Clinical trial NCT02286921
Conditions: Castration Resistant Metastatic Prostate Cancer
Keywords: Testosterone Enzalutamide Abiraterone Androgen Ablative Therapies Bipolar Androgen Therapy
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2015-01-01; Completion date: 2020-02-21
Enrollment: 222 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Asymptomatic men with progressive metastatic Castration-resistant prostate cancer (CRPC) post- treatment with abiraterone acetate (pre-chemotherapy for metastatic disease) will be treated on a randomized, multi-Institutional open label study to determine if treatment with intramuscular T given on a dose/schedule designed to result in rapid cycling from the polar extremes of supraphysiologic to near castrate levels \[i.e. Bipolar Androgen Therapy (BAT)\] will improve primary and secondary objectives vs. enzalutamide as standard therapy.

Detailed description:
Eligible patients will have metastatic CRPC with no disease related symptoms and progression on Androgen deprivation therapy and will have progressed post-treatment with abiraterone. Patients will continue on Androgen deprivation therapy with Luteinising Hormone Releasing Hormone agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or Luteinising Hormone Releasing Hormone antagonist (Degarelix) if not surgically castrated throughout the duration of the study to inhibit endogenous testosterone production. Patients will be randomized 1:1 and stratified based on duration of prior abiraterone acetate therapy (6 months or less or greater than 6 months). Patients randomized to BAT (Arm A) will receive intramuscular injections with either testosterone cypionate or testosterone enanthate at a dose of 400 mg every 28 days. This dose was selected based on data demonstrating that it produces an initial supraphysiologic serum level of T (i.e. \> 1500 ng/dL or 3-10 times normal level) with eugonadal levels achieved at the end of two weeks and near castrate levels after 28 days. Patients randomized to enzalutamide (Arm B) will receive daily oral dose of 160 mg. Each cycle is defined as 28 days.

Patients will have Prostate-specific antigen level and symptoms assessment checked every cycle. Every 3 cycles patients will have repeat bone/CT scans to evaluate treatment response status. On CT scan, radiographic progression will be defined by RECIST criteria (i.e. \>20% increase in the sum of target lesions). On bone scan, radiographic progression will be defined by PCWG2 criteria as ≥ 2 new bone lesions. However, for the first reassessment scan only, patients should remain on study and have a confirmatory scan performed 12 weeks (3 cycles) later. If this confirmatory scan shows 2 or more additional new lesions, this defines progression. The date of progression is the date of the first reassessment bone scan. If the confirmatory scan does not show any additional new lesions, patient remains on study. If progression is observed on subsequent bone scans, a confirmatory scan is not required; the date of this bone scan is the date of progression.

Patients with Prostate-specific antigen progression but with disease response or stable disease on imaging studies will remain on study until radiographic or other clinical progression criteria are met. Patients with radiographic disease progression will not receive continued BAT (arm A) or enzalutamide (arm B) and will be eligible for crossover to the opposite therapy. Patients on the BAT arm A can cross over to receive enzalutamide at time of progression or can choose to go off study and be treated with other standard of care treatments. Patients on the enzalutamide arm B will be allowed to cross-over to receive BAT or can choose to go off study and be treated with other standard of care treatments.

Patients with clinical progression due to prostate cancer must meet study exclusion criteria to be permitted to cross-over to the opposite treatment. Patients with clinical progression due to pain from prostate cancer are not permitted to cross-over.

Arms: arm 1: Patients on BAT will receive testosterone cypionate or testosterone enanthate administered as an intramuscular injection. A dose of 400 mg of either agent will be injected intramuscularly (IM) every 28 days. arm 2: Patients randomized to enzalutamide will be prescribed enzalutamide 40 mg tablets and instructed to take 4 tablets per day orally for 28 days/cycle.
Interventions: intervention 1: Testosterone cypionate intervention 2: Enzalutamide intervention 3: Testosterone Enanthate
Intervention descriptions: intervention 1: Depo-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. Depo-Testosterone Injection is available in two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate. intervention 2: Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. intervention 3: Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is the oil-soluble ester of the androgenic hormone testosterone. Enanthate Injection is available as a colorless to pale yellow solution. Each mL contains 200 mg testosterone enanthate in sesame oil with 5 mg chlorobutanol as a preservative.

Protocol documents:
Prot_002.pdf: 
The TRANSFORMER Trial 
Protocol version 6.0–November 18, 2019  
Page 1 of 77 
 
 
 
A Randomized Phase II Study Comparing Bipolar Androgen Therapy vs. Enzalutamide 
in Asymptomatic Men with Castration Resistant Metastatic Prostate Cancer: 
 
The TRANSFORMER Trial 
(Testosterone Revival Abolishes Negative Symptoms, Fosters Objective Response and 
Modulates Enzalutamide Resistance) 
 
Protocol Version  6.0 
November 18, 2019 
SKCCC Protocol Number: J14146 
 
Principal Investigator:  
 
 
Samuel R. Denmeade 
Co-Principal Investigator:  
 
Mario Eisenberger 
TRANSFORMER Study Manager:         Haiyi (Harry) Cao 
Co-Investigators:   
 
 
Emmanuel Antonarakis 
Michael Carducci 
Noah Hahn 
Jun Luo 
Channing Paller 
Kenneth Pienta 
Caroline Pratz 
Victoria Sinibaldi 
Radiologist:  
 
 
 
Martin Pomper 
Biostatistician: 
 
 
 
Hao Wang 
 
 


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SYNOPSIS: 
 
Title: A Randomized Phase II Study Comparing Bipolar Androgen Therapy vs. Enzalutamide in 
Asymptomatic Men with Castration Resistant Metastatic Prostate Cancer: The TRANSFORMER Trial 
 
Objective: The primary objective of the study is to determine if treatment with supraphysiologic 
testosterone (T) will improve progression free survival compared to enzalutamide in men with 
metastatic castrate-resistant prostate cancer (CRPC) post-treatment with abiraterone.  
 
Study Design: Asymptomatic men with progressive metastatic CRPC post- treatment with abiraterone 
acetate (pre-chemotherapy for metastatic disease) will be treated on a randomized, multi-Institutional 
open label study to determine if treatment with intramuscular T given on a dose/schedule designed to 
result in rapid cycling from the polar extremes of supraphysiologic to near castrate levels [i.e. Bipolar 
Androgen Therapy (BAT)] will improve primary and secondary objectives vs. enzalutamide as standard 
therapy. 
 
Treatment Plan: Eligible patients will have metastatic CRPC with no disease related symptoms and 
progression on ADT and will have progressed post-treatment with abiraterone. Patients will continue on 
ADT with LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH antagonist (Degarelix) if not 
surgically castrated throughout the duration of the study to inhibit endogenous testosterone production.  
Patients will be randomized 1:1 and stratified based on duration of prior abiraterone acetate therapy (6 
months or less or greater than 6 months).  Patients randomized to BAT (Arm A) will receive 
intramuscular injections with either testosterone cypionate or testosterone enanthate at a dose of 400 
mg every 28 days.  This dose was selected based on data demonstrating that it produces an initial 
supraphysiologic serum level of T (i.e. > 1500 ng/dL or 3-10 times normal level) with eugonadal levels 
achieved at the end of two weeks and near castrate levels after 28 days.  Patients randomized to 
enzalutamide (Arm B) will receive daily oral dose of 160 mg.  Each cycle is defined as 28 days. 
 
Patients will have PSA level and symptoms assessment checked every cycle.  Every 3 cycles patients 
will have repeat bone/CT scans to evaluate treatment response status.  On CT scan, radiographic 
progression will be defined by RECIST criteria (i.e. >20% increase in the sum of target lesions).  On 
bone scan, radiographic progression will be defined by PCWG2 criteria as ≥ 2 new bone lesions 
(Appendix 7). However, for the first reassessment scan only, patients should remain on study and have 
a confirmatory scan performed 12 weeks (3 cycles) later.  If this confirmatory scan shows 2 or more 
additional new lesions, this defines progression.  The date of progression is the date of the first 
reassessment bone scan.  If the confirmatory scan does not show any additional new lesions, patient 
remains on study.  If progression is observed on subsequent bone scans, a confirmatory scan is not 
required; the date of this bone scan is the date of progression (Appendix 7). 
 
Patients with PSA progression but with disease response or stable disease on imaging studies will 
remain on study until radiographic or other clinical progression criteria are met.  Patients with 
radiographic disease progression will not receive continued BAT (arm A) or enzalutamide (arm B) and 
will be eligible for crossover to the opposite therapy.  Patients on the BAT arm A can cross over to 
receive enzalutamide at time of progression or can choose to go off study and be treated with other 
standard of care treatments.  Patients on the enzalutamide arm B will be allowed to cross-over to 
receive BAT or can choose to go off study and be treated with other standard of care treatments. 
Patients with clinical progression due to prostate cancer must meet study exclusion criteria to be 
permitted to cross-over to the opposite treatment. Patients with clinical progression due to pain from 
prostate cancer are not permitted to cross-over. 
 
Study Population: Men with CRPC with progressive disease (radiographically and/or biochemically) 


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who have been treated with continuous castrating androgen ablative therapy and abiraterone.  
 
Number of Patients:  194 (97 per treatment arm) 
Inclusion criteria: 
 
1. ECOG Performance status ≤2. 
2. Age ≥18 years. 
3. Histologically-confirmed adenocarcinoma of the prostate. 
4. Treated with continuous androgen ablative therapy (either surgical castration or LHRH 
agonist/antagonist). 
5. Documented castrate level of serum testosterone (<50 ng/dl). 
6. Metastatic disease radiographically documented by CT/MRI or bone scan. 
7. Must have had disease progression while on abiraterone acetate alone or abiraterone acetate in 
combination with other investigational agents based on: 
o PSA progression defined as an increase in PSA, as determined by 2 separate 
measurements taken at least 1 week apart  
 
And/ Or  
o Radiographic disease progression, based on RECIST 1.1 in patients with 
measurable soft tissue lesions or PCWG2 for patients with bone disease  
8. Screening PSA must be ≥ 1.0 ng/mL. 
9. Prior treatment with additional second line hormone therapies is allowed.   
10. No prior treatment with enzalutamide, ARN-509, ODM-201, galeterone or other investigational 
AR targeted treatment is allowed. 
11. Prior docetaxel for hormone-sensitive prostate cancer is permitted if ≤ 6 doses were given in 
conjunction with first-line androgen deprivation therapy and >12 months since last dose of 
docetaxel. 
12. Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if >4 weeks from last 
dose. 
13. Patients must be withdrawn from abiraterone for ≥ 2 weeks.  
14. Patients must be weaned off prednisone and be off therapy for ≥ 1 week prior to starting 
therapy. 
15. Acceptable liver function: 
a. Bilirubin < 2.5 times institutional upper limit of normal (ULN) 
b. AST (SGOT) and ALT (SGPT) < 2.5 times ULN 
16. Acceptable renal function: 
a. Serum creatinine < 2.5 times ULN 
17. Acceptable hematologic status: 
a. Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L) 
b. Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L) 
c. Hemoglobin ≥ 9 g/dL. 
18. At least 4 weeks since prior radiation.  
19. Ability to understand and willingness to sign a written informed consent document. 
20. Patients on either treatment arm will be considered for crossover if they demonstrate evidence 
of radiographic disease progression from the initial treatment. 


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Exclusion criteria: 
 
1. Pain due to metastatic prostate cancer requiring treatment intervention. 
2. ECOG Performance status ≥3 
3. Prior treatment with enzalutamide is prohibited. 
4. Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer 
is prohibited. 
5. Requires urinary catheterization for voiding due to obstruction secondary to prostatic 
enlargement well documented to be due to prostate cancer or benign prostatic hyperplasia 
(BPH). 
6. Evidence of disease in sites or extent that, in the opinion of the investigator, would put the 
patient at risk from therapy with testosterone (e.g. femoral metastases with concern over 
fracture risk, severe and extensive spinal metastases with concern over spinal cord 
compression, extensive liver metastases). 
7. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition 
(including laboratory abnormalities) that could interfere with patient safety or provision  of 
informed consent to participate in this study. 
8. Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C. 
9. Any psychological, familial, sociological, or geographical condition that could potentially interfere 
with compliance with the study protocol and follow-up schedule. 
10. Patients receiving anticoagulation therapy with Coumadin are not eligible for study.  [Patients on 
non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for study. Patients on 
Coumadin who can be transitioned to lovenox prior to starting study treatments will be eligible]. 
11. Patients with prior history of a thromboembolic event within the last 12 months that is not being 
treated with systemic anticoagulation are excluded. 
12. Patients allergic to sesame seed oil or cottonseed oil are excluded. 
13. Major surgery (eg, requiring general anesthesia) within 3 weeks before screening, or has not 
fully recovered from prior surgery (ie, unhealed wound). Note: subjects with planned surgical 
procedures to be conducted under local anesthesia may participate. 
 
Study Endpoints: 
PRIMARY:  
 
PROGRESSION FREE SURVIVAL 
SECONDARY:  
PSA RESPONSE   
 
 
SAFETY 
TIME TO PSA PROGRESSION 
RADIOGRAPHIC PROGRESSION FREE SURVIVAL 
TIME TO DOCETAXEL CHEMOTHERAPY  
 
 
MEASURABLE DISEASE RESPONSE 
 
 
PSA RESPONSE TO ENZALUTAMIDE POST-BAT THERAPY  
 
 
PSA RESPONSE TO BAT POST-ENZALUTAMIDE THERAPY 
 OVERALL SURVIVAL 


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PFS2 (Time from initiation of therapy to progression on crossover 
treatment 
 
 
QUALITY OF LIFE 
 
 
EFFECT OF BAT VS. ENZALUTAMIDE ON EXPRESSION OF AR- 
 
 
V7 AND FREQUENCY OF AR-MUTATION. 
Statistical Plan:   
Primary objective and primary endpoint: The primary objective of the study is to compare progression-
free survival (PFS) between BAT and enzalutamide in patients with castration resistant prostate cancer 
who have progressed on abiraterone.  The primary efficacy endpoint is PFS, defined as the time from 
the date of the randomization to the date of first documented clinical progression due to prostate cancer 
or radiological confirmation of progression per RECIST 1.1 for soft tissue or PCWG2 for bone lesions or 
death, whichever occurs first. If a patient has not had the event at the date of the analysis cut-off, PFS 
will be censored at the time of the last adequate tumor assessment before the cut-off date.  
 
Analysis of primary endpoint: The comparison of PFS will be an intent-to-treat analysis including all 
randomized patients. The PFS will be estimated using Kaplan-Meier method, and the median PFS 
along with 95% confidence intervals (CI) will be reported by the treatment groups. The PFS will be 
compared between the two arms using a stratified log-rank test with the stratification factor of duration 
of prior abiraterone treatment. The Cox regression model, stratified for the same baseline stratification 
factors, will be used to estimate the hazard ratio (HR) of PFS between the two arms and corresponding 
95% CI. Additionally, a Cox regression model, stratified for the baseline stratification factors, will be 
used to explore the potential influences of the other factors on the primary endpoint PFS. 
 
Sample size and power considerations:  Based on published results, radiographic progression in the 
enzalutamide arm post abiraterone will be detected in most patients during the first 6 months of 
treatment and hence we selected the 6 months PFS target as a reasonable endpoint 6 months. This 
trial is designed to detect a 50% improvement in median PFS in the BAT group, from 6 to 9 months 
(corresponding to a HR 0.667 of BAT vs. enzalutamide), at one-sided significance level of 0.05.  The 
study requires at least 156 events to ensure a sequential test procedure will have 80% power. We 
expect a recruitment period of 24 months, 24 months and an additional 12 months of follow-up. After 
accounting for an estimated 15% loss to follow-up, a total of up to 194 patients (97 per arm) will be 
randomized to record 156 events in 36 months of study. Recruitment for the study will stop once a total 
of 156 events have occurred. 
 
Study Schema: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1. 
INTRODUCTION 10 
1.1. 
Overview and Rationale 
10 
1.2. 
Androgen Ablative Therapy for Prostate Cancer 
11 
1.3. 
AR-splice variants in CRPC 
12 
1.4. 
Preliminary Data in Support of Testosterone Therapy in CRPC 
14 
1.4.1. 
Androgen Produces Double Strand Breaks in Human Prostate Cancer Cells 
14 
1.4.2. 
Adaptive Auto-regulation of AR Leads to Over-stabilization of the AR at Origins of 
Replication When Exposed to Supraphysiologic Androgen Levels 
15 
1.5. 
Clinical Experience with Testosterone in Prostate Cancer: 
16 
2. 
STUDY OBJECTIVES 
22 
2.1. 
Primary Objectives 
22 
2.2. 
Secondary Objectives 
23 
3. 
PATIENT POPULATION AND SELECTION 23 
3.1. 
Inclusion Criteria 
23 
3.2. 
Exclusion Criteria 
24 
3.3 
Inclusion of women and minorities 
25 
4. 
TREATMENT PLAN 25 
4.1. 
Study Design 
25 
4.2. 
Study Treatments and Treatment Scheme 
26 
4.2.1. 
Study Treatments 
26 
4.2.2. 
Treatment Scheme 
26 
4.3. 
Dosing Delays and Modifications 
27 
4.4. 
Removal of Patients from Study 
28 
4.5 
Criteria for Discontinuation of Study Treatment due to Development of Worsening Pain 
28 
4.6 
Pain management: 
29 
4.7 
Concomitant Therapy 
29 
4.8 
Prohibited Concomitant Medications 
30 
5 
STUDY ACTIVITIES 30 
5.1 
Screening Period 
30 
5.2 
Randomization 
31 
5.3 
Stratification 
31 
5.4 
Screening Studies (performed within 28 days before Cycle 1 Day 1) 
31 


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5.5 
Treatment Period 
32 
5.6 
End of Initial Treatment (at the time of progression) 
32 
5.7 
Crossover Treatment Period 
33 
5.8 
End of Study Visit (30-day safety follow-up) 
33 
5.9 
Early Discontinuation 
34 
6 
STUDY ASSESSMENTS 34 
6.1 
Assessing Response in Measurable Disease 
34 
6.2 
Assessing PSA Response to BAT 
36 
6.3 
Quality of life (QoL) and metabolic studies: 
36 
6.4 
Correlative Studies 
37 
6.4.1 
AR-Variant Studies 
37 
6.4.2 
AR Mutation Studies 
37 
6.4.3 
Imaging Studies 
37 
6.4.3.1 
18F-DCFPyL PSMA-PET Imaging (Johns Hopkins Only) 
37 
7 
REQUIREMENT FOR AN INDEPENDENT RESEARCH MONITOR 
39 
8 
SAFETY ASSESSMENT 40 
9 
PHARMACEUTICAL INFORMATION-TESTOSTERONE CYPIONATE, 
TESTOSTERONE ENANTHATE , ENZALUTAMIDE 
40 
9.1 
Testosterone Cypionate Drug Characterization 
40 
9.1.1 
Drug Name:  Testosterone Cypionate (DEPO-Testosterone Injection) 
40 
9.1.2 
Chemical Name: androst-4-en-3-one,17-(3-cyclopentyl-1-oxopropoxy)-, (17ß)- 
40 
9.1.3 
Molecular Formula: C27H40O3   Molecular Weight:  412.61 g/mol 
40 
9.1.4 
Description 
40 
9.2 
Testosterone Enanthate Drug Characterization 
41 
9.2.1 
Drug Name:  Testosterone Enanthate (Delatestryl) Structural formula: 
41 
9.2.2 
Chemical Name: (androst-4-en-3-one, 17-[(1-oxoheptyl)-oxy]-, (17β)-. 
41 
9.2.3 
Molecular Formula: C26H40O3  Molecular Weight:  400.6 g/mol 
41 
9.2.4 
Solubility:  Insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and 
soluble in vegetable oils 
41 
9.2.5 
Description 
41 
9.3 
Clinical Pharmacology Testosterone Esters 
41 
9.4 
Precautions 
41 
9.4.1 
General 
42 
9.4.2 
Information for patients 
42 
9.4.3 
Laboratory tests 
42 
9.4.4 
Drug interactions 
42 


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9.4.5 
Drug/Laboratory test interferences 
42 
9.5 
Adverse Reactions 
42 
9.5.1 
Drug Abuse and Dependence 
43 
9.5.2 
Overdosage 
43 
9.6 
Administration, Supply and Storage 
43 
9.6.1 
Administration: 
43 
9.6.2 
Supply 
43 
9.6.3 
Storage 
43 
9.7 
Enzalutamide Drug Characterization [Adapted from FDA prescribing information] 
44 
9.7.1 
Clinical Pharmacology 
44 
9.7.2 
Safety/Precautions 
45 
9.7.2.1 
Seizures 
45 
9.7.2.2 
Laboratory abnormalities 
45 
9.7.2.3 
Infections 
45 
9.7.2.4 
Falls and fall-related injuries 
45 
9.7.2.5 
Hallucinations 
45 
9.7.2.6 
Unforeseeable risks to embryo or fetus 
45 
9.7.2.7 
Information for Patients 
46 
9.7.2.8 
Laboratory tests 
46 
9.7.2.9 
Drug Interactions 
46 
9.7.2.10 
Adverse Reactions 
47 
9.7.2.11 
Administration, Supply and Storage 
47 
9.7.2.12 
Administration 
47 
9.7.2.13 
Supply 
47 
9.7.2.14 
Storage 
47 
10 
STUDY CALENDARS 48 
10.1 
ARM A: BAT with crossover to Enzalutamide 
48 
10.2 
ARM B: Enzalutamide with crossover to BAT 
49 
11 
DATA MONITORING AND REPORTING REQUIREMENTS 
50 
11.1 
Case Report Form Submission 
50 
11.2 
Adverse Event Monitoring and Reporting 
51 
11.3 
Evaluating Adverse Events 
51 
11.3.1 
Documenting Adverse Events 
51 
11.4 
Serious Adverse Events 
52 
11.5 
Expedited Reporting of Serious Adverse Events 
52 
11.6 
Institutional Review Board (IRB) Reporting at Participating Sites: 
53 


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11.7 
Protocol Amendments 
53 
11.8 
Informed consent 
53 
11.9 
Multicenter Guidelines 
54 
12 
STATISTICAL METHODS 
55 
13 
REFERENCES 
59 
APPENDIX I 63 
APPENDIX 2 68 
APPENDIX 3 69 
APPENDIX 4 70 
APPENDIX 5 72 
APPENDIX 6 75 
APPENDIX 7 76 
APPENDIX 8 77 
 
 
 


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1. INTRODUCTION 
1.1. Overview and Rationale 
Prostate cancer is uniformly lethal once it has escaped the confines of the prostate gland, resulting in the 
death of over ~30,000 American men each year (1).  Androgen ablation therapy has remained the standard 
of care for men with recurrent/metastatic cancer since its discovery by Charles Huggins in the 1940s (2).  
While androgen ablation therapy provides significant palliative benefit, all men undergoing androgen 
ablation eventually relapse and no longer respond to androgen ablation no matter how completely 
given(3,4). 
 
This observation led to the labeling of patients progressing on androgen ablative therapies as having 
“androgen independent” or “hormone refractory” prostate cancer.  However, new findings have 
demonstrated that the majority of prostate cancer specimens from androgen ablated patients continue to 
express the androgen receptor (AR) often at higher levels (5, 6).  In addition, variants of AR that do not 
bind to ligand also are upregulated in androgen deprived prostate cancer cells.  Prostate cancer cells from 
these castration refractory patients continue to express AR-regulated genes such as PSA.  This 
observation has resulted in a reclassification of “hormone refractory” disease as “Castration Resistant 
Prostate Cancer” (CRPC) and has opened up new avenues of research into the function of the AR in the 
androgen deprived state.  These findings suggest that “castration-resistant” prostate cancer may continue 
to survive through aberrant AR signaling.  Studies have demonstrated adaptation to chronic androgen 
deprivation through several mechanisms including marked upregulation of the full length AR, AR gene 
amplification, and expression of AR splice variants lacking the ligand binding domain (7-10).  This 
observation has led to a renewed interest in the AR axis as a therapeutic target.  On this basis, 
enzalutamide, a new antiandrogen, and abiraterone acetate, a CYP17 androgen synthesis inhibitor, have 
recently been approved as second line therapy for prostate cancer on the basis of modest observed 
improvements in overall survival vs. placebo in randomized phase III trials (11-14). 
 
A major mechanism for the development of CRPC following chronic exposure to androgen ablative 
therapies is the ability of prostate cancer cells to adapt to the lack of ligand by marked upregulation of the 
full length AR and AR splice variants lacking the ligand binding domain.  AR gene amplification is also 
commonly seen in samples from patients on chronic androgen deprivation.  Laboratory studies have 
documented this upregulation of AR.  These studies have demonstrated that this upregulation of AR may 
be responsible for the resistance to antiandrogens.  In these studies, these re-exposure of androgen 
starved prostate cancer cells readapt upon exposure to androgen by lowering AR expression.  This 
lowered AR expression now re-sensitizes these cells to androgen ablative therapies such as antiandrogens 
(9, 10).    
 
In this background of renewed interest in blocking the AR, there has been the paradoxical observation that 
the growth of both androgen sensitive and androgen resistant prostate cancer cell lines is inhibited by the 
addition of testosterone or other synthetic androgens to the media (10,15-17).  Typically, in vitro data in 
human prostate cancer cell lines demonstrates a biphasic response to androgens, with very low levels 
producing modest growth stimulation and expression of prostate tissue differentiation markers such as 
PSA, while higher levels of androgen in the media suppress growth and PSA production (10, 15-17).  High 
levels in this case can be as low as picomolar concentrations suggesting that these “androgen ablation 
resistant” cells are exquisitely sensitive to androgens.  These in vitro studies are supported by animal 
studies that have demonstrated that androgen receptor positive human prostate cancer cells selected to 
grow in castrated animals’ upregulate androgen receptor levels. Similar to the in vitro response, in these 


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models, systemic testosterone administration produces significant growth inhibition, whereas 
antiandrogens such as bicalutamide promote prostate cancer growth.   
 
