Clinical trial NCT02685267
Conditions: Prostate Cancer
Sponsor: Prostate Cancer Clinical Trials Consortium
Start date: 2016-02-01; Completion date: 2017-08-01
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a prospective randomized phase II clinical trial where patients who are receiving enzalutamide in the pre-chemotherapy space are randomized upon objective progression (radiographic and/or clinical per PCWG2 criteria) to docetaxel/prednisone alone or the same combination plus enzalutamide.

The primary aim is to evaluate whether continuing enzalutamide in combination with docetaxel in patients who failed or progressed while on enzalutamide would increase progression-free survival (PFS) by 4 months. The secondary end points are PSA responses, percent of patients alive at 1 and 2 years, decline in circulating tumor cells (CTCs), and quality of life (QOL) using validated scales.

Detailed description:

Arms: arm 1: Docetaxel 75 mg/m2 day 1 (every 21-days) plus prednisone 5 mg po bid throughout arm 2: Docetaxel 75 mg/m2 day 1 (every 21-days) plus prednisone 5 mg po bid throughout plus Enzalutamide 160 mg daily throughout. Subjects will continue enzalutamide until PD after 10 cycles of docetaxel.
Interventions: intervention 1: Docetaxel intervention 2: Enzalutamide intervention 3: Prednisone
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 
Docetaxel + Enzalutamide 
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A Phase II Randomized Prospective Trial of Docetaxel/Prednisone Versus Docetaxel/Prednisone  
and Enzalutamide in Castration-Resistant Prostate Cancer (CRPC) Patients Progressing on 
Enzalutamide 
 
 
PCCTC #: c13-126 
IRB#: IRB15-1240 
 
University of Chicago 
Sponsor Investigator/Principal Investigator 
Statistician 
Russell Szmulewitz, M.D. 
Theodore Karrison, PhD 
5841 South Maryland Ave, MC2115 
Chicago, IL 60637 
5841 S. Maryland Ave. |  Room R-314, 
MC2000 Chicago, IL  60637 
email: rszmulew@medicine.bsd.uchicago.edu  
email: karr@uchicago.edu  
Protocol Date: April 10, 2015 
Amended Version Date: March 31, 2017     
CONFIDENTIALITY STATEMENT 
The information in this document is provided to you as an investigator, potential investigator, 
consultant, or contractor, for review by you, your staff, and the appropriate Institutional Review 
Board or Ethics Committee. By accepting this document, you agree that the information contained 
herein will not be disclosed to others without written authorization from the lead site, except to the 
extent necessary to initiate the study or conduct study-related activities. 


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APPROVAL OF PROTOCOL 
 
Title: A Phase II Randomized Prospective Trial of Docetaxel/Prednisone Versus Docetaxel/Prednisone  
and Enzalutamide in Castration-Resistant Prostate Cancer (CRPC) Patients Progressing on Enzalutamide 
 
Sponsor Investigator/ 
Principal Investigator Signature:  
_______________________________________________________ 
Print:  _______________________________________________________ 
Date:  _______________________________________________________ 
Principal Statistician Signature:  
_______________________________________________________ 
Print:  _______________________________________________________ 
Date:  _______________________________________________________ 
PCCTC Signature:  
_______________________________________________________ 
Print:  _______________________________________________________ 
Date:  _______________________________________________________ 


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
ensuring the safety of the study subjects enrolled under my supervision and providing University of 
Chicago with complete and timely information, as outlined in the protocol.  It is understood that all 
information pertaining to the study will be held strictly confidential and that this confidentiality 
requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and 
myself, I agree to maintain the procedures required to carry out the study in accordance with 
accepted GCP principles and to abide by the terms of this protocol. 
 
 
 
 
 
Principal Investigator Signature:  
_______________________________________________________ 
Principal Investigator Print:  
_______________________________________________________ 
Date:   
 
 
 
_______________________________________________________ 
 
 
 


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TABLE OF CONTENTS 
1. INTRODUCTION ..................................................................................................................................................................... 6 
1.1 
Disease Background .............................................................................................................................................................6 
1.2 
Treatment Background .......................................................................................................................................................6 
1.3 
Rationale ................................................................................................................................................................................. 10 
2.  
OBJECTIVES ................................................................................................................................................................... 11 
2.1 
Primary Objective ............................................................................................................................................................... 11 
2.2 
Secondary Objectives ........................................................................................................................................................ 11 
2.3 
Correlative/Exploratory/Tertiary Objectives ....................................................................................................... 11 
3. 
PATIENT SELECTION ................................................................................................................................................. 11 
3.1 
Inclusion Criteria ................................................................................................................................................................ 11 
3.2 
Exclusion Criteria................................................................................................................................................................ 13 
4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION ....................................................................................... 14 
4.1 
Enrollment Plan ................................................................................................................................................................... 14 
4.2 
Registration Procedure .................................................................................................................................................... 14 
4.3 
Randomization ..................................................................................................................................................................... 14 
5. 
TREATMENT/INTERVENTION PLAN .................................................................................................................... 14 
5.1 
Screening / Baseline Assessment (Day -28 to Day -1) ....................................................................................... 16 
5.3 
End of Treatment (30 days of discontinuing treatment) .................................................................................. 18 
5.4 
Follow-up (Every 12 weeks (±7 days) following treatment discontinuation) ........................................ 19 
5.6 
Dose Modifications ............................................................................................................................................................. 20 
5.7 
Concomitant Medications and Supportive Care .................................................................................................... 20 
5.8 
Removing Subjects from Study Treatment ............................................................................................................. 21 
6. 
THERAPEUTIC/DIAGNOSTIC AGENT(S)/MODALITY(-IES) .......................................................................... 22 
6.1 
Enzalutamide ........................................................................................................................................................................ 22 
6.2 
Docetaxel ................................................................................................................................................................................ 25 
7. 
SAFETY EVALUATION ................................................................................................................................................ 30 
7.1 
Definitions .............................................................................................................................................................................. 30 
7.2 
Recording and Grading of Adverse Events .............................................................................................................. 32 
7.3 
Reporting Serious Adverse Events .............................................................................................................................. 33 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE........................................................ 34 
8.1 
Outcome Assessment ........................................................................................................................................................ 34 
8.2 
Therapeutic Response ...................................................................................................................................................... 35 
8.3 
Response Criteria for Control/Relieve/Eliminate Endpoints ......................................................................... 37 
8.4 
Confirmatory Measures/Duration of Response .................................................................................................... 39 
9. 
DATA REPORTING AND REGULATORY REQUIREMENTS .............................................................................. 42 
9.1 
Data Collection and Management ................................................................................................................................ 42 
9.2 
Source Documentation Submission for Registration at Participating Sites ............................................. 42 
9.3 
Study Monitoring and Quality Assurance ................................................................................................................ 42 
10. 
STATISTICAL CONSIDERATIONS ........................................................................................................................... 44 
10.1 Study Endpoints .................................................................................................................................................................. 44 
10.2 Analysis Populations ......................................................................................................................................................... 45 
10.3 Safety Analysis ..................................................................................................................................................................... 46 
10.4 Statistical Procedures (see above) .............................................................................................................................. 46 
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS .............................................................................. 47 
11.1 Roles and Responsibilities .............................................................................................................................................. 47 
11.2 Ethical Considerations ...................................................................................................................................................... 48 
11.3 Protocol Amendments ...................................................................................................................................................... 48 
11.4 Written Informed Consent .............................................................................................................................................. 48 


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11.5 Protection of Privacy ......................................................................................................................................................... 49 
11.6 Terminating or Modifying the Study .......................................................................................................................... 49 
12. 
REFERENCES ................................................................................................................................................................. 50 
Appendix A: Performance Status Criteria ............................................................................................................................. 51 
Appendix B: Medications with the Potential for Drug-Drug Interactions .............................................................. 52 
Appendix C: Laboratory Manual ............................................................................................................................................... 53 
Appendix D: M.D. Anderson Symptom Inventory ............................................................................................................. 54 
Appendix E: Glossary of Abbreviations and Acronyms .................................................................................................. 57 
Appendix F. Pill Diary..................................................................................................................................................................... 59 
Appendix G: PCCTC SAE Report form ..................................................................................................................................... 61 
*Date Signed 
                Click here to enter a date. ........................................................................................................... 64 
  
 


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1. INTRODUCTION
1.1 
Disease Background 
Prostate cancer is the second leading cause of cancer deaths in men. According to American 
Cancer Society estimates in 2014, as many as 233,000 American men will be diagnosed with 
prostate cancer, and nearly 29,480 will die of the disease.1 Yet, localized prostate carcinoma 
is often curable, and even metastatic disease frequently responds to treatment. 
The course of prostate cancer from diagnosis to death is best categorized as a series of 
clinical states (Fig. 1). These clinical states involve the complex interplay of a network of 
signaling molecules that collectively promote net cell proliferation relative to cell death. 
Based on the extent of disease, hormonal status, and absence or presence of detectable 
metastases on an imaging study, the states are localized disease, rising levels of prostate-
specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and 
clinical metastases in the noncastrate or castrate state. 
 
Figure 1 
Clinical states of prostate cancer 
 
 
1.2 
Treatment Background 
1.2.1 
Description and mechanism of action 
Enzalutamide (MDV3100) is an androgen receptor (AR) signaling inhibitor that 
targets several steps in the AR signaling pathway. Enzalutamide competitively 
inhibits binding of androgens to ARs, inhibits nuclear translocation of receptors and 
inhibits the association of the AR with DNA, even in the setting of AR overexpression 
and in prostate cancer cells resistant to antiandrogens.  
 
 
 
 
 
 
 
 
 
 


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Astellas Pharma Global Development, Inc. (Astellas) and Medivation, Inc. 
(Medivation) are developing enzalutamide for the treatment of cancer. 
Enzalutamide was approved in the United States on 31 August 2012 under the trade 
name XTANDI® for the treatment of patients with metastatic castration-resistant 
prostate cancer (CRPC) who have previously received docetaxel. Enzalutamide has 
subsequently been approved in more than 35 countries. Clinical development is 
ongoing for other indications. Enzalutamide, which is formulated with Labrasol® 
(caprylocaproyl macrogolglycerides) and filled into soft gelatin capsules containing 
40 mg of the active pharmaceutical ingredient, is provided as an orally available 
immediate-release dosage form. 
 
 
Preclinical studies 
Nonclinical pharmacology data demonstrate that enzalutamide is an AR signaling 
inhibitor that blocks multiple steps in the AR signaling pathway. Enzalutamide 
competitively inhibits androgen-induced receptor activation, inhibits nuclear 
translocation of AR and inhibits the association of the AR with chromatin. These 
inhibitory effects occur even in the setting of AR overexpression and in prostate 
cancer cells that are resistant to antiandrogens. By inhibiting AR signaling, 
enzalutamide elicits several downstream effects, which include reduced expression 
of AR dependent genes, decreased growth of prostate cancer cells, induction of 
cancer cell death and tumor regression. Enzalutamide lacks agonist activities such 
as those that may limit the sustained efficacy of current antiandrogens. 
Enzalutamide is well absorbed after oral administration to mice, rats, rabbits, 
monkeys and dogs. Tissue distribution data in rats after oral administration of 14C-
enzalutamide showed rapid and extensive distribution to all tissues. Enzalutamide 
is eliminated slowly from plasma with a long t1/2 across species; plasma clearance 
is low, and corresponds to ≤ 5% of liver plasma flow in rats and dogs. 
The major metabolites in human plasma, the carboxylic acid metabolite and N-
desmethyl enzalutamide, have been found in mouse, rat, rabbit, dog and monkey 
plasma. The carboxylic acid metabolite is considered an inactive metabolite based 
on primary pharmacodynamic studies. In addition, the carboxylic acid metabolite 
did not bind to the GABA-gated chloride channel in vitro and had low penetration 
into 
rat 
and 
mouse 
brains. 
In 
contrast, 
the 
primary 
and 
secondary 
pharmacodynamics profiles of N-desmethyl enzalutamide are essentially the same 
as those of enzalutamide. Like enzalutamide, N-desmethyl enzalutamide is thought 
to contribute to the safety and efficacy profiles of enzalutamide in patients. Like 
enzalutamide, N-desmethyl enzalutamide inhibits the GABA-gated chloride channel 
and also partitions readily to the brain; therefore, it is possible that N-desmethyl 
enzalutamide may also be associated with convulsions. 
Quantitative structure activity relationship (QSAR) analysis of the carboxylic acid 
metabolite and N-desmethyl enzalutamide using DEREK software did not show any 
structural alerts that are different from enzalutamide. N-desmethyl enzalutamide is 
structurally similar to enzalutamide, and the toxicological profile of N-desmethyl 


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enzalutamide appears to be very similar to enzalutamide based on the dose-range-
finding studies with N-desmethyl enzalutamide in mice. 
The main findings in repeat-dose oral studies in mice, rats, and dogs were 
histopathological and organ weight changes in reproductive and hormone-sensitive 
tissues, consistent with the pharmacological activity of enzalutamide and similar to 
those reported for other antiandrogens. 
Clinical studies 
The efficacy of enzalutamide in patients with metastatic prostate cancer who 
progressed on androgen deprivation therapy has been demonstrated in two 
randomized controlled phase 3 studies including MDV3100-03 in asymptomatic or 
mildly symptomatic patients and CRPC2 in patients with more advanced disease 
who previously received docetaxel. Both studies showed a statistically significant 
advantage of enzalutamide treatment over placebo across multiple clinically 
relevant endpoints such as overall survival, rPFS, time to first skeletal-related event, 
time to PSA progression, PSA response rate, best overall soft tissue response, and 
quality of life as measured by the FACT-P. Notably, Study MDV3100-03 showed a 
significant benefit of enzalutamide in time to initiation of cytotoxic chemotherapy. 
Additional efficacy data from open-label Studies S-3100-1-01, CRPC-MDA-1, and 
9785-CL-0111 in patients with metastatic CRPC provided supportive data on PSA 
response rate, time to PSA progression, and/or best overall soft tissue response, 
although the magnitude of these treatment effects varied based on the 
characteristics of the enrolled populations. In general, the treatment effect across 
these endpoints was larger in patients with metastatic CRPC who had not yet 
received chemotherapy compared with patients who previously received docetaxel, 
but the benefit was consistently demonstrated across endpoints within a patient 
population. 
In both phase 3 studies of patients with metastatic CRPC, the benefit of 
enzalutamide treatment on overall survival as measured by the estimated hazard 
ratio was observed across all prespecified subgroups. The statistically significant 
benefit on overall survival was also observed despite substantially higher and 
earlier use in the placebo groups compared with the enzalutamide groups of 
subsequent therapies that have demonstrated a survival benefit in patients with 
prostate cancer. These findings limit the ability to observe the isolated treatment 
effect of enzalutamide on this endpoint. This is especially true for MDV3100-03, 
based on the wider availability during this study of subsequent therapies 
demonstrated to prolong survival in patients with metastatic CRPC. 
In Study MDV3100-03, rPFS was a coprimary endpoint and was rigorously 
evaluated through use of blinded central reviewers as well as through a variety of 
sensitivity analyses of this endpoint. The magnitude of the relative treatment benefit 
(unstratified hazard ratio 0.186 [95% CI: 0.149, 0.231]) was coupled with a 
statistically greater best overall radiographic soft tissue response of 58.8% in the 
enzalutamide group versus 5.0% in the placebo group (difference of 53.9% [95% CI: 
48.53, 59.17%]). Another clinically important finding in this patient population with 
earlier-stage disease included a 17.2 month delay in the median time to initiation of 
cytotoxic chemotherapy, which also delays treatment-associated morbidities. The 
decrease in risk of a skeletal-related event and PSA progression, and improvement 


