PRAGMA (Prostate Radio Ablation Guided by Magnetic Resonance Imaging Acquisition) in Metastatic Prostate Cancer
Phase: NA
Conditions: Metastatic Prostate Cancer
Sponsor: Weill Medical College of Cornell University

Identifiers: NCT04220983   
Unique Protocol ID: 19-04020263 
Brief Title: 
PRAGMA (Prostate Radio Ablation Guided by 
Magnetic Resonance Imaging Acquisition) in 
Metastatic Prostate Cancer 
 
Version 5.0  
 
Version date: 26JUL2023 
 
IRB approval: 01AUG2023 
 
 
Document History 
 
 
Document Name 
Version number 
Version Date 
Amendment 4 
5.0 
26JUL2023 
Amendment 3 
4.0 
03FEB2022 
Amendment 2 
3.0 
05OCT2021 
Amendment 1 
2.0 
24JAN2020 
Initial Protocol 
1.0 
23JUL2019 
 

 
 
  
1 
 
TITLE: PRAGMA (Prostate Radio Ablation Guided by Magnetic resonance 
imaging Acquisition) in metastatic prostate cancer 
 
 
IRB Protocol #:  19-04020263   
Version 5.0 
Version Date :  26JUL2023 
 
 
Principal Investigator:  
 
Silvia Formenti, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Co-Principal Investigator:   
 
 
 
 
 
 
 
Cora N. Sternberg, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistician: 
 
Karla Ballman, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 19-04020263 
Version  5.0 26JUL2023 
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Confidentiality Statement 
 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others 
without written authorization from WCMC. 

Protocol 19-04020263 
Version  5.0 26JUL2023 
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List of Abbreviations 
 
All abbreviations used throughout the protocol must be defined.  
 
 
AE 
AUA 
Adverse Event 
American Urologic Association 
CBC 
CBCT 
CFR 
Complete Blood Count 
 
Cone Beam Computed Tomography 
Code of Federal Regulations 
CRF 
Case Report Form 
CTCAE 
CTV 
DIN 
DSMB 
Common Terminology Criteria for Adverse Events 
Clinical Target Volume 
Dominant intraprostatic nodule 
Data Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
DVH 
EPIC 
ERB 
FDA 
Dose Volume Histogram 
Expanded Prostate Cancer Index Composite Instrument 
Endorectal Balloon 
Food and Drug Administration 
Fx 
GCP 
Fraction 
Good Clinical Practice 
GI 
GTV 
Gy 
GU 
HIPAA 
Gastrointestinal 
Gross Target Volume 
Gray 
Genitourinary 
Health Insurance Portability and Accountability Act of 1996 
HRBFA 
Human Research Billing Analysis Form 
HRQOL 
ICF 
IG 
IMRT 
IND 
I-PSS 
Health-related Quality of Life 
Informed Consent Form 
Image Guided 
Intensity Modulated Radiation Therapy 
Investigational New Drug 
International Prostate Symptom Score 
IRB 
NCCN 
NLR 
PHI 
Institutional Review Board 
National Comprehensive Cancer Network 
Neutrophil lymphocyte ratio 
Protected Health Information 
PI 
Principal Investigator 

Protocol 19-04020263 
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PIRADS 
PSA 
PSMA 
PTV 
REDCap 
Prostate Imaging Reporting and Data System 
Prostate Specific Antigen 
Prostate Specific Membrane Antigen 
Planning Target Volume 
Research Electronic Data Capture 
RS 
RT 
SAE 
SBRT 
SHIM 
SIB 
STAMPEDE 
 
SUSAR 
TRUS 
UAP 
WCMC 
Rectal Spacer 
Radiation Treatment 
Serious Adverse Event 
Stereotactic Body Radiation Therapy 
Sexual Health Inventory Men 
Simultaneous integrated boost 
Radiotherapy to the primary tumour for newly diagnosed, 
metastatic prostate cancer 
Suspected Unexpected Serious Adverse Reaction  
Transrectal Ultrasound 
Unanticipated Problem 
Weill Cornell Medical College 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 19-04020263 
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Summary of changes for version 5.0 dated 26JUL2023 
 
Sections 
Change 
Rationale 
Principal Investigator 
section 
Changing Principal investigator from 
Dr. Ariel Marciscano to Dr. Silvia 
Formenti 
Changing Principal investigator 
from Dr. Ariel Marciscano to 
Dr. Silvia Formenti, since Dr. 
Marciscano will no longer be at 
WCM. 
No changes to the Informed consent since the study is closed to accrual and only in follow up. 

Protocol 19-04020263 
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Summary of changes for version 4.0 dated 03FEB2022 
 
Sections 
Change 
Rationale 
Primary Objective 
Revising the toxicity measurement 
timeframe stated in the primary 
objective from 30 days to 3-6 months 
post treatment. 
Revising the toxicity 
measurement timeframe stated 
in the primary objective from 30 
days to 3-6 months post 
treatment and keep it consistent 
with the study calendar. 
Personnel changes 
Adding Charles Ekeh to the protocol 
cover page. 
Updating personnel and contact 
information. Admin 
amendment approved on 
16NOV2021. 
No changes to the Informed consent  

Protocol 19-04020263 
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Summary of changes for version 3.0 dated 05OCT2021 
 
 
 
 
Summary of changes for version 2.0 dated 24JAN2020. 
 
1. Inclusion Criteria: Must have metastatic prostate cancer proven on biopsy or imaging 
2. Exclusion Criteria: Removing criteria # 4 - Evidence of disease progression on bone 
scan, MR and/or CT 
3. Revised accrual ceiling to 25 patients as stated in the IRB application 
4. Adding Viji Nagaraj as data manager to the protocol to keep it consistent with the IRB 
personnel list. 
5. Updating QOL – AUA to I-PSS 
6. Study Calendar – clarifying that blood/stool collection is optional at all time points as 
stated in the informed consent. 
 
Informed consent changes: 
 
1. The protocol version date is incorrect - changing the footer of the informed consent. 
2. Making study calendar consistent with the protocol. 
 
Sections 
Change 
Rationale 
Principal Investigator 
section 
Changing Principal investigator from 
Dr. Josephine Kang to Dr. Ariel 
Marciscano 
Changing Principal investigator 
from Dr. Josephine Kang to Dr. 
Ariel Marciscano 
Personnel changes 
Removed Maria Fenton-Kerimian as 
Nurse practitioner and Viji Nagaraj 
as study coordinator, Added Jessica 
Richman. Updated contact details for 
personnel. 
Change of personnel and 
contact information. 
Informed consent changes 
Principal Investigator 
section 
Changing Principal investigator from 
Dr. Josephine Kang to Dr. Ariel 
Marciscano 
Changing Principal investigator 
from Dr. Josephine Kang to Dr. 
Ariel Marciscano 

Protocol 19-04020263 
Version  5.0 26JUL2023 
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Document History 
 
 
Document Name 
Version number 
Version Date 
Amendment 4 
5.0 
26JUL2023 
Amendment 3 
4.0 
03FEB2022 
Amendment 2 
3.0 
05OCT2021 
Amendment 1 
2.0 
24JAN2020 
Initial Protocol 
1.0 
23JUL2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 19-04020263 
Version  5.0 26JUL2023 
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Protocol Summary  
 
PRAGMA (Prostate Radio Ablation Guided by Magnetic resonance imaging 
Acquisition) in metastatic prostate cancer  
 
IRB Protocol #:   19-04020263 
 
Short Title:  
 
 
MRI-guided prostate SBRT for metastatic prostate cancer 
Principal Investigator:  
Dr. Ariel Marciscano 
Sample Size: 
 
