Clinical trial NCT02025010
Conditions: Castration-resistant Prostate Cancer
Keywords: Castration-resistant Prostate Cancer Abiraterone Acetate
Sponsor: Dana-Farber Cancer Institute
Start date: 2014-01-27; Completion date: 2025-04-07
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is comparing the safety and effectiveness of abiraterone acetate alone, followed by the addition of prednisone (when the participant's disease worsens or the physician feels it would lessen symptoms of toxicity) versus the current approved treatment regimen which involves the concomitant use of prednisone in conjunction with abiraterone acetate. Additionally, this study is also examining why participants stop responding to treatment with abiraterone acetate by evaluating blood and tissue.

Detailed description:
Participants will be treated with abiraterone acetate (AA) in 28-day cycles. Participants will be monitored (weekly for the first two cycles, then on Day 1 of each subsequent cycle) for symptoms of persistent or severe mineralocorticoid excess (including hypertension, hypokalemia).

For participants who experience symptoms of persistent or severe hypertension or hypokalemia as detailed in the above schema, prednisone 5 mg by mouth twice daily will be added. We will monitor for other symptoms of AA toxicity to include fluid retention and fatigue.

For participations who tolerate AA monotherapy without the addition of prednisone to manage symptoms of persistent or severe mineralocorticoid excess, prednisone 5 mg by mouth twice daily will be added at Prostate Specific Antigen (PSA) progression. Participants will be continued on study until symptomatic or radiographic progression or taken off study for another reason as detailed in protocol.

Arms: arm 1: Participants will be treated with four 250 mg tablets (1,000 mg) of abiraterone acetate (AA) orally on 28-day cycles. For participants who experience persistent or severe mineralocorticoid excess or have PSA progression, prednisone 5 mg by mouth twice daily will be added.

Patients will be treated until radiographic disease progression and unacceptable AE or taken off study for other reason.
Interventions: intervention 1: abiraterone acetate
Intervention descriptions: intervention 1: Abiraterone acetate is a selective and irreversible inhibitor of CYP17 which has demonstrated clinical efficacy in patients with CRPC. Currently, AA is administered with concomitant prednisone.

Protocol documents:
Prot_SAP_000.pdf: 
TITLE: Phase II clinical trial of abiraterone acetate without exogenous glucocorticoids in men 
with castration-resistant prostate cancer with correlative assessment of hormone intermediates. 
 
 
NCT Number: NCT02025010 
 
 
Protocol Version Date: September 15, 2020 




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ABBREVIATIONS
Abiraterone acetate – AA 
Adrenocorticotropic hormone – ACTH 
Adverse event – AE 
Alanine transaminase – ALT  
American Society of Anesthesiologists – ASA 
ANC – Absolute neutrophil count 
Androgen deprivation therapy – ADT 
Androgen Receptor – AR
Area under the concentration-time curve – AUC 
Aspartate transaminase – AST  
Body-mass-index – BMI 
Cancer and Leukemia Group B – CALGB
Cancer Therapy Evaluation Program – CTEP 
Case Report Form – CRF 
Castration resistant prostate cancer – CRPC
Circulating Tumor Cells – CTCs 
Clinical Trials Research Informatics Office – CTRIO
Code of Federal Regulations – CFR 
Complete response – CR
Partial response – PR 
Computed tomography – CT 
Dana Farber Cancer Institute – DFCI
Dana-Farber/Harvard Cancer Center – DF/HCC 
Dana-Farber/Partners Cancer Care – DF/PCC 
Data Safety and Monitoring Committee – DSMC 
Dehydroepiandrosterone – DHEA 
Dehydroepiandrosterone-sulfate – DHEA-S 
Deoxyribonucleic acid – DNA 
Dihydrotestosterone – DHT 
Eastern Cooperative Oncology Group – ECOG 
Echocardiogram – ECHO 
Electrocardiogram – ECG  
Food and Drug Administration – FDA 
Good Clinical Practice – GCP 
Health Insurance Portability and Accountability Act – HIPAA 
Hematoxylin and eosin – H&E
Human immunodeficiency virus – HIV 
Immunohistochemistry – IHC 
Institutional Review Board – IRB 
International Normalized Ratio – INR 
Investigational New Drug – IND 
Laser capture microdissection – LCM 
Liver function test – LFT
Lower limit of normal – LLN


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Luteinizing hormone-releasing hormone – LHRH 
Magnetic Resonance Imaging – MRI 
Maximum concentration – Cmax  
Mineralocorticoid excess – ME 
Multi Gated Acquisition Scan – MUGA 
National Cancer Institute Common Terminology Criteria for Adverse Events – NCI CTCAE
New York Heart Association – NYHA 
Not Reached – NR 
Office of Data Quality – ODQ
Office for Human Research Studies – OHRS 
Overall survival – OS 
Partial thromboplastin time – PTT 
Positron emission tomography – PET 
Principal Investigator – PI 
Product Quality Complaint - PQC
Progression free survival – PFS 
Progressive disease – PD
Prostate specific antigen – PSA
Prostate Cancer Clinical Trials Working Group – PCWG 
Prothrombin time – PT
Response Evaluation Criteria In Solid Tumors – RECIST 
Reverse transcription polymerase chain reaction – RT-PCR 
Ribonucleic acid – RNA 
Serious adverse event – SAE 
Single-nucleotide polymorphism – SNP 
Stable disease – SD 
Time to PSA Progression – TTPP 
Unknown – UN 
Upper limit of normal – ULN
WBC – White blood cell count 


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STUDY SCHEMA




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SCHEMA OF INITIATING PREDNISONE FOR SYMPTOMS OF HYPOKALEMIA*
 
*For patients with grade 1-2 hypokalemia, initiation of therapy with a mineralocorticoid 
antagonist should be administered only if the Principal Investigator, 
 
, deems the toxicity to be related to abiraterone acetate.  If the grade 1-2 
hypokalemia is not thought to be related to abiraterone acetate, potassium levels should 
be monitored weekly until potassium levels return to the entry criteria.  Entry criteria 
for serum or plasma potassium is greater than or equal to 3.5 mmol/L or Institutional 
LLN (independent of potassium supplementation). 


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STUDY SYNOPSIS 
1. Population: Men with CRPC. 
2. Treatment: Participants will be treated with AA in 28-day cycles. Participants will be 
monitored (weekly for the first two cycles, then on Day 1 of each subsequent cycle) for 
symptoms of persistent or severe mineralocorticoid excess (including hypertension, 
hypokalemia). Day 8, 15, 22 monitoring of cycles 1-2 can occur locally if preferred. 
For participants who experience symptoms of persistent or severe hypertension or 
hypokalemia as detailed in the above schema, prednisone 5 mg by mouth twice daily 
will be added. Specific management of symptoms of hypertension and hypokalemia 
after addition of prednisone is detailed in Section 6.3. We will monitor for other 
symptoms of AA toxicity to include fluid retention and fatigue. Management of these 
symptoms is detailed in Section 6.3. For participations who tolerate AA monotherapy 
without the addition of prednisone to manage symptoms of persistent or severe 
mineralocorticoid excess, prednisone 5 mg by mouth twice daily will be added at PSA 
progression. Participants will be continued on study until radiographic progression or 
taken off study for another reason as detailed in Section 5.4. Toxicity will be defined 
by NCI CTCAE (version 4). 
Participants will undergo optional pre-treatment and progression tumor biopsies. After 
the progression biopsy is performed, protocol therapy will be discontinued. Participants 
who stop protocol therapy before receiving four cycles of AA will not be asked to 
undergo the optional second biopsy.     
3. Correlative Studies: Participants will undergo assessment of serum corticosteroid 
intermediates and ACTH at baseline and subsequent treatment visits for correlation 
with symptoms of mineralocorticoid excess. Participants will also undergo (optional) 
pre-treatment and progression tumor biopsies for assessment of possible mechanisms 
of AA resistance. 
4. Planned Enrollment: 60 participants.
5. Milestone Plan:
Milestone
Timeline 
Planned Interim Analysis (see below)
6 months from enrollment of first subject 
Enrollment of 100% of Target Enrollment
12 months from enrollment of first subject
Last Subject/Last Visit on Study
24 months from enrollment of first subject
Collection and Analysis of Primary and 
Secondary Endpoint Data 
3 months following last subject/last visit 
Completion of Final Study Report 
6 months following last subject/last visit 
Six months following enrollment of the first participant, we will conduct a planned 
analysis to assess the number of participants requiring therapy with prednisone for 
management of symptoms of mineralocorticoid excess. 


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6. DSMC/Safety Review: Quarterly. 


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TABLE OF CONTENTS
1.
OBJECTIVES ......................................................................................................................................................1
1.1
Study Design.....................................................................................................................................................1
1.2
Primary Objectives...........................................................................................................................................1
1.3
Secondary Objectives .......................................................................................................................................1
1.4
Exploratory Objectives.....................................................................................................................................2
2.
BACKGROUND ..................................................................................................................................................4
2.1
Study Agent(s)...................................................................................................................................................4
2.2
Study Disease..................................................................................................................................................11
2.3
Rationale.........................................................................................................................................................11
2.4
Correlative Studies Background.....................................................................................................................12
3.
PARTICIPANT SELECTION .........................................................................................................................14
3.1
Eligibility Criteria ..........................................................................................................................................14
3.2
Exclusion Criteria........................................................................................................................................16
3.3
Inclusion of Minorities and Other Underrepresented Populations................................................................17
4.
REGISTRATION PROCEDURES..................................................................................................................18
4.1
General Guidelines for DF/HCC and DF/PCC Institutions ..........................................................................18
4.2
Registration Process for DF/HCC and DF/PCC Institutions......................................................................18
4.3
General Guidelines for Other Participating Institutions ...............................................................................18
4.4
Registration Process for Other Participating Institutions .............................................................................18
5.
TREATMENT PLAN........................................................................................................................................20
5.1
Pre-treatment Criteria..................................................................................................................................21
5.2
Agent Administration ....................................................................................................................................21
5.3
General Concomitant Medications and Supportive Care Guidelines............................................................23
5.4
Duration of Therapy .....................................................................................................................................23
5.5
Duration of Follow-Up .................................................................................................................................24
5.6
Criteria for Removal from Study..................................................................................................................24
6.
EXPECTED TOXICITIES, TOXICITY MONITORING, TOXICITY MANAGEMENT AND DOSING 
DELAYS/MODIFICATIONS...........................................................................................................................25
6.1
Expected Toxicities.........................................................................................................................................25
6.2
Toxicity Monitoring........................................................................................................................................27
6.3
Toxicity Management and Dosing Delays/Modifications ..............................................................................28
7.
DRUG FORMULATION AND ADMINISTRATION...................................................................................34
7.1
Abiraterone acetate ........................................................................................................................................34


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Pharmacy Storage Requirements..............................................................................................................................34
7.2
Prednisone .....................................................................................................................................................36
8.
CORRELATIVE/SPECIAL STUDIES ...........................................................................................................37
8.1
Data Analysis..................................................................................................................................................37
9.
STUDY CALENDAR ........................................................................................................................................39
10.
MEASUREMENT OF EFFECT ......................................................................................................................41
10.1 Antitumor Effect– Solid Tumors .....................................................................................................................41
10.2 Other Response Parameters...........................................................................................................................48
11.
ADVERSE EVENT REPORTING REQUIREMENT...................................................................................49
11.1 Definitions ......................................................................................................................................................49
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of the PI, it results in any of the 
following outcomes: .................................................................................................................................................50

Death ..............................................................................................................................................................50

A life-threatening AE......................................................................................................................................50
o
Life-threatening AE or life-threatening suspected adverse reaction: An AE or suspected adverse reaction is 
considered ‘‘life-threatening’’ if, in the view of the PI, its occurrence places the participant or subject at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. ....................................................................................................................50

Inpatient hospitalization or prolongation of existing hospitalization............................................................50
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. ....................................................................................................50
11.2 Procedures for AE and SAE Recording..........................................................................................................51
Recording should be done in a concise manner using standard, acceptable medical terms...................................51
The AE recorded should not be a procedure or a clinical measurement (i.e. a laboratory value or vital sign) but 
should reflect the reason for the procedure or the diagnosis based on the abnormal measurement. .....................51
Preexisting conditions that worsen in severity or frequency during the Study should also be recorded (a 
preexisting condition that does not worsen is not an AE)........................................................................................52
Further, a procedure or surgery is not an AE; rather, the event leading to the procedure or surgery is considered 
an AE. Any event requiring in-patient hospitalization that occurs during the course of a subject’s participation in 
a trial must be reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are:...........52

Reasons described in the Protocol, e.g. drug administration, Protocol-required testing..............................52

Surgery or procedure planned prior to entry into the Study..........................................................................52
If, in the PIs judgment, a clinical significant worsening from baseline is observed in any laboratory or other test 
parameter (e.g. EKG, angiogram), physical exam finding, or vital sign, a corresponding clinical AE should be 
recorded. ..................................................................................................................................................................52
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as the AE, 
whenever possible.  However, a complete description of the signs, symptoms and investigations which led to the 


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diagnosis should be provided. For example, if clinically significant elevations of liver function tests are known to 
be secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be recorded. If the cause is 
not known, the abnormal test or finding should be recorded as an AE, using appropriate medical terminology 
(e.g thrombocytopenia, peripheral edema, QT prolongation).................................................................................52
11.3 Reporting Requirements .................................................................................................................................52
11.4 Reporting to the  Sponsor Investigator...........................................................................................................53
11.5 Reporting to the IRB.......................................................................................................................................54
11.6 Reporting to the FDA .....................................................................................................................................55
11.7 Reporting to Hospital Risk Management .......................................................................................................55
11.8 Monitoring of AEs and Period of Observation...............................................................................................55
12.
DATA AND SAFETY MONITORING ...........................................................................................................57
12.1 Data Reporting ...............................................................................................................................................57
12.2 Safety Meetings...............................................................................................................................................57
12.3 Monitoring......................................................................................................................................................58
13.
REGULATORY CONSIDERATIONS ...........................................................................................................59
13.1 Protocol Review and Amendments .................................................................................................................59
13.2 Informed Consent ...........................................................................................................................................59
13.3 Ethics and Research Practices .......................................................................................................................59
13.4 Study Documentation......................................................................................................................................60
13.5 Records Retention...........................................................................................................................................60
13.6 Multi-Center Guidelines.................................................................................................................................60
14.
STATISTICAL CONSIDERATIONS .............................................................................................................62
14.1 Study Design/Endpoints..................................................................................................................................62
14.2 Analysis of Secondary Endpoints ...................................................................................................................63
Safety and tolerability associated with AA monotherapy and AA + prednisone for those with PSA progression 
on AA monotherapy will be evaluated separately. All participants who receive at least 1 dose of study 
drug will be included in these analyses. A summary of all Grade 1-4 treatment-related toxicities will be 
provided by toxicity type and maximum grade. The maximum grade consolidates the reports of a given 
type of toxicity for a participant over time by taking the maximum grade across time (i.e. a participant 
appears only once for a given type of toxicity). Participants with reports of multiple toxicities of 
different types are reported multiple times under the relevant toxicity categories. ‘Treatment-related’ 
toxicities are defined by an attribution as possible, probable or definite.  With 60 participants, the 
maximum width of a 90% CI for a given toxicity rate is 22%. Within a given metastatic status subgroup 
(n=30), the maximum width is 32%. The probability of observing at least one rare severe toxicity (true 
rate=5%) is 95% for the overall cohort and 78.5% within a metastatic status subgroup. The number of 
cycles completed with and without dose modifications and treatment delays as well as prednisone use 
will be tabulated overall and by metastatic status subgroup.........................................................................63
PSA response to AA monotherapy (and AA + prednisone for those with PSA progression on AA 
monotherapy) will be summarized as frequency and percent. Participants who are unevaluable for 
response will be included in the denominator as nonresponders when calculating the response rate. 
Duration of PSA response for the regimen of AA monotherapy (and AA + prednisone for those with 
PSA progression on AA monotherapy) will be defined relative to the first achievement of PSA response 


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and will be estimated using the method of Kaplan and Meier. The above analysis will also be performed 
within metastatic status subgroup....................................................................................................................64
Participants with measurable disease will be evaluated for response using RECIST 1.1 criteria. Time to 
progression of bone lesions or measurable disease will be estimated using Kaplan-Meier estimates. ......64
15.
PUBLICATION PLAN .....................................................................................................................................67
16.
REFERENCES...................................................................................................................................................68
17.
APPENDICES....................................................................................................................................................73
APPENDIX A: Performance Status Criteria ...........................................................................................................73
APPENDIX B: Required Forms at Registration .....................................................................................................73
APPENDIX C: Participant’s Pill Diary ..................................................................................................................73
APPENDIX D: Imaging Procedural Information and Measurement of Tumor Flare ............................................73
APPENDIX E: Data and Safety Monitoring Plan ...................................................................................................73
17.1 APPENDIX A: Performance Status Criteria..................................................................................................74
17.2 APPENDIX B: Required Forms at Registration............................................................................................75
17.3 APPENDIX C: PARTICIPANT’S PILL DIARY .............................................................................................76
17.4 APPENDIX D: Imaging Procedural Information and Measurement of Tumor Flare...................................77
17.5 APPENDIX E: Multi-Center Data and Safety Monitoring Plan....................................................................78
1.0
INTRODUCTION .............................................................................................................................................87
1.1
Purpose...........................................................................................................................................................87
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..........................................................................87
2.0
GENERAL ROLES AND RESPONSIBILITIES...........................................................................................88
2.1
DF/HCC Sponsor ...........................................................................................................................................88
2.2
Coordinating Center.......................................................................................................................................89
2.3
Participating Institution .................................................................................................................................89
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ........................................................90
3.1
Protocol Distribution......................................................................................................................................90
3.2
Protocol Revisions and Closures....................................................................................................................90
3.3
Informed Consent Requirements ....................................................................................................................90
3.4
IRB Documentation ........................................................................................................................................91
3.5
IRB Re-Approval ............................................................................................................................................91
3.6
Participant Confidentiality and Authorization Statement ..............................................................................91
3.7
DF/HCC Multi-Center Registration...............................................................................................................92
3.7.1 Participant Registration and Randomization.................................................................................................92
3.7.2 Initiation of Therapy.......................................................................................................................................93
3.7.3 Eligibility Exceptions......................................................................................................................................93


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3.7.4 Verification of Registration, Dose Levels, and Arm Designation ..................................................................93
3.8
DF/HCC Protocol Case Number....................................................................................................................94
3.9
Protocol Deviations, Exceptions and Violations............................................................................................94
3.9.1 Definitions ......................................................................................................................................................94
3.9.2 Reporting Procedures.....................................................................................................................................94
3.10 Safety Assessments and Toxicity Monitoring .................................................................................................95
3.10.1
Guidelines for Reporting Serious Adverse Events................................................................................95
3.10.2
Guidelines for Processing IND Safety Reports.....................................................................................96
3.11 Data Management ..........................................................................................................................................96
3.11.1
Data Forms Review...............................................................................................................................96
4.0
REQUISITIONING INVESTIGATIONAL DRUG.......................................................................................96
5.0
MONITORING: QUALITY CONTROL........................................................................................................97
5.1
Ongoing Monitoring of Protocol Compliance ...............................................................................................97
5.2
Evaluation of Participating Institution Performance.....................................................................................98
5.2.1 Monitoring Reports ........................................................................................................................................98
6.0
AUDITING: QUALITY ASSURANCE...........................................................................................................98
6.1
DF/HCC Sponsored Trials.............................................................................................................................98
6.2
Participating Institution .................................................................................................................................99
6.3
DF/HCC Sponsor and Coordinating Center..................................................................................................99
6.4
Sub-Standard Performance ............................................................................................................................99
6.4.1 Corrective Actions..........................................................................................................................................99
18.
APPENDIX F: STRONG CYP3A4 INDUCERS AND INHIBITORS .........................................................99


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1. OBJECTIVES
The primary objectives of this trial are to determine the incidence of mineralocorticoid 
toxicity, characterize symptoms of mineralcorticoid toxicity, and evaluate the need for 
exogenous glucocorticoids in participants treated with AA monotherapy for CRPC. A 
correlative aim is to assess clinical signs of mineralocorticoid toxicity with changes in serum 
ACTH and corticosteroid intermediates. Additionally, we will seek to assess the efficacy, in 
terms of PSA response, of the addition of prednisone to AA at PSA progression. Lastly, we 
will evaluate possible mechanisms of AA resistance via optional serial metastasis biopsies.
1.1
Study Design
1. This is a phase II, prospective, multicenter, single-arm study accessing safety of AA 
without exogenous glucocorticoids in participants with CRPC. Participants will be 
treated with AA in 28-day cycles. Participants will be monitored (weekly for the first 
two cycles, then on Day 1 of each subsequent cycle) for symptoms of persistent or 
severe mineralocorticoid excess (including hypertension, hypokalemia). Cycle 1 Day 8 
and 22 monitoring of cycle 1 can occur locally if preferred. For participants who 
experience symptoms of persistent or severe hypertension or hypokalemia as detailed 
in the above schema, prednisone 5 mg by mouth twice daily will be added. Specific 
management of symptoms of hypertension and hypokalemia after addition of 
prednisone is detailed in Section 6.3. Cycle 1 Day 15 mnoitoring must occur at the 
study institution and the participant must be seen by a study MD or NP. We will 
monitor for other symptoms of AA toxicity to include fluid retention and fatigue. 
Management of these symptoms is detailed in Section 6.3. For participations who 
tolerate AA monotherapy without the addition of prednisone to manage symptoms of 
persistent or severe mineralocorticoid excess, prednisone 5 mg by mouth twice daily 
will be added at PSA progression. Participants will be continued on study until 
radiographic progression or taken off study for another reason as detailed in Section 
5.4. Toxicity will be defined by NCI CTCAE (version 4). 
Participants will undergo optional pre-treatment and progression tumor biopsies. After 
the progression biopsy is performed, protocol therapy will be discontinued. Participants 
who stop protocol therapy before receiving four cycles of AA will not be asked to 
undergo the optional second biopsy.     
1.2
Primary Objectives
-
To determine the proportion of participants requiring the addition of prednisone to 
manage symptoms of persistent or severe mineralocorticoid excess. 
1.3
Secondary Objectives 


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-
To assess safety and tolerability associated with AA monotherpy and the addition of 
prednisone to AA. 
-
To determine the proportion of participants requiring the addition of prednisone to 
manage symptoms of severe fatigue. 
-
To assess changes in serum concentrations of corticosteroid intermediates between 
baseline and subsequent assessment visits.
-
To assess changes in serum concentrations of ACTH between baseline and 
subsequent assessment visits.
-
To assess changes in serum concentrations of androgen (including testosterone, DHT 
and androgen precursors) between baseline and subsequent assessment visits.
-
To assess changes in BMI and hemoglobin-A1c between baseline and subsequent 
assessment visits.
-
To assess PSA response and duration of PSA response to AA monotherapy. 
-
To assess PSA response and duration of PSA response to addition of prednisone to 
AA at time of PSA progression on AA monotherapy. 
-
To assess  response of measurable disease and time to progression of measurable 
disease to AA monotherapy. 
-
To assess response of measurable disease and time to progression of measurable 
disease to addition of prednisone to AA at time of PSA progression on AA 
monotherapy. 
-
To investigate subsequent lines of therapy, including line of agent, name of agent, 
and PSA kinetics following study drug discontinuation and to correlate with 
response to study drug.
1.4
Exploratory Objectives 
-
To analyze possible mechanisms of AA resistance in serial CRPC metastasis 
biopsies (including AR expression by IHC, AR regulated gene expression by IHC, 
tissue androgen levels by mass spectrometry, and whole-exome and transcriptome 
sequencing).
-
To measure CTCs as a marker of response/resistance to abiraterone. 
-
To analyze CTCs for mechanisms of AR resistance including AR nuclear 
localization, AR splice variant expression and AR sequence.


