Clinical trial NCT02582749
Conditions: Prostate Cancer Bone Metastases Prostate Neoplasms
Keywords: Androgen Deprivation Therapy Androgen Receptor Antagonist Radium-223 Dichloride Placebo
Sponsor: Ajjai Alva, MD
Start date: 2016-04-01; Completion date: 2017-09-14
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Newly diagnosed metastatic prostate cancer subjects with bone metastases will be accrued to this stratified randomized 2-arm Phase II trial. Subjects will be randomized 1:2 to ADT or ADT with Radium-223 dichloride respectively.

Detailed description:
OUTLINE: This is a multi-center, randomized trial.

STRATIFICATION FACTORS:

Subjects will be stratified based on serum total alkaline phosphatase at baseline and extent of disease (described below). Randomization will occur within stratification group.

* Extent of Disease: \<6 skeletal metastases with no visceral metastases versus ≥6 skeletal metastases or visceral metastases.
* Serum total alkaline phosphatase at baseline: normal vs abnormal. Abnormal alkaline phosphatase is defined as \> 130 IU/L.

Early Induction or Late Induction status will not be a stratification criterion.

TREATMENT SCHEDULE: CONTROL ARM A

All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH antagonist (degarelix) or bilateral orchiectomy, with dosage determined by the treating physician. Route of administration and cycle days will be administered as per package insert. Androgen deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously.

All subjects will receive bicalutamide, 50 mg Oral (PO) Daily

TREATMENT SCHEDULE: EXPERIMENTAL ARM B

All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH antagonist (degarelix) or bilateral orchiectomy, with dosage determined by the treating physician. Route of administration and cycle days will be administered as per package insert. Androgen deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously.

All subjects will receive bicalutamide, 50 mg oral (PO) daily

All subjects will receive Radium-223 dichloride, 50 kBq (1.35 microcurie) per kg body weight, intravenous (IV bolus) every 28 days for 6 injections

The following laboratory values must be obtained within 28 days prior to registration for protocol therapy:

Hematopoietic:

* Hemoglobin (Hgb) ≥ 8.0 g/dL (80 g/L) without packed RBC transfusion
* Platelets ≥ 100 K/mm3
* Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

Hepatic:

* Total Bilirubin ≤ 2 x institutional upper limit of normal (ULN) except subjects with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL
* Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x institutional ULN (≤ 5 x institutional ULN in the presence of liver metastases).
* Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x institutional ULN (≤ 5 × institutional ULN in the presence of liver metastases).

Renal:

* Estimated Creatinine Clearance by Cockcroft-Gault formula ≥ 30 mL/min

Arms: arm 1: All subjects will receive LHRH agonist/antagonist per dosage and route of administration specified by the treating physician. Bicalutamide, 50mg, PO will be administered daily. Cycles will be 28 days. arm 2: All subjects will receive LHRH agonist/antagonist per dosage and route of administration specified by the treating physician. Bicalutamide, 50mg, PO will be administered daily. Cycles will be 28 days. Radium-223 dichloride, 50 kBq/kg body weight, will be administered as a bolus intravenous (IV) injection at intervals of every 28 days for up to 6 cycles.
Interventions: intervention 1: LHRH agonist/antagonist intervention 2: Bicalutamide intervention 3: Radium-223 dichloride
Intervention descriptions: intervention 1: Treating physician will determine LHRH agonist/antagonist, dosage and route of administration, per package insert, during each 28-day cycle. intervention 2: Bicalutamide, 50 mg Oral (PO) will be administered daily in each 28-day cycle. intervention 3: Radium-223 dichloride, 50 kBq (1.35 microcurie) per kg body weight intravenous (IV bolus) every 28 days for 6 injections

Protocol documents:
Prot_SAP_000.pdf: 
 Clinical Study Protocol  
HCRN GU13-170 
 
 
Version Date: 09JAN2017 
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Page 1 of 68 
 
Androgen Deprivation Therapy with or without Radium-223 dichloride in Patients with Newly 
Diagnosed Metastatic Prostate Cancer with Bone Metastases  
HCRN GU13-170 
 
Sponsor Investigator 
Ajjai Alva, MD 
University of Michigan 
ajjai@med.umich.edu 
 
Co- Investigators 
Jason Hearn MD 
University of Michigan 
 
Morand Piert, MD 
University of Michigan 
 
Evan Keller, MD 
University of Michigan 
 
Statisticians 
Stephanie Daignault-Newton, MS 
University of Michigan 
 
Trial Supported by 
Bayer HealthCare Pharmaceuticals, Inc. 
 
Investigational New Drug (IND) Application # 
129126 
 
Initial Protocol Version Date: 11FEB2016 
Amended Protocol Version Date: 
20MAY2016 
24JUN2016 
09JAN2017 
 
 
 


 
 
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PROTOCOL SIGNATURE PAGE 
Protocol title: Androgen Deprivation Therapy with or without Radium-223 dichloride in Patients 
with Newly Diagnosed Metastatic Prostate Cancer with Bone Metastases: HCRN GU13-170 
 
VERSION DATE:  09JAN2017 
I confirm I have read this protocol, I understand it, and I will work according to this protocol and 
to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
guidelines for good clinical practices, or the applicable laws and regulations of the country of the 
study site for which I am responsible, whichever provides the greater protection of the 
individual. I will accept the monitor’s overseeing of the study. I will promptly submit the 
protocol to applicable ethical review board(s). 
 
 
 
 
 
 
 
 
 
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 Signature of Investigator 
 
 
 
 
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PLEASE COMPLETE AND EMAIL COPY TO HCRN 
Instructions to the investigator:  Please SIGN and DATE this signature page. 
PRINT your name and title, the name and location of the facility in which the 
study will be conducted, and the expected IRB approval date. Scan and email 
the completed form to HCRN and keep a record for your files. 
 


 
 
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STUDY SYNOPSIS 
 
 
TITLE 
Androgen Deprivation Therapy with or without Radium-223 dichloride in 
patients with Newly Diagnosed Metastatic Prostate Cancer with Bone 
Metastases: HCRN GU13-170 
PHASE  
Phase II, randomized 
OBJECTIVES 
Primary Objectives: 
1. Determine whether the combination of ADT plus radium-223 dichloride 
is more effective than ADT alone based upon radiologic progression free 
survival (rPFS) in subjects with newly diagnosed metastatic prostate 
cancer with bone metastases. 
 
Secondary Objective(s): 
1. Assess safety and toxicity including incidence of skeletal related events 
(SRE) and secondary neoplasms.  
2. Estimate the proportion of subjects with PSA ≤ 0.2 ng/mL after 7 months 
of androgen deprivation therapy, the proportion of subjects with PSA≤ 4 
ng/mL after 7 months of androgen deprivation therapy, the median time to 
castration resistance, 2-year PSA progression free survival proportion 
(PCWG2 criteria) and 2-year overall survival proportion in both arms. 
3. Determine the proportion of subjects with elevated serum total alkaline 
phosphatase (ALP) at baseline who normalize their alkaline phosphatase 
after 12 weeks of therapy, assess time to ALP progression (≥ 25% 
increase in ALP from baseline/nadir (whichever is lower) and above 
ULN), association of ALP x in both arms. 
4. Evaluate change in pain level and analgesic use using the Brief Pain 
Inventory (BPI short form) and WHO ladder scale, respectively, with 
therapy. 
  
Exploratory Correlative Objectives: 
1. Assess number of circulating tumor cells (CTCs) and gamma H2AX in all 
subjects (number of subjects = 204) 
2. Explore the association of bone turnover markers with clinical outcome 
and change in serum bone turnover markers with therapy in both arms. 
STUDY DESIGN 
Newly diagnosed metastatic prostate cancer subjects with bone metastases will be 
accrued to this stratified randomized 2-arm Phase II trial. Subjects will be 
randomized 1:2 to ADT or ADT with Radium-223 dichloride respectively. The 
primary aim of the study is to determine if the addition of Radium-223 dichloride 
to ADT will improve treatment efficacy in this population. The primary efficacy 
endpoint is radiographic progression-free survival (rPFS).  We expect the control 
arm with ADT alone to have a 12 month median rPFS.  The addition of radium-
223 to ADT will target an improvement of 7 months for a median rPFS of 19 
months.  A total of 140 events are required for at least 90% power to detect 
Hazard Ratio of 0.632 with a one-sided alpha of 0.1. The study powering is based 
on assumptions of 19 months median rPFS in the experimental arm and 12 
months median rPFS in the control arm. Assuming exponential time to event 


 
 
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data, a yearly dropout rate of 10% with accrual in 24 months and study duration 
of 48 months, 204 subjects will provide 90% power with a 10% one-sided type I 
error.  Hypothesis testing for the primary endpoint will be conducted at a one-
sided 0.10 significance level using a stratified log-rank test. Randomization of 68 
subjects to the ADT arm and 136 subjects to the ADT+R arm will be completed 
with stratification by extent of disease (<6 skeletal metastases without visceral 
disease versus ≥6 skeletal metastases or visceral disease) and baseline alkaline 
phosphatase (normal versus abnormal).  If time anticipated for the number of 
events required for analysis significantly exceeds 48 months, the sponsor may 
enroll additional subjects to reach required number of events. 
 
TOTAL  
NUMBER OF 
SUBJECTS  
Targeted Accrual: 204 subjects over 24 months. 
 
ELIGIBILITY 
CRITERIA  
INCLUSION CRITERIA: 
1. Histological or cytological evidence of prostate adenocarcinoma 
2. Men ≥ 18 years of age at the time of informed consent 
3. All subjects must have radiologic or pathologic evidence of ≥ 2 skeletal 
lesions with or without pain at baseline on bone scan or axial imaging or with 
1 skeletal lesion and bone pain within 28 days prior to the registration.  
4. All subjects must have a radiographic assessment (chest or abdominal/pelvic 
CT or MRI) within 28 days prior to registration but do not need to have 
measurable disease. 
5. ECOG performance status of 0-2 (3 is allowed if solely due to bone 
metastases) 
6. Adequate organ function as below: 
 Absolute neutrophil count (ANC) ≥1.5 K/mm3 
 Platelet count ≥100 K/mm3 
 Hemoglobin ≥8.0 g/dL (80 g/L) without packed RBC transfusion 
 Total bilirubin level ≤2 x institutional upper limit of normal (ULN) except 
subjects with Gilbert's Syndrome, who must have a total bilirubin less 
than 3.0 mg/dL 
 Aspartate aminotransferase (AST) ≤ 2.5 x ULN 
 Alanine aminotransferase (ALT) ≤ 2.5 x ULN 
 Estimated Creatinine Clearance by Cockcroft-Gault formula ≥ 30 mL/min 
7. Any prior neoadjuvant or adjuvant androgen-deprivation therapy or 
finasteride must have been discontinued at least 6 months prior to 
registration.  
8. Subjects must fall into one of the two populations below: 
 Early Induction Group: Subjects who have started androgen deprivation 
therapy (luteinizing hormone–releasing hormone (LHRH) agonist or 
antagonist therapy with or without an antiandrogen agent) a maximum of 
28 days before registration. 
 Late Induction Group: Subjects who have NOT started androgen 
deprivation therapy (luteinizing hormone–releasing hormone (LHRH) 


 
 
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agonist or antagonist therapy with or without an antiandrogen agent)  
9. All subjects should provide written informed written consent and HIPAA 
authorization. 
10.Patients with ‘high extent or extensive stage’ of metastases (per 
CHAARTED/E3805) study: visceral metastasis or more than 4 bone 
metastases including at least 1 non-axial bone metastasis or both) should be 
considered unsuitable candidates for docetaxel per the treating physician’s 
clinical judgment, or should have declined docetaxel therapy. 
 
EXCLUSION CRITERIA: 
1. History of or active CNS metastases (brain, leptomeningeal or cord 
compression). 
2. Any neuroendocrine differentiation including small cell component on 
histology or cytology. 
3. Receiving another investigational agent concomitantly or within the previous 
28 days.  
4. Prior or ongoing bisphosphonate or RANKL inhibitor use is not allowed 
except when used solely for osteoporosis and per guidelines for that 
indication.  
5. Prior therapy with systemic radiopharmaceuticals including strontium-89, 
samarium-153, rhenium-186 or rhenium-188 for the treatment of bone 
metastases. 
6. Prior hemibody external radiation is not allowed. Any external radiation 
therapy must have been completed at least 14 days prior to registration. Any 
toxicity from such therapy must have recovered to ≤ grade 1 per CTCAE v4 
criteria by the time of registration. 
7. No prior malignancy is allowed EXCEPT for non-melanomatous skin cancer 
or non-muscle invasive bladder cancer or adequately treated Stage I or II 
cancer (adequacy at discretion of site investigator) from which the subject is 
currently in complete remission, or any other cancer from which the subject 
has been disease-free for at least 3 years. 


 
 
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OUTCOME 
MEASURES 
PRIMARY OUTCOME MEASURES:  
Subjects will be assessed for radiographic progression as described in Section 8.  
Time to radiographic progression or death, whichever occurs first, will be 
calculated for each subject.   
 
SECONDARY OUTCOME MEASURES:  
 AE and SAE data, skeletal related events and secondary neoplasms will 
describe toxicity. 
 Secondary efficacy measures are time to castration resistance, PSA 
progression free survival, overall survival, 7-month PSA ≤ 0.2 ng/mL, and 
7-month PSA ≤ 4 ng/mL. 
 Serum outcomes are ALP normalization among subjects with abnormal 
ALP at randomization and serum bone markers 
 
Pain outcomes from BPI-SF and physician assigned WHO.  
 
STATISTICAL 
CONSIDERATIONS 
 
Primary Analysis     
Subjects will be assessed for radiographic progression as described in Section 8.  
Time from first dose of ADT to radiographic progression or death, whichever 
occurs first, will be calculated for each subject.  For subjects who discontinue 
study treatment due to reasons other than death or investigator assessed 
progression, every effort will be made to continue tumor assessments on schedule 
until radiographic progressive disease or subject death.  Subjects who do not have 
radiographic progression or death will be censored at their last measure for 
radiographic progression.  The primary hypothesis test will be conducted at a 
one-sided 0.1 significance level using a stratified log-rank test. Kaplan-Meier 
methods will be used to report rPFS graphically by arm including the median 
rPFS and 12 and 24 month rPFS proportions in the ITT population.  The log-rank 
test without stratification will be used as a sensitivity analysis. 
 
Secondary analysis  
Toxicity will be described within each arm by type, maximum grade and 
frequency among the safety population.  The proportion of subjects in each arm 
with skeletal related events and secondary neoplasms will be reported 
individually and a mid p-value test will compare the proportions between arms.  
 
Time to castration resistance (TTCR), PSA progression free survival (PCWG2 
criteria), and Overall Survival (OS) will be reported by arm using Kaplan-Meier 
methods and tested using the stratified log-rank test.  The 2 -year PSA PFS and 
OS proportions with 90% confidence intervals and median time to castration 
resistance will be reported using Kaplan-Meier methods.  Analyses will be 
completed on the ITT population.  
 
Binomial proportions with 90% binomial confidence intervals of subjects who 
achieve PSA ≤ 0.2 ng/mL at 7 months after treatment initiation will be reported 
by arm.  Similarly, the proportions and associated confidence intervals of subjects 
who achieve PSA ≤ 4 ng/mL at 7 months after treatment initiation will be 


 
 
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described.   
 
We will evaluate the distribution of pre-randomization marker levels (ALP and 
bone markers) among those who have and have not started ADT prior to 
randomization. If it appears that the prior initiation of ADT impacts the study 
entry bone marker levels to a fair extent, then all marker analyses will be 
conducted stratified by ADT initiation status. Descriptive statistics by arm will 
report the time to ALP progression among all subjects using Kaplan-Meier 
methods.   ALP and serum bone markers will be reported by arm for each time-
point using means or medians and corresponding measures of variability for all 
subjects with serum.  Percentage change in ALP from baseline and changes from 
baseline in bone markers will be calculated for each later time point and tested 
between arms using a t-test or Wilcoxon rank test.  If there is sufficient data, a 
mixed model will be used to model each endpoint over time to determine if the 
changes are different between treatment arms. Exploratory analysis will use 
separate Cox models with rPFS, PSA PFS, TTCR, and OS as the individual 
outcomes and treatment group, one marker, and the interaction between treatment 
and marker as independent covariates to find associations with outcomes. These 
models can be expanded to include other subject factors to determine if the 
marker contributes to outcome above subject factors that are known to be 
associated with the outcome.  Similarly, logistic models can be used with 7-
month PSA outcomes. The model analyses are considered exploratory for this 
trial. Thus, they are not powered and will not use multiple comparisons 
adjustments. 
 
Worst pain will be reported from the BPI (SF) at each time point with a mean or 
median and the associated measure of variability and tested between arms with a 
t-test or Wilcoxon rank test.   Comparisons at the times post-baseline will be 
compared between treatment arms using a paired test (t-test or Wilcoxon rank 
test.)  WHO will be reported categorically by arm at each time point and tested 
between arms using the Mantel-Haenszel chi-square test.  The change in WHO 
score from baseline will be calculated and be the outcome in a cumulative logistic 
model.  Treatment arm will be included as an independent covariate to test if the 
change in pain is different between arms. Each post-baseline measure will be a 
separate model. 
 
ENROLLMENT 
PERIOD 
Estimated 24 months 
TOTAL STUDY 
DURATION  
4 years; 2 years for accrual and 2 years for follow-up 
 


 
 
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TABLE OF CONTENTS 
 
SECTION                                                                                                                                PAGE 
 
SCHEMA ............................................................................................................................................ 
9 
1. 
BACKGROUND AND RATIONALE ............................................................................. 10 
2. 
OBJECTIVES .................................................................................................................... 13 
3 
ELIGIBILITY CRITERIA ............................................................................................... 14 
4 
SUBJECT REGISTRATION ........................................................................................... 16 
5 
TREATMENT PLAN ........................................................................................................ 17 
6 
TREATMENT MODIFICATIONS ................................................................................. 20 
7 
STUDY CALENDAR & EVALUATIONS ...................................................................... 23 
8 
CRITERIA FOR DISEASE EVALUATION AND ENDPOINT DEFINITIONS ....... 31 
9 
EXPLORATORY CORRELATIVES ............................................................................. 36 
10 
DRUG INFORMATION ................................................................................................... 43 
11 
ADVERSE EVENTS ......................................................................................................... 56 
12. 
STATISTICAL CONSIDERATIONS ............................................................................. 60 
13 
TRIAL MANAGEMENT .................................................................................................. 64 
 
 
 


 Clinical Study Protocol  
HCRN GU13-170 
 
 
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SCHEMA 
Androgen Deprivation Therapy with or without Radium-223 dichloride 
in Newly Diagnosed Metastatic Prostate Cancer with Bone Metastases: HCRN GU13-170 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 1:2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligible Prostate Cancer Subjects with Skeletal Metastasis/es 
Prior to Randomization 
 PSA 
 Testosterone (TST) 
 Serum Bone Turnover Markers (BTM) 
 Imaging 
Arm A (Control) 
LHRH agonist/ antagonist 
+ 
Bicalutamide 
Arm B (Experimental) 
LHRH agonist/ antagonist 
Bicalutamide + 
Radium-223 dichloride × 6 doses in cycles 2-7 
After 1 month of CAD 
 PSA 
 Alkaline phosphatase 
Every month for 1 year after registration 
 PSA 
 Alkaline phosphatase 
Off Study for Radiologic Progression/ Intolerable Toxicity 
Note: Radium-223 may continue if there is no bone progression 
End of Treatment: 
 PSA 
 BTM 
 Imaging 


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1. 
BACKGROUND AND RATIONALE 
 
 
1.1. 
Androgen Deprivation Therapy (ADT) 
Androgen Deprivation Therapy (ADT) with Luteinizing Hormone Releasing Hormone (LHRH) 
agonists or antagonists in combination with androgen receptor antagonists such as bicalutamide, 
termed Combined Androgen Deprivation (CAD) is one of the common standard of care options 
in metastatic hormone naïve prostate cancer. ADT alone is also acceptable.  Survival benefit of 
adding anti-androgen to medical or surgical castration was first shown by the SWOG-
coordinated US Intergroup study SWOG-8494 (INT-0036), which randomly assigned 603 men 
with newly diagnosed hormone sensitive metastatic prostate cancer, to combine androgen 
deprivation (CAD) with leuprolide plus flutamide or leuprolide alone1. When compared to 
leuprolide alone, men treated with CAD had significantly longer progression-free and median 
survival (16.5 vs. 13.9 months, and 35.6 vs. 28.3 months, respectively). However, in a 
subsequent Phase III trial (SWOG-8894, INT-0105) with 1387 men, addition of flutamide to 
bilateral orchiectomy did not result in a clinically meaningful improvement in survival2. 
Although more patients treated with CAD achieved a serum PSA < 4 ng/mL (74 versus 62 
percent with placebo), the differences in median and progression-free survival were not 
statistically significant (34 versus 30 months, and 20 versus 19 months, respectively). Since then, 
several meta-analyses have shown improvement in survival outcomes with CAD over castration, 
although with increased toxicity3-5. ASCO guidelines published in 2007 state that CAD should be 
considered an option, and be discussed with the patients with the emphasis that improved overall 
survival may occur at the cost of higher toxicity.  
 
