Image-Adapted Target Volumes Using 68Ga-HBED-CC PSMA-PET/MRI for Unfavorable-Risk Prostate Cancer Patients Receiving Radiation
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC 1908 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
July 24, 2024 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
SUMMARY OF CHANGES 
Protocol Amendment #6 
LCCC 1908: Image-Adapted Target Volumes Using 68Ga-HBED-CC PSMA-
PET/MRI for Unfavorable-Risk Prostate Cancer Patients Receiving Radiation 
AMENDMENT INCORPORATES: 
_X_  Editorial, administrative changes 
__  Scientific changes  
__  Therapy changes  
__   Eligibility Changes  
Rationale for amendment: The purpose of this amendment is to update the 
protocol to support early closure of study due to low patient accrual and subsequent 
lack of funding. It is also important to note that 68Ga-HBED-CC PSMA-PET/MRI 
is no longer investigational. 
Editorial, administrative changes: 
Section 6.6 
Language added to reflect circumstances of patient removal 
from the study 
Section 10.3 
Language added to reflect circumstances of early termination 
of the study  
THE ATTACHED VERSION DATED July 24, 2024 INCORPORATES THE ABOVE 
REVISIONS  

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC 1908 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 24, 2024 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
SUMMARY OF CHANGES 
 
Protocol Amendment #5 
 
LCCC 1908: Image-Adapted Target Volumes Using 68Ga-HBED-CC PSMA-
PET/MRI for Unfavorable-Risk Prostate Cancer Patients Receiving Radiation 
AMENDMENT INCORPORATES: 
_X_  Editorial, administrative changes 
_X_  Scientific changes  
__  Therapy changes  
__   Eligibility Changes  
Rationale for amendment: The purpose of this amendment is to update the 
protocol with respect to the 
68Ga-PSMA-11 radiotracer that was once 
investigational and is now a commercial product. Accordingly, the language within 
the protocol was amended. The appendix was also updated with the most recent 
version of the PCSI questionnaire.  
Editorial, administrative changes: 
 ___ 
Mechanical edits made throughout 
Section 6.2 
Language added referencing package insert 
Section 
11.2___ 
List of required documents updated  
Scientific changes: 
Section 6.1.1.1 
___ 
The 68Ga-PSMA-11 radiotracer will now be via a commercial 
kit. Language regarding the synthesis and quality control of 
[68Ga]-PSMA removed.  
Section 6.2 
Investigational PSMA tracer language removed 
Appendix A.5 
Updated PCSI: QoL questionnaire added.  
THE ATTACHED VERSION DATED April 14, 2023 INCORPORATES THE 
ABOVE REVISIONS  
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC 1908 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 24, 2024 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
 
LCCC 1908: Image-Adapted Target Volumes Using 68Ga-HBED-CC PSMA-
PET/MRI for Unfavorable-Risk Prostate Cancer Patients Receiving Radiation 
 
 
Principal Investigator 
Michael Repka, MD 
Clinical Assistant Professor 
Department of Radiation Oncology 
101 Manning Drive, Campus Box 7512 
Chapel Hill, NC  27599-7512 
984-974-8435 (phone) 
984-974-8607 (fax) 
Email: mcrepka@email.unc.edu 
 
 
 
Biostatistician  
Xianming Tan, PhD 
Professor 
Department of Biostatistics 
450 West Drive 
Chapel Hill, NC  27599 
919-962-8610 (phone) 
Email: xianming@email.unc.edu 
  
 
Sponsor: Lineberger Comprehensive Cancer Center 
 
Funding Source: Department of Radiation Oncology, University of North Carolina 
IND 145379 
Version Date: July 24, 2024 
 
 

LINEBERGER COMPREHENSIVE CANCER CENTER 
LCCC 1908 
CLINICAL ONCOLOGY RESEARCH PROGRAM 
 
July 24, 2024 
UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL 
 
LCCC 1908: Image-Adapted Target Volumes Using 68Ga-HBED-CC PSMA-
PET/MRI for Unfavorable-Risk Prostate Cancer Patients Receiving Radiation 
 
 
Principal Investigator 
Michael Repka, MD 
Clinical Assistant Professor 
Department of Radiation Oncology 
101 Manning Drive, Campus Box 7512 
Chapel Hill, NC  27599-7512 
984-974-8435 (phone) 
984-974-8607 (fax) 
Email: mcrepka@email.unc.edu 
 
 
 
 
 
 
Signature Page 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal regulations 
and ICH guidelines. 
 
Principal Investigator (PI) Name: Michael Repka, MD 
 
PI Signature: via IRBIS certification 
 
 
 
Date: ___________________ 
 
Protocol Version Date: July 24, 2024 
 

LCCC 1908 
 
CONFIDENTIAL 
PI: Michael Repka MD 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
i 
LIST OF ABBREVIATIONS  
ADT 
androgen-deprivation therapy 
BRIC 
Biomedical Research Imaging Center 
CK 
CyberKnife 
CRF 
case report form 
CTCAE 
common terminology criteria for adverse events 
CTV 
clinical target volume 
DIL 
dominant intra-prostatic lesion 
EBRT 
external beam radiation therapy 
EPIC 
expanded prostate cancer index composite 
EQD2 
equivalent dose in 2 Gy per fraction 
68Ga 
gallium 68 
GI 
gastrointestinal 
GU 
genitourinary 
INR 
International Normalized Ratio 
mpMRI 
multi-parametric magnetic resonance imaging 
PCSI 
prostate cancer symptom indices 
PET 
positron emission tomography 
PSA 
prostate-specific antigen 
PSMA 
prostate-specific membrane antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
PTV 
planning target volume 
SBRT 
stereotactic body radiation therapy 
SIB 
simultaneous integrated boost 
XRT 
radiation therapy 
 
 

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ii 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ............................................................................................. i 
LIST OF ABBREVIATIONS ........................................................................................... i 
1.0 
STUDY SCHEMA ..................................................................................................1 
2.0 
BACKGROUND AND RATIONALE ..................................................................1 
2.1 
Study Overview .....................................................................................................1 
2.2 
Study Synopsis ......................................................................................................5 
2.3 
Investigational Imaging Background ....................................................................6 
2.4 
Rationale ................................................................................................................8 
3.0 
STUDY OBJECTIVES ...........................................................................................9 
3.1 
Primary Objective .................................................................................................9 
3.2 
Secondary Objectives ............................................................................................9 
3.3 
Exploratory Objectives ........................................................................................10 
4.0 
STUDY ENDPOINTS ...........................................................................................10 
4.1 
Primary ................................................................................................................10 
4.2 
Secondary ............................................................................................................10 
5.0 
PATIENT ELIGIBILITY ....................................................................................12 
5.1 
Inclusion Criteria .................................................................................................12 
5.2 
Exclusion Criteria ................................................................................................12 
6.0 
TREATMENT PLAN ...........................................................................................13 
6.1 
Treatment Overview ............................................................................................13 
6.2 
Toxicities and Dosing Delays/Dose Modifications .............................................18 
6.3 
Supportive Care/Symptom Management ............................................................19 

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6.4 
Definition of Dose Limiting Toxicity .................................................................19 
6.5 
Duration of Follow Up ........................................................................................19 
6.6 
Removal of Patients from Protocol Therapy .......................................................19 
6.7 
Subjects Lost to Follow-Up .................................................................................19 
6.8 
Study Withdrawal ................................................................................................20 
7.0 
EVALUATIONS AND ASSESSMENTS ............................................................21 
7.1 
Clinical Assessments ...........................................................................................21 
7.2 
Clinical Laboratory Assessments ........................................................................22 
7.3 
Patient Reported Outcomes (Quality of life assessment) ....................................22 
8.0 
EVALUATIONS AND ASSESSMENTS ............................................................24 
8.1 
Time and Events Table ........................................................................................24 
8.2 
Pre-Study Assessments .......................................................................................25 
8.3 
Treatment Assessments .......................................................................................25 
8.4 
Post-Treatment/Follow-up Assessments .............................................................25 
8.5 
Early Termination Visit .......................................................................................25 
8.6 
Assessment of Safety ..........................................................................................25 
8.7 
Assessment of Efficacy .......................................................................................25 
9.0 
ADVERSE EVENTS ............................................................................................26 
9.1 
Definitions ...........................................................................................................26 
9.2 
Documentation of non-serious AEs or SARs ......................................................27 
9.3 
SAEs or Serious SARs ........................................................................................28 
9.4 
Adverse Event Reporting ....................................................................................28 
9.5 
Data and Safety Monitoring Plan ........................................................................30 
10.0 STATISTICAL CONSIDERATIONS ................................................................31 

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UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
iv 
10.1 
Study Design/Study Endpoints ............................................................................31 
10.2 
Sample Size and Accrual .....................................................................................32 
10.3 
Data Analysis Plans .............................................................................................33 
11.0 STUDY MANAGEMENT ....................................................................................34 
11.1 
Institutional Review Board (IRB) Approval and Consent ..................................34 
11.2 
Required Documentation.....................................................................................34 
11.3 
Registration Procedures.......................................................................................35 
11.4 
Data Management and Monitoring/Auditing ......................................................35 
11.5 
Adherence to the Protocol ...................................................................................35 
11.6 
Amendments to the Protocol ...............................................................................36 
11.7 
Record Retention .................................................................................................36 
11.8 
Obligations of Investigators ................................................................................37 
12.0 REFERENCES ......................................................................................................38 
13.0 APPENDICES .......................................................................................................43 
A.1 
NCCN Risk Stratification ....................................................................................43 
A.2. 
ECOG Performance Status ..................................................................................44 
A.3 
Toxicity according to CTCAE ............................................................................45 
A.4 
Quality of Life according to EPIC-26 .................................................................46 
A.5  
The local Quality of Life questionnaire ..............................................................49 
A.6 
Sequences of the mpMRI protocol ......................................................................50 
 

LCCC 1908 
 
CONFIDENTIAL 
PI: Michael Repka MD 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
1 
 
1.0 
STUDY SCHEMA 
 
The purpose of this study is to determine the feasibility and toxicity of using 
prostate-specific membrane antigen-positron emission tomography (PSMA-PET) 
and multi-parametric magnetic resonance imagining (mpMRI) to guide target 
volumes for patients with unfavorable-risk prostate cancer receiving radiation. The 
study schema is shown in Figure 1. 
 
Figure 1. Study Schema 
 
2.0 
BACKGROUND AND RATIONALE 
2.1 
Study Overview 
Title of the study 
Image-Adapted Target Volumes Using 
68Ga-
HBED-CC PSMA-PET/MRI for Unfavorable-Risk 
Prostate Cancer Patients Receiving Radiation  
Short description of the study PSMA-PET/MRI Unfavorable-Risk Target Volume 
Pilot Study 
Indication 
Primary radiation therapy for localized prostate 
cancer 
Primary objective of the 
study 
To determine the safety of using PSMA-PET/MRI 
to define radiotherapy targets, while meeting all the 
current planning criteria. 
Secondary objectives of the 
study 
To further describe the adverse events associated 
with using PSMA-PET/MRI to define radiotherapy 
target volumes in subjects with unfavorable-risk 
prostate cancer. 
 
To evaluate biochemical control after radiotherapy 
in subjects who have received PSMA-PET/MRI to 
define radiotherapy target volumes. 
 
Pre-
treatment 
mpMRI + 
PSMA-PET 
Definitive Course of XRT  
External beam radiation therapy 
(EBRT) + stereotactic body 
radiotherapy with CyberKnife 
(SBRT-CK) + androgen-deprivation 
therapy (ADT) 
Follow-up 
1, 3, 6, 9, 12, 18, 24, 
30, 36, 42, 48, 54 
and 60 months post 
treatment  

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To measure patient-reported quality of life prior to 
radiation therapy and over time in subjects with 
prostate cancer who have received PSMA-PET/MRI 
to define radiotherapy target volumes. 
 
To determine the proportion of screened subjects 
who are enrolled on the study. 
Exploratory objectives of the 
study 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Study design  
One study arm, Phase II   
Inclusion criteria 
 
 
Written informed consent obtained to participate in 
the study and HIPAA authorization for release of 
personal health information. 
 
Male subjects ≥ 18 years of age 
 
Histologically confirmed prostate adenocarcinoma 
 
Unfavorable intermediate or high-risk, based on the 
NCCN criteria31 (Appendix A.1), with appropriate 
staging (e.g. bone scan) 
 
Subject has adequate performance status as defined 
by ECOG performance status of 0-2. (Appendix 
A.2) 
 
Subject is willing and able to comply with the 
protocol as determined by the Treating Investigator. 
 
