Conditions: Adenocarcinoma of the Prostate Recurrent Prostate Cancer Stage IV Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 71
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies if enzalutamide added to standard luteinizing hormone-releasing hormone (LHRH) analogue therapy will improve effects against prostate cancer compared to the standard therapy of LHRH analogue and bicalutamide. Hormone therapies stop the body from producing or block the effect of male sex hormones (testosterone). Enzalutamide blocks the effect of male sex hormones which are responsible for the growth of prostate cancer. Hormonal therapies that lower the level of testosterone are among the most effective treatments for prostate cancer that have spread to other areas of the body (metastasized). It is not yet known whether LHRH analogue therapy with bicalutamide is more effective than LHRH analogue therapy with enzalutamide in treating prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the rates of achieving prostate-specific antigen (PSA) remission at month 7 with LHRH analogue therapy and enzalutamide (Arm A) with that achieved with LHRH analogue and bicalutamide (Arm B) in metastatic hormone sensitive prostate cancer.

SECONDARY OBJECTIVES:

I. To compare the primary endpoint by race. II. To compare the rates of each of 2 types of response by treatment arm: measurable disease response; and PSA response.

III. To compare each of 7 time-to-event endpoints by treatment arm: duration of overall response (RD); duration of stable disease (SDD); time to treatment failure (TTF); time-to-progression (TTP); TTP in patients with bone metastases; progression-free survival (PFS); and overall survival (OS).

IV. To compare the rates of each type of toxicity by treatment arm. V. To compare the incidence rate of skeletal related events (SRE), and the time until SRE, separately by treatment arm.

VI. To compare the rates of circulating tumor cell (CTC) response by treatment arm.

VIII. To explore the molecular mechanisms within the androgen receptor pathway by determining the levels of chemokine (C-X-C motif) receptor 4 (CXCR4) and transmembrane protease, serine 2 (TMPRSS2)-v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) expression, androgen metabolism enzymes; androgen receptor variants, and length of cytosine-adenine-guanine (CAG) repeats within the androgen receptor gene, and to associate them with the primary endpoint.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive enzalutamide orally (PO) once daily (QD) and undergo orchiectomy or receive LHRH analogue therapy (leuprolide acetate, goserelin acetate, or any other Food and Drug Administration \[FDA\] approved preparation). Treatment continues in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive bicalutamide PO QD and undergo orchiectomy or receive LHRH analogue therapy as in Arm A. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Arms:
arm 1: Patients receive enzalutamide orally PO QD and undergo orchiectomy or receive LHRH analogue therapy (leuprolide acetate, goserelin acetate, or any other FDA approved preparation). Treatment continues in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive bicalutamide PO QD and undergo orchiectomy or receive LHRH analogue therapy as in Arm A. Treatment continues in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: enzalutamide intervention 2: bicalutamide intervention 3: orchiectomy intervention 4: leuprolide acetate intervention 5: goserelin acetate intervention 6: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Undergo orchiectomy or receive LHRH analogue therapy intervention 4: Undergo orchiectomy or receive LHRH analogue therapy intervention 5: Undergo orchiectomy or receive LHRH analogue therapy intervention 6: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
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Protocol version 7/1/2013, 9/25/2013, 1/16/2014, 5/15/2014, 6/27/2014, 6/5/2015, 02/17/2017, 7/1/2018, 2/20/2020, 
03/20/20  
  
Karmanos Cancer Institute (KCI) Protocol # 2013-083  
Version: July 1, 2013, Sept 25 2013, Jan 16, 2014, May15, 2014, June 27, 2014, June 5, 2015, 
February 17, 2017, July 1, 2018, Feb 20, 2020, March 20,2020  
    
Title:  Randomized Phase II screening trial of enzalutamide/MDV-3100 and LHRH 
analogue vs combined androgen deprivation (LHRH analogue + bicalutamide) in 
metastatic hormone sensitive prostate cancer  
  
  
Principal Investigator:   
Elisabeth Heath, MD.  
 
  
  
  
4 Hudson-Webber Cancer Research Center  
  
  
  
4100 John R Road   
 
 
  
Detroit MI 48201.  
 
  
  
  
Tel # 313-576-8735  
 
  
  
  
Fax # 313-576-8767  
 
  
  
  
E mail: heathe@karmanos.org  
  
Co-Investigators:                
Frank Cackowski, MD  
                                                4100 John R Road  
                                                Detroit, MI 48201  
                                                Tel# 313-576-8321  
                                                 Fax # 313-576- 8766  
                                                 Email:  cackowskif@karmanos.org  
  
 
Biostatistician :  
  
 
 
Lance Heilbrun, Ph.D.   
Biostatistics Core  
Mid Med Research Building, 3rd Floor  
87 East Canfield  
Detroit MI 48201.  
Tel# 313-576-8652  
E mail: heilbrun@karmanos.org  
Study Coordinator:   
 
Kimberlee Dobson                                          
Clinical Trials Office  
Mid Med Research Building, 5th Floor  
87 East Canfield  
  
  
  
  
Detroit MI 48201  
Tel #  313-576-9837  
E mail: dobsonk@karmanos.org  
Laboratory                   
Sreenivasa R. Chinni, Ph.D.  


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Co-Investigator:  
  
Departments of Urology, Oncology and Pathology, KCI,  
Wayne State University School of Medicine   
9245 Scott Hall,   
540 E Canfield Ave Detroit, MI  48201.  
Tel # 313-577-1833  
E mail: schinni@med.wayne.edu  
  
 
Pharmacodynamics/  
Correlatives   
  
Julie Boerner PhD  
Wayne State University/  
Barbara Ann Karmanos Cancer Institute 
Hudson-Webber Cancer Research Center,  
Correlative Sciences Lab Rm 808  
4100 John R. Street  
Detroit, Michigan 48201 
Tel.: 313-576-8351 (lab)  
Email: boernerj@med.wayne.edu  
  
Karri Stark  
Wayne State University/  
Barbara Ann Karmanos Cancer Institute  
Hudson-Webber Cancer Research Center,  
Correlative Sciences Lab Rm 808  
4100 John R. Street  
Detroit, Michigan 48201 
Tel.: 313-576-8248 (lab)  
Email: starkka@karmanos.org  
  
Susan Land PhD   
Applied Genomics Technology Center 
CS Mott Center Bldg.  
275 East Hancock St.  
Detroit MI 48201  
313-577-9605 (office phone)  
313-577-0024 (lab phone)  
E mail: Sland@med.Wayne.edu  
  
  
Grants and Contracts:  
Mary Jo O’Loughlin  
  
  
  
  
Karmanos Cancer Institute  
4100 John R MM00RA   
Detroit, MI 48201  
Tel # 313-578-4405  


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03/20/20  
Fax # 313-831-4039  
E mail: oloughli@karmanos.org   
  
  
Participating Sites:  
  
Henry Ford Hospital   
PI- Sheila Tejwani M.D.  
2799 W Grand Blvd  
Detroit, MI 48202   
(313) 916-2494 (Office)  
(313) 876-2494 (Fax)  
E mail stejwan1@hfhs.org  
  
Ohio State University   
PI- Paul Monk MD  
320 W 10th Ave Suite A433  
Columbus, OH 43210   
 Phone: (614) 366-7126   
Fax: (614) 293-7525   
E mail paul.monk@osumc.edu  
  
The Cancer Institute of New Jersey  PI- 
Mark Stein MD  
The Cancer Institute of New Jersey,   
195 Little Albany Street,   
New Brunswick, NJ 0890 Phone: 
(732) 235-6031  
Fax: (732) 235-7493  
Email: steinmn@umdnj.edu  
  
The University of Alabama at Birmingham  
PI- Dr Laxminarayanan NandagopalAssistant Professor of Medicine  
UAB Comprehensive Cancer center  
1720 2nd Ave. South  
Birmingham, AL 35294-3280  
Phone: 205-975-5715  
Fax:  205-934-9573  
Email: lnandagopal@uabmc.edu  
  
Mount Sinai School of Medicine PI- 
William K. Oh, M.D.  
Chief, Division of Hematology and Medical Oncology Professor of Medicine and Urology Ezra  
M. Greenspan, MD Professor in Clinical Cancer Therapeutics Icahn School of Medicine at  


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Mount Sinai Associate Director of Clinical Research The Tisch Cancer Institute  
New York, N.Y. 10029 
Phone: 212.659.5549 |  
fax 212.659.8539|   patient 
line 212.659.5429  
E Mail: william.oh@mssm.edu   
Title: Phase II randomized trial of enzalutamide/MDV-3100 and LHRH analogue vs 
combined androgen deprivation (LHRH analogue + bicalutamide) in metastatic hormone 
sensitive prostate cancer  
  
   
  
  
 STUDY SCHEMA ……........................................................................................................... ....6  
  
1.0 OBJECTIVES ...................................................................................................................... ... 7  
  
2.0 BACKGROUND ................................................................................................................. ... 7  
  
3.0 DRUG INFORMATION ..................................................................................................... . 12  
  
4.0 ELIGIBILITY CRITERIA.……………………………………………………………….....19  
  
5.0 TREATMENT PLAN …………………………………………………………………….....21  
  
6.0 TOXICITIES TO BE MONITORED AND DOSAGE 
MODIFICATION………………......23  
  
7.0 STUDY CALENDAR…………………………………………………………………..……25  
  
8.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION .................................. 
...26  
  
9.0 CRITERIA FOR REMOVAL FROM STUDY ................................................................... 
...30  
  
10.0 CORRELATIVE STUDIES ............................................................................................... 
...30  
  
11.0 STATISTICAL CONSIDERATIONS ............................................................................... 
...35  
  
12.0 ADVERSE EVENTS REPORTING………………………………………………….……40  
  
13.0 REFERENCES…………………………………………………………………….……….47  
  


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14.0 DATA AND SAFETY MONITORING PLAN…………………………………………....51  
  
15.0 APPENDICES………………………………...……………………………………………52  
STUDY SCHEMA  
  
Non castrate metastatic prostate cancer  
< 3 months of androgen deprivation for metastatic disease  
At least 6 months since prior androgen deprivation therapy  
  
 
  
PS - 0 - 2,   
Adequate marrow, hepatic & renal function  
No history of seizures or risk factors for seizures  
  
 
  
  
  
  
  
  
        STRATIFY by race (African American or Other) and by bone pain (yes or no)  
                                           
                                                    ( yields 4 strata )  
  
  
  
  
R   A    N   D   O   M   I    Z   E     within strata  
     
  
  
 
          Arm A  
     
  
Arm B  
 
  LHRH analogue 
 
  
  
  
 
 
LHRH analogue    
 
  +  
  
  
  
  
  
  
+  
 
  Enzalutamide  
  
  
  
           Bicalutamide  
 
  160 mg orally daily   
  
                       50 mg orally daily  
  
 
  
  
DETERMINE  PRIMARY  ENDPOINT:  
  
     


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% of patients achieving a PSA nadir of ≤ 4 ng/ml at month 7  
(Patients should continue on study therapy after month 7 unless any of the criteria in 
section 9.0 for withdrawal are met)  
  
  
  
  
  
1.0 OBJECTIVES:  
  
Primary objective:  
  To compare the rates of achieving PSA remission at month 7 with LHRH analogue therapy and 
enzalutamide (Arm A) with that achieved with LHRH analogue and bicalutamide (Arm B) in 
metastatic hormone sensitive prostate cancer .   
  
Secondary Objectives:  
  
1) 
To compare the primary endpoint by race.  
  
2) 
To compare the rates of each of 2 types of response by treatment arm:                      
a)  measurable disease response;    and  
         b)  PSA response.   
  
3) 
To compare each of  7 time-to-event endpoints by treatment arm:  
a) duration of overall response (RD);   
b) duration of stable disease (SDD);  
c) time to treatment failure (TTF);  
d) time-to-progression (TTP);  
e) TTP in patients with bone metastases;    
f) progression-free survival (PFS);    and  
g) overall survival (OS).  
  
4) 
To compare the rates of each type of toxicity by treatment arm.  
  
5) 
To compare the incidence rate of skeletal related events (SRE), and the time until  
SRE, separately by treatment arm.  
  
6) 
To compare the rates of CTC response by treatment arm..  
  
7) 
To explore the molecular mechanisms within the androgen receptor pathway  by 
determining the levels of CXCR4 and TMPRSS2-ERG expression,  androgen 
metabolism enzymes, androgen receptor variants, and length of  CAG repeats 
within the androgen receptor gene, and to associate them with the primary 
endpoint.    


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2.0 BACKGROUND:  
  
Androgen deprivation therapy (ADT) remains the most effective frontline therapy for metastatic 
prostate cancer. Despite this, a proportion of patients demonstrate inadequate response to 
combined androgen blockade (CAB) and demonstrate worse clinical outcomes. The extent of 
response to ADT is reportedly a predictor of OS and PFS outcome related to prostate cancer. The 
Southwest Oncology Group (SWOG) randomized clinical trial evaluating continuous versus 
intermittent ADT in metastatic prostate cancer has completed accrual and Hussain et al [1]  detail  
the prognostic importance of PSA nadir <4ng/ml during the first 7 months of induction of ADT. 
Of the total patients enrolled on SWOG 9346 (INT-0162) study, about 52-57% were eligible for 
randomization after achieving a PSA level of <4 ng/ml with stable or declining levels at months 6 
and 7 after CAB. The median survival was 13 months in the group with PSA nadir > 4 ng/ml, 44 
months in the group with PSA nadir between 4 ng/ml to 0.2 ng/ml and 75 months in the patients 
with undetectable (<0.1 ng/ml). These differences present a great opportunity for use of this 
surrogate endpoint to predict overall disease related outcome. Now the final results of SWOG 9346 
have been reported [2] and reveal that continuous androgen suppression likely confers an OS 
benefit over intermittent androgen deprivation and establishes this as the standard control arm for 
future trials in metastatic prostate cancer.  The results of SWOG 9346 also reveal that despite best 
efforts about half of the patients do not achieve optimal outcome with initial androgen deprivation 
therapy. Hence there is an unmet need to improve on outcomes in metastatic prostate cancer earlier 
on, and subsequently delay the progression to the morbidity of castrate resistant prostate cancer. 
The androgen receptor inhibitor enzalutamide may present an opportunity to make early inroads 
in metastatic hormone sensitive prostate cancer.   
  
Results of clinical investigations and studies on the molecular profiles of these progressing tumors 
show that the androgen receptor remains functional and that the tumors respond to strategies directed 
at the androgen receptor signaling axis. Overexpression of the androgen receptor has been 
documented in upwards of 50% of such prostate cancer specimens and is believed to contribute to 
tumor progression.[3, 4] In addition, currently approved anti-androgens have the potential to act as 
a partial agonist and stimulate androgen receptor signaling in the setting of androgen receptor 
overexpression, therefore exacerbating or accelerating tumor growth. The decline in serum levels 
of prostate-specific antigen (PSA) seen upon discontinuation of these agents is consistent with the 
agonist effects (“anti-androgen withdrawal syndrome”).  
  