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-
To analyze circulating tumor DNA for mechanisms of AR resistance and correlate to 
response to abiraterone.


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2.
BACKGROUND
2.1
Study Agent(s)
2.1.1
Abiraterone acetate (JNJ212082)
Abiraterone (17-(3-pyridyl)androsta-5,16-dien-3β-ol) is a rationally designed, 
inhibitor of CYP17. Key design features of this compound include the 3-pyridyl 
substitute, resulting in more potent inhibition of CYP17, and 16,17-double bond, 
which is essential for irreversible inhibition of CYP17.[1, 2] CYP17 is a key 
enzyme in cortisol synthesis via its 17α-hydroxylase activity and plays a central 
role in androgen biosynthesis via its 17,20-lyase activity (Figure 1).[3] Abiraterone 
is a potent inhibitor with an apparent inhibition constant of 0.5 nM.[2] 
Figure 1. The pro-drug AA is converted to abiraterone after absorption. 
Abiraterone has poor bioavailability. AA is the 3-acetylated analog and pro-drug 
of abiraterone suitable for oral administration (Figure 2). The chemical 
nomenclature of AA is 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene. Its 
empirical formula is C26H33NO2 and it has a molecular weight of 391.55. Once 
absorbed after oral administration, AA is rapidly deacetylated and converted to 
the active form abiraterone. Abiraterone is metabolized by CYP3A4 and is an 
inhibitor of CYP2D6.[4]


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Figure 2. The steroid biosynthesis pathway. Abiraterone inhibits 17α-hydroxylase 
(crossed in red) which results in reduction of serum cortisol and consequent 
increase in ACTH that drives the steroid biosynthesis pathway. Abiraterone also 
inhibits 17,20-lyase (crossed in red) resulting in significant suppression of DHEA, 
androstenedione, and testosterone. Dehydroepiandrosterone sulfate, DHEA-S; 
Dehydroepiandrosterone, DHEA; Dihydrotestosterone, DHT; ST, 
sulfotransferase; STS, steroid sulfatase. 
Physiologic Rational for Safety of Inhibition of CYP17
Congenital CYP17 deficiencies result in a rare form of congenital adrenal 
hyperplasia, which cause impaired adrenal and gonadal steroidogenesis.[3] 
Although the production of cortisol, androgens, and estrogens is impaired, 
corticosterone synthesis is unaffected. Given that corticosterone is a weak 
glucocorticoid, patients do not develop adrenal insufficiency, though they have 
higher levels of ACTH. Raised levels of ACTH result in increased steroid 
precusors upstream of CYP17 which results in a syndrome of mineralocorticoid 
excess, characterized by fluid overload, hypertension, and hypokalemia. This 
syndrome may be effectively managed with mineralocorticoid antagonists with or 
without low doses of glucocorticoids to suppress ACTH production.[5] 
Rational for Using Abiraterone Acetate in Prostate Cancer 
Ketoconazole, a weak and nonspecific CYP17 inhibitor, is commonly used in 
clinical practice. Ketoconazole, an imidazole antifungal agent, inhibits several 
enzymes in the steroid biosynthesis pathway including desmolase and 11β-
hydroxylase, in addition to CYP17.[6] When administered at a dose of 400 mg 
three times daily, ketoconazole reduced testosterone, androstenedione and 
DHEA.[7]
Numerous phase II studies have demonstrated that treatment with ketoconazole 
resulted in PSA response rates (defined as a ≥50% decrease in PSA levels from 
baseline) ranging from 40-62% with median duration of response lasting between 
3.3-7 months.[5] In the CALGB 9583 phase III trial comparing androgen 
withdrawal to androgen withdrawal plus ketoconazole, response rates were 11 and 


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27%, respectively (p=0.02), however there was no difference in overall survival 
between the two groups, which may reflect 82% crossover rate.[8] 
Treatment with ketoconazole has been limited by toxicity. In the phase III 
CALGB trial, grade 3 and 4 toxicity was reported in 21% of patients and 
comprised primarily fatigue, and hepatic, neurologic or respiratory issues. Other 
limitations include multiple drug interactions that limit its use in patients with 
comorbidities. Additionally, it requires frequent daily dosing and hydrocortisone 
daily for glucocorticoid replacement. 
The development of a therapy with once daily administration, limited drug-drug 
interactions, that lacks a requirement for concomitant corticosteroids would 
represent a significant advancement in the management of CRPC and desirable 
alterative to therapy with ketoconazole.
Clinical Data with Abiraterone Acetate
AA has been tested in patients in phase I, II and III trials. Below we will 
summarize the results of these trials with a focus on safety and efficacy (Table 1). 
Table 1. Summary of clinical trials of Abiraterone Acetate. 
Study
Patient
Drug
Efficacy
Toxicity
Phase 1 
Attard et al 
(2008)[9]
21
Chemo-naive
Keto-naive
(non-
metastatic 
and 
metastatic)
AA 250-
2000 mg 
daily, fasting, 
5 dose 
escalations
Increased ACTH, 
upstream steroids; 
decreased 
testosterone, 
downstream 
androgenic steroids; 
PSA decline to 
≥30%, 50%, and 90% 
were 66%, 57%, and 
29%, respectively; 
Median TTPP 69 to ≥ 
578 days; 62% partial 
RECIST response 
Hypertension 
(29%), 
hypokalemia 
(48%), lower-limb 
edema (5%); No 
grade 3 or 4 
toxicities; 
Precipitation of 
migraine and 
asthma, 1 patient 
each, both of 
whom required 
dexamethasone
Phase I 
Ryan et al 
(2010)[10]
33 
Chemo-naive
Keto-naive 
(14) (non-
metastatic 
and 
metastatic)
AA 250-
1000 mg 
daily, fed and 
fasting 
cohorts, 4 
dose 
escalations
Decreased 
testosterone, 
downstream, 
androgenic steroids; 
PSA decline ≥50% at 
week 12 in 55% 
(47% vs. 64% prior 
keto vs. no keto); 
Median TTPP 234 
days (283 vs. 230 
days prior keto vs. no 
keto)
Hypertension 
(36%), 
hypokalemia 
(24%), peripheral 
edema (24%), 
fatigue (67%), 
headache (33%), 
nausea (33%), 
diarrhea (30%); 
Grade 3 
hypertension 


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(12%), grade 3/4 
hypokalemia (9%)
Phase II
Attard et al 
(2009)[11] 
42 
Chemo-naive 
(non-
metastatic 
and 
metastatic)
AA 1000 mg 
daily, fasting
PSA decline ≥50% 
observed in 67% 
(≥90% observed in 
19%); Median TTPP 
225 days; 38% partial 
RECIST response; 
CTC declined to 
<5/7.5 mL in 59%; 
33% from phase I/II 
had reversal of 
resistance with 
dexamethasone
Hypertension 
(40%), 
hypokalemia (8%), 
fluid overload 
(31%); Managed 
with eplerenone 
except in 3 
patients who 
required 
dexamethasone 
Phase II
Danila et al 
(2010)[12]
58 
Chemo-
treated 
Keto-naive 
(27) 
(metastatic 
only)
AA 1000 mg 
daily 
(fasting) + 
prednisone 5 
mg twice 
daily
PSA decline to 
≥30%, 50%, and 90% 
were 47%, 36%, and 
16%, respectively 
(PSA decline ≥50% 
26% vs. 45% prior 
keto vs. no keto); 
Median TTPP 169 
days (99 vs. 198 prior 
keto vs. no keto); 
18% partial RECIST 
response; CTC 
declined <5/7.5 mL 
in 34% 
Hypertension 
(4%), hypokalemia 
(5%), peripheral 
edema (9%), 
abnormal LFTs 
(15%); No grade 
3/4 hypertension, 
hypokalemia, 
peripheral edema; 
No use of 
eplerenone 
Phase II
Reid et al 
(2010)[13]
47 
Chemo-
treated 
(metastatic)
AA 1000 mg 
daily, fasting
PSA decline to 
≥30%, 50%, and 90% 
were 68%, 51%, and 
15%, respectively; 
Median TTPP 169 
days; 27% partial 
RECIST response; 
CTC declined <5/7.5 
mL in 45%
Hypokalemia 
(55%), 
hypertension 
(17%), fluid 
retention (25%); 
Grade 3 
hypokalemia (2%)
Phase III
de Bono et al 
(2011)[14]
1195 
Chemo-
treated 
(metastatic 
only) 
AA 1000 mg 
daily versus 
placebo 
(fasting) + 
prednisone 5 
mg twice 
daily
AA-prednisone vs. 
placebo-prednisone 
median OS 14.8 vs. 
10.9 months 
(p<0.001), TTPP 10.2 
vs. 6.6 months 
(p<0.001), PFS 5.6 
vs. 3.6 months 
AA-prednisone vs. 
placebo-
prednisone 
hypertension 10% 
vs. 8%, 
hypokalemia 17% 
vs. 8%, fluid 


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(p<0.001), PSA 
response rate 29% vs. 
6% (p<0.001)
retention 31% vs. 
22%
Phase III
Ryan et al 
(2012)[15]
1088
Chemo-naive 
(metastatic 
only)
AA 1000 mg 
daily versus 
placebo 
(fasting) + 
prednisone 5 
mg twice 
daily (2:1)
AA-prednisone vs. 
placebo-prednisone 
median OS NR vs. 
27.2 months 
(p=0.01), PFS 16.5 
vs. 8.3 months 
(p<0.001), median 
time-to-opiate use 
NR vs. 23.7 months 
(p<0.001), median 
time to initiation of 
cytotoxic 
chemotherapy 25.2 
vs. 16.8 months 
(p<0.001), median 
time to decline in 
performance status 
12.3 vs. 10.9 months 
(p=0.005), median 
TTPP 11.1 vs. 5.6 
months (p<0.001)
AA-prednisone vs. 
placebo-
prednisone 
hypertension 22% 
vs. 13%, 
hypokalemia 17% 
vs. 13%, fluid 
retention 28% vs. 
24%, increased 
ALT 12% vs. 5%, 
increased AST 
11% vs. 5%, 
cardiac disorder 
19% vs. 16%
AA = abiraterone acetate; keto = ketoconazole; chemo = chemotherapy; ACTH = 
adrenocorticotropic hormone; PSA = prostate specific antigen, TTPP = time-to-PSA progression; 
CTC = circulating tumor cells; LTs = liver function tests; OS = overall survival; PFS = 
progression-free survival; ALT = alanine transaminase; AST = aspartate transaminase. 
Early phase I studies showed good bioavailability at doses of greater than 200 mg, 
a half-life of approximately 28 hours, and significant increased absorption with 
food.[16] The initial studies included men who were not on LHRH agonist. In this 
population, a compensatory surge in luteinizing hormone led to an increase in 
testosterone by day 4 of treatment with AA in some men, suggesting the need for 
AA to be given concomitantly with suppressed testicular function.
A Phase I/II study evaluated AA in chemotherapy-naive men with CRPC resistant 
to multiple prior hormone therapies.[9, 11] The phase I study (n=21) evaluated 
once, daily, continuous AA, which escalated through five doses (250-2,000 mg) 
in three-patient cohorts. In this study, AA was well tolerated. There were no 
treatment related grade 3 and grade 4 toxicities. Hypertension, hypokalemia, and 
lower-limb edema was observed in 29%, 48%, and 5% patients, respectively. 
These side effects were controlled with eplerenone, a selective mineralocorticoid 
receptor antagonist. AA was associated with increased levels of ACTH (5-fold) 
and steroids upstream of CYP17 (10-40-fold) with suppression of serum 
testosterone (<1 ng/dl), downstream androgenic steroids, and estradiol in all 
patients. Declines in PSA ≥30%, 50%, and 90% were observed in 14 (66%), 12 


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(57%), and 6 (29%) patients, respectively and lasted between 69 to ≥ 578 days. 
Five (62%) of eight patients with measurable disease at baseline had confirmed 
partial response by RECIST. The addition of dexamethasone 0.5 mg/d resulted in 
salvage of 4/15 patients who had PSA progression. 
The phase II expansion of this study included 42 patients.[11] A decline in PSA of 
≥50% was observed in 67% of patients and declines of ≥90% were observed in 
19% of patients. The median TTPP was 225 days. Of the 24 patients with 
measurable disease, 38% experienced partial response by RECIST. Decreases in 
CTC counts were documented (decline to <5/7.5 mL in 59% of patients). In an 
exploratory analysis of all 54 patients in the phase I/II trial, addition of 
dexamethasone at PSA progression reversed resistance in 33% of patients. In long 
term follow up, after all patients were discontinued from therapy with AA, 38/42 
(90%) patients experienced signs of mineralocorticoid excess including 
hypertension, hypokalemia, and peripheral edema. This was effectively treated 
with eplerenone without exogenous glucocorticoids in 35/38 (92%) patients. Only 
3/38 (5%) patients required administration of exogenous glucocorticoids 
(dexamethasone 0.5 mg daily). The median time to initiation of eplerenone was 
28 days. 
Two phase II studies in post-docetaxel CRPC patients have also been 
conducted.[12, 13] PSA declines of ≥50% occurred in 22/58 (36%) and 24/47 (51%) 
patients, respectively, with the median TTPP of 169 days for both studies. Partial 
responses were seen in 4/22 (18%) and 8/30 (27%) patients with RECIST-
evaluable target lesions, respectively. 
The efficacy of AA was demonstrated in a phase III trial in which 1,195 men 
previously treated with docetaxel were randomly assigned to AA plus prednisone 
or placebo plus prednisone.[14] After a median follow-up of 13 months, AA 
significantly increased OS (median 14.8 versus 10.9 months, p<0.0001), time to 
PSA progression (10.2 versus 6.6 months, p<0.0001), radiographic PFS (5.6 
versus 3.6 months, p<0.001), and PSA response rate (29% versus 6%, p<0.001) 
compared with placebo plus prednisone. Based on this trial, AA plus prednisone 
was approved by the FDA in April 2011 for the treatment of patients with 
metastatic CRPC following docetaxel.[14] 
A randomized, phase III study evaluated AA in chemotherapy-naive patients with 
metastatic CRPC. The trial showed that treatment with AA plus prednisone 
produced a statistically significant improvement in radiographic PFS (16.5 vs. 8.3 
months, p<0.001) and a strong trend for increased OS (NR vs. 27.2 months, HR 
0.75, 95% CI 0.61-0.93, p=0.01) over placebo plus prednisone. Based on the 
results of this trial, In December 2012, the FDA expanded the indication for AA 
plus prednisone for the treatment of patients with chemotherapy-naive metastatic 
CRPC. On February 7, 2018, abiraterone acetate received FDA approval for use, 
incombination with prednisone, for the treatment of patients with metastatic, high-
risk castration-sensitive prostate cancer (CSPC).


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Clinical Safety Data
The most common AEs related to AA monotherapy, as detailed by the 
aforementioned clinical trials, include fatigue as a result of reduced serum cortisol 
secondary to CYP17 inhibition and hypertension, fluid retention, and 
hypokalemia secondary to mineralocorticoid excess caused by compensatory high 
levels of ACTH. Two phase I and two phase II trials evaluated the safety of AA 
without exogenous glucocorticoids. The rates of hypertension, fluid retention, and 
hypokalemia are detailed in Table 1. In general, symptoms of mineralocorticoid 
excess were managed with eplerenone, a selective mineralocorticoid receptor 
antagonist, or other agents including beta-blockers or diuretics. Exogenous 
glucocorticoids were occasionally used to manage symptoms of mineralocortcoid 
excess. 
Treatment with AA is also associated with LFT abnormalities. In the post-
docetaxel phase III trial, rates of LFT abnormalities were 10% vs. 8% and in the 
AA-prednisone vs. placebo-prednisone, respectively. In the chemotherapy-naive 
phase III trial, increased ALT and AST (12% vs. 5% and 11% vs. 5% for all 
grades) was noted in the AA-prednisone vs. placebo-prednisone arm, respectively.
Pharmacokinetics of Abiraterone Acetate 
Pharmacokinetics were evaluated in two phase I trials and are detailed in table 
2.[9, 10] In the Attard et al study, a plateau of endocrine effects was reported at 
doses >750 mg, and 1000 mg was selected as the dose for phase II evaluation. 
There were significant variations in the AUC and Cmax among patients. When 
administered with food high in fat content, drug exposure increased 4.4 fold 
compared to fasting. There was no significant increase in Cmax, but absorption was 
significantly extended after food. In the Ryan et al study, Cmax was achieved 
within 1.5-5 hours.[10] Less than proportional increases in both Cmax and AUC 
were observed across dose levels in fed and fasted patients.


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Table 2. Abiraterone Acetate Pharmacokinetics Parameters.
Parameter
Abiraterone acetate
Absorption
Systemic absorption (Cmax and AUC) increases with 
increasing fat content of meals. The AUC was 
approximately 5-fold higher when administered with a 
low-fat meal, and approximately 10-fold higher when 
administered with a high-fat meal. Due to normal 
variation and composition of meals, no food should be 
consumed for at least 2 hours before the dose of AA and 
for at least one hour after the dose.
Metabolism
Following oral administration, AA is hydrolyzed to 
abiraterone (active metabolite) through esterases and not 
CYP.  The 2 main circulating metabolites are 
abiraterone sulphate (inactive; formed via SULT2A1) 
and N-oxide abiraterone sulphate (inactive; formed via 
CYP3A4 and SULT2A1).
Elimination
88% recovered in feces and 5% in urine (55% as 
unchanged AA, 22% as abiraterone).
Half-life
Mean terminal half-life= 12 ±5 hours.
Protein 
Binding
Highly protein bound (>99%); it is not a substrate for 
but is an inhibitor of P-glycoprotein.
2.2
Study Disease
Prostate cancer is the most common cancer in men in the United States, with a life time 
risk of 16%, and the second leading cause of death in this population.[17] In 2012, it is 
estimated that 241,740 men will be diagnosed with prostate cancer and 28,170 will die 
of the disease.[17] 
ADT is the mainstay of systemic therapy for patients with prostate cancer. In patients 
with advanced disease, despite initial response rates of 80-90%, nearly all men develop 
progressive disease within 18-24 months of therapy.[18] Men with CRPC have a poor 
prognosis with median survival of 16-18 months and fewer than 20% of patients 
surviving beyond three years.[19] 
2.3
Rationale
In the castrate state, ligands to the AR have been thought to be derived from the 
adrenal glands and intra-tumoral androgen production, which is thought to play a 
critical role in disease progression.[18] ADT removes 90% of circulating androgens, 


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mainly produced in the gonads, however as much as 10% of circulating testosterone 
remains in part due to the peripheral conversion of adrenal steroids to testosterone. 
Furthermore, in patients with castrate levels of testosterone, tissue levels of androgens 
remain sufficient to activate the AR. Additional mechanisms of resistance to castration 
include: 1) increased AR expression leading to activation in the presence of low levels 
of ligand, 2) AR gene mutations leading to promiscuous activation of AR signaling by 
various ligands, 3) AR splice variants leading to constitutive activation of AR 
signaling, and 4) increased intra-tumor expression of enzymes involve in 
steroidogenesis.[6, 8, 20]
Inhibition of extratesticular sources of androgens is a desirable therapeutic strategy in 
the management of men with prostate cancer. CYP17, via its 17,20-lyase activity, plays 
a crucial role in androgen biosynthesis and is considered a key therapeutic target. AA is 
a selective and irreversible inhibitor of CYP17 which has demonstrated clinical 
efficacy in patients with CRPC. 
Currently AA is administered with concomitant prednisone. Point mutations of the AR, 
which appear to cluster in the ligand-binding domain, are rare in therapy naive patients 
but occur in 15-45% of castration-resistant disease and can increase AR affinity for a 
wide range of steroids.[21] Richards et al recently demonstrated that treatment with 
exogenous glucocorticoids in vitro can activate mutant AR at clinically relevant doses 
observed in CRPC patients treated with AA and therefore could serve as a mechanism 
of resistance to AA.[22] 
In addition, numerous toxicities have been attributed to glucocorticoids, including 
dermatologic toxicity, ocular toxicity, gastritis and peptic ulcer disease, osteoporosis, 
hypokalemia and fluid shifts, neuropsychiatric issues, hyperglycemia, lipid 
abnormalities, and increased infections. Estimates of the frequency and severity of 
AEs, as well as the respective dose and duration of therapy that may result in such 
AEs, are limited by the modest number of prospective trials that address this question. 
Several large retrospective reviews (conducted in patients with rheumatoid arthritis on 
chronic low-dose steroids) have shown that long-term glucocorticoid use, even in low 
doses, is a significant independent predictor of numerous SAEs and that risk is both 
dose and time dependent.[23, 24] Given that prostate cancer disproportionately affects the 
elderly (with the highest incidence rates seen in those aged 70 to 80 years of age), who 
frequently suffer from multiple co-morbid medical conditions (with rates of multi-
morbidity at 35% in Americans aged 65-79 and 70% in those ≥80 years), therapy with 
chronic glucocorticoids may be associated with increased toxicity in this population. 
Given the potential toxicity associated with chronic glucocorticoids and the potential 
for glucocorticoids to activate promiscuous AR, we propose to evaluate the safety 
profile of AA monotherapy without the administration of exogenous glucocorticoids. 
2.4
Correlative Studies Background


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Treatment with AA results in elevated levels of upstream intermediates to CYP17. Based 
on phase I data, treatment with AA monotherapy results 5-fold increases in ACTH, 
which provides a positive drive for mineralocorticoid biosynthesis.[9] This results in a 10-
fold increase in deoxycorticosterone and 40-fold increase in corticosterone.[9] Given 
symptoms of mineralocorticoid excess including hypertension, hypokalemia, and volume 
overload, renin is suppressed, providing a negative feedback to decrease aldosterone 
production. In a phase II study, treatment with AA resulted in a marked rise in urinary 
metabolites of steroids upstream of CYP17.[25] In this study, there was no evidence of a 
difference in mean urinary excretion of mineralocorticoid precursor metabolites and the 
dose of eplerenone required to control toxicity. In this study, we hypothesize that 
baseline and on treatment serum ACTH and mineralocorticoid intermediates may predict 
risk for developing mineralocorticoid toxicity. 
Given that AR signaling continues to play a critical role in prostate cancer progression, 
we plan to analyze possible mechanisms of AA resistance in serial CRPC metastasis 
biopsies. AA treatment has been associated with upregulated intratumoral CYP17 and 
increased expression of AR splice variants.[26] Our laboratory has established techniques 
for measuring AR signaling using gene expression profiling.[27] Additionally we are 
able to measure intracellular testosterone and DHT levels using mass spectrometry.[28, 
29] 


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3.
PARTICIPANT SELECTION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following sections. If there is a question about the inclusion or exclusion criteria, the 
investigator should consult 
 and the DFCI study team before 
enrolling the subject in the study. 
3.1
Eligibility Criteria
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study:
3.1.1
Be a male ≥ 18 years of age.
3.1.2
Participants must have histologically or cytologically confirmed adenocarcinoma of 
the prostate without >50% neuroendocrine differentiation or small cell histology.  
3.1.3
Participants must have progressive disease as defined by one or more of the 
following: 

Castrate resistant disease as defined by PCWG2.[30] Participants must have 
a rise in PSA on two successive determinations at least one week apart and 
PSA levels ≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml) and 
testosterone levels < 50 ng/dL.