Until recently, the mechanisms underlying this paradoxical response have been unknown.   However, 
recent data from our group and others have described several possible mechanisms for this effect of 
androgens on the growth of CRPC cells.  The androgen receptor has been shown to be a licensing factor 
involved in DNA relicensing during progression through the cell cycle (14,16).  AR is degraded as the 
prostate cancer cell goes through cycle.  We have demonstrated that the high levels of AR seen in CRPC 
cells do not get sufficiently degraded in the presence of supraphysiologic androgen due to androgen 
stabilization of the AR.  Thus, under these conditions, AR remains bound to origins of replication preventing 
the cell from progressing through subsequent cell cycles and ultimately resulting in cell death.  In addition, 
it has been demonstrated that replenishment of androgen to androgen starved prostate cancer cells rapidly 
produces significant double strand DNA breakage that can result in inhibition of growth, inhibition of protein 
synthesis, growth and loss of clonogenic survival (18).  Finally, androgen starved cells upregulate 
constitutively active AR splice variants that cannot bind androgen due to loss of the ligand binding domain 
(19,20).  CRPC cells may rely on these truncated AR variants for survival under low ligand conditions.  
However, it has been shown that when androgen starved CRPC cells are given high dose androgen, 
expression of these variants is rapidly downregulated to often undetectable levels (21, 22). 
 
On the basis of these observations, the hypothesis of this trial is that a significant clinical response can be 
achieved in men with long standing castration resistant prostate cancer by rapidly cycling from the polar 
extremes of supraphysiologic to castrate serum levels of androgen.  We have termed this approach Bipolar 
Androgen Therapy (BAT) (14).  By pursuing this treatment strategy, high AR–expressing CRPC cells will 
be sensitive to killing by supraphysiologic levels of testosterone according to mechanisms described 
above.  Those cells that try to adapt to high androgen by dropping AR expression to low levels will then 
become sensitive to killing when testosterone levels are lowered to near castrate levels. 
 
1.2. Androgen Ablative Therapy for Prostate Cancer 
The current treatment approach for CRPC: Men with recurrent or metastatic prostate cancer are initially 
treated with LHRH agonists which typically result in castrate levels of serum T (i.e. <50 ng/dL) within 2-4 
weeks post initiation of therapy (24).  The catastrophic loss of androgen as their major growth and survival 
factor results in the death of the majority of prostate cancer cells.  On this basis, the majority (~90%) of 
men have an initial beneficial palliative response to ADT.  However, relapse occurs in all men treated with 
ADT.  Over time prostate cancer cells that survive the initial acute drop in serum androgen adapt to the 
chronic low androgen conditions by upregulating AR through overexpression, gene amplification and 
expression of truncated, transcriptionally active AR splice variants (AR-V) that lack the ligand binding 
domain.  The first clinical manifestation of this adaptive increase in AR signaling is the renewed production 
of PSA.  At this point the patient is considered to have CRPC.  Typically, this patient would continue on 
ADT and begin second-line hormonal therapies.  This approach is based on the concept that a sufficient 
amount of androgen is produced by the adrenal glands and perhaps by the prostate cancer cells 
themselves (18) to support the growth of the surviving adapted CRPC cells.  Thus, second line hormonal 
therapies were developed that either competitively inhibit androgen binding to AR (e.g. anti-androgens 
flutamide, bicalutamide, nilutamide) or inhibit adrenal androgen synthesis (e.g. ketoconazole) (24).  While 
clinical benefit was demonstrated, until recently, the effect of second-line therapy on survival was unknown 
due to lack of appropriately powered studies.  However, recently enzalutamide and abiraterone both 
received FDA-approval for use in metastatic CRPC based on a modest survival benefit observed in large 
randomized studies, Table 1 (11-14).  
  


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The current treatment approach for CRPC is to continue chronic LHRH agonist therapy despite progression 
and administer “second line” hormone therapy.  Based on a demonstrated survival benefit, Abiraterone is 
emerging as the preferred initial second line therapy.  Before the availability of Enzalutamide, standard 
therapy in men with progression on Abiraterone would be to give docetaxel chemotherapy.  Currently, 
Enzalutamide is FDA-approved for use in men post docetaxel based on Phase III results showing an ~ 5 
month improvement in survival in the post-docetaxel setting, Table 1 (8).  However, Enzalutamide is 
frequently being administered to men prior to docetaxel if insurance clearance can be obtained.  It is also 
expected that Enzalutamide, like Abiraterone, will be approved for use in the pre chemotherapy setting 
based on positive results from the PREVAIL study that showed an improvement in median overall survival 
that was estimated at 32.4 months in the enzalutamide group and 30.2 months in the placebo group 
(hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001) (10). 
 
Thus, based on the result of these studies, the ease of administration of these oral agents, and the 
possibility of delaying the need for chemotherapy, the evolving treatment paradigm will likely involve the 
sequential addition of Abiraterone and Enzalutamide to LHRH agonist-based ADT in men with ADT 
progression.  However, several small studies have demonstrated that sequential use these agents in the 
post-chemotherapy setting is associated with significant reduction in time to radiographic progression to <5 
months, decreased PSA response and objective response suggesting cross-resistance between these 
agents, table 1 (23-6).  Limited information is available on progression free survival with enzalutamide post-
abirateroner in the pre-chemotherapy setting but data on small number of patients indicates median rPFS ≤ 
6 mos (27,28).  The mechanisms underlying this reduced response rate are likely multi-factorial and may 
include continued adaptive increase in AR expression, increased expression of ligand independent AR 
variants in resistant cells and emergence of AR mutations that may affect enzalutamide binding. 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3. AR-splice variants in CRPC 
The AR protein contains several functional domains (29).  The N-terminal domain (NTD), encoded by exon 
1, constitutes ∼60% of the 110-kDa full-length protein and is the transcriptional regulatory region of the 
protein.  The central DNA-binding domain (DBD) is encoded by exons 2 and 3, whereas exons 4 to 8 code 
for the highly conserved C-terminal ligand-binding domain (LBD) which is the intended target of all current 
existing AR-directed therapies (29).  Recently, AR variant (AR-Vs) transcripts that are encoded by 
aberrantly spliced AR mRNA have been discovered that lack the reading frames for the ligand-binding 
domain due to splicing of “intronic” cryptic exons to the upstream exons encoding the AR DNA-binding 
domain (29).  A total of 15 AR-Vs have been fully decoded, with the variant AR-V7 representing the single 
most important AR-V for which expression levels of its mRNA and protein can be detected in the vast 
majority of clinical CRPC specimens by variant-specific probes and antibodies (20, 29).   
 


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To evaluate mRNA expression of full length AR and AR-V7 in CTC we modified the AlereTM CTC 
AdnaTest, a commercial diagnostic test in CE-marked countries.  The ProstateCancerSelect kit was used 
to enrich circulating prostate tumor cells in the blood using magnetic beads coated with 3 different 
antibodies (EPCAM and 2 proprietary antibodies).  Cell capture by the optimized antibody combination is 
followed by cell lysis and RT-PCR analysis using a combination of multiple mRNA markers of the AR axis, 
using the ProstateCancerDetect kit and custom probes.  We have developed specific probes to detect both 
the canonical AR-FL and AR-V7 that both increase upon treatment with Enzalutamide and Abiraterone in 
cell line and xenograft models (29).  We used this test and methodology to interrogate CTCs for the 
presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant 
prostate cancer initiating treatment with either enzalutamide or abiraterone (30).  We examined 
associations between AR-V7 status and PSA response rates, PSA-progression-free survival (PSA-PFS), 
and clinical/radiographic progression-free survival (PFS).  Multivariable Cox regression analyses were 
performed to determine the independent effect of AR-V7 status on clinical outcomes (30). 
 
Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 
38.7% and 19.4% had detectable AR-V7 from CTCs, respectively (30).  Among men receiving 
enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-
PFS (median: 1.4 vs 5.9 months, P<0.001), and PFS (median: 2.1 vs 6.1 months, P<0.001) compared to 
AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior 
PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), 
and PFS (median: 2.3 months vs not reached, P<0.001).  The negative prognostic impact of AR-V7 
detection was confirmed in multivariable analyses (30).  The conclusion from this study is that the presence 
of AR-V7 in CTCs from patients with castration-resistant prostate cancer predicts resistance to 
enzalutamide and abiraterone (30). 
 
Recently, Hu et al demonstrated that human CRPC cells LNCaP95 and VCaP rapidly downregulate 
expression of all AR isoforms following exposure to high dose androgen (21) suggesting a potential for re-
sensitization to anti-androgens following exposure to supraphysiologic-T.  Androgen exposure resulted in 
rapid decrease or loss of AR-V7 nuclear staining in these cell lines.  These results were further confirmed 
by Thelen et al, who demonstrated that androgen treatment of the AR-V7 overexpressing human prostate 
cancer cell line VCaP results in rapid downregulation of total AR levels and almost complete loss of AR-V7 
expression (22).  These AR-V expressing cells are profoundly growth inhibited by supraphysiologic levels 
of androgens, Figure 1A. In contrast, these lines are highly resistant to the anti-androgen bicalutamide.  We 
also observed complete loss of AR-V expression in VCaP cells over a 48 hr exposure to the synthetic 
androgen R1881, Figure 1B. 
 
 


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Figure 1. (A) Effect of synthetic androgen R1881 or bicalutamide on growth of ADT-resistant LNCaP and 
VCAP; (B) Expression of full length AR (AR-FL), AR-variants (AR-Vs) using antibody to AR N-terminal domain 
and AR-V& using AR-V7 specific antibody in the absence or presence of R1881 
 
On the basis of these pre-clinical and clinical results, we will use the AlereTM CTC AdnaTest to isolate 
blood samples from patients on each arm at screening, after three months on BAT or Enzalutamide and at 
time of radiographic progression to determine the effect of each treatment arm on the expression of full 
length AR and AR-V7. 
 
1.4. 
Preliminary Data in Support of Testosterone Therapy in CRPC 
1.4.1. Androgen Produces Double Strand Breaks in Human Prostate Cancer Cells 
 
The mechanisms underlying the growth suppressive effects of high levels of androgens in prostate 
cancer cells in vitro and in vivo is likely highly complex.  Recent evidence from our group suggests 
that one mechanism may involve the formation of androgen induced Topoisomerase II beta 
(TOP2B) mediated double strand breaks at AR target genes, Figure 2(18).  Recent studies have 
shown that estrogen signaling in breast cancer cells involves the co-recruitment of Estrogen 
receptor and TOP2B to estrogen receptor target sites, where TOP2B introduces transient double 
strand breaks.  We hypothesized that such a mechanism may be involved in androgen signaling in 
prostate cancer cells and that at high doses of androgens, such breaks may persist and ultimately 
lead to growth suppression.  In support of this, we observed that stimulation of androgen-deprived 
LNCaP cells with dihydrotestosterone (DHT) led to recruitment and catalytic activity of TOP2B at 
AR target sites in the TMPRSS2 enhancer as well as at other known AR target sites.  At high doses 
of DHT, this TOP2B recruitment and catalytic activity was associated with significant formation of 
AR and TOP2-dependent persistent double strand breaks at the TMPRSS2 gene, as observed by 
fluorescence in situ hybridization (FISH) assay capable of detecting genomic breaks on an 
individual cell basis (18).  Such breaks likely occurred throughout the genome at AR target sites 
since we observed numerous γH2A.x foci, a marker for double strand break formation, throughout 
the nucleus in response to stimulation of LNCaP cells with high-dose DHT (Figure 2).  In further 
confirmation of this, we also observed recruitment of ATM, a double strand break repair signaling 
protein, to AR target sites in PSA and TMPRSS2, genes present on different chromosomes in the 
cell.  These findings suggest that exposure of prostate cancer cells from patients with CRPC to high 
doses of testosterone may induce  growth suppression due to the accumulation of androgen-
mediated, TOP2-induced double strand DNA breaks (18).  


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Figure 2.  Androgen induced double strand DNA breaks in prostate cancer cell lines stimulated with high levels 
of androgen.  Stimulation of androgen deprived LAPC4 cells (control) to high levels of DHT (DHT) leads to 
numerous double strand breaks throughout the nucleus as evidenced by the accumulation of numerous 
γH2A.x foci, a marker for formation of double strand breaks. 
 
1.4.2. Adaptive Auto-regulation of AR Leads to Over-stabilization of the AR at Origins of 
Replication When Exposed to Supraphysiologic Androgen Levels 
 
Recently, our laboratory has explored a mechanism for growth inhibition by T in CRPC cells 
(14,16,17).  These studies document that the increase in AR expression observed in these cells in 
the low T environment creates a unique therapeutic vulnerability to selectively kill CRPCs.  This is 
based upon the fact that AR is involved in DNA relicensing and DNA replication AR must degraded 
each cell cycle for proper relicensing to occur.   Overstabilization of the increased levels of AR 
observed in CRPC with supraphysiologic testosterone prevents complete degradation of AR via the 
proteasome during mitosis (14,16,17).  This was demonstrated by in vivo treatment of resistant 
human LNCaP prostate cancer xenografts with T implants to achieve supraphysiologic serum T-
levels (14).  This treatment resulted in significant growth inhibition, Figure 3a.  These growth 
inhibited cells had similar amount of cells with nuclear AR in the nucleus, and Ki-67 positivity, 
Figure 3a.  However, in xenografts treated with supraphysiologic T, the Cell Death Index was ~ 3-
fold higher (14).  More strikingly, the percent of cells staining positive for AR in mitosis was 
approximately 10-fold higher in cells exposed to supraphysiologic T vs. castrate only animals, 
Figure 3b.  This data suggests that CRPC cells that have not properly relicensed DNA can die when 
they attempt to proceed through a subsequent cell cycle.  Thus, based on this proposed 
mechanism, prostate cancer cells that maintain high AR levels will be vulnerable to cell death when 
exposed to supraphysiologic T conditions due to inability to rapidly auto-regulate AR to lower levels.  
Due to the bipolar cycling between high and low serum T achieved with BAT, those cells that do 
manage to survive the high T environment through adaptive down-regulation of AR will become 
vulnerable to cell death when suddenly exposed to low T conditions that occur over the cycle of 
BAT. 
 


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Figure 3: Castrated NOG mice inoculated with LNCaP/A-cells were either exposed to BAT therapy (via an 
implanted testosterone filled capsule that was placed and removed at two week intervals) or left in a 
permanently castrate state (diamond versus box). (A) Evaluation of indicated parameters in LNCaP/A- cells 
growing in castrate mice vs. castrate mice supplemented with subcutaneous testosterone-filled silastic 
implants. (B)  Immunohistochemical staining for AR in harvested LNCaP/A- xenografts growing in castrate vs. 
castrate + T-pelleted mice. Blue arrows indicate mitotic figures. 
 
 
1.5. Clinical Experience with Testosterone in Prostate Cancer:  
Up until recently, there had been very limited clinical experience in the PSA-era treating CRPC patients 
with testosterone.  Brendler et al at the Brady Urological Institute reported in the Archives of Surgery in 
1949 on the use of parenteral testosterone in several men with advanced CRPC (31).  They observed 
considerable improvement in several men that included decreased pain, decreased prostate size and 
decreases in acid and alkaline phosphatase.  In a second study, Prout and Brewer reported in Cancer in 
1967 on the treatment of men who had been either untreated or recently castrated or long term castrates 
with parenteral testosterone (32).  Five relapsed patients in the long term castrate group received 
testosterone for at least one month and 4 of 5 had subjective improvement.  Five remaining patients in the 
long term castrate group received testosterone for 1-19 days, with each progressing and subsequently 
coming off therapy.  Acid phosphatase declined in 2/5 men receiving a longer course of testosterone. 
Remarkably, one man in this group admitted to hospital with severe back pain, weakness and anorexia had 
a 10 month response with complete cessation of pain, excellent appetite and weight gain with decrease in 
acid phosphatase from 50 to 5 units.   
 
 
In contrast, a number of studies during the 1960-70s evaluated the use of T-priming in combination with 
32P-sodium phosphate to treat men with CRPC and severe pain due to widespread bony metastases (33, 
34).  In these studies, initial T-priming using a variety of parenteral dosing regimens was associated with 
transient increase in bone pain during the first week followed by excellent pain palliation following 
administration of 32P.  Similar results were observed in studies led by Manni who evaluated T- priming with 
chemotherapy in the 1980’s (35).  These studies were also conducted in men with CRPC and pain due to 
widely metastatic disease.  In these studies, increased bone pain was also observed in men upon initial 
treatment with oral androgens.  The increased pain in these studies typically occurred within days of T 
administration.  Thus, given this time frame, it is likely the increased pain was due to T-stimulation of 
inflammation/cytokine release within sites of bone metastases rather than a direct effect on tumor growth.  
Such rapid change is also seen in men with bone pain upon initially starting ADT.  Marked improvement in 
pain after ADT often occurs within hours of treatment, an effect not due to tumor death but rather a rapid 
change in expression of pain-promoting gene products.  
 


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More recently, two Phase I studies were reported describing the results of the use of transdermal T as 
therapy for men with CRPC who had minimal to moderate disease burden and no pain due to prostate 
cancer.  In the first study, Szmulewitz et al evaluated the effect of increasing doses of transdermal T in 15 
men with early CRPC (rising PSA and minimal bone disease) (36).  Five men each were treated with 2.5, 
5.0 or 7.5 mg/day of transdermal T which brought the median concentration of T from castrate to 305, 308 
and 297 ng/dl respectively.  In this study no grade 3 or 4 toxicities were observed with the exception of one 
man who was taken off study at week 53 for grade 4 cardiac toxicity.  Only one patient had symptomatic 
progression and three patients (20%) had a decrease in PSA (largest was 43%).  Patients treated at the 
highest T dose had a prolonged time to progression that did not reach statistical significance most likely 
due to the small cohort size.  In the second study, Morris et al evaluated the effect of transdermal T at a 
dose of 7.5 mg/day administered for 1 week (n=3), 1 month (n=3) or until disease progression (n=6) in 12 
patients with CRPC (37).  They observed no grade 3 or 4 toxicities and no pain flares.  Eugonadal serum T 
levels were reported for this study.  No objective responses were observed.  Four patients had at least 20% 
declines and one achieved a >50% PSA decline.  
 
Neither of these Phase I studies achieved the supraphysiologic levels of serum T that can be reached with 
FDA-approved doses of T administered as an intramuscular depot (38).  However, the levels of serum T 
achieved were in the high-end of the eugonadal range.  Remarkably, although the studies were considered 
“negative” from the standpoint of disease response, in both studies the administration of parenteral T to 
men with CRPC was very well-tolerated and did not result in significant worsening of disease or symptoms, 
including pain flares.  While only one patient out of 27 from the combined studies had a reported >50% 
decline in PSA, smaller PSA declines were observed in a few of the patients on these two studies with a 
trend toward a dose-responsive effect, suggesting a potential for therapeutic benefit in some patients (36, 
37).  
 
 


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Figure 4.  Clinical trial of BAT plus etoposide.  (A) Schematic of study design. (B) Baseline characteristics of 
patients on study. (C) Mean serum testosterone levels at indicated time points for patients on study. 
 
Based on the preclinical results and potential mechanisms for growth inhibition that include androgen-
induced double strand breaks and stabilization of AR preventing relicensing, we have conducted a pilot 
study evaluating the efficacy and safety of pharmacologic doses of testosterone to produce 
supraphysiologic T levels in conjunction with oral etoposide in chronically castrated men with rising PSA 
and CRPC, Figure 4a.  Patients who had been continuously castrate for more than one year with minimal 
metastatic disease burden (≤ 5 total bone metastases and ≤ 10 total sites of metastases) and/or rising PSA 
were eligible, Figure 4b.  To achieve rapid cycling between supraphysiologic and near castrate serum T 
(i.e. BAT) patients received intramuscular injection of 400 mg testosterone cypionate every 28 days.  For 
the first 3 cycles of therapy patients received BAT plus oral etoposide 100 mg po/day days 1-14 of a 28 day 
cycle. After 3 cycles PSA response and objective response were assessed.  Those patients with a PSA 
that was declining from peak levels and no objective evidence of disease progression or worsening pain 
were continued on therapy.  Given the toxicity associated with etoposide and the lack of clinical response 
in an earlier trial (39), patients who responding after 3 cycles of testosterone plus etoposide were continued 
on testosterone alone based on protocol amendment.  
 
 


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Figure 5.  Results from the pilot BAT study in men with CRPC. (A) Waterfall plot of best PSA response with 
7/14 men and 4/14 men achieving PSA declines >30% and >50%, respectively (B) Representative patterns of 
PSA response in pilot study PSA and serum T level in non-responder; (C) PSA response in patient receiving 3 
cycles of T+ E and then 13 additional cycles of T alone. Patient demonstrated renewed sensitivity to ADT after 
progressing on BAT; (D) Objective lymph node complete and partial response after 3 cycles of BAT + E.   
 
 
Seven of fourteen patients had a decline in PSA from baseline value, Figure 5a.  An eighth patient 
progressing after testosterone treatment for 6 months had a decline in PSA upon reaching castrate level 
testosterone.  Non-responders came off of trial after 3 cycles due to PSA progression.  Overall three 
patterns of PSA response were observed, Figure 5b.  For the seven patients that had a PSA decline, the 
median time to PSA progression was 221 days (range, 95 to 454 days).   
 
The dose of 400 mg T cypionate produces supraphysiologic levels > 1500 ng/dl within 2 days post 
injection, Figure 4c.  At baseline, ten subjects had RECIST-evaluable soft tissue metastases, Figure 4b.  Of 
these patients, two (20%) had progressive disease (PD), three (30%) had stable disease after a median 
follow up of 91 days (range, 87 to 92 days), four (40%) had partial responses (PRs) and one (10%) had a 
complete response (CR), Figure 5d.  None of the 14 patients completing 3 months of therapy developed 
new bone metastases.  One patient with >50% decrease in PSA had intensification of an isolated tibial 
metastases on bone scan and was removed from study despite decline in PSA levels.  No other patient 
developed worsening pain on study.   


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Adverse Event 
Grade 1-2 
N (%) 
Grade 3-4 
N (%) 
Any Grade 
N(%) 
Anemia 
3 (18.8) 
0 
3 (18.8) 
Dysgeusia 
3 (18.8) 
0 
3 (18.8) 
Weight gain 
3 (18.8) 
0 
3 (18.8) 
Anorexia 
4 (25) 
0 
4 (25) 
Breast sensitivity 
4 (25) 
0 
4 (25) 
Neutropenia 
3 (18.8) 
1 (6.3) 
4 (25) 
Edema 
8 (50) 
0 
8 (50) 
Alopecia 
9 (56.3) 
0 
9 (56.3) 
Fatigue 
9 (56.3) 
0 
9 (56.3) 
Nausea 
10 (62.5) 
0 
10 (62.5) 
Pulmonary embolism 
0 
2 (12.5) 
2 (12.5) 
Death 
0 
1 (6.3) 
1 (6.3) 
 
Adverse Events:  The majority of adverse events (AEs) occurred during the initial phase of treatment and 
were largely consistent with known side effects of etoposide.  Initial-phase side effects were mostly low 
grade (i.e. ≤grade 2) and included: nausea (N=10), fatigue (N=9), alopecia (N=9), edema (N=8) and 
neutropenia (N=3), table 2.  Two patients had grade 3 asymptomatic, subsegmental pulmonary embolism.  
Two subjects did not complete the initial treatment phase, one individual was taken off study after 
developing grade 2 priapism and a second individual expired due to pneumonia/neutropenic sepsis.  AEs 
occurring during the BAT monotherapy phase of the trial were rare and low grade.  Only four subjects 
experienced an AE during this phase, and all but three AEs were grade 1.  Grade 2 events included 
alopecia and an elevated creatinine in one subject and grade 2 nausea in a separate subject.   
 
Table 2: Adverse events occurring in >15% of subjects and severe (grade ≥4) events.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: all of those events listed occurred during the testosterone plus etoposide phase of the trial. 
 
 
None of the 14 patients developed new pain, skeletal events or urinary obstruction due to prostate cancer.  
Although quality of life was not formally evaluated in the study, most subjects reported enhanced well-being 
and increased functional activity.  Patients with intact sexual function prior to ADT had return of sexual 
function and libido on BAT. 
 
PSA Reductions to Subsequent Hormonal Therapies: As part of the aforementioned pilot study, we 
performed a post hoc exploratory analysis on the effect of BAT on subsequent hormonal therapies. Overall, 
12 out of 13 subjects had PSA decline to AR-directed therapy post-BAT (one patient continued to show 
PSA progression upon return to castrate T levels and proceeded to receive docetaxel, the 14th patient 
remains on BAT (table3).  T levels were allowed to return to the castrate range prior to having a second 
line AR-directed therapy initiated (e.g. abiraterone, enzalutamide, bicalutamide) in 12 patients. Of these 12 
subjects, 9 (75%) had a PSA decline below their post-BAT PSA. Of the 6 PSA responders that came off 
study, 4 (66.7%) had a PSA decline below their post-BAT PSA upon becoming castrate again.  All of the 
patients had received at least one anti-androgen prior to starting the study (Table 3). 
 
 


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Subject 
numbera 
Maximum PSA decline 
upon re-castration (%)b 
Secondary HT  
received pre-study 
Secondary HT  
received post-study 
Maximum PSA decline  
upon secondary  
HT initiation (%)c 
1 
NA 
nilutamide, bicalutamide 
nilutamide 
-44.3 
2 
-88.2 
bicalutamide 
none 
NA 
3 
-57.4 
bicalutamide 
abiraterone 
-94.2 
4 
No decline 
 bicalutamide  
abiraterone 
-92.7 
5 
-52.0 
bicalutamide, ketoconazole 
enzalutamide 
-30.4 
6 
-58.2 
bicalutamide 
bicalutamide 
-30.8 
7 
-73.2 
bicalutamide 
abiraterone 
-88.1 
8 
No decline 
bicalutamide, nilutamide 
none 
NA 
9 
-92.5 
bicalutamide 
none 
NA 
10 
No decline 
bicalutamide 
abiraterone 
-63.8 
14 
-38.2 
nilutamide, bicalutamide, 
abiraterone 
enzalutamide 
-99.5 
15 
-35.0 
abiraterone 
enzalutamide 
-78.3 
16 
-68.4 
nilutamide, abiraterone, 
enzalutamide 
enzalutamide 
-53.2 
Table 3. PSA response to secondary hormonal therapy after return to castrate T-levels post-BAT. 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After return to castrate T levels post-BAT, ten of 10 (100%) patients receiving second line therapy with 
either abiraterone (n=4/4) or an anti-androgen [enzalutamide (n=4/4), bicalutamide (n=1/1), nilutamide 
(n=1/1)] had a PSA decline (range 30.8-99.5%) (Figure 5).  Four of 4 patients receiving abiraterone and 3/4 
patients on enzalutamide had >50% PSA decline.  Of note, two subjects were re-challenged with a first 
generation anti-androgen (i.e. nilutamide, bicalutamide) and one with enzalutamide after having previously 
progressed on these agents.  These subjects achieved a 44.3%, 30.9% and 53.2% PSA decline upon 
initiation of nilutamide, bicalutamide and enzalutamide, respectively.  The patient re-challenged with 
enzalutamide had also previously progressed on abiraterone prior to enrolling in this study. 
 
