Phase I Feasibility Trial of Preoperative Adjuvant Stereotactic Body Radiotherapy for Patients at High Risk of Local Failure After Prostatectomy
Phase: NA
Conditions: Stage I Prostate Adenocarcinoma American Joint Committee on Cancer (AJCC) v7, Stage II Prostate Adenocarcinoma AJCC v7, Stage III Prostate Adenocarcinoma AJCC v7
Sponsor: Jonsson Comprehensive Cancer Center

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Phase I feasibility trial of preoperative adjuvant stereotactic body 
radiotherapy for patients at high risk of local failure after prostatectomy 
PRINCIPAL INVESTIGATORS: 
Nicholas Nickols, M.D., Ph.D. 
Assistant Professor, UCLA Radiation Oncology 
CO - INVESTIGATORS: 
Christopher King, Ph.D., M.D. 
Professor, UCLA Radiation Oncology 
Robert Reiter, M.D. 
Professor, UCLA Urology and Molecular Biology 
Michael Steinberg, M.D. 
Professor & Chair, UCLA Radiation Oncology 
Amar Kishan, M.D. 
Assistant Professor, UCLA Radiation Oncology 
Albert J. Chang, M.D. 
Assistant Professor, UCLA Radiation Oncology 
STUDY COORDINATOR: 
Care Felix 
Study Coordinator, UCLA Radiation Oncology 
Colleen Mathis 
Study Coordinator, UCLA Urologic Oncology 
STUDY CENTER: 
UCLA Jonsson Comprehensive Cancer Center 
Department of Radiation Oncology 
200 UCLA Medical Plaza, Suite B265, 
Los Angeles CA 90095 
NCT02830165

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Clinical Rationale: Prostate cancer patients with pathologic T3 disease, extensive 
positive margins, or high gleason grade are at elevated risk of local failure after 
prostatectomy (1–3). Adjuvant radiation improves clinically meaningful outcomes for 
patients at high risk of local failure after radical prostatectomy and is a standard of care 
(2). Adjuvant radiation, typically delivered postoperatively, is clinically underutilized (4). 
Preoperative adjuvant radiotherapy, if clinically feasible, would be a subject of interest for 
future clinical trials. 
Preoperative adjuvant radiotherapy offers the following additional advantages: (1) 
reduced radiation dose to normal tissues; (2) lower prescription dose; (3) ability to utilize 
stereotactic body radiotherapy (SBRT); (4) patient convenience; (5) radiobiologic 
advantage of high dose per fraction treatment delivery. Furthermore, multiparametric (mp) 
MRI can predict extraprostatic extension (EPE) and seminal vesicle invasion (SVI) with 
90% specificity (4), thereby offering a non-invasive method of selecting patients for 
preoperative adjuvant radiation. Prior clinical trials have evaluated the safety of, and 
identified a safe dose for, preoperative radiotherapy in prostate cancer. The feasibility of 
pre-operative adjuvant radiotherapy has yet to be evaluated. 
Hypothesis: Preoperative adjuvant radiotherapy delivered by SBRT prior to 
prostatectomy in patients at high risk of local failure is feasible. 
Design: This is a single arm Phase I feasibility study in prostate cancer patients at high 
risk for recurrence after prostatectomy. 
•
Patients will receive 3 fractions of 8Gy delivered by SBRT over 1-2 weeks, 2-4
weeks prior to prostatectomy and will come to clinic for standard follow- up for one
year after surgery.
Primary Objective: 
To assess feasibility of pre-operative SBRT in prostate cancer patients after 
prostatectomy. We consider the trial feasible when the estimated treatment completion 
rate for an enrolled patient is 75%. A patient is considered to have completed treatment 
if they received the prescribed radiation and undergo prostatectomy within 4 weeks of 
completing radiotherapy. 
Secondary Objectives: 
To assess acute toxicity (CTCAE v 4.0) and quality of life (EPIC and IPSS) 
Correlative molecular analyses of tumor tissue and serum markers in patients that have 
undergone SBRT 

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Translational Significance: From laboratory studies we already know that the  response 
of prostate cancer cells and tissues to high dose per fraction RT (8 Gy) differs from that 
to conventional dose per fraction RT (1.8-2 Gy) in ways beyond what can be expected 
from simple excess tumor cell death alone (6–8). We have evidence that the local and 
systemic immune responses that may be generated towards radiation- damaged prostate 
tumors after SBRT may be responsible for the discrepancy (8). However, the very 
conditions that promote tumor immunity may also enhance radiation- induced 
reprogramming of cancer towards a stem cell phenotype. How these differing outcomes 
play out in individual high-risk patients may be critical to the clinical outcome. The 
correlative analyses of this study will examine the tumor micro-environmental changes 
that might drive these divergent responses. This trial of prostate SBRT followed by 
prostatectomy offers a unique translational opportunity to study the radiobiology of SBRT 
in resected tissues. 
 
