A Phase 2 Randomized Study Comparing Radium Ra 223 Dichloride Plus Enzalutamide With Enzalutamide Alone in Men With Metastatic Castration Refractory Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: University of Utah

Full Study Protocol and Statistical Analysis Plan 
 
 
 
Study Title:  A Phase 2 Randomized Study comparing Radium Ra 223 
dichloride + Enzalutamide with Enzalutamide alone in Men with 
Metastatic Castration Refractory Prostate Cancer 
 
Protocol Version 6: 02/06/2017 
 
 
 
NCT #: NCT02199197 
Unique Protocol ID: HCI68770 
U of U IRB#: IRB_00068770 
 
 
 
Principal Investigator:  Neeraj Agarwal, MD 
Huntsman Cancer Institute 
 

Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
 
 
 
 
 
A Phase 2 Randomized Study comparing Radium Ra 223 dichloride +  
Enzalutamide with Enzalutamide alone in Men with  
Metastatic Castration Refractory Prostate Cancer 
Lead Trial ID: HCI68770/ IRB# 68770 
 
 
Principal Investigator 
Neeraj Agarwal, MD 
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope, Ste 2123 
Salt Lake City, Utah, 84112 
Phone: 801-585-9682 
Email: Neeraj.Agarwal@hci.utah.edu  
 
 
Sub-investigator(s) 
John Hoffman, MD 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, UT 84112 
Email: john.hoffman@hci.utah.edu  
 
Julia Batten, APRN 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, UT 84112 
Email: julia.batten@hci.utah.edu  
 
Jared Thorley, APRN 
Huntsman Cancer Institute 
University of Utah  
Salt Lake City, UT 84112 
Email: jared.thorley@hci.utah.edu 
 
Ken Boucher, PhD (Statistician) 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, UT 84112 
Email: Ken.boucher@hci.utah.edu  
 

Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
Sumati Gupta, MD 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, Utah, 84112 
Email: sumati.gupta@hci.utah.edu 
 
Benjamin Maughan, MD, PharmD 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, Utah, 84112 
Email: Benjamin.Maughan@hci.utah.edu 
 
Kathleen Cooney, MD 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, Utah, 84112 
Email: kathleen.cooney@hsc.utah.edu  
 
Tenzin Phunrab, APRN 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, Utah, 84112 
Email: tenzin.phunrab@hsc.utah.edu 
 
Kathryn Morton, MD 
Huntsman Cancer Institute 
University of Utah 
Salt Lake City, Utah, 84112 
Email: kathryn.morton@hsc.utah.edu 
 
 
 
Drug manufacturer 
Algeta/Bayer 
Medivation 
 
 
 
IND Number 
121340 
 
 
Historical Protocol Versions 
Version 1: 2-7-2014 
Version 2: 4-29-2014 
Version 3: 7-1-2015 
Version 4: 12-11-2015 
Version 5: 02-11-2016 
Version 6: 02-06-2017 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS .................................................................................................... 3 
LIST OF ABBREVIATIONS ............................................................................................. 5 
PROTOCOL SIGNATURE ................................................................................................ 7 
STUDY SUMMARY.......................................................................................................... 8 
SCHEMA .......................................................................................................................... 11 
1 
OBJECTIVES .................................................................................................... 12 
1.1 
Primary Objectives and Endpoint ...................................................................... 12 
1.2 
Secondary Objectives and Endpoint .................................................................. 12 
2 
BACKGROUND ............................................................................................... 12 
2.1 
Rationale for using enzalutamide and radium-223 ............................................ 12 
2.2 
Specific rationale for using markers of bone turnover/metabolism as a             
primary endpoint ................................................................................................ 13 
3 
DRUG INFORMATION ................................................................................... 15 
3.1 
Radium Ra 223 .................................................................................................. 15 
3.2 
Enzalutamide...................................................................................................... 22 
4 
STUDY DESIGN............................................................................................... 27 
4.1 
Description ......................................................................................................... 27 
4.2 
Number of Patients ............................................................................................ 28 
4.3 
Number of Study Centers................................................................................... 28 
4.4 
Duration ............................................................................................................. 28 
5 
ELIGIBILITY CRITERIA................................................................................. 29 
5.1 
Inclusion Criteria ............................................................................................... 29 
5.2 
Exclusion Criteria .............................................................................................. 31 
6 
TREATMENT PLAN ........................................................................................ 33 
6.1 
Administration Schedule .................................................................................... 33 
6.2 
Radium Ra 223 Dichloride Treatment ............................................................... 33 
6.3 
Enzalutamide Treatment .................................................................................... 39 
6.4 
Accountability and Compliance ......................................................................... 39 
6.5 
Concomitant Medications .................................................................................. 39 
6.6 
Protocol specified Duration of Therapy ............................................................. 41 
7 
TOXICITIES AND DOSEAGE MODIFICATION .......................................... 42 
7.1 
Dose Modifications Radium Ra 223 Dichloride ................................................ 42 
7.2 
Dose Modifications Enzalutamide ..................................................................... 44 
8 
STUDY CALENDAR ....................................................................................... 45 
9 
CRITERIA FOR EVALUATION AND ENDPOINT ....................................... 47 
9.1 
Assessment of bone metabolism: ....................................................................... 47 
9.2 
Assessment of clinical outcomes: ...................................................................... 47 
9.3 
Safety ................................................................................................................. 47 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
9.4 
Efficacy .............................................................................................................. 48 
10 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........ 53 
10.1 Primary Endpoint Analyses ............................................................................... 53 
10.2 Secondary Endpoint Analyses ........................................................................... 55 
10.3 Exploratory Analyses ......................................................................................... 56 
11 
REGISTRATION GUIDELINES ...................................................................... 56 
12 
DATA SUBMISSION SCHEDULE ................................................................. 56 
13 
ETHICAL AND REGULATORY CONSIDERATIONS ................................. 57 
13.1 Informed consent ............................................................................................... 57 
13.2 Institutional Review ........................................................................................... 58 
13.3 Data and Safety Monitoring Plan ....................................................................... 58 
13.4 Adverse Events / Serious Adverse Events ......................................................... 58 
13.5 SAE Reporting Requirements ............................................................................ 61 
13.6 Pregnancies ........................................................................................................ 63 
13.7 Protocol Amendments ........................................................................................ 63 
13.8 Protocol Deviations ............................................................................................ 63 
13.9 FDA Annual Reporting ...................................................................................... 64 
13.10 Clinical Trials Data Bank................................................................................... 64 
14 
BIBLIOGRAPHY .............................................................................................. 65 
 
 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
LIST OF ABBREVIATIONS 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
AR 
Androgen receptor 
ALP 
Alkakine phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
β-HCG 
Beta-human chorionic gonadotropin 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HR 
Heart rate 
hr 
Hour or hours 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
Abbreviation or Term1 
Definition/Explanation 
i.e. 
Id est (that is) 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
NIST 
US National Institute of Standards of Technology  
PFS 
Progression Free Survival 
PO 
Per os (administered by mouth) 
PR 
Partial response 
RBC 
Red blood cell 
QD 
Once daily 
SAE 
Serious adverse event 
SD 
Stable disease 
Tmax 
Time of maximum observed concentration 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
 
1 All of these abbreviations may or may not be used in protocol.  
 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
 
PROTOCOL SIGNATURE 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, 
the applicable ICH guidelines for good clinical practice, and the applicable laws and 
regulations of the federal government. I will promptly submit the protocol to the IRB for 
review and approval. Once the protocol has been approved by the IRB, I understand that 
any modifications made during the course of the study must first be approved by the IRB 
prior to implementation except when such modification is made to remove an immediate 
hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the study treatment, the conduct of 
the study, and the obligations of confidentiality. 
Note: This document is signed electronically through submission and approval by the 
Principal Investigator in the University of Utah IRB Electronic Research Integrity and 
Compliance Administration (ERICA) system. 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
STUDY SUMMARY 
Title 
A Phase 2 Randomized Study comparing Radium Ra 223 
dichloride + Enzalutamide with Enzalutamide alone in Men 
with Metastatic Castration Refractory Prostate Cancer 
Short Title 
Radium Ra 223 dichloride + Enzalutamide with Enzalutamide 
alone in mCRPC 
Protocol Number 
IRB # 68770 
IND 
IND Exempt (121340) 
Phase 
Phase 2 
Design 
Open label, randomized two arm study in men with progressive 
metastatic CRPC who are candidates for treatment with 
enzalutamide alone or enzalutamide + Radium Ra 223 
dichloride 
Study Duration 
3.5 years  
Study Center(s) 
Single-center - Huntsman Cancer Institute 
Objectives 
Primary: 
1. To measure the difference between the levels of markers 
of bone formation (Procollagen Type 1 intact N-terminal 
Propeptide [NTP] and bone alkaline phosphatase 
[BAP]) and resorption (N-telopeptide [NT], C-
Telopeptide beta-cross linked [CTB], pyridinoline) in 
serum collected at baseline (C1D1) , C3D1, C5D1, EOT 
and at disease progression (whichever comes earlier) in 
two arms.  
2. To establish safety and feasibility of combining 
enzalutamide and radium-223.  
Secondary: 
The secondary obectives will compare the two arms for the 
following: 
1. Time to progression in serum PSA, total ALP 
concentrations, and radiological progression.  
2. Response rates by serum PSA, total ALP concentrations. 
3. Time to first skeletal related event. 
4. Percent change in opioid use (morphine equivalent) 
during protocol treatment. 
5. Overall Survival at 2 years post enrollment. 
Number of Subjects 
47 patients (50 total to account for any inevaluable patients). 
Combination Arm – 35 evaluable patients (27 randomized 
patients + 8 patients enrolled prior to randomization who will 
be used for secondary and exploratory analyses only). 
Control Arm (enzalutamide alone) – 12 evaluable patients. 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
Diagnosis and Main 
Eligibility Criteria 
• Histologically documented adenocarcinoma of the prostate. 
• Metastatic disease as evidenced by bony metastases on 
baseline bone scan and / or computed tomography (CT) scan 
or MRI of the abdomen and pelvis.  
• Castration resistant prostatic adenocarcinoma. Subjects 
must have castrate levels of testosterone (< 50 ng/dL) 
achieved by orchiectomy or LHRH agonist or antagonist 
therapy.  
• Evidence of disease progression on or after the most recent 
systemic treatment. 
• Prior chemotherapy with docetaxel and cabazitaxel allowed. 
• No known brain metastases, malignant pleural effusions, or 
malignant ascites.  
• No visceral metastases  
• No prior treatment with radium-223 or enzalutamide.  
• No pathologic long-bone fractures, imminent pathologic 
long-bone fracture (cortical erosion on radiography > 50%) 
or spinal cord compression. 
Study Product, Dose, 
Route, Regimen and 
Duration 
Combination Arm: Radium Ra 223 dichloride 55 kBq/kg body 
weight every 4 weeks with daily enzalutamide 160 mg PO for 6 
cycles (each cycle comprises 4 weeks).  
Control Arm: Single agent enzalutamide 160mg PO daily for 6 
cycles. 
Statistical 
Methodology 
Primary Bone Marker Analysis 
Concomitant treatment with radium-223 (a bone targeting 
agent) and enzalutamide (a tumoricidal agent) is expected to 
decrease the level of N-telopeptides. As mentioned in the 
Background Section, serum N-telopeptides levels are inversely 
associated with overall survival, based on data from the SWOG 
0421 trial. The primary endpoint for statistical analysis for this 
study will be the change in log 2 N-telopeptides from baseline 
to EOT or at disease progression (whichever comes earlier) 
between the randomization groups. If a bone marker test is 
missed at a given time point, every effort will be made to obtain 
the bone marker levels as early as possible. If two subsequent 
bone marker tests are missed, patient will be excluded from the 
analysis for the primary endpoint. Equality of the change in log2 
N-telopeptides between the treatment arms will be tested using 
an ANCOVA model with treatment group as the primary 
predictor and initial log 2 N-telopeptides as adjustment variable.  
As a sensitivity analysis an F-test for equality of variance of 
final log2 N telopeptides will be performed. If the null 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
hypothesis is rejected at the 0.1 significance level an additional 
ANCOVA model allowing for unequal variances will be fit.  
Additional Analyses of the Primary Endpoint 
Separate analysis in the combined population will be performed 
in subjects treated with enzalutamide + radium-223 and subjects 
treated with enzalutamide alone. If a bone marker test is missed 
at a given time point, every effort will be made to obtain the 
bone marker levels as early as possible. If two subsequent bone 
marker tests are missed, patient will excluded from the analysis. 
Based on the data from the SWOG 0421 study, the estimated 
baseline mean and standard deviation of log2 N-telopeptides are 
3.95 nM and 1.14 nM respectively. We further assume the 
Pearson correlation of baseline and follow up N-telopeptides is 
0.50. With 35 evaluable subjects there will be 80% power to 
detect a change of 0.556 in log2 N-telopeptides using a paired 
t-test. Extrapolating from SWOG0421, a decrease of 0.556 in 
log2 N-telopeptide concentration would translate into an 
approximate 20% increase in median overall survival. 
Primary Safety Analyses 
An overall proportion of subjects with grade 3 or higher 
hematologic adverse events significantly higher than those 
reported for the radium-223 arm of Parker et al. (2013) would 
be evidence of unacceptable toxicity.8,19. In that study the sum 
of the proportion of subjects with grade 3+ anemia,  
thrombocytopenia, or neutropenia is 21%. An exact binomial 
test will be performed at the one sided 0.05 significance level  
comparing the proportion of subjects with one or more of grade 
3+ anemia, thrombocytopenia, or  neutropenia to 21%. With a 
safety population of 35 evaluable patients, 13 or more patients 
with one or more of grade 3+ anemia, thrombocytopenia, or 
neutropenia would indicate an unacceptable hematologic 
adverse event rate. 
Exact 90% confidence intervals will be calculated for adverse 
events (AEs) and serious AEs (SAEs). With 35 evaluable 
patients an exact 90% confidence interval for an AE will extend 
no more than 17.5% from the observed proportion, and there is 
a 90% probability that an adverse event with a probability of 
6.4% will be observed at least once. 
Secondary Endpoint Analyses 
All other statistical analyses will be descriptive in nature. Please 
refer to section 10.2 for additional detail. 
 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
SCHEMA 
Metastatic CRPC Patients.  
Previously received docetaxel or are not healthy enough per clinical judgment or 
declined to receive it. 
Eligible patients randomized 1:2 (12 patients in the control arm and 27 patients in the 
combination arm). 
Control Arm: Single agent enzalutamide 
 