N = 20 
Accrual Ceiling: 
 
This study plans to enroll a total of 25 patients  
Study Population: 
 
Patients with metastatic prostate cancer 
Accrual Period: 
 
2 years  
Study Design: 
 
Single-arm study for safety 
 
Study Intervention Description: 
 
MR-guided Prostate SBRT:  
Prostate SBRT has become  a standard of care for the treatment of localized prostate cancer. 
Radiation is delivered to the prostate and seminal vesicles in 5 treatment sessions (fractions). 
Doses ranging from 35-45 Gy in 5 fractions have demonstrated good outcomes with acceptable 
toxicity when planning is delivered appropriately. 
There is emerging evidence that patients with non-localized prostate cancer also derive benefit 
from radiation (RT) to the primary tumor. The STAMPEDE multiarm British trial recently 
reported that patients with low burden metastatic prostate cancer have an overall survival benefit 
from prostate RT. Doses of radiation used in the STAMPEDE trial were either 36 Gy in 6 
fractions, or 55 Gy in 20 fractions.  
The MRidian ViewRay offers delivery of prostate SBRT with real-time MR guidance, which 
provides superior soft-tissue differentiation with excellent visualization of the prostate. This 
ViewRay platform offers the ideal setting for this study, that aims at precisely delivering prostate 
SBRT with a simultaneous integrated boost (when indicated) to visible nodules.  
In this study, we hope to demonstrate the safety of using 36.25 Gy in 5 fractions, plus a 
simultaneous integrated boost (when indicated), in patients with metastatic prostate cancer. 
 
Hypothesis:  Patients with metastatic prostate cancer can undergo MRI-guided prostate SBRT 
without significant adverse events, similar to what has been reported for patients with localized 
prostate cancer. 
 
We hypothesize that prostate SBRT will be well-tolerated in metastatic prostate cancer patients, 
with quality of life outcomes similar to what has been reported in non-metastatic prostate cancer 
patients. 
 
We also hypothesize that prostate SBRT will impact lymphocyte counts and neutrophil 

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lymphocyte ratio, as well as the diversity, abundance and composition of the gut microbiome, 
when baseline datapoints are compared to post-RT and follow up datapoints. 
 
Primary objective: To assess safety of  delivering MRI-guided prostate SBRT in patients 
with metastatic prostate cancer.  
 
   Treatment will be deemed safe of there is is no more than 3 acute >G3 likely radiation treatment 
related GI/GU toxicity within 3-6 months after treatment (CTCAE 5.0 criteria) completion.  
Given that the treatment plans will meet rigorous normal tissue constraints used for standard 
prostate SBRT that have been established now with up to 10 year follow up data in patients with 
localized prostate cancer, we do not anticipate any increased toxicity on this study for metastatic 
prostate cancer patients.  
 
  
Secondary objective: To obtain quality of life and toxicity data after prostate SBRT. 
We will measure quality of life (HRQOL) using: 1) the Expanded Prostate Cancer Index 
Composite (EPIC-26) short form questionnaire, 2) International Prostate Symptom Score (I-
PSS). QOL assessments will occur at baseline, 3-6 months, and at 9-12 months. 
Toxicity data will be measured with CTCAE 5.0 at 3-6 months, and at 9-12 months. 
 
Correlative study objectives: 
 
1. To explore gut microbiome changes associated with prostate radiation 
2. To collect complete blood count (CBC) measurements at baseline, post-treatment and 3-6 
month followup to assess impact of SBRT on immune correlates and neutrophil lymphocyte 
ratios. 
 
 
 
 
 
 
 
 
 
 
 
 

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 SCHEMA 
 
  
 
 
 
 
 
 
  
 
  
Patients with Metastatic Prostate Cancer 
 
 
 
Prostate SBRT (36.25 Gy in 5 fx)  
+/- optional SIB to 40 Gy 
 
Baseline and post-RT CBC, microbiome to 
be collected 
 
 
Follow up visit at 3-6 months, and 1 year: 
Assess GI/GU toxicity, EPIC-26, I-PSS  scores  
Collect CBC, microbiome (3-6 month follow up only) 
 

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14  
TABLE OF CONTENTS 
SCHEMA ...................................................................................................................................................................................... 11 
1 
STUDY OBJECTIVES ..................................................................................................................................................... 14 
1.1 
PRIMARY OBJECTIVES ...................................................................................................................................................................... 14 
1.2 
SECONDARY OBJECTIVES ................................................................................................................................................................. 14 
1.3 
CORRELATIVE STUDY OBJECTIVES ................................................................................................................................................. 14 
2 
BACKGROUND ............................................................................................................................................................... 15 
2.1 
RADIATION TO THE PROSTATE: RATIONALE FOR TREATING PATIENTS WITH METASTATIC PROSTATE CANCER .............. 15 
2.2 
PROSTATE CANCER RADIOTHERAPY: RATIONALE FOR EXTREME HYPOFRACTIONATION SBRT ......................................... 16 
2.3 
BIOLOGICAL RATIONALE FOR SBRT .............................................................................................................................................. 16 
2.4 
SBRT OUTCOMES ............................................................................................................................................................................. 17 
2.5 
RATIONALE FOR SIMULTANEOUS INTEGRATED BOOST .............................................................................................................. 18 
2.6 
NEED FOR IGRT IN PROSTATE RADIOTHERAPY ........................................................................................................................... 18 
2.7 
VIEWRAY: A UNIQUE RADIATION DELIVERY APPROACH ............................................................................................................. 19 
2.8 RATIONALE FOR CORRELATIVE STUDIES BACKGROUND: MICROBIOME AND BLOOD SAMPLE COLLECTION .......................... 20 
3 
SUBJECT SELECTION ................................................................................................................................................... 20 
3.1 
STUDY POPULATION ......................................................................................................................................................................... 20 
3.2 
INCLUSION CRITERIA ........................................................................................................................................................................ 20 
3.3 
EXCLUSION CRITERIA ....................................................................................................................................................................... 21 
4 
REGISTRATION PROCEDURES ................................................................................................................................. 21 
4.1 
PATIENT REGISTRATION .................................................................................................................................................................. 21 
5 
STUDY PROCEDURES .................................................................................................................................................. 22 
5.1 
PRE-STUDY VISIT .............................................................................................................................................................................. 22 
5.2 
IMAGING STUDIES ............................................................................................................................................................................. 22 
5.3 
RADIATION TREATMENT PLANNING ............................................................................................................................................. 22 
5.3.1 
Contours ............................................................................................................................................................................... 22 
5.3.2 
Dose/Treatment Planning Parameters .................................................................................................................... 23 
5.4 
SUPPORTIVE CARE GUIDELINES ..................................................................................................................................................... 23 
5.5 
DURATION OF THERAPY AND CRITERIA FOR REMOVAL FROM STUDY ..................................................................................... 24 
5.6 
DURATION OF FOLLOW UP .............................................................................................................................................................. 24 
6 
DOSE MODIFICATIONS ............................................................................................................................................... 24 
7 
ADVERSE EVENT REPORTING REQUIREMENTS ................................................................................................ 24 
7.1 
ADVERSE EVENT DEFINITION ......................................................................................................................................................... 24 
7.2 
RECORDING OF ADVERSE EVENTS .................................................................................................................................................. 25 
7.2.1 
Reporting of AE to WCMC IRB ..................................................................................................................................... 25 
7.3 
DEFINITION OF SAE ......................................................................................................................................................................... 25 
7.3.1 
Reporting of SAE to IRB .................................................................................................................................................. 25 
7.4 
EXPEDITED ADVERSE EVENT REPORTING .................................................................................................................................... 25 
7.4.1 
AE/SAE Follow Up ............................................................................................................................................................ 26 
8 
PHARMACEUTICAL INFORMATION ....................................................................................................................... 26 
9 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................................... 26 
10 
MEASUREMENT OF EFFECT ...................................................................................................................................... 27 
11 
DATA REPORTING / REGULATORY CONSIDERATIONS .................................................................................. 28 