 
 
Protocol Overview 
 
 
SBRT 
Prostatectomy 
Tests at each Follow-up 
24Gy in 3 fractions 
Open or robotic 
CTCAE toxicity scores, QOL-EPIC & IPSS 
(8 Gy per fraction) 
assisted prostatectomy scores, blood (including PSA) 
within 4 weeks 
(preferable 2 weeks) of 
SBRT 
 
 
Study Design: Prospective Phase I 
Sample size: 
12 patients, single-institutional 
Outcome: 
Feasibility assessment (percent of patients completing scheduled 
treatment) Treatment: 
SBRT, prostatectomy 
RT targets: 
Prostate PTV = prostate and SV (only if involved on MRI or biopsy) 
 
Target Prescription Doses: 
Prostate PTV 
24 Gy in 3 fractions, 8 Gy per fraction 
 
 
RT Technique: image-guided SBRT via robotic radiosurgery, IMRT, or VMAT, with 
daily and intra-fraction Image-guidance (MRI-based, fiducial-based or CBCT-
based) 
 
 
 
 
 
 
 

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Trial Flowchart 
 
 
 
Patient with localized prostate cancer, 
eligibility determination 
Registration into study, 
consent 
Baseline labs and QOL questionnaires 
Treatment 
planning 
SBRT treatment 
Prostatectomy 
Primary Aim: Assess 
feasibility (percent of 
patients completing 
scheduled treatment) 
Secondary Aims: 
Assess 
toxicities 
(CTCAE v 4.0) and 
Quality of life (EPIC 
& IPSS QOL), 
histologic and 
molecular analyses 

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Background 
 
Prostate cancer is the most common non-cutaneous malignancy in men and second 
leading cause of cancer death in men (9). There are more than 230,000 incident cases 
per year and 30,000 deaths in the United States – the vast majority of which are from 
metastatic castrate resistant prostate cancer. However, more than 90% of men with 
metastatic prostate cancer are initially diagnosed with localized, not metastatic, prostate 
cancer. Therefore, improving cancer care for localized prostate cancer that is at high  risk 
for recurrence is likely to reduce mortality. 
The standard of care for localized prostate cancer is prostatectomy or definitive 
radiotherapy ± androgen deprivation therapy (ADT) (10). Patients who undergo surgery 
and have adverse features of positive margins, EPE, or SVI have up to 45-75% risk of 
biochemical failure within 5 years. Patients that undergo prostatectomy and have 
pathologic T stage 3 or greater or positive margins benefit from additional adjuvant 
therapy (2,3). Three randomized trials demonstrate improved progression free survival 
with the addition of adjuvant radiotherapy after prostatectomy in patients with pathologic 
T3 or positive margins: SWOG 8794, EORTC 22911, and ARO 96–02. SWOG 8794  was 
powered to detect a survival advantage and it did (2). As such, adjuvant radiotherapy with 
prostatectomy is a standard of care for patients with adverse features of pT3 (EPE or 
SVI),positive margins, or Gleason Grade 8-10 (2015 NCCN guidelines). 
Prostate cancer imaging techniques have advanced such that prostate mp MRI can 
detect EPE and SVI with 90% specificity (5). 
Only 15% of patients who meet the criteria for adjuvant radiation actually undergo this 
treatment (5). This low utilization may result from the inconvenience associated with 
seven to eight weeks of daily treatments, toxicity due to normal tissue irradiation, and the 
possibility that later salvage radiation at PSA recurrence might offer an alternative. The 
latter is unknown and is the subject of current investigations. The safety of pre- operative 
adjuvant radiotherapy has been evaluated in clinical trials and a safe biologically effective 
dose has been identified (12–14). Pre-operative adjuvant radiotherapy, if shown to be 
feasible, would be a subject of interest for a larger clinical trial. 
Prior Studies of pre-operative radiotherapy in prostate cancer assessing safety 
 
Duke University undertook a phase I dose escalation trial of pre-operative fractionated 
intensity modulated RT followed by prostatectomy (12). All patients were treated to the 
prostate and seminal vesicles to 39.6, 45, 50.4, and 54 Gy in fractions of 1.8 Gy. The 
pelvic nodes were also treated, but to a maximal dose of 45 Gy. No intraoperative 
morbidity was observed. Acute toxicity was limited to Grade 1 (GU and GI). Late toxicity, 
primarily GU, was within the range expected for adjuvant post-operative RT. 

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The conclusion was that 54 Gy is a safe dose for preoperative RT followed by 
prostatectomy. 
Princess Margaret Hospital undertook a phase I trial of 15 patients for pre-operative RT 
followed by prostatectomy within four weeks of completing RT (15, 16). Conformal RT 
technique (one patient was treated with IMRT) was used to deliver 5 fractions of 5 Gy 
without image guidance. There were no intraoperative complications, no late GI toxicity. 
Two cases of long-term urinary incontinence were observed. Overall, GU toxicity was 
within the range expected for adjuvant post-operative RT. 
Notably, our study would utilize modern image guidance and precise treatment volumes, 
which have been shown to reduce GU and GI toxicity in prostate radiotherapy as 
compared to conformal techniques. 
Selection of RT dose for the current study 
 