The lessons learned from this pilot trial were that supraphysiologic testosterone could be administered 
safely to men with metastatic CRPC without producing worsening signs or symptoms due to prostate 
cancer.  While formal testing was not performed, most men reported improved quality of life with increased 
energy, less fatigue, increased libido and resumption of erectile function in those men with preserved 
function prior to castrating therapy.  PSA decline/response and objective responses were observed in 50% 
patients who completed three cycles of therapy.  While PSA declines were observed, many patients with 
supposedly CRPC had an initial spike in PSA following the first injection of testosterone.  These results 
suggest that, although these patients demonstrated progressive disease while on chronic castrating 
therapies as a requirement for enrollment in the trial, the CRPC cells must have continued expression of a 
functional AR axis as evidenced by the increased expression of an androgen responsive gene, PSA, in 
response to androgen replacement.  Finally, 100% of patients demonstrated PSA response to androgen 
ablative therapies post-BAT suggesting exposure to BAT has the potential to reverse resistance and re-
sensitize CRPC cells to androgen ablative therapies such as abiraterone and enzalutamide. 
 
 


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2. STUDY OBJECTIVES 
2.1. Primary Objectives 
The primary objective of the study is to determine if treatment with supraphysiologic testosterone (BAT) will 
improve progression free survival compared to enzalutamide in asymptomatic men with evidence of 
progressive metastatic CRPC post-treatment with abiraterone. 
 
Progression free survival is defined as the time from randomization to the development of either clinical or 
radiographic progression as defined below while on therapy with either BAT or enzalutamide. 
 
2.1.1 Clinical Progression 
 
Patients who do not meet the criteria of radiographic progression who are removed from study for 
worsening symptoms that are attributable to prostate cancer progression will be considered to have clinical 
progression. 
 
Time to clinical progression will be defined as the time from randomization to documentation in the CRF of 
any of the following (whichever occurs earlier) 
 
• 
Cancer pain requiring initiation of chronic administration of opiate analgesia (oral opiate use for ≥3 
weeks; parenteral opiate use for ≥7 days.  Patients with cancer pain requiring opiate analgesia for 
relief should also be assessed by the investigator for the need for initiating systemic chemotherapy 
or palliative radiation. 
 
• 
Development of a skeletal-related event (SRE): pathologic fracture, spinal cord compression, or 
need for surgical intervention or radiation therapy to the bone. 
 
• 
Development of clinically significant symptoms due to loco-regional tumor progression (e.g. urinary 
obstruction) requiring surgical intervention or radiation therapy. 
 
Patients who experience worsening pain after the first cycle of BAT or enzalutamide will be considered to 
have tumor flare.  Patients who are removed from study for pain after first cycle of BAT or enzalutamide will 
not be considered as having clinical progression and will be considered non-evaluable.   
 
2.1.2 Radiographic Progression 
 
Radiographic progression-free survival is based on parameters suggested by PCWG2 (Appendix 7) and 
modified RECIST (Appendix 1) as follows: 
 
• 
On CT scan, radiographic progression will be defined by RECIST criteria (i.e. >20% increase in the 
sum of target lesions).  
 
• 
On bone scan, radiographic progression will be defined by PCWG2 criteria as ≥ 2 new bone lesions 
(Appendix 7). However, for the first reassessment scan only, patients should remain on study and 
have a confirmatory scan performed 12 weeks (3 cycles) later.  If this confirmatory scan shows 2 or 
more additional new lesions, this defines progression.  The date of progression is the date of the 


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first reassessment bone scan.  If the confirmatory scan does not show any additional new lesions, 
patient remains on study. If progression is observed on subsequent bone scans, a confirmatory 
scan is not required; the date of this bone scan is the date of progression (Appendix 7). 
 
• 
Death from any cause will also be considered as progression 
 
 
2.2. Secondary Objectives 
• 
Further investigate the safety of cyclical parenteral testosterone in asymptomatic men with recurrent 
castrate resistant prostate cancer.  Safety will be evaluated by the incidence, severity, duration, 
causality, seriousness, and type(s) of adverse events as assessed by the revised National Cancer 
Institute Common Toxicity Criteria (NCI CTC), version 4.0 published 28 May 2009 (Appendix 2). 
• 
PSA response rate [Proportion of patients achieving a PSA decline ≥ 50% according to Prostate 
Cancer Working Group (PCWG2) criteria]  
• 
Objective response rate in patients with measurable disease on CT scan using RECIST criteria  
• 
Time to PSA progression to each arm of therapy based on PCWG2 criteria 
• 
Time to Radiographic progression to each arm based on RECIST 1.1 and PCWG2 criteria 
• 
PSA response rate to enzalutamide post-BAT 
• 
PSA response rate to BAT post-enzalutamide 
• 
Overall Survival 
• 
PFS2 (Time from initiation of therapy to progression on crossover treatment) 
• 
Comparison of effect of each treatment arm on quality of life as assessed by patient completion of 
validated instruments (Appendix 8) 
 
 
3. PATIENT POPULATION AND SELECTION 
Eligible patients will have with metastatic CRPC with no disease related symptoms who have been treated with 
continuous ADT and have progressed after treatment with abiraterone. Patients will continue on ADT with 
LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH antagonist (Degarelix) if not surgically 
castrated throughout the duration of the study to inhibit endogenous testosterone production.  Patients will be 
randomized 1:1 and stratified based on duration of abiraterone acetate therapy (less than or greater than 6 
months).  A total of 194 patients (97 per treatment arm) will be recruited across 20 treatment sites over a 24 
month period. 
 
 
3.1. Inclusion Criteria  
 
Patients must meet the following criteria to be enrolled in this study:  
 
1. ECOG Performance status ≤2. 
2. Age ≥18 years. 
3. Histologically-confirmed adenocarcinoma of the prostate. 


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4. Treated with continuous androgen ablative therapy (either surgical castration or LHRH 
agonist/antagonist). 
5. Documented castrate level of serum testosterone (<50 ng/dl). 
6. Metastatic disease radiographically documented by CT/MRI or bone scan. 
7. Must have had disease progression while on abiraterone acetate alone or abiraterone acetate in 
combination with other investigational agents based on:  
• 
PSA progression defined as an increase in PSA, as determined by 2 separate 
measurements taken at least 1 week apart 
And/ Or 
• 
Radiographic disease progression, based on RECIST 1.1 in patients with measurable soft 
tissue lesions or PCWG2 for patients with bone disease  
8. Screening PSA must be ≥ 1.0 ng/mL. 
9. Prior treatment with additional second line hormone therapies is permitted.   
10. No prior treatment with enzalutamide, ARN-509, ODM-201, galeterone or other investigational AR 
targeted treatment is allowed. 
11. Prior docetaxel for hormone-sensitive prostate cancer is permitted if ≤ 6 doses were given in 
conjunction with first-line androgen deprivation therapy and >12 months since last dose of 
docetaxel. 
12. Prior treatment with Provenge vaccine and 223Radium (Xofigo) is allowed if >4 weeks from last dose. 
13. Patients must be withdrawn from abiraterone for ≥ 2 weeks. 
14. Patients must be weaned off prednisone and be off therapy for ≥ 1 week prior to starting therapy. 
15. Acceptable liver function: 
• 
Bilirubin < 2.5 times institutional upper limit of normal (ULN) 
• 
AST (SGOT) and ALT (SGPT) < 2.5 times ULN 
16. Acceptable renal function: 
• 
Serum creatinine < 2.5 times ULN  
17. Acceptable hematologic status: 
• 
Absolute neutrophil count (ANC) ≥ 1500 cells/mm3 (1.5 ×109/L) 
• 
Platelet count ≥ 100,000 platelet/mm3 (100 ×109/L) 
• 
Hemoglobin ≥ 9 g/dL 
18. At least 4 weeks since prior radiation.  
19. Ability to understand and willingness to sign a written informed consent document. 
20. Patients on either treatment arm will be considered for crossover if they demonstrate evidence of 
radiographic disease progression from the initial treatment. 
 
3.2. Exclusion Criteria 
1. Pain due to metastatic prostate cancer requiring treatment intervention. 
2. ECOG Performance Status ≥ 3. 
3. Prior treatment with enzalutamide is prohibited 
4. Prior treatment with docetaxel or cabazitaxel for metastatic castration-resistant prostate cancer is 
prohibited. 


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5. Requires urinary catheterization for voiding due to obstruction secondary to prostatic enlargement 
well documented to be due to prostate cancer or benign prostatic hyperplasia (BPH). 
6. Evidence of disease in sites or extent that, in the opinion of the investigator, would put the patient at 
risk from therapy with testosterone (e.g. femoral metastases with concern over fracture risk, severe 
and extensive spinal metastases with concern over spinal cord compression, extensive liver 
metastases) 
7. Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including 
laboratory abnormalities) that could interfere with patient safety or provision  of informed consent to 
participate in this study 
8. Active uncontrolled infection, including known history of HIV/AIDS or hepatitis B or C. 
9. Any psychological, familial, sociological, or geographical condition that could potentially interfere 
with compliance with the study protocol and follow-up schedule. 
10. Patients receiving anticoagulation therapy with Coumadin are not eligible for study.  [Patients on 
non-coumadin anticoagulants (Lovenox, Xarelto, etc.) are eligible for study. Patients on Coumadin 
who can be transitioned to lovenox prior to starting study treatments will be eligible] 
11. Patients with prior history of a thromboembolic event within the last 12 months that is not being 
treated with systemic anticoagulation are excluded. 
12. Patients allergic to sesame seed oil or cottonseed oil are excluded. 
13. Major surgery (eg, requiring general anesthesia) within 3 weeks before screening, or has not fully 
recovered from prior surgery (ie, unhealed wound). Note: subjects with planned surgical procedures 
to be conducted under local anesthesia may participate. 
3.3  Inclusion of women and minorities 
This study is focused on prostate cancer, therefore is applicable to men only.  Women and children will not 
be included on this study.  Men from all ethnic and race groups are eligible for this study. 
 
4. TREATMENT PLAN 
4.1. Study Design  
Men with metastatic CRPC with no disease related symptoms who have been treated with continuous ADT 
and have progressed after treatment with abiraterone (pre- chemotherapy for metastatic disease) will be 
treated on a randomized, multi-Institutional open label study to determine if treatment with intramuscular T, 
given on a dose/schedule designed to achieve serum T levels that rapidly cycles from the polar extremes 
of supraphysiologic to near castrate levels [i.e. termed Bipolar Androgen Therapy (BAT)], will improve 
progression free survival, quality of life and metabolic syndrome vs. enzalutamide as standard therapy. 
 
 
 
 
 
 
 
 
 
 


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Study Design Schematic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2. Study Treatments and Treatment Scheme 
4.2.1. Study Treatments 
 
Patients on BAT (Arm A) will receive testosterone cypionate or testosterone enanthate administered 
as an intramuscular injection.  These two forms of testosterone exhibit identical pharmacokinetic 
properties and may be used interchangeably in this study based on availability at individual study 
sites.  These agents are administered as intramuscular injections given deep in the gluteal muscle.  
They should not be given intravenously.  Testosterone cypionate is in cottonseed oil containing 
benzyl alcohol as a preservative.  Testosterone enanthate is in sesame oil with chlorobutanol as a 
preservative.  A dose of 400 mg of either agent will be injected intramuscularly (IM) every 28 days.  
This dose was selected based on data demonstrating that it produces an initial supraphysiologic 
serum level of T (i.e. > 1500 ng/dL or 3-10 times normal level) with eugonadal levels achieved at the 
end of two weeks and near castrate levels after 28 days.   
 
Patients randomized to enzalutamide (Arm B) will be prescribed enzalutamide 40 mg tablets and 
instructed to take 4 tablets per day orally for 28 days/cycle. 
 
4.2.2. Treatment Scheme 
 
Patients will continue on ADT with LHRH agonist (i.e. Zoladex, Trelstar, Eligard or Lupron) or LHRH 
antagonist (Degarelix) if not surgically castrated throughout the duration of the study to inhibit 
endogenous testosterone production.  Patients will be randomized 1:1 and stratified based on 
duration of abiraterone acetate therapy (less than or greater than 6 months).  Patients randomized to 
BAT will receive 400 mg T-cypionate or T-enanthate IM every 28 days.  Patients randomized to 
enzalutamide will receive daily oral dose of 160 mg for 28 days/cycle.  Each cycle is 28 days in 
length. 
 


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Patients will have PSA level checked every cycle.  Every 3 cycles patients will have repeat bone/CT 
scans to evaluate treatment response. Patients will remain on treatment until evidence of disease 
progression on CT scan (per RECIST criteria) or with progressive bone metastatic disease (per the 
PCWG2 definition) or symptomatic progression due to prostate cancer.  Patients with PSA 
progression but with disease response or stable disease on imaging studies will remain on study.   
 
Patients with radiographic disease progression on either arm will be given opportunity to cross-over to 
the opposite treatment. Patients who opt to cross-over must wait 4-6 weeks from time patient has 
confirmed radiographic disease progression before starting cross-over treatment.  Patients on the 
BAT arm A with confirmed radiographic disease progression can cross over to receive enzalutamide 
beginning 4-6 weeks after time of confirmed radiographic progression.  Patients on the enzalutamide 
arm B will be allowed to cross-over to receive BAT beginning 4-6 weeks after time of confirmed 
radiographic progression.  Patients who opt to cross over will remain on study and continue 
respective therapies for at least 3 cycles.  Patients will have PSA checked each cycle (i.e. every 4 
weeks) and repeat bone and CT scans every 3 cycles.  Patients demonstrating PSA response after 3 
cycles will remain on study until evidence of PSA progression per PCWG2 criteria or confirmed 
radiographic disease progression.   
 
Patients with clinical progression due to prostate cancer who meet study exclusion criteria (section 
3.2) will be permitted to cross-over to the opposite treatment.  Patients with clinical progression due 
to pain from prostate cancer are not permitted to cross-over. 
 
 
Patients who opt not to cross-over will complete end of study visit and will be removed from study.   
 
 
4.3. Dosing Delays and Modifications 
Treatment will be given on indicated days ± 5 days. Patients who develop seizures, pulmonary embolus or 
other thromboembolic event will be removed from study.   
 
There will be no dose modifications for testosterone in this study.  
 
Dose modification for enzalutamide will be according to the institution’s standard of care practice. 
Enzalutamide Dose reduction to label recommended dose of 80 mg/day is allowed for patients on 
concomitant CYP2C8 inhibitors (gemfibrozil) or strong CYP3A4 inducers. Dose reduction is at the 
discretion of the treating physician. 
 
Patients may temporarily suspend study treatment if they experience toxicity that is considered to be 
related to study drugs and requires a dose to be held. Treatment delay will be allowed up to 4 weeks due to 
drug related toxicities. 
 
 
 
If, in the judgment of the investigator, the patient is likely to derive clinical benefit from resuming the study 
drugs after 4 weeks, the study drug may be restarted with the approval of the Medical Monitor (Dr. Samuel 
Denmeade). 
 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be allowed with 


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Medical Monitor approval. The acceptable length of interruption will depend on agreement between the 
investigator and the Medical Monitor. 
 
4.4. Removal of Patients from Study 
A patient may be removed from the study for a variety of reasons, including: 
1. As defined by the protocol, evidence of disease progression based on radiographic progression or 
worsening symptoms. 
2. Unacceptable adverse event(s), including:  
• 
Patients develop new or worsening pain deemed by the investigator to be due to disease 
progression 
• 
Patients develop urinary outlet obstruction well documented and thought to be due to prostate 
cancer within the prostate and requiring urinary catheterization 
• 
Patients who develop grade 3 or higher liver function abnormalities with increase in bilirubin, 
AST (SGOT) or ALT (SGPT) ≥ 2.5 times institutional upper limit of normal (ULN) 
• 
Patients develop decreased renal function with serum creatinine ≥ 2.5 times baseline level due 
to prostate cancer progression or drug toxicity. 
• 
Patents develop hypersensitivity or anaphylactoid reactions to testosterone injection. 
• 
Any evidence of severe dose limiting toxicities secondary to treatment with enzalutamide that 
cannot be controlled with standard therapy (e.g. nausea/vomiting not controlled with oral 
antiemetic regimen). 
3. Intercurrent illness that prevents further participation. 
4. Experiencing a treatment delay of longer than 4 weeks due to drug toxicity; however, if the patient is 
receiving clinical benefit, treatment may be delayed for longer than 4 weeks and then resumed at 
the discretion of the Investigator and the approval of the Medical Monitor (Dr. Samuel Denmeade). 
5. Patient refuses further treatment through the study and/or withdraws consent to participate 
6. Patient is noncompliant with respect to taking drugs, keeping appointments, or having tests required 
for the evaluation of drug safety and efficacy. 
7. General or specific changes in the patient's condition that render the patient unacceptable for 
further treatment in this study in the judgment of the investigator. 
8. Under no circumstance will care of a withdrawn patient be adversely affected by a decision to 
withdraw or be withdrawn from the study. 
9. Deterioration in ECOG performance status to grade 3 or higher.   
 
4.5 Criteria for Discontinuation of Study Treatment due to Development of Clinical Progression due 
to Prostate Cancer 
Due to the nature of the treatment, there is concern that patients could experience potential development of 
prostate cancer related pain due to BAT.  This worsening of pain was not observed in any of the three 
studies that previously tested the use of testosterone as therapy for men with asymptomatic CRPC.  In 
addition, men with baseline pain due to prostate cancer are excluded from enrolling in the study.   
 
The primary efficacy endpoint of the study is progression free survival.  Patients that have unequivocal 


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clinical progression without radiographic progression who continue to meet study exclusion criteria (section 
3.2) will be permitted to cross-over to the opposite treatment.  Patients who do not meet these original 
exclusion criteria and patients with clinical progression due to pain from prostate cancer are not permitted 
to cross-over and should be removed from the study and evaluated for standard of care therapy.  Study 
treatment should be stopped and patients advised regarding available treatment options.  For this study, 
unequivocal clinical progression will be characterized as: 
 
1. Cancer pain requiring initiation of chronic administration of opiate analgesia (oral opiate use for ≥3 
weeks; parenteral opiate use for ≥7 days.  Patients with cancer pain requiring opiate analgesia for 
relief should also be assessed by the investigator for the need for initiating systemic chemotherapy 
or palliative radiation. 
2. Development of a skeletal-related event (SRE): pathologic fracture, spinal cord compression, or 
need for surgical intervention or radiation therapy to the bone. 
 
3. Development of clinically significant symptoms due to loco-regional tumor progression (e.g. urinary 
obstruction) requiring surgical intervention or radiation therapy. 
 
All patients meeting the criteria for unequivocal clinical progression should have repeat imaging studies 
(i.e. bone and CT scans) if not done within the past month of meeting said criteria. 
 
 
4.6 Pain management:   
Patients who develop new pain thought by the investigator to be due to prostate cancer should be treated 
according to NCCN guidelines for Adult Cancer Pain (Ver. 1.2014) (Appendix 3) in a stepwise fashion 
using the WHO Analgesic Ladder approach.  Patients with pain that is managed without oral opioids after 3 
weeks can continue on to the next cycle of the study.  Patients with a continued requirement for oral 
opioids after 3 weeks will be removed from study.  Patients who have recurrent pain requiring oral opioids 
on subsequent cycles will also be removed from study. 
 
 
4.7 Concomitant Therapy 
The use of any concurrent medication from screening and while on study, prescription or over-the-counter, 
is to be recorded on the patient's CRF along with the reason the medication was taken.  In addition, 
tobacco and alcohol use will be collected. 
 
Concurrent use of another clinical investigational drug or device while on study is prohibited.   
Supportive care medications are permitted with their use following institutional guidelines.  For patients who 
did not undergo orchiectomy, concurrent treatment with LHRH analogue is mandatory and must be 
recorded. 
The following supportive care medications are considered permissible during the study:  
• 
Conventional multivitamins, selenium and soy supplements  
• 
Systemic glucocorticoid administration such as “stress dose” glucocorticoid up to maximum of 4 
mg/day dexamethasone or dexamethasone equivalent is permitted if clinically indicated. Selection 
of corticosteroid, dose and duration is at the discretion of the treating physician. 


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• 
Dutasteride or finasteride if being used to treat BPH and only if patients are on the medication for at 
least 3 months prior to Study Day 1 
• 
Bisphosphonate and denosumab usage is allowed only if patients are on the medication for at least 
3 months prior to Study Day 1  
• 
Transfusions and hematopoietic growth factors per institutional practice guidelines 
 
 
4.8 Prohibited Concomitant Medications 
Concomitant therapy during the treatment phase of the study with any of the following listed is prohibited:  
• 
Chemotherapy 
• 
Immunotherapy  
• 
Bicalutamide, nilutamide, flutamide  
• 
Systemic ketoconazole (or other azole drugs such as fluconazole and itraconazole)  
• 
Diethylstilbestrol, PC-SPES, and other preparations such as saw palmetto thought to have 
endocrine effects on prostate cancer  
• 
Radiopharmaceuticals such as xofigo (223Ra), strontium (89Sr) or samarium (153Sm)  
• 
Other experimental drugs or treatments 
 
 
5 STUDY ACTIVITIES 
5.1 Screening Period 
All patients must sign a written informed consent form before study specific screening procedures are 
performed.  Screening procedures to evaluate patient eligibility for the study will be conducted within 28 
days prior to Cycle 1 Day 1.  Prior to enrollment, patient must have documented insurance coverage 
demonstrating ability to pay for enzalutamide in event patient is randomized to this treatment arm.  If the 
patient meets eligibility and screening requirements he will be randomized and will return to the site for the 
Cycle 1 Day 1 visit and dosing.  All required treatment and post-treatment study procedures and 
assessments must be done within 5 days (+/-) of the specified study visit date. 
 
Initial Registration Process: 
Eligible patients will be registered on study centrally at the Johns Hopkins Sidney Kimmel Comprehensive 
Cancer Center by the TRANSFORMER Study Manager. 
 
To register a patient, the following documents must be completed and emailed to the Study Manager, Haiyi 
(Harry) Cao, at hcao7@jhmi.edu: 
• 
Signed/dated patient consent form 
• 
Eligibility checklist 
• 
Copies of the prostate cancer pathology report 
• 
Copies of pre hormone therapy/chemotherapy or radiation therapy 
• 
Screening labs 
• 
CT and bone scan reports 


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• 
Other materials may also be sent if considered pertinent for confirming patient eligibility 
 
The Study Manager will review the documents to confirm eligibility.  To complete the registration process 
the Study Manager will: 
• 
Review the eligibility checklist and the related source documents  
• 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log 
• 
Once eligibility is confirmed, patients will be randomized to a treatment group according to the 
randomization schedule.  Patients will be randomized to receive either BAT or enzalutamide in a 1:1 
ratio. A randomization assignment will be emailed to sites with confirmation of registration 
 
All patients must commence treatment within 5 calendar days of randomization. 
 
 
5.2 Randomization 
Once eligibility is confirmed, patients will be randomized to a treatment group according to the 
randomization schedule.  Patients will be randomized to receive either BAT or enzalutamide in a 1:1 ratio.  
All patients must commence treatment within 5 calendar days of randomization. 
 
 
5.3 Stratification 
In this study patients will be stratified according to duration of response to prior therapy with abiraterone 
(i.e. < 6 months or ≥ 6 months response). 
 
5.4 Screening Studies (performed within 28 days before Cycle 1 Day 1) 
1. Comprehensive medical history and physical exam, including height and weight, and medications. 
2. ECOG Performance status (PS) 
3. Body Composition (Body weight, body mass index) 
4. CBC (Complete blood count) with differential and platelet count 
5. CMP (Comprehensive Metabolic Panel - Sodium, Potassium, Chloride, BUN, Serum Creatinine, 
Calcium, Total Protein, Albumin, Total Bilirubin, AST, ALT, Alkaline Phosphatase, HCO3) 
6. Serum PSA, testosterone  
7. Lipid Panel (fasting) 
8. Androgen Panel [dihydrotestosterone (DHT), free testosterone, estradiol, 
dehydroepiandostenedione sulfate (DHEA-S), DHEA and sex hormone binding globulin (SHBG)] 
9. Metabolic Panel (fasting glucose, hemoglobin A1c, fasting insulin, serum C-telopeptide, 
osteocalcin) 
10. C Reactive Protein 
11. Baseline EKG 
12. Partial Prothrombin (PTT) and Prothrombin Times (PT) 
13. Staging imaging with CT and bone scintigraphy (bone scan) 


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14. Blood drawn for to assess level of full length and androgen receptor variant 7in circulating tumor 
cells (CTC-ARV7) (Appendix 4) 
15. Blood drawn for to evaluate presence of AR mutation in circulating tumor DNA (AR-DNA)  
(Appendix 4) 
16. Quality of life surveys (FACIT-Fatigue Scale, RANDSF-36, IIEF, Brief Pain Inventory, International 
Positive and Negative Affect Schedule Short Form (I-PANAS-SF) (mood assessment) (Appendix 8) 
 
5.5 Treatment Period  
All required treatment and post-treatment study procedures and assessments must be done within 5 days 
(+/-) of the specified study visit date. 
 