Combination Arm: Enzalutamide + Radium-223 
 
 
 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
1 OBJECTIVES 
We hypothesize that simultaneous treatment with radium-223 and enzalutamide will 
decrease bone metabolism markers compared to enzalutamide alone and the 
combination will be safe and feasible. This hypothesis will be tested through the 
following aims: 
1.1 Primary Objectives and Endpoint 
1.1.1 To measure the difference between levels of markers of bone 
formation (Procollagen Type 1 intact N-terminal Propeptide [NTP] 
and bone alkaline phosphatase [BAP]) and resorption (N-telopeptide 
[NT], C-Telopeptide beta-cross linked [CTB], pyridinoline) in serum 
collected at baseline (C1D1), C3D1, C5D1, EOT and at disease 
progression (whichever comes earlier) in men enrolled in this trial, 
and compare these levels in both arms.  
1.1.2 To establish safety and feasibility of combining enzalutamide and 
radium-223. 
1.2 Secondary Objectives and Endpoint 
To compare the following objectives between the two arms: 
1.2.1 Time to progression in serum prostate-specific antigen (PSA), total 
alkaline phosphatase (ALP) concentrations, and radiological 
progression.  
1.2.2 Response rates by serum PSA and total ALP concentrations. 
1.2.3 Time to first skeletal related event. 
1.2.4 Percent change in opioid use (morphine equivalent) during protocol 
treatment. 
1.2.5 Overall Survival at 2 years post enrollment. 
2 
BACKGROUND 
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) 
has been revolutionized by the arrival of multiple novel agents in the past 2 years. 
Androgen axis inhibitors including abiraterone acetate and enzalutamide, 
immunotherapy in the form of sipuleucel-T, and a radiopharmaceutical, radium-223, 
have all yielded incremental extensions of survival. Improved survival with radium-
223 and enzalutamide underscores the importance of bone targeting and androgen 
pathway inhibition in mCRPC.  
2.1 Rationale for using enzalutamide and radium-223 
 
Enzalutamide (MDV 3100) is a novel AR antagonist that binds to androgen 
receptors with an eight-times higher affinity than bicalutamide and reduces the 
efficiency of nuclear translocation of the androgen receptor, DNA binding to 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
androgen response elements, and recruitment of coactivators by the androgen 
receptor.1 In contrast to bicalutamide, enzalutamide has no known agonist activity 
when AR is over-expressed. In a phase III trial of men with CRPC with prior 
docetaxel therapy, enzalutamide, when compared to placebo, significantly 
improved overall survival (18.4 vs 13.6 months; p < 0.001), leading to its regulatory 
approval in this setting.2 Another phase III trial of enzalutamide in chemotherapy-
naïve men with CPRC has completed accrual and results are awaiting publication. 
Radium-223 is a calcium-mimetic radiopharmaceutical that accumulates in bones 
and emits alpha radiation from radium-223 decay, releasing relatively high energy 
with a narrow range (2 to 10 cells).3 Following promising results in a phase II trial, 
the phase III ALSYMPCA trial was conducted in mCRPC patients with 
symptomatic bone metastases who either had received or were ineligible for 
docetaxel.4 Patients received 6 doses of radium-223 50 kBq/kg intravenously every 
4 weeks. A pre-planned interim analysis showed a significant 2.8-month median 
OS benefit compared to the placebo arm (14 vs. 11.2 months).5 An updated analysis 
showed a further improvement in overall survival to 3.6 months with a hazard ratio 
of 0.695 (i.e., 30.5% reduction in risk of death).6 Moreover, the toxicity profile 
appeared excellent with grades 3-4 neutropenia in 1.8% and thrombocytopenia in 
4% of patients. Reassuringly, long-term 24 month outcomes in the previous 
randomized phase II trial showed no increase in hematologic toxicities.7 Another 
dose-finding phase II trial demonstrated more frequent PSA and serum alkaline 
phosphatase declines with higher doses up to 80 kBq/kg.8  
Although, improved survival with these novel agents is very encouraging, no data 
exist from randomized trials on how to optimally combine these agents, and the 
effect of rationale combination of these agents on therapeutic outcomes. We 
hypothesize that combinatorial regimen of radium-223 and enzalutamide will 
improve bone health, delay bone events, and improve pain and survival outcomes 
by simultaneously targeting bone metastases and androgen signaling. 
2.2 Specific rationale for using markers of bone turnover/metabolism as a 
primary endpoint   
Bone metabolism is distinguished by two opposing 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 patients with prostate cancer 
and is a frequent source of morbidity, including bone pain or fracture. Many 
prostate cancer patients with bone metastases have elevated circulating biochemical 
markers of bone metabolism, including markers for osteoblast and osteoclast 
activity. These serum-based biomarkers have been explored as indicators of bone 
turnover for their potential as prognostic and / or predictive variables.9,10 Prior 
studies have suggested that elevated markers of bone turnover are strongly 
prognostic for poor survival in castration resistant prostate cancer patients,11 and 
may predict outcome with systemic therapy.12-14  
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
SWOG 0421 was a large placebo-controlled phase III study of docetaxel with or 
without the endothelin antagonist atrasentan in castration resistant prostate cancer 
patients with skeletal metastases. Disappointingly, we did not observe any survival 
advantage for the docetaxel + atrasentan arm.15 However, as a translational science 
component of that randomized trial, pre-treatment and serial serum markers of bone 
turnover were prospectively assessed to validate their prognostic and predictive 
value in these castration-resistant patients. Markers of bone resorption (N-
telopeptide, NTX & Pyridinoline, PYD) and bone formation (C-terminal collagen 
propeptide, CICP & bone alkaline phosphatase, BAP) were measured. Cox 
regression models were developed for overall survival based on baseline bone 
markers (log2 scale), adjusted for potentially confounding clinical variables 
(including PSA, bisphosphonate use, age, race, performance status, Gleason score, 
and pain score, among others). The effect of treatment on bone marker levels in 
week 9 (as compared to baseline) was explored 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 1038 
patients enrolled in SWOG 0421, 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).  
The significant prognostic role of elevated markers of bone turnover (> 
median value) on overall survival is shown in Table 1 below. Hazard ratios are 
reported for a 2-fold increase in bone metabolism markers. Follow-up analysis 
revealed that patients with high marker levels (ie, 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. 
Of the 778 patients 6% (47) had a complete set of baseline markers measurements. 
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.16  
Table 1: Prognostic Value of Markers of Bone Turnover 
Biomarker 
 
Hazard Ratio 
 (95% CI) 
Median Survival, months 
(≤ median BMB value vs. > median) 
p-
value* 
BAP (u/l) 
1.26 (1.19, 1.35) 
22.8 vs. 15.4  
< 0.001 
CICP (ng/ml) 
1.38 (1.27, 1.5) 
24.5 vs. 14.6 
< 0.001 
NTx (nM) 
1.43 (1.31, 1.57) 
22.4 vs. 15.5 
< 0.001 
PYD (nmol/l) 
1.49 (1.32, 1.7) 
20.3 vs. 15.3 
< 0.001 
Significance was set at < 0.006 (Bonferroni adjustment to control overall 2-sided error rate across 
4 tests at 0.05) 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
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 (Table 2).  
Table 2: Association between overall survival and the change from baseline to 
week 9 in the (log2) bone marker concentration, adjusted for baseline bone 
marker concentration and bisphosphonate use 
Marker 
Hazard Ratio 
95% CI 
P-value 
BAP (u/l) 
1.33 
(1.16, 1.51) 
< 0.001 
CICP (ng/ml) 
1.46 
(1.23, 1.72) 
< 0.001 
NTx (nM) 
1.45 
(1.20, 1.75) 
< 0.001 
PYD (nmol/l) 
1.59 
(1.25, 2.02) 
< 0.001 
 