The preceding studies evaluating RT prior to prostatectomy demonstrate safety of pre- 
operative RT at doses of up to 54 Gy in 30 fractions (12). The critical organs at risk in 
prostate RT are the rectum and bladder. The biological effectiveness of RT for a given 
physical dose varies between tissues; different tissues (including tumor) are differentially 
responsive to dose per fraction (quantified by the alpha-beta ratio specific to the tissue or 
tumor) (15). In the rectum and bladder (alpha-beta ratio of 3-4) (16,17), an RT regimen of 
24 Gy delivered in 3 fractions of 8 Gy is biologically equivalent to a dose less than 54 Gy 
delivered in 30 fractions of 1.8 Gy (the dose previously shown to be safe when delivered 
to the prostate and seminal vesicles prior to prostatectomy). However, because prostate 
tumors have a greater sensitivity to changes in dose per fraction than the rectum and 
bladder (alpha-beta ratio of 1.5) (18, 19), 24 Gy delivered in 
3 fractions of 8 Gy deposits a higher biologically effective dose than 54 Gy in 30 fractions 
in prostate tumor tissue. A dose of 24 Gy delivered in 3 fractions is biologically equivalent 
in prostate tumor tissue to a standard post-operative adjuvant dose of 70.2 Gy delivered 
in fractions of 1.8 Gy. 
In summary, our selected dose is: 1- based on prior studies identifying a safe dose; and, 
2- equivalent to the standard adjuvant RT dose delivered postoperatively. Furthermore, 
delivering the radiation by SBRT using modern image guidance systems and precise 
treatment volumes is expected to further reduce toxicity as compared to the prior studies 
which did not use this delivery technique. 
Biologic rationale for combination of preoperative adjuvant radiation delivered by 
SBRT with prostatectomy 
The goal of adjuvant prostate radiotherapy is to eradicate residual disease associated 
with EPE and positive margins.  The target is therefore the prostate surgical bed. 

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However, precise delineation of the clinical target volume (CTV) of the prostate bed is 
complicated by changes in anatomy due to surgery. Not surprisingly, controversy exists 
in the optimal target volume. The CTV must include significant portions of the posterior 
bladder wall and extend to the anterior rectal wall, exposing normal, healthy tissues to full 
dose radiation. A standard post-operative adjuvant dose is 70.2 Gy delivered in 39 
fractions of 1.8 Gy. 
Prostate cancer is highly sensitive to dose per fraction (the prostate cancer alpha-beta 
ratio of 1.5 is much smaller than 10, which is typical of other malignancies) (15). 
Consequently, there is a biologic rationale to use fewer, but relatively larger sized fractions 
(~8 Gy per fraction) of radiation in prostate cancer, compared to conventional fractions of 
1.8 to 2 Gy that are used for most cancers (20). 
Definitive radiotherapy for prostate cancer has benefited greatly from technical 
improvements in image guidance and treatment delivery, enabling large fraction sizes to 
be safely delivered by stereotactic body radiotherapy (SBRT = delivery of up to five 
fractions with tight margins under image guidance). The CTV for prostate SBRT is the 
prostate alone (and seminal vesicles if involved) and the planning target volume (PTV) is 
a small expansion. Unfortunately, the use of SBRT in the postoperative setting (adjuvant 
or salvage) is frustrated by the lack of consensus of the ideal CTV and the necessity of 
including significant volumes of normal tissues. 
Therefore, there is a two-fold rationale to utilize preoperative, adjuvant SBRT in patients 
at risk for local failure after prostatectomy: 1- pre-operative RT delivered by SBRT is more 
convenient for patients (only 3 treatments), which would likely increase utilization of 
adjuvant RT if shown to be clinically feasible; 2- delivery of large fraction sizes are radio-
biologically advantageous. 
Clinical - Translational Relevance 
 
Empiric clinical data has demonstrated that prostate adenocarcinoma is exquisitely 
sensitive to changes in fractional size of radiation dose to a degree larger than even 
surrounding normal tissues (19, 19). It follows that there is no benefit derived from 
fractionating radiation dose to the conventional daily dose of 2 Gy during treatment, and 
that use of larger fractions will increase the therapeutic benefit with more tumor control at 
the same or decreased toxicity. This is in contrast to most other cancer types where 
conventional fractionation to 1.8-2 Gy per day is justified because surrounding normal 
tissues, but not tumors, are spared. 
SBRT is the technique of choice to deliver such higher doses. Surprisingly, though, our 
understanding of the biology behind SBRT have not kept up with the clinical success of 
this modality due to a dearth of translational studies using specimens from patients treated 
with SBRT. This Phase I trial of preoperative SBRT in patients at high risk of local   
recurrence   following   prostatectomy   offers   the   possibility   of   studying   the 
radiobiology of SBRT in the clinic. It also lends itself to examination of the role of radiation-

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induced immunity in preventing recurrences in high-risk disease and to the role of EMT in 
promoting recurrences. The dynamic nature of the relationships between these 
phenomena is of particular interest to our team. 
In vitro and in vivo work has suggested that high dose per fraction RT alters the extent 
and the type of damage to DNA and to vascular structures including endothelial cells, and 
it seems to generate stronger anti-tumor immunity. We already know that irradiation 
generates an immunogenic cancer cell death, in part by inducing genetic programs that 
signal “danger” to the immune system (6). SBRT may therefore drive immune recognition 
and tumor immunity of potentially systemic proportions (8). It starts with the generation of 
a pro-inflammatory microenvironment with up-regulation of MHC and co- stimulatory 
molecules that can enhance tumor antigen cross-presentation by dendritic cells and that 
broadens the antigenic repertoire. Progenitor cells of mesenchymal, endothelial, myeloid 
and lymphoid origin get mobilized to infiltrate the irradiated area. What is important here 
is that according to preclinical evidence, doses considerably higher than the conventional 
1.8-2 Gy are required to generate high enough levels of pro-inflammatory cytokines and 
superior anti-tumor responses. Based  on  our experience with clinical and pre-clinical 
tumor models, we hypothesize that pre- operative, prostate SBRT with 3 fractions of 8 Gy 
given over a relatively short time will lead to measurable immunological changes, locally 
and 
systemically. 
Understanding 
these 
changes 
could 
inform 
the 
use 
of 
immunomodulatory therapies in locally-advanced as well as metastatic prostate cancer. 
Unfortunately, the same pro-inflammatory conditions may drive reprogramming towards 
a more resistant cancer stem cell phenotype that could increase the likelihood of 
recurrence in high-risk patients. The balance between these forces and their correlation, 
if any, in individual high-risk patients will be investigated. 
The translational component of this trial seeks: 1. To investigate the radiobiology of SBRT 
in prostate cancer using resected prostate tumor tissue, and 2. To evaluate the nature of 
the immune response to prostate cancer generated by SBRT. These aims are included 
within the secondary objectives of this trial. 
Scientific impact 
 