Enzalutamide (MDV3100/ Xtandi: Medivation/Astellas Inc) is an androgen receptor (AR) signaling 
inhibitor rationally designed to block multiple steps in the AR signaling pathway and to be devoid 
of agonist activity. Enzalutamide inhibits androgen-induced receptor activation (binding of 
androgens to ARs in the cytosol), inhibits nuclear translocation of activated ARs, and inhibits the 
association of the activated AR with chromatin, even in the setting of AR overexpression and in 
prostate cancer cells resistant to anti-androgens such as bicalutamide. The consequence of 
enzalutamide AR signaling inhibition is decreased growth of prostate cancer cells, induction of 
cancer cell death, and tumor regression.  
  


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The apoptotic effect of enzalutamide is consistent with AR blockade. It also induces cleavage of 
poly adenosine diphosphate-ribose polymerase (PARP), hence causing apoptosis, in prostate cancer 
cells, while bicalutamide treatment has no effect on PARP cleavage. In a mouse xenograft model of 
castration-resistant prostate cancer enzalutamide dose-dependently reduced tumor volume while 
bicalutamide treatment showed  no significant benefit. Safety pharmacology studies in mice, rats, 
and dogs were performed with MDV3100 to assess any acute effects on central nervous system, 
respiratory, and cardiovascular parameters. No enzalutamide -related effects were noted in the 
central nervous system study assessing a functional observation battery and in a respiratory study in 
rats. Enzalutamide inhibits the human ether-a-go-go-related gene (hERG) channel; however, the 
highest free concentrations of MDV3100 expected in patient plasma at a steady-state dose of 160 
mg/day are well below the hERG inhibitory concentration 50% (IC50) value. No drug –related 
effects on cardiac electrophysiology were noted in a safety pharmacology study in conscious, 
telemetered dogs.  
  
As enzalutamide inhibits the gamma amino butyric acid (GABA)-gated chloride channel, 
convulsion potential was assessed in single- and multiple-dose studies in mice. Oral therapy daily 
for 7 days was associated with convulsions in a dose-dependent manner with doses ≥ 200 mg/kg 
being active. When administered as a single dose of 400 mg/kg the treatment was also associated 
with convulsions. At the highest dose at which no convulsions occurred (single dose, 100 mg/kg), 
the maximum plasma concentration (Cmax) and area under the curve at 24 hours after dosing 
(AUC24) were at least 2.5-times higher than those in patients receiving 160 mg/day. The incidence 
of seizures was noted in 0.6% of the patients treated in the registration trial. 5 of 800 patients 
experienced seizures on enzalutamide therapy and none on placebo therapy. The seizures were 
reversible after therapy was discontinued [5]. One case of status epilepticus (confusion associated 
with partial complex-status epilepticus) required medical intervention; the four other seizures were 
self-limited and did not recur after study-drug discontinuation. Four of the seizures were witnessed. 
Potentially predisposing factors were present in several patients. Two patients had brain metastases, 
1 of whom had a seizure reported 26 days after the last dose of enzalutamide. One patient had 
inadvertently been administered lidocaine intravenously immediately before the seizure, and 1 
patient with brain atrophy had an unwitnessed event classified as a seizure, in the context of a history 
of heavy alcohol use, after initiation of haloperidol 7 days beforehand. One additional adverse event 
reported by the investigator as syncope had several features suggestive of seizure. The enzalutamide 
group had a lower incidence of adverse events of grade 3 or above (45.3%, vs. 53.1% in the placebo 
group). The median time to the first such adverse event was 12.6 months in the enzalutamide group, 
as compared with 4.2 months in the placebo group.  There was a higher incidence of all grades of 
fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache in the enzalutamide group than in 
the placebo group. Cardiac disorders were noted in 6% of patients receiving enzalutamide and in 
8% of patients receiving placebo (with cardiac disorders of grade 3 in 1% and 2%, respectively). 
Hypertension or increased blood pressure was observed in 6.6% of patients in the enzalutamide 
group and 3.3% of those in the placebo group.   
There were no significant between-group imbalances in the rates of other adverse events, such as 
hyperglycemia, weight gain, hyperlipidemia, or glucose intolerance. Therefore, there was no 
evidence to suggest the development of a metabolic syndrome associated with enzalutamide, 
although the study was not designed to formally evaluate this event. Liver-function abnormalities 


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were reported as adverse events in 1% of patients receiving enzalutamide and in 2% of those 
receiving placebo.  
  
Clinical data with enzalutamide  
  
The study that led to the FDA approval of enzalutamide was a double blind placebo controlled phase 
III randomized trial. The study revealed an OS benefit with enzalutamide with median survival of 
18.4 months as compared to median survival of 13.6 months with placebo (p<0.0001) [5]. The phase 
I/II study showed very promising efficacy in the chemotherapy naïve patient population with PSA 
response rates at 62% and time to progression of 41 weeks [6]. A placebo controlled randomized 
trial called PREVAIL in castrate resistant, chemotherapy naïve patient population has been 
conducted and completed accrual. The results are awaited but to date after completing enrollment 
of 1680 patients no significantly increased toxicities have been noted.   
  
Androgen deprivation therapy in metastatic prostate cancer  
Testosterone suppression remains the mainstay of initial therapy in metastatic prostate cancer. The 
addition of bicalutamide confers a small but finite improvement in OS outcome in metastatic ca 
prostate. The resistance mechanisms to bicalutamide are attributed to the agonistic effect. 
Enzalutamide has no agonist effect on the androgen receptor and has PARP inhibition effects. The 
mechanism of action of enzalutamide, along with the proven clinical efficacy in metastatic castrate 
resistant disease, provides a rationale to utilize enzalutamide in an earlier setting of hormone 
sensitive prostate cancer.   
  
The results of the CHAARTED (ECOG led) trial [13] were recently presented at the annual ASCO 
meeting in June 2014. The study randomized patients with metastatic prostate cancer to receive 
androgen deprivation therapy +/- docetaxel chemotherapy. The patients on the docetaxel arm 
received a maximum of 6 cycles of docetaxel at a dose of 75mg/m2 and were started on therapy 
within 4 months of initiating androgen deprivation therapy. Patients were stratified based on 
disease volume; low volume and high volume. The latter was defined as the presence of visceral 
metastases and/ or 4 or more bone metastases. 64% of the patients on the hormone therapy only 
arm and 67% on the docetaxel arm had high volume disease.  The overall survival results reveal 
an OS benefit with the addition of docetaxel (Hazard ratio 0.63, p= 0.0006) with median survival 
of 42.3 and 52.7 months in the hormone and chemotherapy arms respectively. A median survival 
improvement of 17 months was noted in the high volume disease patients. (Median survival of 
32.2 months and 49.2 months). Within the  low volume disease  patient population the OS results 
have not been reported. The above results have changed the standard of care to incorporate 
docetaxel based chemotherapy in the management of high volume hormone sensitive metastatic 
prostate cancer. Based on these results and remaining cognizant of the changing standard of care 
we will amend the eligibility criteria of the protocol to include patients with metastatic disease 
who either have   
  
a) low volume disease  
  
or  


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b) patients who are not candidates for docetaxel chemotherapy  
  
or  
  
c) Patients refusing docetaxel chemotherapy.  
  
Race in prostate cancer  
African American (AA) men are 1.6 times more likely to be diagnosed with prostate cancer and 2.4 
times more likely to die of the disease as compared to Caucasian (CA) men. The disparity is not 
entirely related to access to care as was shown by a study conducted in the Veterans Health system 
which found an OS disparity between AA and CA patients[7]. It appears that African American 
patients had a lower chance of maintaining the PSA nadir of 4ng/ml or less as compared to the entire 
group and are likely to have shorter progression free survival.[8] Even in patients treated with 
hormone therapy for advanced prostate cancer on clinical trials the overall survival outcome was 
noted to be shorter in patients of AA racial origin in both SWOG and RTOG trials.  
[9,10]  
The exact causes of this racial disparity are unknown; a number of factors such as diet, comorbid 
conditions and genetic factors have been cited as possible causes. Specifically the length of CAG 
repeats on the androgen receptor gene has been reported to be significantly different in association 
with AA race as compared to CA origin [11]. In addition racial differences have also been found 
among variants of the genes of the enzymes involved in androgen biosynthesis and metabolism, 
such as SRD5A2, CYP17, and CYP3A4. The levels of expression and CAG repeat length of AR 
also show racial divergence and may be critical molecular alterations for racial disparity. Growth 
factors and their receptors, which promote cancer cell growth, are another potential cause of the 
disparity; both EGFR and EPHB2, two of the most studied receptors, show interethnic differences. 
Differences have also been found among genes regulating cell apoptosis, such as BCL2, which is 
increased in prostate cancer in the AA population.[12]  
  
The androgen receptor inhibitor MDV-3100/enzalutamide (Medivation Inc and Astellas Inc) has 
revealed very promising activity in metastatic castrate resistant prostate cancer pretreated with 
docetaxel therapy. The agent revealed an OS benefit as compared to placebo in a double blind 
randomized study. In phase III trials conducted of enzalutamide, both pre and post chemotherapy, 
the number of patients with African American origin was very small and hence the effects of the 
differences in efficacy, if any, have not been studied. This proposal enables an assessment of a 
minority patient population that is reported to have a clinically worse outcome and explores the 
possibility of improving outcome and response by using a more effective androgen receptor 
inhibitor such as enzalutamide. Also this study will plan on tissue and serum collection to explore 
the molecular mechanisms within the androgen receptor pathway by determining the levels of 
CXCR4 and TMPRSS2-ERG expression, androgen metabolism enzymes, androgen receptor 
variants, and length of CAG repeats within the androgen receptor gene, and other correlative 
testing to explore the scientific reasons for the disparity.   
  
Clinical correlates:   
   


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Bio-specimens:  Baseline tumor tissue biopsies (bone is preferable but other sites permitted if 
patient has no accessible bone metastases for biopsy) will be mandatory for study enrollment.  Post 
treatment core biopsies of bone tumor tissues will be encouraged and obtained from the patients 
in both arms.    
Biomarkers:  CXCR4, ERG and key androgen biosynthesis enzymes (SRD5A2, CYP17, 
CYP3A4, AKR1C3 and HSD17b6) will be analyzed in bio specimens.  
Background and rationale:  CXCR4 and TMPRSS2-ERG fusion genes were shown to be 
differentially regulated in human tumor tissues in African American and Caucasian men.  CXCR4 
has been shown to be associated with aggressive disease and could possibly be the reason for racial 
disparity in outcomes noted in African American men.TMPRSS2-ERG fusions were reported to 
be significantly localized to prostate tumors in Caucasian men. CXCR4 expression has been shown 
to be a key molecular predictor of bone metastasis.  TMPRSS2-ERG fusion status is not known in 
bone metastasis.  Published data demonstrate that TMPRSS2-ERG fusions are early markers for 
prostate cancer, but their expression is sustained in advanced cancers suggesting that fusion 
activated ERG factor is still functional in tumor cells.  Both CXCR4 and TMPRSS2-ERG are 
androgen responsive genes in prostate tumor cells.  Androgen biosynthesis enzyme expression has 
been shown to be persistent in advanced patients, who undergo hormonal therapy.   We will 
analyze the expression of key enzymes (SRD5A2, CYP17, CYP3A4, AKR1C3 and HSD17b6) 
contributing to intratumoral androgen biosynthesis and test if the levels of these enzymes has an 
impact on response to ADT in either of the therapeutic arms of the study. Pre and post tumor tissues 
in both arms of the study will be analyzed for marker expression.  
  
3.0 DRUG INFORMATION:  
  
3.1 MDV-3100/Enzalutamide/ (Xtandi) : Astellas/Medivation Inc. (Study Drug)   
  
For patients enrolled and treated on this clinical trial, and randomized to Arm A, the above 
medication will be supplied by Medivation/Astellas Inc and dispensed in the treatment facility.  
  
DESCRIPTION  
Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-
3(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-
Nmethylbenzamide.The molecular weight is 464.44 and molecular formula is C21H16F4N4O2S.   
Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.  
XTANDI is provided as liquid-filled soft gelatin capsules for oral administration. Each capsule 
contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive 
ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated 
hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin,  purified water, titanium dioxide, and 
black iron oxide.  
  
CLINICAL PHARMACOLOGY  
Mechanism of Action  
Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor 
signaling pathway.  


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Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and 
inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, 
Ndesmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide 
decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor 
volume in a mouse prostate cancer xenograft model.  
  
Pharmacokinetics  
The pharmacokinetics of enzalutamide and its major active metabolite (N-desmethyl enzalutamide) 
were evaluated in patients with metastatic castration-resistant prostate cancer and healthy male 
volunteers. The plasma enzalutamide pharmacokinetics are adequately described by a linear two-
compartment model with first-order absorption.  
Absorption  
Following oral administration (XTANDI 160 mg daily) in patients with metastatic 
castrationresistant prostate cancer, the median time to reach maximum plasma enzalutamide 
concentrations (Cmax) is 1 hour (range 0.5 to 3 hours). At steady state, the plasma mean Cmax 
values for enzalutamide and N-desmethyl enzalutamide are 16.6 μg/mL (23% CV) and 12.7 μg/mL 
(30% CV), respectively, and the plasma mean predose trough values are 11.4 μg/mL (26% CV) and 
13.0 μg/mL (30% CV), respectively.  
With the daily dosing regimen, enzalutamide steady state is achieved by Day 28, and enzalutamide 
accumulates approximately 8.3-fold relative to a single dose. Daily fluctuations in enzalutamide 
plasma concentrations are low (mean peak-to-trough ratio of 1.25). At steady state, enzalutamide 
showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 
mg.  
A single 160 mg oral dose of XTANDI was administered to healthy volunteers with a high-fat meal 
or in the fasted condition. A high-fat meal did not alter the AUC to enzalutamide or Ndesmethyl 
enzalutamide.   
  
Distribution and Protein Binding  
The mean apparent volume of distribution (V/F) of enzalutamide in patients after a single oral dose 
is 110 L (29% CV). Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-
desmethyl enzalutamide is 95% bound to plasma proteins.  
  
Metabolism  
Following single oral administration of 14C-enzalutamide 160 mg, plasma samples were analyzed 
for enzalutamide and its metabolites up to 77 days post dose. Enzalutamide, N-desmethyl 
enzalutamide, and a major inactive carboxylic acid metabolite accounted for 88% of the 
14Cradioactivity in plasma, representing 30%, 49%, and 10%, respectively, of the total 14C-
AUC0inf.  
In vitro, human CYP2C8 and CYP3A4 are responsible for the metabolism of enzalutamide. Based 
on in vivo and in vitro data, CYP2C8 is primarily responsible for the formation of the active 
metabolite (N-desmethyl enzalutamide).  
  