The PSA response to ADT at 7 months is a validated prognostic marker in metastatic prostate 
cancer. In the randomized phase 3 SWOG 9346 trial, the depth of PSA response (i.e. < 0.2, 0.2-4 
or > 4 ng/ml at 7 months) predicted overall survival. Based on data from over 1000 patients with 
new M1 prostate cancer undergoing ADT with goserelin and bicalutamide in SWOG 9346, 
Hussain M. and colleagues have reported that failure to achieve a PSA of ≤ 4 ng/ml (or to be 
experiencing a rise in PSA) after 7 months of combined ADT is a very powerful negative 
predictor for survival6,7. The median overall survival for this group of patients was 20 months 
from the start of androgen deprivation therapy. This is to be contrasted with the 45% of the 
patients who achieved undetectable PSA levels (≤ 0.2 ng/ml) at month 7 whose median overall 
survival was of 82 months from the start of androgen deprivation. Therefore, increasing the 
depth of the PSA response to ADT possibly by combination with novel agents is a worthy goal 
in newly diagnosed metastatic prostate cancer.  
 
1.2. 
Bone metastases in newly diagnosed metastatic prostate cancer 
Bone metastases are present in nearly 90% of patients with newly diagnosed metastatic prostate 
cancer8 and account for significant morbidity manifested as bone pain, skeletal related events 
(SREs) such as bone fractures, spinal cord compression, need for palliative radiation or surgery 
and the related cost of managing these complications. Zoledronic acid and denosumab have been 
shown to lower the incidence of skeletal related events in castration resistant prostate cancer but 
do not extend survival9,10. However, there is no proven bone targeted therapy in hormone naïve 
metastatic prostate cancer that improves oncologic outcomes. Effective targeting of skeletal 
metastasis is an important unmet need in clinical management of advanced prostate cancer.  
 


 
 
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1.3. 
Clinical Experience with Radium-223 dichloride 
Radium-223 dichloride (Xofigo®) is a bone seeking alpha radiation emitting radiopharmaceutical 
with a short tissue penetration depth (2-10 cells deep or <100 microns). The alpha particle 
radiation causes double-strand breaks in DNA, killing cells. Radium-223 is given intravenously 
and is a calcium mimetic in that, like calcium, radium-223 accumulates preferentially in areas of 
bone undergoing increased turnover, such as areas where bone metastases are forming. The short 
tissue penetration limits damage to the surrounding tissues.  
 
In a multicenter randomized placebo controlled phase 2 trial in patients with castration resistant 
prostate cancer and symptomatic bone pain needing external beam radiation therapy, radium-223 
was started during external beam radiation therapy and given for 4 doses11.  Median relative 
change in PSA from baseline to 4 weeks after last study injection was –23⋅8% (range –98⋅6 to 
545⋅6) in the radium-223 group and +44⋅9% (–91⋅3 to 563⋅5) in the placebo group (p=0⋅003, 
Wilcoxon ranked-sums test). A confirmed PSA response of more than 50% was seen in 11 of 31 
patients assigned radium-223 and five of 28 assigned placebo (p=0⋅153, Fisher’s exact test). 
Median time to PSA progression was 26 weeks (95% CI 16–39) in the radium-223 arm 
compared with 8 weeks (4–12) in the placebo arm (p=0⋅048, log rank). Censoring for 
concomitant treatment that might affect PSA did not change the overall results that radium-223 
was associated with improved PSA endpoints.  
 
The randomized phase 3 trial, Alpharadin in Symptomatic Prostate Cancer Patients 
(ALSYMPCA), enrolled 921 patients with metastatic, castration-resistant prostate cancer with ≥2 
symptomatic bone metastases, post-docetaxel or ineligible for docetaxel, and no visceral 
metastases12. Men in the trial were randomized in a 2:1 fashion to receive radium-223 (50 
kBq/kg body weight given intravenously every 4 weeks for 6 doses) plus the best standard of 
care or a placebo plus the best standard of care. Systemic chemotherapy was not allowed during 
the treatment period. The primary endpoint of the trial was overall survival. Secondary endpoints 
included time to first symptomatic skeletal related event and quality-of-life measures. 
 
The trial was stopped in early 2011 when a planned interim analysis by an independent data 
safety and monitoring committee from the trial detected that men randomized to radium-223 had 
statistically significantly better overall survival than men assigned to receive the placebo. 
Median overall survival was 14.9 months for the men assigned to receive radium-223 and 11.3 
months for those assigned to the placebo (HR for death 0.695, 95% CI 0.552-0.875, p=0.002). 
An overall survival benefit with radium-223 was seen in all subgroups of men analyzed—for 
example, men benefited whatever the extent of their disease. 
 
In the ALSYMPCA study, increase in PSA level was defined as a relative increase of ≥25% 
from the baseline level and an absolute increase of ≥2 ng per milliliter at ≥12 weeks, in patients 
with no decrease in the PSA level from baseline, or a relative increase of ≥25% and an absolute 
increase of ≥2 ng per milliliter above the nadir, confirmed ≥3 weeks later, in patients with an 
initial decrease from baseline. Radium-223 significantly prolonged the time to an increase in 
PSA level thus defined (HR 0.64; 95% CI, 0.54 to 0.77; P<0.001). A 30% or greater reduction in 
PSA blood levels at week 12 was achieved in 16% of patients in the radium-223 group and in 6% 
of patients in the placebo group (P<0.001).  


 
 
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Radium-223 also delayed time to first SRE which occurred at a median of 15.6 months versus 
9.8 months in the placebo arm (HR=0.61; 95% CI 0.461-0.807, p=0.0005). Fewer men in the 
radium-223 group experienced serious adverse events (47 percent versus 60 percent) or stopped 
treatment because of adverse events (16 percent versus 21 percent) than in the placebo group. 
Compared with men in the placebo group, men assigned to receive radium-223 also reported a 
better quality of life as measured using a standard assessment tool (FACT-P). Radium-223 
showed a tolerable safety profile with the most common adverse effects being bone pain and 
gastrointestinal toxicities (grade 3 and 4 of 1% vs. 1% in the placebo arm). Importantly, for this 
patient population with implications for concurrent or sequential cytotoxic chemotherapy, grade 
3 and 4 hematological toxicity was uncommon (anemia in 11%, neutropenia in 2% and 
thrombocytopenia in 4%). On May 15, 2013, based on interim results from the ALSYMPCA 
trial, the FDA approved radium-223 for the treatment of men with castration-resistant prostate 
cancer with bone metastases that are causing symptoms.  
 
1.4 
United States National Institutes of Standard and Technology (NIST) 
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 (2). 
 
The NIST SRM is used to calibrate the instruments in production and quality control for both the 
drug substance and drug product. Additionally, the NIST SRM is used to prepare the NIST 
traceable Ra-223 reference materials which are then sent to the end-users (e.g., nuclear medicine 
laboratory physicians or technicians) for dial-setting of their dose calibrators, to allow 
verification of the patient dose. 
 
In 2014, NIST performed a re-assessment of the primary standardization based on preliminary 
information suggesting a potential discrepancy of approximately 8-10% between the published 
NIST primary standardization (2) and results obtained by other national metrology institutes 
(United Kingdom, Germany, Japan). After completion of the re-assessment, NIST reported their 
findings (3) 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 were corrected by approx. + 10.5%.  This update for 
dial settings was implemented on April 25, 2016.  At the time of this update, no patients have 
been treated on this protocol. 
 
1.5 
Role of chemotherapy with docetaxel in new hormone sensitive metastatic prostate 
cancer: 
ECOG 3805/CHAARTED was an intergroup Phase III study comparing ADT, with or without 
chemotherapy with docetaxel, with prednisone in men with hormone sensitive metastatic prostate 
cancer (mHSPC). The study enrolled 790 men with mHSPC between July 2006 and November 
2012. Approximately two-thirds of patients had a high extent of disease which, according to the 
study, meant the disease involved the liver, four or more bones, or both. Results of the study 
were presented in the 2014 ASCO annual meeting. There was a significant improvement in the 


 
 
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overall survival (OS) favoring the participants who had received docetaxel chemotherapy in 
addition to the ADT compared to the ADT alone (57.6 vs. 44 months, HR 0.63; 95% CI: 0.48, 
0.82; P = 0.0006). Further analysis showed that patients with a high extent of metastatic disease 
accounted for most of the benefit in the OS from docetaxel plus ADT (49.2 vs. 32.2 months, HR 
0.62; 95% CI: 0.46, 0.83; P = 0.0012). Median follow-up at the time of report was 29 months, 
and at this time, the median survival in the low extent disease patients both arms had not been 
reached. These data support the use of front line doecetaxel with androgen deprivation therapy 
for patients with newly diagnosed mHSPC who are deemed to be suitable candidates for 
docetaxel per the treating physician’s clinical judgment. 
 
1.6 
Hypothesis 
We hypothesize that the combination of ADT and radium-223 dichloride will increase the depth 
of PSA response and will target bone metastases effectively in subjects with newly diagnosed 
prostate cancer and skeletal metastases, reflected in a higher percentage of subjects achieving a 
PSA value of 0.2 ng/mL or less (“undetectable PSA”) after 7 months of combination therapy 
compared to ADT alone and a greater proportion of subjects normalizing an elevated serum total 
alkaline phosphatase level after 12 weeks of combination therapy compared to ADT alone. We 
will use the primary endpoint of 12-month radiologic progression free survival (rPFS). We 
hypothesize that if the trial meets the primary endpoint, radium-223 dichloride would be worthy 
of future testing in phase 3 trials. 
 
2. 
OBJECTIVES 
 
2.1 
Primary Objective 
2.1.1 Determine whether the combination of ADT plus radium-223 dichloride is more effective 
than ADT alone based upon radiologic progression free survival (rPFS) of subjects with 
newly diagnosed metastatic prostate cancer with bone metastases. 
 
 
2.2 
Secondary Objectives 
 
2.2.1 Assess safety and toxicity including incidence of skeletal related events (SRE) and 
secondary neoplasms.  
 
2.2.2 Estimate the proportion of subjects with PSA≤ 0.2 ng/mL after 7 months of androgen 
deprivation therapy, the proportion of subjects with PSA≤ 4 ng/mL after 7 months of 
androgen deprivation therapy, the median time to castration resistance, 2-year PSA 
progression free survival proportion (PCWG2 criteria) and 2-year overall survival 
proportion in both arms. 
 
2.2.3 Determine the proportion of subjects with elevated serum total alkaline phosphatase 
(ALP) at baseline who normalize their alkaline phosphatase after 12 weeks of therapy, 
assess time to ALP progression (≥ 25% increase in ALP from baseline/nadir (whichever 
is lower) and above ULN), association of ALP x in both arms. 
 
2.2.4 Evaluate change in pain level and analgesic use using the Brief Pain Inventory (BPI short 
form) and WHO ladder scale, respectively, with therapy.   


 
 
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2.3 
Exploratory Correlative Objectives 
 
2.3.1 Assess number of circulating tumor cells (CTCs) and gamma H2AX in all subjects 
(number of subjects = 204). 
 
2.3.2 Explore the association of bone turnover markers with clinical outcome and change in 
serum bone turnover markers with therapy in both arms. 
 
3 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
Definitions:  
 Androgen Deprivation Therapy includes LHRH agonist or LHRH antagonist or 
bilateral orchiectomy. Anti-androgen receptor blockers (e.g. bicalutamide) do not 
constitute androgen deprivation therapy.   
 
 Protocol specified therapy refers to the androgen deprivation therapy (see above) 
with or without radium-223 dichloride. 
 
1. All subjects or their legally authorized representative must be informed of the 
investigational nature of the study and provide written informed consent and HIPAA 
authorization for release of personal health information before performance of any study 
related procedure not part of routine medical care. 
NOTE:  HIPAA authorization may be included in the informed consent or obtained 
separately. 
2. Men ≥ 18 years of age at the time of informed consent.   
3. Histological or cytological evidence of prostate adenocarcinoma. 
4. All subjects must have radiologic or pathologic evidence of skeletal metastases with ≥ 2 
skeletal lesions with or without pain at baseline on bone scan or axial imaging or with 1 
skeletal lesion and bone pain within 28 days prior to the registration.  
5. All subjects must have a radiographic assessment (chest or abdominal/pelvic CT or MRI) 
within 28 days prior to registration but do not need to have measurable disease.  
6. ECOG (Eastern Cooperative Oncology Group) Performance Status of 0-2 within 28 days 
prior to registration (see Study Procedures Manual [SPM] for ECOG Performance Status 
definitions). ECOG Performance Status of 3 will only be allowed if judged by the site 
investigator as attributable exclusively to bone pain. 
7. Subjects must fall into one of the two populations below: 
 Early Induction Group: Subjects who have started androgen deprivation therapy 
(luteinizing hormone–releasing hormone (LHRH) agonist or antagonist therapy 
with or without an antiandrogen agent) a maximum of 28 days before registration 
and who otherwise meet all the eligibility criteria. 
 Late Induction Group: Subjects who have NOT started any androgen deprivation 
therapy (luteinizing hormone–releasing hormone (LHRH) agonist or antagonist 
therapy with or without an antiandrogen agent). 


 
 
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8. Anti-androgen receptor antagonist therapy must be bicalutamide. Subjects already started 
on other anti-androgens must be willing to switch over to bicalutamide.  
9. Any prior androgen-deprivation therapy or finasteride as neoadjuvant or adjuvant therapy 
or for biochemical recurrence must have been discontinued at least 6 months prior to 
registration.  
10. Prior surgical treatment for prostate cancer is allowed but must have been completed at 
least 14 days prior to registration and any toxicity from such therapy must have recovered 
to ≤ grade 1 per CTCAE version 4 criteria by the time of registration. 
11. The following laboratory values must be obtained within 28 days prior to registration for 
protocol therapy.   
 Hemoglobin (Hgb) ≥ 8.0 g/dL (80 g/L) without packed RBC transfusion 
 Platelets ≥ 100 K/mm3 
 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 
 Total Bilirubin ≤ 2  institutional upper limit of normal (ULN) except subjects 
with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL 
 Aspartate aminotransferase (AST, SGOT) ≤ 2.5 institutional ULN (≤ 5 x 
institutional ULN in the presence of liver metastases).  
 Alanine aminotransferase (ALT, SGPT) ≤ 2.5 institutional ULN (≤ 5 × 
institutional ULN in the presence of liver metastases). 
 Estimated Creatinine Clearance by Cockcroft-Gault formula ≥ 30 mL/min 
12. All subjects, including those who are surgically sterilized, must be willing to use an 
effective method of contraception (barrier method of birth control or abstinence) from the 
time informed consent is signed until 6 months after completion of protocol therapy.  
13. Subjects must consent to bank whole blood, serum, plasma for future unspecified studies.   
14. Patients with ‘high extent or extensive stage’ of metastases (per CHAARTED (E3805) 
study: visceral metastasis or more than 4 bone metastases including at least 1 non-axial 
bone metastasis or both) should be considered unsuitable candidates for docetaxel per the 
treating physician’s clinical judgment, or should have declined docetaxel therapy. 
 
3.2 Exclusion Criteria 
 
1. Prior cytotoxic chemotherapy for metastatic prostate cancer. Prior cytotoxic 
chemotherapy with curative intent in the neoadjuvant or adjuvant setting is allowed but 
must have been completed at least 6 months prior to registration. No cytotoxic 
chemotherapy is allowed during protocol specified therapy. 
2. Prior concomitant therapy with ketoconazole, aminoglutethimide or abiraterone acetate or 
enzalutamide (MDV3100) or intent to treat with the above. Concurrent megestrol for hot 
flashes is allowed. 
3. Prior or ongoing bisphosphonate (e.g. zoledronic acid) or RANKL inhibitor (e.g. 
denosumab) use is NOT allowed except when used solely for osteoporosis and strictly 
per guidelines for that indication. Bisphosphonate or RANKL inhibitor cannot be 
initiated for any indication during protocol specified therapy without consent of the 
sponsor-investigator of the study. 
4. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or rhenium-
188. 


 
 
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5. Diagnosis of aplastic anemia, pure red cell aplasia, myelodysplasia or any of the other 
bone marrow failure states. 
6. Any neuroendocrine differentiation including small cell carcinoma on histology or 
cytology. 
7. No prior malignancy except for non-melanomatous skin cancer or non-muscle invasive 
bladder cancer or adequately treated Stage I or II cancer (adequacy at discretion of 
treating investigator) from which the subject is currently in complete remission, or any 
other cancer from which the subject has been disease-free for at least 3 years. 
8. History of or active CNS metastasis (brain, leptomeningeal or cord compression).  Brain 
imaging studies are not required for eligibility if the subject has no neurologic signs or 
symptoms suggestive of brain metastasis. Subjects with neurological symptoms are 
recommended to undergo a head CT scan (with or without intravenous contrast) or brain 
MRI (with or without intravenous contrast) to exclude brain metastasis. If brain imaging 
studies are performed, they must be negative for CNS disease. Skull bone involvement 
without neurological impact by prostate cancer is allowed.  
9. Treatment with any other investigational agent within 28 days prior to registration. 
Subjects must not be treated with any other investigational agent while on protocol 
specified therapy. 
10. Prior hemibody external radiation. Any external radiation therapy must have been 
completed at least 14 days prior to registration. Any toxicity from such therapy must have 
recovered to ≤ grade 1 per CTCAE version 4 criteria by the time of registration. 
11. Clinically significant infections as judged by the site investigator. Subjects must not have 
been diagnosed with human immunodeficiency virus (HIV) infection, active chronic 
hepatitis B or C, life-threatening illness unrelated to cancer, or any serious medical or 
psychiatric illness that could, in the investigator’s opinion, potentially interfere with 
participation in this study. Subjects should be tested for hepatitis B or C or HIV infection 
during screening only if they are considered by the investigator to be at high risk for these 
infections.  
12. Known hypersensitivity to bicalutamide.  
13. Known gastrointestinal (GI) disease or procedure that could interfere with the GI 
absorption or tolerance of bicalutamide, including difficulty swallowing oral medications.  
14. Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., 
subjects with cardiac disease resulting in marked limitation of physical activity or 
resulting in inability to carry on any physical activity without discomfort), symptomatic 
pulmonary embolism within 3 months, unstable angina pectoris, myocardial infarction 
within 6 months, or serious uncontrolled cardiac arrhythmia as determined by the treating 
physician.  
 