Soft tissue progression defined by RECIST 1.1.

Bone disease progression defined by PCWG2 with two or more new 
lesions on bone scan.[30]
3.1.4
Participants without orchiectomy must be maintained on LHRH agonist/antagonist 
therapy.
3.1.5
Participants must have a testosterone level < 50 ng/dL. 
3.1.6
Participants may have had any number of previous hormonal therapies 
(antiandrogens including enzalutamide, estrogens, finasteride, dutasteride, 
ketoconazole) provided these were discontinued ≥ 4 weeks before starting the trial. 
Prior therapy with steroids is allowed though these must be discontinued ≥ 2 weeks 
before starting the trial. Inhaled, topical, and intra-articular steroids are allowed. 
3.1.7
Participants may have had up to two previous cytotoxic therapeutic regimens 
provided these were discontinued ≥ 4 weeks before starting the trial. 
3.1.8
At least a 4 week interval from previous prostate cancer treatment other than LHRH 
agonist/antagonist therapy, bisphosphonates, denosumab to the start of protocol 
therapy. 


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3.1.9
Participants receiving bisphosphonates therapy or denosumab can be maintained on 
this therapy. If participants have not started bisphosphonates, it is recommended 
that they start treatment after the first (optional) biopsy.
3.1.10 ECOG performance status < 2 (Karnofsky >60%, see Appendix A). 
3.1.11 Participants must have normal organ and marrow function as defined below:

Platelets > 50,000/mcL

Serum or plasma potassium ≥ 3.5 mmol/L or Institutional LLN 
(independent of potassium supplementation)

Serum albumin ≥ 3.0 g/dL

AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN 

PTT ≤ 60, INR ≤ 1.5 Institutional ULN unless on warfarin therapy 
(investigator would need to determine if safe for participant to stop 
warfarin prior to (optional) biopsy)
3.1.12 Controlled blood pressure (systolic blood pressure <140 and diastolic blood 
pressure <90) on no more than three anti-hypertensive agents. Drug formulations 
containing two or more anti-hypertensive agents will be counted based on the 
number of active agents in each formulation.
3.1.13 Left ventricular ejection fraction ≥ 50%.
3.1.14 Have signed an informed consent document indicating that the subjects understands 
the purpose of and procedures required for the study and are willing to participate in 
the study.
3.1.15 Be willing/able to adhere to the prohibitions and restrictions specified in this 
protocol.
3.1.16 Written Authorization for Use and Release of Health and Research Study 
Information (US sites only) has been obtained.
3.1.17 Able to swallow the study drug whole as a tablet.
3.1.18 Willing to take AA on an empty stomach; no food should be consumed at least two 
hours before and for at least one hour after the dose AA is taken.
3.1.19 Participants who have partners of childbearing potential must be willing to use a 
method of birth control with adequate barrier protection as determined to be 
acceptable by the PI during the treatment period and for 1 week after last dose of 
AA.


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3.2
Exclusion Criteria
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study.
3.2.1
Uncontrolled illness including, but not limited to ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study 
requirements or would make prednisone/prednisolone (corticosteroid) use 
contraindicated.
3.2.2
Clinically significant heart disease as evidenced by myocardial infarction, or 
arterial thrombotic events in the past 6 months, severe or unstable angina, or NYHA 
Class III or IV heart disease or cardiac ejection fraction measurement of < 50 % at 
baseline.
3.2.3
Thromboembolism within 6 months of Cycle 1, Day 1. 
3.2.4
Severe hepatic impairment (Child-Pugh Class C). 
3.2.5
History of pituitary or adrenal dysfunction.
3.2.6
Poorly controlled diabetes. 
3.2.7
History of gastrointestinal disorders (medical disorders or extensive surgery) which 
may interfere with the absorption of the study drug. 
3.2.8
Have a pre-existing condition that warrants long-term corticosteroid use. Inhaled 
steroids are allowed. 
3.2.9
Individuals with a history of a different malignancy are ineligible except for the 
following circumstances: 1) individuals with a history of other malignancies are 
eligible if they have been disease-free for at least 5 years and are deemed by the 
investigator to be at low risk for recurrence of that malignancy, or 2) individuals 
with the following cancers are eligible if diagnosed and treated within the past 5 
years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin.
3.2.10 Known brain metastasis.
3.2.11 Prior therapy with AA. 
3.2.12 Have known allergies, hypersensitivity, or intolerance to AA or prednisone or their 
excipients. 
3.2.13 Surgery or local prostatic intervention within 4 weeks of the first dose. In addition, 
any clinically relevant issues from the surgery must have resolved prior to Cycle 1, 
Day 1.


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3.2.14 Major surgery or radiation therapy within 4 weeks of Cycle 1, Day 1.
3.2.15 Strontium-89, samarium-153, or radium-223 therapy within 4 weeks of Cycle 1, 
Day 1. 
3.2.16 Radiotherapy, chemotherapy or immunotherapy within 4 weeks, or palliative 
radiation to bone metastases within 14 days of administration of Cycle 1, Day 1.
3.2.17 Current enrollment in an investigational drug or device study or participation in 
such a study within 4 weeks of Cycle 1, Day 1.
3.2.18 Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not 
resolved to a NCI CTCAE (version 4) grade of ≤ 1. Chemotherapy induced 
alopecia and grade 2 peripheral neuropathy are allowed. 
3.2.19 Condition or situation which, in the investigator’s opinion, may put the participant 
at significant risk, may confound the study results, or may interfere significantly 
with participant’s participation in the study.
3.2.20 Individuals not willing to comply with the procedural requirements of this protocol.
3.2.21 HIV-positive individuals on combination antiretroviral therapy are ineligible 
because of the potential for pharmacokinetic interactions with AA.
3.3
Inclusion of Minorities and Other Underrepresented Populations
Every effort will be made to include men from minority populations. The enrollment of 
minority men will reflect the proportion of minority participants at the sites 
participating in the trial.


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4.
REGISTRATION PROCEDURES
  
4.1
General Guidelines for DF/HCC and DF/PCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2
Registration Process for DF/HCC and DF/PCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) must be followed.  
4.3
General Guidelines for Other Participating Institutions
Eligible participants will be entered on study centrally at the DFCI by the Study 
Coordinator. All sites should call the DFCI Study Coordinator to verify treatment 
availability.
Following registration, participants should begin protocol treatment within 14 days. 
Issues that would cause treatment delays should be discussed with the Overall PI.  If a 
participant does not receive protocol therapy following registration, the participant’s 
registration on the study may be canceled.  The Study Coordinator should be notified of 
cancellations as soon as possible.
4.4
Registration Process for Other Participating Institutions
To register a participant, the following documents should be completed by the research 
nurse or data manager and faxed to
 or e-mailed to the Study 
Coordinator:

Copy of forms specified in Appendix B

Signed participant consent form

HIPAA authorization form


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The research nurse or data manager at the participating site will then call or e-mail e-mail the 
Study Coordinator to verify eligibility.  To complete the registration process, the Coordinator 
will follow DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject 
Protocol Registration (SOP #: REGIST-101) and register the participant on the protocol.  The 
coordinator will fax or e-mail the participant study number, and if applicable the dose treatment 
level, to the participating site.  The coordinator will also call the research nurse or data manager 
at the participating site and verbally confirm registration


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5.
TREATMENT PLAN 
All protocol required therapy will be prescribed by prescription and taken by the participant 
on an outpatient basis. Participants will be treated with four 250 mg tablets (1,000 mg) of AA 
taken orally. No food should be consumed for at least two hours before the dose and for at 
least one hour after the dose. The tablets should be swallowed whole with water. Tablets 
should not be crushed or chewed.  All participants without orchiectomy will be maintained on 
LHRH agonist/antagonist therapy. 
Participants will be treated with AA in 28-day cycles. Participants will be monitored 
(weekly for the first cycle, then on Day 1 of each subsequent cycle) for symptoms of 
persistent or severe mineralocorticoid excess (including hypertension, hypokalemia). Cycle 
1 Day 8, and 22 monitoring of cycle 1can occur locally if preferred. Cycle 1 Day 15 
monitoring must occur at the study institution and the participant must be seen by a study 
MD or NP. For participants who experience symptoms of persistent or severe hypertension 
or hypokalemia as detailed in the above schema, prednisone 5 mg by mouth twice daily will 
be added. Specific management of symptoms of hypertension and hypokalemia after 
addition of prednisone is detailed in Section 6.3. We will monitor for other symptoms of AA 
toxicity to include fluid retention and fatigue. Management of these symptoms is detailed in 
Section 6.3. For participations who tolerate AA monotherapy without the addition of 
prednisone to manage symptoms of persistent or severe mineralocorticoid excess, 
prednisone 5 mg by mouth twice daily will be added at PSA progression. Participants will 
be continued on study until radiographic progression or taken off study for another reason as 
detailed in Section 5.4. Toxicity will be defined by NCI CTCAE (version 4). 
Participants may undergo an optional pre-treatment and/or progression tumor biopsy.  The 
optional pre-treatment biopsy will be after registration to the trial and prior to starting 
protocol therapy.  If a progression biopsy is done, it should be performed before protocol 
therapy is discontinued. 
Expected toxicities and potential risks as well as dose modifications for AA monotherapy 
are described in Section 6 (Expected Toxicities and Dosing Delays/Dose Modifications). No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant’s malignancy. 


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Treatment Description
Agent
Pre-medications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Abiratereone acetate
No food should be 
consumed for at 
least two hours 
before the dose 
and for at least one 
hour after the 
dose. The tablets 
should be 
swallowed whole 
with water.  Do 
not crush or chew 
tablets.
1000 mg
Oral
Once daily
Prednisone*
*Prednisone will 
only be added to 
manage symptoms of 
mineralocorticoid 
excess or at PSA 
progression. 
Take with food 
5 mg
Oral
Twice daily
28 days
5.1
Pre-treatment Criteria
  
5.1.1
For Cycle 1, Day 1, the following parameters must be met:

Serum or plasma potassium ≥ 3.5 mmol/L or Institutional LLN 
(independent of potassium supplementation)

AST/ALT ≤ 1.5 x Institutional ULN

Total bilirubin ≤ 1.5 x Institutional ULN

Systolic blood pressure < 140 mmHg or diastolic blood pressure < 90 
mmHg
If these parameters are not met, the participant can be evaluated on a weekly 
basis. Hypertension should be treated as appropriate. 
For subsequent cycles, refer to dose modifications as outlined in Section 6. 
5.2
Agent Administration 
5.2.1
Abiraterone acetate 


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
Administration: 1,000 mg orally once daily. Treatment can continue until 
evidence of radiographic progression or the participant is taken off the 
study for another reason as detailed in Section 5.4. 

Dosing: 1,000 mg orally taken once daily as four 250 mg tablets. Possible 
dose modifications are outlined in Section 6. 

Vital Signs: Vital signs including blood pressure, pulse, weight and 
temperature should be taken on day 1 of each cycle, and at the time of any 
symptom evaluation. For the first two cycles, blood pressure will be 
checked weekly and then on day 1 of each subsequent cycle.

Oral Doses: AA must be taken on an empty stomach. No food should be 
consumed for at least two hours before the dose of AA is taken and for at 
least one hour after the dose of AA is taken. AA Cmax and AUC0-∞ 
(exposure) were increased up to 17- and 10-fold higher, respectively, 
when a single dose of AA was administered with a meal compared to a 
fasted state. The safety of these increased exposures when multiple doses 
of AA are taken with food has not been assessed. 
If a dose is skipped, missed or vomited, it should not be taken (or retaken 
if vomited) on the day of the missed dose but dosing should be resumed 
the following day. Doses should be taken no later than 12 hours after the 
scheduled time for dosing. Participants will be asked to record actual 
dosing in a drug diary (Appendix C). There is no specified order of 
administration of the study drugs prescribed in this protocol.
5.2.2
Prednisone 

Administration when required per protocol: 5 mg orally twice daily. 
Treatment can continue until evidence of radiographic progression or the 
participant is taken off the study for another reason. 

Dosing when required per protocol: 5 mg orally twice daily. Dose 
modification is not allowed. 

Vital Signs: Vital signs including blood pressure, pulse, weight and 
temperature should be taken on day 1 of each cycle, and at the time of any 
symptom evaluation. For the first two cycles, blood pressure will be 
checked weekly and then on day 1 of each subsequent cycle.

Oral Doses: Prednisone should be taken with a meal. If a dose is skipped, 
missed or vomited, it should not be taken (or retaken if vomited) on the 
day of the missed dose but dosing should be resumed the following day. 
Doses should be taken no later than 12 hours after the scheduled time for 
dosing. Participants will be asked to record actual dosing in a drug diary. 




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
Radiographic disease progression

Intercurrent illness that prevents further administration of treatment 

Unacceptable AE(s)

Participant decided to withdraw from the study

General or specific changes in the participant’s condition render the 
participant unacceptable for further treatment in the opinion of the treated 
investigator. 
Protocol therapy may be held for up to six weeks in the event of an AE and the 
participant may be restarted on therapy when the toxicity has resolved to ≤ grade 1, In 
the event of therapy being held for more than six weeks, it is recommended that the 
participant come off protocol however the treating physician may obtain permission to 
continue on the protocol with permission of the PI, 
 if the 
treating physician feels it is in the participant’s best interest. 
5.5
Duration of Follow-Up
Participants will be followed for up to 5 years post-study discontinuation or until death, 
whichever comes first. Participants will be followed for subsequent lines of therapy, 
including line of agent, name of agent, and PSA kinetics following study drug 
discontinuation and correlate with response to study drug.  This information will be 
updated every 6 months.  The research team will collect this information during patient 
clinic visits, by phone, or via medical record review.
5.6
Criteria for Removal from Study
Participants will be removed from study when any of the criteria listed in Section 5.4 
applies. The reason for study removal and the date the participant was removed must 
be documented in the study-specific CRF. Alternative care options will be discussed 
with the participant. 
Participants will be removed from treatment at the time of unacceptable AEs but will 
remain on study (i.e. enrolled on the protocol) until resolution or stabilization of any 
AEs. 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the PI, 
 at 
 or page 
 


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6.
EXPECTED TOXICITIES, TOXICITY MONITORING, TOXICITY 
MANAGEMENT AND DOSING DELAYS/MODIFICATIONS 
6.1
Expected Toxicities
 
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in clinical 
practice.
Two randomized placebo-controlled, multicenter clinical trials enrolled patients who 
had metastatic CRPC who were using a LHRH agonist or were previously treated with 
orchiectomy. In both studies, AA was administered at a dose of 1,000 mg daily in 
combination with prednisone 5 mg twice daily in the active treatment arms. Placebo 
plus prednisone 5 mg twice daily was given to control patients.
The most common adverse drug reactions (≥10%) reported in the two randomized 
clinical trials that occurred more commonly (>2%) in the AA arm were fatigue, joint 
swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, 
dyspnea, urinary tract infection and contusion.
The most common laboratory abnormalities (>20%) reported in the two randomized 
clinical trials that occurred more commonly (≥2%) in the AA arm were anemia, 
elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, 
hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated 
ALT and hypokalemia.
In the combined data for the two phase III studies of AA, cardiac failure occurred 
more commonly in patients treated with AA compared to patients on the placebo arm 
(2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking AA 
and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure 
occurred in 0.2% of patients taking placebo. There were no treatment discontinuations 
and one death due to cardiac failure in the placebo group.
In both studies, the majority of arrhythmias were grade 1 or 2. There was one death 
associated with arrhythmia and one patient with sudden death in the AA arms and no 
deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest 
in the AA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or 
myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the 
AA arms.
6.1.1
Adverse Reactions for AA
Hypertension, Hypokalemia and Fluid Retention


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AA may cause hypertension, hypokalemia, and fluid retention as a consequence 
of increased mineralocorticoid levels resulting from CYP17 inhibition. In the two 
randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, 
grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of 
patients treated with AA. 
Co-administration of a corticosteroid suppresses ACTH drive, resulting in a 
reduction in the incidence and severity of these adverse reactions. Use caution 
when treating participants whose underlying medical conditions might be 
compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., 
those with heart failure, recent myocardial infarction or ventricular arrhythmia. 
Use AA with caution in participants with a history of cardiovascular disease. The 
safety of AA in participants with left ventricular ejection fraction < 50% or 
NYHA Class III or IV heart failure (in study of metastatic CRPC following 
chemotherapy) or NYHA Class II to IV heart failure (in study of metastatic 
CRPC prior to chemotherapy) was not established because these participants 
were excluded from these randomized clinical trials. Monitoring participants for 
hypertension, hypokalemia, and fluid retention is detailed in section 6.2.1. 
Management of hypertension, hypokalemia and fluid retention is detailed in 
section 6.3. Control hypertension and correct hypokalemia before and during 
treatment with AA.
Adrenocorticol Insufficiency 
Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of 
patients taking AA and in 0.2% of patients taking placebo. Adrenocortical 
insufficiency was reported in patients receiving AA in combination with 
prednisone, following interruption of daily steroids and/or with concurrent 
infection or stress. Use caution and monitor for symptoms and signs of 
adrenocortical insufficiency, particularly if participants are withdrawn from 
prednisone, have prednisone dose reductions, or experience unusual stress. 
Symptoms and signs of adrenocortical insufficiency may be masked by adverse 
reactions associated with mineralocorticoid excess seen in patients treated with 
AA. If clinically indicated, perform appropriate tests to confirm the diagnosis of 
adrenocortical insufficiency. Increased dosage of corticosteroids may be 
indicated before, during and after stressful situations. 
Hepatotoxicity
In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 
5X ULN) were reported in 4% of patients who received AA, typically during the 
first 3 months after starting treatment. Patients whose baseline ALT or
AST were elevated were more likely to experience liver test elevation than those 
beginning with normal values. Treatment discontinuation due to liver enzyme 
increases occurred in 1% of patients taking AA. No deaths clearly related to AA 
were reported due to hepatotoxicity events. Monitoring participants for 
hepatotoxicity is detailed in section 6.2.3. Management of hepatotoxicity is 
detailed in section 6.3.


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For guidance on management of side effects related AA please contact the PI,
 
 or page 
 
See current package insert for AA (Zytiga) for additional information on AA 
(http://www.zytiga.com/).
6.1.2
AEs for Prednisone 
A daily dose of 10 mg of prednisone is near the physiologic steroid dose and thus 
it is not expected that prednisone will cause significant side effects. Potential side 
effects of prednisone are listed below:
Cardiovascular: Congestive heart failure (in susceptible patients), hypertension
Central nervous system: Emotional instability, headache, intracranial pressure 
increased, psychic derangements (including euphoria, insomnia, mood swings, 
personality changes, severe depression), seizure, vertigo
Dermatologic: Bruising, facial erythema, petechiae, thin fragile skin, urticaria, 
wound healing impaired
Endocrine and metabolic: Adrenocortical and pituitary unresponsiveness (in 
times of stress), carbohydrate intolerance, Cushing’s syndrome, diabetes mellitus, 
fluid retention, hypokalemic alkalosis, hypothyroidism enhanced, menstrual 
irregularities, negative nitrogen balance due to protein catabolism, potassium loss, 
sodium retention
Gastrointestinal: Abdominal distension, pancreatitis, peptic ulcer (with possible 
perforation and hemorrhage), ulcerative esophagitis
Hepatic: ALT increased, AST increased, alkaline phosphatase increased
Neuromuscular and skeletal: Aseptic necrosis of femoral and humeral heads, 
muscle mass loss, muscle weakness, osteoporosis, pathologic fracture of long 
bones, steroid myopathy, tendon rupture, vertebral compression fractures
Ocular: Exophthalmos, glaucoma, intraocular pressure increased, posterior 
subcapsular cataracts
Other: Allergic reactions, anaphylactic reactions, diaphoresis, hypersensitivity 
reactions, infections
Close monitoring of blood sugars is recommended in diabetic participants. Close 
monitoring for infections is also recommended. It is recommended the prednisone 
never be stopped suddenly. Gradual tapering of the dose and/or schedule of 
prednisone is recommended when discontinuing therapy. Monitoring for signs 
and symptoms of adrenal insufficiency during prednisone administration and 
tapering is recommended. 
6.2
Toxicity Monitoring 
6.2.1
Monitoring for Hypertension, Hypokalemia and Fluid Retention


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Participants will be monitored closely for symptoms and signs of hypertension, 
hypokalemia and fluid retention. On Day 1 of each 28-day cycle, participants will 
undergo blood pressure assessment, physical examination to assess for fluid 
retention, and laboratory evaluation to assess for hypokalemia. Additionally, on 
Day 8and 22 of the first 28-day cycle, participants will undergo assessment of 
blood pressure and serum or plasma potassium levels. 
6.2.2
Monitoring for Adrenal Insufficiency 
Participants will be monitored closely for symptoms and signs of adrenal 
insufficiency. On Day 1 of each 28-day cycle, participants will be evaluated via 
history, physical, vital signs and laboratory assessment (including but not limited 
to serum chemistry) for signs of adrenal insufficiency. If clinically indicated, 
appropriate tests to confirm the diagnosis of adrenocortical insufficiency will be 
performed.
6.2.3
Monitoring for Hepatotoxicity 
Participants will be monitored closely for symptoms and signs of hepatotoxicity. 
Measure serum transaminases (ALT and AST) and bilirubin levels prior to 
starting treatment with AA, weekly for the first cycle, then on Day 1 of each 
subsequent cycle thereafter. Promptly measure serum total bilirubin, AST, and 
ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. 
Elevations of AST, ALT, or bilirubin from the participant’s baseline should 
prompt more frequent monitoring. For subjects who developed hepatotoxicity, 
please refer to section 6.3 monitoring parameters and  toxicity management. 
6.3
Toxicity Management and Dosing Delays/Modifications 
The starting dose of AA will be 1,000 mg daily. In the presence of any AA related 
toxicities > grade 2 (NCI CTCAE version 4) during treatment with AA at the starting 
dose level, excluding the management of hypertension, hypokalemia, limb edema, 
fatigue, and hepatotoxicity, which is detailed below, AA will initially be held. Once 
toxicity improves to grade 1 or better, AA can be resumed at 750 mg daily in the 
subsequent dose level. Two levels of dose de-escalation are planned for the study. If > 
grade 2 toxicity occurs at dose level -2, participants will be removed from the protocol. 
Dose Level
Abiraterone acetate
Starting dose level
1000 mg orally once daily 
-1
750 mg orally once daily 
-2
500 mg orally once daily 


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Dose delays and modifications will not necessitate changes in study assessment days. 
Dose delays and modifications will be made using the following recommendations: 
Toxicity assessments will be done using the CTEP Active Version of the NCI CTCAE 
(version 4) which is identified and located on the CTEP website at:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, 
etc.).
All AEs experienced by participants will be collected from the time of signed consent, 
through the study and until 30 days following the last dose of study drug. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible.
6.3.1
Management of Hypertension

For management of hypertension prior to the initiation of prednisone, 
refer to the Hypertension Pathway (Begining of protocol). 