Subject speaks English (quality of life instrument is 
validated in English) 
Exclusion criteria 
Contraindications for MRI 
 

LCCC 1908 
 
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UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
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Other prior or concomitant malignancies with the 
exception of:  
• Non-melanoma skin cancer 
• Other cancer for which the subject has 
been disease free for ≥5 years before the 
first study treatment and of low potential 
risk for recurrence. 
 
Inflammatory bowel disease 
Number of patients 
42 
Primary endpoints 
The planning criteria that will be used are the current 
standard of care and standard practice at UNC and 
includes defined treatment volumes with a 
prescribed dose while respecting the dose constraints 
to all organs at risk. The primary endpoint is grade 
3+ late genitourinary toxicity and gastrointestinal 
toxicity as classified and graded according to the 
National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (CTCAE), version 5.0 at 
12 months after radiation therapy. 
Secondary endpoints 
Grade 3+ acute and late genitourinary and 
gastrointestinal toxicity will be defined according to 
CTCAE, version 5.0 during radiation therapy and at 
1, 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months 
post radiotherapy. 
 
Biochemical control will be defined according to the 
Phoenix criteria33 (PSA rise of 2 ng/mL over nadir) 
at 2 and 5 years after radiation therapy. 
 
Patient reported quality of life will be measured 
using the Expanded Prostate Cancer Index 
Composite 
(EPIC-26) 
and 
the 
Urinary 
Obstruction/Irritation scale of the validated Prostate 
Cancer Symptom Indices (PCSI). Patient reported 
quality of life will be measured before the start of 
radiation therapy at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42, 
48, 54, and 60 months post radiotherapy. 
 
The total number of subjects enrolled on the study 
will be compared to the total number of screened 
subjects. 

LCCC 1908 
 
CONFIDENTIAL 
PI: Michael Repka MD 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
4 
 
 
The feasibility of meeting dose constraints will be 
defined as the proportion of subjects who meet the 
following dose constraint criteria: 
• SBRT-CK boost dose prescription: 6.5Gy 
x 3 
o PTV: 
V19.5Gy > 95% 
o PTVmax > 150%, CI < 1.8 
o CTV:  V19.5Gy > 99% 
o DIL:    V24.0Gy > 99% 
• SBRT-CK boost dose constraints:  
o Rectum 
▪ V21.1Gy< 5 % 
▪ V18.9Gy< 20 % 
▪ V17.5Gy< 10 % 
▪ V16.2Gy< 40 % 
▪ V10.2Gy< 60 % 
▪ V9.3Gy< 40 % 
▪ V19.5Gy< 1cc 
▪ Max<21.2Gy 
o Bladder 
▪ V21.1Gy< 5 % 
▪ V19.5y< 5 cc 
▪ V9.3Gy< 40 % 
▪ Max<21.2Gy 
o Prostatic Urethra 
▪ V19.5Gy > 95% 
▪ V22Gy < 0.03cc 
o Membranous Urethra 
▪ V18 Gy < 50% 
o Large bowel 
▪ V15Gy< 1cc 
o Small bowel 
▪ V15Gy< 1cc 
o Penile bulb 
▪ V15Gy< 3cc 
Performance of PSMA-PET/MRI to PSMA PET/CT 
as defined as: 
• Rate of identification and delineation of 
DIL  
o Compared to a gold standard of 
image-guided prostate biopsy  
• Rate of identification of positive pelvic 
nodes  

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July 24, 2024 
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• Rate 
of 
identification 
of 
distant 
metastatic disease in the pelvis 
 
Rate of identification of positive pelvic nodes by 
PSMA-PET and therefore the proportion of patients 
who have pelvic nodes included in the radiation 
field. 
Schedule 
• Start: January 2023 
• Recruitment period: 24 months 
• Provisional conclusion: January 2026 for 
primary endpoint 
Study will terminate with the completion of the last 
follow-up in the last enrolled patient, unless study 
ends  
Participating centers 
Single center 
2.2 
Study Synopsis 
The goals of this pilot trial are to: 
1. Test the safety and feasibility of designing the radiation treatment plan so 
that the entire prostate receives the prescribed dose of radiation in addition 
to the visible tumor in the prostate (as detected by mpMRI and/or PSMA-
PET (i.e. dominant intra-prostatic lesion (DIL))) receiving any inevitable 
intrinsic plan “hot spots” or areas of dose above the prescription  
2. Test the safety and feasibility of designing the radiation treatment plan so 
that the pelvic lymph nodes are covered (or not covered) depending on 
whether visible tumor is detected by mpMRI and/or PSMA-PET imaging.  
 
It should be noted that the prescription dose given in this study will be no different 
than current practice and that all radiation plans have hot spots. This study will 
focus the hot spots on regions determined by mpMRI + PSMA-PET to have visible 
tumor as opposed to the current practice where hot spot regions are randomly 
located in the target. Additionally, it should be noted that it is not a consensus as to 
whether pelvic nodes should be treated in addition to the prostate in this unfavorable 
risk population and that practice patterns as to whether the pelvic notes are treated 
differ. Simply, this study aims to determine if mpMRI and PSMA-PET imaging 
can help optimize 1) the location of the high dose region of SBRT-CK and 2) pelvic 
lymph node coverage. As all radiation plans designed and delivered to the patient 
as part of this trial will follow current standards on respecting dose constraints to 
organs surrounding the prostate and pelvic lymph nodes, including urethra, bladder, 
small bowel, and rectum, we do not expect the toxicities to differ from those 
observed in standard of care practices.  
 
Of note, the imaging agent, PSMA, has usage guideline-dictated by other countries 
and we do not anticipate any toxicity or safety issues as they relate to the PSMA 

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UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
6 
 
itself. To our knowledge, there have been no reported substantive adverse effects 
due to its use.1,2  
 
The feasibility questions: Is it possible to design “smarter” radiation plans for 
enrolled patients that covers the entire prostate (standard), respects all dose 
constraints to surrounding organs (standard), and also preferentially place the 
inevitable hot spots at the image-identified lesion within the prostate, all without 
violating the standard dose constraints for the normal tissues (organs at risk)? 
Furthermore, is it possible to more intelligently make the decision of whether or 
not to treat the pelvic lymph nodes with guidance from imaging results?  
 
The safety question: Does delivering this treatment to the patient lead to increased 
side effects (compared to historical data)? 
 
2.3 
Investigational Imaging Background 
Interest in using 68Ga-PSMA PET/CT in the setting of unfavorable risk and 
biochemically recurrent prostate cancer has increased tremendously since it was 
introduced in 2012.3  Regarding radiation field design, PSMA-PET has been shown 
to influence the radiation planning in nearly 50% of patients with high risk disease 
(includes patients with recurrent disease as well as those at initial presentation).4,5 
In a prospective study of 108 unfavorable risk prostate cancer patients at initial 
presentation, PSMA-PET imaging influenced treatment design in 21% of patients.6 
Further, Dewes et al. conducted a retrospective study of 15 patients and evaluated 
the utility of PSMA-imaging and if it influenced the radiation treatment target 
volumes. They found the radiation concept changed in 33% of all patients, leading 
to relevant changes in the planning target volumes, including an additional 
irradiation of the pelvic lymph nodes due to tracer uptake in 25% of patients.7 
Therefore it is likely PSMA-PET/CT can be useful in radiation field design.  
 
Corfield et al. conducted a systematic review of 68Ga-PSMA PET for primary 
staging of high-risk prostate cancer and concluded, based on 12 studies of 322 
patients, it outperforms traditional imaging modalities.8 Their study included the 
results from Budaus et al. who conducted a retrospective study of 608 lymph nodes 
removed from men with high risk prostate cancer who had preoperative 68Ga-
PSMA-PET/CT scans and compared them to histologic findings after radical 
prostatectomy with lymph node dissection. They found the sensitivity, specificity, 
positive predictive value, and negative predictive value of 68Ga-PSMA-PET/CT for 
lymph node metastasis detection were 33.3%, 100%, 100%, and 69.2%, 
respectively.9 In a recent systematic review and meta-analysis, the following 
predictive ability of PSMA-PET imaging for primary staging purposes was found. 
Incorporating the results of five different studies with a total of 244 high and 
intermediate risk prostate cancer patients, on a per-lesion analysis the summary 
sensitivity and specificity were 75% and 99%, respectively. On a per-patient 
analysis the summary sensitivity and specificity were 77% and 97%, respectively.10  
 

LCCC 1908 
 
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UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
7 
 
Regarding nodal radiation, there are three published large randomized controlled 
trials looking at the role of pelvic nodal irradiation in nonmetastatic prostate cancer 
which have proved inconclusive.11–13 More recently, a randomized study conducted 
at a single institution in India (POP-RT, Murthy et al., JCO 2021) demonstrated 
improvements in biochemical failure free survival, disease free survival, and distant 
metastasis free survival with the addition of pelvic radiotherapy in patients with a 
nomogram-predicted risk of occult nodal metastasis exceeding 20%.14 There are 
two more trials currently underway (NCT01368588; PEACE 2 - GETUG - AFU 
23) with estimated primary completion dates in 2025-2027.15,16 Collectively, these 
studies demonstrate the clinical equipoise in this area (whether or not to include 
nodes in the treatment field), which has been an area of intense debate for at least 
two decades (Nguyen & D’Amico, JCO 2008; Roach, JCO 2008).17,18  
 
Regarding defining intraprostatic lesions, 68Ga-PSMA-PET alone has not been 
perfect. One meta-analysis found in seven studies that PSMA-expressing lesions 
were identified in only 203 of 273 patients (74%).19 However, this number appears 
to be confounded by lymph node detection rates. When looking at PSMA-PET 
defined DILs alone, the detection rates could be over 95%,20 and may be even 
higher in high-risk disease which have greater PSMA-PET avidity.21 Three separate 
studies have shown that MRI and PSMA can deliver complimentary information 
on the localization of DILs.22–24 Therefore, it is likely PSMA PET-MRI is 
advantageous to PSMA PET-CT alone in identifying DILs. In a slice-by-slice 
analysis with histopathology, the sensitivity for PSMA PET alone, mpMRI alone, 
and PSMA PET-MRI combined, was 75%, 70%, and 82%, respectively for prostate 
cancer tumor detection. The specificity was 87%, 82%, and 67%, respectively.25 
Others have also found PSMA-PET/MRI to be superior to multiparametric MRI 
alone in detecting prostate cancer.26 
 
The concept of biological-guided (e.g. with PET) dose escalation (e.g. to DILs) is 
not new,27 but has never been done with in combination with SBRT-CK. A 
feasibility study such as the current study under investigation will be the first step 
to investigating this question. Based on other studies, know that dose escalation in 
prostate cancer improves progression free survival.28,29   
 
Other nations have been quicker to explore 68Ga-PSMA-PET/CT imaging for 
prostate cancer and guideline standards have been developed in Europe in regards 
to the recommendation, performance, interpretation and reporting of PSMA-
PET/CT for prostate cancer imaging. One such endorsed use is for primary staging 
in high-risk disease before planning external beam radiation.1 Additionally, the 
Australian and New Zealand Radiation Oncology Genito-Urinary group 
recommends considering PSMA-PET in the setting of recurrent disease post-
prostatectomy at low PSA levels because of its sensitivity over other imaging 
modalities.2  
 
Importantly, for all of these studies, the impact on patient-reported quality of life 
of this approach has not been described.  

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Furthermore, in published literature, probability of tumor control for prostate 
cancer has been associated with radiation dose. Martinez et al.30 showed that a dose 
of EQD2 > 100 Gy (using α / β = 1.2 Gy) had a significant effect on the recurrence 
rate of prostate cancer. Converting this EQD2 dose to clinical practice, as relevant 
for the current pilot trial, we will increase area of visible tumor to receive at least 
EQD2 > 100 Gy.30 
2.4 
Rationale 
Radiation therapy is a standard curative option for patients with localized prostate 
cancer. At UNC, patients with unfavorable intermediate and high-risk prostate 
cancer are offered radiation usually given with a long course (18 months) of 
androgen deprivation therapy. The radiation can be given as moderately 
hypoefractionated radiotherapy alone, or with with a combination of conventionally 
fractionated external beam radiation therapy (EBRT) (25 daily treatments) and 
boost utilizing stereotactic body radiotherapy (SBRT) with CyberKnife (CK). Our 
standard practice is to include the pelvic nodes in our treatment field, although as 
previously discussed this topic is controversial. These are standard treatment 
options according to NCCN guidelines.31 With current standard radiation doses, 5-
year recurrence-free survival is reported to be 83% (unfavorable risk disease). 
Additionally, when the radiation fields are designed, the primary tumor location 
within the prostate is not typically taken into account, rather, the entire prostate is 
treated uniformly.  
 