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11.1 
DATA COLLECTION ...................................................................................................................................................................... 28 
11.2 
REDCAP ....................................................................................................................................................................................... 28 
11.3 
REGULATORY CONSIDERATIONS ............................................................................................................................................... 28 
11.4 
DATA MANAGEMENT .................................................................................................................................................................. 28 
12 
STATISTICAL CONSIDERATIONS ............................................................................................................................ 29 
12.1 
STUDY DESIGN/ENDPOINTS ..................................................................................................................................................... 29 
12.1.1 
Primary Objectives ..................................................................................................................................................... 29 
12.1.2 
Secondary Objectives ................................................................................................................................................. 29 
12.1.3 
Correlative Study Objectives ................................................................................................................................... 29 
12.2 
SAMPLE SIZE/ACCRUAL RATE .................................................................................................................................................. 29 
12.3 
ANALYSIS OF PRIMARY AND SECONDARY ENDPOINTS .......................................................................................................... 29 
13 
DATA AND SAFETY MONITORING PLAN (DSMP) .............................................................................................. 31 
13.1 
MONITORING PLAN ..................................................................................................................................................................... 31 
13.2 
STOPPING RULES ......................................................................................................................................................................... 31 
14 
REFERENCES .................................................................................................................................................................. 31 
 

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1 
STUDY OBJECTIVES 
 
HYPOTHESIS 1: Patients with metastatic prostate cancer can undergo MRI-guided prostate 
SBRT w/SIB without significant adverse events, similar to what has been reported for patients 
with localized prostate cancer using CTCAE criteria. 
 
HYPOTHESIS 2: Patients with metastatic prostate cancer who undergo MRI-guided prostate 
SBRT will report good overall quality of life, similar to what has been reported for patients with 
localized prostate cancer. This will be measured using EPIC-26, I-PSS questionnaires, which are 
validated instruments that have been used to report QOL outcomes after prostate RT. 
 
HYPOTHESIS 3: Patients may experience decline in neutrophil:lymphocyte ratios during 
radiation therapy, that is most prominent at end of treatment, but recovers to baseline by follow 
up. There will be alterations in the composition, diversity and abundance of microflora during 
radiation therapy when the microbiome is compared at baseline, to post-treatment, to follow up. 
 
1.1 
Primary Objectives 
 
  
1.11 To assess safety of  delivering MRI-guided prostate SBRT in patients with metastatic 
prostate cancer. 
 
   Treatment will be deemed safe of there is is no more than 3 acute >G3 likely radiation treatment 
related GI/GU toxicity within 3-6 months after treatment (CTCAE 5.0 criteria) completion.  
Given that the treatment plans will meet rigorous normal tissue constraints used for standard 
prostate SBRT that have been established now with up to 10 year follow up data in patients with 
localized prostate cancer, we do not anticipate any increased toxicity on this study for metastatic 
prostate cancer patients.  
 
 
1.2 
Secondary Objectives 
 
 
1.21 We will measure quality of life (HRQOL) using: 1) the Expanded Prostate Cancer Index 
Composite (EPIC-26) short form questionnaire, 2) I-PSS. QOL assessments will occur at 
baseline, 3-6 months, and at 9-12 months. Toxicity data will be measured with CTCAE 5.0 at 3-6 
months, and at 9-12 months. 
 
 
1.3 
Correlative Study Objectives 
 
 
1.31  
To collect complete blood count (CBC) measurements at baseline, post-treatment and 3-6 month 
followup to assess impact of SBRT on immune correlates and neutrophil lymphocyte ratios. 
 

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To describe gut microbiome changes (abundance, composition, diversity) associated with 
prostate radiation. 
 
 
 
2 
 
BACKGROUND 
 
2.1 
Radiation to the prostate: Rationale for treating patients with metastatic prostate cancer 
 
Next to skin cancer, prostate cancer is the most commonly diagnosed cancer in men, and second 
leading cause of cancer death.4 It is estimated that one out of seven men will be diagnosed with 
prostate cancer during their lifetime. Due to improvements in diagnostic imaging, monitoring 
and therapy, an increasing number of patients are being diagnosed with early metastatic prostate 
cancer, where an aggressive approach is hypothesized to yield improved clinical outcomes. 
 
The appropriate management of patients with metastatic prostate cancer has varied widely and 
continues to evolve. In the past, local therapy to the prostate (radical prostatectomy, definitive 
external beam radiation (EBRT)) was offered only to patients with non-metastatic prostate 
cancer, and systemic therapies such as androgen deprivation therapy (ADT) was administered to 
patients with disease outside of the prostate. However, new data suggests that treatment of the 
primary tumor provides clinical benefit to men with metastatic disease. 5,6  
 
The STAMPEDE (Radiotherapy to the Primary Tumour for Newly Diagnosed, Metastatic 
Prostate Cancer) trial results demonstrate that select men with metastatic prostate cancer derive 
an overall survival benefit from prostate-directed EBRT. In this randomized controlled phase 3 
study, men with newly diagnosed metastatic prostate cancer were treated with either standard of 
care, or standard of care plus prostate EBRT. The primary outcome was overall survival. With 
median follow up of 37 months, it was reported that patients with metastatic prostate cancer had 
improved overall survival after prostate EBRT versus none, 3 year OS 81% vs 73% (HR 0.68, 
95% CI 0.52-0.90, P=0.007). Based on these results, prostate EBRT has become a  standard 
treatment option for patients with low metastatic burden prostate cancer.5 Low metastatic burden 
prostate cancer is defined using the CHAARTED (Chemohormonal Therapy in Metastatic 
Hormone Sensitive Prostate Cancer) and STAMPEDE trial criteria: any metastatic prostate 
cancer that does not have a) visceral metastases AND/OR b) four or more bone metastases with 
one or more outside the vertebral bodies or pelvis. Any patients without a) or b) are considered to 
have low metastatic burden.5,7 Furthermore, there is retrospective data suggesting that prostate 
RT improves outcomes in men with metastatic prostate cancer who do not necessarily fit the 
definition of low metastatic burden.32-33 
 
In the STAMPEDE study, patients receiving EBRT were allowed either 20 fractions of radiation 
to 55 Gy over 4 weeks, or 6 fractions of radiation to 36 Gy over 6 weeks. Neither of these 
regimens are commonly utilized in the United States. Stereotactic body radiation therapy delivers 
36.25 Gy over 5 fractions in 1-2 weeks, completing treatment in a short span of time with a low 
overall adverse event rate demonstrated in patients with non-metastatic prostate cancer1-3. In this 
study, we hope to demonstrate the safety and feasibility of delivering SBRT in patients with 
metastatic prostate cancer, using MR-guided treatment delivery. 
 
 

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2.2 
Prostate cancer radiotherapy: Rationale for extreme hypofractionation SBRT  
 
In the past, standard fractionation EBRT was delivered over 9-10 weeks, with 1.8 to 2.0 Gy 
administered daily, in up to 50 treatment sessions. The inconvenience associated with the 
protracted length of a standard course of prostate treatment has stimulated interest in delivering 
more radiation dose per session, to reduce the duration of treatment. Compared to conventional 
fractionation, hypofractionation (higher dose of radiation given in fewer sessions) allows for 
reduced number of treatment visits, increasing patient convenience while lowering health care 
costs. This has resulted in the development of extremely hypofractionated regimens, delivered 
most commonly within 5 fractions, allowing completion of treatment generally within 1-2 weeks. 
Such treatments are delivered using stereotactic or image-guided IMRT approaches, most 
commonly referred to as prostate stereotactic body radiation therapy (SBRT).  
 
