Clinical trial NCT01818986
Conditions: Metastatic Castrate-resistant Prostate Cancer mCRPC
Sponsor: University of Texas Southwestern Medical Center
Start date: 2013-07-10; Completion date: 2021-05-25
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In this i-SABR (immunotherapy + Stereotactic Ablative Body Radiation) trial, the stereotactic radiation to multiple metastatic sites is delivered not only to eradicate sites of bulky progressive disease, but also to provide antigen presentation and immune stimulation which is expected to act synergistically to the concurrently administered immunotherapy Sipuleucel-T and thereby significantly improve the treatment outcome for metastatic castrate resistant prostate cancer patients (mCRPC). Both Sipuleucel-T and SABR are FDA approved therapeutic cancer treatment

Detailed description:

Arms: arm 1: Sipuleucel-T and Stereotactic Ablative Body Radiation (SABR)
Interventions: intervention 1: Sipuleucel-T intervention 2: Stereotactic Ablative Body Radiation
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Official Title: Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation (SABR) for
Patients with metastatic castrate-resistant Prostate Cancer (mCRPC)
NCT#: 01818986
Document Date: 04/05/2019
Version: 13


 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
STU 102012-026 
Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation (SABR) for 
Patients with  metastatic castrate-resistant Prostate Cancer (mCRPC)  
 
 
Principal Investigator:  
Raquibul Hannan, MD, PhD 
 
 
 
 
University of Texas Southwestern 
 
 
 
 
5801 Forest Park Road 
 
 
 
 
Phone: 214-645-8525  
 
 
 
 
Fax: 214-645-8526 
 
 
 
 
Raquibul.Hannan@utsouthwestern.edu 
 
 
 
 
 
Co-Investigator(s): 
 
Hak Choy, MD 
 
 
 
 
Department of Radiation Oncology 
 
 
 
 
 
Kevin Courtney, MD, PhD 
 
 
 
 
Department of Medical Oncology 
 
 
 
 
 
Lori Watumull, MD 
 
 
 
 
Department of Radiology 
 
Biostatistician: 
 
Chul Ahn PhD 
 
 
 
 
Department of Clinical Sciences 
5323 Harry Hines Blvd 
Dallas, TX 75390-9066 
  
 
 
 
(214) 648-9418 
Chul.ahn@utsouthwestern.edu 
 
Study Drug/Intervention: 
SABR 
 
Funding Source:  
Department of Radiation Oncology at UTSW and Dendreon Corporation 
 
 
 
Version 1 
Oct 8, 2012 
Version 2 
March 26, 2013 
Version 3 
November, 15,2013 
Version 4 
March 14, 2014 
Version 5 
March 27, 2014 
Version 6 
May 1, 2014 
Version 7 
July 3, 2014 
Version 8 
August 27, 2014 
Version 9 
September 25, 2014 
Version 10 
January 26, 2017 
Version 11 
July 5, 2017 
Version 12  
January 25, 2018 
Version 13 
April 5, 2019 
 
 
UT Southwestern Medical Center at Dallas 
Department of Radiation Oncology 
Attn: Clinical Research Office 
5801 Forest Park Road 
Dallas, Texas 75390-9183 
 
Signature Page 


 
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CONFIDENTIAL 
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study sponsor. 
 
Protocol v13 April5, 2019 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
Amendment/Version # 13 
PROTOCOL NUMBER: STU 102012-026 
PROTOCOL TITLE: Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body 
Radiation (SABR) for Patients with  metastatic castrate-resistant Prostate Cancer 
(mCRPC) 
 
Principal Investigator (PI) Name: Raquibul Hannan, MD, PhD 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 


STU 102012-026 
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CONFIDENTIAL 
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study sponsor. 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ........................................................................................ 1 
STUDY SCHEMA ......................................................................................................... 2 
STUDY SUMMARY ..................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ................................................................ 4 
1.1 
Disease Background .................................................................................................... 4 
1.2 
Stereotactic Ablative Body Radiation (SABR) ............................................................... 4 
1.3 
Sipuleucel-T ................................................................................................................ 4 
1.4 
Rationale ..................................................................................................................... 5 
1.5 
Correlative Studies ...................................................................................................... 6 
1.6 
Health-related Quality of Life (HRQOL) and Economic Analysis ................................... 7 
2.0 
STUDY OBJECTIVES ...................................................................................... 8 
2.1 
Primary Objectives ....................................................................................................... 8 
2.2 
Secondary Objectives .................................................................................................. 9 
2.3 
Exploratory Objectives ............................................................................................... 10 
2.4 
Endpoints .................................................................................................................. 10 
3.0 
SUBJECT ELIGIBILITY .................................................................................. 12 
3.1 
Inclusion Criteria ........................................................................................................ 12 
3.2 
Exclusion Criteria ....................................................................................................... 13 
4.0 
TREATMENT PLAN: STUDY MEDICATION ............................................... 14 
4.1 
Sipuleucel-T: Treatment Dosage and Administration .................................................. 14 
4.2 
SABR Dose and Techniques ...................................................................................... 15 
4.3 
Toxicities and Dosing Delays/Dose Modifications ....................................................... 21 
4.4 
Concomitant Medications/Treatments ........................................................................ 22 


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study sponsor. 
 
4.5 
Duration of Therapy ................................................................................................... 22 
4.6 
Duration of Follow Up ................................................................................................ 22 
4.7 
Removal of Subjects from Protocol Therapy ............................................................... 23 
5.0 
STUDY PROCEDURES .................................................................................. 23 
5.1 
Screening/Baseline Procedures ................................................................................. 23 
5.2 
Procedures during treatment ...................................................................................... 24 
5.3 
Follow-up Procedures ................................................................................................ 24 
5.4 
Time and Events Table .............................................................................................. 24 
5.5 
Removal of Subjects from Study ................................................................................ 25 
6.0 
Measurement of Effect .................................................................................. 26 
6.1 
Antitumor Effect ......................................................................................................... 26 
6.2 
Quality of Life: ............................................................................................................ 32 
6.3 
Cost effectiveness data collection: ............................................................................. 32 
6.4 
Safety/tolerability ....................................................................................................... 33 
7.0 
ADVERSE EVENTS ........................................................................................ 33 
7.1 
Sipuleucel-T .............................................................................................................. 33 
7.2 
Adverse Event Monitoring .......................................................................................... 34 
7.3 
Definitions.................................................................................................................. 34 
7.4 
Reporting Requirements for Serious Adverse Events ................................................. 36 
7.5 
Steps to Determine If an Adverse Event Requires Expedited Reporting ..................... 39 
7.6 
Reporting Requirements for Adverse Events .............................................................. 40 
7.7 
Stopping Rules .......................................................................................................... 41 
8.0 
DRUG INFORMATION ................................................................................... 41 
8.1 
Sipuleucel-T .............................................................................................................. 41 
9.0 
CORRELATIVES/SPECIAL STUDIES ......................................................... 42 
9.1 
Sample Collection Guidelines .................................................................................... 42 


STU 102012-026 
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CONFIDENTIAL 
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study sponsor. 
 
9.2 
Assay Methodology ................................................................................................... 42 
9.3 
Specimen Banking ..................................................................................................... 44 
10.0 
QUALITY OF LIFE AND COST-EFFECTIVENESS ................................. 45 
10.1 
Health-Related Quality of Life (HRQOL) Analysis ....................................................... 45 
10.2 
Cost-Effectiveness Analysis (CEA)............................................................................. 46 
10.3 
Quality adjusted survival time: .................................................................................... 47 
11.0 
STATISTICAL CONSIDERATIONS .......................................................... 47 
11.1 
Study Design/Study Endpoints ................................................................................... 47 
11.2 
Sample Size and Accrual ........................................................................................... 47 
11.3 
Data Analyses Plans .................................................................................................. 47 
12.0 
STUDY MANAGEMENT ............................................................................. 47 
12.1 
Conflict of Interest ...................................................................................................... 47 
12.2 
Institutional Review Board (IRB) Approval and Consent ............................................. 48 
12.3 
Required Documentation for multi-site........................................................................ 48 
12.4 
Registration Procedures............................................................................................. 48 
12.5 
Data Management and Monitoring/Auditing ................................................................ 48 
12.6 
Adherence to the Protocol .......................................................................................... 50 
12.7 
Amendments to the Protocol ...................................................................................... 51 
12.8 
Record Retention ....................................................................................................... 51 
12.9 
Obligations of Investigators ........................................................................................ 52 
13.0 
REFERENCES ............................................................................................. 52 
14.0 
APPENDICES .............................................................................................. 57 
14.1 
Appendix A: ECOG Performance Status .................................................................... 57 
14.2 
Appendix B: VAS .......................................................... Error! Bookmark not defined. 
14.3 
Appendix C: FACT-P ................................................................................................. 58 
14.4 
Appendix D: EQ-5D ................................................................................................... 61 


STU 102012-026 
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CONFIDENTIAL 
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study sponsor. 
 
14.5 
Appendix E: BPI......................................................................................................... 64 
14.6 
Appendix F  – Patient Perspective Cost and Convenience  of Care Questionnaire ..... 66 


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CONFIDENTIAL 
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study sponsor. 
 
LIST OF ABBREVIATIONS 
ADT 
Androgen depravation therapy 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
Absolute Lymphocyte Count 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
bPFS 
Biochemical progression Free Survival 
BPI 
Brief Pain Inventory 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FACS 
Florescence Activated Cell Sorting 
H&P 
History & Physical Exam 
HRQOL 
Health-related Quality of Life 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IV (or iv) 
Intravenously 
mCRPC 
Metastatic Castrate Resistant Prostate Cancer 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PAP 
Prostate acid phosphatase 
PBMCs 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
p.o. 
peros/by mouth/orally 
PR 
Partial Response 
PCaSS 
Prostate Cancer Specific Survival 
PSA 
Prostate-Specific Antigen 
QL 
Quality of Life 
RT 
Room Temperature 
SABR 
Stereotactic Ablative Body Radiation 
SAE 
Serious Adverse Event 
SBRT 
Stereotactic Body Radiation Therapy 
SD 
Stable Disease 


STU 102012-026 
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CONFIDENTIAL 
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study sponsor. 
 
WBC 
White Blood Cells 
 
 
 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility: mCRPC 
 
Progressed after first line ADT 
o 
Testosterone < 
50ng/ml 
 
Minimally symptomatic or 
asymptomatic  
 
Eligible for Sipuleucel-T 
 
Eligible for SABR to 1-6 lesions 
 
ECOG performance status 0-1 
 
Sipuleucel-T 
 
SABR to metastasis 
 Primary End-point: Time to 
disease progression (TTP) 
 Continue until progression of 
disease or interim analysis 
shows a clear TTP/OS benefit. 
 
 Whole Blood collection for 
baseline immunologic 
assays 
 Baseline Imaging 
o 
Bone scan 
o 
CT AP-w/PO+IV contrast 
 Whole Blood collection and 
repeat Imaging Q6-8 Weeks 
 Metastatic lesion biopsy at 8 
Weeks (optional & if funding 
available) 
 QOL Questionnaires Q12 
Weeks 


STU 102012-026 
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STUDY SUMMARY 
Title 
Phase II Trial of Sipuleucel-T and Stereotactic Ablative Body Radiation 
(SABR) for Patients with  metastatic castrate-resistant Prostate Cancer 
(mCRPC) 
Short Title 
Combination therapy of Sipuleucel-T and SBRT for mCRPC 
Protocol Number 
STU 102012-026 
Phase 
Phase 2 
Methodology 
Single arm, open label. 
Study Duration 
Ten years (seven years for enrollment and 3 years for follow-up). 
Study Center(s) 
Multi-center 
Objectives 
To evaluate the improvement in time to progression (TTP) of disease in 
mCRPC after concurrent treatment with Sipuleucel-T and SABR  
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
mCRPC patients, asymptomatic or minimally symptomatic with ECOG 
0,1. 
Study Product(s), Dose, 
Route, Regimen 
Sipuleucel-T (brand name Provenge)—IV infusion; SABR dose varying 
from 21Gy-33Gy in 1-3 fractions.   
Duration of administration 
Six Weeks. 
Reference therapy 
Sipuleucel-T treatment alone (Published Data—historic control) 
Statistical Methodology 
The Kaplan-Meier method with the 95% confidence interval will be used 
to evaluate the primary endpoint of TTP and one-sample log-rank test 
will be used to compare this with the published value. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STU 102012-026 
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CONFIDENTIAL 
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study sponsor. 
 
 
 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Disease Background 
Prostate cancer is the most prevalent cancer among men in the U.S with an estimated incidence 
of 241,740 and deaths of 28,170 in 2012 (SEER). While there are many effective treatment 
options for localized prostate cancer, the outlook for metastatic disease remains grim with limited 
effective treatment option.  The five-year relative survival for localized disease is 100% whereas 
that for metastatic disease is 27.8% (SEER). Therefore, there remains a great need for 
improvement in the therapeutic management of metastatic prostate cancer.    
1.2 
Stereotactic Ablative Body Radiation (SABR) 
 
Stereotactic ablative body radiation (SABR) is an emerging treatment paradigm defined in the 
American Society of Therapeutic Radiology and Oncology guidelines as a “treatment method to 
deliver a high dose of radiation to the target, utilizing either a single dose or a small number of 
fractions with a high degree of precision within the body” [1] . Potential indications for SABR 
include a broad spectrum of tumor types and locations. 
 
Previous studies have demonstrated multiple immunogenic properties of radiation therapy, 
especially when given at high doses such as with SABR [2, 3].  Since SABR is a highly focused 
therapy, it does not inherently immunocompromise the host. By not surgically removing the 
tumor, the body retains the antigen depot (dying tumor cells) within the host. Furthermore, since 
SABR causes local inflammation, dendritic cells (DCs) are attracted into the tumor. These DCs 
rapidly take up tumor antigens and traffic to regional lymph nodes; during this process they are 
activated. Once in the cortex of the lymph node, tumor antigens on DCs are efficiently presented 
by cell surface Class I MHC molecules to T cells.  Interestingly, radiation causes a dose-
dependent increase in MHC I tumor neo-antigen presentation to tumor cells [4]. The T cells 
initiate an adaptive immune response resulting in antibody production and the expansion of 
cytotoxic T cells. These are delivered to both the primary and metastatic tumor sites. There is 
also evidence from both pre-clinical and clinical studies that radiation therapy, specifically at 
ablative doses typical of SABR, initiates and augments an immune response by altering the tumor 
microenvironment. In a pre-clinical rodent syngeneic model, this was demonstrated for prostate 
cancer using a Listeria-PSA vaccine by Hannan et. al [5].  In the clinic, this was shown recently 
by Postow et. al. who demonstrated that the abscopal effect (whereby SABR delivered to a 
primary site of cancer resulted in a complete response at metastatic sites) was due to an increase 
in tumor-specific T-lymphocytes and a decrease in MDSC and other immune regulatory cells 
following the combination treatment of SABR and CTLA-4 immunotherapy [6]. A phase I trial was 
recently published for metastatic melanoma and renal cell cancer where HD IL-2 was combined 
with SABR with encouraging results [7]. 
1.3 
Sipuleucel-T 
Sipuleucel-T (Provenge) is a therapeutic cancer vaccine consisting of autologous infusion of 
dendritic cells that are activated by ex vivo treatment with prostate acid phosphatase (PAP) and a 
GM-CSF fusion protein, PA2024. Sipuleucel-T has demonstrated approximately 4 months of 
overall survival (OS) benefit in mCRPC patients in three phase III randomized trials and is 
currently FDA approved for this stage of prostate cancer patients[8-10]. The D9901 trial enrolled 
127 patients with asymptomatic mCRPC. The median survival time for patients treated with 
sipuleucel-T was 25.9 months comparing to 21.4 months for placebo-treated patients (P=0.01) 
[9]. A similarly designed trial, the IMPACT trial enrolled 512 mCRPC patients and the median 
survival time for sipuleucel-T patients was 25.8 months comparing to 21.7 months for placebo-
treated patients (P=0.032)[10]. Both of the trials allowed crossover of patients and therefore 


STU 102012-026 
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taking crossover into account, the predicted survival benefit is reported to be approximately seven 
months.  
 
Administration of sipuluecel-T consists of leukapheresis of the patient’s own blood to collect WBC 
consisting of DC. This is followed by activating of the DC by PA2024. Three to four days later this 
product is infused back to the patient. This process is repeated a total of three times two weeks 
apart. The side effects of sipuleucel-T are mostly limited to chills, fever, fatigue, nausea and 
headache which usually occur within the first few days of infusion. In addition, more serious 
cardiovascular events were observed at a rate of 2.4% vs 1.8%, cerebrovascular events of 3.5% 
vs 2.6% and cord compression of 1.7% vs 0.3% in patients treated with sipuleucel-T and placebo 
respectively. 
1.4 
Rationale 
 
As applied in concert with sipuleucel-T in the present study, SABR is intended not only as a 
systemic cytoreductive agent but also an immunostimulant. In the Norton-Simon hypothesis of 
malignant tumor progression, tumor growth can be plotted on a curve that very closely resembles 
the Gompertz model of human population growth [11].  One notable difference, however, is that 
instead of reaching a steady-state level, as would be the case for a society’s population, 
relentless tumor growth will tend to continue steadily to the point of lethality for the host once the 
systemic disease burden reaches an overwhelming level. By aggressively cytoreducing the tumor 
burden at the outset of sipuleucel-T treatment, in addition to maintaining the burden of death 
below the lethal threshold, the growth dynamics may be altered to render the remaining cells 
more susceptible to the immunotherapy. Therefore, the purpose of SABR would be two fold. It 
would irradiate sites of disease that are bulky and resistant to systemic agents, and can 
eventually serve as origins of further tumor spread and metastasis. Simultaneously, SABR would 
act as an in-situ tumor vaccination by initiating antigen presentation and immunocyte infiltration, 
thereby acting synergistically with sipuleucel-T in facilitating an effective immune response and 
eventually affecting disease progression, quality of life and overall survival.  
 
Metastatic prostate cancer can be seen as composed of bulky sites of disease and innumerable 
micrometastatic disease sites that are below the resolution limit of radiographic imaging. 
Systemic therapies like hormonal therapy or chemotherapy alone, which are effective towards 
micrometastatic disease but less so to the bulky sites of metastasis, can result in response, but 
ultimately the tumors progress resulting in declining quality of life and death from cancer.   
Historically, the use of local therapies such as surgical metastectomy or conventional radiation for 
a purpose other than palliation was ineffective since the tumor distribution was systemic.   
However, there is growing evidence that this new, potent, highly focused, and convenient form of 
radiation called SABR can dramatically debulk and even eradicate bulky tumor deposits [12-15].  
Importantly, since SABR is shown to be immunostimulatory, and immunotherapy has 
radiosensitizing properties, the combination of the two is expected to be synergistic [2]. In 
addition to the initiation of antigen presentation by SABR, tumor irradiation will actively recruit 
DCs into the tumor and to the draining lymph nodes by the release of danger-associated 
molecular patterns (DAMPs) that are activated by sipuleucel-T, as shown by pre-clinical studies 
[16, 17]. Therefore a combination treatment that offers eradication of the bulky progressive sites 
and simultaneously synergizes with the concurrent systemic treatment of immunotherapy to 
eliminate the micrometastatic disease is expected to improve outcome dramatically and even 
offer cure to this group of patients that currently only receives palliative treatment. 
 
