Clinical trial NCT01981122
Conditions: Metastatic Prostate Cancer
Sponsor: Dendreon
Start date: 2013-09-01; Completion date: 2017-06-30
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, open-label study designed to assess the effects of sipuleucel-T when administered concurrently or sequentially with enzalutamide.

Detailed description:
This is a randomized, open-label study designed to assess the effects of sipuleucel-T when administered concurrently or sequentially with enzalutamide. This study consists of 3 phases. The screening phase will begin at the completion of the informed consent process and continue through registration. The active phase will begin at registration and continue through the post-treatment visit (30 to 37 days following the last study treatment). The long term follow-up (LTFU) phase will begin after the post-treatment visit and will continue until the subject's death or until Dendreon terminates the study.

Arms: arm 1: Subjects will receive sipuleucel-T concurrently with enzalutamide (160 mg orally once daily). Enzalutamide treatment will start 2 weeks prior to the first leukapheresis and continue for 52 weeks or until disease progression or unacceptable toxicity, whichever occurs first. arm 2: Subjects will receive sipuleucel-T followed by enzalutamide (160 mg orally once daily). Enzalutamide treatment will start approximately 10 weeks after the first infusion of sipuleucel-T and continue for 52 weeks or until disease progression or unacceptable toxicity, whichever occurs first.
Interventions: intervention 1: sipuleucel-T intervention 2: enzalutamide
Intervention descriptions: intervention 1: Sipuleucel-T is an autologous cell product consisting of antigen presenting cells (APCs) loaded with PA2024, a recombinant fusion protein composed of prostatic acid phosphatase (PAP), linked to granulocyte-macrophage colony-stimulating factor (GM-CSF). intervention 2: Enzalutamide is an androgen receptor inhibitor. It is indicated for the treatment of patients with mCRPC who have previously received docetaxel. The enzalutamide dose used in this study will be 160 mg orally once daily.

Protocol documents:
Prot_000.pdf: 
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A RANDOMIZED, OPEN-LABEL, PHASE 2 STUDY OF SIPULEUCEL-T WITH 
CONCURRENT VERSUS SEQUENTIAL ADMINISTRATION OF ENZALUTAMIDE IN 
MEN WITH METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 
 
IND NUMBER: 
BB-IND 6933 
INVESTIGATIONAL PHASE: 
2 
PROTOCOL NUMBER: 
P12-2 
STUDY PRODUCT: 
Sipuleucel-T 
ORIGINAL PROTOCOL ISSUE DATE: 
16 MAY 2013  
STUDY SPONSOR: 
Dendreon Corporation 
1301 Second Ave 
Seattle, WA 98101 
 
Medical Monitor 
 
Biostatistician 
 
Clinical Trial Manager 
Michael Locker, MD 
 
Todd DeVries, PhD 
 
Kara M. Moss 
(206) 829-1635  (Phone)  
 
(206) 219-7214 (Phone) 
 
(206) 829-1486 (Phone) 
(206) 829-1580 (Fax) 
 
(206) 829-1580 (Fax) 
 
(206) 829-1580 (Fax) 
 
24 Hour Contact: (877) 336-3736 
 
CONFIDENTIALITY STATEMENT 
This document is the property of Dendreon Corporation.  It contains confidential and proprietary information 
belonging to Dendreon; therefore, its use is intended solely for physicians, clinical trial site personnel, and contract 
research organizations (“study personnel”) participating in Dendreon clinical studies of sipuleucel-T.  Reproduction 
is authorized for and strictly limited to study personnel for Dendreon.  Reproduction for any other purpose is 
prohibited. 
 


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PROTOCOL SIGNATURE PAGE 
 A RANDOMIZED, OPEN-LABEL, PHASE 2 STUDY OF SIPULEUCEL-T WITH 
CONCURRENT VERSUS SEQUENTIAL ADMINISTRATION OF ENZALUTAMIDE IN 
MEN WITH METASTATIC CASTRATE-RESISTANT PROSTATE CANCER 
Original Protocol:  16 MAY 2013 
By signing below, the principal investigator agrees to adhere to the protocol. 
Investigator Name: 
 
______________________________________________ 
Title:  
 
 
______________________________________________ 
Address: 
 
 
______________________________________________ 
Address: 
 
 
______________________________________________ 
Address: 
 
 
______________________________________________ 
Phone:  
 
 
______________________________________________ 
Facsimile: 
 
 
______________________________________________ 
Signature: 
 
 
______________________________________________ 
Date:  
 
 
______________________________________________ 


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PROTOCOL SYNOPSIS 
 
Protocol Title:  A Randomized, Open-label, Phase 2 Study of Sipuleucel-T with Concurrent 
Versus Sequential Administration of Enzalutamide in Men with Metastatic Castrate-Resistant 
Prostate Cancer 
Protocol Number: P12-2 
Clinical Phase: 2 
Investigational Product, Dosage Form, Route, and Dose Regimen: Sipuleucel-T (Provenge®) 
is an autologous cellular immunotherapy product designed to stimulate an immune response 
against prostate cancer.  It consists of autologous peripheral blood mononuclear cells (PBMCs), 
including antigen presenting cells ([APCs], defined as large CD54-positive PBMCs) that have 
been activated in vitro with prostate antigen PA2024, a recombinant fusion protein composed of 
prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. 
A dose of sipuleucel-T is prepared using PBMCs from a single leukapheresis procedure.  A 
minimum of 50 million APCs (the biologically active component of sipuleucel-T) are 
administered via a single intravenous (IV) infusion.  A complete treatment of sipuleucel-T will 
include 3 doses of autologous cells, infused at approximately 2-week intervals. 
Sipuleucel-T is indicated for use in patients with asymptomatic or minimally symptomatic 
metastatic castrate-resistant prostate cancer (mCRPC). 
Enzalutamide is an androgen receptor inhibitor.  It is indicated for the treatment of patients with 
mCRPC who have previously received docetaxel.  The enzalutamide dose used in this study will 
be 160 mg orally once daily. 
Reference Product, Dosage Form, Route, and Dose Regimen: No reference product will be 
used in this clinical study. 
Primary Objective: 
To evaluate peripheral PA2024-specific T cell immune response to sipuleucel-T over time via a 
T cell stimulation index from a proliferation assay. 
Secondary Objectives: 
 To evaluate time to prostate-specific antigen (PSA) progression. 


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 To estimate the percent of subjects who are PSA progression-free at 12 months. 
 To evaluate overall survival. 
 To determine the magnitude of peripheral immune response over time as determined by the 
following: 
– Peripheral PAP-specific T cell immune response to sipuleucel-T over time via a T cell 
stimulation index from a proliferation assay. 
– T cell interferon-γ enzyme-linked immunosorbent spot assay (ELISPOT) response to 
PA2024 and PAP. 
– Humoral response to PA2024 and PAP by enzyme-linked immunosorbent assay 
(ELISA). 
– Chemokine and cytokine production via fluorescent immunoassay (Luminex® assay). 
 To evaluate safety. 
Exploratory Objectives: 
 To evaluate time to next anticancer intervention. 
 To evaluate time to first cancer-related opioid use. 
 To evaluate time to Eastern Cooperative Oncology Group (ECOG) performance status 
decline. 
Study Design and Duration: 
This is a randomized, open-label study designed to assess the effects of sipuleucel-T when 
administered concurrently or sequentially with enzalutamide.  This study consists of 3 phases.  
The screening phase will begin at the completion of the informed consent process and continue 
through registration.  The active phase will begin at registration and continue through the post-
treatment visit (30 to 37 days following the last study treatment).  The long term follow-up 
(LTFU) phase will begin after the post-treatment visit and will continue until the subject’s death 
or until Dendreon terminates the study. 
Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive 3 infusions of 
sipuleucel-T in addition to a total of 52 weeks of concurrent or sequential treatment with 
enzalutamide.  Subjects will be stratified by screening PSA levels (≥ 25 ng/mL, yes or no) and 


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screening lactate dehydrogenase (LDH) levels (≥ 200 IU/L, yes or no), both obtained from the 
central laboratory. 
Enzalutamide treatment will occur either concurrently with sipuleucel-T (concurrent arm), or 
following administration of sipuleucel-T (sequential arm): 
Concurrent Arm 
Subjects will receive sipuleucel-T concurrently with enzalutamide (160 mg orally once 
daily).  Enzalutamide treatment will start 2 weeks prior to the first leukapheresis and 
continue for 52 weeks or until disease progression or unacceptable toxicity, whichever 
occurs first.  Subjects randomized to the concurrent arm who receive the 2-week 
enzalutamide run-in, but do not subsequently receive at least one partial (> 0 mL) 
infusion of sipuleucel-T will not receive any additional enzalutamide treatment, will 
undergo a post-treatment visit, and will enter the LTFU phase. 
Sequential Arm 
Subjects will receive sipuleucel-T followed by enzalutamide (160 mg orally once daily).  
Enzalutamide treatment will start approximately 10 weeks after the first infusion of 
sipuleucel-T and continue for 52 weeks or until disease progression or unacceptable 
toxicity, whichever occurs first.  Subjects randomized to the sequential arm who do not 
receive at least one partial (> 0 mL) infusion of sipuleucel-T will not receive any 
enzalutamide treatment, will undergo a post-treatment visit, and will enter the LTFU 
phase. 
After 52 weeks of enzalutamide treatment provided by Dendreon, subjects in either 
treatment arm may continue to receive enzalutamide obtained from other sources at the 
discretion of their treating physician.  Dendreon cannot provide enzalutamide beyond the 
protocol-specified duration of 52 weeks. 
During the active phase, subjects in both arms will undergo a standard 1.5 to 2.0 blood volume 
leukapheresis, followed approximately 3 days later by an IV infusion of sipuleucel-T.  This 
process will occur a total of 3 times at approximately 2-week intervals, as shown in the study 
design below.  Immune monitoring blood samples will be drawn and clinical and safety 
assessments will be performed at screening, preleukapheresis visits 2 and 3, and weeks 6, 10, 14, 
20, 26, 40 and 52, with the timing of visits based on the date of the first sipuleucel-T infusion.  
Immune monitoring blood samples will also be drawn following each sipuleucel-T infusion.  
Additional assessments including physical examinations, vital signs, ECOG performance status, 
AE monitoring, anticancer therapies, first opioid use for cancer-related pain, laboratory tests 


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(e.g., hematology and serum chemistries), and PSA monitoring will be performed at scheduled 
times. 
During the LTFU phase, safety (treatment-related AEs, cerebrovascular events, and seizures), 
survival status, PSA, ECOG performance status, first opioid use for cancer-related pain (if 
applicable), and anticancer therapies will be assessed every 3 months until the subject’s death or 
until Dendreon terminates the study. 
The study design is illustrated below. 
 
Abbreviation:  LTFU = long-term follow-up. 
 
Study Population and Sample Size: Approximately 100 men with mCRPC, 18 years of age or 
older will be enrolled.  
Statistical Considerations: 
The study is designed to test the null hypothesis of no difference between the treatment arms for 
immune response over time evaluated on the basis of PA2024-stimulated T cell proliferation via 
tritiated-thymidine uptake.  The immune response population will consist of all subjects who 
receive 3 infusions of sipuleucel-T and at least 10 weeks of enzalutamide.  PA2024-specific T 
cell proliferation responses over time will be compared between the concurrent arm and 
sequential arm using a repeated measurement mixed model analysis. 
With 43 subjects per treatment arm (concurrent and sequential), there is 90% power to detect a 2-
fold difference in mean response between the arms at any time point assuming a coefficient of 


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variation of 1.25.  To allow for drop-outs and subjects who may not receive 3 infusions of 
sipuleucel-T or at least 10 weeks of enzalutamide, approximately 50 subjects per arm will be 
enrolled. 
The intent-to-treat population is defined as all randomized subjects, regardless of whether they 
receive treatment.  Analysis of non-immune response efficacy endpoints will be performed using 
this analysis population. 
The safety population will include all subjects who undergo at least 1 leukapheresis procedure or 
receive at least 1 dose of enzalutamide. 


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TABLE OF CONTENTS 
1.0 
INTRODUCTION............................................................................................................12 
1.1 
Background and Rationale .....................................................................................12 
1.1.1 
Prostate Cancer......................................................................................12 
1.1.2 
Sipuleucel-T ..........................................................................................13 
1.1.3 
Enzalutamide .........................................................................................14 
2.0 
OBJECTIVES ..................................................................................................................15 
2.1 
Primary Objective ..................................................................................................15 
2.2 
Secondary Objectives.............................................................................................15 
2.3 
Exploratory Objectives ..........................................................................................15 
3.0 
INVESTIGATIONAL PLAN .........................................................................................16 
3.1 
Study Design and Duration ....................................................................................16 
4.0 
STUDY POPULATION ..................................................................................................18 
4.1 
Inclusion Criteria ...................................................................................................18 
4.2 
Exclusion Criteria ..................................................................................................20 
4.3 
Discontinuation from Study Treatments or Assessments ......................................22 
4.3.1 
Discontinuation from Sipuleucel-T Treatment .....................................22 
4.3.2 
Discontinuation from Enzalutamide Treatment ....................................23 
4.3.3 
Discontinuation from All Study Treatments .........................................23 
4.3.4 
Discontinuation from the Study ............................................................24 
4.4 
Lost to Follow-Up ..................................................................................................24 
4.5 
Disease Progression ...............................................................................................25 
4.6 
Concomitant Medications ......................................................................................26 
4.7 
Prohibited and/or Restricted Treatments ...............................................................26 
5.0 
STUDY TREATMENTS .................................................................................................27 
5.1 
Handling Study Treatments ...................................................................................27 
5.2 
Sipuleucel-T Treatment .........................................................................................27 
5.2.1 
Leukapheresis and Infusion Scheduling................................................27 
5.2.2 
Preleukapheresis Assessments ..............................................................27 
5.2.3 
Subject Preparation for Leukapheresis..................................................28 
5.2.4 
Leukapheresis ........................................................................................28 
5.2.5 
Sipuleucel-T Infusion ............................................................................28 


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5.2.6 
Sipuleucel-T Product Failures and Leukapheresis Rescheduling .........28 
5.3 
Enzalutamide Treatment ........................................................................................29 
5.4 
Selection and Timing of Dose for Each Subject ....................................................29 
5.5 
Blinding/Unblinding ..............................................................................................29 
5.6 
Treatment Compliance ...........................................................................................29 
5.7 
Destruction and Return of Study Treatments.........................................................29 
5.7.1 
Sipuleucel-T ..........................................................................................29 
5.7.2 
Enzalutamide .........................................................................................30 
6.0 
STUDY ASSESSMENTS AND PROCEDURES ..........................................................30 
6.1 
Schedule of Assessments .......................................................................................30 
6.1.1 
Registration ...........................................................................................35 
6.1.2 
Randomization ......................................................................................35 
6.2 
Demographics ........................................................................................................35 
6.3 
Clinical Assessments .............................................................................................35 
6.3.1 
Medical History .....................................................................................35 
6.3.2 
Physical Examination ............................................................................36 
6.3.3 
Vital Signs .............................................................................................36 
6.3.4 
ECOG Performance Status ....................................................................36 
6.3.5 
Imaging .................................................................................................36 
6.4 
Safety Assessments ................................................................................................37 
6.4.1 
Adverse Events and Serious Adverse Events........................................37 
6.4.2 
Cerebrovascular Events .........................................................................37 
6.4.3 
Seizures .................................................................................................37 
6.5 
Concomitant Medications ......................................................................................38 
6.5.1 
Anticancer Therapies ............................................................................38 
6.5.2 
First Cancer-Related Opioid Use ..........................................................38 
6.6 
Survival Status .......................................................................................................38 
6.7 
Laboratory Test Assessments ................................................................................39 
6.8 
Immune Monitoring Assessments..........................................................................40 
6.8.1 
Immune Response .................................................................................40 
6.8.2 
Sipuleucel-T Lot Release ......................................................................40 
6.8.3 
Product Characterization .......................................................................40 
6.8.4 
Immune Gene Expression Analyses .....................................................41 


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6.8.5 
Sample Retention ..................................................................................41 
6.8.6 
Additional Optional Research ...............................................................41 
6.9 
Study Materials ......................................................................................................42 
7.0 
ADVERSE EVENTS .......................................................................................................42 
7.1 
Categories for Ranking Severity of Adverse Events .............................................42 
7.2 
Relationship of Adverse Events to Study Treatments ...........................................43 
7.3 
Serious Adverse Events .........................................................................................43 
7.3.1 
Serious Adverse Event Collection and Reporting .................................44 
7.3.2 
Cerebrovascular Events .........................................................................44 
7.3.3 
Seizures .................................................................................................45 
7.3.4 
Death Reports ........................................................................................45 
7.3.4.1 
Expedited Reporting Requirements ...............................................45 
7.4 
Laboratory Test Result Abnormalities ...................................................................45 
7.4.1 
Safety Monitoring and Enrollment Suspension ....................................46 
8.0 
STATISTICAL CONSIDERATIONS ...........................................................................46 
8.1 
General Considerations ..........................................................................................46 
8.2 
Sample Size Determination....................................................................................47 
8.3 
Populations for Analyses .......................................................................................47 
8.4 
Endpoints ...............................................................................................................47 
8.4.1 
Primary Endpoint(s) ..............................................................................47 
8.4.2 
Secondary Endpoint(s) ..........................................................................48 
8.4.3 
Exploratory Endpoint(s) ........................................................................49 
8.5 
Analyses .................................................................................................................49 
8.5.1 
Subject Disposition ...............................................................................49 
8.5.2 
Demographics and Baseline Characteristics .........................................50 
8.5.3 
Efficacy Analyses..................................................................................50 
8.5.4 
Safety Analyses .....................................................................................51 
8.5.4.1 
Adverse Events ..............................................................................51 
8.5.4.2 
Laboratory Data .............................................................................51 
8.5.4.3 
Vital Signs ......................................................................................52 
8.5.5 
Study Treatment Administration ...........................................................52 
8.5.6 
Concomitant Medications and Procedures ............................................52 
8.5.6.1 
Other Analyses ...............................................................................53 


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8.6 
Interim Analyses ....................................................................................................53 
9.0 
REGULATORY REQUIREMENTS .............................................................................53 
9.1 
Pre-Study Documentation ......................................................................................53 
9.2 
Investigator Obligations .........................................................................................54 
9.3 
Institutional Review Board ....................................................................................54 
9.4 
Informed Consent...................................................................................................55 
9.5 
Subject Confidentiality ..........................................................................................55 
10.0 
STUDY MANAGEMENT ...............................................................................................56 
10.1 
Study Documentation.............................................................................................56 
10.2 
Data Collection ......................................................................................................56 
10.3 
Protocol Compliance ..............................................................................................56 
10.4 
Monitoring .............................................................................................................57 
10.5 
Quality Assurance ..................................................................................................57 
10.6 
Disclosure of Data and Publication........................................................................57 
11.0 
LIST OF ABBREVIATIONS .........................................................................................58 
12.0 
REFERENCES .................................................................................................................60 
 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments .................................................................................31 
Table 2: 
Clinical Laboratory Tests .................................................................................39 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic...............................................................................................18 
 
LIST OF APPENDICES 
Appendix 1: 
Eastern Cooperative Oncology Group Performance Criteria ..........................63 
Appendix 2: 
Child-Pugh Score .............................................................................................64 
Appendix 3: 
Medications Metabolized by Cytochrome Enzymes .......................................65 
Appendix 4: 
Infusion Guidelines ..........................................................................................66 
 
 


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1.0 
INTRODUCTION 
1.1 
Background and Rationale 
1.1.1 
Prostate Cancer 
In 2012, prostate cancer was the most common solid tumor malignancy in men in the United 
States, comprising 29% of new cancer cases (241,740 new cancer cases).  Approximately 80% of 
prostate cancer cases are diagnosed when the cancer is still confined to the primary site.  An 
additional 12% are diagnosed when locally advanced, and a further 4% when the cancer has 
already metastasized (Howlader 2011).  Prostate cancer-related deaths typically occur as a result 
of complications of metastatic disease, with an estimated 28,170 annual deaths in 2012  
(Siegel 2012). 
Treatment of localized prostate cancer typically has a curative intent and may include radical 
prostatectomy, radiotherapy, brachytherapy, high intensity focused ultrasound, cryotherapy, or 
hormone therapy.  Watchful waiting or active surveillance may be employed where the risks of 
the treatment outweigh the benefits, taking into account the patient’s age and general health 
status. 
Although primary therapy effectively cures the majority of patients, disease does recur in 
approximately 20% to 40% of individuals, where an increased level of serum prostate specific 
antigen (PSA) may be considered to be evidence of biochemical failure and progression to 
advanced disease (Ward 2005). 
In men with recurrent disease, the current standard of care for androgen-dependent, advanced 
prostate cancer is androgen deprivation therapy (ADT) using a luteinizing hormone-releasing 
hormone (LHRH) agonist, an LHRH antagonist, or bilateral orchiectomy, which results in 
similar, and initially high, anticancer activity, with response rates attaining 80%.  A peripheral 
antiandrogen, such as flutamide or bicalutamide, is typically used during the initial treatment 
period with an LHRH agonist to block the transient testosterone flare, but randomized Phase 3 
trials have not consistently demonstrated a survival benefit with continuous combined androgen 
blockade (ADT plus antiandrogen) as compared with ADT alone (Klotz 2001). 
Despite ADT, virtually all patients with recurrent disease will progress and their disease will 
spread to distant sites, most commonly bones and/or regional lymph nodes (Scher 1996,  
Small 1997).  Disseminated or metastatic castrate-resistant prostate cancer (mCRPC) is a 
noncurable and lethal disease with a median survival reported in recent Phase 3 studies ranging 
from 12.2 to 27.2 months (Kantoff 2010, Ryan 2013). 