1. For BAT Arm A patients will have a clinic visits every cycle to receive testosterone injection and 
undergo assessment of toxicity, ECOG performance status and vital signs 
2. For enzalutamide Arm B patients will have a clinic visit every 3 cycle to receive new drug 
prescription, undergo assessment of toxicity, ECOG performance status and vital signs 
3. PSA every cycle for both Arms.  PSA may be performed at outside laboratory for patients 
randomized to Arm B as long as patient can have study done at the same outside lab each time. 
(PSA is not performed at Cycle 1 Day 1) 
4. CBC, Comp Panel, testosterone, QOL surveys after first cycle for both arms (V3)  
5. CBC, Comp Panel, Lipid Panel, Metabolic Panel, CRP after every 3 cycles for both arms (V5, V8, 
V11, etc.)  
6. Androgen Panel after first 3 cycles and at progression 
7. CT scan, bone scan every 3 months for both arms (V5, V8, V11, etc.) 
8. Blood drawn for research testing to assess level of full length and variant androgen receptor and 
circulating DNA for AR mutation at V5 (Appendix 4) 
9. Quality of life surveys after first cycle (V3) and then every 3 months for both arms (V5, V8, V11, 
etc.) 
 
 
5.6 End of Initial Treatment (at the time of progression) 
At the time of progression, the following assessments will be performed:  
1. Physical examination 
2. Vital signs 
3. ECOG  
4. Concomitant medication 
5. Adverse events 
6. Comprehensive metabolic panel, CBC, and serum PSA  
7. Quality of life surveys (FACIT-Fatigue Scale, RANDSF-36, IIEF, Brief Pain Inventory, International 
Positive and Negative Affect Schedule Short Form (I-PANAS-SF) (mood assessment) (Appendix 8) 
8. Patients must also have blood drawn for CTCs to look for changes in AR-V7 and total AR 
expression. The CTCs samples will be either collected at the end of study visit for patients who opt 
not to cross-over, or at the cross over visit for patient who opt to cross over to receive the opposite 


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treatments (CTCs samples will be collected before the start of the opposite therapy for cross over 
patients) 
9. Patients must additional have labs drawn for Lipid Panel, Androgen Panel [dihydrotestosterone 
(DHT), free testosterone, estradiol, dehydroepiandostenedione sulfate (DHEA-S), DHEA and sex 
hormone binding globulin (SHBG)] and Metabolic Panel [fasting glucose, hemoglobin A1c, fasting 
insulin, serum C-telopeptide, osteocalcin] 
 
Patients who demonstrate radiographic progression on CT or bone scan will have the option to cross-over 
to opposite arm of therapy.  Patients with clinical progression due to prostate cancer who continue to meet 
study exclusion criteria (section 3.2) will be permitted to cross-over to the opposite treatment.  Patients with 
clinical progression due to pain from prostate cancer are not permitted to cross-over. 
 
Patients who are not eligible or who opt not to cross-over will complete end of study visit and will be 
removed from study.  
 
Please refer to the study calendar for assessments to be performed at End of Treatment/Progression Visit.  
 
 
5.7 Crossover Treatment Period 
Patients with radiographic disease progression or these with clinical progression who continue to meet 
exclusion eligibility criteria (section 3.2) on either arm will be given opportunity to cross-over to the opposite 
treatment.  Patients who opt to cross-over must wait 4-6 weeks from time patient has confirmed 
radiographic disease progression before starting cross-over treatment.  Patients on the BAT arm A with 
confirmed radiographic disease progression can cross over to receive enzalutamide beginning at least 2 
and no more than 6 weeks after time of confirmed radiographic progression.  Patients on the enzalutamide 
arm B will be allowed to cross-over to receive BAT beginning at least 2 and no more than 6 weeks after 
time of confirmed radiographic progression.  Patients who opt to cross over will remain on study and 
continue respective therapies for at least 3 cycles.  Patients will have PSA checked each cycle (i.e. every 4 
weeks) and repeat bone and CT scans every 3 cycles.  Patients demonstrating PSA response after 3 
cycles will remain on study until evidence of PSA progression per PCWG2 criteria or confirmed 
radiographic disease progression.   
 
 
 
5.8 End of Study Visit (30-day safety follow-up) 
After the initial treatment arm, for those who choose to not cross-over and come off study treatment, they 
will come for an end of study visit within 30 days from their confirmed radiographic progression on CT or 
bone scan. 
 
For those patients who crossed over to receive the opposite arm of therapy, they will come for an end of 
study visit within 30 days from their second disease progression (evidence of PSA progression per PCWG2 
criteria or confirmed radiographic disease progression.  
 
For patients with clinical progression that requires patient to come off study (i.e. worsening pain, 
obstructive symptoms) end of study visit must be scheduled within 30 days of symptoms. 
The following assessment will take place at the End of Study visit: 


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1. Physical examination 
2. Vital signs 
3. ECOG  
4. Concomitant medication 
5. Adverse events 
6. Comprehensive metabolic panel, CBC, and serum PSA 
7. Quality of life surveys (FACIT-Fatigue Scale, RANDSF-36, IIEF, Brief Pain Inventory, International 
Positive and Negative Affect Schedule Short Form (I-PANAS-SF) (mood assessment) (Appendix 8) 
8. All patients meeting the criteria for unequivocal clinical progression should have repeat imaging 
studies (i.e. bone and CT scans) if not done within the past month of meeting said criteria. 
 
5.9 Early Discontinuation 
For patients who come off the study treatments due to an adverse event or unacceptable toxicity related to 
the study drugs, they will come back to the clinic for an end of study visit. 
 
If early discontinuation is due to an adverse event or unacceptable toxicity related to any of the study 
treatments the patient should be followed until resolution of the adverse event/toxicity or at least one 
month, whichever is later. 
 
5.10 Survival 
 
For patients who have died, date of death will be collected and overall survival duration will be calculated 
from randomization to death. 
 
For patients who are still alive, date of last contact (patients who are lost to follow up do not need to be 
contacted) will be collected and overall survival will be censored at this date. 
 
6 STUDY ASSESSMENTS 
6.1 Assessing Response in Measurable Disease 
In patients with measurable disease, tumor response will be evaluated using CT and bone scan. Patients 
will undergo screening CT scan and bone scan every 3 months to determine disease response/progression 
to either BAT or Enzalutamide.  Progression for soft tissue lesions will be based on RECIST 1.1 criteria 
(Appendix 1) and for bone lesions based on PCWG2 criteria.   
 
After 3 cycles of study treatment, patients will remain on study unless they show evidence of clinical or 
radiographic progression.  On CT scan, radiographic progression will be defined by RECIST criteria (i.e. 
>20% increase in the sum of target lesions).  On bone scan, radiographic progression will be defined by 
PCWG2 criteria as ≥ 2 new bone lesions (Appendix 7).  However, for the first reassessment scan only, 
patients should remain on study and have a confirmatory scan performed 12 weeks later.  If this 
confirmatory scan shows 2 or more additional new lesions, this defines progression.  The date of 
progression is the date of the first reassessment bone scan.  If the confirmatory scan is does not show any 


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additional new lesions, patient remains on study. If progression is observed on subsequent bone scans, a 
confirmatory scan is not required; the date of this bone scan is the date of progression (Appendix 7).  
 
 


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6.2 Assessing PSA Response to BAT 
PSA is an androgen-regulated gene. Therefore, BAT therapy is likely to produce an initial increase in PSA 
levels even in patients who will respond to treatment. In the pilot study, we observed PSA increase up to 
10-fold after the first injection of testosterone, even in some patients who eventually had decline in PSA 
below baseline.  Therefore to assess PSA response in this study we will use PCWG2 criteria with some 
modification: 
1. Patient with PSA that continues to increase above baseline will be considered to have PSA 
progression (Figure 6A). 
2. Patient with PSA that decreases >50% below pretreatment baseline while on BAT will be 
considered a PSA responder (Figure 6B).   
3. Patients with initial increase in PSA in response to BAT with subsequent decline >50% below 
baseline will also be considered a PSA responder (Figure 6C).   
4. Patients whose PSA increases and then declines from peak levels but does not >50% decrease 
below baseline will not be considered a PSA responder (Figure 6D).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 6.  Examples of PSA response patterns on study consistent with PSA progression or response 
 
 
6.3 Quality of life (QoL) and metabolic studies:  
QoL will be assessed using , FACIT-F Version 4, RAND-SF36 Quality of Life Survey, IIEF,  Brief Pain 
Inventory,  I-PANAS-SF (Appendix 8).  The surveys will be administered at baseline randomization, one 
month post-randomization, three months post-randomization, six months, 12 months post-randomization 
and at the time of progression.   
For each module, summary statistics of the scores will be reported at baseline randomization, one month 
post-randomization, three months post-randomization, six months, 12 months post-randomization and at 
the time of progression.  
 
 
 


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6.4 Correlative Studies 
6.4.1 AR-Variant Studies 
 
To determine levels of full length AR and AR-V7, blood will be obtained from patients at screening, after 
3 cycles of therapy on each arm and then at time of radiographic progression.  Blood samples are 
collected and shipped to the Johns Hopkins Laboratory within 24 hrs according to procedures 
described in Appendix 4.   
 
 
6.4.2 AR Mutation Studies 
 
An additional documented mechanism of resistance to androgen ablative therapies is mutation of the 
androgen receptor (AR) that can lead to reactivation particularly if the point mutation is in the ligand-
binding domain (LBD) of AR (40).  Beltran et al used a whole exome sequencing approach with 
formalin-fixed paraffin-embedded (FFPE) biopsy tissue and determined that 44% of CRPCs studied 
harbored genomic alterations involving the AR gene (AR), including AR copy number gain (24% of 
CRPCs) or AR point mutation (20% of CRPCs) (41).  AR mutations can also frequently be detected in 
CTCs isolated from patients with CRPC.  Jiang et al used the Veridex system to isolate CTCs and 
documented AR mutations in 20/35 (57%) patients (42).  Many of these mutations occur in the LBD of 
AR and can broaden ligand specificity, and some confer resistance by converting the AR antagonist 
into an agonist of the mutant receptor (43-45).  Recently, a specific mutation F876L that may confer 
response to enzalutamide has been described (46, 47).  Joseph et al (48) analyzed circulating tumor 
DNA (ctDNA) in plasma from 29 patients who participated in the phase I portion of a clinical trial of 
ARN-509 using the sensitive, emulsion PCR-based BEAMing (Beads, Emulsions, Amplification, and 
Magnetics) method (49).  This study specifically looked for the emergence of the F876L LBD mutation 
and found it in 3/29 (10%) ARN-509 treated patients (48). 
 
To detect new AR mutations will require sequencing of the entire AR gene that may be present in rare 
amounts in the circulating tumor DNA pool.  To accomplish this task we will utilize a new approach 
known as the Safe-Sequencing System (Safe-SeqS) developed by our co-investigator Dr. Vogelstein 
and colleagues (50).  This approach is designed to overcome the high error rate seen massive parallel 
sequencing used to detect rare variants of any specific gene.   
 
To detect the effect of BAT on AR mutation in circulating tumor DNA, blood will be obtained from 
patients (n=60) in the BAT arm (Arm A) or enzalutamide arm (Arm B) at screening and after 3 cycles of 
BAT or enzalutamide.  Blood samples are collected and shipped to the Johns Hopkins Laboratory 
within 24 hrs according to procedures described in Appendix 4.  
  
 
6.4.3 Imaging Studies 
6.4.3.1 18F-DCFPyL PSMA-PET Imaging (Johns Hopkins Only) 
 
PSMA is a type II plasma membrane protein expressed abundantly in prostate cancer epithelia and 
has been the focus of a number of therapeutic and imaging strategies (51).  A potential role for 
PSMA as a candidate imaging biomarker of AR activity is based on reports showing that androgen 
suppresses PSMA expression due to the presence of an AR-regulated PSMA enhancer that 
downregulates PSMA transcription in response to androgens (52).    


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To improve upon the pharmacokinetics of 18F-DCFBC, a novel second generation low-molecular 
weight PSMA-targeted PET radiopharmaceutical has been synthesized 2-(3-{1-carboxy-5-[(6-
[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid, (18F-DCFPyL) (54).  18F-
DCFPyL displays high affinity for PSMA with a Ki value of 1.1 ± 0.1 nmol/L.  In an 
immunocompromised mouse model 18F-DCFPyL clearly delineated PSMA expressing PC3 PIP 
prostate tumor xenografts on imaging with PET.  At 2 hours post-injection, 39.4±5.4 percent injected 
dose per gram of tissue (%ID/g) was evident within the PSMA positive PC3 PIP tumor, with a ratio of 
358:1 of uptake within PSMA positive PC3 PIP to PSMA negative PC3 flu tumor placed in the 
opposite flank.  At or after 1 hour post-injection, minimal non-target tissue uptake of 18F-DCFPyL was 
observed.  By 3.5 hours after injection, only the PSMA positive tumor was visible with no 
radiochemical background in liver or the gastrointestinal tract to obscure potential metastases.   
 
Figure below from Chen et al. (54) illustrates PET-CT volume-rendered composite images 
representing the time course of radiochemical uptake after administration of 18F-DCFPyL. PSMA 
positive PC3 PIP (arrow) and PSMA negative PC3 flu (dotted oval) tumors are present in 
subcutaneous tissues posterior to opposite forearms, as indicated.  The mouse was injected 
intravenously with 0.38 mCi (14.1 MBq) 18F-DCFPyL at Time 0.  By 30 minutes post-injection 
radiochemical uptake was evident within the PIP tumor and kidneys.  Radioactivity receded from 
kidneys faster than from tumor, and was not evident within kidneys by 3.5 hours post-injection.  
Radioactivity within bladder was due to excretion.  At no time was radiochemical clearly visualized 
within the PSMA negative PC3 flu tumor.  (kid = kidneys,  bl= urinary bladder) 
 
 
Dosimetry calculations demonstrated a total effective dose of 0.0136 mGy/MBq (50.32 mrem/mCi).  
The organ with the highest mean absorbed dose per unit administered activity was the urinary 
bladder wall, 0.15 mGy/MBq (555 mrem/mCi), followed by the kidneys at 0.05 mGy/MBq (185 
mrem/mCi).  The bladder wall is the dose-limiting organ.  On the basis of the dosimetry results a 


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maximum of 9 mCi (331 MBq) can be administered without exceeding the 50 mGy critical organ 
dose limit (urinary bladder wall in this case), for a single administration of radioactive material for 
research use as specified in Code of Federal Regulations 21, part 361.  These data demonstrates 
18F-DCFPyL as a viable, new PET imaging agent for PSMA-expressing tissues, especially prostate 
cancer, and warrants further evaluation in translational clinical studies to determine its use for 
prostate cancer detection. 
 
18F-DCFPyL is currently only available for testing at Johns Hopkins under FDA IND #121064.  We 
propose to use 18F-DCFPyL PET to detect changes in PSMA expression metastatic prostate cancer in 
response to BAT or enzalutamide.  Expression changes are determined by visual qualitative and 
quantitative SUV analysis. Correlation will be made to sites of suspected metastatic disease 
detected by standard conventional imaging modalities (CIM) for prostate cancer which includes IV 
contrast CT of chest/abdomen/pelvis and whole body bone scintigraphy.  We expect that patients 
progressing on ADT and Abiraterone will have relatively low PSMA signal in metastatic sites due to 
suppression of PSMA expression due to upregulation of AR expression and AR activity despite 
castrate T levels.  Following BAT, we expect to see PSA levels initially increase and PSMA 
expression decrease due to enhanced AR activity.  Following enzalutamide, we expect to see PSA 
levels initially decrease and PSMA expression increase due to decreased AR activity.  
 
Patients on either arm of the trial at Johns Hopkins will be given opportunity to undergo 18F-
DCFPyL-PET imaging (Appendix 5).  Patients will sign separate consent for the imaging portion of 
the study.  Imaging will be performed according to standard PET/CT imaging procedures in place at 
Johns Hopkins, Appendix 5.  Patients (n=10/arm) will have 18F-DCFPyL-PET imaging before 
starting BAT or enzalutamide and then have repeat imaging after 12 weeks of treatment on either 
arm.   
 
The medical imaging devices (PET-CT) are FDA approved.  18F-DCFPyL (FDA IND #121064) will 
be used under the auspices of the IND regulations as provided in the Code of Federal Regulations.  
 
 
7 Requirement for an Independent Research Monitor 
For research defined in this protocol which is considered greater than minimal risk, the DOD requires IRB 
approval, by name, of an independent research monitor with expertise consonant with the nature of risk(s) 
identified within the research protocol.  The monitor for this trial will be Dr. Christine Hann, Assistant Professor 
of Oncology at Johns Hopkins University School of Medicine.  
 
Research Monitor functions will include: 
• 
Observing recruitment, enrollment and consent procedures 
• 
Overseeing study interventions and interactions, 
• 
Reviewing monitoring plans, 
• 
Overseeing data collection and analysis 
• 
Discussion of the protocol with investigators, interview human subjects 
The Research Monitor shall have the authority to stop the research in progress, remove individual human 
subjects from the protocol and take whatever steps are necessary to protect the safety and well-being of 
human subjects until the IRBs can assess the monitor’s report.  The Research Monitor has the responsibility to 
promptly report observations and findings to the IRB and the DHRPO.   


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There should be no apparent conflict of interest and the monitor cannot be under the supervision of the overall 
PI or site PIs or other investigators or research staff involved in the study.   
 
8 Safety Assessment  
Safety will evaluated based on the incidence, severity, duration, causality, seriousness, and type of adverse 
events (AEs), and changes in the patient’s physical examination, vital signs, and clinical laboratory results.  
Investigators will use the NCI CTC version 4.0 published 28 May 2009 to assess the severity of AEs and 
toxicities (see Appendix 2).  All observed or volunteered adverse events regardless of treatment group or 
causal relationship to study drug will be recorded on the adverse event page(s) of the case report form (CRF). 
 
 
9 PHARMACEUTICAL INFORMATION-Testosterone Cypionate, Testosterone Enanthate , 
Enzalutamide 
 
9.1 Testosterone Cypionate Drug Characterization 
9.1.1 Drug Name:  Testosterone Cypionate (DEPO-Testosterone Injection) 
 
 
 
 
 
 
 
 
9.1.2 Chemical Name: androst-4-en-3-one,17-(3-cyclopentyl-1-oxopropoxy)-, (17ß)- 
9.1.3 Molecular Formula: C27H40O3  
 
Molecular Weight:  412.61 g/mol 
9.1.4 Description  
 
DEPO-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the 
oil-soluble of the androgenic hormone testosterone.  Testosterone cypionate is a white or creamy white 
crystalline powder, odorless or nearly so and stable in air. DEPO-Testosterone Injection is available in 
two strengths, 100 mg/mL and 200 mg/mL testosterone cypionate. 
Each mL of the 100 mg/mL solution contains: 
Testosterone cypionate................................................................................... 100 mg 
Benzyl benzoate .............................................................................................. 0.1 mL 
Cottonseed oil ................................................................................................ 736 mg 
Benzyl alcohol (as preservative) ..................................................................... 9.45 mg 
Each mL of the 200 mg/mL solution contains: 
Testosterone cypionate .................................................................................. 200 mg 
Benzyl benzoate .............................................................................................. 0.2 mL 
Cottonseed oil ................................................................................................ 560 mg 
Benzyl alcohol (as preservative) ..................................................................... 9.45 mg 
 


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9.2 Testosterone Enanthate Drug Characterization 
9.2.1 Drug Name:  Testosterone Enanthate (Delatestryl) Structural formula: 
 
 
 
 
 
 
 
 
 
 
 
9.2.2 Chemical Name: (androst-4-en-3-one, 17-[(1-oxoheptyl)-oxy]-, (17β)-.  
9.2.3 Molecular Formula: C26H40O3  Molecular Weight:  400.6 g/mol 
9.2.4 Solubility:  Insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble 
in vegetable oils 
9.2.5 Description  
 
Testosterone Enanthate Injection, for intramuscular injection, contains testosterone enanthate which is 
the oil-soluble ester of the androgenic hormone testosterone.  Enanthate Injection is available as a 
colorless to pale yellow solution.  Each mL contains 200 mg testosterone enanthate in sesame oil with 
5 mg chlorobutanol as a preservative. 
 
 
9.3 Clinical Pharmacology Testosterone Esters 
Testosterone esters are less polar than free testosterone.  Testosterone esters in oil injected 
intramuscularly are absorbed slowly from the lipid phase; thus, Testosterone Cypionate and Testosterone 
Enanthate can be given at intervals of two to four weeks. 
 
Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 
2 percent is free.  Generally, the amount of this sex-hormone binding globulin in the plasma will determine 
the distribution of testosterone between free and bound forms, and the free testosterone concentration will 
determine its half-life. 
 
About 90 percent of a dose of testosterone is excreted in the urine as glucuronic and sulfuric acid 
conjugates of testosterone and its metabolites; about 6 percent of a dose is excreted in the feces, mostly in 
the unconjugated form. Inactivation of testosterone occurs primarily in the liver. Testosterone is 
metabolized to various 17-keto steroids through two different pathways.  The half-life of Testosterone 
Cypionate and Testosterone Enanthate when injected intramuscularly is approximately eight days.  The 
two forms of the drug demonstrate identical pharmacokinetic properties. 
 
9.4 Precautions 


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9.4.1 General 
1. Patients with benign prostatic hypertrophy may develop acute urethral obstruction. Priapism or 
excessive sexual stimulation may develop.  
2. Oligospermia may occur after prolonged administration or excessive dosage. If any of these 
effects appear, the androgen should be stopped and if restarted, a lower dosage should be 
utilized. 
3. Testosterone Cypionate or Enanthate should not be used interchangeably with testosterone 
propionate because of differences in duration of action. 
4. Testosterone Cypionate and Testosterone Enanthate are not for intravenous use. 
 
9.4.2 Information for patients 
Patients should be instructed to report any of the following: nausea, vomiting, changes in skin color, 
ankle swelling, too frequent or persistent erections of the penis. 
 
9.4.3 Laboratory tests 
1. Hemoglobin and hematocrit levels (to detect polycythemia) should be checked periodically in 
patients receiving long-term androgen administration. 
2. Serum cholesterol may increase during androgen therapy. 
 
9.4.4 Drug interactions 
1. Androgens may increase sensitivity to oral anticoagulants.  Dosage of the anticoagulant may 
require reduction in order to maintain satisfactory therapeutic hypoprothrombinemia. 
2. Concurrent administration of oxyphenbutazone and androgens may result in elevated serum 
levels of oxyphenbutazone.  
3. In diabetic patients, the metabolic effects of androgens may decrease blood glucose and, 
therefore, insulin requirements. 
 
9.4.5 Drug/Laboratory test interferences 
Androgens may decrease levels of thyroxine-binding globulin, resulting in decreased total T4 serum 
levels and increased resin uptake of T3 and T4.  Free thyroid hormone levels remain unchanged, 
however, and there is no clinical evidence of thyroid dysfunction. 
 
 
9.5 Adverse Reactions 
The following adverse reactions in the male have occurred with some androgens: 
1. Endocrine and urogenital: Gynecomastia and excessive frequency and duration of penile erections 
(priapism). Oligospermia may occur at high dosages. 
2. Skin and appendages: Hirsutism, male pattern of baldness, seborrhea, and acne. 
3. Fluid and electrolyte disturbances: Retention of sodium, chloride, water, potassium, calcium, and 
inorganic phosphates. 
4. Gastrointestinal: Nausea, cholestatic jaundice, alterations in liver function tests, rarely 
hepatocellular neoplasms and peliosis hepatis. 
5. Hematologic: Suppression of clotting factors II, V, VII, and X, bleeding in patients on concomitant 
anticoagulant therapy, polycythemia, thrombosis.   


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6. Nervous system: Increased or decreased libido, headache, anxiety, depression, and generalized 
paresthesia. 
7. Allergic: Hypersensitivity, including skin manifestations and anaphylactoid reactions. 
8. Miscellaneous: Inflammation and pain at the site of intramuscular injection. 
 
9.5.1 Drug Abuse and Dependence 
Controlled Substance Class: 
Testosterone is a controlled substance under the Anabolic Steroids Control Act, and Testosterone 
Cypionate and Testosterone Enanthate Injection has been assigned to Schedule III. 
 
9.5.2 Overdosage 
There have been no reports of acute overdosage with the androgens. 
 
 
9.6 Administration, Supply and Storage 
9.6.1 Administration: 
 
Testosterone Cypionate and Testosterone Enanthate injection is for intramuscular use only. It should 
not be given intravenously. Intramuscular injections should be given deep in the gluteal muscle. 
9.6.2 Supply 
Testosterone Cypionate Injection, USP, 200 mg/mL is available as follows: 
1 mL vials                     NDC 0574-0820-01 
10 mL vials                   NDC 0574-0820-10 
Testosterone Enanthate Injection, USP, 200 mg/mL is available as follows: 
5 mL multi-dose vials NDC 67979-501-40 
Testosterone will be used in the commercially available formulation, it will be purchased by the 
participant’s site pharmacy; the cost will be covered by the study and will be provided to the patient at 
no charge.   
9.6.3 Storage 
Vials should be stored at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP]. Protect 
from light. Use carton to protect contents from light until used. Warming and rotating the vial between 
the palms of the hands will redissolve any crystals that may have formed during storage at low 
temperatures. 
 
 


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9.7 Enzalutamide Drug Characterization [Adapted from FDA prescribing information] 
 
• 
Chemical Name: 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5dimethyl-4-oxo-2-
sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide 
• 
Molecular Formula: C21H16F4N4O2S 
 
Molecular Weight:  464.44 g/mol 
• 
Description: Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in 
water. Enzalutamide is provided as liquid-filled soft gelatin capsules for oral administration. Each 
capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The 
inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated 
hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and 
black iron oxide. 
9.7.1 Clinical Pharmacology 
Following oral administration of enzalutamide 160 mg daily (the current FDA approved dose) 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 (enzalutamide’s major active metabolit) 
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. 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. 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. In healthy volunteers, a high-fat meal did not alter the AUC to 
enzalutamide or N-desmethyl enzalutamide. 
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). Enzalutamide is primarily eliminated by hepatic metabolism. Following single 
oral administration of 14C-enzalutamide 160 mg, 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).  
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.  