4 
SUBJECT REGISTRATION  
All subjects must be registered and randomized through the Hoosier Cancer Research 
Network (HCRN) electronic data capture (EDC) system OnCore.  A subject is considered 
registered when an “On Study” date is entered into OnCore.  Subjects must be registered 
prior to randomization. Subjects must begin therapy within 5 business days of 
randomization. 
 


 
 
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4.1 
STRATIFICATION FACTORS  
Subjects will be stratified based on serum total alkaline phosphatase at baseline and 
extent of disease (described below).  Randomization will occur within stratification 
group. 
 Extent of Disease: <6 skeletal metastases with no visceral metastases versus ≥6 
skeletal metastases or visceral metastases.  
 Serum total alkaline phosphatase at baseline:  Normal vs Abnormal. Abnormal 
alkaline phosphatase is defined as > 130 IU/L. 
 Early Induction or Late Induction status will not be a stratification criterion. 
 
5 
TREATMENT PLAN 
 
5.1 
Treatment schedule  
Subjects will be randomized in a 2:1 ratio in favor of the experimental arm to one of the 
following treatments:  
 Arm A (Control): LHRH agonist/antagonist + bicalutamide 
 Arm B (Experimental): LHRH agonist/antagonist + bicalutamide + radium-223 
dichloride 
 
5.2 
Androgen Deprivation Therapy 
 All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH 
agonist such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH 
antagonist (degarelix) or bilateral orchiectomy per the treating physician. Androgen 
Deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously. 
 LHRH Agonist will be given as approved for androgen deprivation at a dose necessary to 
maintain castrate levels and equivalent to 22.5 mg of Leuprolide IM every 3 months. 
One, three, four and six month or one year depot injections are acceptable. 
 If LHRH Antagonist (Degarelix) is chosen as the method of androgen deprivation 
therapy, it will be given as approved: Initial, 240 mg subcutaneously given as 2 injections 
of 120 mg each and subsequent maintenance doses of 80 mg subcutaneously every 28 
days. 
 A delay of up to 7 days in administering a scheduled dose of LHRH agonist or LHRH 
antagonist is allowed. 
 
5.3 
Androgen Receptor Antagonist 
All subjects will receive bicalutamide. Subjects may start bicalutamide within 14 days prior to 
starting a LHRH agonist/antagonist or the date of bilateral orchiectomy at the discretion of the 
treating investigator to prevent a clinical flare reaction. Subjects on other anti-androgens prior to 
registration must switch to bicalutamide without lead-in.  
 
5.4 
Radium-223 dichloride  
 Radium-223 dichloride is an alpha particle emitter with a physical half-life of 11.4 days. 
The product is isotonic and has a pH of 6.0-8.0. The radioactive concentration at the 
reference date is 1,100 kBq/mL. The product has a pre-calibration of 14 days. When 
administered on a day other than the reference day, the volume should be corrected 
according to the physical decay table accompanying each shipment.   


 
 
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 The volume per vial is 6 mL, corresponding to 6.6 at the reference day. Radium-223 
dichloride has a shelf life of 28 days from production day, when stored at ambient 
temperature. The shelf life has been demonstrated for temperatures from cold storage (2-
8°C) up to 40°C. In addition, it has been shown that the product quality is not jeopardized 
upon freezing 
 Current NIST standard: Radium-223 dichloride, 55 kBq/kg body weight, will be 
administered as a bolus intravenous (IV) injection (up to 1 minute) at intervals of every 
28 days for up to 6 cycles.  Subjects randomized to this arm will begin treatment on 
C2D1.  
 The dose of radium-223 dichloride will be recalculated prior to each dose and will be 
based on the most recent actual body weight, recorded within 4 weeks. 
 There must be a minimum of 25 days between consecutive radium-223 dichloride doses.  
 
The following hematologic criteria must be met within 3 days prior to first dose of 
Radium 223:  
o ANC ≥ 1.5 K/ mm3 
o Platelets ≥ 100 K/mm3 
o Hemoglobin ≥ 8 g/dL (80 g/L) without PRBC transfusion 
 The following hematologic criteria must be met within 3 days prior to administration of 
remaining doses: 
o ANC ≥ 1.0 K/ mm3 
o Platelets ≥ 50 K/mm3 
o Hemoglobin ≥ 8 g/dL (80 g/L) with or without PRBC transfusion 
 Infusions of radium-223 dichloride may be given within a window of -3 days to +7 days 
for reasons including observed holidays, inclement weather, scheduling conflicts, etc. 
Schedule changes should be clearly documented in the source documents and electronic 
case report forms.  Please see Decay Factor Table if date of radium-223 dichloride 
changes from originally planned. 
 
5.5 
Designation of Cycle 1 Day 1 date 
Cycle 1 Day 1 is designated as the day the subject receives LHRH agonist or antagonist 
(androgen deprivation therapy) or the date of bilateral orchiectomy.  The early induction subjects 
will have already received their first LHRH agonist or antagonist injection or had bilateral 
orchiectomy.  Please verify this date for early induction subjects with source documentation. 
 
5.5.1 Treatment schedule Arm A (Control)  
AGENT 
DOSE 
ROUTE 
DAYS 
LHRH 
agonist/antagonist 
As per treating physician 
See 5.2 
According to 
package insert 
According to 
package insert 
Bicalutamide 
50 mg 
Oral (PO) 
Daily 
 
 


 
 
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5.5.2 Treatment schedule Arm B (Experimental) 
AGENT 
DOSE 
ROUTE 
DAYS 
LHRH 
agonist/antagonist 
As per treating physician 
See 5.2 
According to 
package insert 
According to 
package insert 
Bicalutamide 
50 mg 
Oral (PO) 
Daily 
Standard for Radium-
223 dichloride  
55 kBq (1.5 microcurie) per 
kg body weight 
Intravenous 
 (IV bolus) 
Every 28 days 
for 6 injections 
 
5.5.3 Continuation of ADT/completion of Radium-223 
After the completion of seven cycles of ADT, further treatment with androgen deprivation will 
be up to the treating physician. If radium-223 dichloride doses have been delayed for any reason 
and all 6 doses have not been administered by the 28 weeks’ time-point, they may be 
administered later at the discretion of the site investigator provided laboratory parameters as 
outlined above are satisfied. The site investigator/site should record data on such delayed 
radium-223 administrations including dose of radium-223 dichloride, date of administration and 
hematological parameters obtained within 3 days of administration. 
 
5.6 
PSA Assessments 
PSA values will be assessed: 
 PSA obtained prior to initiating androgen deprivation therapy, should be used as the 
baseline PSA.  For subjects in the early induction group, if a baseline PSA prior to 
initiation of ADT is not available, the baseline PSA will be considered the value 
obtained prior to randomization. 
 Prior to randomization then  
 Day 1 of every Cycle through Cycle 12 then 
 Every 3 months for the following year  
 More frequent PSA monitoring as clinically indicated is acceptable.   
 
5.7 
Pre-medication  
Institutional standards should be followed for hydration and pre-medications for LHRH agonists 
or antagonists. No pre-medications are needed prior to the first dose of radium-223 dichloride. 
Anti-emetics may be used subsequently as clinically indicated. 
 
5.8 
Concomitant Medications 
The use of supportive care medications is allowed according to institutional standards.  We 
strongly recommend supplemental calcium 1200 mg daily and Vitamin D3 1000 IU daily.   
 
However, certain medications are specifically disallowed.  
 Five-alpha reductase inhibitors (e.g. finasteride and dutasteride) are not permitted.  
 Other excluded therapies include ketoconazole, aminoglutethimide, abiraterone acetate, 
enzalutamide (MDV3100), diethylstilbestrol (DES), and other estrogen preparations.  
 Cytotoxic chemotherapy is not allowed during protocol specified therapy. 
 


 
 
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5.9 
Supportive Care 
 Institutional standards should be followed for hydration and pre-medications. 
 The use of packed red blood cell transfusions is allowed as clinically indicated per 
institutional guidelines or at investigator’s discretion but must be clearly documented in 
the source documents. 
 Palliative external beam radiation therapy for prostate cancer during protocol specified 
therapy is allowed as clinically indicated. Radium-223 dichloride doses must be held 
during external beam radiation therapy and may resume after a minimum of 7 days after 
completion of external beam radiation if hematological laboratory parameters are 
adequate (see section 5). 
 Palliative external beam radiation therapy can start without a minimum time interval after 
a radium-223 dose as clinically indicated. 
 Colony stimulating factors (e.g. G-CSF or GM-CSF) are not allowed during protocol 
specified therapy. 
 Prolonged use of systemic corticosteroids for prevention of allergic reactions is 
discouraged because of their potential to cause and exacerbate hyperglycemia. 
Intermittent use of corticosteroids is permitted. 
 
6 
TREATMENT MODIFICATIONS  
Subjects enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study as specified in Section 7. 
 
Subjects will be evaluated for adverse events (all grades), serious adverse events, and adverse 
events requiring protocol therapy interruption or discontinuation at each study visit for the 
duration of their participation in the treatment phase of the study.   
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) v4 
for toxicity and Serious Adverse Event reporting. A copy of the CTCAE v4 can be downloaded 
from the CTEP home page (http://ctep.cancer.gov). All appropriate treatment areas should have 
access to a copy of the CTCAE v4. 
 
6.1 
Treatment-Limiting Adverse Events 
A treatment-limiting adverse event is any adverse event related to protocol therapy experienced 
during the study resulting in treatment termination.   
 
 
6.2 
General Treatment Modification Considerations 
 If multiple toxicities are experienced, treatment modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
6.2.1 Modifications for Androgen Deprivation Therapy (ADT) and Bicalutamide 
 Delay of up to 7 days in administering the scheduled dose of LHRH agonist or antagonist 
is allowed  
 Missed doses of bicalutamide are to be omitted rather than made up.  
 
6.2.1.1 Modifications for Hematologic Toxicity: 
Use of granulocyte colony stimulating factors is not permitted.  


 
 
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6.2.1.2 Modifications for Non-Hematologic Toxicity: 
 
Diarrhea: 
The major toxic effect of bicalutamide is moderate diarrhea which is rarely severe (exclusion of 
other causes of diarrhea should be considered in severe cases). The modifications for toxicity 
related to diarrhea will be as follows: 
 Grade ≥ 3diarrhea, permanently discontinue bicalutamide 
 Grade 2 diarrhea, treat symptomatically with anti-diarrhea drugs. 
 Grade 2 diarrhea unresponsive to symptomatic treatment- hold bicalutamide until 
diarrhea resolves to ≤ Grade 1. 
 
In case of any diarrhea ≥ Grade 1, the following tests are recommended at the discretion of the 
site investigator as clinically indicated:  
 WBC in stools  
 Stool cultures 
 Clostridium difficile titers  
 Further testing will be at the discretion of the site investigator  
 
Abnormal Liver Function Tests (SGOT/AST, SGPT/ALT, Bilirubin):  
 Grade ≥ 3, permanently discontinue bicalutamide 
 Grade 2 toxicity  
o Hold bicalutamide and recheck liver function tests weekly until LFTs are normal 
(Grade 0). LFTs may be performed more frequently at the discretion of the treating 
physician. 
o Hepatitis screening (A, B, C) is recommended in cases of abnormal LFTs which 
could be consistent with infectious hepatitis.  
o Restart bicalutamide when LFTs return to normal. If the toxicity (Grade ≥ 2) recurs or 
if the subject requires a delay greater than 28 days, discontinue bicalutamide. Subjects 
will remain on protocol therapy with ADT and, if applicable, radium-223 dichloride.  
 Symptoms such as flatulence, bloating and mild "gas pains" should not result in changes 
in bicalutamide, ADT or radium treatment. Symptomatic treatment should be employed 
with antacids, simethicone, etc. 
 Asymptomatic Grade 3 or 4 laboratory findings, which are not considered clinically 
significant, may not require dose modification (i.e., dose hold). The decision to hold the 
dose should be based on the site investigator’s clinical judgment.  
 For any other Grade 3-4 adverse events, hold bicalutamide; wait until adverse event has 
resolved to Grade ≤ 1, and then restart bicalutamide. 
 
6.2.2 Modifications for Radium-223 dichloride 
 Delay of up to 8 weeks (56 days) is allowed for radium-223 dichloride doses if 
necessitated by inadequacy of hematologic parameters or drug non-availability or 
necessary time interval between 2 consecutive radium-223 dichloride doses.  
 A delay of 7 days is allowed for scheduling factors. There must be a minimum of 25 days 
between consecutive radium-223 dichloride doses. 


 
 
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 Every effort should be made to administer the full dosing regimen of Radium-223 
dichloride.  Adjustment of dose is not permitted.   
 Study visits during the treatment period should occur at 28-day intervals.  Dosing delays 
may be instituted under the following circumstances listed below. 
 
6.2.2.1 Modifications for Hematologic Toxicity: 
The following hematologic criteria must be met within 3 days prior to first dose of Radium 223:  
 ANC ≥ 1.5 K/ mm3 
 Platelets ≥ 100 K/mm3 
 Hemoglobin ≥ 8 g/dL (80 g/L) without PRBC transfusion 
 
The following hematologic criteria must be met within 3 days prior to administration of 
remaining doses: 
 ANC ≥ 1.0 K/ mm3 
 Platelets ≥ 50 K/mm3 
 Hemoglobin ≥ 8 g/dL (80 g/L) with or without PRBC transfusion 
 
If the hematologic parameters listed above are not met: 
 Radium-223 dichloride will be held. 
 Complete blood counts (CBC) will be measured weekly. Once the counts recover, 
radium-223 dichloride may resume at the same dose level.   
 ADT and bicalutamide will continue without interruption.  
 If there is no recovery to these values within 8 weeks after the last administration of 
radium-223 dichloride, despite receiving supportive care including blood transfusions as 
clinically indicated, further treatment with radium-223 dichloride will be discontinued. 
ADT and bicalutamide can continue and the subject will remain on study. 
 
6.2.2.2 Modifications for Non-Hematologic Toxicity: 
 
For Grade 4 toxicity possibly attributed to radium-223 dichloride 
 Discontinue radium-223 dichloride 
 
For Grade ≥ 2 toxicity attributable to radium-223 dichloride  
 Radium-223 dichloride will be held until the toxicity has resolved to ≤ Grade 1 or 
baseline.  
 Supportive care should be instituted as clinically indicated. 
 Once the toxicity resolves, radium-223 dichloride may resume at the same dose level.  
 ADT and bicalutamide will continue without interruption.  
If there is no recovery to these values within 8 weeks (56 days) after the last 
administration of radium-223 dichloride, despite receiving supportive care including 
blood transfusions as clinically indicated, further treatment with radium-223 dichloride 
will be discontinued. ADT and bicalutamide can continue and the subject will remain on 
study. 
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7 STUDY CALENDAR & EVALUATIONS 
Early Induction Subjects = Have started ADT prior to being screened for study. 
Late Induction Subjects = Have NOT started ADT prior to being screened for this study 
Study Day 
 
Induction and Post Induction Cycles 
 = 28 days (4 weeks) 
 
Maintenance Cycles = 84 days (12 weeks) 
Screening 
(0 - 28 
days)1 
Induction
Cycle  
112  
Induction
Cycles 
2-7 
Post 
Induction 
Cycle  
8  
Post 
Induction 
Cycles 
9-12 
Maintenance 
Cycle 13 
Maintenance 
Cycles 
14-1613 
Maintenance
Cycle 
17 
End of 
Treatment 
and 
Follow 
up14 
 
 Day 1 
Day 1 
(±3) 
Day 1 
(±7) 
Day 1 
(±7) 
Day 1 
 (±7) 
Day 1 
 (±14) 
Day 28 
(±7) 
Day 1  
REQUIRED ASSESSMENTS 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Medical History and Diagnosis/Staging 
X 
 
 
 
 
 
 
 
 
Physical examination2 
X 
X 
X 
X 
 
X 
 
X 
 
Vital signs including BP, weight, height 
(screening ONLY) and ECOG PS 
X 
X 
X 
X 
 
X 
 
X 
 
CBC with diff and platelet 3 
X 
X12 
X 
X 
 
X 
 
X 
 
CMP, Mag, and Phos. 3 
X 
X12 
X 
X 
 
X 
 
X 
 
Alk Phos, PSA4  
X 
X12 
X 
X 
X 
X 
X 
X 
X 
Testosterone5 
X 
X12 
 
X   
 
X 
 
 
 
AEs & concomitant medications6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BPI (short form), WHO ladder7 
 
X6 
X7 
X 
 
 
 
 
 
DISEASE ASSESSMENT 
 
 
 
 
 
 
 
 
 
CT or MRI abdomen/pelvis8 
X 
 
 
X 
 
X 
 
X 
 
Chest X-ray or CT chest if clinically 
indicated 8 
X 
 
 
X 
 
X 
 
X 
 
CT or MRI Brain if clinically indicated8 
X 
 
 
X 
 
X 
 
X 
 
Bone Scan8 
X 
 
 
X 
 
X 
 
 
 
DEXA scan8 
X 
 
 
 
 
X 
 
 
 
TREATMENT EXPOSURE9 
 
 
 
 
 
 
 
 
 
Arm A (Control) 
 
LHRH agonist/antagonist + Bicalutamide 
 
X 
 
 
Arm B (Experimental) 
 
LHRH agonist/antagonist + Bicalutamide 
 
X 
 
 
Radium-223 dichloride 
 
 
X 
 
 
 
 
 
 


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Study Day 
 
Induction and Post Induction Cycles 
 = 28 days (4 weeks) 
 
Maintenance Cycles = 84 days (12 weeks) 
Screening 
(0 - 28 
days)1 
Induction
Cycle  
112  
Induction
Cycles 
2-7 
Post 
Induction 
Cycle  
8  
Post 
Induction 
Cycles  
9-12  
Maintenance 
Cycle 
13 
Maintenance 
Cycles 
14-1613 
Maintenance
Cycle 
17 
End of 
Treatment 
and 
Follow 
up14 
 
 Day 1 
Day 1 
(±3) 
Day 1 
(±7) 
Day 1 
(±7) 
Day 1 
 (±7) 
Day 1 
 (±14) 
Day 28 
(±7) 
Day 1  
CORRELATIVE STUDIES 
 
 
 
 
 
 
 
 
 
Serum for Bone Turnover Markers10 
 
X10 
X10 
 
 
 
 
 
X 10 
Circulating Tumor Cells (CTCs)10 
 
X10 
X10 
 
 
 
 
 
X10 
BANKING SAMPLES 
 
 
 
 
 
 
 
 
 
Whole Blood11 
 
X11 
X11 
 
 
 
 
 
X11 
Serum and plasma11 
 
X11 
X11 
 
 
 
 
 
X11 
FOLLOW UP 
 
 
 
 
 
 
 
 
 
Survival 
 
 
 
 
 
 
 
 
X 
Secondary Malignancies 
 
 
 
 
 
 
 