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Until recently, docetaxel was the only therapy demonstrated to enhance overall survival in 
patients with mCRPC (Petrylak 2004, Tannock 2004).  However, since 2010, sipuleucel-T 
(Provenge®, Provenge 2012), cabazitaxel (Jevtana®, Jevtana 2012), abiraterone acetate (Zytiga®, 
Zytiga 2012), and enzalutamide (Xtandi®, Xtandi 2011) have all received Food and Drug 
Administration (FDA) approval for the treatment of mCRPC based on their demonstrated ability 
to increase overall survival.  This increasing repertoire of approved agents for the treatment of 
mCRPC creates challenges within the treatment paradigm as there are currently no clinical data 
to inform how these agents are best sequenced. 
Although enzalutamide is indicated for the treatment of patients with mCRPC who have received 
prior chemotherapy, it has also been listed in the National Comprehensive Cancer Network 
Guidelines for prechemotherapy treatment of patients with mCRPC who have an evidence level 
2A.  Sipuleucel-T and enzalutamide both have the potential to be administered prior to 
chemotherapy to asymptomatic or minimally symptomatic patients with mCRPC.  Because 
androgen ablation has been demonstrated to have immunostimulatory properties, there is 
potential synergy from combining the androgen receptor inhibitor enzalutamide with  
sipuleucel-T (Mercader 2001, Drake 2005, Gannon 2009, Sutherland 2005, Koh 2009,  
Madan 2008).  An evidence-based approach to assess the consequences of concurrent or 
sequential therapy with enzalutamide and sipuleucel-T is therefore warranted to optimize the 
benefits of these agents within the therapeutic paradigm. 
1.1.2 
Sipuleucel-T 
Sipuleucel-T is an autologous cellular immunotherapy product designed to stimulate an immune 
response against prostate cancer.  It consists of autologous peripheral blood mononuclear cells 
(PBMCs), including antigen presenting cells (APCs, defined as large CD54-positive PBMCs) 
that have been activated in vitro with prostate antigen PA2024, a recombinant fusion protein 
composed of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-
stimulating factor (GM-CSF). 
Sipuleucel-T was approved in the United States in 2010 for the treatment of men with 
asymptomatic or minimally symptomatic (hormone refractory) mCRPC (Provenge 2011).  In the 
pivotal trial D9902B (IMPACT), 512 patients were randomized 2:1 to receive sipuleucel-T 
(N=341 subjects) or control (N=171 subjects).  Overall survival was longer in the sipuleucel-T 
group (median of 25.8 months versus 21.7 months; hazard ratio [HR] = 0.78; 95% confidence 
interval [CI]: 0.62, 0.98; P=0.03).  More than 3,339 infusions of sipuleucel-T and control (a 
product manufactured from PBMCs without activation with the PA2024 antigen), have been 
administered to men with prostate cancer in clinical trials. 


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Clinical data to support the safety of sipuleucel-T are provided from 904 subjects (sipuleucel-T, 
N = 601; control, N = 303) who participated in 4 multicenter, randomized, double-blind, 
controlled Phase 3 studies (Provenge 2011).  Three of these studies were conducted in men with 
mCRPC (studies D9902B, D9901, and D9902A), and 1 study was conducted in men with 
androgen dependent prostate cancer (ADPC).  In the 4 randomized Phase 3 studies, adverse 
events (AEs) reported in ≥ 20% of all subjects were chills, fatigue, pyrexia, and back pain.  The 
most common AEs (observed in ≥ 5% of sipuleucel-T subjects as well as at least twice the rate of 
that in control subjects) included chills, pyrexia, headache, myalgia, influenza-like illness, and 
hyperhidrosis.  The majority of these events occurred within 1 day of infusion; were grade 1 or 2 
in severity; and were generally of short duration (i.e., resolved in ≤  2  days).  Grade 3 or 4 
events were reported in 27.6% of subjects in the sipuleucel-T group, compared with 28.4% in the 
control group.  Cerebrovascular events (CVEs) occurred in 3.5% of subjects in the sipuleucel-T 
group compared with 2.6% in the control group.  A registry of approximately 1,500 patients is 
ongoing and will further evaluate the risk of CVEs in subjects receiving sipuleucel-T. 
1.1.3 
Enzalutamide 
Enzalutamide was approved in the U.S. in August, 2012 for the treatment of men with mCRPC 
who have previously received docetaxel (Xtandi 2012).  Enzalutamide is an androgen receptor 
inhibitor that acts on several steps in the androgen receptor signaling pathway. 
In the pivotal AFFIRM trial, 1199 patients were randomized 2:1 to receive oral enzalutamide 
(160 mg per day, N=800 subjects) or placebo (N=399 subjects).  Overall survival was longer in 
the enzalutamide group (median of 18.4 months versus 13.6 months; HR=0.63; 95% CI: 0.53, 
0.75, P < 0.001) (Scher 2008).  Common AEs associated with enzalutamide included some 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE,  
NCI 2010) grade 3-4 events that had a ≥ 2% absolute increase in frequency in the enzalutamide 
arm compared to the placebo arm.  These included asthenic conditions, peripheral edema, back 
pain, arthralgia, musculoskeletal pain, muscular weakness, musculoskeletal weakness, diarrhea, 
hot flush, hypertension, headache, dizziness, spinal cord compression and cauda equina 
syndrome, paresthesia, mental impairment disorders, hypoesthesia, upper respiratory tract 
infections, lower respiratory tract and lung infection, insomnia, anxiety, hematuria, pollakiuria, 
fall, nonpathologic fractures, pruritus, dry skin, and epistaxis.  Seven out of 800 enzalutamide-
treated subjects (0.9%) experienced a seizure and were discontinued from the study. Grade 3 and 
4 AEs were reported among 47% of enzalutamide-treated subjects and 53% of placebo-treated 
subjects (Xtandi 2012). 
Medivation, Inc., the manufacturer of enzalutamide, is conducting a Phase 3 study of 
enzalutamide vs. placebo in patients with mCRPC who have not undergone chemotherapy for 
prostate cancer.  The randomized, double-blind, placebo-controlled PREVAIL Trial is scheduled 


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to enroll 1680 patients to determine the benefit of enzalutamide versus placebo as assessed by 
overall survival and progression free survival in this population. 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
To evaluate peripheral PA2024-specific T cell immune response to sipuleucel-T over time via a 
T cell stimulation index from a proliferation assay. 
2.2 
Secondary Objectives 
Secondary Objectives: 
 To evaluate time to PSA progression. 
 To estimate the percent of subjects who are PSA progression-free at 12 months. 
 To evaluate overall survival. 
 To determine the magnitude of peripheral immune response over time as determined by the 
following: 
– Peripheral PAP-specific T cell immune response to sipuleucel-T over time via T cell 
stimulation index from a proliferation assay. 
– T cell interferon-γ enzyme-linked immunosorbent spot assay (ELISPOT) response to 
PA2024 and PAP. 
– Humoral response to PA2024 and PAP by enzyme-linked immunosorbent assay 
(ELISA). 
– Chemokine and cytokine production via fluorescent immunoassay (Luminex® assay). 
 To evaluate safety. 
2.3 
Exploratory Objectives 
 To evaluate time to next anticancer intervention. 
 To evaluate time to first cancer-related opioid use (see Section 6.5). 


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 To evaluate time to Eastern Cooperative Oncology Group (ECOG) performance status 
decline. 
3.0 
INVESTIGATIONAL PLAN 
3.1 
Study Design and Duration 
This is a randomized, open-label study designed to assess the effects of sipuleucel-T when 
administered concurrently or sequentially with enzalutamide.  This study consists of 3 phases.  
The screening phase will begin at the completion of the informed consent process and continue 
through registration.  The active phase will begin at registration and continue through the post-
treatment visit (30 to 37 days following the last study treatment).  The long-term follow-up 
(LTFU) phase will begin after the post-treatment visit and will continue until the subject’s death 
or until Dendreon terminates the study. 
Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive 3 infusions of 
sipuleucel-T in addition to a total of 52 weeks of concurrent or sequential treatment with 
enzalutamide.  Subjects will be stratified by screening PSA levels (≥ 25 ng/mL, yes or no) and 
screening lactate dehydrogenase (LDH) levels (≥ 200 IU/L, yes or no), both obtained from the 
central laboratory. 
Enzalutamide treatment will occur either concurrently with sipuleucel-T (concurrent arm), or 
following administration of sipuleucel-T (sequential arm): 
Concurrent Arm 
Subjects will receive sipuleucel-T concurrently with enzalutamide (160 mg orally once 
daily).  Enzalutamide treatment will start 2 weeks prior to the first leukapheresis and 
continue for 52 weeks or until disease progression or unacceptable toxicity, whichever 
occurs first.  Subjects randomized to the concurrent arm who receive the 2-week 
enzalutamide run-in, but do not subsequently receive at least one partial (> 0 mL) 
infusion of sipuleucel-T will not receive any additional enzalutamide treatment, will 
undergo a post-treatment visit, and will enter the LTFU phase. 


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Sequential Arm 
Subjects will receive sipuleucel-T followed by enzalutamide (160 mg orally once daily).  
Enzalutamide treatment will start approximately 10 weeks after the first infusion of 
sipuleucel-T and continue for 52 weeks or until disease progression or unacceptable 
toxicity, whichever occurs first.  Subjects randomized to the sequential arm who do not 
receive at least one partial (> 0 mL) infusion of sipuleucel-T will not receive any 
enzalutamide treatment, will undergo a post-treatment visit, and will enter the LTFU 
phase. 
After 52 weeks of enzalutamide treatment provided by Dendreon, subjects in either 
treatment arm may continue to receive enzalutamide obtained from other sources at the 
discretion of their treating physician.  Dendreon cannot provide enzalutamide beyond the 
protocol-specified duration of 52 weeks. 
During the active phase, subjects in both arms will undergo a standard 1.5 to 2.0 blood volume 
leukapheresis, followed approximately 3 days later by an intravenous (IV) infusion of sipuleucel-
T.  This process will occur a total of 3 times at approximately 2-week intervals.  A course of 
sipuleucel-T treatment comprises 3 infusions.  Immune monitoring blood samples will be drawn 
and clinical and safety assessments will be performed at screening, preleukapheresis visits 2 and 
3, and weeks 6, 10, 14, 20, 26, 40, and 52, with the timing of visits based on the date of the first 
sipuleucel-T infusion.  Immune monitoring blood samples will also be drawn following each 
sipuleucel-T infusion.  Additional assessments including physical examinations, vital signs, 
ECOG performance status (see Appendix 1), AE monitoring, anticancer therapies, first opioid 
use for cancer-related pain, laboratory tests (e.g., hematology and serum chemistries), and PSA 
monitoring will be performed at the times shown in Table 1. 
During the LTFU phase, safety (treatment-related AEs, seizures, and CVEs), survival status, 
PSA, ECOG performance status, first opioid use for cancer-related pain (if applicable), and 
anticancer therapies will be assessed every 3 months until the subject’s death or until Dendreon 
terminates the study. 
The study design is illustrated in Figure 1. 


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Figure 1: 
Study Schematic 
 
Abbreviation:  LTFU = long-term follow-up. 
 
4.0 
STUDY POPULATION 
To participate in this study, subjects must meet all inclusion criteria and none of the exclusion 
criteria. 
4.1 
Inclusion Criteria 
4.1.1 Written informed consent provided prior to the initiation of study procedures. 
4.1.2 Age ≥ 18 years. 
4.1.3 Histologically documented adenocarcinoma prostate cancer confirmed by a pathology 
report from prostate biopsy or a radical prostatectomy specimen.  If prostatic tumor is of 
mixed histology, > 50% of the tumor must be adenocarcinoma.  
4.1.4 Metastatic disease as evidenced by one of the following: 
 Bone metastasis (≥ 1 lesion) by bone scan or by sodium-fluoride positron emission 
tomography (Na-F PET) or carbon-11 acetate positron emission tomography (C11 
acetate PET) with computed tomography (CT).  If a bone scan is used, solitary lesions 
or lesions which could be attributed to causes other than metastatic prostate cancer 
must be confirmed with a second imaging modality (i.e., CT or magnetic resonance 
imaging [MRI]). 
 Lymph node metastasis comprising at least 1 node ≥ 2 cm in short-axis diameter. 


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Histopathological confirmation of metastatic disease is not required. 
4.1.5 Castrate-resistant prostate cancer, in the setting of castrate levels of testosterone  
(≤ 50 ng/dL), defined as current or historical evidence of disease progression concomitant 
with surgical castration or ADT, as demonstrated by one of the following: 
 Prostate specific antigen progression: PSA progression will be defined as 2 rising 
PSA values compared to a reference value, measured at least 7 days apart and the 
second value is ≥ 2 ng/mL (Scher 2008). 
 Progression of measurable disease: ≥ 20% increase in the sum of the longest 
diameters of all measureable lesions or the development of any new lesions.  The 
change will be measurable against the best response to castration therapy or against 
the precastration measurements if there was no response. 
 Progression of non-measurable disease by one of the following: 
– Soft tissue disease: The appearance of 1 or more new lesions, and/or unequivocal 
worsening of non-measurable disease when compared to imaging studies acquired 
during castration therapy or against the precastration studies if there was no 
response. 
– Bone disease: 
 
Bone scan: Appearance of 2 or more new areas of abnormal uptake on bone 
scan when compared to imaging studies acquired during castration therapy or 
against the precastration studies if there was no response.  Increased uptake of 
pre-existing lesions on bone scan does not constitute progression. 
 
Na-F or C-11 acetate PET/CT: Appearance of 2 or more new lesions when 
compared to imaging acquired during castration therapy or against the 
precastration studies if there was no response. 
4.1.6 Castration levels of testosterone (≤ 50 ng/dL) achieved via medical or surgical castration. 
4.1.7 Serum PSA ≥ 2.0 ng/mL. 
4.1.8 Screening ECOG performance status ≤ 1 (see Appendix 1). 


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4.1.9 Adequate screening hematologic, renal, and liver function as evidenced by laboratory test 
results obtained from the central laboratory within the following ranges ≤ 28 days prior to 
registration: 
 Absolute lymphocyte count 
≥ 1 x 103/µL 
 White blood cell count 
≥ 2.5 x 103/µL 
 Neutrophils 
≥ 1 x 103/µL 
 Platelet count 
≥ 100 x 103/µL 
 Hemoglobin 
≥ 10.0 g/dL 
 Creatinine 
≤ 2.0 mg/dL 
 Total bilirubin 
≤ 2 x upper limit of normal (ULN) 
 Aspartate aminotransferase 
≤ 2.5 x ULN 
 Alanine aminotransferase 
≤ 2.5 x ULN 
 
4.1.10 Negative serology test for human immunodeficiency virus 1 and 2. 
4.1.11 Resides within driving distance (round trip within 1 day) of the clinical trial site for the 
duration of the active phase. 
4.2 
Exclusion Criteria 
4.2.1 The presence of known lung, liver, or brain metastases, malignant pleural effusions, or 
malignant ascites.  In the case of suspected or questionable findings, the investigator must 
assess and document each finding in the subject’s medical record prior to registration. 
4.2.2 Spinal cord compression, imminent long bone fracture, or any other condition that, in the 
opinion of the investigator, is likely to require radiation therapy and/or steroids for pain 
control during the active phase. 
4.2.3 History of stage 3 or greater cancer, excluding prostate cancer.  Basal or squamous cell 
skin cancers must have been adequately treated and the subject must be disease free at the 
time of registration.  Subjects with a history of stage 1 or 2 cancer must have been 
adequately treated and been disease free for ≥ 3 years at the time of registration. 
4.2.4 History of seizures or of predisposing factors for seizures, including underlying brain 
injury with loss of consciousness within previous 12 months, transient ischemic attack 
within previous 12 months, cerebral vascular accident or brain arteriovenous 
malformation. 
4.2.5 Child-Pugh Class C hepatic insufficiency (see Appendix 2). 


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4.2.6 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to sipuleucel-T, GM-CSF or granulocyte colony stimulating factor (G-CSF). 
4.2.7 Previous treatment with sipuleucel-T or enrollment in a sipuleucel-T trial, regardless of 
whether the subject received sipuleucel-T or control. 
4.2.8 Previous treatment with enzalutamide. 
4.2.9 Previous treatment with abiraterone acetate. 
4.2.10 Previous treatment with ipilimumab. 
4.2.11 Previous treatment with ketoconazole other than topical use or for treatment of infections 
(e.g., oral thrush); most recent use must have been ≥ 7 days prior to registration. 
4.2.12 Previous treatment with any immunotherapy or investigational vaccine. 
4.2.13 A requirement for ongoing systemic immunosuppressive therapy.  Use of inhaled, 
intranasal, intra-articular, and topical steroids is allowed.  Oral or IV steroids to prevent 
or treat IV contrast reactions are allowed. 
4.2.14 Previous treatment with chemotherapy for mCRPC, or chemotherapy for any reason ≤ 2 
years prior to registration. 
4.2.15 Use of concomitant medications that may lower the seizure threshold or the use of 
antiseizure medications ≤ 1 year prior to registration. 
4.2.16 Received GM-CSF or G-CSF ≤ 90 days prior to registration. 
4.2.17 Ongoing non-steroidal antiandrogen withdrawal response.  Subjects on combined 
androgen blockade with a non-steroidal antiandrogen and LHRH agonist must 
discontinue the non-steroidal antiandrogen.  A PSA level must be obtained < 28 days 
prior to the antiandrogen discontinuation and then again > 28 days following 
discontinuation.  If the PSA has dropped > 25% from the time of antiandrogen 
discontinuation, subjects are not eligible until the PSA rises above the post-antiandrogen 
discontinuation nadir. 
4.2.18 Any of the following medications or interventions ≤ 28 days prior to registration: 
 Radiation therapy, either via external beam or brachytherapy. 
 Any systemic steroid.  Use of inhaled, intra-nasal, intra-articular, and topical steroids 
is allowed.  Oral or IV steroids to prevent or treat IV contrast reactions are allowed. 


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 Any systemic therapy for prostate cancer, except for ADT. 
 Any investigational product for prostate cancer. 
 Major surgery requiring general anesthesia, with the exception of placement of 
central venous catheters. 
 Inducers and inhibitors of cytochrome P450 (CYP) enzyme CYP2C8 (gemfibrozil 
and rifampin [see Appendix 3]). 
 Medications that are metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a 
narrow therapeutic index (see Appendix 3). 
 Inducers of CYP3A4 (including but not limited to phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentine, and phenobarbital [see Appendix 3]). 
4.2.19 A requirement for treatment with opioid analgesics for cancer-related pain ≤ 21 days 
prior to registration. 
4.2.20 An active infection requiring parenteral antibiotic therapy or causing fever (temperature  
> 100.5˚ F or 38.1˚ C) ≤ 1 week prior to registration. 
4.2.21 Any medical intervention, any other condition, or any other circumstance which, in the 
opinion of the investigator or the Dendreon medical monitor, could compromise 
adherence with study requirements or otherwise compromise the study’s objectives. 
4.3 
Discontinuation from Study Treatments or Assessments 
The investigator may withdraw a subject from one or both study treatments, or from study 
assessment, if, in his or her clinical judgment, it is in the best interest of the subject. 
4.3.1 
Discontinuation from Sipuleucel-T Treatment 
Subjects who have received at least 1 partial (> 0 mL) infusion of sipuleucel-T may discontinue 
sipuleucel-T without the requirement to discontinue enzalutamide, provided the criteria for 
removal from all study treatments (see Section 4.3.3) have not been met.  These subjects will 
continue all protocol-specified assessments in the active phase. 
Any toxicity requiring sipuleucel-T discontinuation will be recorded as an AE in the subject’s 
medical record and on the case report form (CRF). 