The availability of the PET-MRI facility at UNC (Biomedical Research Imaging 
Center, BRIC) uniquely allows us to examine these clinically-relevant questions 
using an mpMRI/PSMA-PET scan. Patients participating on this trial will have, 
using the same injection, an mpMRI/PSMA-PET scan and a PSMA-PET/CT scan, 
both of which will be used to help with radiation design. The long-term goal of this 
line of research is to allow smarter radiation design in the future that more 
specifically targets the tumor(s), therefore maximizing the therapeutic window (by 
focusing treatment more where there is cancer and not treating where there is no 
cancer). There is significant long-term potential for this research as imaging 
continues to improve and PSMA-PET/mpMRI becomes more widely adapted. 
UNC’s PET-MRI is one of only a few in the country, which positions UNC to be a 
leader in the development of this technology. This study will also help create new 
knowledge in terms of comparability of PET/MR and PET/CT, and how the 
information gained on PET/MR could potentially be transferred to PET/CT, the 
latter of which is more widely available.    
 
Image-adapted prostate irradiation 
Currently, all radiation treatment is designed to treat the entire prostate to a 
prescribed dose. However, improvements in imaging, such as with multi-
parametric MRI (mpMRI) and PSMA-PET, which can be used to visualize tumor 
locations within the prostate, allow exploration of smarter radiation designs that 
concentrate the inevitable heterogeneous hot spots in a radiation plan on the area(s) 

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July 24, 2024 
9 
 
of visible tumor. Specifically, mpMRI has already revolutionized the way prostate 
biopsies are performed to diagnose or follow men with prostate cancers. 
Historically, prior to the availability of mpMRI when prostate tumors cannot be 
visualized, biopsies are done with random sampling of the prostate. More recently, 
clinical trials have shown that mpMRI-guided prostate biopsies are better than 
random sampling biopsies in diagnosing high-grade, clinically relevant prostate 
cancer.32 This same targeted approach of diagnosis can be adapted to radiation 
treatment.  
 
Image-adapted pelvic nodal irradiation 
Currently, patterns of practice vary as to whether the pelvic lymph nodes are 
included in the radiation field for men with unfavorable risk prostate cancer. The 
NCCN simply states “prophylactic nodal radiation can be considered”.31 
Improvements in imaging may allow the exploration of smarter radiation design by 
better identifying the subset of men who would stand to benefit from the inclusion 
of pelvic lymph nodes in the radiation field. Specifically, mpMRI and PSMA-PET 
may better identify lymph node involvement, and thus their inclusion in the 
radiation fields.   
   
3.0 
STUDY OBJECTIVES 
3.1 
Primary Objective 
3.1.1 To determine the safety of using PSMA-PET/MRI to define radiotherapy 
targets, while meeting all the current planning criteria. 
 
Hypothesis: Using PSMA-PET/MRI to define radiotherapy targets in patients with 
unfavorable-risk prostate cancer does not increase toxicity at 1 year after radiation, 
relative to historical controls.  
3.2 
Secondary Objectives  
3.2.1 To further describe the adverse events associated with using PSMA-
PET/MRI to define radiotherapy target volumes in subjects with 
unfavorable-risk prostate cancer. 
3.2.2 To evaluate biochemical control after radiotherapy in subjects who have 
received PSMA-PET/MRI to define radiotherapy target volumes.  
3.2.3 To measure patient-reported quality of life prior to radiation therapy and 
over time in subjects with prostate cancer who have received PSMA-
PET/MRI to define radiotherapy target volumes. 
3.2.4 To determine the proportion of screened subjects who are enrolled on the 
study. 
 

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3.3 
Exploratory Objectives 
3.3.1 
 
 
  
3.3.2 
 
.  
 
4.0 
STUDY ENDPOINTS 
4.1 
Primary 
The planning criteria that will be used are the current standard of care and standard 
practice at UNC and includes defined treatment volumes with a prescribed dose 
while respecting the dose constraints to all organs at risk. The primary endpoint is 
grade 3+ late genitourinary toxicity and gastrointestinal toxicity as classified and 
graded according to the National Cancer Institute’s Common Terminology Criteria 
for Adverse Events (CTCAE), version 5.0 at 12 months after radiation therapy.  
4.2 
Secondary 
4.2.1 Grade 3+ acute and late genitourinary and gastrointestinal toxicity will be 
defined according to CTCAE, version 5.0 during radiation therapy and at 1, 
3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post radiotherapy. 
Additionally, this will be reported as a cumulative incidence over the entire 
5-year course of the study.  
4.2.2 Biochemical control will be defined according to the Phoenix criteria33 (PSA 
rise of 2 ng/mL over nadir) at 2 and 5 years after radiation therapy. 
4.2.3 Patient reported quality of life will be measured using the Expanded Prostate 
Cancer Index Composite (EPIC-26) and the Urinary Obstruction/Irritation 
scale of the validated Prostate Cancer Symptom Indices (PCSI). Patient 
reported quality of life will be measured before the start of radiation therapy 
at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months post radiotherapy. 
4.2.4 The total number of subjects enrolled on the study will be compared to the 
total number of screened subjects. 
4.2.5 The feasibility of meeting dose constraints will be defined as the proportion 
of subjects who meet the following dose constraint criteria:  
• SBRT-CK boost dose prescription: 6.5Gy x 3 
o PTV: V19.5Gy > 95% 
o PTVmax > 150%, CI < 1.8 
o CTV:  V19.5Gy > 99% 
o DIL:    V24.0Gy > 99% 

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• SBRT-CK boost dose constraints:  
o Rectum 
▪ V21.1Gy< 5 % 
▪ V18.9Gy< 20 % 
▪ V17.5Gy< 10 % 
▪ V16.2Gy< 40 % 
▪ V10.2Gy< 60 % 
▪ V9.3Gy< 40 % 
▪ V19.5Gy< 1cc 
▪ Max<21.2Gy 
o Bladder 
▪ V21.1Gy< 5 % 
▪ V19.5y< 5 cc 
▪ V9.3Gy< 40 % 
▪ Max<21.2Gy 
o Prostatic Urethra 
▪ V19.5Gy > 95% 
▪ V22Gy < 0.03cc 
o Membranous Urethra 
▪ V18 Gy < 50% 
o Large bowel 
▪ V15Gy< 1cc 
o Small bowel 
▪ V15Gy< 1cc 
o Penile bulb 
▪ V15Gy< 3cc 
4.2.6 Performance of PSMA-PET/MRI to PSMA PET/CT as defined as: 
• Rate of identification and delineation of DIL (e.g. sensitivity and 
specificity) 
o Compared to a gold standard of image-guided prostate biopsy  
• Rate of identification of positive pelvic nodes  
• Rate of identification of distant metastatic disease in the pelvis 
4.2.7 Rate of identification of positive pelvic nodes by PSMA-PET and therefore 
the proportion of patients who have pelvic nodes included in the radiation 
field.  
 
 

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5.0 
PATIENT ELIGIBILITY 
5.1 
Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to participate in this 
study.  
5.1.1 Written informed consent obtained to participate in the study and HIPAA 
authorization for release of personal health information.  
5.1.2 Male subjects ≥ 18 years of age 
5.1.3 Histologically confirmed prostate adenocarcinoma 
5.1.4 Unfavorable intermediate or high-risk, based on the NCCN criteria31 
(Appendix A.1), with appropriate staging (e.g. bone scan).  
5.1.5 Subject has adequate performance status as defined by ECOG performance 
status of 0-2. (Appendix A.2) 
5.1.6 Subject is willing and able to comply with the protocol as determined by the 
Treating Investigator.  
5.1.7 Subject speaks English (quality of life instrument is validated in English) 
 
5.2 
Exclusion Criteria 
All subjects meeting any of the following exclusion criteria at baseline will be 
excluded from study participation. 
5.2.1 Contraindications for MRI 
5.2.2 Other prior or concomitant malignancies with the exception of: 
• Non-melanoma skin cancer 
• Other cancer for which the subject has been disease free for ≥5 years before the 
first study treatment and of low potential risk for recurrence. 
5.2.3 Inflammatory bowel disease 
 
 

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with simultaneous acquisition of multi-parametric (mp)MR sequences and 
PET about 60 minutes after radiotracer injection (Siemens Biograph mMR). 
During the uptake period of 60 minutes, the subject should drink at least 500 
mL of fluid (water or fluid of choice). The subject should void immediately 
prior to PET/MR acquisition. The MR sequences to be acquired are shown in 
A.6 
Sequences of the mpMRI protocol). PET/MR acquisition takes 
about 30 minutes. Intravenous contrast will be administered for the mpMRI. 
All PET images will be reconstructed with corrections for attenuation, dead 
time, random events, and scatter, using iterative ordered-subsets expectation 
maximization. PET images in PET/MR will be acquired in list mode and 
reconstructed for several time points after scan start time and durations 
adjusted for radioisotope decay: e.g. 0-5 min, 5-10 min, 15-21 min and 21-28 
min. No Lasix will be used for the PSMA-PET/MRI imaging acquisition. For 
the first five protocol subjects, if real-time reconstruction does not produce 
satisfactory images, the option to have the subject void (i.e. urinate) and re-
image will be considered.  
a. 68Ga-PSMA PET scans co-registered with MRI scan with IV contrast. 
68Ga-PSMA PET scans will be performed with co-registration with MR 
with contrast before starting radiation therapy. A commercial PSMA kit will 
be used to source the 68Ga-PSMA radiotracer and will be infused into the 
subject at the BRIC facility. These images with be acquired on the PET/MR 
scanner available at the Biomedical Research Imaging Center (BRIC).  
PET/MR will of the pelvis. Subjects will remain in a quiet room for 60 
minutes after injection of the 68Ga-PSMA to allow for uptake of the tracer 
and excretion of non-localized radioactivity.  Subjects will then undergo a 
PET/MR scan of the pelvis including multiparametric MR.  Participants 
must have their 68Ga-PSMA PET scan performed at UNC-CH.  
 
b. Administration, scanning and analysis of [68Ga]-PSMA. Initially, a 
venous line will be established for the administration of 68Ga-PSMA, 
irrespective of whether the patient already has a central line (e.g. Mediport, 
Port-a-cath, PICC line). In other words, these central lines will NOT be used 
for infusion of the radionuclide agent. Intravenous administration of 68GA-
PSMA [0.07 mCi/kg ± 10%] will be administered under the supervision of 
Dr. Amir Khandani or another qualified nuclear medicine physician from 
the Nuclear Medicine Department. 68Ga-PSMA PET/MR imaging will 
commence 60 minutes following injection.  
 
3. Per UNC standard practice patients with high-risk disease will undergo elective 
pelvic nodal irradiation. Patients with unfavorable-intermediate risk disease will 
receive elective nodal irradiation at the discretion of the treating physician (e.g. 
secondary to suspicious imaging findings or high nomogram predicted incidence of 
occult nodal disease). If the PSMA imaging alone shows suspicious pelvic nodes, 
a biopsy of the suspicious node will be offered, and upon confirmation, these may 
be included in the external beam radiation treatment field.  

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4. Because the PSMA-PET/MRI may find distant disease that may otherwise not have 
been found, if the use of the PSMA-PET or MRI information suggests that the 
patient has M1 disease, the patient will be re-referred to the UNC multidisciplinary 
Urologic Oncology clinic for consultation to discuss 1) the implication of these 
findings, 2) what additional systemic agents should be used in their treatment 
regimen, if any, and 3) how these findings may impact the utility of this study. This 
would not exclude them from the study.   
6.1.1.1.2 
 External Beam Radiation Therapy  
 
1. Patients will undergo a radiation planning CT and preferably, in those patient to get 
pelvic nodes treated, with intravenous contrast if clinically available. This will be 
done roughly 8 weeks after ADT. Patients will undergo a planning CT. Standard 
departmental protocol will be followed for simulation, including eligibility for 
intravenous contrast, patient immobilization, with a comfortably full bladder.  
6.1.1.1.3 
SBRT with CyberKnife 
 
1. SBRT with the use of CyberKnife will occur roughly 6 weeks after initiation 
of EBRT. Standard departmental protocol will be followed for CK-SBRT 
preparation. Patients with seminal vesicle involvement are eligible and 
seminal vesicles will be covered with CK-SBRT only as clinical indicated.  
 
2. The fusion of the PSMA PET/mpMRI scans with the planning CT will be 
carried out in the treatment planning software; the fiducials will be used for 
soft tissue registration. Initially, the T2w MRI sequence will be registered 
with the planning CT by mutual information registration via fiducials. If 
necessary, manual adjustments may also be applied during image 
registration. The PSMA-PET and rest of the MRI and PET-CT scans will 
share the registration between the T2w MRI scan and planning CT.  
 