Single institutional and pooled reports have demonstrated similar efficacy and toxicity to 
conventionally fractionated regimens. 1-3  The NCCN treatment paradigm  currently includes 
SBRT as an alternative to conventionally fractionated regimens at centers with appropriate 
technology, physics and clinical expertise.8 SBRT enables patients to undergo a non-invasive 
treatment and be finished in five treatments, achieving outcomes equivalent to long-course 
EBRT or surgery, without a surgical procedure, general anesthesia and the risk of associated 
complications. As such, it is an excellent option to deliver prostate EBRT in patients with 
metastatic prostate cancer. 
 
 
2.3 
Biological rationale for SBRT 
 
Proponents of prostate cancer hypofractionation argue that the rectum and bladder are less 
sensitive to increases in dose per fraction than prostate cancer and that therefore 
hypofractionation should yield negligible increases in late toxicity while providing improved 
cancer control. The / is a theoretical measure of a tissue’s predicted response to a dose of 
radiation, relative to the size of the dose delivered per fraction. Conventional daily doses of 
radiation are based on the presumed high / ratios of most malignant tumors. Higher / ratios 
mean that tumor response is less dependent on the amount of radiation administered with each 
fraction when compared to adjacent normal tissue, and therefore that a lower radiation dose per 
treatment can typically be used. Lower tumor / ratios mean that a larger dose of radiation per 
treatment can provide improved efficacy in terms of therapeutic ratio, tumor control versus risk 
of complications. A large body of work theorizes that the / for prostate cancer is low (~1.5), 
implying that a hypofractionated schedule could improve prostate cancer control, while 
maintaining a low risk of severe normal tissue  complications (see Table 1). 9 The radiobiological 
linear-quadratic cell survival model was used to calculate the biologically equivalent doses for 
tumor control and complications to normal organs, using standard 2 Gy fractions delivered five 
times a week.10-12   
 
 
Table 1. Equivalent total doses in 2 Gy per fraction (EQD2) based on / Biologically 
Effective Doses (BED) 
 

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 /  (Gy)
EQD2 
Standard (1.8 
Gy x 45 fx)
EQD2 SBRT 
(7 Gy x 5 fx)
EQD2 SBRT 
(7.5 Gy x 5 fx)
EQD2 SBRT 
(8 Gy x 5 fx)
EQD2 SBRT 
(8.5 Gy x 5 fx)
EQD2 SBRT 
(9 Gy x 5 fx)
Total Dose (Gy)
81
35
37.5
40
42.5
45
Tumor
1.5
76.37 Gy
85 Gy
97.65 Gy
110 Gy
123.07 Gy
135 Gy
Fibrosis/stricture
2
76.95 Gy
78.75 Gy
89.06 Gy
100 Gy
111.56 Gy
123.7 Gy
Telangiectasia
4
78.3 Gy
64.17 Gy
71.88 Gy
80 Gy
88.54 Gy
97.5 Gy
Rectum 
4
78.3 Gy
64.17 Gy
71.88 Gy
80 Gy
88.54 Gy
97.5 Gy
Bladder
4
78.3 Gy
64.17 Gy
71.88 Gy
80 Gy
88.54 Gy
97.5 Gy
 
 
 
2.4 
SBRT Outcomes  
 
To date, results from prospective and retrospective studies demonstrate good biochemical control 
and low toxicity for SBRT, with commonly used doses ranging from 35-45 Gy in 5 fractions (see 
Table 2). Randomized data from the phase III PACE trial, comparing standard fractionation 
EBRT to 78  Gy or moderately hypofractionated EBRT to 62 Gy, versus SBRT to 36.25 Gy in 5 
fractions, show no difference in grade 2 or higher acute urinary or bowel toxicity, suggesting 
SBRT to be a well-tolerated, safe alternative to longer treatment regimens.13 
 
SBRT compares favorably to outcomes for standard fractionation EBRT to 81 Gy, which has 10-
year biochemical RFS of 91%, 78% and 62%, respectively, for low-, intermediate- and high-risk 
prostate cancer, and late Grade 3 gastrointestinal (GI) and genitourinary toxicity of 1% and 5%, 
respectively.14 There is a lack of consensus regarding the appropriate dose to use for prostate 
SBRT. Extrapolating from dose escalation studies in conventionally fractionated EBRT,15,16 a 
higher dose in SBRT is hypothesized to result in improved local control. However, delivery of 
higher dose results in small but significant increase in GU toxicity. Katz and Kang showed 
significantly higher late grade 2-3 GU toxicity with 36.25 Gy compared to 35 Gy (13.2 vs 8.8%, 
P<0.05). With  35 Gy in five fractions, the majority of toxicity was grade 2, and overall toxicity 
was low without impacting GU quality of life. As shown in Table 2, late grade 3 GU/GI toxicity 
after SBRT appears to be comparable to that of conventionally fractionated EBRT, ranging from 
0.6 – 3% 1,3 with longest median follow-up of 7 years.  
 
 
Table 2. Biochechemical control after prostate SBRT. *prospective 
Study 
SBRT Dose 
(5 fx) 
FU  
# Pts Risk Categories 
bPFS 
Toxicity ≥3 
Bolzicco
17* 
35 Gy 
36m  
71 
Low (41%), Int 
(42%), High (17%) 
3y 94.4% 
GI 0%, GU 
1% 
King18* 
35-36.25 Gy 
5y  
41 
Low, Favorable Int 
Risk 
5y 92.7% 
GI 0%, GU 
3.5% 
McBride
19* 
36.25-37.5 
Gy 
44.5
m  
45 
Low 
3y 97.7% 
GI 4.4%, GU 
2.2% 
Madsen2
0* 
33.5 Gy 
41m  
40 
Low 
4y 90% 
GI 0%, GU 
0% 
Fuller21
* 
38 Gy/ 4 fx 
60m  
259 
Low (43%), Int  
(57%) 
5y Low 
100%, 
 Int 88.5% 
GI 0%, GU 
3.1% 

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Kim22 
45-50 Gy 
42m  
47 
Low (38%), Int (62%) 
4y 98% 
GI 0%, GU 
0% 
Loblaw2
3* 
35 Gy 
55m  
84 
Low 
5y 98% 
GI 1%, GU 
1% 
Mantz24
* 
40 Gy 
60m 
102 
Low, Fav Int 
5y 100% 
GI 0%, GU 
0% 
Chen25 
35-36.5 Gy 
2.3y 
100 
Low (37%), Int 
(55%), High (8%) 
2y 99% 
GI 0%, GU 
1% 
Katz 
and 
Kang2 
35-36.25 Gy 
72m  
477 
Low (68%), Int (32%) 
7y Low 
95.6%, 
Fav Int 
93.5%,  
Unfav Int 
79.3% 
GI 0%, GU 
2% 
Katz 
and 
Kang26 
35-36.25 Gy 
84m  
515 
Low (63%), Int 
(30%), High (7%) 
8y Low 
93.6%,  
Int 84.3%,  
High 65.0% 
GI 0%, GU 
2% 
Katz27 
35-36.25 Gy 
108m  230 
Low 
10y 93% 
GI 0%, GU 
2% 
Abbreviations: FU, follow up; Gy, Gray; Fx, fractions; m, months; y, years; IQR, interquartile 
range 
*SBRT monotherapy patients 
** Heterogeneous SBRT planning such that at least 1% of PTV receives ≥ 150% of prescription 
dose. 
 