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4.3.2 
Discontinuation from Enzalutamide Treatment 
Dose reduction for enzalutamide will not be permitted and subjects with any toxicity requiring 
enzalutamide dose reduction must discontinue enzalutamide treatment. 
Subjects who have not received 3 sipuleucel-T infusions may discontinue enzalutamide 
treatment without the requirement to discontinue sipuleucel-T provided the criteria for removal 
from all study treatments (Section 4.3.3) have not been met.  These subjects will undergo a post-
treatment visit after the last sipuleucel-T infusion and enter the LTFU phase. 
Subjects who have already received 3 sipuleucel-T infusions and ≥ 10 weeks of enzalutamide 
treatment when they discontinue enzalutamide will continue all protocol-specified assessments in 
the active phase.  Subjects who have received less than 10 weeks of enzalutamide treatment 
when they discontinue enzalutamide will undergo a post-treatment visit and enter the LTFU 
phase. 
Any toxicity requiring enzalutamide discontinuation or dose reduction will be recorded as an AE 
in the subject’s medical record and on the CRF. 
4.3.3 
Discontinuation from All Study Treatments 
Subjects will discontinue from all study treatments, undergo a post-treatment visit, and enter the 
LTFU phase for any of the following reasons: 
 The subject withdraws consent to receive study treatments. 
 The subject is unable to, or refuses to, undergo leukapheresis.  
 The subject is unable to, or refuses to, receive at least 1 partial (> 0 mL) sipuleucel-T 
infusion. 
 Dendreon is unable to manufacture sipuleucel-T for the subject. 
 The subject develops disease progression as defined in Section 4.5. 
 The subject develops any condition requiring a prohibited treatment (see Section 4.7). 
 Treatment is stopped at the discretion of the investigator or Dendreon. 


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4.3.4 
Discontinuation from the Study 
Subjects may discontinue their participation in the trial at any time without prejudice.  If a 
subject withdraws consent for any further study involvement, complete withdrawal of consent 
must be documented in the subject’s medical record.  The date and reason for withdrawal will be 
recorded in the subject’s medical record and on the CRF. 
Whenever possible, subjects discontinuing from the study will undergo a post-treatment visit.  
All AEs considered by the investigator to be related to study treatment(s) that are ongoing at the 
time of discontinuation will be followed by the investigator until resolution or until the subject 
returns to baseline.  The investigator should make every reasonable attempt to ensure that the 
subject is contacted (via telephone or during a post-treatment visit) to obtain the final status of 
any AEs and concomitant medications.   
Subjects will discontinue from the study (all treatment and subsequent assessments) for any of 
the following reasons: 
 The subject withdraws consent for any reason. 
 The subject loses the ability to freely provide consent. 
 The subject is lost to follow-up. 
 The subject fails to comply with protocol requirements. 
 The subject is discontinued from the study at the discretion of the investigator or 
Dendreon. 
 Dendreon terminates the study. 
Subjects who withdraw consent, or lose the ability to freely provide consent, will be followed by 
the investigator for survival every 3 months using the Social Security Death Index (SSDI) and 
National Death Index (NDI).  Date of death, where available, will be recorded in the subject’s 
medical record and on the CRF. 
4.4 
Lost to Follow-Up 
If the subject fails to respond to requests for follow-up, the clinical trial site will send a registered 
letter, at a minimum, to the subject requesting contact with the clinic.  All attempts to resume 
contact (including copies of written correspondence) will be included in the source 
documentation.  Subjects who do not respond to requests for follow-up after all reasonable 
attempts to establish contact will be considered “lost to follow-up”.  Subjects who are lost to 


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follow-up will be followed by the investigator for survival every 3 months using the SSDI and 
the NDI.  Date of death, where available, will be recorded in the subject’s medical record and on 
the CRF. 
4.5 
Disease Progression 
Disease progression is determined by the investigator per the definition below.  The earliest date 
of disease progression will be recorded in the subject’s medical record and on the CRF.  
Following disease progression, all study treatments will cease, the subject will undergo a post-
treatment visit, enter LTFU, and will be treated at the investigator’s discretion. 
Any 1 or more of the following events constitutes disease progression: 
 PSA Progression (based on Prostate Cancer Working Group 2 criteria, (Scher 2008): 
– Decline from baseline: the 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). 
– No decline from baseline: PSA progression ≥ 25% and ≥ 2 ng/mL after 12 weeks of 
enzalutamide treatment. 
PSA measurements obtained during the first 12 weeks of enzalutamide treatment should not be 
used as the sole criterion for determining progression.  Study treatments may be continued in 
equivocal cases where there is PSA progression but no clear evidence of disease progression or 
clinical deterioration, and where the investigator feels the subject is deriving clinical benefit from 
the study treatments and subject safety is not compromised (Scher 2008). 
 Clinically significant disease-specific event: 
– New spinal cord or nerve root compression. 
– New pathologic fracture. 
– Development of metastatic disease in a new anatomic location. 
– Disease progression based on radiographic imaging and Response Evaluation Criteria 
in Solid Tumors criteria version 1.1. 


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4.6 
Concomitant Medications 
Subjects should receive full supportive care, including transfusions of blood and blood products, 
antibiotics, antiemetics, or other therapies, in accordance with standard practice at the clinical 
trial site.  Subjects receiving ADT, bisphosphonate therapy such as zoledronic acid (Zometa®), or 
denosumab (Xgeva®) at the time of registration should continue the therapy at a stable dose until 
the post-treatment visit or disease progression, whichever occurs first. 
All concomitant medications administered from screening through the post-treatment visit, 
including indication, dose, route, frequency and treatment dates, will be recorded in the subject’s 
medical record and on the CRF.  After the post-treatment visit, only anticancer therapies will be 
recorded.  The first opioid taken for cancer-related pain will be recorded, regardless of when it is 
started. 
4.7 
Prohibited and/or Restricted Treatments 
Subjects on ADT must continue this therapy until the post-treatment visit or disease progression, 
whichever occurs first. 
The following medications and interventions must not be initiated until the post-treatment visit 
or disease progression, whichever occurs first: 
 Investigational vaccines or other investigational products. 
 Ipilimumab. 
 Any therapy for prostate cancer except for that administered in this protocol and ADT. 
 External beam radiation therapy or brachytherapy. 
 Inducers or inhibitors of CYP2C8 (gemfibrozil, rifampin [see Appendix 3]). 
 Medications that are metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow 
therapeutic index (see Appendix 3). 
 Inducers of CYP3A4 (including but not limited to phenytoin, carbamazepine, rifampin, 
rifabutin, rifapentine, and phenobarbital [see Appendix 3]). 


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5.0 
STUDY TREATMENTS 
5.1 
Handling Study Treatments 
Study treatments must be stored, handled, and prepared as specified by the sipuleucel-T 
investigator’s brochure (IB, Sipuleucel-T 2013) and the enzalutamide prescribing information 
(Xtandi 2012).  Dendreon should be notified immediately if concerns regarding the quality or 
appearance of the study treatments arise. 
Accountability documentation, including receipt, storage and applicable storage conditions, 
administration, destruction and use of required processes must be maintained to ensure the study 
treatments are accurately administered. 
Dendreon will supply the study treatments (sipuleucel-T, enzalutamide).  Enzalutamide will be 
labeled with protocol-specific information, including the statement “Caution: New Drug-Limited 
by United States law to investigational use.” 
5.2 
Sipuleucel-T Treatment 
5.2.1 
Leukapheresis and Infusion Scheduling 
The subject’s 3 leukapheresis appointments will be scheduled by Dendreon.  Leukapheresis 
appointments will be scheduled at approximately 2-week intervals.  The clinical trial site will 
receive confirmation of the leukapheresis and infusion dates via email.  The clinical trial site will 
schedule the subject’s infusion appointments based on this schedule.  If the subject is 
subsequently deemed ineligible, the clinical trial site will be informed and the leukapheresis and 
infusion appointments will be canceled. 
5.2.2 
Preleukapheresis Assessments 
Subjects will be evaluated for their ability to tolerate the leukapheresis procedure during 
preleukapheresis assessments that occur during screening and ≤ 5 days prior to the second and 
third leukapheresis.  The assessment may occur on the day of the leukapheresis procedure 
provided it occurs before the leukapheresis procedure. 
Venous access is evaluated to determine if, due to inadequate peripheral veins, placement of a 
central venous catheter is absolutely necessary to undergo leukapheresis.  If there is any question 
about adequate venous access, the subject will be assessed at a leukapheresis center by a 
leukapheresis nurse. 
If a subject has any infection requiring parenteral antibiotic therapy or causing fever 
(temperature > 100.5°F or > 38.1°C) within 1 week prior to a leukapheresis appointment, the 


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appointment should be rescheduled to occur after the fever resolves and the investigator believes 
the subject is healthy enough to undergo the procedure. 
5.2.3 
Subject Preparation for Leukapheresis 
The subject should be instructed to eat calcium-rich foods in advance of the leukapheresis 
procedure.  The subject should drink plenty of fluids a few days prior to the procedure to 
promote adequate venous access during leukapheresis, but drink minimal fluids on the mornings 
of leukapheresis appointments. 
5.2.4 
Leukapheresis 
The collection of blood cells to manufacture sipuleucel-T is analogous to that for autologous 
blood transfusions.  Subjects undergo a standard 1.5 to 2.0 blood volume leukapheresis to 
harvest PBMCs (primarily lymphocytes and monocytes).  Prior mobilization with a colony-
stimulating factor is not performed.  Immediately after completion of the collection procedure, 
the leukapheresis product is transported to one of Dendreon’s regional immunotherapy 
manufacturing facilities.  All of the cells recovered from the leukapheresis procedure will be 
used to produce 1 dose of sipuleucel-T that is infused approximately 3 days following the 
leukapheresis procedure. 
To maintain the chain of identity and ensure subject safety, subject identifiers accompany the 
production of sipuleucel-T throughout the manufacturing process.  The subject’s identifying 
information will be revealed to Dendreon’s apheresis and manufacturing personnel.  The 
sipuleucel-T label with the subject identifier is returned to the clinical trial site. 
5.2.5 
Sipuleucel-T Infusion 
Each sipuleucel-T dose is released by Dendreon for infusion approximately 3 days following the 
leukapheresis procedure.  Subjects will be infused according to the infusion guidelines provided 
in Appendix 4. 
5.2.6 
Sipuleucel-T Product Failures and Leukapheresis Rescheduling 
In the event that a subject’s leukapheresis procedure fails, sipuleucel-T does not meet quality 
release specifications, or infusion is not possible for any other reason, the subject may be 
scheduled to undergo a repeat leukapheresis procedure.  A minimum of 2 days must have elapsed 
since the last leukapheresis procedure.  Scheduling will depend upon capacity of the 
leukapheresis and Dendreon manufacturing facilities.  If the second or third leukapheresis 
appointment is delayed or rescheduled for any reason, a physical examination and all other 


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preleukapheresis procedures must be repeated within the 5 days prior to the next leukapheresis 
procedure.  The preleukapheresis immune monitoring samples will not be drawn again. 
There is a possibility that a subject’s sipuleucel-T may fail to meet quality requirements more 
than once.  In such instances, the subject may not receive all 3 infusions.  In rare instances, it 
may be determined that it is not possible to manufacture sipuleucel-T that passes quality control 
(QC) testing from a subject’s leukapheresis product. 
5.3 
Enzalutamide Treatment 
For the concurrent arm, enzalutamide dispensing visits will occur 2 weeks prior to the first 
leukapheresis, at preleukapheresis visit 2 and at weeks 6, 10, 14, 20, 26, 34, 40, and 46; for the 
sequential arm, these visits will occur at weeks 10, 14, 20, 26, 34, 40, 48 and 52 (see Table 1). 
In the event of multiple sipuleucel-T product failures for a subject in the sequential arm, 
enzalutamide treatment should not be started until the subject has received all 3 sipuleucel-T 
infusions or a determination has been made that the subject will not receive 3 infusions.  Subjects 
randomized to the sequential arm who do not receive at least one partial (> 0 mL) infusion of 
sipuleucel-T will not receive any enzalutamide treatment. 
5.4 
Selection and Timing of Dose for Each Subject 
Subjects who complete the study will receive 3 infusions of sipuleucel-T and 52 weeks of 
enzalutamide (160 mg oral dose once daily).  The timing of doses is described in Section 3.1. 
5.5 
Blinding/Unblinding 
This is an open-label study. 
5.6 
Treatment Compliance 
Sipuleucel-T will be administered at the clinical trial site. 
Enzalutamide compliance will be monitored by reconciliation of returned study treatments 
and/or treatment packaging at every dispensing visit. 
5.7 
Destruction and Return of Study Treatments 
5.7.1 
Sipuleucel-T 
The clinical trial site will dispose of the sipuleucel-T bag and tubing according to institutional 
procedures for disposal of biohazardous waste that contains human blood. 


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All packaging materials and gel packs will be disposed of according to institutional procedures. 
If instructed by Dendreon to return the sipuleucel-T and/or tubing, the remaining sipuleucel-T 
will be placed in the original shipping box with the original packaging materials and shipped per 
Dendreon’s instructions. 
5.7.2 
Enzalutamide 
All undispensed, returned, or expired enzalutamide and any empty enzalutamide bottles will be 
retained until study treatment accountability and treatment compliance are verified by a 
Dendreon clinical research associate.  Following verification, any undispensed, returned or 
expired enzalutamide and any empty enzalutamide bottles will be disposed of according to 
institutional procedures. 
6.0 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Schedule of Assessments 
The schedule of assessments is presented in Table 1. 
 


 
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Table 1: 
Schedule of Assessments 
Active Phase 
LTFU 
Visitsf 
 
Screening 
Enzalutamide 
Dispensing 
Visitsa 
Preleukapheresis 
Visitsb 
Leukapheresis 
Visitsc 
Infusion Visitsd 
Post-
infusion 
Visitse 
Post-
Treatment 
Visit 
Visit Timing 
≤ 28 days 
prior to 
registrationg 
± 1 week 
≤ 5 days prior to 
leukapheresis 
As scheduled 
by Dendreon 
Approximately 
3 days after 
leukapheresis 
± 1 week 
30-37 days 
after last 
study 
treatment 
± 2 
weeks 
Informed Consent 
X 
Registration/ 
Randomization 
X 
 
 
 
 
 
 
 
Pathology (Gleason Sum) 
X 
Leukapheresis 
X 
Sipuleucel-T Infusion 
X 
Enzalutamide Dispensing 
X 
Clinical Assessments  
Medical History 
X 
Physical Examination 
X 
X 
X 
X 
Vital Signs 
X 
X 
Xh 
X 
X 
ECOG Performance 
Status 
X 
 
X 
 
 
X 
X 
Xi 
Bone scan or Na-F or C11 
acetate PET/CT; cross-
sectional imaging (CT or 
MRI) 
X 
 
 
 
 
 
 
 
 


 
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Table 1: 
Schedule of Assessments (Cont'd) 
 
Active Phase 
LTFU 
Visitsf 
 
Screening 
Enzalutamide 
Dispensing 
Visitsa 
Preleukapheresis 
Visitsb 
Leukapheresis 
Visitsc 
Infusion Visitsd 
Post-
infusion 
Visitse 
Post-
Treatment 
Visit 
Visit Timing 
≤ 28 days 
prior to 
registrationg 
± 1 week 
≤ 5 days prior to 
leukapheresis 
As scheduled 
by Dendreon 
Approximately 
3 days after 
leukapheresis 
± 1 week 
30-37 days 
after last 
study 
treatment 
± 2 
weeks 
Safety Assessments 
Record Adverse Events 
X 
X 
X 
X 
X 
X 
Xj 
Record Serious Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
Xj 
Record Cerebrovascular 
Events 
 
X 
X 
X 
X 
X 
X 
X 
Record Seizures 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Xk 
Anticancer Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
First Opioid for Cancer-
related Pain 
 
X 
X 
X 
X 
X 
X 
X 
Survival Status 
X 
Laboratory Assessments 
Hematology 
X 
X 
X 
X 
Chemistry 
X 
X 
X 
X 
Testosterone 
X 
PSA 
X 
Xl 
Xl 
X 
X 
Xm 
Serum PAP 
X 
Xl 
Xl 
X 
X 


 
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Table 1: 
Schedule of Assessments (Cont'd) 
 
Active Phase 
LTFU 
Visitsf 
 
Screening 
Enzalutamide 
Dispensing 
Visitsa 
Preleukapheresis 
Visitsb 
Leukapheresis 
Visitsc 
Infusion Visitsd 
Post-
infusion 
Visitse 
Post-
Treatment 
Visit 
Visit Timing 
≤ 28 days 
prior to 
registrationg 
± 1 week 
≤ 5 days prior to 
leukapheresis 
As scheduled 
by Dendreon 
Approximately 
3 days after 
leukapheresis 
± 1 week 
30-37 days 
after last 
study 
treatment 
± 2 
weeks 
Coagulation 
X 
Serology 
X 
Immune Monitoring Assessments 
100 mL sample 
Xn 
Xo 
X 
X 
10 mL sample 
Xp 
Abbreviations: CT = computed tomography; DNA = deoxyribonucleic acid; ECOG = Eastern Cooperative Oncology Group; LFTU = long-term follow-up; MRI 
= magnetic resonance imaging; Na-F = sodium fluoride; PAP = prostatic acid phosphatase; PET = positron emission tomography; PSA = prostate specific 
antigen. 
a 
For the concurrent arm, enzalutamide dispensing visits will occur 2 weeks prior to the first leukapheresis, at the preleukapheresis 2 visit, and at weeks 6, 10, 
14, 20, 26, 34, 40 and 46; for the sequential arm, these visits will occur at weeks 10, 14, 20, 26, 34, 40, 48 and 52.   
b 
Applies to leukapheresis visits 2 and 3 only; preleukapheresis visits will occur ≤ 5 days prior to each leukapheresis. 
c 
In the concurrent arm, the first leukapheresis should occur 2 weeks after the start of enzalutamide and must occur within 42 days of the start of enzalutamide. 
d 
Infusions will occur approximately 3 days after leukapheresis at approximately 2-week intervals. 
e 
Post-infusion visits will occur at weeks 6, 10, 14, 20, 26, 40, and 52. 
f 
Long term follow-up visits will occur every 3 months until the subject’s death or until Dendreon terminates the study.  The first LTFU visit will occur 3 
months after the post-treatment visit. 
g 
All screening procedures must occur within 28 calendar days prior to registration, with the exception of written informed consent, histological 
documentation of prostate cancer with Gleason grading, and imaging for confirmation of metastatic disease. 
h 
Vital signs will be measured 1 to 30 minutes prior to, and at 30 minutes (± 10 min) following each infusion. 
i 
ECOG performance status will be collected during LTFU as long as the subject continues to receive enzalutamide.  Once the subject discontinues 
enzalutamide, a final ECOG performance status will be collected at the next LTFU visit and subsequent visits will be conducted via telephone. 
j 
Only treatment-related events will be collected. 
k 
Only medications taken for treatment-related adverse events will be collected. 


 
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l 
Serum PAP and PSA will be collected at the first enzalutamide dispensing visit and at the first and third sipuleucel-T infusions. 
m Serum PSA will be collected during LTFU as long as the subject continues to receive enzalutamide.  Once the subject discontinues enzalutamide, a final 
serum PSA will be collected at the next LTFU visit and subsequent visits will be conducted via telephone. 
n 
Baseline DNA analysis sample is collected at screening only. 
o 
Immune monitoring blood samples (100 mL) will be collected from all subjects who receive at least 1 partial infusion (> 0 mL).  If the subject receives only 
1 or 2 infusions, immune monitoring samples will still be drawn at subsequent preleukapheresis visit time points. 
p 
A 10-mL blood sample will be collected 3 hours (allowable window 1-24 hours) after completion of the infusion. 
 