 
X 
 
Footnotes: Please NOTE: unless otherwise specified, all testing will be performed in BOTH arms. 
1. NOTE: Early induction subjects will have initiated ADT prior to registration.  Results of screening procedures should be obtained through medical records 
if available including start date ADT therapy.   
2. Close monitoring for fractures should be done during the physical exam.  If a fracture is suspected, radiological exams should be performed per clinical 
guidelines.  Subjects should be encouraged to contact the site investigator for any new onset pain or increase in pain in sites of known bone disease. 
3. 
CBC w/diff and platelet to include: WBC with differential and platelets, hemoglobin and hematocrit.  Additional monitoring of CBC w/diff and platelet per 
site investigator’s discretion based on subject clinical status. CMP blood chemistries to include: sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, ALT, alkaline phosphatase, total bilirubin.  Magnesium and phosphorus to 
be included.   
4. 
PSA, Alk Phos to be assessed Cycle 1 Day 1 (late induction group) or Cycle 2 Day 1 (early induction group).  Subjects will be followed for PSA and Alk 
Phos every month for a total of 1 year from randomization then every 12 weeks (± 14 days) for the next year (2 years from randomization). If a subject 
withdraws consent, he is deemed “off study” and will NOT be followed further.   
5. 
Testosterone (serum) will be measured on Cycle 1 Day 1 (for late induction group only), Cycle 8 Day 1 (both early and late induction groups) and after 12 
months of ADT.  For early induction subjects, a testosterone value prior to initiation of ADT should be obtained via medical records, if available.  If the 
result is not available, subjects are not ineligible for study. 
6. 
AE and concomitant medication assessment: AE assessment should include a review of any symptoms the subject may be experiencing.  In addition, the 
subject should be assessed for secondary malignancies.  Concomitant medication review will include all medications the subject is taking.   
7. 
Pain assessment with BPI (short form) and assessment of analgesic use with WHO ladder scale will be performed at 3 time-points: Cycle 1 Day 1 (late 
induction group) or Cycle 2 Day 1 (early induction group), on Cycle 4 Day 1 and Cycle 8 Day 1. 
8.  CT and MRI scans if clinically indicated can be performed with or without intravenous contrast as per institutional guidelines at screening, C8D1, C13D1 
and C17D28 (a window of ± 7 days for all scans is allowed).  DEXA scan will be performed at screening and after completion of 1 year of treatment. CT or 
Brain MRI: Brain imaging studies are not required for eligibility if the subject has no neurologic signs or symptoms suggestive of brain metastasis.  Subjects 


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with neurological symptoms are recommended to undergo a head CT scan (with or without intravenous contrast) or brain MRI (with or without intravenous 
contrast) to exclude brain metastasis. If brain imaging studies are performed, they must be negative for CNS disease. Skull bone involvement without 
neurological impact by prostate cancer is allowed.  A bone scan will be performed at baseline, C8D1 and after completion of 1 year of treatment. 
9. 
All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist such as leuprolide acetate or goserelin acetate is acceptable) 
or a LHRH antagonist (degarelix) or bilateral orchiectomy per the treating physician. Androgen Deprivation therapy with LHRH agonist or LHRH 
antagonist will be given continuously.  
10. MANDATORY: Serum submission for Bone Turnover Markers: Pre-Dose Cycle 1 Day 1 (late induction group) and thereafter on Day 1 of each cycle 
during the remaining 6 months of protocol specified therapy and at End of Treatment (both induction groups).  CTCs: For following time points only: C1D1 
(late induction group only); C2D1 (early induction group only); C4D1; EOT visit. CTCs will be collected for all subjects (n = 204).  See Correlative 
Laboratory Manual (CLM) for collection, labeling and shipping instructions. 
11. MANDATORY: Whole blood for banking is to be collected pre dose Cycle 1 Day 1 (late induction group) or pre dose Cycle 2 Day 1 (early induction group) 
and at EOT.  Serum and plasma are to be collected at Pre-Treatment Cycle 1 Day 1 (late induction group) or Cycle 2 Day 1 (early induction group) and at 
EOT. See CLM for collection, labeling, processing and shipping instructions. 
12. For late induction subjects, Cycle 1 Day 1 will occur after screening and upon completion of eligibility. C1D1 lab testing need not be repeated if completed 
within 7 days of starting protocol therapy.  For early induction subjects, C1D1 occurs prior to screening; documentation of initiation of ADT (C1D1) should 
occur after review of the subject chart and completion of eligibility.   
13. For maintenance Cycles 14-17, subjects will continue to be followed every 12 weeks for alkaline phosphatase, PSA values and AE/concomitant medication 
updates, initiation of new anti-cancer therapy and occurrence of secondary malignancies.  This information may be obtained via local treating physician 
medical records.   
14.  The end of treatment/follow up column will be utilized for subjects that come off protocol therapy (both Arm A and Arm B) for toxicity or progression.  If 
this occurs, subjects should have an end of treatment visit 30 days (± 7 days) after discontinuation of protocol therapy.  Subjects will then continue to be 
followed every 3 months for a total of 2 years from the date of randomization. If a subject withdraws consent, he is deemed “off study” and will NOT be 
followed further.  Follow up may occur via phone call, email or other communication.  If available by medical record review, alk phos, PSA, 
AE/concomitant medication should be obtained. 
 


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7.1 
Screening within 28 days prior to registration for protocol therapy 
 Informed Consent 
 Medical history including diagnosis and staging information.  For early induction 
subjects, note details of ADT therapy initiation during medical history.  This review 
should also include laboratory values and radiology imaging completed prior to and 
during ADT. 
 Physical examination and history of secondary malignancies.  Close monitoring for 
fractures should be done during all physical exams.  If a fracture is suspected radiological 
exams should be performed per clinical guidelines.  Subjects should be encouraged to 
contact the site investigator for any new onset pain or increase in pain in sites of known 
bone disease.  
 Vital signs including BP measurement, height (screening only) and weight, and ECOG 
performance status.   
 Assessment of adverse events and concomitant medications  
 Laboratory Testing:  
o Comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, blood 
urea nitrogen (BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, 
ALT, alkaline phosphatase, total bilirubin), magnesium, phosphorus,  
o CBC (WBC with differential and platelet count, hemoglobin and hematocrit)  
o Testosterone; Late induction subjects; may be done during screening or prior to C1D1 
treatment for.  Early induction subjects; if available, an alkaline phosphatase prior to 
initiation of ADT should be obtained through medical record review or prior to 
treatment C2D1. 
o Alkaline phosphatase; Late induction subjects; may be done during screening or prior 
to C1D1 treatment for.  Early induction subjects; if available, an alkaline phosphatase 
prior to initiation of ADT should be obtained through medical record review or prior 
to treatment C2D1. 
o PSA; Late induction subjects; may be done during screening or prior to C1D1 
treatment for.  Early induction subjects; if available, an alkaline phosphatase prior to 
initiation of ADT should be obtained through medical record review or prior to 
treatment C2D1. 
 Imaging:  
o CT or MRI abdomen/pelvis,  
o DEXA scan  
o Bone Scan 
o CT or MRI Brain, Chest X-Ray or Chest CT if clinically indicated.  See eligibility 
criteria. 
 
NOTE: Subjects that have NOT received any ADT prior to screening are considered “Late 
Induction” and subjects that have initiated ADT prior to screening are considered “Early 
Induction.”   
 


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7.2 
Induction: Cycle 1 Day 1  
NOTE: Cycle 1 Day 1 lab testing need not be repeated if completed within 7 days of starting 
protocol therapy.  C1D1 is retrospective for early induction group and verified during Medical 
History with review of medical records. 
 Physical examination.  Close monitoring for fractures should be done during all physical 
exams.  If a fracture is suspected radiological exams should be performed per clinical 
guidelines.  Subjects should be encouraged to contact the site investigator for any new 
onset pain or increase in pain in sites of known bone disease.  
 Vital signs including BP measurement, weight, ECOG performance status 
 Assessment of adverse events and concomitant medications 
 Laboratory Testing:  
o CMP to include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, ALT, 
alkaline phosphatase, total bilirubin.  Including magnesium, phosphorus 
o CBC (WBC with differential and platelet count, hemoglobin and hematocrit) 
Additional monitoring of CBC w/diff and platelet per site investigator’s discretion 
based on subject clinical status. 
o Serum testosterone; late induction subjects.  If done at screening, no need to repeat 
o Alkaline phosphatase; late induction subjects.  If done at screening, no need to repeat 
o PSA; late induction subjects.  If done at screening, no need to repeat 
 Correlative Studies for late induction group:  
o Serum bone turnover markers collected pre-dose 
o Circulating tumor cell’s (CTCs) collected pre-dose 
o Banking Samples (pre-dose): whole blood, serum, plasma 
 Surveys: pain assessment with BPI (short form) and WHO ladder 
 
7.3 
Induction: Cycle 2 - Cycle 7 Day 1 (±7 days) 
 Physical examination.  Close monitoring for fractures should be done during all physical 
exams.  If a fracture is suspected radiological exams should be performed per clinical 
guidelines.  Subjects should be encouraged to contact the site investigator for any new 
onset pain or increase in pain in sites of known bone disease.  
 Vital signs including BP measurement, weight, ECOG performance status 
 Assessment of adverse events and concomitant medications.  
 Laboratory Testing:  
o CMP to include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, ALT, 
alkaline phosphatase, total bilirubin.  Including magnesium, phosphorus 
o CBC (WBC with differential and platelet count, hemoglobin and hematocrit) 
Additional monitoring of CBC w/diff and platelet per site investigator’s discretion 
based on subject clinical status 
o Serum testosterone 
o Alkaline phosphatase 
o PSA 
 Correlative Studies:  
o Serum bone turnover markers collected pre-dose 
 


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EARLY INDUCTION ONLY Cycle 2 Day 1 (In addition to the testing listed above) 
 Alkaline phosphatase 
 PSA 
 Correlative Studies:  
o Circulating tumor cell’s (CTCs): collected pre-dose 
o Banking Samples: whole blood, serum, plasma collected pre-dose 
 Surveys: pain assessment with BPI (short form) and WHO ladder. 
 
7.4 
Cycle 4 Day 1 (in addition to testing listed above) 
 Correlative Studies:  
o Circulating tumor cell’s (CTCs): collected 
 Surveys: pain assessment with BPI (short form) and WHO ladder. 
 
7.5 
Post Induction Cycle 8 Day 1 (± 7 days) 
 Physical examination.  Close monitoring for fractures should be done during all physical 
exams.  If a fracture is suspected radiological exams should be performed per clinical 
guidelines.  Subjects should be encouraged to contact the site investigator for any new 
onset pain or increase in pain in sites of known bone disease.  
 Vital signs including BP measurement, weight, ECOG performance status 
 Assessment of adverse events and concomitant medications.  
 Laboratory Testing:  
o CMP to include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, ALT, 
alkaline phosphatase, total bilirubin.  Including magnesium, phosphorus 
o CBC (WBC with differential and platelet count, hemoglobin and hematocrit) 
Additional monitoring of CBC w/diff and platelet per site investigator’s discretion 
based on subject clinical status 
o Testosterone 
o Alkaline phosphatase 
o PSA  
 Surveys: pain assessment with BPI (short form) and WHO ladder. 
 Imaging:  
o CT or MRI abdomen/pelvis 
o Bone Scan 
o Chest x-ray or Chest CT if clinically indicated 
 
7.6 
Post Induction Cycles 9-12 (± 7 days) 
NOTE: ADT may continue for up to 2 years from randomization 
 Laboratory tests D1 of each cycle:  
o PSA 
o Alkaline phosphatase 
 Assessment of adverse events and concomitant medications. This may be done via email, 
phone call or medical record review 
 


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7.7 
Maintenance: Cycle 13 Day 1; 12 months from ADT initiation (±7 days): 
 Clinical: Physical examination including BP measurement, weight, ECOG performance 
status, assessment of adverse events and concomitant medications. Close monitoring for 
fractures should be done during all physical exams.  If a fracture is suspected radiological 
exams should be performed per clinical guidelines.  Subjects should be encouraged to 
contact the site investigator for any new onset pain or increase in pain in sites of known 
bone disease.  
 Laboratory Testing:  
o CMP to include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, ALT, 
alkaline phosphatase, total bilirubin, magnesium, phosphorus 
o CBC (WBC with differential and platelet count, hemoglobin and hematocrit) 
o Serum testosterone 
o Alkaline phosphatase 
o PSA 
 Imaging:  
o CT or MRI abdomen/pelvis 
o DEXA scan 
o Bone Scan 
o Chest x-ray or Chest CT if clinically indicated 
 
7.8 
Maintenance Cycles 14-16 Day 1 (±14 days) 
NOTE: ADT may continue for up to 2 years from randomization.  Maintenance Cycles will = 84 
days/12 weeks. 
 Laboratory tests:  
o PSA 
o Alkaline phosphatase 
 Assessment of adverse events and concomitant medications. This may be done via email, 
phone call or medical record review 
 
7.9 
Maintenance Cycle 17 Day 28 
 Physical examination.  Close monitoring for fractures should be done during all physical 
exams.  If a fracture is suspected radiological exams should be performed per clinical 
guidelines.  Subjects should be encouraged to contact the site investigator for any new 
onset pain or increase in pain in sites of known bone disease.  
 Vital signs including BP measurement, weight, ECOG performance status 
 Assessment of adverse events and concomitant medications.  
 Laboratory Testing:  
o CMP to include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), serum creatinine, glucose, calcium, total protein, albumin, AST, ALT, 
alkaline phosphatase, total bilirubin.  Including magnesium, phosphorus 
o CBC (WBC with differential and platelet count, hemoglobin and hematocrit) 
Additional monitoring of CBC w/diff and platelet per site investigator’s discretion 
based on subject clinical status 
o Alkaline phosphatase 
o PSA  


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 Imaging:  
o CT or MRI abdomen/pelvis 
o Chest x-ray or Chest CT if clinically indicated 
 
7.10 
End of Treatment (EOT) and Follow Up 
The end of treatment/follow up column will be utilized for subjects that come off protocol 
therapy (radium-223 dichloride if randomized to that Arm and ADT) for toxicity or progression.  
If this occurs, subjects should have an end of treatment visit 30 days (± 7 days) after 
discontinuation of protocol therapy.  Subjects will then continue to be followed every 3 months 
for a total of 2 years from the date of randomization. Follow up may occur via phone call, email 
or other communication.  If available by medical record review, alk phos, PSA, AE/concomitant 
medication should be obtained.  Testing to be done at the EOT visit: 
 Circulating tumor cell’s (CTCs) 
 Serum bone turnover markers  
 Banking Samples: serum, plasma  
 Alkaline phosphatase 
 PSA 
 
If a subject withdraws consent, he is deemed “off study”. “Off study” subjects will not be 
followed further. 
 
A subject will be discontinued from the protocol specified therapy under the following 
circumstances: 
 If there is evidence of radiologic disease progression or symptomatic deterioration 
despite castration range serum testosterone level (< 50 ng/dL). Such subjects can go on to 
other treatment outside the study as clinically indicated including continuation or 
initiation of radium-223 dichloride therapy. They will remain on follow-up portion of the 
study for a total of 2 years from the date of randomization. 
 If there is development of castration-resistant prostate cancer by PSA criteria in 
conjunction with castration range serum testosterone level (< 50 ng/dL). Castration 
resistant prostate cancer is defined as two consecutive increases in PSA over the nadir 
PSA, at least two weeks apart AND an absolute increase of at least 2 ng/mL from the 
nadir PSA (or from baseline PSA if there was no drop in PSA after starting treatment). 
Discontinuation of bicalutamide may be attempted at the investigator’s discretion in such 
cases and would NOT constitute going “off treatment”. If no response to bicalutamide 
discontinuation, such subjects may receive other treatment outside the study as clinically 
indicated including continuation or initiation of radium-223 dichloride therapy. They will 
remain on follow-up portion of the study for a total of 2 years from the date of 
randomization. 
 If a subject requests to discontinue protocol specified therapy for any reason at any time.  
Subjects can stop protocol therapy at any time (off treatment). Such subjects may receive 
other treatment outside the study as clinically indicated including continuation or 
initiation of radium-223 dichloride therapy.  However, subjects will continue to be 
followed for survival status and for secondary malignancies as reported by subjects every 
3 months for a total of 2 years from the date of randomization unless they withdraw 
consent (if consent withdrawn, they will be deemed to be off study).  


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 If androgen deprivation therapy exhibits unacceptable toxicity. Such subjects may receive 
other treatment outside the study as clinically indicated including continuation or 
initiation of radium-223 dichloride therapy.  NOTE: Subjects off bicalutamide or 
radium-223 dichloride for toxicity but continuing on LHRH agonist/antagonist or have 
had surgical castration remain on protocol specified therapy.  
 If ALL protocol specified therapy is interrupted for > 28 days due to a treatment related 
adverse event. NOTE: A delay of up to 7 days in administering the scheduled dose of 
LHRH agonist or LHRH antagonist is allowed. A delay of up to 56 days in administering 
the scheduled dose of radium-223 dichloride is allowed if it is due to inadequate 
hematologic parameters or drug supply issues.  
 
All reasons for protocol therapy discontinuation must be clearly documented. 
 
8. 
CRITERIA FOR DISEASE EVALUATION AND ENDPOINT DEFINITIONS 
RECIST 1.1 criteria will apply to only soft tissue lesions. PCWG2 criteria will apply to bone 
lesions and PSA values.  
 
8.1 
Measurability of lesions 
 
8.1.1 Measurable disease 
All measurable lesions up to a maximum of 2 lesions per organ and up to 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline. 
Measurements must be provided for target measurable lesions, while presence or absence must 
be noted for non-target measurable and non-measurable disease. 
 
1. Lesions that can be accurately measured in at least one dimension (longest diameter to be 
recorded) as ≥ 2.0 cm by chest x-ray, by ≥ 1.0 cm with CT or MRI scans, or ≥ 1.0 cm 
with calipers by clinical exam. All tumor measurements must be recorded in decimal 
fractions of centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the assumption that CT slice 
thickness is 0.5 cm or less. If CT scans have slice thickness greater than 0.5 cm, the 
minimum size for a measurable lesion should be twice the slice thickness. 
 
2. Malignant lymph nodes are to be considered pathologically enlarged and measurable if 
they measure ≥ 1.5 cm in SHORT AXIS (greatest diameter perpendicular to the long 
axis of the lymph node) when assessed by scan (CT scan slice recommended being no 
greater than 0.5 cm). 
 
8.1.2 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 1.0 cm or 
pathologic lymph nodes with ≥ 1.0 cm to <1.5 cm short axis), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or 
MRI), are considered non-measurable, as are previously radiated lesions that have not 
progressed. 


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8.1.3 Notes on measurability 
1. For CT and MRIs, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans. Body scans should by 
performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT, then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT. 
 
2. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. 
3. Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition simple cysts. 
 
4. If a target lesion becomes very small, some radiologists indicate that it is too small to 
measure. If the lesion is actually still present, a default measurement of 0.5 cm should be 
applied. If the radiologist believes the lesion has gone, a default measurement of 0.0 cm 
should be recorded. 
 
8.2 
Progression Criteria 
 
8.2.1 PSA progression is defined by two consecutive increases in PSA over the nadir PSA, at 
least two weeks apart AND an absolute increase of at least 2 ng/mL from the nadir PSA 
(or from baseline PSA if there was no drop in PSA after starting treatment).  
 
8.2.2 Radiographic Skeletal progression on bone scan is defined as 2 or more new lesions 
on radionuclide bone scans (PCWG2 criteria). Should two or more new bone lesions be 
evident at the first imaging assessment (at end of protocol specified therapy), two or more 
additional new lesions must be evident on a confirmatory assessment at least 6 weeks 
later.  
 
