Clinical trial NCT02903368
Conditions: Prostate Cancer
Keywords: abiraterone acetate apalutamide leuprolide prednisone neoadjuvant therapy
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-10-19; Completion date: 2024-07-10
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multicenter randomized phase II trial investigates the impact of intense androgen deprivation on radical prostatectomy (RP) pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368).

Detailed description:
This is a multicenter, phase II, prospective, randomized trial designed to investigate the efficacy of neoadjuvant and adjuvant abiraterone acetate + apalutamide for men with intermediate-high risk prostate cancer who are candidates for RP.

The study includes two parts. In part 1, patients will be randomized in 1:1 ratio to receive 6 months of abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 1A) versus 6 months of abiraterone acetate, leuprolide and prednisone (Arm 1B) followed by RP, stratified by risk factor (intermediate versus high-risk). High-risk factors will be defined as a Gleason score ≥ 8, PSA \> 20 ng/dL, or T3 disease on MRI.

In part 2 (post-RP), patients will be randomized in 1:1 ratio to receive an additional 12 months of abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 2A) or observation (Arm 2B) stratified by type of neoadjuvant therapy and pathological T-stage (\< pT3 versus ≥ pT3) after RP but before cycle 7 day 1 following neoadjuvant therapy. There will be an early stopping rule for Part 2 should a high rate of patients refuse to participate or drop out early while receiving adjuvant therapy (\<6 months).

Arms: arm 1: Eligible Participants will be randomized to receive:

AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 6 months

Pts x weeks to RP arm 2: Eligible Participants will be randomized to receive:

APL: Abiraterone acetate (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/day orally) for 6 months arm 3: Eligible Participants will be randomized to receive:

AAPL: Abiraterone acetate (240 mg/day orally), Apalutamide (1000 mg/day orally), Leuprolide (22.5 mg every 12 weeks intramuscularly), Prednisone (5 mg/twice daily orally) for 12 months arm 4: None
Interventions: intervention 1: Apalutamide intervention 2: Leuprolide intervention 3: Prednisone intervention 4: Abiraterone Acetate
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
STATUS PAGE 
PROTOCOL 16-223 
 
 
 
 
Closed To New Accrual 
 
 
Closure Effective Date: 11/05/2018 
Reason: Study Accrual Goal Met 
 
 
No new subjects may be enrolled in the study- as described above. 
Any questions regarding this closure should be directed to the study’s 
Principal Investigator 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
Protocol Version Date:  January 3, 2019 
 
DF/HCC Protocol #: 16-223 
 
Title: Phase II randomized study of neoadjuvant and adjuvant abiraterone acetate + apalutamide 
for intermediate-high risk prostate cancer undergoing prostatectomy. 
 
Sponsor Investigator:  
Mary-Ellen Taplin, MD 
Associate Professor of Medicine  
Dana-Farber Cancer Institute  
Lank Center for Genitourinary Oncology  
450 Brookline Avenue  
Boston, MA 02215  
Telephone: 617-582-7221 
Fax: 617-632-6328                                                                
mtaplin@partners.org 
 
 
Coordinating Center and Sponsor:  
Dana-Farber Cancer Institute  
450 Brookline Avenue  
Boston, MA 02215  
 
Drug & Funding Support: 
Janssen Scientific Affairs, LLC 
 
IND #: 130502 
IND Sponsor: Mary-Ellen Taplin, MD 
 
Study Agents: 
Abiraterone acetate supplied by Janssen Scientific Affairs, LLC 
Apalutamide supplied by Janssen Scientific Affairs, LLC 
Leuprolide (Commercial Supply) 
Prednisone (Commercial Supply) 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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ABBREVIATIONS 
 
Adrenocorticotropic hormone – ACTH  
Adverse event – AE  
Alanine transaminase – ALT   
American Society of Clinical Oncology – ASCO    
ANC – Absolute neutrophil count  
Androgen deprivation therapy – ADT  
Androgen Receptor – AR 
Apparent diffusion coefficient – ADC  
Area under the concentration-time curve – AUC  
Aspartate transaminase – AST   
Canadian Urologic Oncology Group – CUOG  
Cancer and Leukemia Group B – CALGB 
Cancer Therapy Evaluation Program – CTEP  
Case Report Form – CRF  
Castration-resistant prostate cancer – CRPC 
Center for Molecular Oncologic Pathologies – CMOP 
Circulating Tumor Cells – CTCs  
Code of Federal Regulations – CFR  
Common Terminology Criteria for Adverse Events – CTCAE 
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  
Dynamic contrast-enhanced – DCE  
Dehydroepiandrosterone – DHEA  
Dehydroepiandrosterone-sulfate – DHEA-S  
Dihydrotestosterone – DHT  
Disease-free survival – DFS  
Eastern Cooperative Oncology Group – ECOG  
Echocardiogram – ECHO  
Electrocardiogram – EKG   
Food and Drug Administration – FDA  
Good Clinical Practice – GCP  
Hazard ratio – HR 
Health Insurance Portability and Accountability Act – HIPAA  
Immunohistochemistry – IHC  
IND – Investigation new drug  
Institutional Review Board – IRB  
International Normalized Ratio – INR  
Liquid Chromatography Mass Spectrometery/Mass Spectrometery – LCMS/MS 
Liver function test – LFT 
Luteinizing hormone-releasing hormone – LHRH  
Magnetic Resonance Imaging – MRI  


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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Multiparametric Magnetic Resonance Imaging – mpMRI  
Maximum plasma concentration – Cmax   
Minimal Residual Disease – MRD  
National Cancer Institute – NCI  
National Surgical Adjuvant Breast and Bowel Project – NSABP   
New York Heart Association – NYHA  
Office for Data Quality – ODQ  
Office for Human Research Studies – OHRS  
Overall survival – OS  
Pathologic complete response – pCR  
Principal Investigator – PI  
Progression free survival – PFS  
Prostate specific antigen – PSA 
Partial Prothrombin Time – PTT 
Radical Prostatectomy – RP  
Residual cancer burden – RCB 
Response Evaluation Criteria In Solid Tumors – RECIST  
Serious adverse event – SAE  
Skeletal related event – SRE 
Sponsor Investigator – SI  
Time to PSA Progression – TTPP  
Upper limit of normal – ULN 
WBC – White blood cell count  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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Schema:  
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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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 
Correlative Objectives ..................................................................................................................................... 2 
2. 
BACKGROUND ................................................................................................................................................ 3 
2.1 
Study Disease .................................................................................................................................................. 3 
2.2 
Rationale ......................................................................................................................................................... 4 
2.3 
Study Agent(s) ................................................................................................................................................. 9 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 19 
3.1 
Eligibility Criteria ......................................................................................................................................... 19 
3.2 
Exclusion Criteria ......................................................................................................................................... 21 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 23 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 24 
4.1 
General Guidelines for DF/HCC Institutions ............................................................................................... 24 
4.2 
Registration Process for DF/HCC Institutions ............................................................................................. 24 
4.3 
General Guidelines for Other Participating Institutions ............................................................................... 24 
4.4 
Registration Process for Other Participating Institutions ............................................................................. 24 
5. 
TREATMENT PLAN ...................................................................................................................................... 26 
5.1 
Treatment Summary and Randomization ...................................................................................................... 26 
5.2 
Pre-treatment Criteria ................................................................................................................................... 27 
5.3 Agent Administration ..................................................................................................................................... 28 
5.4 
General Concomitant Medications and Supportive Care Guidelines ........................................................... 30 
5.5 
Duration of Therapy ...................................................................................................................................... 33 
5.6 
Duration of Follow-Up .................................................................................................................................. 34 
5.7 
Criteria for Removal from Study ................................................................................................................... 34 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 36 
6.1 
Anticipated Toxicities .................................................................................................................................... 36 
6.2 
Toxicity Management .................................................................................................................................... 38 
6.3 
Dose Modifications/Delays ........................................................................................................................... 43 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 44 
7.1 
Apalutamide .................................................................................................................................................. 44 
7.2 
Abiraterone acetate ....................................................................................................................................... 45 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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Pharmacy Storage Requirements ............................................................................................................................. 46 
7.3 
Prednisone ..................................................................................................................................................... 47 
There are no specific instructions for handling prednisone. .................................................................................. 47 
7.4 
Leuprolide ..................................................................................................................................................... 48 
8. 
CORRELATIVE STUDIES ............................................................................................................................ 49 
8.1 
Correlative Studies Background.................................................................................................................... 49 
8.2 
Correlative Studies Methodologies ............................................................................................................... 51 
9. 
STUDY CALENDAR ...................................................................................................................................... 55 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 61 
10.1 Primary Variable ........................................................................................................................................... 61 
10.2 Secondary Variables ..................................................................................................................................... 61 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 63 
11.1 Overview ....................................................................................................................................................... 63 
11.2 Management of Safety Data .......................................................................................................................... 63 
11.3 Definitions ..................................................................................................................................................... 63 
11.4 Expectedness ................................................................................................................................................. 66 
11.5 Unlisted (Unexpected) AE/Reference Safety Information ............................................................................. 66 
11.6 Special Reporting Situations ......................................................................................................................... 67 
11.7 Pregnancy ..................................................................................................................................................... 67 
11.8 Maintenance of Safety Information ............................................................................................................... 67 
11.9 Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Janssen Medicinal 
Products to Janssen ................................................................................................................................................ 68 
11.10 Reporting Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for Non-Janssen 
Medicinal Products ................................................................................................................................................. 69 
11.11 Transmission Methods ................................................................................................................................... 69 
11.12 Reconciliation of SAEs .................................................................................................................................. 70 
11.13 Final Study Report ........................................................................................................................................ 70 
11.14 Procedures for AE and SAE Recording and Reporting ................................................................................. 70 
11.15 Reporting Requirements ................................................................................................................................ 70 
11.16 Reporting to the Study Sponsor-Investigator ................................................................................................. 71 
11.17 Reporting to the IRB ...................................................................................................................................... 72 
11.18 Reporting to the FDA .................................................................................................................................... 72 
11.19 Reporting to Hospital Risk Management....................................................................................................... 72 
11.20 Monitoring of AEs and Period of Observation .............................................................................................. 72 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 73 
12.1 Data Reporting .............................................................................................................................................. 73 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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12.2 Safety Meetings ............................................................................................................................................. 74 
12.3 Monitoring ..................................................................................................................................................... 74 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 76 
13.1 Protocol Review and Amendments ................................................................................................................ 76 
13.2 Informed Consent .......................................................................................................................................... 76 
13.3 Ethics and GCP ............................................................................................................................................. 76 
13.4 Study Documentation .................................................................................................................................... 77 
13.5 Records Retention ......................................................................................................................................... 77 
13.6 Multi-Center Guidelines ................................................................................................................................ 77 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 79 
14.1 Study Design and Sample Size ....................................................................................................................... 79 
14.2 Primary Endpoint and Methods of Analysis: ................................................................................................ 79 
14.3 Secondary Endpoint(s) and Methods of Analysis: ......................................................................................... 80 
14.4 Correlative Endpoint(s) and Methods of Analysis: ....................................................................................... 81 
14.5 Sample Size and Accrual Rate ....................................................................................................................... 83 
For a sample size of 120 participants, we expect a total of 15 months to complete the accrual at a rate 8 
participants/month. ................................................................................................................................................. 83 
14.6 Study monitoring ........................................................................................................................................... 83 
15. 
PUBLICATION PLAN .................................................................................................................................... 84 
16. 
REFERENCES ................................................................................................................................................. 85 
17. 
APPENDICES .................................................................................................................................................. 93 
17.1 APPENDIX A: Performance Status Criteria ................................................................................................. 93 
17.2 APPENDIX B: Required Forms at Registration ........................................................................................... 93 
17.3 APPENDIX C: Patient’s Pill Diary .............................................................................................................. 93 
17.4 APPENDIX D: Representative Medications that May Predispose to Seizures ............................................. 93 
17.5 APPENDIX E: Intra-operative and Peri-operative RP Complications Questionnaires ............................... 93 
17.6 APPENDIX F: Post-Operative Complications (Clavian Classification) ...................................................... 93 
17.7 APPENDIX G: The Expanded Prostate Cancer Index Composite Questionnaire (EPIC-26 +) ................... 93 
17.8 APPENDIX H: Family History Questionnaire .............................................................................................. 93 
17.9 APPENDIX I: Multi-Center Data and Safety Monitoring Plan .................................................................... 93 
1.0 
INTRODUCTION .......................................................................................................................................... 113 
1.1 
Purpose ....................................................................................................................................................... 113 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ....................................................................... 113 
2.0 
GENERAL ROLES AND RESPONSIBILITIES ....................................................................................... 114 
2.1 
DF/HCC Sponsor ........................................................................................................................................ 114 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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2.2 
Coordinating Center ................................................................................................................................... 115 
2.3 
DF/HCC Office for Data Quality (ODQ) .................................................................................................... 115 
2.4 
Participating Institution .............................................................................................................................. 115 
3.0 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS ..................................................... 116 
3.1 
Protocol Distribution .................................................................................................................................. 116 
3.2 
Protocol Revisions and Closures................................................................................................................. 116 
3.3 
Informed Consent Requirements ................................................................................................................. 117 
3.4 
IRB Documentation ..................................................................................................................................... 117 
3.5 
IRB Re-Approval ......................................................................................................................................... 117 
3.6 
Participant Confidentiality and Authorization Statement ........................................................................... 117 
3.7 
DF/HCC Multi-Center Protocol Registration Policy .................................................................................. 118 
3.7.1 Participant Registration and Randomization .............................................................................................. 118 
3.7.2 Initiation of Therapy .................................................................................................................................... 119 
3.7.3 Eligibility Exceptions .................................................................................................................................. 119 
3.7.4 Verification of Registration, Dose Levels, and Arm Designation ................................................................ 119 
3.8 
DF/HCC Protocol Case Number................................................................................................................. 119 
3.9 
Protocol Deviations, Exceptions and Violations ......................................................................................... 120 
3.9.1 Definitions ................................................................................................................................................... 120 
3.9.2 Reporting Procedures.................................................................................................................................. 120 
3.10 Safety Assessments and Toxicity Monitoring............................................................................................... 121 
3.10.1 
Guidelines for Reporting Serious Adverse Events ............................................................................. 121 
3.10.2 
Guidelines for Processing IND Safety Reports .................................................................................. 121 
3.11 Data Management ....................................................................................................................................... 121 
3.11.1 
Data Forms Review ........................................................................................................................... 121 
4.0 
REQUISITIONING INVESTIGATONAL DRUG ..................................................................................... 122 
5.0 
MONITORING: QUALITY CONTROL .................................................................................................... 122 
5.1 
Ongoing Monitoring of Protocol Compliance ............................................................................................. 122 
5.2 
Evaluation of Participating Institution Performance .................................................................................. 123 
5.2.1 Monitoring Reports ..................................................................................................................................... 123 
6.0 
AUDITING: QUALITY ASSURANCE ....................................................................................................... 123 
6.1 
DF/HCC Sponsored Trials .......................................................................................................................... 124 
6.2 
DF/HCC Internal Audits ............................................................................................................................. 124 
6.3 
Audit Notification ........................................................................................................................................ 124 
6.4 
Audit Reports ............................................................................................................................................... 124 
6.4.1 Corrective Actions ....................................................................................................................................... 124 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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1. OBJECTIVES 
1.1 
Study Design 
 
This is a multicenter, phase II, prospective, randomized trial designed to investigate the 
efficacy of neoadjuvant and adjuvant abiraterone acetate + apalutamide for men with 
intermediate-high risk prostate cancer who are candidates for RP. The study includes 
two parts. In part 1, patients will be randomized in 1:1 ratio to receive 6 months of 
abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 1A) versus 6 months 
of abiraterone acetate, leuprolide and prednisone (Arm 1B) followed by RP, stratified 
by risk factor (intermediate versus high-risk). High-risk factors will be defined as a 
Gleason score ≥ 8, PSA > 20 ng/dL, or T3 disease on MRI.  In part 2 (post-RP), 
patients will be randomized in 1:1 ratio to receive an additional 12 months of 
abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 2A) or observation 
(Arm 2B) stratified by type of neoadjuvant therapy and pathological T-stage (< pT3 
versus ≥ pT3) after RP but before cycle 7 day 1 following neoadjuvant therapy. There 
will be an early stopping rule for Part 2 should a high rate of patients refuse to 
participate or drop out early while receiving adjuvant therapy (<6 months). 
 
1.2 
Primary Objectives 
Part 1:  
• To determine whether combination of abiraterone acetate + apalutamide 
improves frequency of achieving a pCR or MRD (defined as residual tumor in 
RP specimen measuring ≤ 5 mm) at RP as compared with abiraterone acetate 
alone, in men treated with neoadjuvant leuprolide and prednisone prior to RP.  
 
Part 2: 
• To determine whether the use of adjuvant abiraterone acetate + apalutamide + 
prednisone following RP improves biochemical progression free survival (bPFS) 
at 3 years post-RP as compared with no adjuvant treatment. 
1.3 
Secondary Objectives  
  
 
Part 1:  
• To evaluate the frequency of achieving a pCR at RP following therapy with Arm 
1A compared to Arm 1B. 
 
• To evaluate the frequency of achieving favorable RCB (defined as the 33rd 
percentile of the RCB index which is calculated as the tumor volume x 
cellularity) at RP following therapy with Arm 1A compared to Arm 1B. 
 
• To evaluate the frequency of presenting cribriform or intraductal carcinoma at 
RP following therapy with Arm 1A compared to Arm 1B.   
 
• To evaluate the frequency of positive surgical margins, extracapsular extension, 
positive seminal vesicles, and positive lymph nodes at time of RP following 
treatment with Arm 1A compared to Arm 1B. 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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• To determine changes in PSA (median nadir value, percentage of participants 
with PSA < 0.2 ng/mL, proportion of participants with achieving 50% and 90% 
decrease in PSA, time to PSA nadir) from baseline to prior to RP with Arm 1A 
compared to Arm 1B. 
 
• To assess intra-operative and post-operative complications following RP between 
treatment arms (1A and 1B). 
 
 
 
Part 2: 
• To determine the effect of treatment on freedom from biochemical failure at 2-, 
3-, and 5-years post-RP between Arms 2A and 2B among patients who achieve 
testosterone recovery (defined as a testosterone > 200 ng/dL). 
 
• To determine the effect of treatment on (or freedom from) further prostate cancer 
therapy (to include adjuvant or salvage radiation therapy, ADT, or other 
therapies) at 2-, 3-, and 5-years post-RP between Arms 2A and 2B. 
 
• To assess the safety and tolerability of each treatment arm. 
 
• To assess quality of life parameters over time between treatment arm 2A and 
observation arm 2B.  
 
1.4 
Correlative Objectives  
• To assess time to testosterone recovery, body-mass index, lipids, and 
cardiovascular events for treatment Arms 2A and 2B. 
 
• To assess changes in serum hormone levels (DHEA, androstenedione, 
testosterone, DHT, androsterone, progesterone, pregnenolone, 
deoxycorticosterone, cortisol, DHEA-S) by mass spectroscopy from pretreatment 
to during treatment to prior to RP and to post-RP between treatment Arms 1A and 
1B and Arms 2A and 2B. 
 
• To correlate serum hormone levels from pretreatment to during treatment and to 
prior to RP with pathologic response at RP.  
 
• To compare serum abiraterone acetate and apalutamide levels to tissue abiraterone 
and apalutamide levels and serum and hormone levels with pCR + minimum 
residual disease.  
 
• To compare prostate androgen levels by mass spectroscopy in the RP specimens 
between treatment Arms 1A and 1B. 
 
• To compare the expression of the AR and proteins involved in the androgen 
synthesis, apoptosis, WNT signaling, and PTEN-PI3K-AKT pathways by IHC 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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and expression analysis in the RP specimens between treatment Arms 1A and 1B 
and between patients with MRD compared to those without MRD.   
 
• To assess changes in circulating tumor DNA from pretreatment to during 
treatment to prior to RP and to post-RP between Arms 2A and 2B.   
 
• To assess changes in the whole exome and whole transcriptome by high 
throughput parallel sequencing technologies in evaluable samples from RP 
between treatment Arms 1A and 1B. 
 
• To assess proportion of patients with downstaging on second multi-parametric 
prostate MRI compared to baseline MRI between Arms 1A and 1B. 
 
• To correlate imaging T stage at second multi-parametric prostate MRI with 
pathologic T stage in all patients and by treatment arm. 
 
• To determine if multi-parametric prostate MRI can be used to predict pathologic 
response (defined as pCR, MRD, and RCB) following neoadjuvant hormone 
therapy. 
 
• To assess the prevalence of germline mutations in homologous recombination 
genes in all enrolled patients. 
 
• To correlate homologous recombination gene germline mutation status with 
pathologic response (defined as pCR, MRD, and RCB). 
 
• To evaluate family history of cancers in the study population and correlate family 
cancer history with germline mutation status. 
 
 
2. BACKGROUND 
2.1 
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 cancer death in this population.4 Despite 
ongoing efforts, outcomes in high-risk patients undergoing RP have not significantly 
improved with time, likely related to systemic micrometastatic disease not adequately 
addressed at the time of local treatment.5-7 Following RP upwards of 50% of patients 
with high-risk disease will experience a biochemical recurrence at 5 years.7 In a 
retrospective analysis of 379 men who developed a biochemical recurrence after RP, 
approximately 80-90% of patients with high-risk prostate cancer died from their 
disease.8 Consequently, new treatment strategies, including multimodality therapy, are 
needed to improve outcomes in high-risk patients. 


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2.2 
Rationale 
 
Treatment of patients with high-risk disease presents two therapeutic challenges: the 
need for local control of the primary disease site and need for systemic control of 
microscopic metastatic disease. Neoadjuvant and adjuvant therapy is an approach which 
can potentially maximize survival outcomes in patients with localized disease. This 
approach is under investigation and provides an opportunity to assess pathologic and 
biologic activity of novel treatments. 
 
The paradigm of neoadjuvant systemic therapy is widely accepted in the treatment of 
patients with localized high-risk breast cancer and other solid tumor malignancies. The 
National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was 
designed to determine whether four cycles of doxorubicin + cyclophosphamide 
administered preoperatively improved breast cancer disease-free survival (DFS) and 
overall survival (OS) compared with treatment administered postoperatively. At a 
median follow-up of 16 years, there were no statistically significant differences in DFS 
and OS between the two groups, however, there were trends in favor of preoperative 
chemotherapy for DFS and OS in women less than 50 years old.9 A meta-analysis of 
nine randomized studies, including a total of 3,946 women, demonstrated that 
neoadjuvant cytotoxic therapy was equivalent to adjuvant cytotoxic therapy in terms of 
survival and overall disease progression.10 Few studies have evaluated pCR rates to 
hormonal therapy and theses are on the order of approximately 10% in breast cancer. 
The metrics for neoadjuvant hormonal therapy studies focus on ORR, breast 
conservation, PFS and OS as endpoints.  Additionally, neoadjuvant cytotoxic therapy is 
routinely utilized in the treatment of bladder11,12, esophageal8,13,14, and rectal cancer11. 
 
A central tenant of neoadjuvant therapy is that local tumor response correlates with 
long-term outcomes such as DFS and OS. For breast cancer, pCR is a significant 
predictor of improved clinical outcomes and has been adopted as the primary endpoint 
for neoadjuvant trials. In a review of 6,377 breast cancer patients from seven 
randomized trials receiving neoadjuvant anthracycline-taxane-based chemotherapy, 
pCR was associated with significantly superior DFS and a trend towards improved 
OS.15 Residual disease after neoadjuvant treatment includes a broad range of actual 
responses from near pCR to frank resistance. Symmans and colleagues developed a 
method to measure residual disease in breast cancer by combining histopathologic 
components of residual disease (cellularity, overall diameter, number and extent of 
nodal involvement) into a numerical index of RCB.16 Favorable RCB was defined as the 
40th percentile of the RCB index values which was used as the cutoff point to separate 
favorable RCB (including pCR and minimal residual disease) from moderate or 
extensive residual disease. In a pathologic review of 382 patients treated in two 
different cohorts, RCB was calculated as a continuous index for prediction of distant 
relapse-free survival in multivariate Cox regression analysis.16 They determined that 
RBC was independently prognostic in a multivariate model. 
 
Historically, the development of new drugs in the early disease setting has been 
predicated on a demonstration of improved overall survival. In 2014, the FDA drafted a 


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guidance act, which uses pCR to the neoadjuvant treatment of high-risk early breast 
cancer as an endpoint to support accelerated approval of new drugs. Pertuzumab was 
the first drug which was granted the FDA’s accelerated approval in the neoadjuvant 
setting. The approval was based primarily on results from the NEOSPHERE study, a 
phase II neoadjuvant study using pertuzumab in HER2-positive early stage breast 
cancer.1 
 
ADT is the mainstay of first-line systemic therapy for patients with metastatic prostate 
cancer. However, clinical trials of ADT in the neoadjuvant stetting prior to RP have 
been disappointing. Table 1 provides a review of clinical trials of neoadjuvant ADT 
prior to RP.17-28  
 
Table 1. Trials of neoadjuvant ADT.  
 
