Randomized Phase II Trial of Sipuleucel T Immunotherapy Preceded by Sensitizing Radiation Therapy and Sipuleucel-T Alone in Patients With Castrate Resistant Metastatic Prostate Cancer
Phase: PHASE2
Conditions: Adenocarcinoma of the Prostate, Bone Metastases, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Soft Tissue Metastases, Stage IV Prostate Cancer
Sponsor: City of Hope Medical Center

IRB # 12367 
 
Version Date:  10/24/17 
Version:  09 
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
TITLE: RANDOMIZED PHASE II TRIAL OF SIPULEUCEL T IMMUNOTHERAPY PRECEDED 
BY SENSITIZING RADIATION THERAPY AND SIPULEUCEL-T ALONE IN PATIENTS WITH 
CASTRATE RESISTANT METASTATIC PROSTATE CANCER  
CITY OF HOPE PROTOCOL NUMBER: 
 #12367 
VERSION: 
09 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
 
 
Initial Approval 
Protocol Dated 02/01/2013 
Version 00 
Amendment 01 
Protocol Dated 05/06/13 
Version 01 
Amendment 02 
Protocol Dated 06/05/13 
Version 02 
Amendment 03 
Protocol Dated 07/18/13 
Version 03 
Amendment 04 
Protocol Dated 08/12/13 
Version 04 
Amendment 05 
Protocol dated 10/08/13 
Version 05 
Amendment 06 
Protocol dated 12/11/13 
Version 06 
Amendment 07 
Protocol dated 01/24/14 
Version 07 
Amendment 08 at Continuation Protocol dated 01/10/17 
Version 08 
Amendment 09 
Protocol dated 10/24/17 
Version 09 
 
 
DISEASE SITE: 
PROSTATE CANCER 
 
STAGE (if applicable): 
IV 
 
MODALITY: 
Immunotherapy and Radiation Therapy 
 
PHASE/TYPE: 
II/Randomized 
PRINCIPAL INVESTIGATOR: 
Cy Stein M.D. 
CO-PRINCIPAL INVESTIGATOR: 
Neeraj Agrawal M.D. 
COLLABORATING INVESTIGATOR(S): 
 
Jeffrey Wong M.D. 
Paul Frankel, Ph.D (Biostatistics) 
PARTICIPATING CLINICIANS: 
 
 
Sumanta Pal M.D. 
Yi-Jen Chen M.D. 
Eric Radany M.D 
Sagus Sampath M.D. 
Samuel Chung, M.D. Christina Yeon, M.D. 
Stephen Koehler, M.D.  Helen Chen, M.D. 
Savita Dandapani, M.D.  
PARTICIPATING INSTITUTION: 
City of Hope National Medical Center 
Duarte, CA  
City of Hope National Medical Center 
South Pasadena, CA 

IRB # 12367 
 
Version Date:  10/24/17 
Version:  09 
 
Huntsman Cancer Institute, University of 
Utah 
 

Page 1 of 50 
IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
CITY OF HOPE NATIONAL MEDICAL CENTER 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF MEDICAL ONCOLOGY AND THERAPEUTICS RESEARCH 
TITLE: RANDOMIZED PHASE II TRIAL OF SIPULEUCEL T IMMUNOTHERAPY PRECEDED 
BY SENSITIZING RADIATION THERAPY AND SIPULEUCEL-T ALONE IN PATIENTS WITH 
CASTRATE RESISTANT METASTATIC PROSTATE CANCER  
CITY OF HOPE PROTOCOL NUMBER: 
 #12367 
VERSION: 
9 
DATE(S) OF AMENDMENT(S)/REVISION(S): 
Amendment 01 
Amendment 02 
Amendment 03 
Amendment 04                         
Amendment 05 
Amendment 06 
Amendment 07 
Amendment 08 
Amendment 09 
May 6, 2013 
June 4, 2013 
July 18, 2013 
August 12, 2013 
October 8, 2013 
December 11, 2013 
January 24, 2014 
January 10, 2017 
October 24, 2017 
 
DISEASE SITE: 
PROSTATE CANCER 
 
STAGE (if applicable): 
IV 
 
MODALITY: 
Immunotherapy and Radiation Therapy 
 
PHASE/TYPE: 
II/Randomized 
PRINCIPAL INVESTIGATOR: 
Designs protocol, responsible for study conduct and data 
analysis 
Cy Stein, M.D. 
 
CO-PRINCIPAL INVESTIGATOR: 
Neeraj Agrawal M.D. 
 
COLLABORATING INVESTIGATOR(S): 
 
Andrew Raubitschek M.D. 
Jeffrey Wong M.D. 
Paul Frankel, Ph.D (Biostatistics) 
PARTICIPATING CLINICIANS: 
 
Sumanta Pal M.D. 
Yi-Jen Chen M.D. 
Sagus Sampath M.D.     Eric Radany M.D. 
Samuel Chung, M.D. 
Nayana Vora M.D. 
Stephen Koehler, M.D. Christina Yeon, M.D. 
Helen Chen, M.D.          Savita Dandapani, M.D. 

Page 2 of 50 
IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
 
PARTICIPATING INSTITUTIONS: 
City of Hope National Medical Center 
1500 East Duarte Road 
Duarte, CA 91010 
(626) 256-4673 
 
 
Huntsman Cancer Institute, University of Utah 
2000 Circle of Hope, Ste 2123, 
Salt Lake City, Utah 84112 
Phone: 801-585-0255 
Pager: 801-339-2041 
Fax: 801-585-0124 
 
City of Hope National Medical Center – South 
Pasadena 
209 Fair Oaks 
South Pasadena, CA 91030 
(626) 396-2900 
DATA COORDINATING CENTER 
City of Hope National Medical Center 
1500 East Duarte Road 
Duarte, CA  91010 
(626) 256-4673 
 

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IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
 
Experimental Design Schema 
                                            Registration 
                                                      
                                          Randomization 
                               
 
Arm A (Sipuleucel-T)                     Arm B (Sipuleucel-T and radiation therapy) 
 
Study Schema for Arm A patients: (to simplify comparison between both 
groups, the start of therapy in group A will be counted as week 3)  
 
Week 1-2           Week 3 (Day 19)       Week 4 (Day 22)      Week 5 (Day 33)         Week 6 (Day 36)                
   rest                  Sipuleucel-T              Sipuleucel-T             Sipuleucel-T                Sipuleucel -T 
                           collection                  infusion                     collection                     infusion 
 
 
Week 7 (Day 47)                    Week 8 (Day 50)               Week 4 (Day22), and weeks 12, 24, 36, 48, 60   
Sipuleucel-T                           Sipuleucel-T                      Assays for immune correlates 
collection                                Infusion 
 
 
Study Schema for Arm B patients: 
 
Week 1-2          Week 3     Week 3 (Day 19)   Week 4 (Day 22)    Week 5 (Day 33)    Week 6 (Day 36)                
EBRT to           Rest           Sipuleucel-T          Sipuleucel-T           Sipuleucel-T           Sipuleucel -T 
single met                           collection               infusion                   collection                infusion 
 
 
Week 7 (Day 47)        Week 8 (Day 50)          Week 4 (Day22), and weeks 12, 24, 36, 48, 60   
Sipuleucel-T               Sipuleucel-T                 Assays for immune correlates 
collection                    Infusion 

Page 4 of 50 
IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
Protocol Synopsis 
Protocol Title: 
RANDOMIZED PHASE II TRIAL OF SIPULEUCEL T IMMUNOTHERAPY PRECEDED BY 
SENSITIZING RADIATION THERAPY AND SIPULEUCEL-T ALONE IN PATIENTS WITH 
CASTRATE RESISTANT METASTATIC PROSTATE CANCER 
Brief Protocol Title for the Lay Public (if applicable): 
Sipuleucel-T preceded by sensitizing radiation therapy in patients with metastatic castration resistant 
prostate cancer 
Study Phase: 
Phase II 
Participating Sites: 
City of Hope Cancer Center 
City of Hope South Pasadena 
Huntsman Cancer Institute, University of Utah 
Rationale for this Study: 
The combination of radiation therapy and immunotherapy holds promise as a strategy for cancer 
treatment. Preclinical studies have shown that radiation may act synergistically with immunotherapy 
to enhance or broaden antitumor immune responses, in part, because of radiation-induced phenotypic 
alterations of tumor cells that render them more susceptible to immune-mediated killing(1). Clinical 
trials utilizing the combination of therapeutic vaccines with radiation have supported many of these 
findings, and other clinical trials are both ongoing and planned. Sipuleucel-T is an active cellular 
immunotherapy approved for treatment of patients with castrate - resistant, asymptomatic or 
minimally symptomatic metastatic prostate cancer (2). Our proposal is based on the hypothesis that 
applying sensitizing radiotherapy to selected metastatic site prior to immunotherapy will enhance 
immune response in patients treated with Sipuleucel-T. 
Objectives: 
Primary Objective: 
To assess the feasibility, based on percent able or willing to receive all three infusions of 
Sipuleucel-T immunotherapy, when combining Sipuleucel-T with radiation therapy to a single 
site of metastasis delivered one week prior to beginning of Sipuleucel-T therapy 
Secondary Objectives: 
1.      To assess the effect of radiation therapy to single metastasis on immune response (antibody 
and T-cell proliferation to prostate acid phosphatase PAP and fusion protein PA2024) 
generated by Sipuleucel-T immunotherapy. 
2.      To assess the effect of external beam radiotherapy to single metastasis on PSA response to 
therapy with Sipuleucel-T.  
3.      To assess the effect of external beam radiation therapy to single metastasis on radiographic 
response rate to therapy with Sipuleucel-T.   
4.      To assess the time from the onset of therapy with Sipuleucel-T +/- radiation to the need for 
subsequent therapy for prostate cancer.    
5.      To assess the toxicity associated with Sipuleucel-T +radiation. 
 
 

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IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
 
 
 
 
 
Study Design: 
Eligible patients will meet the standard criteria for approved use of Sipuleucel -T. Patients will be 
randomized to receive standard Sipuleucel-T regimen (Arm A) or Sipuleucel-T preceded by radiation 
therapy to single site of metastatic disease (Arm B). In patients assigned to Arm B one metastatic site 
will be selected for radiation based primarily on the safety of radiation in that location. Radiation to 
bone metastases from L3 down to pelvis and femurs will be excluded provided that patients have 
other areas of metastases. Patients who have metastases only in the above locations (L3 down to 
pelvis and femurs) will be allowed provided that they have normal WBC and they will not receive 
radiation to more than 20% of the bone marrow.  Patients will be treated with 300 cGy/day to 3000 
cGy.  Approximately 7 days after completion of radiation therapy patients will begin therapy with 
Sipuleucel-T autologous vaccine. 
 