Therefore, we propose a single-arm, open-label, phase II trial of sipuleucel-T and SABR 
administered concurrently. The safety profiles of both SABR and sipuleucel-T are excellent and 
therefore there are limited concerns for toxicity when they are administered concurrently. Given 
the three randomized phase III clinical trials of sipuleucel-T available for comparison as historic 
control, a two-arm trial is not necessary.  
 


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study sponsor. 
 
The primary end point of this study is to measure improvement in time to progression (TTP) of 
metastatic prostate cancer compared to the reported TTP of 14.6 weeks with treatment with 
sipuleucel-T alone [10].  A significant improvement on the historically reported values of TTP 
would justify seeking a phase three trial to show the efficacy of this regimen in improving overall 
survival.  One of the secondary endpoints will be augmentation of the immune response. An 
immune response in this case would constitute results of two immunologic assays and also a 
radiographic response to non-target sites. Additional secondary endpoints of this trial will be 
those that are recommended by the Prostate Cancer Working Group and typically assessed in a 
phase III trial of prostate cancer and include progression free survival (PFS), biochemical 
progression free survival (bPFS), prostate cancer-specific survival (PCaSS), overall survival (OS), 
improvements in quality of life (QOL) and cost effectiveness analysis.  
1.5 
Correlative Studies 
The correlative studies will explore the mechanisms of possible immune enhancement by SABR. 
Activation of each arm of the immune response will be evaluated separately utilizing different 
assays. The humeral response will be evaluated using ELISA to measure the titer of tumor-
specific antibodies generated by SABR and sipuleucel-T against not only PAP and PA2024, but 
also an array of known prostate cancer antigens [18]. An overall increase in tumor antigen-
specific antibody will be measured using immunoblotting with patient sera as a source of primary 
antibody [19].  
 
Enhancements of increased cytotoxicity to prostate cancer cells can be measured by cytotoxicity 
assays.  Antibody-dependent cell-mediated cytotoxicity (ADCC) measures the cell-killing ability of 
certain lymphocytes that require the target cell to be marked by an antibody and thus measures 
the humeral response [20]. On the other hand, lymphocyte-mediated cytotoxicity assay will 
measure the formation of tumor-specific CTLs among the lymphocytes collected from patients 
with the controls being lymphocytes collected from the same patients before SABR and before 
sipuleucel-T. Since it is not practical or feasible to obtain sufficient quantities of tumor cells from 
each patients to assess a quantitative cytotoxicity by these assays, established allogenic human 
prostate cancer cell lines LNCaP and PC3 will be used for this purpose. It is a generally accepted 
principle of tumor immunology that there will be many common tumor antigens between different 
patient tumors of same site origin, and therefore tumor cell lines as well [20]. In fact, the tumor 
antigens (PSA, CEA, CA 19-9 etc.) that are in clinical practice are reported to be present in a 
significant portions of patients of the respective tumor site.  This concept of commonality of tumor 
antigens between allogenic tumor cell lines and patients is put into clinical practice by the GVAX 
anti-tumor vaccine which is currently in early phase clinical trials for pancreatic, melanoma and 
prostate cancer [21, 22]. GVAX consists of multiple human tumor cell lines of the respective site, 
that is modified to express GM-CSF, and killed with radiation prior to injection in patients. The 
presence of common tumor antigens in the cell lines and patient’s tumors, leads to induction of an 
immune response. The LNCaP and PC-3 cell lines has been shown to express many of the 
common prostate cancer antigens, and therefore, is an appropriate surrogate to be used instead 
of patient’s own cells and has been used in similar in vitro cytotoxicity assays [23-27].   
 
Cytokines are hormonal messengers responsible for most of the effects in the immune system 
such as activation of innate versus adaptive immune response, cellular versus humeral immune 
response [28, 29]. For example, an increased level of IL-2 and IFN-γ suggests activation of Th1 
cells leading to activation of macrophages and suggests a cell-mediated adaptive immune 
response whereas IL-4 and IL-5 may indicate Th2 activation and induction of humoral immunity 
[20, 29].  An increase in IL-17 may suggest activation of autoimmune responses [30]. Therefore, 
measurements of serum cytokine levels have generally been used previously in clinical trials as 
surrogates to assess specific activation of immune pathways [31, 32].  Serum cytokines from this 
clinical trial before and after SABR will be measured using an extensive array of cytokines to 
explore the specific immune pathways that are initiated by SABR. The planned array of cytokines 
will measure levels of the following cytokines before and after treatment for each patients: 
Th1/Th2/Th17 cytokines: IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; 
pro-inflammatory cytokines: GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-α; 


STU 102012-026 
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Chemokines: Eotaxin, MIP-1β, TARC, IP-10, IL-8, MCP-1, MCP-4, KC, and others including IL-6, 
IL-12, TGF-β and HMGB1.   
 
Many surrogate markers for activated and proliferating lymphocytes have been described. Some 
of these markers include CD25, CD71, CD45RO, CD107a, CD54, CD69, Ki67 and ICOS/CD278 
[33-36]. These markers are easily measured with antibodies specific for the markers that are 
tagged with a fluorophore utilizing FACS analysis. These measurements from PBMCs collected 
from patients before and after treatment will give us further information regarding the intensity of 
the immune response.  
 
The relative levels of different monocyte subpopulations in the tumor biopsy sample after 
treatment as well as in the peripheral circulation often dictate the overall outcome of an immune 
response, and has been reported in previous immunotherapy trials [7]. Exploration of possible 
mechanisms of treatment failure can be explored from this analysis as well. Therefore the 
following subpopulation of cells will be quantified in patient PBMCs (and in tumor biopsy samples 
where applicable) collected before and after treatment utilizing some of the listed markers specific 
for those cells: 
 
Immune Cells 
Markers 
Lymphocytes 
 
Cytotoxic T Lympocyte (CTL) 
CD3, CD8 
NK 
CD3-, CD8, CD16, CD56, CD11b 
NKT 
CD3, CD16, CD1d 
Helper T Cells 
CD3, CD4 
Th1 
IL-18 receptor α, CXCR3, T cell Ig 
domain, TIM-3, T-bet 
Th2 
T1/ST2, TIM-1, TIM-2, GATA-3 
Th17 
Unknown, differentiated by IL-17 
production, ROR-γT 
Treg 
CD4+CD25+FoxP3+ 
Memory T Cells 
CD45RO 
TCM 
CD4/CD8, CD62L, CCR7 
TEM 
CD4/CD8, CCR7−, CD45RA−, CD27 
B Cells 
CD19, mIg, FcR, CR, CD3-, HLA-DR 
MDSC 
CD14+, CD11b, CD33, CD 15, CD4, 
CD8-, HLA-DR-/low 
Neutrophils 
FcR, CR-,CD3-, HLA-DR-, GR-1+high, 
CD11b, Ly6G 
Macrophages 
FcR, CR, HLA-DR, GR-1+mid 
DC 
 
Myeloid DC-1 
CD11c, TLR2,TLR4 
Myeloid DC-2 
CD 141, TLR2,TLR4 
Plasacytoid DC 
CD303, TLR7,TLR9 
 Table 1: PBMC subpopulations and their markers.  
1.6 
Health-related Quality of Life (HRQOL) and Economic Analysis 
In the United States, total national health expenditures (NHE) increased from $7.14 billion in 1990 
to $2.23 trillion in 2007, which represents an average annual growth rate of 7.0%.  In contrast, over 
the same period, U.S. gross domestic product (GDP) increased from $5.8 trillion in 1990 to $13.8 
trillion, or average 5.2% annual growth rate.  Given that national health expenditures have grown 
faster than GDP, the share of GDP devoted to health expenditures has increased from 12.3% in 
1990 to 16.2% in 2007[37].  Moreover, national health expenditure growth is expected to continue 
to outpace income growth, with total NHE reaching $4.35 trillion by 2018, accounting for 20.3% of 
GDP (CMS 2009).  There is growing concern that these trends in health expenditures are not 
sustainable.  For the Medicare program, current estimates of the present value of total unfunded 


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liabilities through the year 2083 (the present value of the difference between projected future 
Medicare expenditures and Medicare revenues over the next 75 years under current Medicare 
policy) total $89 trillion, with Medicare’s Hospital Insurance (“Part A”) trust fund projected to be 
depleted by 2017[38]. 
 
Prior studies have estimated that about half of the recent growth in health expenditures is 
attributable to advances in various forms of health technology, including new pharmaceutical 
products, surgical procedures, imaging modalities, and new biomarkers[38].  While almost all of 
these new technologies offer some potential to improve clinical outcomes, they also more often 
than not add to health expenditures.  Within the context of unsustainable trends in health 
expenditures, a key policy question relates to whether the extent of improvement in outcomes 
associated with the use of a new technology is attained at a “reasonable” additional cost, compared 
to existing technology.  Indeed, the value offered by new technologies is being subjected to 
increasing scrutiny by reimbursement authorities in many health systems worldwide.  For example, 
in the United Kingdom, the National Health Service bases payment policy decisions for new 
technologies on recommendations from the National Institute for Health and Clinical Excellence 
(NICE), which in turn are substantially influenced by cost-effectiveness analysis yielding an 
estimated additional “cost per quality-adjusted life-year (QALY) gained” via use of the new 
technology.  Currently, NICE usually considers technologies offering improved outcomes at a cost 
less than £20,000 to £30,000 per QALY gained (about $33,000 - $50,000) acceptable, though 
exceptions are common[39]. 
 
The American Cancer Society estimates 241,740 newly diagnosed prostate cancer patients with 
28,174 prostate cancer related deaths in 2012 [40].  The NIH estimates that the overall direct cost 
of cancer in the United States in 2010 was $102.8 billion with prostate cancer being the fifth most 
costly cancer accounting for over $12 billion in annual cost in 2010 and $19 billion projected in 2020 
[40, 41]. The rapidly increasing costs of prostate cancer treatment, driven by a combination of 
advanced surgical, radiation, and pharmaceutical treatment technologies, have catalyzed increased 
scrutiny regarding current treatment approaches for prostate cancer [42-44].  In fact, prostate 
cancer has been described as the litmus test for healthcare spending reform efforts [45]. With 
several recent novel therapeutics recently approved in the management of castration-resistant 
prostate cancer, the economic implication of therapeutic modalities for men with mCRPC is 
certainly applicable to this protocol and thus will be studied in a correlative approach [46-48].   
 
Therefore, we propose to evaluate the cost effectiveness of the combined treatment and assess 
patients’ health related quality of life, in order to evaluate the economical consequence of using the 
two new technologies proposed in this study and its impact on quality of life.  Based on the primary 
hypothesis of this study that time to progression will be improved with the combination of SABR and 
sipuleucel-T, we further hypothesize that the addition of SBRT will increase the durability of 
response or lengthen the time to progression thus increasing the cost effectiveness of the 
combined therapies.  Thus, we hypothesize that the added treatment of SBRT while adding 
modestly to the total cost of the combined therapies may be cost saving over the patient’s entire 
treatment course compared to sipuleucel T alone, making the combination a very attractive 
treatment for mCRPC patients.  Additionally, we hypothesize that combination of SBRT and 
sipuleucel T will increase the quality-adjusted life-years for CRPC cancer patients (compared to the 
prior reported chemotherapeutic options for mCRPC) at a reasonable incremental cost, as defined 
by generally accepted cost-effectiveness thresholds.  The sample size would be prohibitively large 
should these secondary endpoints be analyzed beyond simple descriptive statistical purposes.   
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
 
2.1.1 
To evaluate the improvement in the time to progression (TTP) of metastatic 
prostate cancer after the combined treatment with sipuleucel-T and SABR to 


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metastatic sites, as compared to the historically reported data with the treatment 
of sipuleucel-T alone. 
2.2 
Secondary Objectives 
 
2.2.1 
To quantify the amplification in immune response generated by Sipuleucel-T by 
the addition of SABR.  
 
2.2.2 
To evaluate the improvement in the overall survival (OS) of mCRPCa patients 
after the combined treatment with sipuleucel-T and SABR to metastatic sites, as 
compared to the historically reported data with the treatment of sipuleucel-T 
alone. 
 
2.2.3 
To evaluate the improvement in the progression free survival (PFS) of mCRPCa 
patients after the combined treatment with sipuleucel-T and SABR to metastatic 
sites, as compared to the historically reported data with the treatment of 
sipuleucel-T alone. 
 
2.2.4 
To evaluate the improvement in the biochemical progression free survival (bPFS) 
of mCRPCa patients after the combined treatment with sipuleucel-T and SABR to 
metastatic sites, as compared to the historically reported data with the treatment 
of sipuleucel-T alone. 
 
2.2.6 
To evaluate the improvement in the prostate cancer-specific survival (PCaSS) of 
mCRPCa patients after the combined treatment with sipuleucel-T and SABR to 
metastatic sites, as compared to the historically reported data with the treatment 
of sipuleucel-T alone. 
 
2.2.7 
To evaluate the adverse events for the first 6 months after completion of radiation 
therapy associated with Sipuleucel-T when administered in combination with 
SABR to metastatic sites, as compared to the historically reported data with the 
treatment of Sipuleucel-T alone. 
 
2.2.8 
To evaluate the cost effectiveness and health-related quality adjusted life of the 
combination treatment of SABR and sipuleucel T in patients with mCRPC. 


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2.3 
Exploratory Objectives 
2.3.1 Immunologic Correlates: The objective of the correlative immunologic studies is 
to characterize the nature of immune response by the measurement of the 
relative presence of different subpopulations of immunocytes and by the levels 
of their regulatory cytokines in patient sera as well as within the metastatic sites. 
In addition, any correlation between the primary and secondary outcomes to 
cytokine levels or changes in the level of immunocytes will be explored.  
2.3.2 Cost-effectiveness and Quality of Life Correlates: An exploratory objective of 
this study will compare the cost effectiveness and improvement of quality of life 
of this combination treatment to the other current standards of care for mCRPC 
patients (i.e. Docetaxel, sipuleucel-T alone, etc.).  
2.4 
Endpoints 
TTP: The primary endpoint of TTP will be measured as described in the 
recommendations of Prostate Cancer Clinical Trials Working Group 2 [49] and in 
accordance with the Phase III clinical trial by Kantoff et. al. [10] : 
o 
Progressive disease (PD) on serial radiographic imaging tests 
 
Visceral/soft-tissue mets: 
 
PD defined using RECIST 1.1 criterion (www.RECIST.com) 
 
>50% increase (in the sum of the products of diameters for 
index lesions) measurable disease 
 
Clear worsening of non-measurable disease 
 
Bone Lesions: (PCWG2 recommendations; JCO 2008) 
 
Appearance of 2 or more new bone lesions in Bone scan, 
confirmed by a repeat bone scan in ≥6 weeks. 
 
The Appearance of 2 new lesions on the first follow-up scan 
(6 week scan) will require ≥2 additional new lesions in a 
repeat bone scan ≥6 weeks apart.  
o 
Clinical events consistent with progression such as spinal cord compression, 
nerve root compression, or pathologic fracture. 
Radiographic imaging including Bone scan and CT scan (PET scan alone or 
equivocal are acceptable alternatives) will be repeated every 8-12 (+/- 1 week) weeks 
(since the reported TTP with Sipuleucel-T alone is 14.6 wks) for the first two years 
after completion of all study treatment and every 6 months thereafter for two years. 
Bone scans will be repeated every 8-12 (+/- 1 week) weeks for the first 9 months 
after completion of all study treatment should bone lesions be present pre-study. CT 
scans will be performed every 8-12 weeks for the first 9 months after completion of 
study treatment only if soft tissue lesion is present (see section 5 for details). 
2.4.1 Immunologic Endpoint: Reaching an immunologic endpoint by any patient will 
constitute either an amplification of immune response (as compared to 
historically reported values for sipuleucel-T administration alone) or abscopal 
radiographic response.  Immune response will be measured using ELISpot 
assay, T-cell proliferation assay or ELISA.  The assays will first be calibrated by 
measuring the background responses in baseline samples of patients pre-
treatment and an increase of >95th percentile will be considered a positive 
response.  To reach the immunologic end point for this trial, there has to be a 
>100% increase in immune response as measured by ANY of the assays when 
Sipuleucel-T is administered alone as reported by Sheikh et al [32] for patients 
treated in the IMPACT trial: 
 
ELISpot Assay (with PA2024 and PAP) showed that the median # of 
spots were 12, 5 and 8 at Wks 6, 14 and 26 respectively with wk 0 


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showing  0 spots for PA2024;  A 100% increase in the median 
number of spots from these numbers after normalizing to control (pre-
treatment values) at their respective time points will constitute 
reaching the endpoint.  
 
T-Cell proliferation (3H-Thymidine) assay showed a median T-Cell 
Stimulation Index (SI) of 20 at Wk 6 and 18 at Wk 14 and 12 at Wk 
26; therefore a 100% increase of SI from these values at their 
respective time points after normalization to control (pre-treatment 
values) will constitute reaching the endpoint. 
 
ELISA showing an increase in >1:400 increase in the titer of antibody 
to PA2024 is reported by Sheikh et al [32], therefore an increase of 
1:800 titer or more would constitute reaching the endpoint.  
o 
A radiographic abscopal effect will be counted as evidence of an 
immunologic response and will be defined as radiographic response at non-
treated sites  
 
CT measurement of >50% decrease in diameter of a non-target soft-
tissue or visceral lesions (RECIST 1.1) as defined above 
 
PR or CR as defined in (Section 6.1.4) and per RECIST 1.1.  
 
Resolution of bone lesions in bone scan or a significant improvement 
in Bone scan as assessed by a radiologist. 
 
Since, it may be very difficult to assess a radiographic response in 
prostate cancer blastic lesions, if there are no progression of disease 
(as defined above) > 2 standard deviation from the Median TTP (14.6 
wks), it will also constitute as evidence of a durable immune 
response.  