Trial 
Patients 
Clinical 
Stage 
Regimen 
Outcomes  
(Neoadjuvant ADT + RP vs. RP alone)  
Median 
Follow Up 
(Years) 
Positive Surgical 
Margin Rate 
pCR Rate 
PFS  
OS  
Dalkin et al 
(1996) 17  
56 
T1c-T2b 
G x 3 mo  
18% vs. 14% 
NR 
NR 
NR 
 
Labrie et al 
(1997) 18 
161 
T2-T3 
L + F x 3 
mo  
7.8% vs. 33.8%a 
 
6.7% vs. 
0% 
NR 
NR 
 
Fair et al 
(1999) 19 
140 
T1-T3 
L + F x 3 
mo  
19% vs. 37%a 
NR 
No 
difference 
NR 
2.9 
Van Der 
Kwast et al 
(1999) 20 
47 
T1-T3 
L + F x 3 
mo vs. L + 
F x 6 mo  
27.8% (3 mo) vs. 
9.1% (6 mo)a 
 
0 (3 mo) 
vs. 9% (6 
mo) 
NR 
NR 
 
Schulman et 
al (2000) 21 
402 
T2-T3 
 
G + F x 3 
mo  
13% vs. 37% T2a 
42% vs. 61% T3 
NR 
74% vs. 
67% 
No 
difference  
4 
Gleave et al 
(2001) 22 
547 
T1b-T2 
 
L + F x 3 
mo vs. L + 
F x 8 mo  
23% (3 mo) vs. 
12% (8 mo)a 
 
5.1% (3 
mo) vs. 
9.3% (8 
mo) 
NR 
NR 
 
Soloway et al 
(2002) 25 
303 
T2b 
 
L + F x 3 
mo  
18% vs. 48%a 
NR 
64.8% vs. 
67.6%  
NR 
5 
Selli et al 
(2002) 24 
431 
T2-T3 
 
G + B x 3 
mo vs. G + 
B x 6 mo  
27.9% vs. 53.1% 
(3 mo)a 
29.7% vs. 53.1% 
(6 mo)a 
NR 
NR 
NR 
 
Aus et al 
(2002) 23 
126 
T1b-T3a 
 
T x 3 mo  
23.6% vs. 45.5%a  
NR 
49.8% vs. 
51.5% 
No 
difference 
6.85 
Klotz et al 
(2003) 26 
213 
T1b-T2 
 
T x 3 mo  
28% vs. 65%a 
0% vs. 0% 
60.2% vs. 
68.2%  
30.5% 
vs.18.8%a 
for PSA > 
20 ng/ml  
88.4% vs. 
93.9%  
6 
Prezioso et al 
(2004) 27 
167 
T1a-T2b  
L + C x 3 
mo  
39% vs. 60%a 
NR 
NR 
NR 
 
Yee et al 
(2009) 28 
148 
T1b-T3 
G + F x 3 
mo  
19% vs. 38%a 
NR 
80% vs. 
78% 
NR 
8  


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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6 
a Denotes statistical significance.  
ADT = androgen deprivation therapy; pCR = pathologic complete response = PFS = progression free 
survival; OS = overall survival; RP = radical prostatectomy; G = gosereline; mo = months; NR = not 
recorded; L = leuprolide; F = flutamide; B = bicalutamide; T = triptorelin; C = cyproterone. 
 
The concept of utilizing neoadjuvant ADT prior to RP emerged in an attempt to 
improve the rate of organ-confined disease. Labrie and colleagues18 were among the 
first to show improvement in pathologic outcomes with a randomized, prospective trial 
using leuprolide and flutamide for three months prior to RP compared to RP alone. The 
study showed that neoadjuvant combination ADT decreased positive surgical margins 
from 33.8% to 7.8% and resulted in down staging in 54% in the neoadjuvant arm. In 
addition, pCRs were found in six RP specimens (6.7%). The authors postulated that 
longer duration of neoadjuvant ADT would potentially increase the degree of benefit.  
 
Subsequently treatment durations ranging from three to eight months were 
evaluated.20,22,24 The Canadian Urologic Oncology Group (CUOG) conducted the 
largest randomized trial evaluating neoadjuvant ADT prior to RP.22  In this study, 547 
men with cT1b-T2 were randomly assigned to treatment with leuprolide and flutamide 
for three or eight months before RP. Compared to the three month group, the eight 
month group had lower preoperative PSA (0.052 versus 0.133 ug/L, p=0.0141), lower 
positive surgical margin rate (12% versus 23%, p=0.0106), and higher rate of organ-
confined disease (80% versus 68%, p=0.0019).  The pCR rate was higher in the eight 
month group compared to the three month group, though this was not statistically 
significant (9.3% versus 5.1%, p=0.0711). There have been no reports of improvement 
in biochemical relapse rates or other clinical outcomes with longer ADT from this trial.  
 
A meta-analysis of 10 studies of neoadjuvant ADT prior to RP showed that neoadjuvant 
therapy had a beneficial and statistically significant impact in lowering the pathologic T 
stage, increasing the organ-confined rate, lowering the positive surgical margin rate, and 
decreasing the number of pathologic N1 cases.29 The effect on positive surgical margins 
and organ-confined rates was significantly better with eight months of neoadjuvant 
treatment as compared to only three months of treatment. Four trials included 
information about the pCR rate.18,20,22,26 The beneficial effects in pathologic outcomes, 
including pCR rate, did not translate to improved DFS or OS. The DFS at five years, 
defined either as biochemical or clinical progression, remained unchanged between the 
treatment and control groups. Only one trial found local recurrence rates to be 
decreased, but this was only in a subset of patients with T2 disease.21 In the three 
studies which evaluated OS with mean follow-up periods of 4, 6, and 7 years, the meta-
analysis found no significant difference in OS and no assessments with longer follow-
up are available.21,23,26   
 
The discordance between the improvement in immediate pathologic endpoints and the 
lack of benefit in DFS or OS is likely multi-factorial in nature. This is likely 
multifactorial given that these trials included heterogeneous patients populations 
(including patients who did not have high-risk disease), various treatment regimens 
(including an LHRH agonist, an antiandrogen, or combination of both), various 
durations of therapy (with most durations lasting three months), and limited sample size 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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7 
to detect realistic differences between treatment arms. Additionally, this could be 
related to minimal efficacy standard ADT and more maximal suppression of the 
androgen axis is necessary to observe a therapeutic effect. 
 
Additionally, in prostate cancer, neoadjuvant therapy changes the morphology of the 
residual, rendering the Gleason score of the post-therapy specimen inadequate. A study 
of 115 patients with high-risk prostate cancer who had preoperative therapy with 
androgen ablation alone or in combination with chemotherapy evaluated morphologic 
patterns in the RP specimens that may be helpful in assessing prognosis.30 Based on 
hierarchical clustering analysis, three morphologically distinct groups were identified. 
On multivariate analysis, the presence of cribriform or intraductal spread morphology 
were strong predictors of biochemical relapse.  
 
With regard to adjuvant therapy, there are only limited data about the role of adjuvant 
hormone therapy without radiation therapy after RP. ECOG (ECOG3886) evaluated 
immediate versus deferred ADT in men with node-positive prostate cancer.31 Between 
1988 and 1993, 98 men who underwent a radical prostatectomy and pelvic 
lymphadenectomy and found to have microscopic lymph node metastases were 
randomized to receive immediate lifelong ADT or to be observed and receive ADT on 
symptomatic recurrence or detection of distant metastatic disease. At a median follow-
up of 11.9 years, the men assigned to the immediate ADT arm had a significant 
improvement OS (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.01–3.35, P 5 
.04), prostate cancer–specific survival (HR 4.09, CI 1.76–9.49, P 5 .0004), and 
progression-free survival (HR 3.42, CI 1.96–5.98, P<.0001). In this study, patients in 
the observation arm were initiated on ADT only after the development of symptomatic 
recurrence or detectable metastatic disease and not at the time of biochemical 
recurrence, which can occur at a median of 8 years before the onset of radiologic 
evidence of metastatic disease.32  
 
A separate retrospective observational study using Surveillance, Epidemiology, and End 
Results (SEER)–Medicare data was done to evaluate the impact of adjuvant ADT for 
patients who have node-positive prostate cancer in the contemporary era of 
postoperative PSA surveillance to detect biochemical recurrence.33 Wong and 
colleagues used the SEER-Medicare database to construct a cohort of men with lymph 
node– positive disease who had undergone RP between 1991 and 1999 and classified 
them as receiving adjuvant ADT (within 120 days of RP) or not receiving adjuvant 
ADT (subsequent ADT initiated >120 days from surgery or no ADT). Among the 731 
men identified, 209 had received ADT within 120 days of RP. After adjusting for 
potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of 
nodal disease, demographics, receipt of radiotherapy), there was no statistically 
significant difference in the OS between the adjuvant ADT and non-ADT group (HR 
0.97, 95% CI 0.71–1.27). Additionally, there was no statistically significant survival 
difference when various definitions of adjuvant ADT (90, 150, 180, and 365 days) were 
tested. One important limitation of this study is that the indication for ADT (adjuvant 
versus salvage) was not available through the database. 
 


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In the SWOG (Southwest Oncology Group) S9921 trial, 983 men with high-risk 
prostate cancer (extraprostatic extension, positive nodes, positive margin Gleason 7 or 
Gleason grade >7) received adjuvant therapy with ADT (goserelin and bicalutamide for 
2 years) alone or in combination with 6 cycles of mitoxantrone chemotherapy after a 
prostatectomy.34 For the 481 men who received ADT only, the estimated 5-year 
biochemical failure-free survival was 92.5% (95% CI 90–95) and the 5-year OS was 
95.9% (95% CI 93.9–97.9). This trial was closed to accrual in January 2007 after 3 
cases of acute myelogenous leukemia were reported in the mitoxantrone treatment arm. 
The final analysis of the primary end point of OS comparing the 2 arms for this trial has 
not been reported; however, the results seen in the ADT-only arm make a compelling 
argument to counsel patients with high-risk prostate cancer about adjuvant ADT after a 
RP. This study represents the largest prospective cohort of patients with high-risk 
prostate cancer receiving adjuvant ADT and showed favorable results. 
 
Though prior clinical trials of ADT in the neoadjuvant and adjuvant setting have not 
proved effective, promising results of a number of rationally-designed next generation 
hormone therapies in patients with metastatic disease are providing rational for use in 
early disease stages in an attempt to improve survival in high-risk patients with 
localized prostate cancer.   
 
We evaluated abiraterone acetate in a phase II neoadjuvant trial in patients with 
intermediate and high-risk prostate cancer.3 Fifty-eight patients were randomized to 
treatment with AA (1000 mg PO daily) + leuprolide + prednisone (5 mg PO daily) or 
leuprolide alone for 12 weeks. After 12 weeks, patients underwent prostate biopsy. 
Subsequently all patients received an additional 12 weeks of combination AA (1000 mg 
PO daily) + leuprolide + prednisone (5 mg PO daily). After 24 weeks, patients 
underwent RP. This study demonstrated that the pathologic pCR and near pCR rate 
(defined as tumor measuring < 5 mm) was 14% in the overall cohort and was 24% in 
patients treated with abiraterone acetate for 24 weeks and 4% in those treated with 
leuprolide alone followed by 12 weeks of combination therapy (p=0.089). PSA 
measurements did not reflect pathologic outcomes in patients in both arms of the trial. 
Though 86% of all patients had a nadir PSA ≤ 0.2 ng/mL at 24 weeks, 54% had 
pathologic T3 disease. Longer follow-up is needed to evaluate the effect of this therapy 
on long term cancer control. 
 
 
We completed accrual and are analyzing a randomized phase II trial evaluating 
neoadjuvant enzalutamide alone versus enzalutamide, dutasteride, and leuprolide in 
men with localized intermediate and high-risk prostate cancer.35 The primary endpoint 
of this trial is pCR and near pCR rate. Prostate cancer tissue from baseline biopsies and 
from RP specimens will be available for correlative assessment of mechanisms of 
castration resistance including selective changes in the AR and AR associated genes.  
Apalutamide is a novel second-generation anti-androgen, with a similar mechanism of 
action to enzalutamide that binds directly to the ligand-binding domain of the AR, 
impairing nuclear translocation and DNA binding. It has not been investigated in the 
neoadjuvant setting. 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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Though this data is promising, there is an opportunity for further improvement of 
pathologic outcomes. In preclinical models of human castration-resistant prostate cancer 
(CRPC) xenografts, treatment with abiraterone acetate resulted in increased expression 
of full-length AR, which can lead to AR sensitization to lower levels of androgens. 
Additionally, treatment was associated with increased expression of CYP17 and other 
key enzymes mediating conversion of adrenal androgen intermediates to testosterone, 
suggesting de novo steroidogenesis within the tumor microenvironment. This data 
highlights the rationale for combination abiraterone acetate with a potent antiandrogen. 
 
We propose to evaluate the efficacy of neoadjuvant abiraterone acetate + apalutamide + 
prednisone + leuprolide compared to abiraterone acetate + prednisone + leuprolide 
followed by RP and subsequent adjuvant therapy abiraterone acetate + apalutamide + 
prednisone + leuprolide compared to no further adjuvant treatment in patient with 
intermediate to high-risk prostate cancer. The primary objective will be analysis of pCR 
+ minimal residual disease (MRD, defined as residual tumor in RP specimen measuring 
≤ 5 mm) in RP specimens following neoadjuvant therapy as well as of freedom from 
biochemical recurrence post-RP. 
2.3 
Study Agent(s) 
2.3.1 Abiraterone acetate 
2.3.2 Abiraterone acetate (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 CYP17.36,37 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).38 Abiraterone acetate is a potent inhibitor with an 
apparent inhibition constant of 0.5 nM.37  
 
 
 
Figure 1. The pro-drug abiraterone acetate is converted to abiraterone after 
absorption.  
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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Abiraterone acetate is the 3-acetylated analog and pro-drug of abiraterone 
(given poor bioavailability) suitable for oral administration (Figure 2). 
Abiraterone acetate is rapidly deacetylated and converted to the active form 
abiraterone. Abiraterone is metabolized by CYP3A4 and is an inhibitor of 
CYP2D6.39 
 
 
 
Figure 2. The steroid biosynthesis pathway. Abiraterone inhibits 17α-hydroxylase 
(crossed in red) which results in reduction of serum cortisol and consequent 
increase in adrenocorticotropic hormone (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. 
DHEA-S. Dehydroepiandrosterone (DHEA); sehydroepiandrosterone-sulfate 
(DHEA-S); sihydrotestosterone (DHT); sulfotransferase (ST); steroid sulfatase 
(STS).  
 
Rationale 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 CYP17.40 When administered at a dose of 400 mg 
three times daily, ketoconazole reduced testosterone, androstenedione and 
DHEA.41 
 
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.42 In the Cancer and Leukemia Group B (CALGB) 9583 phase III 
trial comparing androgen withdrawal to androgen withdrawal plus ketoconazole, 
response rates were 11 and 27%, respectively (p=0.02), however there was no 
difference in OS between the two groups, which may reflect 82% crossover rate.43  
 
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 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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11 
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 more potent and selective inhibition of 
CYP17, 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 
Abiraterone acetate 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 2).  
 
Table 2. Summary of clinical trials of Abiraterone Acetate.  
 
Study 
Patient 
Drug 
Efficacy 
Toxicity 
Phase 1  
Attard et al 
(2008)44 
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)45 
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 
(12%), grade 3/4 
hypokalemia (9%) 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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Phase II 
Attard et al 
(2009)46  
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)47 
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)48 
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)49 
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 
(p<0.001), PSA 
AA-prednisone vs. 
placebo-
prednisone 
hypertension 10% 
vs. 8%, 
hypokalemia 17% 
vs. 8%, fluid 
retention 31% vs. 
22% 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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response rate 29% vs. 
6% (p<0.001) 
Phase III 
Ryan et al 
(2012)50 
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.51 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 abiraterone acetate in some men, 
suggesting the need for abiraterone acetate to be given concomitantly with 
suppressed testicular function. 
 
A Phase I/II study evaluated abiraterone acetate in chemotherapy-naive men with 
CRPC resistant to multiple prior hormone therapies.44,46 The phase I study (n=21) 
evaluated once, daily, continuous abiraterone acetate, which escalated through 
five doses (250-2,000 mg) in three-patient cohorts. In this study, abiraterone 
acetate 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. Abiraterone acetate 
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 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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≥30%, 50%, and 90% were observed in 14 (66%), 12 (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 
Response Evaluation Criteria In Solid Tumors (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.46 A decline in PSA of 
≥50% was observed in 67% of patients and declines of ≥90% were observed in 
19% of patients. The median time-to-PSA progression (TTPP) was 225 days. Of 
the 24 patients with measurable disease, 38% experienced partial response by 
RECIST. Decreased in circulating tumor cell (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 abiraterone acetate, 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.47,48 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 abiraterone acetate was demonstrated in a phase III trial in which 
1,195 men previously treated with docetaxel were randomly assigned to 
abiraterone acetate plus prednisone or placebo plus prednisone.49 The primary end 
point was OS. After a median follow-up of 12.8 months, abiraterone acetate 
significantly increased OS (median 14.8 versus 10.9 months, p<0.0001), TTPP 
(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. The effect of abiraterone acetate and prednisone on OS 
was consistent across all subgroups.  
 
The most common adverse event was fatigue which occurred at a similar 
frequency in the two treatment groups. Other common AEs including back pain 
(30% in the abiraterone acetate group and 33% in the placebo group). Nausea 
(30% and 32%, respectively), constipation (26% and 31%), bone pain (25% and 
28%), and arthralgia (27% and 23%). Most of these events were grade 1 or 2. 
Urinary tract infection was more frequent in the abiraterone acetate group (12% 
vs. 7% in the placebo group, p=0.02) and were primarily grade 1 or 2 events. AEs 
resulting in treatment discontinuation occurred with similar frequency in the 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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abiraterone acetate and placebo groups (19% and 23%, respectively, p=0.09). AEs 
associated with elevated mineralocorticoid levels, cardiac disorders, and liver 
function test (LFT) abnormalities were more common in the abiraterone acetate 
group than in the placebo group (55% vs. 43%, p<0.001). The incidence of fluid 
retention and edema was higher in the abiraterone acetate group (31% vs. 22% in 
the placebo group). Hypokalemia occurred in a higher proportion of patients in 
the abiraterone acetate group (17% vs. 8%, in the placebo group, p<0.001). 
Cardiac events (primarily grade 1 or 2) occurred at a higher rate in the abiraterone 
acetate group than in the placebo group (13% vs. 11%, p=-.14), but this difference 
was not significant. The most frequently reported cardiac events tachycardia and 
atrial fibrillation. A grade 4 elevation in LFTs early on the study led to a protocol 
amendment to specifying more frequent monitoring of LFTs. Overall however, 
abnormalities in LFTs occurred at a similar frequency in the abiraterone acetate 
and placebo groups. A lower proportion of patients in the abiraterone acetate 
group than in the placebo group had an AE that resulted in death (12% vs. 15%). 
Based on this trial, abiraterone acetate was approved by the FDA in April 2011 
for the treatment of patients with metastatic CRPC following docetaxel.49  
 
A randomized, phase III study evaluated abiraterone acetate in chemotherapy-
naive patients with metastatic CRPC. In this double-blind study, 1,088 patients 
were randomly assigned to treatment with abiraterone acetate plus prednisone or 
placebo plus prednisone. The co-primary end points were radiographic PFS and 
OS. The study was unblinded after a planned interim analysis that was preformed 
after 43% of the expected deaths had occurred. The trial showed that treatment 
with abiraterone acetate 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 (not reached vs. 27.2 months, Hazard Ratio (HR) 0.75, 
95% CI 0.61-0.93, p=0.01) over placebo plus prednisone. Abiraterone acetate 
decreased the risk of decline in performance status score (time to decline 12.3 vs. 
10.9 months, p=0.005), increased the median time to initiation of cytotoxic 
chemotherapy (25.2 vs. 16.8 months, p<0.001), delay in time to opiate use for 
cancer-related pain (not reached vs. 23.7 months, p<0.001), and median TTPP 
(11.1 vs. 5.6 months, p<0.001). 
 
Grade 3 or 4 AEs were reported in 48% of patients in the abiraterone acetate 
group and 42% of the placebo group, serious AEs were reported in 33% and 26% 
of patients, AEs resulting in death were reported in 4% and 2% of patients, 
respectively. Common AEs included fatigue (39% vs. 34%), back pain (32% vs. 
32%), arthralgia (28% vs. 24%), nausea (22% vs. 22%), constipation (23% vs. 
19%), hot flush (22% vs. 18%), diarrhea (22% vs. 18%), bone pain (20% vs. 
19%), muscle spasm (14% vs. 20%), pain in extremity (17% vs. 16%), and cough 
(17% vs. 14%). Grade 3 or 4 hepatotoxicity (elevated LFTs) occurred in 8% of 
patient in the abiraterone acetate group and 3% in the placebo group. AEs 
classified as cardiac disorders were reported in 19% of patient in the abiraterone 
acetate group and 16% in the placebo group. Hypertension (22% vs. 13%), 
hypokalemia (17% vs. 13%), and fluid retention or edema (28% vs. 24%), were 


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mostly grade 1 or 2 events. Based on the results of this trial, in December 2012, 
the FDA expanded the indication for abiraterone acetate for the treatment of 
patients with chemotherapy-naive metastatic CRPC.  
 
Pharmacokinetics of Abiraterone Acetate 
Pharmacokinetics were evaluated in two phase I trials and are detailed in table 
2.44,45 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 area under the curve (AUC) and 
maximum plasma concentration (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.45 Less than proportional increased in both Cmax and AUC were observed 
across dose levels in fed and fasted patients. 
 
 
 
 
 
Table 3. 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. Exposure (area under 
the curve) of abiraterone acetate increases up to 10 fold 
when abiraterone acetate is taken with meals. 
Abiraterone Cmax and AUC0-∞ (exposure) were 
increased up to 17- and 10-fold higher, respectively, 
when a single dose of abiraterone acetate was 
administered with a meal compared to a fasted state.  
Abiraterone AUC0–∞ was approximately 7-fold or 1.6-
fold higher, respectively, when a single dose of 
abiraterone acetate was administered 2 hours after or 1 
hour before a medium fat meal (25% fat, 491 calories) 
compared to overnight fasting.  Systemic exposures of 
abiraterone in patients with metastatic CRPC, after 
repeated dosing of abiraterone acetate were similar 
when abiraterone acetate was taken with low-fat meals 
for 7 days and increased approximately 2-fold when 
taken with high-fat meals for 7 days compared to when 
taken at least 2 hours after a meal and at least 1 hour 
before a meal for 7 days.  Due to normal variation and 
composition of meals, no food should be consumed for 
at least 2 hours before the dose of abiraterone acetate 
and for at least one hour after the dose. 
Metabolism 
Following oral administration, abiraterone acetate is 
hydrolyzed to abiraterone (active metabolite) through 


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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 abiraterone acetate, 22% as abiraterone). 
Half-life 
Mean terminal t1/2= 12 ±5 hours. 
Protein 
Binding 
Highly protein bound (>99%); it is not a substrate for 
but is an inhibitor of P-glycoprotein. 
For detailed information regarding potential drug interactions, refer to section 5.4. 
2.3.3 Apalutamide (JNJ-56021927)  
2.3.4 Apalutamide is synthetic biaryl thiohydantoin compound. It is a 
novel second-generation antiandrogen that binds directly to the 
ligand-binding domain of the AR, impairing nuclear translocation 
and DNA binding.  Apalutamide is approved by the FDA for the 
treatment of non-metastatic castration resistant prostate cancer, 
however in this study apalutamide is still considered investigational 
in this trial setting.  It is currently under investigation as a single 
agent in a Phase I/II study of patients with metastatic CRPC.52  
  
Rationale for Using Apalutamide in Prostate Cancer  
First generation antiandrogens, including bicalutamide, nilutamide, and 
flutamide, are reversible inhibitors of the AR and have a several-fold lower 
affinity to the AR compared with androgens. These agents have been used in 
the management of advanced prostate cancer for decades. Addition of an 
antiandrogen at the time of CRPC has been shown to lower PSA by 50% or 
more in approximately one-quarter of patients.30,53,54 There is no data 
supporting the superiority of one antiandrogen over another, however 
nilutamide has been shown to induce PSA declines in men who have 
developed resistance to AR inhibition with flutamide or bicalutamide.55  
 
It was first noted in the early 1990s that disease progression, despite the 
combination of an LHRH agonist and an antiandrogen, could be stopped and 
reversed simply through discontinuation of the antiandrogen. Stopping the 
antiandrogen in men with a rising PSA, termed antiandrogen withdrawal, can 
result in PSA declines in between 10-20% of men.43 Further work 
demonstrated that in the setting of AR overexpression or mutation, 
conventional antiandrogens have the potential to exhibit paradoxical partial 
agonist activity, promoting prostate cancer progression.52 Thus, more potent 
antagonists lacking agonist activity are necessary.  
 