 
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6.1.1 
Registration 
The clinical trial site will preregister every subject who provides written informed consent and a 
unique subject number will be assigned by Dendreon.  Registration documents will be completed 
and submitted to Dendreon for all subjects who meet all eligibility criteria. 
Subjects who do not meet all eligibility criteria will be considered screen failures and no further 
procedures will be conducted.  The reason(s) for each screen failure will be recorded in the 
subject’s medical record and on the CRF. 
6.1.2 
Randomization 
Eligible subjects will be registered and randomly assigned in a 1:1 ratio to receive 3 infusions of 
sipuleucel-T in addition to a total of 52 weeks of therapy with enzalutamide either concurrently 
with sipuleucel-T (concurrent arm), or following administration of sipuleucel-T (sequential arm).  
Subjects will be stratified by PSA levels (≥ 25 ng/mL, yes or no) obtained from the central 
laboratory and LDH levels (≥ 200 IU/L, yes or no) obtained from the central laboratory.  
Subjects will generally be randomized on the same day as registration. 
6.2 
Demographics 
Demographic information, including birth date, race and ethnicity will be recorded in the 
subject’s medical record and on the CRF.  
6.3 
Clinical Assessments 
Clinical assessments will be performed at the times noted in Table 1. 
6.3.1 
Medical History 
Significant historic and current medical conditions or illness, allergies to medications, and prior 
surgical interventions will be recorded in the subject’s medical record and on the CRF. 
Information regarding the subject’s history of smoking and other risk factors for CVEs will also 
be recorded.  
Symptoms that are ongoing at the time of, or that develop after the subject provides informed 
consent and before registration, will also be considered medical history. 
Medical history will include the subject’s 6 most recent PSA values, vaccinations in the two 
years prior to registration, and all prior anticancer therapies. 


 
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6.3.2 
Physical Examination 
Physical examinations will be performed at the times noted in Table 1 and must be conducted by 
an appropriately qualified investigator listed on the Form FDA 1572. 
The physical examinations conducted at screening and at preleukapheresis visits will include a 
review of the skin, pulmonary, cardiovascular, and neurologic systems, abdomen, and 
extremities.  A review of additional body systems will be at the discretion of the investigator. 
For all other visits that call for a physical examination, the body systems reviewed will be at the 
discretion of the investigator. 
Each physical examination will include weight measurement.  Height will be measured at 
screening only. 
Abnormal physical examination findings at screening will be considered part of the medical 
history and will be recorded on the Medical History CRF.  Any new or worsening physical 
examination findings identified after the subject’s registration will be considered AEs and will be 
recorded in the subject’s medical record and on the CRF. 
6.3.3 
Vital Signs  
Vital signs (respiration rate, temperature, heart rate, and blood pressure) will be measured at the 
times noted in Table 1.  Vital signs will be recorded in the subject’s medical record and on the 
CRF .   
6.3.4 
ECOG Performance Status 
Eastern Cooperative Oncology Group performance status (see Appendix 1) will be assessed at 
the times noted in Table 1.  The assessment must be conducted by an appropriately qualified 
investigator listed on the Form FDA 1572.  The ECOG performance status will be recorded in 
the subject’s medical record and on the CRF. 
6.3.5 
Imaging 
Subjects must have a bone scintigraphy test (bone scan) or Na-F PET or C11 acetate PET and 
CT scan of the abdomen and pelvis within 56 days prior to registration.  If a bone scan is used, 
solitary lesions or lesions which could be attributed to causes other than metastatic prostate 
cancer must be confirmed with a second modality (i.e., CT or MRI). 
When available, standard of care scans will be used to demonstrate metastatic disease at 
screening.  If scans meeting the eligibility criteria are not available, scans may be obtained 


 
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during the screening phase.  If post-screening radiographic imaging is performed per standard of 
care to assess disease progression, the same modalities used at screening should be used.   
6.4 
Safety Assessments 
Safety assessments will be performed in conjunction with all visits as indicated in Table 1. 
6.4.1 
Adverse Events and Serious Adverse Events 
Adverse events, including serious AEs (SAEs), seizures, and CVEs will be assessed at all visits 
and as needed during the course of the study. 
All nonserious AEs and SAEs, regardless of relationship to study treatment, will be collected 
from registration through the post-treatment visit and will be recorded in the subject’s medical 
record and on the CRF. Following the post-treatment visit, only new treatment-related AEs and 
SAEs will be recorded.  Seizures and CVEs (regardless of causality) will be recorded throughout 
the study. 
Only treatment-related AEs, SAEs, seizures, and CVEs (regardless of causality) ongoing at the 
time of the post-treatment visit will be followed by the investigator until resolution, return to 
baseline, or a determination by the investigator that no further improvement is expected. 
See Section 7.0 for information regarding AE and SAE reporting. 
6.4.2 
Cerebrovascular Events 
Cerebrovascular events that occur at any time during the study, regardless of causality, severity, 
or outcome, will be recorded in the subject’s medical record and on the CRF. 
Cerebrovascular events will include all strokes, both ischemic and hemorrhagic in etiology, 
intracranial hemorrhage and transient ischemic attacks.  Transient ischemic attacks are defined as 
episodes of focal neurologic deficit that resolve within 24 hours. 
See Section 7.3.2 for information regarding reporting of CVEs. 
6.4.3 
Seizures 
Seizures that occur at any time during the study, regardless of causality, severity, or outcome, 
will be recorded in the subject’s medical record and on the CRF. 
See Section 7.3.3 for information regarding reporting of seizures. 


 
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6.5 
Concomitant Medications 
The subject’s current prescription and nonprescription medications will be reviewed at the 
screening visit and recorded in the subject’s medical record and on the CRF.  Medications taken 
from registration through the post-treatment visit will also be recorded.  Any medications 
associated with a possible or probable treatment-related AE will be recorded on the CRF, 
regardless of when they are taken.  The concomitant medication administered, indication, dose, 
route, frequency, and start and stop dates will be recorded in the subject’s medical record and on 
the CRF. 
6.5.1 
Anticancer Therapies 
All anticancer therapies received prior to screening and through the end of the LTFU phase will 
be recorded in the subject’s medical record and on the CRF.  Anticancer therapies include, but 
are not limited to, radiation, chemotherapy, hormone therapy, investigational cancer therapies, all 
other systemic therapies, and surgery. 
6.5.2 
First Cancer-Related Opioid Use 
Each subject’s first cancer-related opioid use, as determined by the investigator, will be recorded 
in the subject’s medical record and on the CRF.  Cancer-related opioid use is defined as use for 
cancer-related pain that is of at least 2 consecutive days in duration. 
Opioid analgesic use for treatment or prevention of infusion reactions, such as chills or rigors, 
post-procedural pain, or for indications clearly unrelated to cancer pain (e.g., cough, pain due to 
an injury or accident) should NOT be considered cancer related. 
6.6 
Survival Status 
Confirmation of survival status will be obtained by speaking directly with the subject on the 
telephone or in person.  Death certificates will be obtained as a source document for the date and 
cause of death recorded on the CRF. 
If a death certificate cannot be obtained, one or more of the following documents (in preferential 
order) will be the source document for the date and cause of death: 
1.  SSDI/NDI (date of death only). 
2.  Hospital report. 
3.  Hospice report. 
4.  Clinical chart note. 


 
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5.  Other medical records. 
6.7 
Laboratory Test Assessments 
At the times noted in Table 1, blood samples will be obtained for assessment of the parameters 
presented in Table 2. 
Table 2: 
Clinical Laboratory Tests 
Hematology 
Chemistry 
hemoglobin 
sodium 
hematocrit 
potassium  
erythrocyte count 
bicarbonate  
mean corpuscular volume 
chloride 
mean corpuscular hemoglobin 
lactate dehydrogenase  
mean corpuscular hemoglobin concentration 
blood urea nitrogen 
leukocytes  
creatinine 
neutrophils 
phosphorus 
 
calcium 
lymphocytes 
magnesium 
monocytes 
glucose 
eosinophils 
albumin 
basophils 
total protein 
platelets 
globulin 
cell morphology 
total bilirubin 
 
alkaline phosphatase 
 
alanine aminotransferase  
 
aspartate aminotransferase  
Other Assessments 
total testosterone 
prostatic specific antigen 
serum prostatic acid phosphatase 
Coagulation 
prothrombin time 
 
international normalized ratio 
Serology 
human immunodeficiency virus 
 


 
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All clinical laboratory samples will be sent to a central laboratory for testing. 
6.8 
Immune Monitoring Assessments 
Immune monitoring samples will be obtained at the times outlined in Table 1. 
Neither the subject nor the investigator will receive results from immune monitoring 
assessments. 
6.8.1 
Immune Response 
Cellular and immune responses will be assessed from 100 mL blood samples (9x10 mL heparin 
whole blood tubes and 1x10 mL serum tube) collected at the times noted in the Schedule of 
Assessments (Table 1).  Following infusion of sipuleucel-T, a 10 mL blood sample (1x10 mL 
serum tube) will be collected.   
Immune response assessments will include T cell IFN-γ ELISPOT response to PA2024 and PAP, 
T cell proliferation response to PAP by tritiated thymidine uptake, humoral response to PA2024 
and PAP by ELISA, and chemokine and cytokine production via Luminex assay. 
6.8.2 
Sipuleucel-T Lot Release 
Prior to infusion, small samples (3% to 4%) of cellular components from pre and post-culture 
(PA2024) cells will be used to assess product potency as part of the normal sipuleucel-T 
manufacturing process. 
Sipuleucel-T lot release assessments will include total nucleated cell (TNC) count, CD54+ cell 
count and CD54 upregulation. 
6.8.3 
Product Characterization 
Unused portions of the pre and post-culture samples collected for sipuleucel-T lot release will be 
used for additional analyses including flow cytometry, protein array, and spectral analyses, to 
identify potential biomarkers of the immune response.  Tests to determine cellular composition 
will include assessment of the activation status of T cells, B cells, and NK cells.  In addition, the 
amounts and types of cytokines produced during the manufacture of sipuleucel-T will also be 
profiled. 
Human leukocyte antigen phenotyping will be performed in order to profile the major 
histocompatibility complex for each subject, which will make certain immune response analyses 
possible, such as tetramer analysis (Altman 2006). 


 
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6.8.4 
Immune Gene Expression Analyses 
Castrate-resistant prostate cancer (CRPC) is a heterogeneous disease, with varying symptoms 
and overall survival ranging from several months to several years (Scher 2011).  The ability to 
accurately predict outcome in men with CRPC is a crucial element in understanding response to 
treatment.  While many studies have correlated clinical and laboratory variables with survival, 
the role that the immune system plays in controlling prostate cancer has not been fully studied, 
mainly due to the complexity of the immune system.  Moreover, immune response assays can 
only interrogate discrete pathways 1 at a time, rather than assess the complex interaction between 
the various cellular and secreted components that comprise the entire immune system.  Recent 
studies (Ross 2012, Olmos 2012) have shown that gene-expression profiling of peripheral blood 
cells can yield prognostic information with regards to control of CRPC.  
An integrated and standardized system for collection, transport, and storage of whole blood 
specimens and isolation of either ribonucleic acid (RNA) or genomic deoxyribonucleic acid 
(DNA) (e.g., PAXgene®), will allow analyses of immune gene expression by detection of RNA 
or genetic analysis of germline DNA. 
At screening, an 8.5 mL blood sample will be collected for baseline immune genetic analysis in a 
specialized tube that stabilizes intracellular DNA (e.g., PAXgene® Blood DNA Tube). 
At all immune monitoring assessment time points, a 2.5 mL blood sample will be collected to 
assess immune gene expression profiles through analysis of intracellular RNAs in immune cells.  
These blood samples will be collected in a specialized tube containing an additive that stabilizes 
intracellular RNA (e.g., PAXgene® Blood RNA Tube). 
Neither the subject nor the investigator will receive results from gene expression analysis. 
6.8.5 
Sample Retention 
Samples from subjects who do not provide consent for additional optional research  
(Section 6.8.6) will be retained for up to 5 years following Dendreon’s completion of the trial 
and then will be destroyed. 
6.8.6 
Additional Optional Research 
Subjects will be given the opportunity to allow Dendreon to retain their blood samples (obtained 
for immune response, lot release, product characterization, and gene expression analysis) 
indefinitely and to use them for other testing.  No additional blood draws will be required beyond 
those already being collected as part of the study.  Additional research may include genetic 
testing and retained samples may be sent to outside laboratories for testing. 


 
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Retained samples will be used for research only, will not be sold, and will not be identified using 
subject names or other personal identifiers.  Neither the subject nor the clinical trial site will 
receive results from additional testing. 
6.9 
Study Materials 
The clinical trial site will have a calibrated scale for recording body weight and a calibrated 
sphygmomanometer and thermometer for vital signs assessments.  A current and fully stocked 
advanced cardiac life support cart will be immediately available on the premises.  The clinical 
trial site will also have a refrigerated centrifuge, a monitored and alarmed refrigerator, and a 
freezer (-20°C or below) as well as containers and dry ice for shipment of blood samples. 
The clinical trial site will provide all materials required for accurate documentation of subject 
visits and study activities. 
Dendreon will provide an approved protocol and any required amendments or administrative 
letters, as well as the IB and electronic CRFs.  Materials needed for the collection of laboratory 
samples, including immune monitoring samples, will be provided by Dendreon.  Dendreon will 
also provide all applicable study specific training materials and reference binders. 
7.0 
ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a subject while on study that does not 
necessarily have a causal relationship with the treatment.  An AE can, therefore, be any 
unfavorable and unintended sign (e.g., abnormal laboratory finding), symptom, or disease 
temporally associated with the treatment, whether or not considered related to the treatment.  
Adverse events include exacerbation of a pre-existing illness, an increase in frequency or 
intensity of a pre-existing episodic event or condition, a condition detected or diagnosed after 
product administration (even though it may have been present prior to the start of the study) or a 
continuous persistent disease or symptoms present at screening that worsen following the start of 
the study. 
7.1 
Categories for Ranking Severity of Adverse Events 
The NCI CTCAE (NCI 2010) will be used to score AE severity.  In general, the following 
general severity definitions apply: 
Mild (Grade 1): 
The AE results in mild, easily tolerated symptoms, or is asymptomatic 
with clinical or diagnostic observations only.  Intervention is not usually 
indicated. 


 
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Moderate (Grade 2): The AE produces moderate symptoms with discomfort sufficient to 
interfere with some aspect of the subject’s normal daily activity.  Minimal, 
local, or noninvasive intervention is required. 
Severe (Grade 3): 
The AE is medically significant but not immediately life threatening, 
results in discomfort or disability which is incapacitating and prevents 
most normal daily activities, clearly damaging to the health, requiring 
hospitalization, prolongation of existing hospitalization or complicated 
treatment. 
Life Threatening  
 
(Grade 4):  
The AE could reasonably result in death unless immediate medical 
intervention is undertaken. 
Fatal (Grade 5): 
The AE results in death. 
7.2 
Relationship of Adverse Events to Study Treatments 
The following categories will be used to determine relatedness of AEs to study treatments: 
None: 
The AE is clearly related to other factors, such as the subject’s clinical 
state, environmental factors, or other modes of therapy or concomitant 
medications administered to the subject. 
Possible: 
The AE follows a reasonable temporal sequence from administration of 
study treatment, but could readily have been produced by the subject’s 
clinical state, environmental factors, or other modes of therapy or 
concomitant medications administered to the subject. 
Probable: 
The AE follows a reasonable temporal sequence from administration of 
study treatment and cannot readily have been produced by the subject’s 
clinical state, environmental factors, or other modes of therapy or 
concomitant medications administered to the subject. 
7.3 
Serious Adverse Events 
An SAE is defined as any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  death, a life threatening adverse drug experience, subject hospitalization or 
prolongation of an existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  An important medical event that may not result in death, be life 
threatening, or require hospitalization may be considered a SAE when, based upon appropriate 
medical judgment, it may jeopardize the subject and may require medical or surgical intervention 


 
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to prevent one of the outcomes listed in this definition.  Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in subject hospitalization, or the development of drug 
dependency or drug abuse. 
7.3.1 
Serious Adverse Event Collection and Reporting 
All SAEs reported or observed, regardless of relationship to study treatments, and any remedial 
action(s) required, will be collected at all visits from registration through the post-treatment visit.  
Only treatment-related SAEs, seizures, and CVEs (regardless of causality) ongoing at the time of 
the post-treatment visit will be followed by the investigator until resolution, return to baseline, or 
the investigator determines no further improvement is expected.  Only new treatment-related 
AEs and SAEs, seizures, and CVEs (regardless of causality) will be collected after the post-
treatment visit. 
All SAEs, whether or not considered related to study treatment, must be reported to Dendreon 
within 24 hours by entering the information on the electronic SAE report form.  If access to the 
electronic SAE Form is unavailable for any reason, the SAE information must be reported to 
Dendreon or its designee within 24 hours by phone or by facsimile using the hardcopy SAE 
report form. 
 
Dendreon Corporation 
 
Attn:  
 
Safety Manager 
 
Facsimile: 
 
(206) 829-1647 
 
Phone:  
 
(206) 219-7189 
 
After Hours:  
(206) 274-6774 
Significant new information regarding an ongoing SAE and the resolution must be sent to 
Dendreon within 3 business days of awareness of the new information on either the electronic or 
hardcopy SAE report form.  
The principal investigator is responsible for notifying the relevant IRB of any SAE that occurs in 
a subject participating at their clinical trial site and any Investigational New Drug (IND) Safety 
Reports issued by Dendreon unless otherwise instructed by relevant IRB policy. 
7.3.2 
Cerebrovascular Events 
All CVEs, regardless of causality, severity, or outcome, will be reported as AEs and SAEs when 
they occur from registration until the subject ceases study participation. 


 
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7.3.3 
Seizures 
All seizures, regardless of causality, severity, or outcome, will be reported as AEs and SAEs 
when they occur from registration until the subject ceases study participation. 
7.3.4 
Death Reports 
Death is an expected outcome of this study.  Deaths that meet any of the following criteria must 
be reported as an SAE: 
 Deaths that occur within 30 days of receiving the last study treatment. 
 Deaths that are the outcome of a SAE that occurs within 30 days from the last study 
treatment and are not due to disease recurrence. 
 Deaths due to a seizure or CVE, regardless of causality, that occur at any time during the 
study.  
 Deaths that occur at any time during the study and are considered by the investigator to be 
possibly or probably related to the study treatment. 
Deaths that do not meet these criteria will not be reported as an SAE, but will be recorded on the 
CRF.  
7.3.4.1 
Expedited Reporting Requirements 
Dendreon will notify the FDA and all participating principal investigators of any AE associated 
with the use of study treatments that is serious, unexpected and at least possibly related.  Such 
notification will be provided within 15 calendar days after Dendreon’s initial receipt of the 
information.  If the event was fatal or life threatening, FDA will be notified no later than 7 days 
after Dendreon’s initial receipt of the report. 
The FDA will be notified of all deaths occurring within 30 days of sipuleucel-T infusion, 
regardless of causality, via a written IND Safety Report. 
Serious AEs that are attributable to disease progression will be considered expected, and, 
therefore, will not be reported by Dendreon on an expedited basis. 
7.4 
Laboratory Test Result Abnormalities 
The following laboratory abnormalities should be captured on the AE CRF or SAE Report Form 
as appropriate: 


 
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 
 Any clinically significant result that is not part of another reported clinical diagnosis. 
 Any result that meets the definition of an SAE. 
 Any result leading to study drug discontinuation or interruption. 
 Any result that required therapeutic intervention or a change in subject management. 
Laboratory abnormalities not meeting the above conditions will not be reported on the AE CRF 
or SAE report form. 
7.4.1 
Safety Monitoring and Enrollment Suspension 
An internal Data Monitoring Committee (DMC) will be notified within 48 hours of AEs with an 
outcome of death and nonfatal AEs with Grade ≥ 3 toxicity and that are at least possibly related 
to the study treatment.  Consideration will be given to suspending enrollment to an arm for any 
of the following: 
 An AE with an outcome of death which is at least possibly related to the study 
treatment(s). 
 The occurrence of nonfatal AEs with Grade ≥ 3 toxicities (with the exception of Grade 3 
chills, pyrexia, fatigue, or asthenia) which are at least possibly related to study 
treatment(s) in more than 3 of the first 10 subjects enrolled in an arm, or in more than 
30% of subjects in an arm at any time beyond enrollment of 10 subjects in that arm. 
If enrollment is suspended in either arm, study treatments will be discontinued in all subjects 
meeting any of the criteria for stopping treatment (Section 4.3), but may be continued in all other 
subjects.  Enrollment to the suspended arm will resume only with concurrence of the DMC and 
FDA. 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
General Considerations  
This Phase 2 randomized, open-label study is designed to assess the effects of sipuleucel-T when 
administered concurrently or sequentially with enzalutamide.  Subjects will be randomized 1:1 to 
either the concurrent arm or the sequential arm, stratified by PSA levels (≥ 25 ng/mL, yes or no) 
and LDH levels (≥ 200 IU/L, yes or no).  In general, data will be summarized in aggregate and 
by treatment arm.  All statistical tests will be performed at the 2-sided 0.05 significance level 


 
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unless otherwise noted.  Nominal p-values will be provided with no multiplicity adjustment for 
secondary or exploratory endpoints. 
8.2 
Sample Size Determination 
The study is designed to test the null hypothesis of no difference between the treatment arms for 
immune response over time evaluated using PA2024-stimulated T cell proliferation via tritiated-
thymidine uptake.  The PA2024 proliferation responses over time will be compared between the 
concurrent arm and sequential arm using a repeated measurement analysis.  With 43 subjects per 
treatment arm (concurrent and sequential), there is 90% power to detect a 2.0 fold difference in 
mean response between the arms at any time point assuming a coefficient of variation of 1.25.  
To allow for drop-outs and subjects who may not receive 3 infusions of sipuleucel-T or at least 
10 weeks of enzalutamide, 50 subjects per arm will be enrolled.  Coefficients of variation for 
proliferation responses ranging from 0.69 to 1.40 depending on visit have been observed in a 
recent trial of sipuleucel-T in a similar population (data on file). 
8.3 
Populations for Analyses 
The immune response population will be defined as subjects who receive 3 infusions of 
sipuleucel-T and 10 or more weeks of enzalutamide.  Analysis of immune response endpoints, 
including the primary endpoint, will be performed using this population.  This population will 
also be used to perform supplementary analyses of nonimmune response efficacy endpoints.  
The intent-to-treat (ITT) population is defined as all randomized subjects, regardless of whether 
they received treatment.  Analysis of nonimmune response efficacy endpoints will be performed 
using this analysis population. 
The safety population will include all subjects who receive at least 1 leukapheresis procedure or 
receive at least 1 dose of enzalutamide.  All safety variables (e.g., AEs, laboratory data, and vital 
sign data) will be analyzed based on the safety population. 
8.4 
Endpoints 
8.4.1 
Primary Endpoint(s) 
The primary endpoint is peripheral PA2024-specific T cell immune response to sipuleucel-T 
over time as measured via a T cell stimulation index from a proliferation assay.  This endpoint 
was selected because it has demonstrated the highest signal to noise ratio of all the T cell assays 
Dendreon has evaluated in prior studies of sipuleucel-T (data on file).  