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Elimination  
Enzalutamide is primarily eliminated by hepatic metabolism. Following single oral administration 
of 14C-enzalutamide 160 mg, 85% of the radioactivity is recovered by 77 days post dose: 71% is 
recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), 
and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl 
enzalutamide).   
The mean apparent clearance (CL/F) of enzalutamide in patients after a single oral dose is 0.56 L/h 
(range 0.33 to 1.02 L/h).  
The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days 
(range 2.8 to 10.2 days).  
Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 
for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.  
  
Drug Interactions  
Effect of Other Drugs on XTANDI:  
In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was 
administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). 
Gemfibrozil increased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold 
with minimal effect on Cmax.   
In a drug-drug interaction trial in healthy volunteers, a single 160 mg oral dose of XTANDI was 
administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor). 
Itraconazole increased the AUC0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold 
with no effect on Cmax. The effects of CYP2C8 and CYP3A4 inducers on the exposure of XTANDI 
have not been evaluated in vivo.  
  
CLINICAL STUDIES  
The efficacy and safety of XTANDI in patients with metastatic castration-resistant prostate cancer 
who had received prior docetaxel-based therapy were assessed in a randomized, placebocontrolled, 
multicenter phase 3 clinical trial. The primary endpoint was overall survival. A total of 1199 patients 
were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or 
placebo orally once daily (N = 399). All patients continued androgen deprivation therapy. Patients 
were allowed, but not required to continue or initiate glucocorticoids. Study treatment continued 
until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical 
progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or 
withdrawal. Patients with a history of seizure, taking medicines known to decrease the seizure 
threshold, or with other risk factors for seizure were not eligible   
  
The following patient demographics and baseline disease characteristics were balanced between the 
treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% 
Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an  
ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. 
Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung 
and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 
41% had PSA-only progression on study entry. All patients had received prior docetaxel-based 
therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of 


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patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. The 
pre-specified interim analysis at the time of 520 events showed a statistically significant 
improvement in overall survival in patients on the XTANDI arm compared to patients on the placebo 
arm.  
  
HOW SUPPLIED/STORAGE AND HANDLING  
• XTANDI (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin 
capsules imprinted in black ink with MDV. XTANDI capsules are available in the following 
package sizes:  
• Bottles of 120 capsules (NDC 0469-0125-99)  
Recommended storage: Store XTANDI capsules at 20°C to 25°C (68°F to  77°F) in a dry place 
and keep the container tightly closed.   
Excursions permitted from 15°C to 30°C (59°F to 86°F).  
  
PATIENT COUNSELING INFORMATION  
See FDA-approved patient labeling (PATIENT INFORMATION).  
• 
Instruct patients to take their dose at the same time each day (once daily). XTANDI can be 
taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or 
open the capsules.  
• 
Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss 
conditions that may predispose to seizures and medications that may lower the seizure threshold.  
Advise patients of the risk of engaging in any activity where sudden loss of consciousness could 
cause serious harm to themselves or others.  
• 
Inform patients that XTANDI may cause dizziness, mental impairment, paresthesia, 
hypoesthesia, and falls.  
• 
Inform patients that they should not interrupt, modify the dose, or stop XTANDI without 
first consulting their physician.   
Inform patients that if they miss a dose, then they should take it as soon as they remember. If they 
forget to take the dose for the whole day, then they should take their normal dose the next day. They 
should not take more than their prescribed dose per day.  
• 
Apprise patients of the common side effects associated with XTANDI: asthenia/fatigue, 
back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper 
respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal 
cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.  
  
PATIENT INFORMATION  
 Inform patients that XTANDI may be harmful to a developing fetus. Patients should also be 
informed that they should use a condom if having sex with a pregnant woman A condom and another 
effective method of birth control should be used if the patient is having sex with a woman of child-
bearing potential. These measures are required during and for three months after treatment with 
XTANDI.  
  
3.2 Bicalutamide (Casodex®) (NSC-722665)  
  
For bicalutamide, goserelin acetate, and leuprolide acetate, commercially  


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Available preparations are used as per the FDA approved dose, route and schedule. 
Information about commercial drugs is publicly available in the Physician’s Desk 
Reference (PDR), prescribing information and other resources.  
  
Chemistry: Bicalutamide is a racemic mixture containing two enantiomers, (2RS)-4'-Cyano-3(4-
fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-  
trifluoromethyl) propionanilide. Bicalutamide is an active non-steriodal antiandrogen and 
its antiandrogen activityresides exclusively in the (-) or (R) enantiomer. Unlike flutamide, it 
is peripherally selective and does not cause a rise in serum LH or Testosterone in male rats 
and dogs. This peripheral selectivity may be because it penetrates poorly the CNS and 
Hypothalamus (the site of negative feedback of androgens).  In humans, rises in LH, 
Testosterone and Estradiol concentrations were seen. These rises were not dose related. In 
90%, testosterone levels remained within normal limits. There was no significant rise in 
mean serum FSH.  
Bicalutamide has been given to over 3,500 men in 35 different clinical studies worldwide, 
in doses up to 600 mg daily.   
  
Adverse Effects:  
When bicalutamide is given in combination with an LHRH analog, the pharmacologic adverse 
event profile is dominated by the LHRH analog and includes hot flashes (53%), gynecomastia 
(9%) and breast pain (6%). Other adverse events reported regardless of causality included 
diarrhea (12%), constipation (22%), nausea (15%) and abdominal pain (11%). Other adverse 
were reported, such as fatigue (22%), pain (35%), back pain (25%), pelvic pain (21%), infection  
(18%), peripheral edema (13%), dyspnea (13%), nocturia (12%), hematuria (12%), anemia  
(11%), dizziness (10%). Bicalutamide has been associated with changes in liver 
function, although these are infrequent (7%) and rarely occur with jaundice. 
Many of these changes improved or resolved despite continuation of  
bicalutamide therapy. There have been no reports of fatal hepatotoxicity associated with 
bicalutamide therapy.  
  
Pharmacology  
Pharmacokinetics:  
Animal studies: After oral single dose administration, absorption of the compound was slow with 
peak concentration occurring 3 - 12 hours and plateau between 2 and 48 hours. There was 
nonproportional increase in plasma levels with increasing doses. Elimination half life ranges 
from 17 - 28 hours in male rats, 21 - 29 hours in female rats and 5 - 7.5 days in dogs. 91 - 96% of 
bicalutamide is bound to plasma protein.  
Human studies: After single doses, mean time for peak plasma concentration was 6 hours at 10 
and 30 mg, but at 50 mg, it was 16 hours. Mean plasma elimination half-lives after 12 weeks of 
10, 30, 50, 100 mg/day was 7 - 10 days. This finding was consistent with single dose data. In 
patients given daily doses of 50 mg, mean plasma concentration was 10 ug/ml at 12 weeks. After 
single doses, there was linear increase with doses between 10 and 50 mg, but became non-linear 
at doses of 50 - 100 mg. At 100 mg, the oral bioavailability is reduced by 30% but plasma 
elimination half-life is unchanged. Bicalutamide is extensively metabolized and metabolites are 
excreted by both the biliary and urinary system.  


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Formulation: Bicalutamide is prepared as round, film-coated green or white tablets containing 
standard recipients and 50 mg of the drug.  
Storage and stability: All packages of bicalutamide should be stored securely in a dry place at 
room temperature.  
Route of Administration: Bicalutamide is to be administered in tablet form as a 50 mg once-daily 
oral dose. Patients should be instructed to take one tablet once daily.  
  
3.3 Gonadotropin/Luteinizing Hormone Releasing Hormone (GNRH/LHRH) analogues: The 
commonly used preparations are listed below. However any of the other preparations with FDA 
approval that result in androgen suppression are acceptable.   
  
Goserelin acetate implant (Zoladex®) / Leuprolide (Lupron)  
a. PHARMACOLOGY  
Mechanism of Action: Following initial administration in males, goserelin causes an initial 
increase in serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels with 
subsequent increases in serum levels of testosterone.  
  
Chronic administration of goserelin leads to sustained suppression of pituitary gonadotropins, and 
serum levels of testosterone consequently fall into the range normally seen in surgically castrated 
men approximately 2-4 weeks after initiation of therapy.  
  
b. PHARMACOKINETICS  
1. Absorption: Goserelin 3.6 mg is released slowly in first 8 days, and then rapid and continuous 
release for the remainder of the 28 day dosing period. Time to peak concentration for goserelin 
3.6 mg is 12-15 days in males and 8-22 days in females. Goserelin 10.8 mg exhibits an initial 
rapid release resulting in a peak concentration at 2 hours after dosing. From Day 4 until the end 
of the 12-week dosing interval, the sustained release of goserelin produces a reasonably stable 
systemic exposure.   
   
  
2. Distribution: Apparent volumes of distribution determined after subcutaneous administration 
of 250 mcg aqueous solution of goserelin were 44.1 and 20.3 liters for males and females, 
respectively. Goserelin is approximately 27% protein bound.  
  
3. Metabolism: Metabolism of goserelin by hydrolysis of the C-terminal amino acids is the major 
clearance mechanism. The half-life elimination (t1/2)) is approximately 4 hours in males and 2 
hours in females   
  
4. Elimination: Clearance of goserelin is very rapid and occurs primarily via urinary excretion 
(>90%; 20% as unchanged drug).  
  
  
c. ADVERSE EFFECTS  
1. Refer to the package insert or manufacturer website for the most complete and up to date 
information on contraindications, warnings and precautions, and adverse reactions.  


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Side Effects  
Adverse events associated with the use of Leuprolide/Goserelin may include, but are not limited 
to, the following:   
• 
hot flashes   
• 
injection site reactions   
• 
weight gain   
• 
increase in liver enzymes   
• 
tiredness   
• 
hypertension   
• 
back and joint pain   
• 
chills   
• 
urinary tract infection   
• 
decreased sex drive and trouble with erectile function  
  
Adverse effects occurring in <1%, postmarketing, and/or case reports:  
1. ALT increased, anaphylaxis, AST increased, diabetes, glucose tolerance decreased, 
hypercalcemia, 
hypercholesterolemia, 
hyperlipidemia, 
hypersensitivity 
reactions, 
hypotension, ovarian cyst, pituitary apoplexy, psychotic disorders, urticaria.  
2. Pregnancy and Lactation: Not applicable as this study only enrolls male patients. Pregnancy 
category X in patients with endometriosis and endometrial thinning. Pregnancy category D 
in patients with advanced breast cancer. It is not known if goserelin is excreted in human 
milk, however goserelin is excreted in the milk of lactating rats.  
3. Drug Interactions: Luteinizing hormone-releasing hormone analogs may diminish the 
therapeutic effect of antidiabetic agents. No formal drug-drug interaction studies have been 
performed. Please refer to the current FDA-approved package insert for additional 
information.  
4. The FDA issued a safety communication in October 2010 based on their ongoing safety 
review of LHRH agonists. The safety communication discusses the potential for an increased 
risk of diabetes and cardiovascular disease (myocardial infarction, sudden cardiac death, 
stroke) associated with these agents. The risk is thought to be low in men receiving LHRH 
agonists for prostate cancer. In this trial, LHRH agonists are being administered for a short 
period of time. FDA recommendations include management of cardiovascular risk factors 
according to current standards of practice.   
  
d. DOSING & ADMINISTRATION  
1. Dosing – See Package Insert of preparation used.  
2. Goserelin is administered subcutaneously into the anterior abdominal wall below the navel 
line using aseptic technique.  
  
e. STORAGE & STABILITY  


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Refer to the current FDA-approved package insert for storage, stability and special handling 
information.  
  
f. HOW SUPPLIED  
1. Goserelin acetate implant is available in a 3.6 mg or 10.8 mg disposable syringe device. 
The unit is sterile and comes in a sealed, light- and moisture-proof, aluminum foil laminate 
pouch containing a desiccant capsule.  
2. Goserelin is commercially available and will not be supplied. Refer to the current 
FDAapproved package insert for additional information.   
  
  
Leuprolide (Eligard®, Lupron Depot®) (NSC-377526)  
  
PHARMACOLOGY  
Mechanism of Action: Leuprolide inhibits gonadotropin secretion by acting as a luteinizing 
hormone-releasing hormone (LHRH) agonist. Continuous administration results in suppression of 
ovarian and testicular steroidogenesis due to decreased levels of LH and FSH with subsequent 
decrease in testosterone (male) and estrogen (female) levels. In males, testosterone levels are 
reduced to below castrate levels. Leuprolide may also act directly on the testes as well as act by a 
different mechanism not directly related to reduction in serum testosterone.  
  
DOSING & ADMINISTRATION  
1. Dosing – Per package insert. Typically 7.5 mg monthly or 22.5 mg every 3 months  
2. Leuprolide is administered intramuscular (Lupron Depot®) or subcutaneous (Eligard®) 
injection based on commercial depot formulation. Injection sites should be varied 
periodically.  
  
STORAGE & STABILITY  
Refer to the current FDA-approved package insert for storage, stability and special handling 
information.  
  
HOW SUPPLIED  
1. Leuprolide acetate is available in 3.75 mg, 7.5 mg, 11.25 mg, 22.5 mg, 30mg, or 45 mg 
depot formulation kit with accompanying diluent. The prefilled dual chamber syringe 
contains lyophilized microspheres of leuprolide acetate incorporated in a biodegradable 
lactic acid polymer.  
2. Leuprolide/Goserelin is commercially available and will not be supplied.  
  
Other LHRH agents can be utilized per the FDA approved dose and schedule. GNRH 
antagonists cannot be used.  
  
4.0 ELIGIBILITY CRITERIA  
  
4.1 Inclusion Criteria:   


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1. Histologically confirmed prostate adenocarcinoma with metastasis either starting or 
recently started on LHRH analogue therapy. [Late induction permitted within 3 months of 
starting LHRH analogue therapy or antiandrogen] All patients who have not initiated 
hormone therapy (Early induction patients) must have elevated PSA ≥ 4 ng/ml within 28 
days prior to registration. For late induction registrations, PSA must be ≥ 4 ng/ml prior to 
start of androgen deprivation therapy; either antiandrogen or LHRH analogue or GNRH 
antagonist .If patients are on antiandrogen, this will need to be discontinued for at least 7 
days prior to registration.   
2. Patients with a history of prior neoadjuvant or adjuvant hormone therapy are eligible 
provided they have received twenty four or less months of hormone treatment (single or 
combination treatment, excluding orchiectomy). Neoadjuvant/adjuvant hormone therapy 
must have been discontinued at least 6 months prior to registration. This is intended to 
exclude patients who might have been rendered indirectly androgen insensitive.   
3. There must be no plans to receive concomitant chemotherapy, biological response 
modifiers, radiation therapy or hormonal therapy. Concomitant radiation therapy is 
allowed for the palliation of severe pain/neuropathic compression.   
4. Prior or concomitant use of megestrol acetate for the treatment of hot flashes is allowed.   
5. Patients must have a performance status of 0 - 2 by Zubrod Criteria.  
6. Patients must have recovered from any major infections and/or surgical procedures and, 
in the opinion of the investigator, not have significant active medical illness precluding 
protocol treatment or survival.  
7. No prior malignancy is allowed except for adequately treated basal cell (or squamous 
cell) skin cancer, superficial or in situ cancer of the bladder. For an invasive cancer the 
patients should be disease free for at least 3 years prior to enrollment on study.   
8. For all patients a bone scan must be performed within 60 days prior to registration for 
tumor assessment. CT scans (abdomen and pelvis) and chest x-ray are optional, but must 
be repeated if used for disease assessment. For late induction registrations, tumor 
assessment imaging showing metastatic disease must be available prior to start of 
androgen deprivation therapy.  
  