Please note, addition of prednisone should not be made based on one 
blood pressure reading.  For patients with an elevated blood pressure, 
readings should be checked at least three times over a week before 
determining the grade of hypertension.

After prednisone has been initiation, use the below algorithm for 
management of hypertension. 


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6.3.2
Management of Hypokalemia

For management of hypokalemia prior to the initiation of prednisone, 
please refer to Hypokalemia Pathway.

After prednisone has been initiation, use the below algorithm for 
management of hypokalemia. 

Grade 1-2 Hypokalemia (<LLN – 3.0 mmol/L): 
o
For recurrent grade 1-2 hypokalemia despite the addition and 
uptitration of a mineralocorticoid antagonist, addition of 
prednisone 5 mg twice daily, and potassium supplementation, 
adjust potassium supplementation as clinically indicated. Once 
hypokalemia occurs, potassium levels will be monitored weekly 
until 2 weekly values are documented in the normal range.

Grade 3-4 Hypokalemia (< 3 mmol/L):
o
For recurrent grade 3-4 hypokalemia despite the addition and 
uptitration of a mineralocorticoid antagonist, addition of 
prednisone 5 mg twice daily, and potassium supplementation, hold 
AA. Adjust potassium supplementation as clinically indicated. 
Once hypokalemia occurs, potassium levels will be monitored 


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weekly until 2 weekly values are documented in the normal range, 
at which point AA will be resumed (at first dose reduction level, 
750 mg daily, or if already at first dose reduction then resume at 
second dose reduction, 500 mg daily). When AA is resumed 
potassium will be monitored at least weekly for the first 2 weeks 
and the every 2 weeks for the next 2 weeks. 
o
If grade 3-4 hypokalemia recurs at a separate point in time despite 
two dose level reductions of AA, prednisone 5 mg twice daily, 
potassium supplementation, and optimal medical management, 
discontinue AA. 
6.3.3
Management of Limb Edema 
The syndrome of mineralocorticoid excess is classically associated with 
hypertension, hypokalemia, and limb edema. It is atypical for limb edema to be the 
only symptom of mineralocorticoid excess associated with AA treatment. In a study 
by Attard et al of 42 patients treated with AA monotherapy, zero patients developed 
limb edema as the only symptom of mineralocorticoid excess.[25] Given such, 
prednisone should not be used in the management of isolated limb edema without 
other symptoms of mineralocorticoid excess to include hypertension and/or 
hypokalemia. If hypertension and/or hypokalemia occur, refer to section 6.3.1 and 
6.3.2 respectively for appropriate management. If grade 3 limb edema occurs, 
please refer to section 6.3 for instruction regarding dose delays/reductions.
6.3.4
Management of Fatigue

Grade 1-2 Fatigue: 
o
Management per investigator. No investigational product dose 
reduction.

Grade 3 Fatigue: 
o
Hold AA. Once the toxicity has resolved to ≤ grade 1 or baseline, 
resume AA at the first dose level reduction (750 mg daily). 
o
If grade 3 fatigue recurs at a separate point in time, hold AA and 
initiate prednisone 5 mg twice daily. Once the toxicity has resolved 
to ≤ grade 1 or baseline, resume AA at the second dose level 
reduction (500 mg) and continue prednisone 5 mg twice daily.
o
If grade 3 fatigue recurs at a separate point in time despite two 
dose level reductions of AA, prednisone 5 mg twice daily, and 
optimal medical management, discontinue AA. 
6.3.5
Management of LFT abnormalities 
Hepatic Impairment
In participants with baseline moderate hepatic impairment (Child-Pugh Class B), 
reduce the recommended dose of AA to 250 mg once daily. A once daily dose of 
250 mg in patients with moderate hepatic impairment is predicted to result in an 
AUC similar to the AUC seen in patients with normal hepatic function receiving 
1,000 mg once daily. However, there are no clinical data at the dose of 250 mg 
once daily in patients with moderate hepatic impairment and caution is advised. 


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In participants with moderate hepatic impairment monitor ALT, AST, and 
bilirubin prior to the start of treatment, every week for the first month, every two 
weeks for the following two months of treatment and monthly thereafter. If 
elevations in ALT and/or AST greater than 5X ULN or total bilirubin greater than 
3X ULN occur in participants with baseline moderate hepatic impairment, 
discontinue AA and do not re-treat participants with AA. 
Avoid AA in participants with baseline severe hepatic impairment (Child-Pugh 
Class C), as AA has not been studied in this population, and no dose adjustment 
can be predicted.
Hepatotoxicity

Grade 1 LFT Abnormalities (increase in AST or ALT from ULN to 3.0 x 
ULN; increase in total bilirubin from ULN to 1.5 x ULN): 
o
The frequency of LFT monitoring should be increased, if the 
investigator judges that the laboratory abnormalities are potentially 
related to abiraterone. No abiraterone dose reduction is required.

Grade 2 LFT Abnormalities (increase in AST or ALT > 3.0 – 5 x ULN; 
increase in total bilirubin from > 1.5 – 3 x ULN): 
o
The frequency of LFT monitoring should be increased to ≥ once a 
week, if the investigator judges that the laboratory abnormalities 
are potentially related to abiraterone. No abiraterone dose 
reduction is required.

Grade 3 LFT Abnormalities (increase in AST or ALT to > 5 x ULN – 20.0 
x ULN; increase in total bilirubin to > 3 x ULN – 10.0 x ULN): 
o
Hold abiraterone and all other concomitant medications that are 
potentially hepatotoxic. Frequent laboratory evaluations (at least 
once weekly) should be conducted until the LFTs return to baseline 
value or grade 1. Hold until return to baseline of AST or ALT ≤ 
2.5 x ULN and total bilirubin ≤ 1.5 x ULN. If abiraterone 
resumption is considered for subjects who have experienced grade 
3 increases in AST, ALT, or bilirubin, and the PI agrees, resume 
abiraterone with the first dose level reduction (750 mg) when grade 
3 toxicities resolve to grade 1 or baseline. For participants who 
resume treatment, monitor LFTs at a minimum of every 2 weeks 
for 3 months and monthly thereafter.
o
If grade 3 increases in AST, ALT, or bilirubin recur after the first 
dose reduction hold abiraterone and all other concomitant 
medications that are potentially hepatotoxic. Frequent laboratory 
evaluations should be conducted (at minimum weekly) until the 
LFTs return to baseline value or grade 1. If abiraterone resumption 
is considered for participants who have experienced grade 3 
increases in AST, ALT, or bilirubin with the first dose reduction, 
and the PI agrees, resume abiraterone with the second dose level 
reduction (500 mg) when AST, ALT, or bilirubin returns to 


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baseline value or grade 1. For participants who resume abiraterone, 
monitor LFTs at a minimum of every 2 weeks for 3 months and 
monthly thereafter.

Grade 4 LFT Abnormalities (increase in AST or ALT to > 20 x ULN; 
increase in total bilirubin to > 10 x ULN): 
o
Participants must discontinue abiraterone immediately and will not 
be re-challenged. They should be followed until resolution of LFT 
abnormalities to ≤ grade 1 or baseline.

Concurrent elevation of AST/ALT > 3x ULN with bilirubin >2x ULN 
(unless the concurrent elevation is related to biliary obstruction or other 
causes unrelated to study treatment)
o
Discontinue abiraterone acetate. No change or consider tapering 
prednisone if abiraterone acetate discontinued.
6.3.6
Management of other toxicities 
See beginning of section 6.3. For all other toxicities, once toxicity improves to 
grade 1 or better, AA can be resumed at appropriate dose modification.  Clinical 
need for steroids per treating MD’s discretion and after discussion with the PI,
 
 is allowed but discouraged unless the situations outlined in 
Section 6.3 apply.


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7.
DRUG FORMULATION AND ADMINISTRATION
7.1
Abiraterone acetate
Additional information is provided in the AA Investigator’s Brochure and USPI for 
AA (www.zytiga). 
7.1.1
Description
The chemical nomenclature of AA is 3β-acetoxy-17-(3-pyridyl)androsta-5,16-
diene. Its empirical formula is C26H33NO2 and it has a molecular weight of 
391.55. Once absorbed after oral administration, AA is rapidly deacetylated and 
converted to the active form abiraterone. Abiraterone is metabolized by CYP3A4 
and is an inhibitor of CYP2D6.[4] For pharmacokinetics, refer to section 2.1.1 and 
Table 2. 
7.1.2
Form
AA 250-mg tablets are oval, white to off-white and contain AA and compendial 
(USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, 
croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, 
colloidal silicon dioxide, and purified water, in descending order of concentration 
(the water is removed during tabletting).
7.1.3
Storage and Stability
Pharmacy Storage Requirements
The investigational product must be stored in a secure area and administered 
only to participants entered into the clinical study in accordance with the 
conditions specified in this protocol. Bottles of investigational product should 
be stored at a room temperature between 20º-25º C with the cap kept on tightly 
and should not be refrigerated. Additional information is provided in the AA 
Investigator’s Brochure.
Storage Requirements for the Participant
Bottles of investigational product should be stored at room temperature with 
the cap kept on tightly and should not be refrigerated. Participants should be 
advised to keep all medications out of the reach and out of sight of children.
7.1.4
Compatibility
Treatment with AA monotherapy will be administered via oral tablets and 
should be administered without food. Participants may receive prednisone on 
this study. AA has been tested in combination with prednisone and AA is 
currently approved by the FDA for use with concomitant prednisone. We do 
not anticipate incompatibility from the combination of AA with prednisone. 
7.1.5
Handling 


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Investigational product must only be dispensed by a Pharmacist or medically 
qualified staff. Investigational product is to be dispensed only to participants 
enrolled in this study. Once the investigational product is prepared for a 
participant, it can only be administered to that participant. 
This medicine may cause harm to the unborn child if handled by women who are 
pregnant. It should not be handled by women who are breast-feeding. Women 
who are pregnant or who may be pregnant should wear gloves if they need to 
touch AA tablets. Study staff and caregivers should be notified of this 
information, to ensure the appropriate precautions are taken.
7.1.6
Availability
AA tablets will be provided to each site. Participants will be provided with a 30-
day supply to allow for visits to occur every 28 days with a ± 3 day window. 
Patients will be dispensed a 30, 60, or 90-day supply depending on the frequency 
of their protocol visits determined by the treating physician. Information 
presented on the labels for investigative product will comply with applicable local 
regulations. Site pharmacist will dispense the investigational product to each 
participant in accordance with this protocol under the guidelines of the site’s 
dispensation standard operating procedure. Abiraterone Acetate is supplied and 
will be provided by Janssen Scientific Affairs,  LLC. 
7.1.7
Ordering
Except in very unusual circumstances, each participating institution will order AA 
directly from the supplier. Janssen Scientific Affairs, LLC will not directly 
provide AA to each participating site. This will be coordinated through a third 
party drug distribution supplier. A participating site may order AA only after the 
initial IRB approval for the site has been forwarded by the Coordinating Center to 
the supplier.  
7.1.8
Accountability
Accountability for investigational product is the responsibility of the investigator. 
The study site must maintain accurate records demonstrating dates and amount of 
investigational product (AA) received, to whom dispensed (participant by 
participant accounting), and accounts of any investigational product accidentally 
or deliberately destroyed. At the end of the study, reconciliation must be made 
between the amount of investigational product supplied, dispensed, and 
subsequently destroyed.
At the time of delivery of investigational product to the site, the investigator, 
designee, or Pharmacist (where appropriate) will confirm that the supplies for the 
study have been received. This following information will be confirmed: lot 
numbers, quantities shipped/delivered, and date of receipt.


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7.1.9
Destruction and Return
Drug should be destroyed at the site, after the sponsor–investigator approves the 
drug destruction policy at the site. Drug will not be returned to Janssen Scientific 
Affairs, LLC. Destruction will be documented in the Drug Accountability Record 
Form. Evidence of drug destruction will need to be provided to Janssen Scientific 
Affairs, LLC to verify destruction. 
7.2
Prednisone 
7.2.1
Description
Prednisone is a corticosteroid.
7.2.2
Form
Prednisone 5-mg tablets are small, white tablets.
7.2.3
Storage and Stability
Prednisone should be stored at 25°C, excursions permitted to 15° to 30°C.
7.2.4
Compatibility
We do not anticipate any excess toxicity combining AA with prednisone. There 
are no overlapping toxicities and no apparent drug-drug interactions (either 
pharmacokinetic or combined inhibition of enzymes in the any of the adrenal 
steroid synthesis pathways). Prednisone has been used in phase I-III trials 
combined with AA as described above.
7.2.5
Handling 
There are no specific instructions for handling prednisone.
7.2.6
Availability 
Prednisone will not be provided by the study and will be prescribed by standard 
prescriptions.
Prednisone is commercially available and will NOT be provided free of charge for 
this study.
Prednisone is a commercially available agent that is available from various 
manufacturers.  


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8.
CORRELATIVE/SPECIAL STUDIES 
A correlative aim is to assess clinical signs of mineralocorticoid toxicity with changes in 
serum ACTH and corticosteroid intermediates. The corticosteroids intermediates which 
will be measured will include the following: pregnenolone, progesterone, 
deoxycorticosterone, corticosterone, aldosterone, 17α-hydroxypregnenolone, 17α-
hydroxypregesterone, 11-deoxycortisol, cortisol. These hormones will be assayed by novel 
mass spectrometry techniques.
Additional exploratory correlative studies will include analysis of tumor obtained from 
optional serial CPRC metastasis biopsies for possible mechanisms of AA resistance (AR 
expression by IHC, AR regulated gene expression by IHC, tissue androgen levels by mass 
spectrometry, and whole-exome and transcriptome sequencing). In addition, serum 
androgens will be assayed by novel mass spectrometry techniques. Blood will be collected 
for CTC analysis including enumeration, AR nuclear localization, AR splice variant 
expression and AR sequence and circulating tumor DNA analysis to assess mechanisms of 
AR resistance to AA. The correlative studies (with the exception of the optional biopsies) 
are required. Lastly, blood will be collected for circulating tumor DNA analysis.
Subject samples (including blood and tissue samples) at time of collection will be handled 
and procured by a dedicated technician or physician at each study site. Samples processing 
will take place by dedicated technicians and physicians. Samples will be processed for 
correlative studies and remaining samples will be stored for future use to include 
assessment of biological and molecular predictive and prognostic biomarkers. CTC 
samples and cfDNA samples for circulating tumor DNA analysis will be sent to and 
analyzed at Memorial Sloan-Kettering Cancer Center (MSKCC) and the Lang Lab at the 
University of Wisconsin. Any further future analyses not specified in this protocol or 
above will be agreed upon by prior approval from Janssen Scientific Affairs, LLC.  
Instructions on sample collection and processing are contained in the Laboratory Manual 
with instructions on sample collection and processing.
8.1
Data Analysis
Determination of all molecular endpoints will occur as listed above so as to ensure each 
sample processed will be annotated with respect to: AR activity (continuous variable 
from microarray data); TMPRSS2:ERG translocation status (yes/no from RT PCR); 
AR splice variation (native vs. alternative from RT PCR); quantitative AR and 
AKR1C3 IHC (continuous variable); gene expression of androgen metabolisms genes 
(continuous, from microarray data); testosterone and DHT levels (continuous variable 
from mass spectroscopy data); and the signaling activity of different pathways 
(determined by IHC and/or gene expression analysis). These values will be provided to 
the study statistician (DFCI). Descriptive statistics of levels and changes in measures 
will be provided. Whether AR signaling is augmented with AA will be evaluated along 
with analysis of the association of AR splice variants, TMPRSS2 fusion genes, AR 


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signaling, tumor androgens, serum androgens with PSA and radiographic response to 
AA.
Sequencing results from tumor samples will be compared to matched normal DNA 
samples and analyzed for base mutations, small insertions/deletions, copy number 
alterations, and structural rearrangements present in DNA from CRPC. 


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9.
 STUDY CALENDAR
Pre- 
Studya
Cycle 1 (+/-2 days)b
Cycle 2 (+/- 2 
days)
Cycle 3 
(+/- 2 days)
Cycle ≥ 4 
(+/- 2 
days)
Every 12 
weeks (+/- 
1 week)
End of 
Treatment 
Visitu
1
8c
15c
22c
1
15
1
15
1
Informed Consent
X
History and Physicald
X
X
X
X
X
X
X
Document Anti-
Hypertensive Medications 
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
Vital Signse
X
X
X (BP 
Only)
X
X (BP 
Only)
X
X
X
X
BMIf
X
X
X
X
X
X
X
Hematologyg
X
X
X
X
X
X
X
Serum Chemistryh
X
X
X (K 
Only)
X
X (K 
Only)
X
X
X
X
Liver Function Testsi
X
X
X
X
X
X
X
X
X
Coagulation Factorsj
X
X
HgA1c
X
X
X
X
Fasting Serum Lipids
X
X
X
MUGA scan or ECHO
X
Testosterone
X
Research Labk
X
X
X
X
X
Research Labl
X
X
X
Research Labm
X
Serum ACTHn
X
X
X
X
X
PSAo
X
X
X
X
X
X
CT/MRIp
X
X
Bone Scanq
X
X
AA Distributionr
X
X
X
X
AA Compliance 
Assessment
X
X
X
X
X
Prior and Concomitant 
Medications
X
X
X
X
X
X
Adverse Eventss
X
X
X
X
X
X
X
X
X


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Tumor Biopsyt
X
Xt
a: Baseline evaluations are to be conducted within 30 days prior to registration. Scans must be done within 30 days prior to 
registration. All baseline screening should be done prior to registration. 
b: A cycle will be defined as 28 days. After prednisone is added, if the treating physician feels the patient would benefit from having 
clinic visits and assessments done every 8-12 weeks, that is acceptable. Clinical labs can be collected locally in the interim if clinically 
indicated.
c: Cycle 1 Day 8 and 22 checks can occur locally if preferred. Cycle 1 Day 15 checks must occur at the study institution and the 
participant must be seen by a study MD or NP. 
d: Physical examination should include general description of participant, head, eyes, ears, nose, and throat, chest, abdominal, 
extremities, neurologic, skin, and lymph node examination. Any other evaluation is up to the discretion of the practitioner. It will not 
be considered a violation if the exam is not described as outlined here. 
e: Vital signs included upright blood pressure, heart rate, respiratory rate, body temperature and weight. Blood pressure will be 
checked weekly for the first cycle to monitor for hypertension and then day 1 of every subsequent cycle. The repeated BPs described in 
the Hypertension Pathway may be measured over 7 days.
f: Calculate BMI = weight/(height)2.    
g: Hematology testing to include WBC, ANC, hemoglobin, and platelet count. 
h: Serum or plasma chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose , calcium, albumin, 
magnesium. Potassium levels will be checked weekly for the first cycle to monitor for hypokalemia and then day 1 of every subsequent 
cycle. Cycle 1 Day 8 and Cycle 1 Day 22 potassium checks may be done locally.  
i: LFTs to include AST, ALT, alkaline phosphatase, total bilirubin and direct bilirubin. Measure serum transaminases (ALT and AST) 
and bilirubin levels prior to starting treatment with AA, every two weeks for the first three months of treatment and monthly 
thereafter.  LFTs may be done locally on Cycle 2 Day 15 and Cycle 3 Day 15 only.
j: Coagulation factors to include PT, PTT, and INR. 
k: Blood will be collected for serum corticosteroid analysis (pregnenolone, progesterone, deoxycorticosterone, corticosterone, 
aldosterone, 17α-hydroxypregnenolone, 17α-hydroxypregesterone, 11-deoxycortisol, cortisol). Labs should be drawn prior to the 
administration of the first dose of treatment. As of June 23, 2020, these research samples no longer need to be collected while patients 
are on active treatment. Study teams should only collect these samples at EOT. 
l: Blood will be collected for serum androgen analysis (DHEA, androstenedione, testosterone, DHT). Labs should be drawn prior to 
the administration of the first dose of treatment. Additionally, CTCs will be collected. Cycle 1/day 1 and off study CTC samples 
(whole blood) will be shipped overnight. CTCs collected every 12 weeks will be processed (buffy coat) and stored for delivery.
Lastly, blood for circulating tumor DNA will be collected at the specified time points. As of June 23, 2020, these research samples no 
longer need to be collected while patients are on active treatment. Study teams should only collect these samples at EOT. 
m: Blood will be collected for germline DNA and RNA analysis. 
n: This will be measured by standard testing. Should be checked prior to the administration of the first dose of treatment.    
o: If a digital rectal examination is performed, PSA must be sampled prior to the examination.
p: If the treating physician feels the patient would benefit from having CT/MRI scans done every 4-6 months, that is acceptable. If 
baseline CT chest does not demonstrate prostate cancer, they do not need to be repeated on study unless the investigator suspects new 
findings based on clinical signs/symptoms. 
q. If the treating physician feels the patient would benefit from having bone scans done every 4-6 months, that is acceptable.
r: Study agent is AA. Subjects with be continued on LHRH agonist/antagonist as prescribed. Subjects will begin taking study agent on 
Day 1/Cycle 1. 
s: Adverse events should be collected from the date informed consent is signed until 30 days after discontinuation from the study. 
t: Tumor biopsy is optional .  Participants will need to be screened and registered before having a biopsy. If a pre-treatment biopsy is 
being performed, it must be performed prior to starting study medication. Friday should be avoided due to difficulty of processing bone 
biopsies on the weekend. For DFCI participants,when a pelvic bone biopsy is being performed a bone marrow aspirate will also be 
obtained from the same needle stick.  
u: The optional tumor biopsy at the end of the study can be done +/- 28 days of the determination of progression. 
v: The End of Treatment Visit will be the visit at which it is determined that the patient will no longer be taking treatment given 
disease progression, toxicity, or other reason. Participants will be followed for up to 5 years post-study discontinuation or until death, 
whichever comes first. Participants will be followed for subsequent lines of therapy, including line of agent, name of agent, and PSA 
kinetics following study drug discontinuation and correlate with response to study drug.  This information will be updated every 6 
months.  The research team will collect this information during patient clinic visits, by phone, or via medical record review.