3. The GTV-MRI will be outlined as a joint effort between a radiologist and 
the treating radiation oncologist on the basis of the PI-RADs v2 criteria.34-
35 Additionally, the GTV-PET will be contoured again jointly between the 
radiologist and radiation oncologist by 30% of the SUVmax value.24 This 
will be done by taking into account all additional information (including 
tumor localization in the diagnostic biopsy and physical exam [palpation]). 
An additional volume (GTV-union) is created from both GTVs.  
 
4.  The GTVs ( i.e. DILs), will be biopsied as a joint effort between the treating 
radiation oncologist and a urologist. Two cores will be taken per GTV.  
 
5. Contouring of the prostate, rectum, and urethral will be performed per UNC 
standard practice and SBRT with CyberKnife will be performed per UNC 
standard practice.  

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6. Per UNC standard practice, if the CT or the MRI imaging shows suspicious 
pelvic nodes, these will be included in the radiation treatment field. If the 
PSMA imaging alone shows suspicious pelvic nodes, a biopsy of the 
suspicious node will be offered, and upon confirmation, these may be 
included in the radiation treatment field.  
 
7. Because the PSMA-PET/CT may find distant disease that may otherwise 
not have been found, if the use of the PSMA-PET or MRI information 
suggests that the patient has M1 disease, the patient will be re-referred to 
the UNC multidisciplinary Urologic Oncology clinic for consultation to 
discuss 1) the implication of these findings, 2) what additional systemic 
agents should be used in their treatment regimen, if any, and 3) how these 
findings may impact the utility of this study. This would not exclude them 
from the study.   
 
6.1.1.2 Definition of Target Volumes 
Gross Tumor Volume (GTV) 
• GTV1 = fusion of the prostate GTV-PET and prostate GTV-MRI 
• GTV2 = fusion of nodal GTV-PET and nodal GTV-MRI 
 
Clinical Target Volume (CTV)  
• CTV1 = Prostate + seminal vesicles 
• CTV2 = Pelvic lymph nodes as defined by RTOG contouring guide36 
• CTV3 = Prostate + up to 1 cm of the involved seminal vesicles 
 
Planning Target Volume (PTV) 
• PTV1 = CTV1 + 7 mm (except posteriorly with a only 5mm expansion) 
• PTV2 = CTV2 + 7 mm  
• PTV3 = GTV2 + 5 mm 
• PTV4 = CTV3 + 2 mm isotropically (but 5 mm on the side of disease) – 
Rectum 
• PTV5 = GTV1 + 0 mm – Urethra/Bladder/Rectum 
6.1.1.3 Radiation therapy planning 
The irradiation technique will be a combination of EBRT and SBRT. The highest 
planning priority will be to satisfy the restrictions of the bowel, rectum and 
bladder (see below). 
 
Dose on target volumes: 
• PTV1: EBRT prescription dose of 45 Gy in 1.8 Gy/fraction for 25 fractions.  
• PTV2: EBRT prescription dose 45 Gy in 1.8 Gy/fraction for 25 fractions 
• PTV3: EBRT prescription with simultaneous integrated boost (i.e. dose 
painting) to 56.25 Gy in 2.25 Gy/fraction for 25 fractions 

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V17.5Gy < 10 % 
V16.2Gy < 40 % 
V10.2Gy < 60 % 
Max < 21.2 Gy 
V20.1Gy < 1cc 
Bladder 
V21.1Gy < 5 % 
V19.5y < 5 cc 
V9.3Gy < 40 % 
V19.5 Gy < 5cc 
Max < 21.2 Gy 
Large Bowel 
V15Gy < 1cc 
 
Max *** Gy (assuming a/b of large bowel to be 3 
and *** cGy max dose from first course); BED 
would result in Max dose <60Gy in 1.8Gy/fx 
Small Bowel 
V15Gy < 1cc 
 
Max *** Gy (assuming a/b of large bowel to be 3 
and *** cGy max dose from first course); BED 
would result in Max dose <54 Gy in 1.8Gy/fx 
Penile bulb 
V15Gy< 3cc 
Testicles/ 
Max <1.1Gy 
Membranous Urethra 
V18 Gy < 50% 
Prostatic Urethra 
V19.5Gy > 95% 
V22Gy < 0.03cc 
  
6.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluated for toxicity.  
Each patient will be assessed periodically for the development of any toxicity 
according to the Time and Events Table (Section 8.1).  Patients will be evaluated 
during their external beam radiation therapy at least once/week while on treatment. 
Acute toxicity (<3 months) and/or late radiation associated toxicity (>3 months) 
will be assessed according to the NCI Common Toxicity Criteria for Adverse 
Events (CTCAE), version 5.0 (if appropriate). Treatment holds and delays and dose 
adjustments will be made according to the system showing the greatest degree of 
toxicity per these metrics. Neither dose modifications or treatment delays are 
anticipated and priority will be given to honoring normal tissue dose constraints 
(5.1.1.3).  
 
For further information regarding PSMA please refer to the package insert: 
Galium Ga 68 PSMA-11 Injection  
 

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6.2.1 Radiation Dose Delays/Dose Modifications 
For acute radiation toxicities, treatment breaks should be kept to a minimum. An 
effort will be made to complete the radiotherapy on schedule without significant 
treatment breaks, as prolongation of treatment is known to contribute to treatment 
failure. The need for radiotherapy breaks due to severe acute toxicity will be 
determined by the treating radiation oncologist. Patients on treatment are evaluated 
weekly by the radiation oncologist.  
6.3 
Supportive Care/Symptom Management 
Patients who develop any adverse event while on study will receive standard of 
care treatment.  Radiation and hormone therapy are already standard of care 
treatments for these patients. Standard of care treatments for known potential 
adverse events from these treatments are well established. 
6.4 
Definition of Dose Limiting Toxicity 
A dose-limiting toxicity is defined as all Grade 3 or above acute toxicities attributed 
to the treatment under study. The accrual will be halted if the number of patients 
with dose-limiting toxicities equals to or exceeds a rate of 30%. 
6.5 
Duration of Follow Up 
All patients will be followed for up to 5 years after radiation, or until death, 
whichever occurs first, after removal from study treatment for determination of 
study endpoints.  Patients removed from study treatment for unacceptable adverse 
events (AEs) will be followed for resolution or stabilization of the AEs. All patients 
(including those withdrawn for AEs) should be followed after removal from study 
treatment as stipulated in the protocol.   
6.6 
Removal of Patients from Protocol Therapy 
In case a patient decides to prematurely discontinue protocol therapy (“refuses 
treatment”), the patient should be asked if she or he may still be contacted for 
further scheduled study assessments. The outcome of that discussion should be 
documented in the medical record. Patients may also be removed from the study at 
any time per PI discretion due to unexpected reactions, lack of study compliance or 
for study closure. 
6.7 
Subjects Lost to Follow-Up 
Subject will be considered lost to follow-up if he fails to return for three scheduled 
visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a subject fails to return to the clinic for a 
required study visit: 
• The site will attempt to contact the subject and reschedule the missed 
visit and counsel the subject on the importance of maintaining the 

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assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study. 
• Before a subject is deemed lost to follow-up, the investigator or 
designee will make every effort to regain contact with the subject (where 
possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the subject’s medical 
record or study file.  
Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
6.8 
Study Withdrawal 
If a patient decides to withdraw from the study (and not just from protocol therapy) 
an effort should be made to complete and report study assessments as thoroughly 
as possible.  At the time of withdrawal, the investigator should attempt to establish 
as completely as possible the reason for the study withdrawal.  
• 
The patient should be asked if they are willing to allow for the abstraction 
of relevant information from their medical record in order to meet the long 
term follow up (e.g., biochemical control or survival) objectives outlined in 
the protocol.   
• 
A complete final evaluation at the time of the patient’s study withdrawal 
should be obtained with an explanation of why the patient is withdrawing 
from the study.   
• 
If the patient is noncompliant and does not return for an end of study follow 
up assessment, this should be documented in the case report form (CRF).  
• 
If the reason for removal of a patient from the study is an adverse event, the 
principal specific event will be recorded on the CRF.  
 
 

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7.0 
EVALUATIONS AND ASSESSMENTS 
7.1 
Clinical Assessments 
Clinical assessments will be performed as outlined in the Time and Events Table in 
Section 8.1. 
7.1.1 Demographics  
Demographic information (date of birth, gender, race) will be recorded at screening. 
7.1.2 Medical History  
Relevant medical history, including history of current disease, other pertinent 
respiratory history (e.g., tobacco use), and information regarding underlying 
diseases will be recorded at screening and a focused medical history on 
symptoms/toxicity will be performed thereafter.  
7.1.3 Physical Examination 
A complete physical examination including height (at screening only), weight, 
performance status (ECOG) and vital signs (e.g., temperature, heart rate, 
respiratory rate, pulse oximetry and blood pressure) will be performed by either the 
investigator or a sub-investigator who is a physician at screening and the first study 
visit.    
 
Qualified staff (MD, NP, RN, and PA) may complete the abbreviated physical exam 
at all other visits.   
 
New abnormal physical exam findings must be documented and will be followed 
by a physician or other qualified staff at the next scheduled visit. 
7.1.4 Adverse Events 
Events should be assessed per NCI-CTCAE criteria 5.0. Information regarding 
occurrence of adverse events will be captured throughout the study. Duration (start 
and stop dates), severity/grade, outcome, treatment and relation to study treatment 
will be recorded in the case report form. A dose-limiting toxicity is defined as all 
Grade 3 or above acute toxicities attributed to the treatment under study. The 
accrual will be halted if the number of patients with dose-limiting toxicities equals 
to or exceeds a rate of 30%. 
7.1.5 Disease Assessment 
Patients’ disease will be assessed with prostate-specific antigen (PSA) test draws. 
PSA will be obtained at within three months prior to study enrollment and then at 
each follow up (1, 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months post 
treatment).  

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7.2 
Clinical Laboratory Assessments 
7.2.1 Hematology 
Blood will be obtained at screening and sent to the clinical site hematology lab for 
a complete blood count (hemoglobin, hematocrit, red blood cell count, white blood 
cell count, white blood cell differential, and platelet count), coagulations 
(International Normalized Ratio (INR) or prothrombin time (PT) and partial 
thromboplastin time (PTT)).   
7.2.2 Blood Chemistry Profile 
Blood will be obtained at screening and sent to the clinical site chemistry lab for a 
complete metabolic panel (serum sodium, potassium, chloride, bicarbonate, 
glucose, BUN, creatinine, aspartate aminotransferase (AST/SGOT), alanine 
aminotransferase (ALT/SGPT), alkaline phosphatase, total bilirubin, direct 
bilirubin, gamma-glutamyl transferase (GGT), albumin and LDH). 
7.2.3 Pathology 
At time of fiducial markers placement, GTVs (i.e. DILs) will be biopsied by the 
treating radiation oncologist and a urologist. Two cores will be taken per GTV and 
placed in buffered formalin containers. This is a research only biopsy and will be 
used to evaluate the sensitivity and specificity of PSMA-PET/MRI vs PSMA-
PET/CT. It will not require any additional visits or cost for the subject. These 
samples will be collected and accessioned with coded identifiers by the Tissue 
Procurement Facility (TPF). Specimen processing, embedding and histologic 
sectioning will be performed by the Translational Pathology Laboratory (TPL) and 
slides interpreted by the collaborating pathologist.   
7.3 
Patient Reported Outcomes (Quality of life assessment) 
Quality of life (QOL) will be measured using the EPIC-26 instrument according to 
the time points delineated in the Time and Events Table (Section 8.1).37 Expanded 
Prostate Cancer Index Composite (EPIC-26) is a validated prostate cancer-specific 
health-related QOL (HRQOL) instrument that measures urinary, bowel, sexual, and 
hormonal symptoms related to prostate cancer treatments, including prostatectomy, 
radiotherapy, and hormonal therapy. Summary and subscale scores were derived 
by content and factor analyses. Test-retest reliability and internal consistency were 
high for EPIC urinary, bowel, sexual, and hormonal domain summary scores (each 
r ≥ 0.80 and Cronbach's alpha ≥ 0.82) and for most domain-specific subscales. 
Correlations between function and bother subscales within domains were high (r > 
0.60). Correlations between different primary domains were consistently lower, 
indicating that these domains assess distinct HRQOL components. 
 