These results demonstrate that baseline serum levels of bone metabolism markers 
have significant independent overall survival prognostic value in patients with 
castration resistant disease. In addition, patients with elevated serum bone 
metabolism markers levels appeared to preferentially benefit from a novel systemic 
agent such as atrasentan.  
Presently, it is unclear whether these same observations will be observed in a 
somewhat different therapeutic context, i.e. in men with mCRPC being treated with 
radium-223 plus enzalutamide. This proposed phase II trial of a combinatorial 
regimen of radium-223 with enzalutamide provides a unique opportunity to directly 
address this important clinical question. 
As noted above, radium-223 is a calcium-mimetic radiopharmaceutical that 
accumulates in bones and emits alpha radiation from radium-223 decay and releases 
relatively high energy with a narrow range (2 to 10 cells), thereby targeting bone 
metastatis,17 and has been shown to improve survival and increases the time to first 
skeletal related event (SRE) when compared to placebo (median time to SRE 13.6 
vs 8.4 months, respectively; P = 0.00046; HR = 0.610; 95% CI: 0.461, 0.807).18 
These data support the notion that treatment with radium-223 will result in 
modulation of bone metabolism, and thus improve bone and survival outcomes.  
We hypothesize that simultaneous treatment with radium-223 and enzalutamide 
will significantly decrease bone metabolism markers (thus improving bone and 
clinical outcomes) compared to enzalutamide alone, and will be safe and feasible. 
3 
DRUG INFORMATION 
3.1 Radium Ra 223 
3.1.1 Description 
Radium Ra 223 dichloride, an alpha particle-emitting pharmaceutical, is a 
radiotherapeutic drug. It is supplied as a clear, colorless, isotonic, and sterile 
solution to be administered intravenously with pH between 6 and 8. Each 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
milliliter of solution contains 1100 kBq radium-223 dichloride (30 
microcurie), corresponding to 0.58 ng radium- 223, at the reference date. 
Radium is present in the solution as a free divalent cation. Each vial contains 
6 mL of solution (6,600 kBq (178 microcurie) radium-223 dichloride at the 
reference date). The inactive ingredients are 6.3 mg/mL sodium chloride USP 
(tonicity agent), 7.2 mg/mL sodium citrate USP (for pH adjustment), 0.2 
mg/mL hydrochloric acid USP (for pH adjustment), and water for injection 
USP. The molecular weight of radium-223 dichloride, 223RaCl2, is 293.9 
g/mol. Radium-223 has a half-life of 11.4 days. The specific activity of 
radium-223 is 1.9 MBq (51.4 microcurie)/ng. The six-stage-decay of radium-
223 to stable lead-207 occurs via short-lived daughters, and is accompanied 
predominantly by alpha emissions. There are also beta and gamma emissions 
with different energies and emission probabilities. The fraction of energy 
emitted from radium-223 and its daughters as alpha-particles is 95.3% 
(energy range of 5 - 7.5 MeV). The fraction emitted as beta-particles is 3.6% 
(average energies are 0.445 MeV and 0.492 MeV), and the fraction emitted 
as gamma-radiation is 1.1% (energy range of 0.01 - 1.27 MeV). 
NIST Standardization 
The quantification of radium-223 radioactivity in Xofigo (radium-223 
dichloride; BAY 88-8223) is based on the primary standardization performed 
by the US NIST. The National Institute of Standards and Technology prepares 
the standard reference material (SRM) using an official dial setting (primary 
standardization) as published.20 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 standardization20 
and results obtained by other national metrology institutes (United Kingdom, 
Germany, Japan). After completion of the re-assessment, NIST reported their 
findings21 and had issued a revised NIST SRM in 2015. 
The discrepancy in the NIST standardization was determined to be - 9.5% 
between activity values obtained using the old reference standard relative to 
the new primary standardization. Consequently the current numerical values 
need to be corrected by approx. + 10.5%. 
The current NIST standard for radium-223 dichloride remained in effect until 
4/25/2016. As of that date the FDA approved the regulatory variation 
submitted for Xofigo. The change in the numerical description of the patient’s 
dose, product strength and labeled vial activity does not impact the safety or 
efficacy of Xofigo. The change in the NIST radium-223 standard has no 
impact on subjects; dose subjects are receiving, and will continue to receive. 
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Principal Investigator: Neeraj Agarwal, MD 
Subjects will receive the same actual dose and volume that was studied in 
Study 15245 (BC1-06 dosimetry study) and is associated with the proven 
safety and efficacy of Radium Ra 223 dichloride, though the stated nominal 
radiation dose received is being updated to reflect the new standard.  
3.1.2 Mechanism of Action 
The active moiety of Radium Ra 223 dichloride is the alpha particle-emitting 
isotope radium-223, 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. 
3.1.3 Preclinical 
In single and repeated dose toxicity studies in rats, the main findings were 
reduced body weight gain, hematological changes, reduced serum alkaline 
phosphatase and microscopic findings in the bone marrow (depletion of 
hematopoietic 
cells, 
fibrosis), 
spleen 
(secondary 
extra-medullary 
hematopoiesis) and bone (depletion of osteocytes, osteoblasts, osteoclasts, 
fibro-osseous lesions, disruption / disorganization of the physis / growth line). 
These findings were related to radiation-induced impairment of 
hematopoiesis and a reduction of osteogenesis and occurred beginning in the 
dose range of 20 (0.00056 mCi) – 80 kBq (0.0022 mCi) per kg body weight, 
with the exception of body weight decreases. 
Dose-limiting myelotoxicity was seen in dogs after single administration of 
450 kBq (0.012 mCi) Radium Ra 223 dichloride per kg body weight (9 times 
the clinically recommended dose).  
Osteosarcomas, a known effect of bone-seeking radionuclides, were observed 
at clinically relevant doses in rats 7 to 12 months after the start of treatment. 
Osteosarcomas were not observed in dog studies. The presence of neoplastic 
changes, other than osteosarcomas, was also reported in longer term (12 to 15 
months) rat toxicity studies. Due to its mode of action, and as seen with 
conventional radiotherapy and other radiotherapeutics, radium-223 may have 
the potential to induce secondary malignancies. No case of osteosarcoma has 
been reported in clinical studies with Radium Ra 223 dichloride. The risk for 
patients to develop osteosarcomas with exposure to Radium Ra 223 
dichloride is unknown at present.  
Studies on reproductive and developmental toxicity have not been performed. 
Since Radium Ra 223 dichloride binds to bone, the potential risk for toxic 
effects in the male gonads in cancer patients with castration-resistant prostate 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
cancer is very low, but cannot be excluded. Studies on the mutagenic and 
carcinogenic potential of Radium Ra 223 dichloride have not been performed. 
No histological changes were observed in organs involved in the excretion of 
Radium Ra 223 dichloride. No significant effects were seen on vital organ 
systems, i.e. cardiovascular (dog), respiratory, or central nervous systems 
(rat), after single dose administration of 450 to 1000 kBq (0.012 to 0.027 mCi) 
per kg body weight (9 [dog] to 20 [rat] times the clinically recommended 
dose. 
3.1.4 Clinical Experience Summary 
The clinical development of Radium Ra 223 dichloride includes phase I and 
phase II studies in prostate cancer patients with bone metastases. The results 
of these completed studies indicated that Radium Ra 223 dichloride in CRPC 
/ HRPC patients with bone metastases was safe and well tolerated, and that 
there was evidence of dose related efficacy against bone markers and other 
markers of disease. In addition there was an effect on median overall survival 
in a Phase II (BC1-02) placebo-controlled study. These studies enabled the 
initiation of the Phase III ALSYMPCA (ALpharadin in SYMptomatic 
Prostate CAncer) study. 
The clinical safety and efficacy of Radium Ra 223 dichloride have been 
evaluated in a double-blind, randomized, multiple dose, phase III multicenter 
study (ALSYMPCA) in castration-resistant prostate cancer patients with bone 
metastases. The primary efficacy endpoint was Overall Survival (OS).  
At the cut-off date of the pre-planned interim analysis, a total of 809 patients 
were randomized 2:1 to receive Radium Ra 223 dichloride 50 kBq (0.0014 
mCi)/kg intravenously every 4 weeks for 6 cycles (N = 541) plus best standard 
of care or matching placebo plus best standard of care (N = 268). Best 
standard of care included local external beam radiotherapy, corticosteroids, 
antiandrogens, estrogens, estramustine or ketoconazole.  
An updated descriptive analysis of safety and of OS was performed in 921 
randomized patients prior to implementing crossover (i.e. offering patients in 
the placebo group to receive Radium Ra 223 dichloride treatment). 
The results of both interim and updated analysis revealed that OS was 
significantly longer in patients treated with Radium Ra 223 dichloride plus 
best standard of care compared to patients treated with placebo plus best 
standard of care. For the updated analysis, an increase in median overall 
survival of 3.6 months was seen with Radium Ra 223 dichloride plus best 
standard of care compared to placebo plus best standard of care (HR = 0.695 
(95% CI: 0.581,0.832), median OS 14.9 vs. 11.3 months, respectively). 
In the ALSYMPCA study, the results of the interim analysis and the updated 
analysis also showed a significant improvement in all main secondary 
endpoints in the Radium Ra 223 dichloride arm compared to the placebo arm: 
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• Time to first SRE (defined as time to EBRT, time to first 
pathological bone fracture, time to spinal cord compression and time 
to surgical intervention) was statistically significantly longer in the 
radium-223 chloride group compared to placebo (median number of 
months = 15.6 for radium-223 chloride versus 9.8 months for 
placebo [HR = 0.658, 95% CI: 0.522, 0.830, p = 0.00037]). 
• Time to total ALP progression (defined as ≥ 25% increase compared 
to baseline / nadir) was statistically significantly longer in the 
radium-223 chloride group, 7.4 months compared to 3.8 months in 
the placebo group (HR = 0.167, 95% CI: 0.129, 0.217; p < 0.00001). 
• Time to PSA progression (defined as a ≥ 25% increase and an 
increase in absolute value of ≥ 2 ng/mL compared to baseline/nadir 
) was also significantly prolonged in patients receiving Radium Ra 
223 dichloride compared to patients receiving placebo (HR = 0.643, 
95% CI: 0.539, 0.768; p < 0.00001). 
• A total ALP response (defined as a confirmed ≥ 30% or ≥ 50% 
reduction compared to baseline) at week 12 was observed in higher 
proportions of subjects who were treated with radium-223 chloride 
group (47% and 3% respectively) compared to those in the placebo 
group (3% and < 1% respectively).  
• Subgroup survival analysis showed a consistent survival benefit for 
treatment with Radium Ra 223 dichloride, independent of total 
alkaline phosphatase, current use of bisphosphonates, prior use of 
docetaxel and baseline ECOG status. The results from the phase III 
ALSYMCA study regarding time to external beam radiation therapy 
(EBRT) for pain relief and fewer patients reporting bone pain as an 
adverse event in the Radium Ra 223 dichloride group indicate a 
positive effect on bone pain.  
The most common adverse reactions (≥ 10%) in patients receiving Radium 
Ra 223 dichloride were nausea, diarrhea, vomiting, and peripheral edema 
(Table 3). Grade 3 and 4 adverse events were reported among 57% of Radium 
Ra 223 dichloride-treated patients and 63% of placebo-treated patients. The 
most common hematologic laboratory abnormalities in Radium Ra 223 
dichloride-treated patients (≥ 10%) were anemia, lymphocytopenia, 
leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment 
discontinuations due to adverse events occurred in 17% of patients who 
received Radium Ra 223 dichloride and 21% of patients who received 
placebo. 
The most common hematologic laboratory abnormalities leading to 
discontinuation for Radium Ra 223 dichloride were anemia (2%) and 
thrombocytopenia (2%). 
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Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which 
the incidence for Radium Ra 223 dichloride exceeds the incidence for 
placebo. 
Table 3: Adverse Reactions in the Randomized Trial 
System/Organ Class  
Preferred Term  
Radium Ra 223 
dichloride (n = 600) 
Placebo 
 (n = 301) 
Grades 
1-4 % 
Grades 
3-4 % 
Grades 
1-4 % 
Grades 
3-4 % 
Blood and lymphatic system disorders  
Pancytopenia  
2  
1  
0  
0  
Gastrointestinal disorders  
Nausea  
36  
2  
35  
2  
Diarrhea  
25  
2  
15  
2  
Vomiting  
19  
2  
14  
2  
General disorders and administration site conditions  
Peripheral edema 
13  
2  
10  
1  
Renal and urinary disorders  
Renal failure and impairment  
3  
1  
1  
1  
Laboratory Abnormalities 
Table 4 shows hematologic laboratory abnormalities occurring in > 10% of 
patients and for which the incidence for Radium Ra 223 dichloride exceeds 
the incidence for placebo. 
Table 4: Hematologic Laboratory Abnormalities 
Laboratory values were obtained at baseline and prior to each 4-week cycle. 
Hematologic 
Laboratory 
Abnormalities  
Xofigo (n = 600)  
Placebo (n = 301)  
Grades 1-4  
Grades 3-4  
Grades 1-4  Grades 3-4  
%  
%  
%  
%  
Anemia  
93  
6  
88  
6  
Lymphocytopenia  
72  
20  
53  
7  
Leukopenia  
35  
3  
10  
< 1  
Thrombocytopenia  
31  
3  
22  
< 1  
Neutropenia  
18  
2  
5  
< 1  
As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of 
patients on Radium Ra 223 dichloride and in 2% of patients on placebo. 
Among patients who received Radium Ra 223 dichloride, grade 3-4 
thrombocytopenia occurred in 1% of docetaxel naïve patients and in 4% of 
patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
1% of docetaxel naïve patients and in 3% of patients who have received prior 
docetaxel. 
Fluid Status 
Dehydration occurred in 3% of patients on Radium Ra 223 dichloride and 1% 
of patients on placebo. Radium Ra 223 dichloride increases adverse reactions 
such as diarrhea, nausea, and vomiting which may result in dehydration. 
Monitor patients oral intake and fluid status carefully and promptly treat 
patients who display signs or symptoms of dehydration or hypovolemia. 
Injection Site Reactions 
Erythema, pain, and edema at the injection site were reported in 1% of 
patients on Radium Ra 223 dichloride. 
Secondary malignant neoplasms 
No cases of radiation-induced cancers have been reported in clinical trials 
with radium-223 dichloride in follow-up of up to three years. However, the 
radiation dose resulting from therapeutic exposure may result in higher 
incidence of cancers (e.g. sarcomas of the bone, or leukemia), mutations, and 
a potential for development of hereditary defects. 
Bone Marrow Suppression 
In the randomized trial, 2% of patients on the Radium Ra 223 dichloride arm 
experienced bone marrow failure or ongoing pancytopenia compared to no 
patients treated with placebo. There were two deaths due to bone marrow 
failure and for 7 of 13 patients treated with Radium Ra 223 dichloride, bone 
marrow failure was ongoing at the time of death. Among the 13 patients who 
experienced bone marrow failure, 54% required blood transfusions. Four 
percent (4%) of patients on the Radium Ra 223 dichloride arm and 2% on the 
placebo arm permanently discontinued therapy due to bone marrow 
suppression. 
In the randomized trial, deaths related to vascular hemorrhage in association 
with myelosuppression were observed in 1% of Radium Ra 223 dichloride-
treated patients compared to 0.3% of patients treated with placebo. The 
incidence of infection-related deaths (2%), serious infections (10%), and 
febrile neutropenia (< 1%) were similar for patients treated with Radium Ra 
223 dichloride and placebo. 
Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, 
and leukopenia; has been reported in patients treated with Radium Ra 223 
dichloride. In the randomized trial, complete blood counts (CBCs) were 
obtained every 4 weeks prior to each dose and the nadir CBCs and times of 
recovery were not well characterized. In a separate single-dose phase 1 study 
of Radium Ra 223 dichloride, neutrophil and platelet count nadirs occurred 2 
to 3 weeks after Radium Ra 223 dichloride administration at doses that were 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
up to 1 to 5 times the recommended dose, and most patients recovered 
approximately 6 to 8 weeks after administration. 
In the radium-223 arm of the Phase 3 clinical trial reported in Parker et al. 
(2013),8,19 12.7% (76 / 600) of subjects had grade 3+ anemia, 6.5% (39 / 600) 
of subjects had grade 3+ thrombocytopenia, and 2.2% (13 / 600) of subjects 
had grade 3+ neutropenia. 
Hematologic evaluation of patients must be performed at baseline and prior 
to every dose of Radium Ra 223 dichloride. Before the first administration of 
Radium Ra 223 dichloride, the absolute neutrophil count (ANC) should be ≥ 
1.5 × 109/L, the platelet count ≥ 100 × 109/L, and hemoglobin ≥ 10 g/dL. 
Before subsequent administrations of Radium Ra 223 dichloride, the ANC 
should be ≥ 1 × 109/L and the plateletcount ≥ 50 × 109/L. If there is no 
recovery to these values within 6 to 8 weeks after the last administration of 
Radium Ra 223 dichloride,despite receiving supportive care, further 
treatment with Radium Ra 223 dichloride should be discontinued. Patients 
with evidence of compromised bone marrow reserve should be monitored 
closely and provided with supportive care measures when clinically indicated. 
Discontinue Radium Ra 223 dichloride in patients who experience life-
threatening complications despite supportive care for bone marrow failure. 
The safety and efficacy of concomitant chemotherapy with Radium Ra 223 
dichloride have not been established. Outside of a clinical trial, concomitant 
use with chemotherapy is not recommended due to the potential for additive 
myelosuppression. If chemotherapy, other systemic radioisotopes, or 
hemibody external radiotherapy are administered during the treatment period, 
Radium Ra 223 dichloride should be discontinued. 
3.2 Enzalutamide 
3.2.1 Clinical Experience with Enzalutamide 
In the randomized clinical trial in patients with metastatic castration-resistant 
prostate cancer who had previously received docetaxel, patients received 
XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The 
median duration of treatment was 8.3 months with XTANDI and 3.0 months 
with placebo. All patients continued androgen deprivation therapy. Patients 
were allowed, but not required, to take glucocorticoids. During the trial, 48% 
of patients on the XTANDI arm and 46% of patients on the placebo arm 
received glucocorticoids. All adverse events and laboratory abnormalities 
were graded using NCI CTCAE version 4.  
The most common adverse drug reactions (≥ 5%) reported in patients 
receiving XTANDI in the randomized clinical trial were asthenia / fatigue, 
back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal 
pain, headache, upper respiratory infection, muscular weakness, dizziness, 
insomnia, lower respiratory infection, spinal cord compression and cauda 
equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 
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and higher adverse reactions were reported among 47% of XTANDI-treated 
patients and 53% of placebo-treated patients. Discontinuations due to adverse 
events were reported for 16% of XTANDI-treated patients and 18% of 
placebo-treated patients. The most common adverse reaction leading to 
treatment discontinuation was seizure, which occurred in 0.9% of the 
XTANDI-treated patients compared to none (0%) of the placebo-treated 
patients. Table 5 shows adverse reactions reported in the randomized clinical 
trial that occurred at a ≥ 2% absolute increase in frequency in the XTANDI 
arm compared to the placebo arm.  
Table 5: Adverse Reactions in the Randomized Trial 
 
XTANDI N = 800 
Placebo N = 399 
Grade 1-4 
(%) 
Grade 3-4 
(%) 
Grade 1-4 
(%) 
Grade 3-4 
(%) 
General Disorders 
Asthenic Conditions 
50.6 
9.0 
44.4 
9.3 
Peripheral Edema 
15.4 
1.0 
13.3 
0.8 
Musculoskeletal And Connective Tissue Disorders 
Back Pain 
26.4 
5.3 
24.3 
4.0 
Arthralgia 
20.5 
2.5 
17.3 
1.8 
Musculoskeletal Pain 
15.0 
1.3 
11.5 
0.3 
Muscular Weakness 
9.8 
1.5 
6.8 
1.8 
Musculoskeletal Stiffness 
2.6 
0.3 
0.3 
0.0 
Gastrointestinal Disorders 
Diarrhea 
21.8 
1.1 
17.5 
0.3 
Vascular Disorders 
Hot Flush 
20.3 
0.0 
10.3 
0.0 
Hypertension 
6.4 
2.1 
2.8 
1.3 
Nervous System Disorders 
Headache 
12.1 
0.9 
5.5 
0.0 
Dizziness 
9.5 
0.5 
7.5 
0.5 
Spinal Cord Compression 
and Cauda Equina 
Syndrome 
7.4 
6.6 
4.5 
3.8 
Paresthesia 
6.6 
0.0 
4.5 
0.0 
Mental Impairment 
Disorders 
4.3 
0.3 
1.8 
0.0 
3.2.2 Efficacy 
The efficacy and safety of XTANDI in patients with metastatic castration-
resistant prostate cancer who had received prior docetaxel-based therapy were 
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assessed in a randomized, placebo-controlled, multicenter phase 3 clinical 
trial. The primary endpoint was overall survival. A total of 1199 patients were 
randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once 
daily (N = 800) or placebo orally once daily (N = 399). All patients continued 
androgen deprivation therapy. Patients were allowed, but not required to 
continue or initiate glucocorticoids. Study treatment continued until disease 
progression (evidence of radiographic progression, a skeletal-related event, 
or clinical progression), initiation of new systemic antineoplastic treatment, 
unacceptable toxicity, or withdrawal. Patients with a history of seizure, taking 
medicines known to decrease the seizure threshold, or with other risk factors 
for seizure were not eligible. 
The following patient demographics and baseline disease characteristics were 
balanced between the treatment arms. The median age was 69 years (range 41 
to 92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% 
Asian, and 2.1% Other. Ninety-two percent (92%) of patients had an ECOG 
performance status score of 0-1 and 28% had a mean Brief Pain Inventory 
score ≥ 4. Ninety-one percent (91%) of patients had bone metastases and 23% 
had visceral involvement in the lung and / or liver. Fifty-nine percent (59%) 
of patients had radiographic evidence of disease progression and 41% had 
PSA-only progression on study entry. All patients had received prior 
docetaxel-based therapy and 24% had received two cytotoxic chemotherapy 
regimens. During the trial, 48% of patients on the XTANDI arm and 46% of 
patients on the placebo arm received glucocorticoids.  
The pre-specified interim analysis at the time of 520 events showed a 
statistically significant improvement in overall survival in patients on the 
XTANDI arm compared to patients on the placebo arm (Table 6).  
Table 6. Overall Survival of Patients Treated with Either XTANDI or 
Placebo (intent-to-Treat Analysis) 
 