Endpoints: 
Primary Endpoint: 
The primary endpoint in this trial will be percent of patients able to receive all three infusions of 
Sipuleucel-T following radiation therapy. This endpoint reflects both tolerability and the ability to 
collect adequate numbers of CD54+ cells for the generation of Sipuleucel-T.  
Secondary Endpoint: 
Secondary endpoints will include measurements of immune responses to PAP, PA2024 and PSA 
and radiologic responses to therapy with Sipuleucel-T +/- external beam radiation therapy to single 
metastasis.     Toxicity comparison between the two arms is also a secondary endpoint. 
 
 
Sample Size: 
Total Sample size is 50 randomized in a 1:1 fashion to Arm A and B.  Anticipated accrual is 2-3 
patients a month.   
 
Estimated Duration of the Study 
24 months 
 
Summary of Subject Eligibility Criteria: 
Inclusion Criteria: 
Patients with metastatic castration-resistant prostate cancer who are candidates for Sipuleucel-T 
immunotherapy. Metastatic, minimally symptomatic or asymptomatic disease, ECOG PS 0-2 
Exclusion Criteria: 
Liver metastases, known brain metastases, > 2 prior chemotherapy regimens 
 

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IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
Investigational Product Dosage and Administration: 
Not Applicable. Radiation therapy constitutes investigational component of this study 
 
 
 
 
 
 
Clinical Observations and Tests to be Performed: 
Evaluation for toxicity will be performed at week 4, 6, 8, 12 and every 12 weeks thereafter. PSA will 
be performed at week  4 and 12, radiologic evaluation will be performed at week 12, and immune 
assays will be performed at week 4, 12, 24, 36, 48, 60 
 
Statistical Considerations: 
This is a randomized Phase II study.  The primary endpoint in this trial will be the ability to safely 
combine Sipuleucel-T with radiation therapy and collect adequate numbers of CD54+ cells for the 
generation of Sipuleucel-T.  This is measured by the percent of patients able to receive all three 
infusions of Sipuleucel-T. Secondary endpoints will include toxicity, and measurements of immune 
responses to PAP, PA2024 and PSA and radiologic responses to therapy with Sipuleucel-T +/- 
external beam radiation therapy to single metastasis.   
 
Sponsor/Licensee: 
City of Hope Cancer Center 
 
Case Report Forms 
Not applicable  
 

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IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
Table of Contents 
 
SECTION .............................................................................................................................. PAGE 
1.0 
Goals and Objectives (Scientific Aims) ............................................................................ 11 
2.0 
Background ....................................................................................................................... 11 
2.1 
Introduction/Rationale for Development ............................................................. 11 
2.2 
Overview of Proposed Study ............................................................................... 12 
2.3 
Preclinical Studies ................................................................................. 12 
2.4 
Human Studies ..................................................................................................... 12 
2.5 
STAT3-Activity ................................................................................................... 13 
3.0 
Patient Eligibility .............................................................................................................. 14 
3.1 
Inclusion Criteria ................................................................................................. 14 
3.2 
Exclusion Criteria ................................................................................................ 15 
3.3 
Inclusion of Women and Minorities .................................................................... 15 
4.0 
Screening and Registration Procedures............................................................................. 16 
4.1 
Screening Procedures ........................................................................................... 16 
4.2 
Informed Consent ................................................................................................ 16 
4.3 
Registration Requirements/Process ..................................................................... 16 
4.4 
Randomization ..................................................................................................... 17 
5.0 
Treatment Program ........................................................................................................... 17 
5.1 
Treatment Overview ............................................................................................ 17 
5.2 
Planned Duration of Therapy ............................................................................... 18 
5.3 
Subject Follow-Up ............................................................................................... 18 
5.4 
Supportive Care, Other Concomitant Therapy, Prohibited Medications ............. 18 
5.5 
Additional Studies ................................................................................................ 18 
6.0 
Dose Delays/Modifications for Adverse Events ............................................................... 18 
7.0 
Data and Safety Monitoring, Unanticipated Problems and Adverse Event Reporting ..... 19 
8.0 
Agent Information and Risks ............................................................................................ 26 
8.1 
Sipuleucel –T (Provenge®) ................................................................................. 26 
8.1.1 
Sipuleucel-T overview ......................................................................................... 26 
8.1.2 
Leukapheresis and Collection of Quiescent APCs .............................................. 26 
8.1.3 
Quality Testing .................................................................................................... 26 
8.1.4 
Storage and Time Limitations .............................................................................. 27 
8.1.5 
Administration ..................................................................................................... 27 

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8.1.6 
Toxicity ................................................................................................................ 27 
8.2 
Radiation therapy ................................................................................................. 29 
8.2.1 
Treatment Plan: .................................................................................................... 29 
8.2.2 
Toxicity: ............................................................................................................... 29 
9.0 
Correlative/Special Studies ............................................................................................... 30 
9.1 
Blood Collection .................................................................................................. 30 
9.2 
Immune Assays .................................................................................................... 30 
9.3 
Analysis of PBMCs ............................................................................................. 31 
10.0 
Study Calendar .................................................................................................................. 33 
11.0 
Endpoint Evaluation Criteria/Measurement of Effect....................................................... 35 
11.1 
Measurability of lesions ....................................................................................... 35 
11.2 
Objective status .................................................................................................... 35 
12.0 
Data Reporting/Protocol Deviations ................................................................................. 36 
12.1 
Confidentiality and Storage of Records ............................................................... 36 
12.2 
Subject Consent Form .......................................................................................... 36 
12.3 
Data Collection Forms and Submission Schedule ............................................... 37 
12.4 
Protocol Deviations .............................................................................................. 37 
12.5 
Deviation Policy .................................................................................................. 37 
12.5.1 Reporting of Deviations .......................................................................... 37 
12.5.2 Resolving Disputes ................................................................................. 37 
13.0 
Statistical Considerations .................................................................................................. 38 
13.1 
Study Design ........................................................................................................ 38 
13.2 
Sample Size Accrual Rate .................................................................................... 38 
13.3 
Statistical Analysis Plan ....................................................................................... 38 
14.0 
Human Subject Issues ....................................................................................................... 39 
14.1 
Institutional Review Board .................................................................................. 39 
14.2 
Recruitment of Subjects ....................................................................................... 39 
14.3 
Advertisements .................................................................................................... 39 
14.4 
Study location and Performance Sites ................................................................. 39 
14.5 
Confidentiality ..................................................................................................... 39 
14.6 
Financial Obligations and Compensation ............................................................ 39 
14.7 
Informed Consent Processes ................................................................................ 40 
15.0 
References ......................................................................................................................... 40 
Appendix “A” ................................................................................................................................ 41 
Appendix “B”................................................................................................................................. 42 

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IRB Protocol No. 12367 
 
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Appendix “C”:  
Multicenter Guidelines ........................................................................... 49 
 

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IRB Protocol No. 12367 
 
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Abbreviations 
Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRPC 
Castration Resistant Prostate Cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DSMC 
Data Safety Monitoring Committee 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IDS 
Investigational Drug Services 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
 
 

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IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
1.0 
Goals and Objectives (Scientific Aims) 
Primary Objective: 
To assess the feasibility, based on percent able or willing to receive all three infusions of 
Sipuleucel-T immunotherapy, when combining Sipuleucel-T with radiation therapy to a single 
site of metastasis delivered one week prior to beginning of Sipuleucel-T therapy 
Secondary Objectives: 
1.   To assess the effect of radiation therapy to single metastasis on immune response (antibody and T-cell 
proliferation to prostate acid phosphatase PAP and fusion protein PA2024) generated by Sipuleucel-T 
immunotherapy. 
2.   To assess the effect of external beam radiotherapy to single metastasis on PSA response to therapy 
with Sipuleucel-T.  
3.   To assess the effect of external beam radiation therapy to single metastasis on radiographic response 
rate to therapy with Sipuleucel-T.   
4.   To assess the time from the onset of therapy with Sipuleucel-T +/- radiation to the need for 
subsequent therapy for prostate cancer.    
5.  To assess the toxicity associated with Sipuleucel-T +radiation. 
2.0 
Background 
2.1 
Introduction/Rationale for Development 
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer-
related death in men in the United States1.  Androgen deprivation therapy is effective in the initial 
management of advanced prostate cancer but eventually cancer evolves into the aggressive phenotype 
referred to as castration resistant prostate cancer (CRPC) which is usually fatal within 12-22 months2.  
Sipuleucel-T is an active cellular immunotherapy consisting of autologous, peripheral blood mononuclear 
cells (PBMC’s), including antigen presenting cells (APC’s) that have been activated in vivo with a 
recombinant fusion protein (PA2024).  PA2024 consists of a prostate antigen, prostatic acid phosphatase 
(PAP) that is fused to granulocyte-macrophage colony-stimulating factor (GMCSF), an immune cell 
activator3.  
Sipuleucel-T was evaluated in a randomized placebo-controlled Phase III trial in patients with 
asymptomatic and minimally symptomatic CRPC and demonstrated statistically significant survival 
advantage of 4.1 months4.  Main eligibility criteria included the presence of metastatic CRPC, lack of 
visceral metastases, and lack of significant pain defined by the use of narcotic analgesics. The compound 
was well-tolerated with brief febrile infusion reactions constituting the main side effect. Sipuleucel-T did 
not induce significant PSA or objective responses but there was evidence of immune activation targeting 
prostate antigens. Specifically titers against PA2024 that exceeded 400 at any time after baseline were 
observed in 66.2 % of patients in the Sipuleucel-T and 2.9% in the placebo group. Patients with positive 
antibody titer against PA2024 had improved survival as compared to patients who did not generate such 
response. Antibodies against PAP were observed in 28.5% of patients treated with Sipuleucel-T and 1.4 
% in patients in a placebo group. At week 6 , T-cell proliferation responses (stimulation index>5) to 
PA2024 were seen in 73% of patients in the Sipuleucel-T group and 12.1% in the placebo arm. Responses 
to PAP were observed in 27.3 % in the Sipuleucel-T group and 8.0% in the placebo group. Based on the 
results of this trial Sipuleucel-T was approved by Food and Drug Administration for the treatment of 
patients with metastatic CRPC.  
The combination of radiation therapy and immunotherapy holds promise as a strategy for cancer 
treatment. Preclinical studies have shown that radiation may act synergistically with immunotherapy to 

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IRB Protocol No. 12367 
 
Version Date:  10/24/2017 Version:  09   
enhance or broaden antitumor immune responses, in part, because of radiation-induced phenotypic 
alterations of tumor cells that render them more susceptible to immune-mediated killing. Our internal City 
of Hope data indicates synergistic effect of immunotherapy and radiation in murine model utilizing anti-
CEA antibody (Dr Raubitschek-personnel communication.)  Clinical trials utilizing the combination of 
therapeutic vaccines with radiation have supported many of these findings, and other clinical trials are 
both ongoing and planned. Our proposal is based on the hypothesis that applying sensitizing radiotherapy 
to selected metastatic site prior to immunotherapy will enhance immune response in patients treated with 
Sipuleucel-T. 
  
