Clinical trial NCT01946165
Conditions: Prostate Cancer
Keywords: Prostate Cancer High risk prostate cancer Abiraterone acetate Zytiga Prednisone Enzalutamide MDV3100 XTANDI Androgen ablation LHRHa Hormonal therapy
Sponsor: M.D. Anderson Cancer Center
Start date: 2013-10-31; Completion date: 2017-07-28
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if adding the combination of abiraterone acetate and prednisone with or without enzalutamide to hormonal therapy can help to control prostate cancer when given before surgery. The safety of the drug combination will also be studied.

Detailed description:
Study Groups:

If you are found to be eligible to take part in this study, you will be randomly assigned (like the roll of dice) to 1 of 2 groups. You will have a 2 out of 3 chance of being assigned to Group A and a 1 out of 3 chance of being assigned to Group B.

If you are in Group A, you will receive hormonal therapy (LHRH), abiraterone acetate, prednisone, and enzalutamide.

If you are in Group B, you will receive LHRH, abiraterone acetate, and prednisone.

Study Drug Administration:

The study doctor will decide what hormone therapy you will receive, will explain when and how you should take it, and explain any risks.

In addition, you will take 4 abiraterone acetate tablets by mouth each day (all at the same time) at least 1 hour before a meal or 2 hours after a meal. You will also take 1 tablet of prednisone by mouth 1 time each day to help lower the risk of side effects caused by abiraterone acetate.

If you are in Group A, you will also take 4 capsules of enzalutamide by mouth each day. You should take enzalutamide at about the same time every morning. Enzalutamide can be taken with or without food. If you miss a dose, you should NOT take another dose until the next day. You should tell the study doctor as soon as possible if you miss a dose.

About every 28-days is called a cycle. You should return all unused study drug and/or empty pill bottles at the end of each cycle.

Study Visits:

On Day 1 of Cycle 1:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) will be drawn for routine tests and to check your prostatic specific antigen (PSA) level.

On Day 15 of Cycles 1, 2 and 3, blood (about 2 tablespoons) will be drawn to check your liver function. These tests may be done at your local doctor's office and the results faxed to MD Anderson.

On Day 1 of Cycles 2, 3, 4, 5 and 6:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) will be drawn for routine tests. This blood will also be used to check your PSA level.

The testing on Cycles 2, 4 and 6 may be done at your local doctor's office and the results faxed to MD Anderson.

Within 14 days before surgery and at your End of Treatment Visit:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) and urine will be collected for routine tests. This blood will also be used to check your PSA level, your blood sugar levels, and blood-clotting function. You will be asked to fast for at least 8 hours before these blood draws.
* You will have a chest x-ray or a CT scan of the chest.
* You will have an EKG to check your heart function.

Surgery:

After 6 cycles of study treatment, you will have surgery to remove your prostate. You will be asked to sign a separate consent form for this surgery, and the risks will be discussed with you. Your leftover prostate gland tissue from surgery will be collected and used for biomarker testing.

About 4 to 8 weeks after your surgery:

* You will have a physical exam.
* Blood (about 3-4 tablespoons) drawn for routine tests. This blood will also be used to check your PSA, testosterone, cholesterol, and blood sugar levels.

Length of Study:

You may receive the study drugs for about 6 months. You will be taken off study early if the disease gets worse, if you have intolerable side effects, or if your study doctor thinks it is in your best interest to stop, or of you are unable to follow study directions.

Your participation on the study will be over once you have completed the visits after surgery.

This is an investigational study. Abiraterone acetate is FDA approved in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. Prednisone is FDA approved and commercially available as a corticosteroid. Enzalutamide is FDA approved and commercially available for the treatment of certain types of prostate cancer. Their combination with hormone therapy in patients with prostate cancer is investigational.

Up to 69 patients will be enrolled in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Patients receive abiraterone acetate (1,000 mg daily) plus prednisone (5mg once daily) in combination with enzalutamide (160 mg daily) and LHRHa. Patients receive a LHRHa (monthly injection or three-month injection) for a maximum of 7 months before a prostatectomy is performed. Study doctor will decide what hormone therapy patient receives. arm 2: Patients receive abiraterone acetate (1,000 mg daily) plus prednisone (5mg once daily) and LHRHa. Patients receive a LHRHa (monthly injection or three-month injection) for a maximum of 7 months before a prostatectomy is performed. Study doctor will decide what hormone therapy patient receives.
Interventions: intervention 1: Abiraterone Acetate intervention 2: Prednisone intervention 3: Enzalutamide intervention 4: LHRHa
Intervention descriptions: intervention 1: 1,000 mg by mouth daily for each 28 day cycle. intervention 2: 5 mg by mouth once daily for each 28 day cycle. intervention 3: 160 mg by mouth daily for each 28 day cycle. intervention 4: Patients receive a LHRHa (monthly injection or three-month injection) for a maximum of 7 months before a prostatectomy is performed. Study doctor will decide what hormone therapy patient receives.

Protocol documents:
Prot_SAP_000.pdf: 
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1 
Study Title:   A Pre-Operative Study to Assess the Effects of Abiraterone acetate plus 
LHRH Agonist and Abiraterone acetate plus LHRH Agonist and Enzalutamide for Six 
Months for Prostate Cancer Patients at High-risk for Recurrence 
Study:  
Investigator Initiated – Phase 2 
Supporters:  
Janssen Scientific Affairs, LLC – Drug and Funding Support 
 
Medivation Inc. – Drug Support 
 
Product Name(s):  
Abiraterone Acetate, Enzalutamide 
Principal Investigator:  
 
Christopher J. Logothetis, MD 
 
MD Anderson Cancer Center 
 
 
 
 
 
 
 
 
 
Co-Principal Investigators:     Eleni Efstathiou, MD 
 
MD Anderson Cancer Center 
 
 
 
 
 
 
 
 
   
John Davis, MD 
MD Anderson Cancer Center  
 
 
 
 
 
 
 
 
 
 


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1 
INTRODUCTION 
1.1 
PROSTATE CANCER AND PREOPERATIVE TREATMENT 
 
In the United States, prostate cancer is the most common cancer and the second 
leading cause of male cancer death.  Many patients diagnosed with prostate cancer 
are curable with local therapy as local treatments continue to evolve to minimize 
morbidity.  Notwithstanding the advent of screening, approximately 20% of patients 
in modern series will initially present with locally advanced or high-grade prostate 
cancer not likely amenable to a single therapeutic approach i.e. surgery or radiation 
therapy alone.  Experience with preoperative therapy in locally advanced prostate 
cancer over the past 15 years has been quite different from that anticipated based on 
observations in other solid tumors i.e. breast or colorectal cancer.  Complete 
pathologic remission is rarely if ever achieved with any of the currently available 
therapeutic regimens including hormonal ablation with the use of Human 
luteinizing hormone-releasing (LHRH) analogues or combination of LHRH with 
docetaxel or other chemotherapeutic regimens. More specifically neo-adjuvant 
hormonal therapy prior to prostatectomy has not improved overall survival (OR 
1.11, 95% CI 0.67 to 1.85, P = 0.69).  However, there has been a report of 
significant reduction in the positive surgical margin rate (OR 0.34, 95% CI 0.27 to 
0.42, P < 0.00001) and a significant improvement in other pathological variables 
such as lymph node involvement, pathological staging and organ confined rates.  A 
borderline significant reduction of disease recurrence rates (OR 0.74, 95% CI 0.55 
to 1.0, P = 0.05) in favor of treatment has also been reported. 
 
Androgen deprivation therapy (ADT) remains the mainstay of therapy for patients 
with advanced prostate cancer and has increased survival in this setting1.  In fact, 
earlier introduction of hormonal ablation seems to favor improved survival though 
androgen deprivation side effects need also be accounted for. With the hope of 
extending survival time, neoadjuvant androgen deprivation (NAD) has been 
proposed to treat locally advanced prostate carcinoma.   
 
Introduced in the 1980s, LHRHa and antiandrogens such as flutamide, and 
cyproterone are considered safe and reversible forms of neoadjuvant androgen 
deprivation (NAD). LHRHa are known to act by stimulating the production of 
luteinizing hormone (LH) at the pituitary level, followed by suppression of LH and 
testosterone to castration levels after approximately 2 weeks. Antiandrogens 
compete with adrenal androgen binding at the receptor level in the target cell. 
Together, LHRHa and antiandrogens cause significant androgen blockade. The first 
prospective randomized trial in patients with prostate cancer demonstrated a 
decreased incidence of positive margins and lymph node metastases in the NAD 
group compared with the surgery alone group2. However, the role of NAD used 
preoperatively is still debatable3. 
 


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A number of randomized studies that documented long-term follow-up have shown 
that no significant difference was noted, in recurrence and survival, between the 
groups that included surgery and those that included NAD4-6.  
 
The introduction of new targeted therapeutics such as the irreversible CYP 17,20 
lyase inhibitor (abiraterone acetate) has enabled a more complete depletion of 
androgens resulting in striking responses in the castrate resistant metastatic disease7-
9. Investigators have recently proposed tumor microenvironment production activity 
for inhibition of 17α-hydroxylase/C17,20 lyase.   
 
More recently two  reports  detailing  the outcome  of the pre-operative use of  
introduction androgen biosynthesis  inhibitors suggest a significant increase the 
efficacy with three and  six months of therapy10-11. 
 
Taken together these are in support of the hypothesis that androgen biosynthesis  
inhibitors add the efficacy  of castration and support the hypothesis that their earlier 
use will further increase efficacy. Enzalutamide is a novel androgen receptor 
inhibitor that acts at multiple levels. Recent reports demonstrate that it can 
meaningfully prolong the survival of patients with castrate resistant prostate 
cancer12. Compelling rationale has been provided to combine the two approaches in 
an integrated effort to more effectively interrupt androgen signaling-mediated 
castrate resistant progression, altered steroid metabolome, and alteration in the 
androgen receptor. We are currently assessing the combination in the setting of 
advanced castrate resistant prostate cancer progressing in bone.   
 
Study 9785-CL-0011 is an ongoing phase 2 open-label in approximately 60 patients 
with CRPC. Patients are receiving enzalutamide in combination with abiraterone 
acetate plus prednisone until disease progression or unacceptable toxicity. The 
primary endpoint is to assess the safety and tolerability of enzalutamide in 
combination with abiraterone acetate plus prednisone. Secondary endpoints are to 
assess the effect on AR signaling and androgen levels and explore the antitumor 
activity by serum PSA, imaging of soft tissue and bone metastases and markers of 
bone metabolism. Enzalutamide is dosed at 160 mg/day, abiraterone acetate at 1000 
mg/day and prednisone at 5 mg twice daily. 
 
As of 2 May 2013, 43 patients had been treated with at least 1 dose of enzalutamide 
in combination with abiraterone acetate plus prednisone. The total number of 
patients who comprise the safety population is 40. Overall, 37 patients (92.5%) 
have reported at least 1 treatment-emergent adverse event. The following treatment-
emergent adverse events have been experienced by 6 or more patients: fatigue (17 
patients [42.5%]), blood Alk Phos increase (17 patients [42.5%]), hot flush (16 
patients [40%]), hyperglycaemia (13 patients [32.5%]), blood AST increase (9 
patients [22.5%]), anemia (9 patients [22.5%]), blood ALT increase (6 patients 
[15%]), blood glucose increase (6 patients [15%]), arthralgia (6 patients [15%]) and 
pollakiuria (6 patients [15%]).  There were no Grade 4 or 5 toxicities.  


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Six SAEs occurred in 5 different patients, and all were Grade 3 events with only 2 
being treatment-emergent and 2 being unrelated to any given study drug. No 
patients discontinued the study or interrupted study drug due to the events. 
However, we have noted that the responses in earlier disease states may be 
markedly enhanced and therefore providing compelling rationale for this pre-
operative study that will serve as a companion to the advanced metastatic study10-11. 
 
1.2  
LHRHa Leuprolide Acetate (Lupron®) and Goserelin Acetate (Zoladex®) 
 
At the time of diagnosis localized prostate cancers are categorized as low, 
intermediate or high risk based on clinical stage, prostate specific antigen (PSA) 
level/velocity and tumor Gleason score13. Patients who fall into intermediate and 
high risk categories have unacceptably high relapse rates (30-80%) after primary 
local therapy or salvage local approaches14. The standard systemic treatment for 
prostate cancer is androgen deprivation therapy (ADT) most commonly 
administered with a LHRHa with/without an antiandrogen15. Treatment of systemic 
prostate cancer with ADT is not curative as the patients develop castration resistant 
prostate cancer (CRPC). 
 
To date, ADT using LHRHa alone has reduced prostate volume by roughly 30% 
and decreased the rate of positive surgical margins, but has not been shown to 
improve the biochemical relapse rate for patients who undergo radical 
prostatectomy. However, because the addition of abiraterone to LHRHa further 
lowers androgen levels compared to LHRHa alone, there is a strong scientific 
rationale to now test whether this more potent combination therapy can improve 
surgical outcomes. 
 
1.3  
Abiraterone Acetate  
 
Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen 
biosynthesis inhibitor that inhibits 17 α hydroxylase/C17, 20-lyase (CYP17). This 
enzyme is expressed in testicular, adrenal and prostatic tumor tissues and is required 
for androgen biosynthesis. 
 
CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and 
progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) 
the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, 
respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens 
and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also 
result in increased mineralocorticoid production by the adrenals. 
 
Abiraterone acetate has received marketing approval in more than 50 countries for 
the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) 
after docetaxel treatment. It is also approved for the treatment of mCRPC in men 


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who have not previously received chemotherapy.  The combination proposed in this 
protocol is not FDA approved. 
  