Enzalutamide, formerly known as MDV3100, is a rationally-designed second 
generation AR inhibitor which functions by blocking several steps in the AR 


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signaling cascade. Enzalutamide competitively binds the AR with great 
potency. Additionally, enzalutamide inhibits nuclear translocation of activated 
AR and inhibits the association of activated AR with DNA.56 It has been 
tested in two placebo-controlled, randomized phase III studies (AFFIRM and 
PREVAIL) to evaluate the efficacy and safety of in patients with advanced 
prostate cancer. The AFFIRM study evaluated the safety and efficacy of 
enzalutamide in 1,199 patients with CRPC after chemotherapy with 
docetaxel.57 Patients were randomized in a 2:1 ratio to receive oral 
enzalutamide at a dose of 160 mg per day or placebo. The primary endpoint 
was OS. The study was stopped after a planned interim analysis at the time of 
520 deaths. The median OS was 18.4 months in the enzalutamide group 
versus 13.6 months in the placebo group (HR 0.63, 95% CI 0.53-0.75, 
p<0.001). The superiority of enzalutamide over placebo was shown with 
respect to all secondary endpoints: ≥50% PSA reduction (54% vs. 2%, 
p<0.001), soft-tissue response rate (29% vs. 4%, p<0.001), the quality-of-life 
response rate (43% vs. 18%, p<0.001), time to PSA progression (8.3 vs. 3.0 
months, p<0.001), time to first skeletal-related event (SRE) (16.7 vs. 13.3 
months, p<0.001). The PREVAIL trial is a double-blinded, randomized, 
placebo-controlled trial is investigating the effectiveness of enzalutamide in 
patients with metastatic CRPC who have not yet received chemotherapy. The 
primary endpoints are OS and PFS.  The study was stopped after a planned 
interim analysis showed a benefit of the active treatment. The rate of 
radiographic PFS at 12 months was 65% among patients treated with 
enzalutamide, as compared with 14% among patients receiving placebo (81% 
risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence 
interval [CI], 0.15 to 0.23; P<0.001). Based on this data, enzalutamide was 
approved for treatment of metastatic CRPC prior to chemotherapy. 
 
Clinical Data of Apalutamide 
Apalutamide is currently under investigation as a single agent in a Phase I/II 
study of patients with metastatic CRPC. In the phase I trial, which was 
presented at the 2010 Genitourinary Cancers Symposium, patients with 
metastatic CRPC received apalutamide orally on a continuous daily dosing 
schedule. In the phase 1, 7 doses (30-300 mg) were tested in a standard 3 x 3 
dose escalation design. Twenty-four patients were treated. The most common 
grade 1-2 treatment related AEs were fatigue (38%), nausea (29%), and pain 
(24%). There was only one treatment-related grade 3 AE (abdominal pain) at 
300 mg, likely related to higher pill burden. The pharmacokinetics were linear 
and dose-dependent. Twelve patients (55%) had ≥ 50% PSA declines. Based 
on preclinical assessment of maximum efficacious dose, pharmacokinetics, 
and promising activity across all doses, 240 mg was selected as the 
recommended phase II dose.  
 
Results of the Phase II portion of this multicenter trial were presented at the 
2013 Genitourinary Cancers Symposium. Activity of apalutamide was tested 
in three populations (high-risk non-metastatic CRPC, treatment naive 


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metastatic CRPC, metastatic CRPC progressive after treatment with 
abiraterone acetate). All patients received treatment with apalutamide 240 
mg/day. The primary endpoint was PSA response rate at 12 weeks according 
to the PCWG2 criteria. Twenty-five patients were enrolled on the treatment 
naive arm and 21 patients were enrolled in the post abiraterone acetate cohort. 
Of patients with metastatic disease, to date, 15 patients had discontinued the 
study. The most common treatment related AEs were fatigue (30%), 
abdominal pain (24%), nausea (22%), and diarrhea (17%). There was only one 
treatment-related grade 3 AE of abdominal pain. At 12 weeks, the PSA 
response was 88% (treatment naive) and 29% (post abiraterone acetate). 
Forty-seven patients were enrolled with non-metastatic CRPC. At a median 
treatment duration of 20 weeks, three patients discontinued the study. The 
most common treatment-related AEs were fatigue (30%), diarrhea (28%), 
nausea (17%), rash (13%), and abdominal pain (11%), the incidence of grade 
3 AE was 6.4% and no seizures have been observed. The 12-week PSA 
response was 91% at the time to PSA progression has not been reached.  
 
A phase III clinical trial evaluating apalutamide against placebo in a high-risk, 
non-metastatic castration-resistant prostate cancer population is currently 
ongoing (SPARTAN).  The primary outcome measure is metastasis-free 
survival.  Secondary outcome measures include overall survival, time to 
symptomatic progression, time to initiation of cytotoxic chemotherapy, 
progression free survival, time to metastasis, change in quality of life 
questionnaire scores, AEs, and plasma concentrations of apalutamide and 
metabolites ARN000308 and ARN 000066.  Of the participants treated to date 
on the experimental abiraterone acetate treatment arm, the most common 
grade 3-4 laboratory abnormalities were low phosphorous (7.2%), low 
potassium (5.3), and high AST (2.1%).  The most common laboratory AEs of 
any grade were high triglycerides (62.5%), high AST (30.6%), low potassium 
(28.3%), and low phosphorous (23.8%).  Any grade of laboratory AEs in the 
394 participants on the placebo arm were high triglycerides (53%), high AST 
(36.3%), low potassium (19.8%), and low phosphorous (15.7%).  The most 
common non-laboratory grade 3-4 AEs in the experimental, abiraterone 
acetate plus prednisone arm were joint swelling/discomfort (4.2%)  and 
muscle discomfort (3.0%).  Grade 3-4 urinary tract infection was in 2.1% of 
participants treated with abiraterone acetate and prednisone. 
 
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 
treating investigator should consult with the sponsor investigator before enrolling the 
subject in the study.  
3.1 
Eligibility Criteria 
 


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Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 Male ≥ 18 years of age. 
3.1.2 Histologically confirmed adenocarcinoma of the prostate without 
histological variants comprising >50% of the sample as determined 
by academic center central review (including neuroendocrine 
differentiation, small cell, sarcomatoid, ductal adenocarcinoma, 
squamous or transitional cell carcinoma). 
3.1.3 Must have 3 core biopsies involved with cancer. Prostate biopsy 
must be within seven months from screening.  Less than 3 core 
biopsies is allowed if the patient has >1cm or T3 disease on MRI. 
3.1.4 Patients must have the following features:  
• Gleason ≥ 4+3=7 OR  
• Gleason 3+4=7 AND at least one of the following: PSA 
> 20 ng/mL, or T3 disease (as determined by MRI).  
3.1.5 No evidence of metastatic disease as determined by radionuclide 
bone scans and CT/MRI. Lymph nodes must be less than 20 mm in 
the short (transverse) axis. 
3.1.6 Participants must be candidates for RP and considered surgically 
resectable by urologic evaluation. 
3.1.7 ECOG (Appendix A) performance status 0 to 1.  
3.1.8 Participants must have normal organ and marrow function as 
defined below: 
• Hemoglobin ≥ 9.0 g/dL  
• ANC ≥ 1,500/mcL 
• Platelets ≥ 100,000/mcL, independent of 
transfusions/growth factors within 3 months of treatment 
start 
• Serum potassium ≥ 3.5 mmol/L  
• Serum total bilirubin ≤ 1.5 x ULN (except in subjects 
with Gilbert’s syndrome who have a total bilirubin > 1.5 
x ULN, measure direct and indirect bilirubin and if 
direct bilirubin is ≤ 2 x ULN, subject may be eligible)  
• AST, ALT ≤ 2.5 x ULN  
• Serum albumin ≥ 3.0 g/dL  
• Serum creatinine < 2.0 x ULN 


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• INR ≤ 1.5 ULN unless on warfarin therapy (investigator 
would need to determine if safe for participant to stop 
warfarin prior to surgery and warfarin therapy 
• PTT ≤ 60 
3.1.9 Agrees to use a condom (even men with vasectomies) and another 
effective method of birth control if he is having sex with a woman 
of childbearing potential or agrees to use a condom if he is having 
sex with a woman who is pregnant while on study drug and for 3 
months following the last dose of study drug. Must also agree not 
to donate sperm during the study and for 3 months after receiving 
the last dose of study drug. 
3.1.10 Medications known to lower the seizure threshold must be 
discontinued or substituted prior to study treatment. 
3.1.11 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. 
3.1.12 Be willing/able to adhere to the prohibitions and restrictions 
specified in this protocol. 
3.1.13 Able to swallow the study drug whole as a tablet. 
3.1.14 Willing to take abiraterone acetate on an empty stomach; no food 
should be consumed at least two hours before and for at least one 
hour after the dose abiraterone acetate is taken. 
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 Prior hormone therapy for prostate cancer including orchiectomy, 
antiandrogens (including first-generation antiandrogens, 
enzalutamide, apalutamide and others), CYP17 inhibitors 
(including abiraterone, TAK-700, galeterone, ketoconazole, and 
others), estrogens, Luteinizing Hormone Releasing Hormone 
(LHRH) agonist/antagonists. Prior therapy with 5α-reductase 
inhibitors is allowed. LHRH therapy allowed if begun within 5 
weeks of day 1. Up to 30 days of bicalutamide is allowed if it is 
stopped two weeks prior to day 1.  
3.2.2 Prior chemotherapy, radiation therapy for the treatment of prostate 
cancer, or immunotherapy for prostate cancer. 


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3.2.3 Prior systemic treatment with an azole drug within two weeks of 
start of treatment. Please refer to section 5.4.  
3.2.4 Hypogonadism or severe androgen deficiency as defined by 
screening serum testosterone < 200 ng/dL. Patients who have a low 
screening testosterone due to prior ADT (per 3.2.1) will still be 
allowed to enroll on study if they do not have a known history of 
hypogonadism or severe androgen deficiency. 
3.2.5 Clinically significant cardiovascular disease within 6 months of 
study treatment including: 
• Severe or unstable angina; 
• Myocardial infarction; 
• Symptomatic congestive heart failure; 
• New York Heart Association (NYHA class II-IV heart  
failure) 
• Arterial or venous thromboembolic events (such as 
pulmonary embolism cerebrovascular accident including 
transient ischemic attacks); 
• History of clinically significant ventricular arrhythmias 
(e.g. ventricular tachycardia, ventricular fibrillation, 
torsades de pointes); 
• Prolonged corrected QT interval by the Fridericia 
correction formula (QTcF) on screening EKG > 470 
msec;  
• History of Mobitz II second degree or third degree heart 
block without a permanent pacemaker in place; 
• Uncontrolled hypertension (systolic blood pressure ≥ 
140 mmHg or diastolic blood pressure ≥ 90 mmHg). 
Participants with a history of hypertension are allowed 
provided blood pressure is controlled by anti-
hypertensive therapy. 
3.2.6 History of seizure or any condition or concurrent medication that 
may predispose to seizure (including but not limited to prior stroke, 
transient ischemic attack, loss of consciousness within one year 
prior to randomization, brain arteriovenous malformation; or 
intracranial masses such as schwannomas and meningiomas that 
are causing edema or mass effect).  
3.2.7 History of allergic reactions attributed to compounds of similar 
chemical or biologic composition to apalutamide, abiraterone 
acetate, or other study drugs. 
3.2.8 Severe hepatic impairment (Child-Pugh Class C).  


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3.2.9 Active infection (such as human immunodeficiency virus (HIV) or 
viral hepatitis) or other medical condition that would make 
corticosteroid use contraindicated. 
3.2.10 History of pituitary or adrenal dysfunction. 
3.2.11 Gastrointestinal disorders (medical disorders or extensive surgery) 
which may interfere with the absorption of the study drug.  
3.2.12 Pre-existing condition that warrants long-term corticosteroid use 
greater than the equivalent of 10 mg prednisone daily. Physiologic 
replacement is permitted. Topical, intra-articular steroids or inhaled 
corticosteroids are permitted.  
3.2.13 Concomitant use of medications that may alter pharmacokinetics of 
abiraterone or apalutamide 
3.2.14 Individuals with a history of another malignancy are not eligible if 
the cancer is under active treatment or the cancer can be seen on 
radiology scans or if they are off cancer treatment but in the 
opinion of their oncologist have a high risk of relapse within 5 
years.  
3.2.15 Major surgery or radiation therapy within 4 weeks from start of 
treatment.  
3.2.16 Any condition that in the opinion of the investigator would 
preclude participation in this study. 
3.3 
Inclusion of Women, 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 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 Sponsor-Investigator, Dr. Mary-Ellen Taplin. 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 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 Dana-Farber Cancer 
Institute (DFCI) by the Study Coordinator. All sites must call the Study Coordinator to 
verify treatment availability. The required forms will be provided to all participating 
institutions by the DFCI Study Coordinator.  
 
Following registration, participants should begin protocol treatment within 7 days or as 
soon as possible. Issues that would cause treatment delays should be discussed with the 
PI. If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study must 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 documents listed in Section 3.7.1 of Appendix I should be 
completed by the research nurse or data manager and faxed (617-632-6220) or e-mailed 
to the DFCI Clinical Research Manager and Clinical Research Coordinator.  
 
The research nurse or data manager at the participating site will then call the Clinical 
Research Manager or email the DFCI Study Coordinator to verify eligibility. To 
complete the registration process, the Coordinator will follow DF/HCC Standard 
Operating Procedures for Human Subject Research titled Subject Protocol Registration 


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(SOP #: REGIST-101) and register the participant on the protocol.  The coordinator 
will fax or e-mail the participant study number and treatment arm to the participating 
site.  The coordinator will also call the research nurse or data manager at the 
participating site and verbally confirm registration.   
 
Note: Registration and randomization with ODQ can only be conducted during the 
business hours of 8am – 5pm Eastern Standard Time Monday - Friday. Same day 
treatment registrations will only be accepted with prior notice and discussion with the 
DF/HCC Lead Institution. 
 


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5. TREATMENT PLAN  
5.1 
Treatment Summary and Randomization 
 
5.1.1 In Part 1, eligible patients will be randomized in 1:1 ratio to receive 
6 cycles of neoadjuvant treatment with either: 
• abiraterone acetate, apalutamide, leuprolide and 
prednisone (Arm 1A), OR 
• abiraterone acetate, leuprolide and prednisone (Arm 
1B).  
 
Randomization will be stratified by risk factor: Intermediate (Gleason 4+3) vs. 
high risk (Gleason>7, or PSA>20, or T3 disease). During Part 1, a cycle will be 
defined as 28 days (+/- 2 days). Following neoadjuvant treatment as designated in 
each of the above arms, patients will undergo RP. 
 
5.1.2 In Part 2 (post-RP), patients will be re-randomized in 1:1 ratio to 
receive either:  
• an additional 12 months of abiraterone acetate, 
apalutamide, leuprolide and prednisone (Arm 2A), OR  
• observation (Arm 2B).  
• Patients who do not get randomized to part 2 will follow 
the 2B arm.  
 
Randomization will be stratified by type of neoadjuvant therapy and pathological 
T-stage (< pT3 versus ≥ pT3) after RP but before cycle 7 day 1  following 
neoadjuvant therapy. Patients will be randomized regardless of post-operative 
PSA. Adjuvant or salvage radiation therapy will be allowed at the discretion of 
the treating investigator. Patients do not need to re-meet eligibility criteria at re-
randomization to Part 2 of the study. There will be an early stopping rule for Part 
2 should a high rate of patients refuse to participate or drop out early while 
receiving adjuvant therapy (<6 months). 
 
Participants may enter the study with no more than one month of an LHRH agonist 
treatment prior to cycle 1/day 1. 
 
Expected toxicities and potential risks as well as dose modifications 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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Table 4. Treatment Plan. 
Treatment Description 
Agent1 
Pre-medications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Abiraterone 
acetate 
No food should be 
consumed for at least 
two hours before the 
dose and for at least 
one hour after the dose 
1000 mg 
(four 250 
mg tablets)  
Orally  
Once daily  
28 days 
(+/-2 
days) 
during 
Part 1; 
28 days 
(+/- 14 
days 
during 
Part 2) 
 
Apalutamide 
Can be taken with or 
without food  
240 mg 
(four 60 
mg tablets) 
Orally  
Once daily  
 
 
 
 
Prednisone 
For patients receiving 
abiraterone alone; take 
with food  
5 mg  
Orally  
Once daily 
For patients receiving 
both abiraterone and 
apalutamide; take with 
food 
5 mg  
Orally  
Twice daily  
Leuprolide  
None  
22.5 mg 
every three 
months  
Intramuscular  
Every three 
months  
1. Abiraterone acetate should not be dosed with apalutamide. Apalutamide and prednisone can be 
taken together with food. Abiraterone acetate, apalutamide and prednisone will be prescribed 
by prescription in an unblinded fashion and taken by the participant on an outpatient basis. 
Leuprolide will be administered intramuscularly by a health care professional.  
 
5.2 
Pre-treatment Criteria 
5.2.1 For Cycle 1, Day 1, the following parameters must be met: 
• WBC ≥ 3,000/mcL 
• ANC ≥ 1,500/mcL 
• Serum potassium ≥ 3.5 mmol/L (patients on exogenous potassium 
supplementation will require weekly monitoring of potassium levels for 
one month) 
• AST/ALT ≤ 2.5 x ULN 
• Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except in 
subjects with Gilbert’s syndrome who have a total bilirubin > 1.5 x 
ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 2 x 
ULN, subject may be eligible)  


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• Systolic blood pressure ≤ 160 mmHg or diastolic blood pressure < 90 
mmHg 
 
If these parameters are not met, the participant can be evaluated on a weekly 
basis. Hypertension and hypokalemia should be treated as appropriate.  
 
For subsequent cycles, refer to dose modifications as outlined in Section 6.  
5.3 Agent Administration  
5.3.1 Abiraterone acetate 
- Administration: Patients will be treated with 1,000 mg orally once daily 
of abiraterone acetate prior to RP. Treatment can continue for 6 cycles 
(+/- 2 days). Following RP, patients randomized to further adjuvant 
therapy will continue abiraterone acetate with apalutamide for another 
12 cycles. However, therapy will be held on the day of RP and will 
resume on the cycle 7/day 1 visit.  
- Patients who are not randomized to further adjuvant therapy will 
administer their last dose of abiraterone acetate on the day prior to RP. 
- Dosing: 1,000 mg orally taken once daily as four 250 mg tablets. 
Possible dose modifications are outlined in Section 6.  
- Oral Doses: Abiraterone acetate must be taken on an empty stomach. No 
food should be consumed for at least two hours before the dose of 
abiraterone acetate is taken and for at least one hour after the dose of 
abiraterone acetate is taken. 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. Doses should 
not be crushed, chewed or dissolved.  They should be taken whole.  
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.  
5.3.2 Apalutamide 
- Administration: Patients will be treated with 240 mg orally once daily of 
apalutamide. Treatment can continue for 6 cycles (+/- 2 days). 
Following RP, patients randomized to further adjuvant therapy will 
continue apalutamide with abiraterone acetate for another 12 cycles. 
However, therapy will be held on the day of RP and will resume on the 
cycle 7/day 1 visit. 


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- Patients who are not randomized to further adjuvant therapy will 
administer their last dose of apalutamide on the day prior to RP. 
 
- Dosing: 240 mg orally taken once daily as four 60 mg tablets. Possible 
dose modifications are outlined in Section 6.  
 
- Oral Doses: Apalutamide can be taken with or without food. 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. Doses should not be crushed, chewed or 
dissolved.  They should be taken whole.  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. 
5.3.3 Prednisone  
 
5.3.3.1 
Patients taking Abiraterone Only 
- Administration: Patients will be treated with prednisone 5 mg orally 
once daily. Following RP, patients randomized to further adjuvant 
therapy with abiraterone acetate and apalutamide will take prednisone 5 
mg twice daily, starting at cycle 7/day 1 visit (for a total of 12 cycles). 
Prednisone in Part 1 of the study may be stopped the day prior to RP, 
(same day abiraterone is stopped), or may be tapered at the discretion of 
the treating investigator. The treating physician or surgeon may 
administer a higher dose of corticosteroids if there are signs or 
symptoms of adrenal insufficiency, or concerns for adrenal 
insufficiency. 
- Dosing: Prednisone 5 mg orally once daily taken as one 5 mg tablet. It is 
recommended that prednisone be taken in the morning. Dose reduction 
is not allowed.  
- Oral Doses: Prednisone should be taken once daily with food. If a dose 
is missed for greater than 12 hours, that dose should not be taken, and if 
the dose is missed for less than 12 hours, it should be taken prior to the 
next scheduled dose if possible. Vomited doses should not be re-taken. 
Doses should not be crushed, chewed or dissolved. Tablets should be 
taken whole.  Patients 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. 
 
5.3.3.2 
Patients taking apalutamide in combination with Abiraterone on 
Arm 1A and Arm 2A 


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- Administration: Patients will be treated with prednisone 5 mg orally 
twice daily. Following RP, patients randomized to further adjuvant 
therapy with abiraterone acetate and apalutamide will take prednisone 5 
mg twice daily, starting at cycle 7/day 1 visit (for a total of 12 cycles). 
Prednisone in Part 1 of the study may be stopped the day prior to RP 
(same day abiraterone and apalutamide stopped), or may be tapered at 
the discretion of the treating investigator. The treating physician or 
surgeon may administer a higher dose of corticosteroids if there are 
signs or symptoms of adrenal insufficiency, or concerns for adrenal 
insufficiency.  
- In Part 1A and 2A, if apalutamide is permanently discontinued due to 
toxicity, patients taking abiraterone alone should take prednisone once 
daily. 
- In Part 1A and 2A, if abiraterone is permanently discontinued due to 
toxicity, patients may take apalutamide without prednisone.  
- Dosing: Prednisone 5 mg orally twice daily. It is recommended that 
prednisone be taken with food. Dose reduction is not allowed.  
- Oral Doses: Prednisone should be taken with food twice per day at 
approximately 10-12 hour intervals. If a dose is missed for greater than 
12 hours, that dose should not be taken, and if the dose is missed for less 
than 12 hours, it should be taken prior to the next scheduled dose if 
possible. Vomited doses should not be re-taken. Doses should not be 
crushed, chewed or dissolved. Tablets should be taken whole.  
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.  
- If patients are 80% compliant with their prednisone dosing, missed doses 
do no need to be reported to the IRB as violations. 
5.3.4 Leuprolide  
- Administration: Participants may enter the study with no more than one 
month of LHRH agonist/antagonist treatment with or without an anti-
androgen prior to cycle 1/day 1. Treatment will be administered 
intramuscularly by a health care professional. Leuprolide will be 
administered as two 3-month injections or four 3-month injections 
during Part 2A. Treatment with degarelix or goserelin as a substitute to 
leuprolide is permissible. 
- Dosing: 22.5 mg intramuscularly every three months. 
5.4 
General Concomitant Medications and Supportive Care Guidelines  


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General Concomitant Medications  
Medications taken within 14 days prior to the first dose of study treatment will be 
documented. Medications taken after the first dose of study medication and until 30 
days following the last dose of study treatment will be documented as well. Prior and 
concomitant medications include all vitamins, herbal remedies, over-the-counter, and 
prescription medications.  
 
The following medications are prohibited within two weeks of start of treatment 
(unless otherwise indicated below) and throughout the time on study: 
 
• Androgens (testosterone, DHT), estrogens, or progestational agents 
• 5α-reductase inhibitors 
• Azole medications 
• Spironolactone 
• Diethylstilbestrol, saw palmetto or other preparations thought to have 
endocrine effects on the prostate 
 
Potential Drug Interactions with Abiraterone 
Abiraterone is an inhibitor of the hepatic drug metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial the Cmax and AUC of dextromethorphan (CYP2D6 
substrate) were increased 2.8 and 2.9 fold, respectively, when dextromethorphan 30 
mg was given with abiraterone 1000 mg daily and prednisone 5 mg twice daily.58 The 
AUC for dextrorphan, the active metabolite of dextromethorphan, increased 
approximately 1.3 fold. Avoid co-administration of abiraterone with substrates of 
CYP2D6 with a narrow therapeutic index (i.e. thioridazine).  
 
In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone 
(CYP2C8 substrate) was increased by 46% when pioglitazone was given together with 
a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored 
closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic 
index if used concomitantly with abiraterone. 
Based on in vitro data, abiraterone is a substrate if CYP3A4. The effects of strong 
CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, clarithromycin, atazanavir, 
nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, rifapentine, and 
phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated in vivo. 
In vitro, studies with human hepatic microsomes showed that abiraterone is a strong 
inhibitor of CYP1A2 and CYP2D6 and CYP2C8 and a moderate inhibitor of CYP2C9, 
CYP2C19, and CYP3A4/5.  
In a clinical study to determine the effects of abiraterone 1000 mg daily plus 
prednisone 5 mg twice daily on a single 1000 mg dose of the CYP1A2 substrate 
theophylline, no increase in systemic exposure of theophylline was observed.  
 


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In vitro, abiraterone and its major metabolites were shown to inhibit the hepatic uptake 
transporter OATP1B1. There are no clinical data available to confirm transporter 
based interaction. 
 