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10. MEASUREMENT OF EFFECT 
Although response is not the primary endpoint of this trial, participants will be assessed by 
RECIST (1.1), bone scan and PSA criteria. For the purposes of this study, participants will 
be reevaluated every four weeks by PSA and every 12 weeks by CT and bone scan. 
However, if the treating physician feels the patient would benefit from having scans done 
every 4-6 months, as opposed to every 12 weeks, that is acceptable. At time of PSA 
progression (as defined below by PCGW2 criteria), those participants remaining on AA 
monotherapy, will be treated with prednisone 5 mg orally twice daily. Participants should 
not be taken off treatment with AA plus prednisone until documented progression by 
imaging. 
The following will be used to determine progression in this study:

PSA Progression (based on PCWG2 criteria): For those who experience a decline on 
PSA from baseline, PSA progression will be defined as an increase in PSA that is ≥ 
25% and ≥ 2 ng/mL above nadir which is confirmed by a second value three or more 
weeks later. The first value will be the documented date of progression. For 
participants who do not experience a decline from baseline, PSA progression will be 
defined as PSA ≥ 25% and ≥ 2 ng/mL after 12 weeks.

Radiographic Disease Progression (based on PCWG2 criteria): For bone disease, 
radiographic progression will be defined by PCWG2 criteria for progression of bone 
disease (≥2 new lesion on bone scan and for the first 12 week assessment, defining 
disease progression requires a confirmatory scan performed 6 or more weeks later 
which shows a minimum of 2 additional new lesions).[30] See Appendix D for 
imaging procedural information and measurement of tumor flare. For soft 
tissue/lymph node disease, radiographic progression will be defined using RECIST 
1.1 criteria. 
10.1 Antitumor Effect– Solid Tumors
Response and progression will be evaluated in this study using the new international 
criteria proposed by RECIST 1.1. 
10.1.1 Definitions
Evaluable for Target Disease Response. Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for 
target disease response. These participants will have their response classified 
according to the definitions stated below. Note: Participants who exhibit 
objective disease progression or die prior to the end of cycle 1 will also be 
considered evaluable.


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Evaluable for Non-Target Disease Response: Participants who have lesions 
present at baseline that are evaluable but do not meet the definitions of 
measurable disease, have received at least one cycle of therapy, and have had 
their disease re-evaluated will be considered evaluable for non-target disease 
response. These participants will have their response classified according to the 
definitions stated below. Participants ho exhibit objective disease progression or 
die prior to the end of cycle 1 will also be considered evaluable. 
10.1.2 Disease Parameters
Measurable disease. Measurable disease is the presence of at least one (1) lesion 
that can be accurately measured in at least one dimension with longest diameter  
> 20 mm using conventional techniques (CT, MRI, x-ray) or  >10 mm with spiral 
CT scan. Measurable lesions must be at least 2 times the slice thickness in mm. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Ultrasound cannot be used to measure lesions. A lesion in a 
previously irradiated area is not eligible for measurable disease unless there is 
objective evidence of progression of the lesion prior to study enrollment. Lesions 
in previously irradiated areas must be clearly identified as such. 
Malignant lymph nodes. 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 followed.
Non-measurable disease. All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm) or pathological lymph nodes with > 10 to < 
15mm short axis, are considered non-measurable disease. Leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, abdominal masses identified by physical exam that 
are not measurable by reproducible imaging techniques, and cystic lesions are all 
considered non-measurable.
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline. Lesions must be 
accurately measured in 1 dimension with a minimum size of 10 mm by CT or 
MRI (slice thickness no greater than 5 mm), 20 mm by chest x-ray. Nodes must 
have a short axis > 15 mm. The short axis should be included in the sum of the 
lesions in the calculation of response. Nodes that shrink to < 10 mm are 
considered normal. Target lesions should be selected on the basis of their size, be 
representative of all the involved organs, and should be lesions that can be 
followed with reproducible repeated measurements. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 


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CT or MRI can be considered target lesions if the soft tissue component meets 
the definition of measurability as defined above. Cystic lesions thought to 
represent cystic metastases can be considered as target lesions. However, if non-
cystic lesions are present, these are preferred for selection as target lesions. 
Lesions in previously irradiated areas or areas subject to other loco-regional 
therapy are usually not considered measurable unless there has been 
demonstrated progression of that lesion. 
Non-target lesions. All other lesions, including small lesions < 10 mm or 
pathological lymph nodes measuring > 10 mm to < 15 mm in short axis, as well 
as truly non-measurable lesions, which include leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses identified by physical exam that 
are not measurable by reproducible imaging techniques. 
10.1.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation, using a ruler, 
calipers, or digital measurement tool. All baseline evaluations should be performed 
as closely as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment.
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Imaging-based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumor effect of a 
treatment.
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and > 10 mm in 
diameter as assessed by using calipers. For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the 
lesion, is recommended.
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung; however, CT is 
preferable.
Conventional CT and MRI. These techniques 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.


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Tumor markers. Tumor markers alone cannot be used to assess response. The 
following parameters will be recorded on a monthly basis:

PSA decline will be measuring according to revised PCWG-2 (2008) 
criteria.[30]

PSA changes will be recorded on all participants.

TTPP will be based on revised PCWG-2 (2008) criteria. 

The maximal decline in PSA for each participant will be recorded.

The date of the maximal PSA decline (nadir date) will be recorded for 
each participant, as will the duration from the start of therapy to the 
nadir PSA.  
10.1.4 Response Criteria 
10.1.4.1  Evaluation of Target Lesions
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph node must have reduction in short axis to < 10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study 
with at least a 5 mm absolute increase in the sum of all lesions. The 
appearance of one or more new lesions* denotes disease progression. 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data. In this case, a concise explanation must 
be given.
Note: If tumor response data is missing for target lesions, the overall 
assessment must be UN unless there is new disease that would result in an 
overall assessment of PD. However, if there is missing or unevaluable data 
for non-target lesions, but data is available for all target lesions, the overall 
response for that time point will be assigned based on the sum LD of all 
target lesions. Additionally, the assessment of CR cannot be made if there 
is missing or unevaluable data for non-target lesions. In this case, the 
overall assessment would be PR.
*Definition of New Lesion: The finding of a new lesion should be 
unequivocal (i.e. not due to difference in scanning technique, imaging 
modality, or findings thought to represent something other than tumor (ex: 


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new bone lesions may be healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical location 
that was not scanned at baseline is considered new and will indicate PD. If 
a new lesion is equivocal (because of small size, etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is 
confirmed, progression should be declared using the date of the initial scan 
on which the lesion was discovered. 
10.1.4.2  Evaluation of Non-Target Lesions
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (< 10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they 
must normalize for a subject to be considered in complete clinical 
response.
Non-CR/Non-PD (SD): Persistence of one or more non-target 
lesions and/or maintenance of tumor marker level above the 
normal limits.
Progressive Disease (PD): Appearance of one or more new 
lesions* and/or unequivocal progression of existing non-target 
lesions.
When the participant also has measurable disease, to achieve 
‘unequivocal progression’ on the basis of the non-target disease, 
there must be an overall  level of substantial worsening in non-
target disease such that, even in presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. A modest ‘increase’ in the size 
of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. The designation of 
overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be 
extremely rare. When the participant has only non- measurable 
disease, worsening in non-target disease cannot be easily 
quantified. A useful test that can be applied when assessing non-
targets for unequivocal progression is to consider if the increase in 
overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in 
tumor burden representing an additional 73% increase in ‘volume’ 
(which is equivalent to a 20% increase diameter in measurable 


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lesions), an increase in pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from ‘localized’ to ‘widespread.’
Unknown (UN): Assessment of non-target lesions cannot be made due 
to insufficient or unevaluable data. In this case, a concise explanation 
must be given.
*Definition of New Lesion: The finding of a new lesion should be 
unequivocal (i.e. not due to difference in scanning technique, imaging 
modality, or findings thought to represent something other than tumor 
(ex: new bone lesions may be healing or flare of pre-existing lesions). 
However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size, etc.), 
follow-up evaluation will clarify if it truly represents new disease and if 
PD is confirmed, progression should be declared using the date of the 
initial scan on which the lesion was discovered. 
Note: Bone scan flares have been reported in 33-48% of metastatic, 
CRPC patients treated with AA.[32] In this situation bone scan reports 
frequently describe tumor progression. If a participant has PSA, CT scan 
and clinical stability/response and bone scan progression during the first 
three months of AA therapy (at the 12 week restaging scans), the treating 
physician should consider the possibility of bone scan flare and continue 
the participant on treatment until the next scheduled radiographic 
assessment. The treating physician is encouraged to discuss the diagnosis 
of bone scan flare with the site PI. See Appendix D for imaging 
procedural information and measurement of tumor flare. 
10.1.4.3  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 progressive disease the smallest measurements recorded since the 
treatment started). The participant's best response assignment will 
depend on the achievement of both measurement and confirmation 
criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target
Lesions
New
Lesions
Overall 
Response
Best Overall Response for 
when Confirmation is 
Required:
CR
CR
No
CR
>4 wks confirmation
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
>4 wks confirmation


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PR
Non-CR/Non-PD/Not 
evaluated
No
PR
SD
Non-CR/Non-PD/Not 
evaluated
No
SD
Documented at least once >4 
wks from baseline
PD
Any
Yes or No
PD
Any
PD*
Yes or No
PD
Any
Any
Yes
PD
No prior SD, PR or CR
*In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression.
Note:   Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target 
Disease)
Non-Target Lesions
New
Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
Not all evaluated
No
Not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*Non-CR/non-PD is preferred over stable disease for non-target disease since SD is 
increasingly used an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
10.1.5 Duration of Response
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrence or PD is objectively documented, taking as 
reference for PD the smallest measurements recorded since the treatment started, 
or death due to any cause. Participants without events reported are censored at 
the last disease evaluation.
Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
recurrent or progressive disease is objectively documented or death due to any 


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cause. Participants without events reported are censored at the last disease 
evaluation.
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.
10.1.6 Time to Progression
Time to Progression: Time to progression is defined as the time from 
registration to progression, or censored at the date of last disease evaluation 
for those without progression reported. 
10.1.7 Response Review
Central review of the radiology assessments is planned using tumor metrics core 
at the DFCI.
10.2
Other Response Parameters
Serum androgen levels will be evaluated every 3 cycles. Serum corticosteroid 
intermediates and ACTH will be evaluated every cycle. 
10.2.4 Descriptive statistics (including mean, standard deviation, minim, minimum, 
median, interquartile range) will be provided on levels of serum hormone 
and changes from baseline (serum androgen including DHEA, DHEA-S, 
androstenedione, testosterone, DHT; serum corticosteroid/ mineralocorticoid 
intermediates to include pregnenolone, progesterone, deoxycorticosterone, 
corticosterone, aldosterone, 17α-hydroxypregnenolone, 17α-
hydroxypregesterone, 11-deoxycortisol, cortisol; serum ACTH).


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11. ADVERSE EVENT REPORTING REQUIREMENT
11.1 Definitions
11.1.1 Johnson & Johnson Medicinal Product
The specific Johnson & Johnson drug under study and any other Johnson & 
Johnson medicinal product. 
11.1.2 PQC
Any discrete concern that questions the identity, quality, durability, reliability, 
safety, efficacy or intended performance of a drug product. A complaint may 
allege an injury or malfunction associated with the use of the drug product. It may 
also involve the design, literature, packaging, advertising, availability, physical 
appearance or promotion of the drug product.
11.1.3 Special Reporting Situations 
When a report contains a Johnson & Johnson product, an identifiable patient, and 
identifiable reporter, the following events represent Special Reporting Situations:

overdose of a Johnson & Johnson medicinal product 

pregnancy exposure (maternal and paternal)

exposure to a medicinal product from breastfeeding 

suspected abuse/misuse of a medicinal Johnson & Johnson product

inadvertent or accidental exposure to a medicinal Johnson & Johnson 
product 

any failure of expected pharmacological action (i.e., lack of effect) of a 
Johnson & Johnson medicinal product

unexpected therapeutic or clinical benefit from use of a Johnson & 
Johnson medicinal product

medication error involving a Johnson & Johnson product (with or without 
patient exposure to the medicinal Johnson & Johnson product, e.g., name 
confusion)

suspected transmission of any infectious agent via a medicinal product.
11.1.4 AE 
Any untoward medical occurrence in a participant or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
related to the medicinal product.
11.1.5 AE of Special Interest


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Events that JANSSEN SCIENTIFIC AFFAIRS, LLC  is actively monitoring as a 
result of a previously identified signal (even if non-serious). There are no AEs of 
special interest identified for abiraterone acetate.
11.1.6 Adverse Drug Reaction
A noxious and unintended response to any dose of the drug (or biological) product 
for which there is a reasonable possibility that the product cause the response.  
‘‘Reasonable possibility’’ means there is evidence to suggest a causal relationship 
between the drug and the. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any AE caused by a 
drug.
11.1.7 SAE
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of 
the PI, it results in any of the following outcomes: 

Death

A life-threatening AE
o
Life-threatening AE or life-threatening suspected adverse reaction: An 
AE or suspected adverse reaction is considered ‘‘life-threatening’’ if, 
in the view of the PI, its occurrence places the participant or subject at 
immediate risk of death. It does not include an AE or suspected 
adverse reaction that, had it occurred in a more severe form, might 
have caused death.

Inpatient hospitalization or prolongation of existing hospitalization

A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions

A congenital anomaly/birth defect

Is a suspected transmission of infectious agents by a medicinal product
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the participant or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse.
Events not considered to be SAEs are hospitalizations for:

routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures

elective or pre-planned treatment for a pre-existing condition that did not 
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
emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission

respite care
11.1.8 Expectedness
AEs can be 'Expected' or 'Unexpected.' 

Expected AE
Expected AEs are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, an AE is 
considered expected when it appears in the current AE list, the 
Investigator’s Brochure, the package insert or is included in the informed 
consent document as a potential risk.  
Refer to Section 6.1 for a listing of expected AEs associated with the 
study agent(s).

Unexpected AE
For the purposes of this study, an AE is considered unexpected when it 
varies in nature, intensity or frequency from information provided in the 
current AE list, the Investigator’s Brochure, the package insert or when it 
is not included in the informed consent document as a potential risk.  
11.1.9 Attribution
Attribution is the relationship between an AE or SAE and the investigational 
product. Attribution will be assigned as follows:
Definite – The AE is clearly related to the investigational product.
Probable – The AE is likely related to the investigational product.
Possible – The AE may be related to the investigational product. 
Unlikely - The AE is doubtfully related to the investigational product.
Unrelated - The AE is clearly NOT related to the investigational product.
11.2 Procedures for AE and SAE Recording
Recording should be done in a concise manner using standard, acceptable medical 
terms. 
The AE recorded should not be a procedure or a clinical measurement (i.e. a laboratory 
value or vital sign) but should reflect the reason for the procedure or the diagnosis 
based on the abnormal measurement.


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Preexisting conditions that worsen in severity or frequency during the Study should 
also be recorded (a preexisting condition that does not worsen is not an AE).
Further, a procedure or surgery is not an AE; rather, the event leading to the procedure 
or surgery is considered an AE. Any event requiring in-patient hospitalization that 
occurs during the course of a subject’s participation in a trial must be reported as an 
SAE. Hospitalizations that do not meet the criteria for SAE reporting are:

Reasons described in the Protocol, e.g. drug administration, Protocol-
required testing

Surgery or procedure planned prior to entry into the Study.
If, in the PIs judgment, a clinical significant worsening from baseline is observed in 
any laboratory or other test parameter (e.g. EKG, angiogram), physical exam finding, 
or vital sign, a corresponding clinical AE should be recorded.
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the AE, whenever possible.  However, a complete description of the signs, 
symptoms and investigations which led to the diagnosis should be provided. For 
example, if clinically significant elevations of liver function tests are known to be 
secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be 
recorded. If the cause is not known, the abnormal test or finding should be recorded as 
an AE, using appropriate medical terminology (e.g thrombocytopenia, peripheral 
edema, QT prolongation).
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study. 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 
will be recorded in the participant’s medical record and on the appropriate study-
specific case report forms. 
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will 
be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded 
from the CTEP website at:
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
11.3 Reporting Requirements
The DF/HCC will serve as the Sponsor Investigator 
  of this 
multi-site trial. Each participating investigator is required to abide by the reporting 
requirements set by the DF/HCC. The study must be conducted in compliance with 
FDA regulations, local safety reporting requirements, and reporting requirements of the 
PI. Each investigative site will be responsible to report SAEs that occur at that 
institution to their respective IRB. It is the responsibility of each participating 


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investigator to report SAEs to the Sponsor Investigator 
 and/or 
others as described below. 
11.4 Reporting to the  Sponsor Investigator
11.4.1 Special Reporting Situations 
When a report contains a J&J product, an identifiable patient, and identifiable 
reporter, the following events represent Special Reporting Situations:

Overdose of a Johnson & Johnson medicinal product 

Pregnancy exposure (maternal and paternal)

Exposure to a medicinal product from breastfeeding 

Suspected abuse/misuse of a medicinal Johnson & Johnson product

Inadvertent or accidental exposure to a medicinal Johnson & Johnson 
product 

Any failure of expected pharmacological action (i.e., lack of effect) of a 
Johnson & Johnson medicinal product

Unexpected therapeutic or clinical benefit from use of a Johnson & 
Johnson medicinal product

Medication error involving a Johnson & Johnson product (with or without 
patient exposure to the medicinal Johnson & Johnson product, e.g., name 
confusion)

Suspected transmission of any infectious agent via a medicinal product. 
11.4.2 SAE Reporting
All SAEs that occur after informed consent is signed, during treatment, or within 
30 days of the last dose of treatment must be reported to the DF/HCC Sponsor-
Investigator on the local institutional SAE form and JANSSEN SCIENTIFIC 
AFFAIRS, LLC  (by the Sponsor-Investigator or designee) on a J&J SAE Form. 
This includes events meeting the criteria outlined in Section 11.1.2, as well as the 
following:

Grade 2 (moderate) and Grade 3 (severe) Events – Only events that are 
unexpected and possibly, probably or definitely related/associated with the 
intervention.

All Grade 4 (life-threatening or disabling) Events – Unless expected AND 
specifically listed in the protocol as not requiring reporting.

All Grade 5 (fatal) Events – When the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention. 






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event to be irreversible, or the participant is lost to follow-up. The presence and 
resolution of AEs and SAEs (with dates) should be documented on the appropriate case 
report form and recorded in the participant’s medical record to facilitate source data 
verification. 
For some SAEs, the  Sponsor Investigator 
 or designee may 
follow-up by telephone, fax, and/or monitoring visit to obtain additional case details 
deemed necessary to appropriately evaluate the SAE report (e.g., hospital discharge 
summary, consultant report, or autopsy report). 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall PI and their respective IRB of any unanticipated death or 
AE occurring after a participant has discontinued or terminated study participation that 
may reasonably be related to the study.  


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12. DATA AND SAFETY MONITORING
12.1 Data Reporting
12.1.1 Method 
The Clinical Trials Research Informatics Office (CTRIO) will collect, manage, 
and monitor data for this study. 
12.1.2 Data Submission 
The schedule for completion and submission of case report forms (paper or 
electronic) to the CTRIO is as follows:
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration with CTRIO.
On Study Form
Within 14 days of registration.
Baseline Assessment Form
Within 14 days of registration.
Treatment Form
Within 10 days of the last day of the cycle.
AE Report Form
Within 10 days of the last day of the cycle. If 
AEs are ongoing at the end of the last cycle, 
continue to submit AE reports until 
resolution or 30 days post-treatment.
Response Assessment Form
Within 10 days of the completion of the cycle 
required for response evaluation.
Off Treatment/Off Study 
Form
Within 14 days of completing treatment or 
being taken off study for any reason.
Follow up/Survival Form
Within 14 days of the protocol defined follow 
up visit date or call.
12.2 Safety Meetings
The DF/HCC DSMC will review and monitor toxicity and accrual data from this trial. 
The committee is composed of clinical specialists with experience in oncology and who 
have no direct relationship with the study. Information that raises any questions about 
participant safety will be addressed with the PI and study team.


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The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; dose-limiting toxicity information; 
all grade 2 or higher unexpected AEs that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, 
summary of all deaths while being treated and during active follow-up; any response 
information; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request. 
12.3 Monitoring 
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the DF/HCC Overall PI (or Protocol Chair) or DF/HCC. The purpose of 
these audits or inspections is to examine study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, 
and accurately reported in accordance with the protocol, institutional policy, and any 
applicable regulatory requirements. 
All data will be monitored for timeliness of submission, completeness, and adherence 
to protocol requirements. Monitoring will begin at the time of participant registration 
and will continue during protocol performance and completion. 
See Appendix E (Data Safety Monitoring Plan) section 5: Monitoring :Quality 
Control) for additional details on study monitoring.


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13. REGULATORY CONSIDERATIONS
13.1 Protocol Review and Amendments
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location. 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB and Janssen Scientific Affairs, LLC prior to implementation. Any 
changes in study conduct must be reported to the IRB. The DF/HCC Overall PI (or 
Protocol Chair) will disseminate protocol amendment information to all participating 
investigators. 
All decisions of the IRB concerning the conduct of the study must be made in writing.
13.2 Informed Consent
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file. 
13.3 Ethics and Research Practices
This study is to be conducted according to the following considerations, which 
represent good and sound research practice:

US CFR governing clinical study conduct and ethical principles that have their 
origin in the Declaration of Helsinki
o
Title 21 Part 50 – Protection of Human Subjects 
 
o
Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
 
o
Title 21 Part 56 – Institutional Review Boards 
 




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provide AA to each participating site. This will be coordinated through a third 
party drug distribution supplier. A participating site may order AA only after the 
initial IRB approval for the site has been forwarded by the Coordinating Center to 
the supplier. 