9. Age 18 or older and willing and able to provide informed consent.  
10. Willingness to swallow pills and no medical condition that would interfere with this.  
11. Male patient and his female partner who is of childbearing potential must use 2 
acceptable methods of birth control (one of which must include a condom as a barrier 
method of contraception) starting at screening and continuing throughout the study period 
and for 3 months after final study drug administration. Patients are also required to use a 
condom if having sex with a pregnant woman.  
12. Patient should agree to a tumor tissue biopsy prior to protocol enrollment. Post therapy 
biopsy is optional.   
13. Patients who are being treated with a GNRH antagonist should be willing to switch to a 
LHRH analogue after registration.  
14. Patients must have one of the following a) Low volume disease (defined as no visceral 
metastases and < 4 bone metastases) or b) are not candidates for docetaxel based 
chemotherapy or 3) refused docetaxel chemotherapy  
  


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4.2  Patients must NOT meet any of the following exclusion criteria:  
  
1. History of seizure or any condition that may predispose to seizure (e.g., prior cortical 
stroke, significant brain trauma) at any time in the past. Also, history of loss of 
consciousness or transient ischemic attack within 12 months of Day 1 visit;  
2. Known or suspected brain metastasis or active leptomeningeal disease;  
3. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the 
Investigator, would make the patient inappropriate for enrollment;  
4. Absolute neutrophil count < 1,000/μL, or platelet count < 50,000/μL, or hemoglobin<8 
/dL) at the Screening visit.   
5. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 
2.5 times the upper limit of normal   
6. Creatinine > 177 μmol/L (2 mg/dL)   
    
7. Clinically significant cardiovascular disease including:  
• Myocardial infarction within 6 months;  
• Uncontrolled angina within 3 months;  
• Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients  
with history of congestive heart failure NYHA class 3 or 4 in the past, unless   
screening echocardiogram or multi-gated acquisition scan performed within 3 months results 
in a left ventricular ejection fraction that is ≥ 45%;  
---History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, torsades de pointes);  
---History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place;  
---Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury 
(mmHg) at the Screening visit;  
---Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening 
ECG;  
---Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or  
diastolic blood pressure > 105 mmHg   
8. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer 
disease within last 3 months);  
9. Treatment with concurrent 5-α reductase inhibitors (finasteride, dutasteride), estrogens, 
and/or cyproterone  
10. Treatment with systemic biologic therapy for prostate cancer (other than approved bone 
targeted agents and GnRH-analogue therapy) or other agents with anti-tumor activity 
within 4 weeks of enrollment (Day 1 visit);  
11. History of prostate cancer progression on ketoconazole;  
12. Prior use, or participation in a clinical trial, of an investigational agent that blocks 
androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) or  agents 
that block the androgen receptor (e.g.,ARN-509)  
13. Previous enzalutamide therapy;  
14. Use of an investigational agent within 2 weeks of enrollment (Day 1 visit);  


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15. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are 
known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater 
than the equivalent of replacement steroids or > equivalent of 10 mg of prednisone per 
day within 4 weeks of enrollment (Day 1 visit);  
16. Any condition or reason that, in the opinion of the Investigator, interferes with the ability 
of the patient to participate in the trial, which places the patient at undue risk, or 
complicates the interpretation of safety data.  
17. Prior chemotherapy for metastatic disease.   
18. >30 days of antiandrogen therapy monotherapy without androgen deprivation therapy.  
19. Life expectancy of 6 months or less.  
  
  
5.0 
TREATMENT PLAN:  
  
5.1 
Patient Registration and Data Collection:   
 All patients shall be registered with the Cancer Center Clinical Trials Office at 313-576-9837 
(Kimberlee Dobson).    
  
At the time of registration, a pre-study form and all information required to verify 
eligibility shall be necessary on each patient prior to treatment. This form should be faxed to 
313-576-8974 and eligibility verification will be sent within 48 hours. Data will be collected and 
maintained on study specific electronic case report forms in the Oncore Research Enterprise 
system at  
Karmanos Cancer Institute. Training and support will be provided for all staff entering data. Data 
entry must occur within 2 weeks of visits along with submission of applicable source 
documentation. The only concomitant medication data to be submitted is administration of 
bisphosphonate or denosumab.  
  
5.2 
Stratification and randomization procedures:  
The registering data manager will first stratify the patient by race (AA or other) and cancer 
related bone pain at diagnosis of metastatic disease (present or absent) into one of 4 strata.  Even 
if pain is well controlled/resolved  at present the patient will be considered positive for bone 
pain. The patient will then be randomized to Arm A or Arm B using the stratum-appropriate 
randomization list prepared in advance by the study statistician Dr Lance Heilbrun.   Arms A and 
B are defined in the Study Schema (on page 5) and in Section 5.3 below.   Each of the 4 
randomization sequences will use random permuted blocks of varying sizes.    The treatment arm 
randomization and enrollment confirmation will be communicated to site staff in writing within 
24-48 hours from receipt of all eligibility source documents. Study treatment should start within 
7 days of registration.  
  
5.3 
Study design and plan:   
  
Overall Study Design and Plan  
This study is a multicenter Phase II, randomized, screening study of oral MDV3100 (160 
mg/day) in patients with metastatic hormone sensitive prostate cancer. Patients must not have 
received prior cytotoxic chemotherapy for metastatic disease. Radiation therapy, and initiation of 


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bisphosphonates or other approved bone targeting agents, and standard of care steroid and pain 
management are allowed and should not result in discontinuation of study drug therapy.  
  
For patients eligible for late induction registration the treatment start date will be the date of 
initiation of GNRH analogue or antagonist, with or without antiandrogen. Late induction patient 
visits will be adjusted based on the length of their prior hormone therapy. Study drug therapy 
should be continued as long as the patient is tolerating the study drug and continues androgen 
deprivation therapy or until confirmed radiographic disease progression or a skeletal related 
event AND one of the two following events: 1) initiation of another agent for treatment of 
prostate cancer. Or 2) Intolerance to therapy.  
  
Patients will be randomized to receive either:  
  
ARM A  
Orchiectomy/LHRH analogue Leuprolide or Goserelin or any other FDA approved preparation, 
approved by PI on notification, except GNRH antagonist such as Degarelix) If patients are late 
induction and have started on degarelix (Firmagon;Ferring pharmaceuticals) or any GNRH 
antagonist they will need to be switched to a GNRH analogue.   
  
and   
  
Enzalutamide 160 mg (4Caps of 40 mg each) orally daily (experimental arm)  
  
OR  
  
ARM B  
Orchiectomy/LHRH analogue Leuprolide or Goserelin or any other FDA approved preparation, 
approved by PI on notification, except GNRH antagonist such as Degarelix)   
 If patients are late induction and have started on degarelix(Firmagon;Ferring pharmaceuticals)  
or any other GNRH antagonist they will need to be switched to a LHRH/GNRH analogue.   
  
and   
  
Bicalutamide 50 mg orally daily (standard arm).  
Stratification by ethnic origin (African American or other) and bone pain (Yes/No).  
  
Patients should continue on study therapy after month 7 unless any of the criteria in section 
9.0 for withdrawal are met  
  
5.4   
Agent Administration  
Starting doses of the agents are as follows:  
Enzalutamide is provided as 40 mg soft gelatin capsules in bottles with induction-sealed 
childresistant caps.   
Directions for Administration  


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Study drug doses should be taken as close as possible to the same time each day. All study 
patients on enzalutamide will take 4 capsules of study drug once daily unless dose adjustment 
has been done . Patients randomized to bicalutamide will take 1 tab of 50 mg daily dose. If 
dosing is missed on one day for any reason, double-dosing should NOT occur the following day. 
The oral medications can be taken with or without food. Documentation of daily dose will be 
conducted by patient on a study diary.   
  
Storage and Labeling  
Study drug should be stored in a secure location with limited access within the following 
temperature range: 59°F to 86°F (15°C to 30°C). Bottles will be labeled with the study protocol 
number, medication or bottle number, contents, directions for use, storage directions. Patients 
will be instructed to store study drug at room temperature out of the reach of children.  
  
6.0 TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATION:  
All toxicities will be graded as per NCI Common Toxicity (CTCAE) version 4.0.  
  
Toxicity evaluation will be done monthly for the first 8 visits starting with day 1 and after that 
every 3 months until progression. Radiologic evaluation at months 6 and 12 with scans (CT 
scans and bone scan), and PSA levels every month for the first 8 visits and after that every 3 
months. After 12 months radiologic evaluation is required annually while patient is on study.  
  
Dose Reduction/Dose Adjustment  
  
Patients who experience a Grade 3 or greater toxicity that is attributed to study medication, and 
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, including at a reduced dose (80 mg daily of enzalutamide), with the 
written approval of the PI (or designee). Any reports of seizure activity for patients 
randomized to enzalutamide require immediate and permanent discontinuation of this 
therapy.  
  
There are no dosage adjustments for hematologic toxicity.  
  
Dosage adjustments for Non-hematologic Toxicity: a. 
Diarrhea Toxicity:  
The major toxic effect of bicalutamide is moderate diarrhea which is very rarely severe 
(exclusion of other causes of diarrhea should be considered in severe cases).   
The dose modifications for this will be as follows, if diarrhea is attributed to protocol therapy.  
1. Grade 2 diarrhea, treat symptomatically with anti-diarrhea drugs.  
2. Grade 2 diarrhea unresponsive to symptomatic treatment or Grade 3/4 diarrhea - 
discontinue bicalutamide/enzalutamide until complete recovery.  
  
ABNORMAL LIVER FUNCTION TESTS (AST, ALT, BILIRUBIN)  
Grade 2 or greater toxicity - Stop bicalutamide/enzalutamide; wait until liver function tests 
(LFTs) including AST/ALT and bilirubin are normal (Grade 1 or less).   


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Restart treatment when AST/ALT and bilirubin return to normal/baseline. If toxicity (Grade 2 or 
worse) occurs again, discontinue protocol treatment.  
  
Patients requiring treatment delay greater than 2 months for any reason should be removed from 
protocol treatment.  
Patients may complain of flatulence, bloating and mild "gas pains" which should not result in 
changes in treatment. Symptomatic treatment should be employed with antacids, simethicone, 
etc. Unexpected or fatal toxicities (including suspected reactions) assessed by the investigator to 
be related to study therapy/ies must be reported per serious adverse event reporting guidelines as 
mentioned.  
 


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7.0 STUDY CALENDAR: Visit dates and scans can be within +/- 7 days of planned dates.  
Study treatment must start within 7 days of registration. For patients eligible for late 
induction registration the treatment start date will be the date of initiation of GNRH 
analogue or antagonist, with or without antiandrogen.  
  
Test  
Pre 
study1 
Day 1 Mth 1 Mth 2 Mth 3 Mth  
4  
Mth 5 Mth 6  Mth 7 Post  
Mth 7  
Every  
3mths  
F/U4 
Every3 
mths off 
study  
Hand P  
X  
X  
X  
X  
x  
  
  
X  
X  
X  
  
PS  
X  
X  
X  
X  
X  
  
  
X  
X  
X  
  
Tox  
  
  
X  
X  
X  
  
  
X  
X  
X  
  
VS  
X  
X  
X  
X  
X  
  
  
X  
X  
X  
  
EKG  
X  
  
  
  
  
  
  
  
  
  
  
CBC  
X  
X  
  
  
X  
  
  
X  
  
X  
  
AST  
X  
X  
  
  
X  
  
  
X  
  
X  
  
ALT  
X  
X  
  
  
X  
  
  
X  
  
X  
  
Alk phos  
X  
X  
  
  
X  
  
  
X  
  
X  
  
BUN  
X  
X  
  
  
X  
  
  
X  
  
X  
  
lytes  
X  
X  
  
  
X  
  
  
X  
  
X  
  
creat  
X  
X  
  
  
X  
  
  
X  
  
X  
  
PT/INR2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
PSA  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
  
Testosterone  
X  
  
  
  
X  
  
  
X  
  
X  
  
CXR/CT3  
X  
  
  
  
  
  
  
X  
  
  
  
Bone3 
scan  
X  
  
  
  
  
  
  
X  
  
  
  
OS  
  
  
  
  
  
  
  
  
  
  
X  
Progression  
  
X  
X  
X  
X  
X  
X  
X  
X  
  
X  
Tumor biopsy5 X5  
  
X5  
  
  
  
  
  
  
  
  
CTC5  
  
X5  
X5  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
1. Pre-study H & P, labs, EKG may be done within 28 days of registration. If Labs, and H and P are done 
within 72 hours prior to registration=they do not have to be repeated on day 1 of therapy unless clinically 
indicated.  
2. PT, INR to be done only if patient on therapeutic Coumadin and then will need to be repeated at least 
once every month.  
3. Tumor assessment scans must be within 60 days prior to registration for all patients. Bone scans are 
required for pretreatment and subsequent tumor assessments. CT/MRI of abdomen and pelvis should be 
done if necessary for tumor assessment. Radiologic assessment with bone scans should be done at 6 and 


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12 months on study (+/- 1 month) and then annually (+/- 1 month) as long as patient continues on study 
treatment. For late induction registrations, tumor assessment imaging showing metastatic disease must  
be available prior to start of androgen deprivation therapy.  
4. After completion of therapy patients will be followed every 3 months for disease status and survival.  
5. Fresh tissue should be collected pre-therapy. Archival tissue should be submitted within 28 days of 
registration. Post treatment tumor biopsy (optional) and CTC can be conducted within 28-42 days after 
registration even for late induction patients. Late induction patients will get CTC at time of study entry 
and then 28-42 days later.  
6. Disease progression is defined as evidence of radiographic progression, a skeletal-related event, 
or clinical progression.  Progression of measurable disease is defined by RECIST 1.1 criteria, or 
progression of bone metastases or occurrence of new skeletal related event or by PSA per PCWG 
2 criteria [Appendix B].  
  
8.0 CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION:  
  
The RECIST 1.1 criteria with unidimensional measurement are to be used for measurable 
disease response evaluation [14].  
  