Concomitant use of medications that may alter pharmacokinetics of abiraterone 
acetate or apalutamide will not be allowed on this study. Specifically, strong CYP3A4 
inducers (see Table 5) that decrease the exposure of abiraterone will not be allowed.  
 
Table 5. Strong CYP3A4 Inducers and Inhibitors. 
Strong CYP3A4 Inducers 
Strong CYP3A4 Inhibitors 
Aminoglutethimide 
Itraconazole 
Bexarotene 
Clarithromycin 
Bosentan 
Erythromycin 
Carbamazepine 
Diltiazem 
Dexamethasone 
Verapamil 
Efavirenz 
Delavirdine 
Fosphenytoin 
Atazanavir 
Griseofulvin 
Indinavir 
Modafinil 
Nefazodone 
Nafcillin 
Nelfinavir 
Nevirapine 
Ritonavir 
Oxcarbazepine 
Saquinavir 
Phenobarbital 
Telithromycin 
Phenytoin 
Voriconazole 
Primidone 
Grapefruit juice (or grapefruits) 
Rifabutin 
 
Rifampin 
 
Rifapentine 
 
St. John's wort 
 
 
 
Potential Drug Interactions with Apalutamide 
Prohibited Medications: 
As a class effect, androgen receptor antagonists have been associated with seizures due 
to an off-target mechanism of action (GABAA inhibition). To date, one patient 
receiving apalutamide has experienced seizures, however, in preclinical experiments, 
at very high doses, dogs treated with apalutamide had tremors and generalized 
seizures. Patients will be closely monitored for seizures, but as a precautionary 
measure, the following drugs known to decrease the seizure threshold and/or cause 
seizure will be prohibited while on study: 
• Aminophylline, theophylline 
• Atypical anti-psychotic drugs: clozapine, olanzapine, ziprasidone 
• Bupropion 
• Lithium 
• Meperidine (Demerol) and pethidine 


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• Phenothiazine anti-psychotic drugs: chlorpromazine, mesoridazine, 
thioridazine 
• Tricyclic and tetracyclic anti-depressants: amitriptyline, desipramine, 
doxepine, imipramine, maprotiline, mirtazapine (Remeron) 
 
See Appendix D for a more comprehensive representative list of medications that may 
predispose to seizures.  
 
 
The potential for drug-drug interactions with apalutamide and warfarin (Coumadin) is 
unknown at present. If a subject is taking warfarin, reassess INR as clinically indicated 
and adjuvant the dose of warfarin accordingly.  
 
Restricted Medications: 
Apalutamide is metabolized primarily by human CYP3A4, thus co-administration with 
strong inhibitors or inducers of CYP3A4 must be avoided.  Apalutamide may also 
induce CYP3A4; therefore, apalutamide should not be taken in conjunction with 
CYP3A4 substrates that have a narrow therapeutic index. The CYP3A4 inhibitors and 
inducers listed in Table 5 should be avoided.    
 
If at any time an investigator suspects a drug-drug interaction, the PI, Dr. Mary-Ellen 
Taplin should be contacted at 617-582-7221 or paged at 617-632-3353 (beeper 41225). 
5.5 
Duration of Therapy  
 
Treatment on study will be for 6 cycles (28 days +/- 2 days) of neoadjuvant therapy 
followed by 12 months of adjuvant therapy. In the absence of treatment delays due to 
AEs, treatment may continue for the duration of the study until one of the following 
criteria: 
 
• Intercurrent illness that prevents further administration of treatment;  
 
• Unacceptable AEs; 
 
• Treatment emergent seizure;  
 
• 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 


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to continue on the protocol with permission of the PI, Dr. Mary-Ellen Taplin, if the 
treating physician feels it is in the participant’s best interest.  
5.6 
Duration of Follow-Up 
 
Participants randomized to adjuvant therapy as designated by Arm 2A will be followed 
every 3 months (+/- 28 days) following completion of the 12 cycles of adjuvant therapy 
for years 2-3. After year 3 post-RP, follow-up will take place every 6 months (+/- 28 
days) for up to 5 years post-RP. Long-term follow-up assessments in years 4-5 may be 
done locally and information may be collected via medical record review.  Whenever 
long-term follow-up PSA blood draws are done at the research clinic conducting the 
study, the research team should collect ctDNA samples. 
 
Participants randomized to no adjuvant therapy as designated by Arm 2B will be 
followed every 3 months (+/- 28 days) during years 1-3 post-RP.  After 3 years post-RP,  
follow-up will take place every 6 months (+/- 28 days) for up to 5 years post-RP. Long-
term follow-up assessments in years 4-5 may be done locally and information may be 
collected via medical record review.  Whenever long-term follow-up PSA blood draws 
are done at the research clinic conducting the study, the research team should collect 
ctDNA samples. 
 
Participants who do not get randomized to part 2 will follow the 2B arm.  
 
Participants removed from study for unacceptable AEs will be followed until resolution 
or stabilization of the AEs.  
5.7 
Criteria for Removal from Study 
 
Participants will be removed from study when any of the criteria are met: 
 
• Intercurrent illness that prevents further administration of treatment;  
 
• Unacceptable AEs; 
 
• Treatment emergent seizure;  
 
• 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;  
 
• Participants Lost to Follow-up; 
 
• Death. 
 


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The reason for study removal and the date the participant was removed must be 
documented in the study-specific Case Report Form (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, Dr. Mary-Ellen Taplin, at 617-582-7221 or page 617-
632-3352 (beeper 41225).  
 
 


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6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
It should be noted that we do not anticipate any excess toxicity as there are no overlapping 
toxicities and no apparent drug-drug interactions (either pharmacokinetics or combined 
inhibition of enzymes in the androgen signaling cascade) between abiraterone acetate, 
apalutamide, prednisone, and leuprolide. 
 
Anticipated toxicities ere detailed below. Toxicity assessments will be done using the 
Cancer Therapy Evaluation Program (CTEP) Active Version of the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (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 the first dose of study 
treatment, through the study and until the final study visit. 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. 
6.1 
Anticipated Toxicities 
 
A list of the AEs and potential risks associated with the agents administered in this 
study appear below and will determine whether dose delays and modifications will be 
made or whether the event requires expedited reporting in addition to routine 
reporting. 
6.1.1 AEs for Apalutamide 
Apalutamide has been associated with grade 1-2 AEs up to a dose of 240 mg by 
mouth when administrated as a single agent in a phase I/II study. Anticipated 
AEs from preliminary results of this study include fatigue, nausea, skin rash, 
changes in thyroid function, taste alterations, decreased appetite, itching, 
vomiting, dizziness, falls, insomnia, increase in blood cholesterol, increase in 
blood triglycerides, fractures, constipation, diarrhea, hot flashes and rarely, 
seizures. Reported grade 3 toxicity was abdominal pain, likely related to pill 
burden.  
6.1.2 AEs for Abiraterone  
 
Hypertension, Hypokalemia, Fatigue and Fluid Retention  
Abiraterone may cause hypertension, hypokalemia, fatigue and fluid retention 
as a consequence of increased mineralocorticoid levels resulting from CYP17 
inhibition. In a phase III randomized clinical trial, grade 3 to 4 hypertension 
occurred in 1.3% of patients, grade 3 to 4 hypokalemia in 5.3% of patients, 


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grade 3 or 4 fatigue in 2.2% of patients and grade 3 to 4 edema in 1.9% of 
patients treated with abiraterone. 
 
Co-administration of a corticosteroid suppresses ACTH drive, resulting in a 
reduction in the incidence and severity of these adverse reactions. In this trial 
5 mg daily of steroids will be used. The safety of abiraterone in patients with 
left ventricular ejection fraction < 50% or NYHA Class III or IV heart failure 
(in the COU-AA-301 study) or NYHA Class II to IV heart failure (in the 
COU-AA-302 study) was not established because these patients were 
excluded from these randomized clinical trials. 
 
Adrenocortical Insufficiency 
Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% 
of patients taking abiraterone and in 0.2% of patients taking placebo. 
Adrenocortical insufficiency was reported in patients receiving abiraterone in 
combination with prednisone, following interruption of daily steroids and/or 
with concurrent infection or stress. Symptoms and signs of adrenocortical 
insufficiency may be masked by adverse reactions associated with 
mineralocorticoid excess seen in patients treated with abiraterone. 
 
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 abiraterone, 
typically during the first three 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 abiraterone. 
No deaths clearly related to abiraterone were reported due to hepatotoxicity 
events. 
 
For guidance on management of side symptoms of mineralocorticoid excess, 
symptoms related to androgen deprivation, or other toxicities please contact 
the PI, Dr. Mary-Ellen Taplin at 617-582-7221 or page 617-632-3352 (beeper 
41225).  
See current package insert for abiraterone acetate (Zytiga) for additional 
information on abiraterone (http://www.zytiga.com/). 
6.1.3 AEs for Prednisone  
A daily dose of 5-10 mg of prednisone is below the daily 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, hypertension. 


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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. 
6.1.4 Close monitoring of blood sugars is recommended in diabetic 
patients. 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.  
6.1.5 AEs for Leuprolide  
Side effects of leuprolide are mainly secondary to intended therapeutic effects 
of castrate levels of testosterone. Common AEs include edema, headache, 
depressed mood, fatigue, insomnia, skin reaction at injection site, hot flashes, 
testicular atrophy, hyperlipidemia, decreased libido, nausea/vomiting, bowel 
function alteration, joint pain, weakness, bone loss, and flu-like symptoms.  
6.2 
Toxicity Management 
 
Management of abiraterone and apalutamide related toxicities are detailed below. 
Patients who have abiraterone treatment related toxicities many continue on 
apalutamide and leuprolide. Patients who have apalutamide toxicities may continue on 
abiraterone, prednisone, and leuprolide. If both study drugs are held, a patient will 
remain on schedule for all study assessments.  If a patient requires a dose reduction in 
Part 1 of the study, the dose reduction should also be followed in Part 2, if the patient is 
randomized to part 2A.  


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6.2.1 Management of Apalutamide Related Toxicity  
Apalutamide is generally well-tolerated based on phase I/II data. The starting 
dose of apalutamide will be 240 mg daily. In the presence of any apalutamide 
related toxicities > grade 2 (NCI CTCAE version 4) during treatment with 
apalutamide at the starting dose level, treatment will be held.  Once toxicity 
improves to ≤ grade 1, the dose of apalutamide will be decreased to 180 mg 
daily. Two levels of dose de-escalation are planned for the study. If > grade 2 
toxicity occurs at dose level -2, apalutamide will be discontinued. Therapy 
with apalutamide will be discontinued at first occurrence of seizure of any 
grade or grade 4 neurotoxicity.  
 
Dose Level 
 Apalutamide 
Starting dose 
level 
240 mg orally once daily  
-1 
180 mg orally once daily  
-2 
120 mg orally once daily  
6.2.2 Management of other toxicities is detailed below. 
• 
Grade 1-2 Toxicities: Management per investigator. No study 
treatment dose reduction indicated.  
• 
Grade 3 of Higher Toxicities: Hold apalutamide. When toxicity 
resolves to ≤ grade 1, resume at first dose modification level. 
Prophylactic medications should be considered. If toxicity 
recurs, hold study medication and adjust or add medications to 
mitigate the toxicity. When recurrent toxicity has resolved to ≤ 
grade 1, resume apalutamide at second dose modification level. 
If grade 3 toxicity recurs, the patient will be discontinued from 
the study. 
6.2.3 Management of Abiraterone Related Toxicity 
The starting dose of abiraterone will be 1000 mg daily. For grade 1-2 toxicities, 
unless otherwise described below, management per investigator. In the presence 
of any abiraterone related toxicities > grade 2 (NCI CTCAE version 4) during 
treatment with abiraterone at the starting dose level, treatment with abiraterone 
will be held. When toxicity improves to ≤ grade 1, the dose of abiraterone will 
be decreased to 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. Management of other 
toxicities is detailed below. 


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Dose Level 
Abiraterone Acetate 
Starting dose level 
1000 mg orally once daily  
-1 
750 mg orally once daily  
-2 
500 mg orally once daily  
 
6.2.4 Management of Hypertension 
• Grade 1-2 Hypertension: 
o Management per investigator. No study treatment dose reduction.  
 
•   Grade 3-4 Hypertension:  
o Hold abiraterone. Adjust or add medications to mitigate the 
toxicity and/or consider the specific mineralocorticoid receptor 
antagonist, eplerenone. When toxicity resolves to ≤ grade 1, 
resume abiraterone at full dose.  
o If grade 3 toxicity recurs x 1, hold abiraterone, and adjust or add 
medications to mitigate the toxicity. When toxicity resolves to ≤ 
grade 1, resume abiraterone at first dose level reduction (750 mg).  
o If grade 3 toxicity recurs x 2, hold abiraterone, and adjust or add 
medications to mitigate the toxicity. When toxicity resolves to ≤ 
grade 1, resume abiraterone at second dose level reduction (500 
mg daily).  
o If grade 3 toxicity recurs x 3 despite optimal medical management 
and two dose level reductions, discontinue abiraterone.  
6.2.5 Management of Hypokalemia 
• Subjects entering study on exogenous potassium supplementation: 
o Monitor potassium levels weekly for one month to ensure 
appropriate maintenance of levels.    
• Grade 1-2 Hypokalemia: 
o Initiate oral potassium supplementation and/or consider the 
specific mineralocorticoid receptor antagonist, eplerenone. Once 
toxicity presents potassium will be monitored weekly until 2 
consecutive values are documented in the normal range.  
• Grade 3-4 Hypokalemia: 
o Hold abiraterone. Adjust or add medications to mitigate the 
toxicity and/or consider the specific mineralocorticoid receptor 


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antagonist, eplerenone. Once toxicity presents potassium will be 
monitored at least weekly until 2 consecutive values are 
documented in the normal range. Once toxicity resolves 
(potassium ≥ 3.5 mmol/L), resume abiraterone at first dose level 
reduction (750 mg) after discussion with PI. Once abiraterone is 
reinitiated potassium, should be monitored at least weekly for the 
first two weeks and then every 2 weeks for 4 weeks, and then 
monthly. 
o If grade 3 toxicity recurs, hold abiraterone, and adjust or add 
medications to mitigate the toxicity. Once toxicity presents, 
potassium will be monitored at least weekly until 2 consecutive 
values are documented in the normal range. When toxicity resolves 
to ≤ grade 1, resume abiraterone at second dose level reduction 
(500 mg daily) after discussion with PI. Once abiraterone is 
reinitiated, potassium should be monitored at least weekly for the 
first two weeks and then every two weeks for four weeks, and then 
monthly. 
o If grade 3 toxicity recurs despite optimal medical management and 
two dose level reductions, discontinue abiraterone.  
6.2.6 Management of LFT abnormalities  
• 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. 


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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 
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. 
6.2.7 Rash Management  
• Dose modifications for rash are allowed only for apalutamide and are 
summarized in below table. 
• If the skin rash has any component of desquamation, mucosal 
involvement, or pustules, stop dosing with apalutamide, refer to 
dermatologist for evaluation, and a skin biopsy is recommended (in 
addition to the interventions listed in below Table)  
• If the skin rash is Grade 3 or higher, asking the subject to consent to 
documentation by a photograph and further evaluation by a dermatologist 
should also be considered. 
  
Severity 
Intervention 
Grade 1 
• 
Continue apalutamide at current dose 
• 
Initiate dermatological treatmenta 
o Topical steroid cream AND 
o Oral Antihistamines 
• 
Monitor for change in severitya 
Grade 2 (or symptomatic 
Grade 1)b 
• 
Hold apalutamide for up to 28 days        
• 
 Initiate dermatological treatmenta 
o Topical steroid cream AND 
o Oral Antihistamines 
• 
Monitor for change in severitya 


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o If rash or related symptoms improve, reinitiate 
apalutamide when rash is Grade≤1. Consider dose 
reduction at a 1 dose level reduction. 
Grade ≥3d 
• 
Hold apalutamide for up to 28 days 
• 
Initiate dermatological treatmenta 
o Topical steroid cream AND 
o Oral Antihistamines AND 
o Consider short course of oral steroids 
• 
Reassess after 2 weeks (by site staff), and if the rash is the 
same or has worsened, initiate oral steroids (if not already 
done) and refer the subject to a dermatologist 
o Reinitiate apalutamide at a 1 dose level reductionc 
when rash is Grade≤1. 
o If the dose reduction will lead to a dose less than 
120mg, 
the 
study 
drug 
must 
be 
stopped 
(discontinued) 
• 
If after 28 days, rash has not resolved to Grade≤1, contact 
Janssen to discuss further management and possible 
discontinuation of study drug.  
  
Note: Rash may be graded differently according to the type of rash and associated symptoms. 
For example, maculo-papular rash is graded by body surface area covered and not severity of the 
rash. Please consult NCI-CTCAE Version 4.03 for specific grading criteria for other types of 
rash. 
a Obtain bacterial/viral cultures if infection is suspected 
b Subject presents with other rash related symptoms such as pruritus, stinging, or burning 
c If a subject previously started oral corticosteroids, continue for at least 1 week after 
resumption of reduced dose of apalutamide. If the proposed total oral steroid use will 
exceed 28 days, contact Janssen. 
d If there is blistering or mucosal involvement, stop apalutamide dosing immediately and 
contact Janssen 
6.3 
Dose Modifications/Delays 
 
Instructions on management (including dose modifications and delays) of treatment 
related toxicities > grade 2 (NCI CTCAE version 4) are detailed in section 6.2. 
Instructions on management of abiraterone treatment related toxicities including 
hypertension, hypokalemia, and LFT abnormalities are detailed in section 6.2.  
 
There are no dose modifications for leuprolide and prednisone.  


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7. DRUG FORMULATION AND ADMINISTRATION  
7.1 
Apalutamide 
7.1.1 Description 
Name: Apalutamide 
Chemical Classification: Non-steroidal anti-androgen 
Chemical Name: (4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-
thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide) 
Molecular Formula: C21H15F4N5O2S 
Molecular Weight: 477.44 
Appearance: White to off-white powder 
7.1.2 Form 
The tablet formulation of apalutamide is an immediate release oral tablet 
containing 60-mg of drug substance, with a non-functional green film coat. 
Each 60-mg tablet contains the following inactive ingredients: hydroxypropyl 
methylcellulose acetate succinate (HPMC-AS), colloidal anhydrous silica, 
croscarmellose sodium, microcrystalline cellulose, silicified microcrystalline 
cellulose, and magnesium stearate. Commercially available Opadry® coating 
powder is used for the film coating, which is comprised of polyvinyl alcohol 
(partially hydrolyzed), titanium dioxide, polyethylene glycol, talc, and 
colorants iron oxide yellow and iron oxide black (E172). 
7.1.3 Storage and Stability 
Apalutamide tablets (60-mg) are packaged in 120-count, 160 cc high-density 
polyethylene (HDPE) bottles with child-resistant closure (CRC) and include 
desiccant. For clinical formulation-specific and batch-specific storage 
instructions, see the packaging labels.  At the clinical site and at the patient’s 
home, the study drug should be stored at room temperature and protected from 
heat and should not be frozen. Participants should be advised to keep all 
medications out of the reach and out of sight of children. 
7.1.4 Compatibility  
We do not anticipate any excess toxicity combining apalutamide with 
abiraterone as 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). 
7.1.5 Handling  
There are no specific instructions for handling apalutamide. Study treatment 
must only be dispensed by a pharmacist or medically qualified staff. Study 
treatment is to be dispensed only to participants enrolled in this study. Once 
the study treatment is prepared for a participant, it can only be administered to 
that participant. 
7.1.6 Availability 


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Apalutamide 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 ± 2 day window. Information presented on the labels for investigative 
product will comply with applicable local regulations. Site pharmacist will 
dispense the study treatment to each participant in accordance with this 
protocol under the guidelines of the site’s dispensation standard operating 
procedure. 
7.1.7 Ordering  
Apalutamide is to be ordered directly from Janssen Scientific Affairs, LLC. 
 
7.1.8 Accountability 
Accountability for study treatment is the responsibility of the investigator. The 
study site must maintain accurate records demonstrating dates and amount of 
apalutamide received, to whom dispensed (participant by participant 
accounting), and accounts of any study treatment accidentally or deliberately 
destroyed. At the end of the study, reconciliation must be made between the 
amount of study treatment supplied, dispensed, and subsequently destroyed. At 
the time of delivery of study treatment to the site, the investigator, designee, or 
pharmacist (where appropriate) will confirm that the supplies for the study have 
been received. The following information will be confirmed: lot numbers, 
quantities shipped/delivered, and date of receipt. 
7.1.9 Destruction and Return  
Drug should be destroyed at the site per each research pharmacy’s drug 
destruction policy. Destruction will be documented in the Drug Accountability 
Record Form. 
7.2 
Abiraterone acetate 
 
Refer to the package insert for abiraterone acetate information. 
7.2.1 Description 
The chemical nomenclature of abiraterone acetate (3β)-17-(3-pyridinyl) 
androsta-5,16-dien-3-yl acetate Its empirical formula is C26H33NO2 and it 
has a molecular weight of 391.55. Once absorbed after oral administration, 
abiraterone acetate is rapidly deacetylated and converted to the active form 
abiraterone.   
 
7.2.2 Form 
Abiraterone acetate 250-mg tablets are oval, white to off-white and contain 
abiraterone acetate 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). 
7.2.3 Storage and Stability 


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Pharmacy Storage Requirements 
The study treatment 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 study treatment should be 
stored at a room temperature between 15º-30º C with the cap kept on tightly 
and should not be refrigerated. Additional information is provided in the 
abiraterone acetate Investigator’s Brochure. 
 
Storage Requirements for the Participant 
Bottles of study treatment 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. 
7.2.4 Compatibility 
We do not anticipate any excess toxicity combining apalutamide, abiraterone 
acetate, prednisone and leuprolide. 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).  
7.2.5 Handling 
Study treatment must only be dispensed by a pharmacist or medically 
qualified staff. Study treatment is to be dispensed only to participants enrolled 
in this study. Once the study treatment is prepared for a participant, it can only 
be administered to that participant.  
 
7.2.6 Pregnancy 
Abiraterone may cause fetal harm when administered to a pregnant woman.  
Abiraterone is contraindicated in women who are or may become pregnant. 
Women who are pregnant or who may be pregnant should wear gloves if they 
need to touch abiraterone acetate tablets. This medicine may cause harm to the 
unborn child if taken by women who are pregnant. It should not be taken by 
women who are breast-feeding.  If abiraterone is used during pregnancy, or if 
the participant becomes pregnant while taking this drug, the participant should 
be apprised of the potential hazard to the fetus. Study staff and caregivers 
should be notified of this information, to ensure the appropriate precautions 
are taken. 
7.2.7 Availability 
Abiraterone acetate 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 ± 2-day window. Information presented on the labels for investigative 
product will comply with applicable local regulations. Site pharmacist will 
dispense the study treatment to each participant in accordance with this 
protocol under the guidelines of the site’s dispensation standard operating 
procedure. The agent is supplied and will be provided free-of-charge.  
7.2.8 Ordering 


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Abiraterone acetate is to be ordered directly from Janssen Scientific Affairs, 
LLC. 
7.2.9 Accountability 
Accountability for study treatment is the responsibility of the investigator.  
 
The study site must maintain accurate records demonstrating dates and 
amount of abiraterone acetate received, to whom dispensed (participant by 
participant accounting), and accounts of any study treatment accidentally or 
deliberately destroyed. At the end of the study, reconciliation must be made 
between the amount of study treatment supplied, dispensed, and subsequently 
destroyed. 
 
At the time of delivery of study treatment 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. 
7.2.10 Destruction and Return 
Drug should be destroyed at the site, after the sponsor–investigator approves 
the drug destruction policy at the site. Destruction will be documented in the 
Drug Accountability Record Form. 
7.3 
Prednisone 
7.3.1 Description 
Prednisone is a corticosteroid. 
7.3.2 Form 
Prednisone 5-mg tablets are small, white tablets. 
7.3.3 Storage and Stability 
Prednisone will be prescribed by prescription and prescriptions may be filled 
at a pharmacy chosen by the participant. 
7.3.4 Compatibility 
We do not anticipate any excess toxicity combining apalutamide, abiraterone 
acetate, prednisone and leuprolide. 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).  
 
7.3.5 Handling 
 There are no specific instructions for handling prednisone. 
 
7.3.6 Availability  
Prednisone will not be provided by the study and will be prescribed by standard 
prescriptions. 


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7.4 
Leuprolide 
7.4.1 Description 
Leuprolide is a LHRH agonist. 
7.4.2 Form 
Leuprolide is a sterile solution administered as an intramuscular injection.  
7.4.3 Storage and Stability 
Leuprolide will be stored at the site specific pharmacy.  
7.4.4 Compatibility 
We do not anticipate any excess toxicity combining apalutamide, abiraterone 
acetate, prednisone and leuprolide. 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).  
7.4.5 Handling  
There are no specific instructions for handling leuprolide. 
7.4.6 Availability  
Leuprolide is commercially available and will be ordered by the institution’s 
pharmacy. 