2.5 
 Rationale for Simultaneous Integrated Boost 
 
Both EBRT and SBRT target the entire prostate gland with radiation. Studies on patterns of 
failure following conventional EBRT demonstrate that 85-100% of local failures occur in the 
region of macroscopic tumor.28,29 Modern treatment planning systems have the ability to 
selectively target visible lesions within the prostate to a higher dose, resulting in heterogeneous 
dose distributions that target high-risk nodules to increased dose and surrounding prostate to a 
lower dose. A phase II trial is currently ongoing in the Netherlands (Hypofractionated focal 
lesion ablative microboost in prostate cancer, “hypo-FLAME” NCT02853110), to look at 
feasibility of a focal ablative boost with SBRT, using dose of 35 Gy in 5 fractions with a boost to 
visible nodules up to 50 Gy. Furthermore, our department has a currently ongoing investigator 
initiated protocol in patients with non-metastatic prostate cancer (“MRI-guided Stereotactic 
Body Radiotherapy (SBRT) with Simultaneous Integrated Boost for Prostate Cancer” PI: 
Josephine Kang, Silvia Formenti IRB Protocol #  1802019010), which utilizes a simultaneous 
integrated boost in patients with non-metastatic prostate cancer, and has demonstrated the 
feasibility and safety of such an approach in 9 patients who have thus far enrolled. The dose used 
for simultaneous integrated boost in this protocol, 40 Gy, remains within the acceptable range of 
doses for prostate SBRT. 
 
2.6 
Need for IGRT in prostate radiotherapy  
 

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SBRT delivers high dose to the target with a rapid dose fall-off. Thus, it is important to account 
for prostate motion as much as possible during treatment delivery (intrafraction motion), and 
between each treatment fraction (interfraction motion). A small shift in the prostate, if 
unaccounted for, can result in significantly decreased dose to the target. Position changes are 
inevitable due to bowel gas/stool fluctuation, bladder filling and/or prostate edema from 
radiation.30 There are multiple techniques to account for prostate motion during delivery of 
SBRT. Such techniques include tracking via implanted radiofrequency transponders (e.g., 
Calypso), on-board kV imaging of prostate fiducials at 30-60 second intervals (e.g., Cyberknife), 
and use of multiple cone-beam CTs during treatment. Traditional image-guided radiation is 
unable to provide real-time feedback of target position. Treating multiple radiation targets 
(prostate, seminal vesicles, high-risk nodules) with steep dose gradients becomes particularly 
challenging with standard image guidance systems, because adjustments are made offline or at 
prolonged select intervals during treatment delivery.  
 
 
2.7 
ViewRay: a unique radiation delivery approach 
 
The ViewRay MRIdian Linac system is a radiation delivery machine that integrates a linear 
accelerator with real-time MRI imaging. The ViewRay machine allows fusion of MR imaging 
with treatment planning. The uniqueness of this approach is the image guided delivery 
component,  based on precise MRI-based detection of target and normal tissue during treatment 
in real-time. The ViewRay will provide real-time MRI imaging to ensure that the high-dose 
region is precisely targeted. MRI guided radiation has the benefit of not requiring fiducial 
implantation or excess radiation exposure from multiple cone beam CT. Furthermore, motion 
monitoring can be performed with images acquired up to 4 frames a second, allowing live 
feedback of treatment position. 
 
ViewRay offers  the ideal system for delivery of prostate SBRT, due to its ability to provide 
image guidance “live”, during treatment. Real-time MRI imaging allows superior soft-tissue 
differentiation with excellent visualization of the prostate. This ViewRay platform offers the 
ideal setting for this study, that aims at precisely delivering prostate SBRT with a simultaneous 
integrated boost to visible nodules. MRI guided radiation, a property unique to ViewRay, will  be 
exploited in the current trial to deliver precise treatment with resultant lower dose to surrounding 
normal structures. 
 
The goal of this study is to assess safety of treating patients with metastatic prostate cancer with 
MRI-guided prostate SBRT. Safety is defined  as lack of more than 3 patients with treatment 
related acute >G3 GI or GU toxicity within 3- 6 months post treatment. The proposed SBRT 
dose (36.25 Gy in 5 fractions to the whole prostate) has been reported in the literature to be safe 
and well tolerated (Table 2), with no acute G3 toxicity. The proposed boost dose to 40 Gy in 
applicable patients is within the range of current standard of care SBRT doses, and is also 
expected to be well-tolerated. Furthermore, it has been tested in our currently ongoing 
investigator initiated protocol in patients with non-metastatic prostate cancer (“MRI-guided 
Stereotactic Body Radiotherapy (SBRT) with Simultaneous Integrated Boost for Prostate 
Cancer” PI: Josephine Kang, Silvia Formenti IRB Protocol #  1802019010). As of 4/29/19, 15 
patients with localized prostate cancer have enrolled on this study with planned accrual of 30 
patients, and have demonstrated excellent safety and feasibility with boost doses up to 45 Gy. It 

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is therefore expected that similar outcomes can be achieved in patients with metastatic prostate 
cancer, though it is possible that the addition of systemic therapy may alter likelihood of toxicity. 
  
2.8 Rationale for Correlative Studies Background: Microbiome and blood sample collection 
Patients accrued to the study will donate a stool specimen and a blood sample both before and 
after radiation, to study their changes in the microbiome and circulating immune correlates 
during and after radiotherapy, and at 3-6 month follow up. 
  
Preliminary results from our ongoing study “Effect of Radiotherapy Variables on Circulating 
Effectors of Immnue Response and Local Microbiome” PI: Silvia Formenti,  IRB Protocol #:  
1708018471 demonstrate depletion of circulating lymphocytes in prostate cancer patients 
undergoing protracted standard radiation compared to 5-fraction SBRT (which is the regimen we 
will use on this study) (results submitted to ASTRO). We will study this phenomenon further in 
patients undergoing SBRT on this study. We have also found a temporary increase in 
neutrophil:lymphocyte ratio (NLR) during radiation to the prostate in our dataset of patients; 
patients enrolled on this protocol will also have assessment of NLR at baseline, after RT and at 
3-month follow up. 
 
The host microbiome is an emerging topic of investigation, with growing evidence that 
commensal microbiota impacts anti-tumor immune response, and sensitivity to systemic 
therapies and immunotherapy.  Commensal bacteria outnumber human cells by at least 10-fold, 
colonizing host mucosal surfaces and playing critical roles in metabolism, defense against 
pathogens, and crosstalk between the environment and immune system. Preclinical studies 
suggest that microbiota impact the immune system through a number of mechanisms, including 
possible modulation of myeloid-derived cells; stimulation of T helper cells, and enhancement of 
memory T-cell response. Dysbiosis, or shifts in microbial composition, may modulate response 
to cancer therapy. We hypothesize that the underlying microbial community composition will be 
impacted by administration of radiation to the prostate. Our preliminary data in mice suggests 
fluctuations in composition, abundance and diversity after local tumor-directed radiation. We 
hope to explore this further in patients who are undergoing SBRT by collecting microbiome 
samples at baseline, upon completion of RT, and at follow up. 
 
 
3 
SUBJECT SELECTION 
 
3.1 
Study Population 
 
Men with a histologically confirmed diagnosis of metastatic prostate adenocarcinoma, meeting 
the inclusion and exclusion criteria below, and electing to undergo definitive radiation treatment 
with SBRT, will be eligible for participation in this study. 
 