For the most comprehensive nonclinical and clinical information regarding the 
efficacy and safety of abiraterone acetate, refer to the latest version of the 
Investigator's Brochure/Package Insert for abiraterone acetate. 
 
 
1.3.1       Summary of Key Safety Information for Study Drugs 
 
 
1.3.1.1  Warnings and Precautions 
 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid 
Excess 
 
Use abiraterone acetate with caution in patients with a history of cardiovascular 
disease.  Abiraterone acetate may cause hypertension, hypokalemia, and fluid 
retention as a consequence of increased mineralocorticoid levels resulting from 
CYP17 inhibition.  Co-administration   of a corticosteroid suppresses 
adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the 
incidence and severity of these adverse reactions. Use caution when treating patients 
whose underlying medical conditions might be compromised by increases in blood 
pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent 
myocardial infarction or ventricular arrhythmia. The safety of abiraterone acetate in 
patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart 
failure has not been established because these patients were excluded from the 
randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid 
retention at least once a month. Control hypertension and correct hypokalemia 
before and during treatment with abiraterone acetate. 
 
 
Adrenocortical Insufficiency 
 
Adrenocortical insufficiency has been reported in clinical trials in patients receiving 
abiraterone acetate in combination with prednisone, following interruption of daily 
steroids and/or with concurrent infection or stress. Use caution and monitor for 
symptoms and signs of adrenocortical insufficiency, particularly if patients are 
withdrawn from prednisone, have prednisone dose reductions, or experience 
unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked 
by adverse reactions associated with mineralocorticoid excess seen in patients 
treated with abiraterone acetate. If clinically indicated, perform appropriate tests to 
confirm the diagnosis of adrenocortical insufficiency. Increased dosage of 
corticosteroids may be indicated before, during and after stressful situations. 
 
 
 


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Hepatotoxicity 
 
Marked increases in liver enzymes leading to drug discontinuation or dosage 
modification have occurred.  Measure serum transaminases (ALT and AST) and 
bilirubin levels prior to starting treatment with abiraterone acetate, every two weeks 
for the first three months of treatment and monthly thereafter. In patients with 
baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose 
of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every 
week for the first month, every two weeks for the following two months of 
treatment and monthly thereafter.  Promptly measure serum total bilirubin, AST, 
and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. 
Elevations  of  AST,  ALT,  or  bilirubin  from  the  patient's  baseline  should  
prompt  more frequent monitoring. If at any time AST or ALT rise above five times 
the ULN, or the bilirubin rises above three times the ULN, interrupt abiraterone 
acetate treatment and closely monitor liver function. 
 
Re-treatment with abiraterone acetate at a reduced dose level may take place only 
after return of liver function tests to the patient’s baseline or to AST and ALT less 
than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. 
 
The safety of abiraterone acetate re-treatment of patients who develop AST or ALT 
greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X 
ULN is unknown. 
 
Food effect 
 
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. 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. The safety of these increased exposures when multiple doses of 
abiraterone acetate are taken with food has not been assessed. 
 
1.3.1.2 Drug Interactions 
 
Effects of Abiraterone on Drug Metabolizing Enzymes 
 
Abiraterone acetate 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 was given with abiraterone acetate 1000 mg 
daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone 
acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., 
thioridazine). If alternative treatments cannot be used, exercise caution and consider 
a dose reduction of the concomitant CYP2D6 substrate drug. 


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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 ZYTIGA.  
Drugs that Inhibit or Induce CYP3A4 Enzymes 
 
In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a 
strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single 
dose of abiraterone acetate 1000 mg, the mean plasma AUC∞ of abiraterone was 
decreased by 55%. 
 
Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital) during treatment with ZYTIGA are to be avoided, or 
used with careful evaluation of clinical efficacy. 
 
In a separate clinical pharmacokinetic interaction study of healthy subjects, 
coadministration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically 
meaningful effect on the pharmacokinetics of abiraterone. 
 
1.3.1.3 Packaging and Labeling 
 
Abiraterone acetate tablets will be provided packaged in individual bottles for 
patient assignment at the time of randomization. 
 
Information presented on the labels for investigational product will comply with 
applicable local regulations. 
 
Site pharmacist or medically qualified staff will dispense the study treatment to each 
patient in accordance with this protocol.  
 
1.3.1.4 Pharmacy Storage Requirements 
 
The study treatment must be stored in a secure area and administered only to 
patients entered into the clinical study in accordance with the conditions specified in 
this protocol. Bottles of study treatment should be stored at  20°C to 25°C (68°F to 
77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F) in the original 
container/closure with the cap on tightly; it should never be refrigerated. Additional 
information is provided in the abiraterone acetate Investigator’s Brochure. 
 
Handling 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. Women who are 
pregnant or who may be pregnant should wear gloves if they need to touch 


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abiraterone acetate tablets. Study staff and caregivers should be notified of this 
information, to ensure the appropriate precautions are taken. 
 
1.3.2 Formulation of Study Drug 
 
Abiraterone acetate 250 mg tablets are white to off-white, oval tablets debossed 
with AA250 on one side. ZYTIGA 250 mg tablets are available in high-density 
polyethylene bottles of 120 tablets. 
 
NDC Number 57894-150-12 
 
1.4.1    Enzalutamide 
 
The safety and tolerability of enzalutamide have been evaluated in 13 studies, 
including 2 completed studies (Phase 1), 7 active studies (Phase 1 through 3), 
and 4 enrolling studies (Phase 2 through 3). It is estimated that a total of 124 
healthy volunteers, 16 subjects with hepatic impairment, and approximately 
1800 patients with prostate cancer have been exposed to enzalutamide in 
completed, open-label, and ongoing blinded studies. In the completed 
interim analysis of the randomized, double-blind, placebo-controlled Phase 3 
efficacy and safety study in patients with progressive castration-resistant prostate 
cancer previously treated with docetaxel-based chemotherapy (CRPC2), 800 
patients received enzalutamide (160 mg daily). The duration of enzalutamide 
exposure in this study ranged from 1 day to 23.3 months (median 8.3 months). No 
study has been terminated early for safety reasons. 
 
Safety data are presented from the formal interim analysis of data from the CRPC2 
study, with a data cut-off date of 25 September 2011. Table 3 provides an overview 
of exposure to study drug, adverse events, and deaths. 
 
Table 3: Summary of Study Drug Exposure, Adverse Events, and Deaths 
(CRPC2) 
 
 


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Enzalutamide (160 mg daily) was generally well-tolerated in the placebo-controlled 
CRPC2 study of 1199 patients with progressive castration-resistant prostate cancer 
previously treated with docetaxel-based chemotherapy. Adverse events reported by 
those treated with enzalutamide (160 mg daily) with an incidence of at least 5% and 
by at least 2% greater than by those who received placebo included fatigue (33.6% v 
29.1%), diarrhea (21.4% v 17.5%), hot flush (20.3% v 10.3%), musculoskeletal pain 
(13.6% v 10.0%), headache (11.6% v 5.5%), insomnia (8.6% v 6.0%), anxiety 
(6.4% vs. 4.0%), hypertension (6.1% v 2.8%), and nasopharyngitis (5.1% v 3.0%). 
 
Other adverse events reported less commonly than 5% but that may be associated 
with enzalutamide treatment after careful assessment of the adverse events 
include: falls (4.0% vs. 1.3%), dry skin (3.6% vs. 1.3%), and pruritus (3.5% vs. 
1.3%). A greater proportion of patients in the enzalutamide-treated group (4.1% 
vs. 1.8%) reporting the following adverse event terms: memory impairment, 
cognitive disorder, amnesia, disturbance of attention, and dementia. In addition, 
event terms related to hallucination (visual hallucination, tactile hallucination) 
were reported more frequently in the enzalutamide-treated group (1.6% vs.0.3%). 
 
Serious adverse events that occurred at a ≥ 0.5% absolute difference in event 
frequency and more frequently in the enzalutamide arm than the placebo arm 
included: spinal cord compression (6.0% vs. 3.8%), bone pain (1.5% vs. 1.0%), 
metastatic pain (1.5% vs. 0.8%), pathological fracture (1.5% vs. 0.5%), urinary tract 
infection (0.9% vs. 0.3%), and cauda equina syndrome (0.8% vs. 0.0%). 
 
Seizure is a known potential toxicity of enzalutamide. In vitro studies have shown 
that enzalutamide and its metabolite M2 bind to the GABA-gated chloride channel 
with IC50 values of 1.2 μg/mL and 3.3 μg/mL, respectively and in a cell-based 
assay inhibit the channel’s activity with IC50 values of 1.4 μg/mL and 1.07 μg/mL, 
respectively. Some compounds that inhibit the GABA-gated chloride channel are 
associated with seizures17. 
 
In the first clinical study of enzalutamide (S-3100-1-01), a dose-escalation study in 
men with castration-resistant prostate cancer with and without prior exposure to 
chemotherapy, the following doses were evaluated: 30, 60, 150, 240, 360, 480 (as 
240 mg twice per day [BID]), and 600 (as 300 mg BID) mg/day. Three patients 
were reported to have dose-limiting toxicities of seizure, one each at doses of 360, 
480, and 600 mg/day. The results of this study led to the selection of the clinical 
dose of enzalutamide of 160 mg/day. 
 
As of the database cut-off date for the respective unblinded or open-label studies 
reported in the most current version of the Investigator’s Brochure, 7 patients out of 
a total of 1100 patients (0.6%) exposed to enzalutamide at a dose of 160 mg/day 
have reported a seizure during the enzalutamide treatment emergent adverse event 
reporting period. These include one patient each in studies 9785-CL-0007 and 9785-
CL-0321, and 5 patients in the CRPC2 study. Two additional patients were 
identified to have experienced adverse events that may have been seizures, including 


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one case reported by the Investigator as syncope (CRPC2) and the other reported as 
a transient ischemic attack with an abnormal electroencephalogram (CRPC-MDA-
1). As of the data cut-off date, treatment with enzalutamide at a daily dose of 160 mg 
is associated with a0.6-0.8% risk of seizure in men with late-stage castration-
resistant prostate cancer. 
 
Taking into account information from ongoing blinded studies and events occurring 
after the database cut-off date, the range for seizure risk is unchanged. No seizures 
have been reported in the blinded placebo-controlled Phase 3 study enzalutamide-
03 (PREVAIL) with over 1300 patients enrolled (randomized 1:1 to enzalutamide 
160 mg/day or placebo). One additional patient in the CRPC2 study has been 
reported to have had a seizure after the safety data cut-off date, and one additional 
patient in an ongoing blinded study (9785-CL-0222) has also reported a seizure. 
 
Please see the most current version of the Package Insert for additional details. 
 
1.5 
Rationale for Study Design  
 
Abiraterone, α 17-lyase inhibitor, has demonstrated activity in patients with 
metastatic castration resistant prostate cancer (CRPC) who have failed hormonal 
and currently available chemotherapeutic options; they have few remaining 
therapeutic alternatives. Enzalutamide is a novel, potent inhibitor of the androgen 
receptor that prolongs the survival of patients with far-advanced and treatment-
refractory prostate cancer. Both alterations in the steroid metabolism and the 
androgen receptor are implicated in the clinically observed resistance to castration.  
Taken together, these observations provide compelling rationale to combine 
optimum medical castration, inhibition of the androgen receptor, and altered 
androgen biosynthesis in patients at high risk for recurrence. 
   
 
This knowledge will build on our understanding of the effect of optimum androgen 
inhibition in the setting of newly diagnosed, high-risk prostate cancer.10-11, 16 The 
findings will lead to a framework that will allow us to personalize androgen 
signaling targeted therapy, by stage of progression, within individual patients and 
assure the safe use of the drug and the development of a rational combination 
therapy. 
 
Available evidence indicates that following abiraterone acetate treatment, 
progression is inevitable in patients with advanced prostate cancer despite the 
encouraging initial clinical observations.  Two mechanisms may be implicated in 
this progression. The first could be the presence of alternative androgen signaling, 
which results in further castrate resistant progression.  The other possibility could 
be the existence of alternative stromal-epithelial interacting pathways independent 
of androgen signaling, which could account for the observed resistance implicated 
above, resulting in androgen independent progression.  In order to develop a 
foundation for combination therapies, we would like to prioritize candidate 
pathways, which are implicated in progression of this disease, for further study.  We 


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believe this can be best achieved in the context of the informative pre-operative 
setting that is proposed in this trial. This study will determine the rate of down 
staging achieved, and changes in the steroid biosynthesis metabolome, androgen 
receptor and “driver signaling networks” with abiraterone acetate, prednisone, and 
LHRH, or abiraterone acetate, enzalutamide, prednisone with LHRH in high risk 
prostate cancers. 
 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
The primary objective of this study is: 
 To assess the difference in pathologic stage ≤ pT2 at prostatectomy between 
Group A (abiraterone acetate plus prednisone and androgen ablation [LHRHa] 
plus enzalutamide for 6 months) and Group B abiraterone acetate plus 
prednisone and androgen ablation [LHRHa] for 6 months).  
 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
 To assess and compare the changes in levels of androgens (pre, during, and 
post-treatment) in the serum and primary tumor microenvironment between 
Group A and Group B. 
 To assess changes in biomarkers related to androgen signaling and other cancer-
related pathways between Group A and Group B. 
 To assess the difference in rate of positive surgical margins between Group A 
and Group B. 
 To assess the safety profile of abiraterone acetate and low dose prednisone in 
combination with enzalutamide for six months in a preoperative setting. 
 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a study comparing the effect of abiraterone acetate (1,000 mg daily) plus 
prednisone (5mg once daily)  in combination with enzalutamide (160 mg daily) and 
LHRHa versus LHRHa and abiraterone acetate (1,000 mg daily) plus prednisone 
(5mg once daily) for six months on pathologic and molecular differences in patients 
with locally advanced prostate cancer. Patients will be randomized in a 2:1 ratio to 
Group A (abiraterone acetate plus prednisone and androgen ablation [LHRHa] plus 
enzalutamide) or Group B (androgen ablation [LHRHa] and abiraterone acetate plus 
prednisone), respectively. Patients will receive 6 months of LHRHa therapy on trial 
for a maximum of 7 months before a prostatectomy is performed (patients may 


Protocol 2013-0332 
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12 
enter the study with no more than one (1) month of LHRHa treatment prior to 
C1D1).  
 