 
A bone scan may be ordered at the discretion of the treating physician within the first 7 
months of protocol treatment for symptoms e.g. bone pain. If new bone lesions appear in 
the absence of a rising PSA within the first 7 months of protocol treatment, the site 
investigator at the institution must consult the sponsor-investigator (via the HCRN 
Project Manager) to discuss the possibility of tumor flare.   
 
 
For bone disease documented on bone scan only, increased uptake does not constitute 
unequivocal progression. However, increase in the soft tissue component of a lesion as 
measured by CT or MRI would constitute progression. 
 


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8.2.3  Radiographic Soft Tissue Progression per RECIST 1.1 Criteria (at least 1 of the 
following):  
Twenty percent increase in the sum of appropriate diameters of target measurable lesions over 
smallest sum observed (over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  
 
Unequivocal progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  
 
Appearance of any new lesion/site.  
Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to 
have progressed. 
 
Appearance of new pleural effusions does not constitute unequivocal progression unless 
cytologically proven of neoplastic origin, since some effusions are a toxicity related to therapy or 
other medical conditions. 
 
Increase in the size of an existing effusion does not constitute unequivocal progression, since the 
fluid status of the subject could alter the size of the effusion. 
 
8.2.4 Symptomatic Deterioration  
Global deterioration of health status requiring discontinuation of treatment without objective 
evidence of progression. Efforts should be made to obtain objective evidence of progression after 
discontinuation.  
 
8.3 
Performance Status  
Subjects will be graded according to the ECOG Performance Status Scale. Please see Study 
Procedures Manual (SPM). 
 
8.4 
Two Year PSA Progression-Free Survival 
From date of randomization to first occurrence of PSA progression, symptomatic deterioration, 
or death due to any cause. Subjects without progression are censored at last date of contact.  
 
8.5 PSA Response Categories  
 Undetectable PSA is defined as a PSA level of ≤ 0.2 ng/mL after seven cycles.  
 A PSA partial response (PSA PR) after seven cycles is defined as a PSA that is between 
0.2 and 4 ng/mL. 
 
8.6 
Time to Castration Resistance 
Castration resistant prostate cancer is defined as either PSA progression or radiographic 
progression. Time to Castration resistance will be counted from start of ADT (first LHRH 
agonist/antagonist/surgical castration) to development of castration resistance by either criterion:  
 PSA progression per 10.2.1. Castration resistance will be determined to have occurred at 
the time of the first PSA increase. 


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 Radiographic progression Castration resistance will be determined to have occurred at 
the time of the first imaging assessment showing progression not the confirmatory scan 
(for bone lesions). 
 
8.7 
Time to Radiographic Progression 
Radiographic progression is defined by imaging (also see notes on PET). For soft tissue lesions, 
the smallest measurements recorded since the treatment started will be used as reference. For 
bone scans, the prior scan with least tumor burden scan in bone will be used as reference. Time 
to radiographic progression will be counted from randomization to radiographic progression.  
 
8.8 
Radiographic Progression-Free Survival  
Time to Radiographic progression or death, whichever occurs first, will be calculated for each 
subject.  Subjects who do not have radiographic progression or death upon follow-up will be 
censored at their last radiographic assessment.   
 
8.9 
Symptomatic Skeletal Related Event (SSRE) 
Any of the following: Use of external beam radiotherapy (EBRT) to relieve skeletal related 
symptoms, new pathological vertebral and non-vertebral bone fractures, tumor related orthopedic 
surgical intervention, spinal cord compression. 
 
8.10 
Time to First SSRE 
From time of randomization to occurrence of first SSRE as defined in 10.10. 
 
8.11 
Alkaline Phosphatase End-Points 
The proportion of subjects with elevated (>ULN) serum total alkaline phosphatase (ALP) at 
baseline who normalize their alkaline phosphatase (≤ ULN) after 12 weeks of therapy, assess 
time to ALP progression (above ULN and ≥ 25% increase in ALP from baseline/nadir 
(whichever is lower)) will be determined. 
 
8.12 
Response Criteria for Soft Tissue Lesions; Evaluation of Target Lesions 
*Complete Response (CR): Disappearance of all target lesions. All pathological lymph nodes 
must have decreased to <10mm in short axis. 
 
 
*Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
 
 
*Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment started or the appearance of one or 
more new lesions 
 
*Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment started 
 
8.13 
Response Criteria for Soft Tissue Lesions; Evaluation of non-target lesions 
*Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level 


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*Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of 
tumor marker level above the normal limits 
 
*Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions* 
 
*Although a clear progression of “non target” lesions only is exceptional, in such circumstances, 
the opinion of the treating physician should prevail. 
 
8.14 
Evaluation of best soft tissue overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
Target Lesions 
Non-Target lesion 
New Lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective evidence 
of progression after discontinuation.  
 
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 (fine needle aspirate/biopsy) to confirm the complete response 
status. 
 
8.15 
Definitions for Soft Tissue Response Evaluation –RECIST version 1.1 
 
First Documentation of Response: 
The time between initiation of therapy and first documentation of PR or CR. 
 
Confirmation of Response: 
To be assigned a status of complete or partial response, changes in tumor measurements must be 
confirmed by repeat assessments performed no less than four weeks after the criteria for response 
are first met. 
 


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Duration of Response: 
Duration of overall response—the period measured from the time that measurement criteria are 
met for complete or partial response (whichever status is recorded first) until the date that 
recurrent or progressive disease is objectively documented, taking as reference the smallest 
measurements recorded since treatment started. 
 
Duration of Overall Complete Response: 
The period measured from the time that measurement criteria are met for complete response until 
the first date that recurrent disease is objectively documented. 
 
Objective soft tissue response rate:  
The objective response rate is the proportion of all subjects with confirmed PR or CR according 
to RECIST, from the start of treatment until disease progression/recurrence (taking as reference 
for progressive disease the smallest measurements recorded since the start of treatment). 
 
9. 
EXPLORATORY CORRELATIVES  
 
9.1 
Bone Turnover Markers 
Samples for bone turnover markers will be collected and stored until funding can be secured for 
the analyses described below. 
 
Background and Specific Hypothesis: 
Bone metabolism is distinguished by two activities - the formation of new bone by osteoblasts, 
and the resorption of old bone by osteoclasts. These processes are tightly coupled in space and 
time. Ultimately, bone mass is dependent upon the balance between formation and resorption. In 
prostate cancer, this homeostatic balance tips, such that osteoblastic activity predominates, 
resulting in sclerotic bone metastases. Bone metastasis is a very common event in subjects with 
prostate cancer and is a frequent source of morbidity, including bone pain or fracture. Many 
prostate cancer subjects with bone metastases have elevated circulating biochemical markers of 
bone metabolism, including markers for osteoblast and osteoclast activity. These serum-based 
biomarkers have been investigated as indicators of bone turnover for their potential as prognostic 
and/or predictive variables. Prior studies have suggested that elevated markers of bone turnover 
are strongly prognostic for poor survival in castration resistant prostate cancer subjects. 
However, their prognostic role in newly diagnosed (hormone-naïve) prostate cancer and their 
predictive value to help select those most likely to benefit from systemic therapy remain vexing 
clinical questions. 
 
SWOG S0421 was a large placebo-controlled Phase III study of docetaxel with or without the 
endothelin antagonist atrasentan in castration resistant prostate cancer (CRPC) subjects with 
skeletal metastases. Disappointingly, no overall survival benefit was observed for the 
docetaxel/atrasentan arm. However, as a translational science component of that randomized trial 
SWOG prospectively assessed pre-treatment and serial serum markers of bone turnover to 
validate their prognostic and predictive value in these castration-resistant subjects. The SWOG 
study measured markers of bone resorption (N-telopeptide, NTX & Pyridinoline, PYD) and bone 
formation (C-terminal collagen propeptide, CICP & bone alkaline phosphatase, BAP). Cox 
regression models were developed for overall survival based on baseline BMB (log-2 scale), 


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adjusted for potentially confounding clinical variables (including PSA, bisphosphonate use, age, 
race, performance status, Gleason score, and pain score, among others). The study also explored 
the effect of treatment on bone marker levels in week 9 (as compared to baseline) and sought to 
find an association between a change in marker levels and overall survival outcomes. A Cox 
model was fit with main effects and Bone Marker x Treatment interaction; adjusted for clinical 
variables, to assess the predictive value of atrasentan on overall survival. Of 1,038 subjects 
enrolled in SWOG S0421, 855 (91%) had baseline serum submitted, of which 778 samples 
(75%) were usable and subsequently analyzed. The bone turnover values (median; range) were 
as follows: NTX (14 nM; 9.3-23.9), BAP (64.7 u/L; 35-164), CICP (9.5 ng/mL; 6.5-17.4), & 
PYD (2.8 nmol/L; 2.2-3.9). 
 
Elevated markers of bone turnover (> median value) were prognostic for overall survival in 
SWOG 0421. Hazard ratios are reported for a 2-fold increase in markers. Follow-up analysis 
revealed that subjects with high marker levels (i.e., upper 25%-ile across all markers) not only 
have a very poor prognosis (HR = 4.3, p <0.001) but also appear to have a significant survival 
benefit from atrasentan (interaction-HR=0.33; p=0.002), even with highly conservative statistical 
analysis including Bonferroni adjustment. There were 6% (47) of the 778 subjects with a 
complete set of measurements on baseline markers. The HR in the high marker group was 
estimated at 0.34 (95% CI: 0.13, 0.89); this compares with a HR of 1.04 (95% CI: 0.86, 1.25) in 
the low marker group. 
 
There was also strong evidence for a significant association between the change in bone marker 
concentrations from baseline to Week 9 and overall survival for all bone markers. Presently, it is 
unclear whether these same observations will be observed in a somewhat different subject 
context: i.e., in the newly diagnosed, metastatic prostate cancer setting (non-castrate resistant). 
 
Radium-223 dichloride demonstrated similar declines in bone turnover markers in CRPC 
including BAP in a phase 2 clinical trial in prostate cancer and in the randomized phase 3 
trial11,12. The encouraging results from SWOG S0421 bone marker studies in CRPC and the 
proven effects of radium-223 dichloride on bone turnover lead us to pose several clinically 
relevant questions that can be prospectively explored in this study: 
 Are markers of bone metabolism of prognostic and predictive value only in the CRPC 
setting, or do they have value in newly diagnosed metastatic prostate cancer? 
 How will this radium-223 dichloride-induced bone phenotype behave in terms of 
response and survival when compared to a control group that is not receiving radium-223 
dichloride? 
 Can we use bone turnover biomarkers to explore who will benefit from radium-223 
dichloride inhibitor therapy? 
 
We therefore hypothesize that baseline levels of bone metabolism markers in sera collected 
from subjects with newly diagnosed metastatic prostate cancer will be of strong prognostic value 
and will also be predictive of benefit from radium-223 dichloride in combination with androgen 
deprivation therapy. A secondary hypothesis is that serial assessment of these same markers will 
demonstrate that lower marker levels at end of treatment visit will be associated with improved 
survival. To explore the effects of radium-223 dichloride on bone turnover in hormone naïve 
prostate cancer, serum markers of bone formation and bone resorption will be analyzed before, 


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during and after radium-223 dichloride treatment. Exploratory analyses will be performed to 
correlate the changes in bone turnover markers with clinical outcomes of interest. 
 
These will be tested through the following Specific Aims: 
 
 To measure levels of selected markers of bone formation and resorption in sera in 
subjects enrolled in this proposed randomized Phase II trial of ADT + radium-223 
dichloride versus ADT alone in subjects with newly diagnosed subjects with metastatic 
prostate cancer. 
 To correlate the results of these marker studies with PSA response, tumor response, 
progression-free survival (radiographic and PSA progression free survival), and overall 
survival to detect prognostic (baseline or pre-treatment sera) and/or predictive value 
(baseline biomarker x treatment interaction; serial sera). 
 To identify prognostic groups based on baseline bone markers and other clinical and 
disease-related factors. 
 
Serum biomarkers of bone turnover for bone resorption [N-telopeptide (NTX) expressed in 
nM Bone Collagen Equivalents, C-collagen fragments (CTX-I EIA) expressed in ng/mL] & 
formation [osteocalcin (OC) expressed in ng/mL & bone alkaline phosphatase (BAP) expressed 
in U/L] will be measured using commercially available assays from Quidel (OC, BAP), 
Immunodiagnostic Systems (IDS) (CTX-I) & Osteomark (NTX).  
 
Due to the limited sample size in this Phase II setting, correlative studies will be considered 
exploratory in nature and no adjustments will be made for the multiple marker comparisons 
being explored. We could then attempt to validate hypotheses generated from this study in a 
subsequent phase III study. 
 
Bone Turnover Marker Correlative Study Design: 
Serial serum specimens will be submitted for the proposed correlative studies at the following 
time points: 
 Pre-Dose on Day 1 of Cycle 1 (in the late induction group; for the early induction group, 
there will be no pre-treatment specimen) 
 Thereafter on Day 1 of each Cycle (Cycle 2-Cycle 7) of protocol specified therapy for the 
following biomarkers: N-telopeptide (NTX), C-collagen fragments (CTX-I EIA), 
osteocalcin (OC) & bone alkaline phosphatase (BAP). 
 At end of treatment visit. 
 
Refer to the CLM for collection, labeling, processing and shipping instruction for the serum 
samples. 
 
9.2 
CTCs (Circulating Tumor Cells) 
The EPICTM Sciences CTC platform will be used to detect and characterize the CTCs in this 
study. The platform utilizes no positive selection, allowing for enumeration and characterization 
of all CTCs including traditional CTCs (CK+, CD45- and morphologically distinct), epithelial 
mesenchymal transition (EMT) candidate CTCs (CK-, CD45-, and morphologically distinct) and 
small cell PCa (CK+, CD45-, morphologically similar to white blood cells). We seek to 


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enumerate CTCs and detect evidence of radiation induced DNA double strand repair foci 
on CTCs. 
 
H2AX (H2A histone family, member X- a marker of DNA repair) becomes phosphorylated on 
serine 139, then called gamma-H2AX, as a reaction to DNA Double-strand breaks (DSB). The 
kinases of the PI3-family (Ataxia telangiectasia mutated, ATR and DNA-PKcs) are responsible 
for this phosphorylation, especially ATM. The modification can happen accidentally during 
replication fork collapse or during controlled physiological processes such as V(D)J 
recombination but also of relevance to the current study, in the response to ionizing radiation. 
Gamma-H2AX is a sensitive target for looking at DSBs in cells. The role of the phosphorylated 
form of the histone in DNA repair is under discussion but it is known that because of the 
modification the DNA becomes less condensed, potentially allowing space for the recruitment of 
proteins necessary during repair of DSBs. Mutagenesis experiments have shown that the 
modification is necessary for the proper formation of ionizing radiation induced foci in response 
to double strand breaks. 
 
Sample Collection and Handling: 
Blood samples from will be obtained at 3 time points and shipped to Epic Sciences (San Diego, 
CA) at ambient temperature.: 
 C1D1 (late induction group only) 
 C2D1 (early induction group only) 
 C4D1 
 EOT visit  
 
Blood sample preparation and storage: 
Red blood cells will be lysed and nucleated blood cells are dispensed onto glass microscope 
slides according to methods previously described13-15 and placed at -80°C for long term storage 
at Epic Sciences.  Up to 12 slides are prepared for each blood sample, each containing 
approximately 3 million nucleated cells, while the number of slides created from each individual 
sample is determined by the volume of blood received and the white blood cell (WBC) count.  
CTC slides stored at -80C using this approach are stable over 1 year (unpublished data). 
 
CTC identification and protein characterization: 
CTC analysis will be performed in batches.  Two slides from each subject sample will be 
thawed, then subjected to an IF staining protocol to distinguish CTCs from WBCs as described 
previously13-15. In addition to DAPI, CD45, and cytokeratins, antibodies targeting gamma-H2AX 
will be utilized.  Stained slides were then imaged on Pyxis™, a high speed imaging platform that 
images all 3M cells on each slide in less than 15 minutes.  Captured images were analyzed by 
Atlas™ software that characterizes each cell by over 90 parameters including cell size, cell shape 
and marker intensities, then presents CTC candidates in an interactive report.  All candidates 
were then reviewed by trained technicians, and CK+/CD45- cells with intact, DAPI+ nuclei 
exhibiting tumor-associated morphologies are classified as CTCs.  Candidate CTCs as described 
are tracked and include CK-/CD45- cells with morphological distinction and/or AR positivity, 
CK+/CD45- small cells (morphologically similar or smaller to white blood cells), and apoptotic 
CTCs (identified by nuclear or cytoplasmic fragmentation). We will utilize our optimized 
immunofluorescence assay to detect phospho-ser139-H2AX otherwise known as gamma-H2AX.  


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Refer to the CLM for collection, labeling, processing and shipping instructions for the CTC 
samples. 
 
9.3 
Samples for future studies 
Subject consent will be obtained for additional samples collected for future studies. Hoosier 
Cancer Research Network will manage the banked samples. Samples will be banked indefinitely 
in the Hoosier Cancer Research Network biorepository.  
 
This includes: 
 Whole blood: Mandatory 
o Whole blood will be collected prior to treatment on Cycle 1 Day 1(late induction 
group) or Cycle 2 Day 1 (early induction group).  
 Pre- and Post-treatment plasma: Mandatory 
o Whole blood for plasma will be collected prior to treatment on Cycle 1 Day 1 
(late induction group) or Cycle 2 Day 1 (early induction group) and at End of 
Treatment (both groups).  
 Pre- and Post-treatment serum: Mandatory 
o Whole blood for serum will be collected prior to treatment on Cycle 1 Day 1(late 
induction group) or Cycle 2 Day 1 (early induction group) and at End of 
Treatment (both groups). 
 
Please refer to the CLM for all sample collection, processing, labeling and shipping instructions. 
 
9.4 
Assessment of Pain Level and Analgesic Use  
A key finding in the randomized phase III ALSYMPCA trial was the reduction in pain with 
radium-223 dichloride therapy. In the present study, subject-reported pain will be collected using 
standard paper surveys during clinic visits. Pain will be assessed by means of the Brief Pain 
Inventory Short Form (BPI-SF) questionnaire at baseline, on Cycle 4 Day 1 visit before dose and 
at the end of treatment visit. The worst pain recorded at each time point will be used as a numeric 
score for quantitative comparison across time points and between treatment arms. Analgesic use 
scores will be assigned by the treating physician according to the World Health Organization 
(WHO) scale at baseline, on Cycle 4 Day 1 visit before dose and at the end of treatment visit.  
 
9.5 
BPI-SF  
The severity of subject-reported pain and its impact on daily functions will be self-assessed by 
the study subjects using the Brief Pain Inventory-Short Form (BPI-SF) measure.16. BPI-SF will 
be self-administered by the subject at Cycle 1 Day 1 of (Late Induction group) or Cycle 2 Day 1 
(Early Induction group), Cycle 4 Day 1 and at end of treatment. 
 
BPI-SF allows subjects to rate the severity of their pain and the degree to which their pain 
interferes with common dimensions of feeling and function (e.g., general activity, walking, work, 
mood, enjoyment of life, relations with others, and sleep). BPI-SF is a 15-item, self-
administered, clinically validated, reliable and responsive measure developed to assess pain 
related to cancer. The instrument is available in validated multilingual versions; on average, it 
requires less than 10 minutes to complete the questionnaire.  
 