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9.7.2 Safety/Precautions 
9.7.2.1 Seizures  
In the Phase III post-docetaxel randomized clinical trial, 7 of 800 (0.9%) patients treated with 
enzalutamide 160 mg once daily experienced a seizure. No seizures occurred in patients treated 
with placebo. Patients experiencing seizure were permanently discontinued from therapy and all 
seizures resolved. There is no clinical trial experience re-administering enzalutamide to patients 
who experienced seizures.  
The safety of enzalutamide in patients with predisposing factors for seizure is not known because 
these patients were excluded from the trial. These exclusion criteria included a history of seizure, 
underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 
months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use 
of concomitant medications that may lower the seizure threshold.  
Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk 
of engaging in any activity where sudden loss of consciousness could cause serious harm to 
themselves or others.  
9.7.2.2 Laboratory abnormalities  
In the randomized Phase III post-docetaxel trial, Grade 1-4 neutropenia occurred in 15% of patients 
on enzalutamide (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of 
Grade 1-4 thrombocytopenia was similar in both arms; 0.5% of patients on enzalutamide and 1% on 
placebo experienced Grade 3-4 thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of 
patients on enzalutamide (0.3% Grade 3-4) and 18% of patients on placebo (0.5% Grade 3-4). 
Grade 1-4 elevations in bilirubin occurred in 3% of patients on enzalutamide and 2% of patients on 
placebo. 
9.7.2.3 Infections  
In the randomized Phase III post-docetaxel trial, 1.0% of patients treated with enzalutamide 
compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious 
adverse events were reported in approximately 6% of the patients on both treatment arms. 
9.7.2.4 Falls and fall-related injuries  
In the randomized Phase III post-docetaxel trial, falls or injuries related to falls occurred in 4.6% of 
patients treated with enzalutamide compared to 1.3% of patients on placebo. Falls were not 
associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients 
treated with enzalutamide and included non-pathologic fractures, joint injuries, and hematomas. 
9.7.2.5 Hallucinations  
In the randomized Phase III post-docetaxel trial, 1.6% of patients treated with enzalutamide were 
reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the 
patients with hallucinations, the majority were on opioid-containing medications at the time of the 
event. Hallucinations were visual, tactile, or undefined. 
9.7.2.6 Unforeseeable risks to embryo or fetus  
Enzalutamide is contraindicated in women. In theory, enzalutamide can cause fetal harm if 
administered to a pregnant woman based on its mechanism of action. While there are no human or 
animal data on the use of enzalutamide in pregnancy and enzalutamide is not indicated for use in 
women, it is important to know that maternal use of an androgen receptor inhibitor could affect 
development of the fetus. Women who are pregnant or women who may be pregnant should not 
handle enzalutamide without protection, e.g., gloves. Patients should also be informed that it is not 


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known whether enzalutamide or its metabolites are present in semen and they should use a 
condom if having sex with a pregnant woman. The patient should use a condom and another 
effective method of birth control if he is having sex with a woman of child-bearing potential. These 
measures are required during and for three months after treatment with enzalutamide. 
9.7.2.7 Information for Patients 
• 
Instruct patients to take their dose at the same time each day (once daily). enzalutamide can 
be taken with or without food. Each capsule should be swallowed whole. Do not chew, 
dissolve, or open the capsules.  
• 
Inform patients that enzalutamide has been associated with an increased risk of seizure. 
Discuss conditions that may predispose to seizures and medications that may lower the 
seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss 
of consciousness could cause serious harm to themselves or others. 
• 
Inform patients that enzalutamide may cause dizziness, mental impairment, paresthesia, 
hypoesthesia, and falls. 
• 
Inform patients that if they miss a dose, then they should take it as soon as they remember. 
If they forget to take the dose for the whole day, then they should take their normal dose the 
next day. They should not take more than 160 mg of enzalutamide per day. 
• 
Apprise patients of the common side effects associated with enzalutamide. Direct the patient 
to a complete list of adverse drug reactions in the FDA-approved patient labeling (PATIENT 
INFORMATION). 
• 
Inform patients that enzalutamide may be harmful to a developing fetus. Patients should 
also be informed that they should use a condom if having sex with a pregnant woman. A 
condom and another effective method of birth control should be used if the patient is having 
sex with a woman of child-bearing potential. These measures are required during and for 
three months after treatment with enzalutamide. 
9.7.2.8 Laboratory tests 
• 
Liver function tests (e.g. AST/ALT, bilirubin) should be monitored periodically while on 
enzalutamide. 
• 
Complete blood counts (e.g. white blood cell count, hemoglobin, hematocrit and platelet 
count) should be monitored periodically while on enzalutamide.   
9.7.2.9 Drug Interactions 
Co-administration of a strong CYP2C8 inhibitor (gemfibrozil) increased the composite area under 
the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in 
healthy volunteers. Co-administration of enzalutamide with strong CYP2C8 inhibitors should be 
avoided if possible. If co-administration of enzalutamide with a strong CYP2C8 inhibitor cannot be 
avoided, reduce the dose of enzalutamide.  
The effects of CYP2C8 inducers on the pharmacokinetics 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.  
Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of 
enzalutamide plus Ndesmethyl enzalutamide by 1.3 fold in healthy volunteers.  


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The effects of CYP3A4 inducers on the pharmacokinetics 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. 
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in 
humans. At steady state, enzalutamide reduced the plasma exposure to midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use 
of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and 
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. 
For more detail on specific drug interactions, please refer to the FDA prescribing information. 
9.7.2.10 
Adverse Reactions 
The most common adverse drug reactions (≥ 5%) reported in patients receiving enzalutamide 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 and higher adverse 
reactions were reported among 47% of enzalutamide -treated patients and 53% of placebo-treated 
patients. Discontinuations due to adverse events were reported for 16% of enzalutamide -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 enzalutamide -treated patients 
compared to none (0%) of the placebo-treated patients. Table 2 summarizes the adverse reactions 
reported in the randomized Phase II clinical trials. 
9.7.2.11 
Administration, Supply and Storage 
Enzalutamide is FDA approved for the indication under study. 
9.7.2.12 
Administration 
Enzalutamide 160 mg daily (the current FDA approved dose), or four 40 mg capsules by mouth 
daily, will be administered. A 30 day supply will be provided at the beginning of each month of the 
trial.  
9.7.2.13 
Supply 
Enzalutamide, marketed as Xtandi, comes in 40 mg capsules and are supplied as white to off-white 
oblong soft gelatin capsules imprinted in black ink with MDV. Enzalutamide capsules are available 
in bottles of 120 capsules (NDC 0469-0125-99).   
Enzalutamide will be used in the commercially available formulation as standard of care. 
 
The cost for Enzalutamide will not be covered by the study.  
9.7.2.14 
Storage 
Store enzalutamide capsules at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container 
tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F). 


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10 STUDY CALENDARS 
10.1 
ARM A: BAT with crossover to Enzalutamide 
 
Note: Survival information needs to be collected. Refer to section 5.10 
 
 
 
 
 
 
 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
After C10
End of 
Treatment
CROSSOVER
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Progression
CROSS-1
History and Physical
X
Clinic Visit
X
X
X
X
X
X
X
X
X
X
X
Q MONTH
X
Q 3C
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
QMONTH
X
Q 3C
X
CBC
X
X
X
X
X
Q3C
X
Q 3C
X
COMP PANEL
X
X
X
X
X
Q3C
X
Q 3C
X
PSA
X
X
X
X
X
X
X
X
X
X
Q3C
X
Q MONTH
X
TESTOSTERONE
X
X
X
X
X
Q3C
X
Q 3C
SHBG, DHT, Free Testosterone
X
X
X
ESTRADIOL, DHEA-S, DHEA
X
X
X
Fasting insulin,Fasting glucose
X
X
X
X
Q6C
X
Q 3C
HGBA1c
X
X
X
X
Q6C
X
Q 3C
C REACTIVE PROTEIN
X
X
X
X
Q6C
X
Q 3C
C-TELOPEPTIDE
X
X
X
X
Q6C
X
Q 3C
OSTEOCALCIN
X
X
X
X
Q6C
X
Q 3C
LIPID PANEL
X
X
X
X
Q6C
X
Q 3C
PT/PTT
X
ECG
X
BONE SCAN
X
X
X
X
Q3C
Q 3C
CT SCANg
X
X
X
X
Q3C
Q 3C
18F-DCFPyL PET/CT (JHU only)a
X
X
AR CTC SAMPLEb
X
X
Xf
Tumor DNA AR Mutationc
X
X
FACIT-F
X
X
X
X
X
Q3C
X
Q 3C
X
RANDSF-36
X
X
X
X
X
Q3C
X
Q 3C
X
IIEF SURVEY
X
X
X
X
X
Q3C
X
Q 3C
X
BRIEF PAIN INVENTORY
X
X
X
X
X
Q3C
X
Q 3C
X
PANAS SURVEY
X
X
X
X
X
Q3C
X
Q 3C
X
TESTOSTERONE
X
X
X
X
X
X
X
X
X
X
Q MONTH
ENZALUTAMIDE
Q MONTH
gCT scans should always include chest, abdomen and pelvis.
e  For patients with clinical progression that requires patient to come off study (i.e. worsening pain, obstructive symptoms) end of study visit must be scheduled within 30 days of symptoms.
f At the time of progression, patients must also have blood drawn for CTCs to look for changes in AR-V7 and total AR expression. The CTCs samples will be either collected at the end of study visit for 
patients who opt not to cross-over, or at the cross over visit for patient who opt to cross over to receive the opposite treatments (CTCs samples will be collected before the start of the opposite 
therapy for cross over patients). 
b  AR CTCs are collected screening, after 3 cycles of therapy on both arms and then at time of progression on Enza or BAT 
a 18F-DCFPyL PET/CT scans done at screening only in patients on BAT arm and then repeated after 3 cycles of BAT
Treatment Period (One Cycle is 28 days) (+/- 5 days)
C= Cycle number; V=Visit number
c  Sample  collected for analysis of AR mutation in circulating tumor DNA at screening and after 3 cycles of therapy on BAT or Enzalutamide
End of study 
visitd,e
d  For those patients who choose to not cross-over and come off study treatment, they will come for an end of study visit within 30 days from their confirmed radiographic progression. For those 
patients who crossed over to receive the opposite arm of therapy, they will come for an end of study visit within 30 days from their disease progression (evidence of PSA progression per PCWG2 
criteria or confirmed radiographic disease progression).


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10.2 
ARM B: Enzalutamide with crossover to BAT  
 
 
Note: Survival information needs to be collected. Refer to section 5.10 
 
 
Screening
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
After C10
End of 
Treatment
CROSSOVER
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Progression
CROSS-1
History and Physical
X
Clinic Visit
X
X
X
X
X
X
Q3C
X
QMONTH
X
ECOG PS
X
X
X
X
X
X
Q3C
X
Q 3C
X
CBC
X
X
X
X
X
Q3C
X
Q 3C
X
COMP PANEL
X
X
X
X
X
Q3C
X
Q 3C
X
PSA
X
X
X
X
X
X
X
X
X
X
Q3C
X
Q MONTH
X
TESTOSTERONE
X
X
X
X
X
Q3C
X
Q 3C
SHBG, DHT, Free Testosterone
X
X
X
ESTRADIOL, DHEA-S, DHEA
X
X
X
Fasting insulin,Fasting glucose
X
X
X
X
Q6C
X
Q 3C
HGBA1c
X
X
X
X
Q6C
X
Q 3C
C REACTIVE PROTEIN
X
X
X
X
Q6C
X
Q 3C
C-TELOPEPTIDE
X
X
X
X
Q6C
X
Q 3C
OSTEOCALCIN
X
X
X
X
Q6C
X
Q 3C
LIPID PANEL
X
X
X
X
Q6C
X
Q 3C
PT/PTT
X
ECG
X
BONE SCAN
X
X
X
X
Q3C
Q 3C
CT SCANf 
X
X
X
X
Q3C
Q 3C
AR CTC SAMPLEa
X
X
Xe
Tumor DNA AR mutationb
X
X
FACIT-F
X
X
X
X
X
Q3C
X
Q 3C
X
RANDSF-36
X
X
X
X
X
Q3C
X
Q 3C
X
IIEF SURVEY
X
X
X
X
X
Q3C
X
Q 3C
X
BRIEF PAIN INVENTORY
X
X
X
X
X
Q3C
X
Q 3C
X
PANAS SURVEY
X
X
X
X
X
Q3C
X
Q 3C
X
TESTOSTERONE
Q MONTH
ENZALUTAMIDE
X
X
X
X
X
X
X
X
X
X
Q MONTH
fCT scans should always include chest, abdomen and pelvis.
e At the time of progression, patients must also have blood drawn for CTCs to look for changes in AR-V7 and total AR expression. The CTCs samples will be either collected at the end of study 
visit for patients who opt not to cross-over, or at the cross over visit for patient who opt to cross over to receive the opposite treatments (CTCs samples will be collected before the start of the 
opposite therapy for cross over patients). 
c  For those patients who choose to not cross-over and come off study treatment, they will come for an end of study visit within 30 days from their confirmed radiographic progression. For those 
patients who crossed over to receive the opposite arm of therapy, they will come for an end of study visit within 30 days from their disease progression (evidence of PSA progression per 
PCWG2 criteria or confirmed radiographic disease progression).
d For patients with clinical progression that requires patient to come off study (i.e. worsening pain, obstructive symptoms) end of study visit must be scheduled within 30 days of 
symptoms.
b  Sample  collected for analysis of AR mutation in circulating tumor DNA at screening and after 3 cycles of therapy on BAT or Enzalutamide
Treatment Period (One Cycle is 28 days) (+/- 5 days)
C= Cycle number; V=Visit number
a  AR CTCs are collected screening, after 3 cycles of therapy on both arms and then at time of progression on Enza or BAT
End of study 
visitc,d


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11 DATA MONITORING AND REPORTING REQUIREMENTS 
Data and safety monitoring will follow Level I under the SKCCC Data and Safety Monitoring Plan (DSMP, 
12/6/2012).  Data Monitoring of this protocol will occur on a regular basis with the frequency dependent on the 
rate of subject accrual and the progress of the study.  The protocol will be monitored internally at SKCCC by 
the Principal Investigator and externally by the SKCCC CRO in accordance with SKCCC guidelines.  Trial 
monitoring and reporting will be done through the Safety Monitoring Committee (SMC) at SKCCC. 
 
Additionally, scheduled meetings will take place monthly and will include the protocol principal investigator, 
research nurse, data manager, and, when appropriate, the collaborators, subinvestigators, and biostatistician 
involved with the conduct of the protocol. 
 
During these meetings the investigators will discuss matters related to: safety of protocol participants, validity 
and integrity of the data, enrollment rate relative to expectation, characteristics of participants, retention of 
participants, adherence to protocol (potential or real protocol violations), data completeness, and progress of 
data for secondary objectives. 
 
 
11.1 
Case Report Form Submission 
Data required by the study will be collected in Case Report Forms provided by the Coordinating Center at 
SKCCC. The participating site will be required to complete a paper Eligibility Checklist case report form 
(CRF) at the time of patient registration (please refer to section 5.1 Initial Registration Process).  All other 
data will be collected on the electronic case report forms (eCRFs) in CRAB (Cancer Research And 
Biostatistics) system.  Site staff access to CRAB will be initiated at the time of the site activation.  
 
Case Report Form Completion 
The paper Eligibility Checklist CRF must be completed using black ink.  Any errors must be crossed out so 
that the original entry is still visible, the correction clearly indicated and then initialed and dated by the 
individual making the correction. 
 
eCRFs will be completed within 2 weeks of the patient coming to the clinic and all relevant supporting 
documentation such as scans, progress notes, nursing notes, blood work, pathology reports, etc., will be 
submitted via to the TRANSFORMER Study Manager, Haiyi (Harry) Cao, at hcao7@jhmi.edu.  All patient 
names or other identifying information will be removed prior to being sent to the Coordinating Center 
(SKCCC) or non- redacted source documents can be sent via a password -protected/ secured document 
transfer based on each institution’s guidelines.  
 
Authorized representatives of the Coordinating Center (SKCCC) may visit the satellite sites to perform 
audits or inspections, including source data verification. The purpose of these audits or inspections is to 
systematically and independently examine all trial-related activities and documents to determine whether 
these activities were conducted and data were recorded, analyzed, and accurately reported according to 
the protocol, Good Clinical Practice (GCP), and any applicable regulatory requirements. 
 
 
 


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11.2 
Adverse Event Monitoring and Reporting 
An Adverse Event is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical treatment or procedure 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, possible, probable, or definite).  The PI and/or the research nurse will monitor each patient 
closely for the development of adverse events and toxicities and record all such events.  Patients will be 
evaluated for toxicity if they have received one dose of testosterone cypionate, testosterone enanthat or 
one 28-day cycle of enzalutamide.  The timely reporting of adverse events (including toxic deaths) is 
required by the Food and Drug Administration (FDA). 
 
 
11.3 
Evaluating Adverse Events 
The grade and severity of the event will be determined using the DCT/NCI Common Terminology Criteria, 
CTCAE v.4.0. Links to CTCAE version 4.0 can be found in Appendix 2.  All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0.  Study staff must use one of the CTCAE criteria to 
define the event.  Adverse events not included in the CTCAE v.4.0 should be reported and graded under 
the “Other” adverse event within the appropriate category and grade 1 to 5 according to the general grade 
definitions, mild, moderate, severe, life-threatening, fatal or disabling, as provided in the CTCAE. 
 
The event will be determined to be expected or unexpected.  The determination of whether an AE is 
expected is based on agent-specific adverse event information provided in Section 9 Pharmaceutical 
Information.  Unexpected AEs are those not listed in the agent-specific adverse event information provided 
in Section 9 Pharmaceutical Information.  
 
The event will be evaluated for relationship to the medical treatment or procedure.  The 
Investigator should document his/her opinion of the relationship of the event to study medication as follows: 
• 
Unrelated- The adverse event is clearly not related to the investigational agent(s). 
• 
Possible-The adverse event may be related to the investigational agent(s). 
• 
Probable-The adverse event is most likely related to the investigational agent(s). 
• 
Definite- The adverse event is clearly related to the investigational agent(s). 
Based on this information, a decision will be made whether an adverse event should be reported as an 
expedited report (Serious Adverse Event, section 3.0) in addition to the routinely reported clinical data.  All 
expedited adverse event reports should be submitted to the JHM Institutional Review Board (IRB) and to 
the FDA. 
 
11.3.1 Documenting Adverse Events 
Each individual sign or symptom must be documented separately.  All adverse events (both expected 
and unexpected) will be captured on the appropriate study-specific case report forms (CRFs).  CRFs 
must be signed and dated by person conducting evaluation to be used as source documentation. 
 
The attribution of all adverse events must be verified by an investigator.  Evaluation of laboratory 
toxicities may be documented directly on a printed laboratory report or CRF provided it is signed by the 
investigator.  However, if an action was conducted due to this abnormality (e.g. RBC transfusion due to 
low Hgb) this would be recorded on the AE form also. 


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11.4 
Serious Adverse Events 
A SAE is any sign, symptom or medical condition that emerges during treatment or during a post-treatment 
follow-up period that (1) was not present at the start of treatment and is not a chronic condition that was 
part of the patient’s medical history, OR (2) was present at the start of treatment or as part of the patient’s 
medical history but worsened in severity and/or frequency during therapy, AND that meets any of the 
following regulatory criteria: 
• 
is fatal (i.e., results in death from any cause at any time) or life-threatening (i.e., the patient was in 
the view of the investigator, at immediate risk of death from the reaction as it occurred) 
• 
required or prolonged hospitalization (see exclusions below) 
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly or a birth defect 
• 
is medically significant, may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed above. 
Events not considered to be serious adverse event are hospitalizations for the: 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition 
• 
Treatment, which was elective or pre-planned, for a pre-existing condition that did not worsen 
Any serious adverse event occurring in a patient from the first day of treatment and until 4 weeks after the 
last dose of treatment must be reported.  The period after discontinuing study drug may be extended if 
there is a strong suspicion that the drug has not yet been eliminated. 
 
All serious adverse events must be followed to resolution (≤ 1 or baseline) or until considered stable or 
irreversible. 
 
 
11.5 
Expedited Reporting of Serious Adverse Events 
Serious adverse events and protocol problems will be reported in compliance with JHM 
IRB guideline, “Organization Policy on Reports of Unanticipated Problems Involving Risks to Participants or 
Others” [Policy No. 103.6(b)] (most current version).  A copy of this document is located at: 
http://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/organization_policies/103_6
b.html  
 
All deaths on study regardless of attribution must be reported by the Principal Investigator Dr. Denmeade 
or Co-Principal Investigator Dr. Eisenberger to the JHM IRB.  In addition, all serious adverse events, 
regardless of causality to study drug, will be reported promptly to the TRANSFORMER Study Manager, 
Haiyi (Harry) Cao, at hcao7@jhmi.edu within 24 hours of recognition of the serious adverse event.  If this 
falls on a weekend or holiday, an email notification is acceptable but must be followed by an SAE reporting 
form on the next business day. 
 
Investigators will be notified by the Principal/Co-Principal Investigator and/or by the CRO of all SAEs that 
are unexpected (ie, not previously described in the Pharmaceutical Characterization of each drug in section 


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9 of this protocol), and definitely, probably, or possibly related to BAT or enzalutamide.  This notification will 
be in the form of an expedited safety report (ESR) that is to be faxed to the investigators and the study 
coordinators within 48 hours.  Upon receiving such notices, the site investigator must review and retain the 
notice and where required by local site regulations, the site investigator will submit the ESR to the site IRB.  
The site investigator and IRB will determine if the informed consent requires revision.  The site investigator 
should also comply with the site IRB procedures for reporting any other safety information.  Where 
required, submission of ESRs by the investigator to Health Authorities should be handled according to local 
regulations. 
 
 
11.6 
Institutional Review Board (IRB) Reporting at Participating Sites:  
Participating sites will be responsible for reporting to their IRB. All serious adverse events will be reported 
to the IRB per institutional standards within 3 business days of recognition of the adverse event if the event 
is related and expected, related and unexpected, or related and fatal or life-threatening due to 
administration of the investigational product. If the serious adverse event is unrelated to administration of 
the investigational agents, then it will be reported to the IRB within 15 days of recognition of the serious 
adverse event. Upon receipt of the report of the serious adverse event by IRB, follow-up information will be 
given to the IRB within 15 days. 
 
 
11.7 
Protocol Amendments 
Any changes to the protocol will be made in the form of an amendment and must be approved by the site 
IRB before implementation. 
 
 
11.8 
Informed consent   
Written informed consent will be obtained by a study investigator or study research nurse working on this 
study.  An explanation of the nature of study, its purpose, procedures involved, expected duration, potential 
risks and benefits will be provided to each participant by the investigator or the research nurse.  Each 
participant will be informed that participation in the study is voluntary and that he may withdraw from the 
study at any time, and that withdrawal of consent will not affect his subsequent medical treatment.  
Participants will be allowed time needed to make an informed decision.  Participants will be encouraged to 
ask questions about the study and the consent before signing the consent form.  Consent forms will be filed 
with the Clinical Research Office and copies stored securely with the study coordinator.  No patient will 
enter the study before his informed consent has been obtained. 
 
The following must appear in consent form for each participating site: 
• 
A statement that the DOD or a DOD organization is funding the study 
• 
A statement that representatives of the DOD are authorize to review research records 
• 
In the HIPAA Authorization section of the consent form, representatives of the DOD must be listed 
as one of the parties to whom private information may be disclosed 
• 
Because the study involves a research monitor, the monitor should also be listed in the HIPAA 
Authorization. 


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11.9 
Multicenter Guidelines    
The Protocol Chair 
The Protocol Chair, Samuel Denmeade, MD, is responsible for performing the following Tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as well as its 
subsequent amendments 
• 
Assuring that all participating institutions are using the current IRB approved version of the 
protocol 
• 
Taking responsibility for the overall conduct of the study at all participating institutions and for 
monitoring the progress of the study 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) from all sites  
• 
Reviewing all study data from all sites 
 
Coordinating Center Responsibilities (SKCCC) 
Coordinating Centers must: 
• 
Verify that each participating institution has a Federal Wide Assurance (FWA) number. 
• 
Confirm that IRB approval has been obtained at each participating site prior to their first patient 
registration 
• 
Maintain copies of IRB approvals from each site 
• 
Implement central patient registration 
• 
Prepare all submitted data for review by the Protocol Chair (Samuel Denmeade, MD) 
• 
Establish procedures for documentation, reporting, and submitting of adverse events to the 
Protocol Chair (Samuel Denmeade, MD) and all applicable parties 
• 
Facilitate audits by securing selected source documents and research records from participating 
sites for audit, or by conducting audits at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
• 
Follow the protocol as written and conduct the study within the guidelines of Good Clinical 
Practice. 
• 
Collect and submit data, and report adverse events according to the schedule specified by the 
protocol. 
• 
Register all patients with the Lead Center (SKCCC) by submitting patient registration forms, and 
signed informed consents promptly. 
• 
Provide sufficient experienced clinical and administrative staff; as well as adequate facilities and 
equipment to conduct a collaborative trial according to the protocol. 
• 
Maintain regulatory binders on site, and provide copies of all required documents to the Lead 
Center (SKCCC) 
 
 
 
 


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12 STATISTICAL METHODS 
This is a multi-center, open label, randomized study to evaluate the efficacy of bipolar androgen therapy (BAT) 
vs. enzalutamide in asymptomatic men with castration resistant metastatic prostate cancer post-treatment with 
abiraterone.  Eligible patients will be randomized in a 1:1 ratio to one of two treatment arms: BAT (Arm A) or 
enzalutamide (Arm B). The randomization will be stratified by duration of abiraterone acetate therapy (<6 
months vs ≥6 months). 
 