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8. CORRELATIVE STUDIES 
8.1 
Correlative Studies Background 
 
PTEN and the PI3K Pathway 
The PTEN gene is a tumor suppressor that encodes a protein phosphatase recurrently 
mutated in cancer. PTEN activity removes a phosphate from phosphoinositides at the 
plasma membrane and negatively regulates the PI3K–AKT–mTOR. Thus, either loss 
or inactivation of PTEN genes leads to PI3K pathway activation. Genomic evidence 
of PTEN loss in prostate cancer through point mutation, deletion, or rearrangement 
has been observed in at least 50% of metastatic CRPCs. Interestingly, recent studies 
have demonstrated a relationship for ERG fusions and androgen signaling with PTEN 
loss, suggesting that PTEN loss and ETS fusions are not mutually exclusive events. 
Additionally, preclinical models have demonstrated cross-talk between the PI3K 
pathway and AR signaling axis and regulation via reciprocal feedback.53  We 
hypothesize the PTEN loss may be a mechanism of intrinsic resistance to androgen 
ablation. 
 
Whole Exome and Transcriptome Sequencing 
Considerable evidence now exits that prostate cancer, like all malignancies, is a 
genomic disease. Understanding the genetic basis of prostate cancer is therefore 
crucial for the creation of more powerful preventative interventions, diagnostics, and 
targeted therapies. The prevalence of genomic aberrations in clinically meaningful 
prostate cancer raises the hypothesis that such changes may influence the castration-
resistant phenotype.  
The initial pilot study representing the first whole genome sequencing analysis of 
primary human prostate cancer consisted of radical prostatectomy specimens from 
seven patients with high-risk primary tumors.59 This analysis showed that several 
tumors contained complex chains of balanced rearrangements that occurred within or 
adjacent to known cancer genes. Rearrangement breakpoints were enriched near open 
chromatin, AR, and ERG DNA binding sites in the setting of the ETS gene fusion 
TMPRSS2-ERG, but inversely correlated with these regions in tumors lacking ETS 
fusions. Three tumors contained rearrangements that disrupted CADM2 and four 
harbored events disrupting either PTEN, a prostate tumor suppressor, or MAG12, a 
PTEN interacting protein.  
To gain insights into the genomic alterations that may underpin lethal prostate cancer, 
we plan to perform whole exome and transcriptome characterization of prostate tumor 
samples (obtained from fresh-frozen tissue at pretreatment biopsy and RP) and their 
matched normal counterparts (from whole blood obtained from the same patient).  For 
control purposes, blood will be assessed for germline DNA. This will be 
accomplished by paired-end, massively parallel sequencing of tumor and normal 
DNA using the Illumina platform. 
 
 
 


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AR Signaling Axis and Serum Hormones and Hormone Levels 
Although effective CYP17 inhibition by abiraterone represents a significant advance 
in the treatment of metastatic CRPC, studies of resistance mechanisms to abiraterone 
provide the rational for adding antiandrogen therapy. In vitro, abiraterone treatment 
increases CYP17 expression, AR expression, and expression of AR splice variant. 
Based on preclinical models of enzalutamide resistant cell lines, researchers have 
identified a novel missense mutation in the AR ligand-binding domain (F876L) that 
confers agonistic activity to enzalutamide. This mutation is hypothesized to drive 
phenotypic resistance. Additionally, in preclinical models splice variant AR 
expression driven by AR gene rearrangements demonstrated resistance to 
enzalutamide given activity as independent effectors of the AR transcriptional 
program. Other postulated mechanisms of castration resistance include aberrant AR 
co-regulators leading to altered AR transcriptional activity and cross-talk with 
alternative signaling pathways, including the PI3K/Akt/mTOR and RAS/MAPK 
pathways.  
 
ctDNA 
There is an unmet clinical need for reliable biomarkers that can be used for early 
detection of cancer recurrence and to guide therapy. Detecting ctDNA in plasma or 
serum could serve as a ‘liquid biopsy’, which would be useful for numerous 
diagnostic applications. Use of such a liquid biopsy delivers the possibility of taking 
repeated blood samples, consequently allowing the changes in ctDNA to be traced 
during the natural course of the disease or during cancer treatment. The physiological 
events that lead to the increase of ctDNA during cancer development and progression 
are still not well understood. However, analyses of ctDNA will allow for the detection 
of tumor-related genetic and epigenetic alterations that are relevant to cancer 
development and progression. We and others have previously shown that detection of 
ctDNA is feasible.60,61 In a study of 640 patients with various types of cancer, ctDNA 
was identified in >75% of cases. We have thus far been able to detect ctDNA in post 
RP patients treated on our previously mentioned abiraterone neoadjuvant study. 
 
Multiparametric Prostate MRI 
We previously conducted a pilot study to investigate multiparametric MRI as a 
biomarker for predicting response to neoadjuvant hormone therapy with enzalutamide 
+/- leuprolide + dutasteride for high-risk localized prostate cancer undergoing 
prostatectomy. From this small pilot study of 8 patients, we demonstrated that at 
baseline, there was a significant difference in mpMRI parameters in areas of tumor 
versus normal tissue. Following neoadjuvant therapy, there was no significant change 
in diffusion parameters in response to therapy, but a significant change in parameters 
derived from dynamic contrast imaging (DCE), which may indicate a decrease in 
neovascularity and perfusion, but no significant change in cellular density. Using 
Spearman’s rank correlation, there was a significant correlation between tumor volume 
on post-treatment MRI (Apparent diffusion coefficient (ADC), T2, and Dynamic 
contrast-enhanced (DCE)) and pathology volume, indicating that multiparametric MRI 
post-therapy may be useful to predict tumor volume at prostatectomy. Using Wilcoxon 
means for difference in volumes, there was no significant difference between 


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51 
pathology volumes and multiparametric MRI volumes. There was a significant 
moderate-large correlation between quantitative DCE parameters of the post-treatment 
MRI and RCB: mean AUC (Spearman correlation of 0.79, p=0.028) and mean Ktrans 
(Spearman correlation of 0.76, p=0.037). There was also a strong negative correlation 
between minimal ADC 500 value in the post-treatment MR and RCB (r=-0.91, 
p=0.0046). Again, this may indicate that multiparemteric MRI indices may be useful 
for predicting the RCB at prostatectomy.  
 
Sequencing of Germline DNA for assessment of Aberrations in Homologous 
Recombination Genes  
Pritchard and colleagues reported on the germline DNA analysis of 692 men with 
documented metastatic prostate cancer who were unselected for family history of cancer 
or age at diagnosis. Germline DNA was isolated and multiplex sequencing assays were 
used to assess mutations in 20 DNA-repair genes associated with autosomal dominant 
cancer-predisposition syndromes. These genes included: ATM, ATR, BAP1, BARD1, 
BRCA1, BRCA2, BRIP1, cHek2, FAM17A, GEN1, MLH1, MRE11A, MSH2, MSH6, 
NBN, PALB2, PMS2, RAD51C, RAD51D, XRCC2. A total of 84 germline DNA-repair 
gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); 
mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 
[1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 
[0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to 
whether a family history of prostate cancer was present or according to age at diagnosis. 
Overall, the frequency of germline mutations in DNA-repair genes among men with 
metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 
men with localized prostate cancer (P<0.001), including men with high-risk disease. 
 
For this work, next-generation targeted sequencing of germline DNA will be performed 
using the Illumina TruSight Cancer Sequencing Panel 
(http://www.illumina.com/products/trusight_cancer.html). The panel includes 94 genes, 
35 of which have been identified as being involved in human DNA repair. Libraries will 
be created using 50ng germline DNA and sequenced by Illumina MiSeq platform using 
PE150 chemistry, according to the manufacturer’s instructions. To identify genomic 
variants we will use two independent commonly used standard variant calling pipelines 
(GATK and samtools/bcftools). Bowtie2 aligner will be applied. Alterations will be 
visualized by IGV tool and validated by Sanger Sequencing. 
  
8.2 
Correlative Studies Methodologies 
Detailed methodologies regarding sample collection, processing, storing, shipment 
and analytical methodologies are detailed in the study laboratory manual. Please refer 
to this document for specific details regarding the specifics of the correlative 
laboratory procedures.  
 
 
 
 


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PTEN and the PI3K Pathway 
During this study, we will use IHC analysis to assess PTEN expression in 
pretreatment prostate biopsies and RP specimens to determine whether PTEN status 
(loss or no loss) is associated with pathological response.  
 
IHC will be performed for the following targets on archival prostate biopsies and 
FFPE RP specimens at Center for Molecular Oncologic Pathologies (CMOP)/DFCI: 
AR, apoptosis markers, WNT signaling, PTEN-PI3K-AKT pathway, PSA, ERG, and 
Ki67. Scoring systems will be specific to each target scored, and will follow the 
accepted quantitative and qualitative system for each target. 
 
Whole Exome and Transcriptome Sequencing 
To gain insights into the genomic alterations that may underpin lethal prostate cancer, 
we plan to perform whole exome and transcriptome characterization of prostate tumor 
samples (obtained from fresh-frozen tissue at pretreatment biopsy and RP) and their 
matched normal counterparts (from whole blood obtained from the same patient).  For 
control purposes, blood will be assessed for germline DNA. This will be 
accomplished by paired-end, massively parallel sequencing of tumor and normal 
DNA using the Illumina platform. This will be performed at the Broad Institute.  
 
Upon completion of 24 weeks of neoadjuvant therapy, participants will undergo RP 
according to each institution’s policy. The on-treatment samples will be collected on 
the day of operation with the last dose of oral medications for Part 1 taken the day 
prior to the operation.  Coordination efforts with the interventional radiology and 
pathology teams will vary depending on the institution.  
 
 
Whole Blood for Germline DNA 
Collection 
1. Five (5) mL of blood will be drawn into purple top vacutainers with EDTA. Gently 
invert tubes 8-10 times. DO NOT use heparin as anticoagulant, since the polymer 
will tightly bind downstream PCR enzyme during sequencing. 
2. Immediately transfer the blood into 5 cryovails (1 mL per cryovial) and store in -
80⁰C.   
 
Storage 
 
Store at -80ºC until shipment in batches together with matching tissue specimens.   
 
The whole blood should be shipped to CMOP following the RP and preferably with 
 
RP tissue.   
 
Shipment 
Whole blood and matching tissue specimen should be shipped together to CMOP. 
This specimen will be shipped on dry ice by express overnight courier. Shipping 
reservations must be made to allow delivery, prior to 2:00 PM next day, delivery on 
Tuesday through Friday. Call the receiving laboratory the day prior to shipping to 
confirm plan for receipt. Do not ship on Friday as there is no weekend coverage in the 
laboratory and the frozen samples should not sit in transit over a weekend. 


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CMOP will receive the “Blood for Germline DNA/RNA” and store it at labeled 
conditions (i.e -80 ⁰C) ‘as is’ (package intact and unopened), and will ship this 
package together with RP tissue specimens to the Broad. 
 
Please see the Study Laboratory Manual for specific instructions. 
 
AR Signaling Axis and Serum Hormones and Hormone Levels 
We hypothesize that following treatment with either treatment arm, we will observe 
changes in the AR signaling axis in RP specimens compared to pretreatment biopsy 
specimens. We will assess the AR axis by assaying serum androgens prior to 
treatment, during treatment, and prior to RP. Additionally, we will assay tumor 
androgens from pretreatment biopsy and RP specimens. Additionally, we will 
perform IHC analysis to include, but not limited to, assessment of the following: AR 
signaling pathway, steroidogenesis and hormone receptors, DNA repair pathway, 
PI3K pathways and other AR and AR-regulated genes (PSA, ERG). 
 
Subject samples (including blood and tissue samples) at the time of collection will be 
handled and procured by a dedicated technician or physician at each study site. 
Samples processing will be performed by trained technicians or physician at each 
study site 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. 
Hormone levels assessed will include DHEA, androstenedione, testosterone, DHT, 
androsterone, progesterone, pregnenolone, deoxycorticosterone, cortisol, and DHEA-
S. 
 
Samples will be stored and protected atCMOP.  Multi-center sites will ship samples to 
DFCI on a quarterly or other specified basis as described in the laboratory manual.  
Participants will be de-identified by assigning each participant a unique subject ID.  
 
Instructions on sample collection and processing are contained in the Laboratory 
Manual  
 
ctDNA 
cfDNA plasma will be drawn into (2) 10mL Streck BCT tubes according to 
institutional phlebotomy guidelines. Blood collected at DF/HCC sites will be 
processed in the Balk lab.  Blood collected at outside sites will be processed in local 
laboratories and then sent to the Balk lab.  Samples will be stored in a -80°C freezer.  
Plasma for cfDNA will be collected at C1D1, C4D1, Day 170-179 (+/- 4 days) and q3 
andq6 months following RP. 
 
See Study Lab Manual for further instructions regarding specimen and tissue 
processing.  
 
Multiparametric Prostate MRI 


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On this study, we will be performing baseline and post-treatment multiparametric MRI 
and correlating MRI with pathologic outcomes to determine if this could be a predictor 
of pathologic response to treatment. 
 
Any further future analyses not specified in this protocol or above will be agreed upon 
by prior approval from Janssen Scientific Affairs, LLC. 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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55 
9. STUDY CALENDAR 
 
PART 1 
 
 
Pre-Studya 
Day 1 of Cycle 
1 and Cycle 4 
(+/- 2 days)b 
 
Every Two 
Weeks for the 
first 3 Cycles 
Day 1 of Each Cycle 
(+/- 2 days) 
Pre-Operative Day 
170-179 (+/- 14 days) 
Day 180  
(+/- 14  days) 
Informed Consent 
X 
 
 
 
 
 
History and Physicalc 
X 
X 
 
X 
X 
 
Digital Rectal Examination 
X 
 
 
 
 
 
ECOG Performance Status 
X 
X 
 
X 
X 
 
Vital Signsd 
X 
X 
 
X 
X 
 
Hematologye 
X 
X 
 
X 
X 
 
Serum Chemistryf 
X 
X 
 
X 
X 
 
TSHg 
X 
X 
 
 
 
 
Liver Function Testsh 
X 
X 
                
X 
X 
X 
 
Fasting Lipid Panel 
 
X 
 
 
 
 
Coagulation Factorsi 
X 
 
 
 
X 
 
EKG 
X 
 
 
 
X 
 
ECHO or MUGA 
X 
 
 
 
 
 
Testosterone 
X 
X 
 
 
X 
 
Serum Hormonesj 
 
X 
 
 
X 
 
Research Samplek 
 
X 
 
 
 
 
ctDNA Plasma Sample 
 
X  
 
 
X 
 
PSA 
X 
X 
 
X 
X 
 
Bone Scan 
X 
 
 
 
 
 
CT or MRI abdomen  
X 
 
 
 
 
 
Prostate MRI including 
pelvisl 
X 
 
 
 
X 
 
Dispense Drugm 
 
X 
 
X 
 
 
Administer Leuproliden 
 
X 
 
 
 
 


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56 
AA and Apalutamide 
Compliance Assessment 
 
X 
 
X 
X 
 
Prior and Concomitant 
Medications 
X 
X 
 
X 
X 
 
Adverse Eventso 
X 
X 
 
X 
X 
 
Prostatectomyp 
 
 
 
 
 
X 
Request Diagnostic 
Biopsyq 
X 
 
 
 
 
 
Quality of Life and Family 
Questionnairesr 
 
X 
 
 
X 
 
Randomization 
for Part 2s 
 
 
 
 
X 
 
a: Baseline evaluations are to be conducted within 30 days prior to registration with the exception of scans and DREs. Scans and DREs may be done within 60 
days prior to registration. All baseline screening should be done prior to registration. Note: the treating physician must refer participants to genetic counseling 
within the first year (preferably before RP) of being on study. This must be documented in the clinic note and case report forms.  
b: A cycle will be defined as 28 days (+/- 2 days). Criteria outlined in Section 5.2 must be met prior to treatment on C1D1. 
c: 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. Information regarding cardiovascular events to include the following list will be documented pretreatment and prior to RP during Part 1. This 
includes: CAD (angina, NSTEMI, STEMI and need for intervention such as stent, CABG), cardiomyopathy/heart failure, valvular heart disease, arrhythmia 
(defined as need for intervention (cardioversion) or need for new medication), hypertension (defined as need for new medication, peripheral artery disease, 
cerebrovascular disease (defined by new TIA, CVA)). 
d: Vital signs include upright blood pressure, heart rate, respiratory rate, body temperature, height (baseline only), and weight.  
e: Hematology testing to include WBC, ANC, hemoglobin, and platelet count.  
f: Serum or plasma chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium 
g:TSH will be done at screening, day 1 of cycles 1 and 4..  T3 and T4 will be done only if TSH is abnormal at baseline. 
h: Liver function tests to include: albumin, globulin, AST, ALT, alkaline, phosphatase, total bilirubin, and direct bilirubin.  LFTs will be collected every two 
weeks for the first three cycles of treatment and every cycle thereafter. LFTs on day 15 of cycles 1-3 can be completed locally. Direct bilirubin and globulin do 
not need to be collected if labs are done locally or if a participating institution does not collect it.    
i: Coagulation factors to include PTT, PT and INR.  
j: Serum hormones to include DHEA, androstenedione, testosterone, DHT, androsterone, progesterone, pregnenolone, deoxycorticosterone, cortisol, and 
DHEA-S.  
k: Blood for germline DNA. See the Lab Manual for processing instructions. The lab manual is maintained as a separate document. 
l: The baseline MRI will be standard of care; however, the pre-RP MRI will be conducted as research. The pre-RP MRI is only required for DFCI patients and 
optional for participating site patients.  
m: For Part 1 of the study, participants will be randomized to treatment with AA + prednisone + apalutamide + leuprolide or AA + prednisone + leuprolide.  
n: Participants who have started leuprolide within four weeks of cycle 1/day 1 are eligible to enroll. Participants may receive monthly leuprolide. 
o: Adverse events should be collected from the date informed consent is signed until 30 days after discontinuation from the study. SAEs will reported starting 
from the first dose of study drugs.  
p: RP should occur on day 180 (+/- 14 days). Dosing should continue until 1 day before surgery. Treatment will resume on Cycle 7 Day 1 for Part 2A 
participants.. Preoperative and postoperative evaluation and treatment will be administered as per the instruction of the surgeon.  
q: Tissue from the diagnostic biopsy will be requested (tissue blocks wherever possible; if not possible, 15 unstained slides from each positive core sample for a 
total of 45 to be sent to the central analytical laboratory. See the Lab Manual for processing instructions. Pathology report (including the assessment of the local 
pathologist regarding Gleason score) from diagnostic biopsy must accompany registration materials.  
r: The EPIC-26 with 2 additional questions will be used to evaluate quality of life parameters (see Appendix G). The Family Questionnaire only needs to be 
completed at C1D1 (see appendix H).  
s: The study team will randomize participants to their Part 2 assignments after RP but before cycle 7 day 1. Participants will not need to re-meet eligibility 
criteria prior to Part 2 randomization. Part 2 will commence within 28 days post-RP (Cycle 7 Day 1). Participants who do not get randomized to part 2 will 
follow the 2B arm.   
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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57 
 
 
PART 2A 
 
Year 1 (Adjuvant Treatment) 
(Cycle length 28 days) (+/- 2 days) 
Years 2-3 (Follow-up) 
 
Years 4-5 
(Follow-up)  
 
Day 1 of 
Cycles 7-
18a 
Cycle 7, 10, 
13, and 16 
Cycle 13 
End of 
Treatment (1 
year post-RP) 
Every 3 
Months 
(+/-1 
month) 
 
2 years post-
RP (+/-1 
month) 
Every 6 
Months (+/-
1 month)b 
History and Physicalc 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
X 
 
Vital Signsd 
X 
X 
X 
X 
X 
X 
 
Hematologye 
X 
X 
X 
X 
 
 
 
Serum Chemistryf 
X 
X 
X 
X 
 
 
 
Liver Function Testsg 
X 
X 
X 
X 
 
 
 
 
TSHh 
 
X 
 
X 
 
 
 
Fasting Lipid Paneli 
 
X 
X 
X 
X 
X 
 
Testosteronej 
 
 
 
 
X 
X 
X 
Serum Hormonesk 
 
 
X 
X 
 
X 
 
ctDNAl Plasma 
Sample 
 
X 
X 
X 
X 
X 
X 
PSAm 
X 
X 
X 
X 
X 
X 
X 
Dispense Drugn 
X 
X 
X 
 
 
 
 
Administer 
Leuprolide 
 
X 
X 
 
 
 
 
AA and Apalutamide 
Compliance 
Assessment 
X 
X 
X 
X 
 
 
 
Prior and 
Concomitant 
Medications 
X 
X 
X 
X 
 
 
 
Adverse Eventso 
X 
X 
X 
X 
 
 
 
Intra-Operative/Post-
Operative 
Complicationp 
Xp (Cycles 7 
and 10 Day 1 
only) 
Xp (Cycles 7 
and 10 Day 1 
only) 
 
 
 
 
 
Quality of Life 
Questionnairesq  
 
 
X 
X 
 
X 
 


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a: A cycle will be defined as 28 days (+/- 2 days). During Part 2 of the study, patients randomized to further adjuvant therapy will be seen once 
every cycle for 12 cycles until end of treatment. Cycle 7 Day 1 will take place 28 days (+/- 5 days) post-RP.  All following visits will depend 
upon when the first visit post-RP occurred. Note: the treating physician must refer participants to genetic counseling within the first year 
(preferably before RP) of being on study. This must be documented in the clinic note and case report forms. 
b: After completion of adjuvant therapy on Part 2A of the study, all patients will be followed every 3 months (+/- 1 month) for years 2-3. Follow 
up will take place every 6 months (+/- 1 month) during years 4-5 post-RP. During years 4-5 post-RP, assessments may be done locally, and 
information may be collected via medical record review. It is recommended that testosterone continue to be checked (q3 cycles) until normalized 
according to institutional range. 
c: 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. Information regarding cardiovascular events to include the following list will be 
documented during Part 2 every 3 months (+/- 1 month) for 3 years post-RP, and then every 6 months (+/- 1 month) for up to 5 years post-RP. 
This includes: CAD (angina, NSTEMI, STEMI and need for intervention such as stent, CABG), cardiomyopathy/heart failure, valvular heart 
disease, arrhythmia (defined as need for intervention (cardioversion) or need for new medication), hypertension (defined as need for new 
medication), peripheral artery disease, cerebrovascular disease (defined by new TIA, CVA). 
d: Vital signs include upright blood pressure, heart rate, respiratory rate, body temperature, height (C7D1 only), and weight. During the follow up 
period, BMI (weight in Kg/height in m2) will collected every 3 months (+/- 1 month) 2-3 post-RP and then every 6 months (+/- 1 month) during 
years 4-5 post-RP.  
e: Hematology testing to include WBC, ANC, hemoglobin, and platelet count.  
f: Serum or plasma chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium.  
g: Liver function tests to include albumin, AST, ALT, alkaline phosphatase, total bilirubin, and direct bilirubin. Direct bilirubin and globulin do 
not need to be collected if labs are done locally or if a participating institution does not collect it.    
h: TSH will be done at Cycle 7 Day 1, Cycle 13 Day 1 and End of Treatment.  T3 and T4 will be done only if TSH is abnormal at baseline. 
i: A fasting lipid will be collected every 3 cycles (+/- 2 days) for year 1 and every 6 months (+/- 1 month) for years 2-3. Fasting is defined as no 
food or liquids except for water for 8 hours.  
j: Testosterone will be checked in follow-up every 3 months (+/- 1 month) for the years 2-3 post-RP and then every 6 months (+/- 1 month) for 
years 4-5 post-RP until recovery to the institutional normal range.  
k: Serum hormones to include DHEA, androstenedione, testosterone, DHT, androsterone, progesterone, pregnenolone, deoxycorticosterone, 
cortisol, and DHEA.-S 
l: ctDNA will be collected at all time points that PSA is collected during years 1-3 post-RP. It is recommended that study teams collect ctDNA 
plasma samples from participants whenever long-term follow-up assessments are conducted at the research site during years 4-5, if possible. 
m: PSA will be collected every cycles (+/- 2 days) for year 1 and every 3 months (+/- 1 month) for years 2-3 and then every 6 months (+/- 1 
month) for up to 5 years post-RP. 
n: For Part 2 of the study, participants will be randomized to AA + prednisone + apalutamide + leuprolide versus no further treatment.  
o: Adverse events should be collected from the date informed consent is signed until 30 days after discontinuation from treatment.  
p: Intra-operative and peri-operative (hospital course) complications will be collected via questionnaire (see Appendix E) at Cycle 7 Day 1. Post-
operative complications will be captured via the Clavien classification (Appendix F). The post-operative complications will be collected at Cycle 
7 Day 1 and Cycle 10 Day 1 post-operatively.  
q: The EPIC-26 with 2 additional questions will be used to evaluate quality of life parameters (see Appendix G).  
 