Baseline Disease Assessment  
Measurable lesions must be accurately measured in at least one dimension  
(longest diameter in the plane of measurement is to be recorded) with a minimum size of:  
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm; when CT scans have   slice 
thickness >5 mm, the minimum size should be twice the slice thickness). • 10 mm caliper 
measurement by clinical exam (lesions which cannot be accurately measured with calipers 
should be recorded as nonmeasurable).  
• 20 mm by chest X-ray.  
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph  
node must be ≥15 mm in short axis when assessed by  CT scan (CT scan slice thickness is 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will 
be measured and followed.  
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
measurable if the soft tissue component meets the definition of measurability described above. • 
‘Cystic lesions’ thought to represent cystic metastases can be considered measurable if they 
meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred  for selection 
as  target lesions.  
  
Non-measurable lesions  
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 mm 
or   
Pathological lymph nodes with 10 to <15 mm short axis), as well as truly non-measurable 
lesions.  
• Blastic bone lesions are non-measurable.  


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• Lesions with prior local treatment, such as those situated in a previously irradiated area or in an  
area subjected to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion.  
  
Target Lesions  
• All measurable lesions up to a maximum of two lesions per organ and five lesions in total,  
representative of all involved organs, should be identified as target lesions and recorded and  
measured at baseline.  
• Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, as well as their suitability for reproducible 
repeated  measurements.  
• All measurements should be recorded in metric notation using calipers if clinically assessed.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions  
  
Non-target Lesions  
All lesions (or sites of disease) not identified as target lesions, including pathological lymph 
nodes and all non-measurable lesions, should be identified as non-target lesions and be recorded 
at baseline. Measurements of these lesions are not required and they should be followed as 
‘present’, ‘absent’ or in rare cases, ‘unequivocal progression’.  
  
Evaluation of target lesions  
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.   
  
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum of diameters.  
  
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this may include the baseline sum). The sum must 
also demonstrate an absolute increase of at least 5 mm.  
  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.  
  
Confirmation  
In non-randomized trials where response is the primary endpoint, confirmation of  
PR and CR is required to ensure responses identified are not the result of measurement error. 
This will also permit appropriate interpretation of results in the context of historical data where 
response has traditionally required confirmation in such trials. However, in all other 
circumstances, (i.e., in randomized phase II or III trials or studies where stable disease or 
progression are the primary endpoints), confirmation of response is not required since it will not 
add value to the interpretation of trial results. However, elimination of the requirement for 
response confirmation may increase the importance of central review to protect against bias, in 
particular in studies which are not blinded. In the case of SD, measurements must have met the 


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SD criteria at least once after study entry at a minimum interval (in general not less than 6–8 
weeks) that is defined in the study protocol.  
  
8.1 Primary Endpoint:   
The proportion of patients on either arm achieving a PSA nadir of 4 or less (< 4 ng/ml) at month 
7 of protocol therapy.  
  
8.2 Response Rate  
For measurable disease response, RECIST 1.1 criteria will be used. The Prostate Cancer Clinical 
Trials Working Group (PCWG2) criteria will be used to determine a PSA response [15]. PCWG2 
recommends a two-objective paradigm in metastatic CRPC: (1) controlling, relieving, or 
eliminating disease manifestations that are present when treatment is initiated and (2) preventing 
or delaying disease manifestations expected to occur. PSA decline, changes in imaging will also 
be reported. The progression for measurable disease will be per RECIST1.1 criteria, and for bone 
metastases will be per PCWG2.  
  
8.3 Duration of overall response  
The duration of overall response is measured from the time measurement criteria are met for 
CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease, the smallest measurements 
recorded since the treatment started).  
  
8.4 Duration of stable disease  
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started. Tumor 
evaluations are recommended every three cycles while on protocol therapy and then as clinically 
required by the treating physician.  
  
8.5  
Time to Treatment Failure:   
From date of registration to date of progressive disease, or date patient is taken off study for any 
reason. All patients, regardless of the number of completed cycles of therapy, will be included for 
toxicity evaluation.  All subjective toxicities encountered during the study will be evaluated 
according to the NCI toxicity criteria.  Objective toxicities will be based upon the greatest severity 
that occurred at any time during a treatment cycle and not on the severity noted at the beginning of 
the next cycle.  
  
8.6 Time to Progression:    
From date of registration to date of progressive disease, defined as either progression of measurable 
disease by RECIST 1.1 criteria, or progression of bone metastases or occurrence of new skeletal 
related event or by PSA per PCWG 2 criteria [Appendix B].  
  
8.7 Time to Progression in patients with bone metastases  


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Majority of the patients with prostate cancer have bone metastases which are not considered 
measurable sites of disease. Progression in patients with bone metastases will be defined as either 
the appearance of a minimum of 2 new lesions on bone scan which are related to metastatic disease 
per the judgement of the treating physician, or the occurrence of a new skeletal related event or by 
PSA criteria per PCWG 2. Skeletal-related event is defined as occurrence of new pathologic bone 
fractures (vertebral or nonvertebral), spinal cord compression, requirement of surgery or radiation 
therapy to bone metastases (including the use of radioisotopes), or a requirement to change 
antineoplastic therapy to treat bone pain or other related symptoms.   
  
8.8 Progression Free Survival  
Time from registration to PSA progression as defined by PCWG 2 criteria or measurable disease 
progression by RECIST1.1  or skeletal disease progression by appearance of new metastatic sites 
on bone scan or clinical progression as determined by treating physician assessment, or death from 
any cause, whichever occurs first.  
  
8.9  Follow up /Overall survival  
Overall survival will be measured from date of registration to death or last follow up.   
After treatment is discontinued for any reason patients will be followed every 3 months for 
progression and survival.  
  
8.10 Response Evaluable Patients  
All patients registered on the protocol and completing seven months of androgen deprivation 
therapy and getting the month 6 and 7 PSA levels evaluated are considered evaluable.  
  
8.11 Toxicity- Evaluable patients  
All patients registered on the protocol and starting therapy will be considered toxicity evaluable. 
Toxicity will be graded per the CTCAE criteria 4.0.  
  
8.12 Skeletal-related event   
Defined as occurrence of new pathologic bone fractures (vertebral or nonvertebral), spinal cord 
compression, requirement of surgery or radiation therapy to bone metastases (including the use of 
radioisotopes), or a requirement to change antineoplastic therapy to treat bone pain or other 
related symptoms.   
  
8.13 Circulating Tumor Cells Response    
The outcome measures associated with this definition are the following:  
Measurements of CTC counts pre-therapy, post-therapy and the change between time points. 
To assess the pre-therapy circulating tumor cell (CTC) counts and the changes in CTC after 1 
month of therapy, and to associate them with the primary endpoint.    CTC counts will be 
measured at baseline (day 1), and month 1 (days 28-42) of therapy. The pre and post-therapy 
CTC counts ;<5/7.5 ml which is considered favorable, vs >5/7.5 ml which is considered 
unfavorable, have been shown to be prognostic in metastatic CRPC patients treated with 
cytotoxic chemotherapy.    
  
8.14 Correlative tests:   


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Androgen metabolism enzymes: ERG, CXCR4, Androgen biosynthetic enzymes:  Testing will be 
conducted on paraffin embedded fixed tissue. Analysis will be performed by  
Immunohistochemistry.  Scoring will be between 0 to 3 and will be done by 2 independent 
experienced  investigators.  
  
Androgen biosynthetic enzymes: ERG, CXCR4 testing is conducted on RNA from frozen tumor 
tissue biopsies.  RNA message measurement by qualitative and quantitative RT- PCR (real time  
PCR). Qualitative Scoring for RT-PCR is the presence or absence of band (+/-) when an  
amplified PCR mixture is run on gel.  Quantitative PCR is the level of expression of the test gene 
will be expressed in in terms of folds.    
  
Genomic testing:   
AR splice variants:  Starting material is frozen tissue.  Analysis is RNA message quantitation by 
RT-PCR and QPCR, which is similar to androgen biosynthesis analysis: Qualitative (+/-) and 
quantitative results (copy number) will be obtained.  
  
9.0 CRITERIA FOR REMOVAL FROM STUDY:  
  
9.1 Intercurrent illness which would, in the judgment of the investigator, a) affect assessments 
of clinical status to a significant degree, b) require discontinuation of drug, or c) both a 
and b.  
9.2 Receiving any other treatment, investigational agent or alternative therapy directed at 
prostate cancer.  
9.3 Unacceptable toxicity   
9.4 Disease progression   
9.5 Delay in treatment of > 2 months    
9.6 The patient may withdraw from the study at any time for any reason.  
9.7 In the judgment of the investigator, further treatment would not be in the best interest of 
the patient.  
  
10.0  
CORRELATIVE STUDIES  
  
10.1 Bio-specimens:  Pretreatment tumor tissue biopsies will be mandatory for study enrollment.  
If patient has accessible bone metastases then bone biopsy is required. If patient has no bone  
metastases amenable to biopsy then tumor tissue biopsy can be conducted from other sites. Post 
treatment core biopsies of tumor tissues will be encouraged and obtained from the patients in 
both arms.  Archival primary prostate tissue slides/blocks submission is required. A minimum of 
10 unstained slides or block should be sent to Dr Chinni (see address below in section 10.7). An 
additional optional tumor tissue biopsy will be requested when patients are progressing on 
study medication.  This phase constitutes castrate resistant, where patients were progressing on 
androgen ablation and androgen receptor targeted therapies.  Collection of metastatic biopsy 
from the patients at this phase will be offered as an option. Molecular studies and data on the 
clinical samples at this stage are limited and we have a unique opportunity to collect the patient 
tissues at this phase.  Genomic testing and evaluation  of tumor tissue will be done by Caris Inc. 
and additional analysis will be done in Dr Chinni’s lab. We are collecting tumor biopsy 


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specimens prior to treatment and collection of specimens at the CRPC phase will improve our 
ability to monitor the biomarker response and determine pathways of resistance.  The tissue 
procurement, handling and shipping procedures will be the same for each biopsy.  
  
10.2 Biomarkers:  CXCR4, ERG and key androgen biosynthesis enzymes (SRD5A2, CYP17, 
CYP3A4, AKR1C3 and HSD17b6) will be analyzed for mRNA and protein expression in bio 
specimens. AR CAG repeats and androgen receptor variant expression will be determined in 
tumor tissues.   
  
10.3 Background and rationale:  Prostate cancer cells over express CXCR4 receptor which has 
been critically involved in disease progression [16].  We showed that CXCR4 expression 
regulates key signaling pathways contributing to invasion of tumor cells [17] and bone tumor 
growth [18].  TMPRSS2-ERG fusions are frequently expressed in PC patients where androgens 
regulate ERG factor expression in PC cells [19].  We and others found a link between ERG and 
CXCR4 expression in prostate cancer patient tissues 20, 21].   
  
  CXCR4 and TMPRSS2-ERG fusion genes were shown to be differentially regulated in 
human tumor tissues in African American and Caucasian men.  CXCR4 has been shown to be 
associated with aggressive tumor tissues of African American men, whereas TMPRSS2-ERG 
fusions were significantly localizes to prostate tumors in Caucasian men [22-24]. CXCR4 
expression has been shown to be key molecular predictor of bone metastasis [16,19,25].  
TMPRSS2-ERG fusion status is not known in bone metastasis.  Published data demonstrate that 
TMPRSS2-ERG fusions are early markers for prostate cancer, but their expression is sustained in 
advanced cancers suggesting that fusion activated ERG factor is still functional in tumor cells 
[26].  Both CXCR4 and TMPRSS2-ERG are androgen responsive genes in prostate tumor cells 
[17,18].  Androgen biosynthesis enzyme expression has been shown to be persistent in advanced 
patients, who undergo hormonal therapy [27].   We will analyze the expression of key enzymes 
(SRD5A2, CYP17, CYP3A4, AKR1C3 and HSD17b6) contributing to intratumoral androgen 
biosynthesis. Pre and post treatment tumor tissues in both arms of the study will be analyzed for 
marker expression.  
  
Trinucleotide CAG repeats in AR regulates AR signaling.  AR with shorter repeats 
enhances the AR transcriptional activity compared to the longer repeats [28, 29].  Expression of 
shorter repeats in prostate tumors associates with high grade, PSA expression and high risk of 
biochemical failure [6].  Even though, the length of AR CAG repeat polymorphisms is not risk 
factor for prostate cancer incidence in different ethnic populations[,30, 31], shorter AR CAG 
repeats are highly prevalent in men with African American decent[, 32, 33].  The presence of 
shorter repeats in African American patients translates to stronger AR expression [34, 35] and its 
signaling leading to aggressive disease characteristics.  In the present study we will evaluate AR 
CAG repeat lengths in patient tumor tissues and determine the effect of AR CAG repeat lengths 
on the treatment responsiveness.   
  
Androgen receptor variants lacking ligand binding domain were recently identified in 
castrate resistant prostate cancer patient tumors through deep sequencing of prostate tumor 
tissues[36].  Presence of these variants confer the ligand independent activation of AR thus lead 
to resistant to common AR targeted therapies which commonly attack the AR at ligand binding 
domain.  Even though, there are several types of AR variants identified; their importance in 
prostate cancer progression is currently being actively investigated.  A recent study further shows 


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that expression of AR variant (AR-V7) in hormone naïve patients associated with earlier disease 
relapse in prostatectomy patients [37].  In CRPC patients expression of AR variants inversely 
correlate with survival [34].   Preclinical studies show that expression of AR variants confer 
aberrant androgen independent growth of prostate cancer cells [38].  In addition, AR variant 
expression confers resistance to anti-AR agents.  The prevalence of these AR variants` 
expression in tumor tissues is an active area of investigation to determine the importance of AR 
variant expression on clinical progression of prostate cancer.  In the present study we will 
evaluate the expression of AR variants AR-V1, AR-V6, AR-V7 and AR-v567es expression in 
pretreatment and post treatment groups [39]. Expression of these variants will be evaluated for 
therapy response.     
  
  
10.4 Tissue procurement:  Prostate tumor biopsy specimens will be cut into three pieces, two 
pieces will be snap frozen in liquid nitrogen for RNA and DNA extraction and other will be 
placed in 10% phosphate buffered formalin.  For metastatic tumor biopsies we prefer five core 
biopsies that will be collected for analysis of which two cores will be directly placed into 10 % 
phosphate buffered formalin and processed for decalcification and histological analyses.  
Remaining three core biopsies will be immediately snap-frozen in liquid nitrogen and transported 
to Dr. Chinni’s laboratory, where they will be stored in a -80oC freezer until ready for use.  The 
contact person for tissue collection is Dr. S.R. Chinni at 313 577 1533.   
  
 The technician performing the collection will write on a note sheet  any information on biopsy 
performance, including  comments regarding core quality (long cylindrical core, bone shards, 
mostly blood clot, etc),  the quantity of cores, and any irregularities in the freezing process, along 
with the technician’s name, the biopsy date, and the time of the procedure.  Frozen biopsies 
coming from lesions with more than 60% tumor involvement, as confirmed by review of the 
H&E paraffin-embedded frozen section, will be selected for DNA and RNA extraction and used 
for gene expression and AR CAG repeat measurements and future molecular analysis.  
  
