-ray 
The follow-up visit should be calculated from the date of the safety follow-up visit for 
Radium-223. For the pain and fatigue scale, data will be entered by the subject daily during 
the 7 day reporting period prior to their follow-up visit. Subjects will also update their 
analgesic dairy during this 7 day period as well. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
30 of 75 
 
 
5.4 
Clinical and laboratory assessments 
Medical History 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 
• 
Not pertaining to the study indication 
• 
Start before signing of the informed consent 
• 
Considered relevant to the study 
 
ECOG Performance Status 
 
Performance status will be assessed using ECOG performance status criteria. See Appendix 
A: Performance Status Criteria for a KPS-ECOG conversion chart. 
 
Vital Signs 
 
Vital signs include body temperature, blood pressure, respiratory rate, pulse, weight and 
height. Height will be performed at screening only. 
 
Physical Exam 
 
The physical exam will include a full review of the body systems. 
 
Electrocardiogram (ECG) 
 
A 12-lead ECG will be recorded at screening and whenever an Investigator determines it 
clinically indicated throughout the treatment period. 
 
Adverse Event Monitoring 
 
Patients will be closely monitored throughout the study for adverse events, at least every 
four weeks. Adverse events and other symptoms will be graded according to NCI CTCAE 
v4.0. Adverse events will be monitored from the first dose of Radium-223 through 4 weeks 
following the last administration or until all study drug-related toxicities resolve, stabilize, 
return to baseline or are deemed irreversible, whichever is longer. 
 
Laboratory Test Assessments 
 
Hematology: white blood cells count (WBC), red blood cell count (RBC), hemoglobin (HGB), 
hematocrit (HCT), , platelet count (UNVPLT), neutrophils (NEUTP), lymphocytes (LYMP), 
Serum Biochemistry: calcium (CA), albumin (ALB), total protein (TP),  sodium (NA), 
potassium (K), chloride (CL), blood urea nitrogen (BUN), creatinine (CREAT), alkaline 
phosphatase (ALK), alanine transaminase (ALT), aspartate transaminase (AST), total 
bilirubin (TBILI), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), 
phosphate (PHOS), magnesium (MG), glucose (GLU), carbon dioxide (CO2) 
 
Serum PSA (PSA) 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
31 of 75 
 
 
Bone markers: bone specific alkaline phosphatase (BAP), serum N-telopeptide (SNTX), 
serum C-telopeptide (SCTX), procollagen type I N-terminal propeptide (PINP) 
 
Testosterone level (TEST) 
 
 
BPI short form (pain scale) 
A Patient Reported Outcome (PRO) instrument will be performed by patients to assess level 
of pain which includes a change in BPI worst pain item from baseline (See Appendix I for 
instructions). BPI functional interference index (general activity, sleep) will be collected. 
 
Measure of fatigue 
Patient Reported Outcome (PRO) instrument will be performed by patients to assess fatigue 
using the Brief Fatigue Inventory (BFI). Patients will be asked to “Please rate your fatigue 
(weariness, tiredness) by circling the one number that best describes your WORST level of 
fatigue during the past 24 hours,” with rating via an 11-point numerical rating scale 
anchored by zero demarking “No fatigue” and 10 demarking fatigue “As bad as you can 
imagine.” 
 
Analgesic diary 
Records daily intake of analgesic medications. A question confirming that subject's pain 
medication diary has been completed is included in the PRO instrument. 
 
Tumor Assessment and Bone Scan 
 
Radiographic disease assessment will be obtained every 12 weeks during active treatment 
and every 3 months during the long-term follow-up portion using PCWG2 criteria as 
described in Section 8.3 Therapeutic Response. 
 
5.5 
Dosing Delays and Dose Modifications for Toxicities 
At each study visit for the duration of their participation in the study, patients will be 
evaluated for adverse events (all grades), serious adverse events (SAEs), and adverse events 
that require study drug interruption or discontinuation. Patients discontinued from the 
treatment phase of the study for any reason will be followed for toxicity until approximately 
4 weeks after the last dose of the study drug or until all study drug-related toxicities resolve, 
stabilize, return to baseline or are deemed irreversible, whichever is longer. 
Every effort should be made to administer the full dosing regimen of Ra-223 dichloride. 
Adjustment of dose level is not permitted. 
Study visits during the treatment period should occur at 4 weeks intervals (within a 
window of +/- 7 days). 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 may be on other non-chemotherapy anti- 
cancer treatments, per FDA labeling of Radium-223, provided that these are not changed 
during the period of pain assessments. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
32 of 75 
 
 
Patients with a rising PSA should not be considered to have progressive disease, as a rising 
PSA does not imply lack of clinical benefit with treatment radium-223. 
 
Patients with radiographic progression are not required to discontinue treatment or to be 
defined for this trial as having disease progression, as there are no known data associating 
such radiographic findings with a lack of clinical benefit with radium 223. 
 
Patients with unequivocal clinical progression should be considered treatment failures, and 
treatment under the auspices of the protocol will be discontinued. 
 
Myelosuppression 
If a patient experiences Common Terminology Criteria for Adverse Events1 (CTCAE)grade 
3-4 neutropenia or thrombocytopenia lasting > 14 days, further study drug administrations 
must be discontinued. 
If a patient experiences CTCAE grade 3-4 neutropenia the study drug administration should 
be delayed until recovery to grade 2 (minimum 1.0 x 109 /L) or better. 
In case of thrombocytopenia grade 3-4 the study drug administration should be delayed 
until recovery to CTCAE grade 2 (minimum 50 x 109 /L) or better. 
In case of hemoglobin CTCAE grade 3-4, the value needs to recover to CTCAE grade 2 
(minimum 8.0 g/dL) or better before next study drug administration. Blood transfusion is 
acceptable between study drug administrations. 
Gastrointestinal events: 
Diarrhea: 
No prophylactic treatment for diarrhea is recommended. Antidiarrheals can be used when 
needed. A further dose of study medication should not be given before recovered to CTCAE 
grade 2 or baseline. 
Nausea/Vomiting: 
No prophylactic treatments for nausea or vomiting are recommended, but anti-emetic drugs 
can be used when needed. A further dose of study medication should not be given before 
recovered to CTCAE grade 2 or baseline. 
Constipation: 
Patients can continue laxative as concomitant medication, but start of prophylactic 
treatments before study drug injection are not recommended. Laxative can be used when 
needed. A further dose of study medication should not be given before recovered to CTCAE 
grade 2 or baseline. 
Spinal Cord Compression 
 
 
 
 
 
 
 
 
 
 
1 Common Terminology Criteria for Adverse Events, Version 4.0 (CTC AE); Published May 28, 2009 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
33 of 75 
 
 
Patients, who experience spinal cord compression and require treatment with XRT in the 
treatment period prior to week 8, will be taken off-study and declared non-evaluable. 
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. 
Any Other Toxicity 
If a patient experiences any non-hematological grade CTCAE grade 4 toxicity lasting > 7 
days despite adequate treatment, further study drug administration must be discontinued. 
 
 
5.6 
Removing Patients from the Protocol 
Patients will receive a maximum of 6 doses of Radium-223 on study unless one of the 
following criteria applies: 
• 
Patient decides to withdraw from the study 
• 
Symptomatic disease progression at any time 
• 
Objective clinical disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s) that may or may not be directly related to treatment but 
that, in the judgment of the treating physician, makes it dangerous for the patient to be 
retreated 
• 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator 
Because an excessive rate of withdrawals can render the study uninterpretable, 
unnecessary withdrawal of patients should be avoided. When a patient discontinues 
treatment early, the investigator should make every effort to contact the patient and to 
perform a final evaluation. The reason(s) for withdrawal should be recorded. 
5.6.1 
Withdrawal of subjects from study 
Subjects must be withdrawn from the trial (treatment and procedures) for the 
following reasons: 
• 
Subject withdraws consent from study treatment and 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. 
Subjects may be withdrawn from the study for the following reasons: 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
34 of 75 
 
 
• 
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. 
• 
Use of illicit drugs or other substances that may, in the opinion of the investigator, 
have a reasonable chance of contributing to toxicity or otherwise skewing trial 
result. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the subject's 
medical records. 
Patients who are withdrawn from the protocol per reasons stated above will be 
replaced, unless they are evaluable by criteria specified in Section 10.2.1 Analysis 
Populations. 
 