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14. STATISTICAL CONSIDERATIONS 
14.1 Study Design/Endpoints
Mineralocorticoid excess (ME) failure will be defined as the use of exogenous 
steroids (prednisone) to control symptoms of ME related to hypokalemia and 
hypertenstion. Based on the results of the randomized, phase III study that 
evaluated AA in chemotherapy-naive patients with metastatic CRPC (n=1,088 
patients).[15], the incidence of hypertension was 9.4% grade 2 and 3.9% grade 3. 
The incidence of hypokalemia was 0.9% grade 2, 2.2% grade 3, and 0.2% grade 
4. Therefore, the acceptable rate of ME failure in this study will be 10%. The 
ME failure rate is expected to be similar between metastatic and non-metastatic 
populations. The sample size is 60 participants.
Although the management of hypertension and hypokalemia is expected to be 
adequate according to the prescribed guidelines, the study cohort will be 
continuously monitored for excessive ME failure. Through sequential testing, 
at a given analysis, there will be a rule for suspending or continuing the 
experiment by making additional observations. Specifically, criteria for 
identifying an excessive number of participants with ME failure will be based 
on the sequential probability test with α=0.10, β=0.10, po=0.10 and pa=0.25.[33] 
Every time a participant is classified as having ME failure, the cumulative 
number of participants (X) with ME failure is compared with the number of 
participants evaluable for toxicity (N) and an associated cutoff of evaluable 
participants (Nx). If the number of participants, N, is greater Nx, accrual will 
continue. If the number of participants, N, is less than Nx, accrual will be 
suspended. Table 1 below gives the criteria for suspending accrual to evaluate 
more fully the data on ME toxicity. For example, when the 3rd event of ME 
failure is observed, the trial will suspend for further review of ME toxicity data 
if the number of evaluable participants is less than or equal to 6 participants.


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Table 1. Criteria for Excessive ME Failure
po=10% and pa=25%;      
alpha=0.10 and beta=0.10
# pts who 
experienced 
ME failure
Suspend 
trial if # 
evaluable 
pts N is </= 
Nx
X
Nx
3
</= 6
4
</= 12
5
</= 18
6
</= 24
7
</= 30
8
</= 36
9
</= 42
10
</= 48
11
</= 54
12
</= 60
With the above rules, there is low probability that the trial would be flagged for 
excessive ME failure if the true chance of ME failure were 10% and a high 
probability the trial would be flagged for excessive ME failure if the true 
chance of ME failure were about 25%. The table below summarizes these 
probabilities based on 10,000 simulations. These values are deemed accurate to 
+/- 0.01 based on a 95% confidence interval. If the true underlying proportion 
of ME failure is 10% then the probability of identifying excessive ME failure is 
0.082 whereas if the true underlying proportion is 25% the probability is 0.907.
Table 2. Probability of Identifying Excessive ME Failure Under Various 
True ME Failure Rates
True ME Failure Rate
5%
10%
15%
20%
25%
30%
Probability of 
Identifying Excessive 
ME Failure
0.006
0.082
0.345
0.688
0.907
0.984
The target accrual rate is 4-5 patients per month for an accrual duration of 
approximately 12 - 15 months for enrollment of 60 participants. The accrual 
mix is expected to be divided equally between metastatic and non-metastatic 
participants.
14.2 Analysis of Secondary Endpoints
Safety and tolerability associated with AA monotherapy and AA + prednisone for 
those with PSA progression on AA monotherapy will be evaluated separately. All 


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participants who receive at least 1 dose of study drug will be included in these 
analyses. A summary of all Grade 1-4 treatment-related toxicities will be provided by 
toxicity type and maximum grade. The maximum grade consolidates the reports of a 
given type of toxicity for a participant over time by taking the maximum grade across 
time (i.e. a participant appears only once for a given type of toxicity). Participants with 
reports of multiple toxicities of different types are reported multiple times under the 
relevant toxicity categories. ‘Treatment-related’ toxicities are defined by an attribution 
as possible, probable or definite.  With 60 participants, the maximum width of a 90% 
CI for a given toxicity rate is 22%. Within a given metastatic status subgroup (n=30), 
the maximum width is 32%. The probability of observing at least one rare severe 
toxicity (true rate=5%) is 95% for the overall cohort and 78.5% within a metastatic 
status subgroup. The number of cycles completed with and without dose modifications 
and treatment delays as well as prednisone use will be tabulated overall and by 
metastatic status subgroup.
Serum levels and changes over time of ACTH, corticosteroid intermediates, serum 
androgen concentrations, BMI and Hgb A1-C will be summarized using descriptive 
statistics (mean, median, standard deviation, interquartile range). Correlation between 
measures will be assessed graphically with scatter plots and using Pearson correlation 
coefficients. The paired t-test will be used to determine if treatment with AA 
monotherapy is associated with a change in levels pre- to post- treatment. Assuming the 
standard deviation (SD) of percentage change is 50%, given n=54 treated participants 
with samples at both timepoints (90% sample yield), the paired t-test will have 80% 
power to detect a change pre- to post-treatment of 19.4% (0.39 SD). Within a metastatic 
status subgroup, the effect size is 28% (0.56 SD) If the data display significant non-
normality of distribution, non-parametric tests or data transformations will be 
employed. 
PSA response to AA monotherapy (and AA + prednisone for those with PSA 
progression on AA monotherapy) will be summarized as frequency and percent. 
Participants who are unevaluable for response will be included in the denominator as 
nonresponders when calculating the response rate. Duration of PSA response for the 
regimen of AA monotherapy (and AA + prednisone for those with PSA progression on 
AA monotherapy) will be defined relative to the first achievement of PSA response and 
will be estimated using the method of Kaplan and Meier. The above analysis will also 
be performed within metastatic status subgroup.
Participants with measurable disease will be evaluated for response using RECIST 1.1 
criteria. Time to progression of bone lesions or measurable disease will be estimated 
using Kaplan-Meier estimates.
We estimate that the overall yield of evaluable tissue samples for paired testing will be 
43% of metastatic participants (n=13). This assumes approximately one-half (53%; 
n=16) of metastatic participants will have paired tissues samples submitted optionally. 
Based on our prior experience, we anticipate that 75% of men will undergo bone biopsy 
and 25% soft tissue biopsy. We anticipate that 75% (n=9/12) of bone biopsy specimens 


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and 100% (n=4/4) of soft tissue specimens will have sufficient tumor for nucleic acid 
analysis. Whole exome and transcriptome sequencing results will be analyzed for 
somatic mutations, insertions and deletions, copy number alterations, overexpressed 
genes, chimeric transcripts, and alternatively spliced variants and a complete set of 
potential driver alterations will be compiled at both time points. For each driver 
alteration, the proportion of patients with the alteration present will be calculated along 
with 90% confidence intervals. With the stated evaluable sample sizes, the maximum 
width on a given alteration rate at baseline or progression is approximately 49%. 
Further, there is greater than a 33% probability of observing one or more rare (true 
probability 3%) alteration. 
Tissue androgen concentrations will also be quantified and summarized using 
descriptive statistics (mean, median, standard deviation (SD), minimum, maximum, 
interquartile range). In evaluating the effect of treatment, the paired T-test (or Wilcoxon 
signed-rank test, if appropriate) will be used to evaluate whether the change in level 
between collection time points is significant. With 13 evaluable paired samples, a 42% 
percent change in level can be detected with 80% power assuming a two-sided 0.05 
alpha and standard deviation of percentage change of 50%. The effect size narrows to 
37% assuming two-sided 0.10 alpha. 
CTCs will be isolated and enumerated per standard unit of blood with assessment time 
points at baseline, during treatment (every 28-day cycle), and at progression. Mixed 
models will be used to evaluate longitudinal CTC counts treated as continuous and as 
ordinal according to 4 classes: 0 (undetectable), <5, 5-100, >100.[28] Time will be 
defined as months since start of treatment (day 1/cycle 1). Effects at each time point 
will be reported and evidence of significant change based on 0.05 alpha evaluated. 
CTCs will also be characterized by the percentage of the AR that is localized to the 
nucleus. Descriptive statistics including the median, minimum and maximum 
percentage of AR nuclear localization will be detailed. The relationship between CTC 
counts and nuclear AR localization will be evaluated graphically with scatter plots and 
using Pearson correlation coefficient. AR gene sequencing will also be performed on 
CTC samples with number and type of mutations as well as AR splice variants 
occurring over time tabulated. Agreement between AR mutation status per CTCs versus 
per tissue sequencing will be quantified for common mutations using Cohen’s Kappa. 
Kappa is expected to be of substantial agreement (0.61-0.80). As exploratory, analyses 
will be performed within metastatic status subgroup.
Specific AR mutations will be evaluated in ctDNA pre-treatment, during treatment 
(every 3 cycles), and at progression. Frequency of AR mutations will be tabulated. 
Agreement between AR mutation status per ctDNA versus per tissue sequencing will be 
quantified for common mutations using Cohen’s Kappa. Kappa is expected to be of 
substantial agreement (0.61-0.80). As exploratory, analyses will be performed within 
metastatic status subgroup.


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The two-group t-test will be used to examine the difference in level and/or change pre- 
to post-treatment in biomarker levels by PSA and RECIST (measurable disease 
participants) response outcome overall and within metastatic status subgroup. 
Assuming a 90% sample yield, if PSA response rate is 25% (14 responders and 40 non-
responders), there is 82% power to detect an effect of 0.89 SD at a two-sided 
significance level of 0.05. Continuous levels may be dichotomized at the median for 
further evaluation. Association between response and categorical biomarkers will be 
evaluated using Fisher’s exact test. Analyses of these correlative endpoints will be 
exploratory and adjustments will not be made for multiple comparisons.


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15. PUBLICATION PLAN
The data will be collected by 
 and analyzed by 
 and the statistical team 
at DFCI. The results will be shared with JANSSEN SCIENTIFIC AFFAIRS, LLC. The 
milestone plan is detailed below.
Milestone
Timeline 
Planned Interim Analysis (see below)
6 months from enrollment of first subject 
Enrollment of 100% of Target Enrollment
12 months from enrollment of first subject
Last Subject/Last Visit on Study
24 months from enrollment of first subject
Collection and Analysis of Primary and 
Secondary Endpoint Data 
3 months following last subject/last visit 
Completion of Final Study Report 
6 months following last subject/last visit 


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16. REFERENCES 
1. Jarman M, Barrie SE, Llera JM. The 16,17-double bond is needed for irreversible inhibition 
of human cytochrome p45017alpha by abiraterone (17-(3-pyridyl)androsta-5, 16-dien-3beta-ol) 
and related steroidal inhibitors. J Med Chem. 1998;41:5375-81.
2. Rowlands MG, Barrie SE, Chan F, Houghton J, Jarman M, McCague R et al. Esters of 3-
pyridylacetic acid that combine potent inhibition of 17 alpha-hydroxylase/C17,20-lyase 
(cytochrome P45017 alpha) with resistance to esterase hydrolysis. J Med Chem. 1995;38:4191-7.
3. Auchus RJ. Overview of dehydroepiandrosterone biosynthesis. Semin Reprod Med. 
2004;22:281-8.
4. Stein MN, Goodin S, Dipaola RS. Abiraterone in prostate cancer: a new angle to an old 
problem. Clin Cancer Res. 2012;18:1848-54.
5. Yap TA, Carden CP, Attard G, de Bono JS. Targeting CYP17: established and novel 
approaches in prostate cancer. Curr Opin Pharmacol. 2008;8:449-57.
6. Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for 
prostate cancer. Nat Clin Pract Urol. 2008;5:610-20.
7. De Coster R, Wouters W, Bruynseels J. P450-dependent enzymes as targets for prostate 
cancer therapy. J Steroid Biochem Mol Biol. 1996;56:133-43.
8. Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J et al. Antiandrogen 
withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer 
patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004;22:1025-33.
9. Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S et al. Phase I clinical trial of 
a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate 
cancer commonly remains hormone driven. J Clin Oncol. 2008;26:4563-71.


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10.
Ryan CJ, Smith MR, Fong L, Rosenberg JE, Kantoff P, Raynaud F et al. Phase I clinical 
trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with 
castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 
2010;28:1481-8.
11.
Attard G, Reid AH, A'Hern R, Parker C, Oommen NB, Folkerd E et al. Selective inhibition 
of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant 
prostate cancer. J Clin Oncol. 2009;27:3742-8.
12.
Danila DC, Morris MJ, de Bono JS, Ryan CJ, Denmeade SR, Smith MR et al. Phase II 
multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-
treated castration-resistant prostate cancer. J Clin Oncol. 2010;28:1496-501.
13.
Reid AH, Attard G, Danila DC, Oommen NB, Olmos D, Fong PC et al. Significant and 
sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the 
CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010;28:1489-95.
14.
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L et al. Abiraterone and 
increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005.
15.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P et al. Abiraterone 
in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med. 2012.
16.
O'Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M et al. Hormonal 
impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in 
patients with prostate cancer. Br J Cancer. 2004;90:2317-25.
17.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-
29.


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18.
Vasaitis TS, Bruno RD, Njar VC. CYP17 inhibitors for prostate cancer therapy. J Steroid 
Biochem Mol Biol. 2011;125:23-31.
19.
Nakamura Y, Suzuki T, Fukuda T, Ito A, Endo M, Moriya T et al. Steroid sulfatase and 
estrogen sulfotransferase in human prostate cancer. Prostate. 2006;66:1005-12.
20.
Attard G, Cooper CS, de Bono JS. Steroid hormone receptors in prostate cancer: a hard 
habit to break? Cancer Cell. 2009;16:458-62.
21.
Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK et al. Mutation of 
the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 
1995;332:1393-8.
22.
Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K et al. Interactions 
of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a 
rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Res. 
2012;72:2176-82.
23.
McDougall R, Sibley J, Haga M, Russell A. Outcome in patients with rheumatoid arthritis 
receiving prednisone compared to matched controls. J Rheumatol. 1994;21:1207-13.
24.
Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B et al. 
Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse 
events. Am J Med. 1994;96:115-23.
25.
Attard G, Reid AH, Auchus RJ, Hughes BA, Cassidy AM, Thompson E et al. Clinical and 
biochemical consequences of CYP17A1 inhibition with abiraterone given with and without 
exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol 
Metab. 2012;97:507-16.


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26.
Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM et al. 
Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: 
induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 
2011;17:5913-25.
27.
Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM et al. Increased 
expression of genes converting adrenal androgens to testosterone in androgen-independent 
prostate cancer. Cancer Res. 2006;66:2815-25.
28.
Amato RJ, Melnikova V, Zhang Y, Liu W, Saxena S, Shah PK et al. Epithelial cell 
adhesion molecule-positive circulating tumor cells as predictive biomarker in patients with 
prostate cancer. Urology. 2013;81:1303-7.
29.
Taplin ME, Regan MM, Ko YJ, Bubley GJ, Duggan SE, Werner L et al. Phase II study of 
androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in 
asymptomatic castration-resistant prostate cancer. Clin Cancer Res. 2009;15:7099-105.
30.
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA et al. Design and 
end points of clinical trials for patients with progressive prostate cancer and castrate levels of 
testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin 
Oncol. 2008;26:1148-59.
31.
Chi KN, Tolcher A, Lee P, Rosen PJ, Kollmannsberger CK, Papadopoulos KP et al. Effect 
of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and 
theophylline in patients with metastatic castration-resistant prostate cancer. Cancer Chemother 
Pharmacol. 2013;71:237-44.


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32.
Ryan CJ, Shah S, Efstathiou E, Smith MR, Taplin ME, Bubley GJ et al. Phase II study of 
abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer 
displaying bone flare discordant with serologic response. Clin Cancer Res. 2011;17:4854-61.
33.
Wald A, Sequential Tests of Statistical Hypotheses. The Annals of Mathematical Statistics 
2009; 16 (2); 117-186.


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17. APPENDICES
APPENDIX A: Performance Status Criteria
APPENDIX B: Required Forms at Registration
APPENDIX C: Participant’s Pill Diary
APPENDIX D: Imaging Procedural Information and Measurement of Tumor Flare
APPENDIX E: Data and Safety Monitoring Plan 


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17.1 APPENDIX A: Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Description
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
2
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, 
hospitalization indicated. Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair.
10
Moribund, fatal processes 
progressing rapidly. 
5
Dead.
0
Dead.


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17.2 APPENDIX B: Required Forms at Registration
 
The DFCI coordinator will Fax to DFCI ODQ:

Current IRB approved consent form signed by participant and Investigator (MD 
only)

HIPAA authorization form (if separate from the informed consent document)

 Signed and dated DFCI eligibility checklist (signed by MD or RN)

The following source documentation is typically required: 

Please note: Additional documentation may be required by the lead institution.
o
Labs for PSA values used to determine eligibility (Lab values used to 
determine eligibility, including screening PSA)
o
Documentation of prior treatments/procedures performed to treat 
prostate cancer (e.g. Chemotherapy, Cryotherapy, Hormone Therapy,
o
Radiation therapy with start and stop dates and dosing information if 
applicable)
o
Reports documenting disease status

Chest CT

CT or MRI Abdomen and Pelvis

Bone Scan 
o
Pathology Report 
o
Concomitant medication list
o
Progress note or equivalent documentation of consenting visit
o
Progress note documenting medical history and oncologic history
o
All screening labs
o
Screening visit note, with BP, vital signs, ECOG Performance status
o
MUGA Scan or ECHO


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17.3 APPENDIX C: PARTICIPANT’S PILL DIARY
Today’s Date: ____________________________
Participant Name: ____________________________ 
Participant Study ID: ____________________
Cycle Number: ____________________________
INSTRUCTIONS TO THE PARTICIPANT:
1.
Complete one form for each cycle (28 days).
2.
You will take ____ tablets each day by mouth. No food should be consumed for at least two hours before the 
dose is taken and for at least one hour after the dose is taken.
3.
Record the date, the number of tablets you took, and when you took them.
4.
If you have any comments or notice any side effects, please record them in the comments column. 
5.
Please bring your pill bottle and this form to your physician when you go to your next appointment.
Date 
Day
Number of 
Tablets 
Time
Comments 
Date
Day
Number of 
Tablets
Time
Comments 
1
15
2
16
3
17
4
18
5
19
6
20
7
21
8
22
9
23
10
24
11
25
12
26
13
27
14
28
 
Participant’s Signature: ____________________________________________ Date: ________________________
 Physician’s office will complete this section:
 Date participant started protocol treatment: 
________________________________________________________________
 Date participant was removed from study: 
_________________________________________________________________
 Participant’s planned daily dose: 
________________________________________________________________________
 Total number of pills taken this month: ________________________________________________________________
 Physician/Nurse/Data Manager’s Signature: ________________________ Date: _______________________________


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17.4 APPENDIX D: Imaging Procedural Information and Measurement of Tumor Flare
All participants enrolled in the study will be evaluated with 99mTc-MDP skeletal scintigraphy at 
baseline and every 3 months after commencing therapy, according to the schedule shown in the 
study calendar. It is anticipated that bone scans and diagnostic CT studies will be obtained within 
a few days of each other, preferably over a 2-3 day period. 
Image Acquisition Parameters
Imaging acquisition parameters should follow the local standard of care when possible, within 
the constraints detailed below.
Whole body bone scans should be acquired in the anterior and posterior projections 
approximately 3 hours following the IV administration of approximately 25 
mCi99mTcmethylene diphosphonate (MDP). The imaging parameters should be consistent 
between baseline and follow-up time points. In specific cases of symptoms suggesting cord 
compression or impending fracture, additional imaging may be warranted such as radiographs or 
MRI.
For the purposes of clinical management, each bone scan will be assessed by an experienced 
nuclear medicine physician. For the purposes of the research study, all 99mTc-MDP bone scan 
images will be assessed by three experienced nuclear medicine physicians with final results 
based on consensus. For each participant, each bone scan series will be analyzed side by side on 
the same workstation with special care taken to display images at similar intensity settings. The 
baseline scans will be assessed qualitatively for the presence or absence of bone metastases. 
Bone scans will be called equivocal if scintigraphic abnormalities cannot be confidently 
categorized as benign or malignant. Bone scans obtained 3 months after the initiation of therapy 
will be assessed qualitatively for a change in intensity of lesions present on the baseline scan or 
for the presence of new lesions. Bone scans obtained 6 months after initiation of therapy will be 
compared to the baseline and 3-month scans for the intensity and number of skeletal lesions.
Tumor Flare Measurement
A flare will be recorded if there is stable or decreasing PSA and there is an increase in intensity 
or number of lesions between the baseline and 3-month scan and a subsequent reduction in 
intensity or number of lesions on the 6-month scan. Results will be correlated with RECIST (1.1) 
based on diagnostic CT obtained at baseline, 3-months and 6-months following therapy 
initiation. Results will also be correlated with participant outcome and with tissue analysis.