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In this study, BPI-SF will be scored by worst pain recorded at each time point. Scores range from 
0-10 and a higher score indicates a higher level of pain. The BPI-SF should be self-administered 
by the subject alone during his scheduled visit at the site. The instrument should be administered 
at the start of the visit, before the subject sees the physician so that any interaction between the 
subject and physician will not influence the subject’s responses to the questionnaire. The 
questionnaire should also be administered before the subject is asked about adverse experiences 
and concurrent illnesses, again so that any discussions of health problems do not influence the 
subject’s responses. A quiet place should be provided for the subject to complete the BPI-SF. It 
is important that the subject completes the BPI-SF alone, without any advice from family 
members or friends who may accompany them. 
 
How should the Questionnaire be introduced?  A sample script for introducing the questionnaire 
is given below. 
“Your doctor would like to better understand how you feel, how well you are able to do your 
usual activities, and how you rate your health. To help us better understand these things about 
you, please complete this questionnaire about your health. The questionnaire is easy to fill out. 
The instructions are on the front cover (point to them). You should read each question and then 
circle the appropriate number that matches your answer. Remember that this is not a test and 
there are no right or wrong answers. Choose the answer that best describes the way you feel. I 
will quickly review the questionnaire when you are done to make sure that all the questions have 
been answered. You should answer these questions by yourself. Your spouse or other family 
members should not help you when you answer the questionnaire. I will be nearby in case you 
want to ask me any questions. Please return, the questionnaire to me when you have finished”. 
 
What to do if the subject asks for clarification? 
Some subjects may ask the meaning of specific questions. If this happens, the staff member can 
assist the subject by re-reading the question for them verbatim. If the subject asks what 
something means, do not try to explain what the question means, but tactfully suggest that the 
subject use his own interpretation of the question. All subjects should answer the questions based 
on what they think the questions mean, or the study results may be biased. 
 
Questionnaire completion: 
When the subject returns the questionnaire, check that all of the questions have been answered. If 
the questionnaire is not complete, point out to the subject that some of the questions were not 
answered. If the subject does not quickly volunteer to answer these items, ask him whether he 
had any difficulty completing the questionnaire. If the subject says that he had trouble 
understanding a question, ask him why he had difficulty with that item. Re-read the question for 
him verbatim, but do not attempt to explain or reword the question, as explained before. If the 
subject is still unable to answer the question, accept the questionnaire as is. 
 
Some subjects may be confused by the response choices. They may want to respond with “I 
don’t know” or some other response choice that is not available. If this happens, try to help the 
subject choose one of the response categories by saying something like: “I know that it may be 
difficult for you to choose an answer, but which of these answers do you think comes closest to 
the way that you are thinking or feeling?” If the subject still cannot select an answer, accept the 
questionnaire as is. Occasionally, subjects may not report having difficulty with a question or the 


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response choices, but still may hesitate or refuse to answer an item or items. If this happens, 
accept the questionnaire as is. If a subject asks for interpretation of his responses or asks for his 
scores on the questionnaire, tell him that you are not trained to score or interpret the 
questionnaire. Emphasize that their answers will be kept confidential. 
 
Completed questionnaire: Thank the subject once he has completed the questionnaires and you 
have checked them for completeness. 
 
B. WHO Ladder scale: 
 
 
 
WHO Score 
Description 
Opioid Use 
0 
No pain 
 
1 
Mild pain 
using non-opioid +/- adjuvant daily on average 
2 
Moderate pain 
using weak opioid +/- non-opioid +/- adjuvant 
daily on average.  
Weak opioids include codeine phosphate, 
dextropropoxyphene, dihydrocodeine or tramadol. 
3 
Severe pain 
Strong opioid +/- non-opioid +/- adjuvant daily on 
average.  
Strong opioids include morphine, oxycodone, 
fentanyl, buprenorphine, oxymorphone, 
hydromorphone. 
 
The WHO ladder score will be assigned by the treating physician based on the subject’s daily 
analgesic use on average. Score will be assigned pre-treatment on Cycle 1 Day 1 of (Late 
Induction group) or Cycle 2 Day 1 (Early Induction group), Cycle 4 Day 1 and at end of study 
visit. At each time-point, a single numeric score (0, 1, 2 or 3) will be assigned based on the scale 
as above. 
 


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10 
DRUG INFORMATION 
For this study, bicalutamide, degarelix, goserelin acetate and leuprolide acetate are commercially 
available; therefore, Prescribing Information will be used. Radium-223 dichloride will be 
supplied for this study by Bayer Pharmaceuticals but the product insert for radium-223 
dichloride is freely available as radium-223 dichloride is regulatory approved in castration 
resistant prostate cancer. Information about commercial drugs is publicly available in the 
Physician’s Desk Reference (PDR), prescribing information and other resources. 
 
10.1 
Radium-223 dichloride (XofigoTM) 
 
Pharmacology 
Mechanism of Action: The active moiety of Radium-223 dichloride is the alpha particle-emitting 
isotope radium-223 (as radium -223 dichloride), which mimics calcium and forms complexes 
with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone 
metastases. The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high 
frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on 
bone metastases. The alpha particle range from radium-223 dichloride is less than 100 
micrometers (less than 10 cell diameters) which limits damage to the surrounding normal tissue. 
 
Pharmacokinetics 
The pharmacokinetics of radium-223 dichloride in blood was linear in terms of dose 
proportionality and time independence in the dose range investigated (51 to 276 kBq [1.4 to 7.5 
microcurie]. 
 
Distribution: After intravenous injection, radium-223 is rapidly cleared from the blood and is 
distributed primarily into bone or is excreted into intestine. Fifteen minutes post-injection, about 
20% of the injected radioactivity remained in blood. At 4 hours, about 4% of the injected 
radioactivity remained in blood, decreasing to less than 1% at 24 hours after the injection. At 10 
minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-
injection, the percentage of the radioactive dose present in bone and intestine was approximately 
61% and 49%, respectively. No significant uptake was seen in other organs such as heart, liver, 
kidneys, urinary bladder, and spleen at 4 hours post-injection. 
 
Metabolism: Radium-223 is a radioactive isotope that decays and is not metabolized. Radium-
223 has a physical half-life of 11.4 days.  
 
Elimination: Excretion in urine is minimal and there is no evidence of hepato-biliary excretion. 
The major route of elimination is feces. 
 
Adverse Events 
In the placebo-controlled phase 3 randomized clinical trial ALSYMPCA12 in subjects with 
metastatic castration-resistant prostate cancer with bone metastases, 600 subjects  received 
intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of Radium-223 dichloride and best 
standard of care and 301 subjects received placebo and best standard of care once every 4 weeks 
for up to 6 injections. Prior to randomization, 58% and 57% of subjects had received docetaxel in 
the Radium-223 dichloride and placebo arms, respectively. The median duration of treatment 
was 20 weeks (6 cycles) for Radium-223 dichloride and 18 weeks (5 cycles) for placebo. The 


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most common adverse reactions (≥ 10%) in subjects receiving radium-223 dichloride were 
nausea, diarrhea, vomiting, and peripheral edema. Grade 3 and 4 adverse events were reported 
among 57% of Radium-223 dichloride-treated subjects and 63% of placebo-treated subjects. 
 
The most common hematologic laboratory abnormalities in Radium-223 dichloride-treated 
subjects (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and 
neutropenia. Treatment discontinuations due to adverse events occurred in 17% of subjects who 
received Radium-223 dichloride and 21% of subjects who received placebo. The most common 
hematologic laboratory abnormalities leading to discontinuation for Radium-223 dichloride were 
anemia (2%) and thrombocytopenia (2%). 
 
Adverse Events with Possible Relationship to Radium-223 dichloride 
Likely (>20%)   
Less Likely (≤20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Neutropenia 
 
Lymphocytopenia 
Pancytopenia 
 
Leukopenia 
 
 
Thrombocytopenia 
 
 
GASTROINTESTINAL DISORDERS 
Nausea 
 
 
Diarrhea 
 
 
Vomiting 
 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Peripheral edema 
 
RENAL AND URINARY DISORDERS 
 
Renal failure and 
impairment 
 
 
Dosimetry 
The absorbed radiation doses in major organs were calculated based on clinical biodistribution 
data in five subjects with castration resistant prostate cancer. Calculations of absorbed radiation 
doses were performed using OLINDA/EXM (Organ Level INternal Dose 
Assessment/EXponential Modeling), a software program based on the Medical Internal 
Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma 
emitting radionuclides. For radium-223, which is primarily an alpha particle-emitter, 
assumptions were made for intestine, red marrow and bone/osteogenic cells to provide the best 
possible absorbed radiation dose calculations for Radium-223 dichloride, considering its 
observed biodistribution and specific characteristics. 
 
Special Populations 
Pregnancy and Lactation: Radium-223 dichloride is categorized as Category X. Radium-223 
dichloride can cause fetal harm when administered to a pregnant woman based on its mechanism 
of action. While there are no human or animal data on the use of Radium-223 dichloride in 
pregnancy and Radium-223 dichloride is not indicated for use in women, maternal use of a 
radioactive therapeutic agent could affect development of a fetus. Radium-223 dichloride is 
contraindicated in women who are or may become pregnant while receiving the drug. If this drug 


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is used during pregnancy, or if the subject becomes pregnant while taking this drug, apprise the 
subject of the potential hazard to the fetus and the potential risk for pregnancy loss.  
 
Geriatric Use: Of the 600 subjects treated with Radium-223 dichloride in the randomized trial, 
75% were 65 years of age and over and while 33% were 75 years of age and over. No dosage 
adjustment is considered necessary in elderly subjects.  No overall differences in safety or 
effectiveness were observed between these subjects and younger subjects, and other reported 
clinical experience has not identified differences in responses between the elderly and younger 
subjects, but greater sensitivity of some older individuals cannot be ruled out. 
 
Subjects with Hepatic Impairment: No dedicated hepatic impairment trial for Radium-223 
dichloride has been conducted. Since radium-223 is neither metabolized by the liver nor 
eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-
223 chloride. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not 
needed in subjects with mild hepatic impairment. No dose adjustments can be recommended for 
subjects with moderate or severe hepatic impairment due to lack of clinical data. 
 
Subjects with Renal Impairment: No dedicated renal impairment trial for Radium-223 dichloride 
has been conducted. Based on subgroup analyses in the randomized clinical trial, dose 
adjustment is not needed in subjects with existing mild (creatinine clearance [CrCl] 60 to 89 
mL/min) or moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be 
recommended for subjects with severe renal impairment (CrCl less than 30 mL/min) due to 
limited data available (n = 2). 
 
Males of Reproductive Potential: Because of potential effects on spermatogenesis associated 
with radiation, men who are sexually active are advised to use condoms and their female partners 
of reproductive potential to use a highly effective contraceptive method during and for 6 months 
after completing treatment with Radium-223 dichloride. 
Drug Interactions: No formal clinical drug interaction studies have been performed. Subgroup 
analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did 
not affect the safety and efficacy of Radium-223 dichloride in the randomized clinical trial. 
 
Dosing and Administration 
 The volume to be administered to a given subject should be calculated using the: 
 Subject’s most recent (within 4 weeks) body weight (kg) 
 Current Dosage level 55 kBq/kg body weight (or 1.5 microcurie/kg body weight) 
 Radioactivity concentration of the product (1,100kBq/ml; 30 microcurie/ml at the 
reference date) 
 Decay correction factor to correct for physical decay of radium-223 (see table below) 
 


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Decay Correction Factor Table 
 
Days from Reference 
Date 
Decay Factor 
Days from 
Reference Date 
Decay Factor 
-14 
2.296 
0 
0.982 
-13 
2.161 
1 
0.925 
-12 
2.034 
2 
0.870 
-11 
1.914 
3 
0.819 
-10 
1.802 
4 
0.771 
-9 
1.696 
5 
0.725 
-8 
1.596 
6 
0.683 
-7 
1.502 
7 
0.643 
-6 
1.414 
8 
0.605 
-5 
1.330 
9 
0.569 
-4 
1.252 
10 
0.536 
-3 
1.178 
11 
0.504 
-2 
1.109 
12 
0.475 
-1 
1.044 
13 
0.447 
 
 
14 
0.420 
 
The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To 
determine the decay correction factor, count the number before (-1 to -14) or after (1 to 14) the 
reference date. The Decay Correction Factor Table includes a correction to account for the 7 
hour time difference between 12 noon European Time (CET) at the site of manufacture and 12 
noon US CST, which is 7 hours earlier than CET. 
 
The current total volume to be administered to a subject is calculated as follows: 
 
 
Body weight in kg × 55 kBq/kg body weight (1.5 microcurie/kg body weight) 
Volume to be administered (mL) =      -------------------------------------------------------- 
 
 
 
 
 
Decay factor × 1,100 kBq/mL (30 microcurie/ml) 
 
Instructions for Use / Handling 
General warning: Radium-223 dichloride (an alpha particle-emitting pharmaceutical) should be 
received, used and administered only by authorized persons in designated clinical settings. The 
receipt, storage, use, transfer and disposal of Radium-223 dichloride are subject to the 
regulations and/or appropriate licenses of the competent official organization.  
 
Radium-223 dichloride should be handled by the user in a manner which satisfies both radiation 
safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. 
Radiation protection: The administration of Radium-223 dichloride is associated with potential 
risks to other persons (e.g., medical staff, caregivers and subject’s household members) from 
radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, 
radiation protection precautions must be taken in accordance with national and local regulations. 
After administration, the equipment used in connection with the preparation and administration 


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of drug is to be treated as radioactive waste and should be disposed in accordance with local 
procedure for the handling of radioactive material. 
 
For drug handling: Follow the normal institutional procedures for the handling of 
radiopharmaceuticals and use universal precautions for handling and administration such as 
gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case 
of contact with skin or eyes, the affected area should be flushed immediately and profusely with 
water. In the event of spillage of Radium-223 dichloride, the local radiation safety officer should 
be contacted immediately to initiate the necessary measurements and required procedures to 
decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetra acetic acid 
(EDTA) solution is recommended to remove contamination. 
 
For subject care: Whenever possible, subjects should use a toilet and the toilet should be flushed 
several times after each use. When handling bodily fluids, simply wearing gloves and hand 
washing will protect caregivers. Clothing soiled with Radium-223 dichloride or subject fecal 
matter or urine should be washed promptly and separately from other clothing.  
 
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-
particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-
radiation is 1.1%. The external radiation exposure associated with handling of subject doses is 
expected to be low, because the typical treatment activity will be below 8,000 kBq (216 
microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for 
minimization of radiation exposure, it is recommended to minimize the time spent in radiation 
areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused 
product or materials used in connection with the preparation or administration are to be treated as 
radioactive waste and should be disposed of in accordance with local regulations. 
 
The gamma radiation associated with the decay of radium-223 and its daughter molecules allows 
for the radioactivity measurement of Radium-223 dichloride and the detection of contamination 
with standard instruments. 
 
Dose handling: The Radium Ra 223 dichloride vials must be stored inside their lead container in 
a secure facility. The study drug should be used within 28 days of production. Radium Ra 223 
dichloride is an alpha-pharmaceutical and should be handled by individuals who are qualified by 
training and experience in the safe handling of radionuclides. One dedicated person and a back-
up designee will have responsibility as assigned from the site investigator for handling and 
storage of Radium Ra 223 dichloride. All administrations of Radium Ra 223 dichloride are based 
on the certified activity of Radium Ra 223 dichloride at the calibration date. 
 
1. Instructions for preparation: Parenteral drug products should be inspected visually for 
particulate matter and discoloration prior to administration, whenever solution and container 
permit. Radium-223 dichloride is a ready-to-use solution and should not be diluted or mixed 
with any solutions. Each vial is for single use only. 
 


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2. Administration: Radium-223 dichloride is administered by slow intravenous injection over 1 
minute. The intravenous access line or cannula should be flushed with isotonic saline before 
and after injection of radium-223 dichloride. 
 
3. Updated SRM: upon notification by Bayer each center is required to update the dial settings 
to correspond to the new NIST standard). The current dial settings are to remain in effect 
until Bayer obtains FULL approval from the FDA for implementation.  In preparation for 
implementation of the NEW dial setting, the clinical study center will receive a sealed vial 
labeled NIST standard containing a Radium Ra 223 dichloride solution for calibration only. 
The vial is identical to the vials used for study treatment. The amount of Radium Ra 223 
dichloride in the vial will be stated on the label. Instructions for the dial setting, including the 
calibration log form, will be enclosed with the dispatch of the calibration sample. 
All sites will be notified by Bayer when FINAL regulatory approval from the FDA is in place 
and the updated NIST standardization is to be implemented. 
 
Storage and Stability 
Storage: Store at room temperature, below 40° C (104° F). Store Radium-223 dichloride in the 
original container or equivalent radiation shielding. This preparation is approved for use by 
persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority 
of an Agreement State. Follow procedures for proper handling and disposal of radioactive 
pharmaceuticals 
 
The volume per vial is 6 mL, corresponding to 6.6 MBq at the reference day. Radium Ra 223 
dichloride has a shelf life of 28 days from production day, when stored at ambient temperature. 
The shelf life has been demonstrated for temperatures from cold storage (2-8°C) up to 40°C. In 
addition, it has been shown that the product quality is not jeopardized upon freezing. 
 
How Supplied 
The alpha-pharmaceutical Radium Ra 223 dichloride is a ready-to-use, sterile, non-pyrogenic, 
clear and colorless aqueous solution of Radium Ra 223 dichloride (223RaCl2) for IV 
administration. It should not be diluted or mixed with any solutions. Each vial for a single use 
only. 
 
Radium Ra 223 dichloride is an alpha particle emitter with a physical half-life of 11.4 days. The 
product is isotonic and has a pH of 6.0-8.0.  The radioactive concentration at the reference date is 
1,100 kBq/mL.The product has a pre-calibration of 14 days.  When administered on a day other 
than the reference day, the volume should be corrected according to the physical decay table. 
 
Bayer Healthcare LLC will provide Radium Ra 223 dichloride, which will be manufactured by 
Algeta’s contract manufacturer: Institute for Energy Technology, Isotope laboratories, Kjeller, 
Norway. The product is produced according to Good Manufacturing Practice (GMP). The 
product will be delivered in a glass vial, ready-to-use with a certified activity. Radium Ra 223 
dichloride is shipped in a lead container and Type A radioactive package according to 
international transportation guidelines for radioactive materials.  
 


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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.  
 
10.2 
Bicalutamide (Casodex®) (NSC-722665)  
 
Description 
Bicalutamide is a racemic mixture containing two enantiomers, (2RS)-4'-Cyano-3(4-
fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-trifluoromethyl) propionanilide.  
 
Bicalutamide is an active non-steroidal antiandrogen and its antiandrogen activity resides 
exclusively in the (-) or (R) enantiomer. Unlike flutamide, it is peripherally selective and does 
not cause a rise in serum LH or Testosterone in male rats and dogs. This peripheral selectivity 
may be because it penetrates poorly the CNS and Hypothalamus (the site of negative feedback of 
androgens). In humans, rises in LH, Testosterone and Estradiol concentrations were seen. These 
rises were not dose related. In 90%, testosterone levels remained within normal limits. There was 
no significant rise in mean serum FSH. 
 
Toxicology 
In rats, besides antiandrogenic changes, there was evidence of hepatocyte hypertrophy and 
basophilia. In dogs treated for 6 months, there was increased heart rate with decreased PR 
interval, transient decrease in circulating PMNs and increased plasma cholesterol. No cardiac 
pathology was found. In a mouse oncogenicity study, an increased incidence of hepatocellular 
carcinoma was observed in the top dose male group (75 mg/kg/day). The no effect dose level for 
hepatocellular carcinoma in this study was 15 mg/kg/day with steady state blood levels in excess 
of 10 μg/ml. The mechanism for this tumor formation is a non-genotoxic, phenobarbitone-type 
MFO induction and is not considered to represent a risk for humans. A two-year study in rats and 
female mice at similar doses did not show an increased incidence of hepatic tumors.  
 