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in radiographic response in enzalutamide-treated patients provide additional 
evidence of clinical benefit. Furthermore, the benefit on time to degradation of 
FACT-P scores suggests that treatment with enzalutamide may prolong quality of 
life. 
In summary, the efficacy results in MDV3100-03 provide evidence of the benefit of 
enzalutamide treatment in asymptomatic or mildly symptomatic patients with 
metastatic prostate cancer who progressed on androgen deprivation therapy, which 
is consistent with the benefit observed with enzalutamide treatment in patients 
with metastatic CRPC who previously received docetaxel. The magnitude of the 
treatment benefit across a range of clinically relevant endpoints demonstrates that 
treatment with enzalutamide not only prolongs life in these patients, but delays the 
onset of disease-related and treatment-related morbidities that can negatively 
impact quality of life. 
The benefit of enzalutamide for men with prostate cancer is consistently observed 
across studies of differing patient populations and across the majority of efficacy 
endpoints assessed. 
Combination studies 
Few studies combined docetaxel and enzalutamide.  Fleming et al established safety 
of this combination.  As CYP34A, an active enzyme that plays a critical role in 
docetaxel clearance, is induced by enzalutamide, understanding how these two 
agents are combined was essential.  To that end, the study presented by Fleming et 
al at ASCO-2013 evaluated the safety and pharmacokinetics of docetaxel when co-
administered with enzalutamide in CRPC patients.  Enrolled patients received 
docetaxel at 75 mg/m2 every 3 weeks.  Enzalutamide was started at 160 mg daily at 
24 hours after cycles 1 and 2 of docetaxel to enable within-subject comparisons of 
docetaxel plus/minus enzalutamide.  Twenty-two patients were enrolled at the time 
of that report.  Safety was established at these standard dose levels and biochemical 
responses were observed. 
1.2.2 
Docetaxel 
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle 
biomass of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-
phenylisoserine, N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-
hexahydroxytax-11-en-9-one 4-acetate 2-benzoate. Docetaxel has the following 
structural formula: 


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Docetaxel is a white to almost-white powder with an empirical formula of 
C43H53NO14, and a molecular weight of 807.88. It is highly lipophilic and 
practically insoluble in water. 
 
Mechanism of action 
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular 
network in cells that is essential for mitotic and interphase cellular functions. 
Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable 
microtubules while simultaneously inhibiting their disassembly. This leads to the 
production of microtubule bundles without normal function and to the stabilization 
of microtubules, which results in the inhibition of mitosis in cells. Docetaxel's 
binding to microtubules does not alter the number of protofilaments in the bound 
microtubules, a feature which differs from most spindle poisons currently in clinical 
use. 
1.3 
Rationale 
Mechanisms by which prostate cancer becomes castration-resistant continue to be 
investigated.  The androgen receptor (AR)-dependent pathway is critical in the evolution of 
CRPC and has led to the development of several therapeutic agents targeting the AR.  
Enzalutamide, a potent AR inhibitor that induces apoptosis, is currently approved for CRPC 
patients who have failed standard cytotoxic docetaxel chemotherapy.  This approval was 
based on a pivotal phase III clinical trial that demonstrated improvement in overall survival 
(OS) in patients treated with enzalutamide versus placebo.  Further, another phase III 
prospective clinical trial has recently been completed in chemotherapy-naïve CRPC patients 
with preliminary data showing improvement in OS in this setting as well.  As more agents 
become available in the chemotherapy-naïve space, it is anticipated that the use of cytotoxic 
chemotherapy will be delayed further but it will remain an integral part of managing 
patients with CRPC. 
Whether patients who progress on enzalutamide and require chemotherapy would benefit 
from continuing enzalutamide remains unknown.  While suppressing the AR pathway is 
appealing in this setting, it is unclear whether this is needed in progressing patients 
transitioning to standard docetaxel chemotherapy. 
Accordingly, we propose a prospective phase II clinical trial where patients who are 
receiving enzalutamide in the pre-chemotherapy space are randomized upon objective 


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(radiographic 
and/or 
clinical 
per 
working 
group 
criteria) 
progression 
to 
docetaxel/prednisone alone or the same combination plus enzalutamide. 
Pivotal studies that have led to docetaxel’s approval in CRPC showed that median time to 
objective disease progression was 6.3 months (Petrylak et al, NEJM, 2004).  However, 
patients treated on these studies were not exposed to contemporary AR-targeting agents 
such as enzalutamide.  While not known, patients receiving docetaxel after enzalutamide 
failures could potentially have faster time to progression (TTP) than the 6.3 months 
previously reported. 
Our primary aim is to evaluate whether continuing enzalutamide in combination with 
docetaxel in patients who failed or progressed while on enzalutamide would increase PFS 
by 4 months (HR 0.60).  Our secondary end points are evaluating PSA responses, percent of 
patients alive at 1 and 2 years, measuring the decline in circulating tumor cells (CTCs), and 
assessing quality of life (QOL) in treated patients using validated scales.  Further, we will 
study the existence of androgen receptor splice variant in patients and assess whether 
adding docetaxel chemotherapy overcomes such mutation. 
Patients on the docetaxel/prednisone/enzalutamide arm are allowed to continue on 
enzalutamide monotherapy (maintenance) after 10 cycles of docetaxel are completed 
provided no evidence of objective disease progression is observed. 
 
 
2.  
OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to compare time to progression in the standard 
treatment 
arm 
(Docetaxel/Prednisone 
alone) 
and 
experimental 
treatment 
arm 
(Docetaxel/Prednisone plus Enzalutamide) 
2.2 
Secondary Objectives 
• Overall Survival (OS) at both 1 year and 2 years from treatment start 
• PSA response in the standard treatment arm and experimental treatment arm 
2.3 
Correlative/Exploratory/Tertiary Objectives 
• Quality of life (QOL)  
• Circulating Tumor Cells (CTCs) 
• Analysis of androgen receptor splice variant  
3. 
PATIENT SELECTION 
 
 
3.1 
Inclusion Criteria 
To be included in this study, patients should meet all of the following criteria: 
• Willing and able to provide written informed consent and HIPAA authorization for the 
release of personal health information. 
NOTE: HIPAA authorization may be either included in the informed consent or 
obtained separately. 


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• Males 18 years of age and above 
• Histologically or cytologically confirmed adenocarcinoma of the prostate without 
neuroendocrine differentiation or small cell features  
• Having documented disease progression on enzalutamide within eight weeks of 
randomization defined by 1 or more of the following criteria: 
• PSA progression according to PCWG2 criteria with 3 consecutive rising PSA 
measurements, all collected at least 1 week apart 
• Radiographic progression in soft tissue or bone by modified RECIST 1.1 for 
subjects with measurable disease; or 
• Bone disease progression defined by 2 or more new lesions on 2 consecutive 
bone scans in the absence of falling PSA 
• Patients who have not had a bilateral orchiectomy must have a plan to maintain effective 
GnRG-analogue therapy for the duration of the trial 
• Serum testosterone level < 50 ng/dL at Screening visit 
• ECOG PS: 0-1 
• Throughout the study, male patients and their female partners of childbearing potential 
must use 2 acceptable methods of birth control (1 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.  Two acceptable 
methods of birth control thus include the following: 
• 
Condom (barrier method of contraception even if having sex with a pregnant 
woman) 
• 
One of the following is required: 
o 
Established use of oral, injected, or implanted hormonal method of 
contraception by the female partner 
o 
Placement of an intrauterine device (IUD) or intrauterine system (IUS) by 
the female partner 
o 
Additional barrier method: Occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository by the female 
partner 
o 
Tubal litigation in the female partner 
o 
Vasectomy or other procedure resulting in infertility (eg, bilateral 
orchiectomy) for >6 months 
• Patients must have adequate organ and marrow function as defined below 
• 
Leukocytes 
 
 
>3,000/mm3 
• 
absolute neutrophil count  
>1,500/mm3 
• 
platelets 
 
 
 
>100,000/mm3 


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• 
total bilirubin 
 
 
within normal institutional limits (or <2X the     
upper limit of normal in those with Gilbert’s disease) 
• 
AST(SGOT)/ALT(SGPT) 
 
<1.5 X institutional upper limit of normal 
• 
creatinine  
 
 
within normal institutional limits 
OR 
• 
creatinine clearance* 
 
>45 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal 
• Estimated life expectancy of > 6 months 
• Able to swallow the study drug as prescribed and comply with study requirements 
3.2 
Exclusion Criteria 
• Prior treatment with docetaxel-based chemotherapy. Chemotherapy given in the 
castration-sensitive setting is permissible if stopped at least 6 months prior to initial 
enzalutamide treatment. 
• Prior treatment with abiraterone acetate 
• Prior treatment with cabazitaxelSevere concurrent disease, infection, or co-morbidity 
that, in the judgment of the Investigator, would make the patient inappropriate for 
enrollment 
• Ongoing investigational treatment 
• Medical conditions such as uncontrolled hypertension, uncontrolled diabetes mellitus, 
cardiac disease that would, in the opinion of the investigator, make this protocol 
unreasonably hazardous 
• Major surgery within 4 weeks of treatment start 
• Use of an investigational therapeutic agent with 4 weeks of treatment start. 
• History of seizure or any condition that may predispose to seizure.   
• History of loss of consciousness or transient ischemic attack within 12 months of 
treatment start 
• Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer 
disease) within 3 months of treatment start 
• Grade > 2 treatment-related toxicity from prior therapy 
• History of hypersensitivity to polysorbate 80 
• Any known allergy to the compounds under investigation 
• Any other condition which, in the opinion of the Investigator, would preclude 
participation in this trial 


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4. 
ENROLLMENT PLAN AND SUBJECT REGISTRATION 
4.1 
Enrollment Plan 
 
4.1.1 
Participating Study Centers 
This study is anticipated to be conducted in 5 sites.  
 
 
4.1.2 
Recruitment 
Potential research subjects will be identified by a member of the patient’s treatment 
team, the protocol investigator, or research team at participating centers.  
Investigators will screen the patient’s medical records for suitable research study 
subjects and discuss the study and their potential for enrolling in the research study.  
4.2 
Registration Procedure 
After eligibility screening and confirmation that a subject is eligible, subjects who are 
selected to participate will be registered through PCCTC Caisis EDC, the PCCTC's Clinical 
Data Management System (CDMS). To complete the registration process, the study site must 
email the signed completed study-specific eligibility checklist, the signed informed consent, 
and registration information to PCCTC, LLC at pcctc@mskcc.org. A record of subjects who 
fail to meet eligibility criteria (i.e., screen failures) will be maintained. Once the enrollment 
packet is received and reviewed at PCCTC, LLC, the subject will be enrolled in PCCTC Caisis 
EDC. Subject registration must be complete before beginning any treatment or study 
activities. A complete, signed study consent and HIPAA authorization are required for 
registration. 
4.3 
Randomization 
Eligible subjects who are progressing on enzalutamide will be randomized in a 1:1 fashion 
to receive docetaxel and prednisone alone or to the same combination plus enzalutamide.  
Randomization will be generated by PCCTC Caisis EDC. 
5. 
TREATMENT/INTERVENTION PLAN 
The following assessments and procedures will occur during the study. A schedule of 
assessments is provided in Table 1. 