3.1.1  Endpoints 
 
Primary Endpoint: 
 Proportion of patients with pathologic stage ≤pT2 at prostatectomy. 
 
Secondary Endpoints: 
 Differences in androgen signaling (e.g., Testosterone, DHT) in the serum and 
primary tumor microenvironment (pre, during, and post treatment) between 
Group A and Group B. 
 Related androgen metabolites (e.g., Testosterone, DHT) in the serum and 
primary tumor microenvironment (pre, during, and post treatment) between 
Group A and Group B. 
 Proportion of positive surgical margins rate in Group A and Group B. 
 Proportion of patients with PSA ≤ 0.2 ng/mL in Group A and Group B. 
 Proportion of patients who achieve pathological CR or near pathological CR 
(<5% occupancy) at prostatectomy. 
 
Exploratory Endpoints:   
Molecular effects of treatment will be assessed in the tumor microenvironment in 
both Group A and Group B. Effects on the tumor epithelium, angiogenesis, and the 
broader tumor microenvironment will also be assessed. 
 Assessment of androgen signaling components in tumor in the radical 
prostatectomy specimens (rps), open or robotic, and biopsy specimens in Group 
A and Group B. This will include, but not be limited to, androgen receptor (AR) 
expression by immunohistochemistry, AR copy number determination by 
quantified polymerase chain reaction, and CYP17 expression assessment by 
immunohistochemistry. 
 Assessment of cell proliferation and apoptosis in the tumor epithelium in rps 
and biopsy specimens in Group A and Group B. 
 Assessment of markers of neuroendocrine differentiation in the tumor 
epithelium in rps and biopsy specimens. These will include but may not be 
limited to chromogranin synaptophysin and CD56. 
 Assessment of other molecular pathways of interest in the tumor 
microenvironment as follows: 
o Stromal epithelial pathways of interest will be assessed in tumor in the rps 
and biopsy specimens in Group A and Group B. These will include but not 
be limited Hh signaling components and Src signaling components. 
o Markers of angiogenesis will include, but not be limited to CD31, VEGF,  
VEGFR 
 
Biomarkers, including those described above and in Section 12.4, will be assessed 
by immunohistochemistry in available formalin fixed paraffin embedded tissue. 


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13 
Tissue microarrays (TMAs) will be constructed from rps while biopsies will be 
either individually processed or used to construct TMAs depending on the 
availability of tissue  
 
 Assessment of the steroid hormone metabolome in blood plasma and tissue by 
liquid chromatography tandem mass spectrometry. These will include, but not 
be limited to, testosterone, dihydrotestosterone, androstenedione, and 
pregnenolone. 
 
3.2 
Study Duration and Dates 
The study period will consist of Screening, Treatment, and Follow-up visit. In this 
study, patients will be randomized to receive either abiraterone acetate plus 
prednisone with LHRHa and enzalutamide (Group A) or LHRHa and abiraterone 
acetate plus prednisone (Group B) for 6 months (24 weeks) followed by a radical 
prostatectomy (open or Robotic Assisted Laparoscopic).  The follow-up visit after 
the radical prostatectomy will occur 4 to 8 weeks post-surgery. 
 
Treatment following prostatectomy will be determined by the current practice 
guidelines and individualized to patient needs. Each cycle of treatment will be 28 
days with a ± 4 day window. 
 
 
4 
Study Population Selection 
Approximately 66 patients with pre-operative locally advanced adenocarcinoma of the 
prostate will be enrolled at study site(s). 
4.1 
Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1.  Be willing/able to adhere to the prohibitions and restrictions specified in this 
protocol.  
2. Have signed an informed consent document indicating that the subjects 
understand the purpose of and procedures required for the study and are willing 
to participate in the study. 
3.  Written Authorization for Use and Release of Health and Research Study 
Information has been obtained. 
4.  Male age ≥18 years. 
5.  Histologically or cytologically confirmed adenocarcinoma of the prostate with 
no histological variants (such as small cell, sarcomatoid, pure ductal cancer, 
transitional cell carcinoma). 
6.  Pathology review at treating academic institution or member institution (Note: if 
patient’s prostate biopsy was not read at the treating institution, it must be 
reviewed at the study site to confirm eligibility). 


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14 
7.  At least three core biopsies involved with cancer (a minimum of 6 core biopsies 
must be obtained at baseline). A prostate biopsy within 3 months from screening 
is allowed for entry requirements. Patients must have a Gleason score > 5 
(total). 
8.  At least one of the following features: 
•  PSA >10 ng/ml 
•  PSA velocity >2 ng/ml/year (defined as a rise in PSA of >2 ng/ml in the 
preceding 12 month period)  
•    Gleason score ≥7 
•    Gleason score 6 if either PSA ≥ 10 ng/ml or PSA velocity ≥2 ng/ml/year 
9.   Serum testosterone >200 ng/dL. For patients treated with up to 1 month of 
LHRH agonist, a testosterone measurement prior to the LHRH treatment will be 
used to determine eligibility, and must have been > 200 ng/dL. 
10. Urologist must agree that patient is suitable for prostatectomy. 
11. No evidence of metastatic disease as determined by imaging procedures. 
12. Eastern Cooperative Oncology Group (ECOG) Performance Status of 
0 or 1. 
13. Hemoglobin ≥10.0 g/dL independent of transfusion. 
14. Platelet count ≥100,000/µL. 
15. Patients should have adequate bone marrow function defined as an absolute 
peripheral neutrophil count (ANC) >1,500. 
16. Creatinine clearance ≥60 mL/min  
17. Serum potassium ≥3.5 mmol/L. 
18. Serum albumin ≥3.5 g/dL. 
19. Liver function test with serum bilirubin ≤ 1.5x ULN and ALT and AST ≤ 1.5x 
ULN. 
20. Able to swallow the study drug whole as a tablet. 
21. Patients must have normal coagulation profile and no history of 
substantial non- iatrogenic bleeding diathesis. 
22. Agree to use a double-barrier method of contraception which involves the use of 
a condom in combination with one of the following: contraceptive sponge, 
diaphragm, or cervical ring with spermicidal gel or foam, if having sex with a 
woman of child-bearing potential during the length of the study and for one 
week after abiraterone is discontinued and for at least three months after 
enzalutamide is discontinued. 
23. 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 of 
abiraterone acetate is taken. 
 
4.2 
Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from the study. 
1.   Serious or uncontrolled co-existent non-malignant disease, including 
active and uncontrolled infection. 


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15 
2.   Chronically uncontrolled hypertension, defined conventionally as consistent 
systolic pressures above 140 or diastolic pressures above 90 despite anti-
hypertensive therapy. Note that this is NOT a criterion related to particular BP 
results at the time of assessment for eligibility, nor does it apply to acute BP 
excursions that are related to iatrogenic causes, acute pain or other transient, 
reversible causes.  
3. Requirement for corticosteroids greater than the equivalent of 5 mg of 
prednisone daily. 
4.   Poorly controlled diabetes defined by Hemoglobin A1C > 7.0 at screening 
5.   Active or symptomatic viral hepatitis or chronic liver disease. 
6.   History of pituitary or adrenal dysfunction. 
7.  Clinically significant cardiovascular disease including: 
 Myocardial infarction within 6 months of Screening visit; 
 Uncontrolled angina within 3 months of Screening visit; 
 Congestive heart failure New York Heart Association (NYHA) class 3 or 4, 
or subjects with history of congestive heart failure NYHA class 3 or 4 in the 
past, or history of anthracycline or anthracenedione (mitoxantrone) treatment, 
unless a screening echocardiogram or multi-gated acquisition scan (MUGA) 
performed within three months of the Screening visit results in a left 
ventricular ejection fraction that is ≥ 50%. 
 History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsade de pointes). 
 Prolonged corrected QT interval by the Fridericia correction formula (QTcF) 
on the screening Electrocardiogram (ECG) > 470 msec. 
 History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place. 
 Hypotension (systolic blood pressure < 86 mmHg or bradycardia with a 
heart rate of <50 beats per minute on the Screening ECG., unless 
pharmaceutically induced and thus reversible (i.e. beta blockers). 
8.   Other malignancy, except non-melanoma skin cancer, that is active or has a ≥ 
30% probability of recurrence within 12 months. 
9.  History of gastrointestinal disorders (medical disorders or extensive surgery) 
which may interfere with the absorption of the study drug. 
10. Prior hormone therapy for prostate cancer including orchiectomy, 
antiandrogens, ketoconazole, or estrogens (5-α reductase inhibitors allowed), or 
LHRH agonists/antagonists (*Note: LHRH allowed if begun within 1 month of 
Day 1). Patients having previous or current antiandrogen treatment of greater 
than 4 weeks in duration prior to Cycle 1 Day 1 are eligible with appropriate 
washout. 
11. Prior systemic treatment with an azole drug within four weeks of Cycle 1 Day1. 
12. Current enrollment in an investigational drug or device study or participation 
in such a study within 30 days of Cycle 1 Day 1. 
13. Allergies, hypersensitivity, or intolerance to prednisone, LHRH analog or 
excipients of prednisone LHRH analog, abiraterone acetate and enzalutamide. 


Protocol 2013-0332 
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16 
14. Previous use of abiraterone acetate or other investigational CYP17 inhibitor 
(e.g., TAK-700). 
15. Previous investigational antiandrogens (e.g., Enzalutamide, BMS-641988). 
16. Patients receiving anti-coagulant therapy who are unable to stop prior to 
surgery. 
17. Condition or situation which, in the investigator’s opinion, may put the 
patient at significant risk, may confound the study results, or may 
interfere significantly with patient’s participation in the study. 
18. Severely compromised immunological state, including being positive for 
the human immunodeficiency virus (HIV). 
19. Patients with co-existent medical diseases and competing potential causes of 
death (such as but not limited to, unstable angina, myocardial infarction within 
the previous 6 months, or use of ongoing maintenance therapy for life-
threatening ventricular arrhythmia, uncontrolled hypertension). 
20. Prior chemotherapy, radiation or immune therapy for prostate cancer. 
21. Patients unable to tolerate transrectal ultrasound. 
22. Concomitant therapy with any of the following 
 Chemotherapeutic, biologic, or other agents with anti-tumor activity against 
prostate cancer other than assigned study drug. 
 Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, 
flutamide, nilutamide, bicalutamide, etc. other than assigned study drug. 
 5-α reductase inhibitors such as finasteride, dutasteride, anabolic steroids, etc. 
 Estrogens, progestational agents such as megestrol, medroxyprogesterone, 
DES, cyproterone, spironolactone > 50 mg/kg, etc. 
 Androgens such as testosterone, dehydroepiandrosterone [DHEA], etc. 
 Ketoconazole. 
 Herbal products that may decrease PSA levels (e.g., saw palmetto). 
23. Active infection or other medical condition that would make prednisone/ 
prednisolone (corticosteroid) use contraindicated. 
24. Severe hepatic impairment (Child-Pugh Class C). 
25. History of seizure or any condition that may predispose to seizure 
including, but not limited to underlying brain injury, stroke, primary brain 
tumors, brain metastases, or alcoholism. Also, history of loss of 
consciousness or transient ischemic attack within 12 months of 
enrollment (Day 1 visit). 
26. History of significant bleeding disorder unrelated to cancer, including: 
 Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease). 
 Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-
factor VIII antibodies) of Screening visit. 
 History of GI bleeding within 6 months of Screening visit. 
 
 
 
 
 


Protocol 2013-0332 
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17 
5 
Study Treatment(s) 
 
5.1 
Description of Treatments(s)  
 
 
 
5.1.1    Abiraterone Acetate 
 
Abiraterone acetate is designated chemically as (3β)- 17-(3-pyridinyl)androsta-
5,16-dien-3-yl acetate. It is a white to off-white, non-hygroscopic, crystalline 
powder, its molecular formula is C26H33NO2 and it has a molecular weight of 
391.55. Abiraterone acetate is a lipophilic compound with an octanol-water 
partition coefficient of 5.12 (Log P) and is practically insoluble in water. 
 
Abiraterone acetate 250 mg tablets are white to off-white, oval-shaped tablets 
debossed with AA250 on one side and provided in bottles with child-resistant 
induction seal closure. 
 
5.1.2    Enzalutamide 
 
Enzalutamide has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-
dimethyl-4-oxo-2-thioxoimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. It is a 
white to off-white solid that is insoluble in water and no salt forms are available at 
~pH 2 to 10. 
 