XTANDI N=800 
Placebo N=399 
Number of Deaths (%)  
308 (38.5%)  
212 (53.1%)  
Median Survival 
(months) (95% CI)  
18.4 (17.3, NR)  
13.6 (11.3, 15.8)  
P-value  
< 0.0001  
Hazard Ratio (95% CI) 
0.63 (0.53, 0.75)  
3.2.3 Pharmacokinetics and Drug Metabolism 
The pharmacokinetics of enzalutamide and its major active metabolite (N-
desmethyl enzalutamide) were evaluated in patients with metastatic 
castration-resistant prostate cancer and healthy male volunteers. The plasma 
enzalutamide pharmacokinetics are adequately described by a linear two-
compartment model with first-order absorption.  
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Absorption  
Following oral administration (XTANDI 160 mg daily) in patients with 
metastatic castration-resistant prostate cancer, the median time to reach 
maximum plasma enzalutamide concentrations (Cmax) is 1 hour (range 0.5 to 
3 hours). At steady state, the plasma mean Cmax values for enzalutamide and 
N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL (30% 
CV), respectively, and the plasma mean predose trough values are 11.4 
μg/mL (26% CV) and 13.0 μg/mL (30% CV), respectively.  
With the daily dosing regimen, enzalutamide steady state is achieved by Day 
28, and enzalutamide accumulates approximately 8.3-fold relative to a single 
dose. Daily fluctuations in enzalutamide plasma concentrations are low (mean 
peak-to-trough ratio of 1.25). At steady state, enzalutamide showed 
approximately dose proportional pharmacokinetics over the daily dose range 
of 30 to 360 mg.  
A single 160 mg oral dose of XTANDI was administered to healthy 
volunteers with a high-fat meal or in the fasted condition. A high-fat meal did 
not alter the AUC to enzalutamide or N-desmethyl enzalutamide.  
Distribution and Protein Binding  
The mean apparent volume of distribution (V/F) of enzalutamide in patients 
after a single oral dose is 110 L (29% CV).  
Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. 
N-desmethyl enzalutamide is 95% bound to plasma proteins.  
Metabolism  
Following single oral administration of 160 mg of 14C-enzalutamide, plasma 
samples were analyzed for enzalutamide and its metabolites up to 77 days 
post dose. Enzalutamide, N-desmethyl enzalutamide, and a major inactive 
carboxylic acid metabolite accounted for 88% of the 14C-radioactivity in 
plasma, representing 30%, 49%, and 10%, respectively, of the total 14C-
AUC0-inf.  
In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of 
enzalutamide. Based on in vivo and in vitro data, CYP2C8 is primarily 
responsible for the formation of the active metabolite (N-desmethyl 
enzalutamide).  
Elimination  
Enzalutamide is primarily eliminated by hepatic metabolism. Following 
single oral administration of 160 mg of 14C-enzalutamide, 85% of the 
radioactivity is recovered by 77 days post dose: 71% is recovered in urine 
(including only trace amounts of enzalutamide and N-desmethyl 
enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged 
enzalutamide and 1% as N-desmethyl enzalutamide).  
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The mean apparent clearance (CL/F) of enzalutamide in patients after a single 
oral dose is 0.56 L/h (range 0.33 to 1.02 L/h).  
The mean terminal half-life (t1/2) for enzalutamide in patients after a single 
oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral 
dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-
desmethyl enzalutamide is approximately 7.8 to 8.6 days.  
Pharmacokinetics in Special Populations  
Renal Impairment 
A population pharmacokinetic analysis (based on pre-existing renal function) 
was carried out with data from 59 healthy male volunteers and 926 patients 
with metastatic castration-resistant prostate cancer enrolled in clinical trials, 
including 512 with normal renal function (CrCL ≥ 90 mL/min), 332 with mild 
renal impairment (CrCL 60 to < 90 mL/min), 88 with moderate renal 
impairment (CrCL 30 to < 60 mL/min), and 1 with severe renal impairment 
(CrCL < 30 mL/min). The apparent clearance of enzalutamide was similar in 
patients with pre-existing mild and moderate renal impairment (CrCL 30 to < 
90 mL/min) compared to patients and volunteers with normal renal function. 
The potential effect of severe renal impairment or end stage renal disease on 
enzalutamide pharmacokinetics cannot be determined as clinical and 
pharmacokinetic data are available from only one patient. 
Hepatic Impairment 
The 
plasma 
pharmacokinetics 
of 
enzalutamide 
and 
N-desmethyl 
enzalutamide were examined in volunteers with normal hepatic function (N 
= 16) and with pre-existing mild (N = 8, Child-Pugh Class A) or moderate (N 
= 8, Child-Pugh B) hepatic impairment. XTANDI was administered as a 
single 160 mg oral dose. The composite AUC of enzalutamide plus N-
desmethyl enzalutamide was similar in volunteers with mild or moderate 
baseline hepatic impairment compared to volunteers with normal hepatic 
function. Clinical and pharmacokinetic data are not available for patients with 
severe hepatic impairment (Child-Pugh Class C). 
Body Weight and Age 
Population pharmacokinetic analyses showed that weight (range: 46 to 163 
kg) and age (range: 41 to 92) do not have a clinically meaningful influence 
on the exposure to enzalutamide.  
Gender 
The effect of gender on the pharmacokinetics of enzalutamide has not been 
evaluated.  
 
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Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
Race 
The majority of patients in the randomized clinical trial were Caucasian (> 
92%). There are insufficient data to evaluate potential differences in the 
pharmacokinetics of enzalutamide in other races. 
3.2.4 Summary of Non Clinical Experience 
Long-term animal studies have not been conducted to evaluate the 
carcinogenic potential of enzalutamide.  
Enzalutamide did not induce mutations in the bacterial reverse mutation 
(Ames) assay and was not genotoxic in either the in vitro mouse lymphoma 
thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus 
assay.  
Based on nonclinical findings in repeat-dose toxicology studies, which were 
consistent with the pharmacological activity of enzalutamide, male fertility 
may be impaired by treatment with XTANDI. In a 26-week study in rats, 
atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day 
(equal to the human exposure based on AUC). In 4- and 13-week studies in 
dogs, hypospermatogenesis and atrophy of the prostate and epididymides 
were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on 
AUC).  
Refer to the Investigator’s Brochure for additional information about 
enzalutamide. 
4 
STUDY DESIGN 
4.1 Description 
This is a phase 2, open label, randomized, two arm study in men with 
progressive metastatic CRPC who have previously received docetaxel or are 
ineligible for docetaxel and who are candidates for treatment with 
enzalutamide alone or enzalutamide in combination with radium-223. The 
study will assess the difference between the combinatorial treatment and 
enzalutamide alone on the bone metabolism markers, including the decrease 
in N-telopeptide levels (i.e. decrease of 0.603 in log2 N-telopeptides) from 
baseline to after 6 months of protocol treatment, as well as assess the safety 
and feasibility of the combinatorial regimen.  
The study has an initial non-randomized single arm portion (enzalutamide + 
radium-223, n = 8 patients) followed by a randomized (2:1) portion 
comparing enzalutamide + radium-223 versus enzalutamide alone (n = 39 
patients) as shown in Figure 1 below.  
 
 
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Principal Investigator: Neeraj Agarwal, MD 
Figure 1: Initial Single Arm Non-Randomizd Design Changed to Two 
Arm Randomized 2 to 1 Design 
 
Only those patients enrolled on the randomized portion of the trial will be 
used for primary endpoint analysis. Patients enrolled on the non-randomized 
portion will be used for secondary and exploratory analyses only. 
4.2 Number of Patients 
Forty-seven patients (50 total to account for any inevaluable patients) will be 
enrolled in the study. Twelve patients will be enrolled on the control arm 
(enzalutamide alone) and thirty-five patients (27 randomized patients + 8 
patients enrolled prior to randomization who will be used for secondary and 
exploratory analyses only) will be enrolled on the combination arm 
(enzalutamide + radium-223) . 
4.3 Number of Study Centers 
This is a single-center study to be conducted at Huntsman Cancer Institute at 
the University of Utah, Salt Lake City, Utah.  
4.4 Duration  
It is expected that all patients will be accrued within 18 months. Subjects will 
remain on study treatment for up to 6 months. Patients will be followed for a 
total of two years from the first day of protocol treatment or until death, 
whichever occurs earlier. The total study duration for a patient is expected to 
be 2 years from the time of enrollment.  
 
 
 
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Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
5 
ELIGIBILITY CRITERIA 
 
This eligibility checklist is used to determine patient eligibility and filed with signature 
in the patient research chart.  
  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Histologically documented adenocarcinoma of the prostate.  
5.1.2 _____ Men at least 18 years of age and life expectancy of ≥ 6 months. 
5.1.3 _____ ECOG performance status ≤ 2. 
5.1.4 _____ Metastatic disease as evidenced by both lymphadenopathy and 
bony metastases or just bony metastases on baseline bone scan and / or 
computed tomography (CT) scan or MRI of the abdomen and pelvis 
within 28 days of registration. Chest imaging is only required if 
clinically indicated or if there is known disease in the chest. 
5.1.5 _____ Castration resistant prostatic adenocarcinoma. Subjects must 
have castrate levels of serum testosterone (< 50 ng/dL) achieved by 
orchiectomy or LHRH agonist or antagonist therapy.  
5.1.6 _____ Previously received docetaxel or are not healthy enough per 
clinical judgment or declined to receive it. 
5.1.7 _____ Evidence of disease progression on or after the most recent 
systemic treatment defined by one of the following criteria:   
PSA: Increasing serum PSA levels as defined by the PCWG2, 
determined by 2 consecutive measurements (compared to a 
baseline or nadir value). If the third measurement is below the 
second, then a fourth measurement must be greater than the 
second. The confirming third or fourth measurement must be ≥ 2 
ng/mL. PSA progression must have occurred within 15 months 
of registration (with at least 7 days between each PSA 
measurement). Additionally, the PSA progression as described 
above should have occurred during or after the most recent 
systemic treatment for prostate cancer. 
Measurable disease: ≥ 20% increase in the sum of the short axis 
diameter of all measurable lymph nodes or the development of 
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Principal Investigator: Neeraj Agarwal, MD 
any new measurable lymphadenopathy by RECIST 1.1 and 
PCWG2 criteria. 
Non-measurable disease: 
Lymph node disease: Appearance of 1 or more new 
lymphadenopathy, and / or unequivocal worsening of non-
measurable disease when compared to imaging studies acquired 
during castration therapy or against the pre-castration studies if 
there was no response. 
Bone disease: Appearance of 2 or more new areas of abnormal 
uptake on bone scan when compared to imaging studies acquired 
during castration therapy or against the pre-castration studies if 
there was no response. Increased uptake of pre-existing lesions 
on bone scan does not constitute progression. 
5.1.8 _____ Symptomatic Bone metastases. 
5.1.9 _____ Adequate hematologic, renal, and liver function as evidenced by 
the following: 
1. 
White blood cell (WBC) ≥ 3,000 cells/μL  
2. 
Absolute neutrophil count (ANC) ≥ 1,500 cells/μL  
3. 
Platelet Count ≥ 100,000 cells/μL 
4. 
Hemoglobin (HgB) ≥ 10.0 g/dL  
5. 
Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)  
6. 
Creatinine ≤ 1.5 X ULN  
7. 
Aspartate aminotransaminase (AST, SGOT) ≤ 2.5 x ULN  
8. 
Alanine aminotransaminase (ALT, SGPT) ≤ 2.5 x ULN 
9. 
Albumin > 25 g/L 
10. Creatinine clearance > 30ml/min  
Transfusion of blood products are not allowed to normalize blood 
parameters within 4 weeks of the first Radium treatment. 
5.1.10 _____ Men must agree to use adequate contraception beginning at the 
signing of the ICF until at least 6 months after the last dose of study 
drug. Because of the potential side effect on spermatogenesis associated 
with radiation, men who are sexually active must agree to use condoms 
and their female partners of reproductive potential must agree to use a 
highly effective contraceptive method during and for 6 months after 
completing treatment.  
5.1.11 _____ Able to provide informed consent and have signed an approved 
consent form that conforms to federal and institutional guidelines to 
ensure compliance with HIPAA regulations. 
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5.2 Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
5.2.1 _____ The presence of known brain metastases, malignant pleural 
effusions, or malignant ascites. Brain MRI is required at screening only 
if clinically indicated.  
5.2.2 _____ Visceral metastases as assessed by chest, abdominal, or pelvic 
computed tomography (CT) (or other imaging modality). 
5.2.3 _____ Received systemic therapy with radionuclides (e.g., strontium-
89, samarium-153, rhenium-186, or rhenium-188, or Radium Ra 223 
dichloride) for the treatment of bony metastases. 
5.2.4 _____ Prior treatment with enzalutamide. 
5.2.5 _____ Concurrent anti-cancer therapy (chemotherapy, radiation 
therapy, surgery, immunotherapy, biologic therapy, or tumor 
embolization) other than the protocol based treatment. LHRH agonist or 
antagonist therapy, and supportive non-cancer directed therapies like 
bisphosphonates or denosumab are allowed. 
5.2.6 _____ Prior cytoxic chemotherapy with the exception of docetaxel or 
cabazitaxel. Treatment with docetaxel or cabazitaxel must be 
discontinued ≥ 4 weeks from the time of enrollment, and recovery of 
AEs to grade 1 or baseline (however, ongoing neuropathy is permitted). 
5.2.7 _____ Major surgery within 30 days prior to start of study drug. 
5.2.8 _____ Current, untreated pathologic long-bone fractures or imminent 
long-bone fractures (cortical erosion on radiography > 50%).  
5.2.9 _____ Prior hemi-body external radiotherapy. Subjects who received 
other types of prior external radiotherapy are allowed provided that bone 
marrow function is assessed and meets the protocol requirements for 
hemoglobin, ANC, and platelets. 
5.2.10 _____ Use of biologic response modifiers, such as granulocyte 
macrophage colony-stimulating factor (GM-CSF) or granulocyte 
colony-stimulating factor (G-CSF) within 4 weeks prior to screening.  
5.2.11 _____ Lymphadenopathy exceeding 3 cm in short-axis diameter. 
5.2.12 _____ Any size pelvic lymphadenopathy if it is thought to be a 
contributor to concurrent hydronephrosis. 
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Principal Investigator: Neeraj Agarwal, MD 
5.2.13 _____ Current or imminent spinal cord compression based on clinical 
findings and / or magnetic resonance imaging (MRI). Treatment should 
be completed for spinal cord compression. 
5.2.14 _____ Any other serious illness or medical condition in the opinion of 
the investigator, such as but not limited to: 
o 
Any Grade ≥ 2 infection as defined by NCI-CTCAE version 
4.03.  
o 
Cardiac failure New York Heart Association (NYHA) III or 
IV. 
o 
Crohn’s disease or ulcerative colitis. 
o 
Bone marrow dysplasia. 
o 
Fecal incontinence. 
5.2.15 _____ Concomitant use of narrow therapeutic index drugs that are 
metabolized 
by 
CYP3A4 
(i.e. 
alfentanil, 
cyclosporine, 
dihydroergotamine, 
ergotamine, 
fentanyl, 
pimozide, 
quinidine, 
sirolimus, tacrolimus), CYP2C9 (phenytoin, warfarin), and CYP2C19 
(S-mephenytoin). [Note: Patients on stable doses of anti-coagulation 
with warfarin and fentanyl will be eligible, as long as they are monitored 
closely with additional INR monitoring]. A complete list can be found 
at: http://medicine.iupui.edu/clinpharm/ddis/main-table/. 
5.2.16 _____ Any infection requiring parenteral antibiotic therapy or causing 
fever (temperature > 100.5 °F or 38.1 °C) within 1 week prior to 
registration.  
5.2.17 _____ Concurrent other malignancy with the exception of: a) cutaneous 
squamous cell and basal carcinomas, b) adequately treated stage 1-2 
malignancy , c) adequately treated stage 3-4 malignancy that had been 
in remission for ≥ 2 years at the time of registration.  
5.2.18 _____ Inability to comply with the protocol and/or not willing or not 
available for follow-up assessments. 
5.2.19 _____ Any medical intervention or other condition which, in the 
opinion of the Principal Investigator could compromise adherence with 
study requirements or otherwise compromise the study’s objectives. 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment 
onto this study.  
 