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Table 1 
Study Calendar  
Please note, each cycle is 3 weeks (21 Days).  Subjects receiving maintenance enzalutamide (Cycles 11+) will return for assessments monthly 
  
Screening/
Baseline 
Cycle 1/   
Day 1 
C2/      
D1 
C3/       
D1 
C4/        
D1 
C5/       
D1 
C6/       
D1 
C7/       
D1 
C8/ 
D1 
C9/ 
D1 
C10/D
1 
C11+/ 
D11 
EOT 
 
Follow-Up2 
Informed Consent 
X 
 
Physical Exam 
X 
X 
X 
 
Medical history & 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
 
CBC w/ differential3 
X 
X 
X 
 
CMP4 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
X 
 
Testosterone 
X 
X 
X 
X 
X 
X 
 
LDH 
X 
X 
X 
X 
X 
X 
 
Radionuclide Bone Scan  
X 
X 
X 
X 
X5 
X 
 
CT-Scans C/A/P or MRI 
X 
X 
X 
X 
X5 
X 
 
CT-Head or MRI (as 
indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead EKG 
X 
 
Concomitant Meds 
X 
X 
X 
 
AE assessment 
X 
X 
 
QoL assessment6 
X 
X 
X 
X 
X 
 
Survival Status 
X 
Circulating Tumor Cells 
(CTCs)7 
X 
 
 
 
X7 
 
 
X7 
 
 
X7 
 
X7 
 
Analysis of androgen 
receptor splice variant 7 
X 
 
 
 
X7 
 
 
X7 
 
 
X7 
 
X7 
 
Docetaxel8 
X 
 
Prednisone 
X 
 
Enzalutamide9 
X 
 
1. Subjects randomized to the experimental treatment arm (docetaxel/prednisone + enzalutamide) may continue on enzalutamide as a maintenance approach 
following 10 cycles of docetaxel and will return every 4 weeks for routine assessments until progression 
2. Subjects that have discontinued treatment will enter follow-up during which survival status will be confirmed every 12 weeks until death or 24 months post 
treatment. 
3. CBC with differential: white blood cells count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), red cell distribution width (RDW), 
platelet count  (UNVPLT),  neutrophils (NEUTP).  
4. Comprehensive Metabolic Panel includes calcium (CA), creatinine (CREAT), alkaline phosphatase (ALK), alanine transaminase (ALT), aspartate transaminase 
(AST), total bilirubin (TBILI). 
5. Subjects on maintenance enzalutamide therapy will have imaging assessments performed every 6 months following cycle 10. 
6. Qol will be assessed using the M. D. Anderson Symptom Inventory (MDASI).  Please see appendix D 
7. CTCs and androgen receptor splice variant collection will be repeated every 3 cycles  starting at C4/D1 and during progression  
8. Subjects will receive docetaxel on Day 1 of each 21-day cycle   
9. Only for subjects on the docetaxel/prednisone plus enzalutamide arm  
 


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5.1 
Screening / Baseline Assessment (Day -28 to Day -1) 
Before initiating any screening activities, the scope of the study should be explained to each 
patient. Patients should be advised of any known risks inherent in the planned procedures, 
any alternative treatment options, their right to withdraw from the study at any time for 
any reason, and their right to privacy. After this explanation, patients should be asked to 
sign and date a Notice of Privacy Practice research authorization/HIPAA form and an IRB-
approved statement of informed consent that meets the requirements of the Code of 
Federal Regulations (Federal Register Vol. 46, No. 17, January 27, 1981, part 50).
During the screening period, subject eligibility will be determined according to the inclusion 
and exclusion criteria (Sections 3.1 Inclusion Criteria & 3.2 Exclusion Criteria). The 
following assessments will be performed during this time:  
• 
obtain informed consent and research authorization 
• 
record demographics (including age) and medical history (including prior 
treatment for prostate carcinoma) 
• 
obtain histologic and radiologic confirmation of disease 
• 
details and dates of the primary therapy (e.g., pathologic stage, dose and type of 
radiation therapy) 
• 
details and dates of prior hormonal and nonhormonal therapies 
• 
presence or absence of disease in the primary site 
• 
conduct physical exam (vital signs, weight, etc) 
• 
assess ECOG performance status  (Appendix A) 
• 
discuss concurrent medications (see Enzalutamide Package Insert for a listing of 
medications with the potential for drug interactions) 
• 
perform laboratory tests (CBC, comprehensive metabolic panel, PSA, LDH, 
testosterone (TEST)) 
• 
additional PSA measurements that can be used to estimate PSA doubling times 
(PSA-DTs) 
• 
imaging  
o EKG 
o chest by plain radiograph or computerized tomography (CT) 
o abdomen/pelvis by CT or magnetic resonance imaging (MRI) 
o head CT or MRI as indicated 
o radionuclide bone scan 
• 
Quality of Life assessment 
• 
CTCs 
• 
Analysis of androgen receptor splice variant 
 


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5.2 
Treatment/Intervention Period (Day 1 (-3 days) to Day 21 of each cycle) 
Subjects will be seen before each cycle of therapy (up to 3 days before each cycle) for 
toxicity assessment and evaluation.  Subjects will receive docetaxel either alone or with 
enzalutamide up to 10 cycles of therapy. In both intervention arms, subjects will receive 
prednisone at 5 mg po bid throughout therapy but steroids could be omitted if deemed 
appropriate by the treating physician.  Treatment randomization is as described in the 
schema below.  
 
 
 
 
 
 
 
 
 
 
 
*Patients are enrolled to the study once 
objective disease progression is confirmed 
(confirmed progression must be within 8 weeks 
 of randomization to trial) 
The following assessments will be performed during this time: 
x
conduct physical exam (vital signs, weight, etc) 
x
assess ECOG performance status  (Appendix A) 
x
perform laboratory tests (CBC, comprehensive metabolic panel) 
x
discuss concurrent medications (see Enzalutamide Package Insert for a listing of 
medications with the potential for drug interactions) 
x
toxicity assessment 
x
imaging (response assessment using imaging studies will take place before 
cycles 4, 7, and 10) 
R chest by plain radiograph or computerized tomography (CT) 
R abdomen/pelvis by CT or magnetic resonance imaging (MRI) 
R radionuclide bone scan 
x
Quality of Life assessment every 3 cycles  starting at C4/D1 
x
PSA, LDH, testosterone, CTCs every 3 cycles starting at C4/D1   
CRPC patients (using 
standard definition) 
with measurable disease 
radiographically 
Chemotherapy-
naïve patients 
receiving 
enzalutamide at 160 
mg/day 
*Objective 
Disease 
progression 
Docetaxel 75 
mg/m2 day 1 
(every 21-days) 
plus prednisone 5 
mg po bid 
throughout 
Docetaxel 75 mg/m2 
day 1 (every 21-days) 
plus prednisone 5 mg 
po bid throughout Plus 
Enzalutamide 160 mg 
daily throughout 
 Continue enzalutamide 
until PD after 10 cycles of 
docetaxel 


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Subjects randomized to the experimental arm (docetaxel/prednisone plus enzalutamide) 
may continue on enzalutamide as a maintenance approach following 10 cycles of docetaxel.  
Subjects will be asked to return every 4 weeks for the following assessments: 
• 
conduct physical exam (vital signs, weight, etc) 
• 
assess ECOG performance status  (Appendix A) 
• 
discuss concurrent medications (see Enzalutamide Package Insert for a listing of 
medications with the potential for drug interactions) 
• 
toxicity assessment 
• 
Perform laboratory tests (CBC, comprehensive metabolic panel, PSA, LDH, 
testosterone (TEST)) 
• 
imaging (response assessment using imaging studies will take place every 6 
months) 
o chest by plain radiograph or computerized tomography (CT) 
o abdomen/pelvis by CT or magnetic resonance imaging (MRI) 
o radionuclide bone scan 
5.3 
End of Treatment (30 days of discontinuing treatment) 
A subject may be discontinued from study treatment at any time if the patient or the 
Investigator feels that it is not in the patient’s best interest to continue on study.  Please see 
section 5.8 Removing Subjects from the Protocol for a list of possible reasons for early 
discontinuation.  
Subjects withdrawn from the study because of AEs will be followed until the adverse event 
has either resolved or stabilized. 
The following assessments will be performed during this time:  
• 
conduct physical exam (vital signs, weight, etc) 
• 
perform laboratory tests (CBC, comprehensive metabolic panel, PSA, LDH, 
testosterone (TEST)) 
• 
assess ECOG performance status  (Appendix A) 
• 
discuss concurrent medications (see Enzalutamide Package Insert for a listing of 
medications with the potential for drug interactions) 
• 
toxicity assessment 
• 
imaging 
o chest by plain radiograph or computerized tomography (CT) 
o abdomen/pelvis by CT or magnetic resonance imaging (MRI) 
o radionuclide bone scan 
• 
Quality of Life assessment 
• 
CTCs 


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• 
Analysis of androgen receptor splice variant  
5.4 
Follow-up (Every 12 weeks (±7 days) following treatment discontinuation) 
Subjects will be followed for 24 months after removal from treatment or until death. During 
this time, survival status will be confirmed every 12 weeks.  
5.5        Safety assessments 
Medical History 
Medical history findings (i.e. previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected: 
• Pertaining to the study indication 
• Start before signing of the informed consent 
• Considered relevant to the study 
ECOG Performance Status 
Performance status will be assessed using ECOG performance status criteria. See Appendix 
A. 
Vital Signs 
Vital signs include body temperature, blood pressure, respiratory rate, pulse, weight and 
height. Height will be performed at screening only. 
Physical Exam 
The physical exam will include a full review of the body systems.  
Electrocardiogram (ECG) 
Twelve-lead ECGs should be obtained after the patient has been resting for 5-10 minutes 
prior to each time point indicated. All ECGs should be recorded with the patient in the same 
physical position. 
Adverse Event Monitoring 
Subjects will be closely monitored throughout the study for adverse events. Adverse events 
and other symptoms will be graded according to NCI CTCAE v4.0.   
Laboratory Test Assessments 
• CBC with differential: white blood cells count (WBC), red blood cell count (RBC), 
hemoglobin (HGB), hematocrit (HCT), red cell distribution width (RDW), platelet count  
(UNVPLT),  neutrophils (NEUTP).  
• Comprehensive Metabolic Panel includes calcium (CA), creatinine (CREAT), alkaline 
phosphatase (ALK), alanine transaminase (ALT),  aspartate transaminase (AST), total 
bilirubin (TBILI). 
• Serum PSA (PSA) 
• Lactate dehydrogenase (LDH) 
• Testosterone (TEST) 
 


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Tumor Assessment and Bone Scan 
Radiographic disease assessment will be obtained every 3 cycles during active treatment 
(starting at Cycle 4). 
5.6 
Dose Modifications 
5.6.1     Docetaxel 
Docetaxel should not be given to patients with bilirubin levels above the ULN, with 
AST and/or ALT> 1.5-fold ULN, or with alkaline phosphate >2.5-fold ULN. 
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients who receive 
60 mg/m2 to 100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) 
occurs in approximately 85% of patients who receive 100 mg/m2 and 
approximately 75% of patients who receive 60 mg/m2 of docetaxel.  Febrile 
neutropenia occurs in approximately 12% of patients who receive 100 mg/m2, but 
is uncommon in patients who receive 60 mg/m2 of docetaxel.  The following 
treatment emergent adverse reactions occurred at higher rates (>10%) in patients 
65 years or older compared to younger patients: anemia (71% vs 59%), infection 
(37% vs 24%), nail changes (34% vs 23%), anorexia (21% vs 10%), and weight loss 
(15% vs 5%), respectively. 
Patients who experience either febrile neutropenia, neutrophils <500 cells/mm3 for 
more than 1 week, severe or cumulative cutaneous reactions, or moderate 
neurosensory signs and/or symptoms during docetaxel therapy should have the 
dosage of docetaxel reduced from 75 to 60 mg/m2.  If the patient continues to 
experience these reactions at 60 mg/m2, the treatment should be discontinued.  Any 
other Grade 3 or 4 possibly-related nonhematologic toxicity may be considered dose 
limiting at the discretion of the Investigator. 
• 
Docetaxel is contraindicated in patients who have a history of severe 
hypersensitivity reactions to docetaxel or to other drugs formulated with 
polysorbate 80 
• 
Docetaxel should not be used in patients with neutrophil counts <1500 
cells/mm3 
• 
Hypersensitivity reactions may occur within a few minutes following 
initiation of a docetaxel infusion.  If minor reactions such as flushing or 
localized skin reactions occur, interruption of therapy is not required.  All 
patients should be premedicated with an oral corticosteroid prior to the 
initiation of the infusion of docetaxel. 
5.6.2     Enzalutamide 
Evidence of seizure will be considered a DLT warranting cessation of enzalutamide.  
If a patient experiences a ≥ Grade 3 toxicity or an intolerable side effect, withhold 
dosing for one week or until symptoms improve to ≤ Grade 2, then resume at the 
same or a reduced dose (120 mg or 80 mg).  
5.7 
Concomitant Medications and Supportive Care 
Because of the potential for drug-drug interaction, the concurrent use of all other drugs, 
over-the-counter medications, and alternative therapies must be documented on the CRF. 


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The principal investigator should be alerted if the patient is taking any agent included in the 
list of medications with the potential for drug-drug interactions found in the Enzalutamide 
Package Insert.  
The following medications are prohibited within 4 weeks of Study Day 1, unless otherwise 
indicated below: 
• 
Androgens 
• 
Potent CYP3A4/5 and CYP2C8 inhibitors or inducers 
• 
Use of an investigational agent, unless prior approval by the Investigator for a 
shorter washout period, provided the patient has adequately recovered from any 
ongoing adverse events. 
Hormonal treatment for treating complications of GnRH analogue treatment is allowed. 
The doses of the following medication classes should be maintained during the Screening 
Period and while actively treated with study drug: 
• 
Biphosphonates or other approved bone targeting agents for the treatment of 
metastatic prostate cancer 
• 
GnRH analogues 
The following treatments are allowed during the study (and do not require study drug 
discontinuation) including, but not limited to: 
• 
Blood transfusions and growth factor support per standard of care and institutional 
guidelines 
• 
Pain therapy per standard of care and institutional guidelines 
• 
Radiation therapy including external beam radiotherapy or systemic radionuclides 
(e.g., Samarium or Strontium) 
• 
Palliative surgical procedures to treat skeletal related events 
Androgen deprivation therapy (either bilateral orchiectomy or GnRH analogue hormone 
agonist/antagonist) must be continued during the trial.  If androgen deprivation therapy is 
discontinued, the patient must be withdrawn from study treatment. 
5.8 
Removing Subjects from Study Treatment 
In the absence of treatment delays because of adverse events, treatment will continue for a 
maximum of 10 cycles of docetaxel or until one of the following criteria applies: 
• 
subject decides to withdraw from the study 
• 
disease progression 
• 
symptomatic disease progression at any time 
• 
objective clinical disease progression 
• 
intercurrent illness that prevents further administration of treatment 


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• 
unacceptable adverse event(s) that may or may not be directly related to 
treatment but that, in the judgment of the treating physician, makes it 
dangerous for the subject to be retreated 
• 
general or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment, in the judgment of the investigator 
Because an excessive rate of withdrawals can render the study uninterruptable, 
unnecessary withdrawal of subjects should be avoided. When a subject discontinues 
treatment early, the investigator should make every effort to contact the subject and to 
follow the patient for study endpoints. If the patient withdraws entirely from the trial and 
refuses further follow-up, a final evaluation should be performed. The reason(s) for 
withdrawal should be recorded. 
Patients on the docetaxel/prednisone/enzalutamide arm are allowed to continue on 
enzalutamide monotherapy (maintenance) after 10 cycles of docetaxel are completed 
provided no evidence of objective disease progression was observed. Patients 
on 
the 
docetaxel/prednisone/enzalutamide arm who discontinue docetaxel for treatment-related 
side effects prior to completion of 10 cycles may continue with enzalutamide maintenance 
therapy. 
6. 
THERAPEUTIC/DIAGNOSTIC AGENT(S)/MODALITY(-IES) 
 
6.1 
Enzalutamide 
 
6.1.1     Description of Treatments 
Enzalutamide is provided as liquid-filled soft gelatin capsule for oral administration. 
Each capsule contains 40 mg of enzalutamide. The inactive ingredients are 
caprylocaproyl polyoxylglycerides (Caprylocaproyl macrogolglycerides [European 
Pharmacopoeia]),butylated hydroxyanisole, butylated hydroxytoluene, gelatin, 
sorbitol sorbitan solution, glycerin, purified water, titanium dioxide and black iron 
oxide.  
 