RT causes genotoxicity in irradiated tissue, which is a primary cause of cancer cell killing 
(21). More recent evidence suggests that additional radiation-induced pathways are at 
play which drive immune recognition and tumor-immune eradiation with potentially 
systemic consequences, especially after high dose per fraction RT (6–8).  The promising 
synergy between RT and the immune system is underscored by a multitude of ongoing 
clinical trials that combine local irradiation with systemic immunomodulatory therapeutics. 
Translational studies correlating such systemic and intratumoral responses using freshly 
irradiated tissue, however, are extremely rare. Laboratory studies suggests that the doses 
used in prostate SBRT are close to the optimal fraction sizes to generate such 
measurable immunological changes. Therefore, this pre-operative prostate SBRT trial 
offers a unique opportunity to study the radiobiology of SBRT in the clinic, one that simply 
cannot be ignored. 

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Another level of complexity arises from the fact that RT may induce markers of EMT and 
neuroendocrine differentiation in prostate and other cancers, potentially promoting 
treatment resistance (22,23). If prostate radiotherapy drives such de novo transformations 
above what exists anyway, then strategies targeting these pathways would be particularly 
effective when combined with radiation. What’s more, the hypothesis is that EMT 
transformations are promoted by pro-inflammatory conditions, which would suggest an 
alternative, and less favorable outcome for high-risk patients after receiving SBRT. 
Resolving the relative importance of EMT viz-a-viz immune system activation in individual 
patients is a novel and important long-term goal of this study. It will generate insight by 
studying both EMT and pro-inflammatory and immune SBRT-induced changes within the 
radiation-damaged microenvironment in vivo using IHC and transcriptomics. Currently, 
these changes are largely unknown. Therefore, we believe the correlative genomic 
analyses we have proposed would, at minimum, be hypothesis generating for future 
investigations with high translational impact. 
 
Study design: 
 
This is a single arm, Phase I feasibility study of SBRT followed by prostatectomy within 4 
weeks for patients with prostate cancer at high risk of local failure after prostatectomy. A 
patient is considered to have completed treatment if they received the prescribed 
radiation and undergo prostatectomy within 4 weeks of completing radiotherapy. 
NUMBER OF PATIENTS; 
 
12 patients in 3 years with recruitment at UCLA Jonsson Comprehensive Cancer Center 
 
Objectives: 
 
Primary Objective: To assess feasibility of pre-operative SBRT in prostate cancer 
patients at high risk for recurrence after prostatectomy. We consider the trial feasible 
when the estimated treatment completion rate for an enrolled patient is 75%. A patient is 
considered to have completed treatment if they received the prescribed radiation and 
undergo prostatectomy within 4 weeks of completing radiotherapy. 
 
• Secondary Objectives: 
o To assess safety and acute toxicity of SBRT followed by prostatectomy. This 
will be based on CTCAE version 4.0 and patient reported quality of life (EPIC 
and IPSS questionnaires). 
o Investigation of the radiobiology of SBRT in prostate cancer using resected 
prostate tumor tissue. For the correlative genomic analyses, prostate lesions at 
the time of prostatectomy will be processed for RNA and exome sequencing 
and compared to existing sequencing data for localized prostate cancers.  We  
will  utilize  both  supervised  and  unsupervised  analyses     of 

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Pathway activation from RNA-seq data sets in order to determine which 
pathways are enriched after irradiation. 
o Evaluation of the nature of the immune response to prostate cancer 
generated by SBRT. 
 Systemic immune response. Blood that is collected pre SBRT, between 
0 and 4 weeks after SBRT, and at 3 and 6 month intervals after SBRT 
will be assessed as follows: PBMCs will be isolated over Ficoll-gradients 
and stored frozen until analysis. Lymphoid and myeloid subset 
phenotyping will be assessed by antibody staining and multi- color flow 
cytometry (LSR-Fortessa, BD). Circulating cytokines, PGE2, prostate-
tumor 
specific 
antibodies, 
HMGB-1 
protein 
and 
the 
tryptophan/kynurenine ratio in plasma will be quantified by ELISA. 
Tumor-specific CD4 and CD8 T cell activities to known HLA-matched, 
immunodominant, tumor-associated antigens will be assessed ex  vivo 
by IFNγ -ELISPOT and dextramer staining. The tumor antigens of 
choice will include PSA and PSMA. 
 Local immune response. The immune response at the tumor site will  be 
visualized through immunohistochemistry (IHC), with particular  focus on 
T cells (CD3+), T regulatory cells (CD4+ CD25hi), tumor infiltrating 
myeloid-derived suppressor cells (CD11b+ Gr-1+ CD15+) and tumor-
associated macrophages (CD11b+F4/80+). Levels of CSF1/CSF1R, 
tumor MHC I, PD-1 and PD-L1 are also of interest as are markers for 
EMT 
(vimentin, 
N-cadherin, 
E-canderin), 
for 
neuroendocrine 
differentiation (chromogrannin A, neuron specific enolase), AR protein 
and p53. Comparisons will be made to pre- treatment biopsy material 
when possible and to tissue microarrays of non-irradiated prostatectomy 
specimens. 
 