Primary objective and primary endpoint: The primary objective of the study is to compare progression-free 
survival (PFS) between BAT and enzalutamide in patients with castration resistant prostate cancer who have 
progressed on abiraterone.  The primary efficacy endpoint is PFS, defined as the time from the date of the 
randomization to the date of first documented clinical progression due to prostate cancer or radiological 
confirmation of progression per RECIST 1.1 for soft tissue or PCWG2 for bone lesions or death, whichever 
occurs first. If a patient has not had the event at the date of the analysis cut-off, PFS will be censored at the 
time of the last adequate tumor assessment before the cut-off date.  
 
Sample size and power considerations: No studies have been published that describe PFS on enzalutamide 
after progression on abiraterone in chemo-naive patients.  In the trial of abiraterone plus prednisone in men 
with metastatic prostate cancer without previous chemotherapy the rPFS was 16.5 months vs 8.3 months for 
the prednisone alone arm.  In the phase III trial of enzalutamide in men with metastatic prostate cancer after 
docetaxel chemotherapy, the rPFS was 8.3 months.  In the study of Shrader et al (n=35) and in our own 
unpublished analysis (n=41), the rPFS for patients receiving enzalutamide after Abiraterone (pre- or post- 
chemotherapy) was 4.9 and 4.2 months respectively.  Based on these collective results, we have made the 
reasonable assumption that the median rPFS in the enzalutamide arm post Abiraterone will be 6 months.  This 
trial is designed to detect a 50% improvement in median PFS in the BAT group, from 6 to 9 months 
(corresponding to a HR 0.667 of BAT vs. enzalutamide), at one-sided significance level of 0.05.  Allowing for 
the interim analysis plan discussed below, the study requires at least 156 events to ensure a sequential test 
procedure will have 80% power. We expect a recruitment period of 24 months and an additional 12 months of 
follow-up. After accounting for an estimated 15% loss to follow-up, a total of up to 194 patients (97 per arm) will 
be randomized to record 156 events in 36 months of study. Recruitment for the study will stop once a total of 
156 events have occurred.  The calculation was performed using EAST® software. 
 
Interim analysis: Two interim analyses for PFS are planned that allow the study to stop for efficacy.  The first 
interim analysis will be conducted after approximately 45% of the information (i.e. 70 events of progression) 
has been recorded, and the second interim analysis is planned after 70% of the information (109 events) has 
been observed.  An α-spending function method of Lan and DeMets with an O’Brien-Fleming-type stopping 
boundary, will be used to construct the stopping boundaries for the efficacy analyses.  
 
 


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The details of the planned interim analysis can be found in the table below. 
 
Interim 
and Final 
Analysis 
Percent 
Information 
Estimated Upper 
Boundary for 
Declaring 
Superiority 
Hazard 
Ratio cut-
off 
Approximate 
Time (Months) 
Estimated 
Number of 
Events 
1 
45 
-2.7031 
0.525 
18 
70 
2 
70 
-2.098 
0.670 
24 
109 
3 (Final) 
100 
-1.705 
0.761 
36 
156 
 
The study will also be monitoring for early stopping for futility using Jennison-Turnbull repeated confidence 
interval methodology (56).  At each interim analysis the nominal (1- 2 × alpha) confidence interval on the rPFS 
hazard ratio comparing the BAT arm to the enzalutamide arm (arm A versus B) will be computed, where alpha 
is the nominal one-sided significance level of the boundary from the error spending function at the information 
fraction for the particular analysis time.  If the confidence interval does not contain the target alternative HR of 
0.667, then the data monitoring committee may consider terminating the study early for lack of treatment 
differences.  The monitoring plan has negligible impact on the power of the study.  
 
Toxicity monitoring: We will be monitoring adverse event of pain on the BAT arm, after every cohort of 20 
patients has been treated.  If the toxicity of grade 3 or higher pain appears to be higher than 20%, we will 
temporarily halt the study pending safety evaluations.  Specifically, we will apply a Bayesian toxicity monitoring 
rule that suspends the enrollment if the posterior probability of risk being larger than that threshold is 75% or 
higher.  Based on the data of previous studies of T, monitoring rule uses Beta (1, 10) as prior distribution.  This 
means that our prior estimate of proportion of severe pain is 9%, and there is 90% chance that this proportion 
is 0.5%-26%.  The decision rule for safety stopping is as follows: 
 
Stop if: 
# severe pain 
>= 
6 
10 
13 
16 
19 
23 
Out of   
15 
30 
45 
60 
75 
90 
 
The operating characteristic of the stopping rule based on 10,000 simulations: 
True rate of pain  
0.1 
0.15 
0.2 
0.25 
0.3 
0.35 
% simulated trials declaring unsafe  
0.2 
3.9 
25.1 
63.4 
90.7 
98.8 
 
Analysis of primary endpoint: The comparison of PFS will be an intent-to-treat analysis including all 
randomized patients.  The PFS will be estimated using Kaplan-Meier method, and the median PFS along with 
95% confidence intervals (CI) will be reported by the treatment groups.  The PFS will be compared between 
the two arms using a stratified log-rank test with the stratification factor of duration of prior abiraterone 
treatment.  The Cox regression model, stratified for the same baseline stratification factor, will be used to 
estimate the hazard ratio (HR) of PFS between the two arms and corresponding 95% CI.  Additionally, a Cox 
regression model, stratified for the baseline stratification factor, will be used to explore the potential influences 
of the other factors on the primary endpoint PFS. 
 
Analysis of secondary efficacy endpoints: Time-to-event endpoints including progression-free survival based 
on radiographic or clinical progression, time to initiation of chemotherapy (i.e. time from the date of 
randomization to the date of initiation of docetaxel chemotherapy), and time to PSA progression will be 
analyzed similarly as described for the primary endpoint of PFS.  Overall response, defined as the proportion 


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of subjects who achieve either complete response or partial response per RECIST 1.1, will be tabulated for 
each arm and compared using Chi-square test.  Percent PSA change from baseline for individual patients will 
be presented in waterfall plots.  PSA response rate will be estimated as the proportion of subjects who have 
any decrease in PSA below baseline and as the percentage with ≥50% PSA reduction from baseline level, and 
compared between the two arms using Chi-square test.  Percent PSA change from baseline for individual 
patients will be presented in waterfall plots and the changes over time will be shown using spaghetti plots.  On 
the BAT arm among the patients who repeat ADT post-BAT treatment, we will assess the absolute and percent 
change of PSA levels from the last PSA on BAT to nadir PSA on return to castrate T levels.  To examine the 
effect of BAT to sensitize patients for enzalutamide, we will estimate the objective response rate and PSA 
response among those who subsequently receive enzalutamide on the BAT arm. PFS2 is defined as time from 
randomization to progression on crossover treatment. For those who do not receive crossover treatment, PFS2 
is censored at the end of the initial treatment.  PFS2 will be summarized using Kaplain-Meier method in each 
arm, and compared between the two arms in intent-to-treat population using log-rank test. PFS2 will also be 
analyzed among those who cross over. Overall survival, defined as time from randomization to death for any 
cause, will be characterized using Kaplan-Meier method and compared between the two arms using log-rank 
test. 
 
Analysis of quality of life and metabolic studies: QoL will be assessed using RAND-SF36 Quality of Life 
Survey, FACIT-F Version 4, I-PANAS-SF. Sexual capacity, functional capacity and pain will be assessed using 
IIEF, Global Assessment of Change and BPI, respectively.  For each module, summary statistics of the scores 
will be reported at baseline randomization, one month post-randomization, three months post-randomization, 
six months, and 12 months post-randomization.  In each arm changes in quality of life scores pre- and post-
treatment will be evaluated at each follow-up time by paired-sample t-tests or Wilcoxon signed rank tests as 
appropriate.  In addition, mixture effect models will be fitted for accessing the quality of life changes over time.  
The change of metabolic measures (e.g. bone density, lipid profile, metabolic panel, steroid panel, 
inflammation/cytokines, BMI, lean mass) will be evaluated using the same analysis methods.  We will also 
compare the metabolic parameters between the two arms using regression models. 
 
Analysis populations: 
The Intent-to-Treat (ITT) Population includes all subjects who are randomized with study treatment assignment 
designated according to initial randomization.  The ITT population will be the primary population for evaluating 
efficacy endpoints (e.g. PFS, time to PSA progression, ORR, PSA response) and patient characteristics.  
 
Per Protocol Population will include all patients who are randomized and received at least one dose of study 
medication, and do not have any major protocol violations (for example, incorrect treatment group allocation 
according to randomization, not meeting the major inclusion/exclusion criteria for disease status and prior 
therapies, noncompliance to treatment plan or assessment schedule; additional concurrent prohibited 
therapies).  The per-protocol analysis will serve as supportive.  
 
Safety Population will include all patients who receive at least one dose of study medication, with treatment 
assignments designated according to actual study treatment received.  The safety analyses population will be 
the primary population for evaluating treatment administration/compliance and safety. 
 
Safety analysis: Overall safety profile and toleration of BAT and enzalutamide will be characterized by type, 
frequency, severity, timing and relationship of study therapy of adverse events and laboratory abnormalities.  
Adverse events will be summarized by the frequency of patients experiencing treatment emergent adverse 
events corresponding to body systems and by worst NCI CTCAE (version 4.0) grade. 
 


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AR-variant analysis: We will determine the association between BAT-induced decrease in AR-V7 expression 
and restoration of sensitivity to ADT and enzalutamide.  We will examine the association of the AR-V7 positivity 
at baseline with clinical outcomes, including PFS, objective response rate (ORR) and PSA response, from 
patients receiving BAT or enzalutamide.  For the time-to-event outcome PFS, Kaplan-Meier curves will be 
plotted for each treatment arm stratified by baseline AR-V7 status.  Cox proportional hazards models will be 
used to estimate the hazard ratio with 95% Confidence Intervals for each arm to quantify the effect of AR-V7 
presence/absence on the risk of failures.  The binary outcomes ORR and PSA response will be compared 
between baseline AR-V7(+) and AR-V7(–) groups using chi-square tests.  We will also explore the differential 
effect of BAT vs. enzalutamide in AR-V7 (+) and AR-V7(-) group by examining the interaction of AR-V7 and 
treatment group in the Cox model for PFS. 
 
Power considerations:   Statistical power is based on the primary analysis of the association of AR-V7 and 
PFS.  Based on our previous work, we expect AR-V7 to be present at baseline in approximately 30% of 
patients with CRPC.  We anticipate having baseline blood samples from 160 patients (80 per arm) for AR-V7 
analysis.  Our hypothesis is that AR-V7 drives aberrant AR activity after the canonical AR axis is blocked by 
the AR-targeted therapies; therefore patients who are AR-V7(+) at baseline in the enzalutamide arm will be 
expected to have a higher risk of disease progression.  For the risk difference to be clinically meaningful, we 
are interested in detecting a hazard ratio of 2.5 among AR-V7(+) patients compared to AR-V7(–) patients.  
Assuming median PFS to be about 6 months in the enzalutamide arm, a sample size of 80 patients with blood 
samples evaluable for molecular CTC analyses (24 AR-V7(+) and 56 AR-V7(-)) would achieve 90% power to 
detect a hazard ratio of 2.5 based on a 2-sided log-rank test at a significance level of 0.05.  This corresponds 
to a median PFS of 4.2 mos and 10.5 mos for patients receiving enzalutamide with AR-V7(+) and AR-V7(–) 
tumors, respectively.  
 
AR mutation analysis: We will examine AR mutations in ctDNA and evaluate the change of AR mutation post-
BAT treatment compared to baseline. 
 
Power considerations:  We hypothesize that the mutations of interest will disappear after BAT therapy.  We 
hope to determine if more than 10% patients who carry certain mutations at baseline would lose the mutation 
after the treatment of BAT, and expect that at least 50% of them would turn to mutation negative.  A sample 
size of 14 patients with positive mutations at baseline provides 91% power to reject 10% rate of conversion 
from positive to negative in favor of 50% conversion rate, using a one-sided binomial test at significance level 
0.025.  Assuming the mutation rate is around 25% at baseline, we will test 60 patients before BAT therapy in 
order to have at least 14 positives at baseline for us to evaluate the change of their mutation status with the 
treatment of BAT. 
 


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Appendix I 
 
Response Evaluation Criteria in Solid Tumors Version 1.1 
Definitions 
Baseline: Baseline is defined as the most recent assessment performed prior to randomization. 
Baseline assessments must be performed within the period defined in the protocol eligibility criteria. 
 
Measurable lesions: Except for lymph nodes as described below, measurable lesions are defined as those that 
can be accurately measured in at least 1 dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan 
(if CT scans have slice thickness greater than 5 mm the minimum size for a measurable lesion is twice the slice 
thickness). 
• To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in short axis 
when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and recorded. 
• MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, but not for 
lesions in the lungs. The minimum size for measurability is the same as for CT (10mm) as long as the 
scans are performed with slice thickness of 5 mm and no gap. If MRI is performed with thicker slices, 
the size of a measurable lesion at baseline should be twice the slice thickness. In the event there are 
interslice gaps, this also needs to be considered in determining the size of measurable lesions at baseline. 
Nonmeasurable lesions: All other lesions (or sites of disease), including small lesions (longest diameter < 10 
mm or pathological lymph nodes with ≥10 to < 15 mm short axis), are considered nonmeasurable. Lymph 
nodes that have a short axis < 10 mm are considered nonpathological and are not be recorded or followed. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/ pulmonitis, 
inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as 
nonmeasurable. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, are to be identified as target lesions and measured and recorded at 
baseline. Target lesions are to be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, and be those that lend themselves to reproducible repeated measurements. 
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. Target lesions will 
be measured at each assessment (longest axis for nonnodal lesions, shortest axis for measurable malignant nodal 
lesions). 
 
Nontarget lesions: All other lesions (or sites of disease) including all non-measurable lesions (including 
pathological lymph nodes with ≥ 10 to <15 mm short axis) and all measurable lesions over and above the 5 
target lesions are to be identified as non-target lesions and recorded at baseline. Measurements of these lesions 
are not required, but the presence, absence, or in rare cases unequivocal progression of each is to be recorded 
throughout follow-up. Lymph nodes thathave a short axis < 10mm are considered non-pathological and are not 
to be recorded or followed. 


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Methods of Measurement  
The same method of assessment and the same technique used to characterize each identified and reported 
lesions at baseline should be used during each follow-up assessment. All measurements should be taken and 
recorded in metric notation using a ruler or calipers. Imaging based evaluation is preferred to evaluation by 
clinical examination unless the lesion(s) being followed cannot be imaged but assessed by clinical examination 
(referring to biopsy-proven visible lesion(s) on the chest). 
 
CT and MRI are the best currently available and reproducible methods to measure target lesions selected for 
response assessment.  Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 
thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm.  
This applies to tumors of the chest, abdomen and pelvis.  Head and neck tumors and those of extremities usually 
require specific protocols. 
 
Time Point Assessments 
The frequency and schedule of tumor assessments is defined in the protocol. The schedule is to be maintained 
regardless of whether study treatment is held or discontinued. 
At baseline, tumors and lymph nodes are classified and documented as target or nontarget per the definitions 
provided above. It is possible to record multiple nontarget lesions involving the same organ as a single item (eg, 
‘multiple liver metastases’). At all postbaseline (follow-up) evaluations the baseline classification (target, 
nontarget) is to be maintained and lesions are to be documented and described in a consistent fashion over time 
(eg, recorded in the same order on source documents). 
 
At each assessment, a sum of the diameters (longest for nonnodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and included in source documents. The baseline sum of the diameters (SoD) 
will be used as reference to further characterize any objective tumor regression in the measurable dimension of 
the disease. The lowest SoD (nadir) since (and including) the baseline value will be used as reference for 
evaluating progression. 
 
After baseline, target lesions should have the actual size documented, if possible, even if the lesions become 
very small. If in the opinion of the radiologist the lesion has likely disappeared, 0 mm should be recorded. If the 
lesion is present but too small to measure, an indicator for ‘too small to measure’ this should be included in 
source documents. 
 
For target lesions, measurements should be taken and recorded in metric notation. All tumor measurements 
must be recorded in millimeters. 
 
Nontarget lesions are to be assessed qualitatively (present, resolved, or unequivocal progression) and new 
lesions, if any, are to be documented separately. 
 
At each evaluation, progression status is to be determined based upon the time point status for target 
lesions, nontarget lesions, and new lesions. 


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Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. All pathological lymph 
nodes(whether target or non-target) must have reduction in 
short axis to < 10 mm. 
Partial Response (PR): 
At least a 30% decrease in SoD of target lesions, taking as a 
reference the baseline SoD 
Progressive Disease (PD): 
At least a 20% increase in the SoD of target lesions, taking 
as a reference the smallest (nadir) SoD since (and including) 
baseline. In addition to the relative increase of 20%, the SoD 
must also demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD 
Not Applicable (NA) 
No target lesion identified at baseline. 
Unable to Evaluate 
(UE) 
One or more target lesions are not imaged and the remainder 
of the SoD compared with the nadir SoD does not meet the 
criterion for PD. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions. All lymph nodes 
must be nonpathological in size (<10 mm short axis) 
Non-CR / Non-PD:  
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD): 
Unequivocal progression of non-target lesions. Unequivocal 
progression should normally trump target lesion status. It 
must be representative of overall disease status change, 
not a single lesion increase 
Not Applicable (NA) 
No non-target lesions identified at screening 
Unable to Evaluate 
(UE) 
One or more non-target lesions are not imaged and the 
remaining nontarget lesions do not meet the criterion for 
PD. 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the opinion of 
the treating physician should prevail and the progression status should be confirmed later on by the review 
panel (or study chair). 
 
 
 
 


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New Lesion Time Point Response (TPR) 
Yes 
Lesion present at follow-up visit either for the very first time 
or reappearing (ie, lesion was present at baseline, 
disappeared at a follow-up visit and re-appeared later). On 
bone scan, a single new lesion may not be sufficient to 
qualify as PD. Confirmation should be obtained by 
performing CT or MRI of the area of concern to confirm 
ambiguous results of bone scan. Preferred method for 
confirmation is MRI. 
No 
No new lesions present at follow-up. 
Unable to Evaluate 
(UE) 
Subject not assessed or incompletely assessed for new 
lesions. 
 
 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment 
started).  In general, the patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria.  
 
Target Lesion TPR 
Non-target lesion TPR 
New lesion TPR 
Overall TPR 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
UE 
No 
PR 
PR 
Non-PD or NA or UE 
No 
PR 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Non-PD 
No 
UE 
PD 
Any 
No or Yes or UE 
PD 
Any 
PD 
No or Yes or UE 
PD 
Any 
Any 
Yes 
PD 
NA 
CR 
No 
CR 
NA 
Non-CR/non-PD 
No 
Non-CR/non-PD 
NA 
UE 
No 
UE 
Non-PD 
Non-PD 
UE 
UE 
 
 
 
Confirmation 
 
The main goal of confirmation of objective response is to avoid over-estimating the response rate observed.  In 
cases where confirmation of response is not feasible, it should be made clear when reporting the outcome of 
such studies that the responses are not confirmed. 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
assessments that should be performed no less than 4 weeks after the criteria for response are first met.  
Longer intervals as determined by the study protocol may also be appropriate.  
In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general, not less than 6-8 weeks) that is defined in the study protocol  
 


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Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR or PR 
(whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking 
as reference for PD the smallest measurements recorded since the treatment started. 
 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for disease progression are met, taking as 
reference the smallest measurements recorded since the treatment started.  
The clinical relevance of the duration of SD varies for different tumor types and grades.  Therefore, it is highly 
recommended that the protocol specify the minimal time interval required between two measurements for 
determination of SD.  This time interval should take into account the expected clinical benefit that such a status 
may bring to the population under study.  
 
Response Review 
For trials where response rate is the primary endpoint it is strongly recommended that all responses be 
reviewed by an expert(s) independent of the study at the study’s completion.  Simultaneous review of patients’ 
files and radiological images is the best approach.  
 
Reporting of Results 
All patients included in the study must be assessed for response to treatment, even if there are major protocol 
treatment deviations or if they are ineligible.  Each patient will be assigned one of the following categories: 1) 
complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from 
malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data). 
All of the patients who met the eligibility criteria should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered as failing to respond to treatment (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in exclusion from 
the analysis of the response rate.  Precise definitions for categories 4-9 will be protocol specific. 
All conclusions should be based on all eligible patients. 
Sub-analyses may then be performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these sub-analyses may not serve as the basis for 
drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis 
should be clearly reported.  
The 95% confidence intervals should be provided. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2 
NCI COMMON TOXICITY CRITERIA, VERSION 4.0 
 
Version 4.0 of the NCI CTC, dated May 28, 2009, may be viewed and/or downloaded by accessing the 
following websites 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcae_4_with_lay_terms.pdf 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 
 
 
  
 
 


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Appendix 3 
NCCN Guidelines for Adult Cancer Pain (Version 1.2014) can be may be viewed and/or downloaded by 
accessing the following website: 
 
http://oralcancerfoundation.org/treatment/pdf/pain.pdf 
 
 
 
 
 


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Appendix 4 
Blood Collection and Shipping for TRANSFORMER Study 
 
 
Blood draws should be scheduled on Monday-Thursday.  Samples will be shipped the same day of blood 
collection to allow overnight delivery on weekdays before the weekend. 
 
Two sets of blood samples for AR and AR-V7 will be collected at screening visit, cycle 4 (visit 5) visit, 
and at the visit where patients have radiographic progression on CT or bone scan: 
 
Instructions for First Set of Blood Samples (AR):   
 
1. Collect Blood in two Becton Dickinson (BD) Vacutainer ACD Solution A tubes (BD ACD-A). 
Product number for the BD ACD-A tube is 364606. 
 
2. Ensure that at least 8.5 mL of blood is drawn into each tube.  Avoid low volume to minimize 
agitation during shipping. 
 
3. Invert the tubes gently 180 degree and back 3-4 times. 
 
4. Store samples until shipping at 4-8oC in a refrigerator.  
 
Instructions for Second Set of Blood Samples (AR-V7): 
 
1. Collect 2.5 mL blood into each of the two 5 mL PAXgene tubes.  Product number from 
Becton Dickinson is 762165. 
 
2. Invert the tubes gently 180 degrees and back 8-10 times. 
 
3. Maintain blood at room temperature (6oC to 37oC) until shipping.  Do Not place tubes in 
Refrigerator or Freezer. 
 
One set of blood samples for Circulating Tumor DNA will be collected at screening visit, cycle 4 (visit 
5) visit: 
 
Instructions for Circulating Tumor DNA Blood Samples: 
 
1. Collect blood in two Streck Cell-Free DNA BCT tubes.  Product number from Streck, Inc., 
Omaha NE is 218961. 
 
2. Ensure that at least 10 mL of blood is drawn into each tube.  Avoid low volume to minimize 
agitation during shipping. 
 
3. Invert the tubes gently 180 degree and back 8-10 times. 


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4. Maintain Blood at room temperature (6oC to 37oC) until shipping. Do Not place tubes in 
Refrigerator or Freezer. 
 
Instructions for Shipping:   
 
1. Activate the small standard duration FEDEX cold box (purchased from http://orderboxesnow.com) and 
place the tubes wrapped in bubble wraps snugly in the shipping box.  
 
2. Complete the shipping manifest and ship the six tubes (2 tubes Circulating Cells, 2 tubes Circulating 
Tumor DNA, 2 tubes whole blood PAXgene) by FEDEX to the address below the same day of blood 
draw.  Notify the recipient of the tracking number on the day of shipment by email.  
 
The Fedex cold boxes are available at http://orderboxesnow.com.  Bubble wraps can be purchased from 
Staples or other shipping supply stores. 
 
Jun Luo, Ph.D. 
415A Marburg, Johns Hopkins Hospital 
600 N. Wolfe Street 
Baltimore, MD 21287  
Tel: 443-287-5625 
 
Email shipping notifications to:  
 
jluo1@jhmi.edu 
 
denmesa@jhmi.edu 
 
hcao7@jhmi.edu  
 
 
 


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Appendix 5 
 
18F-DCFPyL PET/CT Imaging (JHU only) 
 
1. Patients must be enrolled on either arm of the randomized study and receiving treatment at Johns 
Hopkins.   
2. A total of up to 20 patients will be enrolled. Once twenty patients are enrolled recruitment of patients will 
stop. 
3. Patients will undergo 18F-DCFPyL-PET prior to starting BAT or enzalutamide and after 12 weeks of 
treatment on either arm. 
4. Patients must have Radiologic evidence of new or progressive metastatic prostate cancer 
demonstrated on CT imaging or bone scintigraphy.   
5. Patient must be able to tolerate lying flat for the duration of the PET/CT scan (up to 60  minutes) 
6. Patient should not eat or drink (except for water) for at least six hours prior to DCFpyL administration. 
Drinking water for hydration is encouraged. Multi- vitamins and folic acid supplements should also not 
be take the day of 18F-DCFPyL PET/CT imaging. 
7. An intravenous peripheral intravenous catheter is placed (or an existing central line accessed in the 
arms or hands only; no lower extremity peripheral lines will be used) to inject the radioactive tracer. 
8. Vital signs (blood pressure, heart rate, respiratory rate, pulse oximetry), height, weight will be taken 
prior to administration of the radiotracer. 
9. Intravenous fluid 5% dextrose + 0.45% normal saline at 15 ml/kg (maximum 1000 ml) delivered over 30 
to 60 minutes prior to the injection of the radiopharmaceutical. The intravenous infusion is continued at 
a low flow rate for the remainder of the study. 
10. PET/CT will be performed on a Discovery DRX PET/CT scanner (GE Healthcare) operating in 3-
dimensional emission PET acquisition mode and using CT for attenuation correction.  There will be an 
initial CT scan for attenuation correction followed by two successive PET scans, attenuation corrected 
to the same initial CT. 
11. A bolus of less than or equal to 9 mCi (333 MBq) of 18F-DCPyL will be injected into the IV line by slow 
IV push. 
12. At approximately 60 minutes after the administration of 18F-DCFPyL, a whole-body CT and PET scan 
will be acquired from the vertex of skull to mid-thigh. PET/CT will be performed on a Discovery DRX 
PET/CT scanner (GE Healthcare) operating in 3-dimensional emission acquisition mode.  Scans will 
include approximately 8 to 9 fields-of-view, depending on patient height.  Images will be reconstructed 
as per routine clinical PET/CT scan by OSEM reconstruction algorithm. 
13. Vital signs (blood pressure, heart rate, pulse oximetry) will be taken within 1 hour after completion of 
PET/CT imaging. 
14. Peripheral IV catheter will be removed by radiology staff prior to patient leaving the PET center. 
 