6.1.2 
Pharmacokinetics 
The pharmacokinetics and metabolism of enzalutamide have been evaluated in 
more than 2500 patients with prostate cancer and in more than 200 volunteers, 
including healthy male subjects and subjects with mild or moderate hepatic 
impairment. Individual daily doses have ranged from 30 to 600 mg. 
Pharmacokinetic studies of enzalutamide in women have not been completed. 
Tissue distribution data in rats after oral administration of 14C-enzalutamide 
showed rapid and extensive distribution to all tissues. Data in rodents suggest that 
enzalutamide and N-desmethyl enzalutamide readily partition into the brain. In 
vitro protein binding of enzalutamide in human plasma is 97% to 98% and is 
comparable across species. The extent of plasma protein binding is constant over a 
wide range of concentrations (0.05 to 25 μg/mL). Albumin is the major binding 
protein for enzalutamide in human plasma; other human plasma proteins to which 
enzalutamide binds (in order of decreasing importance) are high density 
lipoprotein, low density lipoprotein, α1-glycoprotein and γ-globulin. In vitro protein 


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binding of N-desmethyl enzalutamide in human plasma was 95%, comparable 
across species and constant over a wide range of concentrations (0.5 to 25 μg/mL). 
Oral absorption of enzalutamide, whether administered as single or multiple doses, 
is rapid and independent of dose. Peak concentrations of enzalutamide are generally 
achieved 1 to 2 hours postdose in both patients and healthy subjects. The rapid 
attainment of Cmax is consistent with rapid dissolution of the capsule and release of 
solubilized enzalutamide into the gut lumen. Enzalutamide is well absorbed 
(estimated bioavailability based on mass balance data ≥ 84.2%); an expected finding 
for a low extraction ratio drug that displays high permeability and that is not a 
substrate for P-gp or BCRP.  A high-fat meal reduces the rate of enzalutamide 
absorption but the extent of absorption is unaffected. Enzalutamide has been 
administered without regard to meals in clinical trials in patients, including the 
pivotal phase 3 Studies MDV3100-03 and CRPC2. 
A single dose of 160 mg (100 μCi) 14C-enzalutamide was administered orally to 
healthy subjects to assess mass balance and to obtain metabolic profiles (Study 
9785-CL-0001). A total of 7 phase I metabolites were identified in plasma, urine and 
feces by comparison with reference standards and liquid chromatography with 
multiple stage mass spectrometry methods (Study 9785-ME-0020). These 
metabolites were formed via demethylation, oxidation and hydrolysis reactions. No 
phase II conjugation products were observed. The major metabolites in humans 
were an inactive carboxylic acid metabolite and an active Ndesmethyl metabolite of 
enzalutamide (N-desmethyl enzalutamide). Biotransformation pathways in animals 
and humans were similar. As 14C recovery was generally 100% during sample 
extraction procedures, there do not appear to be reactive metabolites in humans. 
The carboxylic acid metabolite and N-desmethyl enzalutamide are formed slowly. 
After a single 160 mg dose of enzalutamide in healthy subjects, peak plasma 
concentrations of the carboxylic acid metabolite are typically achieved 4 to 6 days 
postdose and peak plasma concentrations of N-desmethyl enzalutamide are 
typically achieved 5.5 to 6 days postdose. At steady state, the active metabolite N-
desmethyl enzalutamide circulates at approximately the same plasma concentration 
as enzalutamide; whereas, plasma concentrations of the inactive carboxylic acid 
metabolite are approximately 25% lower than enzalutamide (Study 9785-CL-0001). 
In vitro studies show that enzalutamide is metabolized by CYP2C8 and CYP3A4/5, 
both of which play a role in the formation of N-desmethyl enzalutamide (Study 
9785-ME-0001). A clinical DDI study in healthy volunteers (Study 9785-CL-0006) 
revealed that CYP2C8 plays an important role in the metabolism of enzalutamide 
and the formation of N-desmethyl enzalutamide. 
6.1.3 
Dosage Selected, Preparation, and Schedule of Administration 
Enzalutamide will be administered at the standard dose of 160 mg orally. Patients 
will continue on that dose unless toxicities that require dose reductions are 
observed.  Docetaxel will be given at the standard dose of 75 mg/m2 intravenously 
every 21-days. Prednisone will be given at 5 mg orally twice daily. Prednisone may 
be tapered or omitted per investigators discretion. In the experimental arm, and 
after 10 cycles of docetaxel, patients are allowed to continue on enzalutamide 


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monotherapy at 160 mg daily as a maintenance approach.  Patients on the 
enzalutamide arm will be asked to keep a drug diary.  Premedications and 
precautions for both agents (docetaxel and enzalutamide) are as specified above.  
Treatment will be delivered as an outpatient. 
 
6.1.3.1 Supply, storage requirements, and special handling 
Supply and packaging 
Capsules are packaged as a 1-month supply in bottles with child-resistant 
caps or 4- to 5-week supply in blister packs. 
 
Storage requirements 
Store at room temperature (≤ 25°C). For more information please follow the 
storage instructions provided on the drug product label.  
6.1.4     Supportive Care Medications 
Medications taken within 7 days before the Screening visit and up to the first dose of 
study medication will be documented on the appropriate case report form (CRF) as 
a prior medication.  Medications taken after the first dose of study medication up to 
the Study Completion visit will be documented on the appropriate CRF as 
concomitant medication. All concomitant medication(s) must be reported on the 
appropriate CRF.  Prior and concomitant medications include all vitamins, herbal 
remedies, over the counter, and prescription medications.  If an intermittent or as 
needed use of any medication during the study is due to an adverse event, then the 
adverse event must also be recorded on the PCCTC SAE Report form. 
6.1.5     Prohibited before enrollment and during administration of study treatment 
Patients should have not received any investigational therapeutic agent for 28-days 
before being randomized.  If radiotherapy was given, a 2-week washout period must 
elapse before randomization. 
6.1.6     Potential for drug-drug interactions 
The potential for enzalutamide to affect the pharmacokinetics of other drugs was 
assessed through a series of in vitro experiments. Based on in vitro findings, an in 
vivo phenotypic cocktail DDI trial was performed in patients with CRPC (Study 
9785-CL-0007). In this study, a single oral dose of the CYP probe substrate cocktail 
(for CYP2C8, CYP2C9, CYP2C19 and CYP3A4) was administered before and 
concomitantly with enzalutamide (following at least 55 days of dosing at 160 mg 
daily). At steady state, enzalutamide is a strong CYP3A4 inducer and a moderate 
CYP2C9 and CYP2C19 inducer. Enzalutamide did not cause clinically meaningful 
changes in exposure to the CYP2C8 substrate. 
In a DDI trial in patients with metastatic CRPC, intravenously administered 
docetaxel (CYP3A4 substrate) was given before and concomitantly with 
enzalutamide (after at least 21 days of dosing at 160 mg daily). The results showed 
that enzalutamide did not cause a clinically meaningful change in exposure to the 
intravenously administered CYP3A4 substrate. 
An in vitro study to assess the potential for DDIs with enzalutamide via 
displacement from protein binding sites in human plasma showed that 


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enzalutamide does not displace the binding of other highly bound drugs (warfarin, 
ibuprofen, and salicylic acid; Study 9785-ME-0017). 
6.2 
Docetaxel 
 
 
6.2.1  
Description of Treatments 
 
 
 
 
Docetaxel is a white to almost-white powder with an empirical formula of 
C43H53NO14, and a molecular weight of 807.88. It is highly lipophilic and 
practically insoluble in water.  Docetaxel Injection is a clear, colorless to pale yellow 
solution. Docetaxel Injection is sterile, non-pyrogenic, and is available in multiple 
dose vials, supplied as 20 mg/2 mL, 80 mg/8 mL and 160 mg/16 mL. 
Each mL of Docetaxel Injection contains 10 mg docetaxel, 275.9 mg alcohol 96% 
(v/v), 4 mg citric acid, 648 mg polyethylene glycol 300, and 80 mg polysorbate 80. 
 
6.2.2 
Pharmacokinetics 
Absorption 
The pharmacokinetics of docetaxel have been evaluated in cancer patients after 
administration of 20 mg/m2 to 115 mg/m2 in phase 1 studies. The  area under the 
curve (AUC) was dose proportional following doses of 70 mg/m2 to  115 
mg/m2 
with infusion times of 1 to 2 hours. Docetaxel's pharmacokinetic profile is consistent 
with a three-compartment pharmacokinetic model, with half-lives for the α, β, and γ 
phases of 4 min, 36 min, and 11.1 hr, respectively. Mean total body  clearance was 
21 L/h/m2. 
Distribution 
The initial rapid decline represents distribution to the peripheral compartments and 
the late (terminal) phase is due, in part, to a relatively slow efflux  
of 
docetaxel 
from the peripheral compartment. Mean steady state volume of distribution was 
113 L. In vitro studies showed that docetaxel is about 94% protein  bound, mainly 
to α1-acid glycoprotein, albumin, and lipoproteins. In three cancer  patients, the in 
vitro binding to plasma proteins was found to be approximately 97%. 
Dexamethasone does not affect the protein binding of docetaxel. 
Metabolism 
In vitro drug interaction studies revealed that docetaxel is metabolized by the 
CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant 
administration of compounds that induce, inhibit, or are metabolized by cytochrome 
P450 3A4.  
Elimination 
A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was 
eliminated in both the urine and feces following oxidative metabolism of the tert-
butyl ester group, but fecal excretion was the main elimination route. Within 7 days, 
urinary and fecal excretion accounted for approximately 6% and 75% of the 
administered radioactivity, respectively. About 80% of the radioactivity recovered 
in feces is excreted during the first 48 hours as 1 major and 3 minor metabolites 
with very small amounts (less than 8%) of unchanged drug. 


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Effect of age  
A population pharmacokinetic analysis was carried out after docetaxel treatment of 
535 patients dosed at 100 mg/m2. Pharmacokinetic parameters estimated by this 
analysis were very close to those estimated from phase 1 studies. The 
pharmacokinetics of docetaxel were not influenced by age. 
Effect of gender  
The population pharmacokinetics analysis described above also indicated that 
gender did not influence the pharmacokinetics of docetaxel. 
 
Hepatic impairment 
The population pharmacokinetic analysis described above indicated that in patients 
with clinical chemistry data suggestive of mild to moderate liver impairment (AST 
and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times 
ULN), total body clearance was lowered by an average of 27%, resulting in a 38% 
increase in systemic exposure (AUC). This average, however, includes a substantial 
range and there is, at present, no measurement that would allow recommendation 
for dose adjustment in such patients. Patients with combined abnormalities of 
transaminase and alkaline phosphatase should not be treated with Docetaxel 
Injection. Patients with severe hepatic impairment have not been studied.  
 
Effect of race  
Mean total body clearance for Japanese patients dosed at the range of 10 mg/m2 to 
90 mg/m2 was similar to that of European/American populations dosed at 100 
mg/m2, suggesting no significant difference in the elimination of docetaxel in the 
two populations. 
 
6.2.3 
Dosage Selected, Preparation, and Schedule of Administration 
 
How supplied 
 
 
Docetaxel Injection is supplied in a multiple dose vial as a sterile, pyrogen-free  
 
 
solution. Docetaxel Injection requires NO prior dilution with a diluent and is ready  
 
 
to add to the infusion solution. The following strengths are available: 
 
Strength 
NDC Number 
Volume 
20 mg/2 mL 
66758-050-01 
Carton of 1 x 2 mL Multiple Dose Vial 
80 mg/8 mL 
66758-050-02 
Carton of 1 x 8 mL Multiple Dose Vial 
160 mg/16 mL 
66758-050-03 
Carton of 1 x 16 mL Multiple Dose Vial 
 
Storage 
Store between 2°C and 25°C (36°F and 77°F). Retain in the original package to 
protect from bright light. Freezing does not adversely affect the product. 
After initial puncture, Docetaxel Injection multiple dose vials are stable for 28 days 
when stored between 2°C to 8°C and at room temperature, with or without 
protection from light. 
Docetaxel is approved for the treatment of breast cancer, gastric cancer, lung cancer, 
head and neck cancer, and prostate cancer.  In prostate cancer, the drug is currently 


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approved in the CRPC state at a dose of 75 mg/m2 given every 3 weeks along with 
prednisone given at 5 mg twice daily.   
Docetaxel Injection is a cytotoxic anticancer drug and, as with other potentially toxic 
compounds, caution should be exercised when handling and preparing Docetaxel 
Injection solutions. The use of gloves is recommended. 
 