Another scoring protocol to assess the quality of life is the Prostate Cancer 
Symptom Indices (PCSI). This assessment will be performed per timing described 
in the Time and Events Table (Section 8.1). The PCSI has 4 domains: urinary 
obstruction and irritation (5 items), urinary incontinence (3 items), sexual 
dysfunction (5 items), and bowel problems (6 items). Each domain is scored from 

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0 to 100, with a higher score indicating more or worse dysfunction. Minimal 
clinically important differences for PCSI domains have not been defined. Parallel 
to each of the 4 domains are additional questions that ask patients about the 
magnitude of bother related to urinary obstruction and irritation, urinary 
incontinence, sexual, and bowel symptoms. In addition to numerical scoring for 
each domain described above, the PCSI has established functional levels (normal, 
intermediate, and poor) that incorporate the symptom as well as bother questions. 
These function levels complement the score reporting because QOL score changes 
are well recognized to be difficult for patients and physicians to interpret. Normal 
function describes a patient with essentially no dysfunction or distress in a domain 
(eg, normal function in the urinary incontinence domain describes a man who has 
full urinary control without incontinence). Intermediate function describes a patient 
with at least 1 distressful symptom but none very distressful (e.g., intermediate 
urinary incontinence represents leaking only at certain times, and no more than a 
few drops). Poor function describes patients with at least 1 very distressful 
symptom (eg, poor sexual function represents no erections capable of intercourse 
or a lot of difficulty getting and keeping an erection). This classification adds 
clinical meaning to numerical scores, and also allowed analysis of QOL outcomes 
stratified by each participant’s baseline level. Effect sizes between functional levels 
of the PCSI are large. 
 
 
 

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8.0 
EVALUATIONS AND ASSESSMENTS 
8.1 
Time and Events Table 
Study Assessments  
Pre-
radiation1 
Radiation 
Therapy 
1, 3, 6, 9, 12 
months post-
radiation1,3 
2-5 years 
post-
radiation1, 3 
Assessment, consultation 
X 
 
 
 
Informed Consent 
X 
 
 
 
History and PE1 
X 
 
 
X 
Performance Status 
X 
 
 
X 
Quality of Life2 
X 
 
X 
X 
Toxicity Evaluations3 
X 
 
X 
X3 
PSA Measurements 
X 
 
X 
X 
PSMA-PET/MRI+CT4 
X 
 
 
 
CBC, coagulations5, CMP 
X 
 
 
 
Fiducials6 
 
X 
 
 
Radiation planning7 
 
X 
 
 
Androgen deprivation therapy8 
X 
 
Radiation Therapy9 
 
X 
 
 
Biopsy10 
 
X 
 
 
Footnotes to Time and Events Table 
1. History and physical exam may be performed within 8 weeks prior to day 1 of study treatment.  
Other evaluations must be performed within 8 weeks priors to Day 1 (D1) of study treatment.  
Screening labs performed within 8 weeks prior to D1 of study treatment do not need to be 
repeated on D1. A window of +/- 30 days applies to all study visits unless otherwise specified. 
2. EPIC-26 (A.4 
Quality of Life according to EPIC-26) and PCSI (A.5  
The 
local Quality of Life questionnaire) 
3. Subject will be regularly followed and seen by the treating physician every 6 months for up to 
5 years after treatment. Patients who have an ongoing ≥grade 2 or serious AE (SAE) will 
continue to be followed until the event is resolved or deemed irreversible by the investigator.   
4. PSMA-PET/MRI+CT should be no later than the day of starting ADT.  
5. INR or PT and PTT 
6. During CK-SBRT, the subject will have MRI-compatible fiducials (e.g. gold) placed into the 
prostate by the radiation oncologist. These will be used for image guided radiation therapy.  
7. The irradiation technique will be a combination of EBRT and BT. The highest planning priority 
will be to satisfy the restrictions of the bowel, rectum and bladder. Refer to Section 6.1.1.3 for 
additional details including dose on target volumes and planning priorities.  
8. Androgen deprivation therapy will start no earlier than the same day of the PSMA-PET/CT 
scan. Duration per standard of care.  
9. Radiation therapy will consist of: 
a. 
5 weeks of external beam radiation (EBRT). Typically 8 weeks after initiation of ADT. 
i. Prostate +/- pelvic LNs (determined by radiographic findings): 1.8 Gy/fx x 25fx 
ii. Regional radiographically pos LNs: 2.25 Gy/fx x 25 fx 
b. SBRT with CyberKnife 
i. DIL: 8.0 Gy/fx x 3fx. 
10. At time of fiducial markers placement, prostate GTVs (i.e. DILs) will be biopsied. Refer to 
Section 7.2.3 for additional details. 

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8.2 
Pre-Study Assessments 
Patients will undergo the standard UNC work up for patients diagnosed with 
unfavorable intermediate/high-risk prostate cancer. They will undergo the standard 
pre-treatment evaluations for external beam radiotherapy and SBRT and androgen 
deprivation therapy. Their care will not deviate from any other patient that comes 
through the multi-disciplinary clinic. 
8.3 
Treatment Assessments 
Patients will undergo the standard UNC treatment assessment for patients with 
unfavorable intermediate/high-risk prostate cancer under treatment. They will 
undergo the treatment assessments for external beam radiotherapy and SBRT and 
androgen deprivation therapy. Their care will not deviate from any other patient 
that comes through the radiation oncology clinic. 
8.4 
Post-Treatment/Follow-up Assessments 
Subjects will be followed for five years after radiation therapy, with a final study 
follow-up visit at 5 years after the end of treatment. Subjects who have an ongoing 
≥grade 2 or serious AE (SAE) will continue to be followed until the event is 
resolved or deemed irreversible by the investigator.   
8.5 
Early Termination Visit 
Subjects may withdraw voluntarily from participation in the study at any time.  
Subjects may also withdraw voluntarily from receiving the study intervention for 
any reason.  No specific evaluations will be required in the setting of early 
termination.  
8.6 
Assessment of Safety  
All patients who received treatment (i.e. radiation) will be evaluated for toxicity at 
specified time points throughout the study; toxicity will be measured according to 
CTCAE version 5.0. 
8.7 
Assessment of Efficacy 
Patients will be followed with routine PSA tests at follow up visits, as is standard 
practice.  
8.7.1 Other Efficacy Parameters 
Biochemical control after radiation is measured by PSA and defined by the Phoenix 
criteria.33 
 
 

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9.0 
ADVERSE EVENTS 
9.1 
Definitions  
9.1.1 Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal 
laboratory finding, symptom, or disease temporally associated with the use of a 
drug) in a patient or clinical investigation subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not related to the medicinal product.   
 
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) need not be considered AEs 
and should not be recorded as an AE.  Disease progression should not be recorded 
as an AE, unless it is attributable by the investigator to the study therapy. 
9.1.2 Suspected Adverse Reaction (SAR) 
A suspected adverse reaction (SAR) is any AE for which there is a reasonable 
possibility that the drug is the cause.   Reasonable possibility means that there is 
evidence to suggest a causal relationship between the drug and the AE.  A suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.   
 
Causality assessment to a study drug is a medical judgment made in consideration 
of the following factors: temporal relationship of the AE to study drug exposure, 
known mechanism of action or side effect profile of study treatment, other recent 
or concomitant drug exposures, normal clinical course of the disease under 
investigation, and any other underlying or concurrent medical conditions.  Other 
factors to consider in considering drug as the cause of the AE: 
• Single occurrence of an uncommon event known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome) 
• One or more occurrences of an event not commonly associated with drug 
exposure, but otherwise uncommon in the population (e.g., tendon rupture); 
often more than once occurrence from one or multiple studies would be 
needed before the sponsor could determine that there is reasonable 
possibility that the drug caused the event.   
• An aggregate analysis of specific events observed in a clinical trial that 
indicates the events occur more frequently in the drug treatment group than 
in a concurrent or historical control group 
9.1.3 Unexpected AE or SAR 
An AE or SAR is considered unexpected if the specificity or severity of it is not 
consistent with the applicable product information (e.g., Investigator’s Brochure 

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(IB) for an unapproved investigational product or package insert/summary of 
product characteristics for an approved product).  Unexpected also refers to AEs or 
SARs that are mentioned in the IB as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically 
mentioned as occurring with the particular drug under investigation.   
9.1.4 Serious AE or SAR 
An AE or SAR is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
• Death; 
• Is life-threatening (places the subject at immediate risk of death from 
the event as it occurred); 
• Requires inpatient hospitalization (>24 hours) or prolongation of 
existing hospitalization;* 
• Results in congenital anomaly/birth defect; 
• Results in a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions; 
• Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a serious 
adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in 
the definition.  For reporting purposes, also consider the occurrences of 
pregnancy as an event which must be reported as an important medical 
event. 
 
*Hospitalization for anticipated or protocol specified procedures such as 
administration of chemotherapy, central line insertion, metastasis interventional 
therapy, resection of primary tumor, or elective surgery, will not be considered 
serious adverse events. 
9.2 
Documentation of non-serious AEs or SARs 
For non-serious AEs or SARs, documentation must begin from day 1 of study 
treatment (i.e. radiation) and continue through the 5-year follow-up period after 
treatment is discontinued.   
 
Collected information should be recorded in the Case Report Forms (CRF) for that 
patient.  Please include a description of the event, its severity or toxicity grade, 
onset and resolved dates (if applicable), and the relationship to the study drug.    
Documentation should occur at least monthly.  

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9.3 
SAEs or Serious SARs  
9.3.1 Timing 
After informed consent but prior to initiation of study medications, only SAEs 
caused by a protocol-mandated intervention will be collected (e.g. SAEs related to 
invasive procedures such as biopsies, medication washout.  
 
For any other experience or condition that meets the definition of an SAE or a 
serious SAR, recording of the event must begin from day 1 of study treatment (i.e. 
radiation) and continue through the 5 year follow-up period after treatment is 
discontinued.  
9.3.2 Documentation and Notification 
SAEs or Serious SARs must be recorded in the SAE console within Oncore™ for 
that patient within 24 hours of learning of its occurrence.  Additionally, the UNC 
Study Coordinator must also be notified via email of all SAEs within 24 hours of 
learning of its occurrence. 
9.4 
 Adverse Event Reporting  
9.4.1 IRB Reporting Requirements: 
The UNC-IRB will be notified of all SAEs that qualify as an Unanticipated Problem 
as per the UNC IRB Policies using the IRB’s web-based reporting system within 7 
days of the Investigator becoming aware of the problem.  Please note, these events 
must be reported to the sponsor within 24 hours of learning of the occurrence. 
 
9.4.2 FDA Expedited Reporting requirements for studies conducted under an 
IND:  
A sponsor must report any suspected adverse reaction that is both serious and 
unexpected to the FDA. The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between 
the drug and the adverse event. SARs are defined in Section 9.1.2. 
 
The sponsor must submit each IND safety report on FDA Form 3500A. Each 
notification to FDA must bear prominent identification of its contents, i.e., “IND 
Safety Report,” and must be transmitted to the review division that has the 
responsibility for review of the IND. In each IND safety report, the sponsor must 
identify all IND safety reports previously submitted to FDA concerning a similar 
suspected adverse reaction, and must analyze the significance of the suspected 
adverse reaction in light of previous, similar reports or any other relevant 
information.  
 
Timing 
FDA must be notified of potential serious risks within 15 calendar days after the 
sponsor determines the event requires reporting. FDA must be notified of 

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unexpected fatal or life-threatening suspected adverse reactions as soon as possible 
but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information. The sponsor must be notified of the SAE by the investigator within 24 
hours of the event. If the results of a sponsor’s investigation show that an adverse 
event not initially determined to be reportable is reportable, the sponsor must report 
such suspected adverse reaction in an IND safety report as soon as possible, but in 
no case later than 15 calendar days after the determination is made. 
 
Follow-up 
The sponsor must promptly investigate all safety information it receives. Relevant 
follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., “Follow-up IND Safety 
Report.” Additionally, upon request from FDA, the sponsor must submit to FDA 
any additional data or information that the agency deems necessary, as soon as 
possible, but in no case later than 15 calendar days after receiving the request.  
 
Notification of Investigators 
The sponsor must notify all participating investigators (i.e., all investigators to 
whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks, from clinical trials or any 
other source, as soon as possible, but in no case later than 15 calendar days after 
the sponsor determines that the information qualifies for reporting.  
 
Process 
If the sponsor deems that an event is both a serious adverse reaction (SAR) AND 
unexpected, it must also (in addition to Oncore) be recorded on the MedWatch Form 
3500A as per 21 CFR 312.32. Unexpected adverse events or adverse reaction refers 
to an event or reaction that is not listed in the investigator’s brochure or is not listed 
at the specificity or severity that has been observed; or if an investigator’s brochure 
is not required or available, is not consistent with the risk information described in 
the general investigation plan or elsewhere in the current IND application.   
 
The MedWatch 3500a form can be accessed at:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm.  
 