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17.5 APPENDIX E: Multi-Center Data and Safety Monitoring Plan
TABLE OF CONTENTS
1.
OBJECTIVES ......................................................................................................................................................1
1.1
Study Design.....................................................................................................................................................1
1.2
Primary Objectives...........................................................................................................................................1
1.3
Secondary Objectives .......................................................................................................................................1
1.4
Exploratory Objectives.....................................................................................................................................2
2.
BACKGROUND ..................................................................................................................................................4
2.1
Study Agent(s)...................................................................................................................................................4
2.1.1
Abiraterone acetate (JNJ212082)
4
2.2
Study Disease..................................................................................................................................................11
2.3
Rationale.........................................................................................................................................................11
2.4
Correlative Studies Background.....................................................................................................................12
3.
PARTICIPANT SELECTION .........................................................................................................................14
3.1
Eligibility Criteria ..........................................................................................................................................14
3.1.1
Be a male ≥ 18 years of age.
14
3.1.2
Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate 
without >50% neuroendocrine differentiation or small cell histology.
14
3.1.3
Participants must have progressive disease as defined by one or more of the following:
14
3.1.4
Participants without orchiectomy must be maintained on LHRH agonist/antagonist therapy.
14
3.1.5
Participants must have a testosterone level < 50 ng/dL.
14
3.1.6
Participants may have had any number of previous hormonal therapies (antiandrogens including 
enzalutamide, estrogens, finasteride, dutasteride, ketoconazole) provided these were discontinued ≥ 4 weeks 
before starting the trial. Prior therapy with steroids is allowed though these must be discontinued ≥ 2 weeks 
before starting the trial. Inhaled, topical, and intra-articular steroids are allowed.
14
3.1.7
Participants may have had up to two previous cytotoxic therapeutic regimens provided these were 
discontinued ≥ 4 weeks before starting the trial.
14
3.1.8
At least a 4 week interval from previous prostate cancer treatment other than LHRH 
agonist/antagonist therapy, bisphosphonates, denosumab to the start of protocol therapy.
14
3.1.9
Participants receiving bisphosphonates therapy or denosumab can be maintained on this therapy. If 
participants have not started bisphosphonates, it is recommended that they start treatment after the first 
(optional) biopsy.
15
3.1.10
ECOG performance status < 2 (Karnofsky >60%, see Appendix A).
15
3.1.11
Participants must have normal organ and marrow function as defined below:
15
3.1.12
Controlled blood pressure (systolic blood pressure <140 and diastolic blood pressure <90) on no 
more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents 
will be counted based on the number of active agents in each formulation.
15
3.1.13
Left ventricular ejection fraction ≥ 50%.
15
3.1.14
Have signed an informed consent document indicating that the subjects understands the purpose of 
and procedures required for the study and are willing to participate in the study.
15
3.1.15
Be willing/able to adhere to the prohibitions and restrictions specified in this protocol.
15
3.1.16
Written Authorization for Use and Release of Health and Research Study Information (US sites 
only) has been obtained.
15
3.1.17
Able to swallow the study drug whole as a tablet.
15


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3.1.18
Willing to take AA on an empty stomach; no food should be consumed at least two hours before 
and for at least one hour after the dose AA is taken.
15
3.1.19
Participants who have partners of childbearing potential must be willing to use a method of birth 
control with adequate barrier protection as determined to be acceptable by the PI during the treatment period 
and for 1 week after last dose of AA.
15
3.2
Exclusion Criteria........................................................................................................................................16
3.2.1
Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 
limit compliance with study requirements or would make prednisone/prednisolone (corticosteroid) use 
contraindicated.
16
3.2.2
Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic 
events in the past 6 months, severe or unstable angina, or NYHA Class III or IV heart disease or cardiac 
ejection fraction measurement of < 50 % at baseline.
16
3.2.3
Thromboembolism within 6 months of Cycle 1, Day 1.
16
3.2.4
Severe hepatic impairment (Child-Pugh Class C).
16
3.2.5
History of pituitary or adrenal dysfunction.
16
3.2.6
Poorly controlled diabetes.
16
3.2.7
History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere 
with the absorption of the study drug.
16
3.2.8
Have a pre-existing condition that warrants long-term corticosteroid use. Inhaled steroids are 
allowed. 16
3.2.9
Individuals with a history of a different malignancy are ineligible except for the following 
circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free 
for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) 
individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: superficial 
bladder cancer, basal cell or squamous cell carcinoma of the skin.
16
3.2.10
Known brain metastasis.
16
3.2.11
Prior therapy with AA.
16
3.2.12
Have known allergies, hypersensitivity, or intolerance to AA or prednisone or their excipients. 16
3.2.13
Surgery or local prostatic intervention within 4 weeks of the first dose. In addition, any clinically 
relevant issues from the surgery must have resolved prior to Cycle 1, Day 1.
16
3.2.14
Major surgery or radiation therapy within 4 weeks of Cycle 1, Day 1.
17
3.2.15
Strontium-89, samarium-153, or radium-223 therapy within 4 weeks of Cycle 1, Day 1.
17
3.2.16
Radiotherapy, chemotherapy or immunotherapy within 4 weeks, or palliative radiation to bone 
metastases within 14 days of administration of Cycle 1, Day 1.
17
3.2.17
Current enrollment in an investigational drug or device study or participation in such a study 
within 4 weeks of Cycle 1, Day 1.
17
3.2.18
Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to a 
NCI CTCAE (version 4) grade of ≤ 1. Chemotherapy induced alopecia and grade 2 peripheral neuropathy are 
allowed.
17
3.2.19
Condition or situation which, in the investigator’s opinion, may put the participant at significant 
risk, may confound the study results, or may interfere significantly with participant’s participation in the 
study.
17
3.2.20
Individuals not willing to comply with the procedural requirements of this protocol.
17
3.2.21
HIV-positive individuals on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with AA.
17
3.3
Inclusion of Minorities and Other Underrepresented Populations................................................................17
4.
REGISTRATION PROCEDURES..................................................................................................................18
4.1
General Guidelines for DF/HCC and DF/PCC Institutions ..........................................................................18
4.2
Registration Process for DF/HCC and DF/PCC Institutions......................................................................18
4.3
General Guidelines for Other Participating Institutions ...............................................................................18
4.4
Registration Process for Other Participating Institutions .............................................................................18


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5.
TREATMENT PLAN........................................................................................................................................20
All protocol required therapy will be prescribed by prescription and taken by the participant on an outpatient 
basis. Participants will be treated with four 250 mg tablets (1,000 mg) of AA taken orally. No food should be 
consumed for at least two hours before the dose and for at least one hour after the dose. The tablets should be 
swallowed whole with water. Tablets should not be crushed or chewed.  All participants without orchiectomy 
will be maintained on LHRH agonist/antagonist therapy.
20
5.1
Pre-treatment Criteria..................................................................................................................................21
5.1.1
For Cycle 1, Day 1, the following parameters must be met:
21
5.2
Agent Administration ....................................................................................................................................21
5.2.1
Abiraterone acetate
21
5.2.2
Prednisone
22
5.3
General Concomitant Medications and Supportive Care Guidelines............................................................23
5.4
Duration of Therapy .....................................................................................................................................23
5.5
Duration of Follow-Up .................................................................................................................................24
5.6
Criteria for Removal from Study..................................................................................................................24
6.
EXPECTED TOXICITIES, TOXICITY MONITORING, TOXICITY MANAGEMENT AND DOSING 
DELAYS/MODIFICATIONS...........................................................................................................................25
6.1
Expected Toxicities.........................................................................................................................................25
6.1.1
Adverse Reactions for AA
25
Hypertension, Hypokalemia and Fluid Retention
25
See current package insert for AA (Zytiga) for additional information on AA (http://www.zytiga.com/).
27
6.1.2
AEs for Prednisone
27
A daily dose of 10 mg of prednisone is near the physiologic steroid dose and thus it is not expected that 
prednisone will cause significant side effects. Potential side effects of prednisone are listed below:
27
Close monitoring of blood sugars is recommended in diabetic participants. Close monitoring for infections is 
also recommended. It is recommended the prednisone never be stopped suddenly. Gradual tapering of the dose 
and/or schedule of prednisone is recommended when discontinuing therapy. Monitoring for signs and 
symptoms of adrenal insufficiency during prednisone administration and tapering is recommended.
27
6.2
Toxicity Monitoring........................................................................................................................................27
6.2.1
Monitoring for Hypertension, Hypokalemia and Fluid Retention
27
6.2.2
Monitoring for Adrenal Insufficiency
28
6.2.3
Monitoring for Hepatotoxicity
28
Participants will be monitored closely for symptoms and signs of hepatotoxicity. Measure serum 
transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AA, weekly for the first 
cycle, then on Day 1 of each subsequent cycle thereafter. Promptly measure serum total bilirubin, AST, and 
ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or 
bilirubin from the participant’s baseline should prompt more frequent monitoring. For subjects who 
developed hepatotoxicity, please refer to section 6.3 monitoring parameters and  toxicity management.
28
6.3
Toxicity Management and Dosing Delays/Modifications ..............................................................................28
6.3.1
Management of Hypertension
29
6.3.2
Management of Hypokalemia
30
6.3.3
Management of Limb Edema
31
The syndrome of mineralocorticoid excess is classically associated with hypertension, hypokalemia, and limb 
edema. It is atypical for limb edema to be the only symptom of mineralocorticoid excess associated with AA 
treatment. In a study by Attard et al of 42 patients treated with AA monotherapy, zero patients developed limb 
edema as the only symptom of mineralocorticoid excess.[25] Given such, prednisone should not be used in the 
management of isolated limb edema without other symptoms of mineralocorticoid excess to include 
hypertension and/or hypokalemia. If hypertension and/or hypokalemia occur, refer to section 6.3.1 and 6.3.2 
respectively for appropriate management. If grade 3 limb edema occurs, please refer to section 6.3 for 
instruction regarding dose delays/reductions.
31


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6.3.4
Management of Fatigue
31

Grade 1-2 Fatigue:
31
o
Management per investigator. No investigational product dose reduction.
31

Grade 3 Fatigue:
31
o
Hold AA. Once the toxicity has resolved to ≤ grade 1 or baseline, resume AA at the first dose level 
reduction (750 mg daily).
31
6.3.5
Management of LFT abnormalities
31
6.3.6
Management of other toxicities
33
7.
DRUG FORMULATION AND ADMINISTRATION...................................................................................34
7.1
Abiraterone acetate ........................................................................................................................................34
7.1.1
Description
34
7.1.2
Form
34
AA 250-mg tablets are oval, white to off-white and contain AA and compendial (USP/NF/EP) grade lactose 
monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium 
stearate, colloidal silicon dioxide, and purified water, in descending order of concentration (the water is 
removed during tabletting).
34
7.1.3
Storage and Stability
34
Pharmacy Storage Requirements..............................................................................................................................34
7.1.4
Compatibility
34
7.1.5
Handling
34
7.1.6
Availability
35
7.1.7
Ordering
35
7.1.8
Accountability
35
7.1.9
Destruction and Return
36
7.2
Prednisone .....................................................................................................................................................36
7.2.1
Description
36
7.2.2
Form
36
7.2.3
Storage and Stability
36
7.2.4
Compatibility
36
7.2.5
Handling
36
7.2.6
Availability
36
Prednisone will not be provided by the study and will be prescribed by standard prescriptions.
36
8.
CORRELATIVE/SPECIAL STUDIES ...........................................................................................................37
8.1
Data Analysis..................................................................................................................................................37
9.
STUDY CALENDAR ........................................................................................................................................39
10.
MEASUREMENT OF EFFECT ......................................................................................................................41
10.1 Antitumor Effect– Solid Tumors .....................................................................................................................41
10.1.1
Definitions
41
10.1.2
Disease Parameters
42
10.1.3
Methods for Evaluation of Disease
43
10.1.4
Response Criteria
44
10.1.5
Duration of Response
47
10.1.6
Time to Progression
48
Time to Progression: Time to progression is defined as the time from registration to progression, or censored 
at the date of last disease evaluation for those without progression reported.
48
10.1.7
Response Review
48
10.2 Other Response Parameters...........................................................................................................................48


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10.2.4
Descriptive statistics (including mean, standard deviation, minim, minimum, median, interquartile 
range) will be provided on levels of serum hormone and changes from baseline (serum androgen including 
DHEA, DHEA-S, androstenedione, testosterone, DHT; serum corticosteroid/ mineralocorticoid intermediates 
to include pregnenolone, progesterone, deoxycorticosterone, corticosterone, aldosterone, 17α-
hydroxypregnenolone, 17α-hydroxypregesterone, 11-deoxycortisol, cortisol; serum ACTH).
48
11.
ADVERSE EVENT REPORTING REQUIREMENT...................................................................................49
11.1 Definitions ......................................................................................................................................................49
11.1.1
Johnson & Johnson Medicinal Product
49
The specific Johnson & Johnson drug under study and any other Johnson & Johnson medicinal product.
49
11.1.2
PQC
49
Any discrete concern that questions the identity, quality, durability, reliability, safety, efficacy or intended 
performance of a drug product. A complaint may allege an injury or malfunction associated with the use of the 
drug product. It may also involve the design, literature, packaging, advertising, availability, physical 
appearance or promotion of the drug product.
49
11.1.3
Special Reporting Situations
49
When a report contains a Johnson & Johnson product, an identifiable patient, and identifiable reporter, the 
following events represent Special Reporting Situations:
49

overdose of a Johnson & Johnson medicinal product
49

pregnancy exposure (maternal and paternal)
49

exposure to a medicinal product from breastfeeding
49

suspected abuse/misuse of a medicinal Johnson & Johnson product
49

inadvertent or accidental exposure to a medicinal Johnson & Johnson product
49

any failure of expected pharmacological action (i.e., lack of effect) of a Johnson & Johnson medicinal 
product
49

unexpected therapeutic or clinical benefit from use of a Johnson & Johnson medicinal product
49

medication error involving a Johnson & Johnson product (with or without patient exposure to the 
medicinal Johnson & Johnson product, e.g., name confusion)
49

suspected transmission of any infectious agent via a medicinal product.
49
11.1.4
AE
49
Any untoward medical occurrence in a participant or clinical investigation subject administered a medicinal 
product and which does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not related to the medicinal 
product.
49
11.1.5
AE of Special Interest
49
Events that JANSSEN SCIENTIFIC AFFAIRS, LLC  is actively monitoring as a result of a previously 
identified signal (even if non-serious). There are no AEs of special interest identified for abiraterone acetate.50
11.1.6
Adverse Drug Reaction
50
A noxious and unintended response to any dose of the drug (or biological) product for which there is a 
reasonable possibility that the product cause the response.  ‘‘Reasonable possibility’’ means there is evidence 
to suggest a causal relationship between the drug and the. Suspected adverse reaction implies a lesser degree 
of certainty about causality than adverse reaction, which means any AE caused by a drug.
50
11.1.7
SAE
50
An AE or suspected adverse reaction is considered ‘‘serious’’ if, in the view of the PI, it results in any of the 
following outcomes: .................................................................................................................................................50

Death ..............................................................................................................................................................50

A life-threatening AE......................................................................................................................................50
o
Life-threatening AE or life-threatening suspected adverse reaction: An AE or suspected adverse reaction is 
considered ‘‘life-threatening’’ if, in the view of the PI, its occurrence places the participant or subject at 
immediate risk of death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. ....................................................................................................................50


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
Inpatient hospitalization or prolongation of existing hospitalization............................................................50
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. ....................................................................................................50
11.1.8
Expectedness
51
11.1.9
Attribution
51
11.2 Procedures for AE and SAE Recording..........................................................................................................51
Recording should be done in a concise manner using standard, acceptable medical terms...................................51
The AE recorded should not be a procedure or a clinical measurement (i.e. a laboratory value or vital sign) but 
should reflect the reason for the procedure or the diagnosis based on the abnormal measurement. .....................51
Preexisting conditions that worsen in severity or frequency during the Study should also be recorded (a 
preexisting condition that does not worsen is not an AE)........................................................................................52
Further, a procedure or surgery is not an AE; rather, the event leading to the procedure or surgery is considered 
an AE. Any event requiring in-patient hospitalization that occurs during the course of a subject’s participation in 
a trial must be reported as an SAE. Hospitalizations that do not meet the criteria for SAE reporting are:...........52

Reasons described in the Protocol, e.g. drug administration, Protocol-required testing..............................52

Surgery or procedure planned prior to entry into the Study..........................................................................52
If, in the PIs judgment, a clinical significant worsening from baseline is observed in any laboratory or other test 
parameter (e.g. EKG, angiogram), physical exam finding, or vital sign, a corresponding clinical AE should be 
recorded. ..................................................................................................................................................................52
If a specific medical diagnosis has been made, that diagnosis or syndrome should be recorded as the AE, 
whenever possible.  However, a complete description of the signs, symptoms and investigations which led to the 
diagnosis should be provided. For example, if clinically significant elevations of liver function tests are known to 
be secondary to hepatitis, “hepatitis” and not “elevated liver function tests” should be recorded. If the cause is 
not known, the abnormal test or finding should be recorded as an AE, using appropriate medical terminology 
(e.g thrombocytopenia, peripheral edema, QT prolongation).................................................................................52
11.3 Reporting Requirements .................................................................................................................................52
11.4 Reporting to the  Sponsor Investigator...........................................................................................................53
11.4.1
Special Reporting Situations
53
When a report contains a J&J product, an identifiable patient, and identifiable reporter, the following events 
represent Special Reporting Situations:
53

Overdose of a Johnson & Johnson medicinal product
53

Pregnancy exposure (maternal and paternal)
53

Exposure to a medicinal product from breastfeeding
53

Suspected abuse/misuse of a medicinal Johnson & Johnson product
53

Inadvertent or accidental exposure to a medicinal Johnson & Johnson product
53

Any failure of expected pharmacological action (i.e., lack of effect) of a Johnson & Johnson medicinal 
product
53

Unexpected therapeutic or clinical benefit from use of a Johnson & Johnson medicinal product
53

Medication error involving a Johnson & Johnson product (with or without patient exposure to the 
medicinal Johnson & Johnson product, e.g., name confusion)
53

Suspected transmission of any infectious agent via a medicinal product.
53
11.4.2
SAE Reporting
53
11.4.3
Non-SAE Reporting
54
11.5 Reporting to the IRB.......................................................................................................................................54


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11.6 Reporting to the FDA .....................................................................................................................................55
11.7 Reporting to Hospital Risk Management .......................................................................................................55
11.8 Monitoring of AEs and Period of Observation...............................................................................................55
12.
DATA AND SAFETY MONITORING ...........................................................................................................57
12.1 Data Reporting ...............................................................................................................................................57
12.1.1
Method
57
12.1.2
Data Submission
57
12.2 Safety Meetings...............................................................................................................................................57
12.3 Monitoring......................................................................................................................................................58
13.
REGULATORY CONSIDERATIONS ...........................................................................................................59
13.1 Protocol Review and Amendments .................................................................................................................59
13.2 Informed Consent ...........................................................................................................................................59
13.3 Ethics and Research Practices .......................................................................................................................59
13.4 Study Documentation......................................................................................................................................60
13.5 Records Retention...........................................................................................................................................60
13.6 Multi-Center Guidelines.................................................................................................................................60
14.
STATISTICAL CONSIDERATIONS .............................................................................................................62
14.1 Study Design/Endpoints..................................................................................................................................62
14.2 Analysis of Secondary Endpoints ...................................................................................................................63
Safety and tolerability associated with AA monotherapy and AA + prednisone for those with PSA progression 
on AA monotherapy will be evaluated separately. All participants who receive at least 1 dose of study 
drug will be included in these analyses. A summary of all Grade 1-4 treatment-related toxicities will be 
provided by toxicity type and maximum grade. The maximum grade consolidates the reports of a given 
type of toxicity for a participant over time by taking the maximum grade across time (i.e. a participant 
appears only once for a given type of toxicity). Participants with reports of multiple toxicities of 
different types are reported multiple times under the relevant toxicity categories. ‘Treatment-related’ 
toxicities are defined by an attribution as possible, probable or definite.  With 60 participants, the 
maximum width of a 90% CI for a given toxicity rate is 22%. Within a given metastatic status subgroup 
(n=30), the maximum width is 32%. The probability of observing at least one rare severe toxicity (true 
rate=5%) is 95% for the overall cohort and 78.5% within a metastatic status subgroup. The number of 
cycles completed with and without dose modifications and treatment delays as well as prednisone use 
will be tabulated overall and by metastatic status subgroup.........................................................................63
PSA response to AA monotherapy (and AA + prednisone for those with PSA progression on AA 
monotherapy) will be summarized as frequency and percent. Participants who are unevaluable for 
response will be included in the denominator as nonresponders when calculating the response rate. 
Duration of PSA response for the regimen of AA monotherapy (and AA + prednisone for those with 
PSA progression on AA monotherapy) will be defined relative to the first achievement of PSA response 
and will be estimated using the method of Kaplan and Meier. The above analysis will also be performed 
within metastatic status subgroup....................................................................................................................64
Participants with measurable disease will be evaluated for response using RECIST 1.1 criteria. Time to 
progression of bone lesions or measurable disease will be estimated using Kaplan-Meier estimates. ......64
15.
PUBLICATION PLAN .....................................................................................................................................67


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16.
REFERENCES...................................................................................................................................................68
17.
APPENDICES....................................................................................................................................................73
APPENDIX A: Performance Status Criteria ...........................................................................................................73
APPENDIX B: Required Forms at Registration .....................................................................................................73
APPENDIX C: Participant’s Pill Diary ..................................................................................................................73
APPENDIX D: Imaging Procedural Information and Measurement of Tumor Flare ............................................73
APPENDIX E: Data and Safety Monitoring Plan ...................................................................................................73
17.1 APPENDIX A: Performance Status Criteria..................................................................................................74
17.2 APPENDIX B: Required Forms at Registration............................................................................................75
17.3 APPENDIX C: PARTICIPANT’S PILL DIARY .............................................................................................76
17.4 APPENDIX D: Imaging Procedural Information and Measurement of Tumor Flare...................................77
17.5 APPENDIX E: Multi-Center Data and Safety Monitoring Plan....................................................................78
1.0
INTRODUCTION .............................................................................................................................................87
1.1
Purpose...........................................................................................................................................................87
1.2
Multi-Center Data and Safety Monitoring Plan Definitions..........................................................................87
2.0
GENERAL ROLES AND RESPONSIBILITIES...........................................................................................88
2.1
DF/HCC Sponsor ...........................................................................................................................................88
2.2
Coordinating Center.......................................................................................................................................89
2.3
Participating Institution .................................................................................................................................89
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ........................................................90
3.1
Protocol Distribution......................................................................................................................................90
3.2
Protocol Revisions and Closures....................................................................................................................90
3.3
Informed Consent Requirements ....................................................................................................................90
3.4
IRB Documentation ........................................................................................................................................91
3.5
IRB Re-Approval ............................................................................................................................................91
3.6
Participant Confidentiality and Authorization Statement ..............................................................................91
3.6.1
DF/HCC Multi-Center Protocol Confidentiality
92
3.7
DF/HCC Multi-Center Registration...............................................................................................................92
3.7.1 Participant Registration and Randomization.................................................................................................92
3.7.2 Initiation of Therapy.......................................................................................................................................93
3.7.3 Eligibility Exceptions......................................................................................................................................93
3.7.4 Verification of Registration, Dose Levels, and Arm Designation ..................................................................93
3.8
DF/HCC Protocol Case Number....................................................................................................................94
3.9
Protocol Deviations, Exceptions and Violations............................................................................................94
3.9.1 Definitions ......................................................................................................................................................94
3.9.2 Reporting Procedures.....................................................................................................................................94


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3.10 Safety Assessments and Toxicity Monitoring .................................................................................................95
3.10.1
Guidelines for Reporting Serious Adverse Events................................................................................95
3.10.2
Guidelines for Processing IND Safety Reports.....................................................................................96
3.11 Data Management ..........................................................................................................................................96
3.11.1
Data Forms Review...............................................................................................................................96
4.0
REQUISITIONING INVESTIGATIONAL DRUG.......................................................................................96
5.0
MONITORING: QUALITY CONTROL........................................................................................................97
5.1
Ongoing Monitoring of Protocol Compliance ...............................................................................................97
5.2
Evaluation of Participating Institution Performance.....................................................................................98
5.2.1 Monitoring Reports ........................................................................................................................................98
6.0
AUDITING: QUALITY ASSURANCE...........................................................................................................98
6.1
DF/HCC Sponsored Trials.............................................................................................................................98
6.2
Participating Institution .................................................................................................................................99
6.3
DF/HCC Sponsor and Coordinating Center..................................................................................................99
6.4
Sub-Standard Performance ............................................................................................................................99
6.4.1 Corrective Actions..........................................................................................................................................99
18.
APPENDIX F: STRONG CYP3A4 INDUCERS AND INHIBITORS .........................................................99


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1.0
INTRODUCTION
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP should serve as a reference for any sites external to DF/HCC 
that will be participating in the research protocol.
1.1
Purpose
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center 
Multi-Center protocol will comply with Federal Regulations, Health Insurance 
Portability and Accountability Act (HIPAA) requirements and applicable DF/HCC 
Standard Operating Procedures 
1.2
Multi-Center Data and Safety Monitoring Plan Definitions
DF/HCC Multi-center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where a 
DF/HCC investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer 
Care (DF/PCC) Network Clinical Trial Affiliates. 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium 
members (Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital 
(MGH), Beth Israel Deaconess Medical Center (BIDMC), Children’s Hospital Boston 
(CHB), Brigham and Women’s Hospital (BWH)) responsible for the coordination, 
development, submission, and approval of a protocol as well as its subsequent 
amendments per the DFCI IRB and applicable regulatory guidelines (Food and Drug 
Administration (FDA)).  The Lead Institution is typically the home of the DF/HCC 
Sponsor. The Lead Institution also typically serves as the Coordinating Center for the 
DF/HCC Multi-Center Protocol.  
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  
Within DF/HCC, this person is the Overall Principal Investigator who takes 
responsibility for initiation, management and conduct of the protocol at all research 
locations. In applicable protocols, the DF/HCC Sponsor will serve as the single liaison 
with any regulatory agencies (i.e. FDA). The DF/HCC Sponsor has ultimate authority 
over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as 
the DF/HCC Principal Investigator; however, both roles can be filled by two different 
people. 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC 
Sponsor as having the ultimate authority and responsibility for the overall conduct of 
the study.   