 
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8.4.2 
Secondary Endpoint(s) 
Immune responses over time for ELISPOT and ELISA are secondary endpoints as are peripheral 
PAP-specific T cell immune response to sipuleucel-T over time via a T cell stimulation index 
from a proliferation assay, and cytokine production by Luminex assay.  Additionally, responder 
analyses by time point will be performed for the data generated from the proliferation assays, 
ELISPOT, and ELISA.  A positive response will be defined as having a post-baseline result 
exceeding a threshold value, determined on the basis of baseline and historical sipuleucel-T data, 
that ensures a sufficiently low false positive rate (i.e., 5% or less) for each immune response 
parameter.  The threshold will be antigen and assay dependent.   
Time to PSA progression is defined as: 1) the time from randomization to PSA progression, and 
2) the time from first enzalutamide treatment to PSA progression.  Those subjects who do not 
experience PSA progression will be censored in the analysis at the date of their last PSA 
assessment.  PSA progression, based on the randomization date (i.e., definition 1) will be defined 
for those subjects who experience a decline in PSA compared to baseline as the date that a 25% 
or greater increase in PSA and an absolute increase of 2 ng/mL or more from the nadir is 
documented, which is confirmed by a second value obtained 3 or more weeks later (Scher 2008).  
For those subjects who do not experience a decline in PSA compared to baseline, PSA 
progression is defined as the date a 25% or greater increase from the baseline value along with 
an increase in absolute value of 2 ng/mL or more after 12 weeks of enzalutamide treatment 
(Scher 2008).  PSA progression based on the first enzalutamide treatment (i.e., definition 2) will 
be defined in a similar manner except the most recent PSA value prior to the first enzalutamide 
treatment will be used as the baseline value. 
PSA progression time, based on the randomization date, will be calculated as follows for those 
subjects with PSA progression:  
Progression time (days) = [(PSA progression date) – (randomization date)] + 1. 
PSA progression time, based on the randomization date, will be calculated as follows for subjects 
who are censored:  
PSA progression time (days) = [last PSA assessment date – (randomization date)] + 1. 
PSA progression time based on the first enzalutamide treatment will be defined in a similar 
manner except the first enzalutamide treatment date will be used instead of the randomization 
date. 
Overall survival is defined as the time from randomization to death due to any cause.  Those 
subjects alive at the time of database cut-off or lost to follow-up will be censored in the analysis 
at the earlier of the cut-off date or the day of their last documented visit or contact date. 


 
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Overall survival time will be calculated as follows for subjects who died prior to data cut-off:  
Survival time (days) = [(death date) – (randomization date)] + 1. 
Overall survival time will be calculated as follows for subjects who are censored: 
Survival time (days) = [(last contact date) – (randomization date)] + 1. 
8.4.3 
Exploratory Endpoint(s) 
The time to next anticancer intervention is defined as the time from randomization to the first 
anticancer intervention.  Those subjects without an anticancer intervention will be censored at 
their last follow-up assessment when anticancer therapy information is collected. 
The time to first opioid use for cancer-related pain is defined as the time from randomization to 
the first use of an opioid for cancer-related pain.  Those subjects without a record of opioid use 
for cancer-related pain will be censored at their last follow-up assessment when opioid use for 
cancer-related pain is collected. 
The time to first ECOG performance status decline (i.e., increase in numerical value of ECOG 
performance status) is defined as the time from randomization to the first decline in ECOG 
performance status by 1 point or more.  Those subjects without an ECOG performance status 
decline will be censored at their last follow-up assessment for ECOG performance status. 
8.5 
Analyses 
8.5.1 
Subject Disposition 
Subject disposition will be summarized by treatment group for the ITT population.  This 
summary will include, but will not be limited to, the following: 
 Number of subjects randomized. 
 Number of subjects infused. 
 Number of subjects who prematurely discontinued the study (i.e., refused further study 
assessments [with the possible exception of survival status]). 
 Reason(s) for premature discontinuation from the study. 
 Number of subjects who died. 
 Cause of death summary. 


 
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 Number of subjects in the immune response and safety analysis sets. 
In addition, the number of subjects screened for the trial will be summarized for the overall study 
population. 
8.5.2 
Demographics and Baseline Characteristics 
Demographic information and baseline disease information and characteristics will be 
summarized with descriptive statistics for all analysis populations and compared between 
treatment groups using the Wilcoxon test for continuous variables and Fisher’s exact test for 
categorical variables. 
8.5.3 
Efficacy Analyses 
The primary efficacy analysis will consist of a repeated measurement analysis of immune 
response over time evaluated using PA2024-stimulated T cell proliferation via tritiated-
thymidine uptake based on the immune response population.  The logarithm of response will be 
used for analysis.  Fixed effect terms in the model will include treatment arm, visit as a class 
effect, and treatment by visit interaction.  The correlation of responses across time within a 
subject will be modeled using several candidate variance-covariance structures including 
unstructured, compound symmetry, heterogeneous compound symmetry, autoregressive (1), and 
heterogeneous autoregressive (1).  The variance-covariance structure providing the smallest 
Bayesian information criteria will be selected for the final model.  Fixed effect terms in the 
model will be tested for significance using type III sums of squares.  The formal test for 
difference between the treatment arms will be based on the p-value for the treatment arm effect 
unless a significant treatment by visit interaction (p < 0.05) is observed, in which case by-visit 
treatment comparisons will be made using appropriate contrast statements.  Estimates of 
treatment effect and corresponding 95% confidence intervals (CIs) will be provided on the ratio 
scale obtained by exponentiation of the model derived treatment effect and CI on the logarithm 
scale.  Immune responses over time for other assays will be analyzed using identical methods 
described for the primary efficacy analysis except for the ELISPOT, which will be analyzed 
using ranks instead of on the logarithm scale. 
The response rate for each assay and for each antigen will be compared between treatment arms 
at each visit using Fisher’s exact test based on the immune response population.  In addition, 
analyses will be performed modeling response rates over time using appropriate methods to 
account for the correlation of responses over time within a subject. 
Time to PSA progression will be compared between the treatment arms using a Cox regression 
model with terms for treatment, baseline PSA (logarithm scale), and baseline LDH (logarithm 
scale) in the model based on the ITT population.  The estimated HR of the treatment effect and 


 
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its 2-sided, 95% CI, using the sequential arm as the denominator will be provided.  The 
percentage of subjects free of PSA progression with an associated 95% CI at landmark time 
points such as 6 and 12 months will be provided by treatment arm as well as pooled over 
treatment arms using the Kaplan-Meier method. 
Overall survival, time to next anticancer intervention, time to first chemotherapy, time to first 
cancer-related opioid use, and time to first ECOG performance status decline will be analyzed in 
a similar manner as described for time to PSA progression. 
8.5.4 
Safety Analyses 
Safety data will be summarized descriptively in aggregate and by treatment group within the 
safety population. No formal statistical testing is planned for the safety data. 
8.5.4.1 
Adverse Events 
Adverse events will be summarized and listed by treatment arm and by the Medical Dictionary 
for Regulatory Activities (MedDRA) terms, by preferred term within each system organ class.  
Summary tables will include all AEs reported in the treatment arms from the first leukapheresis 
or enzalutamide dose.  Summaries to be produced include the following: 
 Incidence within system organ class (MedDRA). 
 Incidence by decreasing frequency. 
 Incidence by NCI CTCAE severity grade, by decreasing frequency. 
 Incidence of Grade ≥ 3 AEs, by decreasing frequency. 
 Incidence of SAEs. 
 Incidence of AEs within 1 day of infusion. 
 Incidence of AEs that resulted in premature discontinuation of study treatments. 
Adverse events that occur multiple times for a subject will be counted only once per subject in 
incidence summary tables.  In tables that enumerate AEs by severity, only the greatest severity 
for an AE occurring multiple times for a subject will be counted. 
8.5.4.2 
Laboratory Data 
Summaries of laboratory data collected from baseline until study completion will include: 


 
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 Incidence of clinically significant laboratory abnormalities by NCI CTCAE Version 4.03 
(NCI 2010).  A clinically significant laboratory toxicity is defined as a post-baseline grade 3 
or higher toxicity where the baseline value was grade 2 or lower. 
 Summary statistics (mean, median, standard deviation, minimum, and maximum) for 
laboratory values and their change from baseline by time point. 
Baseline results will be defined as the most recent nonmissing value obtained on or prior to the 
randomization date. 
8.5.4.3 
Vital Signs 
Vital sign data (blood pressure, respiration rate, heart rate, and body temperature) will be 
summarized descriptively by time point. 
8.5.5 
Study Treatment Administration 
Leukapheresis and sipuleucel-T infusion information will be summarized by treatment group.  
This will include the following: 
 Number of subjects who received a total of 0, 1, 2, or 3 infusions. 
 Reason(s) for not completing 3 infusions. 
 Number of subjects who receive a total of 0, 1, 2, 3, 4, or 5 or more leukaphereses. 
 Number of subjects who receive a total of 3 leukaphereses and 3 infusions. 
The duration of treatment with enzalutamide will be summarized by treatment group.  The 
percent compliance with enzalutamide treatment will be computed as the number of pills taken 
divided by the expected number of pills to be taken and will be summarized by treatment group. 
8.5.6 
Concomitant Medications and Procedures 
Concomitant medications and procedures will be presented in data listings by treatment group 
and will be coded using the World Health Organization Drug Dictionary.  A summary table will 
be provided by treatment group and for all subjects combined.  Separate summaries will be 
provided for medications that were started prior to randomization and for medications started 
after randomization. 


 
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8.5.6.1 
Other Analyses 
Use of select anticancer treatments during the study will be summarized by treatment group.  
This summary will include types of therapies used and will be based on the ITT population. 
Data from sipuleucel-T lot release assessments will be summarized.  Data to be summarized 
include CD54 upregulation, CD54+ cell count, and TNC count.  These data will be summarized 
descriptively by infusion (1, 2, and 3) and cumulative (summed across infusions).  Cumulative 
lot release assessment data will be compared between both arms using a t-test on the logarithm 
scale based on the immune response analysis population. 
Prostate specific antigen data, including change from baseline, will be summarized descriptively 
by treatment arm at each time point for the ITT population.  Additionally, the maximal decline of 
serum PSA from baseline at any time point will be summarized using waterfall plots. Baseline 
will be defined as the value collected immediately prior to the registration PSA value.  
Additional analyses of PSA will be performed using the most recent PSA value prior to the 
initiation of enzalutamide as the baseline value. 
8.6 
Interim Analyses 
No formal interim analysis will be performed in this study.  For this open-label study, descriptive 
summaries of safety assessments and immune response parameters may be generated on a 
periodic basis. 
9.0 
REGULATORY REQUIREMENTS 
9.1 
Pre-Study Documentation 
The principal investigator will sign and return to Dendreon the Protocol Signature Page for the 
original protocol and each amendment, if applicable, and provide current medical licenses, 
curriculum vitae, and the Form FDA 1572 Statement of Investigator.  All forms must be updated 
as applicable throughout the study. 
Dendreon must receive the following documentation prior to study initiation: 
 
 Signed Protocol Signature Page. 
 FDA Form 1572 signed by the principal investigator. 
 Curriculum vitae of the all investigators listed on Form FDA 1572, updated within the past 2 
years. 


 
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 Copies of current medical licenses for all investigators listed on Form FDA 1572. 
 Financial disclosure forms for all investigators listed on Form FDA 1572. 
 Copy of the IRB approval letter for the study. 
 Copy of the IRB-approved ICF. 
 IRB membership list or Department of Human and Health Services Assurance Number. 
9.2 
Investigator Obligations 
The principal investigator will ensure all clinical trial site personnel, including sub investigators, 
conduct the study in compliance with the Declaration of Helsinki the International Conference 
on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP) and the FDA Guidance 
for Industry:  Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment  
(FDA 2005).  The investigator will follow all national, state, and local laws. 
The principal investigator will be responsible for the subject’s compliance to the study protocol, 
and must meet periodically with the Dendreon study monitor. 
All investigators listed on Form FDA 1572 must complete financial disclosure forms (including 
information on spouses, legal partners, or dependent children) before study initiation.  
Investigators must promptly update this information if any relevant changes occur in the course 
of the study or in the year after the study is completed (21 CFR §54.4).  Investigators must also 
complete a new financial disclosure form annually throughout the study, regardless of whether 
any information has changed. 
In addition, the principal investigator is responsible for providing Dendreon an adequate final 
report shortly after study participation is complete, in accordance with 21 CFR §312.64. 
9.3 
Institutional Review Board 
The investigator is responsible for ensuring that this protocol and relevant supporting data are 
submitted to the appropriate Institutional Review Board (IRB) for review and approval before 
the study is initiated.  Dendreon must receive a letter documenting the IRB approval prior to 
initiation of the study.  Amendments to the protocol will also be submitted to, and approved by, 
the IRB prior to implementation of any change(s).  The investigator is also responsible for 
informing the IRB of the progress of the study and for obtaining annual IRB renewal.  The IRB 
must be informed by the investigator when the study is complete and should be provided with a 
summary of the results of the study as required by the IRB. 


 
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9.4 
Informed Consent 
The investigator is responsible for ensuring that all subjects are clearly and fully informed about 
the purpose, potential risks, and other critical issues regarding this study, including their right to 
withdraw at any time. 
Prior to the initiation of any study procedures, including medication washouts, all subjects must 
provide written consent on the Informed Consent Form (ICF) indicating their consent to 
participate.  The investigator or an appropriately qualified delegate listed on FDA Form 1572 
will provide a full explanation of the study and allow the subject to read the ICF and ask any 
questions that may arise.  The subject will be given sufficient time to properly consider the 
information and to make an informed decision prior to signing the ICF.  The investigator or an 
appropriately qualified delegate listed on FDA Form 1572 will document the informed consent 
process in the subject’s medical record and will provide a copy of the signed ICF to the subject. 
The ICF, including any amendments, must first be reviewed and approved by Dendreon and then 
by the designated IRB prior to use in the study. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or increases the potential risk to subjects, the ICF will be revised and submitted to the IRB for 
review and approval.  The revised ICF must be used to obtain consent from subjects currently 
participating in the study if the information is relevant, or per the IRB’s instructions.  The revised 
ICF will be used to obtain consent from any new subject who is enrolled in the study after the 
approval date of the amendment. 
9.5 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  Subjects’ 
individual identifying information will be kept as confidential as possible under local, state, and 
federal law.  Medical information may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare.  Data generated as a result of 
this study will be available for inspection on request by the FDA, Dendreon or its 
representatives, or the IRB.  Dendreon may retain in its files copies of subject medical 
information, with subject identifiers redacted. 
Individual subject identities will not be disclosed in any report or publication related to the trial, 
and will not be obtained on any CRFs maintained by Dendreon. 
Sipuleucel-T therapy is similar to an autologous blood transfusion; revealing subject identifying 
information is critical for ensuring subject safety.  To maintain the chain of identity and thereby 


 
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ensure subject safety, the sipuleucel-T label will contain subject identifying information that will 
be revealed to Dendreon’s apheresis and manufacturing personnel. 
10.0 
STUDY MANAGEMENT 
10.1 
Study Documentation 
The principal investigator and clinical trial site personnel are responsible for maintaining a 
comprehensive and centralized filing system containing all study-related documentation.  These 
files must be suitable for inspection by Dendreon, representatives of Dendreon, or the FDA at 
any time, and should consist of the following elements: 
 Copies of completed CRFs. 
 Subject files, containing supporting source documentation from the subject’s medical record, 
including laboratory data, pathology reports, and the signed ICF. 
 Regulatory files, containing the protocol with all amendments and protocol signature pages, 
copies of all other required regulatory documentation, and all correspondence between the 
clinical trial site and the IRB and Dendreon. 
 Drug accountability files, containing a complete account of the receipt and disposition of all 
study treatments. 
The investigator shall retain records required to be maintained under this part for a period of 2 
years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and FDA is so 
notified. 
10.2 
Data Collection 
Dendreon will provide electronic CRFs for reporting data.  All required fields on the CRFs must 
be completed.  All data recorded on CRFs must be supported by original (source) documentation. 
10.3 
Protocol Compliance 
To ensure accurate interpretation and implementation of the study, the procedures and endpoints 
defined in the protocol will be carefully reviewed by the principal investigator and the clinical 
trial site personnel prior to the time of study initiation. 


 
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Dendreon, after consultation with the principal investigator, will be the final arbiter of eligibility, 
toxicity, and other endpoints should a difference of opinion exist. 
10.4 
Monitoring 
A representative from Dendreon will visit the clinical trial site periodically to monitor adherence 
to the protocol, adherence to applicable FDA regulations, and the maintenance of adequate and 
accurate records.  Case report forms will be reviewed to ensure that key safety and efficacy data 
are reported as specified by the protocol.  The Dendreon representative must be permitted to 
access subjects’ complete medical records, laboratory data, and other source documentation as 
needed to appropriately monitor the trial. 
10.5 
Quality Assurance 
Dendreon Quality Assurance may arrange to visit the clinical trial site to audit the performance 
of the study and the study documents originating at the site.  The audit may be conducted by a 
Dendreon representative or designee.  The principal investigator will be informed of the outcome 
of the audit. 
In addition, inspections by health authority representatives and/or the IRB are possible at any 
time.  The investigator must inform Dendreon of any such inspection immediately. 
Direct access to source documentation and subjects’ medical records must be provided for audits 
and inspections. 
10.6 
Disclosure of Data and Publication 
The principal investigator, sub investigators, and other clinical trial site personnel working on the 
study will submit all proposed publications, papers, abstracts or other written materials related to 
the study, or an outline of any proposed oral presentation with respect thereto, to Dendreon at 
least 1 month prior to (i) submission of such written materials for publication, or (ii) any 
proposed oral disclosure to a third party.  Dendreon shall have the right to comment on such 
written material or outline; such comments shall be considered in good faith by the principal 
investigator in determining the final form of disclosure.  Notwithstanding any of the above, 
neither the principal investigator nor anyone else working on the study may include any 
confidential information in any such publication or disclosure. 