Bicalutamide has been given to over 3,500 men in 35 different clinical studies worldwide, in 
doses up to 600 mg daily. When bicalutamide is given in combination with an LHRH analogue, 
the pharmacologic adverse event profile is dominated by the LHRH analogue and includes hot 
flashes (53%), gynecomastia (9%) and breast pain (6%). Other adverse events reported 
regardless of causality included diarrhea (12%), constipation (22%), nausea (15%) and 
abdominal pain (11%). Other adverse events were reported, such as fatigue (22%), pain (35%), 
back pain (25%), pelvic pain (21%), infection (18%), peripheral edema (13%), dyspnea (13%), 
nocturia (12%), hematuria (12%), anemia (11%), and dizziness (10%). Bicalutamide has been 
associated with changes in liver function, although these are infrequent (7%) and rarely occur 
with jaundice. Many of these changes improved or resolved despite continuation of bicalutamide 
therapy. There have been no reports of fatal hepatotoxicity associated with bicalutamide therapy. 
 
Pharmacology 
Pharmacokinetics: Animal studies: After oral single dose administration, absorption of the 
compound was slow with peak concentration occurring 3 - 12 hours and plateau between 2 and 
48 hours. There was non-proportional increase in plasma levels with increasing doses. 


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Elimination half-life ranges from 17 - 28 hours in male rats, 21 - 29 hours in female rats and 5 - 
7.5 days in dogs. 91 - 96% of bicalutamide is bound to plasma protein. 
 
Human studies: After single doses, mean time for peak plasma concentration was 6 hours at 10 
and 30 mg, but at 50 mg, it was 16 hours. Mean plasma elimination half -lives after 12 weeks of 
10, 30, 50, 100 mg/day was 7 - 10 days. This finding was consistent with single dose data. In 
subjects given daily doses of 50 mg, mean plasma concentration was 10 ug/ml at 12 weeks. After 
single doses, there was linear increase with doses between 10 and 50 mg, but became non-linear 
at doses of 50 - 100 mg. At 100 mg, the oral bioavailability is reduced by 30% but plasma 
elimination half -life is unchanged. Bicalutamide is extensively metabolized and metabolites are 
excreted by both the biliary and urinary system. 
 
Formulation: Bicalutamide is prepared as round, film-coated green or white tablets containing 
standard recipients and 50 mg of the drug. 
 
Storage and stability: All packages of bicalutamide should be stored securely in a dry place at 
room temperature. 
 
Route of Administration: Bicalutamide is to be administered in tablet form as a once-daily oral 
dose. Subjects should be instructed to take one tablet once daily. 
 
Supplier: Bicalutamide is commercially available and should therefore be purchased by a third 
party. This drug will not be supplied by the study. Please refer to the Physician Desk Reference 
and package insert for complete information. 
 
Common side effects include: 
 hot flashes, or short periods of feeling warm and sweating whole body pain in your back, 
pelvis, stomach  
 feeling weak 
  constipation  
 Infection 
 nausea  
 swelling in your ankles, legs or feet  
 diarrhea  
 blood in your urine  
 waking from sleep to urinate at night  
 a decrease in red blood cells (anemia)  
 feeling dizzy 
 
Refer to the package insert or manufacturer website for the most complete and up to date 
information on contraindications, warnings and precautions, and adverse reactions. 
 


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10.3 
Degarelix (Firmagon ®) 
 
Description 
DEGARELIX is a sterile lyophilized powder for injection containing degarelix (as the acetate) 
and mannitol. Degarelix is a synthetic linear decapeptide amide containing seven unnatural 
amino acids, five of which are D-amino acids. The acetate salt of degarelix is a white to off-
white amorphous powder of low density as obtained after lyophilization. 
 
The chemical name of degarelix is D-Alaninamide, N-acetyl-3-(2-naphthalenyl)-D-alanyl-4-
chloro-Dphenylalanyl-3-(3-pyridinyl)-D-alanyl-L-seryl-4-[[[(4S)-hexahydro-2,6-dioxo-
4pyrimidinyl]carbonyl]amino]-L phenylalanyl-4-[(aminocarbonyl)amino]-D-phenylalanyl-L 
leucyl-N6–(1-methylethyl)-L-lysyl-L-prolyl. It has an empirical formula of C82H103N18O16Cl and 
a molecular weight of 1632.3 Da. 
 
DEGARELIX delivers degarelix acetate, equivalent to 120 mg of degarelix for the starting dose, 
and 80 mg of degarelix for the maintenance dose. The 80 mg vial contains 200 mg mannitol and 
the 120 mg vial contains 150 mg mannitol.  DEGARELIX is for subcutaneous administration 
only. 
 
Dosing and Administration  
DEGARELIX is administered as a subcutaneous injection in the abdominal region. As with other 
drugs administered by subcutaneous injection, the injection site should vary periodically. 
Injections should be given in areas of the abdomen that will not be exposed to pressure, e.g., not 
close to waistband or belt nor close to the ribs. 
 
DEGARELIX is supplied as a powder to be reconstituted with Sterile Water for Injection, USP 
(WFI). Reconstituted drug must be administered within one hour after addition of Sterile Water 
for Injection, USP. Do not shake the vials. The instruction for reconstitution needs to be carefully 
followed. Administration of other concentrations is not recommended. See package insert for full 
reconstitution and administration instructions. 
 
How Supplied 
Starting dose: One starting dose comprises 240 mg given as two 3 mL injections of 120 mg each. 
 
Powder for injection 120 mg: 
One vial of DEGARELIX 120 mg contains 120 mg degarelix. Each vial is to be reconstituted 
with a prefilled syringe containing 3 mL of Sterile Water for Injection. 3 mL is withdrawn to 
deliver 120 mg degarelix at a concentration of 40 mg/mL. 
 
Maintenance dose: One maintenance dose comprises 80 mg given as one 4 mL injection. 
 
Powder for injection 80 mg: 
One vial of DEGARELIX 80 mg contains 80 mg degarelix. Each vial is to be reconstituted with 
a prefilled syringe containing 4.2 mL of Sterile Water for Injection. 4 mL is withdrawn to deliver 
80 mg degarelix at a concentration of 20 mg/mL. 
 


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Storage and Stability 
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). 
 
Caution should be exercised in handling and preparing the solution of DEGARELIX. Several 
guidelines on proper handling and disposal of anticancer drugs have been published. To 
minimize the risk of dermal exposure, always wear impervious gloves when handling 
DEGARELIX. If DEGARELIX solution contacts the skin, immediately wash the skin 
thoroughly with soap and water. If DEGARELIX contacts mucous membranes, the membranes 
should be flushed immediately and thoroughly with water  
 
Clinical Pharmacology 
Degarelix is a GnRH receptor antagonist. It binds reversibly to the pituitary GnRH receptors, 
thereby reducing the release of gonadotropins and consequently testosterone. 
A single dose of 240 mg DEGARELIX causes a decrease in the plasma concentrations of 
luteinizing hormone (LH) and follicle stimulating hormone (FSH), and subsequently 
testosterone. 
 
DEGARELIX is effective in achieving and maintaining testosterone suppression below the 
castration level of 50 ng/dL. 
 
Pharmacokinetics: DEGARELIX forms a depot upon subcutaneous administration, from which 
degarelix is released to the circulation. Following administration of DEGARELIX 240 mg at a 
product concentration of 40 mg/mL, the mean Cmax was 26.2 ng/mL (coefficient of variation, 
CV 83%) and the mean AUC was 1054 ng•day/mL (CV 35%). Typically, Cmax occurred within 
2 days after subcutaneous administration. In prostate cancer subjects at a product concentration 
of 40 mg/mL, the pharmacokinetics of degarelix were linear over a dose range of 120 to 240 mg. 
The pharmacokinetic behavior of the drug is strongly influenced by its concentration in the 
injection solution. 
 
The distribution volume of degarelix after intravenous (> 1 L/kg) or subcutaneous administration 
(> 1000L) indicates that degarelix is distributed throughout total body water. In vitro plasma 
protein binding of degarelix is estimated to be approximately 90%. 
 
Degarelix is subject to peptide hydrolysis during the passage of the hepato-biliary system and is 
mainly excreted as peptide fragments in the feces. No quantitatively significant metabolites were 
detected in plasma samples after subcutaneous administration. In vitro studies have shown that 
degarelix is not a substrate, inducer or inhibitor of the CYP450 or p-glycoprotein transporter 
systems. 
 
Excretion: Following subcutaneous administration of 240 mg DEGARELIX at a concentration of 
40 mg/mL to prostate cancer subjects, degarelix is eliminated in a biphasic fashion, with a 
median terminal half-life of approximately 53 days. The long half-life after subcutaneous 
administration is a consequence of a very slow release of degarelix from the DEGARELIX depot 
formed at the injection site(s). Approximately 20-30% of a given dose of degarelix was renally 
excreted, suggesting that approximately 70-80% is excreted via the hepato-biliary system in 


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humans. Following subcutaneous administration of degarelix to prostate cancer subjects, the 
clearance is approximately 9 L/hr. 
 
There was no effect of age, weight or race on the degarelix pharmacokinetic parameters or 
testosterone concentration. 
 
Common side effects include:  
 hot flashes  
 injection site pain, redness, and swelling, especially with the first dose  
 weight gain  
 increase in some liver enzymes  
 tiredness  
 hypertension  
 back and joint pain  
 chills  
 urinary tract infection  
 decreased sex drive and trouble with erectile function (impotence)  
 
Refer to the package insert or manufacturer website for the most complete and up to date 
information on contraindications, warnings and precautions, and adverse reactions. 
 
10.4 
Goserelin acetate implant (Zoladex®) (NSC-606864) 
 
Pharmacology 
Mechanism of Action: Following initial administration in males, goserelin causes an initial 
increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with 
subsequent increases in serum levels of testosterone. Chronic administration of goserelin leads to 
sustained suppression of pituitary gonadotropins, and serum levels of testosterone consequently 
fall into the range normally seen in surgically castrated men approximately 2-4 weeks after 
initiation of therapy. 
 
In females, a similar down-regulation of the pituitary gland by chronic exposure to goserelin 
leads to suppression of gonadotropin secretion, a decrease in serum estradiol levels consistent 
with the postmenopausal state, and would be expected to lead to a reduction in ovarian size and 
function, reduction in the size of the uterus and mammary gland, as well as a regression of sex 
hormone responsive tumors, if present. Serum estradiol is suppressed to levels similar to those 
observed in postmenopausal women within 3 weeks following initial administration; however, 
after suppression was attained, isolated elevations of estradiol were seen in 10% of the subjects 
enrolled in clinical trials. Serum LH and FSH are suppressed to follicular phase levels within 
four weeks after initial administration of drug and are usually maintained at that range with 
continued use of goserelin. 
 
Pharmacokinetics 
1. Absorption: Goserelin 3.6 mg is released slowly in first 8 days, and then rapid and 
continuous release for the remainder of the 28-day dosing period. Time to peak concentration 
for goserelin 3.6 mg is 12-15 days in males and 8-22 days in females. Goserelin 10.8 mg 


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exhibits an initial rapid release resulting in a peak concentration at 2 hours after dosing. From 
Day 4 until the end of the 12-week dosing interval, the sustained release of goserelin 
produces a reasonably stable systemic exposure. 
2. Distribution: Apparent volumes of distribution determined after subcutaneous administration 
of 250 mcg aqueous solution of goserelin were 44.1 and 20.3 liters for males and females, 
respectively. Goserelin is approximately 27% protein bound. 
3. Metabolism: Metabolism of goserelin by hydrolysis of the C-terminal amino acids is the 
major clearance mechanism. The half-life elimination (t1/2)) is approximately 4 hours in 
males and 2 hours in females. 
4. Elimination: Clearance of goserelin is very rapid and occurs primarily via urinary excretion 
(>90%; 20% as unchanged drug). 
 
Dosing and Administration 
Goserelin is administered subcutaneously into the anterior abdominal wall below the navel line 
using aseptic technique. 
 
Storage and Stability 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information. 
 
How Supplied 
1. Goserelin acetate implant is available in a 3.6 mg or 10.8 mg disposable syringe device. The 
unit is sterile and comes in a sealed, light- and moisture-proof, aluminum foil laminate pouch 
containing a desiccant capsule. 
2. Goserelin is commercially available and will not be supplied by the study. Refer to the 
current FDA-approved package insert for additional information. 
 
Common side effects 
 
Problems getting an erection (impotence)  
 
Hot flushes and sweats  
 
Lowered interest in having sex (low libido) 
 
Temporary bruising and sore skin where you have the injection 
 
Breast tenderness and swelling  
 
Refer to the package insert or manufacturer website for the most complete and up to date 
information on contraindications, warnings and precautions, and adverse reactions. 
 
10.5 
Leuprolide (Eligard®, Lupron Depot®) (NSC-377526) 
 
Pharmacology 
Mechanism of Action: Leuprolide inhibits gonadotropin secretion by acting as a luteinizing 
hormone-releasing hormone (LHRH) agonist. Continuous administration results in suppression 
of ovarian and testicular steroidogenesis due to decreased levels of LH and FSH with subsequent 
decrease in testosterone (male) and estrogen (female) levels. In males, testosterone levels are 
reduced to below castrate levels. Leuprolide may also act directly on the testes as well as act by a 
different mechanism not directly related to reduction in serum testosterone. 


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Pharmacokinetics 
1. Absorption: After the initial increase of leuprolide following each injection, mean serum 
concentrations remain relatively constant. 
2. Distribution: The mean steady-state volume of distribution of leuprolide following intravenous 
bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma 
proteins ranged from 43% to 49%. 
3. Metabolism: Upon administration with different leuprolide acetate formulations, the major 
metabolite of leuprolide acetate is a pentapeptide (M-I) metabolite. 
4. Elimination: Less than 5% of the leuprolide dose was recovered as parent and M-I metabolite 
in the urine following the 3.5 mg depot injection. 
 
Dosing and Administration 
Leuprolide is administered intramuscular (Lupron Depot®) or subcutaneous (Eligard®) injection 
based on commercial depot formulation. Injection sites should be varied periodically. 
 
Storage and Stability 
Refer to the current FDA-approved package insert for storage, stability and special handling 
information. 
 
How Supplied 
Leuprolide acetate is available in 3.75 mg, 7.5 mg, 11.25 mg, 22.5 mg, 30mg, or 45 mg depot 
formulation kit with accompanying diluent. The prefilled dual chamber syringe contains 
lyophilized microspheres of leuprolide acetate incorporated in a biodegradable lactic acid 
polymer. 
 
Leuprolide is commercially available and will not be supplied by this study. Refer to the current 
FDA-approved package insert for additional information. 
 
Common side effects include: 
 arm, back, or jaw pain  
 bloody or cloudy urine  
 blurred vision  
 burning while urinating  
 chest pain or discomfort  
 chest tightness or heaviness  
 difficult or labored breathing  
 difficult, burning, or painful urination  
 difficulty with moving  
 dizziness  
 frequent urge to urinate  
 headache  
 increased urge to urinate during the night  
 muscle pain or stiffness  
 nausea  
 nervousness  


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 pain in the joints  
 pale skin  
 pounding in the ears  
 slow or fast heartbeat  
 sweating  
 troubled breathing with exertion  
 unusual bleeding or bruising  
 unusual tiredness or weakness  
 waking to urinate at night  
 
Refer to the package insert or manufacturer website for the most complete and up to date 
information on contraindications, warnings and precautions, and adverse reactions  
 
11 
ADVERSE EVENTS  
 
11.1 
Definitions of Adverse Events 
 
11.1.1 Adverse Event (AE): 
In a clinical study, an AE is any untoward medical occurrence (i.e. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a subject after 
providing written informed consent for participation in the study. Therefore, an AE may or may 
not be temporally or causally associated with the use of a medicinal (investigational) product. An 
adverse event may include the following: an adverse event occurring in the course of the use of a 
drug in professional practice; an adverse event occurring from drug overdose whether accidental 
or intentional; an adverse event occurring from drug withdrawal and any failure of expected 
pharmacological action. 
 
11.1.2 Serious Adverse Event (SAE): 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria: 
 Results in death, other than death related to disease progression 
 Is life-threatening. 
o The term ‘life-threatening’ in the definition refers to an event in which the subject 
was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
o A hospitalization or prolongation of hospitalization will not be regarded as an SAE if 
at least one of the following exceptions is met: 
o The admission results in a hospital stay of less than 24 hours. 
o The admission is pre-planned.  
(i.e. elective or scheduled surgery arranged prior to the start of the study) 
o The admission is not associated with an AE (e.g. social hospitalization for purposes 
of respite care). 
o However, it should be noted that invasive treatment during any hospitalization may 
fulfill the criterion of ‘medically important’ and as such may be reportable as an SAE 


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dependent on clinical judgment. In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence. 
 Results in persistent or significant disability/incapacity. 
o Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
 Is a congenital anomaly / birth defect. 
 Is another medically important serious event. 
o An event may be considered an important medical event when, based upon 
appropriate medical judgment, it may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in the definitions above. 
 
11.1.3 Adverse Drug Reaction 
Adverse reaction means any adverse event for which there is a reasonable possibility that the 
drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the adverse event. 
A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug. 
 
11.1.4 Serious Adverse Drug Reaction 
A serious adverse drug reaction is an event that meets any of the criteria for seriousness as 
previously defined and has a possible causal relationship to the study drugs. 
 
11.2 
Adverse Event (AE) Reporting 
 
11.2.1 Site Requirements for Recording Adverse Events 
Adverse events (AEs) will be recorded from the time of consent and for 30 days after the last 
dose of study drugs, regardless of whether or not the event(s) are considered related to the study 
drugs. The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) v4 will be utilized for AE reporting. A copy of the 
CTCAE v4 can be downloaded from the CTEP website at http://ctep.cancer.gov. 
 
All AEs considered related to study drug will be followed until resolution, return to baseline, or 
deemed clinically insignificant, even if this occurs post-trial. 
 
11.2.2 Site Requirements for Reporting Serious Adverse Events to HCRN 
Site investigators and other site personnel must report any SAEs occurring from the time of 
informed consent to 30 days after the last dose of study drugs. This includes events both related 
and unrelated to the study drugs.   
 


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The definition of “related” being that there is a reasonable possibility the drug caused the adverse 
experience. 
 
Unrelated 
The Adverse Event is clearly not related to the study drug(s) 
Unlikely 
The Adverse Event is doubtfully related to the study drug (s) 
Possible 
The Adverse Event may be related to the study drug (s) 
Probable 
The Adverse Event is likely related to the study drug (s) 
Definite 
The Adverse Event is clearly related to the study drug (s) 
 
The completed SAE Submission Form must be sent to HCRN within 24 hours of discovery of 
the event. The form may be sent to HCRN either electronically to safety@hoosiercancer.org or 
by fax to 317-921-2053. The site investigator is responsible for informing the IRB and/or the 
Regulatory Authority of the SAE as per local requirements.  The original copy of the SAE 
Submission Form and the fax confirmation sheet must be kept within the Trial Master File at the 
study site. 
 