2.2 
Overview of Proposed Study 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the 
applicable regulatory requirements. Sipuleucel-T (APC8015, Provenge®) is an autologous cell product 
consisting of antigen presenting cells (APCs) loaded with prostate antigen PA2024, a recombinant 
fusion protein composed of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage 
colony-stimulating factor (GM-CSF). GM-CSF acts as a targeting molecule that directs the PAP 
antigen to APCs and promotes antigen uptake and processing. A dose of sipuleucel-T is prepared 
from cells from a single leukapheresis procedure, with a minimum of 20 million CD54+ cells (the 
biologically active component of sipuleucel-T), which is administered via a single intravenous 
infusion at Weeks 0, 2, and 4. Sipuleucel-T has been approved based on the demonstration of 4.1 
months survival advantaged when applied to patients with asymptomatic or minimally symptomatic 
CRPC. Eligible patients will meet the standard criteria for approved use of Sipuleucel -T. Patients will be 
randomized to receive standard Sipuleucel-T regimen (Arm A) or Sipuleucel-T preceded by radiation 
therapy to single site of metastatic disease (Arm B). In patients assigned to Arm B, one metastatic site 
will be selected for radiation based primarily on the safety of radiation in that location. Radiation to bone 
metastases from L3 down to pelvis and femurs will be excluded provided that patients have other areas of 
metastases.  Patients who have metastases only in the above locations (L3 down to pelvis and femurs) 
will be allowed provided that they have normal WBC and they will not receive radiation to more than 
20% of the bone marrow.  Patients will be treated with following fractionation schemes: 1) 300 cGy/day 
to 3000 cGy. Approximately 7 days after completion of radiation therapy, patients will begin therapy with 
Sipuleucel-T autologous vaccine. 
2.3 
Preclinical Studies 
Sipuleucel-T-Pre-clinical studies in rats demonstrated that APCs loaded with a fusion protein consisting 
of rat prostatic acid phosphatase (rPAP) coupled to a targeting molecule, rat granulocyte-macrophage 
colony-stimulating factor (rGM-CSF), induced strong cellular immune responses in vivo to tissues and 
tumors that express PAP (Laus 2001). Based on these observations, an APC product, designated 
APC8015 (sipuleucel-T), was developed for the treatment of men with prostate cancer 
2.4 
Human Studies 
Sipuleucel-T Separate Phase 1 and Phase 2 trials of sipuleucel-T were performed at the University of 
California, San Francisco (UCSF) (Small 2000) and the Mayo Clinic (Burch 2000, Burch 2004). Data 
from the Phase 1 and Phase 2 trials demonstrated that intravenous infusions of sipuleucel-T were 
generally well tolerated and effectively stimulated T cell responses to the immunogen. In addition, 
following therapy with sipuleucel-T, several subjects had decreases in PSA levels or objective tumor 
regressions suggesting anti-tumor activity. A dose of 3 million CD54+ cells was adequate to generate an 
immune response. There were no apparent dose related or dose limiting toxicities, warranting the 
conclusion that the maximum cell dose that could be manufactured from a single leukapheresis product 
was safe. PR-0292.08, 03 JAN 2008 Page 14 of 55 Dendreon Corporation Sipuleucel-T (APC8015) 
 

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IRB Protocol No. 12367 
 
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A randomized, placebo-controlled, Phase 3 trial (D9901, n = 127 subjects) was subsequently conducted. 
A statistically significant survival benefit was demonstrated, with the relative risk of death 70% greater 
for subjects randomized to placebo (P = 0.010, 2-sided log rank; HR = 1.71). The median survival was 
25.9 months for subjects randomized to sipuleucel-T compared to 21.4 months for those randomized to 
placebo. At 36 months from randomization, the survival rate for subjects receiving sipuleucel-T was 3.1 
times higher than the survival rate for subjects receiving placebo (34% vs. 11%; P = 0.0046, chi square) 
(Small 2006). In addition, when the Kaplan-Meier curves for time to disease progression were compared, 
there was a delay in the time from randomization to disease progression in the sipuleucel-T group 
compared with the placebo group (HR = 1.45 [95% CI: 0.99, 2.11], P = 0.052). A second smaller, 
randomized, placebo-controlled Phase 3 trial (D9902A, n = 98 subjects) with the same design as D9901 
demonstrated a 20% improvement in median survival for subjects who were randomized to receive 
sipuleucel-T compared to placebo. Furthermore, at the 3-year follow-up, the percentage of subjects alive 
in the sipuleucel-T treated group was substantially greater than the percentage of subjects alive who 
received placebo. The results from this study did not reach statistical significance based on the log rank 
test. A secondary analysis using a Cox multivariable regression analysis of overall survival, which 
adjusted for prognostic factors known to influence survival, met the criteria for statistical significance. 
The HR observed in this Cox multivariable regression analysis was similar to that seen using the same 
analysis in D9901. The overall AE profile observed in Phase 3 studies (D9901 and D9902A) was similar 
to that observed in the Phase 2 studies, although infusion-related fevers and rigors appeared to be more 
common. The following infusion-related AEs occurred more frequently (P ≤ 0.05) in subjects treated with 
sipuleucel-T than those treated with placebo: chills, pyrexia, headache, asthenia, dyspnea, vomiting, and 
tremor. However, these events generally resolved within 1 to 2 days. 
Sipuleucel-T was subsequently evaluated in a randomized placebo-controlled Phase III trial in patients 
with asymptomatic and minimally symptomatic CRPC (IMPACT Trial) and demonstrated statistically 
significant survival advantage of 4.1 months.  Main eligibility criteria included the presence of metastatic 
CRPC, lack of visceral metastases, and lack of significant pain defined by the use of narcotic analgesics. 
The compound was well-tolerated with brief febrile infusion reactions constituting the main side effect. 
Sipuleucel-T did not induce significant PSA or objective responses but there was evidence of immune 
activation targeting prostate antigens. Specifically titers against PA2024 that exceeded 400 at any time 
after baseline were observed in 66.2 % of patients in the Sipuleucel-T and 2.9% in the placebo group. 
Patients with positive antibody titer against PA2024 had improved survival as compared to patients who 
did not generate such response. Antibodies against PAP were observed in 28.5% of patients treated with 
Sipuleucel-T and 1.4 % in patients in a placebo group. At week 6, T-cell proliferation responses 
(stimulation index>5) to PA2024 were seen in 73% of patients in the Sipuleucel-T group and 12.1% in 
the placebo arm. Responses to PAP were observed in 27.3 % in the Sipuleucel-T group and 8.0% in the 
placebo group. Based on the results of this trial Sipuleucel-T was approved by Food and Drug 
Administration for the treatment of patients with metastatic CRPC. 
2.5 
STAT3-Activity 
STAT3 activity in tumor-associate myeloid cells is known to orchestrate tumor angiogenesis (Kujawski 
JCI 2008). Our recent studies assessed whether STAT3 activity in the tumor microenvironment can limit 
the antitumor effect of the local tumor irradiation. We observed that tumor irradiation can enhance, rather 
than interrupt, STAT3-mediated crosstalk between cancer and myeloid immune cells. The radiation-
induced cell death led to release of endogenous TLR agonists for TLR9, including mitochondrial DNA 
(mtDNA), which in turn sustain high STAT3 activity in myeloid cells. We demonstrated that STAT3 
activation post-irradiation is mostly TLR9-mediated and depends on rapid expression of cytokines 
inducing Jak/STAT3 signaling, such as IL-6. Cancer cell repopulation was significantly delayed in TLR9-
deficient mice compared to wild-type animals, which correlated with reduced STAT3 activation in tumor-
infiltrating myeloid cells and impaired reconstitution of tumor blood vessels. In addition, lack of TLR9 

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expression correlated also with decreased numbers of lung metastases suggesting the role of TLR9 
signaling in tumor dissemination. We further verified the negative role of STAT3 for the efficacy of 
radiation therapy using conditional STAT3 gene deletion in myeloid cells as well as STAT3 silencing 
using CpG-STAT3siRNA. Both approaches confirmed that elimination of tumorigenic TLR9/STAT3 
signaling axis in tumor-associated myeloid cells prevents cancer recurrence following the local tumor 
irradiation. Targeting STAT3 using immune cell-specific CpG-siRNA strategy is likely to provide a 
future therapeutic approach to support cancer radiotherapy. In this study we will perform the exploratory 
analysis of the effect of radiation therapy on the levels of pSTAT3 in Peripheral Blood Mononuclear Cells 
(PBMCs) and serum levels of proinflammatory cytokines and TLR9 ligands.   
3.0 
Patient Eligibility 
Prior to the initiation of screening procedures, the purpose and procedures of the study will be explained 
to each subject, and each subject will then sign an Institutional Review Board (IRB) approved consent 
form. The subject will subsequently undergo screening assessments to determine if he meets the 
eligibility criteria for the study. 
3.1 
Inclusion Criteria  
3.1.1. Histologically documented adenocarcinoma of the prostate.  
3.1.2. Men at least 18 years of age and life expectancy of ≥ 6 months, ECOG performance status ≤ 2. 
3.1.3  Metastatic disease as evidenced by soft tissue and/or bony metastases on baseline bone scan 
and/or computed tomography (CT) scan or MRI of the abdomen and pelvis.  
3.1.4  Castration resistant prostatic adenocarcinoma. Subjects must have current or historical evidence 
of disease progression despite castrated level of testosterone (< 50 ng/dL) achieved by 
orchiectomy or LHRH agonist or antagonist therapy.  Disease progression has to be demonstrated 
by PSA progression OR progression of measurable disease OR progression of non-measurable 
disease as defined below:  
3.1.4.1  PSA:  Two consecutive rising PSA values, at least 7 days apart. 
3.1.4.2  Measurable disease:  ≥ 20% increase in the sum of the longest diameters of all 
measurable lesions or the development of any new lesions. The change will be measured 
against the best response to castration therapy or against the pre-castration measurements 
if there was no response.  
3.1.4.3  Non-measurable disease   
3.1.4.3.1  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 pre-castration studies 
if there was no response.  
3.1.4.3.2  Bone disease:  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 pre-castration studies if there was no response. Increased uptake of 
pre-existing lesions on bone scan does not constitute progression.  
3.1.5  Following criteria are suggested guidelines and exceptions will be allowed at the discretion of 
Principal Investigator. Transfusion of blood products are not allowed to normalize blood 
parameters. Please see the Study Calendar (10.0) for details of the timing of required 
tests.Adequate hematologic, renal, and liver function as evidenced by the following 
White blood cell (WBC) ≥ 2,500 cells/μL  

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Absolute neutrophil count (ANC) ≥ 1,000 cells/μL  
Platelet Count ≥ 75,000 cells/μL   
Hemoglobin (HgB) ≥ 9.0 g/dL  
Creatinine ≤ 2.5 mg/dL  
Total Bilirubin ≤ 2 x institutional upper limit of normal (ULN)  
Aspartate aminotransaminase (AST, SGOT) ≤ 2.5 x institutional ULN  
Alanine aminotransaminase (ALT, SGPT) ≤ 2.5 x institutional ULN  
3.1.6. Prior chemotherapy with 0-2 regimens is allowed. 
3.1.7. Prior radiation therapy to prostate or prostate bed is allowed provided it occurred > 3 months 
before enrollment to the study. 
3.2 
Exclusion Criteria 
3.2.1  The presence of liver, or known brain metastases, malignant pleural effusions, or malignant 
ascites.  
3.2.2  Moderate or severe symptomatic metastatic disease defined as a requirement for treatment with 
opioid analgesics for cancer-related pain within 21 days prior to registration.  
3.2.3  Eastern Cooperative Oncology Group (ECOG) performance status > 2 (see Appendix 1).  
3.2.4 
Treatment with chemotherapy within 3 months of registration. 
3.2.5  Treatment with any of the following medications or interventions within 28 days of registration:  
 
Systemic corticosteroids. Use of inhaled, intranasal, and topical steroids is acceptable.  
 