(Please be sure and access form 3500a, and not form 3500).  
 
The MedWatch form should also be sent to the IND Specialist within 48 hours of the 
sponsor being aware of the event.  The IND Specialist will submit the IND Safety 
Report via IND serial submission to the FDA review division. 
 
All IND safety reports must be submitted on Form 3500A and be accompanied by 
Form 1571. The FDA must be notified or any unexpected or life-threatening 
suspected adverse reactions as soon as possible, but no later than 7 calendar days of 
learning of the event. 
Additional Reporting Requirements 

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The following additional items must be reported via IND safety report: 
• Findings from other studies. The sponsor must report any findings from 
epidemiological studies, pooled analysis of multiple studies, or clinical 
studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor, that suggest a significant risk to humans exposed 
to the drug.  
• Findings from animal or in vitro testing. The sponsor must report any 
findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, such 
as reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of 
significant organ toxicity t or near the expected human exposure. 
• Increased rate of occurrence of serious suspected adverse reactions. 
 
Additional Guidance 
Please refer to 21CFR312.32 and “Guidance for Industry and Investigators: Safety 
Reporting Requirements for INDs and BA/BE Studies” for additional information 
and reporting requirements. All IND Safety Reports will be submitted in accordance 
with these regulations/guidances.  
9.5 
Data and Safety Monitoring Plan 
The Principal Investigator will provide continuous monitoring of patient safety in 
this trial with periodic reporting to the Data and Safety Monitoring Committee 
(DSMC).  
 
Meetings/teleconferences will be held at a frequency dependent on study accrual, 
and in consultation with the study Biostatistician.  These meetings will include the 
investigators as well as study coordinators, data coordinator, regulatory associates, 
clinical data management associates, and any other relevant personnel the principal 
investigators may deem appropriate.  At these meetings, the research team will 
discuss all issues relevant to study progress, including enrollment, safety, 
regulatory, data collection, etc. 
 
The team will produce summaries or minutes of these meetings. These summaries 
will be available for inspection when requested by any of the regulatory bodies 
charged with the safety of human subjects and the integrity of data including, but 
not limited to, the oversight (Office of Human Research Ethics (OHRE) Biomedical 
IRB, the Oncology Protocol Review Committee (PRC) or the North Carolina 
TraCS Institute Data and Safety Monitoring Board (DSMB).   
 
The UNC LCCC Data and Safety Monitoring Committee (DSMC) will review the 
study on a regular (quarterly to annually) basis, with the frequency of review based 
on risk and complexity as determined by the UNC Protocol Review Committee.  
The UNC PI will be responsible for submitting the following information for 
review: 1) safety and accrual data including the number of patients treated; 2) 
significant developments reported in the literature that may affect the safety of 
participants or the ethics of the study; 3) preliminary response data; and 4) 

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summaries of team meetings that have occurred since the last report.  Findings of 
the DSMC review will be disseminated by memo to the UNC PI, PRC, and the 
UNC IRB and DSMB.   
10.0 STATISTICAL CONSIDERATIONS 
10.1 
Study Design/Study Endpoints 
This will be a prospective, single-arm, non-randomized, phase II study to examine 
the feasibility and acute and late toxicities of standard radiation treatment for 
unfavorable intermediate and high risk prostate cancer - this involves a combination 
of external beam radiation therapy and SBRT-CK and androgen deprivation 
therapy – while using advanced imaging modalities (PSMA/PET-mpMRI) to 
intelligently adapt the radiation fields. The radiation therapy usually takes 2 months 
and the follow up is 60 months, while the duration of the evaluation of the final 
results will be about 12 months after the end of treatment. 
 
There is one primary endpoint:  
(1) Late genitourinary toxicity and gastrointestinal toxicity at 12 months (these will 
be recorded at 1, 3, 6, 9, 12, 24, 36, 48 and 60 months after radiotherapy, 
according to CTCAE v5). 
Table 1 shows an overview of late toxicities in randomized studies of 
conventionally fractionated schemes in primary prostate carcinoma. On average, 
the rate of late GI / GU toxicities of grade 2 or higher averaged a rate of 
approximately 16%. 
 
Table 1 Summary of results from recent clinical trials with 
external beam radiotherapy.  
Study 
138 
239 
340 
441 
542 
643 
Patient # 
296 
151 
101 
478 
372 
1065 
Total dose (Gy) 
76 
76 
75.6 
86.4 
76 
74 
Fractions # 
38 
38 
42 
39 
38 
37 
Dose/fraction (Gy) 
2 
2 
1.8 
2 
2 
2 
Late Reactions – RTOG G2+ 
GI (%) 
9 
22.5 
5.1 
3.7 
8 
13.7 
GU (%) 
19 
13.4 
16.5 
15.5 
24 
9.2 
 
 
 

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Table 2 shows an overview of late toxicities in randomized studies of combination 
external beam radiotherapy and SBRT in primary prostate carcinoma. On average, 
the rate of late Grade 2 or higher GU toxicities is ~11.4% and for GI toxicities ~6%.  
 
Table 2 Summary of results from randomized clinical trials treating with combination 
external beam radiation therapy and SBRT. 
Study 
144 
245 
346 
447 
548 
649 
750 
851 
Patient # 
121 
26 
76 
39 
108 
48 
41 
45 
EBRT dose (Gy) 
45 
44 
46 
45 
45-50.4 
45 
45 
45 
EBRT Fractions # 
25 
20 
23 
25 
25-28 
25 
25 
25 
CK dose (Gy) 
21 
18 or 21 
18 
21 
19.5 
19 or 21 
21 
18-21 
CK Fractions # 
3 
3 
3 
3 
3 
2 
3 
3 
Late Toxicity – Grade 2+ 
GI (%) 
3.4 
4.0 
9.3 
12.8 
5.0 
0.0 
0.0 
13.3 
GU (%) 
20.6 
4.0 
1.4 
10.3 
13.7 
27.0 
11.0 
2.9 
 
We denote 𝑝 the probability that a patient experiences a late grade 2+ GU/GI 
toxicity. We want 𝑝 to be small enough to claim the new imaging strategy 
(PSMA/PET-mpMRI) as feasible with no greater late toxicity. Specifically, the null 
and alternative hypotheses are:  
 
𝐻0: 𝑝≥0.30 𝑣𝑠 𝐻1: 𝑝≤0.15 
That is, we accept the claim that the new strategy is safe if the observed toxicity 
rate is not too high, and hope to reject the claim (H0) with sufficient power when 
the true toxicity rate is about 20%.  With a sample size of 38, we reach 80% 
power to reject (if we observe  ≤ 7 cases with late toxicity) the null hypothesis 
(H0) at alpha = 0.1. To account for 10% loss follow-up, we will enroll 42 patients 
to ensure 38 evaluable patients. 
10.2 
Sample Size and Accrual 
 
Accrual will take place at UNC. The design as proposed in the above section leads 
to 80% power at an alpha level of 10%. Taking into account that the dominant intra-
prostatic lesion (DIL, image-identified tumor in the prostate) can be safely defined 
in around 75% of the patients, and assuming a 10% patient drop-out (non-
evaluable) rate, we will plan to enroll 42 patients in order to achieve the primary 
objective of this study. Based on a previous study conducted with a similar 
population, we anticipate averaged accrual of 2 patients per month, corresponding 
to 21 months to enroll 42 patients out of which we can accrue the 38 evaluable 
patients for this study. 
 
Sequential boundaries will be used to suspend the trial if excessive grade 4 toxicity 
of any type, attributed to the treatment under study, is seen. If the study reaches a 
stopping boundary, it may be terminated by the PI, or submitted to the Data and 
Safety Monitoring Committee with a description of the failures to date and a 
rationale for why the study should be continued.  

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correlation analyses will be conducted to identify biomarkers correlated with the 
diagnosis and the course of the disease, as well as gastrointestinal and urogenital 
toxicity. 
 
In the event of an early termination of this study, the same analysis plan as described 
above will be followed, but based on the data available at the time of study 
termination. 
11.0 STUDY MANAGEMENT 
11.1 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in 
accordance with federally mandated regulations.  The IRB should approve the 
consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply 
with the applicable regulatory requirement(s) and should adhere to Good Clinical 
Practice (GCP) and to ethical principles that have their origin in the Declaration of 
Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent 
form. Each consent form must include all the relevant elements currently required 
by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the patient and the investigator is assured that the 
patient understands the implications of participating in the study, the patient will be 
asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form 
should be signed and personally dated by the patient and by the person who 
conducted the informed consent discussion. 
11.2 
Required Documentation 
Before the study can be initiated at any site, the following documentation must be 
provided to the LCCC Study Coordinator. 
• A copy of the official IRB approval letter for the protocol and informed 
consent 
• IRB membership list 
• CVs and medical licensure for the principal investigator and any sub-
investigators who will be involved in the study. 
• CAP and CLIA Laboratory certification numbers and institution lab 
normal values 

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11.3 
Registration Procedures 
All subjects must be registered with the Lineberger Comprehensive Cancer Center 
via OnCore®. 
11.4 
Data Management and Monitoring/Auditing 
The Department of Radiation Oncology will serve as the coordinating center for 
this trial. Data will be collected through a web based clinical research platform, 
OnCore®.  
 
The sponsor will provide direct access to source data/documents for trial-related 
monitoring, audits, IRB/IEC review, and regulatory inspection. As an investigator 
initiated study, this trial will also be audited by the LCCC compliance committee 
every six or twelve months. It will also be monitored according to LCCC SOPs, 
within 8 weeks of the first patient enrolled, and subsequently every 4 months while 
there are subjects in the treatment period. Monitoring will occur annually once the 
study is closed to accrual and all subjects are in the follow-up period. 
11.5 
Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, 
and well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.   
11.5.1 Emergency Modifications 
UNC investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior UNC or their 
respective institution’s IRB/IEC approval/favorable opinion.   
11.5.2 Single Patient/Subject Exceptions 
Eligibility single subject exceptions are not permitted for Lineberger 
Comprehensive Cancer Center Investigator Initiated Trials under any 
circumstances. Other types of single subject exceptions may be allowed if proper 
regulatory review has been completed in accordance with Lineberger 
Comprehensive Cancer Center’s Single Subject Exceptions Policy. 
11.5.3 Other Protocol Deviations/Violations 
According to UNC’s IRB, a protocol deviation is any unplanned variance from an 
IRB approved protocol that:  
• Is generally noted or recognized after it occurs 
• Has no substantive effect on the risks to research participants 
• Has no substantive effect on the scientific integrity of the research plan 
or the value of the data collected  
• Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance meets 
any of the following criteria:  

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• Has harmed or increased the risk of harm to one or more research 
participants. 
• Has damaged the scientific integrity of the data collected for the study. 
• Results from willful or knowing misconduct on the part of the 
investigator(s). 
• Demonstrates serious or continuing noncompliance with federal 
regulations, State laws, or University policies. 
 
If a deviation or violation occurs please follow the guidelines below: 
 
Protocol Deviations: UNC personnel will record the deviation in OnCore®, and 
report to any sponsor or data and safety monitoring committee in accordance with 
their policies.   
 
Protocol Violations: Violations should be reported by UNC personnel within one 
(1) week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.   
 
Unanticipated Problems: 
Any events that meet the criteria for “Unanticipated Problems” as defined by 
UNC’s IRB must be reported by the study personnel using the IRB’s web-based 
reporting system.   
11.6 
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated 
and documented by the Principal Investigator at UNC.  It should also be noted that 
when an amendment to the protocol substantially alters the study design or the 
potential risk to the patient, a revised consent form might be required.   
11.7 
Record Retention 
Study documentation includes all eCRFs, data correction forms or queries, source 
documents, Sponsor correspondence to Investigators, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction 
of the clinical research study. 
 
Government agency regulations and directives require that all study documentation 
pertaining to the conduct of a clinical trial must be retained by the study 
investigator.  In the case of a study with a drug seeking regulatory approval and 
marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization 
(ICH) region.  In all other cases, study documents should be kept on file until three 
years after the completion and final study report of this investigational study. 

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11.8 
Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally 
overseeing the treatment of all study patients.  The Principal Investigator must 
assure that all study site personnel, including sub-investigators and other study staff 
members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
At the completion of the study, all eCRFs will be reviewed by the Principal 
Investigator and will require his/her final signature to verify the accuracy of the 
data. 
 