Enzalutamide capsules are white to off-white oblong capsules, printed with 
“MDV” in black ink. The soft gelatin capsules are filled with a clear, yellowish 
solution which contains the two antioxidants, butylated hydroxyanisole, and 
butylated hydroxytoluene , and enzalutamide active ingredient (40 mg), all 
dissolved in the non-ionic surfactant, Labrasol® (Caprylocaproyl 
Polyoxylglycerides). Enzalutamide capsules are provided in white, opaque, high-
density polyethylene (HDPE) bottles with child-resistant induction seal closure. 
 
5.1.3    Prednisone 
 
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both 
naturally occurring and synthetic, which are readily absorbed from the 
gastrointestinal tract. The molecular formula for prednisone is C21H26O5. 
Chemically, it is 17, 21-dihydroxypregna-1, 4- diene-3, 11, 20-trione. Prednisone is a 
white to practically white, odorless, crystalline powder and has a molecular weight 
of 358.44. It melts at about 230°C with some decomposition. Prednisone is very 
slightly soluble in water, slightly soluble in alcohol, chloroform, dioxane, and 
methanol. 
 
Prednisone inactive ingredients are: anhydrous lactose, colloidal silicon dioxide, 
magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and talc. 
 


Protocol 2013-0332 
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18 
Prednisone 5 mg tablets are white round-shaped tablets and provided in bottles 
with child- resistant induction seal closure. 
 
5.2      Packaging and Labeling 
 
Abiraterone acetate tablets will be provided packaged in individual bottles for 
patient assignment at the time of randomization. Patients will be provided with a 
60-day supply to allow for visits to occur every 8 weeks. 
 
Information presented on the labels for investigational product will comply with 
applicable local regulations. 
 
Site pharmacist or medically qualified staff will dispense the study treatment to 
each patient in accordance with this protocol. 
 
Enzalutamide used in this study will be labeled and supplied to the study 
subjects through the site designated pharmacy. 
 
Site pharmacist or medically qualified staff will dispense the study treatment to 
each subject in accordance with this protocol. 
 
5.3      Study Drug Handling 
 
Current ICH GCP Guidelines require the investigator to ensure that study drug 
deliveries are received by a responsible person (e.g. pharmacist), and 
 
 that such deliveries are recorded 
 that study drug is handled and stored safely and properly, and should explain the 
correct use/handling of the investigational product to each subject. 
 that study drug is only dispensed to study subjects in accordance with the 
protocol that any unused study drug is returned or standard procedures for the 
alternative disposition of unused study drug are followed. 
 
Drug inventory and accountability records for the study drugs will be kept by the 
investigator/ pharmacist.  Study drug accountability throughout the study must be 
documented.  The following guidelines are therefore pertinent: 
 
 The investigator agrees not to supply study drugs to any persons except the 
subjects is this study. 
 The investigator/pharmacist will keep the study drugs in a pharmacy or other 
locked and secure storage facility under controlled storage conditions, 
accessible only to those authorized by the investigator to dispense these test 
drugs. 


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19 
 A study drug inventory will be maintained by the investigator/pharmacist. The 
inventory will include details of material received and a clear record of when 
they were dispensed and to which subject. 
 At the conclusion or termination of this study, the investigator/pharmacist 
agrees to conduct a final drug supply inventory and to record the results of this 
inventory on the Drug Accountability Record. It must be possible to reconcile 
delivery records with those of used and returned medication. Any discrepancies 
must be accounted for. Appropriate forms of deliveries and returns must be 
signed by the person responsible. 
 Returned or expired study drug will be destroyed on site per MDACC 
Investigational Pharmacy policies.  
 
Enzalutamide will be provided by Medivation and will be stored and handled 
according to the manufacturer specifications and the pharmacy standards of 
operation. 
 
Abiraterone Acetate will be provided by Janssen Scientific Affairs, LLC and will 
be stored and handled according to the manufacturer specifications and the 
pharmacy standards of operation. 
 
 
6 
Treatments Administered 
6.1      Dosing and Administration of Study Drugs and Other Medications 
 
6.1.1    Dose/Dose Regimen and Administration Period 
 
Abiraterone acetate: Subjects will be instructed to take 4 tablets (250 mg each) 
orally once daily at least 1 hour before a meal or 2 hours after a meal and should be 
swallowed whole with water. Tablets may not be crushed or chewed. 
 
Prednisone: Subjects will be instructed to take 5-mg oral prednisone, once daily.  
 
Enzalutamide: Subjects will be instructed to take 4 capsules (40 mg each) per day 
orally. Enzalutamide may be taken with or without food. Enzalutamide should be 
taken as close to the same time each day as possible. 
6.1.2 Reduction in Dose or Discontinuation of the Study Drugs 
 
In subjects who experience toxicity who cannot be ameliorated by the use of adequate 
medical intervention, dose reductions can be performed. In these cases dose 
reductions of abiraterone acetate should be performed first, followed by reduction in 
enzalutamide doses (if needed). 
 


Protocol 2013-0332 
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20 
For abiraterone acetate, 2 dose reductions are allowed, though dosing may be 
interrupted without a dose reduction. Patients who experience a Grade 3 or greater 
toxicity considered to be related to abiraterone acetate will be dose reduced per the 
following schema.  At each dose reduction, one tablet of abiraterone acetate will be 
removed, e.g., 4→3 tablets, and 3→2 tablets. Any return to protocol dose level after 
dose reduction or after treatment interruption must follow documentation of adverse 
event resolution and a discussion with the Principal Investigator. Dosing with 
abiraterone may be held for up to 2 weeks without discontinuation from therapy. 
 
Patients who experience a Grade 3 or greater toxicity considered to be related to 
enzalutamide that cannot be ameliorated by the use of adequate medical intervention 
should have their treatment interrupted until the toxicity improves to a Grade 2 or 
lower severity. Patients may subsequently be re-started on study drug at a reduced 
dose as per the discretion of the Principal Investigator. Subjects will remain on 
abiraterone acetate and prednisone during enzalutamide dose interruption.  
 
No dose reductions for prednisone are allowed. Subjects experiencing toxicity 
considered to be related to the use of prednisone for which a dose reduction is needed 
will require discontinuation of study drugs. 
 
Subjects should be able to take all three study drugs (abiraterone acetate, 
enzalutamide, and prednisone) to participate in the study. An interruption of one of 
these drugs is allowed as per instruction above. Permanent discontinuation of one of 
the drugs, while continuing the two other drugs, is not allowed. 
6.1.3 Previous and Concomitant Medication (Drugs and Therapies) 
6.1.3.1 Previous Medication (Drugs and Therapies) 
 
Medication taken within four weeks prior to registration must be captured in the 
medical record.  
At each visit, all concomitant treatments, including blood and blood products, must 
be reported on the source documentation. Concomitant medications must also be 
documented at the time of discontinuation and at the 30 day follow-up visit. 
The dosage and regimen of the following medications and any chronic permitted 
concomitant medications should be stabilized for 4 weeks prior to Day 1 and held 
constant throughout the study: 
 Bisphosphonates 
 Denosumab 
 GnRH agonist/antagonist 
No other new systemic therapy or new radiotherapy for treatment of prostate cancer 
is permitted while subject is on study.  


Protocol 2013-0332 
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21 
 
 
The following medications are prohibited while the subject is on study drug:  
 Chemotherapeutic, biologic, or other agents with anti-tumor activity against 
prostate cancer other than assigned study drug. 
 Anti-androgens (steroidal or non-steroidal) such as cyproterone acetate, 
flutamide, nilutamide, bicalutamide, etc. other than assigned study drug. 
 5-α reductase inhibitors such as finasteride, dutasteride, anabolic steroids, etc. 
 Estrogens, progestational agents such as megestrol, medroxyprogesterone, DES, 
cyproterone, spironolactone > 50 mg/kg, etc. 
 Androgens such as testosterone, dehydroepiandrosterone [DHEA], etc. 
 Ketoconazole. 
 Herbal products that may decrease PSA levels (e.g., saw palmetto). 
Medications that inhibit platelet function and anticoagulants should be used with 
caution while the subject is on study drug: 
Src-family kinase inhibitors potentially reduce platelet aggregation. Caution should 
thus be exercised if subjects are required to take one of the following medications that 
inhibit platelet function or anticoagulants. 
 aspirin or aspirin-containing combinations. 
 clopidogrel, dipyridamole, tirofiban, dipyridamole, epoprostenol, eptifibatide, 
cilostazol. 
 abciximab, ticlopidine, cilostazol warfarin. 
 heparin/low molecular weight heparin [eg, danaparoid, dalteparin, tinzaparin, 
enoxaparin]. 
 
Use of heparin for flushes of intravenous lines is allowed. 
 
Cytochrome P 450 inhibitors, Inducers, and Substrates  
It is currently unknown which CYP enzyme pathways are responsible for clearing 
enzalutamide. To limit the risk of unpredictable increases or decreases in circulating 
concentrations of enzalutamide, potent inhibitors or inducers should be taken with 
caution, and alternative products used when available. In vitro data suggest that 
enzalutamide may have the potential to induce CYP3A4 and inhibit CYP1A2, 
CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5; therefore, 
concomitant medications that are substrates of any of these enzymes should be used 
with caution, and relevant monitoring should be considered, especially for substrates 
known to cause seizure, because the possibility of drug-drug interactions cannot be 
fully excluded. To determine if a particular drug is a potent CYP inhibitor or inducer, 
the investigator should consult the product label.  
 
Drugs metabolized through the CYP2D6 and CYP1A2 pathways should be used with 
caution while participating in this study.  
 


Protocol 2013-0332 
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22 
In vitro studies showed that enzalutamide is an inhibitor of CYP2C8 and CYP2C19 
with lesser inhibitory effects on CYP2B6 and CYP2C9. Substrates of CYP2B6, 
CYP2C8, CYP2C9, and CYP2C19 that have a narrow therapeutic index (e.g., 
phenytoin, warfarin) should be used with caution.  
 
In vitro studies showed that enzalutamide may be an inducer of CYP3A4. Co-
administration of enzalutamide with CYP3A4/5 substrates may affect oral 
bioavailability and/or elimination of the CYP3A4/5 substrate. Substrates of 
CYP3A4/5 that have a narrow therapeutic index should be used with caution. Co-
administration of enzalutamide and Abiraterone may lower circulating levels of 
Abiraterone Acetate.  
 
In vitro studies showed that enzalutamide is metabolized by CYP2C8 and 
CYP3A4/5. Use caution when co-administering a strong CYP2C8 inhibitor (e.g., 
gemfibrozil) or strong CYP3A4/5 inhibitors (e.g., clarithromycin, itraconazole, 
ketoconazole, grapefruit juice) during enzalutamide treatment. 
 
Use caution when co-administering a CYP2C8 inducer (e.g., rifampin) or strong 
CYP3A4/5 inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s wort) 
during enzalutamide administration.  
 
Please refer to the following link for an up to date list of CYP inhibitors and inducers.  
http://medicine.iupui.edu/clinpharm/ddis/ 
 
Caution is advised when considering the concomitant use of medications known to 
lower the seizure threshold. These include but are not limited to: 
 Aminophylline/theophylline. 
 Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone). 
 Bupropion. 
 Lithium. 
 Pethidine. 
 Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine). 
 Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine). 
 
6.1.3.2 Effects of Abiraterone on Drug Metabolizing Enzymes 
 
Abiraterone acetate 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 was given with abiraterone acetate 1000 mg 
daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone 
acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., 
thioridazine). If alternative treatments cannot be used, exercise caution and consider 
a dose reduction of the concomitant CYP2D6 substrate drug. 


Protocol 2013-0332 
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23 
 
In vitro, abiraterone acetate was shown to inhibit the hepatic drug-metabolizing 
enzyme CYP2C8. There are no clinical data on the use of abiraterone acetate with 
drugs that are substrates of CYP2C8. 
 
Drugs that Inhibit or Induce CYP3A4 Enzymes 
Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. The effects of 
strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, 
atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, 
voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been 
evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of 
CYP3A4 during abiraterone acetate treatment. 
 
6.1.4 Treatment Compliance 
Study drug accountability will be performed to document compliance with the dosing 
regimen. Subjects will be asked to bring back all remaining study drug at each study 
visit for drug accountability.  
6.1.5 Emergency Procedures and Management of Overdose 
There is no specific antidote for an overdose of enzalutamide or abiraterone acetate. 
Patients who develop adverse reactions from a suspected overdose should receive 
appropriate symptomatic treatment.  
 