3.2 
Inclusion Criteria 
 
1. Biopsy-proven diagnosis of prostate adenocarcinoma 
2. Age ≥ 18 
3. Must have metastatic prostate cancer proven on biopsy or imaging  
 

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3.3 
Exclusion Criteria  
 
1. History of prior pelvic radiation (external beam or brachytherapy) 
2. Inability to undergo MRI 
3. AUA score >20 
5. For patients on systemic therapy, enrollment must be within six months of start of therapy 
unless exception is made by protocol PIs (Drs. Kang, Formenti or Sternberg) 
 
 
 
4 
REGISTRATION PROCEDURES 
 
 
4.1 
  Patient Registration 
 
 
Before any protocol specific procedures can be carried out, investigators/staff will 
fully explain the details of the protocol, the study procedures and the aspects of patient 
privacy regarding research information. Patients will be provided a comprehensive 
explanation of the proposed treatment including the type of therapy, the rationale for 
treatment on the protocol, alternative treatments that are available, any known adverse 
events, the investigational nature of the study and the potential risks and benefits of the 
treatment. The informed consent document will meet all requirements of the Institutional 
Review Board (IRB). All subjects/patients are informed in the consent that participation or 
refusal to participate in the research study will not affect any of the clinical treatment or 
services to which they would otherwise be entitled. 
The physicians who may obtain informed consent are listed on the title page of 
this protocol. The informed consent form will be signed by the participant and the 
registering physician. Once signed, a copy will be given to the patient and one will be 
maintained with the patient’s medical record. Once eligibility is confirmed and informed 
consent is documented, the patient will be registered by the study coordinator/data 
manager. 
Patients will be centrally registered with the Office of Billing Compliance. To register a 
patient, submit the following documents via the JIRA Registration Process:  
 
• 
Legible copy of the HRBAF 
• 
Signed informed consent  
 
 Registration must be completed within 24 hours of the signing of informed consent.  
 

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5 
STUDY PROCEDURES 
 
              
Pre-Study Fx 1 Fx2 Fx 
3 
Fx 
4 
Fx 5* 
Post-RT Visits 
(3-6  months, 9-
12 months s/p 
RT) 
Informed consent 
X  
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA 
 
X 
 
  
 
  
 
  
 
  
 
  
 
 X 
 
Acute/Late 
Toxicity 
Assessment 
(CTCAE) 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
EPIC-26, I-PSS 
 
X 
 
  
 
  
 
  
 
  
 
  
 
X 
Imaging: 
Planning 
CT/MR;  
 
       X 
 
 
 
 
 
 
Blood 
draw 
and 
microbiome sample 
      X 
 
 
 
 
 X 
X** 
 
 
 
 
** no blood draw at 9-12 months. 
 
5.1 
Pre-Study Visit 
 
At the initial screening visit, patient will undergo: 
o Informed consent 
o Medical history  
o Baseline EPIC-26 Questionnaire, I-PSS forms 
 
5.2 
Imaging Studies 
 
Placement of a rectal spacer is optional. Treatment planning CT and MR will be performed with 
appropriate immobilization. Patients will be advised to drink approximately 1-2 cups of water 1 
hour prior to the CT simulation to allow for a comfortably full bladder, if tolerated; this will be 
modified according to physicians discretion.  A radiation planning MR will be obtained at the 
physician’s discretion. 
 
 
5.3 
Radiation Treatment Planning 
 
5.3.1 
Contours 
 

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The prostate +/- seminal vesicles (SV) will be contoured as the clinical target volume (CTV) as 
per usual practice. For patients with identifiable dominant intraprostatic nodules 
(Select PIRADS 3-5 and/or PSMA avid (if PSMA PET/MR is available) and/or biopsy 
positive nodules (chosen based on physician's clinical judgment and correlation with biopsy 
findings)), there is the option for DIN to be contoured as gross tumor volume(s) (GTV). There 
will be no planning target volume (PTV) expansion for the DIN GTV. The PTV expansion for 
the CTV will be 0-5 mm on the prostate, depending on physician discretion as per standard care. 
 
The rectum will be drawn from the bottom of the ischial tuberosities to the sigmoid flexure. The 
urethra will be delineated on MRI from the prostatic apex, to entry of urethra into the penile 
bulb, using a 5-6 mm brush.   
 
The bladder, femoral heads, penile bulb will also be contoured as normal structures. 
 
5.3.2 
Dose/Treatment Planning Parameters 
 
The CTV (prostate +/- SV) will be treated to dose of 36.25 Gy in 5 fractions. For patients with 
identifiable DINs, at the physician’s discretion, there is an option for a simultaneous integrated 
boost to PIRADS 3-5 or PSMA avid nodules and/or biopsy positive nodules, delivering 40 Gy to 
the contoured nodule(s) as a mean dose while respecting normal tissue constraints to rectum and 
urethra. (If normal tissue constraints to the rectum and urethra can not be achieved, the DIN will 
be boosted to a lower dose, or not boosted) 
 
Volume of the PTV receiving prescribed SBRT dose should ideally be ≥ 95%; acceptable 
suggested deviation is dose >85% 
 
Critical organ limits (SBRT monotherapy): 
1. Rectum: Maximum dose to 1 cc 38.5 Gy, Max dose to 3 cc 34.4 Gy,, Max point dose 40 
Gy. Acceptable deviation is maximum dose to 1 cc 39 Gy, max dose to 3 cc 36 Gy and max 
point dose of 42 Gy. 
 
2. Bladder: Maximum dose to 1 cc 38.5 Gy, Max point dose 40 Gy. Acceptable deviation is 
max point dose of 42 Gy. 
3. Penile Bulb: No more than 105% of prescription dose; D3cc 25 Gy. This is a soft 
constraint. 
 
4. Femoral heads: Maximum point dose 30 Gy 
 
5. Small bowel: Maximum point dose 25 Gy   
6. Urethra: Max dose 40 Gy. Will allow up to 42 Gy point dose. Urethra planning organ at 
risk volume (PRV) can be created around the contoured urethra if there is uncertainty 
 
 
5.4 
Supportive Care Guidelines 
 
a. Urinary: A proportion of patients undergoing prostate SBRT can expect increase in 
urinary frequency or urgency. If this becomes bothersome to the patient, medication to 
alleviate symptoms can be prescribed at the discretion of the treating radiation oncologist 
and documented in patient chart. 

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b. Bowel: Bowel symptoms during time of prostate SBRT can occur. If patients develop 
rectal urgency, tenesmus or diarrhea, medication to alleviate symptoms can be prescribed 
at the discretion of the treating radiation oncologist, and documented in patient chart. 
 
 
 
 
5.5 
Duration of Therapy and Criteria for Removal from Study 
 
In the absence of treatment delays, the SBRT is anticipated to complete within 2-3 weeks time. 
Patients will undergo radiation 2-3 times a week, but treatment can be slowed down to once a 
week at the physician’s discretion; these differing fractionation patterns fall within standard of 
care for SBRT. Patients can be removed from the study at any point should they decide they no 
longer wish to participate. They will continue to receive routine medical care as necessary 
outside the confines of this study. 
 
Patients will be placed in a prospective database patients undergoing prostate SBRT in our 
department. As per our usual care, they will fill out I-PSS and EPIC-26 quality of life forms at 
each follow up visit. 
 
5.6 
Duration of Follow Up 
 
Patients will be followed as per standard care. For purposes of this study, patients will be 
followed with CTCAE evaluation, EPIC-26 quality of life questionnaire, I-PSS scores at each 
follow up visit (3-6 months; 9-12 months); afterwards they will be prospectively followed as per 
usual care in the Radiation Oncology department with quality of life questionnaires and adverse 
event evaluation, I-PSS scores. 
 