5.7 
Concomitant Medications 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, or alternative therapies taken within 2 weeks prior to the 
start of the study must be documented on the case report form (CRF). 
Patients receiving bisphosphonates or denosumab (RANK-L inhibitor) may continue on 
these agents as standard practice throughout the study. 
Patients who enter the trial receiving prednisone or steroids must continue on the same 
dose they were receiving at the time of baseline assessment. 
Permitted 
• 
Pain Regimen Modification Guidelines: 
o An attempt to optimize a pain regimen should be made prior to subject 
enrollment. The investigator will optimize the subject's pain regimen under 
advisement/guidance of the 2.2014 NCCN Adult Cancer Pain guidelines. Opioid 
rotation, use of adjuvants, institution of a sustained release medication to 
minimize frequent prn dosing will be utilized depending on the severity of pain, 
degree of opioid tolerance and side effects under advisement/guidance of the 
NCCN guidelines. Use and optimization of short acting opioids followed, if 
needed, by adding an extended-release or long-acting formulation described in 
the protocol reflect NCCN guidelines. The patient will usually be allowed rescue 
doses of short-acting opioids of 10% to 20% of 24-h oral dose (mg) as needed as 
per the NCCN guidelines. 
o At the time of enrolment, the subjects pain regimen will be graded according to 
the WHO analgesia ladder: 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
35 of 75 
 
 
▪ 
Step 1- non-opioid analgesics 
▪ 
Step 2- weak opioid (tramadol, codeine, hydrocodone) 
▪ 
Step 3- strong opioid analgesic (morphine, oxycodone, fentanyl, 
oxymorphone, levorphanol, and methadone). 
▪ 
NSAIDs, steroids and other adjuvant non-opioid analgesics can be 
included at each step of the analgesics ladder. 
• 
Treatment with non-conventional therapies (e.g., herbs [with the exception of St. John’s 
Wart], acupuncture) and vitamin/mineral supplements is acceptable provided that, in 
the opinion of the investigator, such treatment will not interfere with the trial 
endpoints. 
• 
Subjects may receive standard of care for any underlying illness. 
• 
In the event of neutropenia, anemia, or thrombocytopenia, subjects may receive 
appropriate supportive care (e.g., transfusion, biologic response modifiers such as G- 
CSF or GM-CSF, prophylactic antibiotics, antifungals and/or antivirals, hematopoietic 
growth factors). 
• 
Blood transfusions and erythropoietin are allowed during the study period but not 
within 4 weeks prior to first dose of study drug. 
• 
If surgery is required during study drug treatment, the surgeon needs to be notified that 
the patient has been treated with a radioactive product and adequate precautions for 
radioactive protection should be applied during the surgical procedure. The patient 
should continue with study treatment if considered safe in the treating Investigator's 
opinion. 
Concomitant treatments other than chemotherapy for prostate cancer are permissible, 
provided that they are started before the patient’s pain assessments, and are not changed 
during the pain assessments. These agents will be recorded in the CRFs. These treatments 
may include, but are not necessarily limited to: Luteinizing-Hormone-Releasing hormone 
(LHRH) analogs, surgery, flutamide, bicalutamide, nilutamide, estramustine, ketoconazole, 
corticosteroids, estrogens, abiraterone, and enzalutamide. 
 
6. 
THERAPEUTIC AGENT 
6.1 
Description of Treatments 
Radium -223 (will be supplied as ready to use vial solutions for intravenous administration. 
The dose will be (50 kBq (0.00135 mCi) (55kBq (.0015 after NIST update) administered 
every 4 weeks for 6 doses. 
Ra-223 will be administered as slow bolus injection over 1 minute. 
Written instructions for handling and administration of Ra-223 will be given. 
Ra-223 injection is a ready-to-use, sterile, free from endotoxins, clear and colorless aqueous 
solution of Radium-223 dichloride (223RaCl2) for intravenous administration. The volume 
per vial is 6 mL, corresponding to 6.6 MBq after implementation of the NIST with a 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
36 of 75 
 
 
radioactive concentration of 1,100 kBq/mL after implementation of the new NIST standard 
at the reference date. The product has a pre-calibration of 14 days. 
Radium-223 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 - 8.0. The radioactive concentration at the reference date is 
1,100 kBq/mL after implementation of the NIST. The product has a pre-calibration of 14 
days. When administered in a day other than the reference day, the volume should be 
corrected according to the physical decay table supplied with each shipment. 
Radium Ra 223 dichloride is manufactured in Norway at a Bayer-contracted manufacturing 
site, IFE (Institute for Energy Technology), a specialized facility with a long history of 
manufacturing radiopharmaceuticals. The product is produced according to Good 
Manufacturing Practice (GMP). 
Radium Ra 223 dichloride is then shipped to Cardinal Health for distribution in the United 
States. Cardinal Health prepares individualized patient ready doses based on patient weight 
and intended time of administration. The product is delivered in a glass vial, ready-to-use 
with a certified activity. Radium Ra 223 dichloride is shipped in a lead container with Type 
A radioactive packaging according to international transportation guidelines for radioactive 
materials. Patient ready doses to be utilized within study 14-098/c13-124 will be over- 
labeled with an “investigational use only” label at Cardinal prior to distribution to 
administering sites. 
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. 
 
6.2 
Dosage Selected, Preparation, and Schedule of Administration 
If the vials have been stored in a refrigerator, they should be left at room temperature for 
1 hour prior to use. Ra-223 should not be diluted or mixed with any solutions. 
The dose of Ra-223 is (50 kBq (0.00135 mCi) (55kBq (.0015 after NIST update) (unless, 
following discussions between the investigator(s) and sponsor, additional cohort(s) are 
added at intermediate Ra-223 dose levels between 25 and 55 kBq/kg). Radium Ra 223 
dichloride will be administered as a bolus intravenous (IV) injection (up to 1 minute) at 
intervals of every 4 weeks for up to 6 cycles. 
The dosage of Radium Ra 223 dichloride after implementation of the new 2015 NIST 
standard is 55kBq/kg body weight 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. After implementation of the NIST the radioactive concentration at the reference 
date is 1,100 kBq/mL 
The volume to be administered for dosing is calculated as follows: 
 
 
Volume to be 
= 
Body weight (kg)  dose (55kBq/kg 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
37 of 75 
 
 
administered after 
implementation of the 
new NIST standard (mL) 
b.w.) 
DK factor  1,100 kBq/mL 
 
 
Filling of the syringe should take place in a fume cupboard or safety bench in the 
Radiopharmacy/Nuclear Medicine department. Personnel should wear medical gloves and 
eye protection during syringe filling to prevent contamination of the radioactive solution to 
skin and eyes. The individual responsible for study drug preparation will draw the correct 
volume of study drug into a syringe. Data regarding activity and volume to be injected for 
the various patients should be recorded on the study drug administration CRF page. 
To maintain traceability, there is one syringe label set per injection, with three identical 
removable stickers with a unique serial number, in addition to information of the 
radioactive material. One sticker with the serial number should be attached to the drug 
preparation page, the other on the syringe and the third to the CRF study drug 
administration page. 
The syringe should be handed over to the individual who will perform the administration. 
There is no need for shielding from alpha particle radiation during preparation and 
administration of the patient doses. Alpha particles from radioactive decay of Radium-223 
and progeny are easily stopped by the thickness of a sheet of a paper or the walls of a glass 
vial. 
Aseptic technique should be used in the administration of Ra-223. The investigational drug 
will be administered as a slow bolus intravenous injection. After administration, the 
equipment used in connection with the preparation and administration of Ra-223, is to be 
treated as radioactive waste and should be disposed of in accordance with hospital 
procedure for the handling of radioactive material. Written information about Ra-223 and 
instruction about handling and administration of radioactive material will be given to study 
personnel. 
Treatment will be administered on an outpatient basis. 
 
6.2.1 
Supply, storage requirements, and special handling 
A dedicated person, who has the responsibility delegated from the Principal 
Investigator, will have the overall responsibility for handling and storage of study 
drug at the centre; i.e., that the vials with study drug are correctly received and 
recorded, handled and stored safely and properly, and used in accordance with this 
protocol. A deputy person should also be nominated. The study drug is a 
radiopharmaceutical and should be handled by individuals who are qualified by 
training and experience in the safe handling of radiopharmaceuticals. 
 
The Ra-223 vials must be stored inside their lead container (of approximately 4 mm 
thickness) in a secure facility. The study drug should be used within the designated 
expiration date by manufacturer. The radioactivity of Ra-223 is measured by use of 
a radioisotope dose calibrator, calibrated for the isotope Radium-223. The 
radioactivity in the vial will be controlled at the hospital as part of the drug 
accountability, upon receipt of Ra-223 and after dispensing. The radioactivity of the 
syringe will be controlled before and after administration. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
38 of 75 
 
 
6.2.2 
Radiation protection 
In general, the administration of radioactive drugs involves a potential risk for third 
persons due to radiation from the patient and possible contamination by spilt urine, 
feces, blood, etc. An advantage of using Radium-223 is that once injected, both alpha 
and beta particles are stopped by the patient’s tissue. Some gamma radiation is 
emitted from Radium-223 and its daughters. However, due to the low activity 
injected and attenuation in the patient’s body mass, the gamma radiation outside 
the patient’s body is minimal, and therefore the product can be administered on an 
outpatient basis. The patient and his caretakers will receive instructions in 
accordance to regulatory requirements regarding hygiene precautions after 
receiving the radioactive drug, to minimize the risk of contamination. The exposure 
rate constants from patients receiving Ra-223 or from handling vials or syringes 
with Ra-223 have been measured and are felt to not be of clinical concern. 
 
6.3 
NIST Standardization 
The quantification of radium-223 radioactivity in Xofigo (radium-223 dichloride; BAY 88- 
8223) is based on the primary standardization performed by the US NIST.  National  
Institute of Standards and Technology prepares the standard reference material (SRM) using 
an official dial setting (primary standardization) as published.16 The NIST SRM is used          
to calibrate the instruments in production and quality control for both the drug substance 
and drug product. Additionally, the NIST SRM is used to prepare the NIST traceable Ra-223 
reference materials which are then sent to the end-users (e.g., nuclear medicine laboratory 
physicians or technicians) for dial-setting of their dose calibrators, to allow verification of 
the patient dose. In 2014, NIST performed a re-assessment of the primary standardization 
based on preliminary information suggesting a potential discrepancy of approximately 8- 
10% between the published NIST primary standardization16 and results obtained by other 
national metrology institutes (United Kingdom, Germany, Japan). After completion of the re- 
assessment, NIST reported their findings17 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 change in the numerical description of the patient’s dose, product strength and labeled 
vial activity does not impact the safety or efficacy of Xofigo. The change in the NIST radium- 
223 standard has no impact on subjects; dose subjects are receiving, and will continue to 
receive. 
 