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2.4.2 PFS: Progression-free survival (PFS) is defined as the length of time from start of 
treatment (week 0) to the time of disease progression (as defined in Section 6) 
or death from any cause. 
2.4.3 bPFS: Biochemical progression-free survival (bPFS) is defined as the time from 
start of treatment (week 0) to the time of PSA disease progression with PSA 
progression defined as the first documented date of an increase in PSA by > 
2ng/ml from baseline AND an increase >25% from baseline value that is 
confirmed by a second measurement >3 weeks apart according to the 
recommendations of PCWG2 [49], or death from any cause. 
2.4.4 OS: OS is defined as the duration of time from start of treatment (week 0) to the 
time of death from any cause. 
2.4.5 Prostate cancer specific survival (PCaSS): PCaSS is defined as the 
percentage of patients who have not died from prostate cancer at the time of 
analysis. 
2.4.6 Toxicity: Toxicity will be measured and reported based on NCI’s CTCAE v4.0 
toxicity criteria 
2.4.7 Quality of Life: FACT-P, EQ-5D and modified BPI will be used to assess quality 
of life. 
2.4.8 Cost Assessment: Health care utilization data needed to assess costs will be 
obtained from treatment records to include costs of hospitalization, treatment, 
ER visits, physician and clinic visits and medications (See section 6.3 and 10 for 
detail) 
3.0 
SUBJECT ELIGIBILITY 
Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria 
to be registered to the study. Study treatment may not begin until a subject is registered. 
3.1 
Inclusion Criteria 
 
3.1.1 
History of metastatic prostate cancer 
 
3.1.2 
Patient must currently be on androgen deprivation or anti-androgen therapy with 
castrate levels of testosterone (< 50ng/dl) 
 
3.1.2.1 Medical castration should continue until disease progression 
 
3.1.3 
Radiographic evidence of metastatic disease documented with bone scan, (CT 
scan, MRI or any form of PET scan (Axumin, PSMA etc.) are acceptable 
alternatives)  
 
3.1.3.1 Patients with any number of metastatic sites are allowed to enroll. 
However, only up to six sites will be selected for SBRT treatment and will be at 
the discretion of the treating radiation oncologist. 
 
3.1.4 
PSA ≥  0.2 ng/ml that is confirmed with a second PSA measurement 
 
 
3.1.5 
Adequate hematologic, renal, and liver function as evidenced by the following: 
White blood cell (WBC) ≥ 2,500 cells/μL 
Absolute neutrophil count (ANC) ≥ 1,000 cells/μL 


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Platelet Count ≥ 100,000 cells/μL 
Hemoglobin (HgB) ≥ 9.0 g/dL 
Creatinine ≤ 2.0 mg/dL 
Total Bilirubin ≤ 2 x upper limit of normal (ULN) 
Aspartate aminotransaminase (AST, SGOT) ≤ 2.5 x ULN 
Alanine aminotransaminase (ALT, SGPT) ≤ 2.5 x ULN 
 
3.1.6 
Previous treatment with surgery, radiation or hormonal therapy is allowed. 
 
3.1.7 
Performance status ECOG 0 or 1. 
 
3.1.8 
Life expectancy of at least 6 months 
 
3.1.9 
Age ≥ 18 years. 
 
 
3.1.10 Ability to understand and the willingness to sign a written informed consent. 
3.2 
Exclusion Criteria 
 
3.2.1 
Subject has received chemotherapy within the past 14 days.   
 
3.2.2 
Subjects with metastatic disease exclusively present within a previously 
irradiated field. 
 
 
3.2.3 
Subject is receiving any other investigational agents for the treatment of prostate 
cancer. 
 
3.2.4 
Subjects with known brain metastases.. 
 
3.2.5 
Subjects with malignant pleural effusions and malignant ascites 
 
3.2.6 
Systemic corticosteroid use within past 14 days, unless prescribed in conjunction 
with Abiraterone. Use of inhaled, intranasal, and topical steroids is acceptable. 
 
 
3.2.7 
Use of any of the following within the past 14 days:  Megestrol acetate 
(Megace®), diethyl stilbestrol (DES), or cyproterone acetate, Ketoconazole, high 
dose calcitriol [1,25(OH)2VitD] (i.e., > 7.0 μg/week). 
 
 
3.2.8 
Initiation or discontinuation of bisphosponate use within past 14 days.  
 
3.2.9.1 Continuation of use is allowed but patients must continue bisphosphonate 
throughout the treatment and follow up period until disease progression. 
 
3.2.9 
Subjects with spinal cord compression 
 
3.2.10 Paget’s disease of bone. 
 
3.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 


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3.2.12 History of positive serology tests for human immunodeficiency virus (HIV) 1 and 
2, human T cell lymphotropic virus (HTLV)-1, Hepatitis B and C 
4.0 
TREATMENT PLAN: STUDY MEDICATION 
4.1 
Sipuleucel-T: Treatment Dosage and Administration – The administration of 
Sipuleucel-T follows standard-of-care treatment.  The following treatment plan is 
recommended.  
4.1.1 
Preparation of sipuleucel-T:  
Sipuleucel-T will be administered for three cycles, two weeks each as per manufacturer's 
recommendation. SABR will be administered on the third-fourth week.  SABR planning 
takes place during the first two weeks and sipuleucel-T administration and treatment 
administration takes place on the third or fourth week, prior to the last leukapheresis.  All 
treatments can be carried out as out-patient. Further information regarding the 
manufacture and characterization of sipuleucel-T is provided in the sipuleucel-T 
Prescriber Information (Appendix G). 
4.1.2 
Leukapheresis and Collection of Quiescent APCs 
Collection of blood cells to generate sipuleucel-T 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), which takes place in the regional Carter Bloodcare center 
over approximately 4 hours. Prior mobilization with a colony-stimulating factor is not 
performed.  Immediately after collection, the leukapheresis product is transported to a 
regional manufacturing facility. 
4.1.3 
Sipuleucel-T 
Sipuleucel-T is an autologous cell product consisting of APCs loaded with prostate 
antigen PA2024. PA2024 is a 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 
[50]. PAP is secreted by the prostate tumor cells in vivo, and an elevated serum level is 
found in most subjects with advanced prostate cancer [51]. 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.  
 
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. 


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4.1.4 
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. Dendreon will  provide 
instructions for product return or destruction of cell products that are not approved or not 
infused. 
4.1.5 
Storage and Time Limitations 
The infusion of sipuleucel-T or placebo must begin prior to the expiration time indicated 
on the product label. Expired cell products must not be infused. 
4.1.6 
Administration (Recommended) 
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).  The infusion of sipuleucel-t contains at least 50 million CD54+ 
activated DC.  Subjects are observed for at least 30 minutes following the infusion.   
 
REGIMEN DESCRIPTION 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Cycle 
Length  
Leukapheresis 
 
 
IV over 4 hours 
before 
Sipuleucel-T 
Week 
1,3,5 
2 
weeks 
(14 days) 
 
Sipuleucel-T 
Acetaminophen, 
diphenhydramine,  
30min prior to 
infusion 
>50,000000 
CD54+ cells 
in 250ml LR 
IV infusion, 3-4 
days after 
completion of 
Leukapheresis 
week 1, 3, 
5 
SABR 
 
21-33Gy/1-3 
fractions 
 
Week 3-4 
 
 
Sipuleucel-T is an autologous DC therapy, which must be administered only to the 
patients the cells are derived from. It is essential to confirm identity of the patient and the 
specimen before infusion. Do not initiate infusion of expired Sipuleucel-T. If Sipuleucel-T 
is expired, another leukapheresis will have to be scheduled.  Infuse Sipuleucel-T 
intravenously over a period of approximately 60 minutes. Interrupt or slow infusion for 
acute infusion reactions, depending on the severity of the reaction. The most common 
adverse reactions (incidence ≥ 15%) are chills, fatigue, fever, back pain, nausea, joint 
ache, and headache. Sipuleucel-T is not routinely tested for transmissible infectious 
diseases and may transmit diseases to health care professionals handling the product. 
Universal precautions should be followed. 
4.2 
SABR Dose and Techniques 
4.2.1 
SABR Dose 
 
The SABR dose and fractionation scheme is generated to deliver a potent dose to ablate the 
targeted lesions and at the same time maximize an immune response. Since multiple studies 
have shown an influx of lymphocytes and monocytes within 24-48 hours after tumor irradiation 
[52-55] and these cells play a critical role in antigen presentation and initiation of an adaptive 
immune response, multiple fraction irradiation which would kill these infiltrating immunocytes, is 


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discouraged. Therefore a single fraction or three fraction treatment regimen is allowed, and a 
single fraction treatment is preferred over three fractions.  Due to normal organ toxicity and limits 
of dose constraints, sometimes a three fraction treatment must be undertaken in those cases it is 
recommended that the treatment course is completed within 7-10 days.  Radiation dose-
(immune) response studies have shown a linear increase in immune response with increased 
dose per fraction of radiation without demonstration of a plateau [4, 52, 55, 56]. Two studies have 
compared 15Gy x 1 with 5Gy x3, and 20Gy x1 with 5Gy x4 and have showed a superior immune 
response generated by the single fraction radiation [52, 55]. Clinical experience with 
oligometastatic patients treated at 1-5 sites of disease has also showed an increase in 
progression free survival with the increasing radiation dose per fraction [57]. A dose of less than 
7.5 Gy per fraction has demonstrated lower induction of systemic INF-γ producing cells and 
therefore 8Gy per fraction is the lowest permitted dose [56].  
 
The SABR prescription dose will be delivered to the periphery of the planning target volume 
(PTV, see below for definitions).  Investigators will have discretion in choosing from either of the 
biologically equivalent dose levels using one or three fractions, although a single fraction is 
preferred over three fraction treatments.  Treating physician will have further discretion in 
selecting up to six sites to treat if >6 sites of disease are present. Preference should be given to 
the largest feasible disease site, bulky progressive sites, symptomatic sites, and sites where 
palliative and preventative (i.e. to prevent a pathologic fracture in weight bearing bone) 
indications are applicable.  Treating physicians should choose their dose based on established 
planning guidelines at their center including their ability to respect normal tissue tolerance listed 
below.  It is not required that all targets be treated with the same dose fractionation.  A dose from 
the following table should be used: 
 
Prescription Dose 
 
Total Cumulative Dose Encompassing 95% of Planning 
Target Volume (Gy) 
Number of 
Fractions 
Protocol Compliant 
Minor Deviation * 
Major Deviation 
1 
21-27 Gy 
≥16 Gy, <21 Gy 
>27 Gy, <16 Gy 
3 
26.5-33 Gy 
≥24.5 Gy, <26.5 Gy 
>33 Gy, <24.5 Gy 
 
*This column is protocol compliant for tumors abutting the spinal cord (major deviation remain as 
listed) 
 
Dose tolerance limits should be adhered to for all treatments.  Protocol compliant dose should be 
used in all cases, if possible.  When treating tumors abutting the spinal cord, tolerance limits 
should not be exceeded.  To facilitate this requirement, minor deviation dose ranges listed above 
in the table will be considered fully compliant for tumors abutting the spinal cord The gross 
target/tumor volume (GTV) should be at least 2cm3 in size, corresponding to roughly a 1.5 cm 
diameter tumor. This is to ensure that adequate tumor volume and therefore adequate tumor cells 
(roughly 108 -109 cells/cm3 [58]) are killed for antigen presentation. In addition, it is recognized 
that for parrallal tissues (i.e. Lung, Liver and Kidney), if tumor lesions are larger than a certain 
percentage of its total volume, then it becomes exceedingly difficult to reach the tissue constraints 
and its critical volume dose limit.  Therefore, the following GTV volume guidelines should be 
followed, which is defined for a single lesion: 
 
GTV Volume: 
GTV Volume (cc)* 
Protocol Compliant 
Minor Deviation * 
Major Deviation 
2-100 
>100; <2; >20% of organ volume 
<1.5  
*the volume limits only applies to Liver, Lung and Kidney lesions. 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
4.2.2 
Planning Constraints and Concerns  
The tolerance dose of SBRT to the gastrointestinal tract is not established, and patients with 
metastatic disease involving the esophagus, stomach, intestines, or mesenteric lymph nodes will 
not be eligible. Patients with renal or adrenal metastases are potentially eligible if normal tissue 
constraints are otherwise met.  
 
It is well established that for palliative effect for a painful bone metastasis, a single dose of 8 Gy is 
usually as effective as 30 Gy [59]. However, in this protocol the goal is not just to relieve pain 
within an osseous metastasis but also to dramatically debulk the cancer cells present and induce 
an immune response, and the higher dose is more likely to accomplish this goal given a higher 
biological potency [60]. Long term survival after bone metastasectomy has been reported [61].  
Irradiation of non-spinal skeletal sites does not generally require specialized techniques of 
treatment. Metastases in major lower extremity and weight-bearing bones should undergo 
surgical stabilization if there is radiographic evidence of cortical erosion. Similarly, whenever 
treating organs of the GI tract (Esophagus, stomach, small/large bowel, rectum), if there are 
concerns for bowel obstruction, a GI or surgical referral must be placed.  
4.2.3 
Treatment Technique 
 
Each cycle of Sipuleucel-T consists of two weeks. The first day is a leukapheresis procedure that 
takes place in the Carter BloodCare: 4201 Gaston Avenue, Dallas, TX 75246; (214) 217-5676. 
On day 3-4, Sipuleucel-T, which is commercially available from Dendreon, is infused to the 
patients. This cycle is repeated every two weeks for a total of three times. SABR planning 
simulation takes place during the first cycle of Sipuleucel-T and the SABR treatment is 
administered over the two weeks of cycle 2.  
4.2.3.1 
Simulation, beam arrangements, tumor prescription dose 
Treatment to skeletal lesions other than spine, may be accomplished with any 3D conformal 
radiotherapy or intensity-modulated radiotherapy (IMRT) technique suitable for this application 
with performance specifications adequate to provide proper tumor dose distribution and normal 
tissue sparing. The bone lesions can be treated with a conformal 3D or IMRT technique, which is 
different than SBRT/SABR technique. The difference lies in immobilization technique and 
dosimetric planning, but otherwise all the descriptions of SBRT in terms of contouring and tissue 
constraints that needs to be met remains the same. Immobilization for 3D or IMRT does not 
require a body frame but rather a Vac-lock bag is used with appropriate additional devices (i.e. 
head rest, knee sponge, etc.).   
At the time of simulation for patients who will receive SBRT to the lung and/or liver, the movement 
of the dome of the diaphragm (superior portion of the liver) is to be observed under fluoroscopy or 
other acceptable means to estimate respiratory movement during treatment if no breathing 
control device is used.  Patients will be assessed for suitability for tolerance of a respiratory 
control device using a breath-hold technique, respiratory gating, or abdominal compression to 
limit diaphragmatic excursion during respiration. Patients with severe lung disease and patients 
who cannot tolerate diaphragmatic or breathing control devices for other reasons will be treated 
without them. A larger margin to account for breathing related intra-fractional organ movement is 
required. 
With the patient immobilized in a vacuum-type or equivalent body mold preferably in a body 
frame, a planning CT scan with 3-5 mm slices is performed. Intravenous contrast is 
recommended for lesions near mediastinal structures and lesions within the liver. The form of 
respiratory control to be used during treatment should also be used during the simulation. Oral GI 
contrast to highlight the stomach and duodenum is recommended for patients with medial liver 
lesions or lesions of the caudate lobe.  
For treatment to the liver, the following structures are contoured: entire liver, each individual liver 
gross tumor volume (GTV), each kidney, and the spinal cord. The planning target volume (PTV) 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
is constructed to account for the positional uncertainty of the GTV during treatment. The PTV for 
each contoured GTV should be at least 5mm larger than the GTV in the axial plane and 1.0 cm 
larger than the GTV in the craniocaudal plane. Larger margins may be used in cases where 
greater motion of the hemidiaphragm is observed in simulation despite standard maneuvers to 
diminish motion.  For lung SBRT the same principles apply; the entire lung volumes are 
contoured, as are each individual GTV within the lung. 
The prescription dose for each lesion is listed in the table in section 4.1, prescribed to the 
periphery of the PTV. In case of IMRT or 3D conformal technique, a PTV coverage of >95% of 
the prescription dose is required with no restrictions on dose heterogeneity other than minimal 
PTV dose >90%. There is no restriction on the dose “hotspot” except that it must be located 
within the PTV. A Linear Accelerator with effective photon energies of ≥ 6 MV is required. The 
use of a Multi-leaf collimator (MLC) or custom blocks are acceptable.  A stereotactic relocalization 
system that relies upon stereoscopic radiographs, implanted fiducials, or near real-time CT based 
verification will be used.  
The PTV may be treated with any combination of coplanar or non-coplanar three-dimensional 
conformal fields, shaped to deliver the specified dose while restricting the dose to the normal 
tissues.  Field arrangements will be determined by the planning system to produce the optimal 
conformal plan in accordance with volume definitions.  
4.2.3.2 Normal Tissue Dose Constraints 
 
In accordance with the prior Phase I studies [62], certain normal tissue dose constraints must be 
respected.  
 
The possibility that SBRT-induced fibrosis might cause occlusion of large central airways, thus 
impeding ventilation distal to the occlusion has been well considered [63]. An adjustment to the 
fractionation scheme may be made if, in the opinion of the treating radiation oncologist, the 
following conditions apply: (1) the location of a lung lesion is close enough to a large proximal 
bronchial airway such that occlusion might occur, and (2) compromised ventilation to the 
segment(s) of lung potentially affected would cause clinically significant adverse consequences. 
In such a case, the treating radiation oncologist should discuss any proposed dose modifications 
with the PI to decide whether a regimen of similar biological potency can be safely given. 
 
The same special situations apply whenever a lesion is close to the spinal cord, small bowel, 
great vessels, porta hepatis and renal pelvis. In these situations, in addition to meeting dose 
constraints, additional tests must be performed to ensure adequate reserve of normal tissue 
function. For example, in the situation of a renal pelvis lesions, a functional renal scan must be 
performed to ensure ample renal reserve for the patient.  In case of a patient with COPD 
receiving radiation to lung lesions, PFT must be performed to demonstrate FEV1>1.2L and DLCO 
>60%. In case of a patient with peripherial lung lesion close to the ribs, to decrease the chance of 
a rib fracture, the lesion must be >3mm from the rib. In case of treating liver lesions, LFTs must 
be within normal range.   
 
Special condition applies in the setting of a patient whose primary prostate disease has been 
irradiated previously and is present as a site of disease. Since re-irradiation toxicity is a concern, 
these patients will not receive SABR to the sites of previous irradiation. These patients will only 
be included in the trial if they have metastatic disease that are eligible for SABR outside the 
previously irradiated field.  Re-irradiation to a site that has received previous SBRT is also not 
allowed.   
 