6 
DOSE MODIFICATIONS 
 
None. 
 
7 
ADVERSE EVENT REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
investigator will be required to provide appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects, or precautions pertinent to the safe 
use of the drug or device under investigation.  Safety will be monitored by evaluation of adverse 
events reported by patients or observed by investigators or research staff, as well as by other 
investigations such as clinical laboratory tests, x-rays, electrocardiographs, etc. 
 
7.1 
Adverse Event Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with treatment, and does not imply any judgment about causality.   
 
 
Adverse Event Characteristics and Related Attributions 
 

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CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for grade 3 or higher AE reporting.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site (http://ctep.cancer.gov). 
 
• Attribution of the AE: 
- 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 is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 
 
 
 
7.2 
Recording of Adverse Events 
 
All adverse events will be recorded on a patient specific AE log. The AE log will be maintained 
by the research staff and kept in the patient’s research chart.    
 
 
7.2.1 
Reporting of AE to WCMC IRB 
 
All AEs occurring on this study will be reported to the IRB according to 
the IRB policy, which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immed
iate_Reporting_Policy.pdf.  
 
7.3 
Definition of SAE 
 
SAE’s include death, life threatening adverse experiences, hospitalization or prolongation 
of hospitalization, disability or incapacitation, overdose, congenital anomalies and any 
other serious events that may jeopardize the subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
7.3.1 
Reporting of SAE to IRB 
 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, which 
can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Policy
.pdf.  
 
7.4 
Expedited Adverse Event Reporting 
 
 
The principal investigator is responsible for monitoring the safety of patients who enroll in 
the study.  All AEs occurring after treatment will be followed until resolution.  The 
descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be used for 
adverse event reporting.  A copy of the CTCAE version 4.0 can be downloaded from the 
CTEP web site (http://ctep.cancer.gov/reporting/ctc.html). 
A serious adverse event (SAE) is any adverse experience that results in any of the following 
outcomes: 

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- 
Death. 
- 
Life-threatening adverse experience. 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
- 
Persistent or significant disability/incapacity. 
- 
A congenital anomaly/birth defect. 
• Important medical events: Defined as AEs that, based upon appropriate medical 
judgment, may jeopardize the patient and may require medical or surgical intervention to 
prevent 1 of the outcomes listed above, even though these events may not be immediately 
life-threatening or result in death or hospitalization. 
All SAEs occurring on this study will be reported to the IRB according to the IRB policy, 
which can be accessed via the following link:  
http://researchintegrity.weill.cornell.edu/forms_and_policies/forms/Immediate_Reporting_Po
licy.pdf.  
 
7.4.1 
AE/SAE Follow Up 
 
All SAEs and AEs reported during this study will be followed until resolution or until the 
investigator confirms that the AE/SAE has stabilized and no more follow-up is required. 
This requirement indicates that follow-up may be required for some events after the patient 
discontinues participation from the study. 
 
 
8 
PHARMACEUTICAL INFORMATION 
 
There is no investigative agent used on this protocol. 
 
9 
CORRELATIVE/SPECIAL STUDIES 
 
 
9.1 Correlative Study: Blood draws for immune correlates and microbiome collection 
Patients will provide blood draw prior to, at the completion of radiation and at 3-6 months post 
treatment  follow up. They will also be providing a stool sample for microbiome analysis at 
baseline, end of completion and 3-6 month follow up (last stool sample is optional). This is a 
correlative study. 
 
Blood Sample Collection and Procedure 
Blood samples (40-ml) will be collected in heparinized “Green Top” tubes (for PBMC 
and plasma isolation) and processed within 4 h of sample receipt. The PBMC will be 
isolated using a 1.077 g/ml Ficoll layer to enrich the leukocytes and remove the dead cells 
and any red cells, and cryopreserved in 10% DMSO, 90% human AB serum at 10 x 106 

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cells/vial and stored in liquid nitrogen for batch analysis. Plasma will also be aliquoted and 
stored at -800C for batch analysis. We anticipate analyses of T cell subsets and 
neutrophil/lymphocyte ratios, as well as cytokine measurement and proliferation analyses (all 
markers of peripheral immune correlates to assess status over time). 
  
 
Microbiome collection 
Collection of Specimen(s): Patients will be provided with a stool collection container and be 
instructed on providing a specimen appropriately, which can be done from home or in the clinic. 
 
Handling of Specimens(s):  Samples received will be promptly frozen at 20 degrees C, and 
transferred within the next week to a -80 degree freezer or liquid nitrogen for long-term storage. 
DNA extractions and 16sRNA analysis will be performed once all samples are collected.  
 
The microbial DNA will be isolated and used to provide DNA sequence information. We will 
perform taxonomic characterization of bacteria (using 16S rRNA). Prokaryotic diversity will be 
screened using massively parallel DNA sequencing, exploiting a multiplexing technique to 
generate 16S rRNA sequence tags, followed by analyses (statistical, clustering, and 
phylogenetic) to estimate the distribution of phylotypes, differential abundance, and the relative 
contributions between phylotypes and community dissimilarities to the overall diversity in 
individuals.  
  
We will examine whether there are metagenome sequence content changes during radiation 
treatment, and study whether differences in gene content indicate differences in functional 
pathways between the normal and irradiated microbiome using pathway analysis.   
 
Samples will be collected by the research team and the samples will be stored in -80C freezer in 
Dr. Silvia Formenti’s lab until sample analysis.  
 
 
10 MEASUREMENT OF EFFECT 
 
This is a safety study.  
 
Treatment will be deemed safe of there are no more than 3 acute greater than  grade 3 radiation 
treatment related GI/GU adverse events within  3-6 months of treatment (CTCAE 5.0 criteria).   
 
The primary endpoint will be safety, as measured by the percentage of treatments that are 
delivered without radiation treatment related GI/GU toxicity within 3-6 months from start of 
treatment. Given that the treatment plans will meet standard normal tissue constraints used for 
SBRT, and rigorous safety metrics need to be met before radiation is delivered, we do not 
anticipate any increased toxicity on this study compared to standard SBRT.  
 
 
 

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11 DATA REPORTING / REGULATORY CONSIDERATIONS 
 
11.1 Data Collection 
 
The data collection plan for this study is to utilize REDCap to capture all treatment, 
toxicity, efficacy, and adverse event data for all enrolled patients.  
 
11.2 REDCap 
 
REDCap (Research Electronic Data Capture) is a free data management software system that is 
fully supported by the Weill-Cornell Medical Center CTSC.  It is a tool for the creation of 
customized, secure data management systems that include Web-based data-entry forms, 
reporting tools, and a full array of security features including user and group based privileges, 
authentication using institution LDAP system, with a full audit trail of data manipulation and 
export procedures.  REDCap is maintained on CTSC-owned servers that are backed up nightly 
and support encrypted (SSL-based) connections.  Nationally, the software is developed, 
enhanced and supported through a multi-institutional consortium led by the Vanderbilt 
University CTSA. 
 
 
11.3 Regulatory Considerations 
 
All protocol amendments and consent form modifications will be made by the Principal 
Investigator.   
 