 
If Docetaxel Injection or diluted solution for intravenous infusion should come into 
contact with the skin, immediately and thoroughly wash with soap and water. If 
Docetaxel Injection or diluted solution for intravenous infusion should come into 
contact with mucosa, immediately and thoroughly wash with water. 
Contact of the Docetaxel Injection with plasticized PVC equipment or devices used to 
prepare solutions for infusion is not recommended. In order to minimize patient 
exposure to the plasticizer DEHP (di-2-ethylhexyl phthalate), which may be leached 
from PVC infusion bags or sets, the final Docetaxel Injection dilution for infusion 
should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, 
polyolefin) and administered through polyethylene-lined administration sets. 
Docetaxel Injection requires dilution prior to administration. Please follow the 
preparation instructions provided below. 
Preparation and administration 
Docetaxel Injection (10 mg/mL) requires NO prior dilution with a diluent and is 
ready to add to the infusion solution. 
Dilution for infusion 
1. Aseptically withdraw the required amount of Docetaxel Injection solution (10 
mg docetaxel/mL) with a calibrated syringe and inject (as a single injection) into 
a 250 mL infusion bag or bottle of either 0.9% Sodium Chloride solution or 5% 
Dextrose solution to produce a final concentration of 0.3 to 0.74 mg/mL.  If a 
dose greater than 200 mg of Docetaxel Injection is required, use a larger volume 
of the infusion vehicle so that a concentration of 0.74 mg/mL Docetaxel Injection 
is not exceeded. 
2. Thoroughly mix the infusion bag or bottle manually by gentle inversion and 
rotation in a controlled manner and avoid foaming. Shaking or vigorous 
agitation should be avoided during preparation and transportation to the 
patient for administration. 
3. As with all parenteral products, Docetaxel Injection should be inspected visually 
for particulate matter or discoloration prior to administration whenever the 
solution and container permit. If the Docetaxel Injection vial or diluted solution 
is not clear or appears to have precipitation, these should be discarded.  The 
Docetaxel Injection diluted solution for infusion should be administered 
intravenously as a 1-hour infusion under ambient room temperature below 
25°C (77°F) and lighting conditions. 
Overdosage 
There is no known antidote for Docetaxel Injection overdosage. In case of 
overdosage, the patient should be kept in a specialized unit where vital functions 
can be closely monitored. Anticipated complications of overdosage include: bone 


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marrow suppression, peripheral neurotoxicity, and mucositis. Patients should 
receive therapeutic G-CSF as soon as possible after discovery of overdose. Other 
appropriate symptomatic measures should be taken, as needed. 
In two reports of overdose, one patient received 150 mg/m2 and the other received 
200 mg/m2 as 1-hour infusions. Both patients experienced severe neutropenia, mild 
asthenia, cutaneous reactions, and mild paresthesia, and recovered without 
incident. 
 
 
 
Toxic deaths 
Breast Cancer. Docetaxel administered at 100 mg/m2 was associated with deaths 
considered possibly or probably related to treatment in 2.0% (19/965) of 
metastatic breast cancer patients, both previously treated and untreated, with 
normal baseline liver function and in 11.5% (7/61) of patients with various tumor 
types who had  abnormal baseline liver function (AST and/or ALT >1.5 times ULN 
together with AP >2.5 times ULN). Among patients dosed at 60 mg/m2, mortality 
related to treatment occurred in 0.6% (3/481) of patients with normal liver 
function, and in 3 of 7  patients with abnormal liver function. Approximately half of 
these deaths occurred  during the first cycle. Sepsis accounted for the majority of the 
deaths. 
Non-Small Cell Lung Cancer. Docetaxel administered at a dose of 100 mg/m2 in 
patients with locally advanced or metastatic non-small cell lung cancer who had a 
history of prior platinum-based chemotherapy was associated with increased 
treatment-related mortality (14% and 5% in two randomized, controlled studies). 
There were 2.8% treatment-related deaths among the 176 patients treated at the 75 
mg/m2 dose in the randomized trials. Among patients who experienced treatment-
related mortality at the 75 mg/m2 dose level, 3 of 5 patients had an ECOG PS of 2 at 
study entry  
 
 
 
Hepatic impairment 
 
 
Patients with combined abnormalities of transaminases and alkaline phosphatase  
 
 
should not be treated with Docetaxel Injection  
 
 
Hematologic effects 
Perform frequent peripheral blood cell counts on all patients receiving Docetaxel 
Injection. Patients should not be retreated with subsequent cycles of Docetaxel 
Injection until neutrophils recover to a level >1500 cells/mm3 and platelets recover 
to a level > 100,000 cells/mm3. 
A 25% reduction in the dose of Docetaxel Injection is recommended during 
subsequent cycles following severe neutropenia (<500 cells/mm3) lasting 7 days or 
more, febrile neutropenia, or a grade 4 infection in a Docetaxel Injection cycle  
Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 
mg/m2 to 100 mg/m2 of docetaxel and grade 4 neutropenia (<500 cells/mm3) 
occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. 
Frequent monitoring of blood counts is, therefore, essential so that dose can be 
adjusted. Docetaxel Injection should not be administered to patients with 


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neutrophils <1500 cells/mm3. 
Febrile neutropenia occurred in about 12% of patients given 100 mg/m2 but was 
very uncommon in patients given 60 mg/m2. Hematologic responses, febrile 
reactions and infections, and rates of septic death for different regimens are dose 
related. 
Three breast cancer patients with severe liver impairment (bilirubin >1.7 times 
ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced 
thrombocytopenia. In gastric cancer patients treated with docetaxel in combination 
with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic 
infection occurred in 12% of patients receiving G-CSF compared to 28% who did 
not. Patients receiving TCF should be closely monitored during the first and 
subsequent cycles for febrile neutropenia and neutropenic infection  
Hypersensitivity reactions 
Patients should be observed closely for hypersensitivity reactions, especially during 
the first and second infusions. Severe hypersensitivity reactions characterized by 
generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal 
anaphylaxis, have been reported in patients premedicated with 3 days of 
corticosteroids. 
Severe 
hypersensitivity 
reactions 
require 
immediate 
discontinuation of the Docetaxel Injection infusion and aggressive therapy. Patients 
with a history of severe hypersensitivity reactions should not be rechallenged with 
Docetaxel Injection. 
Hypersensitivity reactions may occur within a few minutes following initiation of a 
Docetaxel Injection infusion. If minor reactions such as flushing or localized skin 
reactions occur, interruption of therapy is not required. All patients should be 
premedicated with an oral corticosteroid prior to the initiation of the infusion of 
Docetaxel Injection  
Fluid retention 
Severe fluid retention has been reported following docetaxel therapy. Patients 
should be premedicated with oral corticosteroids prior to each Docetaxel Injection 
administration to reduce the incidence and severity of fluid retention.  Patients with 
pre-existing effusions should be closely monitored from the first dose for the 
possible exacerbation of the effusions. 
When fluid retention occurs, peripheral edema usually starts in the lower 
extremities and may become generalized with a median weight gain of 2 kg. 
Among 92 breast cancer patients premedicated with 3-day corticosteroids, 
moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The 
median cumulative dose to onset of moderate or severe fluid retention was 819 
mg/m2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid 
retention: 4 patients discontinued with severe fluid retention; the remaining 5 had 
mild or moderate fluid retention. The median cumulative dose to treatment 
discontinuation due to fluid retention was 1021 mg/m2. Fluid retention was 
completely, but sometimes slowly, reversible with a median of 16 weeks from the 
last infusion of docetaxel to resolution (range: 0 to 42+ weeks). Patients developing 


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peripheral edema may be treated with standard measures, e.g., salt restriction, oral 
diuretic(s). 
Acute myeloid leukemia 
Treatment-related acute myeloid leukemia (AML) or myelodysplasia has occurred 
in patients given anthracyclines and/or cyclophosphamide, including use in 
adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) 
AML occurred in 3 of 744 patients who received docetaxel, doxorubicin and 
cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, 
doxorubicin and cyclophosphamide.  In TAC-treated patients, the risk of delayed 
myelodysplasia or myeloid leukemia requires hematological follow-up. 
 
Cutaneous reactions 
Localized erythema of the extremities with edema followed by desquamation has 
been observed. In case of severe skin toxicity, an adjustment in dosage is 
recommended.  The discontinuation rate due to skin toxicity was 1.6% (15/965) for 
metastatic breast cancer patients. Among 92 breast cancer patients premedicated 
with 3-day corticosteroids, there were no cases of severe skin toxicity reported and 
no patient discontinued docetaxel due to skin toxicity. 
 
Neurologic reactions 
Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed 
in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment 
discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If 
symptoms persist, treatment should be discontinued.. Patients who experienced 
neurotoxicity in clinical trials and for whom follow-up information on the complete 
resolution of the event was available had spontaneous reversal of symptoms with a 
median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor 
neuropathy mainly manifested as distal extremity weakness occurred in 4.4%  
(42/965). 
 
Asthenia 
Severe asthenia has been reported in 14.9% (144/965) of metastatic breast cancer 
patients but has led to treatment discontinuation in only 1.8%. Symptoms of fatigue 
and weakness may last a few days up to several weeks and may be associated with 
deterioration of performance status in patients with progressive disease. 
7. 
SAFETY EVALUATION 
7.1 
Definitions 
7.1.1 
Adverse Event (AE) 
 
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment (ICH E2A).  
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not related to the medicinal product. 


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An adverse event will be recorded and followed from treatment administration to 
30 days post treatment or resolution.  
 
 
7.1.2  
Expected Adverse Events 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. An adverse event can be considered expected 
when it appears in the current adverse event list, the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk. 
 
7.1.3 
Unexpected Adverse Events 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator's Brochure for an unapproved investigational 
medicinal product) (ICH E2A). 
Contact the Principal Investigator to confirm unexpected adverse events when 
necessary.   
 
7.1.4 
Adverse Drug Reaction (ADR) 
All noxious and unintended responses to a medicinal product related to any dose 
should be considered adverse drug reactions (ICH E2A).  
The phrase "response to a medicinal product" means that a causal relationship 
between a medicinal product and an adverse event is at least a reasonable 
possibility, i.e., the relationship cannot be ruled out.  ‘‘Reasonable possibility’’ 
means there is evidence to suggest a causal relationship between the drug and the 
adverse event. 
  
7.1.5 
Serious Adverse Event (SAE) 
An SAE/ADR as defined in the Code of Federal Regulations (21CFR312.32) is any 
event that: 
• 
results in death 
• 
is life-threatening 
• 
results in inpatient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability or incapacity 
• 
results in congenital anomaly or birth defect 
• 
is medically significant in the opinion of the investigator 
 
Events that are not considered serious adverse events include: 
• 
routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not 
worsen 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
• 
respite care 


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7.1.6 
Progression of malignancy 
Progression of a patient’s malignancy should not be considered an AE, unless in the 
investigator’s opinion, study treatment resulted in an exacerbation of the patient’s 
condition. If disease progression results in death or hospitalization while on study 
or within 30 days of the last dose, progressive disease will be considered an SAE. 
7.1.7 
Life-threatening  
An adverse event or suspected adverse reaction is considered “life-threatening “if,  
in the view of the Principal Investigator, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event or suspected 
adverse reaction that, had it occurred in a more severe form, might have caused 
death (FDA 21 CFR 312.32). 
7.1.8 
Hospitalization (or prolongation of hospitalization) 
Hospitalization encompasses any inpatient admission (even for less than 24 hours) 
resulting from a precipitating, treatment-emergent adverse event. For chronic or 
long-term patients, inpatient admission also includes transfer within the hospital to 
an acute or intensive care inpatient unit. Hospitalizations for administrative reasons 
or a non-worsening preexisting condition should not be considered AEs (e.g., 
admission for workup of a persistent pretreatment laboratory abnormality, yearly 
physical exam, protocol-specified admission, elective surgery). Preplanned 
treatments or surgical procedures should be noted in the baseline documentation. 
Hospitalization because of an unplanned event will be deemed an SAE. 
Prolongation of hospitalization is any extension of an inpatient hospitalization 
beyond the stay anticipated or required for the original reason for admission. 
7.1.9 
Persistent or Significant disability/incapacity 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the patient’s ability to conduct normal life functions. 
7.1.10 Congenital anomaly 
If the female partner of a male patient becomes pregnant during the course of the 
study, the treating physician must be notified immediately. All confirmed 
pregnancies must be immediately reported to the lead site and PCCTC, LLC. All 
pregnancies will be followed until resolution (i.e., voluntary or spontaneous 
termination or birth) and assessed for congenital anomalies and birth defects. 
7.2 
Recording and Grading of Adverse Events 
7.2.1 
Recording 
All observed or volunteered adverse events, regardless of treatment group, severity, 
suspected causal relationship, expectedness, or seriousness will be recorded. 
A clinically significant change in a physical examination finding or an abnormal test 
result should be recorded as an AE, if it: 
• 
is associated with accompanying symptoms 
• 
requires additional diagnostic testing or medical or surgical intervention 
• 
leads to a change in study dosing or discontinuation from the study 


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• 
requires additional concomitant drug treatment or other therapy, or 
• 
is considered clinically significant by the investigator 
An abnormal test result that is subsequently determined to be in error does not 
require recording as an adverse event, even if it originally met one or more of the 
above criteria. 
7.2.2 
Grading severity 
All adverse events will be graded based on the NCI CTCAE version 4.0. 
7.2.3 
Attributing causality 
After assigning a grade to an adverse event, the investigator must evaluate all AEs 
for possible causal relationship to docetaxel/prednisone and enzalutamide 
administration.  Causality attribution will be decided using the criteria outlined in 
Table 2.  
Table 2 Relationship of Adverse Event to Study Drug 
Relationship 
Description 
Unrelated 
AE is clearly not related  
Unlikely 
AE is doubtfully related  
Possible 
AE may be related  
Probable 
AE is likely related  
Definite 
AE is clearly related  
 
7.3 
Reporting Serious Adverse Events 
7.3.1 
Reporting serious adverse events 
• 
All SAEs, events determined to be medically significant by the treating 
Investigator, and unknown reactions or unexpected events should be reported 
to Principal Investigator, UC CCC and PCCTC, LLC within 24 hours of knowledge 
of the event using the contact information below. The initial report should 
include the following information at a minimum:  
• protocol # and title 
• study identification number, sex, age at event 
• date the event occurred 
• description of the SAE 
• causal relationship to the study drug 
The PCCTC SAE Report Form (Appendix G) will be used for reporting each SAE and 
should be submitted to PCCTC, LLC within 5 business days.  The PCCTC, LLC will 
facilitate all SAE report form submissions to UC CCC. 
Severity, causality, action taken, concomitant medications, outcome, etc should be 
reported to the PCCTC, LLC as soon as possible.    