7 
STUDY PROCEDURES 
A signed, Institutional Review Board (IRB) approved, written informed consent must be 
obtained from patients before any study specific procedures or randomization can occur.  
Confirmation of the patient’s informed consent and the informed consent process must also 
be documented in the patient’s medical record. A copy of the fully signed informed consent 
should be given to the patient. The study period will consist of screening, treatment, 
prostatectomy and post-prostatectomy follow up. 
7.1 
Screening 
The following activities/procedures will be conducted during the screening period 
which may occur within 30 days prior to enrollment on the study: 
 Consent prior to study related activities 
 Medical history including prior prostate cancer therapies, Stage, and Gleason 
score at diagnosis 
 Demographics  
 Physical examination, weight, and height  


Protocol 2013-0332 
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24 
 12-lead ECG  
 Baseline MUGA scan or cardiac ECHO 
 Vital signs including upright blood pressure, heart rate, respiratory rate, and oral 
or aural body temperature  
 Assessment of ECOG Performance Status 
 Baseline Symptoms/Adverse Event evaluation 
 Laboratory tests: 
o CBC: WBC with differential count, RBC, hemoglobin, hematocrit, platelets. 
o Coagulation studies (PT/PTT, INR).  Note: patients receiving anticoagulants 
during the course of therapy should be monitored closely during the study. 
o Chemistry with electrolytes:  albumin, calcium, lactate dehydrogenase 
(LDH), sodium, potassium, chloride, magnesium, carbon dioxide, 
creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, total 
protein, glucose, total cholesterol, high density lipoprotein (HDL), low 
density lipoprotein (LDL), cholesterol and triglycerides. 
o HgbA1C 
o PSA: All PSAs must be drawn prior to the DRE and within 2 weeks prior to 
the start of the study.  
o Serum testosterone  
o Urinalysis 
o Optional Blood for Correlative Studies 
A total of 20ml peripheral blood will be drawn for correlative studies (see 
section 12) 
 
 Baseline tumor assessment:  
o At least three core biopsies positive for prostate cancer (a minimum of 6 
core biopsies must be obtained at baseline). Pre-treatment prostate tumor 
biopsy tissue from within 6 months from screening is allowed for entry 
requirements from paraffin blocks and will be analyzed for 
immunohistochemistry (IHC) testing 
 Bone Scan 
 CXR (PA/lateral) or chest CT 
 CT of the abdomen and pelvis or MRI of the pelvis (w/wo endorectal coil) 
 Concomitant medications listing: Obtain a listing of all prescription and 
nonprescription (over-the-counter) medications currently taken including pain 
medications.  This also includes any nutritional supplements and/or herbal 
preparations. 
Patients who are eligible will be randomized and start study treatment within 30 
days after eligibility is confirmed.   
Randomization may occur on the same day as study registration provided that all 
screening assessments have been completed and screening results are reviewed 
prior to randomization.  


Protocol 2013-0332 
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25 
 
7.2 
Treatment Period 
The following procedures should be carried out prior to study drug 
administration: 
7.2.1 Both Study Groups (Groups A and B) 
Cycle 1 Day 1 (If visit occurs within 7 days of screening visit, Cycle 1 Day 1 
procedures will not be repeated). 
 Physical Exam (includes monitoring of fluid retention) and weight 
 Record current signs and symptoms with associated NCI CTCAE V4.0 
grading (0-4) with any event that may have occurred since screening 
 Concomitant Medications listing 
 Vital signs including upright blood pressure, heart rate, respiratory rate, and 
oral or aural body temperature. Vital signs will be reviewed to monitor for 
hypertension. 
 Assessment of ECOG Performance Status 
 PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE. 
 Laboratory tests 
o CBC: WBC with differential, RBC, hemoglobin, hematocrit, platelets 
o Chemistry with electrolytes:  albumin, calcium, lactate dehydrogenase 
(LDH), sodium, potassium, chloride, magnesium, carbon dioxide, creatinine, 
BUN, AST, ALT, alkaline phosphatase, total bilirubin, total protein, glucose 
o Optional Blood for Correlative Studies (see section 12) 
 
Cycle 1 Day 15, Cycle 2 Day 15 and Cycle 3 Day 15 Procedures (± 3 days) 
 
Safety laboratory screening (Liver Function Tests: AST, ALT, LDH, ALKP and 
Total Bilirubin) 
 
Day 15 lab tests (Cycles 1, 2 and 3) may be done at a local laboratory or physician’s 
office. Results should be faxed to MDACC. 
 
7.2.2 Treatment Period (Both Groups) 
 
Cycles 2-6 Day 1 Procedures (± 3 days) 
 Physical Exam (includes monitoring of fluid retention) and weight 
 Concomitant Medications listing 
 Vital signs including upright blood pressure, heart rate, respiratory rate, and oral 
or aural body temperature. Vital signs will be reviewed to monitor for 
hypertension. 
 AE evaluation and recording 


Protocol 2013-0332 
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26 
 Assessment of ECOG Performance Status 
 Laboratory tests 
o Chemistry with electrolytes: albumin, calcium, lactate dehydrogenase 
(LDH), sodium, potassium, chloride, magnesium, carbon dioxide, 
creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, total 
protein, and glucose 
o PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE 
o Cycle 3 only: Blood for Correlative Studies (see section 12.1) 
 
Testing on Cycles 2, 4, and 6 may be done at a local physician’s office. Results 
should be faxed to MDACC. 
 
7.2.3 Pre-surgery Visit and End of Treatment Visit (Patients in ALL Study 
Groups) 
 
The following procedures and evaluations must be performed within 1 to 14 days 
prior to surgery: 
 Complete physical examination (includes monitoring of fluid retention) 
 Vital signs including upright blood pressure, heart rate, respiratory rate, and oral 
or aural body temperature 
 Assessment of ECOG performance status 
 CXR (PA/lateral) or chest CT 
 12-lead ECG 
 Concomitant Medications listing 
 AE evaluation and recording 
 Laboratory tests 
o CBC: WBC with differential, RBC, hemoglobin, hematocrit, platelets 
o Chemistry with electrolytes: albumin, calcium, lactate dehydrogenase 
(LDH), sodium, potassium, chloride, magnesium, carbon dioxide, 
creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, total 
protein, fasting glucose , total cholesterol, high density lipoprotein (HDL), 
low density lipoprotein (LDL), cholesterol and triglycerides 
o Urinalysis 
o HgbA1C 
o Coagulation tests (PT/PTT) 
o PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE. 
o Blood for Correlative Studies (see section 12.1) 
 
7.2.4 Surgery 
 Tissue from the prostatectomy will be collected for Correlative Studies (see 
section 12.2) 


Protocol 2013-0332 
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27 
 
7.3. 
Assessment of Radical Prostatectomy Specimen 
7.3.1. 
Extent of Operation 
All patients will have a planned prostatectomy. 
7.3.2 
Timing of Prostatectomy 
The surgery will be planned at the end of Cycle 6. Patients must be off therapy no 
less than 48 hours prior to surgery. To permit flexibility in surgical scheduling a 
study window of a maximum of four weeks will be allowed. In the event the 
surgery is delayed, the patient will be required to return to the clinic for safety 
assessment.  
 
Surgery will be performed only after recovery from any side effects from 
abiraterone acetate or enzalutamide to a level considered safe for surgery. In the 
event of delayed recovery, the patient will be maintained on LHRHa until the 
clinical condition permits surgery. 
 
7.3.3 Criteria for Completion of Surgery 
Grossly enlarged and clinically unresectable appearing lymph node disease will be 
assessed by frozen section.  If under such circumstances viable cancer is detected, 
or if distant intra-abdominal metastases are encountered, surgery will be abandoned.  
Routine frozen section analysis will not be performed on patient in whom the 
visible lymph node enlargement is within the planned operative field or in patients 
without clinically detectable lymph node enlargement. 
7.3.4 Assessment of Surgical Complications 
It will be the responsibility of the attending surgeon to accurately tabulate 
complications and the progress of the surgical procedure.  Specifically tabulated 
will be the duration of anesthesia, blood product requirement, and fluid requirement 
of the gross description of the operative field (presence for absence of desmoplasia).   
 
7.4 
Post-Treatment Follow-up Period 
Once a patient has undergone a radical prostatectomy and has completed the study 
treatment, the 4 to 8 weeks post-surgery follow-up visit will be performed as 
described below. 
 
 
 
 


Protocol 2013-0332 
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28 
7.4.1 Therapy Following Prostatectomy 
 
Treatment following prostatectomy will be determined by the current practice 
guidelines and individualized to patient’s needs. 
 If the cancer extends to the surgical margins the patient may be considered for 
adjuvant radiation therapy with the same criteria and following consent of the 
patient. 
 In the event of detectable metastatic disease, the optimal therapy at recurrence 
will be recommended. 
7.4.2 Post-Radical Prostatectomy Evaluation 
 
Note: These procedures and assessments will be collected at the follow-up visit 
which will occur 4 to 8 weeks post-surgery. 
o Complete physical examination 
o Vital signs including upright blood pressure, heart rate, respiratory rate, and oral 
or aural body temperature 
o Assessment of ECOG performance status 
o Concomitant Medications listing 
o AE evaluation and recording 
o Laboratory tests 
o CBC: WBC with differential, RBC, hemoglobin, hematocrit, platelets 
o Chemistry with electrolytes: albumin, calcium, lactate dehydrogenase 
(LDH), sodium, potassium, chloride, magnesium, carbon dioxide, 
creatinine, BUN, AST, ALT, alkaline phosphatase, total bilirubin, total 
protein, glucose 
o HgbA1C 
o PSA 
o Serum testosterone 
o Blood for Correlative Studies (see section 12.1)  
 
 
7.5 
Study Calendar 
 
 
  
Screening 
C1D1c 
C1 
Day 
15 
D1 of 
C2-C6 
C2-3 
Day 15 
Pre-Surgery 
Visit/End of 
Treatment 
Surgeryf 
4 to 8 weeks 
post-surgery 
Medical History 
xa 
  
 
  
  
  
 
  
Physical Exam 
xa 
x  
 
x 
 x 
 
x 
Vital Signs 
xa 
x  
 
x 
 x 
 
x 
Weight 
xa 
 x 
 
x 
  
 
Height 
xa 
  
 
 
  
  
 
  
ECOG PS 
xa 
 x 
 
x 
 x 
 
x 
CBC/ diff. and plt. 
xa 
 x 
 
  
x 
 
x 


Protocol 2013-0332 
August 11, 2015 
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29 
Serum Chemistry 
xa,b 
xb 
xd 
xb  
xd 
xb 
 
xb 
PT/PTT 
xa 
  
 
  
  
x 
 
  
PSA 
xa 
 x 
 
 x 
 x 
 
x 
HGB A1C 
xa 
 
 
 
 
x 
 
x 
Serum Testosterone 
xa 
 
 
 
 
 
 
x 
Urinalysis 
xa 
  
 
  
x  
 
  
CT Scan Abd/ CT 
Scan or MRI Pelvis 
xa 
  
 
  
  
  
 
  
Chest X-ray or CT 
Chest 
xa 
  
 
  
  
x 
 
  
MUGA or ECHO 
Xa 
  
 
  
  
 
  
ECG 
Xa 
  
 
  
  
x 
 
  
Bone Scan 
Xa 
  
 
  
  
 
  
Monitor Adverse 
Events 
 
<-------------------------------------------------------------------------------> 
Concomitant 
Medications 
 
<-------------------------------------------------------------------------------> 
Blood for 
Correlative Studies 
xa 
x  
 
x        
(cycles 3 
only) 
 
x 
 
 xe 
Tissue for 
Correlative Studies 
 
 
 
 
 
 
x 
 
Archived Tissue for 
Correlative Studies 
x 
  
 
  
  
  
 
  
 
 
a. Within 30 days of registration 
 
 
b. Serum Chemistry with electrolytes:  albumin, calcium, lactate dehydrogenase (LDH), sodium, 
potassium, chloride, magnesium, carbon dioxide, creatinine, BUN, AST, ALT, alkaline 
phosphatase, total bilirubin, total protein, and glucose. At screening and the pre-surgery visit, the 
following will also be done: total cholesterol, high density lipoprotein (HDL), low density 
lipoprotein (LDL), cholesterol and triglycerides. 
 
 
c. If visit occurs within 7 days of screening visit, C1D1 procedures will not be repeated. 
d. Liver Function Tests ONLY: AST, ALT, LDH, ALKP and Total Bilirubin. These LFTs may be 
done at a local physician’s office. Results should be faxed to MDACC. 
 
 
e.  testosterone only 
f.  study medication will be continued up to 48 hrs prior to surgery 
 
 
8 
Adverse Events and Other Safety Aspects 
 
8.1  
Safety Assessments and Reporting Requirements  
 
All patients 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 to the investigator by patients. 
An adverse event is any untoward or unfavorable medical occurrence in a human 
subject, including any abnormal sign (for example, abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the subject’s 
participation in the research. All adverse events encountered after the patient has 
provided informed consent and until 4 weeks after the patient has stopped treatment 


Protocol 2013-0332 
August 11, 2015 
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30 
will be evaluated according to the NCI Common Toxicity Criteria (CTCAE) 
version 4.0. Prior treatment associated toxicities present at the time of informed 
consent but before study treatment initiation, will be recorded as baseline 
abnormalities and graded according to CTCAE version 4.0 criteria.  
 
 
8.1.1  
Definitions 
 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not related to 
the medicinal product. 
 
Adverse Events of Special Interest  
Events that Janssen Scientific Affairs, LLC is actively monitoring as a result of a 
previously identified signal (even if non-serious), and are typically defined in the 
Protocol. 
  
Adverse Drug Reaction (ADR) 
A noxious and unintended response to any dose of the drug (or biological) product 
for which there is a reasonable possibility that the product cause the response.  
‘‘Reasonable possibility’’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. Suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse 
event caused by a drug. 
 
J&J Medicinal Product 
The specific J&J drug under study and any other J&J medicinal product. 
 
Product Quality Complaint (PQC) 
Any discrete concern that questions the identity, quality, durability, reliability, 
safety, efficacy or intended performance of a drug product. 
A complaint may allege an injury or malfunction associated with the use of the drug 
product. It may also involve the design, literature, packaging, advertising, 
availability, physical appearance or promotion of the drug product. 
 
Serious Adverse Event (SAE) 
A serious adverse event is – any adverse drug experience occurring at any dose that 
results in any of the following outcomes:  
•  Death  
•  A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from 
the adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death.  


Protocol 2013-0332 
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31 
•  Inpatient hospitalization or prolongation of existing hospitalization  
•  A persistent or significant disability/incapacity – a substantial disruption of a 
person’s ability to conduct normal life functions.  
•  A congenital anomaly/birth defect.  
•  A suspected transmission of infectious agents by a medicinal product 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse (21 CFR 312.32).  
 