10.5 Methods:  
  
Immunohistochemistry:  Formalin fixation will be performed for 24 hours followed by routine 
procedure of dehydration, paraffin embedding and preparation of tissue sections.  For bone 
biopsy specimens decalcification will be performed in EDTA solution prior to dehydration and 
paraffin embedding.  Histological analyses of the tissue sections will be performed with 
hematoxylin and eosin staining and immunohistochemical analysis will be performed for 
CXCR4, ERG and androgen biosynthesis enzymes (SRD5A2, CYP17, CYP3A4, AKR1C3 and 
HSD17b6).      
  
Gene expression analysis: Frozen tissues will be homogenized and total RNA will be extracted 
using Trizol method.  cDNA will be synthesized from RNA and RT-PCR analysis will be 
performed with gene specific primers to determine the expression of genes in biopsy samples.  
Real Time PCR will be performed with cDNA, gene specific primers and reaction mixture in 
Eppendorf  PCR machine.  CXCR4, ERG, androgen biosynthesis enzymes (SRD5A2, CYP17, 
CYP3A4, AKR1C3 and HSD17b6) and AR variants (AR-V1, AR-V6, AR-V7 and AR-v567es) 


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primers will be used in RT-PCR and amplified band will be analyzed on 0.7 % acrylamide gel 
for detecting presence or absence of gene expression.  The gene expression will be quantitated u  
using the 2-ΔΔCt method, where ΔΔCt = (ΔCttarget gene - ΔCtGAPDH)sample - (ΔCttarget gene - 
ΔCtGAPDH)control. A prostate cancer cell line, VCaP expresses ERG, CXCR4, androgen 
biosynthetic enzymes and AR variants and will be used as a positive control in the experiment.  
  
  
DNA Isolation:  DNA will be isolated from frozen tissue using a Qiagen EZ1 Advanced using 
magnetic bead technology with the “Isolation of DNA from Soft Tissue using the TissueLyser” 
user-developed protocol, the EZ1 DNA Tissue Card, and the EZ1 DNA Tissue Kit.  Purified 
DNA will be quantified by UV spectrophotometry using a DropSense96® Microplate 
Spectrophotometer (Trinean) and the purity assessed based on the A260/A280 and A260/A230 
ratios. A260/A280 ratio of 1.8 is considered good quality DNA.  
  
  
Genotyping:  The Androgen Receptor CAG length polymorphism will be interrogated by PCR 
amplification carried out in a 15 µl reaction containing 20 µmol/l of the gene specific primers 
NED-gcgcgaagtgatccagaa and gttgctgttcctcatcca (Rosa et al, 2006), 1X True Allele PCR Mix  
(Applied Biosystems), and 25 ng genomic DNA. The amplification will be performed on a  
Mastercycler Gradient thermocycler (Eppendorf) with reaction conditions 950C for 10 minutes, 
40 cycles of amplification of 950C for 30 seconds, 60.60C for 30 seconds, and 720C for 30 
seconds followed by a final extension of 720C for 10 minutes. The NED-labeled PCR products 
will be mixed with LIZ-labelled GeneScan™ 500 size standard (Applied Biosystems) and 
electrophoresed on a QuantStudio 12K Flex (Life Technologies). Two DNA standards have been 
established in the Wayne State University Applied Genomics Technology Center by Sanger 
sequencing (AB 3730) for 18 (CEPH 1347-02, Life Technologies) and 21 CAG repeats.  These 
samples will be run on each 96-well plate as positive controls.  No template controls will also be 
run.  The data will be analyzed with GeneMapper (Life Technologies).  
  
DNA Sequencing:  DNA sequencing reactions will be carried out using the 0.5X protocol for  
ABI PRISM BigDye Terminator Cycle Sequencing Ready Reaction Kit (Applied Biosystems).  
The sequencing extension products will be purified utilizing Sephadex.  The purified products 
will be analyzed on an ABI PRISM 3730 DNA Analyzer using a 50 cm capillary array.  
  
10.6 Packaging instructions:  
  
The bone tumor core biopsies will be directly ejected into 10 % formalin PBS and should be sent 
directly to Dr. S.R. Chinni.  Technician collecting the core biopsies should write study ID 
number of the patient and the time and date of collection.  The tubes should be wrapped with a 
bubble wrap to prevent accidental breakage of tube during shipping. The tubes containing core 
biopsies in 10 % formalin PBS should be sent to Dr. SR. Chinni, in a FedEx envelope in a next 
day delivery.  An email should be sent toschinni@med.wayne.edu about the delivery of FedEx 
shipment.  
  
Formalin preserved biopsies of bone tumor cores will be processed in Dr. Chinni’s lab  


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10.7 Shipping instructions for frozen tumor biopsies:   
  
The core should be directly dropped into an empty sterile tube.  The tube containing core biopsy 
should be placed immediately on dry ice.  The dry ice package should be sent on that day (cannot 
be batched) to Dr. SR. Chinni for next day delivery.    
  
Any deviations in collection procedure should be noted and information should be sent to Dr. SR. 
Chinni schinni@med.wayne.edu.  
  
  
Please email Dr Chinni and the data manager Kimberlee Dobson (dobsonk@karmanos.org or Tel 
no 313-576-9837) or a covering data manager regarding the samples that will be sent, with a 
copy of the specimen worksheet that will be mailed with the specimen  
  
A specimen collection worksheet must accompany each shipment. All samples (tumor tissue 
biopsies and archival tissue slides/block) should be clearly labeled with study site, patient 
ID number, date of collection (for fresh biopsies) and then sent to:  
  
Sreenivasa R. Chinni, Ph.D.  
Departments of Urology, Oncology and Pathology,   
KCI, Wayne State University School of Medicine,  
  
9245, Scott Hall 540 
E Canfield Ave 
Detroit, MI 48201.  
Tel # 313-577-1833  
E mail : schinni@med.wayne.edu  
  
Signaling via steroid receptors including androgen receptor (AR) requires sustained ligand 
synthesis.  The hydroxysteroid dehydrogenase (HSD) family of enzymes (such as HSD3B1) are 
critical for AR signaling and the development of CRPC, and likely the development of resistance 
to next generation hormonal therapies including enzalutamide.  We plan to interrogate expression 
of HSD family enzymes pre-enzalutamide treatment, in treatment and with the development of 
resistance.  We suspect that expression of some of these enzymes required for ligand synthesis 
will increase with resistance. One paraffin embedded slide from four patients which have both 
pre and post met biopsy will be sent for this testing. Additional samples maybe sent based on 
availability.  
  
Please contact Marianne Petro Tel no 216 445-9751, E mail petrom@ccf.org prior to sending 
specimen.  
The slides will be sent (depending on tissue availability) to:  
Marianne Petro, Sharifi lab  
Cancer Biology, NB4-137  
Lerner Research Institute  


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Cleveland Clinic Foundation  
2111 East 96th Street  
Cleveland, OH 44106  
  
Additional testing is proposed on metastatic biopsies collected in this study.  Fluorescence in situ 
hybridization will be conducted to determine the gene fusions in biopsy specimens.  This assay 
will be performed by Dr. Nallasivam Palanisamy at Henry Ford Health Systems.  One paraffin 
embedded tissue slide will be given to Dr. Palanisamy and he will utilize fluorescent probes to 
determine the gene fusions.  
Further analysis proposed includes metastatic tissue RNA samples and paraffin embedded slides 
for gene expression studies relevant to prostate cancer growth, metastasis and therapy resistance. 
This testing will be performed in Dr. Chinni laboratory.  
  
10.8 Circulating Tumor Cells (CTC)  
  
In metastatic CRPC, CTC are gaining importance as a method to assess response. In a disease 
where the sites of metastases are mainly in bone which is not measurable disease the CTC counts 
are a critically important less invasive method of predicting response and outcome. CTC counts 
will be measured at baseline (day 1), and month 1 (days 28-42) of therapy. The pre and 
posttherapy CTC counts ;<5/7.5 ml which is considered favorable, vs >5/7.5 ml which is 
considered unfavorable, have been shown to be prognostic in metastatic CRPC patients treated 
with cytotoxic chemotherapy [40].  In multivariable analysis, CTC count using Veridex technology 
was an independent risk factor, influencing overall survival (OS) in a multivariable analysis.  The 
differences in survival associated with CTC count status were clinically and statistically significant 
(e.g., ~1 year, depending on the comparison).  Investigators are now exploring the role of CTC 
counts as surrogate markers of survival in CRPC, especially when used in conjunction with 
cytotoxic chemotherapy.   
  
The CTC counts will be performed by the Correlative Sciences Lab at Karmanos cancer Institute.  
Cell save tube (8ml) for CTC to be collected at baseline, and after 28-42 days of therapy. Cell Save 
Tubes will be provided and should be labeled after collection with study site, patient study ID and 
date and time of collection and shipped within 24 hours (cannot be batched) to:  
A specimen collection worksheet must accompany each shipment. CTC and tumor biopsy 
specimens should only be collected on Mon, Tue or Wed of any week for participating sites 
other than those within Detroit area to allow for prompt shipping and delivery.  
  
Attn: Karri Stark PhD  
Barbara Ann Karmanos Cancer Institute  
Hudson-Webber Cancer Research Center,   
Correlative Sciences Lab Rm 808  
4100 John R. Street  
Detroit, Michigan 48201  
Tel.: 313-576-8248 (lab)  
E mail: starkka@karmanos.orgEmail:wuji@karmanos.org  
  


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Please email Dr Stark and the data manager Kimberlee Dobson (dobsonk@karmanos.org 
or Tel no 313-576-9837) or a covering data manager regarding the samples that will be 
sent, with a copy of the specimen worksheet that will be mailed with the specimen.  
  
           
11.0 STATISTICAL CONSIDERATIONS:  
  
11.1 Primary objective:  
  
To compare the rates of achieving PSA remission at month 7 with LHRH analogue therapy and 
enzalutamide (Arm A) and compare with that achieved with LHRH analogue and bicalutamide 
(Arm B) in metastatic hormone sensitive prostate cancer.   
  
11.2 Secondary Objectives:  
  
1) To compare the primary endpoint by race (African American [AA] vs Other).  
  
2) To compare the rates of each of 2 types of response by treatment arm:  
a) Measurable disease response;     and  
b) PSA response.   
  
3) To compare each of 7 time-to-event endpoints by treatment arm:   
a)  Duration of overall 
response (RD);  
b) Duration of stable disease (SDD);  
c) Time to treatment failure (TTF);  
d) time-to-progression (TTP);  
e) TTP in patients with bone metastases;      
f) progression-free survival (PFS);    and  
g) Overall survival (OS).  
  
4) To compare the rates of each type of toxicity by treatment arm.  
  
5) To compare the incidence rate of skeletal related events (SRE), and the time until SRE, 
separately by treatment arm.  
  
6) To compare the rates of CTC response by treatment arm..  
  
7) To explore the molecular mechanisms within the androgen receptor pathway by determining  
the levels of CXCR4 and TMPRSS2-ERG expression, androgen metabolism enzymes,  
androgen receptor variants, and length of CAG repeats within the androgen receptor gene, and 
to associate them with the primary endpoint.    
  
11.3  Endpoints  
  


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11.3.1 For the primary objective, the binary endpoint will be the achievement of PSA remission 
at month  7 (yes or no).  This endpoint is described in the Study Schema and in Section 
8.1.   
  
11.3.2 For secondary objective (1), the primary endpoint is described in the Study Schema and 
in Section 8.1.   The two race groups to be compared are AA vs Other, as described in the 
Study Schema.  
  
11.3.3 For secondary objective (2), the endpoints will be the achievement of:  
a) measureable disease response (yes or no), (defined in Sections 8.0 and 8.9);  and  
b) PSA response (as defined in Section 8.2).   
  
11.3.4  For secondary objective (3), the endpoints will be the length of censored:  
a) duration of overall response (RD), as defined in Section 8.3;  
b) duration of stable disease (SDD), as defined in Section 8.4;  
c) time to treatment failure (TTF), as defined in Section 8.5;  
h) time-to-progression (TTP), as defined in Section 8.6;  
i) TTP in patients with bone metastases, as defined in Section 8.7;      
j) progression-free survival (PFS), as defined in Section 8.8;    and  
k) overall survival (OS), as defined in Section 8.9.  
  
11.3.5  For secondary objective (4), the endpoints will be the occurrence rate of each specific 
type of toxicity observed (defined in Section 6.0) and treatment arm (A or B, defined in Study 
Schema, Section 5.3, and Section 11.1).     
  
11.3.7 For secondary objective (5), the endpoints will be the occurrence rate of SRE (defined in 
Section 8.12), the distribution of time until SRE, and treatment arm (A or B).   Follow-up for 
SRE will continue until SRE, PSA progression, or death, whichever occurs first.  
  
11.3.8 For secondary objective (6), the endpoints will be the occurrence rate of CTC response 
(defined in Section 8.13), and treatment arm (A or B).  
  
11.3.9 For secondary objective (7), the endpoints will be the expression levels of the selected 
genes or enzymes stated in Section 11.2, length of CAG repeats, and the primary endpoint of 
PSA remission at month 7 (yes or no).   The correlatives are defined and described in Section 
10.0.   The expression level of those biomarkers will be determined in both pre- and 
posttreatment prostate tumor tissues, and in post-treatment bone biopsy samples  
  
11.4  Design, Stratification, and Randomization   
  
11.4.1 Design  
  
   This trial will use a randomized Phase 2 screening design (RP2SD) as described by Rubinstein 
et al [41].   The RP2SD permits a non-definitive comparison of the primary outcome by 
treatment.   With its associated relaxed alpha and/or beta, we are looking for a clinically relevant 


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signal of efficacy differential in the primary endpoint, to determine whether to plan a larger 
subsequent study.  
  
11.4.2 Stratification and Randomization  
  
   Patients will be stratified by race (AA or other) and bone pain (present or absent) into one of 4 
strata.   A separate randomization list for each stratum will prepared in advance by the study 
biostatistician.   Patients will then be randomized to Arm A or Arm B using the 
stratumappropriate randomization list.   Each of the 4 randomization lists (sequences) will 
consist of random permuted blocks of varying sizes.    
  
11.5  
Sample Size Determination  
  
 The assumptions made to permit sample size determination are:  
  
1) The population reference value of  the  proportion of patients achieving (and then  
 
  
2) The hypothesized rate of patients achieving (and then sustaining) PSA  ≤ 4.0 within 7 
months of starting therapy on the experimental arm (i.e., enzalutamide, or Arm A) is 75%;   
  
3) significance level of 0.10, one-sided (in view of the directional hypothesis);   
  
4) power = 0.80;  
  
5) balanced (i.e., 1:1) randomization.  
  
 11.5.1  Under those assumptions, the required sample size is N=41 response-evaluable (r-e)  
patients (defined in Section 8.10) on each arm.   That calculation used the method of Fleiss et al 
[42], and was performed with the nQuery Advisor software, Version 7.0.   The total sample size 
required is 82 patients.   Allowing for up to 10% of patients who might not become r-e, up to 46 
patients per arm (a total of 92 patients) may need to be enrolled.  
  