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Follow-up of adverse events should continue until the event and any sequela resolve 
or stabilize at a level acceptable to the investigator. 
SAE Contact Information for PCCTC: 
Prostate Cancer Clinical Trials Consortium 
Phone: 646-888-0434/646-422-4383 
Email: pcctc@mskcc.org  
 
SAE Contact Information for UC CCC: 
UC CCC Cancer Clinical Trials Office Quality Assurance 
Email: qaccto@bsd.uchicago.edu 
 
UC CCC Phase II CRA General 
Phone: 773-834-3095 
Fax: 773-702-4889 
Email: phaseiiCRA@medicine.bsd.uchicago.edu 
Within 24 hours of awareness of a serious adverse event, whether or not related to 
the study drug, the PCCTC, on behalf of the Principal Investigator, will complete and 
submit a PCCTC SAE Report Form (Appendix G) to FDA, containing all required 
information (reference 21 CFR 312.32).  The PCCTC will submit a copy of this PCCTC 
SAE Report form to Astellas by either e-mail or fax, within the same timeframe. If 
submission of this SAE to FDA or Astellas or is not possible within 24 hours, the 
Investigator’s local drug safety contact (IRB, etc.) should be informed by phone. 
The SAE documentation, including the PCCTC SAE Report 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 
8. 
CRITERIA FOR OUTCOME ASSESSMENT/THERAPEUTIC RESPONSE 
8.1 
Outcome Assessment 
All baseline evaluations will be performed as closely as possible to the beginning of 
treatment (<21 days). For subsequent evaluations, the method of assessment and 
techniques will be the same as those used at baseline. 
• 
Measurement of clinical lesions 
Superficial clinical lesions such as skin nodules, biopsy-proven skin rashes that are 
consistent with prostate cancer, and palpable lymph nodes are considered 
measurable.  For skin lesions, documentation with a photograph and measurement 
of the lesion using a ruler is required. 
• 
Conventional CT/ MRI 
• 
Bone scan  


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• 
Tumor markers:  Tumor markers alone cannot be used to assess response or 
progression.  We use the PCWG2 definition for biochemical responses. 
8.1.1 
Primary endpoint 
The primary endpoint will be progression-free survival (PFS), defined as the time 
from randomization to disease progression.    
8.1.2 
Secondary endpoints 
Secondary endpoints are overall survival (OS), defined as the time from 
randomization to death from any cause, and PSA response rates, as defined in 
PCWG2. Exploratory outcome variables will include quality of life (QOL) and 
circulating tumor cells (CTCs).  QOL will be measured at baseline and every 4 cycles.  
In addition, we will analyze androgen receptor splice variant on all patients. 
8.2 
Therapeutic Response 
Response and progression will be evaluated in this study using a combination of the 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee4 and the guidelines for prostate cancer endpoints developed by the 
Prostate Cancer Clinical Trials Working Group (PCWG2).5 
Patients will need to be reevaluated for biochemical and radiographic response as dictated 
in the study schema/table above and according to the guidelines below.
8.2.1 
PSA 
Perform PSA testing at a minimum of 1-week intervals with the threshold PSA level 
at 2.0 ng/mL. To report PSA-based outcomes, PCWG2 recommends that the percent 
of change in PSA from baseline to 12 weeks (or earlier for those who discontinue 
therapy) and the maximum decline in PSA that occurs at any point after treatment 
be reported for each patient using a waterfall plot. Because the rate of rise has 
shown prognostic significance, estimate a pretreatment PSA doubling time (PSA-DT) 
if at least 3 values are available, but do not delay either treatment or enrollment 
onto the trial simply to estimate PSA-DT. Because declines in serum PSA, if they 
occur, may not do so for several weeks, PSA measurements obtained during the first 
12 weeks should not be used as the sole criterion for clinical decision making.5   
8.2.2 
Measurable disease 
According to RECIST, measurable disease is defined as at least 1 lesion > 20 mm in 
its longest diameter as measured with conventional techniques (i.e., CT [nonspiral 
or nonhelical], MRI, physical exam) or > 10 mm as measured with spiral CT scan. All 
tumor measurements will be taken using a ruler or calipers and recorded in 
millimeters (or decimal fractions of centimeters). 
8.2.3 
Nonmeasurable disease 
Following RECIST, all other lesions (or sites of disease) will be considered 
nonmeasurable disease. This includes small lesions (longest diameter < 20 mm with 
conventional techniques or < 10 mm using spiral CT scan) and any of the following: 
• 
bone lesions 
• 
ascites 
• 
pleural or pericardial effusion 


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• 
lymphangitis cutis or pulmonis 
• 
abdominal masses that are not confirmed and followed by imaging techniques 
• 
cystic lesions 
• 
lesions occurring within a previously irradiated area unless they are 
documented as new lesions since the completion of radiation therapy 
Note: If only a single, asymptomatic bone lesion is present at baseline, and 
will be irradiated, the metastatic nature of this lesion must be confirmed by 
x-ray, CT, or MRI. 
8.2.4 
Target (nodal and visceral) lesions 
Following RECIST, progression in a nodal or visceral site (i.e., liver and lung) is 
sufficient to document disease progression. The presence or absence of nodal and 
visceral disease before and after treatment should be recorded separately. 
All measurable lesions (up to a maximum of 5 lesions per organ and 10 lesions in 
total) will be identified as target lesions to be measured and recorded at baseline. 
The target lesions should be representative of all involved organs. Target lesions 
will be selected on the basis of size (i.e., the largest area) and suitability for accurate, 
repeated measurements (either by imaging techniques or clinically). The sum of the 
longest diameter (LD) of all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as a reference by which to 
characterize the objective tumor response. 
Because small lymph nodes are difficult to measure accurately and may not be 
malignant, the greatest diameter of a lymph node must measure at least 2 cm by 
spiral CT to be considered a target lesion.5 
8.2.5 
Bone lesions 
When the bone scan is the sole indicator of progression, disease progression in bone 
is defined as 2 or more new lesions seen on bone scan compared with a prior scan 
used for trial entry.5 In situations where scan findings suggest a flare reaction or 
where new lesion(s) may represent trauma, confirm these results with other 
imaging modalities (e.g., MRI or fine-cut CT). If many new areas of uptake are 
observed, confirmation is generally not necessary. 
8.2.6 
Nontarget lesions 
All other lesions (or sites of disease) will be identified as nontarget lesions and 
recorded at baseline. Nontarget lesions will include measurable lesions that exceed 
the maximum number per organ (5) or total of all involved organs (10), as well as 
nonmeasurable lesions. The presence or absence of these lesions will be recorded 
on the CRF and should be evaluated at the same assessment time points as all target 
lesions. 
8.2.7 
New lesions 
The appearance of up to 10 new measurable lesions should be recorded. Each new 
lesion should be reassessed using the same imaging modality at each time point. If 
measurable, the LD of each new lesion should be recorded in the CRF and the sum 


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LD of new and old lesions should be calculated. See Table 5 for a description of the 
determination of progression based on the presence of new lesions. 
Note: The appearance of a new lesion does not by itself satisfy the criteria 
for confirmed progressive disease. Rather, the tumor burden imposed by the 
new lesions must be evaluated within the context of the total tumor burden 
(i.e., preexisting plus new lesions). Confirming progression in target lesions, 
nontarget (i.e., other than bone) lesions, and bone lesions requires 2 
assessment time points. The first must occur at Week 12 (or later) and the 
second occurring at least 6 weeks after the first. Progression declared at the 
first time point remains unconfirmed unless assessments at the second time 
point demonstrate continuing or worsening progression, as described in 
Section8.4. 
8.3 
Response Criteria for Control/Relieve/Eliminate Endpoints 
8.3.1. 
Measurable soft-tissue lesions 
When evaluating soft-tissue lesions, the definitions in Table 3 apply. 
Table 3 RECIST response criteria for target (soft-tissue) lesions 
Response 
Evaluation of Soft-Tissue Lesions 
Complete response (CR) 
the disappearance of clinical and radiological evidence of all target 
lesions and normalization of tumor marker levels 
Partial response (PR) 
a decrease from baseline ≥ 30% in the sum of the LD of all target 
lesions 
Progressive disease (PD)  
an increase ≥ 20% in the sum of the LD of all target lesions based on 
the smallest sum LD since treatment started or the appearance of one 
or more new lesions or the appearance of new lesions 
Stable disease (SD) 
neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD based on the smallest sum LD recorded since treatment 
started  
Abbreviations: LD, longest diameter. 
 
In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (e.g., fine 
needle aspirate or biopsy) before confirming the complete response status. 
Changes in nodal and visceral sites should be recorded and reported separately, and 
lymph nodes in the pelvis must measure at least 2 cm in greatest diameter to be 
considered target lesions. Complete elimination of disease at a particular site 
should be recorded separately. Any favorable change should be confirmed using a 
second follow-up scan. 
8.3.2 
PSA 
As long as patient safety is the primary concern, in the absence of other indicators of 
disease progression, therapy should not be discontinued solely on the basis of a rise 
in PSA. 


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8.3.3 
Bone 
Record post-treatment changes as either “no new lesions” or “new lesions.” 
In the absence of clearly worsening soft-tissue (nodal and visceral) disease or 
disease-related symptoms, progression at the first scheduled assessment should be 
confirmed on a second scan performed 6 or more weeks later. In the rare case where 
visible lesions disappear, this too should be confirmed. 
8.3.4 
Nontarget lesions 
When assessing nontarget lesions, the definitions in Table 4 will apply. 
Table 4 RECIST response criteria for nontarget lesions 
Response 
Evaluation of Nontarget Lesions 
Complete response (CR) 
the disappearance of all nontarget lesions and normalization of tumor 
marker levels 
Incomplete response/ 
stable disease (SD) 
the persistence of one or more nontarget lesions and/or maintenance 
of tumor marker levels above the normal limits 
Progressive disease (PD) 
the appearance of one or more new lesions and/or unequivocal 
progression of existing nontarget lesions 
 
A clear progression of nontarget lesions only is exceptional. In such circumstances, 
the progression status, as assigned by the investigator, may be reviewed by a PCCTC 
panel. 
8.3.5 
Symptoms 
Transient increases in pain may occur before improvement, and those occurring in 
the first 12 weeks should not affect the course of treatment in the absence of other 
compelling evidence of disease progression. Changes in symptoms should be 
confirmed as for other outcome measures. Monitor other domains that may help 
determine whether the disease is progressing, including worsening in global quality 
of life, developing urinary or bowel compromise, or needing to change anticancer 
therapy. 
8.3.6 
Evaluating best overall response 
The best overall response is the best response recorded from the start of treatment 
until either disease progression or recurrence. The investigator’s determination of 
best overall response will be based both on response criteria and on confirmation 
criteria. To be assigned a status of partial response or complete response, changes in 
tumor measurements must be confirmed by repeat assessment performed 
4-6 weeks after the criteria for response are first met. To confirm stable disease, 
follow-up measurements must meet SD criteria at a minimum interval of 3 weeks 
after SD was first documented. Table 5 can be used as an assessment tool. 


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Table 5 Assessing Overall Response 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. 
 
Subjects with global deterioration of health status who require treatment to be 
discontinued without objective evidence of disease progression should be classified 
as having symptomatic deterioration. Every effort should be made to document 
their objective progression, even after discontinuing treatment. 
Subjects who do not have tumor response assessment due to rapid progression or 
toxicity will be considered nonresponders, will be included in the denominator for 
the response rate, and will be classified into one of the categories listed below: 
• 
death attributed to disease progression 
• 
early discontinuation attributed to disease progression 
• 
death attributed to drug toxicity 
• 
early discontinuation attributed to drug toxicity 
Note: If a subject receives subsequent therapy before tumor progression is 
documented, the reason for changing therapy must be reported. Reasons 
include clinical progression, drug toxicity, or secondary therapy for 
maintaining tumor response. 
8.4 
Confirmatory Measures/Duration of Response 
8.4.1 
Confirming time-to-event outcomes 
Any post treatment change in disease status, be it favorable or unfavorable, should 
be confirmed using a second assessment at a later time point after a minimum of 3 
weeks. 
8.4.2 
Duration of overall response 
Duration of overall response is measured from the time when partial response or 
complete response is first noted until the date when recurrent or progressive 
disease is objectively documented. Duration of overall complete response is 
measured from the time the criteria for complete response are first met until the 
first date that recurrent disease is objectively documented. Duration of stable 
disease is measured from the start of treatment until the criteria for progression are 
met. 


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8.4.3 
Progression-free survival 
Progression-free survival (PFS) is defined as the time from randomization to 
disease progression. All assessments of the PFS endpoint (i.e., PSA, bone, and CT 
scans) are performed at the same time points. All assessments of disease should be 
collected at the same time interval (as per the study schema above).  In addition to 
PSA, post treatment changes in measurable target lesions, radionuclide bone 
scans, and symptoms should be confirmed within 3 weeks minimum intervals. 
 


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Table 6 Prostate Cancer Clinical Trials Working Group Outcome Measures5 
Variable 
Control/Relieve/Eliminate Endpoints 
Prevent/Delay Endpoints 
PSA 
Record the percent change from baseline 
(rise or fall) at 12 weeks and, separately, the 
maximal change (rise or fall) at any time 
using a waterfall plot 
Decline from baseline: record time from start 
of therapy to first PSA increase that is ~25% 
and ~2 ng/mL above the nadir, and which is 
confirmed by a second value 3 or more weeks 
later (i.e., a confirmed rising trend)† 
Recording the duration of PSA decline of little 
value 
No decline from baseline: PSA progression 
~25% and ~2 ng/mL after 12 weeks 
Soft-tissue lesions 
Use RECIST with caveats: 
Only report changes in lymph nodes that 
were ~2 cm in diameter at baseline 
Record changes in nodal and visceral soft 
tissue sites separately 
Record complete elimination of disease at 
any site separately 
Confirm favorable change with second scan 
Record changes using waterfall plot 
Use RECIST criteria for progression, with 
additional requirement that progression at 
first assessment be confirmed by a second 
scan 6 or more weeks later 
Note that for some treatments, a lesion may 
increase in size before it decreases 
Bone 
Record outcome as either new lesions or  
no new lesions 
First scheduled reassessment: 
No new lesions: continue therapy 
New lesions: perform a confirmatory scan 6 
or more weeks later 
Confirmatory scan: 
No new lesions: continue therapy 
Additional new lesions: progression 
Subsequent scheduled reassessments: 
No new lesions: continue 
New lesions: progression 
The appearance of ~2 new lesions, and, for the 
first reassessment only, a confirmatory scan 
performed 6 or more weeks later that shows 
at least 2 or more additional new lesions 
The date of progression is the date of the first 
scan that shows the change 
Symptoms 
Consider independently of other outcome measures 
Document pain and analgesia at entry with a lead-in period and measure repeatedly at 3- to 
4-week intervals 
Perform serial assessments of global changes in HRQOL, urinary or bowel compromise, pain 
management, additional anticancer therapy 
Ignore early changes (~12 weeks) in pain or HRQOL in absence of compelling evidence of 
disease progression 
Confirm response or progression of pain or HRQOL endpoints ~3 weeks later 
Abbreviations: PSA, prostate-specific antigen; HRQOL, health-related quality of life. †Particularly important when anticipated effect on PSA is 
delayed or for biologic therapies. 