 

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12.0 REFERENCES 
1.  
Fendler WP, Eiber M, Beheshti M, et al. Ga-PSMA PET / CT : Joint EANM and 
SNMMI procedure guideline for prostate cancer imaging : version 1 . 0. 2017:1014-
1024. doi:10.1007/s00259-017-3670-z 
2.  
Lieng H, Hayden AJ, Christie DRH, et al. Radiotherapy for recurrent prostate 
cancer : 2018 Recommendations of the Australian and New Zealand Radiation 
Oncology Genito-Urinary group. Radiother Oncol. 2019;129(2):377-386. 
doi:10.1016/j.radonc.2018.06.027 
3.  
Zschaeck S, Lohaus F, Beck M, et al. PSMA-PET based radiotherapy: A review of 
initial experiences, survey on current practice and future perspectives. Radiat Oncol. 
2018;13(1):1-9. doi:10.1186/s13014-018-1047-5 
4.  
Sterzing F, Kratochwil C, Fiedler H, et al. 68Ga-PSMA-11 PET/CT: a new 
technique with high potential for the radiotherapeutic management of prostate 
cancer 
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Eur 
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Nucl 
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doi:10.1007/s00259-015-3188-1 
5.  
Wu S, Boreta L, Shinohara K, et al. Impact of Staging 68Ga-PSMA-11 PET Scans 
on Radiation Treatment Plans in Patients With Prostate Cancer. Urology. 2018:1-9. 
doi:10.1016/j.urology.2018.09.038 
6.  
ROACH PJ, Francis R, Emmett L, et al. The impact of 68 Ga-PSMA PET/CT on 
management intent in prostate cancer: results of an Australian prospective 
multicenter 
study. 
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2017;59(1):jnumed.117.197160. 
doi:10.2967/jnumed.117.197160 
7.  
Dewes S, Schiller K, Sauter K, et al. Integration of 68Ga-PSMA-PET imaging in 
planning of primary definitive radiotherapy in prostate cancer: a retrospective study. 
Radiat Oncol. 2016;11(1):73. doi:10.1186/s13014-016-0646-2 
8.  
Corfield J, Perera M, Bolton D, Lawrentschuk N. 68Ga-prostate specific membrane 
antigen (PSMA) positron emission tomography (PET) for primary staging of high-
risk prostate cancer: a systematic review. World J Urol. 2018;36(4):519-527. 
doi:10.1007/s00345-018-2182-1 
9.  
Budäus L, Leyh-Bannurah SR, Salomon G, et al. Initial Experience of68Ga-PSMA 
PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical 
Prostatectomy. Eur Urol. 2016;69(3):393-396. doi:10.1016/j.eururo.2015.06.010 
10.  
Perera M, Papa N, Roberts M, et al. Gallium-68 Prostate-specific Membrane 
Antigen Positron Emission Tomography in Advanced Prostate Cancer-Updated 
Diagnostic Utility, Sensitivity, Specificity, and Distribution of Prostate-specific 
Membrane Antigen-avid Lesions: A Systematic Review and Meta-analysis. Eur 
Urol. 2019;0(0). doi:10.1016/j.eururo.2019.01.049 
11.  
Lawton CA, DeSilvio M, Roach M, et al. An Update of the Phase III Trial 
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Pommier P, Chabaud S, Lagrange JL, et al. Is There a Role for Pelvic Irradiation in 
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the GETUG-01 Randomized Study. Int J Radiat Oncol Biol Phys. 2016;96(4):759-
769. doi:10.1016/j.ijrobp.2016.06.2455 

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13.  
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Radiotherapeutic Outcome in RTOG 77-06, a phase III Study for T1BN0M0 (A2) 
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Murthy V, Maitre P, Kannan S, et al. Prostate-only versus whole-pelvic radiation 
therapy in high-risk and very high-risk prostate cancer (POP-RT): Outcomes from 
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15.  
RTOG. NCT01368588 RTOG 0924 Androgen Deprivation Therapy and High Dose 
Radiotherapy With or Without Whole-Pelvic Radiotherapy in Unfavorable 
Intermediate or Favorable High Risk Prostate Cancer: A Phase III Randomized 
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of Cabazitaxel and Pelvic Radiotherapy in Patients With Localized Prostate Cancer 
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Nguyen PL, D'Amico AV. Targeting pelvic lymph nodes in men with intermediate- 
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18. 
Roach M 3rd. Targeting pelvic lymph nodes in men with intermediate- and high-
risk prostate cancer, and confusion about the results of the randomized trials. J Clin 
Oncol. 
2008;26(22):3816-3817; 
author 
reply 
3817-8. 
doi: 
10.1200/JCO.2008.17.9879. 
19.  
von Eyben FE, Picchio M, von Eyben R, Rhee H, Bauman G. 68Ga-Labeled 
Prostate-specific 
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Antigen 
Ligand 
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and 
Meta-analysis. 
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Urol 
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doi:10.1016/j.euf.2016.11.002 
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gross tumour volume delineation in radiation treatment planning of primary prostate 
cancer. Eur J Nucl Med Mol Imaging. 2016;43(5):889-897. doi:10.1007/s00259-
015-3257-5 
21.  
Fendler WP, Schmidt DF, Wenter V, et al. 68Ga-PSMA PET/CT Detects the 
Location and Extent of Primary Prostate Cancer. J Nucl Med. 2016;57(11):1720-
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Rhee H, Thomas P, Shepherd B, et al. Prostate Specific Membrane Antigen Positron 
Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric 
Magnetic Resonance Imaging in Localized Prostate Cancer. J Urol. 
2016;196(4):1261-1267. doi:10.1016/j.juro.2016.02.3000 
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PET/MRI Improves the Localization of Primary Prostate Cancer. Eur Urol. 
2016;70(5):829-836. doi:10.1016/j.eururo.2015.12.053 
24.  
Zamboglou C, Schiller F, Fechter T, et al. 68Ga-HBED-CC-PSMA PET/CT versus 
histopathology in primary localized prostate cancer: A voxel-wise comparison. 
Theranostics. 2016;6(10):1619-1628. doi:10.7150/thno.15344 
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Zamboglou C, Drendel V, Jilg CA, et al. Comparison of68Ga-HBED-CC PSMA-

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PET/CT and multiparametric MRI for gross tumour volume detection in patients 
with primary prostate cancer based on slice by slice comparison with 
histopathology. Theranostics. 2017;7(1):228-237. doi:10.7150/thno.16638 
26.  
Hicks RM, Simko JP, Westphalen AC, et al. Diagnostic Accuracy of 68 Ga-PSMA-
11 PET / MRI Compared with Multiparametric MRI in the Detection of Prostate 
Cancer. Radiology. 2018;289:730-737. 
27.  
Lips IM, van der Heide UA, Haustermans K, et al. Single blind randomized Phase 
III trial to investigate the benefit of a focal lesion ablative microboost in prostate 
cancer (FLAME-trial): Study protocol for a randomized controlled trial. Trials. 
2011;12(1):255. doi:10.1186/1745-6215-12-255 
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Al-Mamgani A, van Putten WLJ, Heemsbergen WD, et al. Update of Dutch 
Multicenter Dose-Escalation Trial of Radiotherapy for Localized Prostate Cancer. 
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Randomized Dose-Escalation Trial for Prostate Cancer. Int J Radiat Oncol Biol 
Phys. 2008;70(1):67-74. doi:10.1016/j.ijrobp.2007.06.054 
30. 
Martinez AA, et al. Dose escalation improves cancer-related events at 10 years for 
intermediate- and high-risk prostate cancer patients treated with hypofractionated 
high-dose-rate boost and external beam radiotherapy. Int J Radiat Oncol Biol Phys. 
2011;79(2):363-370. 
31.  
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Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;378(19):1767-1777. 
doi:10.1056/NEJMoa1801993 
33.  
Roach M, Hanks G, Thames H, et al. Defining biochemical failure following 
radiotherapy with or without hormonal therapy in men with clinically localized 
prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus 
Conference. 
Int 
J 
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Oncol 
Biol 
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2006;65(4):965-974. 
doi:10.1016/j.ijrobp.2006.04.029 
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guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. 
Brachytherapy. 2012;11(1):6-19. doi:10.1016/j.brachy.2011.07.005 
35.  
Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS Prostate Imaging – Reporting 
and 
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Eur 
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2016;69(1):16-40. 
doi:10.1016/j.eururo.2015.08.052 
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abbreviated version of the expanded prostate cancer index composite instrument for 
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Pederson AW, Fricano J, Correa D, Pelizzari CA, Liauw SL. Late toxicity after 

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intensity-modulated radiation therapy for localized prostate cancer: an exploration 
of dose-volume histogram parameters to limit genitourinary and gastrointestinal 
toxicity. 
Int 
J 
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doi:10.1016/j.ijrobp.2010.09.058 
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results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol 
Phys. 
2002;53(5):1097-1105. 
http://www.ncbi.nlm.nih.gov/pubmed/12128107. 
Accessed September 15, 2018. 
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Hoffman KE, Voong KR, Pugh TJ, et al. Risk of Late toxicity in men receiving 
dose-escalated hypofractionated intensity modulated prostate radiation therapy: 
Results from a randomized trial. Int J Radiat Oncol Biol Phys. 2014;88(5):1074-
1084. doi:10.1016/j.ijrobp.2014.01.015 
41.  
Spratt DE, Pei X, Yamada J, Kollmeier MA, Cox B, Zelefsky MJ. Long-term 
Survival and Toxicity in Patients Treated With High-Dose Intensity Modulated 
Radiation Therapy for Localized Prostate Cancer. Int J Radiat Oncol. 
2013;85(3):686-692. doi:10.1016/j.ijrobp.2012.05.023 
42.  
Chennupati SK, Pelizzari CA, Kunnavakkam R, Liauw SL. Late toxicity and quality 
of life after definitive treatment of prostate cancer: redefining optimal rectal sparing 
constraints for intensity-modulated radiation therapy. Cancer Med. 2014;3(4):954-
961. doi:10.1002/cam4.261 
43.  
Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated 
high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of 
the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 
2016;17(8):1047-1060. doi:10.1016/S1470-2045(16)30102-4 
44.  
Wang SC, Ting WC, Chang YC, Yang CC, Lin LC, Ho HW, Chu SS, Lin YW. 
Whole Pelvic Radiotherapy With Stereotactic Body Radiotherapy Boost vs. 
Conventionally Fractionated Radiotherapy for Patients With High or Very High-
Risk 
Prostate 
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2020 
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29;10:814. 
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10.3389/fonc.2020.00814.  
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Kim YJ, Ahn H, Kim CS, Kim YS. Phase I/IIa trial of androgen deprivation therapy, 
external beam radiotherapy, and stereotactic body radiotherapy boost for high-risk 
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10.1186/s13014-020-01665-6. 
46.  
Pasquier D, Peiffert D, Nickers P, Maingon P, Pommier P, Lacornerie T, Martinage 
G, Tresch E, Lartigau E. A Multicenter Phase 2 study of Hypofractionated 
Stereostatic Boost in Intermediate Risk Prostate Carcinoma: A 5-Year Analysis of 
the CKNO-PRO Trial. Int J Radiat Oncol Biol Phys. 2020 Jan 1;106(1):116-123. 
doi: 10.1016/j.ijrobp.2019.09.039. 
47. 
Kim HJ, Phak JH, Kim WC. Clinical outcomes of whole pelvis radiotherapy and 
stereotactic body radiotherapy boost for intermediate- and high-risk prostate cancer. 
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48. 
Mercado C, Kress MA, Cyr RA, Chen LN, Yung TM, Bullock EG, Lei S, Collins 
BT, Satinsky AN, Harter KW, Suy S, Dritschilo A, Lynch JH, Collins SP. Intensity-
Modulated Radiation Therapy with Stereotactic Body Radiation Therapy Boost for 
Unfavorable Prostate Cancer: The Georgetown University Experience. Front Oncol. 
2016 May 6;6:114. doi: 10.3389/fonc.2016.00114. 

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49. 
Anwar M, Weinberg V, Seymour Z, Hsu IJ, Roach M 3rd, Gottschalk AR. Outcomes 
of hypofractionated stereotactic body radiotherapy boost for intermediate and high-
risk prostate cancer. Radiat Oncol. 2016 Jan 21;11:8. doi: 10.1186/s13014-016-
0585-y. 
50. 
Lin YW, Lin LC, Lin KL. The early result of whole pelvic radiotherapy and 
stereotactic body radiotherapy boost for high-risk localized prostate cancer. Front 
Oncol. 2014 Oct 31;4:278. doi: 10.3389/fonc.2014.00278. 
51. 
Katz A, Kang J. Stereotactic body radiotherapy with or without external beam 
radiation as treatment for organ confined high-risk prostate carcinoma: a six year 
study. Radiat Oncol. 2014 Jan 1;9:1. doi: 10.1186/1748-717X-9-1. 
 