 11.5.2   Enrollment to this study is expected to be approximately 25-30% AA (from all 
participating institutions).   For better generalization of our study results, we seek a minimum 
accrual of 25 (approximately 30%) evaluable AA patients.   To achieve that goal, it may become 
necessary to close accrual to non-AA patients at some point during the study.   Let p = the 
primary endpoint (the proportion of patients achieving PSA  ≤ 4.0 within 7 months).   With 25 
AA patients, p can be estimated to within 0.183 of its true value with 95% confidence, regardless 
of the level of p.  
  
11.6   Analysis  


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11.6.1 For the primary objective, the binary endpoint (PSA remission at month 7, yes/no) will be 
summarized with its point estimate (an occurrence rate), and 2-sided Wilson type 95% 
confidence interval (CI).   This analysis will be performed two ways:  a) for all randomized 
patients (the intention to treat subset);  and b) for all r-e patients (the per protocol subset). PSA 
response rates will be compared by treatment arm in a stratified logistic regression model, with 
stratification by race (AA, Other) and bone pain (yes, no).    
   
11.6.2 All binary endpoints in secondary objectives 1-2 and 4-7, will be summarized with point 
estimates (occurrence rates), and 2-sided Wilson type 95% CIs.   The analysis of toxicity rates 
will be performed using only the toxicity-evaluable (t-e) patients (defined in Section 8.11).   
  
11.6.3 For secondary objective 4, the grade of each type of toxicity (an ordinal categorical 
variable) will be summarized with 1-way frequency distributions.   A similar descriptive analysis 
will be performed for any correlatives in secondary objective 7 to be assayed by IHC, resulting in 
ordinal categorical variables (intensity levels of 0, 1+, 2+, or 3+).     
    Dichotomized versions (e.g., the occurrence rate of Grade 3-4 neutropenia) will be 
summarized as described in Section 11.6.2.    A similar descriptive analysis will be performed for 
the presence/absence of any correlatives in secondary objective 7 to be assayed by IHC, with 
presence defined as intensity level of 1+ through 3+.  
    For any correlatives in secondary objective 7 that are assayed in both pre- and post-treatment 
prostate tumor tissues, the change in IHC expression level will be described using a 2-way 
frequency distribution.   If the effective sample size appears to be sufficient relative to the size of 
the 2-way table, the association of these paired variables can be tested with the exact version of 
McNemar’s test.   
  
11.6.4 All censored time-to-event distributions for secondary objectives 3 and 5 will be estimated 
with standard Kaplan-Meier (K-M) methodology.   Point and CI estimates of the median and 
various time point-specific rates will be derived from the K-M life table.   The censored K-M 
distributions will be compared with the log-rank test, stratified by race (AA, Other) and bone 
pain (yes, no).    
  
11.6.5 All (uncensored) continuous variables from secondary objective 7 (e.g., ERG or CXCR4 
or AR splice variant level measured by QPCR in frozen tissue, or length of CAG repeats) will be 
summarized with descriptive statistics including the point estimate of the mean, its associated 
95% CI (or 90% CI, depending on N), median, IQR, standard deviation, minimum, and 
maximum.   Gene expression levels reported in terms of the number of fold increases will be 
log2-transformed before summary statistics are calculated.  
   If such variables are pseudo-continuous (e.g., 10-15 unique values), they will also be analyzed 
as categorical variables using 1-way frequency distributions, as described in Section 11.6.3.        
Pre- and post-treatment CTC counts (required to determine CTC response for secondary 
objective 6), will be similarly analyzed as continuous variables.   Depending on their distribution, 
CTC counts will also be analyzed as categorical variables in the manner described in Section 
11.6.5 for length of CAG repeats.  
  


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11.6.6 The association of correlative markers (whether binary, or ordinal categorical, or 
continuous) with a binary clinical outcome (e.g., the primary endpoint of achievement of PSA 
remission at month 7, yes/no) will be explored using exact logistic regression models.   Point and 
CI estimates of the odds ratio (OR) will be calculated, but the statistical interpretation will be 
limited to only the direction, magnitude, and precision of the association (i.e., the OR) as these 
are only exploratory analyses.  
  
11.6.7 The association of correlative markers (whether binary, or ordinal categorical, or 
continuous) with a time-to-event clinical outcome (e.g., OS, PFS, TTP, or time to SRE) will be 
explored using Cox proportional hazards (PH) regression models.   Point and CI estimates of the 
hazard ratio (HR) will be calculated, but the statistical interpretation will be limited to only the 
direction, magnitude, and precision of the association (i.e., the HR) as these are only exploratory 
analyses.  
  
11.7   Accrual rate, accrual duration, and study duration  
  
11.7.1 Six institutions are expected to enroll patients onto this study:   KCI, Henry Ford Hospital, 
University of Alabama at Birmingham, Ohio State University (OSU), Mount Sinai School of 
Medicine, and the Cancer Institute  of New Jersey (CINJ ).   Their accrual rates are expected to 
be similar, at about 5-7 patients/year.  
   
11.7.2 That yields a combined 6-institution expected accrual rate of  30-42 patients/year.   At that 
expected accrual rate, it should take  27-37 months to enroll 92 patients (46 per treatment arm) 
among whom we should have at least 82 (41 per treatment arm) who are r-e for the primary 
endpoint.  
  
11.7.3 Since a follow-up period of up to 7 months is required to determine the primary endpoint 
of the study, then the expected total study duration is  34-44 months.  
  
  
12.0 
ADVERSE EVENTS REPORTING  
  
12.1 
Regulatory and reporting requirements- These will be followed per IND 
requirements (if applicable) as well as sponsor requirements and WSU IRB 
requirements   
12.2 
Definition of Adverse Events (AE)  
  
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered a study drug and which does not necessarily 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 study drug, whether or not related to the study OR   
  


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An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, 
ECG data, physical exam) should be defined as an AE only if the abnormality meets one 
of the following criteria:  
•induces clinical signs or symptoms.  
• 
requires active intervention.  
• 
requires interruption or discontinuation of study medication.  
• 
the abnormality or investigational value is clinically significant in the opinion of the 
investigator.  
  
  
12.3 WSU IRB Adverse Event Reporting Guidelines  
  
Unexpected Problem – Risk to participant or others. A problem that is a) unforeseen b) indicates 
that participants or others are at increased risk of harm, and c) is related or possibly related to the 
research. The following are examples of unexpected problems:  
1. Adverse Event: Any harm experienced by a participant regardless of whether the event was 
internal (on-site) or external (off-site) and regardless of whether the event meets the FDA 
definition of “serious adverse event”, which in the opinion of the principal investigator are 
both unexpected, related (definitely, probably, or more likely than not), and suggests 
that participants are at greater risk than was previously known or recognized.  
a. An adverse event is “unexpected” when its specificity and severity are not 
accurately reflected in the informed consent document, the protocol or the 
investigator’s brochure.  
b. An adverse event is “related to the research procedures” if in the opinion of the 
principal investigator it was more likely than not to be caused by the research 
procedures, or if it is more likely than not that the event affects the rights and 
welfare of current participants.  
2. 
Any harm experienced by a participant or others as a result of involvement in 
research activities (internal or external excluding adverse events).  
3. 
Information that indicates a change to the risks or potential benefits of the 
research. For example:  
a. An interim analysis or safety monitoring report indicates that frequency or 
magnitude of harm or benefit may be different than initially presented to the IRB.  
b. A paper is published from another study that shows the risks or potential benefits 
to your research may be different than initially presented to the IRB.  
c. Study put on hold by the PI, FDA, or the Sponsor for reasons that may include 
safety, toxicity and/or efficacy.  
4. 
A change in FDA labeling or withdrawal from marketing of a drug, device, or 
biologic used in a research protocol.  
5. 
Change to the protocol taken without prior IRB review to eliminate an apparent 
immediate hazard to a research participant.  
6. 
Research conducted without prior WSU IRB approval.  
7. 
Event that requires prompt reporting to the sponsor.  
8. 
Unanticipated adverse device effect: Any serious adverse effect on health or 
safety, or any life-threatening problem or death caused by, or associated with, a 


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device if that effect, problem, or death was not previously identified in natured, 
severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects.  
9. 
Sponsor-imposed suspension for risk.  
10. 
Complaint of a participant when the complaint indicates unexpected risks or 
cannot be resolved by the research team.  
11. 
A breach of confidentiality.  
12. 
Protocol violation/deviation (meaning an accidental or unintentional change to 
the IRB-approved protocol) that harmed participants or others, that indicates 
participants or others may have been placed at increased risk of harm, or rights of 
research participants were violated. For example:  
a. Failure to draw safety labs  
b. Request for continuation submitted late to the IRB three years in a row  
c. Wrong informed consent signed or failure to obtain informed consent  
13. 
Incarceration of a participant in a protocol not approved to enroll prisoners.  
14. 
All deaths that have happened at WSU or one of its affiliates within 30 days 
of the last study intervention, and not related to progressive disease.  
15. 
Any death, if the PI feels that it is significant no matter when it occurs.  
  
IRB Policy  
  
Principal investigators must report any of the above to the IRB as soon as possible, but in all 
cases within 5 working days.  
 


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12.4  
Definition of Serious Adverse Events (SAES)  
  
An AE is considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes:   
  
• 
results in death,  
• 
is life threatening (an ae is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of death. it 
does not include an AE that, had it occurred in a more severe form, might have caused 
death.),  
• 
results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions,   
• 
results in congenital anomaly, or birth defect,  
• 
requires inpatient hospitalization or leads to prolongation of hospitalization  
(hospitalization for treatment/observation/examination caused by ae is to be considered as 
serious),  
• 
other medically important events.  
12.5  
Serious Adverse Event Reporting (SAE)  
The SAE reporting will begin at the time of registration until 30 days after the last dose of either 
Enzalutamide or Bicalutamide. Within 24 hours of awareness of a serious adverse event, 
whether or not related to the study drug, the investigator will complete and submit a 
Medwatch 3500a form, containing all required information (reference 21 CFR 312.32).  
The investigator will submit a copy of this Medwatch 3500a form to the coordinating 
institution (PI- Dr Heath) and Astellas by either e-mail or fax, within the same timeframe. 
Reporting to Astellas is only required for SAEs occurring on patients randomized to Arm 
A.  
The SAE documentation, including the Medwatch 3500A form and available source records 
should be emailed or faxed to:  
Astellas pharma global development – United States  
Email: safety-us@us.astellas.com  
Fax number: (847) 317-1241  
  


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The following minimum information is required:  
• 
study number/IIT regulatory identifier  
• 
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. Follow-up information for the event should be sent 
within 7 days as necessary. Copy of above should also be sent to coordinating site (PI- Dr  
Heath).  
Study Coordination Center/Principal Investigator:   
Elisabeth Heath, MD..D.  
Contact Information 4HWCRC, 4100 John R Detroit 
MI 48201.   
Tel# 313-576-8717 and fax # 313-576-8767 E 
mail: heathe@karmanos.org  
  
Every institution should also report SAE to their respective IRB per institutional guidelines.  


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12.6  
Procedure in case of Pregnancy  
  
The effect of enzalutamide in pregnant and lactating women is not known, and the exposure of a 
fetus or nursing infant is considered a potential risk. enzalutamide can cause fetal harm when 
administered to a pregnant woman based on its mechanism of action. Subjects receiving 
enzalutamide are advised to use 2 acceptable methods of birth control (one of which must 
include a condom as a barrier method of contraception) starting at the time of screening for an 
enzalutamide study and continuing throughout the course of treatment and for at least three 
months after enzalutamide is discontinued.   
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject 
should report the pregnancy to the investigator. the investigator should report the pregnancy to 
the sponsor as an SAEwithin 24 hours of awareness of the event. The expected date of delivery 
or expected date of the end of the pregnancy, last menstruation, estimated fertility date, 
pregnancy result and neonatal data etc., should be included in this information.  
The investigator should report the outcome of the pregnancy (independent of outcome, eg. full 
term delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death of 
newborn, congenital anomaly [including anomaly in a miscarried fetus, etc]  in accordance with 
the same reporting procedure as for SAEs.  The date of outcome of the pregnancy, gestational 
age, date of birth and neonatal data etc., should be included in this information.  
12.7 Protocol amendments, or changes in study conduct  
Any change or addition (excluding administrative) to this protocol requires a written protocol 
amendment that must be reviewed and approved. Amendments significantly affecting the safety 
of subjects, the scope of the investigation or the scientific quality of the study require additional 
approval by the IRB at each study center.  A copy of the written approval of the IRB must be 
provided to. Examples of amendments requiring such approval are:  
1. increases in drug dose or duration of exposure of subjects,  
2. significant changes in the study design (e.g. addition or deletion of a control group),  
3. increases in the number of invasive procedures,  
4. addition or deletions of a test procedure required for monitoring of safety.  
These requirements for approval should in no way prevent any immediate action from being taken 
by the investigator or by in the interests of preserving the safety of all patients included in the trial.  
If an immediate change to the protocol is felt to be necessary by the investigator and is 
implemented for safety reasons PI must be notified and the IRB at the center must be informed 
immediately.   Amendments affecting only administrative aspects of the study do not require 
formal protocol amendments or IRB approval but the IRB must be kept informed of such 


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administrative changes. Examples of administrative changes not requiring formal protocol 
amendments and IRB approval include: 1. changes in the staff used to monitor trials   
2.  
minor changes in the packaging or labeling of study drug    
  
13.0 References:  
  
1. Hussain M, Tangen CM, Higano C, et al. Absolute prostate-specific antigen value after 
androgen deprivation is a strong independent predictor of survival in new metastatic 
prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162). J Clin 
Oncol. 2006 Aug 20;24(24):3984-90.  
2. Hussain M, Tangen CM, Berry DL et al. N Engl J Med 2013 Intermittent versus 
continuous androgen deprivation in prostate cancer. N Engl J Med. 2013 Apr 
4;368(14):1314-25.  
3. Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for 
treatment of advanced prostate cancer. Science 2009; 324(5928):787-790.  
4. AR Pienta KJ, Bradley D. Mechanisms underlying the development of androgen 
independent prostate cancer. Clin Cancer Res 2006; 12(6):1665-1671.  
5. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer 
after chemotherapy. N Engl J Med. 2012 Sep 27;367(13):1187-97  
6. Scher HI, Beer TM, Higano CS et al. Antitumour activity of MDV3100 in castration 
resistant  prostate cancer: a phase 1-2 study. Lancet 2010; 375(9724):1437-1446.   
7. I. Al-Howaidi, L. Shatat, T. Tashi, W, et al. GU ASCO 2011 abstract 199.  
8. Thatai LC, Banerjee M, Lai Z, Vaishampayan U. Racial disparity in clinical course and 
outcome of metastatic androgen-independent prostate cancer. Urology. 2004 
Oct;64(4):738-43.  
9. Thompson I, Tangen C, Tolcher A, et al. Association of African-American ethnic 
background with survival in men with metastatic prostate cancer.J Natl Cancer Inst. 2001 
Feb 7;93(3):219-25.   
10. Roach M 3rd, Lu J, Pilepich MV, Asbell SO, et al. Race and survival of men treated for 
prostate cancer on radiation therapy oncology group phase III randomized trials. J Urol. 
2003 Jan;169(1):245-50.  
11. Bennett CL, Price DK, Kim S,et al. Racial variation in CAG repeat lengths within the 
androgen receptor gene among prostate cancer patients of lower socioeconomic status. J 
Clin Oncol. 2002 Sep 1;20(17):3599-604.  
12. Hatcher D, Daniels G, Osman I, Lee P. Molecular mechanisms involving prostate cancer 
racial disparity. Am J Transl Res. 2009 Apr 20;1(3):235-48.  
13. Sweeney C, Chen YH, Carducci mA, et al. Impact on overall survival (OS) with 
chemohormonal therapy versus hormonal therapy for hormone-sensitive newly metastatic 
prostate cancer (mPrCa): An ECOG-led phase III randomized trial. J Clin Oncol 32;5S 
LBA2, 2014..  
14. Eisenhauer A, Therasse P, Bogaert J, et al. New response evaluation criteria in solid 
tumors. Eur J Cancer 2009, 45: 228-47.  