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9. 
DATA REPORTING AND REGULATORY REQUIREMENTS 
9.1 
Data Collection and Management 
Data collected during this study will be entered into a secure database. 
9.1.1 
Electronic Case Report Forms (eCRFs) 
Standardized eCRFs and completion guidelines will be created by the PCCTC, LLC 
for the collection of all study data.   Access and training for PCCTC Caisis EDC will 
be made available to participating sites upon local regulatory approval.  The 
participating site PI is responsible for ensuring eCRFs are completed accurately 
and in a timely manner. 
9.1.2 
Source documents 
Source documentation refers to original records of observations, clinical findings 
and evaluations that are subsequently recorded as data. Source documentation 
will be made available to support the subject’s research record.  
9.1.3 
Record retention 
The investigator will maintain adequate and accurate records to enable the 
conduct of the study to be fully documented and the study data to be 
subsequently verified. After study closure, the investigator will maintain all 
source documents and study-related documents. Records are to be retained and 
securely stored until the later of:  (a) two (2) years following the date a New Drug 
Application is approved for the Study Drug that is the subject of the Clinical Trial; 
or (b) two (2) years after the Investigational New Drug Application for such Study 
Drug is terminated or withdrawn, or such longer period of time as may be 
required by Participant policies, applicable laws, rules or regulations. 
9.2 
Source Documentation Submission for Registration at Participating Sites 
 
9.2.2 
Data Submission Timelines 
All data should be transmitted to PCCTC, LLC within 14 days of visit except for SAE 
submission (see section 7.3.1). 
 
9.2.3 
Data Review and Queries 
PCCTC, LLC will review data and source documentation as it is submitted. Data will be 
monitored against source documentation as necessary and discrepancies will be sent 
as queries to the participating sites. In addition, PCCTC, LLC will review data for logic, 
consistency, and obvious anomalies. Queries will be sent by PCCTC, LLC to 
participating sites as needed. 
Participating sites should respond to data queries within 14 days of receipt. 
9.3 
Study Monitoring and Quality Assurance 
9.3.1 
Data and Safety Monitoring 
Consistent with NCI guidelines, this trial will be carefully monitored through both 
institutional and UCCCC-specific central processes and committees including, the 
Institutional Review Board (IRB), the UCCCC Clinical Research Advisory 


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Committee (CRAC), the Clinical Trials Review Committee (CTRC), the Scientific 
and Accrual Monitoring (SAM) Committee, and regular safety monitoring 
conferences. 
Under the governance of the CRAC, initial scientific review is conducted by the 
CTRC and annual monitoring of trial progress by the SAM Committee. This is 
managed internally through safety monitoring conferences, a rigorous adverse 
event reporting system, and the UCCCC audit program.  
CRAC ensures that all aspects of the clinical research process at the UCCCC are 
conducted according to prescribed standard operating procedures. CRAC 
meetings are held quarterly with additional meetings on an as-needed basis.  
The Scientific and Accrual Monitoring (SAM) Committee meets monthly and is 
responsible for performing annual protocol reviews, including reviews of all 
amendments, to: 
a) Evaluate scientific progress of the study, including accrual to date 
compared to projected accrual and any new scientific findings which 
might alter the significance or objectives of the original study; and 
b) Ensure that the conduct of the study is in compliance with the 
approved DSM plans, including review of documentation that audits have 
been carried out per CTRC recommendations. 
If the committee determines that the study is not progressing and should be 
terminated and/or closed to accrual, a recommendation is made to the CTRC, 
which reviews the data and makes the final determination.  The PI can provide 
additional information and/or appeal to the CTRC.  
The PCCTC, LLC will provide a listing of all reported AEs and SAEs occurring 
during the reporting period for this clinical trial for submission to the CRAC and 
SAM Committee as needed. 
9.3.2  
Data Auditing and Quality Assurance 
In addition to review by safety conferences, CRAC and SAM; PCCTC, LLC will 
conduct regularly scheduled monitoring visits according to the Monitoring Plan 
(MP). 10% of all subjects, but at least 2 from each site will be 100% source data 
verified. This study is subject to audit after it has been open to accrual for 12 
months or at the discretion of the UCCCC.  If the study accrues >50 subjects 
annually, a minimum of 10 charts will undergo full review. 
Registration reports will be generated by the PCCTC, LLC to monitor subject 
accruals and the completeness of registration data. Routine data quality reports 
will be generated to assess missing data and inconsistencies. Accrual rates and the 
extent and accuracy of evaluations and follow-up will be monitored periodically 
throughout the study period, and potential problems will be brought to the 
attention of the Principal Investigator for discussion and action. 
Each site participating in the accrual of participants to this protocol will be 
monitored by the PCCTC, LLC once shortly after initiation of subject recruitment at a 


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site, annually during the study (or more frequently if indicated), and at the end or 
closeout of the trial, for protocol and regulatory compliance, data verification and 
source documentation. Monitoring may be accomplished in one of two ways: 
(1) sending source documents and research records for selected patients from 
participating sites to the PCCTC, LLC for review, or (2) on-site monitoring of 
selected patient records at participating sites. 
The monitoring visit will include a review of source documentation to evaluate 
compliance for: 
1. Regulatory/IRB compliance (review of current protocol and amendments, 
Informed consent documents and procedures, annual continuing review 
reports, AEs/SAEs) 
2. Protocol defined treatment compliance 
3. Subject records  
• 
Each subject is monitored to determine that there is a signed and dated 
consent form 
• 
Adherence to eligibility criteria 
• 
Baseline, on study and follow-up protocol testing 
• 
eCRF completion  
At the end of each monitoring visit, an exit interview with the monitor, PI (if 
possible), and study staff will take place.  During this time, all findings are 
reviewed and discussed, and any questions can be answered.  Additionally, the PI 
and study staff will receive a copy of the monitoring report, which will include 
corrective action items.  
A monitoring report is issued within 30 days and sent to the protocol PI. A copy is 
filed in the CCTO Audit Binder. The PI is given 30 days to respond in writing to the 
deficiencies identified. Responses are reviewed by the Scientific and Technical 
Directors of the CCTO, the Associate Director for Clinical Sciences, and the CRAC, if 
necessary. 
All clinical work conducted under this protocol is subject to Good Clinical Practice 
(GCP) guidelines. This includes inspection of study-related records by the lead site, 
its designee, or health authority representatives at any time. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints 
10.1.1 Analysis of the primary endpoint 
The primary endpoint will be progression-free survival (PFS), defined as the time 
from randomization to disease progression.  Progression will be evaluated using a 
combination of RECIST4 and PCWG25 guidelines, as described in section 8.2 above.  
One hundred patients (50 per arm) will be randomized.  This sample-size will 
provide 85% power to detect an increase in the median PFS from 6 months in the 


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standard arm to 10 months in the experimental (triple combination) group, or a 
hazard ratio (HR) of 0.6, using on a one-sided test at the alpha=0.10 significance 
level. This calculation assumes 2 years of accrual and 1 further year of follow-up.  
PFS will be estimated using the Kaplan-Meier6 procedure and compared between 
the two treatment arms by logrank test.  Confidence intervals for the median PFS 
times will be generated using the Brookmeyer-Crowley7 method.  Cox8 proportional 
hazard models will also be fit to estimate the HR and to assess and adjust for the 
effects of baseline covariates.   The proportional hazards assumption will be 
checked graphically using log(-log) survival plots9 and Schoenfeld residuals10.  
Martingale residuals will be inspected to determine the best functional form for 
covariates entered into the Cox model.   
10.1.2 Analysis of secondary  and exploratory endpoints 
Secondary endpoints are overall survival (OS) and PSA response rates. OS will be 
analyzed as described above for PFS.  PSA response rates in the two groups will be 
compared via chi-square test. Exploratory outcome variables will include quality of 
life (QOL), circulating tumor cells (CTCs) and analysis of androgen receptor splice 
variant.  QOL will be measured at baseline and every 4 cycles.  Mixed effects 
regression models will be fit to compare QOL over time. Total symptom scores 
obtained across the M. D. Anderson Symptom Inventory (MDASI), as well as 
subscores derived from specific questions, will be analyzed. CTCs will be measured 
at baseline, every 3 cycles starting at C4D1 (C4D1, C7D1, C10D1, etc), and upon 
disease progression.  Changes from baseline to 4 weeks will be compared using two-
sample t-tests.  The distribution of CTC cells at the time of disease progression will 
be summarized descriptively.  The prognostic value of analyzing androgen receptor 
splice variant at baseline will be assessed by Cox regression analysis. 
10.2 
Analysis Populations 
10.2.1 Evaluable population 
All subjects who meet eligibility criteria will be included in the main analysis of the 
response rate, even if there are major protocol deviations (e.g., incorrect treatment 
schedule or drug administration). Each subject will be assigned to one of the 
following categories: 
Table 7 Categories for Response to Treatment 
Category 
Response 
1 
Complete response 
2 
Partial response 
3 
Stable disease 
4 
Progressive disease 
5 
Early death from malignant disease 
6 
Early death from toxicity 
7 
Early death from other causes 
9 
Unknown (not assessable/insufficient data) 
NOTE: By arbitrary convention, category 9 designates unknown status in a clinical database. Subjects in response 


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categories 4 to 9 will be considered to have treatment failure (disease progression). 
 
Conclusions are to be based on the population of all eligible subjects. Subanalyses 
may be performed on various subsets of subjects, such as those with no major 
protocol deviations or those who continued in the study for the entire treatment 
period (i.e., did not withdraw prematurely). Subanalyses will not serve as the basis 
for drawing conclusions concerning treatment efficacy. 
10.2.2 Safety population 
All subjects enrolled in the study will be included in the safety analysis population 
and considered evaluable for toxicity and safety from the time of their first dose. 
Demographic and baseline characteristics for the safety population will be 
summarized by number and percent for categorical data (e.g., sex, race/ethnicity) 
and by descriptive statistics for continuous data (e.g., weight, vital signs, EKG 
readings, disease status). 
10.3 
Safety Analysis 
10.3.1 Evaluation of adverse events 
Treatment-emergent adverse events will be translated from investigator terms to 
MedDRA v6.0 terminology and summarized (number and percentage of subjects) 
for each treatment arm for all subjects who receive at least 1 cycle. Adverse event 
summaries will be organized by body system, frequency of occurrence, intensity 
(i.e., severity grade), and causality or attribution. Subjects who experience an 
adverse event more than once will be counted only once. The occurrence with the 
maximum severity will be used to calculate intensity.  Comparison of rates between 
the two treatment arms will be performed using chi-square or Fisher’s exact test.   
10.3.2 Evaluation of serious adverse events and premature withdrawals 
Adverse events deemed serious and those resulting in treatment withdrawal or 
death will be summarized separately.  
10.3.3 Evaluation of laboratory parameters and assays 
Selected clinical laboratory parameters will be summarized for each treatment arm 
and clinically significant changes from baseline will be discussed.  
10.3.4 Extent of exposure 
Treatment exposure will be summarized for all subjects, including dose 
administration, number of cycles, dose modifications or delays, and duration of 
therapy. 
10.4 
Statistical Procedures (see above) 
Summary statistics include the number of observations, mean, standard deviation, median, 
minimum, and maximum values. A P value of 0.05 will be used to declare statistical 
significance. 
10.4.1 Sample size calculation 
The sample-size of 100 patients (50 per treatment group) will provide 85% power 
to detect an increase in the median PFS from 6 months in the standard arm to 10 
months in the experimental (triple combination) group, corresponding to a HR of 


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0.6, using on a one-sided test at the alpha=0.10 significance level. This calculation 
assumes 2 years of accrual and 1 further year of follow-up.  The assumption of a 6 
month median PFS for the docetaxel/prednisone arm is based on the findings 
reported by Petrylak et al. (2004), in which median time to progression for 
advanced, refractory prostate cancer patients receiving docetaxel plus estramustine 
was 6.3 months.  While not known, patients receiving docetaxel after enzalutamide 
failure could potentially have faster time to progression; if so, this would serve to 
increase the number of events and enhance  statistical power.  
11. 
REGULATORY AND PROTECTION OF HUMAN SUBJECTS 
11.1 
Roles and Responsibilities 
 
11.1.1   Sponsor Investigator 
The Sponsor Investigator is responsible for performing the following tasks: 
• 
Responsibility for the overall conduct of the study at all participating sites and 
for monitoring the progress of the study 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAEs) 
• 
Reviewing data from all participating sites 
 
11.1.2  PCCTC, LLC 
The PCCTC, LLC is responsible for performing the following tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site prior to 
the first patient registration at that site, and maintaining copies of IRB approvals 
and required regulatory documents from each site. 
• 
Managing subject registration 
• 
Developing and maintaining Clinical Data Management documents and 
procedures 
• 
CRF development, setup of study database, and subsequent design changes 
• 
Participating in review of content of the CRF against the protocol requirements 
• 
EDC system administration (user/site accounts setup, maintenance and 
revocation) 
• 
Data review, cleaning, query management and resolution 
• 
Establishing procedures for documentation, reporting and submitting of AE’s 
and SAE’s to the PCCTC, LLC. 
• 
Reviewing Serious Adverse Events (SAEs) 
• 
Training participating sites on EDC 
• 
Collecting and compiling data from each participating site 
• 
Data reviewing from all participating sites 
• 
Facilitating monitoring and audits by securing selected source documents and 
research records from participating sites for review, or by monitoring at 
participating sites. 
 