______________________________ 
 
_____________ 
_______ 
Investigator Signature  
 
 
 
Date 
 
 
Time 
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Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
6 
TREATMENT PLAN 
6.1 Administration Schedule 
1 cycle = 28 days 
Repeat for a total of 6 cycles 
Control Arm: 
Enzalutamide 160 mg will be orally administered once a day (continuously) for 6 
cycles. 
Combination Arm: 
Radium Ra 223 dichloride, 55 kBq/kg** body weight, will be administered as a 
bolus intravenous (IV) injection (up to 1 minute) on Day 1 of each cycle.  
Enzalutamide 160 mg will be orally administered once a day (continuously).  
 
** The dose of radium was 50 kBq/kg body weight prior to implementation of 
the NIST update. 
6.2 Radium Ra 223 Dichloride Treatment  
6.2.1 How Supplied, Stored, Packaged and Labeled 
The alpha-pharmaceutical Radium Ra 223 dichloride is a ready-to-use, 
sterile, non-pyrogenic, clear and colorless aqueous solution of Radium Ra 223 
dichloride (223RaCl2) for IV administration. It should not be diluted or mixed 
with any solutions. Each vial is supplied for 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 1100 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 (table 7). 
** The radioactive concentration at the reference date was 1000 kBq/mL 
prior to implementation of the NIST update. 
Radium Ra 223 dichloride will be obtained through commercial supply. It is 
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.  
The volume per vial is 6 mL, corresponding to 6.6 MBq** at the calibration 
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 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
demonstrated for temperatures from cold storage (2 to 8 °C) up to 40 °C. In 
addition, it has been shown that the product quality is not jeopardized upon 
freezing. 
** The volume per vial (6 mL) corresponded to 6.0 MBq prior to 
implementation of the NIST update. 
The Radium Ra 223 dichloride vials must be stored inside their lead container 
in a secure facility. The study drug should be used within 28 days of 
production. Radium Ra 223 dichloride is an alpha-pharmaceutical and should 
be handled by individuals who are qualified by training and experience in the 
safe handling of radionuclides. One dedicated person and a back-up designee 
will have responsibility as assigned from the Primary Investigator for 
handling and storage 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. 
6.2.2 Preparation and Administration 
Radium Ra 223 dichloride, 55 kBq/kg body weight (50 kBq/kg body weight 
prior to implementation of the NIST update), will be administered as a bolus 
intravenous (IV) injection (up to 1 minute) at intervals of every 4 weeks for 
up to 6 cycles. 
6.2.2.1 Dose Calibration 
Radium Ra 223 dichloride can be measured in a normal dose 
calibrator instrument, available at cancer centers and clinics 
certified to administer radium-223.  
When written approvals for the use of Radium Ra 223 dichloride 
from the Radiation Protection Agency for the specific center have 
been received by the sponsor, a vial of Radium Ra 223 dichloride 
for technical use will be sent to the study center (a new reference 
vial will be sent to each center corresponding to the updated NIST 
reference material). 
Each center must perform the Radium Ra 223 dichloride dial 
setting on their relevant dose calibrator(s) (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, 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
including the calibration log form, will be enclosed with the 
dispatch of the calibration sample. 
The updated NIST standardization became effective on 
4/25/2016. 
6.2.2.2 Dosimetry 
The absorbed radiation dose calculation was performed based on 
clinical biodistribution data. Calculations of absorbed doses were 
performed using OLINDA/EXM (Organ Level INternal Dose 
Assessment/EXponential Modeling), a software based on the 
Medical Internal Radiation Dose (MIRD) algorithm, which is 
widely used for established beta and gamma emitting 
radionuclides. For radium-223, which is primarily an alpha 
emitter, additional assumptions were made for the intestine, red 
marrow and bone/osteogenic cells to provide the best possible 
absorbed dose calculations for Radium Ra 223 dichloride, 
considering 
its 
observed 
biodistribution 
and 
specific 
characteristics. 
For an administered activity of 3.65 MBq or 0.0987 mCi (which 
corresponds to 50 kBq or 0.00135 mCi per kg body weight to a 
73-kg adult), the calculated absorbed doses to the bone 
(osteogenic cells) is 4.2050 Gy (420.5 rad) and to the red marrow 
is 0.5066 Gy (50.66 rad). The calculated absorbed doses to the 
main excretory organs are 0.0265 Gy (2.65 rad) for the small 
intestine wall, 0.1180 Gy (11.8 rad) for the upper large intestine 
wall and 0.1696 Gy (16.96 rad) for the lower large intestine wall.  
The calculated absorbed doses to other organs are low, e.g. heart 
wall (0.0063 Gy, 0.63 rad), lung (0.0003 Gy, 0.03 rad), liver 
(0.0109 Gy, 1.09 rad), kidneys (0.0117 Gy, 1.17 rad), urinary 
bladder wall (0.0147 Gy, 1.47 rad), testes (0.0003 Gy, 0.03 rad), 
and spleen (0.0003 Gy, 0.03 rad).  
The hematological adverse drug reactions observed in the clinical 
studies with Ra-223 are much lower in frequency and severity than 
what could be expected from the calculated absorbed doses to the 
red marrow. This may be related to spatial distribution of alpha 
particle radiation resulting in non-uniform radiation dose to the red 
marrow. 
6.2.2.3 Dose Calculation 
The dosage of Radium Ra 223 dichloride is 55 kBq (1.49 
microcuries) per kg body weight (it was 50 kBq/kg or 1.35 µCi/kg 
prior to implementation of the NIST update). 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
The patient dose is calculated based on date of injection, a decay 
correction (DK) factor specific to number of days from reference 
date applied to correct for physical decay of radium-223 , and 
patient weight. A table with DK values according to physical 
decay of the study medication will be provided with every 
shipment of Radium Ra 223 dichloride (also see table 7).  
Radium-223 is an alpha particle emitter with a physical t1/2 of 11.4 
days. The radioactive concentration at the reference date is 1100 
kBq/mL (it was 1000 kBq/mL prior to implementation of the 
NIST update).  
The volume to be administered for the current dose is calculated 
as follows: 
Body weight (kg) ×  dose (55 kBq kg body weight)
⁄
DK factor × 1100 kBq kg body weight
⁄
  