Any other systemic therapy for prostate cancer (except for medical castration).  
3.2.6  History of external beam radiation therapy to metastatic sites within 1 year of enrollment to the 
study. 
3.2.7  Participation in any previous study involving sipuleucel-T.  
3.2.8  Pathologic long-bone fractures, imminent pathologic long-bone fracture (cortical erosion on 
radiography > 50%) or spinal cord compression.  
3.2.9  Concurrent other malignancy with the exception of: a) cutaneous squamous cell and basal 
carcinomas, b) adequately treated stage 1-2 malignancy , c) adequately treated stage 3-4 
malignancy that has been  in remission for ≥ 2 years at the time of registration.  
3.2.10  A requirement for systemic immunosuppressive therapy for any reason.  
3.2.11  Any infection requiring parenteral antibiotic therapy or causing fever (temperature > 100.5°F or 
38.1°C) within 1 week prior to registration.  
3.2.12  Any medical intervention or other condition which, in the opinion of the Principal Investigator 
could compromise adherence with study requirements or otherwise compromise the study’s 
objectives. 
3.3 Inclusion of Women and Minorities 
Prostate cancer is exclusively disease of men. The study is open anyone regardless of race and ethnicity.  
Efforts will be made to extend the accrual to a representative population, but in a trial which will accrue 
approximately 50 subjects, a balance must be struck between subject safety considerations and limitations 
on the number of individuals exposed to potentially toxic or ineffective treatments on the one hand and 
the need to explore racial, and ethnic aspects of clinical research on the other.  If differences in outcome 
that correlate to racial or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 

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4.0 
Screening and Registration Procedures 
4.1 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial will be done 
only after obtaining written informed consent.  Studies or procedures that were for clinical indications 
(not exclusively to determine study eligibility) may be used for baseline values, even if the studies were 
done before informed consent was obtained.  Reference is made to Section 10.0 – Study Calendar. 
4.2 
Informed Consent  
The investigational nature and objectives of the trial, the procedures and treatments involved and their 
attendant risks and discomforts, and potential alternative therapies will be carefully explained to the 
subject and a signed informed consent will be obtained.  Documentation of informed consent for 
screening will be maintained in the subject’s research chart and medical record.   
4.3 
Registration Requirements/Process 
 
 
 
 
Registration Process              To register a patient, the treating physician should contact the 
protocol nurse or the responsible Clinical Research Associate (CRA) in Clinical Trial Office (CTO) to 
complete the eligibility/registration form. The protocol nurse or CRA will contact the Data Coordinating 
Center at the City of Hope (626-256-4673, ext. 64267 or e-mail dcc@coh.org), EMAIL a copy of the 
completed eligibility checklist, required pre-study tests (per protocol – and may include laboratory, CT 
and pathology reports), signed Informed Consent, signed Patients' Bill of Rights and HIPAA 
authorization form to dcc@coh.org. 
 
The patient registration process will be handled by the Department of  
Clinical Research 
Information Support (CRIS) Data Coordinating Center (DCC) at City of Hope.   Documentation of 
current IRB approval must be on file with the DCC prior to registration of  
patients on this study 
for participating institution.  
 
The steps below are to be taken when registering a patient: 
 
The research staff must assure they have the most current and updated version of the protocol 
and informed consent prior to enrolling a patient.  If a question arises, please contact the Data 
Coordinating Center at 626-256-4673 extension 64267 or via email at  dcc@coh.org.   
 
The study staff must assure that all prestudy laboratory tests, scans and x-rays have been 
completed prior to registration according to the study calendar 
 
The  study staff must assure that the patient has signed an approved informed consent prior to 
registration/randomization, including the Experimental Subject Bill of Rights and appropriate 
HIPAA authorization. 
 
The study staff must confirm that the patient meets all inclusion and exclusion eligibility 
criteria for the protocol.  The eligibility checklist (provided by the COH DCC) must be 
completed in its entirety. 
 
Patients must be registered prior to initiation of treatment but no more than 2 weeks  prior to 
planned start of treatment.  A patient failing to meet all protocol requirements may not be 
registered.   
 
Once a patient is eligible, all the pre-study requirements have been fulfilled, and the informed 
consent obtained, the research nurse or the data manager (study coordinator) will inform the 

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COH Data Coordinating Center at (626) 256-4673, extension 64267; email dcc@coh.org and 
FAX (fax number 626 256-8794) a copy of the patient’s signed informed consent, , 
completed eligibility checklist and corresponding source documentation confirming 
eligibility (including pathology reports, lab reports, x-ray reports, etc.). 
 
The City of Hope Data Coordinating Center will: 
 
Review all materials/source documentation to ensure the patient is eligible.   
 
Ensure the consent form is valid and is signed correctly by all parties.  If additional 
information is needed or should there be any questions, the Data Coordinating Center will 
immediately contact the participating institution and registration will not occur until all issues 
are resolved.   
 
If there are questions regarding exceptions to the eligibility criteria, please contact he study 
Principal Investigator, as well as the COH DCC.  Documentation of IRB approval of 
exception will need to be submitted as well as the COH DCC. 
 
The patient will be registered and randomized centrally at City of Hope. 
 
Confirmation of Registration/Randomization will be emailed/faxed to the  study staff noting 
the patient’s study number as well as assigning the randomization arm within 24 hours post 
receipt of a complete eligibility packet. 
 
The COH DCC will call the research nurse or data manager (study coordinator) and verbally 
confirm the registration (if needed). 
 
If the patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be cancelled.  The COH DCC should be notified of 
cancellations as soon as possible. 
 
The COH DCC will log into the Electronic Data Capture (EDC) system and enter the 
patient’s study number. 
 
 
4.4 
Randomization 
Randomization will be performed by the Department of Biostatistics 
5.0 
Treatment Program 
5.1 
Treatment Overview 
Treatment will be performed on an outpatient basis. Patients randomized to Arm A will we treated with 
standard Sipuleucel - T.  Leukapheresis will be performed at the contracted, designated Dendreon facility 
and Sipuleucel-T infusion will be performed at the City of Hope infusion clinic approximately 72 hours 
after leukapheresis. This process will be repeated every 2 weeks times three. Patients randomized to Arm 
B will undergo 2 weeks of radiation therapy to single metastatic site followed by 7 days of rest followed 
by treatment with Sipuleucel- T on an identical schedule as Arm A  (see study schema) Delays in 
leukapheresis of up to 2 weeks for each cycle are acceptable regardless of cause.  

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For a tabular view of the treatment, monitoring, and follow-up schedule, see study calendar in Section 10. 
5.2     Planned Duration of Therapy 
5.2.1  Therapeutic portion of the protocol will last 6 weeks for Arm A patients, and 8 weeks for Arm B 
 patients.  
 
5.2.2  Criteria for Removal from Treatment 
Treatment may continue until one of the following criteria applies: 
 
Completion of 3 courses of Sipuleucel-T 
 
Symptomatic disease progression 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Patient decides to withdraw from the study,  
 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 
Treatment delays of > 2 weeks due to adverse events. 
 
Patient’s preference  
5.3 
  Subject Follow-Up 
Following completion of therapy patients will be followed clinically and will undergo periodic laboratory 
and radiographic tests until week 60 or until disease progression requiring additional therapy (see Study 
calendar 10.0) 
5.4 
  Supportive Care, Other Concomitant Therapy, Prohibited Medications 
Approximately 30 minutes prior to infusion of Sipuleucel-T subjects must be premedicated with 
acetaminophen (650 mg) and an antihistamine such as diphenhydramine (Benadryl®, 50 mg). Common 
treatment-related AEs such as pyrexia and/or rigors may warrant reduction of the infusion rate. If such 
adverse reactions occur, subsequent infusions should be administered over the shortest period, not less 
than 60 minutes, that is well tolerated. Subjects must be observed for at least 30 minutes after the 
infusion. No corticosteroids are to be used for the management of common infusion related AEs. Subjects 
should receive full supportive care, including transfusions of blood and blood products, antibiotics, 
antiemetics, etc., when appropriate.  
5.5 
Additional Studies 
Please see Section 9.0 for the description of correlative studies 
6.0 
Dose Delays/Modifications for Adverse Events 
This study will use Common Terminology Criteria for Adverse Events v 4, which can be found at the 
CTEP, website: http://ctep.cancer.gov/reporting/ctc.html  
Management of Anticipated Toxicities:  Missed doses of radiation therapy and Sipuleucel -T will not be 
made up. Treatment should be stopped for any protocol treatment related Grade 3 toxicity or greater that 
cannot be controlled with good medical practice intervention. Treatment may be resumed upon resolution 
of that toxicity to Grade 2. A patient who experiences a Grade 3 or higher toxicity again will be removed  
from the study. There are no provisions for dose reductions of radiation therapy or Sipuleucel-T. The 
maximum delay in treatment will be 14 days. Patients who received at least one infusion of Sipuleucel-T 

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will not be replaced. Patients who received at least 50 % of anticipated dose of radiation therapy will not 
be replaced. Patients who received <50 % of anticipated dose of radiation therapy and / or who did not 
receive any infusions of Sipuleucel-T will be replaced.   
7.0 
Data and Safety Monitoring, Unanticipated Problems and Adverse 
Event Reporting 
7.1 
Definition of Risk Level 
This is a Risk Level 3 study, as defined in the “City of Hope Data and Safety Monitoring Plan”, 
http://www.coh.org/dsmc/Pages/forms-and-procedures.aspx because it is a Phase II clinical trial where 
the risks are at least balanced by the potential benefit to subjects and the importance of the knowledge that 
may result. 
7.2 
Monitoring and Personnel Responsible for Monitoring 
The Protocol Management Team (PMT) consisting of the PI, Collaborating Investigator, CRA, protocol 
nurse, and statistician are responsible for monitoring the data and safety of this study, including 
implementation of any stopping rules for safety and efficacy. 
 
 
Table 1:  City of Hope PMT Reporting Timelines for the DSMC 
 
Risk Level 
Phase 
Standard Reporting 
Requirement 
RL 1, RL2, and Compassionate 
Use Studies 
No reports required 
3 
I 
Every 3 months from 
activation date, as 
indicated in MIDAS 
3 
Pilot, 
Feasibility, 
II-IV 
Every 6 months from 
activation date, as 
indicated in MIDAS 
4 
Pilot, 
Feasibility, 
I-IV 
Every 3 months from 
activation date, as 
indicated in MIDAS 
 
Data and safety will be reported to the COH DSMC using the PMT report and submitted according to the 
timelines in Table 1 above.  Protocol specific data collection will include the following items: summary 
of accrual, adverse events and treatment-related mortality. 
 