Events not considered to be serious adverse events are hospitalizations for the 
purposes of this protocol and include:  
 
• 
Routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.  
• 
Treatment, which was elective or pre-planned, for a pre-existing condition that 
did not worsen  
• 
Treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of serious given above and not resulting in hospital admission.  
• 
Symptoms related to progressive disease such as bone pain will not be reported 
as toxicity or serious adverse events  
 
Serious Adverse Events will be reported immediately to the MD Anderson IRB per 
the IRB policy for reporting adverse events. 
 
Special Reporting Situations  
When a report contains a J&J product, an identifiable patient, and identifiable 
reporter, the following events represent Special Reporting Situations: 
 overdose of a Johnson & Johnson medicinal product  
 pregnancy exposure (maternal and paternal) 
 exposure to a medicinal product from breastfeeding  
 suspected abuse/misuse of a medicinal Johnson & Johnson product 
 inadvertent or accidental exposure to a medicinal Johnson & Johnson product  
 any failure of expected pharmacological action (i.e., lack of effect) of a Johnson 
& Johnson medicinal product 
 unexpected therapeutic or clinical benefit from use of a Johnson & Johnson 
medicinal product 
 medication error involving a Johnson & Johnson product (with or without 
patient exposure to the medicinal Johnson & Johnson product, e.g., name 
confusion) 


Protocol 2013-0332 
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32 
 suspected transmission of any infectious agent via a medicinal product. 
 
8.2  
Site Reporting Obligation to Janssen Scientific Affairs, LLC 
 
All serious adverse events (regardless of relationship or expectedness) will be 
reported and documented on the Johnson & Johnson SAE form and forwarded 
directly to Janssen Scientific Affairs, LLC within 24 hours of becoming aware of 
the event(s). 
 
All non-serious AEs should be reported according to the timeframe outlined by MD 
Anderson policies. 
 
8.2.1 Management of Adverse Events, Serious Adverse Events and Special 
Reporting Situations 
 
In general, the INSTITUTION/PRINCIPAL INVESTIGATOR must immediately 
report to Janssen Scientific Affairs, LLC any serious adverse event and Special 
Reporting Situations, whether or not considered drug related. Study endpoints that 
are serious adverse events (e.g., all-cause mortality) must be reported in accordance 
with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g., death as a result of anaphylactic reaction or fatal 
hepatic necrosis). In that case, the investigator must immediately report the event to 
Janssen Scientific Affairs, LLC. The INSTITUTION/PRINCIPAL 
INVESTIGATOR must record non-serious adverse events and report them to 
Janssen Scientific Affairs, LLC according to the timetable for reporting as specified 
either in the protocol or to fulfill regulatory reporting requirements. 
 
For each subject, AEs SAEs, and Special Reporting Situations should be recorded 
after informed consent is obtained until the subject has completed participation in 
the study as follows: 
 
A Serious Adverse event or Special Reporting Situations must be reported if it 
occurs during a subject’s participation in the Study (whether receiving Study 
Product or not) and within 30 days of receiving the last dose of Study Product. 
 
Any serious adverse event or Special Reporting Situations that is ongoing when a 
subject completes his/her participation in the Study must be followed until any of 
the following occurs: 
 the event resolves or stabilizes; 
 the event returns to baseline condition or value (if a baseline value is available); 
 the event can be attributed to agents(s) other than the Study Product, or to 
factors unrelated to Study conduct. 
 
8.2.2 Recording of Adverse Events, Serious Adverse Events and Special 
Reporting Situations 


Protocol 2013-0332 
August 11, 2015 
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33 
 
Recording should be done in a concise manner using standard, acceptable medical 
terms. 
 
The adverse event recorded should not be a procedure or a clinical measurement 
(i.e. a laboratory value or vital sign) but should reflect the reason for the procedure 
or the diagnosis based on the abnormal measurement. 
 
Preexisting conditions that worsen in severity or frequency during the Study should 
also be recorded (a preexisting condition that does not worsen is not an adverse 
event). 
 
Further, a procedure or surgery is not an adverse event; rather, the event leading to 
the procedure or surgery is considered an adverse event. Any event requiring in-
patient hospitalization that occurs during the course of a subject’s participation in a 
trial must be reported as an SAE. Hospitalizations that do not meet the criteria for 
SAE reporting are: 
 
 Reasons described in the Protocol, e.g. drug administration, Protocol-required 
testing 
 Surgery or procedure planned prior to entry into the Study. 
 
If, in the PRINCIPAL INVESTIGATOR’s judgment, a clinical significant 
worsening from baseline is observed in any laboratory or other test parameter (e.g. 
electrocardiogram (ECG), angiogram), physical exam finding, or vital sign, a 
corresponding clinical adverse event should be recorded. 
 
If a specific medical diagnosis has been made, that diagnosis or syndrome should be 
recorded as the adverse event, whenever possible.  However, a complete description 
of the signs, symptoms and investigations which led to the diagnosis should be 
provided. For example, if clinically significant elevations of liver function tests are 
known to be secondary to hepatitis, “hepatitis” and not “elevated liver function 
tests” should be recorded. If the cause is not known, the abnormal test or finding 
should be recorded as an adverse event, using appropriate medical terminology (e/g/ 
thrombocytopenia, peripheral edema, QT prolongation). 
 
8.2.3 Maintenance of Safety Information 
 
Safety information will be maintained in a clinical database/repository in a 
retrievable format. At a minimum, at the end of the treatment phase (=”last patient 
off treatment”) as well as the end of the follow-up phase (=”last patient out”) of the 
Study, the INSTITUTION/PRINCIPAL INVESTIGATOR shall provide all adverse 
events, both serious and non-serious, in report format. However, in certain 
circumstances more frequent review of the safety data may be necessary, e/g/ to 
fulfill a regulatory request, and as such the data shall be made available within a 
reasonable timeframe at Janssen Scientific Affairs, LLC’s request. 


Protocol 2013-0332 
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34 
 
8.2.4 Transmission Methods 
 
The following methods are acceptable for transmission of safety information to 
Janssen Scientific Affairs, LLC: 
 
 Facsimile (fax- 1-866-451-0371), receipt of which is evidences in a successful 
fax transmission report, 
 Electronically subject to strict compliance with the following condition: 
Reporting may be done electronically only upon written approval by Janssen 
Scientific Affairs, LLC, which approval must acknowledge that the electronic 
transmission is in an acceptable encrypted email format. Without such 
acknowledgement, the approval to use an electronic transmission shall not be 
valid. The Parties hereby acknowledge the importance of strict precautions with 
the use of electronic transmission for the security, protection and maintenance 
of confidentiality of patient health information contained in the reports, or 
 Telephone (for business continuity purposes, if fax or authorized electronic 
system is non-functional). 
 
Please use the contact information and process information provided by Janssen 
Scientific Affairs, LLC 
 
8.2.5 Procedures for Reporting Adverse Events (AE), Serious Adverse Events 
(SAE), Special Reporting Situation, and Product Quality Complaints (PQCs) 
to Janssen Scientific Affairs, LLC 
 
8.2.5.1 Serious Adverse Events (SAE), Adverse Events of Special Interest, 
and Special Reporting Situations 
 
In clinical trials involving the Study Product regardless of whether causality with 
the administration of the Study Product is suspected by the PRINCIPAL 
INVESTIGATOR.  
 
The INSTITUTION/PRINCIPAL INVESTIGATOR will transmit these reports in a 
form to be provided (or a form substantially similar to the form provided and 
approved for use by Janssen Scientific Affairs, LLC in writing) in accordance with 
Section VII Transmission methods, in English within 24 hours of becoming aware 
of the event(s) along with their determination of whether the event was caused by a 
J&J product. 
 
All available clinical information relevant to the evaluation of an SAE, Adverse 
Events of Special Interest, and Special Reporting Situations including pregnancy 
reports (with or without an AE) including paternal exposure are required. 
 


Protocol 2013-0332 
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35 
 The INSTITUTION and/ or PRINCIPAL INVESTIGATOR is responsible for 
ensuring that these cases from clinical studies are complete and if not are 
promptly followed-up. This includes ensuring the reports are fully investigated 
and thoroughly documented by the PRINCIPAL INVESTIAGTOR and that 
follow-up information is summarized e.g. hospital records, coroner’s reports, 
autopsy results and recorded on the appropriate forms. 
 A study case is not considered complete until all clinical details needed to 
interpret the case are received and the event has resolved, or otherwise 
explained, or the patient is lost to follow-up. 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 Study Drug in the course of the Study, by facsimile within 
24 hours of such report or correspondence being sent to applicable health 
authorities. 
 
8.2.5.2 Product Quality Complaints 
 
Any PQC, with or without an AE, (including reports of suspicion of counterfeiting, 
diversion, or tampering, and suspected transmission of pathogens) will be 
transmitted by the INSTITUTION and the PRINCIPAL INVESTIGATOR in the 
form provided by Janssen Scientific Affairs, LLC in accordance with Section VII 
Transmission methods, in English, within 24 hours of becoming aware of the 
event(s). 
 
8.2.5.3 Reconciliation of SAEs 
 
At a minimum, on a quarterly basis and at the end of the Study, Janssen Scientific 
Affairs, LLC will provide to the INSTITUTION and/or PRINCIPAL 
INVESTIGATOR, a listing of all SAEs reported to Janssen Scientific Affairs, LLC.  
PRINCIPAL INVESTIGATOR will review this listing and provide any 
discrepancies to the Janssen Scientific Affairs, LLC. 
 
Upon request, INSTITUTION and PRINCIPAL INVESTIGATOR shall provide 
Janssen Scientific Affairs, LLC with a summary list of all SAEs, and AEs of 
Special Interest and Special Reporting Situation reports to date, for reconciliation 
purposes. 
 
8.2.5.4 Dissemination of Safety Information from Janssen Scientific Affairs, 
LLC to INSTITUTION/PRINCIPAL INVESTIGATORS 
 
Janssen Scientific Affairs, LLC will provide to the  INSTITUTION/PRINCIPAL 
INVESTIGATOR IND safety reports/SUSAR (Serious Unexpected Suspect 
Adverse Reaction) reports generated by the Janssen Scientific Affairs, LLC for the 
Study Product as they become available until all subjects in the Protocol have 


Protocol 2013-0332 
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36 
completed their last Study visit according to the Protocol  (i.e. Last Subject Last 
Visit has occurred). 
 
 
8.3  
Site Reporting Obligation to Medivation 
 
In the case of a serious adverse event (SAE) for a patient receiving enzalutamide, 
the investigator must contact the delegated CRO by telephone or fax immediately 
(within 24 hours of awareness).The investigator should complete and submit an 
SAE Worksheet containing all information that is required by the Regulatory 
Authorities to the delegated CRO by fax immediately (within 24 hours of 
awareness). Please fax the SAE form to: 
 
 
 
 
 
 
 
Full details of the SAE should also be recorded on the medical records. 
 
The following minimum information is required: 
 ISN/Study number 
 Subject number, sex and age 
 The date of report 
 A description of the SAE (event, seriousness of the event) 
 Causal relationship to the study drug 
 
Collection of all SAEs must continue for 30 days after the last administration of the 
investigational product.  
 
 
8.4 
Abnormal Laboratory Results 
 
The criteria for determining whether an abnormal laboratory test result should be 
reported as an adverse event are as follows: 
 
1.  Test result is associated with accompanying symptoms, and/or 
2.  Test result requires additional diagnostic testing or medical/surgical 
intervention (merely repeating an abnormal test, in the absence of any of the 
above conditions, does not meet criteria for reporting and an AE), and/or 
3.  Test result leads to a change in study dosing or death from the study, 
significant additional concomitant drug treatment or other therapy, and/or 
4.  Test result leads to any of the outcomes included in the definition of a serious 
adverse event, and/or 


Protocol 2013-0332 
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37 
5. Test result is considered to be an adverse event by the investigator 
 
Any abnormal test result that is determined to be an error does not require 
reporting as an adverse event, even if it did meet one of the above conditions 
except for condition #4. Clinically significant laboratory results must be recorded 
in the patient’s CRF. 
 
9 
Dose Modification/Toxicity Management 
 
9.1 
Abiraterone Acetate  
If a patient experiences ≥ Grade 3 adverse events (AE) that are, in the opinion of 
the investigator, possibly related to the study drug, treatment will be withheld until 
the toxicity resolves to within NCI CTCAE grade 1 criteria or normal limits.  After 
resolution of a grade 3 adverse event, the patient may be retreated at full dose of 
therapy.  Recurrence of the same toxicity (grade 3) will require dose reduction as 
outlined below.  
 
If dose-reduction is used for AE management, 2 dose reductions are allowed. At 
each dose reduction, one tablet of abiraterone acetate will be removed, i.e., 4→3 
tablets, and 3→2 tablets. If abiraterone acetate is held, prednisone therapy should 
continue uninterrupted. Any return to protocol dose level must follow 
documentation of AE resolution. 
 
Management of Study Drug-Related Events 
 
The most common adverse drug reactions (≥ 10%) reported in the two randomized 
clinical trials that occurred more commonly (> 2%) in the abiraterone acetate arm 
were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, 
cough, hypertension, dyspnea, urinary tract infection and contusion. 
 
The most common laboratory abnormalities (> 20%) reported in the two 
randomized clinical trials that occurred more commonly (≥ 2%) in the abiraterone 
acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, 
lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, 
hypophosphatemia, elevated ALT and hypokalemia. 
  