 
Table 7: Decay Correction Factor Table (DK factor) 
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 
6.2.2.4 Dose Preparation 
Personnel should use appropriate protective clothing and 
equipment during syringe filling and application to prevent 
contamination with the radioactive solution (medical gloves / 
protective glasses). The individual responsible for study drug 
preparation will draw the correct volume of study drug into a 
syringe. The size of the syringe should be chosen according to the 
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Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
applied volume to reach the required dosing accuracy. Radium Ra 
223 dichloride should not be diluted or mixed with any solutions. 
Do not store above 40 °C (104 °F). If the vials have been stored in 
a refrigerator, they should be left at room temperature for 1 hour 
prior to use, since cold material should not be injected in a patient. 
Store Radium Ra 223 dichloride in the original container or 
equivalent radiation shielding. This preparation is approved for 
use by persons under license by the Nuclear Regulatory 
Commission or the relevant regulatory authority of an Agreement 
State. 
6.2.2.5 Dose Administration 
Before administration of study drug, the patient must be well 
hydrated; the patient should be instructed to drink ad libitum. 
Aseptic technique should be used in the administration of Radium 
Ra 223 dichloride. The syringe should be handed over to the 
individual who will perform the injection. The study medication 
will be administered as a bolus intravenous (IV) injection (up to 1 
minute). After administration, the equipment used in connection 
with the preparation and administration of drug is to be treated as 
radioactive waste and should be disposed in accordance with local 
procedure for the handling of radioactive material.  
If a patient has travel or insurance difficulties with standard of care 
administration of Radium Ra 223 dichloride, the investigator may 
prescribe drug administration through the patient’s local 
oncologist’s office as long as source documentation of dosing 
calculations and administration can be provided to the study site. 
All study visits including day one procedures for each cycle, 
however, must be conducted at the study site. This option should 
only be used in rare situations for the benefit of the patient. 
6.2.3 General Warning 
Radium Ra 223 dichloride should be received, used and administered only by 
authorized persons in designated clinical settings. The receipt, storage, use, 
transfer and disposal Radium Ra 223 dichloride are subject to the regulations 
and / or appropriate licenses of the competent official organization. Radium 
Ra 223 dichloride should be handled by the user in a manner which satisfies 
both radiation safety and pharmaceutical quality requirements. Appropriate 
aseptic precautions should be taken. 
6.2.4 Radiation Protection 
The administration of Radium Ra 223 dichloride is associated with potential 
risks for other persons (e.g. medical staff, care givers and members of the 
patient’s family) from radiation or contamination from spills of body fluids 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
such as urine, feces, or vomit. Therefore, radiation protection precautions 
must be taken in accordance with national and local regulations. 
For drug handling 
Follow 
the 
normal 
working 
procedures 
for 
the 
handling 
of 
radiopharmaceuticals and use universal precautions for handling and 
administration such as gloves and barrier gowns when handling blood and 
bodily fluids to avoid contamination. In case of contact with skin or eyes, the 
affected area should be flushed immediately with water. In the event of 
spillage of Radium Ra 223 dichloride, the local radiation safety officer should 
be contacted immediately to initiate the necessary measurements and required 
procedures to decontaminate the area. A complexing agent such as 0.01 M 
ethylene-diaminetetraacetic acid (EDTA) solution is recommended to remove 
contamination. 
For patient care 
Whenever possible, patients should use a toilet and the toilet should be 
flushed several times after each use. When handling bodily fluids, simply 
wearing gloves and hand washing will protect caregivers. Clothing soiled 
with Radium Ra 223 dichloride or patient fecal matter or urine should be 
washed promptly and separately from other clothing. 
Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy 
emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and 
the fraction emitted as gamma-radiation is 1.1%. The external radiation 
exposure associated with handling of patient doses is considerably lower in 
comparison to other radiopharmaceuticals for therapeutic purposes as the 
administered radioactivity will usually be below 8000 kBq or 216 µCi. In 
keeping with the As Low As Reasonably Achievable (ALARA) principle, for 
minimization of radiation exposure, it is recommended to minimize the time 
spent in radiation areas, to maximize the distance to radiation sources, and to 
use adequate shielding. Any unused product or materials used in connection 
with the preparation or administration are to be treated as radioactive waste 
and should be disposed of in accordance with local regulations. The gamma 
radiation associated with the decay of radium-223 and its daughters allows 
for the radioactivity measurement of Radium Ra 223 dichloride and the 
detection of contamination with standard instruments. 
6.2.5 Destruction and Return 
At the end of the study, unused supplies of Ra 223 dichloride should be 
destroyed according to institutional policies. Destruction will be documented 
in the Drug Accountability Record Form. The certificate of destruction should 
be sent to Bayer. 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
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6.3 Enzalutamide Treatment 
6.3.1 How Supplied, Stored, Packaged and Labeled 
Enzalutamide 
has 
the 
chemical 
name 
4-{3-[4-cyano-3-
(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-
1-yl}-2-fluoro-N-methylbenzamide. It is a white to off-white solid that is 
insoluble in water and no salt forms are available at approximately pH 2 to 
10. The drug substance is formulated in the surfactant caprylocaproyl 
polyoxylglycerides, or Labrasol®. The product will be supplied as white to 
off-white gelatin capsules containing 40 mg of enzalutamide. 
6.3.2 Preparation and Administration 
Patients will take 160 mg (4 capsules) of enzalutamide orally once daily. 
Study drug should be taken as close to the same time each day as possible. 
Study drug can be taken with or without food. 
6.4 Accountability and Compliance 
All study drugs will be stored at the investigational site in accordance with Good 
Clinical Practice (GCP) and Good Manufacturing Practices (GMP) requirements 
and the instructions given by the clinical supplies department of the Institution and 
will be inaccessible to unauthorized personnel. 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the agent 
(investigational or free of charge) using the NCI Drug Accountability Record or 
another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the 
drug accountability form). 
6.5 Concomitant Medications 
All medication that is considered necessary for the subject’s welfare, and which is 
not expected to interfere with the evaluation of the study treatment, may be given 
at the discretion of the investigator. Collection of opioid-use in morphine equivalent 
will be captured on the case report forms  
Permitted  
• Treatment with non-conventional therapies (e.g., herbs [with the exception 
of St. John’s Wart], acupuncture) and vitamin / mineral supplements is 
acceptable provided that, in the opinion of the investigator, such treatment 
will not interfere with the trial endpoints. 
• Subjects may receive standard of care for any underlying illness. 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
• In the event of neutropenia, anemia, or thrombocytopenia, subjects may 
receive appropriate supportive care (e.g., transfusion, biologic response 
modifiers such as G-CSF or GM-CSF, prophylactic antibiotics, antifungals 
and/or antivirals, hematopoietic growth factors). This supportive care 
should not substitute a recommended dose modification. Once the 
recommended dose modification has occurred, prophylactic G-CSF or GM-
CSF may be used per institutional standard of care to prevent future events. 
• Blood transfusions and erythropoietin are allowed during the study period 
but not within 4 weeks prior to the first dose of Radium.  
• Bisphosphonates and denosumab are allowed at screening and throughout 
the study. Concomitant use with these agents should be documented in the 
patient records. 
• LHRH agonists and antagonists are allowed at screening and throughtout 
the study. Concomitant use with these agents should be documented in the 
patient records. 
• If surgery is required during study drug treatment, the surgeon needs to be 
notified that the patient has been treated with a radioactive product and 
adequate precautions for radioactive protection should be applied during the 
surgical procedure. The patient should continue with study treatment if 
considered safe in the treating Investigator's opinion. 
Excluded concomitant therapies and medications 
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, or tumor embolization) other than 
Radium Ra 223 dichloride. 
• Concurrent use of another investigational drug or device therapy (i.e., 
outside of study treatment) during, or within 4 weeks of trial entry (signing 
of the informed consent form). 
• Clinical data indicate that enzalutamide is a strong inducer of CYP3A4 and 
a moderate inducer of CYP2C9 and CYP2C19. Concomitant use of 
enzalutamide with narrow therapeutic index drugs that are metabolized by 
CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g., 
phenytoin, warfarin), and CYP2C19 (e.g., S-mephenytoin) should be 
avoided as enzalutamide may decrease their exposure. If co-administration 
with warfarin cannot be avoided, conduct additional INR monitoring. 
• Co-administration of a strong CYP2C8 inhibitor (e.g., gemfibrozil) 
increased the composite AUC0-∞ of enzalutamide plus its active metabolite 
in healthy volunteers; therefore, co-administration of enzalutamide with 
strong CYP2C8 inhibitors should be avoided if possible. If co-
administration of enzalutamide with strong CYP2C8 inhibitors cannot be 
avoided, reduce the enzalutamide dose to 80 mg once daily. If co-
administration of the strong inhibitor is discontinued, the enzalutamide dose 
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should be returned to the dose used prior to initiation of the strong CYP2C8 
inhibitor. 
The effects of CYP2C8 inducers on the PK of enzalutamide have not been 
evaluated in vivo. Co-administration of enzalutamide with strong or 
moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure 
of enzalutamide and should be avoided if possible. Selection of a 
concomitant medication with no or minimal CYP2C8 induction potential is 
recommended. 
• The effects of CYP3A4 inducers on the PK of enzalutamide have not been 
evaluated in vivo. Co-administration of enzalutamide with strong CYP3A4 
inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, 
rifampin, rifapentine) may decrease the plasma exposure of enzalutamide 
and should be avoided if possible. Selection of a concomitant medication 
with no or minimal CYP3A4 induction potential is recommended. Moderate 
CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, 
nafcillin) and St. John’s Wort may also reduce the plasma exposure of 
enzalutamide and should be avoided if possible. 
6.6 Protocol specified Duration of Therapy  
Patients will receive up to 6 cycles of single agent enzalutamide or Radium Ra 223 
dichloride and enzalutamide. If patients have a radium cycle delayed, the study 
visits will continue per the calendar and the dose will be missed.Treatment may be 
discontinued earlier if one of the following below criteria is met. 
Subjects must be withdrawn from the trial (during protocol treatment and follow-
up) for the following reasons:  
• Subject withdraws consent from study treatment and study procedures. A 
subject must be removed from the trial at his / her own request or at the 
request of his / her legally acceptable representative. At any time during the 
trial and without giving reasons, a subject may decline to participate further. 
The subject will not suffer any disadvantage as a result. 
• Subject is lost to follow-up. 
• Anti-cancer therapy not prescribed by the study protocol is required. 
• A treatment delay of more than 9 weeks between 2 injections of Radium Ra 
223 dichloride.  
• Disease Progression. During the protocol specified treatment, disease 
progression will be defined per PCWG2 progression criteria. After protocol 
defined therapy, the progression will be defined per clinical discretion of 
the treating clinician. 
• Death. 
Subjects may be withdrawn from the study for the following reasons: 
• The subject is non-compliant with study drug, trial procedures, or both.  
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• If, in the investigator's opinion, continuation of the trial would be harmful 
to the subject's well-being. 
• Development of a second cancer (other than superficial skin cancers, such 
as squamous cell carcinoma or basal cell carcinoma).  
• Development of an intercurrent illness or situation which would, in the 
judgment of the investigator, significantly affect assessments of clinical 
status and trial endpoints. 
• Deterioration of ECOG performance status to 4. 
• Use of illicit drugs or other substances that may, in the opinion of the 
investigator, have a reasonable chance of contributing to toxicity or 
otherwise skewing trial result. 
In all cases, the reason for withdrawal must be recorded in the CRF and in the 
subject's medical records. 
A subject who discontinues study participation prematurely for any reason is 
defined as a “dropout” if the subject has already been enrolled / registered. 
A subject who, for any reason (e.g. failure to satisfy the selection criteria), 
terminates the study before the time point used for the definition of “dropout” (see 
above) is regarded a “screening failure”. 
Patients withdrawn prior to the C3D1 blood draw or determined to be not evaluable 
for the primary objectives may be replaced per investigators discretion.  
7 
TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 4.03 for adverse event and serious adverse event reporting. A copy of 
the CTCAE 
Version 
4.03 can 
be 
downloaded 
at 
http://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx. 
7.1 Dose Modifications Radium Ra 223 Dichloride 
Every effort should be made to administer the full dosing regimen of Radium Ra 
223 dichloride. Adjustment of dose level is not permitted.  
Study visits during the treatment period should occur at 4 weeks intervals (within a 
window of ± 7 days). If a patient requires a toxicity related dose delay of more than 
9 weeks between 2 injections, then the patient must be discontinued from the study. 
If patients have a radium cycle delayed, the study visits will continue per the 
calendar and the dose will be missed. Dosing delays may be instituted under the 
following circumstances: 
7.1.1 Myelosuppression  
Treatment-related changes in hematology parameters may occur. Results 
from the CBC must be reviewed prior to drug administration on Day 1. The 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
following parameters must be met for the patient to proceed with treatment: 
platelets ≥ 50 × 109/L, ANC ≥ 1.0 × 109/L and hemoglobin ≥ 8 g/dL. 
• 
If a patient experiences CTCAE v4.03 Grade 3 or 4 neutropenia, 
thrombocytopenia, or anemia the administration of study drug should 
be delayed until recovery to Grade 2 or better.  
• 
If a patient experiences CTCAE v4.03 Grade 3 or 4 neutropenia, 
thrombocytopenia, or anemia lasting > 14 days, further study drug 
administrations must be discontinued.  
• 
Blood transfusion is acceptable between study drug administrations 
but not within 4 weeks prior to the start of Radium treatment. Use of 
biologic response modifiers, such as G-CSF or GM-CSF, is allowed 
in the management of acute toxicity. After the appropriate dose 
modification for acute toxicity, G-CSF or GM-CSF may be used 
prophylactically for subsequent study treatments per institutional 
standard of care. 
7.1.2 Gastrointestinal events 
Diarrhea should be treated as per local practice. For Grade 3 or 4 diarrhea, a 
further dose of study medication should not be given before diarrhea is 
recovered to CTCAE v4.03 Grade 2 or baseline levels.  
Nausea or vomiting should be treated as per local practice. For Grade 3 nausea 
or grade 3 or 4 vomiting, a further dose of study medication should not be 
given before nausea or vomiting is recovered to CTCAE v.4.03 Grade 2 or 
baseline levels. 
7.1.3 
Spinal Cord Compression 
If the patient experiences spinal cord compression during the treatment 
period, the patient should be treated for the event, and may receive further 
study drug administration if adequately recovered.  
7.1.4 
Surgical Intervention 
If surgery is required, the patient should continue with study treatment, if this 
is considered safe in the treating Investigator’s opinion. The surgeon needs to 
be notified that the patient has been given radioactive drug, and needs to 
follow the guidelines for radioactive protection.  
7.1.5 
Non-pathological fractures 
For traumatic fractures in weight-bearing bones during treatment phase, the 
study drug administration should be delayed for 2-4 weeks from the time of 
fracture.  
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7.1.6 
Pathological fractures 
Pathological fractures may occur as the result of either progressive disease or 
increased physical activity associated with significant pain palliation. 
Pathologic fractures are to be treated in a manner that attempts to maintain 
the best functional status and quality of life. Study treatment may continue as 
planned. 
7.1.7 
Any Other Toxicity 
If a subject experiences any non-hematological CTCAE v4.03 Grade 4 
toxicity, attributable to the study drugs, lasting more than 7 days despite 
adequate treatment, further study drug administration must be discontinued. 
7.2 Dose Modifications Enzalutamide 
Patients who experience a Grade 3 or greater toxicity attributed to enzalutamide, 
which cannot be ameliorated by the use of adequate medical intervention, may have 
their drug treatment interrupted for 1 week or until the toxicity grade improves to 
Grade 2 or lower severity. Enzalutamide may then be restarted at the same or a 
reduced dose (120 mg then 80 mg). 
 
 
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Principal Investigator: Neeraj Agarwal, MD 
8 STUDY CALENDAR 
1 cycle = 28 days12 
Examination 
Screening1 
C1 
C2 
C3 
C4 
C5 
C6 
End of 
Treatment10 
Survival 
Follow-up11 
 
 
Day 1 
Day 1 
Day 16,7 
Day 1 
Day 17 
Day 16,7 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
Vital signs (including weight) 
X 
X14 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X14 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X14 
X 
X 
X 
X 
X 
X 
 
Hematology2, 12 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry3, 12 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bone alkaline phosphatase 
(BAP)4 
X 
X 
X 
X 
X 
X 
X 
X 
 
PSA5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INR monitoring13 
X 
Imaging Studies (CT & bone 
scans)6 
X 
 
 
 
X 
 
 
X 
X 
Bone Markers7 
 
X 
 
X 
 
X 
 
X7 
 
Assessment of Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
Enzalutamide9 
 
X 
X 
X 
X 
X 
X 
 
 
Combination arm only: 
Radium Ra 223 dichloride8 
 
X 
X 
X 
X 
X 
X 
 
 

Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
1  
ALL Pre-study / Screening procedures should be completed within 4 weeks of study enrollment - with the exception of laboratory tests 
which need to be completed within 2 weeks prior to study enrollment. 
2  
Hematology includes CBC with differential and platelets. CBC must be completed within 2 weeks of study enrollment and prior to treatment 
(± 7 days) on day 1 of each cycle.  
3  
Chemistry includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Calcium, 
Carbon Dioxide, Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, and Urea Nitrogen. 
4  
Bone alkaline phosphatase (BAP) should be done every four weeks until the end of treatment visit or disease progression (whichever comes 
earlier).  
5  
PSA is required within 28 days at screening, on day 1 of each cycle and at the end of treatment visit. PSA laboratory assessments should be 
performed every 4 – 6 weeks after the end of treatment visit until disease progression, or the start of another treatment.  
6  
CT and bone scans should be conducted at screening, end of cycle 3 (prior to C4D1 treatment), and at the end of treatment visit (4 weeks 
post last treatment). Follow-up scans will be performed as clinically indicated until documented PD per treating clinician or until the start 
of another treatment. Scans should include CT scan of abdomen and pelvis. Imaging of the chest is only required if clinically indicated.  
7  
Bone markers collected at baseline (C1D1), C3D1, C5D1, EOT and at disease progression (whichever comes earlier); to include procollagen 
Type 1 intact N-terminal Propeptide (NTP) and resorption (N-telopeptide [NT], C-Telopeptide beta-cross linked [CTB] and pyridinoline). 
8  
Radium Ra 223 dichloride 55 kBq/kg** on day 1 of every cycle for up to 6 cycles (** 50 kBq/kg prior to implementation of the NIST 
update). 
9  
Enzalutamide 160 mg daily.  
10  
End of Treatment visit should be conducted 4 weeks post C6D1. 
11  
For all patients who receive study treatment, follow-up for survival will occur approximately every 8 weeks following end of treatment or 
as clinically indicated for up to 2 years post enrollment or death. 
12  
All procedures for day 1 of each treatment cycle have a ±7 day window. 
13  
Subjects receiving concomitant medication with warfarin should have INR monitored more frequently as clinically indicated. 
14  
If the physical exam, ECOG score, and vital signs are done with in 28 days of C1D1 they do not need to be repeated at this time-point. 
 
 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
9 
CRITERIA FOR EVALUATION AND ENDPOINT 
9.1 Assessment of bone metabolism:  
Serum will be collected at various time points (at baseline and during protocol 
treatment). Markers of bone formation (C-terminal collagen propeptide, CICP and 
bone alkaline phosphatase, BAP) and resorption (N-telopeptide, pyridinoline) will 
be analyzed using standard technical methods at the ARUP lab at the University of 
Utah.  
9.2 Assessment of clinical outcomes:  
Clinical outcomes (time to PSA progression, time to first skeletal event, opioid 
usage, overall survival) will be assessed at various time points from the start of 
protocol treatment. Patients will be followed for a total of two years from the day 
of start of protocol treatment 
9.3 Safety  
All subjects who receive at least one dose of study treatment will be valid for the 
safety analysis.  
All observations pertinent to the safety of the study treatment will be recorded and 
included in the final report. 
All AEs whether considered drug-related or not, will be reported with a diagnosis, 
start / stop dates, action taken, whether treatment was discontinued, any corrective 
measures taken, outcome, and other possible causes. For all events, the relationship 
to treatment and the intensity of the event will be determined by the investigator. 
This trial will use the NCI-CTCAE v4.03 criteria for assessment of toxicity and 
SAE reporting with regard to toxicity grade.  
Safety variables may include but not limited to the following: laboratory changes 
(complete blood counts, electrolytes, chemistry, and coagulation), changes in vital 
signs (blood pressure, heart rate, respiratory rate, and temperature), ECG, and, in 
some instances, changes in chest x-ray images, as produced at the investigator’s 
discretion (e.g., for evaluation for pneumonia). 
Routine safety and tolerability will be evaluated from the results of reported signs 
and symptoms, scheduled physical examinations, vital sign measurements, and 
clinical laboratory test results. More frequent safety evaluations may be performed 
if clinically indicated or at the discretion of the investigator.  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a 
licensed physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be 
obtained in the sitting position. Patients should be sitting for 3-5 minutes prior to 

Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
obtaining vital signs. Weight will be taken at the start of each cycle while the patient 
is on Radium Ra 223 dichloride. 
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the calendar.  
9.3.1 Interim Analysis for Safety 
There will be no formal interim analysis of the efficacy data. 
An interim analysis of the safety data will be conducted during the study. The 
interim analysis will be conducted when 10 subjects have completed 
treatment with 6 injections of radium-223 dichloride or discontinued study 
treatment early. The purpose of this interim analysis is to formally review 
safety data and to assess whether it is acceptable to continue enrollment of 
subjects. The review of the safety data in this interim analysis will be 
conducted by the HCI Data Safety Review Committee (DSMC). A proportion 
of subjects with grade 3 or higher hematologic adverse events significantly 
more than those reported for the radium-223 arm of the Phase 3 trial would 
be evidence of unacceptable toxicity. In particular, four or more grade 3+ 
anemias, three or more grade 3+ thrombocytopenias, or three or more grade 
3+ neutropenias in ten subjects would be statistically significantly higher than 
expected (at the one-sided 0.05 significance level).19 An adjustment may be 
made to these numbers if the proportion of patients with prior chemotherapy 
is higher than the 59% reported in Parker et al (2013).19 
A final safety analysis will be conducted when all 35 evaluable subjects have 
completed 6 doses of treatment, plus the end of treatment visit (30 days post-
last dose), or discontinued treatment early. 
9.4 Efficacy 
9.4.1 Pre-study Documentation of Progressive Disease 
Patients must have documented PD either by radiographic or PSA criteria as 
defined in Inclusion Criterion # 5.1.6 in Section 5.1. 
Both radiographic PD and PSA PD must be assessed to evaluate eligibility; 
however, only one criterion (radiographic PD or PSA PD) must be met for 
Inclusion Criterion # 5.  
PSA will be assessed at time points shown in the Schedules of Events. 
Scans (CT/MRI) of the abdomen and pelvis and radionuclide bone scans will 
be used to monitor and assess disease response and progression, as described 
in the Schedule of Events. CT imaging of the chest is only required at baseline 
if clinically indicated. If disease is found in the chest, lesions should be 
followed by CT scan. The imaging modality for each patient must remain 
constant throughout the study. Additional scans should be performed at the 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
investigator’s discretion if progression is suspected or to confirm the 
existence of bone lesions.  
During the protocol specified treatment, disease progression will be defined 
per PCWG2 progression criteria. After completion of protocol defined 
therapy, the progression will be defined per clinical discretion of the treating 
clinician. Patients who complete study treatment without documented disease 
progression will continue to be followed by scans and PSA per the follow-up 
outlined in the study calendar until progression is seen or new treatment is 
started. All patients, regardless of date of progression, will be followed for 2 
years post study enrollment for overall survival. 
9.4.2 
Radiographic Disease Assessment According to Prostate Cancer 
Clinical Trials Working Group (PCWG2) and Modified Response 
Criteria in Solid Tumors (RECIST Version 1.1) 
Radiographic Disease Assessment will be performed using the PCWG2 
guidelines. The PCWG2 recommends that for soft tissue lesions RECIST 1.1 
assessment be applied and that results be compiled separately from the overall 
disease assessment, which includes both bone scan and RECIST 1.1 results. 
Under RECIST 1.1, radionuclide bone scan lesions are considered not 
measurable, and hence nontarget. Under RECIST, bone scan progression 
occurs when the changes are “unequivocal.” Under PCWG2, however, 
radionuclide bone scan results are treated semi-quantitatively and occurrence 
of new lesions may define progression as outlined further below. For this 
protocol, soft tissue and bone scan disease are evaluated separately, and the 
results of each are then considered in an overall radiographic disease 
assessment. 
9.4.3 Recording Baseline Assessments 
All sites of disease, target and nontarget lesions must be assessed at baseline. 
Patients with visceral metastases will be excluded from the protocol. 
Objective disease status is to be recorded at each evaluation using the 
response categories and definitions provided in this section. 
9.4.4 Soft Tissue Lesion Assessment 
Selection of Target and Nontarget Lesions 
Selection of a Lymph Node as a Target Lesion 
Only lymph nodes with a longest diameter ≥ 2 cm and a minimum short axis 
diameter ≥ 1.5 cm by CT scan will be considered as target lesions at baseline. 
All other lesions may be considered as nontarget, and are to be identified but 
not specifically measured at baseline, with the exception of bone scan 
metastases, which are identified and enumerated. 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
9.4.5 Response Definitions for RECIST-Evaluable Soft Tissue Lesions 
9.4.5.1 
Definition of Complete Response (CR) 
 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) must have reduction in short 
axis to < 10 mm. 
9.4.5.2 
Definition of Partial Response (PR) 
 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum of longest diameters of non-
lymph node lesions and of the short diameter(s) or short axis 
(SA) of lymph nodes. 
9.4.5.3 
Definition of Stable Disease (SD) 
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
of diameters while on study. 
9.4.5.4 
Definition of Soft Tissue Progression 
 
At least a 20% increase in the sum of longest diameters of target 
lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. 
 
NOTE: The appearance of 1 or more new measurable lesions is 
also considered progression. 
9.4.5.5 
Assessment of Soft Tissue Time Point Response 
 
The following table summarizes the RECIST 1.1 response status 
calculation at each time point for patients who have measurable 
soft tissue disease at baseline. Note that this assessment does not 
include bone scan assessment and is not the overall assessment 
of radiographic disease status. 
Table 8: Time Point Response: Patients with Target ( + Nontarget) 
Disease 
Target lesions 
Nontarget lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
Version Date: 02-06-17 
Principal Investigator: Neeraj Agarwal, MD 
SD 
Non-PD or not all 
evaluated 
No  
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any  
Any 
Yes 
PD 
 
Source: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford 
R, et al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. 
Abbreviations: CR = complete response; PR = partial response; SD = stable 
disease; PD = progressive disease; NE = not evaluable. 
9.4.6 Radionuclide Bone Scan Assessment 
9.4.6.1 Assessment 
Bone scan lesions should be enumerated at baseline. Questionable 
lesions, eg, sites of previous fracture, may require confirmation by 
CT or MRI. 
9.4.6.2 Post baseline Assessments and Definition of Progression of 
Bone Metastatic Disease Based on Radionuclide Bone Scan 
Bone scan lesions should be assessed and enumerated at each 
follow-up assessment. 
Progression on bone scan is defined as 2 or more new lesions on 
radionuclide bone scans. Should 2 or more new bone lesions be 
evident at the first assessment on treatment (end of cycle 3), 2 or 
more additional new lesions must be evident on a confirmatory 
assessment at least 6 weeks later (and no sooner than end of cycle 
6). This confirmation is not required when 2 or more new lesions 
(compared to baseline or to the end of cycle 3 assessment) first 
appear after the first follow-up assessment, ie, at end of cycle 6 or 
thereafter. 
Should new bone lesions be documented at end of cycle 3 but not 
confirmed at end of cycle 6, then end of cycle 3 scan becomes the 
new baseline and 2 or more new lesions at subsequent assessments 
relative to end of cycle 3 defines bone scan progression. 
Stable disease (SD) on bone scan stable disease is defined as the 
absence of progression. Bone scan lesions are considered non-
evaluable under RECIST, and thus there can be no partial 
response. Complete response is very rare. Thus, almost all bone 
scans will be rated as NE (no lesions present), SD, or PD. 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
9.4.7 Overall Response Assessment 
The following table summarizes the overall response status calculation at 
each time point for patients who have either RECIST 1.1 evaluable soft tissue 
lesions and / or radionuclide bone scan lesions. Note that CR can only occur 
if there are RECIST 1.1-evaluable lesions and no bone lesions based on 
radionuclide bone scan. PR can occur if patients have CR or PR based on soft 
tissue evaluation and bone scan lesions that are stable. 
Table 9: Overall Assessment Time Point Response 
PCWG2 Target/Nontarget soft 
tissue/RECIST 1.1 
Bone Scan (PCWG2) 
 