 
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11.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ADT 
androgen deprivation therapy 
CI 
confidence interval 
COI 
chain of identity 
CPDF 
Clinical Cell Product Disposition Form 
CRF 
case report form 
CRPC 
castrate-resistant prostate cancer  
CT 
computed tomography 
CVE 
cerebrovascular event 
CYP 
cytochrome P450 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot assay 
FDA 
Food and Drug Administration 
FPL 
Final Product Label 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HR 
hazard ratio 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
LHRH 
luteinizing hormone-releasing hormone 
LTFU 
long term follow-up 
mCRPC 
metastatic castrate-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
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Abbreviation 
Definition 
MRI 
magnetic resonance imaging 
Na-F 
sodium fluoride 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NDI 
National Death Index 
PAP 
prostatic acid phosphatase 
PBMC 
peripheral blood mononuclear cell 
PET 
positron emission tomography 
PSA 
prostate specific antigen 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SSDI 
Social Security Death Index 
TNC 
total nucleated cells 
ULN 
upper limit of normal 
 


 
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12.0 
REFERENCES 
Drake 2005 
Drake CG, Doody AD, Mihalyo MA, et al. Androgen ablation mitigates tolerance 
to a prostate/prostate cancer-restricted antigen. Cancer Cell 2005;7(3):239-49. 
FDA 2005 
Guidance for Industry: Good Pharmacovigilance Practices and 
Pharmacoepidemiologic Assessment. U.S. Department of Health and Human 
Services, Food and Drug Administration. Mar 2005. 
Gannon 2009 Gannon PO, Poisson AO, Delvoye N, et al. Characterization of the intra-prostatic 
immune cell infiltration in androgen-deprived prostate cancer patients. J Immunol 
Methods 2009;348(1-2):9-17. 
Howlader 2011 
Howlader N, Noone AM, Krapcho M, Neyman N, et al. SEER Cancer 
Statistics Review, 1975–2008. National Cancer Institute; Bethesda, MD; 2011. 
Jevtana 2012 Jevtana Prescribing Information. Oct 2012. Sanofi-Aventis, US LLC. Available 
at:  http://products.sanofi.us/jevtana/jevtana.html. 
Kantoff 2010 Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for 
castration-resistant prostate cancer. N Engl J Med 2010;363(5):411-22. 
Klotz 2001 
Klotz L. Combined androgen blockade in prostate cancer: meta-analyses and 
associated issues. BJU Int 2001;87(9):806-13. 
Koh 2009 
Koh YT, Gray A, Higgins SA, et al. Androgen ablation augments prostate cancer 
vaccine immunogenicity only when applied after immunization. Prostate 
2009;69(6):571-84. 
Madan 2008 Madan RA, Gulley JL, Schlom J, et al. Analysis of overall survival in patients 
with nonmetastatic castration-resistant prostate cancer treated with vaccine, 
nilutamide, and combination therapy. Clin Cancer Res 2008;14(14):4526-31. 
Mercader 2001 
Mercader M, Bodner BK, Moser MT, et al. T cell infiltration of the 
prostate induced by androgen withdrawal in patients with prostate cancer. Proc 
Natl Acad Sci USA 2001;98(25):14565-70. 
NCI 2010 
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 
National Cancer Institute; 14 Jun 2010. Available at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 


 
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Olmos 2012 
Olmos D, Brewer D, Clark J, Danila DC, et al. Prognostic Value of Blood mRNA 
Expression Signatures in Castration-resistant Prostate Cancer: a Prospective, 
Two-stage Study. Lancet 2012; 2045(12)70372-8. 
Petrylak 2004 Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine 
compared with mitoxantrone and prednisone for advanced refractory prostate 
cancer. N Engl J Med 2004;351(15):1513-20. 
Provenge 2011 
Provenge Prescribing Information. Jun 2011. Dendreon Corporation, 
Seattle WA. Available at:  http://www.provenge.com/pdf/prescribing-
information.pdf. 
Ross 2012 
Ross RW, Galsky MD, Scher H, et. Al. William K Oh. A Whole-blood RNA 
Transcript-based Prognostic Model in Men with Castration-resistant Prostate 
Cancer: A Prospective Study. Lancet 2012; 2045(12): 70263-2. 
Ryan 2013 
Ryan CJ, Smith MR, de Bono JS, Molina A, et. al. Abiraterone in metastatic 
prostate cancer without previous chemotherapy. N Engl J Med 2013; 369:138-48. 
Sipuleucel-T 2013 
Sipuleucel-T Investigator’s Brochure. 07 MAR 2013. Dendreon 
Corporation, Seattle, WA. 
Scher 1996 
Scher HI, Zhang ZF, Nanus D, et al. Hormone and antihormone withdrawal: 
implications for the management of androgen-independent prostate cancer. 
Urology 1996;47(1A Suppl):61-9. 
Scher 2008 
Scher H, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for 
Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin 
Oncol 2008;26(7):1148-1159. 
Scher 2011 
Scher HI, Morris MJ, Basch E, Heller G. Endpoints and Outcomes in Castration-
Resistant Prostate Cancer: From Clinical Trials To Clinical Practice. J Clin Oncol 
2011; 29: 3695–704. 
Siegel 2012 
Siegel R, Naishadham D, and Jemal J. Cancer statistics, 2012. CA Cancer J Clin 
2012; 62(1):10-29. 
Small 1997 
Small EJ, Vogelzang NJ. Second-line hormonal therapy for advanced prostate 
cancer: a shifting paradigm. J Clin Oncol 1997;15(1):382-8. 


 
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Sutherland 2005 
Sutherland JS, Goldberg GL, Hammett MV, et al. Activation of thymic 
regeneration in mice and humans following androgen blockade. J Immunol 
2005;175(4):2741-53. 
Tannock 2004 Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or 
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 
2004;351(15):1502-12. 
Ward 2005 
Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer 
therapy. Nat Clin Pract Urol. 2005 Apr;2(4):174-82. 
Xtandi 2012 Xtandi Prescribing Information. Aug 2012. Astellas Pharma, Inc. Northbrook, IL. 
Available at:  http://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf 
Zytiga 2012 
Zytiga Prescribing Information. Dec 2012. Janssen Biotech Horsham, PA. 
Available at:  http://www.zytigahcp.com/pdf/full_prescribing_info.pdf 
 
 


 
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APPENDIX 1: 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE 
CRITERIA 
 
Grade 
 
Performance Criteria 
Karnofsky Scale 
Equivalent 
0 
Normal activity.  Fully active, able to carry on all 
predisease performance without restriction. 
90-100 
1 
Symptoms but ambulatory.  Restricted in physically 
strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, 
office work). 
70-80 
2 
In bed < 50% of the time.  Ambulatory and capable of 
self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
50-60 
3 
In bed > 50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
30-40 
4 
100% bedridden.  Completely disabled.  Cannot carry on 
any self-care.  Totally confined to bed or chair. 
10-20 
5 
Dead 
0 
 


 
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APPENDIX 2: 
CHILD-PUGH SCORE 
 
 
 


 
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APPENDIX 3: 
MEDICATIONS METABOLIZED BY CYTOCHROME ENZYMES 
Cytochrome system inducers and inhibitors relevant to enzalutamide: 
Strong CYP2C8 inhibitor:  gemfibrozil 
CYP2C8 inducer:  rifampin 
Medications metabolized by CYP3A4, CYP2C9, or CYP2C19 that have a narrow 
therapeutic index: 
midazolam 
quinidine 
warfarin 
sirolimus and tacrolimus 
omeprazole 
phenytoin 
alfentanil 
s-mephenytoin 
cyclosporine 
lansoprazole 
dihydroergotamine 
pantoprazole 
ergotamine 
esomeprazole 
fentanyl 
rabeprazole 
pimozide 
 
 
Strong and moderate CYP3A4 inducers: 
carbamazepine 
etravirine 
phenobarbital 
nevirapine 
phenytoin 
modafinil 
oxcarbazepine 
nafcillin 
rifabutin 
pioglitazone 
rifampin 
troglitazone 
rifapentine 
glucocorticoids 
bosentan 
St. John’s Wort 
efavirenz 
 
 


 
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APPENDIX 4: 
INFUSION GUIDELINES 
Preinfusion Procedures 
DO NOT OPEN THE CLIMATE-CONTROLLED INNER COMPARTMENT OF THE 
SHIPPING PACKAGE UNTIL THE INFUSION STAFF IS READY TO INFUSE. 
DO NOT INFUSE SIPULEUCEL-T UNTIL YOU RECEIVE WRITTEN APPROVAL 
SIGNED BY THE IMMUNOTHERAPY MANUFACTURING FACILITY (IMF) 
QUALITY ASSURANCE (QA) PERSONNEL VIA THE CLINICAL CELL PRODUCT 
DISPOSITION FORM (CPDF). 
Delivery Time Notification 
A courier service contracted by Dendreon arranges and provides transportation of sipuleucel-T 
from the IMF to the clinical trial site infusion center. 
When the manufacturing schedule is determined for each subject, Dendreon Clinical Scheduling 
forwards a Subject Schedule Report to the Clinical Research Coordinator (CRC), indicating the 
approximate delivery times for all 3 infusions.  The CRC is contacted immediately if there is a 
change in delivery time. 
Sipuleucel-T Shipping, Receipt, and Storage 
Sipuleucel-T is transported to the infusion center in an insulated polyurethane container.  
Sipuleucel-T must remain in the original, unopened shipping package, which is designed to 
maintain sipuleucel-T at 2ºC to 8°C until it is infused.  Quality control testing is performed on 
each sipuleucel-T product.  Due to shipping logistics and expiration times, sipuleucel-T is 
routinely shipped to the infusion center before required QC release testing is complete.  
Dendreon’s QA personnel review the results and issue a written release called the CPDF, 
indicating whether the sipuleucel-T is “Approved” or “Rejected” for infusion, or if 
manufacturing was “Terminated” in process.     
The CPDF is faxed to the infusion center or pharmacy.  Upon receipt, the pharmacy, infusion 
staff, or CRC completes the section of the CPDF marked “Infusion Site Use Only” and faxes it to 
Dendreon at the number provided on the form.  This notifies Dendreon that the CPDF was 
received.  
If the sipuleucel-T does not meet Dendreon quality specifications and is rejected or terminated, 
Dendreon Clinical Scheduling contacts the clinical trial site to notify them of the sipuleucel-T 


 
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rejection or termination.  If necessary, Dendreon Clinical Scheduling arranges for the return to 
the IMF of any delivered and rejected or terminated sipuleucel-T.  Dendreon Clinical Scheduling 
will also reschedule the subject as necessary.  The clinical trial site may also contact the 
Dendreon medical monitor for additional information regarding a sipuleucel-T rejection or 
termination.    
Subject Preparation for Infusion  
It is recommended subjects are premedicated approximately 30 minutes prior to infusion with 
650mg acetaminophen orally and an antihistamine such as diphenhydramine 50mg orally. 
Obtain the subject’s vital signs within 1 to 30 minutes prior to the start of the infusion.  
Document the subject’s blood pressure, heart rate, temperature, and respirations in his medical 
record.  
Sipuleucel-T Inspection and Expiration Time 
When the infusion staff and subject are ready for the infusion, open the polyurethane container 
and inspect the sipuleucel-T and the Final Product Label (FPL) affixed to the sipuleucel-T bag.  
The sipuleucel-T expiration time is indicated on the CPDF and on the FPL.  The expiration 
time is noted in the time zone of the infusion center.  Contact Dendreon Clinical Scheduling 
immediately if the expiration times on both documents do not match.  Confirm the infusion 
will begin prior to the sipuleucel-T expiration time noted on the CPDF and the FPL.  If 
sipuleucel-T administration cannot begin prior to the expiration time shown on the label, do not 
infuse and contact Dendreon Clinical Scheduling for further instructions. 
Occasionally, there is a delay in obtaining the CPDF due to operational or technical reasons. 
 If Dendreon indicates the CPDF is imminently pending, it is acceptable to administer the 
recommended premedications 30 minutes prior to the sipuleucel-T expiration time.     
 If a CPDF marked “Approved” is obtained within 30 minutes prior to the sipuleucel-T 
expiration time, it is acceptable to administer the recommended antihistamine intravenously 
rather than orally, in order to achieve higher systemic concentrations at the time the infusion 
is initiated. 
Two different infusion center staff members must confirm the subject identifiers (name, initials, 
subject number, and lot or chain of identity [COI] number) on the CPDF and FPL match the 
intended subject.  Document this verification process in the subject’s medical record.  If any 
information on the CPDF or FPL is incorrect or is inconsistent, contact Dendreon Clinical 
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The contents of the sipuleucel-T bag are generally slightly cloudy, with a cream-to-pink color.  
Examine the sipuleucel-T bag for leakage.  Gently re-suspend the contents by slowly rocking the 
bag back and forth, inspecting for clumps and clots. Small clumps of cellular material should 
disperse with gentle manual mixing. 
If the sipuleucel-T bag leaks or if clumps remain in the bag do not infuse and contact the 
Dendreon Clinical Safety line. 
Sipuleucel-T Infusion Supplies 
Use a large-bore intravenous (IV) line suitable for blood transfusions to infuse sipuleucel-T; 18- 
or 20-gauge is recommended, but 22-gauge may be used when necessary.  The typical IV tubing 
set used for sipuleucel-T infusions has a universal spike, a 10-20 drip/mL macro-drip chamber 
WITHOUT a cell filter, and a minimum of one injection port.  An infusion pump may be used, 
but is not required, to ensure the rate of infusion is controlled.   
Infusion Procedures 
DO NOT INFUSE SIPULEUCEL-T PRIOR TO RECEIPT OF A CPDF INDICATING 
SIPULEUCEL-T IS APPROVED FOR INFUSION. 
Sipuleucel-T Infusion 
Infuse sipuleucel-T over the shortest period that is well tolerated but not less than 60 minutes.  
Record the infusion start and stop times in the subject’s medical record.  
If the subject develops an acute infusion reaction, slow the infusion and consult the section 
below on “Managing Acute Infusion Reactions” for recommendations regarding administration 
of additional medications.  It may not be necessary to immediately discontinue the infusion. 
If the infusion of sipuleucel-T is interrupted, do not resume the infusion if the sipuleucel-T bag 
will be held at room temperature for more than 3 hours following removal from the shipping 
container.  Record all sipuleucel-T infusion re-start and stop times in the subject’s medical 
record. 
Adverse Event and Concomitant Medication Documentation 
Record all concomitant medications administered to the subject and all AEs. 
Document all concomitant medications administered, including all premedications, using the 
generic drug names, doses, routes, frequencies, indications, and start and stop dates in the 
subject’s medical record. 


 
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Describe any AEs, including start and stop dates (and duration if less than 24 hours), whether or 
not the event was serious, severity (based on the NCI CTCAE), relationship to sipuleucel-T 
(none, possible, or probable), and the outcome in the subject’s medical record. 
Refer to Section 7.0 of the protocol for more information regarding AEs and SAEs, including 
reporting requirements. 
Post-infusion Procedures 
Subject Follow-up 
Observe the subject for at least 30 minutes after the infusion.  Obtain vital signs within 30 
minutes (± 10 min) after completion of the infusion.  Document the subject’s blood pressure, 
heart rate, temperature, and respirations in the subject’s medical record. 
Documentation 
Retain the original CPDF and file it in the subject’s medical record. 
Sipuleucel-T Return or Disposal 
Dispose of the sipuleucel-T bag and tubing according to institutional procedures for disposal of 
biohazardous waste that contains human blood.  Dispose of all packaging materials and gel packs 
appropriately.  
If instructed by Dendreon to return the sipuleucel-T, place the remaining sipuleucel-T in the 
original shipping box with the packaging materials and ship per Dendreon instructions. 
Managing Acute Infusion Reactions 
Refer to the current sipuleucel-T IB for a complete list of acute infusion reactions, including 
severity.  Some common acute infusion reactions, such as pyrexia and/or rigors (chills), may 
warrant slowing of the infusion rate.  If acute infusion reactions occur, the current infusion time 
and subsequent infusion times can be increased up to a total infusion time of 1.5 to 2.0 hours.  If 
the infusion of sipuleucel-T is interrupted, do not resume the infusion if the sipuleucel-T bag will 
be held at room temperature for more than 3 hours following removal from the shipping 
container.   
For subjects who experience a significant acute infusion reaction, including rigors, during or 
immediately following an infusion, the following guidelines may be helpful: 


 
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1. 
As prophylaxis during subsequent infusions, the dose or intensity of the recommended 
premedications may be increased. For instance, acetaminophen may be given at a higher 
oral dose than used previously and an IV rather than oral antihistamine may be 
administered.  In addition, IV administration of an H2 antagonist may be considered as an 
additional premedication. 
2. 
A narcotic such as meperidine may be used as treatment for an AE or as prophylaxis 
during subsequent infusions.   
3. 
Additional or other premedications may be considered according to institutional practices 
and/or local standards of care.  Steroids should not be used for premedication or 
treatment during sipuleucel-T infusions.  The use of steroids may suppress any 
immune response elicited by sipuleucel-T. 
4. 
For severe acute infusion reactions supportive care measures such as supplemental 
oxygen, bronchodilator therapy for wheezing, and epinephrine should be used as 
clinically indicated.  
Contact the Dendreon Clinical Safety line at any time during the study for urgent medical 
concerns. 
Dendreon Contact Information 
Dendreon Connect  
Support for day of infusion issues such as cancellations and delivery or disposition delays. 
Email (preferred): dendreonconnect@dendreon.com 
Phone (if urgent): (877) 340-3844 
Dendreon Clinical Scheduling 
Support for scheduling related issues. 
Email (preferred):  clinicalscheduling@dendreon.com 
Phone: (206) 219-7218 
Dendreon Clinical Safety Line 
Support at any time during the study for urgent medical concerns. 
Phone:  (206) 274-6774 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
 
 
 
 
 
PROTOCOL P12-2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 A RANDOMIZED, OPEN-LABEL, PHASE 2 TRIAL OF 
SIPULEUCEL-T WITH CONCURRENT VERSUS SEQUENTIAL 
ADMINISTRATION OF ENZALUTAMIDE IN MEN WITH 
METASTATIC CASTRATE RESISTANT PROSTATE CANCER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name Of Test Drug : 
Sipuleucel-T (Provenge®) 
Protocol Number: 
P12-2 
Sponsor: 
Dendreon Pharmaceuticals, LLC 
Statistician: 
Matthew Harmon 
Date of Approval: 
26 July 2017 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Table of Contents 
 
 
1 
STUDY DESIGN .................................................................................................................................. 1 
2 
STUDY OBJECTIVES ........................................................................................................................ 2 
2.1 
PRIMARY STUDY OBJECTIVE ........................................................................................................... 2 
2.2 
SECONDARY STUDY OBJECTIVES .................................................................................................... 2 
2.3 
EXPLORATORY STUDY OBJECTIVES ............................................................................................... 3 
3 
STATISTICAL CONSIDERATIONS ............................................................................................... 3 
3.1 
SAMPLE SIZE CONSIDERATIONS ...................................................................................................... 3 
3.2 
ANALYSIS POPULATIONS .................................................................................................................. 3 
3.2.1 
Immune Response ....................................................................................................................... 3 
3.2.2 
Safety ........................................................................................................................................... 4 
3.2.3 
Efficacy ........................................................................................ Error! Bookmark not defined. 
3.3 
MISSING DATA .................................................................................................................................. 4 
3.4 
DATA RULES ...................................................................................................................................... 4 
3.5 
VISIT WINDOWS ................................................................................................................................ 4 
4 
STATISTICAL METHODS ............................................................................................................... 5 
4.1 
PRODUCT CHARACTERIZATION....................................................................................................... 6 
4.2 
IMMUNE RESPONSE .......................................................................................................................... 6 
4.3 
PSA .................................................................................................................................................... 7 
4.4 
OVERALL SURVIVAL ......................................................................................................................... 8 
4.5 
SAFETY .............................................................................................................................................. 8 
4.5.1 
Adverse Events ............................................................................................................................ 8 
4.5.2 
Laboratory Data ......................................................................................................................... 9 
4.5.3 
Vital Signs ................................................................................................................................. 10 
4.6 
OTHER DATA ................................................................................................................................... 10 
4.6.1 
Demographic and Baseline Characteristics ............................................................................. 10 
4.6.2 
Disposition ................................................................................................................................ 10 
4.6.3 
Concomitant Medications and Procedures ............................................................................... 11 
4.6.4 
Baseline Smoking History and Cerebrovascular Event Risk Factors ....................................... 11 
4.6.5 
Baseline Medical History .......................................................................................................... 11 
4.6.6 
ECOG Performance Status ....................................................................................................... 11 
4.6.7 
Protocol Deviation and Eligibility Deviation ........................................................................... 11 
4.6.8 
Study Treatment Administration ............................................................................................... 11 
4.6.9 
Anti-Cancer Therapies .............................................................................................................. 12 
4.7 
SCHEDULE OF ANALYSES ............................................................................................................... 12 
4.7.1 
Interim Analysis ........................................................................................................................ 12 
4.7.2 
Final Analysis ........................................................................................................................... 12 
5 
TABLES, LISTINGS, AND FIGURES ............................................................................................ 13 
6 
REFERENCES .................................................................................................................................. 17 
 


 
                                              
 
            