If abiraterone acetate is held, prednisone should be continued if the patient is 
expected to resume abiraterone acetate after resolution of the precipitating cause of 
the interruption in therapy. 
 
Fluid Retention 
 
Monitor for symptoms of fluid retention at least monthly. 
 


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38 
Hypertension 
 
Control hypertension before and during treatment with abiraterone acetate.  Monitor 
blood pressure at least monthly. 
 
Adrenocortical insufficiency 
 
Use caution and monitor for symptoms and signs of adrenocortical insufficiency, 
particularly if patients are withdrawn from prednisone, have prednisone dose 
reductions, or experience unusual stress.  Symptoms and signs of adrenocortical 
insufficiency may be masked by adverse reactions associated with 
mineralocorticoid excess seen in patients treated with abiraterone acetate.  If 
clinically indicated, perform appropriate tests to confirm the diagnosis of 
adrenocortical insufficiency.  Increased dosage of corticosteroids may be indicated 
before, during and after stressful situations. 
 
Management of Hypokalemia 
 
Correct hypokalemia before and during treatment with abiraterone acetate.  Monitor 
serum potassium at least monthly. 
 
At the initial observation of Grade 1 hypokalemia (serum potassium < 3.5 mM or 
below lower limit of normal range, but ≥ 3.0 mM), oral potassium supplement will 
be initiated. The dose of potassium supplement must be carefully titrated to 
maintain serum potassium at ≥ 3.5 mM but ≤ 5.0 mM. Any patient with low 
potassium while on study or a history of hypokalemia from a pre-existing or 
concurrent medical condition will undergo weekly or more frequent laboratory 
electrolyte evaluation. The investigator should consider maintaining the patient’s 
potassium level at ≥ 4.0 mM in these patients. 
 
If any patient experiences Grade 3 hypokalemia (serum potassium levels < 3.0 mM 
– 2.5mM, NCI CTCAE v4.0) or life-threatening hypokalemia with potassium levels 
< 2.5 mM (NCI CTCAE v4.0 hypokalemia Grade 4), abiraterone acetate treatment 
will be withheld, and the patient hospitalized for intravenous potassium replacement 
and cardiac monitoring. 
 
Re-initiation of abiraterone acetate treatment after normalization of potassium 
levels must be discussed with the PI. No dose reduction is required when 
abiraterone acetate is resumed after hypokalemia. 
 
Management of Hepatic Impairment 
 
For subjects with baseline hepatic impairment or those that develop hepatoxicity, 
please refer to mandatory dose modification guidelines below.  
 


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In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce 
the recommended dose of abiraterone acetate to 250 mg once daily.   A once daily 
dose of 250 mg in patients with moderate hepatic impairment is predicted to result 
in an area under the concentration curve (AUC) similar to the AUC seen in patients 
with normal hepatic function receiving 1,000 mg once daily. However, there are no 
clinical data at the dose of 250 mg once daily in patients with moderate hepatic 
impairment and caution is advised. In patients with moderate hepatic impairment 
monitor ALT, AST, and bilirubin prior to the start of treatment, every week for the 
first month, every two weeks for the following two months of treatment and 
monthly thereafter. If elevations in ALT and/or AST greater than 5X upper limit of 
normal (ULN) or total bilirubin greater than 3X ULN occur in patients with 
baseline moderate  hepatic  impairment,  discontinue  abiraterone acetate  and  do  
not  re-treat  patients  with abiraterone acetate. 
 
Avoid abiraterone acetate in patients with baseline severe hepatic impairment 
(Child-Pugh Class C), as abiraterone acetate has not been studied in this population, 
and no dose adjustment can be predicted. 
 
Hepatotoxicity 
 
Serum transaminases (ALT and AST) and bilirubin levels should be measured prior 
to starting treatment with abiraterone acetate, every two weeks for the first three 
months of treatment and monthly thereafter.   Promptly measure serum total 
bilirubin, AST, and ALT, if clinical symptoms or signs suggestive of hepatotoxicity 
develop.  Elevations of AST, ALT, or bilirubin from the patient’s baseline should 
prompt more frequent monitoring.  
 
For patients who develop hepatotoxicity during treatment with abiraterone acetate 
(ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), 
interrupt treatment with abiraterone acetate. Treatment may be restarted at a 
reduced dose of 750 mg once daily following return of liver function tests to the 
patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total 
bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, 
monitor serum transaminases and bilirubin at a minimum of every two weeks for 
three months and monthly thereafter. 
 
If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be 
restarted at a reduced dose of 500 mg once daily following return of liver function 
tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN 
and total bilirubin less than or equal to 1.5X ULN. 
 
If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue 
treatment with abiraterone acetate. The safety of abiraterone acetate re-treatment of 
patients who develop AST or ALT greater than or equal to 20X ULN and/or 
bilirubin greater than or equal to 10X ULN is unknown. 
 


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40 
Drug/Drug Interaction 
 
Per Section 1.3.1.2: Drug Interactions, Strong inducers of CYP3A4 (e.g., phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during treatment 
with ZYTIGA are to be avoided, or used with careful evaluation of clinical efficacy. 
Closely monitor clinical efficacy in patients taking strong inducers of CYP3A4. 
 
9.2  
Enzalutamide 
 
Subjects who experience a Grade 3 or greater toxicity considered to be related to 
enzalutamide that cannot be ameliorated by the use of adequate medical 
intervention should have their treatment interrupted until the toxicity improves to a 
Grade 2 or lower severity. Subjects may subsequently be re-started on study drug at 
a reduced dose follow a discussion between the Principal Investigator. Subjects will 
remain on abiraterone acetate and prednisone during enzalutamide dose 
interruption. 
 
No dose reductions for prednisone are allowed. Subjects experiencing toxicity 
considered to be related to the use of prednisone for which a dose reduction is 
needed cannot participate in the study any longer. 
 
9.3 
General 
 
Subjects should be able to take all three study drugs (abiraterone acetate, 
enzalutamide, and prednisone) to participate in the study. An interruption of one of 
these drugs is allowed as per instruction above. Permanent discontinuation of one of 
the drugs, while continuing the two other drugs, is not allowed. 
 
 
10   Criteria for Discontinuation of Study Treatment 
 
To discontinue Study Treatment, either of the criteria below must be met: 
 
 The patient completed 6 months of study treatment; 
 Sustained side effects: patients who have sustained toxicities, such as hyperglycemia 
or hypertension  that  do  not  return  to  NCI  CTCAE  (version  4.0)  grade  1  or  less  
with appropriate medical management, should be discontinued from the study treatment 
phase. All end-of-study treatment procedures should be conducted.  The patient will be 
followed to the EOS visit; 
 Dosing noncompliance:   study treatment administration and dosing compliance will 
be assessed on D a y  1  o f  a l l  c y c l e s , and at Pre-surgery/End of Study Visit.   
A count of study treatment will be conducted during this visit and patient dosing 
compliance will be assessed.  If dosing compliance is not >75% in the absence of 
toxicity, patient should be re-instructed   regarding   proper   dosing   procedures and   
continue   in the protocol. Subsequent dosing compliance procedure will be 
conducted at each study visit.   If a patient misses 14 or more doses within 4 weeks, 


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41 
the patient should be discontinued from the study treatment phase.   All end-of-study 
treatment procedures should be followed. The patient will be followed to the EOS visit; 
 Initiation  of  new  anticancer  treatment:  patients  will  be  discontinued  from  the  
study treatment  when  investigator,  in  his  or  her  judgment,  determines  new  
treatment  for prostate cancer is warranted.  All end-of-study treatment procedures 
should be conducted and the patient will be followed to the EOS Visit; 
 Administration of prohibited medications:  the patient will be discontinued from the 
protocol treatment when prohibited drug is administered (Section 6.1.3.1).  All end-
of-study treatment procedures should be conducted and the patient will be followed 
to the EOS visit.   Supportive care medications are permitted with their use following 
institutional guidelines.     The  concurrent  administration  of  other   anticancer   
therapy,  including cytotoxic,  hormonal  (except  LHRHa),  or  immunotherapy  is  
prohibited  during  study treatment phase.  Use of other investigational drug therapy 
for any reason is prohibited; 
 Patient met Grade 4 criteria for elevated Liver Function Tests or the criteria for 
dose discontinuation of non-mineralocorticoid based side-effects. 
 Subjects experiencing toxicity considered to be related to the use of prednisone for 
which a dose reduction is needed will require discontinuation of study drugs. 
 
10.1 
Withdrawal from Study 
 
An investigator may withdraw a patient from the study at any time based on clinical 
judgment or if a patient withdraws consent. In this event, the reason(s) for 
withdrawal must be documented and clarification if withdrawal of consent includes 
Post-Radical Prostatectomy Evaluation data collection. A patient’s decision to take 
part in the study is voluntary and he may choose not to take part in the study or to 
stop taking part at any time. If he chooses not to take part or to stop at any time, it 
will not affect his future medical care or medical benefits. A patient may withdraw 
from study treatment phase for any reason. In general, subjects who withdraw will 
not be replaced unless the number of completed subjects falls below the 
estimated sample size required to provide the desired precision. 
 
 
11 
Planned Statistical Methods 
 
11.1  General Considerations 
All statistical analyses will be performed using SAS®.  Unless otherwise  
specified,  all continuous endpoints will be summarized using descriptive 
statistics, which will include the number of patients (n), mean, standard 
deviation, median, minimum, and maximum.   All categorical endpoints will be 
summarized using frequencies and percentages.  The baseline measurement will 
be the last value on or before the date of first study treatment. 
 
11.2   Determination of Sample Size 
 


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42 
A total of approximately 66 patients will be randomized in a ratio of 2:1 to 
Group A (approximately 44 patients) and Group B (approximately 22 patients), 
respectively.   This sample size will have 80% power to detect the difference of 
proportions of <pT2 disease between Group A (proportion of 0.8) versus Group 
B (proportion of 0.5), using a two-sided Chi-squared test at a significance level 
of 0.1.  All patients randomized to the study will be considered for the summary 
of baseline characteristics.    Patients who have undergone prostatectomy will be 
evaluable for the primary endpoint, pT2.   In general, subjects who withdraw 
will not be replaced unless the number of completed subjects falls below the 
estimated sample size required to provide the desired precision. Patients who drop 
out of the study or are withdrawn prior to the evaluation of the primary endpoint 
will be counted as failures in the primary efficacy analysis.  
 
11.3   Analysis Population 
 
All patients randomized into the study will be included in the analysis of 
efficacy/biochemical related endpoints.  Patients who received any part of a study 
drug will be included in the analysis of safety (Safety Population). 
 
11.4   Demographics and Baseline Characteristics 
 
Demographic variables will include age, race, ethnicity, height, and weight.  
Baseline disease characteristics include time from diagnosis and other clinical 
characteristics (as documented in the CRF) will be provided in summary tables. 
 
11.5   Study Endpoints 
 
11.5.1 Primary Efficacy Endpoint 
 
The proportion of patients with ≤pT2 will be descriptively summarized and 
compared using Chi-squared test.  Other tests may be used if appropriate. 
 
11.5.2  Secondary Efficacy Endpoints 
 
The proportion of patients expressing differences in androgen signaling and 
related genes markers, the difference in the rate of positive surgical margins 
between the two groups, and proportion of patients with PSA≤0.2 ng/mL will be 
descriptively summarized. 
 
No interim analysis is planned. 
 
11.6   Safety Evaluations 
 
11.6.1  Summary of Safety Monitoring 
 


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43 
The safety monitoring will be based on a beta-binomial distribution 18. With 
prostatectomy alone, the historical probabilities of death and rectal injury in this 
patient group (based on about 60 patients) are 0.15 and 0.30, respectively. Denote 
the probabilities of death and rectal injury within a given treatment group by pH,D 
and pH,R for historical data, and pE,D and pE,R for the experimental data. Group 
A will be terminated early if either Pr[pH, D<pE, D | data] > 0.95 or Pr[pH, R < 
pE, R | data] > 0.95. The prior of pH, D is beta (9, 51) and theprior of pH, R is beta 
(18, 42); the prior of pE, D and pE, R is beta(1,1). Applying these rules and starting 
from the 4th patient, Group A will be terminated if [# deaths]/[# patients 
evaluated]> 2/4, 3/5-8, 4/9-12, 5/13-15, 6/16-19, 7/20-23, 8/24-27, 9/28-32 or 
10/33-36, 11/37-40, or 12/41-43; or [#patients with a rectal injury]/[# patients 
evaluated] > 3/4, 4/5-6, 5/7-8, 6/9-10, 7/11-13, 8/14-15, 9/16-17, 10/18-20, 11/21-
22, 12/23-24, 13/25-27, 14/28-29, 15/30-32, 16/33-34, 17/35-36, 18/37-39, 19/40-
41, or 20/42-43.  Tables 1 and 2 below demonstrate the operating characteristics 
for the Bayesian monitoring rules for death and rectal injury, respectively. If 
complications from LHRH agonist, abiraterone acetate, or enzalutamide delay 
prostatectomy by greater than 3 months, the study enrollment will be temporarily 
held for safety analysis.  
 
Table 1. Operating characteristics of the Bayesian monitoring rule for death.  
 
True death rate 
Early stopping 
probability 
Average 
sample size 
0.10 
0.083 
40.9 
0.15 
0.218 
36.4 
0.20 
0.431 
29.9 
0.30 
0.851 
16.4 
0.40 
0.988 
8.7 
 
Table 2. Operating characteristics of the Bayesian monitoring rule for rectal injury.  
 