Overall 
 
CR 
No Metastases 
CR 
CR,PR 
SD 
PR 
SD 
SD 
SD 
PD 
SD 
PD 
SD 
PD 
PD 
9.4.8 Progression Free Survival  
Progression Free Survival by prostate-specific antigen (PSA) will be assessed 
for each patient on this study. Time to PSA progression is the time from the 
date of the first study drug administration to the first date that PSA 
progression is observed, according to the definitions below. Patients will have 
their PSA levels measured monthly while on study treatment. After the end 
of treatment visits, PSA assessments should be performed every 4-6 weeks 
visit until disease progression, or the start of another treatment.  
Definition of PSA response: 
• ≥ 30% reduction of the blood level, compared to the baseline value. 
• ≥ 50% reduction of the blood level, compared to the baseline value. 
• ≥ 90% reduction of the blood level, compared to the baseline value. 
• Confirmed PSA response: ≥ 50% reduction of the blood level, 
compared to the baseline value, confirmed by a second PSA value 
approximately 4 or more weeks later. 
Definition of PSA Progression:  
• In patients with no PSA decline from baseline; ≥ 25% increase from 
baseline value and an increase in absolute value of ≥ 2 ng/mL, at least 
12 weeks from baseline.  
• In patients with initial PSA decline from baseline; the PSA increase 
that is ≥ 25% and at least 2 ng/mL above the nadir value, which is 
confirmed by a second value obtained three or more weeks later.  
Changes and time to progression in total-ALP: 
• Total-ALP response and progression; defined as for PSA above. 
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Protocol name: Radium Ra 223 Dichloride + Enzalutamide in mCRPC 
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Principal Investigator: Neeraj Agarwal, MD 
10 STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
General considerations 
Statistical analyses will be performed using Statistical Analysis Software®; the version 
to be used will be specified in the SAP. 
Determination of sample size of the randomized cohort 
Serum N-telopeptides levels are inversely associated with overall survival, based on 
data from the SWOG 0421 trial. The primary endpoint for statistical analysis for this 
study will a comparison of the change in N-telopeptides from baseline to EOT or at 
disease progression (whichever comes earlier) between the randomization groups. The 
change in log 2 N-telopeptides will be compared to the change in a control group treated 
with enzalutamide alone using an ANCOVA model with the final value as response, 
treatment group as predictor and initial log 2 N-telopeptides as an adjustment variable. 
Based on the data from the SWOG 0421 study, the estimated baseline mean and 
standard deviation of log2 N-telopeptides are 3.95 nM and 1.14 nM respectively. We 
further assume the Pearson correlation of baseline and follow up N-telopeptides is 0.50. 
With these assumptions, and with 27 evaluable patients in the radium-223 + 
enzalutamide arm and 12 evaluable patients in the enzalutamide only arm there will be 
85% power to detect a difference of 1.14 in the change in log 2 N-telopeptides between 
treatment arms using a two-sample t-test at the two-sided 0.05 significance level. 
Randomization 
A total of 39 patients will be randomized, 27 patients to the enzalutamide + radium-
223 arm and 12 patients to the control enzalutamide only arm. The Research 
Compliance Office will randomize patients and maintain the randomization table for 
this trial. 
Analysis sets 
The safety population, which includes all subjects who receive at least one dose of 
study drug, will be used for the safety analysis. 
The randomized population, which includes randomized subjects with follow up to 
EOT or disease progression (which ever comes earlier) will be used for the primary 
efficacy analysis. This population excludes patients enrolled prior to randomization. 
The combined population includes all subjects treated with enzalutamide + radium-223 
or enzalutamide alone with follow up to EOT or disease progression (which ever comes 
earlier). This population includes subjects enrolled prior to randomization with 
sufficient follow up. The combined population will be used for secondary and 
exploratory analyses. 
10.1 Primary Endpoint Analyses 
The co-primary endpoints are efficacy, safety and feasibility: 
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1. The primary efficacy endpoint is the change in serum N-telopeptides from 
baseline to end of treatment or progression (whichever comes earlier).  
2. The primary safety endpoint is grade 3 or higher non hematological adverse 
events. The safety population will be used for all safety analyses. Safety 
analyses will be stratified by treatment arm. 
10.1.1 Primary Bone Marker Analysis 
Concomitant treatment with radium-223 (a bone targeting agent) and 
enzalutamide (a tumoricidal agent) is expected to decrease the level of N-
telopeptides. As mentioned in the Background Section, serum N-telopeptides 
levels are inversely associated with overall survival, based on data from the 
SWOG 0421 trial. The primary endpoint for statistical analysis for this study 
will be the change in log 2 N-telopeptides from baseline to EOT or at disease 
progression (whichever comes earlier) between the randomization groups. If 
a bone marker test is missed at a given time point, every effort will be made 
to obtain the bone marker levels as early as possible. If two subsequent bone 
marker tests are missed, the patient will be excluded from the analysis. 
Equality of the change in log2 N-telopeptides between the treatment arms will 
be tested using an ANCOVA model with treatment group as the primary 
predictor and initial log 2 N-telopeptides as adjustment variable. 
As a sensitivity analysis an F-test for equality of variance of final log2 N 
telopeptides will be performed. If the null hypothesis is rejected at the 0.1 
significance level an additional ANCOVA model allowing for unequal 
variances will be fit. 
10.1.2 Additional Analyses of the Primary Endpoint 
Separate analyses in the combined population will be performed in subjects 
treated with enzalutamide + radium-223 and subjects treated with 
enzalutamide alone. If a bone marker test is missed at a given time point, 
every effort will be made to obtain the bone marker levels as early as possible. 
If two subsequent bone marker tests are missed, patient will excluded from 
the analysis. 
Based on the data from the SWOG 0421 study, the estimated baseline mean 
and standard deviation of log2 N-telopeptides are 3.95 nM and 1.14 nM 
respectively. We further assume the Pearson correlation of baseline and 
follow up N-telopeptides is 0.50. With 35 evaluable subjects there will be 
80% power to detect a change of 0.556 in log2 N-telopeptides using a paired 
t-test. Extrapolating from SWOG0421, a decrease of 0.556 in log2 N-
telopeptide concentration would translate into an approximate 20% increase 
in median overall survival. 
10.1.3 Primary Safety Analyses 
An overall proportion of subjects with grade 3 or higher hematologic adverse 
events significantly higher than those reported for the radium-223 arm of 
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Parker et al. (2013) would be evidence of unacceptable toxicity.8,19 The sum 
of the proportion of subjects in Parker et al. (2013) with grade 3+ anemia, 
thrombocytopenia, or neutropenia is 21%. An exact binomial test will be 
performed at the one sided 0.05 significance level comparing the proportion 
of subjects with one or more of grade 3+ anemia, thrombocytopenia, or 
neutropenia to 21%. With a safety population of 35 evaluable patients, 13 or 
more patients with one or more of grade 3+ anemia, grade 3+ 
thrombocytopenia, or grade 3+ neutropenia would indicate an unacceptable 
hematologic adverse event rate.  
Exact 90% confidence intervals will be calculated for adverse events and 
serious AEs. With 35 evaluable patients an exact 90% confidence interval for 
an AE will extend no more than 17.5% from the observed proportion, and 
there is a 90% probability that an adverse event with a probability of 6.4% 
will be observed at least once. 
10.2 Secondary Endpoint Analyses 
All other statistical analyses will be descriptive in nature. Exploratory comparisons 
may be made between treatment arms of the randomized population. For all 
analyses of the combined population each treatment arm will be analyzed 
separately. In general, summary statistics (n, mean, standard deviation, median, 
minimum, and maximum for continuous variables, and number of subjects and 
percentage in each category for categorical variables) will be provided. Time to 
event variables will be summarized using Kaplan-Meier curves, and their medians 
will be estimated using the Kaplan-Meier method. 
Additionally, source data for summaries will be presented as subject data listings. 
The details for analyses will be specified in the SAP. 
Secondary and Exploratory Variables 
The exploratory variables include: 
• 
rPFS 
• 
Time to radiological bone progression 
• 
Total ALP response rate 
• 
Time to total ALP progression 
• 
Percentage change in total ALP 
• 
PSA response rate 
• 
Time to PSA progression 
• 
Time to first skeletal related event (as defined below) 
• 
OS for 2 years after enrollment 
• 
Percent change in opioid requirement (in morphine equivalent) during 
protocol treatment. 
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Skeletal related events include the following: 
• 
Time to occurrence of first use of external beam radiotherapy to relieve 
skeletal symptoms 
• 
Time to occurrence of first tumor related orthopedic surgical intervention 
• 
Time to occurrence of first spinal cord compression 
• 
Time to occurrence of first new symptomatic pathological bone fractures 
(vertebral and non-vertebral) 
10.3 Exploratory Analyses 
Exploratory analyses will be performed on the combined population. For additional 
exploratory purposes, Kaplan-Meier curves and estimates will be presented for time 
to event variables (rPFS, time to radiological bone progression, time to total ALP 
progression, time to PSA progression, OS, time to first SRE). 
Frequencies and percentages will be provided for categorical variables (total ALP 
response rate, PSA response rate, pain response rate). Summary statistics (n, mean, 
standard deviation, median, minimum, and maximum) will be presented for 
continuous variables (percentage change in total ALP). 
Further details, including handling missing data and additional censoring details, 
will be described in the SAP. 
11 REGISTRATION GUIDELINES 
Patients must meet all of the eligibility requirements listed in Section 5 prior to 
registration.  
Study related screening procedures can only begin once the patient has signed a 
consent form. Patients must not begin protocol treatment prior to registration. 
Treatment should start within fourteen days after registration. The date of registration 
will be the date of enrollment. 
To register eligible patients on study, complete a Clinical Trials Office Patient 
Registration Form and submit to: CTORegistrations@hci.utah.edu. 
Treatment to Enzalutamide and Radium or Enzalutamide alone will be assigned at the 
time of enrollment. A randomization code will be created by a biostatistician and given 
to the Research Compliance Office to maintain and assign treatment to each patient as 
they are enrolled.  
12 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient 
that provides a record of the data generated according to the protocol. CRF’s should be 
created prior to the study being initiated and updated (if applicable) when amendments 
to the protocol are IRB approved. Data capture should be restricted to endpoints 
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and relevant patient information required for planned manuscripts. Data capture 
will also include a form identifying which patients received bisphosphonates or 
denosumab prior to study entry. These forms will be completed on an on-going basis 
during the study. The medical records will be source of verification of the data. During 
the study, the CRFs will be monitored for completeness, accuracy, legibility and 
attention to detail by a member of the Research Compliance Office. The CRFs will be 
completed by the Investigator or a member of the study team as listed on the Delegation 
of Duties Log. The data will be reviewed no less than annually by the Data and Safety 
Monitoring Committee. The Investigator will allow the Data and Safety Monitoring 
Committee or Research Compliance Office personnel access to the patient source 
documents, clinical supplies dispensing and storage area, and study documentation for 
the above-mentioned purpose. The Investigator further agrees to assist the site visitors 
in their activities. 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 Informed consent  
Informed consent will be obtained from all research participants prior to 
performing any study procedures using the most recent IRB approved version.  
Each subject / legal representative or proxy consenter will have ample time 
and opportunity to ask questions and will be informed about the right to 
withdraw from the study at any time without any disadvantage and without 
having to provide reasons for this decision. 
Only if the subject / legal representative or proxy consenter voluntarily agrees 
to sign the informed consent form and has done so, may he/she enter the study. 
Additionally, the investigator and other information provider (if any) will 
personally sign and date the form. The subject / legal representative or proxy 
consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site 
file or, if locally required, in the patient’s note/file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study 
procedures are performed, the study record or subject’s clinical record must 
clearly show that informed consent was obtained prior to these procedures. 
If the patient is not capable of providing a signature, a verbal statement of 
consent can also be given in the presence of an impartial witness (independent 
of Bayer and the investigator). This is to be documented by a signature from 
the informing physician as well as by a signature from the witness. 
The informed consent form and any other written information provided to 
subjects / legal representatives or proxy consenters will be revised whenever 
important new information becomes available that may be relevant to the 
subject’s consent, or there is an amendment to the protocol that necessitates a 
change to the content of the subject information and / or the written informed 
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consent form. Any revised written informed consent form and written 
information must receive the IEC/IRB`s approvaln 
13.2 Institutional Review 
Study will be approved by the Institutional Review Board of University of 
Utah. 
13.3 Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at 
Huntsman Cancer Institute (HCI) and approved by the NCI to assure the well-
being of patients enrolled on Investigator Initiated Trials that do not have an 
outside monitoring review. Roles and responsibilities of the DSMC are set 
forth in the NCI approved plan. The activities of this committee include a 
quarterly review of adverse events including SAEs, important medical events, 
significant revisions or amendments to the protocol, and approval of 
cohort/dose escalations. If the DSMC and/or the PI have concerns about 
unexpected safety issues, the study will be stopped and will not be resumed 
until the issues are resolved. The DSMC also reviews and approves audit 
reports generated by the Research Compliance Office.  
All phase II studies are reviewed by the full committee at each quarterly 
DSMC meeting. This includes a review of all serious adverse events (SAEs) 
occurring in patients treated at HCI or its affiliates as well as all grade 3 or 
greater toxicities for patients on treatment and within 30 day follow-up 
window (only if possibly, probably or definitely related).  
13.4 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for 
Adverse Events) Version 4.03 for AE and SAE reporting. An electronic copy 
of the CTCAE Version 4.03 can be downloaded from:  
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 
The sponsor is responsible to comply with the local regulation and legislation 
for adverse events reporting. 
All subjects who receive at least one dose of study treatment will be valid for 
the safety analysis.  
All AEs whether considered drug-related or not, will be reported with a 
diagnosis, start/stop dates, action taken, whether treatment was discontinued, 
any corrective measures taken, outcome, and other possible causes. For all 
events, the relationship to treatment and the intensity of the event will be 
determined by the investigator. 
Safety variables may include but not limited to the following: laboratory 
changes (complete blood counts, electrolytes, chemistry, and coagulation), 
changes in vital signs (blood pressure, heart rate, respiratory rate, and 
temperature) and ECG and, in some instances, changes in chest x-ray images, 
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as produced at the investigator’s discretion (e.g., for evaluation for 
pneumonia). 
13.4.1 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even if 
the event is not considered to be related to study drug. For the purposes of this 
study, the terms toxicity and adverse event are used interchangeably. Medical 
conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug.  
The collection of adverse events will begin after the first dose of study 
treatment and end 30 days after the last dose of study treatment (or until new 
cancer treatment is initiated, if sooner). 
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded 
and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive 
questioning of the patient at each visit or phone contact during the study. 
Adverse events also may be detected when they are volunteered by the patient 
during or between visits or through physical examination, laboratory test, or 
other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. the severity grade based on CTCAE v 4.03 (grade 1-5). 
2. its relationship to the study drug(s) (definite, probable, possible, 
unlikely, not related). 
3. its duration (start and end dates or if continuing at final exam). 
4. action 
taken 
(no 
action 
taken; 
study 
drug 
dosage 
adjusted/temporarily 
interrupted; 
study 
drug 
permanently 
discontinued due to this adverse event; concomitant medication 
taken; 
non-drug 
therapy 
given; 
hospitalization/prolonged 
hospitalization). 
5. whether it constitutes an SAE. 
All adverse events will be treated appropriately. Such treatment may include 
changes in study drug treatment as listed in the dose modification section of 
this protocol (see section 7 for guidance). Once an adverse event is detected, 
it should be followed until its resolution, and assessment should be made at 
each visit (or more frequently, if necessary) of any changes in severity, the 
suspected relationship to the study drug, the interventions required to treat it, 
and the outcome. 
Investigators should refer to the Safety Information section of the current IB 
for Ra 223 dichloride and the current IB for enzalutamide, including the DCSI 
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(development core safety information), for the expected side effects of Ra 223 
dichloride. This information will be included in the patient informed consent 
and will be discussed with the patient during the study as needed. As with any 
agent, there is always the potential for unexpected AEs, including 
hypersensitivity reactions. The IB will be updated if any new relevant safety 
data are obtained. 
Therapeutic monitoring should be performed following dose selection of Ra 
223 dichloride in a manner consistent with the local clinical standard of care. 
In general, subjects should be closely monitored for side effects of all 
concomitant medications regardless of the path of drug elimination. 
All adverse events will be immediately recorded in the patient research chart.  
13.4.2 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. 
A serious adverse event is an undesirable sign, symptom or medical condition 
which: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• is medically significant, i.e., defined as an event that jeopardizes the 
patient or may require medical or surgical intervention to prevent 
one of the outcomes listed above 
• causes congenital anomaly or birth defect 
• requires inpatient hospitalization or prolongation of existing 
hospitalization, unless hospitalization is for: 
o routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition (procedures such 
as central line placements, paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition 
that is unrelated to the indication under study and has not 
worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not 
fulfilling any of the definitions of a SAE given above and not 
resulting in hospital admission 
o social reasons and respite care in the absence of any 
deterioration in the patient’s general condition 
If progressive disease leads to signs and symptoms that meet the criteria for 
an SAE (i.e., hospitalization, disability, death, or important medical event), 
the signs and symptoms should be reported as an SAE and not the underlying 
progressive disease. 
Any death from any cause while a patient is receiving treatment on this 
protocol or up to 30 days after the last dose of protocol treatment, or any death 
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which occurs more than 30 days after protocol treatment has ended but which 
is felt to be treatment related, must be reported. 
Toxicities which fall within the definitions listed above must be reported as 
an SAE regardless if they are felt to be treatment related or not. Toxicities 
unrelated to treatment that do NOT fall within the definitions above, must 
simply be documented as AEs in the patient research chart.  
13.5 SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, the IRB, and Bayer, according to 
the requirements described below. 
A 
MedWatch 
3500A 
form 
must 
be 
completed 
and 
submitted 
to 
compliance@hci.utah.edu as soon as possible, but no later than 10 days of first 
knowledge or notification of event (5 days for fatal or life threatening event).  
The 
Medwatch 
3500A 
form 
can 
be 
found 
at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
DSMC Notifications: 
• An HCI Research Compliance Officer (RCO) will process and submit 
the MedWatch form to the proper DSMC member as necessary for 
each individual study.  
• The RCO will summarize and present all reported SAEs according to 
the Data and Safety Monitoring Plan at the quarterly DSMC meeting. 
FDA Notifications: 
• Adverse events occurring during the course of a clinical study that 
meet the following criteria will be promptly reported to the FDA: 
o Serious 
o Unexpected 
o Definitely, Probably or Possibly Related to the investigational 
drug 
• Fatal or life-threatening events that meet the criteria above will be 
reported within 24 hours after first knowledge of the event by the 
investigator; followed by as complete a report as possible within 8 
additional calendar days. 
• All other events that meet the criteria above will be reported within 15 
calendar days after first knowledge of the event by the investigator. 
• The RCO will review the MedWatch report for completeness, 
accuracy and applicability to the regulatory reporting requirements. 
• The RCO will ensure the complete, accurate and timely reporting of 
the event to the FDA. 
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• For non-IND studies - The MedWatch report will be submitted to the 
FDA through the voluntary reporting method by the Regulatory 
Coordinator. 
IRB Notification: 
• Events meeting the University of Utah IRB reporting requirements 
(http://www.research.utah.edu/irb/) will be submitted through the 
IRB’s electronic reporting system within 10 working days. 
Bayer: 
• All serious adverse events should be reported to Bayer within 24 
hours of awareness of the event and must include the 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 patient identified by one or more of the following:  
a. Patient initials  
b. Patient number  
c. Knowledge that a patient who experienced the adverse 
event exists  
d. Age  
e. Sex  
5. An investigator assessment of study drug causality. For studies 
with combination therapy, a separate causality assessment 
should be provided for each study drug.  
• Additional data which would aid the review and causality assessment 
of the case include but are not limited to:  
The date of onset  
The severity  
The time from administration of study drug(s) to start of the event  
The duration and outcome of the event  
Any possible etiology for the event  
The final diagnosis or syndrome, if known 
• All Medwatch 3500A reports shall be sent electronically to:  
Electronic mailbox: DrugSafety.GPV.US@bayer.com  
Facsimile: 
 
(973) 709-2185  
Address: 
 
Global Pharmacovigilance - USA  
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Mail only 
 
Bayer HealthCare  
 
 
 
P.O. Box 915  
 
 
 
Whippany, NJ 07981-0915  
Address: 
 
100 Bayer Blvd., Whippany, NJ 07981 
FDX or UPS only: 67 Whippany Road, Whippany NJ 07981  
Reports for all Bayer products can also be phoned in via our 
Medical Communications Department: 
Phone: 
 
1-888-842-2937 
The Principal Investigator commits to respond promptly to 
any query from Bayer regarding SAE reports. 
13.6 Pregnancies 
The investigator must report to Bayer any pregnancy occurring in a study subject’s 
partner during the subject’s participation in this study. The report should be 
submitted within the same timelines as an SAE, although a pregnancy per se is not 
considered an SAE. 
For the pregnancy of a study subject’s partner, all efforts should be made to obtain 
similar information on course and outcome, subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
13.7 Protocol Amendments 
Any amendments or administrative changes in the research protocol during the 
period, for which the IRB approval has already been given, will not be initiated 
without submission of an amendment for IRB review and approval. 
These requirements for approval will in no way prevent any immediate action 
from being taken by the investigator in the interests of preserving the safety of 
all patients included in the trial.  
13.8 Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures 
and treatment plans as outlined in the protocol version submitted and previously 
approved by the IRB. Protocol deviations have the potential to place participants at 
risk and can also undermine the scientific integrity of the study thus jeopardizing 
the justification for the research. Protocol deviations are unplanned and 
unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety 
or scientific integrity, reporting is left to the discretion of the PI within the context 
of the guidelines below. The IRB requires the prompt reporting of protocol 
deviations which meet any of the following criteria: 
• 
Exceptions to eligibility criteria. 
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• 
Intended to eliminate apparent immediate hazard to a research 
participant.  
• 
Harmful (caused harm to participants or others, or place them at 
increased risk of harm - including physical, psychological, 
economic, or social harm).  
• 
Possible serious or continued noncompliance.  
13.9 FDA Annual Reporting  
This study is IND exempt therefore there are no annual reporting requirements to 
the FDA.  
13.10 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical 
Trials Reporting Program) by the Clinical Trials Office. 
 
 
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14 BIBLIOGRAPHY 
1. 
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Nilsson S, Franzen L, Parker C, et al: Bone-targeted radium-223 in symptomatic, 
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Nilsson S, Franzen L, Parker C, et al: Two-Year Survival Follow-Up of the 
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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 
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Fontana A, Delmas PD: Markers of bone turnover in bone metastases. Cancer 
88:2952-60, 2000. 
10. Ali SM, Demers LM, Leitzel K, et al: Baseline serum NTx levels are prognostic 
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11. Lara PN, Jr., Stadler WM, Longmate J, et al: A randomized phase II trial of the 
matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate 
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12. Kamiya N, Suzuki H, Yano M, et al: Implications of serum bone turnover markers 
in prostate cancer patients with bone metastasis. Urology 75:1446-51, 2010. 
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13. Thurairaja R, Iles RK, Jefferson K, et al: Serum amino-terminal propeptide of type 
1 procollagen (P1NP) in prostate cancer: a potential predictor of bone metastases 
and prognosticator for disease progression and survival. Urol Int 76:67-71, 2006. 
14. Smith JA, Jr., Lange PH, Janknegt RA, et al: Serum markers as a predictor of 
response duration and patient survival after hormonal therapy for metastatic 
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