Follow-up information should be submitted to HCRN either electronically to 
safety@hoosiercancer.org or by fax to 317-921-2053, using a SAE Submission Form stating that 
this is a follow-up to the previously reported SAE and providing the follow-up number if 
appropriate. Each re-occurrence, complication, or progression of the original event should be 
reported as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was treated, whether 
the blind was broken or not (if applicable), and whether the subject continued or withdrew from 
study participation. 
 
11.2.3 HCRN Requirements for Reporting Serious Adverse Events to Bayer 
HCRN will report all SAEs to Bayer within 24 hours of receipt of the SAE Submission Form 
from the site and to regulatory authorities (FDA) per federal guidelines.   
 
HCRN will report SAEs using a MedWatch form available at http://www.fda.gov/medwatch/ for 
SAEs reportable to FDA; all other SAEs will be reported using the HCRN SAE Submission 
Form. All SAE reports 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 
4.  A subject identified by one or more of the following:  
a.  Subject initials 
b.  Subject number  
c.  Knowledge that a subject 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. 
 


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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 
 
All reports shall be sent electronically to:  
 
Electronic Mailbox:  
DrugSafety.GPV.US@bayer.com  
Facsimile: 
(973) 709-2185  
Address: 
Global Pharmacovigilance - USA  
Mail only: 
Bayer HealthCare  
 
P.O. Box 915  
 
Whippany, NJ 07981-0915  
 
Address:   
100 Bayer Boulevard, Whippany, NJ 07981  
FDX or UPS only 
67 Whippany Road, Whippany NJ 07981 for UPS 
 
Reports for all Bayer products can also be phoned in via Bayer’s Medical Communications 
Department 
 
Phone:                  
1-888-842-2937 
 
11.2.4 Expedited Reporting of Other Safety Information: 
Sites will report to HCRN within 24 hours of discovery of event and HCRN shall report to 
Bayer within 24 hours of receipt of report:   
 An adverse event related to study specific procedures which the site investigator 
reasonably believes impacts subject safety (For Non-SAEs: site investigator decision 
whether to file to Bayer and other regulatory authorities). 
 Any new and important event related to treatment with the study drug(s) which the site 
investigator reasonably believes impacts subject safety (this is up to the site investigator 
to determine what is new and important and related to the study drug.  Site investigator 
decision whether to file to Bayer and other regulatory authorities). 
 Any pregnancy during which a female patient was exposed to the study drug(s). 
Any pregnancy in the partner of a male subject, where the male subject was exposed to 
study drug at the time of conception or conception occurred within two weeks of the last 
dose of study drug(s). 
 


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Any communication, other than communication provided by Bayer, concerning safety related 
information to regulatory authorities or ethics committees including but not limited to: 
 
Development Safety Update Reports (DSUR) / relevant parts of IND reports for study drugs.  
Any other safety related reports, issues and queries that are either raised by or communicated to 
regulatory authorities or ethics committees. 
 
11.2.5 Sponsor-Investigator Responsibilities  
HCRN will send a SAE summary to the sponsor-investigator within 1 business day of receipt of 
SAE Submission Form from a site.  The sponsor-investigator will promptly review the SAE 
summary and assess for expectedness and relatedness. 
 
11.2.6 HCRN Reporting to the Food and Drug Administration (FDA) 
HCRN will manage the Investigational New Drug Application (IND) associated with this 
protocol on behalf of the sponsor-investigator. HCRN will cross-reference this submission to 
Bayer’s parent IND at time of submission.  
 
For protocols conducted under an IND, HCRN will be responsible for all communication with 
the FDA in accordance with 21CFR312 including but not limited to the 7 and 15 Day Reports, as 
well as an Annual Progress Report.  
 
11.2.7 IND Safety Reports Unrelated to this Trial 
Bayer will provide to HCRN IND safety reports from external studies that involve the study 
drug(s) per their guidelines.  HCRN will forward safety reports to the sponsor-investigator who 
will review these reports and determine if revisions are needed to the protocol or consent. HCRN 
will forward these reports to participating sites within 1 business day of receiving the sponsor-
investigator’s review.  Based on the sponsor-investigator’s review, applicable changes will be 
made to the protocol and informed consent document (if required).  All IND safety reports will 
also be made available to sites via OnCore®.    
 
Upon receipt from HCRN, site investigators (or designees) are responsible for submitting these 
safety reports to their respective IRBs, as per their IRB policies. 
 
12. 
STATISTICAL CONSIDERATIONS 
 
12.1 
Study Design 
Newly diagnosed metastatic prostate cancer subjects with ≥ 2 bone metastases will be accrued 
and randomized 1:2 to ADT without or with Radium-223 dichloride respectively.  The primary 
aim of the study is to determine if the addition of Radium-223 dichloride to ADT will improve 
efficacy in this prostate cancer population.  The primary efficacy endpoint is radiographic 
progression-free survival (rPFS). We expect the control arm with ADT alone to have a 12 month 
median rPFS. The addition of radium-223 to ADT will target an improvement of 7 months for a 
median rPFS of 19 months. A total of 140 events are required for at least 90% power to detect 
Hazard Ratio of 0.632 with a one-sided alpha of 0.1. The study powering is based on 
assumptions of 19 months median rPFS in the experimental arm and 12 months median rPFS in 
the control arm. Assuming exponential time to event data, a yearly dropout rate of 10% with 


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accrual in 24 months and study duration of 48 months, 204 subjects will provide 90% power 
with a 10% one-sided type I error.  Hypothesis testing for the primary endpoint will be 
conducted at a one-sided 0.10 significance level using a stratified log-rank test. Randomization 
of 68 subjects to the ADT arm and 136 subjects to the ADT+R arm will be completed with 
stratification by extent of disease (<6 skeletal metastases without visceral disease versus ≥6 
skeletal metastases or visceral disease) and baseline alkaline phosphatase (normal versus 
abnormal), abnormal alkaline phosphatase defined as > 130 IU/L.  If time anticipated for the 
number of events required for analysis significantly exceeds 48 months, the sponsor may enroll 
additional subjects to reach required number of events. 
 
12.2 
General Considerations 
This is a randomized phase II study to assess the efficacy of ADT with Radium-223 dichloride 
compared to ADT alone in newly diagnosed metastatic prostate cancer subjects with bone 
metastases. 
 
12.3 
Interim Analysis 
An interim analysis of safety is planned after treatment of 51 safety evaluable subjects.  If 
probably or definitely related (attribution = probably, or definitely) SAE proportion is 40% or 
greater in ADT+R arm compared to the ADT arm then reassessment of dose in combination will 
be adjusted by lowering radium-223 dose to 27.5 kBq/Kg/dose for subsequent subjects17. 
 
In addition, at 24 months, assessment of the number of events will be completed, blind to the arm 
of treatment.  If time anticipated for the number of events required for analysis significantly 
exceeds 48 months, the study may enroll additional subjects to reach the required number of 
events. 
 
12.4 
Analysis Datasets 
 
Methods of Statistical Analysis 
The definitions of the study populations are listed below.  
 
Population 
Definition 
Enrolled 
This will comprise all subjects who meet the 
eligibility criteria and are registered onto the study.  
Evaluable 
This will comprise all subjects who receive at least 
one dose of trial drug and either undergo at least 
one post-baseline assessment or die before any 
evaluation.   
Intention-to-treat (ITT) 
This will comprise all subjects who meet the 
eligibility criteria and are registered onto the study 
irrespective of their compliance to the planned 
course of treatment. (See Intent-To-Treat principle 
below). 


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Population 
Definition 
Per Protocol Set   
 
This will comprise all subjects who received ADT 
or ADT+R for 1 cycle and have a radiographic 
assessment post-baseline.  
Safety 
All subjects who receive 1 dose of treatment will be 
included in the safety population. 
Treated 
This will comprise all subjects who have been 
exposed to the planned course of treatment to any 
extent. 
ALP normalization 
Subjects with abnormal ALP at baseline and at least 
one other post-baseline ALP measure. 
 
Intention-To-Treat Principle - The principle that asserts that the effect of a treatment 
policy can be best assessed by evaluating on the basis of the intention to treat a subject 
(i.e. the planned treatment regimen) rather than the actual treatment given. It has the 
consequence that subjects allocated to a treatment group should be followed up, assessed 
and analyzed as members of that group irrespective of their compliance to the planned 
course of treatment. 
 
12.5 
Sample Size/Accrual/Study Duration/Replacement Rules  
The sample size is 204 eligible and safety evaluable subjects.  Accrual of 204 eligible and safety 
evaluable subjects is expected to take 24 months.  Subjects will be followed for 2 years or until 
the last enrolled subject has progressed, died, has been followed for 24 months, or study is 
terminated, whichever occurs first.  Subjects who are enrolled but do not receive any treatment 
will be replaced.   
 
12.6 
Analysis of Primary Objective 
Subjects will be assessed for radiographic progression as described in section 8.  Time from first 
dose of ADT to radiographic progression or death, whichever occurs first, will be calculated for 
each subject.  For subjects who discontinue study treatment due to reasons other than death or 
investigator assessed progression, every effort will be made to continue tumor assessments on 
schedule until radiographic progressive disease or subject death.  Subjects who do not have 
radiographic progression or death will be censored at their last measure for radiographic 
progression.  The primary hypothesis test will be conducted at a one-sided 0.1 significance level 
using a stratified log-rank test. Kaplan-Meier methods will be used to report rPFS graphically by 
arm including the median rPFS and 12 and 24 month rPFS proportions in the ITT population.  
The log-rank test without stratification will be used as a sensitivity analysis. 
 
12.7 
Analysis of Secondary Objectives 
Toxicity will be described within each arm by type, maximum grade and frequency among the 
safety population.  The proportion of subjects in each arm with skeletal related events and 
secondary neoplasms will be reported individually and a mid p-value test will compare the 
proportions between arms.  


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Time to castration resistance (TTCR), PSA progression free survival (PCWG2 criteria), and 
Overall Survival (OS) will be reported by arm using Kaplan-Meier methods and tested using the 
log-rank test.  The –time to castration resistance, the 2-year PSA PFS and OS proportions with 
90% confidence intervals will be reported using Kaplan-Meier methods.  Analyses will be 
completed on the ITT population. 
 
Binomial proportions with 90% binomial confidence intervals of subjects who achieve PSA ≤ 
0.2 ng/mL at 7 months after treatment initiation will be reported by arm.  Similarly, the 
proportions and associated confidence intervals of subjects who achieve PSA ≤ 4 ng/mL at 7 
months after treatment initiation will be described.   
 
We will evaluate the distribution of pre-randomization marker levels (ALP and bone markers) 
among those who have and have not started ADT prior to randomization. If it appears that the 
prior initiation of ADT impacts the study entry bone marker levels to a fair extent, then all 
marker analyses will be conducted stratified by ADT initiation status. Descriptive statistics by 
arm will report the time to ALP progression among all subjects using Kaplan-Meier methods.   
ALP and serum bone markers will be reported by arm for each time-point using means or 
medians and corresponding measures of variability for all subjects with serum.  Percentage 
change in ALP from baseline and changes from baseline in bone markers will be calculated for 
each later time point and tested between arms using a t-test or Wilcoxon rank test.  If there is 
sufficient data, a mixed model will be used to model each endpoint over time to determine if the 
changes are different between treatment arms. Exploratory analysis will use separate Cox models 
with rPFS, PSA PFS, TTCR, and OS as the individual outcomes and treatment group, one 
marker, and the interaction between treatment and marker as independent covariates to find 
associations with outcomes. These models can be expanded to include other subject factors to 
determine if the marker contributes to outcome above subject factors that are known to be 
associated with the outcome.  Similarly, logistic models can be used with 7-month PSA 
outcomes. The model analyses are considered exploratory for this trial.  Thus, they are not 
powered and will not use multiple comparisons adjustments. 
 
Worst pain will be reported from the BPI (SF) at each time point with a mean or median and the 
associated measure of variability and tested between arms with a t-test or Wilcoxon rank test.   
Comparisons at the times post-baseline will be compared between treatment arms using a paired 
test (t-test or Wilcoxon rank test.)  WHO will be reported categorically by arm at each time point 
and tested between arms using the Mantel-Haenszel chi-square test.  The change in WHO score 
from baseline will be calculated and be the outcome in a cumulative logistic model.  Treatment 
arm will be included as an independent covariate to test if the change in pain is different between 
arms. Each post-baseline measure will be a separate model. 
 


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13 
TRIAL MANAGEMENT 
 
13.1 
Data and Safety Monitoring Plan: 
The study will be conducted in accord with University of Michigan Comprehensive Cancer 
Center’s Data and Safety Monitoring Plan.  
HCRN data and safety monitoring activities include: 
 Conduct review of clinical trial for progress and safety 
 Review of all adverse events requiring expedited reporting as defined in the protocol 
 Provide sponsor-investigator with trial progress and safety information monthly.  
 Notification of participating sites of adverse events requiring expedited reporting  
 Submit data summary reports to the DSMB for review according to DSMB Charter 
 
13.2 
Data Safety Monitoring Board 
This study will have a Data and Safety Monitoring Board (DSMB) that will review and monitor 
study progress, toxicity, safety and other data from this trial. The DSMB is separate from the 
Data and Safety Monitoring Committee (DSMC) referred to above. The board is chaired by an 
independent medical oncologist external to this trial. Questions about subject safety or protocol 
performance will be addressed with the sponsor-investigator, statistician, and study team 
members. Should any major concerns arise; the DSMB will offer recommendations regarding 
whether or not to suspend the trial.  
 
The DSMB will meet quarterly to review accrual, toxicity, response, and reporting information. 
Information to be provided to the DSMB may include subject accrual, treatment regimen 
information, adverse events, and serious adverse events reported by category, summary of any 
deaths on study, audit, and/or monitoring results.  
 
The DSMB will provide a recommendation to the sponsor-investigator and HCRN after all 
information is reviewed. HCRN will provide this information to participating sites, who will 
submit it to their IRB at the time of continuing review. 
 
13.3 
Data Quality Oversight Activities 
Remote validation of OnCore data will be completed on a continual basis throughout the life 
cycle of the study.  A summary report (QC Report) of these checks together with any queries 
resulting from manual review of the eCRFs will be generated for each site and transmitted to the 
site and the site monitor. Corrections will be made by the study site personnel.  
 
There will be at least one routine visit per site per year for sites that have accrued.  Additional for 
cause visits may occur as necessary. Source documents will be reviewed for verification of 
agreement with data entered into OnCore.  It is important for the site investigator and their 
relevant personnel to be available for a sufficient amount of time during the monitoring visits or 
audit, if applicable. The site investigator and institution guarantee access to source documents by 
HCRN or its designee. 
 
The trial site may also be subject to quality assurance audit by Bayer or its designee as well as 
inspection by appropriate regulatory agencies. 
 


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13.4 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the sponsor-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. All 
results of primary and secondary objectives must be posted to CT.gov within a year of 
completion.  The sponsor-investigator has delegated responsibility to HCRN for registering the 
trial and posting the results on clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and study 
site contact information.   
 
14 
DATA HANDLING AND RECORD KEEPING 
 
14.1 
Data Management 
HCRN will serve as the Clinical Research Organization for this trial. Data will be collected 
through a web based clinical research platform, OnCore, a system compliant with Good Clinical 
Practices and Federal Rules and Regulations.  HCRN personnel will coordinate and manage data 
for quality control assurance and integrity. All data will be collected and entered into OnCore by 
study site personnel from participating institutions.   
 
14.2 
Case Report Forms and Submission 
Generally, clinical data will be electronically captured in OnCore and correlative results will be 
captured in OnCore or other secure database(s). If procedures on the study calendar are 
performed for standard of care, at minimum, that data will be captured in the source document. 
Select standard of care data will also be captured in OnCore, according to study-specific 
objectives.  
 
The completed dataset is the sole property of the sponsor-investigator’s institution and should 
not be exported to third parties, except for authorized representatives of appropriate 
Health/Regulatory Authorities, without permission from the sponsor-investigator and HCRN. 
 
14.3 
Record Retention 
To enable evaluations and/or audits from Health Authorities/HCRN, the site investigator agrees 
to keep records, including the identity of all subjects (sufficient information to link records; e.g., 
hospital records), all original signed informed consent forms, copies of all source documents, and 
detailed records of drug disposition. All source documents are to remain in the subject’s file and 
retained by the site investigator in compliance with the site contract with HCRN.  No records 
will be destroyed until HCRN confirms destruction is permitted. 
 
14.4 
Confidentiality 
There is a slight risk of loss of confidentiality of subject information. All records identifying the 
subjects will be kept confidential and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. Information collected will be maintained on 
secure, password protected electronic systems. Paper files that contain personal information will 
be kept in locked and secure locations only accessible to the study site personnel.  


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Subjects will be informed in writing that some organizations including the sponsor-investigator 
and his/her research associates, HCRN, Bayer, IRB, or government agencies, like the FDA, may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
If the results of the study are published, the subject’s identity will remain confidential. 
 
15 
ETHICS 
 
15.1 
Ethics Review 
The final study protocol, including the final version of the Written Informed Consent Form, must 
be approved or given a favorable opinion in writing by an IRB. The site investigator must submit 
written approval to the HCRN office before he or she can enroll any subject into the study.   
 
The sponsor-investigator is responsible for informing the IRB of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB must approve all advertising used to 
recruit subjects for the study. The protocol must be re-approved by the IRB annually, as local 
regulations require.  
 
Progress reports and notifications of serious unexpected adverse drug reactions will be provided 
to the IRB according to local regulations and guidelines. 
 
The investigator is also responsible for providing the IRB with reports of any serious adverse 
drug reactions from any other study conducted with the investigational product. Bayer 
HealthCare Pharmaceuticals will provide this information to the Sponsor Investigator. These 
reports will be reviewed by the Sponsor Investigator and those considered unexpected and 
possibly related to protocol therapy plus all deaths within 30 days of discontinuing treatment will 
be forwarded to participating sites for submission to their Institutional Review Boards per their 
guidelines. All other events will be held and submitted to the sites for continuing review. 
 
15.2 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles originating from the 
Declaration of Helsinki, which are consistent with ICH Good Clinical Practice, and applicable 
regulatory requirements. 
 
15.3 
Informed Consent 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study. Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The investigator must store the original, signed Informed 
Consent Form. A copy of the signed Informed Consent Form must be given to the subject. 


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16. 
REFERENCES 
 
 
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Eisenberger MA, Blumenstein BA, Crawford ED, et al: Bilateral orchiectomy with or 
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Schmitt B, Bennett C, Seidenfeld J, et al: Maximal androgen blockade for advanced 
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Samson DJ, Seidenfeld J, Schmitt B, et al: Systematic review and meta-analysis of 
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Hussain M, Goldman B, Tangen C, et al: Prostate-specific antigen progression predicts 
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Hussain M, Tangen CM, Higano C, et al: Absolute prostate-specific antigen value after 
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Hussain M, Tangen CM, Berry DL, et al: Intermittent versus continuous androgen 
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Smith MR, Saad F, Coleman R, et al: Denosumab and bone-metastasis-free survival in 
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Nilsson S, Franzen L, Parker C, et al: Bone-targeted radium-223 in symptomatic, 
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Parker C, Nilsson S, Heinrich D, et al: Alpha emitter radium-223 and survival in 
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14. 
Marrinucci D, Bethel K, Bruce RH, et al: Case study of the morphologic variation of 
circulating tumor cells. Hum Pathol 38:514-9, 2007 
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Marrinucci D, Bethel K, Kolatkar A, et al: Fluid biopsy in patients with metastatic 
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Cleeland CS, Ryan KM: Pain assessment: global use of the Brief Pain Inventory. Ann 
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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. Eur Urol 63:189-97, 2013