Deviations from the intended dose regimen will be documented, with calculations of the BED of 
the applied regimen included in the patient’s research chart along with documentation of the 
discussions pertaining to the idiosyncrasies of the case. 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
Prescription Volume (ml) 
 
Total Cumulative Dose Encompassing 95% of Planning 
Target Volume (Gy) 
Number of 
Fractions 
Protocol Compliant 
Minor Deviation * 
Major Deviation 
1 
21-27 Gy 
≥16 Gy, <21 Gy 
>27 Gy, <16 Gy 
3 
26.5-33 Gy 
≥24.5 Gy, <26.5 Gy 
>33 Gy, <24.5 Gy 
 
*This column is protocol compliant for tumors abutting the spinal cord (major deviation remain as 
listed) 
 
 
The following table lists the specific organ and dose fractionation constraints on normal tissues. 
 
For One Fraction: 
Serial Tissue 
Volume 
Volume Max 
(Gy) 
Max Point 
Dose 
(Gy)** 
Endpoint (≥Grade 
3) 
Optic Pathway 
<0.2 cc 
8 Gy 
10 Gy 
neuritis 
Cochlea 
 
 
9 Gy 
hearing loss 
Brainstem (not medulla) 
<0.5 cc 
10 Gy 
15 Gy 
cranial neuropathy 
Spinal Cord and medulla 
<0.35 cc 
<1.2 cc 
10 Gy 
8 Gy 
14 Gy 
myelitis 
Spinal Cord Subvolume (5-6 
mm above and below level 
treated per Ryu) 
<10% of 
subvolume 
10 Gy 
14 Gy 
myelitis 
Cauda Equina 
<5 cc 
14 Gy 
16 Gy 
neuritis 
Sacral Plexus 
<5 cc 
14.4 Gy 
16 Gy 
neuropathy 
Esophagus* 
<5 cc 
11.9 Gy 
15.4 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
13.6 Gy 
16.4  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
16 Gy 
22 Gy 
pericarditis 
Great vessels 
<10 cc 
31 Gy 
37 Gy 
aneurysm 
Trachea and Large Bronchus* 
<4 cc 
17.4 Gy 
20.2 Gy 
stenosis/fistula 
Bronchus- smaller airways 
<0.5 cc 
12.4 Gy 
13.3 Gy 
stenosis with 
atelectasis 
Rib 
<5 cc 
28 Gy 
33 Gy 
Pain or fracture 
Skin 
<10 cc 
25.5 Gy 
27.5 Gy 
ulceration 
Stomach 
<5 cc 
17.4 Gy 
22 Gy 
ulceration/fistula 
Bile duct 
 
 
30 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
11.2 Gy 
9 Gy 
17 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
12.5 Gy 
22 Gy 
enteritis/obstruction 
Colon* 
<20 cc 
18 Gy 
29.2 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
39 Gy 
22 Gy 
44.2 Gy 
proctitis/fistula 
Ureter 
 
 
35 Gy 
stenosis 
Bladder wall 
<15 cc 
12 Gy 
25 Gy 
cystitis/fistula 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Penile bulb 
<3 cc 
16 Gy 
 
impotence 
Femoral Heads  
<10 cc 
15 Gy 
 
necrosis 
Renal hilum/vascular trunk 
15 cc 
14 Gy 
 
malignant 
hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume (cc) 
Critical 
Volume Dose 
Max (Gy) 
 
Endpoint (≥Grade 
3) 
Lung (Right & Left) 
1500 cc 
7 Gy 
 
Basic Lung Function 
Lung (Right & Left) 
1000 cc 
7.6 Gy 
V-8Gy 
<37% 
Pneumonitis 
Liver 
700 cc 
11 Gy 
 
Basic Liver 
Function 
Renal cortex (Right & Left) 
200 cc 
9.5 Gy 
 
Basic renal function 
 
For Three Fractions: 
 
Serial Tissue 
Volume 
Volume Max 
(Gy) 
Max Point Dose 
(Gy)** 
Endpoint (≥Grade 
3) 
Optic Pathway 
<0.2 cc 
15.3 Gy  
17.4 Gy  
neuritis 
Cochlea 
 
 
14.4 Gy  
hearing loss 
Brainstem (not 
medulla) 
<0.5 cc 
15.9 Gy 
23.1 Gy  
cranial neuropathy 
Spinal Cord and 
medulla 
<0.35 cc 
<1.2 cc 
15.9 Gy 
13 Gy 
22.5 Gy 
myelitis 
Spinal Cord Subvolume 
(5-6 mm above and 
below level treated per 
Ryu) 
<10% of 
subvolume 
18 Gy 
22.5 Gy 
myelitis 
Cauda Equina 
<5 cc 
21.9 Gy  
25.5 Gy 
neuritis 
Sacral Plexus 
<5 cc 
22.5 Gy 
24 Gy 
neuropathy 
Esophagus* 
<5 cc 
17.7 Gy 
25.2 Gy 
stenosis/fistula 
Brachial Plexus 
<3 cc 
22 Gy 
26  Gy 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy 
30 Gy 
pericarditis 
Great vessels 
<10 cc 
39 Gy 
45 Gy 
aneurysm 
Trachea and Large 
Bronchus* 
<5 cc 
25.8 Gy 
30 Gy 
stenosis/fistula 
Bronchus- smaller 
airways 
<0.5 cc 
18.9 Gy 
23.1 Gy 
stenosis with 
atelectasis 
Rib 
<5 cc 
40 Gy 
50 Gy 
Pain or fracture 
Skin 
<10 cc 
31 Gy 
33 Gy 
ulceration 
Stomach 
<5 cc 
22.5 Gy 
30 Gy 
ulceration/fistula 
Bile duct 
 
 
36 Gy 
stenosis 
Duodenum* 
<5 cc 
<10 cc 
15.6 Gy 
12.9 Gy 
22.2 Gy 
ulceration 
Jejunum/Ileum* 
<30 cc 
17.4 Gy 
27 Gy 
enteritis/obstruction 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Colon* 
<20 cc 
24 Gy 
34.5 Gy 
colitis/fistula 
Rectum* 
<3.5 cc 
<20 cc 
45 Gy 
27.5 Gy 
49.5 Gy 
proctitis/fistula 
Ureter 
 
 
40 Gy 
stenosis 
Bladder wall 
<15 cc 
17 Gy 
33 Gy 
cystitis/fistula 
Penile bulb 
<3 cc 
25 Gy 
 
impotence 
Femoral Heads  
<10 cc 
24 Gy 
 
necrosis 
Renal hilum/vascular 
trunk 
15 cc 
19.5 Gy 
 
malignant 
hypertension 
 
 
 
 
 
Parallel Tissue 
Critical 
Volume 
(cc) 
Critical Volume 
Dose Max (Gy) 
 
Endpoint (≥Grade 
3) 
Lung (Right & Left) 
1500 cc 
10.5 Gy 
 
Basic Lung 
Function 
Lung (Right & Left) 
1000 cc 
11.4 Gy 
V-11Gy<37% 
Pneumonitis 
Liver 
700 cc 
17.1 Gy 
 
Basic Liver 
Function 
Renal cortex (Right & 
Left) 
200 cc 
15 Gy 
 
Basic renal 
function 
 
*Avoid circumferential irradiation. 
** “point” defined as 0.035cc or less 
Exceeding these dose tolerances by more than 2.5% constitutes a minor protocol violation.  
Exceeding these dose tolerances by more than 5% constitutes a major protocol violation. 
4.2.4 
Radiation Therapy Quality Assurance 
 
Dr. Timmerman will perform an RT Quality Assurance Review after complete data for the first 15 
cases enrolled has been received at the University of Texas Southwestern.  
4.3 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each patient will 
be assessed for the development of toxicity for 6 months following the completion of radiation 
therapy( see Time and Events table (5.4)). Toxicity will be assessed according to the NCI 
Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be 
made according to the system showing the greatest degree of toxicity.  
 
Both treatments of sipuleucel-T and SABR have excellent safety profile. The most commonly 
reported toxicity for sipuleucel-T (incidence ≥ 15%) are chills, fatigue, fever, back pain, nausea, 
joint ache, and headache (see Section 7.0 and 8.0 for detail). Acute infusion reactions (reported 
within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events 
(dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and 
tachycardia. In controlled clinical trials, 71.2% of patients in the sipuleucel-T group developed an 
acute infusion reaction. The most common events (≥ 20%) were chills, fever, and fatigue. In 
95.1% of patients reporting acute infusion reactions, the events were mild or moderate. Fevers 
and chills generally resolved within 2 days (71.9% and 89.0%, respectively).  In controlled clinical 
trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the 
sipuleucel-T group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, 
bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The 
incidence of severe events was greater following the second infusion (2.1% vs. 0.8% following 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the 
sipuleucel-T group were hospitalized within 1 day of infusion for management of acute infusion 
reactions. No Grade 4 or 5 acute infusion reactions were reported in patients in the sipuleucel-T 
group.  
 
In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion 
stopped, depending on the severity of the reaction. Appropriate medical therapy should be 
administered as needed. 
 
Hematologic toxicity is not reported or expected for either sipuleucel-T or SABR.  
Non-hematological Toxicities should be managed as follows: 
 
Non-hematological Toxicity Dose Reductions 
NCI CTC Grade 
Sipuleucel-T 
SABR 
0-2 
No change from original 
starting dose 
No change from original starting dose 
3  
Hold until resolved to 
<Grade 2, then proceed  
Hold until resolved to <Grade 2, then 
proceed 
Second episode of 
grade 3 or 4 toxicity 
Hold until resolved to 
<Grade 2, then proceed 
Hold until resolved to <Grade 2, then 
proceed 
Third episode of 
grade 3 or 4 toxicity 
Remove subject from trial 
Remove subject from trial 
 
4.4 
Concomitant Medications/Treatments 
Drugs that are prohibited during or within the follow up time of the protocol therapy include 
chemotherapy, glucocorticoids and any other treatments directed to mCRPC patients. 
Bisphosphonates or treatment for bony metastatic disease and androgen deprivation therapy 
should not be initiated, but if patient is already on the treatment, then it should be continued 
throughout the duration of the study.  
4.5 
Duration of Therapy 
Treatment administration is typically completed within 6 weeks from the start of first Sipuleucel-T. 
In case of delay, the recommended time for completion of both Sipuleucel-T and SABR is within 8 
weeks. In the absence of treatment delays due to adverse events, treatment may continue until: 
 Inter-current illness that prevents further administration of treatment 
 Unacceptable adverse event(s) 
 Subject  decides to withdraw from the study, OR 
 General or specific changes in the patient’s condition render the subject unacceptable for 
further treatment in the judgment of the investigator. 
 
4.6 
Duration of Follow Up 
Subjects will be followed for four years or death, whichever occurs first. Subjects removed from 
treatment for unacceptable adverse events will be followed until resolution or stabilization of the 
adverse event. The follow-up will be every 8-12 weeks for the first 6-36 weeks or until 9 months 
with physical exam., then every 12 weeks until two years, then every 6 months for two years. 
PSA for bRFS will be measured every three months for 2 years and every 6 months thereafter for 
the following 2 years. See section 5.0 for detail. Once the subject demonstrates progressive 
disease (documented by two sets of imaging at least 8 weeks apart), they will no longer adhere to 
the study calendar and will be followed for survival only. 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
4.7 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.5 apply. Notify 
the Principal Investigator, and document the reason for study removal and the date the subject 
was removed in the Case Report Form. The subject should be followed-up per standard of care.  
 
5.0 
STUDY PROCEDURES 
5.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. If the (specially radiographic) studies were done before 
informed consent was obtained for clinical indications (not exclusively to determine study 
eligibility), they may be used for baseline values ONLY if they were done within 30 days 
prior, to keep within the limits of starting Sipuleucel-T within 30 days(+/-7days) of 
baseline radiologic study.   
 
All screening procedures must be performed within 30 days (+/-7) prior to registration 
unless otherwise stated. The screening procedures include: 
5.1.1 Informed Consent 
5.1.2 Medical history 
Complete medical and surgical history 
5.1.3 Demographics 
Age, gender, race, ethnicity 
5.1.4 Review subject eligibility criteria 
5.1.5 Review previous and concomitant medications 
5.1.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.1.7 Performance status 
Performance status evaluated prior to study entry according to Appendix A. 
5.1.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 7 for Adverse Event 
monitoring and reporting. 
5.1.9 Hematology 
 
CBC with differential. 
5.1.10 Blood draw for correlative studies 
Only if patient has met the eligibility and has signed informed consent. See 
Section 9.0 for details. 
5.1.11 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase, 
ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, potassium, 
calcium, chloride, bicarbonate), glucose and total bilirubin. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
Additional required lab work: 
 
Uric acid, C-Reactive protein (CRP), beta-2 microglobulin, LDH 
 
Prostate cancer specific tests: PSA, testosterone 
5.1.12 Serologic Tests 
HLA typing (Human Leukocyte Antigen). This test is genetic so may be performed 
at any time prior to registration.  
5.1.13 Radiographic Imaging 
Bone scan, CT chest, abdomen and pelvis with IV contrast. PET scan alone can 
replace both the bone and CT scans.  
5.1.15 QoL Questionnaires  
FACT-P, EQ-5D, modified BPI, cost and convenience questionnaire.  These forms 
will be referred to collectively as QoL Questionnaires. 
5.2 
Procedures during treatment (performed per MD discretion) 
Each cycle of Sipuleucel-T consists of two weeks. The first day is a leukapheresis 
procedure that takes place in the Carter BloodCare: 4201 Gaston Avenue, Dallas, TX 
75246; (214) 217-5676. On day 3-4, Sipuleucel-T, which is commercially available from 
Dendreon, is infused to the patients. This cycle is repeated every two weeks for a total of 
three times. SABR planning simulation takes place during the first cycle of Sipuleucel-T 
and the SABR treatment is administered over the two weeks of cycle 2.  
5.3 
Follow-up Procedures 
Subject will be followed every 8-12 weeks after completion of (or early withdrawal from) 
study treatment (Sipuleucel-T) until nine months. After nine months, subjects will be 
followed for every 12 weeks for a total of 2 years; every six months for another two years. 
After four years, the subject follow up will be at the discretion of the treating physician. 
Once the subject demonstrates progressive disease (documented by two sets of imaging 
at least 6 weeks apart) they will no longer adhere to the study calendar and will be 
followed for survival only. 
 
5.4 
Time and Events Table 
 
Pre-
study 
Cycle 1, 
Day1 
Cycle 2,  
Day15 – 
28 (+/- 5 
days) 
Cycle3, 
Day29 
– 32 
(+/- 5 
days) 
Week 6-36 
(9 months):  
Q8-12 
weeks 
Months 9-24:  
q12 weeks 
Months 24-48: 
q6 months 
Informed Consent 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
        X 
X 
X 
History and PE 
X 
 
 
 
 X2 
X 
X 
Performance 
Status 
X 
 
 
 
X 
X 
X 
Adverse 
event 
monitoring 
X 
 
 
 
XA 
 
 
Bone Scan9 
X 
 
 
 
 X1 
X 
X 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
1 Bone scan performed every 8-12 weeks only if bone lesions present at baseline. All other 
patients receive bone scan every 12 weeks.  
2 Physical Exam only. 
3 CT scans performed every 8-12 weeks only if soft tissue lesion is present. All other patients 
receive CT scans every 12 weeks.  
4 Immunologic blood collection is pre-study, after SABR tx, and 6 weeks, 12 weeks, and 24 
weeks after completion of cycle 3 Sipuleucel-T. 
5 Cost and Convenience Questionnaire will only be administered at the first follow up visit. QoL 
surveys will take place pre study, 24 weeks and one year after completion of cycle 3 Sipuleucel-T 
6  HLA typing (baseline only)  
 
 
             7Post tx biopsy of metastatic site – (elective post-tx bx at 8 weeks see Section 5.3) 
 
 
 
9 PET scan alone is an acceptable alternative to both CT CAP and bone scan. 
A Adverse events will only be collected and documented from baseline to the first 6 months 
following completion of radiation therapy   
 
Note that the study calendar is based on the ideal subject.  The schedule should be followed as 
closely and realistically as possible, but may be modified due to problems such as scheduling 
delays, weekends, conflicts such as clinic closure or poor weather conditions, or other 
unforeseeable events.  
5.5 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
5.5.1 
Subject voluntarily withdraws from treatment (follow-up permitted); 
CT 
Chest, 
Abd, 
pelvis w/ Contrast9 
X 
 
 
 
 X3 
X 
X 
CBC 
X 
 
 
 
X 
X 
X 
Comprehensive 
Chemistry  
X 
 
 
 
X 
X 
X 
Uric acid, Beta-2 
microglobulin, C 
reactive protein, 
LD  
X 
 
 
 
X  
(at 6 weeks 
and 12 
weeks 
only) 
 
 
HLA typing6 
X  
 
 
 
 
 
 
PSA, Testosterone 
X 
 
 
 
X 
X 
X 
Blood collection for 
Immune Assays 
X 
 
X 
 
 X4 
 
 
SABR 
 
 
X 
 
 
 
 
QOL 
Questionnaires 
(baseline, 6 
months and 1 year 
only) 
 
X 
 
 
 
X5 
X 
 
Cost and 
Convenience 
Questionnaire  
 
 
 
 
X  
(at first f/u 
only) 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
5.5.2 
Subject withdraws consent (termination of treatment and follow-up); 
5.5.3 
Subject is unable to comply with protocol requirements; including if patient fails to 
receive at least two cycles of Sipuleucel-T. 
5.5.4 
Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.5.5 
Treating physician judges continuation on the study would not be in the subject’s 
best interest; 
5.5.6 
Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
5.5.7 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of six months, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the six months must be documented. 
6.0 
Measurement of Effect 
6.1 
Antitumor Effect 
 
Response and progression will be evaluated in this study using the modified new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1) Committee [JNCI 92(3):205-216, 2000] with modifications suggested by 
PCWG2 [49] recommendations and as used in the Phase III clinical trial by Kantoff et. 
al.[10].  Changes in only the largest diameter (one-dimensional measurement) of the 
tumor lesions are used in the RECIST v1.1 criteria as outlined in http://www.recist.com/.  
6.1.1 
Definitions 
Evaluable for toxicity. All subjects will be evaluable for toxicity from the time of 
their first treatment with Sipuleucel-T. 
 
Evaluable for objective response.  Only those subjects who have measurable 
disease or bone lesions present at baseline, have received at least two cycle of 
therapy and at least one fraction SABR, and have had their disease re-evaluated 
will be considered evaluable for response. These subjects will have their 
response classified according to the definitions stated below. (Note: Subjects 
who exhibit objective disease progression prior to the end of cycle 1 will also be 
considered evaluable.) 
6.1.2 
Disease Parameters 
6.1.2.1 Bone Lesions: PCWG2 recommendations will be followed for bone 
lesions as follows:  
Bone Lesions: (PCWG2 recommendations; JCO 2008) 
 
Radiotracer uptake in a radionuclide bone scan consistent 
with metastatic disease as read by a radiologist.  