11.4 Data Management 
 
All patient data will be entered and maintained in REDCap.  These data include clinical data 
and all patient safety data. The REDCap provides audit trails that track creation and 
modification of records that include user id and timestamp. Once entered, the data is 
subjected to validation procedures that are executed either immediately or upon saving the 
eCRF page or during the batch validation process. Validation failures that are identified 
before the page is saved can be corrected immediately. Validation failures during saving of 
the eCRF page and during batch validation processes will generate a discrepancy. Depending 
on the database account privileges, the data managers may be able to correct a discrepancy or 
if not, route it to the project data manager at WCMC who can take appropriate action to 
correct the problem. Data clarification forms can also be printed out when necessary to be 
sent to the project data manager at JCTO. Once the discrepancy is closed, by marking 
“resolved” or “irresolvable”, the data is marked clean and an audit trail is generated by the 
system. 
All key end points will be source verified by a second person at each site and errors will be 
corrected. Once the data is verified and all discrepancies are closed, the data can be 
locked/frozen. Locking and freezing can be done at different granular levels and will follow 
institutional SOPs and any specific requirements for the project. 
Security measures that will be taken in order to protect patient data will include firewall 
technology and database level security which will be achieved by assigning roles and 

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privileges to different levels of users and by requiring that the users authenticate themselves 
using user id and password. Additional security for data transfer between remote clients and 
servers will be achieved by using digital certificates/SSL. All data will be backed-up to tape 
periodically according to the Institutional SOPs. All data will be stored for at least 5 years 
following the termination of this study. 
 
 
12 STATISTICAL CONSIDERATIONS 
 
12.1  Study Design/Endpoints 
 
12.1.1 
Primary Objectives   
Safety of this approach will be determined by assessing acute GI/GU toxicity (CTCAE 5).  The 
treatment will be deemed safe if no more than 3 patients experience a grade 4 likely radiation 
treatment related GI/GU (or higher) adverse event within 3-6 months from the end of treatment. 
 
 
12.1.2 
Secondary Objectives 
 
 
Secondary objectives include quality of life (HRQOL) measures including: 1) the Expanded 
Prostate Cancer Index Composite (EPIC) short form questionnaire, 2) International Prostate 
Symptom Score (I-PSS). These will be assessed at baseline, at the 3-6 month follow-up visit and 
at the 9-12 month follow-up visit.   
Toxicity data will also be assessed at 3-6 months and at 9-12 months follow up visit using 
CTCAE criteria. 
 
12.1.3 
Correlative Study Objectives 
 
Microbiome and labs will be collected for exploratory analyses to see how radiation impacts the 
host microbiome and peripheral immune correlates found in blood.   
 
 
12.2 Sample Size/Accrual Rate 
 
We plan to accrue 20 patients over 2 years, or about 4-6 patients every 6 months.   
 
12.3 Analysis of Primary and Secondary Endpoints 
 
Primary Endpoint: 
The treatment will be deemed safe if the grade 4+ likely radiation treatment related GI/GU 
adverse event rate is less than 10% within 3-6 months of the end of treatment.   The proportion of 
patients that experience a >grade 3 GU/GU adverse event will be determined with a binomial 

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point estimate and corresponding exact 95% binomial confidence interval. If the lower bound of 
the interval is below 10%, the treatment will be considered safe. 
 
Secondary Endpoints: 
QOL measures at baseline and at follow up (3-6 months post treatment start, and 9-12 months) 
will be summarized numerically and graphically using mean (sd), median (interquartile range), 
or count (percent) as appropriate, and 95% confidence intervals estimated where possible. The 
QOL value will be plotted over time with a line for each patient and a smoothed curve super-
imposed on the plot. Changes in scoring from pre- to post-treatment will also be determined. 
EPIC-26 overall scores as well as domain summary scores (urinary incontinence, urinary 
irritative/obstructive, bowel, sexual, hormonal) and individual item responses will be evaluated. 
Similarly, overall score as well as individual item responses will be assessed for the  I-PSS 
survey.  
Toxicity will be assessed using CTCAE 5.0 criteria at 3-6 months and 9-12 months. 
These analyses will be descriptive.  
 
Correlative study endpoints: 
Microbiome 
Statistical analysis of microbiome and metagenome composition will be performed in the R 
statistical programming environment using package phyloseq, which incorporates and builds 
upon community ecology packages such as ade4 and vegan and employs the flexible graphic 
system ggplot2, to easily visualize complex data relationships. For 16S data, we will evaluate the 
adequacy of sequencing efforts using rarefaction plots. Alpha diversity index for each will be 
characterized through dominance, equitability, richness, evenness. The diversity metrics will be 
calculated at OTU and higher taxonomical levels to best characterize the community structure. 
We will test for associations of each of these alpha diversity metrics with the time relative to 
radiation exposure, using one-way ANOVA after even-sampling the observations to a depth cut-
off maximizing the number of samples and depth. In addition, rank-abundance plots will be used 
to visualize differences in abundance of dominant taxa in the clinical and phenotypic groups. We 
will utilize skyline plots to visualize the patterns of community structure in terms of relative 
abundances in the collected samples between before and after the radiation treatment. Similarly, 
for metagenomic data, skyline plots will be used to reveal functional compositions of the 
samples. Heat-maps will be plotted to visualize clustering patterns in the data. 
 
We will study the evolution of microbiome over time as a consequence of the radiation 
treatment.  The relative abundances at each taxonomical level will be first normalized by log-
ratio transformation. Then the transformed relative abundance of each individual taxa at multiple 
time points will be fitted by the linear mixed model along with the time effect and all subject-
specific characteristics as the independent covariates. For the nonlinear trend, we will combine 
the nature splines with linear mixed model in the data analysis.  The same model will be applied 
on the indices calculated in the ecology microbial analysis.    
 

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CBC collection 
Plasma samples will be collected at three time points: before radiation, following completion, 
and 3-6 months after completion. We hope to understand the impact of radiation on the 
distribution and frequency of peripheral immune mediators at these time points. To this effect, 
NLR will be numerically and graphically summarized in several ways. The average ratio at each 
time will be estimated, as well as average changes from baseline, and individual trajectories will 
be plotted in “spaghetti plots.”   Parallel summaries will be presented dichotomizing N/L ratio at 
4%, counting the proportion of patients above this threshold at each time point. 
  
Several markers beyond N/L ratio are of interest in order to thoroughly characterize changes 
throughout radiation treatment, including continuous (e.g. T cell panel and TREG panel, IL-7, 
IL-15, IL-6, IL-10, IL-17, IL-2 cytokines), and categorical (e.g. proliferative ability) measures. 
These will be summarized and analyzed in an exploratory manner in parallel methods to N/L 
ratio, if funding is secured for these analyses. 
  
13  Data and Safety Monitoring Plan (DSMP) 
 
The WCMC Data and Safety Monitoring Committee (DSMC) is the central monitoring board 
for this study. 
 
13.1 Monitoring plan 
 
This study will be conducted in accordance with the guidelines in the 2001 NCI approved 
data Safety and Monitoring plan for the WCMC Cancer Institute Monitoring will occur on a 
yearly basis from the date the first patient is enrolled. Reports to the Data Safety and 
Monitoring Committee will include the following information: accruals, targets, responses, 
adverse events and evidence of reporting to appropriate review committees. The WCMC 
Data and Safety Monitoring Board (DSMB) will review the IRB approved protocol, the data 
and safety monitoring plan and any stopping guidelines during protocol initiation. During the 
course of the study, the DSMB will review cumulative study data twice a year to evaluate 
safety, efficacy, study conduct, and scientific validity and integrity of the trial. The WCMC 
DSMB may also convene as needed if stopping criteria are met or other safety issues arise 
that the Principal Investigator and/or IRB would like the WCMC DSMB to address. 
 
13.2 Stopping rules  
 
If more than 2 patients experience a grade 4 likely radiation treatment related adverse event, 
the study will suspend accrual and the study team will evaluate the adverse events to 
determine whether they were at least possibly related to treatment. A decision will be made 
with approval of the DSMB to either modify the protocol or to terminate the trial due to an 
unacceptable adverse event rate. 
 
 
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