11.1.3  Participating Sites 
Participating sites are responsible for performing the following tasks: 
• 
Following the protocol as written, the guidelines of Good Clinical Practice (GCP), 
and applicable Standard Operating Procedures (SOPs).Registering all patients 


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with the PCCTC, LLC by submitting the eligibility checklist, supporting source 
documentation, and signed informed consent promptly 
• 
Providing sufficient experienced clinical and administrative staff and adequate 
facilities and equipment to conduct a collaborative trial according to the 
protocol 
• 
Maintaining regulatory binders on site and providing copies of all required 
documents to the PCCTC, LLC  
• 
Collecting and submitting data according to the schedule specified by the 
protocol 
• 
Responding to queries in a timely manner 
 
 
11.2 
Ethical Considerations 
This study will be conducted in compliance with the protocol, GCP guidelines established by 
the International Conference on Harmonisation, and the ethical standards set forth in the 
Declaration of Helsinki 2004 (available at: www.laakariliitto.fi/e/ethics/helsinki.html). 
11.3 
Protocol Amendments 
Before starting the study, the protocol must be approved by each institution’s IRB or 
Independent Ethics Committee (IEC). Amendments to the protocol may be made only with 
consent of the Sponsor Investigator and are subject to IRB approval before instituting. 
11.4 
Written Informed Consent 
Before obtaining consent, members of the study team will review the rationale for the 
treatment program with the patient. The discussion will review the alternatives available 
(including hormonal therapy, chemotherapy, or supportive care as appropriate), the 
potential benefits of this program, the risks and the probability of their occurrence, and the 
procedures to minimize these risks. Should an adverse event occur, the provisions available 
to ensure medical intervention will also be reviewed. Why the risks are reasonable in 
relation to the anticipated benefits, incentives, or costs that will or may be incurred as a 
result of participating in the study, as well as the efforts to maintain confidentiality, will also 
be discussed with the patient. 
Patients will be required to sign and date an informed consent form that meets the 
requirements of the Code of Federal Regulations (Federal Register Vol. 46, No. 17, January 
27, 1981, part 50) and the IRB. The medical record will include a statement that written 
informed consent was obtained (and document the date that it was obtained) before the 
patient is enrolled in the study. The original signed document will become part of the 
patient’s medical record, a copy will be forwarded to the lead site and to the PCCTC, LLC, 
and a copy will be sent home with each patient. 
The consent form will include the following: 
• 
the nature and objectives, potential toxicities, and benefits of the intended study 
• 
the length of therapy and likely follow-up required 
• 
alternatives to the proposed therapy (including available standard and 
investigational therapies) 
• 
the name of the investigator(s) responsible for the protocol 


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• 
the right of the patient to accept or refuse treatment and to withdraw from 
participation in this study 
• 
Text regarding the consortium and the coordinating center should be added to 
all institutional informed consent documents and sections in the research 
authorization/HIPAA forms (e.g., “Prostate Cancer Clinical Trial Consortium”) 
11.5 
Protection of Privacy 
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. After this discussion, they 
will be asked to sign a Notice of Privacy Practice research authorization/HIPAA form. The 
original signed documents will become part of the patient’s medical records, and each 
patient will receive a copy of the signed documents. The use and disclosure of protected 
health information will be limited to the individuals described in the research authorization 
form. The research authorization form must be completed by the principal investigator and 
approved by the IRB. 
11.6 
Terminating or Modifying the Study 
Adverse event and laboratory data from this trial will be assessed by the Principal 
Investigator on an ongoing basis. At least quarterly, data from the clinical database will be 
reviewed. The results of this review will be shared with all investigators either in writing or 
as part of a teleconference. SAEs will be reviewed as they are reported to the lead site, and 
the Principal Investigator will make an assessment regarding the safety of continuing or 
modifying the study. This assessment will be shared with the investigators either in writing 
or as part of a teleconference. Should the assessment of either the lead site or the Principal 
Investigator be that the study should be terminated, the study will be closed to further 
accrual. Patients who are on the experimental arm will be assessed individually by the 
investigator to see if it is in the patients’ best interest to continue, which might be the case 
for a patient that is responding to the intervention. Follow-up safety assessments will be 
performed for all patients who are terminated from the study prematurely. 


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12. 
REFERENCES 
1 
The American Cancer Society. Prostate Cancer Statistics 2014. Available at: 
http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-key-
statistics. Accessed March 2014. 
2 
Scher HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end 
points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223–5232. 
3 
National Cancer Institute/Cancer Therapy Evaluation Program. CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements. January 1, 2005. Available at: 
http://ctep.cancer.gov/reporting/newadverse_2006.pdf. Accessed November 2008. 
4 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New 
guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 
2000;92:205–216. 
5 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg C, Carducci MA, et al. Design and end 
points of clinical trials for patients with progressive prostate cancer and castrate levels of 
testoterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin 
Oncol. 2008;29:1148–1159. 
6 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations.  J Am Stat 
Assoc 1958;53:457-481. 
7. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
8.  
Cox DR. Regression models and life tables (with discussion).  J Royal Stat Soc B 
1972:34:187-220. 
9. 
Kay R. Proportional hazard regression models and the analysis of censored survival data. 
Applied Statist 1977;26:227-237. 
10.  
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted 
residuals. Biometrika 1981;81:515-526. 
11. 
Petrylak DP, Tangen CM, Hussain MHA, Lara PN, Jones JA, Taplin ME et al. Docetaxel and 
estramustine compared with mitoxantrone and prednisone for advanced refractory 
prostate cancer.  NEJM 2004;35;1513-1520. 
 


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Appendix A: Performance Status Criteria 
ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to continue all predisease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or sedentary nature (eg, light 
housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or 
chair  
> 50% of waking hours. 
4 
100% bedridden. Completely disabled, cannot carry on any self-care, totally 
confined to bed or chair. 
5 
Dead 
 


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Appendix B: Medications with the Potential for Drug-Drug Interactions 
Please see the Enzalutamide Package Insert for medications with the potential for drug-drug 
interactions 


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Appendix C: Laboratory Manual 
 
Please see the Laboratory & Correlative Studies Manual 


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Appendix D: M.D. Anderson Symptom Inventory  


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Appendix E: Glossary of Abbreviations and Acronyms 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
bid 
bis in die (twice a day) 
C 
Celsius 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cm 
centimeter 
Cmax 
maximum plasma concentration 
CMP 
Comprehensive Metabolic Panel 
CR 
complete response 
CRAC 
Clinical Research Advisory Committee 
CREAT 
creatinine 
CRF 
case report form 
CRPC 
castration resistant prostate cancer 
CT 
computerized tomography 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRC 
Clinical Trials Review Committee 
DLT 
dose-limiting toxicity 
DSM 
data and safety monitoring 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
EKG 
electrocardiogram 
FACT-P 
Functional Assessment of Cancer Therapy-Prostate scale 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
GnRH 
gonadotropin-releasing hormone  
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Hazard ratio 
HRQOL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 


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IRB 
Institutional Review Board 
IV 
intravenous 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
N 
number of subjects or observations 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
OS 
overall survival 
PCCTC 
Prostate Cancer Clinical Trials Consortium 
PD 
progressive disease 
PFS 
progression-free survival 
PI 
principal investigator 
PO 
per os (by mouth) 
PR 
partial response 
PSA 
prostate-specific antigen 
PSA-DT 
prostate-specific antigen doubling time 
QOL 
quality of life 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAM 
Scientific and Accrual Monitoring 
SD 
stable disease 
SOP 
Standard Operating Procedures 
TEST 
TTP 
testosterone 
time to progression 
UCCC 
The University of Chicago Comprehensive Cancer Center 
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO 
World Health Organization 


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Appendix F. Pill Diary 
 
A Phase II Randomized Prospective Trial of Docetaxel/Prednisone Versus Docetaxel/Prednisone  
and Enzalutamide in Castration-Resistant Prostate Cancer (CRPC) Patients Progressing on 
Enzalutamide 
PCCTC 13-126 
PLEASE FILL OUT AND BRING THIS SHEET AT YOUR NEXT VISIT (Docetaxel/Prednisone plus 
Enzalutamide Arm only). 
Instructions: 
• 
Medications to be taken:  
o Enzalutamide:  # Tablets to be taken daily:  4 tablets (40mg each, 160mg total) 
o Prednisone: # Tablets to be taken daily: 2 tablets (5mg each, 10mg total) 
• 
Please record the date, time and number of pills taken each day (see example row). Please 
note reason if (1) dose was not taken or (2) full dose was not taken (indicate the actual 
amount taken)  
Please return all unused study medication to your research nurse. 
Day Date 
Time that 
Enzalutamide 
was taken 
Number of 40 
mg Pills of 
Enzalutamide 
taken 
If dose not taken 
or if full dose not 
taken for 
Enzalutamide, 
provide reason 
Number of 5 
mg pills of 
prednisone 
taken 
Ex 
1/1/2011 
9:00 AM 
4 
N/A 
2 
1 
  
  
  
  
  
2 
  
  
  
  
  
3 
  
  
  
  
  
4 
  
  
  
  
  
5 
  
  
  
  
  
6 
  
  
  
  
  
7 
  
  
  
  
  
8 
  
  
  
  
  
9 
  
  
  
  
  
10 
  
  
  
  
  


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11 
  
  
  
  
  
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20 
 
 
 
 
 
21 
 
 
 
 
 
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28 
 
 
 
 
 
 
Patient Signature: ________________________________________________________________Date: ______________________ 
MD/RN Signature: ________________________________________________________________Date: ______________________ 
Comments:_____________________________________________________________________________________________________
__________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________ 
 
 
 


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Appendix G: PCCTC SAE Report form 
 
SERIOUS ADVERSE EVENT REPORTING FORM 
 
*Event #  Click here to enter text. 
*Protocol Title:  A Phase II Randomized Prospective Trial of Docetaxel/Prednisone Versus 
Docetaxel/Prednisone  and Enzalutamide in Castration-Resistant Prostate Cancer (CRPC) 
Patients Progressing on Enzalutamide                                                                                                                          
*PCCTC Protocol #  c13-126 
*Site Protocol #  Click here to enter text.  
*Site Name:         Click here to enter text. 
 
*Date of Report: Click here to enter a date.   
*Reported By: Click here to enter text. 
☐ Initial Report          ☐ Follow-up Report      
*Date of Original Report: Click here to enter a 
date.           
     SUBJECT INFORMATION 
*Subject Identifier (Study ID) Click here to enter 
text. 
*Age at Time of Event: Click here to enter text. 
*Sex   ☒ Male  
Weight: Click here to enter text.   ☐ lb  ☐ kg 
SERIOUS ADVERSE EVENT 
*CTCAE Term: Click here to enter text. 
 
*Start Date:       Click here to enter a date. 
*End Date: Click here to enter a date. OR ☐ ongoing 
*Grade:              Click here to enter text. 
 
*Type (check all that apply) 
 
☐ Death  Click here to enter a date. 
☐ Disability or Permanent Damage         


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☐ Life-threatening 
☐ Congenital Anomaly/Birth Defect  
☐ Hospitalization 
☐ Other Medically Important Condition 
   *Event Description              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                           
 
                                                                                                                                                                               
*Outcome 
☐ Recovered/Resolved 
☐ Not Recovered/Not Resolved 
☐ Fatal 
☐ Recovering/Resolving 
☐ Recovered/Resolved sequelae 
☐ Unknown 
RELEVANT TESTS/LABORATORY DATA 
Date mm/dd/yyyy 
Test 
Result 
Unit 
Notes 
Click here to enter a date. 
 
 
 
 
Click here to enter a date. 
 
 
 
 
Click here to enter a date. 
 
 
 
 
 
OTHER RELEVANT HISTORY 
Disease/surgical 
procedure/etc. 
Start Date  
mm/dd/yyyy 
Continuing 
Y/N/U 
End Date  
mm/dd/yyyy 
Comments 
 
Click here to enter a 
date. 
 
Click here to enter a 
date. 
 
 
Click here to enter a 
date. 
 
Click here to enter a 
date. 
 
 
Click here to enter a 
date. 
 
Click here to enter a 
date. 
 
 
 
 


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SUSPECT PRODUCT(S) 
 
CHALLENGE/RECHALLENGE OF SUSPECT PRODUCT(S) 
*Name 
Relationship 
to Study 
Treatment 
Action Taken 
Dose Frequency 
Route 
Start Date 
mm/dd/yyyy 
Last Date 
Prior to SAE     
mm/dd/yyyy 
 
☐Unrelated      
☐Unlikely 
☐Possibly   
☐Probably        
☐Definite 
☐Drug 
withdrawn          
☐Dose reduced 
☐Dose 
Increased 
☐Dose not 
changed                
☐Unknown 
☐Not 
applicable 
 
 
 
Click here to 
enter a date. 
Click here to 
enter a date. 
 
☐Unrelated      
☐Unlikely 
☐Possibly   
☐Probably        
☐Definite 
☐Drug 
withdrawn          
☐Dose reduced 
☐Dose 
Increased 
☐Dose not 
changed                
☐Unknown 
☐Not 
applicable 
 
 
 
Click here to 
enter a date. 
Click here to 
enter a date. 
 
☐Unrelated      
☐Unlikely 
☐Possibly   
☐Probably        
☐Definite 
☐Drug 
withdrawn          
☐Dose reduced 
☐Dose 
Increased 
☐Dose not 
changed                
☐Unknown 
☐Not 
applicable 
 
 
 
Click here to 
enter a date. 
Click here to 
enter a date. 


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CONCOMITTANT MEDICAL PRODUCT(S) 
Name 
Start Date  
mm/dd/yyyy 
Last Date Prior to SAE 
mm/dd/yyyy 
 
Click here to enter a date. 
Click here to enter a date. 
 
Click here to enter a date. 
Click here to enter a date. 
 
Click here to enter a date. 
Click here to enter a date. 
 
INVESTIGATOR NAME AND SIGNATURE 
*Investigator Name 
               Click here to enter text. 
*Investigator Signature 
______________________ 
*Date Signed  
               Click here to enter a date.       
*Name 
Did the Adverse 
Event abate after 
discontinuation of 
the suspect drug? 
(Dechallenge) 
Did the Adverse 
Event re-occur after 
the suspect drug 
was re-introduced? 
(Rechallenge) 
 
☐Yes    
☐No 
☐Not applicable 
☐Yes    
☐No 
☐Not applicable 
 
☐Yes    
☐No 
☐Not applicable 
☐Yes    
☐No 
☐Not applicable 
 
☐Yes    
☐No 
☐Not applicable 
☐Yes    
☐No 
☐Not applicable 
mm/dd/yy