Eligibility Criteria 
 
• Histologically confirmed primary non-metastatic adenocarcinoma of the prostate 
• Patient desires and is medically fit to undergo prostatectomy 
• Age ≥ 18 
• KPS ≥ 70 
• Patients on ADT are allowed 
• For confirmation of high risk local failure status, patients will have any one of the 
following: 
o CT or MRI demonstrating SVI or EPE within 1 year of enrollment into 
the study 
o Pre-biopsy PSA ≥ 20 
o Gleason score 7-10 (Gleason 7 must be 4+3), presence of any 
Gleason 5 (even if a tertiary score) as determined at diagnostic 
biopsy 

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o Gleason score 7 and >50% of biopsy cores positive for prostate 
cancer 
o Clinical stage ≥ T3 (staging by imaging acceptable) 
• An image-guided biopsy (via Artemis Ultrasound with MRI co-registration) is 
encouraged but not required if not performed as standard of care biopsy 
Ineligibility Criteria 
 
• Distant metastases, based upon: 
o CT scan or MRI of the abdomen/pelvis or PSMA PET/CT within 120 
days prior to registration and 
o Bone scan or PSMA PET/CT within 120 days prior to registration; if 
the bone scan is suspicious, a plain x-ray and/or MRI must be 
obtained to rule out metastasis prior to registration. 
 
• Patient is unable or unwilling to sign consent. 
• Patient is considered low-risk and would not have received adjuvant RT outside 
of this study 
REGISTRATION PROCEDURES 
 
General guidelines 
 
Subjects will be identified by physicians in Urology or Radiation Oncology. 
The Study Coordinator will enter eligible patients on study centrally at the 
UCLA Jonsson Comprehensive Cancer Center. Subjects will be recruited 
through self- referral and the advice of their attending physician. 
 
Registration process 
 
A member of the research team will enroll the patient onto the trial. Consent 
will be obtained after a clear and thorough discussion between the patient 
and the principal investigator or any of the co-investigators in clinic. Any 
patients that are deemed by the principal investigator or co-investigators to 
be mentally or physically incapable of consent will not be included in the 
study. 
Once a candidate has provided full consent, the following will be 
completed/collected to fully determine eligibility: 
o Signed patient informed consent form 
o HIPAA authorization form 
o Medical history, clinical examination and consultations with Radiation 

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Oncology and Interventional Radiology departments 
o Verification of clinical stage ≥ T3 (staging by imaging acceptable) 
o Verification of no distant metastases, based upon: 
 
 
 
 
 
 
REGISTRATION 
• CT scan or MRI of the abdomen/pelvis or PSMA PET/CT within 
120 days prior to registration and 
• Bone scan or PSMA PET/CT within 120 days prior to 
registration; if the bone scan is suspicious, a plain x-ray and/or 
MRI must be obtained to rule out metastasis

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Study team will register subject with the UCLA Data Safety Monitoring Board to assure 
eligibility, prior to undergoing any further study-related procedures. 
 
PRIOR TO RADIATION TREATMENT 
 
Prior to radiation treatment, approximately 60 mLs of blood will be drawn for serum 
translational biomarker study. 
 
TREATMENT PLAN 
 
Radiation Simulation: 
Enrolled patients will undergo radiation simulation and planning as per routine for prostate 
cancer patients. A custom vacloc bag, alpha cradle, or equivalent immobilization device. 
A simulation scan will be performed. A pelvic mp MRI will be obtained if not available 
within the prior 4 months. The MRI will be utilized as a supplement for anatomical contour 
delineation. The urethra will be delineated with the MRI. These procedures are 
considered standard-of-care for prostate radiotherapy planning. 
 
Radiation Planning (Target Areas): 
• The study investigator will delineate the prostate, seminal vesicles on the pelvic 
simulation CT. 
• The prostate PTV will consist of an expansion of the prostate gland up to 7mm in 
all directions, (expansion may be reduced to 3mm posteriorly). 
• The SV PTV will consist of the contoured SV without expansion. 
• For all PTVs, the Prescription Dose will be defined to cover 95% of the PTVs. 
• Target Prescription Doses: 
Prostate 
24 Gy in 3 fractions, 8 Gy per fraction 
SV (if involved) 
24 Gy in 3 fractions, 8 Gy per fraction 
• Technique: image-guided SBRT via robotic radiosurgery, IMRT, or VMAT, with 
daily and intra-fraction Image-guidance fiducial-based, CBCT-based, MRI-based. 
 
Immediately after the 3rd (final) fraction of radiation treatment up to 4 weeks post SBRT, 
approximately 60 mls of blood will be drawn for serum translational biomarker study. 
 