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15. Scher H, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
with Progressive Prostate Cancer and Castrate Levels of Testosterone: Recommendations 
of the Prostate Clinical Trials Working Group. J Clin Oncol 26(7):1148-59, 2008.  
16. Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, Pienta KJ, 
Taichman RS: Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers 
(PCa) in vivo. J Cell Biochem 2003, 89(3):462-473.  
17. Chinni SR, Sivalogan S, Dong Z, Filho JC, Deng X, Bonfil RD, Cher ML:  
CXCL12/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer 
cells: The role of bone microenvironment-associated CXCL12. The Prostate 2006, 
66(1):32-48.  
18. Chinni SR, Yamamoto H, Dong Z, Sabbota A, Bonfil RD, Cher ML: CXCL12/CXCR4 
Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of 
Metastatic Deposits in Bone. Mol Cancer Res 2008, 6(3):446-457.  
19. Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, Varambally 
S, Cao X, Tchinda J, Kuefer R et al: Recurrent fusion of TMPRSS2 and ETS 
transcription factor genes in prostate cancer. Science 2005, 310(5748):644-648.  
20. Cai J, Kandagatla P, Singareddy R, Kropinski A, Sheng S, Cher ML, Chinni SR:  
Androgens Induce Functional CXCR4 through ERG Factor Expression in TMPRSS2- 
ERG Fusion-Positive Prostate Cancer Cells. Translational oncology 2010, 3(3):195-203.  
21. King JC, Xu J, Wongvipat J, Hieronymus H, Carver BS, Leung DH, Taylor BS, Sander 
C, Cardiff RD, Couto SS et al: Cooperativity of TMPRSS2-ERG with PI3-kinase 
pathway activation in prostate oncogenesis. Nat Genet 2009, 41(5):524-526.  
22. Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, Yfantis HG, Stephens RM, 
Caporaso NE, Loffredo CA, Ambs S: Tumor immunobiological differences in prostate 
cancer between African-American and European-American men. Cancer research 2008, 
68(3):927-936.  
23. Rosen P, Pfister D, Young D, Petrovics G, Chen Y, Cullen J, Bohm D, Perner S, Dobi A, 
McLeod DG et al: Differences in frequency of ERG oncoprotein expression between 
index tumors of Caucasian and African American patients with prostate cancer. Urology 
2012, 80(4):749-753.  
24. Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, Klein E, 
Rubin MA, Zhou M: TMPRSS2-ERG gene fusion prevalence and class are significantly 
different in prostate cancer of Caucasian, African-American and Japanese patients. The 
Prostate 2011, 71(5):489-497.  
25. Mochizuki H, Matsubara A, Teishima J, Mutaguchi K, Yasumoto H, Dahiya R, Usui T, 
Kamiya K: Interaction of ligand-receptor system between stromal-cell-derived factor-1 
and CXC chemokine receptor 4 in human prostate cancer: a possible predictor of 
metastasis. Biochem Biophys Res Commun 2004, 320(3):656-663.  


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26. Cai C, Wang H, Xu Y, Chen S, Balk SP: Reactivation of androgen receptor-regulated 
TMPRSS2:ERG gene expression in castration-resistant prostate cancer. Cancer research 
2009, 69(15):6027-6032.  
27. Stanbrough M, Bubley GJ, Ross K, Golub TR, Rubin MA, Penning TM, Febbo PG, Balk 
SP: Increased expression of genes converting adrenal androgens to testosterone in 
androgen-independent prostate cancer. Cancer research 2006, 66(5):2815-2825.  
28. Ding D, Xu L, Menon M, Reddy GP, Barrack ER: Effect of a short CAG (glutamine) 
repeat on human androgen receptor function. The Prostate 2004, 58(1):23-32.  
29. Strom SS, Gu Y, Zhang H, Troncoso P, Babaian RJ, Pettaway CA, Shete S, Spitz MR, 
Logothetis CJ: Androgen receptor polymorphisms and risk of biochemical failure among 
prostatectomy patients. The Prostate 2004, 60(4):343-351.  
30. Zeegers MP, Kiemeney LA, Nieder AM, Ostrer H: How strong is the association between 
CAG and GGN repeat length polymorphisms in the androgen receptor gene and prostate 
cancer risk? Cancer epidemiology, biomarkers & prevention : a publication of the 
American Association for Cancer Research, cosponsored by the American Society of 
Preventive Oncology 2004, 13(11 Pt 1):1765-1771.  
31. Lange EM, Sarma AV, Ray A, Wang Y, Ho LA, Anderson SA, Cunningham JM, Cooney 
KA: The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer 
susceptibility in African-American men: results from the Flint Men's Health Study. 
Journal of human genetics 2008, 53(3):220-226.  
32. Esteban E, Rodon N, Via M, Gonzalez-Perez E, Santamaria J, Dugoujon JM, Chennawi 
FE, Melhaoui M, Cherkaoui M, Vona G et al: Androgen receptor CAG and GGC 
polymorphisms in Mediterraneans: repeat dynamics and population relationships. Journal 
of human genetics 2006, 51(2):129-136.  
33. Kittles RA, Young D, Weinrich S, Hudson J, Argyropoulos G, Ukoli F, Adams-Campbell 
L, Dunston GM: Extent of linkage disequilibrium between the androgen receptor gene 
CAG and GGC repeats in human populations: implications for prostate cancer risk. 
Human genetics 2001, 109(3):253-261.  
34. Gaston KE, Kim D, Singh S, Ford OH, 3rd, Mohler JL: Racial differences in androgen 
receptor protein expression in men with clinically localized prostate cancer. The Journal 
of urology 2003, 170(3):990-993.  
35. Olapade-Olaopa EO, Muronda CA, MacKay EH, Danso AP, Sandhu DP, Terry TR, 
Habib FK: Androgen receptor protein expression in prostatic tissues in Black and 
Caucasian men. The Prostate 2004, 59(4):460-468.  
36. Watson PA, Chen YF, Balbas MD, Wongvipat J, Socci ND, Viale A, Kim K, Sawyers 
CL: Constitutively active androgen receptor splice variants expressed in 
castrationresistant prostate cancer require full-length androgen receptor. Proceedings of 
the National Academy of Sciences of the United States of America 2010, 
107(39):1675916765.  


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37. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Kong X, Melamed J, Tepper CG, 
Kung HJ et al: A novel androgen receptor splice variant is up-regulated during prostate 
cancer progression and promotes androgen depletion-resistant growth. Cancer research 
2009, 69(6):2305-2313.  
38. Chan SC, Li Y, Dehm SM: Androgen receptor splice variants activate androgen receptor 
target genes and support aberrant prostate cancer cell growth independent of canonical 
androgen receptor nuclear localization signal. The Journal of biological chemistry 2012, 
287(23):19736-19749.  
39. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM: Androgen receptor 
splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell 
lines. Cancer research 2013, 73(2):483-489.  
40. de Bono, J.S., et al., Circulating tumor cells predict survival benefit from treatment in 
metastatic castration-resistant prostate cancer. Clin Cancer Res, 2008. 14(19): p. 6302-9.  
41. Rubinstein L., E. Korn, B. Freidlin, et al.   Design issues of randomized Phase II trials 
and a proposal for Phase II screening trials.   J. of Clinical Oncology, 23(28):7199-7206, 
2005.  
42. Fleiss, J.L., Tytun, A., Ury, S.H.K.    A simple approximation for calculating sample 
sizes for comparing independent proportions.    Biometrics, 36:343-346, 1980.  
  
  
  
  
  
  
                      
14.0 Data and Safety Monitoring   
  
Scheduled meetings/ teleconferences will be held monthly or more frequently depending on the 
activity of the protocol.  These meetings will include the protocol investigators and data 
managers involved with the conduct of the protocol. The Data and Safety Monitoring Committee 
at the coordinating site (Karmanos Cancer Institute) will have oversight of all patients enrolled 
on the trial at all participating sites.   
  
14.1  
During these meetings the investigators will discuss matters related to:  
  
• 
Safety of protocol participants (Adverse Event reporting)  
• 
Validity and integrity of the data  
• 
Enrollment rate relative to expectation of target accrual, characteristics of  
 
participants  
• 
Retention of participants, adherence to the protocol (potential or real protocol 
violations)  


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• 
Data completeness on case report forms and complete source documentation  
  
14.2  Completed Data and Safety Monitoring Reports of these regular investigator meetings 
will be kept on file in the office of the Clinical Trials Core (see form in appendix C). The 
data manager assigned to the clinical trial will be responsible for completing the report 
form.  The completed reports will be reviewed and signed off by the Principal 
Investigator (PI) or by one of the Co-investigators in the absence of the PI.  The signed 
off forms will then be forwarded to the Director, Clinical Trials Core for review of 
completeness and processing with the Data and Safety Monitoring Committee.  
  
14.4  The Barbara Ann KARMANOS Cancer Institute, Data and Safety Monitoring Committee 
will meet on a regular basis to review the prior Serious Adverse Event forms and Data 
and Safety Monitoring study specific reports that have been filed.  
  
15.0 APPENDICES  
  
APPENDIX A: Guidance on Reducing the Risks of Pharmacokinetic Drug-Drug  
Interactions with enzalutamide/MDV3100  
There is a potential for other medicinal products to affect MDV3100 exposures and for 
MDV3100 to affect exposures to other medicinal products. Examples of drugs with the 
potential for drug-drug interactions with MDV3100 are provided below. For the most 
current list of drugs that may be subject to drug-drug interactions, consult the following 
sources:  
  
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionsl 
abeling/ucm093664.htm  
 http://medicine.iupui.edu/clinpharm/ddis/table.aspx  
Potential for Other Medicinal Products to Affect MDV3100 Exposures  
CYP2C8 inhibitors and inducers  
Clinical data indicate that CYP2C8 plays an important role in the metabolism of MDV3100; 
therefore, strong inhibitors (e.g., gemfibrozil) or inducers (e.g., rifampicin) of CYP2C8 
should be used with caution during MDV3100 treatment.  
Potential for MDV3100 to Affect Exposures to Other Medicinal Products  
Enzyme induction  


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Clinical data indicate that MDV3100 is a strong inducer of CYP3A4 and a moderate inducer 
of CYP2C9 and CYP2C19. UGT may be induced as well. These results suggest that 
MDV3100 causes enzyme induction via activation of PXR. Medicinal products with a 
narrow therapeutic range that are substrates of CYP3A4, CYP2C9, CYP2C19, or UGT 
should be used with caution when administered concomitantly with MDV3100 and may 
require dose adjustment to maintain therapeutic plasma concentrations. Such substrates 
include, but are not limited to:  
- Macrolide antibiotics (e.g., clarithromycin)  
- Benzodiazepines (e.g., diazepam, midazolam)  
- Immune modulators (e.g., cyclosporine, tacrolimus)  
- HIV antivirals (e.g., indinavir, ritonavir)  
- Anti-epileptics (e.g., phenobarbitone, phenytoin,)  
- Coumarins (e.g., warfarin)  
- Certain anti-cancer agents (e.g., cabazitaxel, irinotecan, sunitinib)  
In consideration of the long half-life of MDV3100 (approximately 1 week), effects on 
enzymes may persist for 1 month or longer after stopping MDV3100.  
P-gp substrates  
In vitro data indicate that MDV3100 may be a P-gp inhibitor. The effects of MDV3100 on  
P-gp substrates have not been evaluated in vivo; however, under conditions of clinical use, 
MDV3100 may be an inducer of P-gp via activation of PXR. Medicinal products with a 
narrow therapeutic range that are substrates for P-gp (e.g., colchicine, dabigatran etexilate, 
digoxin) should be used with caution when administered concomitantly with MDV3100   


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APPENDIX B  
  
Determination of progression by PSA per PCWG2 criteria  
  
  
  
  
  
Prostate-specific antigen (PSA) progression. An increase of 25% and absolute increase of 2 
ng/mL or more above the nadir. Values A, B, and C show rising PSA values that do not meet the 
criteria. Value D is the first PSA value that is greater than 25% and more than 2 ng/mL above 
the nadir, confirmed with a further rise in PSA shown by value E. For reporting purposes, PSA 
progression would be recorded on the date value D was obtained. (See example above) 
APPENDIX C  
  
Barbara Ann  KARMANOS Cancer Institute Protocol Specific Data and Safety 
Monitoring Report  
  
  
 PROTOCOL  
#:  
  
  
DATE:  


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s 
and date approv ed.  
  
  
OTHER COMM ENTS  
  
  
PROTOCOL TITLE  
  
  
ATTENDANCE  
  
  
  
  
  
  
  
  
  
  
  
  
PROTOCOL ACTIVITY SINCE LAST REPORT  
Accrual Goal: 
List multi-stages 
individually  
  
Accrual to Date: 
List multi-stages 
individually  
  
Date of Last 
Report:  
  
Accrual Since Last 
Report:  
  
Eligible:  
  
Ineligible (provide 
reason):  
  
Specifically for Phase I Trial &/or Dose Escalating Trials:  
Dose Level  Accrual  
  1  
  
  2  
  
  3  
  
SAE REPORTING  List date of occurrence and date IRB notified [attach SAE report 
& SAE spreadsheet].  
1 
  
]  
2 
  
]  
OFF TREATMENT  Provide reason [progression, death, toxicity, completed 
therapy, etc].  
  
  
PROTOCOL VIOLATIONS  Deviations from protocol treatment, monitoring, 
or study calendar.  
  
  
  
PROTOCOL AMENDMENTS  Include date submitted to regulatory bodies  


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Investigator 
Signature:  
  
Data Manager 
Signature: