Stereotactic Body Radiation Therapy and Short-Term Androgen Ablation for Intermediate-Risk, Localized, Adenocarcinoma of the Prostate
Phase: PHASE1
Conditions: Adenocarcinoma of the Prostate
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
1 
 
Cover Page 
 
 
Clinical Protocol: Stereotactic Body Radiation Therapy and Short-Term 
Androgen Ablation for Intermediate-Risk, Localized Adenocarcinoma of the 
Prostate  
 
NCT Number: NCT01517451 
 
Version Date: 12/20/2021 
 
RE: Protocol with included statistical plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
2 
 
Clinical Protocol: Stereotactic Body Radiation Therapy and Short-Term Androgen Ablation for 
Intermediate-Risk, Localized Adenocarcinoma of the Prostate  
 
Phase: Phase I/II  
 
Coordinating Center  
Principal Investigator:  
Danny Song, MD (Johns Hopkins) 
Department of Radiation Oncology and Molecular Radiation Sciences  
Johns Hopkins University School of Medicine  
401 N Broadway, Suite 1440 
Baltimore, MD 21231  
Phone: (410) 502-5875 
Fax: (410) 502-1419  
Email: dsong2@jhmi.edu 
 
Co-Investigators:  
 
Theodore L. DeWeese, MD (Johns Hopkins) 
Russell Hales, MD (Johns Hopkins) 
Stephen Greco, MD (Suburban) 
Fariba Asrari, MD (Green Spring) 
Greg Sibley, MD (Sibley) 
Curtiland Deville, MD (Sibley) 
 
Other personnel:  
  
Dana Kaplin (Research Manager)  
Shirl DiPasquale, RN (Study Nurse)  
Peng Huang, PhD (Statistician) 
 
Time required to complete the study accrual: The study is expected to begin June 2013 and be 
completed August 2015. 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
3 
Table of Contents 
 
 
1.0 
 BACKGROUND AND RATIONALE……………………………………………..4 
2.0  
OBJECTIVES………………………………………………………………………..6 
3.0  
PATIENT SELECTION………………………………………………………….....7 
4.0  
PRETREATMENT EVALUATIONS……………………………………………...8 
5.0  
RADIATION THERAPY AND RESEARCH INTERVENTIONS………………9 
6.0  
PATIENT ASSESSMENTS………………………………………………………..12 
7.0 
STUDY CALENDAR………………………………………………………………14 
8.0  
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS………………..16 
9.0  
ACCRUAL AND STUDY DURATION…………………………………………...18 
10.0  
REPORTING OF SERIOUS OR UNEXPECTED ADVERSE EVENTS………18 
11.0  
DISPOSTION OF DATA…………………………………………………………...19 
12.0  
PROTOCOL MODIFICATIONS………………………………………………….19 
13.0  
DEPARTURE FROM PROTOCOL………………………………………………19 
14.0  
CRITERIA FOR WITHDRAWAL FROM STUDY……………………………..20 
15.0  
ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL……………….20 
16.0 
PARTICIPATING SITES GUIDELINES…………………………………………21 
17.0  
ETHICAL AND REGULATORY CONSIDERATIONS………………………...25 
18.0  
DATA SAFETY AND MONITORING PLAN……………………………………26 
19.0  
LIST OF DATA COLLECTION SHEETS……………………………………….26 
20.0  
REFERENCES………………………………………………………………………27 
 
APPENDIX A………………………………………………………………………..28 
  
APPENDIX B……………………………………………………………………..…30 
 
APPENDIX C……………………………………………………………………..…31

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
4 
1.0 BACKGROUND AND RATIONALE  
 
Radiation therapy is an effective and frequently utilized modality for the treatment of clinically 
localized prostate cancer. Traditionally, external beam radiation has been delivered in a fractionated 
manner using daily doses of 1.8-2.0 Gy. This daily dose was derived from early animal experiments 
and clinical experience, supported by mathematical models of normal tissue and tumor response to 
fraction size. The most widely used of these models is the linear-quadratic formula, which predicts 
responses to different fraction sizes based on the alpha/beta ratio of any given tissue.1  
 
One of the main motivations for delivering a treatment at low dose rate or with many fractions is that 
late-responding normal tissue are generally more sensitive than early-responding tissues (i.e. tumor) 
to increases in fraction size. So increasing the number of fractions generally spares late-responding 
tissues more than the tumor. This can be quantified in terms of the alpha/beta (α/β) ratio :  
 
• Small alpha/beta (α/β) ratio (2-4 Gy), typical of late sequelae, means high sensitivity to large doses 
given per fraction.  
• Large alpha/beta (α/β) ratio (>8 Gy), typical of tumor control, means low sensitivity to fractionation 
changes.  
 
It is generally assumed that the mechanistic basis for the different fractionation response of tumors 
and late-responding normal tissues relates to the larger proportion of cycling cells in tumors. But 
prostate tumors contain unusually small fractions of cycling cells.2  Brenner and Hall as well as 
Duchesne and Peters have reasoned that prostate tumors might not respond to changes in 
fractionation in the same way as other cancers; both papers hypothesize that prostate tumors might 
respond to changes in fractionation or dose rate more like a late-responding normal tissue.3,4  In 
mathematical terms, the suggestion is that the alpha/beta ratio for prostate cancer might be low, 
comparable to that for late-responding tissues or even lower.  Previous estimates of alpha/beta ratios 
of normal tissue and tumor tissue have generally been 3 and 10, respectively. Recent evidence has 
estimated the alpha/beta ratio of prostate cancer to be as low as 1.5.  If these hypotheses are true, then 
the optimal therapeutic ratio for prostate cancer would be achieved using daily doses higher than 2 
Gy.5 
 
Recent clinical reports have demonstrated excellent results utilizing high dose, short course radiation 
(or hypofractionated) therapy for prostate cancer.  The typical treatment course lasts between 35 and 
40 treatments for a course of definitive treatment for prostate cancer.  Integrating the calculations 
suggested above, recent studies have evaluated using a definitive course of therapy in a much shorter 
time period with stereotactic body radiation therapy (SBRT).  SBRT incorporates higher doses of 
radiation over a short time course.  Recent publications by King and Boike demonstrate the 
increasing utility of this technology in the treatment of prostate cancer.6,7  King and colleagues 
demonstrated the safety and utility of a 5 day course of radiation therapy using the CyberKnife for 
SBRT treatment in a Phase I-II prospective study.6  The dose utilized was 7.25 Gy in 5 fractions.  
Grade 3 or greater rectal toxicity was seen in only 2 of 32 patients, and 78% of patients achieved a 
PSA nadir of ≤ 0.4 ng/mL at a minimum follow-up of 12 months.  Boike and his colleagues in a 
separate Phase I-II study used three different dose regimens of 45 Gy, 47.5 Gy, and 50 Gy in 5 
fractions.7  Grade 3 or greater GI toxicity was seen in ≤ 2% of patients and grade 3 or greater GU 
toxicity was seen in ≤ 4% of patients.  The study noted 100% PSA control by the nadir + 2 ng/mL 
(ASTRO Phoenix) criteria with a short follow-up of 12-30 months.  Both of these studies with short 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
5 
followup suggest safe and successful treatment of prostate cancer with hypofractionated radiation 
utilizing SBRT. 
 
A useful formalism in clinical radiation oncology is using the biologically equivalent dose (BED) 
equation to compare different fractionation schemes: [(n x d x (1 + d/(α/β)]  where n=fraction 
number and d = dose per fraction.  The table below compares the effective doses of different 
fractionation schemes based on the alpha/beta ratios discussed earlier.   If the alpha/beta ratio for 
prostate is between 1.5-3.0, then the King regimen, 7.25 Gy x 5, should be at least as effective or 
more effective for tumor control than 90 Gy given in conventional 2 Gy fractions.  Put in another 
way, if we assume an alpha/beta ratio of 1.5 for the prostate, as shown in the table below we would 
be able to deliver a BED of 211 Gy, as opposed to 187 Gy with standard fractionation (80 Gy in 2 Gy 
fractions).   
 
 
  
Fraction 
Size (Gy) 
#  
Fractions 
Acute 
(10) 
Prostate 
(1.5) 
Prostate 
(3) 
Late 
(3) 
Total 
dose 
(Gy) 
Conventional 
2 
40 
96 
187 
133 
133 
80 
Conventional 
2 
45 
108 
210 
150 
150 
90 
Boike 
10 
5 
100 
383 
217 
217 
50 
Yoshioka 
6 
9 
86 
270 
162 
162 
54 
King  
7.25 
5 
63 
211 
124 
124 
36.25 
 
 
Just as important is the fact that acute and late effect biologically equivalent doses would be lower 
with the fractionation scheme 7.25 Gy x 5 fractions.  Using the BED equation the dose regimen used 
by King and colleagues is calculated to be iso-effective for late effects to a conventionally 
fractionated total dose of 74 Gy, a lower dose than what is typically used in definitive external beam 
treatment currently (which is 78-80 Gy).  Furthermore, the study from King and colleagues suggested 
that patients with every other day fractions had a statistically significant lower rate of GI and GU 
complications.6  Taken altogether, in theory, the King fractionation regimen could offer a higher dose 
for elimination of the patient’s prostate cancer while potentially reducing the side effects currently 
associated with standard fractionation radiotherapy. 
 
Although the results of these hypofractionation studies are promising, they require further validation. 
If the hypothesis that prostate cancer alpha/beta ratio is lower than normal tissue is correct, then the 
optimal fractional dose is likely to be even higher than the doses tested thus far, but if incorrect, the 
result may be increased normal tissue toxicity. 
 
The above studies, while demonstrating an acceptable toxicity profile and good efficacy, were 
completed primarily in low risk prostate cancer patients.  That is, patients in whom there is a greater 
than 90% biochemical progression free survival after treatment.  However, intermediate risk prostate 
cancer have a known lower biochemical progression free survival and cause specific survival and 
strategies composed of conventional fractionated radiation alone are not sufficient.  RTOG 9408 
demonstrated an improved 10 year biochemical progression-free survival with the addition of 4 
months (2 months neoadjuvant and 2 months concurrent) of combined androgen deprivation therapy 
(ADT) with standard fractionated radiation therapy versus standard fractionated radiation alone (74% 
versus 59%, respectively).8  This has since become the standard of care for patients with intermediate 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
6 
risk prostate cancer.  Consequently, the vast majority of patients with intermediate risk prostate 
cancer at our institution are treated with short term androgen deprivation therapy and 8 weeks of 
external beam radiation.  In spite of excellent results with SBRT in the low risk prostate cancer 
population, no studies have addressed androgen deprivation therapy with SBRT in the intermediate 
risk population.  As shown in the figure below, preclinical data suggests that high dose per fraction of 
7 Gy with androgen ablation may have equal and potentially more potent tumoricidal effects then 
more standard fractionated radiation doses given in 2.5 Gy fractions.9  Recent clinical data looking at 
such an approach was published recently by Yoshioka and colleagues who performed a retrospective 
analysis of patients treated at their institution with high dose rate (HDR) brachytherapy to 54 Gy in 9 
fractions and 6 to 12 months of androgen deprivation.10  While brachytherapy and SBRT may not be 
well compared in terms of their toxicity profile, the 5-year PSA control rate in intermediate risk 
patients treated with this protocol was 93%.  Toxicity was also very favorable with no grade 4 or 5 
toxicities and only <5% manageable acute and late GI and GU toxicity. 10 
 
 
 
2.0 OBJECTIVES 
  
2.1 Primary objectives:  
 
Assess 5-year biochemical failure free rate (BFFR) associated with the combined 
hypofractionated dose regimen and ADT. The BFFR is defined as a binary indicator whether 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
7 
PSA has increased by 2 ng/ml or more above the nadir PSA any time before the end of 5 
years. 
 
2.2 Secondary objectives:  
 
1) Assess the incidence of grade 3 or greater late GU and GI toxicity and self-reported quality 
of life data. 
 
2) Assess clinical and pathologic control rates associated with the combined hypofractionated 
dose regimen and ADT using Kaplan-Meier estimates. 
 
3) Collect dose/volume and imaging data to allow normal tissue complication probability 
modeling and targeting assessment for patients treated with hypofractionated radiation 
therapy.  
 
4) Collect whole blood to perform correlative studies for serum cytokine profiling and future 
biomarker studies. 
 
3.0 PATIENT SELECTION: The target population will be patients with a diagnosis of 
adenocarcinoma of the prostate who are seen in consultation in the Department of Radiation 
Oncology (approximately >1000 patients per year).  
 
3.1 Eligibility criteria  
- Age >18 years old 
- Histologically confirmed, locally confined adenocarcinoma of the prostate  
- Patient must fit D’Amico intermediate-risk criteria by clinical stage (T2b-T2c), PSA (10-20 
ng/mL), and/or Gleason score (Gleason 7). 
- The patient has decided to undergo external beam radiation as treatment choice for his 
prostate cancer. 
- Signed study-specific consent form prior to registration  
 
3.2 Exclusion criteria  
- Stage T3-4 disease.  
- Gleason 8 or higher score.  
- PSA > 20 ng/ml.  
- IPSS >15 
- Clinical or Pathological Lymph node involvement (N1). 
- Evidence of distant metastases (M1).  
- Radical surgery for carcinoma of the prostate.  
- Previous Chemotherapy unless intervention was greater than 5 years from beginning 
treatment for prostate cancer.   
- Pelvic radiation therapy.  
- Previous or concurrent cancers other than basal or squamous cell skin cancers or superficial 
bladder cancer unless disease free for at least 5 years.  
- History of inflammatory bowel disease.  
- Major medical or psychiatric illnesses which, in the investigator’s opinion, would prevent 
completion of treatment and would interfere with follow up. 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
8 
- Myocardial infarction or cerebrovascular accident within one year from consultation, or 
other major vascular risk factor which would prevent a patient from receiving appropriate 
androgen deprivation therapy.11 
- Liver function tests (LFTs) greater than twice the upper limit of normal. 
4.0 PRETREATMENT EVALUATIONS 
 
4.1 Subject Screening Procedures:  
- History and physical (including digital rectal examination).  
- Histological diagnosis and Gleason score provided on the pathology report. All patients, per 
institutional policy, will have pathology reviewed at Johns Hopkins.  
- Prostate specific antigen (PSA) within 4 months prior to registration.  
- CT scan or MRI of the pelvis within 6 months prior to registration*. Lymph nodes 
evaluated negative by imaging methods will be classified as NX. Only nodes evaluated 
negative by surgical sampling will be classified as N0. 
- Bone scan within 2 months prior to registration*. 
- Cardiovascular risk assessment if the patient is determined to be “high risk” for a vascular 
event.  
- Quality of life measures: IPSS, SHIM, and modified EPIC bowel questionnaires (See 
Appendix A, B, and C for questionnaires).  
 
* CT/MRI and bone scan optional except for the patients who are: 
1.  Gleason 4+3 
2.  >50% cores positive 
3.  >1 intermediate risk factor (GS 7, PSA >10 and T2b-T2c). 
 
4.2 Registration procedures  
 
4.2.1 Subject Identification: Patient confidentiality will be maintained in accordance with 
Health Information Portability and Accountability Act (HIPAA) guidelines. All participants 
must sign an informed consent that will describe the objectives of the study and potential 
risks. All patient data reported on the case reports forms will be identified by the patient’s 
initials and study code number only. Patients shall not be identified by name. This should 
serve to protect the confidentiality of subjects enrolled on the trial. Clinical data and records 
for all subjects studied including history and physical findings, laboratory data, and results of 
interventions are to be maintained by the investigators in a secure, locked location. 
Computerized data will require password authorization(s) for access.  
 
4.2.2 Description of the Recruitment Process: Potential patients will be approached by 
investigators as identified on the protocol and approved by the IRB. Recruitment is expected 
to be initiated in the clinic, as patients will most likely be approached during routine visits for 
standard clinical care. Discussions regarding trial participation and study specifics will take 
place in private areas. Patients will be provided with the IRB approved consent form and will 
be given as much time as needed to consider study participation, resulting in multiple visits 
or calls with study staff, if necessary. 
 
4.2.3 Description of the Informed Consent Process: Only physicians who are also 
investigators or research nurses listed on the project will perform the informed consent 
interview.  During the informed consent interview the interviewer (investigator physician or 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
9 
research nurse) will take as much time as needed to ensure that the potential subject 
understands the research project and also clearly understands that he does not have to 
participate in this project to receive his cancer treatment at Johns Hopkins. If the patient 
decides to enroll into the research project he will sign an informed consent form. One will be 
for his own records, one will be kept in the Clinical Research Office at Johns Hopkins, and 
the third one will be kept in his medical records. 
 
4.2.4 Registration Procedures 
Eligible patients will be entered on study centrally at the Johns Hopkins Hospital by the Study 
Coordinator.  
To register a patient, the following documents should be completed by the research nurse or 
data manager and sent to the Coordinating Center Study Coordinator via fax or email. 
• 
Source documentation verifying eligibility (PHI will be redacted) 
• 
Eligibility checklist 
• 
Signed patient consent form 
If the patient is deemed eligible for the study, the Study Coordinator will register the patient and assign 
a study number. This registration will be confirmed by a mass email sent out by the Coordinating 
Center Study Coordinator to all participating sites. 
 
5.0 RADIATION THERAPY AND RESEARCH INTERVENTIONS  
Rather than receiving combined 40 fractions of radiation over 8 weeks and 4 months of ADT, 
patients enrolling on the study will receive combined radiation in 5 fractions over 2 weeks and 4 
months of ADT (≥ 1 month prior to radiation therapy). There will be no alteration in what patients 
experience in a treatment session other than a longer (estimated at 2-3 minutes for VMAT and 30 
minutes for CyberKnife) duration of beam-on time.  A schema of the treatment plan is presented 
below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADT (At least 4 weeks pre RT) 
Combination of androgen deprivation therapy (ADT) with an LHRH agonist (goserelin, 
leuprolide, or triptorelin), with at least 2 weeks of bicalutamide prior to RT start. 
SBRT                                       
5 fractions x 7.25Gy = 36.25Gy 
Treatment to be performed every other day.  
*Bicalutamide may be continued through 
duration of RT at the physician’s discretion. 
ADT  
(4 months total) 
Registration 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
10 
5.1 Simulation procedure  
 
5.1.1 Prior to simulation, patients will undergo transrectal or transperineal insertion of at least 
3 gold seeds to improve accuracy in daily prostate alignment and decrease residual 
positioning errors.  Seed placement will occur at least 1 week prior to CT simulation and 
should aim for at least 1 seed at each of the follow 3 locations: right apex, right base, and left 
mid prostate.  Patients are strongly recommended to ask their referring urologist to place the 
seeds.  If the patients referring urologist is unavailable then the patient will be scheduled for 
seed placement at Johns Hopkins. However, fiducials are optional if additional image 
guidance is being used.  
 
5.1.2 Patients will undergo CT simulation and an MRI simulation is preferred but not 
necessary in the Department of Radiation Oncology. Patients will undergo CT simulation at 
two time points.  The first CT simulation is standard of care and will occur prior to radiation 
therapy.  The second will occur during radiation therapy anytime after the third fraction.  The 
second CT simulation is a Quality Assurance (QA) procedure to confirm if there is any 
rotation occurring with the prostate in relation to the seeds placed. Second CT simulation is 
not necessary if patient did not have fiducial placement.  CT slice thickness of 3mm will be 
used.  
Simulation is to be performed in the supine position, with either an alpha cradle or adaptable 
leg bolster. Patients will be instructed to empty their rectum prior to simulation, and to have a 
moderately full bladder (drink 30 cc of water 30-60 minutes prior to simulation). Oral 
contrast will be utilized at the discretion of the treating physician, but in general is 
discouraged given the confounding effect on dose calculation in the radiation planning 
algorithm due to heterogeneity correction.  
In order that extreme rectal filling not be present at the time of the planning CT scan as well 
as during treatment, patients will be advised to: 
a) Take 2 tablespoons of magnesium hydroxide (milk of magnesia) beginning 2 days before 
the date of simulation as well as 6-12 hours prior to daily treatment.  
b) Use gas-reducing agents (such as simethicone or Bean-O) and avoid gas-producing foods 
in order to minimize presence of rectal gas during therapy (as described in handouts provided 
by nursing staff at consultation).  
If a patient is determined to have a distended rectum at the time of initial scanning, patient 
will be given opportunity to evacuate and a repeat CT scan performed until treating physician 
determines it is satisfactory.  
 
5.1.3 A rectal balloon may be inserted at simulation and during daily therapy to minimize 
variability in rectal contents/dosimetry.12 
 
5.2 Target and Normal Tissue Volumes  
The target volume definitions are, for the most part, based upon the ICRU Report 58, Dose 
and Volume Specification for Reporting Interstitial Therapy.  
a) Gross Target Volume (GTV): The GTV is the entire prostate, as well as any extraprostatic 
spread visualized on imaging or clinical examination.  
b) Clinical Target Volume (CTV): In the case of intermediate risk disease, the CTV will 
include the prostate and will also encompass the proximal 1 cm of seminal vesicle (overlap of 
seminal vesicle with 1 cm expansion on prostate; in Pinnacle this can be accomplished by 
contouring entire seminal vesicle, then using auto-expand ROI function with prostate as 
‘source’ and seminal vesicle turned on as ‘avoid exterior’).  

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
11 
c) Planning Target Volume (PTV): The PTV is the CTV plus 3-5 mm margin expansion in all 
directions except posteriorly, for which a 1-3 mm expansion will be utilized.  
d) Rectum will be contoured from approximately the level of the bottom of the ischial 
tuberosities (where the rectum joins the anal canal) superiorly to the rectosigmoid junction 
(generally below the sacroiliac joints, or until the rectum no longer is adjacent to the sacrum 
which is typically greater than 10 cm).  
e) Anus (the inferior-most 3cm of the anorectal canal, or 10 slices on 3mm CT cuts)  
f) Penile bulb (contoured on the proximal/superior 3 slices or 1cm on CT)  
g) Bladder (entire bladder)  
h) Small bowel (contoured up to the level of the top of the sacroiliac joints)  
i) Femoral heads  
 
ROI designation  
Description 
GTV  
Gross Tumor Volume (prostate)  
CTV 
Clinical Target Volume (Prostate plus 
expansion)  
PTV 
Planning Target Volume (CTV plus 
expansion)  
Bladder  
Bladder  
Bulb  
Penile bulb  
Rectum  
Rectum  
Anus 
Anus 
SV  
Seminal Vesicles  
Femur right  
Right Femur  
Femur left  
Left Femur  
 
 
5.3 Treatment planning  
Intensity-modulated radiation will be utilized to achieve a plan meeting the criteria for dose 
coverage of the PTV and minimizing dose to critical structures. Dose-volume histograms 
(DVHs) must be generated for all critical normal structures.  
 
5.3.1 Compliance criteria  
a) No variation (total coverage): Prescription isodose covers greater than or equal to 95% of 
the PTV and 99-100% of the CTV.  
b) Minor variation (marginal coverage): Prescription isodose coverage between 90-95% of 
the PTV and 95-98.9% of the CTV. 
c) Major variation: Prescription isodose coverage less than 90% of PTV or less than 95% of 
CTV.  
 
5.3.2 Dose constraints  
Based on an alpha/beta ratio of 3 for rectum and bladder late toxicity, as well as dose 
constraints for rectal and bladder toxicity as determined from prior studies with conventional 
fractionation, dose constraints for rectum will be:  
a) no more than 50% of rectum receives greater than 50% of the prescribed dose  
b) no more than 20% of rectum receives greater than 80% of the prescribed dose 
c) no more than 10% of rectum receives greater than 90% of the prescribed dose  
d) no more than 5% of rectum receives greater than 100% of the prescribed dose 
e) Dose constraints for bladder will follow the same dose constraints as those outlined above 
for the rectum.  

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
12 
f) femoral head DVH goal is no more than 5% of femoral head receives greater than 40% of 
the prescribed dose 6 
 
5.3.3 Dose Heterogeneity  
a) IMRT/VMAT - Maximum dose to the PTV volume should not exceed prescription dose by 
more than 7% (1 cc <38.78 Gy). Maximum point dose to critical normal structures outside 
the PTV including unspecified tissue should not exceed prescription dose by more than 5% (1 
cc  <38.06 Gy).   
b) CyberKnife - Maximum dose to the PTV volume should not exceed prescription dose by 
more than 20% (1 cc <43.5 Gy). Maximum point dose to critical normal structures outside 
the PTV including unspecified tissue should not exceed prescription dose by more than 5% (1 
cc  <38.06 Gy). 
 
5.4 Image-guided and adaptive therapy  
 
5.4.1. If volumetric modulated arc therapy (VMAT) is used then the patient will be aligned 
with the fiducials* and/or daily cone beam CT scan on the treatment machine.  If a rectal 
balloon is used and requires adjustment, images will be re-taken to ensure appropriate set-up.  
At the completion of each rotation of the treatment gantry, another kV image and/or CBCT 
will be taken to ensure set-up accuracy prior to the initiation of the next rotation.  A total of 
three rotations of the gantry will comprise a single day of treatment (2.42 Gy per rotation 
with three rotations producing a total dose of 7.25 Gy per day). 
 
*Fiducials is optional if additional image guidance is being used  
 
5.4.2. If the CyberKnife is used then image-guided treatment will proceed using the near real-
time tracking features of system. The CyberKnife consists of a 6-MV linear accelerator 
mounted on a robotic arm. A unique feature of the CyberKnife image-guidance system is that 
the robotic arm is automatically repositioned to track the target using stereoscopic in-room 
kV x-ray source and a pair of amorphous silicon flatpanels. 
 
5.5 Androgen Deprivation Therapy (ADT) 
Androgen deprivation therapy, also known as hormonal ablation, is designed to inhibit the 
effects of testosterone on prostate cancer cells.  This will be accomplished by medications 
designed to block testosterone production in the hypothalamus 
(goserelin/leuprolide/triptorelin) and medications designed to block testosterone receptors at 
the cell surface (bicalutamide).  Each of these drugs is approved by the FDA for the treatment 
of prostate cancer.  Goserelin, leuprolide, or triptorelin will be used for four months (≥ 1 
month prior to radiation therapy), with at least two weeks of bicalutamide prior to start of RT.  
Bicalutamide may be continued through the duration of radiation at the physician’s 
discretion.  Doses and drug information may be found at the websites below: 
- Goserelin (Zoladex®) – http://www1.astrazeneca-us.com/pi/zoladex3_6.pdf 
- Leuprolide (Lupron®) - http://pitap.abbott.com/lupron3month22_5mg.pdf  
- Triptorelin (Trelstar®) - 
http://pi.actavis.com/data_stream.asp?product_group=1684
&p=pi&language=E 
- Bicalutamide (Casodex ®) - http://www1.astrazeneca-us.com/pi/casodex.pdf 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
13 
5.6 Patient management during treatment  
All patients will be seen one time by the radiation oncologist during treatment. Radiation 
reactions will be recorded with attention toward the following:  
a) Rectal or small bowel symptomatology (cramping, diarrhea, rectal urgency, hematochezia)  
b) Bladder symptomatology (frequency, urgency, nocturia, dysuria)  
c) Radiation dermatitis  
d) Side effects will be treated based on the discretion of the radiation oncologist, and 
documentation kept in the medical record. Rectal side effects such as diarrhea may be treated 
with diphenoxylate or loperamide. Bladder or rectal spasms can be treated with 
anticholinergic agents or tolterodine. Irritative or obstructive voiding symptoms can be 
managed with alpha-blockers or phenazopyridine. 
 
6.0 PATIENT ASSESSMENTS 
 
6.1 Study Parameters  
- H&P – at initial consult and following treatment protocol 
- PSA – At baseline, 3 and 6 months after treatment, then every 6 months until 3 years, and 
then annually until year 5 
- Testosterone – At baseline, 3 and 6 months after treatment, then every 6 months until 3 
years, and then annually until year 5 
- Bone Scan - at baseline*  
- Pelvic CT or other lymph node assessment - at baseline* 
- Symptom assessment (IPSS, SHIM, modified EPIC sheet, as per Appendix I) – At 
baseline, 3 and 6 months after treatment, then every 6 months until 3 years, and then 
annually until year 5 
- Serum ALT, AST and AP at baseline and one month following initiation of ADT. 
- Optional Blood draw collected at baseline and at 3 and 24 months following treatment 
completion.  Patients who have initiated ADT prior to consent for optional blood samples 
will be ineligible to give extra blood samples. 
- Seed placement of at least 3 gold seeds at least 1 week prior to first CT simulation if 
additional image guidance is not being used 
- CT simulation will occur prior to radiation treatment as standard of care and then again 
during radiation any time after fraction 3 as a QA procedure for monitoring prostate 
rotation in relation to seed placement. However, second CT simulation after fraction 3 is 
only necessary if patient had fiducial placement.  
 
* CT/MRI and Bone scan optional except for the patients who are:  
1. Gleason 4+3 
2. >50% cores positive 
3. >1 intermediate risk factor (GS 7, PSA >10 and T2b-T2c). 
 
Safety run-in phase 
A phase I trial of SBRT in prostate cancer (n=45) composed of 60% intermediate-risk, 
localized patients where 22% of men were treated with androgen deprivation has been 
recently reported (ref. 7).  This trial used considerably higher SBRT doses than our current 
trial (9-10 Gy x5 versus 7.25 Gy x5) and still reported no Grade 3 or 4 GI or GU acute 
toxicities (<90 days).  Therefore, we believe our more modest SBRT fractionation scheme 
of 7.25 Gy x5 is likely safe in combination with androgen deprivation.  To ensure that this 
combination is safe, the first six patients will be treated and analyzed for toxicity for 3 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
14 
months after radiation.  Six patients will be enrolled at the proposed dose of SBRT and 
androgen deprivation therapy and if 0 or 1 patient experiences a dose limiting toxicity (DLT) 
then this regimen will be considered safe (note: accrual will continue while the interim 
analysis is being conducted).  If >1 patient experiences a DLT than this regimen will be 
considered unsafe and the trial will stop at this point.  DLT for the purpose of calculation of 
the maximum tolerated dose (MTD) includes medically unmanageable Grade 3 or any Grade 
4 toxicity with an attribution of probably related to protocol intervention (see section 10.2).   
 
 
 
 
6.2 Follow-up Schedule  
 
6.2.1 Patients will be assessed at three months and at six months after treatment, then every 6 
months until 3 years, then annually until year 5. The patient will be off study after 5 years. 
 
6.2.2 Patients who develop a rise in PSA of greater than 25% and of at least 0.3 ng/ml 
compared to the prior PSA will have PSA drawn every 3 months until PSA either returns to 
nadir value or rises to a value 2 ng/ml or more above the nadir. The nadir PSA is defined as 
the lowest PSA value after initiation of treatment. Time of failure will be the date of the first 
PSA that is 2 ng/ml or more above the nadir.  
 
6.2.3 At any point in time, patients may undergo biopsy for histopathologic assessment of 
disease response, if there is evidence of recurrence. 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
15 
7.0 STUDY CALENDAR 
  
Pre-treatment 
Radiation14 
Follow-Up16 (in time post radiation treatment) 
1 mo 
2 mo 
3 mo 
6 mo 
12 mo 
18 mo 
24 mo 
30 mo 
36 mo 
Year 4 
Year 5 
Initial Consult 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Digital Rectal Exam15 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biopsy12 
 
 
 
 
 
 
 
 
 
 
 
 
 
Histological Diagnosis1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI * 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
Pelvic CT scan * 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
Bone scan * 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiovascular risk assessment 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life measures6 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment9 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker blood draw (optional) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Serum ALT, AST, and AP10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Seed placement7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT Simulation17 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
PSA11 
X2 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Testosterone 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LHRH agonist13 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Bicalutamide8 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
1Histological diagnosis and Gleason score provided on the pathology report. All patients, per institutional policy, will have pathology reviewed at Johns Hopkins 
2PSA within 4 months prior to registration 
3CT scan or MRI of the pelvis within 6 months prior to registration. Lymph nodes evaluated negative by imaging methods will be classified as NX. Only nodes evaluated negative by surgical sampling will 
be classified as N0. 
4Bone scan within 2 months prior to registration 
5Cardiovascular risk assessment if the patient is determined to be "high risk" for vascular event – prior MI or stroke within 5 years 
6IPSS (less than 16 or patient is excluded from trial participation), SHIM, and modified EPIC bowel questionnaires 
7At least 1 week prior to simulation, patients will undergo transrectal or transperineal inserting of at least 3 gold seeds to improve accuracy in daily prostate alignment and decrease residual positioning errors. 
However, if additional image guidance is being used, fiducials will be optional.  
8At least two weeks of bicalutamide at the initiation of hormone therapy and may be continued through the duration of radiation at the physician's discretion. 
9Patients will be seen one time by the radiation oncologist during treatment 
10Serum ALT, AST and AP collected before the initiation of ADT and one month (+/- 14 days) following initiation of ADT 
11Patients who develop a rise in PSA of greater than 25% and of at least 0.3 ng/ml compared to prior PSA will have PSA drawn every 3 months until PSA either returns to nadir value or rises to a value 2 
ng/ml or more above the nadir. The nadir PSA is defined as the lowest PSA value after initiation of treatment. Time of failure will be the date of the first PSA that is 2 ng/ml or more above the nadir. 
12At any point in time, patients may undergo biopsy for histopathologic assessment of disease response, if there is evidence of recurrence. 
13Androgen deprivation therapy will be given for 4 months total, (must be given ≥ 1 month prior to the start of radiation therapy) 
14Radiation will be given in 5 fractions over 2 weeks (treatment to be performed every other day) 
15Rectal exam is required at baseline. During follow-up it is at the discretion of the treating physician 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
16 
16 Follow-up appointments for 1 month, 2 months, and 3 months have a +/- 7 day tolerance window and all other follow-up appointments have a +/- 30 day tolerance window. 
17 CT simulation will occur prior to radiation therapy and then again during radiation therapy as a QA procedure after fraction 3 only if patients had fiducial placement. 
*CT/MRI and bone scan optional except for the patients who are: 
1.  Gleason 4+3 
2.  >50% cores positive 
3.  >1 intermediate risk factor (GS 7, PSA >10 and T2b-T2c). 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
17 
8.0 DATA ANALYSIS AND SPECIAL CONSIDERATIONS  
 
8.1 Primary Analysis:  
The primary objective is to estimate the 5-year biochemical failure free rate (BFFR) 
associated with the combined hypofractionated dose regimen and ADT. The BFFR is 
defined as a binary indicator whether PSA has increased by 2 ng/ml or more above the 
nadir PSA any time before the end of 5 years. The primary analysis will be performed 
by first obtaining the Kaplan-Meier (K-M) estimate of the biochemical failure free 
survival, and then estimating the 5-year biochemical failure free rate (BFFR) from this 
K-M curve together with 95% confidence interval. Greenwood formula will be used to 
calculate the variance of K-M estimate. 
 
8.2 Secondary objectives:  
 
8.2.1. Assess the incidence of grade 3 or greater late GU and GI toxicity and self-reported 
quality of life data.   
 
Kaplan-Meier estimate of the incidence of grade 3 or greater late GU and GI toxicity 
will be constructed together with 95% confidence interval. Patient reported quality of 
life will be summarized using means and standard deviation for continuous measures, 
the contingency tables for categorical measures. 
8.2.2 Assess clinical and pathologic control rates associated with the combined 
hypofractionated dose regimen and ADT.  
 
Assessments will be performed 3 and 6 months after treatment and then every 6 months 
until 3 years, then annually until year 5. These rates will be estimated from Kaplan-
Meier curves together with 95% confidence intervals. 
 
Disease-Free Survival, measured from the date of enrollment to the date of documented 
progression or date of death using Kaplan-Meier estimates. Progression will be 
documented by PSA, bone scan, or biopsies.  
 
Time to Local Progression (TLP) will be measured from the date of enrollment to the 
date of documented local progression using Kaplan-Meier estimates. Patients with new 
palpable abnormality on digital rectal examination or PSA failure at any point in time 
will also be offered biopsy to distinguish between local and distant failures. Patients who 
do not undergo biopsy will be censored at the last point of time they were considered 
locally controlled by digital rectal examination and PSA and considered not evaluable 
for further assessment.  
 
Time to Distant Failure (TDF) will be measured from the date of enrollment to the date 
of documented metastastic disease. Patients who have negative biopsy following PSA 
failure or palpable abnormality will be considered to have only distant failure.  
 
Overall survival (OS), measured from date of enrollment to date of death using Kaplan-
Meier estimates. Every effort will be made to document the cause of death.  
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
18 
8.2.3 Collect dose/volume and imaging data to allow normal tissue complication probability 
modeling and targeting assessment for patients treated with hypofractionated radiation 
therapy and ADT.  
 
Voxel level dose distribution, normal tissue complication, and tumor control will be 
collected. All images will be co-registered and normalized. Functional principal 
component analysis will be used to develop dose response and tumor control models. 
 
8.2.4 To explore the changes in serum levels of inflammatory and angiogenic cytokines as 
biomarkers of treatment response, we will use Bioplex 200 technology to batch analyze a 27 
cytokine panel in paralllel at baseline and after 3 and 24 months of completing treatment.  
The blood collected in one 8 ml serum separation tube (BD vacutainer, lavender-top) will be 
allowed to stand 45-60 minutes and processed within one hour. The tube will be centrifuged 
at 1200g for 10 min in a swing out rotor (approximately 2500rpm). The serum will be 
transferred into a clean empty 15ml tube using Pasteur pipette. The serum will be aliquoted 
into 1.05 ml volume in each cryopreservation vial and stored in –80oC or -20oC freezer.  We 
will process the samples as described previously by our Co-I Dr. Drake13.  Briefly, The 
Bioplex 200 (Bio-Rad, Hercules, CA) platform will be used to determine the absolute 
concentration (in pg/ml) of 27 target proteins in banked sera samples. A multiplexed bead-
based immunoassay is performed in duplicate for each serum sample following the 
manufacturer’s protocols and using the supplied cytokine standards. The concentration of 
each cytokine will be determined using a 5-parameter log curve fit using the supplied 
software. The Human 27-plex panel includes validated assays for IL-1b, IL-1ra, IL-2, IL-4, 
IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL- 13, IL-15, IL-17, eotaxin, basic FGF, G-
CSF, GM-CSF, IFNg, IP-10, MCP-1, MIP1a, MIP1b, PDGF-BB, vascular endothelial 
growth vactor (VEGF), and TNFa.  This data will be correlated with primary and other 
secondary objectives. 
 
8.3 Sample size  
The primary endpoint is the 5-year biochemical failure free rate (BFFR) associated with the 
combined hypofractionated dose regimen and ADT. All patients will be followed for at least 
5 years. We expect to observe 5-year BFFR 85% or higher. The annual dropout rate is 
expected to be at most 1% ~ 2% (or cumulative 5 year dropout rate is less than 10%). If 100 
patients will finish 5 year follow up, the width of 95% confidence interval of BFFR will be 
less than 0.14. To incorporate the dropout rate, the total required sample size will be 110. 
 
 
8.4 Safety monitoring.  
An early stopping boundary will be used to test the hypotheses H0: Rt≤10% versus H1: 
Rt>10% where Rt is the rate of grade 3 or greater on either GU or GI toxicity. We derive the 
one-sided stopping boundary using exact binomial test: at the first stage with 50 patients 
recruited, if 12 or more patients have experienced grade 3 or greater toxicity with an 
attribution of probably related (see section 10.2), the trial will be stopped. Otherwise, the trial 
will continue to recruit all 100 patients. If no more than 16 patients out of total 100 patients 
have experienced grade 3 or greater toxicity as detailed previously, the treatment is 
considered safe for further investigation. Based on EAST 5 (Copyright © 2009 Cytel Inc) 
Bionomial one-sample exact test for single proportion, this stopping rule gives 87% power to 
reject unsafe treatment regime if the true toxicity rate is 20%. 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
19 
9.0 ACCRUAL AND STUDY DURATION  
Of approximately 90 patients per month seen in consultation for prostate cancer each month 
in the department of radiation oncology (East Baltimore, Green Spring Station, Sibley and 
Suburban sites total), we anticipate approximately 25% of patients to be eligible. All eligible 
patients will be offered enrollment on the study, and we estimate a 30% accrual rate with 5% 
dropout rate, resulting in an average of at least 7 patients enrolled per month. The planned 
study open date is June 2013 for the East Baltimore site and May 2014 for Sibley and 
Suburban sites. The projected closure date of accrual is August 2015.   The total length of the 
study would be from June 2013-August 2020. 
 
10.0 REPORTING OF ADVERSE EVENTS  
 
10.1 General 
Adverse event collection and reporting is a routine part of every clinical trial. This study will 
use the descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events version 4.0 (CTCAE v 4.0) and the LENT-SOMA criteria.14  The CTCAE v 
4.0 is available at http://ctep.cancer.gov/reporting//ctc.html.  
 
Information on all adverse events, whether reported by the participant, directly observed, or 
detected by physical examination, laboratory test or other means, will be collected, recorded, 
followed and reported as described in the following sections. 
 
Adverse events experienced by participants will be collected and recorded from initiation of 
study, throughout the study, and within 5 years post radiation therapy. Participants who 
experience an ongoing adverse event related to a study procedure beyond 5 years post RT 
will continue to be contacted by a member of the study team until the event is resolved, 
stabilized, or determined to be irreversible by the participating investigator. 
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. The investigator should notify the IRB 
and any other applicable regulatory agency of any unanticipated death or adverse event 
occurring after a participant has discontinued or terminated study participation that may 
reasonably be related to the study. 
 
10.2 Definitions  
 
Adverse Event (AE): An adverse event is any undesirable sign, symptom or medical 
condition or experience that develops or worsens in severity after starting the first dose of 
study treatment or any procedure specified in the protocol, even if the event is not considered 
to be related to the study. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests. 
 
Serious Adverse Event: means an event that is  
• fatal  
• life-threatening  
• persistent or significantly disabling or incapacitating  
• inpatient hospitalization or prolongation of hospitalization  

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
20 
• congenital anomaly or defect and/or  
• a significant medical incident (considered to be a serious study related event because, based 
upon appropriate medical judgment, it may jeopardize the subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.)  
 
Events not considered to be serious adverse events are hospitalizations for: 
• 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
• 
emergency outpatient treatment for an event not fulfilling the serious criteria outlined 
above and not resulting in inpatient admission 
• 
respite care 
 
Important Adverse Event: means an event, although not a Serious Adverse Event, which still 
presents an undesirable occurrence that interferes with the subject’s usual activities and may 
be persistent or require treatment. (For example, serious rash, cough, or fever.)  
 
Expectedness: 
• 
Expected: Expected adverse events are those that have been previously identified as 
resulting from administration of protocol intervention. For the purposes of this study, an 
adverse event is considered expected when it appears in the current adverse event list, 
package inserts or is included in the informed consent document as a potential risk. 
• 
Unexpected: An adverse event is considered unexpected when it varies in nature, 
intensity or frequency from information provided in the current adverse event list, 
package inserts or when it is not included in the informed consent document as a 
potential risk 
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
• 
Definite – The AE is clearly related to the study treatment. 
• 
Probable – The AE is likely related to the study treatment. 
• 
Possible – The AE may be related to the study treatment. 
• 
Unlikely - The AE is doubtfully related to the study treatment. 
• 
Unrelated - The AE is clearly NOT related to the study treatment. 
 
10.3 Reporting Procedures  
 
10.3.1 General 
All adverse events will be captured on the appropriate study-specific case report forms 
(CRFs). 
 
10.3.2 All fatal events, both expected and unexpected, must be reported to the JHM IRB 
within a time period as specified by current institutional guidelines after the PI learns of the 
event, whether or not the PI believes the event to be related to the study. All other events, 
which are both serious and unexpected, must be reported to the JHMI IRB within a time 
period as specified by current institutional guidelines after the PI learns of the event. Events 
which are serious but expected, should be reported as part of the continuing review 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
21 
application. If any of these Serious Adverse Events requires a change to the protocol or 
consent form, the PI must make those changes promptly and submit the revised documents to 
the JHM IRB. 
 
10.3.3 Important Adverse Events that are unexpected must be reported to the JHM IRB 
within a time period as specified by current institutional guidelines. If the Important Adverse 
Event requires changes to the protocol or consent form, the PI must make those changes 
promptly and submit the revised documents to the JHM IRB. 
 
10.3.4 All other unexpected Adverse Events or changes to the protocol and consent form 
must be reported to the JHM IRB, within a time period as specified by current institutional 
guidelines  
 
10.4 Following a Study Related Adverse Event  
If a patient experiences an adverse event while on study, the following steps will be taken:  
1) Establish the cause and severity of the adverse event and determine if said event is related 
to study participation.  
2) Principal Investigator will decide what treatment(s), if any, is/are required.  
3) Depending on the type and severity of adverse event, an appropriate follow-up schedule 
will be constructed which will allow for determination of event outcome.  
4) Patient will be followed by principal investigator until the adverse event has resolved.  
 
11.0 DISPOSITION OF DATA  
Clinical records for all subjects studied including history and physical findings, laboratory 
and clinical data, and operative and dosimetric records are to be maintained by the 
investigators in a secure location at Johns Hopkins Cancer Center. Any records that are 
stored electronically will be password protected and only those who are involved in the 
research will have a password. These records are to be stored for a minimum of 8 years after 
last clinical visit.  
 
12.0 PROTOCOL MODIFICATIONS  
All revisions or amendments (that are not required for immediate patient safety) to the 
protocol must be approved by the Johns Hopkins Institutional Review Board prior to 
implementation.  
 
13.0 DEPARTURES FROM PROTOCOL  
If there is a departure from the Clinical Protocol, the Principal Investigator will notify in 
writing the local IRB at Johns Hopkins at the time of annual review (continuing review). The 
research coordinator will keep a log of all deviations/departures that occur on this project and 
this log will be reviewed by the research team on a monthly basis. During the review the 
research team will discuss corrective action plans to minimize future deviations/departures. If 
there are departures to the protocol that effects patient safety the principal investigator will 
notify in writing the IRB within 24 hours of discovering the departure/deviation. 
  
14.0 CRITERIA FOR WITHDRAWAL FROM STUDY  
Patients may be withdrawn from the study for the following reasons:  
a) Consent for participation is withdrawn  
b) Noncompliance to study procedures  

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
22 
c) Development of intercurrent, non-cancer related illness that prevents either continuation of 
therapy or regular follow-up. 
 
15.0 ROLES AND RESPONSIBILITIES OF STUDY PERSONNEL  
 
Principal Investigator: Oversees all aspects of the trial. Recruits and consents patients and 
administrates protocol specific procedures. Provides medical care to research subjects during 
the conduct of the study. Follows and advises regarding the treatment of adverse events. 
Reports SAE's to the IRB within the required time frame. Amends the trial as necessary to 
reflect unforeseen adverse events, new scientific data and for the general integrity of the 
study. Monitors the trial. Is ultimately responsible for the conduct of protocol. 
 
Co-Investigators: If a physician: can recruit and consent patients and can administrate 
protocol specific procedures. Can provide medical care to research subjects during the 
conduct of the study. Has input on the course of action for adverse events.  
If not a physician: Collaborates with the Principal Investigator according to area of expertise.  
 
Research Nurses: Executes protocol specific procedures requiring nursing qualifications. 
Provide nursing care to research subjects during the conduct of the study. May consent 
patients for study enrollment.  
 
Data Manager/Study Coordinator: Collects data from subject's medical records and codes 
it onto the study's case report forms. Notifies principal investigator of any deviations that 
he/she finds while managing the data. Prepares annual IRB renewals and termination report 
upon study completion, assists with management of regulatory issues governing the trial. 
Monitors the trial.  

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
23 
16.0 
PARTICIPATING SITE GUIDELINES 
 
This study will be conducted in accordance with the Sidney Kimmel Comprehensive Cancer 
Center’s Coordinating Center Protocol. 
 
Patient Registration 
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an IRB 
approved consent form.  All patients must be registered centrally at the Sidney Kimmel 
Comprehensive Cancer Center.  
 
To register a patient, the following documents must be completed and faxed (443-
287-8354) or e-mailed to the Coordinating Center: 
• 
Signed patient consent form 
• 
Registration Form 
• 
Copies of pertinent lab results, pathology reports, etc. (please specify what source 
documents are required to confirm eligibility, if applicable) 
 
 
The Coordinating Center will review the documents to confirm eligibility.  To 
complete the registration process, the Coordinating Center will: 
• 
assign a patient study number 
• 
register the patient on the study with the Sidney Kimmel Comprehensive Cancer 
Center’s Clinical Research Office 
• 
fax or e-mail the patient study number to the participating site. 
 
 
 
Multicenter Guidelines 
 
 
Protocol Chair 
 
 
The Protocol Chair is responsible for performing the following tasks: 
• 
Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments. 
• 
Assuring that all participating institutions are using the correct version of the protocol. 
• 
Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
• 
Reviewing and ensuring reporting of Serious Adverse Events (SAE) 
• 
Reviewing data from all sites. 
 
 
 
 
 
Coordinating Center 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
24 
 
 
The Coordinating Center is responsible for performing the following tasks: 
• 
Ensuring that IRB approval has been obtained at each participating site prior to the first 
patient registration at that site, and maintaining copies of IRB approvals from each site. 
• 
Managing central patient registration. 
• 
Collecting and compiling data from each site. 
• 
Establishing procedures for documentation, reporting, and submitting of AE’s and SAE’s 
to the Protocol Chair, and all applicable parties. 
• 
Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
 
 
Participating Sites 
 
 
Participating sites are responsible for performing the following tasks: 
• 
Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
• 
Submitting data to the Coordinating Center. 
• 
Registering all patients with the Coordinating Center by submitting patient registration 
form, and signed informed consent promptly. 
• 
Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol. 
• 
Maintaining regulatory binders on site and providing copies of all required documents to 
the Coordinating Center. 
• 
Collecting and submitting data according to the schedule specified by the protocol. 
 
Quality Assurance 
This is a Level I study under the SKCCC Data Safety Monitoring Plan.  Data Monitoring of 
this protocol will occur on a regular basis with the frequency dependent on the rate of subject 
accrual and the progress of the study.  The protocol will be monitored by the SKCCC CRO in 
accordance with SKCCC guidelines.  Trial monitoring and reporting will be done through the 
Safety Monitoring Committee at SKCCC. The Coordinating Center PI and study team at 
Johns Hopkins will conduct semimonthly teleconferences with all the sub-sites participating. 
Dr. Joseph Herman from Johns Hopkins will serve as the unbiased and impartial internal 
physician monitor and will attend these semimonthly teleconferences. These conferences will 
include a comprehensive overview (across all sites) of SAE’s, AEs, regulatory, enrollment, 
data capture, and overall study progress.     
Authorized representatives of the Coordinating Center may visit participating sites to perform 
audits or inspections, including source data verification.  The purpose of these audits or 
inspections is to systematically and independently examine all trial related activities and 
documents to determine whether these activities were conducted and data were recorded, 
analyzed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
and any applicable regulatory requirements. 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
25 
Data Submission 
Completed case report forms along with their corresponding redacted source documentation 
must be transmitted by secure facsimile report, email, or internet database to the 
Coordinating Center monthly. Case report forms will be provided to participating sites by the 
Coordinating Center. 
Adverse Event Reporting 
 
Definition of Adverse Event (AE) 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical 
product, whether or not considered causally related to the product.  An undesirable medical 
condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) 
or the abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In 
clinical trials, from the time of signing an informed consent, an AE can include an 
undesirable medical condition occurring at any time, including run-in or washout periods, 
even if no trial treatment has been administered. 
Definition of Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any trial phase (i.e., run-in, treatment, 
washout, follow-up), and at any dose of the investigational product, comparator or placebo, 
that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above 
 
Protocol Chair 
The Protocol Chair is ultimately responsible for the required reporting of all adverse events. 
Coordinating Center 
The Coordinating Center is the central location for the collection and maintenance of 
documentation of adverse events and is responsible for submitting adverse event reports to 
the Protocol Chair promptly.  The Coordinating Center will maintain documentation of all 
adverse event reports for each participating site.  Adverse event reports submitted to the 
Coordinating Center must be signed and dated by the participating site’s Principal 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
26 
Investigator.  The Coordinating Center will provide appropriate forms to be used by all 
participating sites for reporting adverse events.  Information to be provided must include: 
• 
Subject ID number, and initials 
• 
Date of the event 
• 
Description of the event 
• 
Description of site's response to the event 
• 
Assessment of the subject's condition 
• 
Subject's status on the study (on study, off study, etc.) 
• 
Attribution of event to study drug 
 
Participating Sites 
Participating sites are responsible for reporting adverse events to their IRB according to its 
specific requirements and to the Coordinating Center as follows: 
Fatal Events whether anticipated or unanticipated, and whether or not related to the 
study must be reported to the Coordinating Center within 24 hours of the participating 
site Principal Investigator's learning of the event. 
Serious and Unanticipated Adverse Events as defined above must be reported to the 
Coordinating Center within 24 hours of the participating site Principal Investigator's 
learning of the event.  
Other Serious Adverse Events which may result in a change to the protocol, informed 
consent, or risk to subjects as specified in the protocol must be reported within three (3) 
working days of the participating site Principal Investigator's learning of the event.  
Adverse Events which result in no change to protocol, informed consent, or risk to 
subjects must be reported to the Coordinating Center on a monthly basis.  
Adverse event reports are to be faxed to the Coordinating Center at 443-287-8354. 
Follow-up reports are faxed, mailed, or sent electronically to the Coordinating Center as 
necessary. 
The investigator must also report follow-up information about SAEs within the same time 
frames. 
If a non-serious AE becomes serious, this and other relevant follow-up information must 
also be provided within the same time frames described above. 
All SAEs must be collected whether or not they are considered causally related to the 
investigational product.  Investigators and other site personnel are responsible for 
reporting all casually related SAEs to their IRB and the Protocol Chair. 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS  

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
27 
 
17.1 IRB: Prior to initiating the study, the Principal Investigator must obtain written approval 
to conduct the study from the appropriate IRB. Should changes to the study protocol become 
necessary, protocol amendment will be submitted in writing to the IRB by the Principal 
Investigator for IRB approval prior to implementation.  
 