Subjects will receive the same actual dose and volume that was studied in Study 15245 
(BC1-06 dosimetry study) and is associated with the proven safety and efficacy of radium- 
223 dichloride, though the stated nominal radiation dose received has been updated to 
reflect the new standard. 
 
7. 
ADVERSE EVENTS 
7.1 
Definitions 
7.1.1 
Adverse Event (AE) 


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An adverse event is any untoward medical occurrence in a research patient during a 
clinical study or within 4 weeks post treatment, regardless of causality. This includes 
adverse clinical or laboratory findings, any adverse drug reaction (ADR),                 
and an illness with onset during the study, or an exacerbation of preexisting illness 
or condition. 
 
7.1.2 
Serious Adverse Event (SAE) 
The investigator must assess each event to determine if it meets the criteria for 
classification as an SAE or serious adverse drug reaction. 
 
All SAEs that occur any time a patient is on study (i.e., as soon as the informed 
consent has been signed) or within 4 weeks of the last dose of Radium-223 must be 
recorded, regardless of the suspected relationship to the investigational agent. Any 
SAE occurring more than 4 weeks after the last dose of Radium-223 must be 
recorded if a causal relationship to the investigational agent is suspected. 
 
An SAE/ADR as defined in the Code of Federal Regulations (21CFR312.32) is any 
event that: 
• 
Results in death 
• 
Is life-threatening 
• 
Results in inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Results in congenital anomaly or birth defect 
• 
Is medically significant in the opinion of the investigator 
 
7.1.3 
Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation of the patient’s 
condition. If disease progression results in death or hospitalization while on study 
or within 4 weeks of the last dose, progressive disease will be considered an SAE. 
 
7.1.4 
Life-threatening events 
A life-threatening event is any AE that places the patient at immediate risk of death 
from the reaction as it occurs. It is not a reaction that, had it occurred in a more 
severe form, might have caused death. 
 
7.1.5 
Hospitalization or prolongation of hospitalization 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) 
resulting from a precipitating, treatment-emergent adverse event. For chronic or 
long-term patients, inpatient admission also includes transfer within the hospital to 
an acute or intensive care inpatient unit. Hospitalizations for administrative reasons 
or a non-worsening preexisting condition should not be considered AEs (e.g., 
admission for workup of a persistent pretreatment laboratory abnormality, yearly 
physical exam, protocol-specified admission, elective surgery). Preplanned 
treatments or surgical procedures should be noted in the baseline documentation. 
Hospitalization because of an unplanned event will be deemed an SAE. 


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Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 
 
7.1.6 
Significant disability 
Disability is a substantial disruption of the patient’s ability to conduct normal life 
functions. 
 
7.1.7 
Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the 
study, the treating physician must be notified immediately. All confirmed 
pregnancies must be immediately reported to Bayer and PCCTC and recorded in 
PCCTC Caisis EDC. All pregnancies will be followed until resolution (i.e., voluntary or 
spontaneous termination or birth) and assessed for congenital anomalies and birth 
defects. Patients receiving Ra-223 will be instructed to avoid conception for at least 
6 month after last administration of Ra-223. 
 
7.1.8 
Medical significance 
An event that is not fatal or life-threatening and that does not necessitate 
hospitalization may be considered serious if, in the opinion of the investigator, it 
jeopardizes the patient’s status and might lead to medical or surgical intervention to 
prevent any of the above outcomes. Such medically significant events could include 
allergic bronchospasm requiring intensive treatment in the emergency room or at 
home, blood dyscrasias that do not result in inpatient hospitalization, or the 
development of drug dependency or abuse. 
 
The NCI CTCAE v4.0 handbook will be used for adverse event descriptions and grading. 
 
Follow-up of adverse events should continue until the event and any sequelae resolve or 
stabilize at a level acceptable to the investigator and the study site/sponsor or medical 
monitor. 
Events that are not considered serious adverse events include: 
• 
Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
• 
Elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• 
Emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
• 
Respite care 
 
 
7.2 
Recording and Grading 
 
7.2.1 
Recording 
All observed or volunteered adverse events, regardless of treatment group, severity, 
suspected causal relationship, expectedness, or seriousness will be documented. 


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A clinically significant change in a physical examination finding or an abnormal test 
result (i.e., laboratory, x-ray, EKG) should be recorded as an AE, if it: 
• 
Is associated with accompanying symptoms 
• 
Requires additional diagnostic testing or medical or surgical intervention 
• 
Leads to a change in study dosing or discontinuation from the study 
• 
Requires additional concomitant drug treatment or other therapy, or 
• 
Is considered clinically significant by the investigator 
An abnormal test result that is subsequently determined to be in error does not 
require recording as an adverse event, even if it originally met one or more of the 
above criteria. 
 
7.2.2 
Grading severity 
All adverse events will be graded based on NCI CTCAE version 4.0 
 
7.2.3 
Attributing causality 
After grading for severity, the investigator must evaluate all clinical AEs and 
abnormal laboratory values for possible causal relationship to the investigational 
agent. Causality attribution will be decided using the criteria outlined in Table 6. 
 
Table 6  Relationship of Adverse Event to Study Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related to Ra-223 
Unlikely 
AE is doubtfully related to Ra-223 
Possible 
AE may be related to Ra-223 
Probable 
AE is likely related to Ra-223 
Definite 
AE is clearly related to Ra-223 
 
Abnormal laboratory values of clinical significance that were present at baseline and 
did not change in severity or frequency during experimental therapy or intervention 
and those that can obviously be attributed to underlying disease will be recorded as 
unrelated and will not be considered when evaluating the maximum tolerated dose 
(MTD). 
 
7.3 
Reporting Adverse Events 
 
7.3.1 
Reporting serious adverse events 
All SAEs, events determined to be medically significant by the treating Investigator, 
and unknown reactions or unexpected events should be reported lead site/sponsor 
and PCCTC within 24 hours of knowledge of the event using the contact information 
below. The initial report should include the following information at a minimum: 
• 
Protocol # and title 


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• 
study identification number, sex, age at time of event 
• 
Date the event occurred 
• 
Description of the SAE 
• 
Causal relationship to the study drug 
The PCCTC SAE Report Form (Appendix B) will be used for reporting each SAE and 
should be submitted to the PCCTC within 3 calendar days of learning of the event. 
Severity, causality, action taken, concomitant medications, outcome, etc should be 
reported to the PCCTC as soon as possible. 
 
Follow-up of adverse events should continue until the event and any sequela resolve 
or stabilize at a level acceptable to the investigator. 
 
The PCCTC will facilitate all SAE reporting to the MSKCC IRB/PB within 5 calendar 
days of PCCTC awareness or identification of the event. 
SAE contact information for the PCCTC, lead site/sponsor is listed below: 
Lead Site Study PI 
Michael Morris, MD 
Memorial Sloan Kettering Cancer Center 
Genitourinary Oncology Service 
1275 York Avenue 
New York, NY 10065 
morrism@mskcc.org 
 
PCCTC: 
Prostate Cancer Clinical Trials Consortium 
Phone: 646-888-0434/646-422-4383 
Email: PCCTC@mskcc.org 
 
 
7.3.2 
Reporting SAEs to Bayer Pharmaceuticals, the drug supplier 
 
All serious adverse events should be reported to Bayer within 24 hours of learning 
of the event. If any subject dies during the trial or within 30 days of the end-of- 
treatment visit, the investigator will inform Bayer and record the cause of death in 
detail (using the SAE Form) within 24 hours of learning of the event. 
 
Requirements for Reporting of Serious Adverse Events: 
All SAEs must be reported to Bayer within 24 hours of the Principal Investigator’s 
awareness and must include the following minimum information: 
 
1. The name and contact information of the reporter 
2. The name of the study drug(s) 
3. A description of the reported SAE 


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4. A patient identified by one or more of the following: 
a. Patient initials 
b. Patient number 
c. Knowledge that a patient who experienced the adverse event exists 
d. Age 
e. Sex 
5. An investigator assessment of study drug causality. For studies with combination 
therapy, a separate causality assessment should be provided for each study drug. 
Additional data which would aid the review and causality assessment of the case 
include but are not limited to: 
The date of onset 
The severity 
The time from administration of study drug(s) to start of the event 
The duration and outcome of the event 
Any possible etiology for the event 
The final diagnosis or syndrome, if known 
Action(s) taken, if any 
 
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com 
 
Facsimile: 
(973) 709-2185 
 
Address: 
Global Pharmacovigilance - USA 
Mail only: 
Bayer HealthCare 
P.O. Box 1000 
Montville, NJ 07045-1000 
 
Address: 
340 Changebridge Road 
FDX or UPS only 
Pine Brook, NJ 07058 
 
Reports for all Bayer products can also be phoned in via our Clinical Communications 
Dept: 
 
Phone: 
1-888-842-2937 
 
 
7.4 
Safety Reports 
PCCTC will distribute outside safety reports to the participating sites immediately upon 
receipt. Participating sites are responsible for submitting safety reports to their local 
IRB/PB as per their local IRB guidelines. All local IRB approvals/acknowledgments of safety 
reports must be sent to PCCTC upon receipt. 


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8. CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE 
8.1 
Primary endpoint 
The primary endpoint of the study is a 30% decline in the BPI worst pain item from baseline 
to week 8, with a confirmed reduction at week 12 without an escalation of the subject’s pain 
regimen from Step 1 to Step 2 or Step 2 to Step 3 of the WHO analgesic ladder. 
The baseline BPI worst pain score average will be based on the worst pain scores completed 
by the patient in the 7 consecutive pretreatment days. A minimum of 4 days of pain scores 
must be completed by the patient in the 7 day window in order to calculate the average 
worst pain score. 
 
8.2 
Secondary endpoints 
• 
Bone-ALP response will be described as: 
o 
Percentage of change from baseline to 12 weeks (or earlier for those who 
discontinue study therapy) 
o 
Maximum change (rise or fall) in bone-ALP during the treatment period reported for 
each patient as a waterfall plot 
• 
Changes in total-ALP will be defined as for bone-ALP above 
• 
PSA decline will be reported on all patients. Using PCWG2 guidelines 1, the percentage of 
change in PSA from baseline to 12 weeks, as well as the maximum decline in PSA will be 
reported for each patient using a waterfall plot. 
• 
Progression, for those patients showing an initial decline in PSA from baseline, is 
defined as an increase in PSA that is ≥25% and ≥2 ng/mL above the nadir, and which is 
confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend). 
• 
Progression, for those patients with no decline in PSA from baseline, is defined as an 
increase in PSA that is ≥25% and ≥2 ng/mL after 12 weeks. Note: PSA progression as 
such will not lead to study discontinuation 
• 
Time to First Radiographic or Clinical Progression (TTFROCP) based on RECIST version 
1.1 and Prostate Cancer Working Group 2 (PCWG2) definitions 
• 
Changes in other bone markers: 
o 
Serum C-telopeptide (sCTX-1) 
o 
N-terminal propeptide of procollagen type 1 (PINP) 
• 
Radiographic response through the RECIST criteria 1.1 will also be determined using 
FDG PET/CT to assess for treatment effect in bone. 
• 
Time to pain progression, defined as time until a >2 point increase in pain compared to 
baseline confirmed at least 4 weeks later. 
• 
Change in analgesic use assessed by the WHO analgesic ladder 
• 
Changes in measure of tiredness measured by the worst fatigue item (item #3) from the 
Brief Fatigue Inventory. 
• 
Measures of pain interference specifically evaluating its affect on general activity and 
sleep as assessed on BPI 
• 
Evaluate the short and long term toxicity to treatment 
 
 
8.3 
Therapeutic Response 
Response and progression will be evaluated in this study using a combination of the revised 


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international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) committee and the guidelines for prostate cancer endpoints developed by the 
Prostate Cancer Clinical Trials Working Group (PCWG2). 
 
Trial objectives are defined based on controlling, relieving, or eliminating disease 
manifestations that are present when treatment is initiated. Traditional measures of 
response reflect when a treatment is working and measures of progression indicate when a 
drug should be stopped. Because assessing response in bone (the most common site of 
prostate cancer spread) is uncertain and the clinical significance of PSA changes in response 
to therapy is not a reliable predictor of response, measures of response have been expanded 
in consortium trials to include measures of progression. 
 
 
Patients will need to be reevaluated for response every 12 weeks ± 1 week during protocol 
therapy according to the guidelines below. 
 
8.3.1 
PSA 
Perform PSA testing at a minimum of 1‐week intervals with the threshold PSA level 
at 2.0 ng/mL To report PSA‐based outcomes, PCWG2 recommends that the percent 
of change in PSA from baseline to 12 weeks (or earlier for those who discontinue 
therapy) and the maximum decline in PSA that occurs at any point after treatment 
be reported for each patient using a waterfall plot. Because declines in serum PSA, if 
they occur, may not do so for several weeks, PSA measurements obtained during the 
first 12 weeks should not be used as the sole criterion for clinical decision making. 
 
8.3.2 
Measurable disease 
According to RECIST 1.1, measurable disease is defined as at least 1 lesion ≥ 10 mm 
in its longest diameter as measured with conventional techniques (i.e., CT or MRI). 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 
15 mm in short axis when assessed by CT scan. All tumor measurements will be 
taken using a ruler or calipers and recorded in millimeters (or decimal fractions of 
centimeters). 
 
8.3.3 
Nonmeasurable disease 
Following RECIST 1.1, all other lesions (or sites of disease) will be considered 
nonmeasurable disease. This includes small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥10 to <15mm short axis) and any of the following: 
• 
Bone lesions 
• 
Ascites 
• 
Pleural or pericardial effusion 
• 
Lymphangitis cutis or pulmonis 
• 
Abdominal masses that are not confirmed and followed by imaging techniques 
• 
Cystic lesions 
• 
Lesions occurring within a previously irradiated area unless they are 
documented as new lesions since the completion of radiation therapy 


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• 
Leptomeningeal disease 
Note: If only a single, asymptomatic bone lesion is present at baseline, and 
will be irradiated, the metastatic nature of this lesion must be confirmed by 
x-ray, CT, or MRI. 
 
8.3.4 
Target (nodal and visceral) lesions 
Following RECIST 1.1, progression in a nodal or visceral site (i.e., liver and lung) is 
sufficient to document disease progression. The presence or absence of nodal and 
visceral disease before and after treatment should be recorded separately. 
 
All measurable lesions (up to a maximum of 2 lesions per organ and 5 lesions in 
total) will be identified as target lesions to be measured and recorded at baseline. 
The target lesions should be representative of all involved organs. Target lesions  
will be selected on the basis of size (i.e., the largest area) and suitability for accurate, 
repeated measurements (either by imaging techniques or clinically). A sum of the 
diameters (longest for non‐nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline 
sum of diameters will be used as a reference by which to characterize the objective 
tumor response. 
 
Pathological nodes which are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of ≥ 15mm by CT scan. 
 
8.3.5 
Bone lesions 
On bone scan, progression of bone metastases is defined as the appearance of 2 or 
more new bone lesions. 
 
•If 2 or more new bone lesions are observed on the first reassessment scan only, a 
confirmatory scan performed at least 6 weeks later needs to show 2 or more 
additional new lesions (for a total of 4 or more new lesions since the baseline 
assessment) for progression to be documented. 
 
• If 2 or more new bone lesions are observed on scans obtained after the first 
reassessment, a confirmatory scan performed at least 6 weeks later needs to show 
the persistence of or an increase in the number of bone lesions compared to the 
prior scan. 
 
The date of progression is always the date of the scan in which the change was first 
observed. 
 
8.3.6 
Nontarget lesions 
All other lesions (or sites of disease) will be identified as nontarget lesions and 
recorded at baseline. Nontarget lesions will include measurable lesions that exceed 
the maximum number per organ (2) or total of all involved organs (5), as well as 
nonmeasurable lesions. The presence or absence of these lesions will be recorded 
on the CRF and should be evaluated at the same assessment time points as all target 
lesions. 


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8.3.7 
New lesions 
The appearance of up to 5 new measurable lesions should be recorded. Each new 
lesion should be reassessed using the same imaging modality at each time point. If 
measurable, the diameter of each new lesion should be recorded in the CRF and the 
sum diameters of new and old lesions should be calculated. 
 
Note: The appearance of a new lesion does not by itself satisfy the criteria 
for confirmed progressive disease. Rather, the tumor burden imposed by the 
new lesions must be evaluated within the context of the total tumor burden 
(i.e., preexisting plus new lesions). Confirming progression in target lesions, 
non-target (i.e., other than bone) lesions, and bone lesions requires 2 
assessment time points. The first must occur at Week 12 (or later) and the 
second occurring at least 6 weeks after the first. Progression declared at the 
first time point remains unconfirmed unless assessments at the second time 
point demonstrate continuing or worsening progression, as described in Section 9.4. 
 
8.4 
Response Criteria for Control/Relieve/Eliminate Endpoints 
 
8.4.1. 
Measurable soft-tissue lesions 
When evaluating soft-tissue lesions, the definitions in Table 3 apply. 
 
Table 3  RECIST response criteria for target (soft-tissue) lesions 
Response 
Evaluation of Soft-Tissue Lesions 
Complete response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non‐target) must have reduction in short axis to 
<10 mm. 
Partial response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
Abbreviations: LD, longest diameter. 
 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (e.g., fine 
needle aspirate or biopsy) before confirming the complete response status. 
Changes in nodal and visceral sites should be recorded and reported separately, and 
lymph nodes in the pelvis must measure at least 2 cm in greatest diameter to be 
considered target lesions. Complete elimination of disease at a particular site 


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should be recorded separately. Any favorable change should be confirmed using a 
second follow-up scan. 
 
8.4.2 
PSA 
As long as patient safety is the primary concern, in the absence of other indicators of 
disease progression, therapy should not be discontinued solely on the basis of a rise 
in PSA. 
For each patient, use a waterfall plot to report the percent change in PSA from 
baseline to 12 weeks (or earlier for those who discontinue therapy) and the 
maximum decline in PSA that occurs at any point after treatment. 
 
8.4.3 
Bone 
Record the number of post‐treatment lesions. In the absence of clearly worsening 
soft‐tissue (nodal and visceral) disease or disease‐related symptoms, progression at 
the first scheduled assessment should be confirmed on a second scan performed at 
least 6 weeks later. In the rare case where visible lesions disappear, this too should be 
confirmed. 
 
8.4.4 
Non-target lesions 
When assessing non-target lesions, the definitions in Table 4 will apply. 
 
Table 4  RECIST response criteria for non-target lesions 
Response 
Evaluation of Non-target Lesions 
Complete response (CR) 
The disappearance of all non-target lesions and normalization of 
tumor marker levels. All lymph nodes must be non-pathological in size 
(<10 mm short axis). 
Incomplete response/ 
stable disease (SD) 
The persistence of one or more non-target lesions and/or 
maintenance of tumor marker levels above the normal limits 
Progressive disease (PD) 
The appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions 
 
A clear progression of non-target lesions only is exceptional. 
 
8.4.5 
Symptoms 
BPI short form used to assess pain which includes change in BPI pain severity index, 
BPI functional interference index. Fatigue based on the BFI will also be used. 
 
8.5 
Confirmatory Measures/Duration of Response 
 
8.5.1 
Confirming time-to-event outcomes 
Any posttreatment change in disease status, be it favorable or unfavorable, should 
be confirmed using a second assessment at a later time point not less than 6 weeks 
later. 
 
8.5.2 
Duration of overall response 
Duration of overall response is measured from the time when partial response or 
complete response is first noted until the date when recurrent or progressive 


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disease is objectively documented. Duration of overall complete response is 
measured from the time the criteria for complete response are first met until the 
first date that recurrent disease is objectively documented. Duration of stable 
disease is measured from the start of treatment until the criteria for progression are 
met. 
 
8.5.3 
Progression-free survival 
Progression-free survival (PFS) is a composite endpoint defined as the time from 
study entry or random assignment to disease progression in bone or soft-tissue, 
symptoms, or death. Use an interval-censored approach in which all assessments 
of the composite PFS endpoint (i.e., PSA, bone, CT scans, and symptom 
assessments) are performed at the same time points. All assessments of disease 
should be collected at the same time interval (e.g., bone scan, CT scan, and PSA at 12- 
week intervals). In addition to PSA, confirm posttreatment changes in measurable 
target lesions, radionuclide bone scans, and symptoms. 


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Table 6  Prostate Cancer Clinical Trials Working Group Outcome Measures5 
 
Variable 
Control/Relieve/Eliminate   Endpoints 
PSA 
Record the percent change from baseline (rise or fall) at 12 weeks and, separately, the 
maximal change (rise or fall) at any time using a waterfall plot 
Soft-tissue lesions 
Use RECIST with caveats: 
Record changes in nodal and visceral soft tissue sites separately 
Record complete elimination of disease at any site separately 
Confirm favorable change with second scan 
Record changes using waterfall plot 
Bone 
Record outcome as either new lesions or no new lesions 
First scheduled reassessment: 
No new lesions: continue therapy 
2 new lesions: perform a confirmatory scan at least 6 weeks later 
Confirmatory scan of first reassessment: 
No new lesions: continue therapy 
2 additional new lesions: progression 
Subsequent scheduled reassessments: 
No new lesions: continue therapy 
2 new lesions: continue therapy and perform a confirmatory scan at least 6 weeks 
later 
Confirmatory scan of subsequent reassessments: 
Lack of persistence of the previously observed new lesions: continue therapy 
Persistence of or an increase in the number of new lesions: progression 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a lead-in period and measure repeatedly at 3- to 
4-week intervals 
Ignore early changes (~12 weeks) in pain or HRQOL in absence of compelling evidence of 
disease progression 
Confirm response or progression of pain or HRQOL endpoints ~3 weeks later 
Abbreviations: PSA, prostate-specific antigen; HRQOL, health-related quality of life. †Particularly important when anticipated effect on PSA is 
delayed or for biologic therapies. 
 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 


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9.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
 
9.1.1 
Electronic Case Report Forms (eCRFs) 
The participating sites will enter data remotely into electronic Case Report Forms 
(eCRFs) using the internet based PCCTC Caisis Electronic Data Capture (EDC) 
system. Completion Guidelines will be created by the PCCTC for the collection of all 
study data.  Access and training for PCCTC Caisis EDC will be made available to 
participating sites upon local regulatory approval. The participating site PI is 
responsible for ensuring eCRFs are completed accurately and in a timely manner. 
 
9.1.2 
Source documents 
Source documentation refers to original records of observations, clinical findings 
and evaluations that are subsequently recorded as data. Source documentation will 
be made available to support the subject’s research record. 
 
9.1.3 
Record retention 
The investigator will maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. 
The investigator will ensure that all regulatory documents and participating site IRB 
correspondences are maintained in an onsite regulatory binder. After study closure, 
the investigator will maintain all source documents and study-related documents.. 
Records are to be retained and securely stored until the later of: (a) two (2) years 
following the date a New Drug Application is approved for the Study Drug that is the 
subject of the Clinical Trial; or (b) two (2) years after the Investigational New Drug 
Application for such Study Drug is terminated or withdrawn, or such longer period 
of time as may be required by Participant policies, applicable laws, rules or 
regulations. 
9.1.4 
Source Documentation Submission for Registration at Participating Sites 
Participating sites should email any source documentation that corresponds to data 
entered at registration to PCCTC at PCCTC@mskcc.org within 24 hours (see Section 
4.2.1). 
9.1.5 
Data Submission Timelines 
All study data should be transmitted to PCCTC within 14 days of visit except for SAE 
submission (see Section 8.3.1) as described in the Data Management Plan. 
9.1.6 
Data Review and Queries 
PCCTC will review data and source documentation as it is submitted. Data will be 
monitored and source data verified as necessary and discrepancies will be sent as 
queries to the participating sites. In addition, PCCTC will review data for logic, 
consistency, and obvious anomalies. Queries will be sent by PCCTC to participating 
sites as needed. 
Participating sites should respond to data queries within 14 days of receipt. 
 
9.2 
Study Monitoring  and Quality Assurance 
9.2.1 
Data and Safety Monitoring 


Memorial Sloan Kettering Cancer Center 
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IRB#: 14-098 A (5) 
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The Data and Safety Monitoring Plans (DSMP) at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001.  The 
plans address the new policies set forth by the NCI in the document entitled “Policy 
of the National Cancer Institute for Data and Safety Monitoring of Clinical Trials” 
which can be found at: http://www.cancer.gov/clinicaltrials/conducting/dsm-  
guidelines/page1. The DSMPs at MSKCC were established and are monitored by the 
Office of Clinical Research.  The MSKCC DSMPs can be found on the MSKCC Intranet 
at:  
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20M  
onitoring%20Plans.pdf. 
 
There are several different mechanisms by which clinical trials are monitored for 
data, safety, and quality. There are institutional processes in place for quality 
assurance (e.g., protocol monitoring, compliance and data verification audits, 
therapeutic response, and staff education on clinical research quality assurance)  
and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials 
programs. There are several committees: Data and Safety Monitoring Committee 
(DSMC) for Phase I and II clinical trials, and the Data and Safety Monitoring Board 
(DSMB) for Phase III clinical trials, report to the MSKCC Research Council and 
Institutional Review Board. As a moderate risk trial, this study will be monitored by 
DSMC twice per year. 
Since therapeutic efficacy is a stated primary objective, all sites participant’s 
responses are subject to review by MSKCC’s Therapeutic Response Review 
Committee (TRRC). Radiology and additional lab reports will need to be obtained 
from the participating sites for MSKCC TRRC review and confirmation of response 
assessment. These materials must be sent to MSKCC promptly upon request 
 
 
9.2.2 
Data Auditing and Quality Assurance 
In addition to review by DSMC, PCCTC will conduct regularly scheduled remote 
monitoring every 6 weeks and audits as specified below.  Registration reports will 
be generated by the PCCTC to monitor subject accruals and the completeness of 
registration data. Routine data quality reports will be generated to assess missing 
data and inconsistencies. Accrual rates and the extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period, and 
potential problems will be brought to the attention of the Principal Investigator for 
discussion and action. 
Each site participating in the accrual of participants to this protocol will be audited 
at a minimum of 10% of all subjects, but at least 2 from each site will be 100% 
source data verified by the PCCTC. Auditing will occur once shortly after initiation 
of subject recruitment at a site, annually during the study (or more frequently if 
indicated), and at the end or closeout of the trial, for protocol and regulatory 
compliance, data verification and source documentation. Audits may be 
accomplished in one of two ways: (1) sending source documents and research 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
53 of 75 
 
 
records for selected patients from participating sites to the PCCTC for audit, or 
(2) on-site auditing of selected patient records at participating sites. 
The audit will include a review of source documentation to evaluate compliance for: 
 
• 
Regulatory/IRB compliance (review of current protocol and amendments, 
Informed consent documents and procedures, annual continuing review reports, 
AEs/SAEs) 
• 
Protocol defined treatment compliance 
• 
Subject records 
1. Each subject is reviewed to determine that there is a signed and dated 
consent form 
2. Adherence to eligibility criteria 
3. Baseline, on study and follow-up protocol testing 
4. eCRF completion 
 
Audit findings will be reviewed and disseminated to the site PIs and staff. 
 
In addition, each participating site accruing participants to this protocol will be 
audited by MSK for protocol and regulatory compliance, data verification and source 
documentation. Audits of selected participant records may be conducted on-site or 
remotely. 
 
Audits will be conducted annually at minimum, and more often if significant and/or 
repeated findings are identified during monitoring visits. The number of 
participants audited will be determined by the outcome of monitoring visits and 
complexity of the protocol. 
 
Each audit will be summarized and a final report will be sent to the PI at the audited 
participating site within 30 days of the audit. The report will include a summary of 
findings, participant-specific case review, recommendations on any performance 
and/or shortcomings and request for corrective action, when necessary. When 
corrective action is required, the participating site must reply within 45 days of 
receipt of the audit report with their corrective action plan. 
 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
 
10.1.1 Analysis of the primary endpoint 
The primary objective of this phase II study is to determine the effect of Radium-223 
on pain improvement for patients with symptomatic metastatic castration-resistant 
disease. The primary endpoint of the study is a 30% decline in the BPI worst pain 
item from baseline to week 8, with a confirmed reduction at week 12 without an 
escalation of the subject's pain regimen from Step 1 to Step 2 or Step 2 to Step 3 of 
the WHO analgesic ladder. The baseline BPI worst pain score average will be based 
on the worst pain scores completed by the patient in the 7 consecutive pretreatment 
days.  A minimum of 4 days of pain scores must be completed by the patient in the 7 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
54 of 75 
 
 
day window in order to calculate the average worst pain score. We define this event 
as a response and propose declaring the treatment effective if the probability of a 
response in the population exceeds 0.20. 
 
A maximum of 63 patients will be entered onto the study. A two-stage design that 
differentiates between response rates of 0.20 and 0.35 will be used to assess 
treatment efficacy. In the first stage of the study 27 patients will be enrolled. If at 
most 5 patients respond, accrual will be terminated. If at least 6 patients respond, an 
additional 36 patients will be entered onto the study. At the conclusion of this 
second stage, if at least 17/63 patients respond, the treatment will be declared 
effective. The probability of declaring the treatment effective is 0.10 when the 
response rate in the population is 0.20 and increases to 0.90 when the response rate 
is 0.35. 
 
10.1.2 Analysis of secondary endpoints 
 
A summary of adverse events will be tabulated at baseline and during treatment. 
Analgesic use will be tabulated, converted into equivalent units, and changes in 
opiate equivalents before and after treatment will be compared.  Descriptive 
statistics will be used to report the proportion of patients with changes in fatigue 
scores compared to baseline according to the worst fatigue item (Item #3) of the 
Brief Fatigue Inventory, at weeks 8 and 12. Descriptive statistics will also be used to 
report the proportion of patients with changes in pain interference scores compared 
to baseline based on the interference with activities item of the BPI, at weeks 8 and 
12. 
 
The time to radiographic progression and pain progression will be summarized 
using the cumulative incidence function. The percent change in PSA and bone 
turnover markers from baseline to 12 weeks will be summarized with descriptive 
statistics. Longitudinal assessments of BPI, and tiredness will be recorded and 
summarized over time. 
 
Radiographic progression using PCWG2 criteria for bone scans, and RECIST for soft 
tissue/measurable disease will be used. The use of FDG PET imaging to demonstrate 
post-treatment effects is exploratory in nature – the impact of radium on the actual 
cancer cell is not known. Furthermore, there is no standard method for assessing 
post-treatment FDG PET changes that have been prospectively validated in prostate 
cancer. Because Ra-223 is a bone directed agent, bone lesions will be treated 
separately from soft tissue lesions. We will therefore examine multiple methods of 
examining post-treatment changes in FDG PET in order to explore which of those 
will most closely correlate with both pain response. These will include: 
 
A. We will analyze up to 5 bone lesions. Analysis will be performed either on 
HERMES or AWS workstation. For each lesion, a five point confidence scale will 
be employed as follows: 1: negative for tumor; 2: probably negative for tumor; 3: 
equivocal for tumor; 4: probably positive for tumor; 5: definitely positive for 
tumor. The SUV for each lesion will also be recorded along with its location. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
55 of 75 
 
 
SUVpeak lean body mass will be determined in each of these lesions.  The sum of 
these values at baseline will be compared to that of the sum at followup. 
B. If feasible, we will apply the above technique not only to 5 index lesions, but to 
all of the lesions, using the PET VCAR software or its equivalent. 
C. As a comparison, we will explore FDG PET interpretation using the PERCIST 1.0 
criteria (Wahl et al J Nucl Med 2009 50: 122S-150S). 
PSA decline will be reported per PCWG2 criteria 1 
 
10.2 
Analysis Populations 
 
10.2.1 Evaluable population 
Responders will be defined by a 30% decline in the BPI worst pain item from 
baseline to week 8, with a confirmed reduction at week 12 without an escalation of 
the subject's pain regimen from Step 1 to Step 2 or Step 2 to Step 3 of the WHO 
analgesic ladder. 
Patients with progressive pain will be defined by time until a > 2 point increase in 
the average “worst pain” item on the BPI over a 7 day period compared to baseline 
is seen and confirmed at least 2 weeks later. 
Patients who are neither categorized as pain responders or are categorized as ones 
with progressive pain will be recorded as non-responders. 
All patients who meet eligibility criteria and receive at least 1 dose of study 
medication will be included in the main analysis of the response rate, even if there 
are major protocol deviations (e.g., incorrect treatment schedule or drug 
administration). Each patient will be assigned to one of the above categories. 
10.2.2 Safety population 
All patients enrolled in the study will be included in the safety analysis population 
and considered evaluable for toxicity and safety from the time of their first dose. 
Demographic and baseline characteristics for the safety population will be 
summarized by number and percent for categorical data (e.g., sex, race/ethnicity) 
and by descriptive statistics for continuous data (e.g., weight, vital signs, EKG 
readings, disease status). 
 
10.3 
Safety Analysis 
 
10.3.1 Evaluation of adverse events 
Pain will be assessed using PBI and fatigue by the BFI. 
Treatment-emergent adverse events will be translated from investigator terms to 
NCI CTCAE v4.0 terminology and summarized (number and percentage of patients) 
for all patients who receive at least 1 dose. Adverse event summaries will be 
organized by body system, frequency of occurrence, intensity (i.e., severity grade), 
and causality or attribution. Patients who experience an adverse event more than 
once will be counted only once. The occurrence with the maximum severity will be 
used to calculate intensity. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
56 of 75 
 
 
10.3.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in treatment withdrawal or 
death will be summarized separately. 
 
10.3.3 Evaluation of laboratory parameters and assays 
Selected clinical laboratory parameters will be summarized and clinically significant 
changes from baseline will be discussed. 
 
10.3.4 Extent of exposure 
Treatment exposure will be summarized for all patients, including dose 
administration, number of cycles, or delays, and duration of therapy. 
 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
11.1 
Roles and Responsibilities 
11.1.1 Lead Site/Sponsor Principal Investigator 
The Sponsor Principal Investigator at the lead site is responsible for performing the 
following tasks: 
• 
Responsibility for the overall conduct of the study at all participating sites and 
for monitoring the progress of the study 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
• 
Reviewing data from all participating sites 
 
11.1.2 PCCTC 
The PCCTC is responsible for performing the following tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site prior to 
the first patient registration at that site, and maintaining copies of IRB approvals 
and required regulatory documents from each site. 
• 
Managing subject registration 
• 
Developing and maintaining Clinical Data Management documents and 
procedures 
• 
CRF development, setup of study database, and subsequent design changes 
• 
Participating in review of content of the CRF against the protocol requirements 
• 
EDC system administration (user/site accounts setup, maintenance and 
revocation) 
• 
Data review, cleaning, query management and resolution 
• 
Establishing procedures for documentation, reporting and submitting of AE’s 
and SAE’s to the PCCTC. 
• 
Reviewing Serious Adverse Events (SAEs) 
• 
Training participating sites on EDC 
• 
Collecting and compiling data from each participating site 
• 
Data reviewing from all participating sites 
• 
Facilitating audits by securing selected source documents and research records 
from participating sites for audit, or by auditing at participating sites. 
 
11.1.3 Participating Sites 


Memorial Sloan Kettering Cancer Center 
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Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
57 of 75 
 
 
Participating sites are responsible for performing the following tasks: 
 
• Following the protocol as written, the guidelines of Good Clinical Practice (GCP), 
and applicable Standard Operating Procedures (SOPs). Registering all patients 
with the PCCTC by submitting the eligibility checklist, supporting source 
documentation, and signed informed consent promptly. 
• Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the protocol 
• Maintaining regulatory binders on site and providing copies of all required 
documents to the PCCTC 
• Collecting and submitting data according to the schedule specified by the 
protocol 
• Responding to queries in a timely manner 
 
11.2 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonisation, and the ethical standards set forth in the 
Declaration of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
 
11.3 
Regulatory Documentation 
Prior to implementing this protocol at MSK, the protocol, informed consent form, HIPAA 
authorization and any other information pertaining to participants must be approved by the 
MSK Institutional Review Board/Privacy Board (IRB/PB). There will be one protocol 
document and each participating site will utilize that document. 
 
The following documents must be provided to PCCTC before the participating site can be 
initiated and begin enrolling participants: 
 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
 
• Participating Site IRB approved informed consent form and HIPAA authorization 
 
• Participating Site IRB membership list 
 
• Participating Site IRB’s Federal Wide Assurance number and OHRP Registration number 
 
• Curriculum vitae and medical licenses for each investigator and consenting professional 
 
Consenting Professionals Lists (consenting professionals at each participating site that 
may obtain informed consent and care for the participants according to good clinical 
practice and protocol guidelines) 
 
• Documentation of Human Subject Research Certification training for investigators and key 
staff members at the participating site 
 
• Documentation of Good Clinical Practice (GCP) training for the PI and co-PI at the 
participating site 
 
• Participating site laboratory certifications and normals 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
58 of 75 
 
 
Upon receipt of the required documents, PCCTC will submit a participating site activation 
request to MSKCC. Once approved, MSKCC will formally contact PCCTC and grant the site 
permission to proceed with enrollment. 
 
11.4 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics Committee (IEC). Each change to the protocol document must be 
organized and documented by MSKCC and first approved by the MSKCC IRB/PB. Once 
approval of the MSKCC IRB/PB has been granted, PCCTC will distribute all non expedited 
amendments to the participating sites for submission to their local IRBs. 
 
Participating sites must obtain approval for all non expedited amendments from their IRB 
within 90 calendar days of MSK IRB/PB approval. If the amendment is the result of a safety 
issue or makes eligibility criteria more restrictive, sites will not be permitted to continuing 
enrolling new participants until the participating site IRB approval has been granted. 
 
The following documents must be provided to PCCTC for each amendment within the stated 
timelines: 
 
• Participating Site IRB approval 
 
• Participating Site IRB approved informed consent form and HIPAA authorization 
 
PCCTC is responsible for submitting all participating site local IRB approvals and/or 
acknowledgments to MSK upon receipt. 
 
11.5 
Additional IRB Correspondences 
 
Continuing Review Approval 
The Continuing Review Approval letter from the participating site’s IRB and the most 
current approved version of the informed consent form should be submitted to PCCTC 
within 7 days of expiration. Failure to submit the re-approval in the stated timeline will 
result in suspension of new participant enrollment. PCCTC is responsible for submitting all 
participating site local IRB approvals and/or acknowledgments to MSK upon receipt. 
 
Deviations and Violations 
A protocol deviation on this study is defined as a request to treat a research participant who 
does not meet all the eligibility criteria, pretreatment evaluation, or who requires alteration 
in their study plan. If a deviation from this protocol is proposed for a potential or existing 
participant at MSK or a participating site, approval from the MSK IRB/PB is required prior  
to the action. To request a protocol deviation, participating sites should contact PCCTC who 
will in turn work with MSK to seek approval from the MSK IRB/PB. 
 
A protocol violation is any change or departure from the research protocol that occurred 
without prior approval from the MSK IRB/PB. For protocol violations that are identified 
after they occur, the participating site should report the event(s) to PCCTC as soon as 
possible. PCCTC will in turn work with MSK to report the violation to the MSK IRB/PB. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
59 of 75 
 
 
Participating sites should report deviations and violations to their institution’s IRB as soon 
as possible per that site’s institutional guidelines. Approvals/acknowledgments from the 
participating site IRB for protocol deviations and violations should be submitted to PCCTC 
as received. PCCTC is responsible for submitting all participating site local IRB approvals 
and/or acknowledgments to MSK upon receipt. 
 
Other correspondence 
Participating sites should submit other correspondence to their institution’s IRB according 
to local guidelines, and submit copies of that correspondence to PCCTC. PCCTC is 
responsible for submitting all participating site local IRB correspondences to MSK upon 
receipt 
 
11.6 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the 
potential benefits of this program, the risks and the probability of their occurrence, and the 
procedures to minimize these risks. Should an adverse event occur, the provisions available 
to ensure medical intervention will also be reviewed. Why the risks are reasonable in 
relation to the anticipated benefits, incentives, or costs that will or may be incurred as a 
result of participating in the study, as well as the efforts to maintain confidentiality, will also 
be discussed with the patient. 
Patients will be required to sign and date (in triplicate) a statement of informed consent  
that meets the requirements of the Code of Federal Regulations (Federal Register Vol. 46, 
No. 17, January 27, 1981, part 50) and the IRB. The medical record will include a statement 
that written informed consent was obtained (and document the date that it was obtained) 
before the patient is enrolled in the study. The original signed document will become part of 
the patient’s medical record, a copy will be forwarded to the lead site/sponsor pursuant to 
sponsor registration and to the PCCTC and a copy will be sent home with each patient. 
The consent form will include the following: 
• 
The nature and objectives, potential toxicities, and benefits of the intended study 
• 
The length of therapy and likely follow-up required 
• 
Alternatives to the proposed therapy (including available standard and investigational 
therapies) 
• 
The name of the investigator(s) responsible for the protocol 
• 
The right of the patient to accept or refuse treatment and to withdraw from 
participation in this study 
• 
Text regarding the PCCTC should be added to all institutional informed consent 
documents and sections in the research authorization/HIPAA forms (e.g., “Prostate 
Cancer Clinical Trial Consortium”) 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
60 of 75 
 
 
11.7 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they 
will be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. The 
original signed documents will become part of the patient’s medical records, and each 
patient will receive a copy of the signed documents. The use and disclosure of protected 
health information will be limited to the individuals described in the research authorization 
form. The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
 
11.8 
Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the lead site or the 
sponsor’s medical monitor on an ongoing basis. SAEs will be reviewed as they are reported 
to the lead site/sponsor and PCCTC, and the medical monitor will make an assessment 
regarding the safety of continuing or modifying the study. This assessment will be shared 
with the investigators either in writing or as part of a teleconference. Should the assessment 
of either the lead site/sponsor or the principal investigator be that the study should be 
terminated; the study will be closed to further accrual. Patients who are receiving Ra-223 
will be assessed individually by the investigator to see if it is in the patients’ best interest to 
continue, which might be the case for a patient that is responding to the intervention. 
Follow-up safety assessments will be performed for all patients who are terminated from 
the study prematurely. 
 
11.9 
Noncompliance 
If a participating site is noncompliant with the protocol document, accrual privileges may be 
suspended and/or contract payments may be withheld, until the outstanding issues have 
been resolved. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
61 of 75 
 
 
12. 
REFERENCES 
1. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the 
Prostate Cancer Clinical Trials Working Group. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. Mar 1 2008;26(7):1148-1159. 
 
2. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, 
England : 1990). Jan 2009;45(2):228-247. 
 
3. 
Autio KA, Bennett AV, Jia X, et al. Prevalence of pain and analgesic use in men with 
metastatic prostate cancer using a patient-reported outcome measure. Journal of oncology 
practice / American Society of Clinical Oncology. Sep 1 2013;9(5):223-229. 
 
4. 
Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic 
prostate cancer. The New England journal of medicine. Jul 18 2013;369(3):213-223. 
 
5. 
Nilsson S, Larsen RH, Fossa SD, et al. First clinical experience with alpha-emitting radium- 
223 in the treatment of skeletal metastases. Clinical cancer research : an official journal of 
the American Association for Cancer Research. Jun 15 2005;11(12):4451-4459. 
 
6. 
Nilsson S, Franzen L, Parker C, et al. Bone-targeted radium-223 in symptomatic, hormone- 
refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. 
The lancet oncology. Jul 2007;8(7):587-594. 
 
7. 
Nilsson S, Strang P, Aksnes AK, et al. A randomized, dose-response, multicenter phase II 
study of radium-223 chloride for the palliation of painful bone metastases in patients with 
castration-resistant prostate cancer. European journal of cancer (Oxford, England : 1990). 
Mar 2012;48(5):678-686. 
 
8. 
Parker CC, Pascoe S, Chodacki A, 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. European urology. Feb 2013;63(2):189-197. 
 
9. 
Kantoff PW, Halabi S, Conaway M, et al. Hydrocortisone with or without mitoxantrone in 
men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 
9182 study. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. Aug 1999;17(8):2506-2513. 
 
10. 
Morris MJ, Akhurst T, Larson SM, et al. Fluorodeoxyglucose positron emission tomography 
as an outcome measure for castrate metastatic prostate cancer treated with 
antimicrotubule chemotherapy. Clinical cancer research : an official journal of the American 
Association for Cancer Research. May 1 2005;11(9):3210-3216. 
 
11. 
Meirelles GS, Schoder H, Ravizzini GC, et al. Prognostic value of baseline [18F] 
fluorodeoxyglucose positron emission tomography and 99mTc-MDP bone scan in 
progressing metastatic prostate cancer. Clinical cancer research : an official journal of the 
American Association for Cancer Research. Dec 15 2010;16(24):6093-6099. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
62 of 75 
 
 
12. 
Jacques L, Jensen TS, Rollins J, Caplan S, JC R. Decision Memorandum for Positron Emission 
Tomography (FDG) for Solid Tumors 2013; http://www.cms.gov/medicare-coverage-  
database/details/nca-decision-  
memo.aspx?NCAId=263&NcaName=Positron+Emission+Tomography+(FDG)+for+Solid+Tu  
mors&bc=AAAAAAAACAAAAA%3D%3D&. 
 
13. 
Coleman R, Aksnes AK, Naume B, et al. A phase IIa, nonrandomized study of radium-223 
dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer 
Res Treat. Apr 13 2014 [Epub ahead of print]. 
 
14. 
Mendoza TR, Wang XS, Cleeland CS, et al. The rapid assessment of fatigue severity in cancer 
patients: use of the Brief Fatigue Inventory. Cancer. Mar 1 1999;85(5):1186-1196. 
 
15. 
Atkinson TM, Mendoza TR, Sit L, et al. The Brief Pain Inventory and its "pain at its worst in 
the last 24 hours" item: clinical trial endpoint considerations. Pain medicine (Malden, Mass.). 
Mar 2010;11(3):337-346. 
 
16. 
Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation counting. 
Appl. Radiat. Isot. 2010;68:1523-8. 
 
17. 
Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R. Revision of the NIST Standard for 
223Ra: New Measurements and Review of 2008 data.J Res Natl InstStand Technol. 
2015;120:37-57. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
63 of 75 
 
 
APPENDIX A: PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Description 
% 
Description 
0 
Normal activity. Fully active, able to 
continue all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease 
1 
Symptoms, but ambulatory. Restricted in 
physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort, some signs or 
symptoms of disease 
70 
Cares for self, unable to carry on normal 
activity or to do active work 
2 
In bed < 50% of the time. Ambulatory and 
capable of all self-care but unable to carry 
out any work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance but is able 
to care for most needs 
50 
Requires considerable assistance and 
frequent medical care 
3 
In bed > 50% of the time. Capable of only 
limited self-care, confined to bed or chair 
> 50% of waking hours. 
40 
Disabled, requires special care and 
assistance 
30 
Severely disabled, hospitalization indicated. 
Death not imminent. 
4 
100% bedridden. Completely disabled, 
cannot carry on any self-care, totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly 
5 
Dead 
0 
Dead 


64 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
 
APPENDIX B: PCCTC SERIOUS ADVERSE EVENT REPORT FORM 
 
Please see the supplemental PCCTC Serious Adverse Event Report Form 


65 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
APPENDIX C: GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
 
ADR 
adverse drug reaction 
ADT 
androgen-deprivation therapy 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
androgen receptor 
ASAEL 
Agent Specific Adverse Event List 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
A-V 
atrioventricular 
BP 
blood pressure 
BSA 
Body Surface Area 
BUN 
blood urea nitrogen 
C 
Celsius 
CBC 
complete blood count 
CDE 
common data element 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cl- 
chloride 
CR 
complete response 
CRC 
Clinical Research Center 
CRDB 
Clinical Research Database 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTO 
Clinical Trials Office 
DEV 
deviation from the nominal value 
%DEV 
percent deviation 
dL 
deciliter 
DLT 
dose-limiting toxicity 
DSM 
data and safety monitoring 
EA 
extent of absorption 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EEG 
electroencephalogram 
EKG 
electrocardiogram 
ESF 
eligibility screening form 
ESR 
expedited safety report 
F 
bioavailability 
FDA 
Food and Drug Administration 


66 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
FDG-PET 
2-[18F]fluoro-2-deoxyglucose positron emitting tomography 
FDHT 
18-fluoro-dehydrotestosterone 
GCP 
good clinical practice 
GCPII 
glutamate carboxypeptidase II enzyme 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
GnRH 
gonadotropin-releasing hormone 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
heart rate 
HRPC 
hormone-refractory prostate cancer 
HRT 
hormone replacement therapy 
ICD 
International Classification of Diseases 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunochemical 
IM 
intramuscular 
IND 
investigational new drug 
INR 
international normalized ratio 
IP 
intraperitoneal 
IRB 
Institutional Review Board 
ITT 
IV 
intent-to-treat population 
intravenous 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LOI 
letter of intent 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MSKCC 
Memorial Sloan-Kettering Cancer Center 
MS 
mass spectrometry 
MTD 
maximum tolerated dose 
N 
number of subjects or observations 
NA 
not applicable 
N/A 
not available 
NBN 
National Biospecimen Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NIST 
NSAID 
National Institute of Standards and Technology 
nonsteroidal anti-inflammatory drug 
NTX 
N-telopeptide cross-link 
NVB 
neurovascular bundle 
OCR 
Office of Clinical Research at MSKCC 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PCRP 
Department of Defense Prostate Cancer Research Program 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 


67 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
PI 
principal investigator 
PIN 
prostatic intraepithelial neoplasia 
PK 
pharmacokinetics 
PMB 
Pharmaceutical Management Branch 
PO 
per os (by mouth) 
PR 
PRO 
partial response 
Patient Reported Outcome 
PSA 
prostate-specific antigen 
PSA-DT 
prostate-specific antigen doubling time 
PSMA 
prostate specific membrane antigen 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QC 
quality control 
qd 
quaque die (every day) 
qRT-PCR 
quantitative reverse transcription-polymerase chain reaction 
QOL 
quality of life 
RBC 
red blood cell 
RC 
Research Council 
RDRC 
Radioactive Drug Research Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP 
radical prostatectomy 
RPC 
Research Program Coordinator 
RSA 
Research Study Assistant 
%RSD 
percent relative standard deviation 
SAE 
serious adverse event 
SD 
standard deviation 
SD 
stable disease 
SKI 
Sloan-Kettering Institute for Cancer Research 
SMD 
stable metabolic disease 
SOP 
Standard Operating Procedures 
SUV 
standardized uptake value 
t 
temperature 
t1/2 
terminal half-life 
T 
time 
TDP 
time to disease progression 
TGP 
prostate-specific transglutaminase 
tid 
ter in die (3 times a day) 
TMA 
tissue microarray 
Tmax 
time of maximum observed concentration 
TMPRSS2 
transmembrane protease, serine 2 
TNM 
tissue, lymph node, metastases 
TX 
treatment 
ULN 
upper limit of normal 
ULQ 
upper limit of quantitation 
UR 
urinary recovery 
VEGF 
vascular endothelial growth factor 
Vss 
volume of distribution at steady-state 


68 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
WBC 
white blood cell 
WHO 
World Health Organization 


69 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
APPENDIX D: DOSIMETRY 
 
Dosimetry for Ra-223 dichloride 
Target Organ 
SINGLE 
TREATMENT 
6 TREATMENTS 
Mean 
(Rad/mCi) 
Rad/ 0.0946 mCi 
Rad/0.568 mCi 
Adrenals 
0.44 
0.04 
0.25 
Brain 
0.37 
0.04 
0.21 
Breasts 
0.18 
0.02 
0.10 
Gallbladder wall 
0.85 
0.08 
0.48 
LLI1 Wall 
171.88 
16.26 
97.56 
Small Intestine 
Wall 
26.87 
2.54 
15.25 
Stomach Wall 
0.51 
0.05 
0.29 
ULI2 wall 
119.58 
11.31 
67.87 
Heart wall 
6.40 
0.61 
3.63 
Kidneys 
11.86 
1.12 
6.73 
Liver 
11.01 
1.04 
6.25 
Lungs 
0.27 
0.03 
0.15 
Muscle 
0.44 
0.04 
0.25 
Ovaries 
1.80 
0.17 
1.02 
Pancreas 
0.41 
0.04 
0.23 
Red Marrow 
513.51 
48.58 
291.47 
Osteogenic cells 
4262.60 
403.24 
2419.45 
Skin 
0.27 
0.03 
0.15 
Spleen 
0.33 
0.03 
0.19 
Testes 
0.31 
0.03 
0.18 
Thymus 
0.21 
0.02 
0.12 
Thyroid 
0.26 
0.02 
0.15 
Urinary Bladder 
Wall 
14.90 
1.41 
8.46 
Uterus 
0.94 
0.09 
0.53 
Whole body 
85.50 
8.09 
48.53 
based on package insert 
*typical dose 70 kg at 1.3514 
mCi/kg 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
70 of 75 
 
 
APPENDIX E: BRIEF FATIGUE INVENTORY14 
Please see attached supplemental Brief Fatigue Inventory survey. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
71 of 75 
 
 
APPENDIX F: BRIEF PAIN INVENTORY 
 
Please see attached supplemental Brief Pain survey. 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
72 of 75 
 
 
APPENDIX G: RADIATION SAFETY PRECAUTIONS FOLLOWING RADIUM-223 
DICHLORIDE, INJECTION 
 
You will be given a card which informs people that you have received radioactive medicine, always carry this 
card with you. 
 
There are NO restrictions regarding contact with other people after receiving the study drug. 
 
During the first week after Radium-223 Dichloride injection there may be some radioactivity in your blood, 
urine, and stools, therefore you should take the following precautions: 
• Use medical gloves when wiping up blood, urine, stools, or vomit, or when handling stained clothes. 
• A normal toilet should be used in preference to a urinal. The sitting position should be used instead of the 
standing position. 
• Wipe up any spilled urine or stool with a tissue and flush it away. 
• If you are sick, wipe up spilled vomit with a tissue and flush it away. 
• Ensure that you always thoroughly wash your hands after using the toilet or after wiping up spilled fluids. 
• Wash any linen or clothes that become stained with urine, blood or stools separately from other clothes and 
rinse them thoroughly. 
• If you are sexually active, the use of a condom is recommended during the first week after injection because 
there may be some slight radioactivity in the body fluids (but most in blood, urine and stools). 
• If sampling of blood, urine or stools is necessary during the first week following administration, please 
inform the personnel that you have been treated with radioactive Radium-223. 
• If you need medical care such as an operation or hospital admission during the first week following 
administration, please inform the personnel that you have been treated with radioactive Radium-223. 
 
 
 
 
Radiation Safety Service 
Memorial Sloan-Kettering Cancer Center 
Telephone: 1-212-639-7391 


Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
73 of 75 
 
 
 
APPENDIX H: PRO INSTRUMENT SCREENSHOT 
 
Please see attached supplemental PRO Instrument Screenshot. 


74 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
APPENDIX I: PRO INSTRUMENT INSTRUCTIONS 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
 
 
Please see attached supplemental PRO Instrument Instructions. 


75 of 75 
Memorial Sloan Kettering Cancer Center 
IRB #: 14-098 A(5) 
Approved: 01-FEB-2017 
Radium-223 
MSKCC 
APPENDIX J: RADIUM DOSE TRACKING SHEET (MSK SITE ONLY) 
PCCTC LOI: c13-124 
IRB#: 14-098 A (5) 
 
 
 
 
Please see attached supplemental Radium Dose Tracking Sheet.