 
  
 
 

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13.0 APPENDICES 
A.1 
NCCN Risk Stratification 
 
Unfavorable intermediate risk disease:  
• T2b-T2c OR 
• Gleason score 3+4=7/grade group 2 or Gleason score 4+3=7/grade 
group 3 OR 
• PSA 10-20 ng/mL 
 
 
High risk disease: 
• T3a OR 
• Gleason score 8/grade group 4 or Gleason score 4+5=9/grade group 5 
OR 
• PSA>20 ng/mL 
 
 
 
 

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A.3 
Toxicity according to CTCAE 
Common Terminology Criteria for Adverse Events (CTCAE v5) 
Source: https://evs.nci.nih.gov/ftp1/CTCAE/About.html  
 
 
 
MedDRA Code
MedDRA SOC
CTCAE Term
Grade 1   
Grade 2   
Grade 3   
Grade 4   
Grade 5   
10002153
Gastrointestinal disorders
Anal fissure
Asymptomatic
Symptomatic
Invasive intervention indicated
 -
 -
10002156
Gastrointestinal disorders
Anal fistula
Asymptomatic
Symptomatic, invasive intervention not 
indicated
Invasive intervention indicated
Life-threatening consequences; 
urgent intervention indicated
Death
10055226
Gastrointestinal disorders
Anal hemorrhage
Mild symptoms; intervention not indicated
Moderate symptoms; intervention indicated
Transfusion indicated; invasive intervention 
indicated; hospitalization
Life-threatening consequences; 
urgent intervention indicated
Death
10065721
Gastrointestinal disorders
Anal mucositis
Asymptomatic or mild symptoms; 
intervention not indicated
Symptomatic; medical intervention indicated; 
limiting instrumental ADL
Severe symptoms; limiting self care ADL
 -
 -
10065722
Gastrointestinal disorders
Anal necrosis
 -
 -
TPN or hospitalization indicated; invasive 
intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10002167
Gastrointestinal disorders
Anal pain
Mild pain
Moderate pain; limiting instrumental ADL
Severe pain; limiting self care ADL
 -
 -
10002176
Gastrointestinal disorders
Anal stenosis
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function
Symptomatic and severely altered GI function; 
non-emergent operative intervention 
indicated; TPN or hospitalization indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10002180
Gastrointestinal disorders
Anal ulcer
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function
Severely altered GI function; TPN indicated; 
elective invasive intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10009995
Gastrointestinal disorders
Colonic fistula
Asymptomatic
Symptomatic, invasive intervention not 
indicated
Invasive intervention indicated
Life-threatening consequences; 
urgent intervention indicated
Death
10009998
Gastrointestinal disorders
Colonic hemorrhage
Mild symptoms; intervention not indicated
Moderate symptoms; intervention indicated
Transfusion indicated; invasive intervention 
indicated; hospitalization
Life-threatening consequences; 
urgent intervention indicated
Death
10010000
Gastrointestinal disorders
Colonic obstruction
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function
Hospitalization indicated; invasive intervention 
indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10010001
Gastrointestinal disorders
Colonic perforation
 -
Invasive intervention not indicated
Invasive intervention indicated
Life-threatening consequences; 
urgent intervention indicated
Death
10010004
Gastrointestinal disorders
Colonic stenosis
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function
Severely altered GI function; tube feeding or 
hospitalization indicated; elective operative 
intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10010006
Gastrointestinal disorders
Colonic ulcer
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function
Severely altered GI function; TPN indicated; 
elective invasive intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10010774
Gastrointestinal disorders
Constipation
Occasional or intermittent symptoms; 
occasional use of stool softeners, laxatives, 
dietary modification, or enema
Persistent symptoms with regular use of 
laxatives or enemas; limiting instrumental ADL
Obstipation with manual evacuation indicated; 
limiting self care ADL
Life-threatening consequences; 
urgent intervention indicated
Death
10012727
Gastrointestinal disorders
Diarrhea
Increase of <4 stools per day over baseline; 
mild increase in ostomy output compared to 
baseline
Increase of 4 - 6 stools per day over baseline; 
moderate increase in ostomy output compared 
to baseline; limiting instrumental ADL
Increase of >=7 stools per day over baseline; 
hospitalization indicated; severe increase in 
ostomy output compared to baseline; limiting 
self care ADL
Life-threatening consequences; 
urgent intervention indicated
Death
10036774
Gastrointestinal disorders
Proctitis
Rectal discomfort, intervention not indicated
Symptomatic (e.g., rectal discomfort, passing 
blood or mucus); medical intervention 
indicated; limiting instrumental ADL
Severe symptoms; fecal urgency or stool 
incontinence; limiting self care ADL
Life-threatening consequences; 
urgent intervention indicated
Death
10064993
Gastrointestinal disorders
Rectal fissure
Asymptomatic
Symptomatic
Invasive intervention indicated
 -
 -
10038062
Gastrointestinal disorders
Rectal fistula
Asymptomatic
Symptomatic, invasive intervention not 
indicated
Invasive intervention indicated
Life-threatening consequences; 
urgent intervention indicated
Death
10038064
Gastrointestinal disorders
Rectal hemorrhage
Mild symptoms; intervention not indicated
Moderate symptoms; intervention indicated
Transfusion indicated; invasive intervention 
indicated; hospitalization
Life-threatening consequences; 
urgent intervention indicated
Death
10063190
Gastrointestinal disorders
Rectal mucositis
Asymptomatic or mild symptoms; 
intervention not indicated
Symptomatic; medical intervention indicated; 
limiting instrumental ADL
Severe symptoms; limiting self care ADL
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10065709
Gastrointestinal disorders
Rectal necrosis
 -
 -
Tube feeding or TPN indicated; invasive 
intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10065707
Gastrointestinal disorders
Rectal obstruction
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function; limiting 
instrumental ADL
Hospitalization indicated; invasive intervention 
indicated; limiting self care ADL
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10038072
Gastrointestinal disorders
Rectal pain
Mild pain
Moderate pain; limiting instrumental ADL
Severe pain; limiting self care ADL
 -
 -
10038073
Gastrointestinal disorders
Rectal perforation
 -
Invasive intervention not indicated
Invasive intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10038079
Gastrointestinal disorders
Rectal stenosis
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function
Severely altered GI function; tube feeding or 
hospitalization indicated; elective operative 
intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10038080
Gastrointestinal disorders
Rectal ulcer
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; altered GI function (e.g., altered 
dietary habits, vomiting, diarrhea)
Severely altered GI function; TPN indicated; 
elective invasive intervention indicated
Life-threatening consequences; 
urgent operative intervention 
indicated
Death
10063575
Renal and urinary disorders
Bladder perforation
 -
Invasive intervention not indicated
Invasive intervention indicated
Life-threatening consequences; 
organ failure; urgent operative 
intervention indicated
Death
10048994
Renal and urinary disorders
Bladder spasm
Intervention not indicated
Antispasmodics indicated
Hospitalization indicated
 -
 -
10063057
Renal and urinary disorders
Cystitis noninfective
Microscopic hematuria; minimal increase in 
frequency, urgency, dysuria, or nocturia; new 
onset of incontinence
Moderate hematuria; moderate increase in 
frequency, urgency, dysuria, nocturia or 
incontinence; urinary catheter placement or 
bladder irrigation indicated; limiting 
instrumental ADL
Gross hematuria; transfusion, IV medications, 
or hospitalization indicated; elective invasive 
intervention indicated
Life-threatening consequences; 
urgent invasive intervention 
indicated
Death
10013990
Renal and urinary disorders
Dysuria
Present
 -
 -
 -
 -
10068405
Renal and urinary disorders
Glucosuria
Present
 -
 -
 -
 -
10019450
Renal and urinary disorders
Hematuria
Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic; urinary catheter or bladder 
irrigation indicated; limiting instrumental ADL
Gross hematuria; transfusion, IV medications, 
or hospitalization indicated; elective invasive 
intervention indicated; limiting self care ADL
Life-threatening consequences; 
urgent invasive intervention 
indicated
Death
10065368
Renal and urinary disorders
Urinary fistula
 -
Symptomatic, invasive intervention not 
indicated
Invasive intervention indicated
Life-threatening consequences; 
urgent invasive intervention 
indicated
Death
10046539
Renal and urinary disorders
Urinary frequency
Present
Limiting instrumental ADL; medical management 
indicated
 -
 -
 -
10046543
Renal and urinary disorders
Urinary incontinence
Occasional (e.g., with coughing, sneezing, 
etc.), pads not indicated
Spontaneous; pads indicated; limiting 
instrumental ADL
Intervention indicated (e.g., clamp, collagen 
injections); operative intervention indicated; 
limiting self care ADL
 -
 -
10046555
Renal and urinary disorders
Urinary retention
Urinary, suprapubic or intermittent catheter 
placement not indicated; able to void with 
some residual
Placement of urinary, suprapubic or intermittent 
catheter placement indicated; medication 
indicated
Elective invasive intervention indicated; 
substantial loss of affected kidney function or 
mass
Life-threatening consequences; 
organ failure; urgent operative 
intervention indicated
Death
10061574
Renal and urinary disorders
Urinary tract obstruction Asymptomatic; clinical or diagnostic 
observations only; intervention not indicated
Symptomatic but no hydronephrosis, sepsis, or 
renal dysfunction; urethral dilation, urinary or 
suprapubic catheter indicated
Altered organ function (e.g., hydronephrosis 
or renal dysfunction); invasive intervention 
indicated
Life-threatening consequences; 
urgent intervention indicated
Death
10062225
Renal and urinary disorders
Urinary tract pain
Mild pain
Moderate pain; limiting instrumental ADL
Severe pain; limiting self care ADL
 -
 -
10046593
Renal and urinary disorders
Urinary urgency
Present
Limiting instrumental ADL; medical management 
indicated
 -
 -
 -
10046628
Renal and urinary disorders
Urine discoloration
Present
 -
 -
 -
 -

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A.4 
Quality of Life according to EPIC-26 
The Expanded Prostate Cancer Index Composite (EPIC-26) scoring protocol was 
designed to measure Quality of Life issues in patients with Prostate cancer. 
 
 

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CONFIDENTIAL 
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UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
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A.5  
The local Quality of Life questionnaire 
 
Prostate Cancer Symptom Indices (PCSI): The Quality of Life (QoL) questionnaire 
that is given to the patients before the beginning of their radiation therapy.  
 
 

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A.6 
Sequences of the mpMRI protocol 
 
Sequence 
 
Plane 
TR* TE** Flip 
Angle 
Thickness/Gap FOV*** Matrix 
Localizer 
 
3-plane 
 
 
 
 
 
 
SS-ETSE# 
 
 
Coronal 
1500 85 
170 6 mm/20% 
350–400 192 × 
256 
SS-ETSE 
 
 
Axial 
1500 85 
170 6 mm/20% 
350–400 192 × 
256 
SS-ETSE 
 
 
Sagittal 
1500 85 
170 6 mm/20% 
350 
192 × 
256 
SS-ETSE fat-
suppressed 
 
 
Axial 
1500 85 
170 8–10 mm/20% 350–400 192 × 
256 
T1 TSE  
 
Axial 
647 
11 
140  3 mm  
180 
256x256 
T2 TSE (0.7 x 0.7 x 3.0 
mm)+ 
Axial 
8500 94 
120 3 mm 
230 
320x240 
T2 TSE (0.4 x 0.4 x 3.0 
mm)+ 
Coronal 
8500 115 120 3 mm 
230 
320x240 
T2 TSE (0.7 x 0.7 x 3.0 
mm)+ 
Sagittal 
8500 115 120 3 mm 
230 
320x240 
Diffusion Weighted 
Imaging  
(1 x 1 x 4 mm)+ (b50 
800 1500)@ 
Axial 
3400 71 
90 
4 mm 
260 
128 x 
128 
Post-Gadolinium 
Sequences 
 
 
 
 
 
 
 
 
T1 3D GE DCE (80 
measurements) 
Axial 
3.05 1.06 12 
3 mm 
250 
128x128 
T1 3D GE fat-
suppressed*  
 
 
Axial / 
Coronal / 
Sagittal 
3.8 
1.7 
10 
3 mm 
350–400 160 × 
256 
 
*TR: Repetition time. 
**TE: Echo time 
***FOV: Field of view. 
#SS-ETSE: Single shot echo train spin echo 

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CONFIDENTIAL 
PI: Michael Repka MD 
 
UNIVERSITY OF NORTH CAROLINA 
 
 
 
July 24, 2024 
51 
 
TR between slice acquisitions. 
&SGE: Spoiled gradient echo 
$3D GE: Three dimensional gradient echo 
*Optional: T1 TSE fat-suppressed images could also be acquired in two planes including 
axial and sagittal planes. 
+Voxel size 
@b values