 
7.3 
Definitions 

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Adverse event (AE) - An adverse event is any untoward medical experience or change of an existing 
condition that occurs during or after treatment, whether or not it is considered to be related to the protocol 
intervention.  
 
Unexpected Adverse Event [21 CFR 312.32 (a) – An adverse event is unexpected if it is not listed in the 
investigator’s brochure and/or package insert; is not listed at the specificity or severity that has been 
observed; is not consistent with the risk information described in the protocol and/or consent; is not an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
 
Expected Adverse Event - Any event that does not meet the criteria for an unexpected event OR is an 
expected natural progression of any underlying disease, disorder, condition, or predisposed risk factor of 
the research participant experiencing the adverse event. 
Serious Adverse Event (SAE) [21 CFR 312.32] is defined as any expected or unexpected adverse event 
that results in any of the following outcomes: 
 Death 
 Is life-threatening experience (places the subject at immediate risk of death from 
the event as it occurred) 
 Unplanned hospitalization (equal to or greater than 24 hours) or prolongation of 
existing hospitalization 
 A persistent or significant disability/incapacity 
 A congenital anomaly/birth defect 
 Secondary Malignancy 
 Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention 
to prevent one of the outcomes listed above (examples of such events include 
allergic bronchospasm requiring intensive treatment in the emergency room or 
at home, blood dyscrasisas of convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Unanticipated problem (UP) – Any incident, experience, or outcome that meets all three of the 
following criteria: 
1. Unexpected (in term nature, severity, or frequency) given the following: a) the 
research procedures described in the protocol-related documents such as the IRB 
approved research protocol, informed consent document or Investigator Brochure 
(IB); and b) the characteristics of the subject population being studied; AND 
2. Related or possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or outcomes may have 
been caused by the drugs, devices or procedures involved in the research); AND 
3. Suggests that the research places subjects or others at greater risk of harm 
(including physical, psychological, economic, or social harm) than previously 
known or recognized. 
 
7.4 
Reporting of Unanticipated Problems and Adverse Events 

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Unanticipated Problems: Most unanticipated problems must be reported to the COH DSMC 
and IRB within 5 calendar days according to definitions and guidelines at 
http://www.coh.org/hrpp/Pages/hrpp-policies.aspx.  Any unanticipated problem that occurs 
during the study conduct will be reported to the DSMC and IRB by submitting electronically in 
iRIS (http://iris.coh.org). 
 
Serious Adverse Events - All SAEs occurring during this study, whether observed by the 
physician, nurse, or reported by the patient, will be reported according to definitions and 
guidelines at http://www.coh.org/hrpp/Pages/hrpp-policies.aspx and Table 2 below.  Those SAEs that 
require expedited reporting will be submitted electronically in iRIS (http://iris.coh.org/). 
 
Adverse Events - Adverse events will be monitored by the PMT.  Adverse events that do not 
meet the criteria of serious OR are not unanticipated problems will be reported only in the 
protocol continuation reports and PMT report (see Table 2 below). 

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Table 2:  City of Hope Adverse Event and Unanticipated Problem Reporting Timelines for 
the DSMC and IRB 
 
 
Required Reporting Timelines to DSMC for AE/SAEs 
Investigator Initiated Studies  
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
5 calendar days 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
5 calendar days 
No reporting required 
Unlikely, Unrelated 
No reporting required 
No reporting required 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
5 calendar days 
10 calendar days 
  
Grades 1 and 2 AND resulting in "hospitalization" 
Possibly, Probably, 
Definitely 
5 calendar days 
10 calendar days 
Unlikely, Unrelated 
10 calendar days 
10 calendar days 

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Externally Sponsored Studies 
Required Reporting Timeframe to DSMC 
Attribution 
UNEXPECTED1 
EXPECTED 
  
Death while on active treatment or within 30 days of last 
day of treatment 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Death after 30 days of last active treatment/therapy 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 3 and 4 AND meeting the definition of "serious" 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
Unlikely, Unrelated 
  
Grades 1 and 2 
Possibly, Probably, 
Definitely 
No DSMC reporting required - IRB reporting may be 
necessary 
 
An event determined by the IRB of record to be an Unanticipated Problem (UP) will be 
communicated to the Investigator and COH DSMC through the COH IRB Operations Director. 
The DSMC will review the case and make a determination as to whether the study will be 
suspended, terminated, amended, or allowed to continue without amendment. 

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Required Reporting Timeframe to IRB of Record 
Attribution 
UNEXPECTED 
EXPECTED 
 
Death  
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
Grades 3 and 4 AND meeting the definition of a UP 
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual  
Annual 
 
Grade 1 and 2 AND meeting the definition of a UP   
Possibly, Probably, 
Definitely 
5 calendar days 
Annual 
Unlikely, Unrelated 
Annual 
Annual 
 
 
 
 
7.5 Sponsor-Investigator Adverse Event Reporting 
All SAEs that occur from t he signing of the study specific consent through the duration of the post-
therapy adverse event collection period must be reported to Dendreon within 24 hours of being made 
aware of the SAE. Notification can be made via phone or telefacsimile using an SAE Report Form to be 
provided by Dendreon. 
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 to Dendreon on the SAE Report Form.  
 
7.6 Safety Reporting Requirements and Timelines – Participating Institutions Only 

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The guideline is to provide a procedure for accurate and timely reporting of serious adverse events 
(SAEs) from the participating institution to the FDA, to the Principal Investigator (PI) at City of Hope 
(COH) as well as to Dendreon.  The participating institution, participating institution PI and/or study 
coordinators are responsible for reporting all serious adverse events immediately (within 24 hours after 
learning of the event) to their local IRB, the PI at City of Hope, the Data Coordinating Center at COH and 
to Dendreon. 
The participating investigator must report each serious adverse event, regardless of attribution, to the 
Principal Investigator and to Dendreon within 24 hours of learning of the occurrence. In the event that the 
participating investigator does not become aware of the serious adverse event immediately (e.g., 
participant sought treatment elsewhere), the participating investigator is to report the event within 24 
hours after learning of it and document the time of his or her first awareness of the adverse event. 
After review of Section 7.3 and Section 7.4 above, please report to City of Hope all serious adverse 
events meeting criteria by telephone (to Dr. Przemyslaw Twardowski and the COH DCC) AND 
immediately send via fax a copy of the following forms as noted below. 
 
Participating Institution SAE Notification Contact Numbers: 
 
 
Dr. Przemyslaw Twardowski 
Phone:   
626-256-4673, ext. 68218 
 
 
 
 
 
 
 
 
Fax:  
 
626-301-8233  
 
 
Data Coordinating Center 
Phone:   
626-256-4673 x63968  
 
 
 
 
 
 
Fax:    
626-301-8422 
Dendreon SAE Form (obtain from COH DCC) 
 Fax Dendreon SAE Form as specified by Dendreon within 24 hours (refer to Section 7.5) to 
(206) 829-1647 
 Fax Dendreon SAE Form to City of Hope Data Coordinating Center within 24 hours to (626) 
301-8422, along with: 
1. Notification of Unanctipated Problem/Adverse Event (Appendix “A”).  This is a 
coversheet for all reports submitted as required. 
2. Participating institutions internal serious adverse event form.  This is the form/report 
that the participating institutions submit to their IRB of record. 
3. Adverse Event/Unanticipated Problem Reporting Form (Appendix “B”).   
The participating institution will notify their local IRB as per their local established guidelines and 
include a copy of the completed Dendreon SAE Form.   
The Data Coordinating Center at City of Hope will send a copy of the participating institutions serious 
adverse event (reported via Dendreon SAE Form and institutional SAE report) to the following internal 
departments: 

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City of Hope IRB and DSMC (as applicable) 
City of Hope Office of IND Development and Regulatory Affairs (as applicable) 
Any supporting documentation to the reports (i.e., laboratory, pathology, progress notes,  discharge 
summary, autopsy, etc.) explaining the adverse event should also be submitted to the Data Coordinating 
Center at City of Hope.  The Data Coordinating  Center will then submit to our COH IRB/DSMC. 
 
 
8.0 
Agent Information and Risks 
8.1 Sipuleucel –T (Provenge®) 
8.1.1 
Sipuleucel-T overview 
Sipuleucel- T (Provenge ®) is commercially available autologous therapeutic cancer vaccine made of 
recombinant fusion protein consisting of human PAP and GM-CSF. GM-CSF acts as a targeting molecule 
that directs the PAP antigen to APCs and promotes antigen uptake and processing. PAP is a tissue-
specific target antigen rather than a tumor-specific target antigen. Studies with specific monoclonal 
antibodies and RNA probes indicate that the antigen is strictly prostate-specific. Immunohistochemical 
studies reveal that the antigen is expressed by normal prostate tissue, and > 90% of all prostatic 
adenocarcinomas, but is not expressed by other tissues (Goldstein 2002). PAP is secreted by the prostate 
tumor cells in vivo, and an elevated serum level is found in most subjects with advanced prostate cancer 
(Kuriyama 1982). The cDNA for PAP has been isolated. Analysis of sequence homology with other 
known proteins reveals a low risk of cross-reactivity of immune responses. GM-CSF is a multilineage 
factor that may also activate mature granulocytes and macrophages, and may activate quiescent APCs. 
Sipuleucel-T is an autologous cell product consisting of APCs loaded with prostate antigen PA2024. 
Preparation of sipuleucel-T entails isolating quiescent APCs from a subject’s peripheral blood 
leukapheresis product by buoyant density techniques and then culturing them for approximately 2 days in 
the presence of PA2024. The culture medium does not contain serum or exogenous cytokines. During the 
culture process, APCs specifically and selectively pick up antigen (PA2024) and differentiate into antigen 
loaded APCs capable of presenting antigen to T cells. These APCs thus represent the cells responsible for 
the biological activity of sipuleucel-T. Other cell populations in sipuleucel-T co-purify with APCs during 
buoyant density centrifugation, but do not incorporate or present antigen, and are therefore referred to as 
“non-APCs.” After the culture period, the cells are washed and suspended in Lactated Ringer’s Injection, 
USP. The final preparation of PA2024-loaded APCs is designated sipuleucel-T. Sipuleucel-T is placed in 
a refrigerated package and transported to the clinical site for infusion. 
8.1.2 
Leukapheresis and Collection of Quiescent APCs  
Leukapheresis and collection of blood cells to generate sipuleucel-T is performed at the facility contracted 
by the manufacturer Dendreon and is analogous to that for autologous blood transfusions. Briefly, 
subjects undergo a standard 1.5 to 2.0 blood volume leukapheresis to harvest peripheral blood 
mononuclear cells (PBMCs; primarily lymphocytes and monocytes). Prior mobilization with a colony-
stimulating factor is not performed. Immediately after collection, the leukapheresis product is transported 
to a regional manufacturing facility 
8.1.3 
Quality Testing  
Quality control (QC) testing is performed at several time points during the manufacturing process and on 
samples of the final product. If the final product passes all required release tests, an approval to infuse the 
product (Cell Product Disposition Form) is faxed to the infusion center. If a cell product does not meet 
Dendreon quality specifications, Dendreon will contact the infusion center by telephone and by fax. 