STU 102012-026 
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CONFIDENTIAL 
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study sponsor. 
 
6.1.2.2 
Measurable Disease: Tumor lesions: Must be accurately measured in at 
least one dimension (longest diameter in the plane of measurement is to be 
recorded) with a minimum size of:  
1. 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
2. 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
3. 20 mm by chest x-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). Lymph nodes merit special 
mention since they are normal anatomical structures which may be visible by imaging 
even if not involved by tumor. Pathological nodes which are defined as measurable 
and may be identified as target lesions must meet the criterion of a short axis of ≥ 15 
mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to 
judge if a node is involved by solid tumor. Nodal size is normally reported as two 
dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane; for MRI the plane of acquisition may be axial, sagittal or 
coronal). The smaller of these measures is the short axis. For example, an abdominal 
node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have 
a short axis < 10 mm are considered non-pathological and should not be recorded or 
followed. 
Note: Previously irradiated lesions are non-measurable except in cases of 
documented progression of the lesion since the completion of radiation therapy. 
Non-measurable disease.  
All other lesions are considered non-measurable, including small lesions (longest 
diameter < 10mm or pathological lymph nodes with ≥ 10 to < 15 mm short 
axis) as well as truly non-measurable lesions. Lesions considered truly non-
measurable include: leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
Target lesions.  
All measurable lesions up to a maximum of five lesions total (and a maximum of two 
lesions per organ) representative of all involved organs should be identified 
as target lesions 
6.1.3 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the five target lesions should be 
identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up. Methods for 
Evaluation 


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study sponsor. 
 
All measurements should be taken and recorded in metric notation using a ruler 
or calipers.  
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up 
using appropriate radiologic imaging.  
 
Bone scans and CT scan of Chest, abdomen and pelvis with IV contrast will be 
performed at baseline.  If patient has bone lesions, then bone scan will be 
performed every 8-12 week intervals for 36 weeks and CT scan performed every 
12 weeks. If patient has soft-tissue lesions, then CT scan will be performed every 
8-12 weeks and bone scan performed every 12 weeks until 36 weeks (Please 
see section 5.3 and 5.4 for detail).   
 
Spiral CT and MRI. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  
6.1.4 
Response Criteria 
6.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.   
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm (the sum may not be “0” if there are target nodes).  Determined by 
two separate observations conducted not less than 4 weeks apart. There 
can be no appearance of new lesions. 
 
Partial Response (PR): At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as reference the baseline 
sum LD. There can be no appearance of new lesions. 
 
Progressive Disease (PD): > 20% increase in the SLD taking as 
reference the smallest SLD recorded since the treatment started (nadir) 
and minimum 5 mm increase over the nadir.   
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
LD since the treatment started. There can be no unequivocal new 
lesions. 
6.1.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target 
lesions and normalization of tumor marker level. All lymph nodes must 
be non-pathological in size (< 10 mm short axis). 
 
 
 
Incomplete Response/Stable Disease (Non-CR/Non-PD): 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
 
 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions 
6.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference 


STU 102012-026 
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study sponsor. 
 
for progressive disease the smallest measurements recorded since the 
treatment started). The subject’s best response assignment will depend 
on the achievement of both measurement and confirmation criteria. 
 
 
Time point response: patients with target (+/– non-target) disease. 
Target lesions 
Non-target lesions 
New 
lesions 
Overall 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all 
evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial 
response, SD = stable disease. 
 
Time point response: patients with non-target disease only. 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, NE = not evaluable, PD = progressive disease 
A ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
 
6.1.5 
Duration of Response 
Duration of overall response: The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively 
documented. 
 
 
Duration of stable disease: Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started.  


STU 102012-026 
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study sponsor. 
 
6.1.6 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of 
treatment to time of progression. 
6.1.6.1 Evaluation of Bone Lesions:  
6.1.6.1.1 
Progression of bone lesions will be defined according to the 
PCWG2 criterion:  
 
Appearance of 2 or more new bone lesions in Bone scan, confirmed 
by a repeat bone scan in ≥8 weeks. 
 
The Appearance of 2 new lesions on the 6 week scan will require ≥2 
additional new lesions in a repeat bone scan ≥8 weeks apart.  
6.1.6.1.2 
Response of bone lesions will be defined by either a complete 
resolution (CR) at the metastatic sites or partial resolution (PR) of 
radiotracer uptake by a radiologist.   
6.1.6.2 Evaluation of Pathologic Fracture:  
Any clinical suspicion of pathologic fracture will prompt radiologic 
evaluation with plain film, CT or MRI as appropriate and if confirmed by a 
radiologist, will constitute progression.  
6.1.6.3 Evaluation of spinal cord Compression or Cauda equina 
compression:  
Any clinical suspicion of cord or cauda equine compression will prompt 
radiologic evaluation with MRI (CT myelography if patient is not eligible 
for MRI) as appropriate and if confirmed by a radiologist, will constitute 
progression. 
6.1.7 
Time to Progression (TTP) 
TTP is measured from the time treatment is started (week 0) until the first date 
that progressive disease is objectively documented as defined by one of the 
response criterions in 6.1.4. 
6.1.8 
Measurement of Immunologic Response:  
Reaching an immunologic endpoint by any patient will constitute either an 
amplification of immune response (as compared to historically reported values for 
sipuleucel-T administration alone) or abscopal radiographic response.  Immune 
response will be measured using ELISpot assay, T-cell proliferation assay or 
ELISA.  The assays will first be calibrated by measuring the background 
responses in baseline samples of patients pre-treatment and an increase of >95th 
percentile will be considered a positive response.  To reach the immunologic end 
point for this trial, there has to be a >100% increase in immune response as 
measured by ANY of the assays when Sipuleucel-T is administered alone as 
reported by Sheikh et. a.[32] for patients treated in the IMPACT trial: 
 
ELISpot Assay (with PA2024 and PAP) showed that the median # of 
spots were 12, 5 and 8 at Wks 6, 14 and 26 respectively with wk 0 
showing  0 spots for PA2024;  A 100% increase in the median 
number of spots from these numbers after normalizing to control (pre-
treatment values) at their respective time points will constitute 
reaching the endpoint.  
 
T-Cell proliferation (3H-Thymidine) assay showed a median T-Cell 
Stimulation Index (SI) of 20 at Wk 6 and 18 at Wk 14 and 12 at Wk 


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26; therefore a 100% increase of SI from these values at their 
respective time points after normalization to control (pre-treatment 
values) will constitute reaching the endpoint. 
 
ELISA showing an increase in >1:400 increase in the titer of antibody 
to PA2024 is reported by Sheikh et.al [32], therefore an increase of 
1:800 titer or more would constitute reaching the endpoint.   
  
o 
A radiographic abscopal effect will be counted as evidence of an 
immunologic response and will be defined as radiographic response at non-
treated sites  
 
CT measurement of >50% decrease in diameter of a non-target soft-
tissue or visceral lesions (RECIST 1.1) as defined above 
 
PR or CR as defined in (Section 6.1.4) and per RECIST 1.1.  
 
Resolution of bone lesions in bone scan or a significant improvement 
in Bone scan as assessed by a radiologist. 
 
Since, it may be very difficult to assess a radiographic response in 
prostate cancer blastic lesions, if there are no progression of disease 
(as defined above) > 2 standard deviation from the Median TTP (14.6 
wks), it will also constitute as evidence of a durable immune 
response.  
6.1.9 PFS:  
Progression-free survival (PFS) is defined as the length of time from start of 
treatment (week 0) to the time of disease progression (as defined in Section 6) or 
death from any cause.  
6.1.10 bPFS:  
Biochemical progression-free survival (bPFS) is defined as the time from start of 
treatment (week 0) to the time of PSA disease progression with PSA progression 
defined as the first documented date of an increase in PSA by > 2ng/ml from 
baseline AND an increase >25% from baseline value that is confirmed by a 
second measurement >3 weeks apart according to the recommendations of 
PCWG2 [49], or death from any cause. 
6.1.11 OS:  
OS is defined as the duration of time from start of treatment (week 0) to the time 
of death. 
6.1.12 Prostate cancer specific survival (PCaSS):  
PCaSS is defined as the percentage of patients who have not died from prostate 
cancer at the time of analysis and will be calculated according to the following 
equation:   
 
 
 


STU 102012-026 
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6.2 
Quality of Life:  
6.2.1 Functional Assessment of Cancer Therapy-P (FACT-P) 
Patient-reported functional status will be assessed with prostate cancer subscales of 
the Functional Assessment of Cancer Therapy-Prostate (FACT-P) (See appendix for 
form). The FACT-P is a 39-item questionnaire that uses 5-point Likert-type response 
choices (0 = not at all; 1 = a little bit; 2 =somewhat; 3 = quite a bit; 4 = very much). It will 
take less than 10 minutes to complete the questionnaire. The Trial Outcome Indices 
(TOI) also will be utilized to measure the summed functional well-being, physical well-
being, and the additional concerns (prostate) subscales of the FACT-P [64, 65]. A 5-
point deterioration in the FACT-P TOI between pre-treatment and at year 1 will be 
considered clinically significant [66].  
 
The first analysis of change in QOL from baseline to 6 weeks will only be performed on 
patients who are still alive at 6 weeks. Changes in QOL will be also analyzed using all 
available data at pre study, 6 months and one year with semiparametric generalized 
estimating equations (GEE).  
 
Additionally, similarly we will also compare the percentage of patients with an effect 
size for the change in FAPSI (FACT Advanced Prostate Symptom Index) scores 
between pre-treatment and 1 months which will allow us to compare the percentage of 
patients whose functional status remains more similar to baseline levels. 
6.2.2 EQ-5D  
The EQ-5D is a patient self-administrated questionnaire that takes approximately 5 
minutes to complete (See appendix for form). The first part consists of 5 items covering 
5 dimensions including: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. Each dimension can be graded on 3 levels: 1-no problems, 2-
moderate problems, and 3-extreme problems. Health states are defined by the 
combination of the leveled responses to the 5 dimensions, generating 243 health states 
to which unconsciousness and death are added. 
 
The 5-item index score is transformed into a utility score between 0, “Worst health 
state,” and 1, “Best health state.” The index score or the cost-utility equation can be 
used in the quality adjusted survival analysis depending on the health state(s) of 
interest.  
6.3 
Cost effectiveness data collection: 
Health care utilization data needed to assess costs will be obtained from treatment 
records.  Additionally, in order to assess the treatment related indirect costs and patient 
out of pocket costs, at the first follow up visit 6 weeks after the completion of cycle 3 
Sipuleucel-T(see Appendix VII). 
 
Hospitalizations:.  For hospitalizations with physician billing records, impatient physician 
costs will be estimated by applying Medicare payment rates under the RBRVS-based 
Medicare Fee Schedule to billed procedures in the physician billing records.   
Treatment Cost: Direct costs of radiation treatment including consultation, simulation, 
treatment planning, and treatment delivery.  Patient bills related to treatment will be 
obtained and estimated by total billed charges adjusted by facility-specific cost-to-charge 
ration from Medicare cost reports as described above. 
Emergency Room visits: The date of ER visit and name of the facility, and whether the 
ER visit resulted in a hospital admission.  ER costs will be estimated using Medicare 
average payment rates for facility and physician charges, using the merged MEDPAR 
and MBS data as described above. 


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CONFIDENTIAL 
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Physician  and Clinic Visits: The date of the visit, the name of the physician or physician 
clinic, and the service provided (physician exam, lab test, physical therapy, etc.).  Costs 
for physician and clinic visits will be calculated based on billing records obtained for such 
visits, using Medicare payment rates for procedures indicated in the clinic billing records.   
Medications: Prescription drugs used, including dosage strength and frequency of 
administration.  Information about name, dose, and frequency of all prescription 
medications will be recorded.  The medications used by the study patients will be 
assigned an NDC drug code.  Unit costs for these drugs will be estimated as the “AWP” 
price published in the Red Book less 15%.  Outpatient drug costs will be calculated by 
multiplying unit cost by the number of pills used per day times the length of time the 
patient received the medication.  Note that costs of drugs administered through a clinic 
(e.g., reimbursed under Medicare Part B) are included under “clinic visit costs” and 
impatient drug costs are included under “inpatient facility costs.”  For example: Cost 
estimated for the Sipuleucel-T infusions will be based on Medicare allowable utilizing J 
code J3490 and associated facility charges for administration of Sipuleucel-T.  
 
6.4 
Safety/tolerability 
 
 Analyses will be performed for all subjects having received at least one dose of study 
therapy. The study will use the CTCAE version 4.0 for reporting of non-hematologic 
adverse events (http://ctep.cancer.gov/reporting/ctc.html) and modified criteria for 
hematologic adverse events. 
 
7.0 
ADVERSE EVENTS 
* To be collected from baseline to six months post-radiation therapy.  
7.1 
Sipuleucel-T 
For the most recent safety update, please refer to the manufacturer’s website: 
http://www.provenge.com/ 
7.1.1 
Contraindications: None 
7.1.2 
Special Warnings and Precautions for Use:  
Sipuleucel-T is intended solely for autologous use 
7.1.3 
Interaction with other medications: 
 
 
No studies of drug interactions have been performed with Sipuleucel-T 
7.1.4 
Adverse Reactions 
The most common adverse reactions (incidence ≥ 15%) are chills, fatigue, fever, 
back pain, nausea, joint ache, and headache.  To report suspected adverse 
reactions, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-
FDA-1088 or www.fda.gov/medwatch. 
 
 
 
 
 
 
 
 


STU 102012-026 
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study sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject safety 
and care.  
 
All subjects experiencing a probably or definitely related to adverse event will be 
monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
7.2.1 
Definitions  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam, imaging finding or clinically significant laboratory finding), symptom, 
clinical event, or disease, temporarily associated with the subject’s participation in the 
research, whether or not it is considered related to the subject’s participation in the 
research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
 


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can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Acute Adverse Events  
Adverse events occurring in the time period from the signing of the informed consent, 
through 90 days post treatment will be considered acute adverse events.   
Late Adverse Events (as applicable) 
7.2.2 Adverse events occurring in the time period from the end of acute 
monitoring, to 2 years post treatment, will be defined as late adverse 
events.Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The 
CTCAE v4 is available at http://ctep.cancer.gov/reporting/ctc.html 
 
Adverse events not specifically defined in the NCI CTCAE will be scored on the 
Adverse Event log according to the general guidelines provided by the NCI 
CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
If no CTCAE grading is available, the severity of an AE is graded as follows: 
Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
Life-threatening (grade 4): the subject was at risk of death at the time of the 
event. 
Fatal (grade 5): the event caused death. 
7.2.3 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.2.3.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.2.3.2 
Is immediately life-threatening. 
(The subject was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe). 


STU 102012-026 
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7.2.3.3 
Requires in-patient hospitalization for greater than 24 hours 
7.2.3.4 
Results in persistent or significant disability or incapacity. 
7.2.3.5 
Is a congenital anomaly/birth defect 
7.2.3.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the subject, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event“.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring >24 hour inpatient admission to the hospital would be a serious 
adverse event for any research participant; likewise, in a study investigating end-stage 
cancer care, any hospitalization or death which occurs during the protocol-specified 
period of monitoring for adverse and serious adverse events would be a serious adverse 
event, even if the event observed is a primary clinical endpoint of the study. 
1Pre-planned hospitalizations or elective surgeries are not considered SAEs. Note: If 
events occur during a pre-planned hospitalization or surgery, that prolong the existing 
hospitalization, those events should be evaluated and/or reported as SAEs.   
2 NCI defines hospitalization for expedited AE reporting purposes as an inpatient hospital 
stay equal to or greater than 24 hours. Hospitalization is used as an indicator of the 
seriousness of the adverse event and should only be used for situations where the AE 
truly fits this definition and NOT for hospitalizations associated with less serious events. 
For example: a hospital visit where a patient is admitted for observation or minor 
treatment (e.g. hydration) and released in less than 24 hours. Furthermore, 
hospitalization for pharmacokinetic sampling is not an AE and therefore is not to be 
reported either as a routine AE or in an expedited report. 
7.2.4 
Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs): 
The phrase “unanticipated problems involving risks to subjects or others” is found, but not 
defined in the HHS regulations at 45 CFR 46, and the FDA regulations at 21 CFR 
56.108(b)(1) and 21 CFR 312.66. For device studies, part 812 uses the term 
unanticipated adverse device effect, which is defined in 21 CFR 812.3(s). Guidance from 
the regulatory agencies considers unanticipated problems to include any incident, 
experience, or outcome that meets ALL three (3) of the following criteria: 
• 
Unexpected in terms of nature, severity or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 


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protocol and informed consent document; and (b) the characteristics of the subject 
population being studied;  
 
 
 
 
AND 
• 
Related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); 
 
AND  
• 
Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. Note: According to OHRP, if the adverse event is serious, it would always 
suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
7.3 
Reporting Requirements for Serious Adverse Events 
All SAEs 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.  Sponsor investigator shall notify institution, co-investigators and IRB immediately 
during the conduct of the study and/or after the study is completed should it become aware of 
information related to the study that would impact participant safety or clinical care. Institution 
shall promptly disclose such information to study participants. 
 
Dendreon Corporation 
Attn:                             Safety Manager 
Facsimile:                    (206) 829-1647 
Phone:                         (206) 219-7899 
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. 
 
For serious adverse event reporting please see table below. 
 
Local Adverse Event - Serious (Occurring to 
a subject enrolled on a protocol under the UT 
Southwestern IRB jurisdiction)  
 
• All local Serious Adverse Events are 
reportable to the IRB based on current 
guidelines. 
 
Within 2 working days of PI 
Awareness 
 
*Reporting of Serious 
Adverse Events unrelated to 
study participation is 
required for interventional 
studies only. 
 
 
 
 
All clinical trials are reviewed on a monthly basis for enrollment.  All local SAEs are reviewed by 
Radiation Oncology DSMC monthly for severity and attribution. For investigator-initiated trials, all 
SAEs at affiliated institutions are monitored as local SAEs.  The principle investigator and study 
coordinator will present a study treatment summary and SAEs for review.  Source documents will 
be available for the DSMC members during the review. NCI Common Toxicity Criteria Version 4 
will be used for grading and attributing adverse events. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
7.3.1 
Reporting SAEs and UPIRSOs to the Simmons Comprehensive Cancer Center 
(SCCC) Data Safety Monitoring Committee (DSMC) 
 
All SAE/UPIRSOs at all sites, which occur in research subjects on protocols for which the SCCC 
is the DSMC of record require reporting to the DSMC regardless of whether IRB reporting is 
required. All SAEs/UPIRSOs occurring during the protocol-specified monitoring period should be 
submitted to the SCCC DSMC within 5 business days of the PI or delegated study team members 
awareness of the event(s). In addition, for participating centers other than UTSW, local IRB 
guidance should be followed for local reporting of serious adverse events. 
 
The UTSW study team is responsible for submitting SAEs/UPIRSOs to the SCCC DSMC 
Coordinator.  Hardcopies or electronic versions of the eIRB Reportable Event report; FDA Form 
#3500A forms, or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be submitted to the DSMC Coordinator.  The DSMC Coordinator forwards the 
information onto the DSMC Chairman who determines if immediate action is required.  Follow-up 
eIRB reports, and all subsequent SAE/UPIRSO documentation that is available are also 
submitted to the DSMC Chair who determines if further action is required. (See Appendix III of the 
SCCC DSMC Plan for a template Serious Adverse Event Form which may be utilized when a 
sponsor form is unavailable and SAE submission to the eIRB is not required). 
  
 
If the event occurs on a multi-institutional clinical trial coordinated by the UTSW Simmons 
Comprehensive Cancer Center, the DOT Manager or lead coordinator ensures that all 
participating sites are notified of the event and resulting action, according to FDA guidance for 
expedited reporting. DSMC Chairperson reviews all SAEs/UPIRSOs upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required and either takes 
action immediately, convenes a special DSMC session (physical or electronic), or defers the 
action until a regularly scheduled DSMC meeting.  
 
 
Telephone reports to: 
Dr. Raquibul Hannan (Ph. No: 214-645-8525 
 
 
Written reports to: 
Sarmsitha Sen, Clinical Research Manager 
Phone: 214-645-1477 
 
 
UTSW SCCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-5949 or deliver to BLB.306 
 
 
UTSW Institutional Review Board (IRB) 
Submit a Reportable Event via eIRB with a copy of the final sponsor report as 
attached supporting documentation 
 
 
 
Reporting Unanticipated Problems Involving Risks to Subjects or Others (UPIRSOs) to the 
UTSW HRPP/IRB 
 
UTSW reportable event guidance applies to all research conducted by or on behalf of UT 
Southwestern, its affiliates, and investigators, sites, or institutions relying on the UT Southwestern 
IRB. Additional reporting requirements apply for research relying on a non-UT Southwestern IRB. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
According to UTSW HRPP/IRB policy, UPIRSOs are incidents, experiences, outcomes, etc. that 
meet ALL three (3) of the following criteria: 
1. Unexpected in nature, frequency, or severity (i.e., generally 
not expected in a subject’s underlying condition or not 
expected as a risk of the study; therefore, not included in the 
investigator’s brochure, protocol, or informed consent 
document),AND 
2. Probably or definitely related to participation in the research, 
AND 
3. Suggests that the research places subjects or others at a 
greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or 
recognized.  Note: According to OHRP, if the adverse event 
is serious, it would always suggest a greater risk of harm. 
 
For purposes of this policy, UPIRSOs include unanticipated adverse device effects (UADEs) and 
death or serious injury related to a humanitarian use device (HUD).  
 
UPIRSOs must be promptly reported to the UTSW IRB within 5 working days of 
PI awareness. 
 
For research relying on a non-UT Southwestern IRB (external, central, or single IRB): 
 
Investigators relying on an external IRB who are conducting research on behalf of UT 
Southwestern or its affiliates are responsible for submitting LOCAL UPIRSOs to the UT 
Southwestern IRB within 5 working days of PI awareness. Investigators must report to their 
relying IRB according to the relying IRB’s policy. In addition, the external IRB’s responses or 
determinations on these local events must be submitted to the UT Southwestern IRB within 10 
working days of receipt. 
 
Events NOT meeting UPIRSO criteria: 
 
Events that do NOT meet UPIRSO criteria should be tracked, evaluated, summarized, and 
submitted to the UTSW HRPP/IRB at continuing review. 
 
For more information on UTSW HRPP/IRB reportable event policy, see 
https://www.utsouthwestern.edu/research/research-administration/irb/assets/policies-
combined.pdf. 
 
7.4 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE may NOT be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
7.5 
Reporting Requirements for Adverse Events 
7.5.1 
Expedited Reporting 
 
The Principal Investigator must be notified within 24 hours of learning of any 
serious adverse events, that is study drug related, occurring during the 
study or within 30 days of the last administration of the study drug.  
 
Suspected adverse reactions will also be reported to Dendreon Corporation 
at 1-877-336-3736 and FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
 
The IRB must be notified within 10 business days of “any unanticipated 
problems involving risk to subjects or others” (UPR/UPIRSO). 
The following events meet the definition of UPR: 
1. Any serious event (injuries, side effects, deaths or other problems), 
which in the opinion of the Principal Investigator was unanticipated, 
involved risk to subjects or others, and was possibly related to the 
research procedures. 
2. Any serious accidental or unintentional change to the IRB-approved 
protocol that alters the level of risk. 
3. Any deviation from the protocol taken without prior IRB review to 
eliminate apparent immediate hazard to a research subject. 
4. Any new information (e.g., publication, safety monitoring report, updated 
sponsor safety report), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio for the research. 
5. Any breach in confidentiality that may involve risk to the subject or 
others. 
6. Any complaint of a subject that indicates an unanticipated risk or that 
cannot be resolved by the Principal Investigator. 
7.5.2 
Routine Reporting 
 
All other adverse events- such as those that are expected, or are unrelated 
to the study participation- are to be reported annually as part of regular data 
submission.  


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
7.6 
Stopping Rules 
The study will be stopped if the combination treatment of SABR and Sipuleucel-T in the 
interim annual analysis is determined to confer significantly increased Grade 3-5 toxicity 
as reported in the literature from the treatments performed alone.  
8.0 
DRUG INFORMATION 
8.1 
Sipuleucel-T 
 
Other names for the drug(s): Provenge 
 
 
Classification - type of agent: autologous cellular immunotherapy 
 
 
Mode of action: Sipuleucel-T is an autologous cellular immunotherapy. While the 
precise mechanism of action is unknown, Sipuleucel-T is designed to induce an 
immune response targeted against PAP, an antigen expressed in most prostate 
cancers. During ex vivo culture with PAP-GM-CSF, APCs take up and process the 
recombinant target antigen into small peptides that are then displayed on the APC 
surface. 
 
 
Storage and stability: Sipuleucel-T arrives in a cardboard shipping box with a special 
insulated polyurethane container inside. The insulated container and gel packs within 
the container are designed to maintain the appropriate transportation and storage 
temperature of Sipuleucel-T until infusion. Once the Sipuleucel-T infusion bag is 
removed from the insulated container, it should remain at room temperature for no 
more than 3 hours. 
 
 
Protocol dose: Each dose of sipuleucel-T contains a minimum of 50 million 
autologous CD54+ cells activated with PAP-GM-CSF 
 
 
Preparation: Upon receipt, the outer cardboard shipping box should be opened to 
verify the product and patient-specific labels located on the top of the insulated 
container. Infusion must begin prior to the expiration date and time indicated on the 
cell product disposition form and Product Label. Once the patient is prepared for 
infusion and the cell product disposition form has been received, remove the 
sipuleucel-T infusion bag from the insulated container and inspect the bag for signs 
of leakage. Contents of the bag will be slightly cloudy, with a cream-to-pink color. 
Gently mix and re-suspend the contents of the bag, inspecting for clumps and clots. 
Small clumps of cellular material should disperse with gentle manual mixing. Do not 
administer if the bag leaks or if clumps remain in the bag. Prior to Sipuleucel-T 
infusion, match the patient’s identity with the patient identifiers on the cell product 
disposition form and the Sipuleucel-T infusion bag. 
 
 
Route of administration for this study: IV infusion 
 
 
Incompatibilities: There are no known incompatibilities of sipuleucel-T. 
 
 
Availability: Commercially available from Dendreon Corporation. 
 
 
Side effects: The most commonly reported toxicity for sipuleucel-T (incidence ≥ 15%) 
are chills, fatigue, fever, back pain, nausea, joint ache, and headache. Acute infusion 
reactions (reported within 1 day of infusion) included, but were not limited to, fever, 
chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, 
fatigue, hypertension, and tachycardia. Please refer the package insert for a detailed 
list of adverse reactions.  


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
9.0 
CORRELATIVES/SPECIAL STUDIES 
 
The goal of the planned laboratory correlative studies is to measure the induced immune 
response to not only PAP but to other prostate cancer antigens as well (see section 1.5 for 
detail).  In addition, the correlative studies will evaluate the immune response generated by 
Sipuleucel-T and the augmentation of the anti-tumor immune response. The submission of 
collected whole blood before, during and post treatment at 8wk intervals is mandatory. Patient 
specimen may be shipped to companies or outside institutions to perform specialized assays, a 
non-extensive list of which is provided below. Specimens will be shipped de-identified.    
9.1 
Sample Collection Guidelines 
Samples will be labeled with the subject’s de-identified study number and collection date 
and delivered for analysis during regular business hours to: NC7: 208; Attn Dr. Raquibul 
Hannan. These samples will be kept indefinitely, unless the participant withdraws 
participation in this clinical trial in which case they will then be destroyed. 
9.1.1 
Whole blood sample: Patient’s whole blood will be collected in EDTA (Lavender 
top) tubes for ~ 100 ml at baseline (pre-study), after SABR, at 6 weeks post 
treatment (post treatment defined as being after administration of cycle 3 
Sipuleucel-T), at 12 weeks and at 24 weeks post treatment. In addition, 10 ml will 
be collected in anti-coagulant-free tubes for the collection of sera. The blood will 
be processed by centrifugation (1000g, 15min, 4oC), collecting the supernatant 
and freezing at -80oC in 5 aliquots for future experiments. The pellet will be re-
suspended in PBS and PBMC will be isolated using standard protocol. Briefly, 
the cell suspension will be carefully placed on 10ml polystyrene tube containing 
1ml ficoll and centrifuged (400g, 30min, RT).  Collect the PBMC region from the 
ficoll and washed 3x with PBS. Count and freeze cells in 5 aliquots with 
10%DMSO 90%FBS in -80oC.  
9.2 
Assay Methodology 
9.2.1 
Elispot: IFN- ELISpot assays will be performed according to manufacturer’s 
protocol using a commercial ELISpot kit (MabTECH). Brieﬂy, 96 well plates are 
coated overnight with 0.015 mg/ml of an anti-human IFN-g monoclonal antibody.  
PBMC from patients will be incubated in triplicates wells and stimulated in the 
presence of either PA2024 (10µg/ml), protein lysate from patient biopsy (50µg/ml) 
or 5 ng/ml PMA and 0.5 ng/ml ionomycin as positive control and albumin as 
negative control.  For ELISPOT assays, plates are incubated for 48 hours, 
washed, probed with biotinylated anti-IFNg, further washed, and then incubated 
with streptavidin alkaline phosphatase. Spot development is achieved with 5-
bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium (BCIP/NBT; Invitrogen) 
and spots are enumerated by an automatic ELISpot reader. 
9.2.2 
ELISA: In this procedure, purified antigen (PAP imunodominant epitope, PA2024, 
PSA or etc.) is first adsorbed to an EIA 96 well microplate (Fischer).  Patient 
plasma is then added to each well as a source of primary antibody and serially 
diluted.  After extensive washes, detection enzyme (HRP)-linked anti-human mAb 
is then added to each well and allowed to bind.  Appropriate substrate is then 
added to each well and color development occurs within 5-60 min.  UV Microplate 
Reader will be used to read the plates 
9.2.3 
3H-thymidine Proliferation Assay: PBMC from patients will be incubated in a 
similar manner as above for five days at 37 oC then overnight with 0.5 mCi tritiated 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
3H-thymidine, harvested onto a glass-fiber filter using a 96-well FilterMate cell 
harvester. The radioactivity of the 3H-thymidine is detected by a direct betaplate 
counter. The degree of antigen-specific clonal T cell expansion will be expressed 
as a stimulation index (SI) of the ratio of 3H-thymidine incorporation by cells 
incubated with PA2024 compared with media controls. An alternate method 
utilizing FACS analysis with carboxy fluorescein diacetate succinimidyl ester 
(CFSE) is also available [69]. 
9.2.4 
Chromium Release Cytotoxicity Assays: For cell-mediated cytotoxicity 
analysis, A 50 µl sample of 51Cr-labeled target cells (LNCaP or PC3 human 
prostate cancer cell) is mixed with 100µl of effector cells (patient PBMC) at 
various target to effector ratio (E:T ratios). After centrifugation at 100 X G, the 
cells are incubated for 2 hr at 37°C. The radioactivity of culture supernatant is 
measured using a gamma counter and percentage of cytotoxicity is calculated. 
For antibody-dependent cytotoxicity analysis this procedure will be performed with 
patient’s plasma instead of PBMC and the percentage of cytotoxicity is calculated 
in similar manner. An alternate and non-radioactive labeling method utilizes 
GAPDH enzyme release from lysed cells called Bioluminescence Non Radioactive 
Cytotoxicity Assay (aCella-TOX, T Cell Technology, INC) [70, 71]. 
9.2.5 
Flow cytometric analysis (FACS):  For FACS analysis of cell-surface molecules, 
the cell samples are stained with fluorescent dye – conjugated monoclonal 
antibodies against the selected markers on ice followed by fixation with 4% 
paraformaldahyde. Data are acquired on a LSRII (BD Biosciences) and analyzed 
using FACSDiva software (BD Biosciences). The PBMC of each patient before 
and after treatment will be analyzed to identify the relative sub-population of CTLs, 
regulatory T-Cells, effector memory T cells, MDSCs, neutrophils and NK cells 
utilizing appropriate cell surface markers (see section 1.5).   
9.2.6 
Immunohistochemical staining (IHC): Standard immunohistochemistry staining 
procedure will be performed using the Benchmark XT automated stainer 
(Ventana) for both antibodies. Briefly, formalin-fixed, paraffin-embedded tissue 
sections will be cut at 3-4 micron and air-dried overnight. The sections will be 
deparaffinized, rehydrated, and subjected to heat-induced epitope retrieval. 
Sections will then be incubated with appropriate primary antibody. For signal 
detection, ultraView universal detection system (Ventana) will be used. The slides 
will be developed using 3-3’-diaminobenzidine chromogen and counterstained 
with hematoxylin. Appropriate positive and negative controls will be utilized for 
each run of immunostains.  The evaluation of the immunostaining will be carried 
out by a genitourinary pathologist without knowledge of any clinicopathologic data. 
Only nuclear reactivity will be considered positive. An H score will be assigned as 
the product of average intensity of staining (0 for negative, 1 for weakly positive, 2 
for moderately positive, and 3 for strongly positive) and extent of 
immunoexpression (0-100% percentage of cells staining). In addition,  Dual-
antibody ISH will be performed to identify and analyze TILs, CTL (CD3+,CD8+), 
Tregs (CD4+FoxP3), DC (CD11c) , NK/T (CD3+, CD1d), neutrophils (CD11b, 
Ly6G} and MDSC (CD14+,CD11b) in the tumor tissue before and after treatment, 
when available (see section 1.5). 
9.2.7 
Serum Cytokine Analysis: Multiplex cytokine analysis in patient’s plasma will be 
performed in precoated 96 well plates (Human TH1/TH2 10 plex ultrasensitive 
assay, Meso Scale Discovery – MSD, Maryland, USA) according to 
manufacturer’s instructions. 25 µL of diluent 2 is dispersed into each well. The 
plate is sealed and incubated by vigorous horizontal shaking for 30 minutes at RT. 
25 L of the patient plasma is added per well and all samples measured in 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
triplicates. Plates are sealed and incubated by vigorous horizontal shaking for two 
hours at RT. Plates are washed three times with 0.05% Tween 20 in PBS . 25 µL 
of 1× detection antibody solution is placed per well and sealed plates are 
incubated by vigorous horizontal shaking for two hours at RT. Plates are washed 
three times with 0.05% Tween 20 in PBS. 150 µL of 2× Read Buffer T is added to 
each well. Plates are analysed using the MSD SECTOR Imager 2400 and 
Discovery Workbench 3.0 software (both from Meso Scale Discovery, USA). The 
mean value of two wells is taken as the recorded reading, provided that the 
coefficient of variation (CV) was less than 10%. Concentrations recorded lower 
than the standard curve are kept as absolute values. For purposes of logarithmic 
analysis, readings of 0 are adjusted to 0.01 pg/ml.  The following cytokines will be 
measured before and after treatment for each patients: Th1/Th2/Th17 cytokines, 
IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13, IL-17 TNF-α; pro-
inflammatory cytokines: GM-CSF, IFN-γ, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, 
TNF-α; Chemokines: Eotaxin, MIP-1β, TARC, IP-10, IL-8, MCP-1, MCP-4 and 
others including IL-6, TGF-β and HMGB1 (see section 1.5). 
9.2.8 
Western-blot/Immuno-blot: LNCaP or PC3 human prostate cancer cell lysate 
will be used to perform immune-blott using plasma collected from patients before 
and after treatment.  The LNCaP or PC3 cell 106 cells/mL will be lysed in 
immunoprecipitation assay buffer on ice for 30 min. Standard western blott 
methodology will be utilized. Briefly, 400 µg of protein will be separated using pre-
made gradient 4% to 12% Bis-Tris gels (Invitrogen, Burlington, ON, Canada) and 
transferred to nitrocellulose. Patient sera/plasma will be diluted 1/500 in Blotto 
(5% dry milk powder; 0.1% Tween 20; 50 mmol/L Tris; 150 mmol/L NaCl) and 
incubated with nitrocellulose membranes for 1 h at room temperature using a 
multichannel immuoblotting device (Mini Protean II Multiscreen, Bio-Rad, 
Missassauga, ON, Canada). The membrane will then incubated for 1 h at room 
temperature with horseradish peroxidase–conjugated goat anti-human IgG (H+L; 
Jackson ImmunoResearch, West Grove, PA) diluted 1/10,000 in Blotto and 
visualized by enhanced chemiluminescence. 
9.3 
Specimen Banking 
Subject samples collected for this study will be retained at the department of pathology 
and at the lab of Dr. Hannan. Specimen may be shipped to companies or outside 
institutions to perform specialized assays, a non-extensive list of which is provided 
above. Specimen will be shipped de-identified. Specimens will be stored indefinitely or 
until they are used up.  If future use is denied or withdrawn by the subject, best efforts will 
be made to stop any additional studies and to destroy the specimens. 
 
Raquibul Hannan will be responsible for reviewing and approving requests for clinical 
specimen from potential research collaborators outside of UTSW.Any data obtained from 
the use of clinical specimen will be the property of UTSW for publication and any 
licensing agreement will be strictly adhered to.  
 