Prostatectomy: 
 
Radical prostatectomy will be performed, either open or robot assisted, within 4 weeks 
after SBRT (preferably 2 weeks). After resection, the prostate is sectioned from base to 
apex into 5-7 slices depending on the size of the prostate. Slices 2 and 4 are kept fresh 
on ice, while all other slices are fixed in formalin and embedded in paraffin. A slide is cut 
and stained from the paraffin sections for pathologic diagnosis and the remaining tissue 
will be kept indefinitely in pathology and can be used for research. 
Frozen section is prepared from the fresh tissue (slices 2 and 4) for rapid diagnosis.  Part 

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of the fresh tissue is used for research and the remaining fresh tissue is frozen indefinitely 
and can be used for research. 
Follow-up: 
 
• 0 to 4 weeks after the final fraction of radiation, patients will have approximately 
60 mLs of blood drawn for serum translational biomarker research. Patients will 
also be evaluated by their physician and Adverse Events and Concomitant 
Medications will be assessed. EPIC and IPSS questionnaires will also be 
administered at this time. 
• Patients are followed every three months (± 4 weeks) for one year post surgery. 
At each follow-up visit, patients are evaluated for CTCAE (version 4.0) toxicity 
scores, and the EPIC and IPSS questionnaires will  be  administered.  Blood draws 
(~5 mLs) to assess PSA are drawn at each of the follow-up visits unless PSA lab 
evaluations have already been done within 4 weeks of the study visit. In addition, 
at the 3 month and 6 month follow-up visits, approximately 60 mLs of blood will be 
drawn for serum translational biomarker study. After one year of follow-up, patients 
will be seen as per routine care. 
 
OUTCOME MEASURES 
 
Primary objective, feasibility: A patient is considered to have completed treatment if 
they received the prescribed radiation dose of 24 Gy delivered in 3 fractions of 8 Gy 
within a span of 2 weeks and subsequently undergo prostatectomy within 4 weeks of 
completing radiotherapy. 
 
Secondary objective, safety and acute toxicity: Patients will be evaluated during RT, 
prostatectomy, and at intervals of 3 months following completion of treatment for one 
year. At each visit, patients will complete the EPIC and IPSS questionnaires and will be 
assessed for CTCAE v4 toxicities. 

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Secondary objective, correlative studies: Assessments of the systemic immune 
response will utilize blood that is collected pretreatment, after completion of SBRT, and 
at 3 and 6 months post treatment completion. The local immune response (intratumoral) 
will utilize the resected prostatectomy specimen, pre-treatment biopsies, and archived 
tissue arrays of prostatectomy specimens that did not undergo RT. RNA- and exome- 
sequencing of irradiated prostate tumors will utilize the resected prostatectomy 
specimens, which will be compared to existing sequencing analyses of localized 
prostate cancers (TCGA) matched for histology and Gleason grade. 
 
 
STATISTICAL CONSIDERATIONS 
 
Feasibility and sample size determination. Our primary objective is to determine 
feasibility of preoperative adjuvant stereotactic body radiotherapy for patients who are at 
high risk of local failure after prostatectomy. A confidence interval approach is used to 
estimate the sample size appropriate for this feasibility study (24, 25). We consider 
preoperative adjuvant stereotactic body radiotherapy feasible when the estimated 
treatment completion rate for an enrolled patient is at least 75%. For a two-sided 90% 
exact binomial confidence interval, a sample size of 12 patients yields a lower limit of 
the 90% confidence interval of at least 75% if the true proportion of patients completing 
treatment is 93%. A feasibility assessment of preoperative adjuvant stereotactic body 
radiotherapy is a required step prior to designing a larger trial. 
 
Estimation of eligible patients and enrollment. Numbers of eligible patients are 
estimated based on projected patient populations. Eligible patients for the study are 
drawn from prostate cancer patients referred for treatment evaluation at UCLA Medical 
Center by the study investigators. This is anticipated to be 200 patients in 2016. At least 
25% are anticipated to be eligible based on the risk classification of patients for our 
protocol (patients at high risk of recurrence). We estimate 75% of these patients will be 
surgical candidates. Standard treatments for these patients include either surgery (that 
includes adjuvant radiotherapy with or without androgen deprivation therapy) or 
definitive radiotherapy with concurrent androgen deprivation therapy. We estimate 40% 
of the patients will elect definitive radiotherapy with androgen deprivation. Of the 
remaining 60% of eligible patients, we anticipate that between 20 and 50% would be 
amenable to preoperative adjuvant radiotherapy. Our study is planned to accrue 
patients within three years. Therefore, there are sufficient numbers of patients eligible to 
participate in this study. 
 
Measurements of serological markers (secondary objective). Circulating cytokines, 
PGE2, prostate-tumor specific antibodies, HMGB-1 protein and the 
tryptophan/kynurenine ratio in plasma will be quantified by ELISA. Tumor-specific CD4 
and CD8 T cell activities to known HLA-matched, immunodominant, tumor-associated 
antigens will be assessed ex vivo by IFNγ-ELISPOT and dextramer staining. The tumor 
antigens of choice will include PSA and PSMA. A repeated measures analysis of 
variance will be used to assess differences in these serological markers over time. In 
addition to the overall time effect in the ANOVA model, we plan to test specific contrasts 

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between serological markers pre-treatment (baseline) and the first measurement post 
SBRT (pre surgery), where we anticipate to observe an increase in circulating tumor- 
specific CD4 and CD8 T cell activity. 
 
Multivariate profile analyses may be used when patterns for various markers emerge. 
These statistical analyses will be performed using IBM SPSS Statistics for Windows, 
Version 20.0. (Armonk, NY) statistical software. 
 
Measurements of intra-tumoral and intra-prostatic markers (secondary 
objective). The immune response at the tumor site will be visualized through 
immunohistochemistry (IHC), with particular focus on T cells (CD3+), T regulatory cells 
(CD4+ CD25hi), tumor infiltrating myeloid-derived suppressor cells (CD11b+ Gr-1+ 
CD15+) and tumor-associated macrophages (CD11b+F4/80+). Levels of CSF1/CSF1R, 
tumor MHC I, PD-1 and PD-L1 are also of interest as are markers for EMT (vimentin, 
N- cadherin, E-canderin), for neuroendocrine differentiation (chromogrannin A, neuron 
specific enolase), AR protein and p53. IntMax (scale of 0-300) = (% of positive tumor 
cells [scale of 0-100]) X (intensity of staining based on 0-3 scale [scale of 0-3]) will be 
assessed for each marker. Comparisons in markers will be made between: 1- post 
SBRT prostatectomy specimens vs biopsy material pre-SBRT; and 2- post SBRT 
prostatectomy specimens vs archival tissue of prostatectomy specimens (that did not 
undergo RT). 
 