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Dendreon will provide instructions for product return or destruction of cell products that are not approved 
or not infused.  
8.1.4 
Storage and Time Limitations  
The infusion of Sipuleucel-T must begin prior to the expiration time indicated on the product label. 
Expired cell products must not be infused.  
8.1.5 
Administration  
The administration of Sipuleucel-T is performed in the City of Hope infusion clinic. Subjects are 
premedicated with acetaminophen and an antihistamine such as diphenhydramine prior to the infusion. 
After the site receives the Cell Product Disposition Form indicating the cell product is approved, the 
infusion is administered over approximately 60 minutes through an intravenous (IV) line suitable for 
blood transfusion (without a cell filter). Subjects are observed for at least 30 minutes following the 
infusion. 
8.1.6 
Toxicity 
The safety evaluation of Sipuleucel-T is based on 601 prostate cancer patients in the Sipuleucel-T group 
who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The 
control was non-activated autologous peripheral blood mononuclear cells.  
Almost all (98.3%) patients in the Sipuleucel-T group and 96.0% in the control group reported an adverse 
event. The most common adverse events, reported in patients in the Sipuleucel-T group at a rate ≥ 15%, 
were chills, fatigue, fever, back pain, nausea, joint ache, and headache. In 67.4% of patients in the 
Sipuleucel-T group, these adverse events were mild or moderate in severity. Severe (Grade 3) and life-
threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the Sipuleucel-T 
group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events 
were reported in 3.3% of patients in the Sipuleucel-T group compared with 3.6% of patients in the control 
group. The most common (≥ 2%) Grade 3-5 adverse events reported in the Sipuleucel-T group were back 
pain and chills.  
Serious adverse events were reported in 24.0% of patients in the Sipuleucel-T group and 25.1% of 
patients in the control group. Serious adverse events in the Sipuleucel-T group included acute infusion 
reactions, cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia 
gravis, myositis, and tumor flare.  
Sipuleucel-T was discontinued in 1.5% of patients in Study 1 due to adverse events. Some patients who 
required central venous catheters for treatment with PROVENGE developed infections, including sepsis. 
A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in 
patients with central venous catheters is recommended.  
Each dose of Sipuleucel-T requires a standard leukapheresis procedure approximately 3 days prior to the 
infusion. Adverse events that were reported ≤ 1 day following a leukapheresis procedure in ≥ 5% of 
patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia 
(11.4%), and fatigue (8.3%).  
Table 1 provides the frequency and severity of adverse events reported in ≥ 5% of patients in the 
Sipuleucel-T group of randomized, controlled trials of men with prostate cancer.  
 
 
 
Table 1 Incidence of Adverse Events Occurring in ≥ 5% of Patients Randomized to Sipuleucel-T  

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                                                  Sipuleucel-T  
                                                    (N = 601)  
                               Control*  
                              (N = 303)  
     All Grades 
          n (%) 
Grade 3-5 
   n (%) 
 All Grades 
   n (%) 
Grade 3-5 
   n (%) 
Any Adverse Event  
591 (98.3)  
186 (30.9)  
    291 (96.0)  
  97 (32.0)  
Chills  
319 (53.1)  
13 (2.2)  
33 (10.9)  
0 (0.0)  
Fatigue  
247 (41.1)  
6 (1.0)  
105 (34.7)  
4 (1.3)  
Fever  
188 (31.3)  
6 (1.0)  
29 (9.6)  
3 (1.0)  
Back pain  
178 (29.6)  
18 (3.0)  
87 (28.7)  
9 (3.0)  
Nausea  
129 (21.5)  
3 (0.5)  
45 (14.9)  
0 (0.0)  
Joint ache  
118 (19.6)  
11 (1.8)  
62 (20.5)  
5 (1.7)  
Headache  
109 (18.1)  
4 (0.7)  
20 (6.6)  
0 (0.0)  
Citrate toxicity  
89 (14.8)  
0 (0.0)  
43 (14.2)  
0 (0.0)  
Paresthesia  
85 (14.1)  
1 (0.2)  
43 (14.2)  
0 (0.0)  
Vomiting  
80 (13.3)  
2 (0.3)  
23 (7.6)  
0 (0.0)  
Anemia  
75 (12.5)  
11 (1.8)  
34 (11.2)  
7 (2.3)  
Constipation  
74 (12.3)  
1 (0.2)  
40 (13.2)  
3 (1.0)  
Pain  
74 (12.3)  
7 (1.2)  
20 (6.6)  
3 (1.0)  
Paresthesia oral  
74 (12.3)  
0 (0.0)  
43 (14.2)  
0 (0.0)  
Pain in extremity  
73 (12.1)  
5 (0.8)  
40 (13.2)  
1 (0.3)  
Dizziness  
71 (11.8)  
2 (0.3)  
34 (11.2)  
0 (0.0)  
Muscle ache  
71 (11.8)  
3 (0.5)  
17 (5.6)  
0 (0.0)  
Asthenia  
65 (10.8)  
6 (1.0)  
20 (6.6)  
2 (0.7)  
Diarrhea  
60 (10.0)  
1 (0.2)  
34 (11.2)  
3 (1.0)  
Influenza-like illness  
58 (9.7)  
0 (0.0)  
11 (3.6)  
0 (0.0)  
Musculoskeletal pain  
54 (9.0)  
3 (0.5)  
31 (10.2)  
3 (1.0)  
Dyspnea  
52 (8.7)  
11 (1.8)  
14 (4.6)  
3 (1.0)  
Edema peripheral  
50 (8.3)  
1 (0.2)  
31 (10.2)  
1 (0.3)  
Hot flush  
49 (8.2)  
2 (0.3)  
29 (9.6)  
1 (0.3)  
Hematuria  
46 (7.7)  
6 (1.0)  
18 (5.9)  
3 (1.0)  
Muscle spasms  
46 (7.7)  
2 (0.3)  
17 (5.6)  
0 (0.0)  

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8.2 Radiation therapy 
8.2.1 
Treatment Plan: 
In patients assigned to Arm B one metastatic site will be selected for radiation based primarily on the 
safety of radiation in that location. Radiation to bone metastases in L3-S5, pelvis and femurs will be 
excluded provided that patients have other areas of metastases. Patients who have metastases only in the 
above locations (L3-S5, pelvis and femurs) will be allowed provided that they have normal WBC and 
they will not receive radiation to more than 20% of the bone marrow. The gross tumor volume (GTV) 
will be defined as the radiological dimensions of the lesion as identified by CT and/or MRI. The planning 
tumor volume (PTV) is defined as the GTV plus 1 cm. For lesions that move with respiration (Rib and 
lung parenchymal lesions for example) CT simulation will be performed at inspiration and expiration to 
define lesion position during the respiratory cycle. The GTV will be defined based on lesion position 
during the respiratory cycle. Radiation treatment fields will arranged to minimize dose to the marrow and 
whole body. Conventional AP/PA technique will be used. Field will be limited to 10 by 10 cm.Patients 
will be treated with 300 cGy/day to 3000 cGy; Approximately 7 days after completion of radiation 
therapy, patients will begin therapy with Sipuleucel-T autologous vaccine. 
8.2.2 
Toxicity: 
The risks of radiation therapy depend on the part of the body being treated. These side effects are 
generally mild and expected to resolve 1-2 weeks after radiation is completed:  
-fatigue,  
-anorexia 
-gastroesophageal reflux 
-diarrhea 
-nausea 
-dysuria 
-urinary frequency 
-pain flare 
-skin rash,  
-neutropenia,  
-thrombocytopenia,  
-anemia 
Long term effects of radiation also depend on the specific location being treated and include:  
- pneumonitis  
- cystitis  
- hematuria 
- secondary malignancy 
- chronic diarrhea 
- bowel perforation 

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9.0 
Correlative/Special Studies 
Blood collection must be scheduled Monday to Thursday to allow for overnight shipping to be 
received by Friday.  Specimens will be labeled with the subjects research participant number. 
9.1 Blood Collection  
ALL SUBJECTS 
 
100ml total whole blood (90mL collected in sodium heparin vacutainer tubes and 10mL 
collected in no-anticoagulant vacutaine tubes- from Becton Dickinson) collected at each 
time point specified in the study calendar (pre-study, and during weeks 4, 12, 24, 36, 48, 
and 60) will be sent to: 
Send the sample(s) priority overnight via FedEx Next Day to: 
Dendreon Corporation 
Attention: Clinical Immunology 
1208 Eastlake Avenue E, Seattle, WA   98102 
Phone: 206-829-1639 
 
ONLY SUBJECTS RECEIVING RADIATION AT CITY OF HOPE  
 
10ml of the whole blood in the BD Vacutainer CPT tube (with Heparin) will collected at 
baseline (week 0) and at week 4 after radiation to be sent to the laboratory of Dr. Marcin 
Kortylewski within 4 hours of collection to avoid degradation of the phosphomoieties 
(i.e., pSTAT3) assessed in this protocol.  CPT tubes will be centrifuged at 1800g 
(approximately 2800 rpm on a Sorvall RT6000 centrifuge) for 20 min. at room 
temperature.  After centrifugation, plasma in the CPT tubes will be gently pipetted 
against the gel plug to dislodge cells stuck to the top of the gel.  The cell suspension will 
be transferred to a 50 mL conical polypropylene tube.  cRPMI will be added to a total of 
40 mL.  A 10 mL aliquot of cell suspension for counting will be removed.  The 50 mL 
tubes will then be centrifuged at 250g for seven minutes at room temperature.  When 
centrifugation is complete, the supernatant will be aspirated.  PMBCs will be either 
cryopreserved or used fresh. 
 
9.2 Immune Assays 
9.2.1 
Cellular immune response assays – Elispot 
Antigen-specific memory T cell responses are assayed by means of a IFN ELISPOT 
assay.  PVDF ELISPOT (enzyme-linked immunoSPOT) plates (Millipore) are coated 
with an anti-IFN monoclonal antibody (mAb) (clone D1K, MabTech) overnight, after 
which time plates are blocked and washed with phosphate-buffered saline/Tween 
(PBST).  Cryopreserved PBMC, thawed and rested overnight in medium are then plated 
in triplicate at 3x105 PBMC/well in a total volume of200L/well with either medium 
alone or with medium containing antigen (PA2024: PAP-GMCSF fusion protein, PAP or 
PHA – Phytohaemagglutinin, an assay control).  Plates are then incubated for 40-48 hrs 
after which time plates are washed then incubated with Strepatavidin conjugated anti-

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IFN mAb (clone B6-1, MabTech).  After incubation plates are further washed with 
PBST and then incubated biotin conjugated with alkaline peroxidase for a further hour.  
Afterwards plates are then washed with PBST and then incubated with a substrate, BCIP 
(5-Bromo-4-chloro-3-indolyl phosphate) to visualize IFN secreting cells.  ELISPOT 
data are presented as the median of triplicates with background (PBMCs incubated with 
media) IFN spots subtracted.  
 