 
 
 
 
 
 
 


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PART 2B 
 
Year 1 (NO Adjuvant Treatment) 
(Cycle length 28 days) (every 3 cycles +/- 2 weeks) 
Years 2-3 (Follow-up) 
Every 3 months (+/- 1 month) 
Years 4-5 
(Follow-up)  
 
Day 1 of cycle 7, 
10,13, 16 Post-RP a 
Cycle 13  
End of 
Treatment (1 
year post-RP) 
 Every 3 
Months (+/- 1 
month) 
2 years post-RP 
(+/- 1 month) 
Every 6 
Months (+/- 1 
month)b  
History and Physicalc 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
X 
X 
X 
 
Vital Signsd 
X 
X 
X 
X 
X 
 
Hematologye 
X 
X 
X 
 
 
 
Serum Chemistryf 
X 
X 
X 
 
 
 
Liver Function Testsg 
X 
X 
X 
 
 
 
Fasting Lipid Panelh 
X 
X 
X 
X 
X 
X 
Testosteronei 
X 
X 
X 
X 
X 
X 
Serum Hormonesj 
 
X 
X 
 
X 
 
ctDNA Plasma 
Samplek 
X 
X 
X 
X 
X 
X 
PSAl 
X 
X 
X 
X 
X 
X 
Prior and Concomitant 
Medications 
X 
X 
X 
 
 
 
Adverse Eventsm 
X 
X 
X 
 
 
 
Intra-Operative/Post-
Operative 
Complicationn 
X (Cycle 7 Day 1 and 
Cycle 10 Day 1 only) 
 
 
 
 
 
Quality of Life 
Questionnaireso 
 
X 
X 
 
X 
 


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a: A cycle will be defined as 28 days (+/- 14 days). Patients randomized to no further adjuvant treatment will be seen once every 3 months 
beginning at cycle 7. Cycle 7 Day 1 will take place within 28 days (+/- 5 days) post-RP.  All following visits will depend upon when the first visit 
was post-RP. Note: the treating physician must refer participants to genetic counseling within the first year (preferably before RP) of being on 
study. This must be documented in the clinic note and case report forms. 
b: Participants in Part 2B will be followed every 3 cycles (+/- 2 weeks) for the first 1 year, every 3 months (+/- 1 month) for ears 2-3 and then 
every 6 months (+/- 1 month for up to 5 years post-RP during which time assessment may be done locally and information may be collected via 
medical record review.  It is recommended that testosterone continue to be checked until normalized according to institutional range. It is also 
recommended that study teams collect ctDNA plasma samples from participants whenever PSA blood tests occur and whenever long-term follow-
up assessments are conducted at the research site, if possible. 
c: 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. Information regarding cardiovascular events to include the following list will be documented during 
Part 2 every 3 cycles (+/- 2 weeks) for year 1, every 3 months (+/- 1 month) for years 2-3 and then every 6 months (+/- 1 month) for up to 5 years 
post-RP. This includes: CAD (angina, NSTEMI, STEMI and need for intervention such as stent, CABG), cardiomyopathy/heart failure, valvular 
heart disease, arrhythmia (defined as need for intervention (cardioversion) or need for new medication), hypertension (defined as need for new 
medication), peripheral artery disease, cerebrovascular disease (defined by new TIA, CVA). 
d: Vital signs include upright blood pressure, heart rate, respiratory rate, body temperature, height (C7D1 only), and weight. During the follow up 
period, BMI (weight in Kg/height in m2) will collected every 3 cycles (+/- 2 weeks) for year 1, every 3 months (+/- 1 month) for years 2-3 and then 
every 6 months (+/- 1 month) for up to 5 years post-RP.  
e: Hematology testing to include WBC, ANC, hemoglobin, and platelet count.  
f: Serum or plasma chemistry to include sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, and magnesium.  
g: Liver function tests to include albumin, AST, ALT, alkaline phosphatase, total bilirubin, and direct bilirubin. Direct bilirubin and globulin do 
not need to be collected if labs are done locally or if a participating institution does not collect it.   
h: During Part 2B, fasting lipid will be collected every 3 months (+/- 2 weeks) for year 1 and every 6 months (+/- 1 month) for years 2-3. Fasting is 
defined as no food or liquids except for water for 8 hours.  
i: Testosterone will be checked in follow-up every 3 cycles (+/- 2 weeks) for year 1, every 3 months (+/- 1 month) for years 2-3 and then every 6 
months (+/- 1 month) for up to 5 years post-RP until recovery to the institutional normal range.  
j: Serum hormones to include DHEA, androstenedione, testosterone, DHT, androsterone, progesterone, pregnenolone, deoxycorticosterone, 
cortisol, and DHEA-S. 
k: ctDNA will be collected whenever PSA blood draws are being collected during years 1-3 post-RP.  During years 4-5 post-RP, when follow-up 
assessments may be done locally, ctDNA is recommended only if follow-up assessments are being conducted at the research clinic conducting the 
study. 
l: PSA will be collected every 3 cycles (+/- 2 weeks) for year 1, every 3 months (+/- 1 month) for years 2-3 and then every 6 months (+/- 1 month) 
for up to 5 years post-RP. 
m: Adverse events should be collected from the date informed consent is signed until 30 days after RP.  
n: Intra-operative and peri-operative (hospital course) complications will be collected via questionnaire (see Appendix E) at Cycle 7 Day 1. Post-
operative complications will be captured via the Clavien classification (Appendix F). The post-operative complications will be collected at Cycle 7 
Day 1 and Cycle 10 Day 1 post-operatively.  
o: The EPIC-26 with 2 additional questions will be used to evaluate quality of life parameters (see Appendix G).  


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10. MEASUREMENT OF EFFECT 
 
10.1 Primary Variable  
Pathological Response (Part 1): The primary efficacy measure is pathological 
response, defined as achieving   either pCR or MRD at RP. pCR is defined as the 
absence of morphologically identifiable carcinoma in the RP specimen. MRD will be 
defined as residual tumor in the RP specimen measuring ≤ 5 mm. If the tumor is 
multifocal, the size of the largest focus will be used to determine the size of the 
residual tumor. RP specimens will initially be evaluated by the site pathologist using 
standard methods. Prostate biopsy specimens will be evaluated by central pathology 
review at completion of the study.  
 
Biochemical Progression Free Survival (bPFS) (Part 2): The primary efficacy 
measure is the rate of 3-year biochemical progression-free survival (bPFS). bPFS will 
be defined as the time from the date of randomization to the date of first evidence of 
disease progression (defined below) or death from all causes, censored at the date of 
last disease follow-up 
− Biochemical failure (defined as a serum PSA ≥0.2 ng/mL, which is confirmed by a 
second determination with a PSA ≥0.2 ng/Ml, according to the 2007 American 
Urological Association Prostate Guidelines). It is expected that the majority of 
patients will relapse biochemically with a rising PSA. 
− Any new evidence of metastatic disease based on bone or CT/MRI scan. 
− Local recurrence in prostate bed as demonstrated onCT/MRI scan. 
− Treatment with post-operative radiotherapy for a rising PSA or adjuvant radiation 
initiated more than 6 months following surgery. 
10.2 Secondary Variables 
Pathologic Outcomes: RCB will be calculated as tumor volume x percent cellularity. 
A favorable RCB is defined as the 33rd percentile of the RCB index. Tumor volume 
and percent cellularity will be evaluated by central pathology review at completion of 
the study. Cribriform or intraductal spread will be evaluated by central pathology 
review at the completion of the study. At the time of RP, pathologic specimens will be 
assessed for positive surgical margins, extracapsular extension, positive seminal 
vesicles, and positive lymph nodes, which will be determined by each site pathologist.  
 
PSA Kinetics prior to RP: PSA kinetics prior to RP include nadir value, achieving 
nadir PSA < 0.2 ng/mL, achieving 50% or achieving 90% decrease in PSA from 
baseline, and time to PSA nadir. 
 
Safety and Tolerability: CTCAE version 4 will be used to characterize toxicity during 
treatment.  
 
Peri-Operative and Post-Operative Complications: Peri-operative and post-
operative complications will be determined via questionnaires that will be completed at 
time of surgery, at discharge and in the post-operative period. The Clavian 


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Classification will be used to determine post-operative complications and will be 
collected at 30 and 90 days post-operatively.  
 
Quality of Life: The Expanded Prostate Cancer Index Composite (EPIC-26) with 2 
additional questions will be used to evaluate quality of life parameters. This will be 
completed by the patient pretreatment, prior to RP, and every 3 months for 2 years 
post-RP. 
 
Body-Mass Index, Lipids, and Cardiovascular Events: Weight, height, fasting lipid 
panel, and cardiovascular events will be collected.   
 
Serum Hormone Levels: Pregnenolone, progesterone, deoxycorticosterone, cortisol, 
DHEA, DHEA-S, androstenedione, testosterone, DHT, androsterone will be assessed 
at baseline, during treatment, prior to RP and post-RP. Hormones will be assayed by 
mass spectroscopy. Additionally, testosterone levels will be checked by routine 
laboratory at baseline and every 3 months until recovery. Recovery will be defined as a 
testosterone level > 200 ng/dL.  
 
Prostate Hormone Levels: DHEA, DHEA-S, androstenedione, testosterone, DHT will 
be assayed from pretreatment prostate biopsy and RP specimens by mass spectroscopy. 
 
Ki-67 Expression: Ki-67 expression will be assessed by IHC staining. This will be 
scored on the percentage of cells that display nuclear staining for Ki67.  
 
AR and AR-Regulated Gene Expression: AR and AR-regulated gene (PSA, ERG) 
expression will be assessed by IHC staining. This will be scored based on the 
percentage of cells staining for the specific protein and the intensity of the staining.  
 
PTEN Status: PTEN status (loss versus presence) will be assessed by IHC staining via 
a dichotomous scoring system. Staining will be classified as negative if the intensity 
was markedly decreased or entirely negative across tumor cells (either all cells or if 
>5% cells are negative/markedly reduced) compared with the surrounding benign 
glands and/or stroma. 
 
ctDNA: Blood will be collected for ctDNA and will be processed in the Balk 
Laboratory. Plasma will be used to extract ctDNA. DNA will be analyzed using PCR 
and will be compared to genome analysis of residual primary tumor. The PCR will be 
will be based on patient specific mutations identified from sequencing the primary 
tumors. Emergence of specific ctDNA alterations will be correlated with disease 
progression. 
 
Whole Exome and Transcriptome Sequencing: Whole exome and transcriptome 
sequencing will be performed at the Broad Institute Sequencing platform, which has 
vast experience in cancer sequencing. Following sequencing, exome data will be 
analyzed for somatic mutations, insertions and deletions, and copy number alterations 
using established pipelines at the Broad Institute. Transcriptome data will be analyzed 


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63 
for overexpressed genes, chimeric transcripts (possibly indicative of structural genomic 
rearrangements), and alternatively spliced variants. Sequencing information will be 
analyzed using novel computations algorithms, which have been developed at the 
Broad Institute.  
 
Quantitative MRI: From T2, ADC and DCE MR sequences, quantitative parameters 
will be extracted from all loci within a lesion. The attributed PI-RADS score from each 
MR sequence and the final overall PI-RADS score (1-5 scale: 1-normal, 5-definite 
cancer) will be recorded for each lesion per ESUR 2012 guideline 
 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 Overview 
As the sponsor of the Study, DFCI and Mary-Ellen Taplin, MD shall be solely responsible 
for complying, within the required timelines, any safety reporting obligation to competent 
Health Authorities, IRB/ECs and any participating (co or sub) investigators, as defined in 
applicable laws and regulations.  Safety data includes adverse events, product quality 
complaints (PQCs), and special situations including pregnancies. 
The DFCI and Mary-Ellen Taplin, MD will provide safety information to Janssen on adverse 
events, special situations including pregnancies and product quality complaints. 
11.2 Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events 
regardless of causality and special situations excluding those from subjects not exposed to a 
Janssen Medicinal Product and product quality complaints with or without an adverse event 
as described in this Exhibit will be reported from the time a subject has signed and dated an 
Informed Consent Form (ICF) until completion of the subject’s last study-related procedure 
(which may include contact for follow-up safety).  Serious adverse events will be reported 
for 30 days after the last dose of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: 
  
Apalutamide (56021927, Apalutamide) 
Abiraterone acetate 
11.3 Definitions 
11.3.1 Adverse Events (AEs) 
An adverse event (AE) is any untoward medical occurrence in a clinical study 
subject administered a medicinal (investigational or non-investigational) 
product. An AE does not necessarily have a causal relationship with the 
treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated 


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with the use of a medicinal (investigational or non- investigational) product, 
whether or not related to that medicinal (investigational or non-investigational) 
product. (Definition per International Conference on Harmonization [ICH]) 
This includes any occurrence that is new in onset or aggravated in severity or 
frequency from the baseline condition, or abnormal results of diagnostic 
procedures, including laboratory test abnormalities. 
 
Adverse Events of Special Interest (AESIs) 
There are no adverse events of special interest identified for apalutamide or 
abiraterone acetate. 
11.3.2 Individual Case Safety Report (ICSR) 
A valid ICSR must contain the four minimum criteria required to meet 
regulatory reporting requirements. 
− An identifiable subject (but not disclosing personal information such as the 
subject’s name, initials or address) 
− 
An identifiable reporter (investigational site) 
− 
A Janssen medicinal product 
− 
An adverse event, outcome, or certain special situations 
 
The minimum information required is: 
− 
Suspected Janssen medicinal product (doses, indication) 
- 
Date of therapy (start and end date, if available) 
- 
Batch or lot number, if available 
- 
Subject details (subject ID and country) 
- 
Gender 
- 
Age at AE onset 
- 
Reporter ID 
- 
Adverse event detail (AE verbatim in English), onset date, relatedness, 
causality, action taken, outcome, (if available) 
- 
Janssen protocol ID 
11.3.3 Product Quality Complaint (PQC) 
A PQC is defined as any suspicion of a product defect related to a potential 
quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or 
delivery system.  Not all PQCs involve a subject.  Lot and batch numbers are 
of high significance and need to be collected whenever available. 
  
 
 
 
 Examples of PQC include but not limited to: 
− 
Functional Problem: e.g., altered delivery rate in a controlled release 
product 
− 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
− 
Potential Dosing Device Malfunction: e.g., autoinjector button not 
working, needle detaching from syringe 


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− 
Suspected Contamination 
− 
Suspected Counterfeit 
11.3.4 Serious Adverse Event (SAE) 
An SAE based on ICH and EU Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at 
any dose: 
- 
Results in death 
- 
Is life-threatening (The subject was at risk of death at the time of the event. 
It does not refer to an event that hypothetically might have caused death if 
it were more severe.) 
- 
Requires inpatient hospitalization or prolongation of existing 
hospitalization 
- 
Results in persistent or significant disability/incapacity 
- 
Is a congenital anomaly/birth defect 
- 
Is a suspected transmission of any infectious agent via a medicinal product 
- 
Is medically important* 
 
*Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is also appropriate in other situations, such as important 
medical events that may not be immediately life threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed in the definition above. These should 
usually be considered serious. 
 
NOTE: DEATH FOR ANY REASON SHOULD BE REPORTED AS A 
SERIOUS ADVERSE EVENT. 
Hospitalization 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to 
the hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that 
occurs during the study must be reported as a serious adverse event, except 
hospitalizations for the following: 
• Hospitalizations not intended to treat an acute illness or adverse event 
(e.g., social reasons such as pending placement in long-term care facility) 
• Surgery or procedure planned before entry into the study. [Note: 
Hospitalizations that were planned before the start of data collection and 
where the underlying condition for which the hospitalization was planned 
has not worsened will not be considered serious adverse events. Any 
adverse event that results in a prolongation of the originally planned 
hospitalization is to be reported as a new serious adverse event.] 
 
Life-Threatening Conditions 


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The cause of death of a subject in a study within 30-days of the last dose of 
apalutamide or abiraterone acetate drug, whether or not the event is expected 
or associated with the study drug, is considered a serious adverse event. 
 
Disease progression should not be recorded as an adverse event or serious 
adverse event term; instead, signs and symptoms of clinical sequelae resulting 
from disease progression/lack of efficacy will be reported if they fulfill the 
serious adverse event definition. 
11.4 Expectedness  
11.4.1 AEs can be 'Expected' or 'Unexpected.'  
• 
Expected adverse event 
 
Expected AEs are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, an 
adverse event is considered expected when it appears in the current 
adverse event list, the Investigator’s Brochure, the package insert or is 
included in the informed consent document as a potential risk.   
• 
Unexpected adverse event 
 
 
For the purposes of this study, an adverse event is considered unexpected 
when it varies in nature, intensity or frequency from information 
provided in the current adverse event list, the Investigator’s Brochure, 
the package insert or when it is not included in the informed consent 
document as a potential risk.   
11.4.2 Attribution 
Attribution is the relationship between an adverse event or SAE and the study 
treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely - The AE is doubtfully related to the study treatment. 
• Unrelated - The AE is clearly NOT related to the study treatment. 
11.5 Unlisted (Unexpected) AE/Reference Safety Information 
 
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For a medicinal product(s) with a marketing 
authorization, the expectedness of an adverse event will be determined by whether or not 
it is listed in the applicable product information.  


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For abiraterone acetate, the link to the package insert is  
https://www.zytiga.com/shared/product/zytiga/zytiga-prescribing-information.pdf 
For apalutamide, the expectedness of an adverse event will be determined by whether or 
not it is listed in the Informed Consent Form, which includes the latest risk information 
listed in the Investigator’s Brochure.   
11.6 Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting 
reporting and/or safety evaluation include, but are not limited to: 
• Drug exposure during pregnancy (maternal and paternal) 
• Overdose of a Janssen medicinal product  
• Exposure to a Janssen medicinal product from breastfeeding  
• Suspected abuse/misuse of a Janssen medicinal product 
• Inadvertent or accidental exposure to a Janssen medicinal product  
• For abiraterone acetate only, failure of expected pharmacological action (i.e., lack 
of effect) of a Janssen medicinal product 
• Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 
• Suspected transmission of any infectious agent via administration of a medicinal 
product 
• For abiraterone acetate only, unexpected therapeutic or clinical benefit from use 
of a Janssen medicinal product 
These safety events may not meet the definition of an adverse event; however, from 
the standpoint of Janssen, they are treated in the same manner as adverse events. 
Special situations should be recorded on the Adverse Event page of the CRF. 
Any special situation that meets the criteria of a serious adverse event should be 
recorded on a Serious Adverse Event Report Form and be reported to Janssen within 
24 hours of becoming aware of the event. 
11.7 Pregnancy  
 
Because the Janssen medicinal product may have an effect on sperm, pregnancies in 
partners of male subjects exposed to a Janssen medicinal product will be reported by 
the PI within 24hours of their knowledge of the event using the Serious Adverse Event 
Form.  Depending on local legislation this may require prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
11.8 Maintenance of Safety Information 
All safety data should be maintained in a clinical database in a retrievable format. DFCI 
and the PI shall provide all adverse events, both serious and non-serious, in report 
format. However, in certain circumstances more frequent provision of safety data may 


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be necessary, e.g. to fulfill a regulatory request, and as such the data shall be made 
available within a reasonable timeframe at Janssen’s request. 
11.9 Procedures for Reporting Safety Data and Product Quality Complaints (PQCs) for 
Janssen Medicinal Products to Janssen 
 
All adverse events and special situations, whether serious or non-serious, related or not 
related, following exposure to a Janssen medicinal product are to be documented by 
the investigator and recorded in the CRF and in the subject’s source records. Investigators 
must record in the CRF their opinion concerning the relationship of the adverse event to 
a Janssen medicinal product.  
All (serious and non-serious) adverse events reported for a Janssen medicinal product 
should be followed-up in accordance with clinical practice. 
11.9.1 SAEs and Special Reporting Situations 
All serious adverse events that have not resolved by the end of the study, or that 
have not resolved upon discontinuation of the subject's participation in the 
study, must be followed until any of the following occurs: 
• The event resolves 
• The event stabilizes 
• The event returns to baseline, if a baseline value/status is available 
• The event can be attributed to agents other than the study drug or to 
factors unrelated to study conduct 
• It becomes unlikely that any additional information can be obtained 
(subject or health care practitioner refusal to provide additional 
information, lost to follow-up after demonstration of due diligence with 
follow-up efforts) 
Participating investigators must report each SAE to the Sponsor Investigator 
(Dr. Mary-Ellen Taplin) within 24 hours of learning of the occurrence.  In the 
event a participating investigator is not made aware of the SAE immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is 
to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.  Non DF/HCC sites participating in 
this research are expected to submit each SAE to its local ethics committee 
according to FDA and local IRB guidelines.  
 
All follow-up information for serious adverse events that are not resolved at 
the end of the study or by the time of patient withdrawal must be reported 
directly by the PI, within 24 hours becoming aware, to Janssen using 
Janssen’s Serious Adverse Event Report  
All available clinical information relevant to the evaluation of a related SAE 
or special situation is required. 
• 
DFCI and/or PI is responsible for ensuring that these cases are 
complete and if not are promptly followed-up. A safety report is not 


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considered complete until all clinical details needed to interpret the 
case are received. Reporting of follow-up information should follow 
the same timeline as initial reports. 
• 
Copies of any and all relevant correspondences with regulatory 
authorities and ethics committees regarding any and all serious 
adverse events, irrespective of association with the Janssen Product 
under study, are to be provided to the COMPANY within 24 hours of 
such report or correspondence being sent to applicable health 
authorities. 
11.9.2 Non-Serious AEs 
All non-serious adverse events should be reported to Janssen according to the 
timeframe outlined in the Research Funding Agreement section entitled 
Reporting of Data. 
 
11.9.3 PQC Reporting 
A PQC may have an impact on the safety and efficacy of the product. Timely, 
accurate, and complete reporting and analysis of PQC information from 
studies are crucial for the protection of patients, investigators, and Janssen, 
and are mandated by regulatory agencies worldwide. Janssen has established 
procedures in conformity with regulatory requirements worldwide to ensure 
appropriate reporting of PQC information. Lot and/or Batch #s shall be 
collected or any reports failure of expected pharmacological action (i.e., lack 
of effect). The product should be quarantined immediately and if possible, 
take a picture. 
 
All initial PQCs involving a Janssen medicinal product under study must be 
reported to Janssen by the PI within 24hours after being made aware of the 
event. The Janssen contact will provide additional information/form to be 
completed. 
 
If the defect for a Janssen medicinal product under study is combined with 
either a serious adverse event or non-serious adverse event, the PI must report 
the PQC to Janssen according to the serious adverse event reporting timelines.  
A sample of the suspected product should be maintained for further 
investigation if requested by Janssen. 
11.10 Reporting Procedures for Reporting Safety Data and Product Quality Complaints 
(PQCs) for Non-Janssen Medicinal Products  
 
For SAEs, special reporting situations and PQCs following exposure to a non-Janssen 
medicinal product under study, the PI should notify the appropriate 
regulatory/competent authority or the manufacturer of that medicinal product (in the 
absence of appropriate local legislation) as soon as possible. 
11.11 Transmission Methods 


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The following methods are acceptable for transmission of safety information to 
Janssen: 
• Electronically via Janssen SECURE Email service (preferred) to the Janssen 
IIS-BIO/VIRO-GCO central mailbox <RA-OMPUS-
COBS_Cen_E@its.jnj.com> 
• For business continuity purposes, if SECURE Email is non-functional: 
o Facsimile (fax – 866.451-0371), receipt of which is evidenced in a 
successful fax transmission report 
Please use the contact information and process information provided by Janssen.  
 
11.12 Reconciliation of SAEs 
At a minimum, on a quarterly basis and at the end of the Study, Janssen will provide to the 
INSTITUTION and/or SPONSOR INVESTIGATOR, a listing of all SAEs reported to 
Janssen.  SPONSOR INVESTIGATOR will review this listing and provide any discrepancies 
to the Janssen. 
Upon request, INSTITUTION and SPONSOR INVESTIGATOR shall provide Janssen with 
a summary list of all SAEs, and AEs of Special Interest and Special Reporting Situation 
reports to date, for reconciliation purposes. 
 
11.13 Final Study Report 
The INSTITUTION/SPONSOR INVESTIGATOR will prepare a final report including a 
complete and full summary of all adverse events, special situations and pregnancy reports 
according to the timeframe outlined in the executed Research Funding Agreement with 
Janssen. 
 
11.14 Procedures for AE and SAE Recording and Reporting 
 
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.  
11.15 Reporting Requirements 


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The DF/HCC will serve as the Sponsor 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 Food and Drug Administration (FDA) 
regulations, local safety reporting requirements, and reporting requirements of the 
Sponsor. 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 
investigator to report SAEs to the study sponsor and/or others as described below.  
 
11.16 Reporting to the Study Sponsor-Investigator 
11.16.1 SAE Reporting 
 
All SAEs that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported 
to the DF/HCC Overall PI on the local institutional 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.  
 
Note: If the participant is in long term follow up, report the death at the 
time of continuing review.  
 
Participating investigators must report each SAE to the DF/HCC Overall PI 
within 24 hours of learning of the occurrence. In the event that the 
participating investigator does not become aware of the SAE immediately 
(e.g., participant sought treatment elsewhere), the participating investigator 
is to report the event within 24 hours after learning of it and document the 
time of his or her first awareness of the AE. Report SAEs by telephone, 
email or facsimile to: 
   
  Mary-Ellen Taplin, MD 
  Phone: 617-582-7221 
  Email: Mary_Taplin@DFCI.harvard.edu 
  Fax: 617-632-2165 
 


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Within the following 24-48 hours, the participating investigator must 
provide follow-up information on the SAE. Follow-up information should 
describe whether the event has resolved or continues, if and how the event 
was treated, and whether the participant will continue or discontinue study 
participation. 
 