For comparison between post SBRT prostatectomy specimens and biopsy material pre- 
SBRT, average IntMax will be compared using a paired t-test or Wilcoxon signed-rank 
test (if the IntMax scores do not follow a normal distribution). For comparison between 
post SBRT prostatectomy specimens and archived material, average IntMax will be 
compared using a t-test or Wilcoxon rank-sum test (if the IntMax scores do not follow a 
normal distribution). 
 
RNA and DNA exome sequencing (secondary objective). Quality control will be 
performed on the raw sequence data from RNA-seq experiments, which contain 
multiple short-read sequences with Phred quality score information using FastQC and 
FASTX-Toolkit. Bowtie2 will be used to align reads, which will then be mapped to the 
reference genome by TopHat2. Raw reads from exome sequencing will be aligned 
via BWA and converted to BAM format, and processed with the Genome Analysis 
Toolkit software package. Comparisons will be made to existing sequencing data 
(TCGA) for localized prostate tumors matched for histology and Gleason grade. 
Functional annotation will be performed using Gene Ontology, KEGG, and 
Reactome. 
 
Stopping Rules for Toxicity. Prior studies evaluating RT prior to prostatectomy 
demonstrate safety of pre-operative RT at doses of up to 54 Gy in 30 fractions (12). It is 
anticipated that toxicity in this study will be low because our dose is selected based on 
the prior studies. 
 
Nevertheless, our trial will be stopped for toxicity if any treatment related toxicity of 
CTCAE v4.0 grade 3 or above is observed in more than two subjects during the study 

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Amendment 5 (dated 04Apr2018) 
  
 
period in the following categories: gastrointestinal, urinary, with the exception of 
temporary use of a catheter and urinary incontinence, which can occur after 
prostatectomy in the absence of radiotherapy. 
 
DATA and SAFETY MONITORING: 
 
The JCCC DSMB meets monthly to review all SAE reports for trials overseen by the 
JCCC DSMB. All SAE reports, which have been filed since the previous meeting, are 
presented to the committee for review. 
For trials overseen by the JCCC DSMB, the DSMB reviews all dose-limiting toxicities 
(DLTs) for dose-escalation studies. Protocol suspensions and re-opening of accrual to 
the next cohort based on DLT evaluation fall under the purview of the DSMB. 
For all JCCC oncology trials and TRIO-US studies where the JCCC DSMB has primary 
oversight, all SAEs shall be reported to the JCCC DSMB in a timely manner [ten days, 
two days for a death] regardless of relationship and expectedness. The JCCC ORC will 
review all submissions and the ORC staff will enter the information into the JCCC 
Clinical Trials database.  Reports are generated for full JCCC DSMB review. 
For trials 
where the JCCC DSMB has primary DSMB review responsibility, the DSMB requires 
that the PI generate cumulative adverse event reports for quarterly, biannual or annual 
review. 
The DSMB reviews each SAE report and determines whether or not protocol 
modifications are warranted to ensure subject safety.  In this review, prior occurrences 
of similar toxicity with the therapy under study are taken into consideration, as well as 
the severity of the event and the likelihood that it was related to a study drug.  The 
DSMB may recommend no changes to the study if the event is expected or related to 
other causes such as the subject’s underlying condition. The DSMB may request an 
expert’s advice of another non-Principal Investigator with national experience to support 
their deliberations and decisions. 
The JCCC DSMB has the authority to recommend to the UCLA IRB the immediate halt 
to a study (i.e., discontinuation of any further treatment of enrolled subjects and 
discontinuation of enrollment of new subjects) should there be any serious unexpected 
toxicity that warrants further investigation. 
Requests for single subject exceptions/waivers from the approved study protocol, 
including out of window procedures and eligibility deviations, must be reviewed and 
approved by a member of the DSMB. Each trial is assigned a primary and secondary 
reviewer who is responsible for reviewing each exception/waiver request for that trial. 
Approvals and disapprovals of the request are sent to the Principal Investigator via 
email and copied to the UCLA IRB. Requests for single subject exceptions/waivers are 
made by the Principal Investigator via email utilizing the “Single Subject Exception 

IRB#15‐001580 
 
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Amendment 5 (dated 04Apr2018) 
  
 
Request Form.” 
JCCC DSMB correspondences are addressed to the Principal Investigator and copied 
to the UCLA IRB. Minutes of the DSMB meetings are maintained in a computer file. 
Confidentiality: Each member of the JCCC DSMB is responsible for maintaining strict 
confidentiality of the study data. Members will not share any study data or information 
about the study with any individual external to the JCCC DSMB or the statistical working 
group for the study. The DSMB members may contact the statistical working group 
directly with questions regarding the operational details associated with the data 
analysis and summary presentations. Communication of deliberations or 
recommendations of the JCCC DSMB, either written or oral, should not be made 
outside of the Committee or the statistical working group. Outcome results are strictly 
confidential and must not be divulged to any non-member of the JCCC DSMB except in 
those cases where DSMB is required to inform the UCLA IRB of its determinations. 
Disclosure of outcome results to the IRB must only occur with written approval of the 
DSMB. A member who believes he or she may have a potential intellectual or financial 
conflict of interest during the course of review of the data must inform the chairperson of 
the DSMB. In such case, the meeting minutes will record the disclosure of the potential 
conflict of interest and that the individual recuse himself from the discussions and 
abstains from voting on the DSMB decision. 
Level of Risk of a Study 
 