 
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1 
STUDY DESIGN 
Protocol P12-2 is a randomized, open-label study designed to examine the effects on cumulative 
CD54 upregulation of concurrent and sequential administration of enzalutamide administered in 
combination with sipuleucel-T in mCRPC subjects.  All subjects will be scheduled to receive 
three infusions of sipuleucel-T as well as a total of 52 weeks of therapy with enzalutamide either 
concurrently with or following administration of sipuleucel-T.  This study consists of 3 phases. 
The screening phase will begin at the completion of the informed consent process and continue 
through registration. The active phase will begin at registration and continue through the post-
treatment visit (30 to 37 days following the last study treatment). The long term follow-up 
(LTFU) phase will begin after the post-treatment visit and will continue until the subject’s death 
or until Dendreon terminates the study. 
Registered subjects will be randomized (1:1) to either the Concurrent Arm or the Sequential 
Arm.  Subjects will be stratified by screening PSA levels (≥ 25 ng/mL, yes or no) and screening 
lactate dehydrogenase (LDH) levels (≥ 200 IU/L, yes or no), both obtained from the central 
laboratory. 
Enzalutamide treatment will occur either concurrently with sipuleucel-T (concurrent arm), or 
following administration of sipuleucel-T (sequential arm): 
 Concurrent Arm:  Subjects will receive sipuleucel-T concurrently with enzalutamide (160 
mg orally once daily). Enzalutamide treatment will start 2 weeks prior to the first 
leukapheresis and continue for 52 weeks or until disease progression or unacceptable 
toxicity, whichever occurs first. Subjects randomized to the concurrent arm who receive 
the 2-week enzalutamide run-in, but do not subsequently receive at least one partial (> 0 
mL) infusion of sipuleucel-T will not receive any additional enzalutamide treatment, will 
undergo a post-treatment visit, and will enter the LTFU phase. 
 Sequential Arm:  Subjects will receive sipuleucel-T followed by enzalutamide (160 mg 
orally once daily). Enzalutamide treatment will start approximately 10 weeks after the 
first infusion of sipuleucel-T and continue for 52 weeks or until disease progression or 
unacceptable toxicity, whichever occurs first. Subjects randomized to the sequential arm 
who do not receive at least one partial (> 0 mL) infusion of sipuleucel-T will not receive 
any enzalutamide treatment, will undergo a post-treatment visit, and will enter the LTFU 
phase. 
After 52 weeks of enzalutamide treatment provided by Dendreon, subjects in either treatment 
arm may continue to receive enzalutamide obtained from other sources at the discretion of their 
treating physician. Dendreon cannot provide enzalutamide beyond the protocol-specified 
duration of 52 weeks.   
All subjects will receive a total of 52 weeks of enzalutamide.  The active phase will begin at 
registration and continue through the post-treatment visit (30 to 37 days following the last study 


 
                                              
 
            
 
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treatment).   The long term follow-up (LTFU) phase will begin after the post-treatment visit and 
will continue until the subject’s death or until Dendreon terminates the study.   
All immune monitoring (IM) endpoints will be collected from all subjects who receive at least 
one infusion. Cellular and serological peripheral immune responses will be assessed for subjects 
in both arms.  In both arms, IM blood samples will be collected at baseline (screening); pre-
leukapheresis 2 and 3; and weeks 6, 10, 14, 20, 26, 40, and 52, with the timing of visits based on 
the date of the first sipuleucel-T infusion (Day 0). 
During the Active phase, safety assessments in both arms will include AE monitoring, laboratory 
tests (complete blood count (CBC) collection serum chemistries, and liver function tests [LTFs]), 
vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, anticancer 
therapies, first opioid use for cancer-related pain, PSA monitoring, and physical examinations. 
During the LTFU phase, safety (treatment-related AEs, cerebrovascular events, and seizures), 
survival status, PSA, ECOG performance status, first opioid use for cancer-related pain (if 
applicable), and anticancer therapies will be assessed every 3 months until the subject’s death or 
until Dendreon terminates the study. 
 
Sponsor’s decision to terminate the study: During the first quarter of 2017, a decision was made 
to terminate the study during 2017 after at least 3 years of follow-up data was collected on all 
subjects participating in the study and still being followed. The end of follow-up period was 
defined as 3 years after the date that the last enrolled subject received the last infusion of 
sipuleucel-T. 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Study Objective 
 To evaluate peripheral PA2024-specific T cell immune response to sipuleucel-T over 
time via a T cell stimulation index from a proliferation assay. 
 
2.2 
Secondary Study Objectives 
 To evaluate time to PSA Progression   
 To estimate the percent of subjects who are PSA progression-free at 2 months.  
 To evaluate overall survival. 
 To evaluate the magnitude of peripheral immune response over time as determined by 
the following: 
o Peripheral PAP-specific T cell immune response to sipuleucel-T over time 
via T cell stimulation index from a proliferation assay. 
o T cell interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) 
response to PA2024 and PAP  
o Humoral response by enzyme-linked immunosorbent assays (ELISA) to 
PA2024 and PAP  


 
                                              
 
            
 
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o Chemokine and cytokine production via fluorescent immunoassay 
(MesoScale Discovery assay system).  
 To evaluate safety. 
 
2.3 
Exploratory Study Objectives 
 To evaluate time to next anticancer intervention. 
 To evaluate time to first cancer-related opioid use. 
 To evaluate time to Eastern Cooperative Oncology Group (ECOG) performance status 
decline.  
 
3 
STATISTICAL CONSIDERATIONS 
3.1 
Sample Size Considerations 
Approximately 100 subjects will be registered and randomized 1:1 to the Concurrent Arm or the 
Sequential Arm, with 50 subjects per arm.   
PA2024-specific T cell proliferation responses over time will be compared between the 
concurrent arm and sequential arm using a repeated measurement mixed model analysis. With 43 
subjects per arm, there is approximately 90% power to detect a 2-fold difference in mean 
response between the arms at any time point assuming a coefficient of variation of 1.25. To 
allow for drop-outs and subjects who may not receive 3 infusions of sipuleucel-T or at least 10 
weeks of enzalutamide, approximately 50 subjects per arm will be enrolled. 
 
In the fourth quarter of 2013 Dendreon modified the enrollment goals for this study pursuant to a 
corporate reorganization plan. Planned enrollment was reduced from 100 subjects to the 
approximately 50 subjects known to have enrolled at the time of this reorganization. Comparing 
PA2025-specific T cell proliferation responses over time between the concurrent arm and the 
sequential are with 25 subjects per arm, there is approximately 70% power to detect a 2-fold 
difference in mean response between the arms at any time point assuming a coefficient of 
variation of 1.25.  A determination was made that no protocol amendment was required and on 
February 14, 2014, all participating sites were notified of the decision to stop enrolling subjects.  
Ultimately, 52 subjects were enrolled: 25 in the Concurrent Arm and 27 in the Sequential Arm 
 
3.2 
Analysis Populations 
3.2.1 Immune Response 
The immune response population will be defined as subjects who receive 3 infusions of 
sipuleucel-T and 10 or more weeks of enzalutamide. Analysis of immune response endpoints, 
including the primary endpoint, will be performed using this population. This population will 
also be used to perform supplementary analyses of nonimmune response efficacy endpoints. 
 


 
                                              
 
            
 
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3.2.2  Intent-to-treat (ITT)  
The ITT population is defined as all randomized subjects regardless of whether they received 
treatment.  Analysis of nonimmune response efficacy endpoints will be performed using this 
analysis population.  Efficacy data for all randomized subjects will be included in the data 
listings. All the subjects in the ITT population will be analyzed according to the treatment that 
they are randomized to receive.  
 
3.2.3 Safety 
The safety population is defined as all randomized subjects who undergo at least one 
leukapheresis procedure or receive at least 1 dose of enzalutamide.  All immune response 
variables and safety variables will be analyzed and summarized based on this analysis set.  
Immune response data and safety data for all subjects in the safety population will be included in 
the data listings. All the subjects in the safety population will be analyzed according to the 
treatment actually received. 
 
3.3 
Missing Data 
Missing data will not be imputed for any variables except in the case of time-to-event variables. 
The rules for imputing missing event or censor dates are defined below (section 3.4).  
 
3.4 
Data Rules 
 Study Day = [(visit date) – (date of first infusion [Day 0])]. If the infusion does not occur, 
Day 0 will be the date of the first leukapheresis, unless it fails, in which case, Day 0 will 
be the date of registration.  
 Baseline: baseline is defined as the value closest to but prior to the randomization data.  
 Change from baseline: change from baseline is the post-baseline value minus the baseline 
value.  
 Percent change from baseline: percent change from baseline is calculated as 100 × (post-
baseline value minus the baseline value) / baseline value.  If the baseline or post-baseline 
value is missing, then the change from baseline and percent change are set to missing.  If 
the baseline value is zero and the post-baseline is non-zero, then the percent change from 
baseline is set to missing. If the baseline value is zero and the post-baseline value is also 
0, then the percent change from baseline is set to 0.  
 Partial Dates: Dates missing the day, month and year and the day and month will not be 
imputed. However, if the month and year are present, the day may be set to the 15th of the 
month or to a date consistent with a more conservative approach to the analysis of the 
data point. 
 Missing event or censor date:  If the date of an event or the date of censoring is missing 
for a time-to-event variable, the last known study date will be used.  Subjects who 
prematurely discontinue from the study before having the event will be censored at their 
last known alive date. 
 
3.5 
Visit Windows 
Visit based data will be analyzed according to the nominal visit.   


 
                                              
 
            
 
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In cases where two or more assessments for the same subject have the same nominal visit label, 
the visit closest in time to the protocol schedule for the visit will be selected for analysis and the 
other visit regarded as an interim visit. If two visits are equally close in time to the scheduled 
visit, the visit with the ‘worst-case’ data will be selected. If no time collected, the worst of these 
assessments will be selected. 
 
4 
STATISTICAL METHODS 
All analyses will be conducted using SAS Version 9.4 or higher. 
 
Subjects will be stratified by screening PSA levels (≥ 25 ng/mL, yes or no) and screening lactate 
dehydrogenase (LDH) levels (≥ 200 IU/L, yes or no), both obtained from the central laboratory. 
Due to the modification of the sample size for this study, any statistical analyses should be 
considered descriptive or ‘exploratory.’   Any statistical tests will be performed only to generate 
hypotheses or for data exploration. 
Continuous data will be described using descriptive statistics (i.e., n, arithmetic mean, standard 
deviation (SD), median, minimum, and maximum). 1st quartile (Q1) and 3rd quartile (Q3) will 
also be presented. Categorical data will be described using the subject count and percentage in 
each category. For the summary statistics of all numerical variables unless otherwise specified, 
minimum and maximum will be displayed to the same level of precision as reported. Mean and 
median will be displayed to one level of precision greater than the data collected. Standard 
deviation/standard error will be displayed to two levels of precision greater than the data 
collected. P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will 
be reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999.”  
 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of subjects in that treatment within the 
analysis set of interest, unless otherwise specified.  No adjustment for multiple comparisons 
across efficacy or safety variables will be performed.   
 
For each time point where change from Baseline is evaluated for continuous variables, 
descriptive statistics will be displayed for the values at Baseline, values at the time point, and 
values for change from baseline at the time point for the set of subjects who have data at both 
baseline and the time point being assessed. 
 
Any subject receiving a next anti-cancer intervention (as described in section 4.6.9) may have 
their efficacy observations after the date of that next anti-cancer intervention censored at the 
earliest date of the next intervention.  Overall survival will be assessed censoring at the subjects 
last-known alive date. 
 


 
                                              
 
            
 
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4.1 
Product Characterization  
Product parameters to be summarized are: CD54 upregulation, CD54+ cell count, and TNC 
count.  Product parameters will be summarized descriptively (n, mean [geometric mean], 
standard error, median, minimum, and maximum) by Infusion (1, 2, and 3) and cumulative 
(summed across infusions).   Cumulative product parameters will be compared between both 
arms using a Wilcoxon test based on the immune response population.  Cumulative CD54 
upregulation is the primary endpoint for the study. 
4.2 
Immune Response 
To evaluate the magnitude of peripheral immune response over time as determined by the 
following: 
 Peripheral PAP-and PA2024 specific T cell immune response to sipuleucel-T over time 
via T cell stimulation index from a proliferation assay. 
 T cell interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) response to 
PA2024 and PAP  
 Humoral response by enzyme-linked immunosorbent assays (ELISA) to PA2024 and 
PAP  
 Chemokine and cytokine production via fluorescent immunoassay (MesoScale Discovery 
assay system). 
The PAP and PA2024 IFN ELISPOT response over time will be compared between the 
Concurrent Arm and the Sequential Arm, beginning with the immune sample taken at the 
baseline, using a repeated measurement mixed model analysis stratified by screening PSA levels 
and screening lactate dehydrogenase. The unit of analysis will be the background subtracted 
counts, computed as the median count of 3 wells exposed to antigen minus the median count of 3 
wells exposed to media alone.  The background subtracted counts will be ranked prior to 
analysis. The model will include treatment and visit as fixed effects as well as treatment by visit 
interaction, subject as random effect, and the two stratification factors at randomization as 
covariates.   Visit will be considered as a categorical variable for the modeling.  Several 
variance-covariance structures will be investigated to determine which model fit is best based on 
the model with the lowest Bayesian Information Criteria (BIC).  Variance-covariance structures 
that will be investigated are unstructured (UN), auto-regressive (1) AR(1), heterogeneous 
autoregressive (1) (ARH (1)), compound symmetry (CS), and heterogeneous compound 
symmetry (CSH).  Comparisons between the treatment arms at specific timepoints visits will be 
made using a linear contrast statement.  A proper transformation (such as log-scale or rank 
transformation) will be applied if the data are not normally distributed. A secondary analysis of 
this endpoint will be based on a categorical response/no response basis.  Categorical response 
will be defined on the basis of a threshold value determined from PA2024 ELISPOT background 
subtracted counts measured at baseline that ensures a sufficiently low false positive rate (i.e., 5% 
or less).  The two treatment arms will be compared using a Fisher’s exact test for a response at 
any time point post-baseline and by time point.   


 
                                              
 
            
 
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The T cell proliferation in response to PAP and PA2024, and PAP and PA2024 humoral 
responses of both arms will be compared using methods as described for the PA2024 ELISPOT 
response for IFN-.  The unit of analysis for the T cell proliferation data is the stimulation index, 
defined as the median 3H uptake of 3 wells exposed to antigen divided by the median 3H 
thymidine uptake of 3 wells exposed to media.  The stimulation index will be log-transformed 
prior to analysis.  The unit of analysis for the humoral response data is the antibody titer, which 
will be log-transformed prior to analysis. In addition, the responder rate will be summarized by 
time point for the data generated from the proliferation assays, ELISPOT, and ELISA. A responder at 
a time point is a subject with a post-baseline result at the time point exceeding the 95th percentile at 
baseline.  
AIM-V Cytokine data will be collected after each infusion of sipuleucel-T.  Each cytokine 
parameter over time will be compared between the Concurrent Arm and the Sequential Arm, 
using a repeated measurement mixed model analysis.  The same modeling strategy as outlined 
for PA2024 ELISPOT response for IFN-will be applied to the AIM-V cytokine data.  
Comparisons between treatment arms at specific time points will be made using a linear contrast 
statement.  The data will be analyzed on a log-scale with a count of 1 added prior to taking the 
log so that the log will always be defined.  Serum cytokine data will be analyzed in a manner 
similar to the AIM-V cytokine data.     
4.3 
PSA 
PSA data, including change from baseline and percent change from baseline, will be summarized 
descriptively by treatment arm at each time point. For each time point where change from 
baseline is evaluated for continuous variables, descriptive statistics will be displayed for the 
values at baseline, values at the time point, values for change from baseline, and percent change 
from baseline at the time point for the set of subjects who have data at both baseline and the time 
point being assessed. Additionally, the maximal percent decline of serum PSA from baseline at 
any time point will be summarized using waterfall plots and will be compared between the 
treatment groups using a Wilcoxon test.  Baseline will be defined as the pre-randomization PSA 
value.  The percent of subjects with a 50% or more maximal decline in PSA at any post-baseline 
time point will be compared between the treatment arms using a Fisher’s exact test.   
 
Time to PSA progression will be compared between the treatment arms using a Cox regression 
model with terms for treatment, baseline PSA (logarithm scale), and baseline LDH (logarithm scale) 
in the model based on the ITT population. The estimated HR of the treatment effect and its 2-sided, 
95% CI, using the sequential arm as the denominator will be provided. The percentage of subjects 
free of PSA progression with an associated 95% CI at landmark time points such as 6 and 12 months 
will be provided by treatment arm as well as pooled over treatment arms using the Kaplan-Meier 
method. 
 
Time to PSA progression is defined as: 1) the time from randomization to PSA progression, and 2) 
the time from first enzalutamide treatment to PSA progression. Those subjects who do not experience 
PSA progression will be censored in the analysis at the date of their last PSA assessment. PSA 
progression, based on the randomization date (i.e., definition 1) will be defined for those subjects 


 
                                              
 
            
 
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who experience a decline in PSA compared to baseline as the date that a 25% or greater increase in 
PSA and an absolute increase of 2 ng/mL or more from the nadir is documented, which is confirmed 
by a second value obtained 3 or more weeks later (Scher 2008). For those subjects who do not 
experience a decline in PSA compared to baseline, PSA progression is defined as the date a 25% or 
greater increase from the baseline value along with an increase in absolute value of 2 ng/mL or more 
after 12 weeks of enzalutamide treatment (Scher 2008). PSA progression based on the first 
enzalutamide treatment (i.e., definition 2) will be defined in a similar manner except the most recent 
PSA value prior to the first enzalutamide treatment will be used as the baseline value. 
  
4.4 
Overall survival 
Overall survival is defined as the time from randomization to death due to any cause.  Subjects 
will be followed for survival for 3 years from the date of randomization.  Those subjects alive at 
study end will be censored in the analysis at the day of their last documented visit or contact 
date.  Overall survival time will be calculated as follows: 
 For subjects who died prior to the study end: 
o Survival time (days) = [(death date) – (randomization date) + 1] 
 For subjects who did not die prior to the study end or whose death status is unknown: 
o Survival time (days) = [(last contact date) – (randomization date) + 1] 
 
Overall survival will be compared between the two arms using a stratified log-rank test.  The 
estimated adjusted hazard ratio of the treatment effect and its 2-sided 95% CI, using the 
sequential arm as the reference group, will be generated using a Cox regression model adjusted 
for baseline PSA (natural log scale) and baseline LDH (natural log scale).  Median survival and 
survival rates at specific time points will be estimated for each treatment arm using the Kaplan-
Meier method, with corresponding 95% CIs. 
 
 
4.5 
Safety 
Safety data will be summarized descriptively in aggregate within the safety population.  All AEs 
observed through the post-treatment visit will be summarized.  Following the post-treatment 
visit, only new treatment-related AEs, SAEs, seizures, and CVEs (regardless of causality) 
through the end of the study will be recorded and summarized.  No formal statistical testing is 
planned for any safety summaries.   
 
4.5.1 Adverse Events 
Adverse events (AEs) will be summarized and listed by treatment group and by the Medical 
Dictionary for Regulatory Activities (MedDRA) preferred term within each system organ class 
using the most current version of MedDRA at the time of study closure.  Summary tables will 
include all AEs reported in the Concurrent Arm and Sequential Arm from the first leukapheresis. 
 


 
                                              
 
            
 
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Tables/listings to be produced will include the following: 
 
 Incidence within system organ class (MedDRA) 
 Incidence by preferred term and decreasing frequency 
 Incidence by NCI CTCAE (Version 4.03) severity grade, by decreasing frequency 
 Incidence of Adverse Events Occurring ≤1 Day After Infusion by  preferred term and 
decreasing frequency 
 Incidence of ≥ Grade 3 AEs, by preferred term and decreasing frequency 
 Incidence of AEs that led to premature discontinuation of study therapy or study  
 Incidence of SAEs within system organ class (MedDRA) 
 Incidence of SAEs by preferred term and decreasing frequency 
 Incidence of Cerebrovascular Adverse Events by preferred term and decreasing 
frequency 
Adverse events that occur multiple times for a subject will be counted only once per subject in 
incidence summary tables. In tables that enumerate AEs by severity, only the worst severity for 
an AE occurring multiple times for a patient will be counted. 
 
No formal statistical testing is planned for the above AE summaries.  A 2-sided Fisher’s exact 
test may be used to assess any potential trend, if appropriate, and be interpreted as hypothesis 
generating. 
 