If the significant other of a study participant becomes pregnant while the 
study subject is in the trial, the pregnancy must be reported within the SAE 
reporting timelines (24 business hours). 
11.16.2 Non-SAE Reporting  
 
Non-SAEs will be reported to the DF/HCC Overall PI on the toxicity 
CRFs.   
11.17 Reporting to the IRB 
 
Investigative sites within DF/HCC will report all SAEs directly to the DFCI Office of 
Human Research Studies (OHRS). 
 
Other investigative sites should report SAEs to their respective IRB according to the 
local IRB’s policies and procedures in reporting AEs. A copy of the submitted 
institutional SAE form should be forwarded to: 
 
 
 
Mary-Ellen Taplin, MD 
 
 
Phone: 617-582-7221 
 
 
Email: Mary_Taplin@DFCI.harvard.edu 
 
 
Fax: 617-632-2165 
 
The DF/HCC PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting AEs.  
11.18 Reporting to the FDA 
 
The Overall PI, as study sponsor, will be responsible for all communications with the 
FDA. The Overall PI will report to the FDA, regardless of the site of occurrence, any 
serious adverse event that meets the FDA’s criteria for expedited reporting following 
the reporting requirements and timelines set by the FDA. 
11.19 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any 
subject safety reports or sentinel events that require reporting according to institutional 
policy. 
11.20 Monitoring of AEs and Period of Observation 


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All AEs, both serious and non-serious, and deaths that are encountered from initiation 
of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating 
investigator assesses them as stable, or the participating investigator determines the 
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 study sponsor 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 
adverse event occurring after a participant has discontinued or terminated study 
participation that may reasonably be related to the study.   
 
12. DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1 Method  
 The ODQ will collect, manage, and monitor data for this study.  
12.1.2 Data Submission  
The schedule for completion and submission of CRF (paper or electronic) to the 
ODQ is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with ODQ. 
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. 


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Adverse Event 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 adverse event 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 Data Safety and Monitoring Board (DSMB) will review and monitor 
study progress, toxicity, safety, and other data from this trial. The board is chaired by a 
medical oncologist from outside of DF/HCC and has external and internal 
representation. Information that raises any questions about participant safety or protocol 
performance will be addressed with the PI, a statistician and study team members. 
Should any major concern arise, the DSMB will offer recommendations regarding 
whether or not to suspend the trial.  
 
The DSMB will meet twice a year to review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMB may include: participant accrual 
treatment regimen information, AEs and SAEs reported by category, summary of any 
deaths on study, audit results, and summary provided by the study team. Other 
information (i.e. 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 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, Good Clinical Practice 
(GCP), 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.  
 


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To ensure proper oversight of local and external study conduct, on-site and virtual 
monitoring will take place at the beginning of the study and periodically for the 
duration of the clinical trial.  The lead site will host monthly teleconferences with 
external sites to discuss amendments, SAEs, data, sample processing, and more. 
 


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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 prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall PI 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 GCP 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
• 
E6 GCP: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  


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o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/  
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant. This information enables the study to be fully documented and the 
study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are 
not limited to hospital records, clinical charts, laboratory and pharmacy records, 
recorded data from automated instruments, microfiches, photographic negatives, 
microfilm or magnetic media, and/or x-rays.  
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
13.6 Multi-Center Guidelines 
This protocol will adhere to the policies and requirements of the DF/HCC. The specific 
responsibilities of the DF/HCC Overall PI, Coordinating Center, and Participating 
Institutions are presented in the DF/HCC Multi-Center Data and Safety Monitoring 
Plan (see Appendix H). 
• The DF/HCC Overall PI/Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required. 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  


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• Except in very unusual circumstances, each participating institution will order the 
agent(s) directly from the supplier. A participating site may order the agent(s) 
only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center.  


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14. STATISTICAL CONSIDERATIONS  
14.1  Study Design and Sample Size  
 
This is a multicenter, phase II, prospective, randomized trial designed to investigate the 
efficacy of neoadjuvant and adjuvant abiraterone acetate + apalutamide for men with 
intermediate-high risk prostate cancer who are candidates for RP. The study includes 
two parts. In part 1, patients will be randomized in 1:1 ratio to receive 6 months of 
neoadjuvant abiraterone acetate, apalutamide, leuprolide and prednisone (Arm 1A) 
versus 6 months of abiraterone acetate, leuprolide and prednisone (Arm 1B) followed 
by RP. Randomization will be stratified by disease risk factor (intermediate versus high 
risk). In part 2 (post-RP adjuvant), patients will be randomized in 1:1 ratio to receive 
additional 12 months of adjuvant abiraterone acetate, apalutamide, leuprolide and 
prednisone (Arm 2A) or observation (Arm 2B) stratified by type of neoadjuvant 
therapy and pathological T-stage (< pT3 versus ≥ pT3). 
 
For part I, the primary analysis will compare the proportion of patients with pCR or 
MRD (pCR plus MRD, see section 10.1) at RP following therapy with Arm 1A and 
Arm 1B. We hypothesize that treatment with abiraterone acetate, leuprolide and 
prednisone (Arm 1B) will have a pCR plus MRD rate of 15% based on our prior 
experience.3 We hypothesize that with the addition of apalutamide (Arm 1A), the rate of 
pCR plus MRD will increase to 35%. 120 patients will be enrolled and randomized in 
part 1. This sample size provides 81% power to distinguish a pCR plus MRD rate of 
35% in Arm 1A (N=60) from a rate of 15% in Arm 1B (N=60), using a chi-square test 
for binomial proportion (one sided a=0.05). 
 
For part 2, the primary analysis will compare the rate of bPFS (see section 10.1) at 3 
years after RP between the two arms with and without adjuvant therapy. There is 
limited data with regard to long term outcomes of use of novel hormonal agents. Based 
on the institutional experience of patients treated with neoadjuvant abiraterone acetate, 
3-year bPFS rate is expected to be approximately 70%. Assuming that 90% of the 
population is able to complete RP and agrees to participate  the adjuvant part of the 
study, there is 83% power to  distinguish a 3-year bPFS rate of 90% in Arm 2A 
(adjuvant arm: N=54) from a rate of 70% in Arm 2B (observation arm: N=54),  using a 
chi-square test for binomial proportion (one sided a=0.05). 
14.2 Primary Endpoint and Methods of Analysis:  
 
Part 1: The number and percent of patients achieving pCR plus MRD will be 
summarized with two-sided 90% exact binomial CI by treatment arm. All patients who 
are randomized in part 1 will be included. The primary comparison between Arm1A 
and Arm1B will be conducted using the chi-square test for binomial proportion, with 
one-sided P value of ≤ 0.05 considered statistically significant. The Cochran-Mantel-
Haenszel test accounting for the stratification factor at randomization will be 
performed as a sensitivity analysis.  
 


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Part 2: At time of final analysis, the 3-year bPFS rate (SE and two-sided 90% CI) will 
be estimated using the Kaplan-Meier method according to treatment arm. bPFS is 
defined in section 10.1. All patients who are randomized in part 2 will be included in 
the analysis. If the lower limit of 90% CI (two sided) for the difference in 3-year bPFS 
(estimated from the Kaplan Meier method, as adjuvant treatment arm 2A minus 
observation arm 2B) is greater than 0, we will consider there is a statistically 
significant difference between the two treatment arms.  
 
This approach to hypothesis testing is used instead of using the observed rate at 3-years 
post-surgery, or instead of comparing the bPFSdistribution using logrank test for 
multiple reasons. It is the 3year timepoint that is of clinical interest. There may be 
censored data prior to 3 years that can be included using a time-to-event endpoint. In 
addition there may be different hazards during the first year (i.e. when one group 
receives active treatment and the other is observed) than in the next 2-year period and 
may not meet a proportionality assumption. The analysis will include plotting hazard 
functions over time to assess whether there are different hazards in the first and 
subsequent year   periods. Proportional hazard assumption will also be assessed in 
order to estimate hazard ratio from Cox proportional hazards model.   
 
It is anticipated that the primary analysis of bPFS will be conducted when the last 
subject enrolled in part 2 has been followed up to 3 years post RP, or has experienced 
biochemical progression (as defined in section 10.1), or has been removal from study, 
whichever occurs first.   
14.3 Secondary Endpoint(s) and Methods of Analysis: 
 
Pathological endpoints (part 1) 
Other pathological analyses include (1) proportion of participants with pCR at RP, (2) 
proportion of participants with favorable RCB (see section 10.2) at RP, (3) proportion 
of participants with cribriform or intraductal spread at RP, and (4) proportion of 
participants with positive surgical margins, extracapsular extension, positive seminal 
vesicles, and positive lymph nodes at time of RP following therapy with Arm 1A and 
Arm 1B. Number and percent of participants with pCR, favorable RCB or presenting 
each of these pathological features as described above will be summarized by arms with 
a two-sided 90% confidence interval; comparison between arms will be conducted 
using chi-square test or Fisher’s exact test as appropriate.  
 
PSA kinetics prior to RP (part 1) 
PSA kinetics prior to RP include nadir value, achieving nadir PSA < 0.2 ng/mL, 
achieving 50% or achieving 90% decrease in PSA from baseline, and time to PSA 
nadir. PSA kinetics will be summarized with descriptive statistics (e.g. median, range, 
and proportions) and presented by arm (Arm 1A and 1B). Comparison between arms 
will be conducted using chi-square test for categorical variables and Wilcoxon rank-
sum test for continuous variables. 
 
Safety endpoints (part 1 and 2) 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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81 
Safety analysis will be conducted using the Safety Population defined as any participant 
receiving one dose of study treatment. All safety endpoints will be summarized 
according to treatment arm, separately for part 1 (neoadjuvant part) and part 2 (adjuvant 
part). 
 
For toxicity reporting, all adverse events will be graded and analyzed using CTCAE 
version 4. Type of adverse events, intensity (grading), and attribution will be provided 
in a listing. The worst grade will be used if any toxicity event is reported multiple times 
on the same participant. All adverse events resulting in discontinuation, dose 
modification, and/or dosing interruption, and/or treatment delay of drug will also be 
summarized. All laboratory test results will be classified according to the CTCAE 
version 4.  
 
Quality of Life (QOL) endpoints (part 1 and 2) 
The QOL will be measured using the Expanded Prostate Cancer Index Composite 26 
(EPIC-26). The questionnaires will be administered at baseline, prior to RP and every 3 
months for 2 years post RP.  Analysis will be conducted separately for part 1 
(neoadjuvant part) and part 2 (adjuvant part). 
 
Resulting domain scores for EPIC-26 (urinary incontinence, urinary obstruction, sexual, 
bowel, hormonal/vitality) is on a 0–100 scale, with higher values representing a more 
favorable health-related QOL. For each treatment group, calculated scores on each 
domain and changes from baseline will be summarized by time points. The effect of 
treatment will be evaluated using a repeated measures model to incorporate assessments 
across time into a single analysis, using model contrasts to compare treatment groups at 
selected time points, prior to RP and 2 years post-RP.  
 
Quantitative MRI 
Prostate gland volumes and quantitative indices (T2, ADC DCE metrics) will be 
compared pre- and post neoadjuvant therapy (by lesion or by patient) using Wilcoxon 
signed-rank test. Their changes from baseline will be correlated, using Spearman’s rank 
correlation, with (1) pathological RCB index (2) changes in PSA values (3) changes in 
serum/tissue androgen levels. Comparison of quantitative changes between pathological 
response groups will be conducted using Wilcoxon rank-sum test or t-test. Logistical 
regression will be conducted to predict pathological response using different mpMRI 
parameters or their combination. Model performance will be evaluated by the AUC 
index.  
14.4  Correlative Endpoint(s) and Methods of Analysis: 
 
              Time to testosterone recovery (part 2)  
The Kaplan-Meier product limit method will be used to estimate the distribution of the 
time from RP until testosterone recovery, or censored at date of last test of testosterone 
level, for Arm 2A and 2B. Comparison between treatment arms will be assessed using 
the log rank test.  
 


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Serum/Tissue androgen concentrations (part 1 and part 2) 
Serum androgen concentrations will be measured at multiple timepoints (see section 
10.2) by mass spectroscopy. Tissue androgens will only be assayed in RP specimens. 
Mean change in serum androgen concentrations from baseline to during neoadjuvant 
treatment and to prior to RP will be summarized for Arm 1A and 1B (part 1). Mean 
change during follow-up post RP will be summarized for Arm 2A and 2B (Part 2). 
Comparisons between arms will be conducted using the ANOVA methods (with log 
transformation as appropriate) or the non-parametric Wilcoxon rank-sum test.  
 
IHC staining (part 1) 
The expression of the AR and proteins involved in the androgen synthesis, apoptosis, 
WNT signaling, and PTEN-PI3K-AKT pathways from the RP specimens will be 
assessed by the IHC staining, scored as percentage of cells staining for the specific 
protein (i.e. categorized as 0, <5, 5-25, 25-50, >50%) and/or the intensity of the 
staining. These semi-quantitative measurements will be compared between treatment 
arms (Arm 1A versus 1B) using the Cochran–Armitage test for trend or other 
appropriate methods. 
 
 
  Whole Exome and Transcriptome Sequencing (part 1) 
Changes in whole exome and whole transcriptome between pretreatment prostate 
biopsy and RP specimens between treatment arms (Arm1A and 1B) will be analyzed 
using novel computational algorithms developed at the Broad Institute. It is anticipated 
that whole genome sequencing of prostate cancer will be undertaken in about 60% of 
participants (N=72)  using fresh-frozen tissue at pretreatment biopsy and RP to study de 
novo or acquired resistance to neoadjuvant therapy in terms of genomic alterations such 
as base mutations, small insertions/deletions (indels), copy number changes, and 
structural rearrangements. 
 
Gene mutation frequencies and mean ± SD of quantitative gene expression profile will be 
summarized pre and post neoadjuvant therapy. For detection of rare gene mutations, with 
72 participants, there are 0.98, 0.89 and 0.52 probabilities to observe ≥1 mutation if the 
true underlying mutation rate is 5%, 3% and 1% respectively. For more prevalent 
mutations, the 90% exact binominal CI width is 0.13 and 0.19 with the observed mutation 
rate of 0.1 and 0.3 respectively. To compare pre-post therapy changes in gene expression, 
there is 80% power to detect a 0.34 SD mean change between time points with n=72 
using a paired t-test (two-sided α=0.05). To compare gene expression between groups 
(e.g. treatment arms, pathology response), we will use student t-test for continuous values 
or Fisher’s exact test if the data are summarized as % of patients with up- or down-
regulated expression.  
 
Germline mutations (Part 1) 
The prevalence of germline mutations in homologous recombination genes will be 
assessed in all enrolled patients. With N=120, the 90% exact binominal CI width is 0.10~ 
0.15 with the observed mutation rate of 0.1~ 0.3 respectively. Fisher’s exact test will be 
used to compare pathologic response (such as pCR, MRD, and RCB) with homologous 
recombination gene germline mutation status as an exploratory analysis. 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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83 
 
14.5 Sample Size and Accrual Rate  
For a sample size of 120 participants, we expect a total of 15 months to complete the accrual 
at a rate 8 participants/month. 
14.6 Study monitoring 
 
The DF/HCC DSMB on a semi-annual basis will review the study for safety, progress 
toward completion and the status of case report forms.  Interim analysis of efficacy 
endpoints is not planned. However, the following events will be monitored to ensure that the 
study has sufficient statistical power for the analysis of the primary efficacy endpoint in part 
2. 
    
Rate of participation in part 2 
We assume that 90% of the population agrees to participate in the adjuvant part of the study 
(part 2) after completion of RP. The statistical power reduces to 61% if only 50% of subjects 
are randomized into part 2. Therefore, among the first 40 patients who complete RP, if 21 or 
more subjects refuse to be randomized into part 2, “part 2(adjuvant therapy post RP)” of the 
study will be terminated early due to insufficient participation rate.   
 
The following table gives the statistical power if various numbers of patients are enrolled in 
the part 2 under the same design parameters.  
 
% enrolled in part 2  90% 
80% 
70% 
60% 
50% 
N per arm 
54 
48 
42 
36 
30 
Power 
83% 
79% 
74% 
68% 
61% 
 
 
Treatment compliance in Arm 2A 
We will also monitor the rate of early discontinuation of adjuvant hormone therapy (defined 
as receiving <6 months of adjuvant therapy in Arm 2A). Among the first 20 (out of 54, 37%) 
subjects on the Arm 2A, if 8 or more patients withdraw therapy within 6 months, “part 2” of 
the study may be terminated early due to low treatment compliance in part 2. Using this rule, 
the probability that the study may be terminated early is 0.03 if the true early discontinuation 
rate is 20% and 87% if the rate is 50%.  
 
 
True but unknown rate of early 
discontinuation  
 
10% 
20% 30% 
40% 
50% 
60% 
Probability of observing 8 or more 
receiving<6month adjuvant therapy in the 
first 20 patients in Arm 2A 
<0.1 
0.03 0.23 
0.58 
0.87 
0.98 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
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15. PUBLICATION PLAN 
 
The data will be collected by Dr. Taplin and study team and analyzed by Dr. Taplin and the 
statistical team at DFCI. It is anticipated that the results will be made public within 12 months of 
the end of data collection. A report is planned to be published in a peer-reviewed journal, 
however initial release may be an abstract that meets the requirements of the International 
Committee of Medical Journal Editors.  


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17. APPENDICES 
17.1 APPENDIX A: Performance Status Criteria 
17.2 APPENDIX B: Required Forms at Registration 
17.3 APPENDIX C: Patient’s Pill Diary 
17.4 APPENDIX D: Representative Medications that May Predispose to Seizures  
17.5 APPENDIX E: Intra-operative and Peri-operative RP Complications Questionnaires  
17.6 APPENDIX F: Post-Operative Complications (Clavian Classification)  
17.7 APPENDIX G: The Expanded Prostate Cancer Index Composite Questionnaire (EPIC-
26 +) 
17.8 APPENDIX H: Family History Questionnaire  
17.9 APPENDIX I: Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 


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


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95
APPENDIX B:  
 
Please notify the lead clinical research coordinator at the time a participant is identified or 
consented to the study.  The DFCI coordinator will register the participant once the below 
documentation is finalized using the DFCI OnCore registration system.  Non-DF/HCC 
participating sites will send the documents to the DFCI research coordinator to complete 
registration.  Please allow a one-week turn-a-round time for the DFCI research team to determine 
participant eligibility. The following documentation is required prior to participant registration:  
 
• 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 and 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, 
Radiation therapy with start and stop dates and dosing information if 
applicable) 
o Reports documenting disease status 
 CT abdomen 
 MRI prostate including 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 Screening ECG 
o MUGA Scan or ECHO 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
96
  
APPENDIX C: PATIENT’S PILL DIARY 
 
Today’s Date:  
____________________________ 
Patient Name:  
____________________________  
Patient Study ID: ____________________________ 
Cycle Number:  ____________________________ 
 
 
PART 1:  
ARM 1A:  Apalutamide + Abiraterone Acetate + Prednisone + Leuprolide 
ARM 1B: Abiraterone Acetate + Prednisone + Leuprolide 
 
PART 2:  
ARM 2A:  Apalutamide + Abiraterone Acetate + Prednisone + Leuprolide 
 
 
INSTRUCTIONS TO THE PATIENT: 
1.  Study Drug A: Apalutamide Dose: ________________ (enter N/A if not in Arm 1A) 
Study Drug B: Abiraterone Acetate Dose: ________________  
Study Drug C: Prednisone Dose: ________________  
2. You should take your full dose of abiraterone acetate at the same time once daily. For abiraterone acetate 
administration, 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. 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. Abiraterone acetate should not 
be taken at the same time as apalutamide or prednisone. 
3. You should take prednisone at the same time daily. Prednisone should be taken with food.  
4. For ARM 1A or 2A participants: You should take your full dose of apalutamide at the same time once 
daily with or without food.  Apalutamide may be taken with prednisone (and food).  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. 
5. Your study medications should not be crushed, chewed, or dissolved in water. 
6. You may not consume grapefruit or grapefruit-containing products while taking the study medications. 
7. Record the date, time and the number of tablets you took. 
8. If you have any comments or notice any side effects, please record them in the comments column.  
9. Please bring your pill bottle and this form to your physician when you go to your next appointment. 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
97
 
APPENDIX C: PATIENT’S PILL DIARY (Part 1) 
Today’s Date:  
____________________________  Cycle Number: ______________________ 
Patient Name:  
____________________________  Patient Study ID: ____________________ 
 
Date  
Day 
Number of Tablets or Capsules/Time of Day  
Comments 
Abiraterone 
Acetate 
Apalutamide 
Prednisone 
(AM) 
Prednisone 
(PM) 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
Patient’s Signature: ____________________________________________ Date: ___________________________ 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
98
 
APPENDIX C: PATIENT’S PILL DIARY (Part 2A) 
Today’s Date:  
____________________________  Cycle Number: ______________________ 
Patient Name:  
____________________________  Patient Study ID: ___________________ 
 
Date  
Day 
Number of Tablets or Capsules/Time of Day  
Comments 
Abiraterone 
Acetate 
Apalutamide 
Prednisone 
(AM) 
Prednisone 
(PM) 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
29 
 
 
 
 
 
 
30 
 
 
 
 
 
Patient’s Signature: ____________________________________________ Date: ___________________________ 