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Coordinating Center: The entity (i.e. Lead Institution,) that provides administrative 
support to the DF/HCC Sponsor in order that he/she may fulfill the responsibilities 
outlined in the protocol document and DSMP, and as specified in applicable regulatory 
guidelines .  In general, the Lead Institution is the Coordinating Center for the 
DF/HCC Multi-Center Protocol. Should the DF/HCC Sponsor decide to use a CRO, 
the CRO will be deemed the Coordinating Center.  
DF/HCC Quality Assurance Office for Clinical Trials: A unit within DF/HCC 
developed to computerize and manage data, and to provide a Quality Control and 
Quality Assurance function for DF/HCC trials.  
2.0
GENERAL ROLES AND RESPONSIBILITIES
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general responsibilities: 
2.1
DF/HCC Sponsor
The DF/HCC Sponsor, 
 will accept responsibility for all aspects 
of conducting a DF/HCC Multi-Center protocol which includes but is not limited to: 
Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments. 
Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.  
Submit the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol.
Assure all Participating Institutions are using the correct version of the protocol.
Ensure that each participating investigator and study team receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and 
throughout trial’s conduct as needed.
Ensure the protocol will be provided to each participating site in a language 
understandable to all site personnel when English is not the primary language. 
Monitor progress and overall conduct of the study at all Participating Institutions. 
Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(FDA) reporting requirements are met. 
Review data and maintain timely submission of data for study analysis. 
Act as the single liaison with the FDA (investigator-held IND trials) as applicable.
Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol.
Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor.
Identify and qualify Participating Institutions and obtain accrual commitments prior 
to extending the protocol to that site. 


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2.2
Coordinating Center 
The Coordinating Center will assume the following general responsibilities:
Assist in protocol development 
Maintain copies of Federal Wide Assurance and Institutional Review Board (IRB) 
approvals from all Participating Institutions.
Maintain FDA correspondence, as applicable.
Maintain updated roster of participants. 
Verify eligibility.
Verify response.
Oversee the data collection process from Participating Institutions.
Maintain documentation of Serious Adverse Event (SAE) reports submitted by 
Participating Institutions and submit to DF/HCC Sponsor for timely review.  
Distribute adverse events reported to the DF/HCC Sponsor that fall under the DFCI 
IRB Adverse Event Reporting Policy to all participating investigators.
Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with.
Monitor Participating Institutions either by on-site or virtual monitoring. 
Maintain Regulatory documents of all Participating Institutions. 
Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc). 
Maintain documentation of all communications.
Ensure that each Participating Institution has the appropriate assurance on file with 
the Office of Human Research Protection (OHRP).    
2.3
Participating Institution
Each Participating Institution is expected to comply with all applicable Federal 
Regulations and DF/HCC requirements, the protocol and HIPAA requirements. All 
Participating Institutions will provide a list of personnel assigned to the role for 
oversight of data management at their site to the Coordinating Center. 
The general responsibilities for each Participating Institution are as follows:
Commit to the accrual of participants to the protocol.
Submit protocol and/or amendments to their local IRB.
Maintain a regulatory binder in accordance with DF/HCC requirements.
Provide the Coordinating Center with regulatory documents as requested.
Participate in protocol training prior to enrolling participants and throughout the 
trial as needed (i.e. teleconferences).
Update Coordinating Center with research staff changes on a timely basis.
Register participants through the Coordinating Center. 
Submit source documents, research records, and CRFs per protocol specific 
submission guidelines to the Coordinating Center.
Submit Serious Adverse Event (SAE) reports to local IRB per local requirements 


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and to the Coordinating Center, in accordance with DF/HCC requirements. Submit 
protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements.
Secure and store investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements.
Have office space, office equipment, and internet access that meet HIPAA 
standards.
3.0
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol. 
3.1
Protocol Distribution
The Coordinating Center will distribute the final DFCI IRB approved protocol and 
any subsequent amended protocols to all Participating Institutions.   
3.2
Protocol Revisions and Closures
The Participating Institutions will receive notification of protocol revisions and 
closures from the Coordinating Center.  It is the individual Participating Institution’s 
responsibility to notify its IRB of these revisions.

Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification.

Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol 
revisions required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-
threatening protocol revisions will be implemented immediately followed by IRB 
request for approval.

Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center, will update the Participating Institutions on an ongoing 
basis about protocol accrual data so that they will be aware of imminent protocol 
closures.
3.3
Informed Consent Requirements
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent 


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form must follow the consent template as closely as possible and should adhere to 
specifications outlined in the DF/HCC Guidance Document on Model Consent 
Language for PI-Initiated Multi-Center Protocols.  This document will be provided 
separately to each Participating Institution.
Participating Institutions are to send their version of the informed consent document 
and HIPAA authorization, if a separate document, to the Coordinating Center for 
review and approval prior to submission to their local IRB. The approved consent form 
must also be submitted to the Coordinating Center after approval by the local IRB.
The Principal Investigator (PI) at each Participating Institution will identify the 
physician members of the study team who will be obtaining consent and signing the 
consent form for therapeutic protocols. Participating institutions must follow the 
DF/HCC requirement that only attending physicians obtain informed consent and re-
consent to interventional trials (i.e. drug and/or device trials).  
3.4
IRB Documentation
The following must be on file with the Coordinating Center:
Approval letter of the Participating Institution's IRB 
Copy of the Informed Consent Form approved by the Participating Institution’s 
IRB 
Participating IRB’s approval for all amendments
It is the Participating Institution's responsibility to notify its IRB of protocol 
amendments.  Participating Institutions will have 90 days from receipt to provide the 
Coordinating Center their IRB approval for amendments to a protocol.   
3.5
IRB Re-Approval
Verification of IRB re-approval from the Participating Institutions is required in order 
to continue research activities.  There is no grace period for continuing approvals.
The Coordinating Center will not register participants if a re-approval letter is not 
received from the Participating Institution on or before the anniversary of the previous 
approval date.  
3.6
Participant Confidentiality and Authorization Statement
In 1996, congress passed the first federal law covering the privacy of health 
information known as the Health Insurance Portability and Accountability Act 
(HIPAA). Any information, related to the physical or mental health of an individual 
is called Protected Health Information (PHI). HIPAA outlines how and under what 
circumstances PHI can be used or disclosed. 


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In order for covered entities to use or disclose protected health information during 
the course of a study, the study participant must sign an Authorization.  This 
Authorization may or may not be separate from the informed consent document.  The 
Coordinating Center, with the approval from the DFCI IRB. 
The DF/HCC Sponsor will use all efforts to limit its use of protected health 
information in its trials.  However, because of the nature of these trials, certain 
protected health information must be collected per NCI requirements. These are the 
primary reasons why DF/HCC has chosen to use Authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements.
3.6.1  DF/HCC Multi-Center Protocol Confidentiality
All documents, investigative reports, or information relating to the participant are 
strictly confidential. Whenever reasonably feasible, any participant specific reports 
(i.e. Pathology Reports, MRI Reports, Operative Reports, etc.) submitted to the 
Coordinating Center must have the participant’s full name & social security number 
“blacked out” and the assigned DF/HCC QACT case number (as described below) 
and DF/HCC protocol number written in (with the exception of the signed informed 
consent document). Participant initials may only be included or retained for cross 
verification of identification
3.7
DF/HCC Multi-Center Registration 
3.7.1 Participant Registration and Randomization 
To register a participant, the following documents should be completed by the 
Participating Institution research nurse or data manager  and emailed to the DFCI 
Study Coordinator and Research Manager: 

Current IRB approved informed consent document signed by participant and 
investigator (participant information must be de-identified and participant initials 
should be written at the bottom of each page of the signed informed consent 
document). 

HIPAA authorization form (if separate from the informed consent document)

Signed and dated DFCI eligibility checklist 

The following source documentation is typically required. Please note 
additional documentation may be required by the lead institution:
–
Labs for PSA values used to determine eligibility (lab values used to 
determine eligibility, including screening PSA)
–
Documentation of prior treatments/procedures performed to treat 
prostate cancer (e.g. Chemotherapy, Cryotherapy, Hormone Therapy, 
Radiation therapy with start and stop dates and dosing information if 
applicable)
–
Reports documenting disease status: Chest CT, CT or MRI Abdomen 
and Pelvis. Bone Scan 
–
Pathology Report 
–
Concomitant medication list
–
Progress note or equivalent documentation of consenting visit


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–
Progress note documenting medical history and oncologic history
–
All screening labs
–
Screening visit note, with BP, vital signs, ECOG Performance status
–
MUGA Scan or ECHO
Participant identifiers must be redacted with the exception of participant initials 
and date of birth. 
The Participating Site must review the source documents against the eligibility 
checklist to ensure eligibility prior to sending to the Coordinating Center.  Source 
documents should not be sent to the Coordinating Center until all necessary 
documents are available.  The Coordinating Center will begin its review of the 
source documents once the full registration packet is received.  The Coordinating 
Center will review the submitted documents in order to verify eligibility and 
consent. To complete the registration process, the Coordinating Center will:

Register the participant on the study with the DF/HCC ODQ

Upon receiving confirmation of registration by the ODQ, the Coordinating Center 
will inform the Participating Institution and provide the study specific participant 
case number, and if applicable the dose treatment level. 
Treatment may not begin without confirmation from the Coordinating 
Center that the participant has been registered. 
Randomization can only occur during ODQ’s normal business hours, Monday through 
Friday from 8:00 AM to 5:00 PM Eastern Time.
3.7.2 Initiation of Therapy
Participants must be registered with the DF/HCC ODQ before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives a faxed or e-
mailed copy of the participant’s registration confirmation memo from the 
Coordinating Center. Therapy must be initiated per protocol guidelines.  The DF/HCC 
Sponsor and DFCI IRB must be notified of any exceptions to this policy.
3.7.3 Eligibility Exceptions
The DF/HCC ODQ will make no exceptions to the eligibility requirements for a 
protocol without DFCI IRB approval. The DF/HCC ODQ requires each institution to 
fully comply with this requirement.
3.7.4 Verification of Registration, Dose Levels, and Arm Designation
A registration confirmation memo for participants registered to DF/HCC Multi-Center 
Protocol will be faxed or emailed to the registering institution within one business day 


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of the registration. Treatment may not be initiated until the site receives a faxed or e-
mailed copy of the registration confirmation memo.
3.8
DF/HCC Protocol Case Number
Once eligibility has been established and the participant successfully registered, the 
participant is assigned a five digit protocol case number.  This number is unique to the 
participant on this trial and must be used for ODQ CRF/eCRF completion and 
correspondence, and correspondence with the Coordinating Center.  
3.9
Protocol Deviations, Exceptions and Violations
Federal Regulations require an IRB to review proposed changes in a research activity 
to ensure that researchers do not initiate changes in approved research without IRB 
review and approval, except when necessary to eliminate apparent immediate hazards 
to the participant. DF/HCC requires all departures from the defined procedures set 
forth in the IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn 
is responsible for reporting to the DFCI IRB.
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and 
“exception” to describe derivations from a protocol. All Participating Institutions must 
adhere to these requirements for reporting to the DF/HCC Sponsor and will follow 
their institutional policy for reporting to their local IRB.
3.9.1 Definitions
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation.
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g.
enrollment of a participant who does not meet all inclusion/exclusion criteria.
Protocol Violation: Any protocol deviation that was not prospectively approved by the 
IRB prior to its initiation or implementation. 
3.9.2  Reporting Procedures
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available 
in the medical record and/or regulatory documents to describe all protocol exceptions, 
deviations and violations. The DF/HCC Sponsor will also be responsible for ensuring 
that all protocol violations/deviations are promptly reported per DFCI IRB 
guidelines. 
Participating Institutions: Protocol deviations require prospective approval from the 
DFCI IRB. The Participating Institution must submit the deviation request to the 
Coordinating Center who will then submit the deviation request to the DFCI IRB. 


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Upon DFCI IRB approval the deviation is submitted to the Participating Institution 
IRB, per institutional policy. A copy of the Participating Institution’s IRB report and 
determination will be forwarded to the Coordinating Center within 10 business days 
after the original submission. 
All protocol violations must be sent to the Coordinating Center in a timely manner. 
Coordinating Center:  Upon receipt of the violation/deviation report from the 
Participating Institution, the Coordinating Center will submit the report to the 
DF/HCC Sponsor for review. Subsequently, the Participating Institution’s IRB 
violation/deviation report will be submitted to the DFCI IRB for review per DFCI 
IRB reporting guidelines. 
3.10 Safety Assessments and Toxicity Monitoring
The study teams at all participating institutions are responsible for protecting the 
safety, rights and well-being of study participants. Recording and reporting of 
adverse events that occur during the course of a study help ensure the continuing 
safety of study participants. 
All participants receiving investigational agents and/or other protocol mandated 
treatment will be evaluated for safety. The safety parameters include all laboratory 
tests and hematological abnormalities, physical examination findings, and 
spontaneous reports of adverse events reported by participants.  All toxicities 
encountered during the study will be evaluated according to the NCI criteria specified 
in the protocol. Life-threatening toxicities must be reported immediately to the 
DF/HCC Sponsor via the Coordinating Center. 
Additional safety assessments and toxicity monitoring will be outlined in the 
protocol.
3.10.1 Guidelines for Reporting Serious Adverse Events 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) 
are detailed in protocol section 11.
Participating Institutions must report the AEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB SAE Reporting Requirements. 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting 
Requirements.  Participating Investigators will review any distributed AE reports, 
send a copy to their IRB according to their local IRB’s policies and procedures, and 
file a copy with their regulatory documents.


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3.10.2 Guidelines for Processing IND Safety Reports 
FDA regulations require sponsors of clinical studies to notify the FDA and all 
participating investigators of any adverse experience associated with the use of the 
investigational agent that is both serious and unexpected. The DF/HCC Sponsor will 
review all IND Safety Reports and ensure that all IND Safety Reports are distributed 
to the Participating Institutions.  The Participating Investigators are to review, send 
a copy to their IRB according to their local IRB’s policies and procedures, and file 
a copy with their regulatory documents.
3.11 Data Management
The DF/HCC QACT develops a set of either paper or electronic case report forms 
(CRF/eCRFs), for use with the protocol.  These forms are designed to collect data 
for each study. The DF/HCC QACT provides a web based training for eCRF users. 
See section 12 of protocol.
  
3.11.1 Data Forms Review
When data forms arrive at the DF/HCC ODQ, they are reviewed for completeness, 
protocol treatment compliance, adverse events (toxicities) and response. Data 
submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in 
accordance with the following:
Incomplete or Questionable Data
If study forms are received with missing or questionable data, the submitting 
institution will receive a written or electronic query from the DF/HCC ODQ Data 
Analyst or study monitor.  Responses to all queries should be completed and 
submitted within 14 calendar days.  Responses may be returned on the written query 
or on an amended paper case report form, or in the case of electronic queries, within 
the electronic data capture (eDC) system. In the case of a written query for data 
submitted on a paper case report form, the query must be attached to the specific 
data being re-submitted in response.  
Missing Forms
If study forms are not submitted on schedule, the Participating Institution will 
receive a Missing Form Report from the Coordinating Center noting the missing 
forms.  These reports are compiled by the DF/HCC ODQ and distributed a minimum 
of four times a year. 
4.0
REQUISITIONING INVESTIGATIONAL DRUG 


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Participating Institutions should order their own agent regardless of the supplier (i.e., NCI or 
a pharmaceutical company.)  
If the agent is commercially available, check with the local Director of Pharmacy and/or the 
Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, ensure 
that the agent can be ordered once the protocol is approved by the local IRB. 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed of 
who will supply the agent (i.e., NCI or a pharmaceutical company) so that any regulatory 
responsibilities can be met in a timely fashion. 
See section 7.0 of study protocol for additional details on ordering study drug.
5.0
MONITORING: QUALITY CONTROL
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the ODQ provides quality 
control oversight for the protocol.
5.1 Ongoing Monitoring of Protocol Compliance
Source documents confirming eligibility are to be sent to DFCI by the participating 
institutions and reviewed by DFCI study staff including a clinician prior to external 
site participant registration. 
The DF/HCC Lead Institution will implement monitoring activities ongoing to 
ensure that Participating Institutions are complying with regulatory and protocol 
requirements, data quality, and subject safety. Additional monitoring practices may 
include but are not limited to; source verification, review and analysis of the 
following: eligibility requirements of all participants , informed consent procedures, 
adverse events and all associated documentation, study drug administration / 
treatment, regulatory records and site trial master files, protocol deviations, 
pharmacy records, response assessments, and data management. 
Site visits will generally occur twice a year for sites that are actively enrolling 
participants and have participants in treatment. Virtual monitoring (source 
documents are sent to DFCI for review) may be performed in lieu of a site visit if the 
study staff and PI determine that virtual monitoring is appropriate for the site. The 
decision to perform virtual monitoring in lieu of a site visit will be based upon the 
site’s enrollment, study compliance history, history collaborating with DFCI on 
other multi-center studies, and number of participants in active treatment.


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We hope to monitor approximately 50% of participants enrolled from external sites. 
The target number of participants monitored may change depending upon monitor 
findings. 
Monitoring will occur before the clinical phase of the protocol begins and will 
continue during protocol performance through study completion. 
Teleconferences between DFCI and the participating sites will be conducted on 
approximately a monthly basis. Meeting minutes for teleconferences will be issued 
to all participating sites. Site initiation visits will be conducted via teleconference. 
Ongoing training will also be conducted via teleconference as needed. The 
Coordinating Center, Dana Farber Cancer Institute will be available to all 
participating sites for resolving questions, concerns and facilitating compliance.
5.2 Evaluation of Participating Institution Performance
All data submitted to the DF/HCC ODQ will be monitored for timeliness of 
submission, completeness, and adherence to protocol requirements. The Lead 
Institution or designee and if applicable ODQ Data Analysts assigned to the Protocol 
will perform the ongoing protocol data compliance monitoring with the support of 
the Participating Institution’s Coordinators, the Principal Investigators, and the 
Protocol Chair.
5.2.1 Monitoring Reports
The DF/HCC Sponsor will review all monitoring reports for on-site and virtual 
monitoring of Participating Institutions to ensure protocol compliance and ability to 
fulfill responsibilities of participating in the study. The DF/HCC Sponsor may 
increase the monitoring activities at Participating Institutions that are unable to comply 
with the protocol, DF/HCC Sponsor requirements or federal and local regulations. 
Participating Institutions may also be subject to an audit as determined by the DF/HCC 
Sponsor.
6.0
AUDITING: QUALITY ASSURANCE
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards 
and procedures were followed. Auditing is the systematic and independent examination of 
all trial related activities and documents.  Audits determine if evaluated activities were 
appropriately conducted and whether data was generated, recorded and analyzed, and 
accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR).
6.1 DF/HCC Sponsored Trials


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The DF/HCC Sponsor may request that an audit be performed by the ODQ if instances 
of serious non-compliance are found during routine monitoring.
6.2 Participating Institution
It is the Participating Institution’s responsibility to notify the Coordinating Center of 
all scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which 
involve this protocol. All institutions will forward a copy of final audit and/or re-audit 
reports and corrective action plans (if applicable) to the Coordinating Center, within 12 
weeks after the audit date. 
6.3 DF/HCC Sponsor and Coordinating Center 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if 
applicable. The Coordinating Center, must forward these reports to the DF/HCC QACT 
per DF/HCC policy for review by the DF/HCC Audit Committee. Based upon the audit 
assessments the DF/HCC Audit Committee could accept or conditionally accept the 
audit rating and final report. Conditional approval could require the DF/HCC Sponsor 
to implement recommendations or require further follow-up.  For unacceptable audits, 
the DF/HCC Audit Committee would forward the final audit report and corrective 
action plan to the DFCI IRB as applicable.
6.4 Sub-Standard Performance
The DF/HCC Sponsor, DFCI IRB is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol.
6.4.1 Corrective Actions
Participating Institutions that fail to meet the performance goals of accrual, submission 
of timely accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, will be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during 
the probation period that deficiencies have been corrected, as evidenced by the 
improved performance measures. Participating Institutions that fail to demonstrate 
significant improvement will be considered by the DF/HCC Sponsor for revocation of 
participation.
18. APPENDIX F: STRONG CYP3A4 INDUCERS AND INHIBITORS


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Strong 3A4 Inducers
Carbamazepine (Tegretol)
Enzalutamide
Mitotane
Fosphenytoin (Cerebyx) (IV only)
Pentobarbital (Nembutal) (IV only)
Phenobarbital
Phenytoin (Dilantin)
Primidone
Rifampin
St. John's Wort 
Strong 3A4 Inhibitors
Atazanavir
Boceprevir
Ceritinib
Clarithromycin (Biaxin)
Conivaptan
Darunavir
Idelalisib
Grapefruit juice
Indinavir
Itraconazole
Ketoconazole
Lopinavir/ritonavir
Mibefradil
Nefazodone
Nelfinavir
Ombitasvir-paritaprevir-ritonavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Voriconazole
A more comprehensive list and additional information can be found at the following address: 
http://medicine.iupui.edu/flockhart/