True death rate 
Early stopping 
probability 
Average 
sample size 
0.20 
0.041 
42.4 
0.30 
0.184 
37.7 
0.40 
0.528 
27.7 
0.50 
0.878 
16.1 
0.60 
0.991 
9.0 
 
MultcLeanDestop: Version 2.0 was used to generate the above design output, 
including the safety stopping boundaries and the operating characteristic tables.  
 
The theoretical definition for rectal injury is surgically induced perforation 
requiring a temporary colostomy.  
 


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44 
 
 
11.6.2 Safety Analysis 
 
Safety analysis will be summarized using the Safety Population.   AEs will be 
graded and summarized according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. 
  
Extent of exposure to study drug will be summarized and details will be 
provided. 
 
Treatment emergent adverse events (AEs) are those events that occur or worsen 
on or after first dose of study drug up through 30 days post last dose.   
 
Incidence of adverse events will be summarized by system organ class (SOC) 
and preferred term (PT), and will be presented for overall and by treatment period, 
as appropriate.  Adverse events will be summarized by grade.  In addition, most 
frequently observed adverse events will be summarized by treatment groups.  In 
the summary of AE, an AE occurs more than once within a SOC and PT will be 
counted only once using the worst grade experienced. 
 
Serious adverse events and deaths will be provided in a listing. All adverse 
events resulting in discontinuation, dose modification, dosing interruption, 
and/or treatment delay of study drug will also be listed and tabulated by preferred 
term. 
 
Clinical laboratory test results will be collected pretreatment and through 30 
days post last dose of study treatment.  All laboratory test results will be 
classified according to the NCI CTCAE 4.0 criteria.  Standard reference ranges 
will be used for missing or discrepant normal ranges.  Baseline laboratory test 
values are the results from the last blood samples drawn on or prior to the first 
day of study treatment.  On-study laboratory test values are those results from 
blood samples drawn after the first study treatment up until 30 days after the last 
dose of study treatment. 
 
Mean change from baseline in laboratory test values at each visit will be provided.  
On-study clinical laboratory test abnormalities will be summarized.  Shifts in 
laboratory test values will also be provided. 
 
 
12  Correlative Procedures (for exploratory endpoints)  
The specimens collected in the context of this protocol are blood and tissue. These will be 
stored in a manner that will allow us to address the secondary aims in this protocol. Any 
future additional analyses not specified in this protocol will be agreed upon by prior 


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45 
approval from Janssen Scientific Affairs, LLC.  All analyses will be performed after IRB 
approval for patients who have consented to the testing. 
 
All specimens will be prospectively encoded with de-linked numbers such that the 
receiving lab will not have access to patient identifiers. Investigators involved in this 
project will ensure confidentiality of patients by restricting access to the GU Research 
Laboratory database in which the unique identification numbers cross-referenced to the 
MDACC patient medical record number will be kept. Clinical information will be accessed 
by investigators using the institutional Web-based custom application Clinic Station, which 
stores clinical information and care reports of patients who are being treated at MDACC. 
Access to Clinic Station is restricted with a security password. Any individual patient's 
information will not be reused or disclosed to any other person or entity, or for other 
research. All requests for use of this material must be in the context of IRB approved 
protocols.  Unused samples will be destroyed 5 years after the last study visit. 
 
12.1  Steroid Metabolome and Proteonomics  
 
Steroid Metabolome and Proteonomics will be assayed in the Laboratory of Dr 
Mark Titus at MD Anderson using Agilent 6490 mass spectrometer. Peripheral 
Blood will be obtained at baseline (screening), on day one of cycles 1, 2 plus 3, pre-
prostatectomy and at post-prostatectomy visit. A total of  twenty (20) ml of blood 
will be collected in Serum No Additive (2 red top no additive tubes) for study 
hormone levels Peripheral blood will be collected into the vacutainer and allowed to 
clot (upright) at room temperature for 20 minutes prior to centrifugations. Samples 
are centrifuged at 4oC for 20 minutes at 1200xg. The serum is removed and 
aliquoted into multiple cryovials (minimum of three). All samples are processed 
and frozen within 2 hours of collection. The serum will stored frozen at -80OC in 
the GU biorepository located at MDACC until they are transported to the laboratory 
for analysis. Serum will be assayed for total testosterone, DHT, androstenedione, 
DHEA, DHEA-S, estradiol, progesterone, 3α-diol-G, steroid biosynthesis 
metabolome, and applied markers of minimal residual disease.  Post prostatectomy 
only serum testosterone, DHT, steroid biosynthesis metabolome, and applied 
markers of minimal residual disease will be measured.  
 
12.2  Prostate Tissue Handling  
12.2.1   Archival prostate biopsies 
 
An archival tumor tissue block (or at least 10 unstained slides from the tumor tissue 
block; archived or recent) or fresh frozen tissue in liquid nitrogen will be required 
from the patient’s initial prostate biopsy.  These will be reviewed by the pathologist 
for confirmation of cancer and Gleason scoring. The patient will not be required to 
undergo a second biopsy procedure prior to starting study therapy (screening) if 
archival biopsies are available.  
 
 


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46 
12.2.2  Prostatectomy specimen  
 
In order to preserve androgen levels in tissues, open intraoperative cores biopsies 
will be obtained prior to prostatectomy. The biopsies must be obtained prior to 
ligation of the vascular supply to the prostate. A minimum of 6 biopsies will be 
obtained attempting to focus on known regions of cancer. Each biopsy core should 
be placed in a separate 2 ml screwtop cryotube and immediately snap frozen in 
liquid nitrogen or dry ice/ethanol bath and stored at -80°C. If there is palpable 
tumor, it is recommended that at least 3 cores be obtained from the area of 
suspected tumor.  
 
To process the radical prostatectomy specimen post-operatively, the following 
procedures must be followed.  
 The prostate will be inked in four colors depicting left, right, superior and 
inferior sections and serially sectioned.  
 Alternate coronal sections will be numbered sequentially from apex to base, 
divided into 4 quadrants (also labeled clockwise from the superoposterior 
quadrant as A, B, C, D) and immediately frozen in OCT (liquid nitrogen or 
dry ice/ethanol bath) for subsequent evaluation. The alternate sections will be 
placed in formalin, then processed and imbedded in paraffin using the tissue-
tek®vip® 6 system (for histology analysis) and stored in the Prostate Tissue 
Bank at MDACC for future analysis. The coronal sections embedded in OCT 
will be stored, in the GU biorepository located at MDACC, for future 
analysis. Any future additional analyses not specified in this protocol will be 
agreed upon by prior approval from Janssen Scientific Affairs, LLC.  
 
12.3  Tissue Androgen Measurements  
 
Prostate tumor and normal prostate tissue will be obtained by macrodissection when 
possible. Testosterone and DHT will be analyzed by a research laboratory at MD 
Anderson. 
 
12.4  Immunohistochemistry  
 
Standard methods will be used to assess prostate tumor for AR, CYP17, CD31, VEGF, 
VEGFR, and other relevant biomarkers plus proteins associated with steroid 
metabolism and prostate cancer. 
 
Comprehensive  characterization of the process of known and candidate  pathways  
implicated  in PCa progression  and  resistance to therapy:  cellular PTEN,P53, Rb : 
stromal  epithelial  pathways  : Src, Phos  CMet ,Hedgehog, VEEGFR2   
 
 
 
 


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47 
12.5 
RNA Analysis 
 
Transcriptomic characterization of the tumor will be conducted in the Laboratory of 
Dr Mark Titus at MD Anderson. Where available, analysis will be carried out 
on the pre-prostatectomy specimens and prostatectomy specimens using fresh frozen 
tissue (section 12.3) for primary tumor, normal tissue and metastatic tissue.  RNA 
Analysis will include long non coding RNA (lnRNA) examples as per 
www.lncrnadb.org ; oncomir RNA; and micro RNA (miRNA) such as #205, 146, 1256 
and let7. 
 
 
13 
Reference List 
1.   Denis,L., Murphy,G.P., 1993. Overview of phase III trials on combined androgen treatment 
in patients with metastatic prostate cancer. Cancer 72, 3888-3895. 
 
2.   Labrie,F., Belanger,A., Simard,J., Van,L., Labrie,C., 1995. DHEA and peripheral androgen 
and estrogen formation: intracinology. Ann N Y Acad Sci 774, 16-28. 
 
3.   Abbas,F., Scardino,P.T., 1996. Why neoadjuvant androgen deprivation prior to radical  
prostatectomy is unnecessary. Urol Clin North Am 23, 587-604. 
 
4.   Goldenberg,S.L., Klotz,L.H., Srigley,J., Jewett,M.A., Mador,D., Fradet,Y., Barkin,J., 
Chin,J., Paquin,J.M., Bullock,M.J., Laplante,S., 1996. Randomized, prospective, controlled 
study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the 
treatment of localized prostate cancer. Canadian Urologic Oncology Group. J Urol 156, 
873-877. 
 
5.   Soloway,M.S., Sharifi,R., Wajsman,Z., McLeod,D., Wood,D.P., Jr., Puras-Baez,A., 1995. 
Randomized prospective study comparing radical prostatectomy alone versus radical 
prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate 
cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol154, 424-428. 
 
6.   Witjes,W.P., Schulman,C.C., Debruyne,F.M., 1997. Preliminary results of a prospective 
randomized study comparing radical prostatectomy versus radical prostatectomy associated 
with neoadjuvant hormonal combination therapy in T2-3 N0 M0 prostatic carcinoma. The 
European Study Group on Neoadjuvant Treatment of Prostate Cancer. Urology 49, 65-69. 
 
7.   Ryan,C., Rosenberg,J., Lin,A., Small,E., 2007. Phase I evaluation of abiraterone acetate 
(CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate 
cancer (AiPCa). ASCO Annual Meeting Proceedings. ASCO Annual Meeting J Clin Oncol 
25 Abstract 278. 
 
8.   Attard,G., Reid,A., Yap,T., Raynaud,F., Dowsett,M., Settatree,S., 2008. Phase I, 
pharmacokinetic and pharmacodynamic, first-in-human continuous oral dosing study of 


Protocol 2013-0332 
August 11, 2015 
Page 48 
 
48 
abiraterone acetate, a specific and irreversible CYP17 inhibitor, in patients with castration-
resistant prostate cancer. J Clin Oncol In Press. 
 
9.  Efstathiou E, Titus M, Tsavachidou D, Vassiliki Tzelepi, Wen S, Hoang A, et al. Effects of 
Abiraterone Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone. J Clin 
Oncol 2011. 
 
10. Eleni Efstathiou, John W. Davis, Patricia Troncoso, Mark Anton Titus, Anh Hoang, Sijin 
Wen, Amado J. Zurita, Namphuong Tran, Arturo Molina, Christopher Logothetis: 
Cytoreduction and androgen signaling modulation by abiraterone acetate (AA) plus 
leuprolide acetate (LHRHa) versus LHRHa in localized high-risk prostate cancer (PCa): 
Preliminary results of a randomized preoperative study. J Clin Oncol 30, 2012 (suppl; abstr 
4556). 
 
11. Mary-Ellen Taplin, Robert B. Montgomery, Christopher Logothetis, Glenn J. Bubley, 
Jerome P. Richie, Bruce L. Dalkin, Martin G. Sanda, Massimo F. Loda, Lawrence D. True, 
Patricia Troncoso, Elizabeth M. Genega, Steven P. Balk, Peter Nelson, Wanling Xie, 
Christopher M. Haqq, Namphuong Tran, Cameron S. Liu, Thian San Kheoh, Arturo 
Molina, Philip Kantoff: Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide 
acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in 
localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. J 
Clin Oncol 30, 2012 (suppl; abstr 4521). 
 
 
12. Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumor 
activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 
2010; 375: 1437–46. 
 
13. D'Amico,A.V., Whittington,R., Malkowicz,S.B., Wu,Y.H., Chen,M., Art,M., 
Tomaszewski,J.E., Wein,A., 2000. Combination of the preoperative PSA level, biopsy 
gleason score, percentage of positive biopsies, and MRI T-stage to predict early PSA 
failure in men with clinically localized prostate cancer. Urology 55, 572-577. 
 
14. Stephenson,A.J., Scardino,P.T., Eastham,J.A., Bianco,F.J., Jr., Dotan,Z.A., DiBlasio,C.J., 
Reuther,A., Klein,E.A., Kattan,M.W., 2005. Postoperative nomogram predicting the 10- 
year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol 23, 
7005-7012. 
 
15. Loblaw,D.A., Mendelson,D.S., Talcott,J.A., Virgo,K.S., Somerfield,M.R., Ben-Josef,E., 
Middleton,R., Porterfield,H., Sharp,S.A., Smith,T.J., Taplin,M.E., Vogelzang,N.J., 
Wade,J.L., Jr., Bennett,C.L., Scher,H.I., 2004. American Society of Clinical Oncology 
recommendations for the initial hormonal management of androgen-sensitive metastatic, 
recurrent, or progressive prostate cancer. J Clin Oncol 22, 2927-2941. 
 
16. Efstathiou E, Logothetis CJ. A New Therapy Paradigm for Prostate Cancer Founded on 
Clinical Observations. Clin Cancer Res 2010; 16(4):1100-1107. 


Protocol 2013-0332 
August 11, 2015 
Page 49 
 
49 
 
17. Barrie,S.E., Potter,G.A., Goddard,P.M., Haynes,B.P., Dowsett,M., Jarman,M., 1994. 
Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alpha- 
hydroxylase/C17-20 lyase). J Steroid Biochem Mol Biol 50, 267-273. 
 
18. Thall,P.F., Simon,R.M., Estey,E.H., 1995. Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med 14, 357-379