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APPENDIX D: Representative Medications that May Predispose to Seizure 
Generic Name 
Brand Name* 
aminophylline 
Aminocont; Aminomal; Diaphyllin; Filotempo; Neophyllin; Norphyl; 
Phyllocontin; Syntophyllin; Tefamin; Truphylline; Xing You Shan;  
aminophylline in 
combination 
Asmeton; Cha Xin Na Min; Emergent-Ez; Fufang Dan An Pian; Ke Zhi 
 
amitriptyline 
Amirol; Amitrip; Amixide; Deprelio; Diapatol; Elatrol; cElatrolet; Elavil; 
Endep; Enovil; Emitrip; Klotriptyl; Laroxyl; Levate; Limbitrol; Limbitryl; 
Mutabase; Mutabon; Nobritol; Novo-Triptyn; Pertriptyl; Redomex; 
Saroten; Sarotex; Sedans; Syneudon; Teperin; Triptizol; Triptyl; Tryptizol 
amitriptyline in 
combination 
PMS-Levazine 
 
bupropion 
 
Aplenzin; Buproban; Contrave; Elontril; Forfivo; Fortivo XL; Le Fu Ting; 
Prexaton; Quomem; Voxra; Wellbutrin; Wellbutrin XL; Wellbutrin SR; 
Yue Ting; Zyban 
chlorpromazine 
Aminazin; Chlorazin; Hibernal; Klorproman; Largactil; Megaphen; 
Ormazine; Plegomazin; Solidon; Taroctyl;Thorazine; Vegetamin; 
Wintermin; Zuledin 
Note: in Ireland  also called “Clonazine” – very easy to confuse with 
clozapine. 
clozapine 
Azaleptin; Clopine; Closastene; Clozaril; CloZAPine; Denzapine; Elcrit; 
Fazacio ODT; Klozapol; Lanolept; Leponex; Lozapine; Nemea; Ozapim; 
Synthon, Versacloz; Zaponex 
desipramine  
Deprexan; Norpramin; Nortimil; Pertofrane 
doxepin 
Adapin; Anten; Aponal; Deptran; Gilex; Li Ke Ning; Quitaxon; Silenor; 
Sinepin; Sinequan; Zonalon 
imipramine 
Impril; Melipramin; Mipralin; Norfranil,; Novo-Pramine; Persamine; 
Pertofram; Pryleugan; Talendep; Tofranil; Tolerade 
lithium 
Arthriselect; Camcolit; Carbolith; Carbolithium; Eskolith; Hypnorex; Li-
Liquid; Licarbium; Limas; Liskonum; Litarex; Lithane; Lithicarb; 
Lithioderm; Lithionit; Lithobid; Liticarb; Litiomal; Lito; Maniprex; 
Neurolepsin; Plenur; Priadel; Quilonorm; Quilonum; Saniquiet; Sedalit; 
Teralithe 
lithium in combination 
Boripharm No 23; Emser Salz; Girheulit HOM; Helidonium-Plus; 
Heweurat N; rheuma-loges; Rhus Toxicodendron Compose; Rhus-Plus; 
Ricinus Compose 
maprotiline 
Cronmolin; Deprilept; Ludiomil; Mapromil; Melodil; Neuomil; Psymion 
meperidine/pethidine 
Alodan ; Atropine and Demerol; Centralgine ; Demerol ; Dolantin ; 
Dolantina,; Dolantine ; Dolargan,; Dolcontral,; Dolestine ; Dolosal ; Dolsin; 
Fada; Hospira; Liba; Mepergan ; Meprozine,; Mialgin,; Opystan; Pethidine 
; Petigan Miro ; Psyquil compositum 
meperidine/pethidine  
in combination 
Pamergan P100 
 
mesoridazine 
Serentil, Mesorin 
mirtazapine 
 
Arintapin; Avanza; Axit; Combar; Esprital; Mi Er Ning; Miro; Mirta TAD; 
Mirtabene; Mirtachem; Mirtadepi; Mirtagamma; Mirtalan; MirtaLich; 
Mirtamylan; Mirtaron; Mirtaz; Mirtazelon; Mirtazon; Mirtazonal; Mirtel; 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
100
Mirtin; Mirtor; Mirzaten; Norset; Noxibel; Paidisheng; Psidep; Remergil; 
Remergon; Remeron; Remirta; Rexer; Yarocen; Zispin 
olanzapine 
Anzorin, Arenbil; Arkolamyl; Atyzyo; Bloonis; Clingozan; Egolanza; 
Lansyn; Lanzek; Lazapix; Nolian; Nykob; Olafid; Olanzaran; Olanzep; 
Olanzin; Olanzine; Olapin; Olasyn; Olazax; Olpinat; Olzapin; Olzin; Ou 
Lan Ning; Ozilormar; Parnassan; Ranofren; Sanza; Stygapon; Synza; 
Ximin; Zalasta; Zamil; Zappa; Zapris; Zerpi; Zolafren; Zolaxa; Zonapir; 
Zopridoxin; Zylap; Zypadhera; Zypine; Zyprexa; Zyprexa Relprew; Zydis 
olanzapine in 
combination 
Symbyax 
 
risperidone 
Aleptan; Apo-Risperid; Arketin; Calmapride; Diaforin; Doresol; 
Hunperdal; Jing Ping; Ke Tong; Leptinorm; Lergitec; Orizon; Ozidal; 
Perdox; Ranperidon; Resdone; Ridal; Ridonex; Rileptid; Ripedon; Risepro; 
Rispa; Rispaksole; Rispefar; Rispemylan; Rispen; Rispera; Risperanne; 
Risperdal; Risperdalconsta; Risperdaloro; Risperigamma; Risperon; 
Rispolept; Rispolux; Rispond; Rispons; Risset; Rixadone; Rorendo; 
Ryspolit; Si Li Shu; Sizodon; Speridan; Suo Le; Torendo; Zhuo Fei; Zhuo 
Fu; Ziperid; Zoridal 
theophylline 
Aerolate; Afonilum; Aminomal; An Fei Lin; Apnecut; Apo-Theo; Asmalix; 
Asmalon; Bi Chuan; Bronchoparat; Bronchoretard; Cylmin; Diffumal; 
Elixifilin; Elixophyllin; Etipramid; Euphyllin; Euphyllina; Euphylline; 
Euphylong; Frivent; Gan Fei Lin; Nuelin; Protheo; Pulmophylline; 
Quelesu; ratio-Theo-Bronc; Respicur; Retafyllin; Shi Er Ping; Slo-Bid; Slo-
Phyllin; Telbans; Teotard; Terdan; Teromol; Theo-24; Theo-Dur; Theo; 
Theochron; Theodur; Theofol; Theolair; Theoplus; Theospirex; Theostat ;  
Theotard; Theotrim; Theovent; Tromphyllin; Unicon; Unicontin; Unifyl; 
Uniphyl; Uniphyllin Continus; Uniphyllin; UniXan; Xanthium; Xi Fu Li; 
Yan Er 
theophylline in 
combination 
Antong; Baladex; Bi Chuan; Binfolipase; Broncho-Euphyllin; Broncomar; 
Do-Do ChestEze; Elixophyllin-GG; Elixophyllin-KI; Insanovin; Marax ; 
Neoasma; Theofol Comp; Theophedrinum-N; Xu Hong; Yi Xi Qing 
thioridazine 
Detril; Elperil; Melleril; Ridazin; Ridazine; Thiodazine; Thioril; Sonapa 
ziprasidone 
Geodon; Li Fu Jun An; Pramaxima; Si Bei Ge; Ypsila; Zeldox; Zipwell; 
Zypsila; Zypsilan 
** Note:  this document is intended as an aid in identifying prohibited meds, but due to the global 
scope of the apalutamide studies may not be all inclusive.  
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
101
APPENDIX E: Intra-operative and Post-operative RP Complications Questionnaires 
 
Intraoperative Surgical Questionnaire 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date ___/___/___ 
 
  
 
 
 
 
 
 
 
I. Patient Data 
 
A. Patient’s First Name __________________ B. Patient’s Last Name __________________ 
 
C. ID# __________________ 
 
II. Operative Information  
 
A. Age at Surgery: ___________ yrs 
 
B. Date of Surgery: ___/___/___ 
 
C. Surgical Approach: Retropubic____, Perineal____, Laparoscopic____, Robotic_____ 
 
D. Neurovascular Bundle Preserved: Two_____, One_____, None_____ 
 
E. Ease of Neurovascular Bundle Preservation: Easy____, Moderate____, Difficult_____ 
 
F. Lymph Node Dissection: Yes____, No____  
 
G. Technical Modifications: ______________________________________________ 
 
H. Estimated Blood Loss (cc) _______________ 
 
I. Blood Transfusion Required: Yes____, No____; if yes, 
 
Intraoperative Autologous Units_____, Postoperative Autologous Units_____ 
 
Intraoperative Nonautologous Units_____, Postoperative Nonautologous Units_____ 
 
J. Hemodiluted: Yes____, No_____  
 
K. Intraoperative Complication: Yes____, No_____; if yes, type of intraoperative  
 
complication:___________________________________________ 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
102
In Hospital Complications Surgical Questionnaire 
(to be completed after surgery) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date ___/___/___ 
 
 
I. Patient Data 
 
 
A. Patient’s First Name __________________ B. Patient’s Last Name ________________ 
 
 
 
C. ID# __________________ 
 
 
II. Patient Data 
 
 
 
A. Post-operative days admitted_______ 
 
 
 
 
 
B. In Hospital Complication: Yes ____, No _____. If yes, circle all appropriate. 
 
 
 
General:  
 
 
 
1. Fever 
 
 
 
2. Paralytic ileus 
 
 
 
3. Deep vein thrombosis 
 
 
 
 
4. Pulmonary embolism 
 
 
 
 
5. Myocardial infarction 
 
 
 
 
6. Cerebrovascular stroke 
 
 
 
Specific:  
 
 
 
1. Prolonged tube drainage 
 
 
 
2. Foley Catheter Fell Out 
 
 
 
3. Wound infection  
 
 
 
4. Wound dehiscence 
 
 
 
5. Hematuria with clots 
 
 
 
6. Obstructed catheter 
 
 
 
Other (not listed above): ________________________________________________ 
 
 
 
 
 
C. Transfusion Yes ____, No _____. If yes, # of units: ________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
103
APPENDIX F: Post-Operative Complications (Clavian Classification) 
Note: For any question answered “Yes”, please grade and attribute in the patient note. 
 
Cardiac 
• Arrhythmia (Y____N____) 
• Myocardial Infarction (Y____N____) 
• Not otherwise specified (Y____N____) 
Lymphovascular 
• Lymphocele (Y____N____) 
• Infected lymphocele (Y____N____) 
• Lymphedema (Y____N____) 
• Postop bleeding (Y____N____) 
Gastrointestinal 
• Diarrhea (Y____N____) 
• Ileus (Y____N____) 
• Enterotomy (Y____N____) 
• Rectal laceration (Y____N____) 
• Rectal Bleeding (Y____N____) 
• SBO (Y____N____) 
• Not otherwise specified (Y____N____) 
Infectious 
• C. Difficile (Y____N____) 
• Pneumonia (Y____N____) 
• UTI (Y____N____) 
• Abscess (Y____N____) 
• Epididymitis/orchitis (Y____N____) 
Neurologic 
• Neuropraxia (Y____N____) 
• Transient Ischemic Attack – Stroke (Y____N____) 
• Syncope (Y____N____) 
• Psychiatric event (Y____N____) 
• Pain not otherwise specified (Y____N____) 
Pulmonary 
• Respiratory distress/failure (Y____N____) 
• Pulmonary Embolus (Y____N____) 
• Deep Vein Thrombosis (Y____N____) 
Renal 
• Acute renal failure (Y____N____) 
Urologic 
• Ureteral trauma (Y____N____) 
• Intractable bladder spasms (Y____N____) 
• Clot retention (Y____N____) 
• Disrupted anastomosis (Y____N____) 
• Gross hematuria (Y____N____) 
• Retention (Y____N____) 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
104
• Foley malfunction (Y____N____) 
• Urine leak / urinoma (Y____N____) 
Wound 
• Dehiscence (Y____N____) 
• Infection (Y____N____) 
• Hernia (Y____N____) 
Ophthalmologic 
• Xerophthalmia (Y____N____) 
Other 
• Dehydration (Y____N____) 
• Allergic reaction (Y____N____) 
• Unplanned Admission (Y____N____) 
• Unplanned Emergency Room Visit (Y____N____) 
 
 
 
 
 
 
 
Provider Signature: _________________________________ Date: __________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
105
APPENDIX G: The Expanded Prostate Cancer Index Composite (EPIC-26 +) 
 
This questionnaire is designed to measure Quality of Life issues in patients with Prostate 
Cancer. To help us get the most accurate measurement, it is important that you answer all 
questions honestly and completely.  Remember, as with all medical records, information 
contained within this survey will remain strictly confidential. 
 
Name: ________________________ 
ID: __________________________ 
Cycle: ______________________ 
Today’s Date: ___/____/____ 
 
 
1. Over the past 4 weeks, how often have you leaked urine? (Circle one number) 
 
More than once a day........................... 
1 
About once a day.................................. 2 
More than once a week......................... 3    
About once a week............................... 
4 
Rarely or never..................................... 5 
 
2. Which of the following best describes your urinary control during the last 4 weeks? 
(Circle one number) 
 
No urinary control whatsoever............. 1 
Frequent dribbling................................ 2 
Occasional dribbling............................ 
3 
Total control......................................... 
4 
 
3. How many pads or adult diapers per day did you usually use to control leakage during 
the last 4 weeks? (Circle one number) 
 
None.......................................... 
0 
1 pad per day............................. 
2 
2 pads per day............................ 3 
3 or more pads per day.............. 
4 
 
4. How big a problem, if any, has each of the following been for you during the last 4 
weeks? (Circle one number on each line) 
 
 
No 
Problem 
Very 
Small 
Problem 
Small 
Problem 
Moderate 
Problem 
Big 
Problem 
a. Dripping or leaking 
urine........................ 
0 
1 
2 
3 
4 
b. Pain or burning on 
urination.................. 
0 
1 
2 
3 
4 


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106
c. Bleeding 
urination.................. 
 
0 
 
1 
 
2 
 
3 
 
4 
d. Weak urine stream 
or incomplete 
emptying.................. 
0 
1 
2 
3 
4 
e. Need to urinate 
frequently during 
the day..................... 
0 
1 
2 
3 
4 
 
5. Overall, how big a problem has your urinary function been for you during the last 4 
weeks? (Circle one number) 
 
No problem....................................................... 1 
Very small problem.......................................... 2 
Small problem.................................................. 
3 
Moderate problem............................................ 
4 
Big problem...................................................... 5 
 
6. How big a problem, if any, has each of the following been for you? (Circle one number 
on each line) 
 
No 
Problem 
Very 
Small 
Problem 
Small 
Problem 
Moderate 
Problem 
Big 
Problem 
a. Urgency to have a 
bowel 
movement........... 
0 
1 
2 
3 
4 
b. Increased frequency of 
bowel movements....... 
0 
1 
2 
3 
4 
c. Losing control of your 
stools........................... 
0 
1 
2 
3 
4 
d. Bloody stools.............. 
0 
1 
2 
3 
4 
e. Abdominal/Pelvic/Rec
tal Pain........................ 
0 
1 
2 
3 
4 
 
7. Overall, how big a problem have your bowel habits been for you during the last 4 
weeks? (Circle one number) 
 
No problem....................................... 
1 
Very small problem........................... 
2 
Small problem.................................. 
3 
Moderate problem............................ 
4 
Big problem...................................... 
5 
 
8. How would you rate each of the following during the last 4 weeks? (Circle one number 
on each line) 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
107
 
Very 
Poor to 
None 
Poor 
Fair 
Good 
Very 
Good 
a. Your ability to have an erection?.. 
1 
2 
3 
4 
5 
b. Your ability to reach orgasm 
(climax)?........................................ 
1 
2 
3 
4 
5 
 
9. How would you describe the usual QUALITY of your erections during the last 4 
weeks? (Circle one number) 
 
None at 
all.................................................................................. 
1 
Not firm enough for sexual 
activity........................................... 
2 
Firm enough for masturbation and foreplay 
only...................... 
3 
Firm enough for 
intercourse....................................................... 
4 
 
10. How would you describe the FREQUENCY of your erections during the last 4 weeks? 
(Circle one number) 
 
I NEVER had an erection when I wanted 
one........................... 
1 
I had an erection LESS THAN HALF the time I wanted 
one... 
2 
I had an erection ABOUT HALF the time I wanted 
one........... 
3 
I had an erection MORE THAN HALF the time I wanted 
one. 
4 
I had an erection WHENEVER I wanted 
one............................ 
5 
 
11. Overall, how would you rate your ability to function sexually during the last 4 weeks? 
(Circle one number) 
 
Very poor........................................... 
 
1 
Poor.................................................... 
2 
Fair..................................................... 
3 
Good.................................................. 
4 
Very good.......................................... 
5 
 
12. Overall, how big a problem has your sexual function or lack of sexual function been for 
you during the last 4 weeks? (Circle one number) 
 
No problem....................................... 
1 
Very small problem.......................... 
2 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
108
Small problem................................... 3 
Moderate problem............................. 4 
Big problem...................................... 
5 
 
13. How big a problem during the last 4 weeks, if any, has each of the following been for 
you? (Circle one number on each line) 
 
 
No 
Problem 
Very 
Small 
Problem 
 
Small  
Problem 
 
Moderate 
Problem 
 
Big 
Problem 
a. Hot Flashes.................... 
0 
1 
2 
3 
4 
b. Breast 
tenderness/enlargement.. 
 
0 
 
1 
 
2 
 
3 
 
4 
c. Feeling depressed.......... 
0 
1 
2 
3 
4 
d. Lack of energy............... 
0 
1 
2 
3 
4 
e. Change in body weight.. 
0 
1 
2 
3 
4 
 
Supplemental Questions 
 
1. Are you currently using any of the following medications, treatment, or devices for 
urinary incontinence?  Check all that apply: 
___A. Oral Medications (Ditropan, Detrol, Sancture, etc.) 
___B. Surgical Sling 
___C. Artificial Sphincter 
___D. None of the above 
 
2. Are you currently using any of the following medications, treatment, or devices for 
erectile dysfunction?  Check all that apply: 
 
___A. Oral Medications (Viagra, Levitra, Cialis) 
___B. MUSE (intra-urethral alprostadil suppository) 
___C. Vacuum erection device (such as Erect-Aid) 
___D. Penile prosthesis 
___E. No treatment (none of the above) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
109
 
 
APPENDIX H: Family History Questionnaire  
 
Name: 
                                                                     Date of Birth 
 
Please complete this form by listing all family members (blood relatives) known to you with a cancer diagnosis.  
Please identify your relatives using their first name, and first letter of their last name only.   
 
 
Relative 
 
Cancer(s) – What Type(s)? 
Approximate Age 
at Diagnosis 
Mother 
 
 
Father 
 
 
Children 
 
 
 
Grandchildren 
 
 
 
Mother’s Mother (grandmother) 
 
 
 
Mother’s Father (grandfather) 
 
 
 
Father’s mother (grandmother) 
 
 
 
Father’s father (grandfather) 
 
 
 
Brothers  
Example:  John C. 
 
 
 
 
Prostate Cancer 
 
58 
Sisters 
 
 
 
 
 
Nieces (children of brothers/sisters) 
 
 
 
 
Nephews (children of 
brothers/sisters) 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
110
Other Relatives on Mother’s side 
Describe how related: 
Example: Mary S.   Maternal aunt 
 
 
 
 
 
 
Ovarian Cancer 
 
 
67 
Other Relatives on Father’s side 
Describe how related: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
111
 
 
 
 
 
 
 
 
APPENDIX I 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Neoadjuvant abiraterone acetate plus leuprolide with or without apalutamide 
 
 
112
 
TABLE OF CONTENTS 
1. 
INTRODUCTION 
 
1.1 Purpose 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
2. 
GENERAL ROLES AND RESPONSIBILITIES 
 
2.1 DF/HCC Sponsor 
2.2 Coordinating Center  
2.3 Participating Institution 
 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
3.1 Protocol Distribution 
3.2 Protocol Revisions and Closures 
3.3 Informed Consent Requirements 
3.4 IRB Documentation 
3.5 IRB Re-Approval 
3.6 Participant Confidentiality and Authorization Statement  
3.7 
DF/HCC Multi-Center Protocol Registration Policy 
3.8 DF/HCC Protocol Case Number 
3.9 Safety Assessments and Toxicity Monitoring 
3.10 Data Management 
 
4. 
REQUISITIONING INVESTIGATIONAL DRUG 
 
 
5. 
MONITORING: QUALITY CONTROL 
 
5.1 Ongoing Monitoring of Protocol Compliance 
5.2 Monitoring Reports 
5.3 Accrual Monitoring 
 
6. 
AUDITING: QUALITY ASSURANCE 
 
6.1 DF/HCC Internal Audits 
6.2 Audit Notifications 
6.3 Audit Reports  
6.4 Participating Institution Performance 
 
 
 


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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 Sponsor 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.    
 
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 


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general, the Lead Institution is the Coordinating Center for the DF/HCC Multi-Center 
Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within 
DF/HCC responsible for providing a comprehensive data management platform for 
managing clinical trial data. 
 
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, Dr. Mary-Ellen Taplin 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 
(i.e. FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials). 
• 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.  
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 


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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 DF/HCC Office for Data Quality (ODQ) 
 
In addition to the Coordinating Center, the DF/HCC ODQ provides the following support 
services to assist the DF/HCC Sponsor: 
• Develop protocol specific case report forms (CRF/eCRFS). 
• QA/QC data of protocol specific CRFs.  
• Provide a central participant registration, which includes review of consent and 
eligibility. 
• Provide auditing services (funding and ODQ approval required). 
 
2.4 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: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 


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• 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 
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. 
• Order, store and dispense 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. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
Promptly provide follow-up and/or corrective action plans for any monitoring queries or audit 
findings. 
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. Approval memo 
and documents must be submitted to the Coordinating Center.  
 
• 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. 
 


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• 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 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: 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
 
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 
 


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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.  
 
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 will provide a consent template, which covered entities 
(Participating Institutions) must use.  
 
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 ODQ 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 Protocol Registration Policy 
 
3.7.1 Participant Registration and Randomization  
To register a participant, the following documents should be completed by the 
Participating Institution and faxed to the Coordinating Center at Dana-Farber Cancer 
Institute at (617) 632-6220 or e-mailed to the DFCI Clinical Research Manager and 
Clinical Research Coordinator.  
Please notify the DFCI team in advance that a registration packet is to be expected with 
the following items: 
• Current IRB approved informed consent document signed by participant and 
investigator.  Participant name and MRN must be redacted. Please ensure the 
participant’s initials are written on each page of the 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) 


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– Reports documenting disease status: CT or MRI Abdomen and Pelvis. 
Bone Scan  
– Pathology Report  
– Concomitant medication list 
– Progress note or equivalent documentation of consenting visit 
– Progress note documenting medical history and oncologic history 
– All screening labs 
– Screening visit note, with BP, vital signs, ECOG Performance status 
– Screening ECG 
– MUGA Scan or ECHO 
 
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 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 


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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. 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.  
 


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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. 
 
3.10.2 Guidelines for Processing IND Safety Reports  
 
 The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review/submit to their IRB according to their institutional policies and procedures.  
 
 
3.11 Data Management 
 DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.These 
forms are designed to collect data for each study. DF/HCC CTRIO provides a web based 
training for all eCRF users.   
3.11.1 Data Forms Review 
 


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Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will receive 
a written or electronic query from the DF/HCC Office of Data Quality, Coordinating Center, 
or designee.  
 
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.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.  
4.0    REQUISITIONING INVESTIGATONAL DRUG 
 
The ordering of investigational agent is specified in the protocol sections 7.1.8, and 7.2.7. 
 
Participating Institutions should order their own agent regardless of the supplier 
(pharmaceutical company, commercial supply, etc.)   
 
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.  
 
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 / 


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treatment, regulatory records and site trial master files, protocol deviations, pharmacy 
records, response assessments, and data management.  
 
Site visits will generally occur once a year for sites that are actively enrolling 
participants and have participants in treatment.  Additional monitoring activities may 
occur if incidences of non-compliance are discovered or at the request of the DF/HCC 
Sponsor.   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. 
 
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 


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accurately reported per the protocol, Standard Operating Procedures (SOPs), and the Code 
of Federal Regulations (CFR). 
 
6.1 DF/HCC Sponsored Trials 
 
This study may be audited by the DF/HCC Office of Data Quality (ODQ) if the Sponsor-
Investigator determines that an audit of the participating site is necessary. 
 
6.2 DF/HCC Internal Audits 
 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality 
(ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2 day 
period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited.  
 
6.3 Audit Notification 
 
 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.  
 
6.4 Audit Reports 
 
 The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4.1 Corrective Actions 
 
The DF/HCC Sponsor and DFCI IRB are charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may 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. A 
DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 
 
  


Protocol #16-223: Drafted (09/14/16)(JEP)/Approved (9/14/16)(AFP) 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16-223 
Protocol Name: 
Phase II randomized study of neoadjuvant and adjuvant abiraterone acetate + ARN-509 for 
intermediate-high risk prostate cancer undergoing prostatectomy 
DFCI Site PI: 
Mary-Ellen Taplin MD 
DFCI Research Nurse: 
Judy Prisby, Meghara Walsh, Amanda Pace , Ralph Eugene 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
 
Study Drugs: Section 2.3. – Abiraterone CYP17 inhibitor, second generation antiandrogen (Section 2.3.2) 
 
ARN-509 (Aptilutamide)- novel second generation antiandrogen that binds directly to the ligand binding domain 
of the androgen receptor impairing nuclear translocation and DNA binding (Section 2.3.4) 
 
Leuprolide – GNRH agonist – lowers testosterone (Lexicomp) 
 
Study Design – Section 1.1 
 
Study Rationale – Section 2.2 
 
A cycle is defined as 28 days – Section 5, Table 4, Study Calendar, Section 9 
 
Dose Calc. 
 
All drugs are in fixed doses, dosing Section 5 
 
Leuprolide Section 5.3.4 
 
Pre-Prostatectomy 
o 
Arm 1A – Abiraterone +Prednisone + ARN-509 + Leuprolide X 6 cycles (Section 1.1; Study 
schema) 
o 
Arm 1B – Abiraterone + Prednisone + Leuprolide X 6 cycles (Section 1.1; Study schema) 
 
Post prostatectomy 
o 
Arm 2A – Abiraterone + Prednisone + ARN-509 + Leuprolide X 12 cycles (Section 1.1; Study 
schema) 
o 
Arm 2B - Observation (Section 1.1; Study schema) 
Study Drug  
Administration 
Agent Administration Guidelines are found in Section 5 
 
Abiraterone is taken orally, daily, on an empty stomach (nothing to eat 2 hours pre and 1 hour post) – Section 
5.3.1 
 
Prednisone is taken orally, daily, with food – Section 5.3.3, Table 4 
 
ARN-509 is taken orally, daily, with or without food, may be taken with prednisone – Section 5.3.2, Table 4 
 
Leuprolide – given IM for 6 cycles pre prostatectomy (both arms) and 12 cycles post prostatectomy (if in Arm 
2A) – Section 5.3.4 
 
 
Criteria to treat – Section 5.2 and Section 6 
 
Oral Agents cannot be crushed, chewed, or dissolved, must be taken whole. – Section 5.3 
 
Missed doses should be taken no later than 12 hours after the scheduled time for dosing. – Section 5.3 
 
Vomited doses should not be made up. – Section 5.3 
 
 
Dose  
Mods & 
Toxicit
y
Dose Modifications/Dosing Delay for Toxicity are outlined in Section 6 
 
This protocol uses NCI CTCAE criteria, version 4.0 
 
Con 
Med
s 
Concomitant Therapy Guidelines are in Section 5.4 and Appendix D 
 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Section 9 
 
The study calendar is in Section 9 
 
Vital signs:  Study Calendar 
 
ECGs:  Study Calendar & Section 3 –Fridericia correction formula 
 
Correlative studies:  Section 8, 8.2, Study Calendar and Lab Manual 
 


Protocol #16-223: Drafted (09/14/16)(JEP)/Approved (9/14/16)(AFP) 
 
Charting 
Tips 
All study drugs require documentation of exact administration time. 
Abiraterone, Prednisone, and ARN-509 are under Oncology Research Plan, Leuprolide under Oncology 
Supplemental Plan in EPIC. 
Please be sure to also DOCUMENT routes of administration, injection sites, and exact time of any correlative 
sample collection