The specimens, DNA, and their derivatives may have significant therapeutic or 
commercial value. The Informed Consent form contains this information and informs the 
subject that there is the potential for financial gain by UTSW, the investigator or a 
collaborating researcher or entity.  
 
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available: 
 
Diagnosis  
 
Collection time in relation to study treatment 
 
Clinical outcome – if available 
 
Demographic data 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
10.0 
QUALITY OF LIFE AND COST-EFFECTIVENESS 
10.1 Health-Related Quality of Life (HRQOL) Analysis 
The study design is to prospectively analyze the HRQOL among patients with mCRPC 
treated with SABR and sipuleucel T. While hypofractionation is hypothesized to yield greater 
tumor cell kill, it may also increase the normal tissue toxicity, in which case there may be a 
decrease in HRQOL. The primary normal tissue toxicities in patients receiving radiation 
depend on the location of the treatment. Prior studies have demonstrated that the most 
sensitive and clinically meaningful method for accurately capturing the normal tissue 
toxicities is via patients reported outcomes (PROs), such as HRQOL. 
 
In this non-randomized trial, we plan to assess the FACT-P at 3 specific time points to 
minimize patient burden: baseline (pretreatment), first follow up visit, and at one year (See 
Appendix).  In order to analyze the QOL, we plan to use a brief, validated instrument that is 
user friendly and has clinical relevance [72].  FACT-G is a measure that sums the functional 
well-being (FWB), physical well-being (PWB), the social/family well-being (S/FWB), and 
emotional well-being(EMB).  FACT-P adds to the FACT –G (27 items) by including 12 items 
specific to prostate cancer patients.  The FACT-P has been validated as well and used in 
other studies evaluating treatment options for patients with mCRPC. It takes about 5-
10minutes to complete and has been written at the 6th grade level.  FACT has been 
translated into 26 languages and is available free of charge to institutions with the 
completion of an agreement to share data, accessible at 
http://www.facit.org/translation/licensure.aspx.  
 
In a HRQOL study focused on patient with advanced prostate cancer, the components of the 
FACT-P which showed a frequency greater than 17% were retained in a measure renamed 
the FACT Advanced Prostate Symptom Index -8 (FAPSI-8) [66].  Since pain was a major 
component of this simplified scale, we propose obtaining a Brief Pain Inventory to 
supplement the pain assessment of the FACT-P especially given the nature of this protocol 
likely accruing patients with minimally painful osseous metastases [73].   
 
In addition, the EQ-5D and modified BPI HRQOL questionnaire will be used as well.  EQ-5D 
is a standardized instrument for use as a measure of health outcome. Applicable to a wide 
range of health conditions and treatments, it provides a simple descriptive profile and a 
single index value for health status.  The US version of the EQ-5D will be used, to enable 
mapping of general HR-QoL scores from EQ-5D scores into health state utility scores 
(ranging from 0 to 1) for the US population.  These utility scores are needed for cost-utility 
analysis (estimates of costs per “quality adjusted” life-year gained) [74, 75]. 
 
HRQoL of patients with mCRPC is unfortunately not well described in the literature for either 
treatment modalities in this study or other standard of care treatments as well. [76].   
 
A Canadian phase II study of docetaxel administered every 3 weeks with prednisone in men 
with metastatic hormone-refractory prostate cancer progressing after 
mitoxantrone/prednisone assessed quality of life as a secondary endpoint.  A significant 
improvement (p=0.018) from 66 % pretreatment to 75% post 7 cycles of docetaxel was 
reported in the 30 patients treated on the trial [67]. The overall quality of life was maintained 
in these patients as well despite side effects associated with the treatment with docetaxel.  
 
In another phase II study looking at mitoxantrone, estramustine, and vinorelbine (MEV) 
versus 13-cis retinoic acid (CRA), interferon-alpha2b (IFN), and paclitaxel (Tax) 
CRA/IFN/TAX,  the patients treated in the CRA/IFN/TAX arm experienced a significant 
decrease in HRQOL as measured by the FACT-P [78].  This is one of the few studies that 
reports QoL in patients treated with mCRPC.  
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
However, clearly, the lack of radiation given in the above mentioned studies and the various 
systemic treatments do not allow for the abovementioned studies to be appropriate 
comparisons for our study.   
 
There is little reported on the effect on HRQOL for patients treated with Sipuleucel T, 
abiraterone, MDV3100, docetaxel, carbazitaxel, or other emerging treatment options for 
patients with mCRPC.  Regarding the pain response to various treatment options for 
osseous metastases in the metastatic prostate cancer, there are innumerous reports [48].  
Thus, we propose utilizing the FACT-P and a modified BPI questionnaire  in the patients 
enrolled on this study for descriptive purposes as recommended in the PCWG2 [49]. .     
 
Additionally, in order to calculate the indirect costs associated with hypofractionated 
radiation treatment, a single administration of a short economic questionnaire will take place 
at the first available follow up.  This questionnaire which has been adopted for administration 
in the United States has been used in economic assessment in rural Canadian cancer 
health service research [79].   
10.2 Cost-Effectiveness Analysis (CEA) 
For the primary CEA analysis, we will estimate cost accumulated within 1 years. A larger 
limit is possible if we have a reasonable number of people surviving at that time. 
 
Since patients are enrolled into the study over time and some patients are still alive at the 
end of the study, their survival time and costs are censored.  Due to the presence censoring, 
we cannot use a simple average of the patients’ total costs, a simple average of the patients’ 
costs for those with complete cost information, or a Kaplan-Meier estimator on censored 
costs, since these all produce biased estimators of the mean costs[74].  Instead, we will use 
the inverse-probability weighting method to calculate average costs.[75, 80]  The 
assumption used in this method is that censoring is independent of the survival time, or cost 
collection process, which is often satisfied in well-conducted clinical trials. If the new 
treatment can both extend patients’ survival time (or quality-adjusted survival time), and 
save costs at the same time, the new treatment will be preferred to the current standard 
treatment under any willingness to pay threshold. 
 
However, if the new treatment extends survival time but costs more, cost-effectiveness 
analysis provides an estimate of the incremental cost of greater incremental effectiveness.  
For traditional cost-effectiveness analysis, treatment effectiveness is measured simply as 
survival time.  The incremental cost-effectiveness ratio indicates the additional cost required 
to attain one additional year of survival.  For cost-utility analysis, treatment effectiveness is 
measured as quality-adjusted survival time (which accounts for the impact of treatment on 
both mortality and morbidity, including any differences in adverse affects of treatment 
affecting HR-QoL).  For cost-utility analysis, the incremental cost-effectiveness ratio 
indicates the additional cost required to attain one additional year of quality adjusted 
survival.    
10.2.1 
Projection Model and Sensitivity Analysis 
If the new treatment is implemented in usual practice, some of its potential benefits 
to patients may extend beyond the time horizon of the clinical trial.  We will explore 
the potential to use results from the clinical trial based cost-effectiveness analysis, 
augmented with information from secondary sources, to develop a model to project 
costs and effectiveness beyond the time horizon included in the clinical trial.  Any 
such model projections would be subjected to probabilistic sensitivity analysis, to 
assess the impact of parameter uncertainty on estimated cost effectiveness results.  
This is typically done via Markov Modeling with probabilistic sensitivity analysis. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
10.3 
Quality adjusted survival time:  
The quality-adjusted survival time estimates need to account for the presence of 
censoring.  Due to the induced informative censoring problem, the ordinary survival 
method (e.g., Kaplan-Meier estimator) cannot be applied in this case [75,80,81].  
Accordingly, we will use the inverse-probability weighted method of Zhao and Tsiatis to 
carry out the survival time analysis [75, 80].  To estimate quality adjusted survival time, 
data from EQ-5D will first be translated into utility measures. These measures are 
obtained at discrete time points, so they will be interpolated into the time intervals 
between the visits. The quality-adjusted survival time is just an integration of the utility 
measures over a patient’s survival time, or until the time limit similar as the cost 
calculation, whichever occurs earlier. 
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is an open label phase II non-randomized single arm prospective clinical trial. The 
primary end point is TTP, while the secondary end points include improvement in 
immunologic response, PFS, bPFS, PCaSS, OS, quality of life and cost-effectiveness 
(Please see endpoint details in section 2 and 6)  
11.2 
Sample Size and Accrual 
Sample size estimation is based on the assumption that Sipuleucel-T + SABR will 
improve the reported TTP with Sipuleucel-T alone by 80%. The TTP for Sipuleucel-T as 
reported by Kantoff et. al. is 14.6 weeks [10]. Assuming an 80% improvement would lead 
to a TTP of 26.28 weeks. According to the CRAB website 
(https://stattools.crab.org/Calculators/oneArmSurvivalColored.html), the estimated 
sample size with 2-sided test significance level of 10% and 80% power, assuming that 
the accrual time is 3 years, with a follow-up time of 4 years after the end of accrual, is 20. 
The secondary endpoints (i.e. OS, PFS etc.) will be followed for a total of four years.  The 
estimated response rate using 20 patients can be measured with a maximum standard 
error of 11.2%. 
11.3 
Data Analyses Plans 
This is a single-arm Phase II trial of SABR for mCRPC patients. TTP, OS, bPFS, PCaSS 
and duration of response will be estimated using the Kaplan-Meier approach along with 
the 95% confidence interval using Greenwood variance formula. Exact binomial method 
will be used to calculate the response rate and the corresponding 95% confidence 
interval.  One-sample log-rank test [82] will be used to test if the survival endpoints such 
as TTP is significantly different from those in the historical control reported in Kantoff et. 
al [10].   
Wilcoxon signed-rank test will be used to test if the median number of spots in Elispot of 
the PBMC collected from patients at 6, 14 and 26 weeks are at 100% increase in the 
median number of spots by ELISpot assay as reported in Sheikh et al [32]. T-Cell 
proliferation SI and ELISA antibody titer will also be evaluated in the same manner. 
Statistical analysis plans for cost-effectiveness and health-related quality adjusted life are 
described in Section 10.  
12.0 
STUDY MANAGEMENT 
12.1 
Conflict of Interest 
 
12.2 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) 
must have the conflict reviewed by the UTSW COI Committee and IRB according to UTSW 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Policy on Conflicts of Interest.  All investigators will follow the University conflict of 
interest policy.Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
12.3 
Required Documentation for multi-site 
Before the study can be initiated at any site, the following documentation must be 
provided to the Clinical Research Office, Department of Radiation Oncology, UTSW. 
 
 
A copy of the official IRB approval letter for the protocol and informed consent 
 
IRB membership list or Federal wide Assurance letter 
 
CVs and medical licensure for the principal investigator and any associate 
investigators who will be involved in the study 
 
A copy of the IRB-approved consent form 
 
CAP and CLIA Laboratory certification numbers and institution lab normal values 
 
Executed clinical research contract 
12.4 
Registration Procedures 
All subjects must be registered with the Clinical Research Office, Department of 
Radiation Oncology, UTSW, before enrollment to study.  
New subjects will receive a 3-digit number.  The first subject enrolled receives the 
number 101, the second subject enrolled receives the number 102, etc.  
 
Each newly consented subject should be numbered using the schema provided above. 
Upon registration, the registrar will assign the additional registration code according to 
the numbering schema outlined above, which should then be entered as the patient study 
id in Velos upon updating the status to enrolled. 
12.5 
Data Management and Monitoring/Auditing 
REDCap is the UTSW SCCC institutional choice for the electronic data capture of case 
report forms for SCCC Investigator Initiated Trials. REDCap will be used for electronic 
case report forms in accordance with Simmons Comprehensive Cancer Center 
requirements, as appropriate for the project. All subjects consenting to participate in any 
aspect of the trial must be registered on REDCap before initiating protocol activities. All 
research data will be recorded and entered into Case Report Forms using REDCap. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Toxicity will be reviewed on an ongoing basis and will be reported per SCCC-DSMC 
guidelines.   
 
In order to facilitate remote source to case report form verification, the Simmons 
Comprehensive Cancer Center study team will require other institutions participating in 
this trial as sub-sites to enter data into the selected EDC system and upload selected de-
identified source materials when instructed  
 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT and/or the CRO 
Multi-Center IIT Monitor. This review includes but is not limited to accuracy of case report 
forms, protocol compliance, timeless and accuracy of Velos entries and AE/SAE 
management and reporting. Documentation of trial monitoring will be maintained along 
with other protocol related documents and will be reviewed during internal audit.   
 
For further information, refer to the UTSW SCCC IIT Management Manual. 
 
The UTSW Simmons Comprehensive Cancer Center (SCCC) Data Safety Monitoring 
Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
UTSW SCCC clinical trials.  As part of that responsibility, the DSMC reviews all local 
serious adverse events and UPIRSOs in real time as they are reported and reviews 
adverse events on a quarterly basis.  The quality assurance activity for the Clinical 
Research Office provides for periodic auditing of clinical research documents to ensure 
data integrity and regulatory compliance.  A copy of the DSMC plan is available upon 
request. 
 
The SCCC DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it serves as the DSMC of record. The QAC works as part 
of the DSMC to conduct regular audits based on the level of risk. Audit findings are 
reviewed at the next available DSMC meeting.  In this way, frequency of DSMC 
monitoring is dependent upon the level of risk.  Risk level is determined by the DSMC 
Chairman and a number of factors such as the phase of the study; the type of 
investigational agent, device or intervention being studied; and monitoring required to 
ensure the safety of study subjects based on the associated risks of the study. Protocol-
specific DSMC plans must be consistent with these principles.  
 
Clinical trials are assessed for safety on a continual basis throughout the life of the trial. 
All SAE’s and any AEs that are unexpected and possibly/likely related to study 
participation are reported to UTSW IRB through an electronic research system per UTSW 
IRB guidelines. SAEs are reported to the sponsor per specific sponsor requirements. 
These SAEs are reported to the SCCC DSMC on a real time basis. All local SAEs will be 
reported to the SCCC DSMC. SAE reports can be either scanned/emailed to the 
coordinator of SCCC DSMC or sent through interoffice mail.  
 
RADIATION ONCOLOGY DATA SAFETY MONITORING PLAN 
 
  
1. 
The purpose of the Radiation Oncology Data and Safety Monitoring Plan is to 
ensure that clinical trial data is accurate and valid and to ensure the safety of trial 
participants.  The plan complies with the Simmons Comprehensive Cancer 
Center (SCCC) Data Safety Monitoring Plan and the University of Texas 
Southwestern Medical Center (UTSW) IRB guidelines.   
 
2. 
The Radiation Oncology Safety Assurance Committee (ROSAC) is charged with 
developing, implementing, and maintaining the Data and Safety Monitoring Plan. 
The membership consists of a Medical Director of Clinical Research as well as 
representation from the following groups:  clinical research, nursing, regulatory, 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
pharmacy, physicists, radiation therapists, and faculty. Ad hoc members are 
contacted to participate as needed.   
 
3. 
Clinical trials are assessed for safety on a continual basis throughout the life of 
the trial.  Serious Adverse Effects (SAEs) and any Adverse Effects (AEs) that are 
unexpected and possibly/likely related to study participation are reported to 
UTSW IRB through an electronic research system per UTSW IRB guidelines.  
SAEs are reported to the sponsor per specific sponsor requirements. All SAEs 
are reported to the SCCC DSMC on a real time basis. SAE reports can be either 
scanned/emailed to the coordinator of SCCC DSMC or sent through interoffice 
email.   
 
4. 
All clinical trials are reviewed by ROSAC on a monthly basis for enrollment.  All 
local SAEs are reviewed by ROSAC monthly for severity and attribution. For 
investigator-initiated trials, SAEs at affiliated institutions are monitored as local 
SAEs.  The principle investigator and study coordinator will present a study 
treatment summary and SAEs for review.  Source documents will be available for 
the ROSAC members during the review. NCI Common Toxicity Criteria Version 4 
will be used for grading and attributing adverse events.  The documentation of 
these monthly reviews will be submitted to the SCCC DSMC on a monthly basis.   
5. 
If a related SAE occurs on a multi-institutional clinical trial coordinated by the 
Radiation Oncology Clinical Research Office, the Clinical Research Manager or 
designee ensures that all participating sites are notified of the event and resulting 
action, within one (1) working day of the determination. 
 
6. 
All participating sites will be monitored annually.  At least 5 charts for each site 
will be reviewed each time a site is monitored. Monitoring will include verification 
of source documentation as per SCCC DSMC plan.  Results of data monitoring 
along with any necessary responses, if applicable, will be documented and filed 
within the Department of Radiation Oncology.   These documents are available 
upon request at time of audit.  All monitoring will be performed remotely, however 
on-site visits may be scheduled as necessary per DSMC policy. 
12.6 
Adherence to the Protocol 
Except for an emergency situation, in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
12.6.1 Exceptions (also called single-subject exceptions or single-subject waivers): 
include any departure from IRB-approved research that is not due to an 
emergency and is: 
 intentional on part of the investigator; or 
 in the investigator’s control; or 
 not intended as a systemic change (e.g., single-subject exceptions to eligibility 
[inclusion/exclusion] criteria) 
 Reporting requirement: Exceptions are non-emergency deviations that require prospective 
IRB approval before being implemented. Call the IRB if your request is 
urgent. If IRB approval is not obtained beforehand, this constitutes a major 
deviation. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
12.6.2 Emergency Deviations: include any departure from IRB-approved research that 
is necessary to:  
 avoid immediate apparent harm, or 
 protect the life or physical well-being of subjects or others 
 Reporting requirement: Emergency deviations must be promptly reported 
to the IRB within 5 working days of occurrence. 
 
12.6.3 Major Deviations (also called violations): include any departure from IRB-
approved research that: 
 
Harmed or placed subject(s) or others at risk of harm (i.e., did or has the 
potential to negatively affect the safety, rights, or welfare of subjects or 
others), or 
 
Affect data quality (e.g., the completeness, accuracy, reliability, or validity of 
the data) or the science of the research (e.g., the primary outcome/endpoint of 
the study) 
 Reporting requirement: Major deviations must be promptly reported to  
the IRB within 5 working days of PI awareness. 
 
12.6.4 Minor Deviations: include any departure from IRB-approved research that: 
 
Did not harm or place subject(s) or others at risk of harm (i.e., did not or did 
not have the potential to negatively affect the safety, rights, or welfare of 
subjects or others), or 
 
Did not affect data quality (e.g., the completeness, accuracy, reliability, or 
validity of the data) or the science of the research (e.g., the primary 
outcome/endpoint of the study) 
 Reporting requirement: Minor deviations should be tracked and 
summarized in the progress report at the next IRB continuing review.
 
12.7 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  When an amendment to the protocol 
substantially alters the study design or the potential risk to the patient, a revised consent 
form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
12.8 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
12.9 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 
13.0 
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Finkelstein, S.E., et al., The confluence of stereotactic ablative radiotherapy and tumor 
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STU 102012-026 
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STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
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STU 102012-026 
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STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
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localized prostate cancer: an update. August 13,2010. 
44.
 