9.2.2 
Cellular immune response assays – Proliferation 
Antigen-specific T cell proliferation to PA2024, PAP and PHA are assayed by means a 
standard tritiated thymidine (3H-thymidine) incorporation assay using round bottom 96 
well tissue culture plates.  Cryopreserved PBMC, thawed and rested overnight in medium 
are then plated in triplicate at 1x105 PBMC/well in a total volume of200L/well with 
either medium alone or with medium containing antigen (PA2024: PAP-GMCSF fusion 
protein, PAP or PHA).  Plates are incubated for 5 days, after which the wells are pulsed 
with 0.5Ci of 3H-thymidine overnight, and the amount of 3H-thymidine incorporation 
into the nucleus Is quantified by means of a -radiation counter with the degree of 
proliferation expressed as a stimulation index (SI), defined as 3H-thymidine incorporation 
in the presence of antigen divided by 3H-thymidine incorporation with media alone. 
 
9.2.3 
Humoral response assays 
Antibody responses against PA2024 and PAP are determined by means of standard 
antibody ELISA (enzyme-linked immunosorbent assay).  96 well flat bottomed plates are 
coated with either PA2024, PAP or Tetanus (an assay control, and measure of 
immunocompetence) overnight, after which time plates are blocked with PBS/casein and 
then washed with PBST.  Serially diluted serum is then added in duplicate to each set of 
plates and incubated at room temperature for 2 hours, after which time plates are washed 
with PBST and then incubated with a mixture of anti-IgM and anti-IgG (Jackson 
Immunoresearch) for an hour.  After this time plates are washed again with PBST and 
then incubated for an hour with horse radish phosphatase conjugated anti IgG+amti-IgM.  
Plates were further washed with PBST and O-phenylenediamine dihydrochloride 
substrate (Sigma) was then added for 15 minutes after which the developing reaction was 
stopped by the addition of 50 µl/well of 2N HCL (Sigma).  Plates were read on a Synergy 
HT spectrophotometer (BioTEK) at 492 nm and the endpoint titer was determined as 
being the last dilution of serum that yielded an O.D. reading equivalent to assay 
background. 
 
9.3 Analysis of PBMCs 
9.3.1 
Analysis of pSTAT3 in PBMCs 
Analysis of pSTAT3 will be conducted through previously reported techniques 
(Kortylewski et al. Nature Med 2007).  PBMCs will be immersed  in a mixture of PBS, 
2% FCS and 0.1% (wt/vol) sodium azide with Fc III/IIR-specific antibody to block 
nonspecific binding and stained the cells with different combinations of fluorochrome-
coupled antibodies to CD4, CD14, CD15, CD25, CD33, FoxP3 or HLA-DR as well as 
7AAD for dead cell exclusion (BD Biosciences). We collected fluorescence data on 

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FACSCalibur (Beckton Dickinson) and analyzed them using FlowJo software (Tree 
Star).  This method has been previously published by Chalmin et al.11 
 
9.3.2 Determination of serum cytokine and chemokine levels 
Serum levels of proinflammatory cytokines and chemokines induced by radiation therapy 
will be ascertained through the Luminex Protein Assay (Invitrogen) as per manufacturer 
instructions. 
 
9.3.3 Detection of circulating mtDNA and other TLR9 ligands 
Levels of TLR9 ligands (e.g. mtDNAs), will be assessed using quantitative qPCR as 
described by Zhang et al.(Blood 2013). Briefly, DNA will be isolated from plasma 
samples using QIAamp DNA Mini kit (Qiagen). The presence of human mitochondrial 
genes, such as cytochrome B, cytochrome C oxidase subunit III and NADH 
dehydrogenase, will be detected by qPCR using specific pairs of primers on CFX96 
thermocycler (Biorad). 
 

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10.0 Study Calendar 
Table 1 Schedule of Events (time scale in weeks)                                                                                                                                                                    
ARM B # 
 
Week f 
 
Pre-Study 
* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 b 
Off Study Visiti 
Radiation therapy #  (Arm B only) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Sipuleucel-T collection 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Sipuleucel-T infusion 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Physical exam 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
Performance Status 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
X 
Xe 
Serum chemistry a 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
Xe 
PSA 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
Xe 
Testosterone 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CXR (if no CT chest done) 
X 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Xc 
Radiologic evaluation(bone 
scan, CT (Chestg) Abd/pelvis g 
X 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Xc 
Tumor measurements 
X 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Xc 
Adverse event evaluation 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Xc 
Xc 
Immune Assays 
X 
 
 
 
X 
 
 
 
 
 
 
 
Xd 
 
Analysis of PBMCsh 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 Patients on ARM A will not undergo radiation therapy, otherwise  they will follow the same schedule as ARM B beginning on week 3  
*     Prestudy tests should be performed within 28 days of registration 
a. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus,   
        potassium, total protein, SGOT[AST], SGPT[ALT], sodium. 
 b.    and every 12 weeks thereafter until off the study    

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 c.    after week 12 radiologic evaluation and tumor measurement will be done at the discretion of treating physician  
 d.    after week 12  Immune Assays will be performed at following time intervals :  week  24, 36, 48, 60 
 e.    Off study visit laboratory tests will b performed at the discretion of treating physician 
 f.     this protocol allows for flexibility of suggested timing of visits and tests : +/- 1 week during first 8 weeks of study and +/- 2 weeks thereafter  
g.    Chest CT is optional. If not done it can be replaced with PA and LAT Chest XRay. MRI of the abdomen and pelvis can be used instead of CT 
h.    City of Hope subjects who receive radiation only 
i.    done approximately 30 days post study completion  

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11.0 Endpoint Evaluation Criteria/Measurement of Effect 
 
11.1 
Measurability of lesions 
a.  Measurable disease:  Lesions that can be accurately measured in at least one dimension by 1) medical 
photograph (skin or oral lesion), palpation, plain x-ray, CT, MRI or other conventional technique with 
longest diameter 2 cm or greater in the axial plane (bone lesions not included), or 2) spiral CT with 
longest diameter 1 cm or greater.  Ultrasound is suitable only for superficial disease (superficial palpable 
nodes, subcutaneous lesions, thyroid nodules). 
Conventional CT and MRI should be performed with cuts of 10 mm or less in slice thickness 
contiguously.  Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. 
b.  Non-measurable disease:  All other lesions including lesions too small to be considered measurable, 
pleural or pericardial effusions, ascites, bone disease, inflammatory breast disease, leptomeningeal 
disease, lymphangitis, pulmonitis, abdominal masses not confirmed and followed by imaging techniques, 
cystic lesions or disease documented by indirect evidence only (e.g., by lab values), previously radiated 
lesions that have not progressed. 
11.2 
Objective status    
Objective Status is to be recorded at baseline, at week 12  (or at the time of disease progression if it 
happened earlier than 12 weeks)  All measurable lesions up to a maximum of 5 lesions per organ and 10 
lesions in total, representative of all involved organs, should be identified as target lesions at baseline.  All 
measurable lesions not identified as target lesions are non-target lesions and are included as non-
measurable disease.  Measurements must be provided for target measurable lesions, while presence or 
absence must be noted for non-target measurable and non-measurable disease. 
a.   Complete Response (CR):  Complete disappearance of all measurable and non-measurable disease.  
No new lesions.  No disease related symptoms, normalization of disease-related abnormal lab values. 
Normalization of PSA marker to ≤.0.2 in patients who had prior prostatectomy. In patients who had 
primary radiation therapy to prostate gland  PSA decrease to  < nadir +2. All disease must be assessed 
using the same technique as baseline. 
b.   Partial Response (PR):  Radiographic PR applies only to patients with at least one measurable 
lesion.  Greater than or equal to 30% decrease under baseline of the sum of longest diameters of all 
target measurable lesions.  No unequivocal progression of non-measurable disease.  No new lesions.  
All target measurable lesions must be assessed using the same techniques as baseline. PSA PR refers 
to PSA decline by >50% from baseline and confirmed at least 3 weeks later.  
c.   Stable:  Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  All target 
measurable lesions must be assessed using the same techniques as baseline. 
d.   Progression:  One or more of the following must occur:  20% increase in the sum of longest 
diameters of target measurable lesions over smallest sum observed (over baseline if no decrease 
during therapy) using the same techniques as baseline.  Unequivocal progression of non-measurable 
disease in the opinion of the treating physician (an explanation must be provided).  Appearance of any 
new lesion/site.  PSA increase by 25 % form baseline or nadir (whichever was smaller) and by ≥ 2 
ng/mL at 12 weeks. Death due to disease without prior documentation of progression and without 
symptomatic deterioration.  

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e.    Symptomatic deterioration:  Global deterioration of health status requiring discontinuation of 
treatment without objective evidence of progression.  Efforts should be made to obtain objective 
evidence of progression after discontinuation. 
f.    Assessment inadequate, objective status unknown:  Progression or symptomatic deterioration has 
not been documented, and one or more target measurable lesions have not been assessed or 
inconsistent assessment methods were used. 
g.   Objective status notes: 
1.   Non-measurable and non-target measurable disease do not affect objective status except in 
determination of CR (must be absent--a patient who otherwise has a CR, but who has non-
measurable or non-target measurable disease present or not assessed, will be classified as having 
a PR), and in determination of progression (if new sites of disease develop or if unequivocal 
progression occurs in the opinion of the treating physician).  
2. An objective status of PR or stable cannot follow one of CR.  Stable can follow PR only in the 
rare case that tumor increases too little to qualify as progression, but enough that a previously 
documented 30% decrease no longer holds. 
3. In cases for which initial flare reaction is possible (hypercalcemia, increased bone pain, erythema 
of skin lesions), objective status is not progression unless either symptoms persist beyond 4 
weeks or there is additional evidence of progression. 
4. Lesions that appear to increase in size due to presence of necrotic tissue will not be considered to 
have progressed.  
5. For bone disease documented on bone scan only, increased uptake does not constitute 
unequivocal progression. 
6. Appearance or worsening of pleural effusions does not constitute unequivocal progression unless 
cytologically proven of neoplastic origin. 
7. If CR determination depends on a lesion for which the status is unclear by the required tests, it is 
recommended the residual lesion be investigated with biopsy or fine needle aspirate. 
12.0 Data Reporting/Protocol Deviations 
12.1 
Confidentiality and Storage of Records 
The original data collection forms will be stored at the originating institution in a secure location. Study 
data will be entered into an electronic case report form (eCRF) using an encrypted, password protected, 
secure electronic data capture (EDC) application that meets all HIPAA requirements.  When results of 
this study are reported in medical journals or at meetings, identification of those taking part will not be 
disclosed.  Medical records of subjects will be securely maintained in the strictest confidence, according 
to current legal requirements.  They will be made available for review, as required by the FDA, HHS, or 
other authorized users such as the NCI, under the guidelines established by the Federal Privacy Act and 
rules for the protection of human subjects. 
12.2 
Subject Consent Form 
The original signed and dated Informed Consent form, HIPAA research authorization form, and the 
California Experimental Subject’s Bill of Rights will be stored in the research record. At the time of 
registration, a copy of the original signed and dated consent documents will be available to the patient and 
another copy will be stored in the medical record.  All Institutional, NCI, Federal, and State of California 
requirements will be fulfilled. 