 
4.5.2 Laboratory Data 
Summaries of laboratory data collected from baseline onward will include: 
o Incidence of laboratory toxicities by NCI CTCAE toxicity version 4.03 grade.  
Separate summaries will be provided by time point, for the minimum post-baseline 
value, and for the maximum post-baseline value. 
o Incidence of clinically significant toxicities by NCI CTCAE toxicity version 4.03.  A 
clinically significant laboratory toxicity is defined as a toxicity with NCI grade < 3 at 
baseline that increased in severity to NCI grade ≥ 3.  Subjects with multiple 
occurrences of the same toxicity are counted only once.    
o Shifts from baseline.  The following shifts will be computed:  a) Shifts from baseline 
to minimum post-baseline value, b) Shifts from baseline to maximum post-baseline 
value, c) Shifts from baseline to last post-baseline value or end of treatment, and d) 
Shifts from baseline to worst post-baseline value.  Laboratory values will be 
categorized as Normal, High, or Low based on the normal reference range. 
o Summary statistics (mean, median, standard deviation, minimum, maximum) for 
laboratory values and their change from baseline by time point. 
 
 


 
                                              
 
            
 
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4.5.3 Vital Signs 
Vital sign change from baseline data (blood pressure, heart rate and body temperature), will be 
summarized descriptively by time point.  
  
Data collected pre- and post-infusion will be summarized for each of the 3 infusions.  Summaries 
of change values will be included in these summaries where change values will be calculated as 
post-infusion – pre-infusion.  
 
A summary of clinically significant abnormal vital signs at the post-infusion visit and the shift 
table from pre-infusion visit will be provided for each of the 3 infusions.  Clinically significant 
abnormal vital signs are defined as: 
 
 
Low 
High 
Comments 
Blood 
Pressure: 
Systolic  
(mm Hg) 
< 90 
≥ 140 
High corresponds to NCI CTCAE 
Grade 2 hypertension.   
Diastolic  
(mm Hg) 
< 40 
≥ 90 
Heart Rate (bpm) 
< 60 
> 100 
NCI CTCAE defines sinus brady- and 
tachycardia using these cut-offs (in 
presence of dysrhythmia) 
Respiration (bpm) 
< 10 
> 28 
 
Temperature (°F/°C) 
≤ 95.0/35.0 
≥ 100.4/38.0 
High corresponds to NCI CTCAE 
Grade 1 fever.  Low corresponds to 
NCI CTCAE Grade 1 hypothermia. 
 
 
4.6 
Other Data 
4.6.1 Demographic and Baseline Characteristics 
Demographic information and baseline disease information and characteristics will be 
summarized with descriptive statistics by treatment arm and overall for all analysis populations.  
The Wilcoxon test will be used to compare the treatment arms for continuous variables and 
Fisher’s exact test will be used to compare the treatment arms for categorical variables. 
 
4.6.2 Disposition 
Subject disposition will be summarized by treatment group for the randomized population. This 
summary will include, but will not be limited to, the following: 
 Number of subjects randomized 
 Number of subjects who had at least one leukapheresis 
 Number of subjects receiving at least one infusion of sipuleucel-T 
 Number of subjects receiving Enzalutamide 
 Number of subjects who prematurely discontinued each study treatment 
 Reason(s) for premature discontinuation of each study treatment 


 
                                              
 
            
 
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 Number of subjects who prematurely discontinued the study (i.e., refused further 
study evaluations [with the possible exception of survival status]) 
 Reason(s) for premature discontinuation from the study 
 Number of subjects who died 
 Cause of death summary 
 Number of subjects in the immune response, safety analysis, and efficacy analysis 
sets 
In addition, the number of subjects screened for the trial will be summarized. 
 
4.6.3 Concomitant Medications and Procedures 
Concomitant medications and procedures will be presented in data listings by treatment group 
based on coded terms using the most current version at the time of analysis of the World Health 
Organization dictionary, “WHODRUG”.  All subjects randomized will be included.  Summary 
tables by treatment arm will be provided with separate tables for medications and procedures 
started prior to the day of randomization and medications and procedures started on or after the 
day of randomization. 
 
4.6.4 Baseline Smoking History and Cerebrovascular Event Risk Factors 
Baseline smoking history regarding cigarette smoking status and cigarette smoking pack years 
will be summarized descriptively by treatment group.  Baseline cerebrovascular event risk 
factors will be summarized.  
 
4.6.5 Baseline Medical History 
Baseline medical history will be listed. 
 
4.6.6 ECOG Performance Status 
ECOG performance status will be summarized descriptively by treatment group by time point.  
In addition, the last ECOG collected will be compared to the baseline ECOG for each subject to 
determine the percentage of subjects whose ECOG score improved (ECOG score lower 
compared to baseline), stayed the same, or worsened (ECOG score higher compared to baseline) 
Shifts in ECOG from baseline to post-baseline at each visit and worst post-baseline ECOG will 
be presented. 
4.6.7 Protocol Deviation and Eligibility Deviation  
Protocol deviations will be summarized in a table and all the protocol deviations including 
significant protocol deviations will be presented in a listing. Eligibility deviations will be 
summarized in a separate table.    
 
4.6.8 Study Treatment Administration 
To evaluate the sipuleucel-T infusion success and failure rate over the course of the study, the 
following information will be summarized: 


 
                                              
 
            
 
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a)  Number of subjects who received a total of 0, 1, 2, or 3 infusions 
b)  Number of subjects undergoing leukapheresis for infusions 1, 2, and 3 
d)  Number of subjects undergoing leukapheresis more than once for infusions 1, 2, and 3 
e)  Number of subjects failing to receive three infusions due to insufficient TNC count    
and/or CD54 upregulation   
f)  Elapsed time between infusions 
g)  Elapsed time between randomization and infusion 1 
Items a) through e) will be summarized by their frequency distribution and by treatment group.  
Items f) and g) will be summarized with descriptive statistics (mean, median, standard deviation, 
minimum, and maximum) by treatment group. 
 
The duration of treatment with enzalutamide will be summarized descriptively by randomized 
treatment groups.  The reasons for stopping enzalutamide will be summarized descriptively by 
randomized treatment groups. 
 
 
4.6.9 Anti-Cancer Interventions and Cancer-Related Opioid Use 
All anticancer therapies received prior to screening and through the end of the LTFU phase were 
collected.  Anticancer therapies included, but were not limited to, radiation, chemotherapy, 
hormone therapy, investigational cancer therapies, all other systemic therapies, and surgery.  
Each subject’s first cancer-related opioid use will be collected and is defined as an opioid used 
for cancer-related pain that is of at least 2 consecutive days in duration. 
 
The time to next anticancer intervention will be summarized by treatment group and is defined as 
the time from randomization to the first anticancer intervention as described above. Subjects who 
do not received any anti-cancer therapies will be censored at the last available contact date. A 
Cox regression model with treatment arm as the independent variable and stratified by screening 
PSA levels and screening lactate dehydrogenase will be used to compare the treatment arms with 
respect to time to first anti-cancer therapy.  A similar summary will be produced for the time to 
first chemotherapy post randomization and time to first cancer-related opioid use.  
 
4.7 
Schedule of Analyses 
4.7.1 Interim Analysis 
No formal interim analysis will be performed in this study.  For this open-label study, descriptive 
summaries of safety assessments, product characteristics, and immune response parameters may 
be generated on a periodic basis.    
4.7.2 Final Analysis 
The final analysis for this trial will occur when every subject has completed approximately 3 
years of survival follow-up.  A nominal significance level of 0.05 will be used for all final 
analyses. 


 
                                              
 
            
 
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5 
TABLES, LISTINGS, AND FIGURES 
The content and format of all tables, listings, and figures will be specified in a separate report 
plan prior to final database lock of the trial.  
 
The tables, listings, and figures specified below are intended to be a representation of the content 
that will be included in the clinical study report.  It should be noted that the final outputs 
included in the actual clinical study report may not necessarily be an exact match of the content 
specified below.    
 
Proposed tables.  Title names and numbering subject to change.   
Number 
Title 
14.1.1 
Summary of Subject Disposition 
14.1.2 
Summary of Eligibility Criteria Not Met 
14.1.3 
Summary of Eligibility Deviations 
14.1.4 
Summary of All Protocol Deviations 
14.1.5.1 
Summary of Demographics and Baseline Characteristics – Intent-to-Treat Subjects 
14.1.5.2 
Summary of Demographics and Baseline Characteristics – Subjects Receiving 3 Infusions of 
Sipuleucel-T 
14.1.6 
Summary of Baseline Cerebrovascular Event (CVE) Risk Factors 
14.2.1 
Summary of Leukaphereses and Product Infusions 
14.2.2 
Summary of Time Interval (Days) Between Infusions 
14.2.3 
Summary of the Duration of Infusions (Minutes) 
14.2.4 
Summary of Subjects Undergoing > 1 Leukapheresis in Order to Receive a Given Infusion 
14.2.5 
Summary of Number of Leukaphareses by Infusion 
14.2.6.1 
Duration of Exposure to Enzalutamide 
14.2.6.2 
Summary of Reasons for Stopping Enzalutamide 
14.2.6.3 
Duration of Exposure to Non-Protocol Enzalutamide 
14.2.6.4 
Summary of Reasons for Stopping Non-Protocol Enzalutamide 
14.2.7.1 
Summary of CD54 Upregulation by Infusion Number for Subjects Receiving At Least 1 Infusion of 
Sipuleucel-T 
14.2.7.2 
Summary of CD54 Upregulation by Infusion Number for Subjects Receiving 3 Infusions of 
Sipuleucel-T 
14.2.8.1 
Summary of CD54+ Counts by Infusion Number for Subjects Receiving At Least 1 Infusion of 
Sipuleucel-T 
14.2.8.2 
Summary of CD54+ Counts by Infusion Number for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.9.1 
Summary of TNC Counts by Infusion Number for Subjects Receiving At Least 1 Infusion of 
Sipuleucel-T 
14.2.9.2 
Summary of TNC Counts by Infusion Number for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.10.1 
Analysis of ELISPOT Counts (3 x 105 per PBMC) for Subjects Receiving At Least 1 Infusion of 
Sipuleucel-T 
14.2.10.2 
Estimation of ELISPOT Treatment and Visit Effects for Subjects Receiving At Least 1 Infusion of 
Sipuleucel-T 
14.2.10.3 
Analysis of ELISPOT Counts (3 x 105 per PBMC) for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.10.4 
Estimation of Treatment and Visit Effects for ELISPOT Data for Subjects Receiving 3 Infusions of 
Sipuleucel-T 


 
                                              
 
            
 
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14.2.10.5 
ELISPOT Responder Analysis for Subjects Receiving At Least 1 Infusion of Sipuleucel-T 
14.2.10.6 
ELISPOT Responder Analysis for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.11.1 
Analysis of ELISA Antibody Titers for Subjects Receiving At Least 1 Infusion of Sipuleucel-T 
14.2.11.2 
Estimation of Treatment and Visit Effects for ELISA Antibody Titer Data for Subjects Receiving at 
Least 1 Infusion of Sipuleucel-T 
14.2.11.3 
Analysis of ELISA Antibody Titers for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.11.4 
Estimation of Treatment and Visit Effects for ELISA Antibody Titer Data for Subjects Receiving 3 
Infusions of Sipuleucel-T 
14.2.11.5 
ELISA Antibody Titer Responder Analysis for Subjects Receiving At Least 3 Infusions of  
Sipuleucel-T 
14.2.11.6 
ELISA Antibody Titer Responder Analysis for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.12.1 
Analysis of Cellular Proliferation for Subjects Receiving At Least 1 Infusion of Sipuleucel-T 
14.2.12.2 
Estimation of Treatment and Visit Effects for Cellular Proliferation Data for Subjects Receiving At 
Least 1 Infusion of Sipuleucel-T 
14.2.12.3 
Analysis of Cellular Proliferation for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.12.4 
Estimation of Treatment and Visit Effects for Cellular Proliferation Data for Subjects Receiving 3 
Infusions of Sipuleucel-T 
14.2.12.5 
Cellular Proliferation Responder Analysis for Subjects Receiving At Least 1 Infusion of Sipuleucel-T 
14.2.12.6 
Cellular Proliferation Responder Analysis for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.13.1 
Analysis of AIM-V Cytokine Data for Subjects Receiving At Least 1 Infusion of Sipuleucel-T 
14.2.13.2 
Estimation of Treatment and Visit Effects for AIM-V Cytokine Data for Subjects Receiving At Least 
1 Infusion of Sipuleucel-T 
14.2.13.3 
Analysis of AIM-V Cytokine Data for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.13.4 
Estimation of Treatment and Visit Effects for AIM-V Cytokine Data for Subjects Receiving 3 
Infusions of Sipuleucel-T 
14.2.14.1 
Analysis of Serum Cytokine Data for Subjects Receiving At Least 1 Infusion of Sipuleucel-T 
14.2.14.2 
Estimation of Treatment and Visit Effects for Serum Cytokine Data for Subjects Receiving At Least 1 
Infusion of Sipuleucel-T 
14.2.14.3 
Analysis of Serum Cytokine Data for Subjects Receiving 3 Infusions of Sipuleucel-T 
14.2.14.4 
Estimation of Treatment and Visit Effects for Serum Cytokine Data for Subjects Receiving 3 Infusions 
of Sipuleucel-T 
14.2.15.1 
Summary of PSA (ng/mL) at Each Sampled Time Point 
14.2.15.2 
Summary of PSA Change from Baseline (ng/mL) at Each Sampled Time Point 
14.2.15.3 
Summary of PSA Percent Change from Baseline (ng/mL) at Each Sampled Time Point 
14.2.15.4 
Summary of PSA Change from Pre-Enzalutamide Baseline at Each Sampled Time Point 
14.2.15.5 
Summary of PSA Percent Change from Pre-Enzalutamide Baseline at Each Sampled Time Point 
14.2.15.6 
Summary of Maximal Percent Reduction in PSA - Baseline Defined as Last Value Prior to  
Sipuleucel-T Dosing 
14.2.15.7 
Summary of Maximal Percent Reduction in PSA -
 Baseline Defined as Last Value Enzalutamide Dosing 
14.2.15.8 
 Analysis of Time to PSA Progression  
14.2.16 
Analysis of Overall Survival 
14.2.17 
Summary of First Anticancer Intervention After Randomization 
14.2.18 
Summary of Time to First Anti-Cancer Intervention Use After Randomization 
14.2.19 
Summary of First Chemotherapy After Randomization 


 
                                              
 
            
 
SA-2675.00, 26-07-2017 
- 15 - 
Dendreon Pharmaceuticals LLC 
P12-2 Statistical Analysis Plan 
Confidential 
BB-IND # 6693 
 
14.2.20 
Summary of Time to First Chemotherapy After Randomization 
14.2.19.1 
Summary of First Cancer-related Opioid Use After Randomization 
14.2.20.1 
Summary of Time to First Cancer-related Opioid Use After Randomization 
14.2.21 
Summary of Disease Progression As Reported By the Investigator After Randomization 
14.2.22 
Summary of ECOG Performance Status 
14.2.23 
Summary of ECOG Performance Status at Last Visit Compared to Baseline 
14.2.24 
Sift Tables ECOG By Visit and Worst Post-Baseline ECOG 
14.3.1.1 
Incidence of Adverse Events by System Organ Class and Preferred Term 
14.3.1.2 
Incidence of Adverse Events by Preferred Term and Decreasing Frequency 
14.3.1.3 
Incidence of Adverse Events by System Organ Class, Preferred Term, and NCI Toxicity Grade 
14.3.1.4 
Incidence of Adverse Events Occurring ≤1 Day After Infusion by Decreasing Frequency 
and Preferred Term 
14.3.1.5 
Incidence of NCI Toxicity Grade 3-5  Adverse Events  by  Decreasing Frequency and Preferred Term 
14.3.1.6 
Incidence of Adverse Events Leading to Death 
14.3.1.7 
Incidence of Adverse Events That Resulted in Premature Discontinuation of Study Treatment 
14.3.1.8 
Incidence of Serious Adverse Events by System Organ Class and Preferred Term 
14.3.1.9 
Incidence of Serious Adverse Events by Preferred Term and Decreasing Frequency 
14.3.1.10 
Incidence of Cerebrovascular Adverse Events 
14.3.2.1 
Laboratory Toxicities by NCI Grade and Study Period 
14.3.2.2 
Clinically Significant  Laboratory Toxicities by Decreasing Frequency 
14.3.2.3 
Summary of Laboratory Values Change From Baseline by Time Point 
14.3.2.4 
Laboratory Shift Table 
14.3.3.1 
Summary of Vital Signs Change From Baseline by Time Point 
14.3.3.2 
Changes in Vital Signs (Post- vs. Pre-Infusion) by Infusion Number 
14.3.3.3 
Incidence of Clinically Significant Abnormal Vital Signs (Post-Infusion) 
14.3.4.1 
Incidence of Concomitant Medications by ATC Text and Preferred Term Before Randomization 
14.3.4.2 
Incidence of Concomitant Medications by ATC Text and Preferred Term After Randomization 
14.3.5 
Summary of Causes of Deaths 
 
 
 
 
 
 
 
 


 
                                              
 
            
 
SA-2675.00, 26-07-2017 
- 16 - 
Dendreon Pharmaceuticals LLC 
P12-2 Statistical Analysis Plan 
Confidential 
BB-IND # 6693 
 
Proposed listings.  Title names and numbering subject to change. 
Number 
Title 
16.2.1.1 
Screening Failures 
16.2.1.2 
Study Terminations 
16.2.2 
Protocol Deviations 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2 
Baseline Physical Examination Findings – Abnormal Results Only 
16.2.4.3 
Medical History 
16.2.4.4 
PSA Values Collected Prior to Randomization 
16.2.4.5 
Listing of Cerebrovascular Event (CVE) Risk Factors 
16.2.4.6 
Prostate Cancer History: Local Therapies 
16.2.4.7 
Prior Prostate Cancer Hormone Therapies 
16.2.4.8 
Other Prior Systemic Prostate Cancer Therapies 
16.2.4.9 
Metastatic Status at Screening 
16.2.4.10 
Concomitant Medications 
16.2.4.11 
Vital Signs 
16.2.5.1 
Leukapheresis 
16.2.5.2 
Product Infusion 
16.2.5.3 
Product Infusion Summary 
16.2.5.4 
Central Venous Catheter (CVC) Summary 
16.2.5.5 
Enzalutamide Treatment Compliance 
16.2.5.6 
Non-Protocol Enzalutamide use 
16.2.6.1 
Subject Deaths 
16.2.6.2 
Long Term Follow Up 
16.2.6.3 
Listing of ELISPOT Response 
16.2.6.4 
Listing of Proliferation Response 
16.2.6.5 
Listing of ELISA Antibody Titer Response 
16.2.6.6 
Listing of PSA Values 
16.2.6.7 
Cell Product Parameters 
16.2.6.8 
Anti Cancer Interventions 
16.2.6.9 
First Chemotherapy 
16.2.6.10 
Disease Progression 
16.2.7.1 
Adverse Events 
16.2.7.2 
Adverse Events Occurring Prior to First Leukapheresis 
16.2.7.3 
Adverse Events Occurring Within 1 Day of Infusion 
16.2.7.4 
Adverse Events – NCI Toxicity Grade ≥ 3 
16.2.7.5 
Adverse Events that Led to Discontinuation of Study Treatment 
16.2.7.6 
Serious Adverse Events 
16.2.8.1 
Laboratory Results: Hematology Tests Part 1 
16.2.8.2 
Laboratory Results: Hematology Tests Part 2 
16.2.8.3 
Laboratory Results: Serum Chemistry Tests Part 1 
16.2.8.4 
Laboratory Results: Serum Chemistry Tests Part 2 
16.2.8.5 
Laboratory Results: Serum Chemistry Tests Part 3 


 
                                              
 
            
 
SA-2675.00, 26-07-2017 
- 17 - 
Dendreon Pharmaceuticals LLC 
P12-2 Statistical Analysis Plan 
Confidential 
BB-IND # 6693 
 
16.2.8.6 
Laboratory Results: Coagulation Tests 
16.2.8.7 
Laboratory Results: Viral Tests 
16.2.8.8 
Laboratory Results: NCI Toxicity Grade 3 – 5 
 
 
 
Proposed Figures.  Title names and numbering subject to change. 
Number 
Title 
1 
CD54 Upregulation by Infusion 
2 
Cumulative CD54 Upregulation 
3 
CD54+ Counts by Infusion  
4 
Cumulative CD54+ Counts  
5 
TNC Counts by Infusion  
6 
Cumulative TNC Counts 
7 
ELISPOT Counts Over Time 
8 
ELISA Antibody Titers Over Time 
9 
Cellular Proliferation Over Time 
10 
Overall Survival 
11 
Time To First Anti-Cancer Intervention 
12 
Time to First Chemotherapy 
13  
Time to PSA Progression 
 
 
6 
REFERENCES 
       None