General Concomitant Medication and Supportive Care Guidelines 
 
 
There are no known contraindicated medications. 
 
 
 


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Post-Imaging Evaluation 
 
The research nurse will contact the patient around 7 days (3 - 10 days) after the PET/CT study to inquire about 
delayed side effects. If there are suspected problems the patient will be asked to return for a clinic visit for a 
follow-up clinic visit 
 
Image Acquisition, Archiving, and Interpretation 
 
1. PET/CT will be performed on a Discovery DRX PET/CT scanner (GE Healthcare) operating in 3-
dimensional emission acquisition mode and using CT for attenuation correction. Patients will be 
scanned in the supine position of the pelvis or starting from the vertex of the skull to mid-thigh (whole 
body protocol) which will include approximately 8 to 9 fields-of-view, depending on patient height. An 
initial low dose x-ray CT transmission scan, preceding the serial PET emission acquisitions, will be 
used for tissue attenuation correction and anatomical correlation. PET/CT images will be stored on our 
institutional radiology PACS system. PET/CT images will be anonymized for image analysis on a rolling 
basis.  Data from a series of the dynamic pelvic PET scan and whole body PET will be analyzed. PET 
images will be analyzed on the GE Advanced Workstation software. Reconstruction of the PET data will 
be performed by means of iterative reconstruction (IR) by the ordered subset-expectation- maximization 
(OSEM) method with CT attenuation correction. 
2. PET/CT and bone scan analysis will be conducted by two experienced nuclear medicine physicians 
with consensus interpretation. 
3. PET - Anonymized PET scans will be analyzed with accompanying non- IV contrast CT, which is the 
standard of clinical care, but without knowledge of bone scan or CT results. 
4. Bone Scans - Anonymized bone scans, coded differently from PET/CT scans, will be analyzed on a 
separate day from the PET/CT reading session.  The bone scans will be analyzed with the 
accompanying CT scan available for anatomical correlation of bone scan findings, as is the standard of 
care. Prior two bone scans will be available for comparison to determine new, progressive, and stable 
disease. 
5. Chest/abdomen/pelvis CT analysis will be conducted by an experienced radiologist without knowledge 
of bone scan or PET/CT results, as is also the standard of care. 
 
 
Statistical Plan: 
Index lesions on 18F-DCFPyL scans will be scored based on SUVmax as previously described (53).  We will 
correlate the uptake within these index lesions with radiographic response on CT or bone scan to determine if 
uptake in a given lesion might be associated with therapeutic response.  The semi-quantitative measures of 
lesion uptake before and after BAT will be compared using paired –sample Wilcoxon signed rank tests. PSA 
and other serum markers in patients with positive or negative PET studies will be compared using the Mann-
Whitney test. 
 
 
 
 
 
 


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Pharmaceutical Information 
(Additional radiopharmaceutical information not listed below is downloaded on the FDA IND application in the 
supporting documents section of eIRB and available there for review). 
Common Name: DCFPyL 
Chemical Name: (S)-2-(3-((S)-1-carboxy-5-(6-fluoronicotinamido)pentyl)ureido)pentanedioic acid 
Characteristics: white powder 
Chemical formula: C18H23FN4O8 
C.A.S. number: 1423758-00-2 
 
Structure: 
           
 
Molecular Weight: 442.40 
Solubility: DMSO, 6.7% ethanol in 0.9% sodium chloride, methanol, 1:1 acetonitrile:water 
 
 
 
 
 
Initial Phase I study Adverse Events with 18F-DCFPyL 
An initial phase I study of the biodistribution and dosimetry of 18F-DCFPyL was performed in nine men with 
metastatic prostate cancer..  
Participants did not experience any severe adverse events. One participant reported 2 adverse events that were 
classified as either unrelated or unlikely to be attributable to the radiopharmaceutical. Another participant 
experienced a grade 1 adverse event according to the Common Terminology Criteria for Adverse Events 
(National Cancer Institute). This participant experienced a decrease in platelet count on routine investigation 
assessment during the post imaging follow up which has not resolved. This is likely due to the participant 
starting prostate cancer treatment prior to the follow-up visit. There were no other adverse events reported. 
 
 
 
 
N
N
O
OH
O
OH
O
NH
HO
O
H
H
O
N
F


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Appendix 6 
 
Data and safety monitoring will follow Level I under the SKCCC Data and Safety Monitoring Plan (DSMP, 
Version 5.0: 12/6/2012, NCI Approval Date: 12/11/2012).    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 7 
Assessment of Progression on Bone Scan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 8 
Quality of Life Instruments 
 

SAP_001.pdf: 
Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 1 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
 
TRANSFORMER Trial Statistical Analysis Plan 
 
 
Full Title of Study 
The TRANSFORMER Trial  
(Testosterone Revival Abolishes Negative Symptoms, Fosters 
Objective Response and Modulates Enzalutamide Resistance) 
Protocol Number 
J14146 
Protocol Version 
1.10  (03 Nov., 2014) 
IND Reference 
Number 
N/A 
Version of Plan 
1.0 
Date of Plan 
27 March 2017 
Replaces 28 October 2016 
Sponsor Name 
Department of Defense (DOD)  
Prostate Cancer Research Program  
 
 
 


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 2 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
 
Revision History 
  
 
 
Revision   
Date 
Description of Change 
1 
March 27, 2017 
  
 
 
Primary endpoint changed to PFS, 
including both radiographic and 
clinical progression  
 
 
Definition of radiographic 
progression clarified   
 
 
Secondary objectives revised 
 
 
Sample size changed to be 
consistent with protocol version 5.0  


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 3 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
TRANSFORMER Trial Statistical Analysis Plan........................................................................... 1 
List of Abbreviations........................................................................................................................... 6 
1.0 
Introduction ................................................................................................................................ 8 
2.0 
Study Overview, Objectives and Endpoints ...................................................................... 8 
2.1 
Overview of Study .............................................................................................................................. 8 
2.1.1 
Stratification and Randomization Scheme ......................................................................................... 8 
2.2 
Study Objectives: Primary ............................................................................................................... 9 
2.3 
Study Objectives: Secondary.......................................................................................................... 9 
2.4 
Clinical Trial Endpoints .................................................................................................................... 9 
2.4.1 
Radiographic Progression-Free Survival (rPFS) ............................................................................... 9 
2.4.2 
Progression-Free Survival (PFS) ......................................................................................................... 10 
2.4.3 
Time to initiation of Docetaxel chemotherapy ................................................................................. 11 
2.4.4 
Objective Response Rate (ORR) ......................................................................................................... 11 
2.4.5 
PSA Response Rate................................................................................................................................ 11 
2.4.6 
Time to PSA Progression ...................................................................................................................... 12 
2.4.7 
Safety Endpoints ..................................................................................................................................... 12 
2.4.8 
Quality of Life (QoL) Endpoints ........................................................................................................... 12 
2.4.9 
Correlative Endpoints ............................................................................................................................ 13 
3.0 
Populations For Analysis ..................................................................................................... 13 
3.1 
Screened Population ....................................................................................................................... 13 
3.2 
Intent to Treat (ITT) Population ..................................................................................................... 13 
3.3 
Safety Population ............................................................................................................................. 13 


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 4 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
3.4 
Per Protocol Population (PPP) ...................................................................................................... 13 
3.5 
Correlative Studies Population (CSP) ......................................................................................... 13 
4.0 
Statistical Methods and Determination of Sample Size ............................................... 15 
4.1 
Determination of Sample Size ....................................................................................................... 15 
4.2 
Interim Analyses ............................................................................................................................... 15 
4.2.1 
First Interim Analysis for rPFS ............................................................................................................ 15 
4.2.2 
Second Interim Analysis for rPFS ....................................................................................................... 16 
4.2.3 
Toxicity Monitoring ................................................................................................................................. 16 
4.3 
Data Monitoring Committee (DMC) .............................................................................................. 17 
4.4 
Statistical Methods .......................................................................................................................... 17 
4.4.1 
Demographic and Baseline Characteristics ..................................................................................... 18 
4.4.2 
Patient Disposition.................................................................................................................................. 18 
4.4.3 
Efficacy Analysis ..................................................................................................................................... 19 
4.4.3.1 
Primary Endpoint Analysis ............................................................................................................... 19 
4.4.3.2 
Secondary Endpoint Analyses ........................................................................................................ 20 
4.4.3.2.1 
Radiographic Progression-Free Survival (rPFS) .................................................................... 20 
4.4.3.2.2 
PSA response rate from randomization to crossover .......................................................... 20 
4.4.3.2.3 
PSA response rate following crossover ................................................................................... 20 
4.4.3.2.4 
Objective response rate (ORR) ................................................................................................... 20 
4.4.3.2.5 
Time to PSA progression ............................................................................................................. 20 
4.4.3.2.6 
Time to Initiation of Docetaxel .................................................................................................... 21 
4.4.3.2.7 
Quality of Life and Metabolic Endpoints .................................................................................. 21 
4.4.3.3 
Exploratory Endpoint Analyses ...................................................................................................... 22 


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 5 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
4.4.3.3.1 
AR-V7 Correlative Analyses ........................................................................................................ 22 
4.4.4 
Safety Analysis ........................................................................................................................................ 22 
4.4.4.1 
Adverse Events ................................................................................................................................... 22 
4.4.4.2 
Serious Adverse Events .................................................................................................................... 23 
4.4.4.3 
Clinical Laboratory Toxicities .......................................................................................................... 23 
4.4.4.4 
Toxicity Monitoring for Pain ............................................................................................................. 23 
4.5 
Other Issues and Further Details ................................................................................................. 24 
4.5.1 
Imputation Rules for Primary Endpoint (rPFS) ................................................................................ 24 
4.5.2 
General Imputation Rules for Partial Dates ...................................................................................... 24 
4.5.3 
Conversions from Days to Years, Months or Weeks ..................................................................... 24 
4.5.4 
Computation of Duration ....................................................................................................................... 24 
4.5.5 
Missing normal ranges for laboratory parameters ......................................................................... 25 
4.5.6 
Non-Numeric Laboratory Results and Calculation of Normal Ranges ...................................... 25 
4.5.7 
Procedures for Reporting Deviations to Original Statistical Analysis Plan ............................. 25 
4.6 
Statistical Software used in data analysis ................................................................................. 25 
4.7 
Additional analyses not referenced in this document ........................................................... 25 
5.0 
References ......................................................................................................................................... 26 
6.0 
Appendices ............................................................................................................................... 27 
7.0 
Approvals .................................................................................................................................. 33 
 
 
 


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 6 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
List of Abbreviations 
 
Abbreviation 
Full Term 
BAT 
Bipolar Androgen Therapy  
BPI 
Brief Pain Inventory 
BSA 
Body Surface Area 
CR 
Complete Response 
CRPC 
Castration-Resistant Prostate Cancer 
CTC 
Common Terminology Criteria 
DMC 
Data Monitoring Committee 
ECOG 
Eastern Cooperative Group 
eCRF  
Electronic Case Report Form 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
HR 
Hazard Ratio 
IIEF 
International Index of Erectile Function  
I-PANAS-SF 
International Positive and Negative Affect Schedule Short-Form 
ITT 
Intent to Treat 
NCI 
National Cancer Institute 
ORR 
Objective Response Rate 


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 7 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
PCWG2 
Prostate Cancer Working Group 2  
PPP 
Per Protocol Population 
PR 
Partial Response 
PSA  
Prostate-Specific Antigen 
RECIST  
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic Progression-Free Survival 
SAP 
Statistical Analysis Plan 
T 
Testosterone 
TRANSFORMER 
Testosterone Revival Abolishes Negative Symptoms, Fosters Objective 
Response and Modulates Enzalutamide Resistance 
WBC 
White Blood Cell 
 


Cancer Research And Biostatistics 
 
TRANSFORMER SAP 
 
  
Page 8 of 33 
 
Copyright 2007 Cancer Research And Biostatistics (CRAB).  All Rights Reserved.  Confidential. 
 
 
1.0 
Introduction 
This draft Statistical Analysis Plan (SAP) describes the proposed statistical analysis of the 
study entitled: The TRANSFORMER Trial (Testosterone Revival Abolishes Negative 
Symptoms, Fosters Objective Response and Modulates Enzalutamide Resistance).  
The purpose of this document is to ensure the credibility of the study outcomes by pre-
specifying the statistical approaches and data handling conventions for key analyses.  This 
draft plan will focus on the analysis of the primary endpoint, radiographic Progression-Free 
Survival (rPFS), and the secondary endpoints, PSA response rate, objective response rate 
(ORR), time to PSA progression, quality of life, and safety according to the NCI CTC, version 
4. The primary analyses of these endpoints will be described, the populations for analysis 
defined, and specific rules for “data handling” relevant to undertaking the key analyses will be 
described. 
 
2.0 
Study Overview, Objectives and Endpoints 
 
2.1 
Overview of Study 
This study will treat asymptomatic men with progressive metastatic castration-resistant 
prostate cancer (CRPC) after treatment with abiraterone acetate).  This study is  a 
randomized, multi-institutional, open label study to determine if treatment with 
intramuscular supraphysiologic testosterone (T) given on a dose/schedule designed to 
result in rapid cycling from the polar extremes of supraphysiologic to near castrate 
levels [i.e. Bipolar Androgen Therapy (BAT)] will improve primary and secondary 
objectives vs. enzalutamide. 
2.1.1 Stratification and Randomization Scheme 
At randomization, patients will be stratified based on duration of prior 
abiraterone acetate therapy (6 months or less or greater than 6 months).  Only 
patients determined to be eligible following completion of the Randomization 
eCRF will be randomized.  A dynamic balancing randomization algorithm will be 
used to ensure assignment of the treatments is balanced across the 
stratification factor.  This procedure balances the marginal distribution of the 


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stratification factor between the treatment regimens.  The approach is based on 
the method described by Pocock and Simon (Pocock and Simon, 1975). 
 
2.2 
Study Objectives: Primary 
The primary objective of the study is to determine if treatment with supraphysiologic 
testosterone (T) will improve PFS compared to Enzalutamide in men with CRPC post-
treatment with abiraterone. 
 
2.3 
Study Objectives: Secondary 
Secondary objectives are to investigate: 
• 
the safety of cyclical parenteral testosterone in asymptomatic men with recurrent 
castrate resistant prostate cancer, 
• 
PSA response rate prior to crossover, 
• 
PSA response rate in patients that choose to crossover, 
• 
Radiographic Progression-free Survival (rPFS) 
• 
Objective response rate, 
• 
Time to PSA progression, 
• 
Time to initiation of docetaxel chemotherapy 
• 
Comparison of quality of life (QoL) as assessed by multiple validated instruments. 
• 
The effect of BAT vs. Enzalutamide on expression of AR- V7 and frequency of AR-
mutation. 
 
2.4 
Clinical Trial Endpoints 
2.4.1 Radiographic Progression-Free Survival (rPFS) 
Radiographic progression-free survival (rPFS) is defined as the time from the 
date of randomization to the date of first documented radiological confirmation 
of progression (per RECIST 1.1 for soft tissue or Prostate Cancer Working 
Group 2 (PCWG2) for bone lesions) or death, whichever occurs first, before the 


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patient begins alternate anti-cancer treatment or crossover treatment. The 
standard RECIST 1.1 criteria for soft tissue are described in detail in the 
Protocol Appendix 1. On bone scan, radiographic progression will be defined by 
PCWG2 criteria as ≥2 new bone lesions (Appendix 7 of the Protocol). 
Specifically, for the first reassessment scan on treatment only (Cycle 3 of 
treatment), the patient is kept on study for 3 more cycles and have a 
confirmatory scan performed 12 weeks (3 cycles) later. If this confirmatory scan 
shows 2 or more additional new lesions, this defines progression; the 
progression date is the date of the first reassessment scan. Subjects who have 
unconfirmed progression will continue the treatment. If progression is observed 
on subsequent scans, then the date of that scan will be the date of progression 
and subsequent radiologic confirmation is not required. If there are 
inconsistencies between the progression date reported on the crossover 
treatment form and the disease assessment form, the progression date from 
the disease assessment form prior to the crossover treatment date will be used. 
If a patient has not had an event at the date of the analysis cut-off, initiation of 
crossover treatment, or alternate treatment, rPFS will be censored at the time of 
the last tumor assessment before the cut-off date. Subjects who die without a 
reported radiographic progression while on study drug (and before crossover) 
will be considered to have progressed on the date of their death. Subjects who 
do not progress or die while on study drug or before crossover will be censored 
on the date of their last evaluable tumor assessment prior to the initiation of 
subsequent anti-cancer therapy or crossover. Subjects who do not have any 
on-study tumor assessments and did not die will be censored on their date of 
randomization.  
 
2.4.2 Progression-Free Survival (PFS) 
Patients who do not meet the criteria of radiographic progression who are 
removed from study for worsening symptoms that are attributable to prostate 
cancer progression will be considered to have clinical progression.  
Clinical progression will be defined as documentation in the CRF of any of the 
following (whichever occurs earlier): 
  
• Cancer pain requiring initiation of chronic administration of opiate 
analgesia (oral opiate use for ≥3 weeks; parenteral opiate use for ≥7 
days. Patients with cancer pain requiring opiate analgesia for relief 


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should also be assessed by the investigator for the need for initiating 
systemic chemotherapy or palliative radiation.  
 
• Development of a skeletal-related event (SRE): pathologic fracture, 
spinal cord compression, or need for surgical intervention or radiation 
therapy to the bone.  
 
• Development of clinically significant symptoms due to loco-regional 
tumor progression (e.g. urinary obstruction) requiring surgical 
intervention or radiation therapy.  
 
PFS is defined as the time from randomization to the earliest of clinical 
progression, radiographic progression or death, before the patient starts 
alternate anti-cancer treatment or crossover treatment.  Patients alive without 
clinical or radiographic progression will be censored at the date of their last 
tumor assessment prior to initiation of alternate anti-cancer therapy and the cut-
off date. 
 
2.4.3 Time to initiation of Docetaxel chemotherapy 
Time to Initiation of Docetaxel is defined as the time from the date of 
randomization to the date of initiation of Docetaxel therapy. If a patient is known 
to be alive at the time of analysis cut-off without previously starting docetaxel 
therapy, this endpoint will be censored at the last date the patient is known to 
be alive. Patients will be censored at the date of randomization if no additional 
data are obtained. 
2.4.4 Objective Response Rate (ORR) 
Objective response rate (ORR) will be measured in patients with measurable 
disease using RECIST criteria. The number of patients in each arm achieving at 
least partial response (PR) prior to removal from the study, radiographic 
progression, or death will be divided by the number randomized to each arm. 
Patients with no response assessments will be analyzed as non-responders. 
2.4.5 PSA Response Rate 
The PSA response rate will be calculated in each arm as the number of 
subjects with a PSA response (decrease > 50% from baseline, confirmed with a 
second measurement at least 4 weeks after the first measurement) prior to 


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radiographic progression or crossover divided by the number of subjects 
randomized. 
For patients that crossover following radiographic progression, the PSA 
response rate after crossover will be calculated as the number of subjects in 
each crossover arm with a PSA response after initiation of crossover treatment 
divided by the number of subjects in each crossover arm. 
2.4.6 Time to PSA Progression 
The time to PSA progression will be calculated as the number of days from 
randomization to the earliest of PSA progression, death from any cause, 
crossover treatment or removal from the study prior to completion of 
randomized study treatment. PSA progression will be defined per PCWG2 
criteria as PSA increasing to 25% above baseline level and a minimum of 2 
ng/ml, confirmed with another measurement at least 4 weeks later (see 
Protocol Section 6.2). Death, treatment crossover and removal from the study 
will be treated as competing events.  Patients without a PSA progression or 
competing event at the time of analysis will be censored at the last PSA 
assessment date. Patients with no post-baseline PSA assessments will be 
censored at the date of randomization. 
2.4.7 Safety Endpoints 
The overall safety profile and toleration of BAT and enzalutamide will be 
characterized by incidence of adverse events categorized by type, frequency, 
severity, timing and relationship to study therapy as well as laboratory 
abnormalities. Adverse events will be summarized by the frequency of patients 
experiencing treatment emergent adverse events by body system and preferred 
term, by worst NCI CTCAE grade (version 4.0). 
2.4.8 Quality of Life (QoL) Endpoints 
QoL will be assessed using RAND-SF36 Quality of Life Survey, FACIT-F 
Version 4, I-PANAS-SF. Sexual capacity, functional capacity and pain will be 
assessed using IIEF, Global Assessment of Change and BPI, respectively. For 
each instrument, summary statistics of the scores will be reported at baseline 
randomization, one month post-randomization, three months post-
randomization, six months, and 12 months post-randomization. In each arm 
changes in quality of life scores pre- versus post-treatment will be evaluated at 
each follow-up time by paired-sample t-tests or Wilcoxon signed rank tests as 


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appropriate. In addition, mixture effect models may be fitted for accessing the 
quality of life changes over time.  
2.4.9 Correlative Endpoints 
AR variant status (detectable vs. not detectable) will be determined at baseline.    
 
3.0 
Populations For Analysis 
Figure 3-1 describes the respective patient populations being defined for the study in a flow 
chart format.   
3.1 
Screened Population 
The screened population is defined as all patients who have signed an informed 
consent and participated in screening procedures to assess eligibility. 
3.2 
Intent to Treat (ITT) Population 
The Intent-to-Treat population includes all patients who have been randomized to 
receive study treatment; this is the analysis population for all efficacy endpoints as well 
as patient characteristic summaries. The treatment group used in the analyses will be 
the treatment assigned by randomization.   
3.3 
Safety Population 
The safety population is defined as all ITT patients who receive at least one dose of 
study treatment.  This population will be used for all safety analyses.  The treatment 
group used in the analyses will be the actual treatment received.   
3.4 
Per Protocol Population (PPP) 
The Per Protocol Population (PPP) is defined as the subset of ITT patients who meet 
all inclusion and exclusion criteria (i.e. eligible patients). and are treated according to 
their randomization assignment, and protocol compliant. Patients with major protocol 
violations will be excluded from this population. All major violations will be determined 
before treatment group unblinding. 
3.5 
Correlative Studies Population (CSP) 
The Correlative Studies Population (CSP) is defined as the subset of ITT patients who 
have non-missing correlative data. 
 


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Figure 3-1: Patient Disposition for Protocol Defined Populations
 
Intent-to-Treat 
population (ITT) 
All randomized patients 
Screened Population 
Patients who sign informed consent and 
evaluated for eligibility at investigator site  
Safety Population  
Treated ITT patients
Per Protocol 
Population (PPP) 
Randomized, eligible, 
treated, protocol 
compliant 
Correlative Studies 
Population (CSP) 
ITT Patients with 
Correlative Data 


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4.0 
Statistical Methods and Determination of Sample Size 
4.1 
Determination of Sample Size 
This trial is designed to detect a 50% improvement in median PFS in the BAT group 
compared to enzalutamide, from 6 to 9 months (corresponding to a hazard ratio (HR) 
of 0.667 for BAT vs. enzalutamide), at one-sided significance level of 0.05. Allowing for 
the interim analysis plan discussed below, the study requires at least 156 events to 
ensure a sequential test procedure will have 80% power. With an expected recruitment 
period of 24 months and an additional 12 months of follow-up, and accounting for 15% 
loss to follow-up, a total of 194 patients (97 per arm) will be randomized to observe 156 
events in the 36 total months of this study. This calculation was performed using 
EAST® software. 
4.2 
Interim Analyses 
Two interim analyses for PFS are planned that allow the study to stop early for efficacy.  
An α-spending function method of Lan and DeMets with an O’Brien-Fleming-type 
stopping boundary (1983), will be used to construct the stopping boundaries for the 
efficacy analyses.  At each interim analysis, a one-sided stratified log-rank test will be 
used to compare the experimental arm (BAT) with the control arm (enzalutamide) and 
a hazard ratio will be calculated. The study will also be monitoring for early stopping for 
futility using Jennison-Turnbull repeated confidence interval methodology (1993). At 
each interim analysis the nominal (1- 2 × α) confidence interval on the PFS hazard 
ratio comparing the BAT arm to the enzalutamide arm (arm A versus arm B) will be 
computed, where α is the nominal one-sided significance level of the boundary from 
the error spending function at the information fraction for the particular analysis time. If 
the confidence interval does not contain the target alternative HR of 0.667, then the 
Data Monitoring Committee may consider terminating the study early for lack of 
treatment differences. The monitoring plan has negligible impact on the power of the 
study. 
4.2.1 First Interim Analysis for PFS 
The first interim analysis will be conducted after 70 events (approximately 45% 
of the information) have been entered in the database.  Based on 70 events, a 
one-sided p-value < 0.0034 from a stratified log-rank test will be sufficient to 
declare superiority of BAT compared to enzalutamide.  Under the assumption of 
exponentially distributed survival times, this p-value corresponds to a hazard 
ratio less than or equal to 0.525.   Additionally, a two-sided nominal 99.3% 


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confidence interval for the hazard ratio will be computed.  If the lower bound of 
this interval is greater than the target alternative hazard ratio of 0.667, then the 
data monitoring committee may consider terminating the study early for futility. 
4.2.2 Second Interim Analysis for PFS 
The second interim analysis will be conducted after 109 events (approximately 
70% of the information) have been entered in the database.  Based on 109 
events, a one-sided p-value < 0.0179 from a stratified log-rank test will be 
sufficient to declare superiority of BAT compared to enzalutamide.  Under the 
assumption of exponentially distributed survival times, this p-values 
corresponds to a hazard ratio less than or equal to 0.670.  Additionally, a two-
sided nominal 96.4% confidence interval for the hazard ratio will be computed.  
If the lower bound of this interval is greater than the target alternative hazard 
ratio of 0.667, then the data monitoring committee may consider terminating the 
study early for futility. 
 