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12.3 
Data Collection Forms and Submission Schedule  
All data will be collected using Medidata EDC electronic case report forms.   
12.3.1 
Eligibility Checklist 
The Eligibility Checklist must be completed by a protocol nurse or clinical research associate and 
signed by an authorized investigator prior to registering the subject.  See Section 4.3 for the 
registration procedure. 
12.3.2 
Prior Therapy Forms and On-Study Forms 
Within two weeks of registration, the clinical research associate will submit Prior Therapy Forms 
and On-Study Forms. 
12.3.3         Treatment Forms, Adverse Event Collection Forms, Response/Off Study/Follow Up 
Forms 
Within four weeks of completion of therapy, the clinical research associate will submit the 
Treatment Forms.  Completed adverse events collection forms are due within four weeks of 
assessments per study calendar (refer to Section 10.0).  Response/Follow Up/Off Study Forms are 
to be submitted within four weeks of the patient being evaluated for response and/or new follow 
up information is obtained. 
 
12.4 
Protocol Deviations 
12.5 
Deviation Policy 
This protocol will be conducted in accordance with COH’s “Clinical Research Protocol Deviation Policy” 
located at http://www.coh.org/dsmc/Documents/Institutional%20Deviation%20Policy.pdf. 
Deviations from the written protocol that could increase patient risk or alter protocol integrity require 
prior IRB approval of a single subject exception (SSE) request.  In addition, if contractually obligated, the 
sponsor must also approve the deviation.  IRB pre-approved SSE protocol modifications are considered 
an amendment to the protocol and not a deviation.  The submission of a deviation report is not required. 
Brief interruptions and delays may occasionally be required due to travel delays, airport closure, 
inclement weather, family responsibilities, security alerts, government holidays, etc.  This can also extend 
to complications of disease or unrelated medical illnesses not related to disease progression.  The PI has 
the discretion to deviate from the protocol when necessary so long as such deviation does not threaten 
patient safety or protocol scientific integrity.  Examples include, but are not limited to:  a) dose 
adjustments based on excessive patient weight; b) alteration in treatment schedule due to non-availability 
of the research participant for treatment; c) laboratory test results which are slightly outside the protocol 
requirements but at levels that do not affect participant safety.  These instances are considered to be 
deviations from the protocol.  A deviation report will be submitted to the DSMC/IRB within five days. 
12.5.1 Reporting of Deviations 
All deviations will be reported to the COH DSMC within five days.  The DSMC will forward to report to 
the IRB following review. 
12.5.2 Resolving Disputes 
The COH Investigational Drug Service (IDS) cannot release a research agent that would cause a protocol 
deviation without approval by the PI.  Whenever the protocol is ambiguous on a key point, the IDS 
should rely on the PI to clarify the issue. 

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In situations where there is misperception or dispute regarding a protocol deviation among the persons 
involved in implementing the protocol, it is the responsibility of the PI to resolve the dispute and the PI 
may consult with the DSMC chair (or designee) to arrive at resolution. 
 
13.0 Statistical Considerations  
13.1 
Study Design 
This is a randomized Phase II study.   The primary endpoint is to assess the feasibility, based on percent 
able or willing to receive all three infusions of Sipuleucel-T immunotherapy, when combining Sipuleucel-
T with radiation therapy to a single site of metastasis delivered one week prior to beginning of Sipuleucel-
T therapy.  The ability to deliver three infusions of Sipuleucel-T, reflects the ability to collect adequate 
numbers of CD54+ cells for the generation of  Sipuleucel-T, and tolerability reflected in the patient’s 
willingness or ability to receive the three infusions.     Secondary endpoints will include toxicity, and 
measurements of immune responses to PAP, PA2024 and PSA and radiologic responses to therapy with 
Sipuleucel-T +/- external beam radiation therapy to single metastasis.      
13.2 
Sample Size Accrual Rate 
Patients with metastatic castration-resistant prostate cancer who are candidates for Sipuleucel-T 
immunotherapy.  Total Sample size 50.  Anticipated accrual is 2-3 patients a month. Likely duration of 
the study is 2 years.  Randomization is 1:1.  
13.3 
Statistical Analysis Plan 
Primary Endpoint: Previous publications suggest 8% were unable or unwilling to receive all three 
infusions of Sipuleucel-T.  We will stop accrual at any time if more than 2 patients are unable to receive 
all three infusions and more than 30% of the patients are unable to receive all three infusions.  This rule 
has a 4% of stopping if 8% are unable or unwilling to receive all three infusions, and a 82% chance of 
stopping early if 33% are  unable or unwilling to receive all three infusions (based on 1000 simulations). 
In addition, if 3 patients in the first 10 are unable to initiate Sipulecel-T immunotherapy on Arm B, the 
study will hold accrual pending review by the COH DSMB, sponsor and PI. This slightly increase the 
chance of early stopping (3 of 10 is not “more than 30%” but equal to 30%).    Previous publications 
suggest only 2% of patients are unwilling or unable to begin Sipuleucel-T immunotherapy. 
In addition, to the above stopping boundaries, there will be a safety review of the toxicities after 10 
patients have been treated on Arm B, or after any grade 3 or higher treatment related toxicity on Arm B.  
These rules are in place to limit patient exposure to arm B if it proves poorly tolerated or too toxic. 
Secondary Endpoint: 
From the IMPACT study, titers of antibodies against prostatic acid phosphatase exceeded 400 in 28.5% of 
the patients treated with Sipuleucel-T.  By having a control group, a Fisher's exact test with a 0.200 one-
sided significance level will have 86% power to detect the difference between non-radiation proportion, 
0.285 and a radiation-treated group proportion of 0.570 when the sample size in each group is 25. Also, 
with 25 patients, if the true proportion about 400 is 28.5% in the control arm, and 48.5% in the radiation 
arm, there is less than a 5% chance (~1% if the radiation proportion is 57%) that the observed proportion 
will be higher in the control arm, and there is an 85% chance that difference will exceed 8% between the 
two arms.  In addition, secondary endpoints will include measurements of immune responses to PA2024 
and PSA and radiologic responses to therapy with Sipuleucel-T +/- external beam radiation therapy to 
single metastasis.      
As a result, by having a concurrently randomized control arm, initial comparisons of Arm A and Arm B 
including the influence of radiation on PSA kinetics and response, toxicity and tolerability will help 

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motivate future studies.  For this exploratory secondary analysis, we will not include patients (if any) who 
do not start Sipuleucel-T immunotherapy, but will include all patients who start.  A subset analysis of 
patients able to complete the planned three infusions will also be conducted. 
14.0 Human Subject Issues 
14.1 
Institutional Review Board 
In accordance with City of Hope policies, an Institutional Review Board (IRB) that complies with the 
federal regulations at 45 CFR 46 and 21 CFR 50, 56 and State of California Health and Safety code, Title 
17,  must review and approve this protocol and the informed consent form prior to initiation of the study.  
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
14.2 
Recruitment of Subjects 
Patients for the study with will be recruited from patients undergoing therapy for metastatic castration 
resistant prostate cancer at the City of Hope Cancer Center    
14.3 
Advertisements  
Advertisements to include print, media (radio, television, billboards), telephone scripts, lay summary to 
be posted on City of Hope’s public Clinical Trials On-LineSM website, etc., will be reviewed and 
approved by the IRB prior to their use to recruit potential study subjects. 
14.4 
Study location and Performance Sites 
This study will be performed at City of Hope, City of Hope South Pasadena, and Huntsman Cancer 
Institute, University of Utah. 
14.5 
Confidentiality  
This research will be conducted in compliance with federal and state of California requirements relating 
to protected health information (PHI).  The study will record individual immunological response to the 
Sipuleucel-T +/- radiation and any side effects, and this will be linked to the subject’s identity using a 
coded study number.  The principal investigator, co-investigators, and laboratory technicians will have 
access to this information, but all information will be treated confidentially.  No identifiers will be used in 
any subsequent publication of these results.}   
14.6 
Financial Obligations and Compensation 
Therapy on the protocol utilizes standard of care procedures. The standard of care drug 
(Sipuleucel-T) and radiation therapy will be the responsibility of the research participant and/or the 
insurance carrier.  The research participant will be responsible for all copayments, deductibles, and 
other costs of treatment and diagnostic procedures as set forth by the insurance carrier.  The 
research participant and/or the insurance carrier will be billed for the costs of treatment and 
diagnostic procedures in the same way as if the research participant were not in a research study.  
However, neither the research participant nor the insurance carrier will be responsible for the 
research procedures related to this study. 
 
In the event of physical injury to a research participant, resulting from research procedures, 
appropriate medical treatment will be available at the participating site to the injured research 
participant, however, financial compensation will not be available.  The research participant will not 
be paid for taking part in this study. 

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14.7 
Informed Consent Processes  
The Principal Investigator or IRB approved named designate will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Research subjects will be informed that they may withdraw from the 
study at any time and for any reason without prejudice, including as applicable, their current or future 
care or employment at City of Hope or any relationship they have with City of Hope.  Research subjects 
will be afforded sufficient time to consider whether or not to participate in the research. 
Should sufficient doubt be raised regarding the adequacy of comprehension, further clarifications will be 
made and the questionnaire repeated until a satisfactory result is obtained.  Prospective research subjects 
who cannot adequately comprehend the fundamental aspects of the research study with a reasonable 
amount of discussion, education and proctoring will be ineligible for enrollment.  For those subjects who 
do comprehend the fundamental aspects of the study, consent will be obtained and documented, followed 
by eligibility testing.  The research team will review the results of eligibility testing and determine if the 
subject is a candidate for study enrollment.  
15.0 References 
1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009; 
59:225-49 
2. Kantoff PW, Carroll PR, D’Amico AV, Prostate cancer: principles and practice. 
Philadelphia:Lippincott Williams & Wilkins, 2002. 
3. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic 
therapy with Sipuleucel-T (APC 8015) in patients with metastatic, asymptomatic hormone refractory 
prostate cancer. J Clin Oncol 2006; 24: 3089-94. 
4. Kantoff, P. W., et al. "Sipuleucel-T immunotherapy for castration-resistant prostate cancer." 
N.Engl.J.Med. 363.5 (2010): 411-22. 
5. Ferrara TA, Hodge JW, Gulley JL. Combining radiation and immunotherapy for synergistic antitumor 
therapy. Curr Opin Mol Ther.2009 Feb;11: 37-42.