All interventional clinical trials undergo scientific review by the Internal Scientific Peer 
Review Committee (ISPRC) which requires that a Data and Safety Monitoring Plan is in 
place before a trial can be approved to begin. For trials overseen by the JCCC DSMB, 
the JCCC DSMB will determine the degree of risk of the study and will ensure that there 
are procedures in place to ensure the safety of the subjects that are enrolled in the trial. 
The intensity level of study oversight is determined by the risk category. Some of the 
factors that are considered when assigning the Level of Risk category include: 
• 
A biostatistical design and appropriate procedures for proper data management 
so that the information collected can be properly validated. 
• 
Appropriate Serious Adverse Event reporting procedures must be in place. 
 
• 
The study duration must be appropriate and must be based on a realistic rate of 
enrollment. 
• 
Data collection and data management must be adequate to verify and ensure 
subject eligibility. 

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Amendment 5 (dated 04Apr2018) 
  
 
 
Assignment of risk 
 
Assigning risk ensures that the data and safety monitoring is based on the level of risk 
(low, medium, or high) to ensure that the data and safety monitoring activities are 
appropriate. Below are some of the criteria used to make a decision regarding the 
assignment of risk: 
• 
Expected duration of the study based upon the estimated rate of enrollment. 
 
• 
Type of study population (e.g., children, geriatric) 
 
• 
The procedures used in the trial are commensurate with the degree of risk. 
 
• 
Adequate data management systems in place and appropriate case report forms 
 
• 
Proper serious adverse event reporting procedures in place 
 
• 
Proper biostatistical design and data analysis procedures in place. 
 
Level of Risk 
 
Level 2 
 
Example of type of trial: 
 
Institutional study for which IND is exempt by FDA or has an IND, but the drug is 
approved by the FDA for a different indication and is in Phase II or III. Examples are 
studies using commercially available agents for an unapproved indication based on 
standard regimen. 
• 
Compliance Officer meets with PI/Staff prior to study initiation; review regulatory 
requirements and operating system. Compliance Officer provides real time monitoring 
to determine eligibility prior to enrollment onto the protocol. 
• 
Real time QA monitoring of the subjects and data collection occurs for all 
subjects entered onto the trial. 
• 
Comprehensive QA auditing within first year or first 10 subjects enrolled, 
whichever comes first.  Subsequent audit frequency will be annually. 
• 
Frequency of DSMB Summary Report is typically on a biannual basis or 
approximately every six months. 

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TABLE OF STUDY ASSESSMENTS 
Assessment 
Pre- 
Study 
Pre- 
SBR
T 
SBRT 0-4 
weeks 
post 
SBRT 
Within 4 
weeks of 
final 
SBRT 
3 Month 
Follow- 
up 
(± 4wks) 
6 Month 
Follow- 
up 
(± 4wks) 
9 Month 
Follow- 
up 
(± 4wks) 
12 Month 
Follow-
up 
(± 4wks) 
Informed Consent 
X 
Demographics 
X 
Medical History 
X 
Initial RadOnc 
Consultation 
X 
Confirmation of High 
Risk local failure 
status 
X 
Surgical 
Evaluation & 
Clearance 
X 
PSA 
X 
(Pre- 
diagnostic 
biopsy) 
X 
X 
X 
X 
Translational 
Research Blood 
Draw1 
X 
X 
X 
X 
Radiation 
Treatment 
3 fxs 
within 
1-2 
Prostatectomy 
X 
EPIC Qxr 
X 
(Anytime 
pre-tx) 
X 
X 
X 
X 
X 
IPSS Qxr 
X 
(Anytime 
pre-tx) 
X 
X 
X 
X 
X 
Adverse Event 
Evaluation 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
CT or MRI of 
Abdomen/Pelvis 
(within 120 days 
prior to 
registration) 3 
X2 
Bone scan 
(within 120 days 
prior to 
registration) 
X2 
Treatment 
Planning scan 
X 
Follow-up visit 
 
X 
X 
X 
X 
1   Translational Research blood draw will consist of 5 x 10 ml EDTA lavender top tubes, 1 x 5 ml gold top tube and 1 x 5 ml CTAD blue top tube (a 
total of approximately 60 mLs) 
2   To verify no distant metastases, the subject must have CT or MRI of the abdomen/pelvis and a bone scan within 120 days prior to registration. If the 
bone scan is suspicious, a plain x-ray or MRI must be obtained to rule out metastasis. 
3   CT/MRI scan of Abdomen/Pelvis is not required if patient gets PSMA PET scan

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1. 
Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM, et al. 
Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term 
results of a randomised controlled trial (EORTC trial 22911). Lancet Lond Engl. 2012 Dec 
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2. Thompson IM, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, et al. Adjuvant 
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7. Finkelstein SE, Timmerman R, McBride WH, Schaue D, Hoffe SE, Mantz CA, et al. The 
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8. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with 
fractionated radiation. Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1306–10. 
 
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14. King CR, Freeman D, Kaplan I, Fuller D, Bolzicco G, Collins S, et al. Stereotactic body 
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