Figure 4.1: 
Interim Analyses and Final Analysis Details for PFS 
 
 
4.2.3 Toxicity Monitoring 
The adverse event of pain on the BAT arm will be monitored after every cohort of 15 
patients has been treated for 12 weeks. If the toxicity of grade 3 or higher pain appears 
Hazard Ratio (HR)
Study Time
0.667
Study Start
Events=0
Inf. %=0
1st Interim
Events=70
Inf. %=45
2nd Interim
Events=109
Inf. %=70
Final
Events=156
Inf. %=100
Null Hypothesis Rejection Region
HR Upper Bound = 0.525
p < 0.0034
HR Upper Bound = 0.670
p < 0.0179
HR Upper Bou
p < 0.0441


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in over 20% of the BAT-treated patients, the trial will temporarily be halted pending 
safety evaluations. Specifically, we will apply a Bayesian toxicity monitoring rule that 
suspends the enrollment if the posterior probability of risk of pain being larger than that 
threshold is at least 75%. Based on the data of previous studies the monitoring rule 
uses Beta (1, 10) for the prior distribution. This means that our prior estimate of 
proportion of severe pain is 9%, and there is 90% chance that this proportion is 0.5%-
26%.  
The decision rule for safety stopping is as follows:  
Stop if: 
# patients with 
severe pain is 
at least: 
6 
10 
13 
16 
19 
23 
Out of: 
15 
30 
45 
60 
75 
90 
 
4.3 
Data Monitoring Committee (DMC) 
The DMC will be responsible for safeguarding the interests of trial participants, 
assessing the safety and efficacy of the clinical trial intervention during the trial, and for 
monitoring the overall conduct of the trial. The DMC membership will be comprised of 
clinicians and a Biostatistician who have experience in the management of patients in 
oncology and in the conduct and monitoring of randomized clinical trials. The DMC 
membership will be restricted to individuals free of apparent significant conflicts of 
interest. The DMC will be advisory to the study sponsor.  
The sponsor will be responsible for promptly reviewing the DMC recommendations, for 
deciding whether to continue or terminate the trial, and for determining whether 
amendments to the protocol or changes in the study conduct are required. 
4.4 
Statistical Methods  
The total counts and percentages of patients will be presented for categorical 
variables, both overall and by treatment arm. The mean, median, standard deviation, 
and range, will be presented for continuous variables, both overall and by treatment 
arm.   All statistical outputs will present results by treatment arm and over both 


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treatment arms except where noted below.  All listings will include treatment group. 
See Appendix 1 for a proposed list of tables, listings and figures. 
4.4.1 Demographic and Baseline Characteristics 
Demographics 
Demographic characteristics will be summarized for all analysis populations as 
defined in section 3.0 (ITT population, Safety population, and Per-Protocol 
population).  Age in years will be calculated as the date of randomization minus 
the date of birth divided by 365.25 truncated to the lowest integer. 
Baseline Patient Characteristics   
The following patient characteristics collected at the Pre-Study visit and/or pre-
dose will be summarized by treatment arm and overall: height; weight; BSA; 
ECOG Performance Status; vital signs; laboratory evaluations, and physical 
examination. Additional by-treatment arm summaries will reflect prior therapies 
and duration of prior abiraterone acetate therapy.  Baseline characteristics will 
be summarized for all analysis populations as defined in section 3.0 (ITT 
population, Safety population, and Per-Protocol population).   
Baseline values are defined as the last recorded value prior to the first dose of 
study drug. For physical examination findings, baseline is defined as the last 
value for each body system prior to receiving the first dose of study drug.  
4.4.2 Patient Disposition 
The numbers and percentages of patients who were registered and who are 
included in the analysis populations will be summarized. 
The number and percentages of patients who discontinued from the study and 
the reason for termination will be presented.  
The number of patients that crossover will be summarized, based on crossover 
for any reason and, in separate analyses, based on crossover after 
radiographic progression.  The null hypothesis of equal crossover rates in each 
arm will be tested using Fisher’s Exact Test. 
The date of randomization, date of first dose, date of last dose, date of 
termination, and reason for termination will be listed for each patient. 
Length of time on study will be analyzed using Kaplan-Meier techniques, with 
time computed from date of randomization to the latest of the last on-study 


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date, date of last contact or date of death.  Length of time on study will be 
computed for prior to crossover, after crossover and overall. 
4.4.3 Efficacy Analysis 
All efficacy analyses will be performed using the ITT analysis population unless 
otherwise noted.   Efficacy analyses will be presented by treatment arm and 
overall and for each randomization stratum; results by randomization stratum 
will not present p-values.  For all treatment comparisons involving odds ratios or 
hazard ratios, these ratios will be computed using BAT values in the numerator 
and the control arm values in the denominator.  The following sections assume 
crossover will only occur following radiographic progression as described in the 
study protocol.  If crossover occurs without prior radiographic progression, 
follow-up will be censored at the date of crossover. 
4.4.3.1 Primary Endpoint Analysis 
Primary efficacy analyses  of PFS will be performed using the ITT 
population.  For the primary endpoint analysis, a stratified log-rank test 
will be used to compare the experimental arm (BAT) to the control arm 
(enzalutamide).  The test will be stratified by the stratification factor 
defined in section 2.1.1.  The analysis for the primary endpoint will be 
performed after 156 events have occurred.  A one-sided p-value less 
than 0.0441 from a stratified log-rank test will be sufficient to declare 
superiority of BAT compared to enzalutamide based on 156 events.  
Under the assumption of exponentially distributed failure times, this 
corresponds to a hazard ratio less than or equal to 0.761.  Additionally, 
a two-sided nominal 91.18% confidence interval for the hazard ratio will 
be computed in accordance with the critical values derived from the α-
spending function method described above.   
This analysis will also be repeated in the Per-Protocol Population to 
assess the sensitivity of the results to eligibility and protocol compliance. 
Exploratory subgroup analyses of PFS will stratify the above analysis by 
ECOG (0 vs 1+2), age group (<65 versus ≥ 65), duration of response to 
prior abiraterone (< 6 months versus ≥ 6 months) and race (White 
versus Non-White).  
 


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4.4.3.2 Secondary Endpoint Analyses 
4.4.3.2.1 
Radiographic Progression-Free Survival (rPFS) 
rPFS will be analyzed using the ITT population.  A stratified log-
rank test will be used to compare the experimental arm (BAT) to 
the control arm (enzalutamide).  The test will be stratified by the 
stratification factor defined in section 2.1.1.   
4.4.3.2.2 
PSA response rate from randomization to crossover 
The PSA response rate prior to crossover will be 
estimated for each arm.  A 95% confidence interval will 
be calculated for each estimate using the Clopper-
Pearson method.  The null hypothesis of equal PSA 
response rates in each arm will be tested using Fisher’s 
Exact Test. 
4.4.3.2.3 
PSA response rate following crossover 
The PSA response rate after crossover will be estimated 
for each crossover arm.  A 95% confidence interval will 
be calculated using the Clopper-Pearson method.  The 
null hypothesis of equal PSA response rates in each arm 
will be tested using Fisher’s Exact Test. 
4.4.3.2.4 
Objective response rate (ORR) 
Objective response rate will be summarized for each arm. 
A 95% confidence interval will be calculated for each arm 
using the Clopper-Pearson method.  The null hypothesis 
of equal response rates in each arm will be tested using 
Chi-Square test.  If the assumptions of the Chi-Sqare test 
are not met, Fisher’s Exact Test will be used. 
4.4.3.2.5 
Time to PSA progression 
The probability of observing a PSA progression will be 
calculated using the cumulative incidence method 
described by Gooley, et al; the equivalence between 


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arms will be tested using a log-rank test.  Death, 
radiographic progression and discontinuation from the 
study will be treated as competing events.  Patients 
without a PSA progression or competing event at the time 
of analysis will be censored at the last PSA assessment 
date. Note that this analysis differs from the one 
described in the protocol. 
 
4.4.3.2.6 
Time to Initiation of Docetaxel  
Time to initiation of Docetaxel will be analyzed using 
Kaplan-Meier techniques; the treatment arms will be 
compared using the stratified log-rank test. 
4.4.3.2.7 
Quality of Life and Metabolic Endpoints 
Quality of life (QoL) will be assessed using the RAND-
SF36 Quality of Life Survey, Functional Assessment of 
Chronic Illness Therapy-Fatigue (FACIT-F) Version 4, 
and International Positive and Negative Affect Schedule 
Short-Form (I-Panas-SF). Sexual capacity, functional 
capacity and pain will be assessed using the International 
Index of Erectile Function (IIEF), Global Assessment of 
Change and the Brief Pain Inventory (BPI), respectively. 
For each instrument, summary statistics of the scores 
and change scores will be reported at baseline and post-
randomization at 1, 3, 6 and 12 months.  The null 
hypothesis of equal change between arms will be tested 
at each time point using a Wilcoxon signed rank test with 
a multiple comparison adjusted significance level of 
0.0125. In addition, repeated measures models will be 
used to access changes in QoL summary measures over 
time. 
The change from baseline in metabolic measures (e.g. 
bone density, lipid profile, metabolic panel, steroid panel, 
inflammation/cytokines, BMI, lean mass) will be 
evaluated using the same analysis methods as for QoL. 


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Metabolic parameters will be compared between the two 
treatment arms using regression models. 
 
4.4.3.3 Exploratory Endpoint Analyses 
4.4.3.3.1 
AR-V7 Correlative Analyses 
The association between BAT-induced decrease in AR-
V7 expression and restoration of sensitivity to ADT and 
enzalutamide will be assessed.    
The association of AR-V7 at baseline with clinical 
outcomes of rPFS, objective response rate (ORR) and 
PSA response will be examined by treatment arm. For 
rPFS, Kaplan-Meier curves will be generated for each 
treatment arm stratified by baseline AR-V7 status. Cox 
proportional hazards models will be used to estimate the 
hazard ratio with 95% Confidence Intervals for each arm 
to quantify the effect of AR-V7 presence/absence on the 
risk of progression. The binary outcomes of ORR and 
PSA response will be compared between baseline AR-
V7(+) and AR-V7(–) groups using Chi-square tests (or 
Fisher’s Exact test if the assumptions of the Chi-square 
test are not met). The interaction of treatment and AR-
V7 status may also be explored using Cox Proportional 
Hazards modelling for rPFS. 
4.4.4 Safety Analysis 
Safety analyses will be performed using the Safety Analysis Population unless 
otherwise specified.  Safety analyses will be presented separately for the pre- 
and post-crossover treatment periods.  Safety analyses pre-crossover will 
include all events from the date of first treatment to the earliest of removal from 
the study, radiographic progression or crossover. Safety analyses post-
crossover will include all events from the date of first crossover treatment until 
removal from the study. 
4.4.4.1 
Adverse Events 


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All Adverse Event summaries will be presented by treatment period 
(randomization versus crossover).  An overall summary of adverse 
events will be presented by NCI CTCAE grade.  Tabulations of 
events by maximum grade, system organ class and preferred term 
will also be presented.  The number and proportion of patients 
experiencing each event will be presented according to the maximum 
grade experienced.  Separate summaries of drug-related adverse 
events will be generated using drug-related attribution corresponding 
to the actual drug received in the treatment period reflected in the 
analysis (randomization versus crossover).  For example, for patients 
on BAT in a given treatment period, the BAT drug-relationship 
response will be used to ascribe relationship in AE summaries for 
that treatment period.     
4.4.4.2 
Serious Adverse Events 
Serious adverse events will be tabulated by system organ class and 
preferred term.  The number and proportion of patients experiencing 
each event will be presented.  A separate summary of serious drug-
related adverse events will be generated. 
Serious adverse event data will also be reflected in a listing. 
4.4.4.3 
Clinical Laboratory Toxicities 
Selected clinical laboratory assessments will be graded according to   
CTC version 4.  The following lab values will be summarized 
according to maximum grade when available: WBC, Neutrophils, 
Lymphocytes, Platelets, Hemoglobin, Sodium, Serum Potassium, 
Calcium, Creatinine, and Total Bilirubin.  An overall summary will be 
presented for the treatment periods before and after crossover.  A 
shift table will be generated indicating change from baseline to 
maximum grade observed during the pre-crossover treatment period. 
If local lab normal ranges cannot be determined from data entered in 
the study database, standard lab ranges will be used.  When there 
are potential conflicts between local lab normal ranges and ranges 
used in CTC grading, CTC normal ranges will be used.  See 
Appendix 2 for the lab toxicity grade definitions. 
4.4.4.4 
Toxicity Monitoring for Pain 


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Continuous monitoring of adverse events of pain on the BAT arm will 
be carried out by the statistician named in the protocol. 
 
4.5 
Other Issues and Further Details 
4.5.1 Imputation Rules for Primary Endpoint (PFS) 
If a radiographic progression date or death date must be imputed to calculate 
the primary endpoint, the following algorithm will be used: 
• 
If the date is missing month and day and the subject was last known to 
be progression free and alive in the same year, the last radiographic 
assessment date will be used as the progression date. 
• 
If the subject’s last assessment date was in the previous year, the 
month and day will be imputed as the first day of the year (JAN01). 
• 
If the year and month are known, the date will be imputed as the 
maximum of the last assessment date and the first day of the known 
year and month.   
4.5.2 General Imputation Rules for Partial Dates 
When imputation of partial dates is required for calculation of durations, a 
method like the one described in Section 4.5.1 of this document will be utilized.   
4.5.3 Conversions from Days to Years, Months or Weeks 
Years = # of days / 365.25 
Months = # of days / 30.4375 (i.e. 365.25/12) 
Weeks = # of days / 7 
Summaries based on the above computations will be rounded to tenths. 
4.5.4 Computation of Duration 
Duration for time variables based on two dates, e.g., Start Date and End Date, 
will be calculated as (End Date – Start Date + 1) (in days) unless otherwise 
specified. 


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4.5.5 Missing normal ranges for laboratory parameters 
When either the lower limit of normal, the upper limit of normal or both are 
missing or are not machine readable, a standardized reference range will be 
used.  
4.5.6 Non-Numeric Laboratory Results and Calculation of Normal Ranges 
Laboratory values including symbols (“<” or “>”, for example) will not be used in 
summary analyses.   These values will be reflected in listings of the data. 
4.5.7 Procedures for Reporting Deviations to Original Statistical Analysis Plan 
Any deviations from this plan will be described in an appendix to the final study 
report. 
 
4.6 
Statistical Software used in data analysis 
All statistical analyses will be performed using SAS (version 9.4 or greater) or R 
(version 3.1 or greater). 
4.7 
Additional analyses not referenced in this document 
All additional analyses not referenced in this document will be considered exploratory.   
 
 


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5.0 
References 
• 
Pocock, S., and Simon, R. (1975). Sequential treatment assignments with balancing for 
prognostic factors in the controlled clinical trial. Biometrics 31: 103-115. 
• 
Lan, K. K. G., and DeMets, D. L. (1983) Discrete sequential boundaries for clinical 
trials. Biometrika 70 (3): 659-663  
• 
Jennison C, Turnbull BW (1993) Sequential equivalence testing and repeated 
confidence intervals, with applications to normal and binary responses. 
Biometrics.49:31-43. 
• 
Mantel, N. (1966).  Evaluation of survival data and two new rank order statistics arising 
in its consideration.  Cancer Chemotherapy Reports, 50:163-170. 
• 
Kaplan, E.L., and Meier P. (1958).  Nonparametric estimation from incomplete 
observations.  J Am Stat Assoc, 53:457-481. 
• 
Agresti, Alan. (1992)  A survey of Exact Inference for Contingency Tables, Statistical 
Science 7(1): 131-153. 
• 
Clopper, CJ and Pearson, ES, (1934) The use of confidence or fiducial limits illustrated 
in the case of the binomial. Biometrika 26:404-413. 
• 
Gooley TA, Leisenring W, Crowley J, et al. (1999) Estimation of failure probabilities in 
the presence of competing risks: new representations of old estimators.  Stat Med 
18:695-706. 
• 
Hosmer, D.W., and Lemeshow, S. (2000).  Applied logistic regression, second edition.  
Hoboken: John Wiley & Sons, Inc. 
• 
Cox, D.R. (1972).  Regression models and life tables (with discussion).  Journal of the 
Royal Statistical Society, B34:187-220. 
 
 


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6.0 
Appendices 
Appendix 1.  Proposed list of outputs 
Tables 
Subject Demographics - ITT Analysis Population 
Subject Demographics - Safety Analysis Population  
Subject Demographics - PP Analysis Population 
Subject Demographics – Correlative Studies Population 
Summary of Prior Therapy – ITT Analysis Population 
Baseline Physical Examination – ITT Analysis Population  
Baseline Vital Signs – ITT Analysis Population 
Baseline Laboratory Values – ITT Analysis Population 
Patient Disposition – ITT Analysis Population 
Summary of Inclusion Criteria – ITT Analysis Population 
Summary of Exclusion Criteria – ITT Analysis Population 
Length of Follow-up – ITT Analysis Population 
Summary of  rPFS – ITT Analysis Population 
Summary of   rPFS – PP Analysis Population 
Summary of rPFS by Subgroup – ITT Analysis Population 
Summary of PSA Response  – ITT Analysis Population, Randomization to Cross-over 
Summary of PSA Response  – ITT Analysis Population, post-Crossover 
Summary of Secondary Endpoint, Time to PSA Progression – ITT Analysis Population 
Summary of Quality of Life Measures:  RAND-SF36 – ITT Analysis Population 
Summary of Quality of Life Measures:  FACIT-F– ITT Analysis Population 
Summary of Quality of Life Measures:  I-PANAS-SF – ITT Analysis Population 
Summary of Quality of Life Measures:  IIEF – ITT Analysis Population 
Summary of Quality of Life Measures BPI – ITT Analysis Population 


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Overall Summary of AEs - Safety Analysis Population, Randomization 
Overall Summary of AEs - Safety Analysis Population, Crossover 
Adverse Events by NCI CTC System Organ Class and Preferred Term – Safety Analysis Population, Randomization 
Adverse Events by NCI CTC System Organ Class and Preferred Term – Safety Analysis Population, Crossover 
Serious Adverse Events by NCI CTC System Organ Class and Preferred Term – Safety Analysis Population, Randomization 
Serious Adverse Events by NCI CTC System Organ Class and Preferred Term – Safety Analysis Population, Crossover 
Adverse Events by NCI CTC System Organ Class, Preferred Term and Maximum Grade– Safety Analysis Population, Randomization 
Adverse Events by NCI CTC System Organ Class, Preferred Term and Maximum Grade– Safety Analysis Population, Crossover 
Drug-Related Adverse Events by NCI CTC System Organ Class, Preferred Term and Maximum Grade– Safety Analysis Population, 
Randomization 
Drug-Related Adverse Events by NCI CTC System Organ Class, Preferred Term and Maximum Grade– Safety Analysis Population, 
Crossover 
Clinical Laboratory Events by NCI CTC Preferred Term and Maximum Grade – Safety Analysis Population, Randomization 
Clinical Laboratory Events by NCI CTC Preferred Term and Maximum Grade – Safety Analysis Population, Crossover 
AR-V7 Correlative Analysis:  rPFS 
AR-V7 Correlative Analysis:  ORR 
AR-V7 Correlative Analysis:  PSA Response 
Figures 
rPFS by Treatment Arm- ITT Analysis Population 
rPFS by Treatment Arm - PP Analysis Population 
Time to PSA Progression by Treatment Arm- ITT Analysis Population 
rPFS Forest Plot for Pre-Specified Subgroups 
rPFS by Treatment Arm and AR-V7 -  
Listings 
Subject Demographics and Randomization 
Patient Disposition 
Inclusion and Exclusion Criteria 


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Adverse Events 
Death Information 
Radiographic Progression 
Metabolic Measurements 
PSA Measurements 
Tumor Response 
Treatment after Radiographic Progression 
 


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Appendix 2.  Toxicity Grading Definitions for Clinical Lab Results 
 
Form 
Lab variable 
CTCAE v 4.0 
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Reporting 
units 
Reference 
Range 
Source 
Young & 
Huth 
Page # 
LLN 
ULN 
Hematology 
Platelets 
Platelet count 
decreased 
<LLN - 
75,000/mm3; 
 <LLN - 75.0 
x 10e9 /L 
<75,000 - 
50,000/mm3;  
<75.0 - 50.0 
x 10e9 /L 
<50,000 - 
25,000/mm3; 
 <50.0 - 25.0 x 
10e9 /L 
<25,000/mm3;  
<25.0 x 10e9 
/L 
 103/uL 
* 
209 
150 
450 
WBC 
White blood 
cell decreased 
<LLN - 
3000/mm3; 
 <LLN - 3.0 x 
10e9 /L 
<3000 - 
2000/mm3;  
<3.0 - 2.0 x 
10e9 /L 
<2000 - 
1000/mm3;  
<2.0 - 1.0 x 
10e9 /L 
<1000/mm3; 
 <1.0 x 10e9 
/L 
 103/uL 
* 
175 
3.2 
9.8 
Leukocytosis 
 - 
 - 
>100,000/mm3 
  
 103/uL 
* 
175 
3.2 
9.8 
Neutrophil % 
Neutrophil 
count 
decreased 
<LLN - 
1500/mm3;  
<LLN - 1.5 x 
10e9 /L 
<1500 - 
1000/mm3;  
<1.5 - 1.0 x 
10e9 /L 
<1000 - 
500/mm3;  
<1.0 - 0.5 x 
10e9 /L 
<500/mm3;  
<0.5 x 10e9 /L 
 103/uL 
* 
193 
3 
5.8 
Lymphocyte % 
Lymphocyte 
count 
decreased 
<LLN - 
800/mm3;  
<LLN - 0.8 x 
10e9/L 
<800 - 
500/mm3;  
<0.8 - 0.5 x 
10e9 /L 
<500 - 
200/mm3;  
<0.5 - 0.2 x 
10e9 /L 
<200/mm3;  
<0.2 x 10e9 /L 
 103/uL 
* 
178 
1.5 
3 
Lymphocyte 
count 
increased 
 - 
>4000/mm3 
- 
20,000/mm3 
>20,000/mm3 
 - 
 103/uL 
* 
178 
1.5 
3 


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Hemoglobin 
Anemia 
(Hgb) <LLN - 
10.0 g/dL; 
 <LLN - 6.2 
mmol/L;  
<LLN - 100 
g/L 
Hgb <10.0 - 
8.0 g/dL; 
 <6.2 - 4.9 
mmol/L; 
  <100 - 
80g/L 
Hgb <8.0 g/dL;  
<4.9 mmol/L;  
<80 g/L 
  
g/dL 
* 
151 
13.5 
17.5 
Hemoglobin 
increased 
Increase in 
>0 - 2 gm/dL 
above ULN 
or above 
baseline if 
baseline is 
above ULN 
Increase in 
>2 - 4 gm/dL 
above ULN 
or above 
baseline if 
baseline is 
above ULN 
Increase in >4 
gm/dL above 
ULN or above 
baseline if 
baseline is 
above ULN 
- 
g/dL 
* 
151 
13.5 
17.5 
Chemistry 
Creatinine 
Creatinine 
increased 
>ULN - 1.5 x 
ULN;  
>1 - 1.5 x 
baseline;  
 >1.5 - 3.0 x 
ULN; 
>1.5 - 3.0 x 
baseline 
 >3.0 - 6.0 x 
ULN; 
>3.0 baseline 
>6.0 x ULN 
mg/dL 
* 
114 
0.6 
1.2 
Calcium 
Hypocalcemia 
Corrected 
serum 
calcium of 
<LLN - 8.0 
mg/dL; <LLN 
- 2.0 mmol/L 
Corrected 
serum 
calcium of 
<8.0 - 7.0 
mg/dL; <2.0 
- 1.75 
mmol/L 
Corrected 
serum calcium 
of <7.0 - 6.0 
mg/dL; <1.75 - 
1.5 mmol/L 
Corrected 
serum 
calcium of  
<6.0 mg/dL; 
<1.5 mmol/L 
mg/dL 
* 
92 
8.4 
10.2 
Hypercalcemia 
Corrected 
serum 
calcium of 
>ULN - 11.5 
mg/dL; 
>ULN - 2.9 
mmol/L 
Corrected 
serum 
calcium of 
>11.5 - 12.5 
mg/dL; >2.9 
- 3.1 mmol/L 
Corrected 
serum calcium 
of >12.5 - 13.5 
mg/dL;>3.1 - 
3.4 mmol/L 
Corrected 
serum 
calcium of 
>13.5 mg/dL; 
>3.4 mmol/L 
mg/dL 
* 
92 
8.4 
10.2 
Total bilirubin 
Blood bilirubin 
increased 
>ULN - 1.5 x 
ULN 
>1.5 - 3.0 x 
ULN 
>3.0 - 10.0 x 
ULN 
>10.0 x ULN 
mg/dL 
* 
87 
0.2 
1.3 
Sodium 
Hyponatremia 
<LLN - 130 
mmol/L 
 - 
<130 - 120 
mmol/L 
<120 mmol/L 
mmol/L 
* 
228 
137 
145 


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Hypernatremia 
>ULN - 150 
mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 mmol/L 
mmol/L 
* 
228 
137 
145 
Potassium 
Hypokalemia 
  
<LLN - 3.0 
mmol/L 
<3.0 - 2.5 
mmol/L 
<2.5 mmol/L 
mmol/L 
** 
  
3.5 
5 
Hyperkalemia 
>ULN - 5.5 
mmol/L 
>5.5 - 6.0 
mmol/L 
>6.0 - 7.0 
mmol/L 
>7.0 mmol/L 
mmol/L 
** 
  
3.5 
5 
*  E, Young D and Huth. SI Units for Clinical Measurement. Philadelphia, Pennsylvania : Americal College of Physicians, 1998. ISBN 0-943126-51-7. 
**  Merck & Co, Inc. Normal Laboratory Values. The Merck Manual Professional Edition. [Online] April 2013.  
http://www.merckmanuals.com/professional/appendixes/normal_laboratory_values/normal_laboratory_values.html. 
 


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7.0 
Approvals 
 
Printed Name 
Signature 
Date 
Antje Hoering 
 
 
Lynn Shemanski 
 
 
Sam Denmeade 
 
 
Hao Wang 
 
 
Grace Powell  (CRAB QA)