CenterforMedicareandMedicaidServices(MedicareEvidenceDevelopment&Cover
ageAdvisoryCommittee), Outcomes of Sipuleucel-T Therapy. February 10,2011. 
45. 
Leonhardt, D., Health Reform, a Cancer Offers an Acid Test, in The New York Times. 
2009. 
46. 
Vasani, D., et al., Recent advances in the therapy of castration-resistant prostate cancer: 
the price of progress. Maturitas, 2011. 70(2): p. 194-6. 
47. 
Chambers, J.D. and P.J. Neumann, Listening to Provenge--what a costly cancer 
treatment says about future Medicare policy. N Engl J Med, 2011. 364(18): p. 1687-9. 
48. 
Lee, D.J., et al., Novel therapeutics for the management of castration-resistant prostate 
cancer (CRPC). BJU Int, 2012. 109(7): p. 968-85. 
49. 
Scher, H.I., et al., Design and end points of clinical trials for patients with progressive 
prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): p. 1148-59. 
50. 
Goldstein, N.S., Immunophenotypic characterization of 225 prostate adenocarcinomas 
with intermediate or high Gleason scores. Am J Clin Pathol, 2002. 117(3): p. 471-7. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
51. 
Kuriyama, M., et al., Multiple marker evaluation in human prostate cancer with the use 
of tissue-specific antigens. J Natl Cancer Inst, 1982. 68(1): p. 99-105. 
52. 
Lugade, A.A., et al., Local radiation therapy of B16 melanoma tumors increases the 
generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol, 
2005. 174(12): p. 7516-23. 
53. 
Rubner, Y., et al., How does ionizing irradiation contribute to the induction of anti-tumor 
immunity? Front Oncol, 2012. 2: p. 75. 
54. 
Takeshima, T., et al., Local radiation therapy inhibits tumor growth through the 
generation of tumor-specific CTL: its potentiation by combination with Th1 cell therapy. 
Cancer Res, 2010. 70(7): p. 2697-706. 
55. 
Lee, Y., et al., Therapeutic effects of ablative radiation on local tumor require CD8+ T 
cells: changing strategies for cancer treatment. Blood, 2009. 114(3): p. 589-95. 
56. 
Schaue, D., et al., Maximizing tumor immunity with fractionated radiation. Int J Radiat 
Oncol Biol Phys, 2012. 83(4): p. 1306-10. 
57. 
Salama, J.K., et al., An initial report of a radiation dose-escalation trial in patients with 
one to five sites of metastatic disease. Clin Cancer Res, 2008. 14(16): p. 5255-9. 
58. 
Del Monte, U., Does the cell number 10(9) still really fit one gram of tumor tissue? Cell 
Cycle, 2009. 8(3): p. 505-6. 
59. 
Hartsell, W.F., et al., Randomized trial of short- versus long-course radiotherapy for 
palliation of painful bone metastases. J Natl Cancer Inst, 2005. 97(11): p. 798-804. 
60. 
Koswig, S. and V. Budach, [Remineralization and pain relief in bone metastases after 
after different radiotherapy fractions (10 times 3 Gy vs. 1 time 8 Gy). A prospective 
study]. Strahlenther Onkol, 1999. 175(10): p. 500-8. 
61. 
Agarwala, A.K. and N.H. Hanna, Long-term survival in a patient with stage IV non-
small-cell lung carcinoma after bone metastasectomy. Clin Lung Cancer, 2005. 6(6): p. 
367-8. 
62. 
Schefter, T.E., et al., A phase I trial of stereotactic body radiation therapy (SBRT) for 
liver metastases. Int J Radiat Oncol Biol Phys, 2005. 62(5): p. 1371-8. 
63. 
Timmerman, R. and F. Lohr, Normal tissue dose constraints applied in lung stereotactic 
body radiation therapy., in Stereotactic Body Radiation Therapy. , R. Timmerman and B. 
Kavanagh, Editors. 2005, Lippincott, Williams, and Wilkins: Philadelphia. 
64. 
Cella, D.F., et al., Reliability and validity of the Functional Assessment of Cancer 
Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer, 1995. 12(3): p. 199-
220. 
65. 
Brady, M.J., et al., Reliability and validity of the Functional Assessment of Cancer 
Therapy-Breast quality-of-life instrument. J Clin Oncol, 1997. 15(3): p. 974-86. 
66. 
Yount, S., et al., Brief assessment of priority symptoms in hormone refractory prostate 
cancer: the FACT Advanced Prostate Symptom Index (FAPSI). Health Qual Life 
Outcomes, 2003. 1: p. 69. 
67. 
Saad, F., et al., The Canadian Uro-Oncology Group multicentre phase II study of 
docetaxel administered every 3 weeks with prednisone in men with metastatic hormone-
refractory prostate cancer progressing after mitoxantrone/prednisone. BJU Int, 2008. 
102(5): p. 551-5. 
68. 
Tannock, I.F., et al., Chemotherapy with mitoxantrone plus prednisone or prednisone 
alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial 
with palliative end points. J Clin Oncol, 1996. 14(6): p. 1756-64. 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
69. 
Brenchley, J.M. and D.C. Douek, Flow cytometric analysis of human antigen-specific T-
cell proliferation. Methods Cell Biol, 2004. 75: p. 481-96. 
70. 
Corey, M.J., et al., A very sensitive coupled luminescent assay for cytotoxicity and 
complement-mediated lysis. J Immunol Methods, 1997. 207(1): p. 43-51. 
71. 
Schafer, H., et al., A highly sensitive cytotoxicity assay based on the release of reporter 
enzymes, from stably transfected cell lines. J Immunol Methods, 1997. 204(1): p. 89-98. 
72. 
Weitzner, M.A., et al., The Functional Assessment of Cancer Therapy (FACT) scale. 
Development of a brain subscale and revalidation of the general version (FACT-G) in 
patients with primary brain tumors. Cancer, 1995. 75(5): p. 1151-61. 
73. 
Esper, P., et al., Measuring quality of life in men with prostate cancer using the 
functional assessment of cancer therapy-prostate instrument. Urology, 1997. 50(6): p. 
920-8. 
74. 
Lin, D.Y., et al., Estimating medical costs from incomplete follow-up data. Biometrics, 
1997. 53(2): p. 419-34. 
75. 
Tsiatis, A.A., Estimating the distribution of quality-adjusted life with censored data. Am 
Heart J, 2000. 139(4): p. S177-81. 
76. 
Ansari, J., et al., Role of second-line systemic treatment post-docetaxel in metastatic 
castrate resistant prostate cancer- current strategies and future directions. Anticancer 
Agents Med Chem, 2011. 11(3): p. 296-306. 
77. 
Moore, M.J., et al., Use of palliative end points to evaluate the effects of mitoxantrone 
and low-dose prednisone in patients with hormonally resistant prostate cancer. J Clin 
Oncol, 1994. 12(4): p. 689-94. 
78. 
DiPaola, R.S., et al., A randomized phase II trial of mitoxantrone, estramustine and 
vinorelbine or bcl-2 modulation with 13-cis retinoic acid, interferon and paclitaxel in 
patients with metastatic castrate-resistant prostate cancer: ECOG 3899. J Transl Med, 
2010. 8: p. 20. 
79. 
Longo, C.J. and B.G. Bereza, A comparative analysis of monthly out-of-pocket costs for 
patients with breast cancer as compared with other common cancers in Ontario, Canada. 
Curr Oncol, 2011. 18(1): p. e1-8. 
80. 
Zhao, H. and L. Tian, On estimating medical cost and incremental cost-effectiveness 
ratios with censored data. Biometrics, 2001. 57(4): p. 1002-8. 
81. 
Gelber, R.D., R.S. Gelman, and A. Goldhirsch, A quality-of-life-oriented endpoint for 
comparing therapies. Biometrics, 1989. 45(3): p. 781-95. 
82. 
Woolson, R.F., Rank tests and a one-sample logrank test for comparing observed 
survival data to a standard population. Biometrics, 1981. 37: p. 687-696. 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
14.0 
APPENDICES 
14.1 
Appendix A: ECOG Performance Status 
ECOG/ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction (Karnofsky 
90-100). 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry work of a 
light or sedentary nature.  For example, light housework, office work (Karnofsky 70-
80). 
 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours (Karnofsky 50-60). 
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of waking 
hours (Karnofsky 30-40). 
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed or (Karnofsky 
10-20). 
 
5 
Death (Karnofsky 0). 
 
KARNOFSKY PERFORMANCE SCALE 
 
100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 
 
 
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
14.2 
Appendix C: FACT-P 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your 
response as it applies to the past 7 days. 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
14.3 
Appendix D: EQ-5D 
 
 
 
 
 
 
 
 
 
       (English version for the USA) 
Under each heading, please check the ONE box that best 
describes your health TODAY 
 
MOBILITY 
I have no problems walking   
 
 
 
 
I have slight problems walking  
 
 
 
 
I have moderate problems walking 
  
 
 
 
I have severe problems walking 
  
 
 
 
I am unable to walk 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
I have slight problems washing or dressing myself   
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself   
 
I am unable to wash or dress myself   
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework,  
family or leisure activities) 
I have no problems doing my usual activities  
 
 
I have slight problems doing my usual activities  
 
 
I have moderate problems doing my usual activities   
 
I have severe problems doing my usual activities  
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
I have moderate pain or discomfort   
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
I have severe pain or discomfort  
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
I am moderately anxious or depressed  
 
 
 
I am severely anxious or depressed   
 
 
 
I am extremely anxious or depressed  
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 We would like to know how good or bad your health is  
TODAY. 
 This scale is numbered from 0 to 100. 
 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 Mark an X on the scale to indicate how your health is TODAY. 
 Now, please write the number you marked on the scale in the box 
below.  
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The worst health you can imagine 
The best health you can imagine 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
14.4 
Appendix E: BPI 
Brief Pain Inventory 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
14.5 
Appendix F  – Patient Perspective Cost and Convenience  of Care Questionnaire 
 
We would like to ask you about your health coverage and the “out-of-pocket” costs 
you have had related to your cancer treatment. 
 
1. Do you have any coverage that helps pay for your medicines, when you are NOT in the 
hospital: (Check ALL that apply) 
  Yes by Government (e.g. ,Medicare Part D,Tricare, etc.) 
      Yes by private or employer-paid health insurance (supplemental) 
       No coverage 
     Don’t Know 
 
2. Do you have any coverage that helps pay for home or community care, when you are NOT in 
the hospital (i.e. nursing, physiotherapy, cleaning, etc.): (Check ALL that apply) 
   Yes by Government (Medicare, Medicaid, Tricare) 
   Yes by private or employer-paid health insurance 
   No coverage 
 Don’t Know 
 
 
If you do NOT have private or employer paid health insurance      Go to Question 4 
 
                                                           
TYPE OF SERVICE 
Don’t 
Know 
Not  
Covered 
Partial  
Coverage 
Full 
Coverage 
Hospital supplemental charges (e.g. 
Private room, telephone, TV, etc.) 
 
 
 
 
Prescription drugs (e.g. Antibiotics, 
pain medication, etc.) 
 
 
 
 
In home healthcare (e.g. nursing, 
physiotherapist, etc.) 
 
 
 
 
Homemaking services (e.g. cleaning, 
cooking, etc.) 
 
 
 
 
Alternate Therapy (e.g. 
Homeopathy, Chinese medicine, 
over the counter drugs, etc.) 
 
 
 
 
Other (Specify)  
_____________________________
______________________ 
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
3. If you have Private/Employer-paid health insurance, please describe your coverage for each 
type of service:  (For each service, check the box that best describes your level of coverage.) 
 
 
 
 
 
 
 
 
 
 
 
 Proceed to Question 4 
 
 
4. Please supply the following details regarding your “out-of-pocket” costs for trips to and from 
your treatments and family doctor visits related to your cancer in the last 30 days. 
 
 
 
 
 
Type of Visit 
Number 
of trips 
in the 
last 30 
days 
Distance  ONE 
WAY  OR origin 
and destination 
points 
Method of 
transport 
(car, taxi, 
bus, train 
etc.) 
 
 
 
Parking 
or Fare 
 
Paid for by  
Insurance/ 
Government  
(circle one) 
Cancer Clinic/ 
Radiation 
Facility 
 
 
    Miles 
 
$ 
None – Partial - Full 
Hospital 
 
 
Miles 
 
$ 
None – Partial - Full 
Family Doctor 
 
 
Miles 
 
$ 
None – Partial - Full 
Other (Specify, 
i.e. 2nd Hospital 
or 2nd Doctor, 
ER) 
___________ 
 
 
Miles 
 
$ 
None – Partial - Full 
 
5. For questions listed below indicate if you had cancer related costs, paid by yourself, private 
insurance or government programs (e.g. Home Oxygen, Homecare, etc.) during the last 30 
days. If you do not know the exact amount make your best estimate, rounded to the nearest 
dollar.  
 
a) Copays 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
  Amount (if known): 
 
 
 $ ____________ 
 
N/A 
N/A 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
b) Prescription Drugs 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 
      Amount 
(if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
 
c) In home healthcare (nursing, physical therapy, respiratory therapy, etc.) 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
 
d) Homemaking (cleaning, cooking, etc.) 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
e) Complementary and Alternative Therapy (homeopathy, massage, acupuncture,  
counseling, etc.) 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
f) Vitamins and Supplements including special diets 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 
      Amount 
(if known): 
 
 
  $ ______________ 
 
$ _______________ 
$  _____________ 
 
g) Family Care (child or elder) 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
h) Accommodation/Meals 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
i) Devices or Equipment (home oxygen, wheelchair, walker, etc.) 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ______________ 
 
$ _______________ 
$  _____________ 
 
 
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
j) Other (telephone costs, pagers,  etc..) 
 
 
   
No 
 
   Yes  (Check all that apply and fill in related estimate of dollar amount) 
   paid by yourself 
  paid by private insurance   paid by government 
 Amount (if known): 
 
 
 $ ____________ 
 
$ _______________ 
$  _____________ 
 
 
6. 
Would you say this last month  your “out-of-pocket” expenses related to your cancer       
were:  
 
   More than other months        Typical         Less than other months       Don’t Know 
 
 
We would like to ask you some questions about your healthcare visits related to this 
cancer as well as the impact these visits have had on your work. 
 
7. 
Since you finished radiation, have you had:  (Check all that apply) 
                 NOTE: We will ask you specific questions about these in a separate form. 
 
 Doctor visits 
 
 
 Emergency room visits 
 Overnight hospitalization – indicate duration 
  one      or ______ nights.  
 Home nursing services 
 Respiratory/ Physiotherapists/ Occupational Therapy services 
 Medication changes 
 Started oxygen treatment 
 
 
8. 
How much time over the last 30 days did you take off work to receive treatment   
related to your cancer 
 
         Unemployed           No time off work          ________ days        Don’t 
Know 
   Retired          
 
 
9. 
Was this time away from work: (Check ALL that apply) 
 
  Not Applicable (not working)    Vacation     Time off with pay    Time off without 
pay 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
10. 
Did friends or family take time away from work in the last 30 days related to your 
treatment 
 
         No time off work        
OR 
 
   _________ days 
 
 
We would now like to ask you a little bit about you, your work and your education: 
 
11. 
Year of Birth   _________ 
 
12. 
Sex: 
 
 Male    
       Female 
 
13. 
Marital Status: 
 
   Married 
 
 Common Law 
 
   Single (never married) 
 
  Widowed 
 
 Separated  
 
  Divorced 
 
14. 
How many other people do you share your home with (do not include people who are 
only visiting): 
 
 Live alone (  Go to Question 16) 
 
 
  Myself and one other   
 
 2 others  
 
 
  3 others 
 
 
  More than 3 others 
 
15. 
Are these people you share your home with: 
 
  Family      Friends      Both Family and Friends  
 
16. 
City or Town where you live _____________________________ 
 
17.  
How would you rate your current health? 
 
  Excellent 
  Very good 
 
   Good 
 
   Fair    Poor 
 
 
 
18. 
What do you do for a living: 
 
  Full time work : Specify ______________    Part time work: Specify ____________ 
  Retired  
 
  Homemaker 
 Unemployed 
 Student 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
19. 
What is the highest level of schooling you have completed? 
 
 
  No schooling, some elementary school, or completed elementary school 
 
  Some high school 
 
  Completed high school 
 
  Some university or community college 
 
  Completed university or community college 
  Post Graduate (MSc/MBA/PhD) or professional training (MD/LLB/DDS) 
 
 
20. 
What was your total family income before taxes in the last year. 
 
(include wages, salaries and self-employment earnings) 
 
Less than $5,000 
$5,000- $9,999 
$10,000- $14,999 
$15,000- $19,999 
$20,000-$29,999 
$30,000-$39,999 
$40,000-$49,999 
$50,000-$59,999 
$60,000-$79,999 
More than $80,000 
Don’t Know 
 
21. 
How much of a financial burden are these out-of-pocket expenses listed in Q 4 & 5: 
    
Not a burden at all 
Only a slight burden 
Somewhat of a burden 
Significant burden, but manageable 
Unmanageable burden 
 
24. What treatments or services that are not currently available would you like to see paid for 
through government or private insurance: 
____________________________________________________________________________________________________________
________________________________________________ 
25. Was this questionnaire completed by: 
 
 The patient 
 
 
 A caregiver  
 
  Both the patient and a 
caregiver  
 
 
 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 
 
 
 
We would like to learn more about your personal reactions to the treatment and the 
impact it had on your typical activities: 
 
 
 
26. To what extent has your treatment disrupted your normal daily activities? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
27. To what extent has your treatment disrupted your normal recreation activities? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
28. To what extent has your treatment disrupted your normal activities with your family and 
friends? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
29. To what extent has your treatment disrupted your sleep pattern? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
30. To what extent has your treatment disrupted your enjoyment of life? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
31. How satisfied are you with the length of time your treatment has taken to this point of time? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
32. How disruptive has your treatment been to the other important people in your life (example: 
family, spouse, close friends, coworkers)? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Additional Comments 
_____________________________________________________________________________________________
_____________________________________________________________________________________________
_____________________________________________________________________________________________
___________________________________________________________________________________-
____________________________ 
 
 
Thank you for helping us with our survey.  If you have completed all sections please 
place the survey in the envelope, seal it, and return it to the attending clinic staff. Retain 
the information sheet. 
 
 


STU 102012-026 
________________________________________________________________________ 
STU102012-026, Hannan, Form A3, Mod_36, 06-24-19 (1) 
CONFIDENTIAL 
This material is the property of the UTSW Department of Radiation  Oncology. Do not disclose or use except as authorized in writing by the 
study sponsor.