17.2 Informed Consent: All potential candidates for the study will be given a copy to read 
of the Informed Consent for the study. The investigator will explain all aspects of the study in 
lay language and answer all the candidate’s questions regarding the study. If the candidate 
desires to participate in the study, he/she will be asked to sign the Informed Consent. No 
study procedures will be performed on a patient until after they have signed the informed 
consent document. Subjects who refuse to participate or who withdraw from the study will be 
treated without prejudice. 
 
17.3: The principal investigator will ensure that the study is conducted in compliance with 
the protocol and according ICH Guidelines for Good Clinical Practices, the Declaration of 
Helsinki, and all regulatory and institutional requirements, including those for patient 
privacy, informed consent, Institutional Review Board approval and record retention.  
 
18.0 DATA SAFETY AND MONITORING PLAN 
 
The principal investigator, co-investigator radiation oncologist, research nurses, and study 
coordinator will review the data on a regular basis through regularly scheduled study team 
meetings. This trial will be audited annually by the central clinical research office at Johns 
Hopkins as well as by the Hopkins Safety Monitoring Committee.  
 
This is a DSMP Level I study under the SKCCC Data Safety Monitoring Plan (12/06/2012). 
The Clinical Research Office QA Group will perform an audit after the first subject has been 
treated and then periodically depending on the rate of accrual and prior audit results. All trial 
monitoring and reporting will be reviewed annually by the SKCCC Safety Monitoring 
Committee. The PI is responsible for monitoring the study. Data must be reviewed to assure 
the validity of data, as well as, the safety of the subjects. The PI will also monitor the 
progress of the trial, review safety reports, and clinical trial efficacy endpoints and to confirm 
that the safety outcomes favor continuation of the study. The PI will be responsible for 
maintaining the clinical protocol, reporting adverse events, assuring that consent is obtained 
and documented, reporting of unexpected outcomes, and reporting the status of the trial in the 
continuing renewal report submitted to the IRB and to the trial monitoring review group. 
Content of the continuing renewal report at a minimum should include year-to-date and full 
trial data on: accrual and eligibility, protocol compliance, treatment administration, toxicity 
and ADR reports, response, survival, regulatory compliance, compliance with prearranged 
statistical goals. The report should be submitted in a timely manner according to the schedule 
defined by Johns Hopkins Medicine Institutional Review Board. 
 
19.0 LIST OF DATA COLLECTION SHEETS 
 
IPSS Scoring Form  
EPIC questionnaire  
SHIM questionnaire 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
28 
20.0 REFERENCES 
 
1. 
Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J 
Radiol. Aug 1989;62(740):679-694. 
2. 
Haustermans KM, Hofland I, Van Poppel H, et al. Cell kinetic measurements in prostate 
cancer. Int J Radiat Oncol Biol Phys. Mar 15 1997;37(5):1067-1070. 
3. 
Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate 
carcinoma. Int J Radiat Oncol Biol Phys. Mar 15 1999;43(5):1095-1101. 
4. 
Duchesne GM, Peters LJ. What is the alpha/beta ratio for prostate cancer? Rationale for 
hypofractionated high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys. Jul 1 
1999;44(4):747-748. 
5. 
Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat 
Oncol Biol Phys. Jul 15 2001;50(4):1021-1031. 
6. 
King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC, Jr. Stereotactic body 
radiotherapy for localized prostate cancer: interim results of a prospective phase II 
clinical trial. Int J Radiat Oncol Biol Phys. Mar 15 2009;73(4):1043-1048. 
7. 
Boike TP, Lotan Y, Cho LC, et al. Phase I dose-escalation study of stereotactic body 
radiation therapy for low- and intermediate-risk prostate cancer. J Clin Oncol. May 20 
2011;29(15):2020-2026. 
8. 
Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen 
deprivation for localized prostate cancer. N Engl J Med. Jul 14 2011;365(2):107-118. 
9. 
Joon DL, Hasegawa M, Sikes C, et al. Supraadditive apoptotic response of R3327-G rat 
prostate tumors to androgen ablation and radiation. Int J Radiat Oncol Biol Phys. Jul 15 
1997;38(5):1071-1077. 
10. 
Yoshioka Y, Konishi K, Sumida I, et al. Monotherapeutic high-dose-rate brachytherapy 
for prostate cancer: five-year results of an extreme hypofractionation regimen with 54 Gy 
in nine fractions. Int J Radiat Oncol Biol Phys. Jun 1 2011;80(2):469-475. 
11. 
Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate 
cancer and cardiovascular risk: a science advisory from the American Heart Association, 
American Cancer Society, and American Urological Association: endorsed by the 
American Society for Radiation Oncology. CA Cancer J Clin. May-Jun 2010;60(3):194-
201. 
12. 
D'Amico AV, Manola J, Loffredo M, et al. A practical method to achieve prostate gland 
immobilization and target verification for daily treatment. Int J Radiat Oncol Biol Phys. 
Dec 1 2001;51(5):1431-1436. 
13. 
Zabransky DJ, Smith HA, Thoburn CJ, et al. Lenalidomide modulates IL-8 and anti-
prostate antibody levels in men with biochemically recurrent prostate cancer. Prostate. 
Apr 2012;72(5):487-498. 
14. 
Pavy JJ, Denekamp J, Letschert J, et al. EORTC Late Effects Working Group. Late 
Effects toxicity scoring: the SOMA scale. Int J Radiat Oncol Biol Phys. Mar 30 
1995;31(5):1043-1047. 
 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
29 
APPENDIX A 
 
INTERNATIONAL PROSTATE SYMPTOM SCORE (I-PSS) 
 
Name   ______________________________ 
Date  ______________________________ 
 
Not at 
all 
Less than 
1 time in 
5 
Less 
than half 
time 
About 
half the 
time 
More 
than half 
the time 
Almost 
always 
1. Incomplete emptying 
 
Over the past month, how often have you had a 
sensation of not emptying your bladder completely 
after you finished urinating? 
0 
1 
2 
3 
4 
5 
2. Frequency 
 
Over the past month, how often have you had to 
urinate again less than two hours after you finished 
urinating? 
0 
1 
2 
3 
4 
5 
3. Intermittency 
 
Over the past month, how often have you found you 
stopped and started again several times when you 
urinated? 
0 
1 
2 
3 
4 
5 
4. Urgency 
 
Over the past month, how often have you found it 
difficult to postpone urination? 
0 
1 
2 
3 
4 
5 
5. Weak stream 
 
Over the past month, how often have you had a 
weak urinary stream? 
0 
1 
2 
3 
4 
5 
6. Straining 
 
Over the past month, how often have you had to 
push or strain to begin urination? 
0 
1 
2 
3 
4 
5 
 
None 
1 time 
2 times 
3 times 
4 times 
5 times 
or more 
7. Nocturia 
 
Over past month, how many times did you most 
typically get up to urinate from the time you went 
to bed at night until the time you got up in the 
morning? 
0 
1 
2 
3 
4 
5 
 
Total I-PSS Score____________ 
 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
30 
(questionnaire continued on next page) 
 
 
 
Quality of Life Due to Urinary 
Symptoms 
 
 
 
Delighted 
 
Pleased 
 
Mostly 
satisfied 
 
Mixed -About 
equally satisfied 
and dissatisfied 
 
Mostly 
dissatisfied 
 
Unhappy 
 
Terrible 
 
If you were to spend the rest of your life with 
the urinary condition just the way it is now, 
how would you feel about that? 
0 
1 
2 
3 
4 
5 
6 
Urinary incontinence 
 
 
 
Rarely or 
never 
 
About once a 
week 
 
More than once 
a week 
 
About once a 
day 
 
More than once a 
day 
Over the past 4 weeks, how often have you 
leaked urine? 
0 
1 
2 
3 
4 
 
Urinary incontinence 
 
 
 
Total control 
 
Slight 
occasional 
leakage after 
voiding 
 
Occasional 
leakage 
associated with 
urgency 
 
Some control 
but frequent 
uncontrollable 
leakage 
 
No control at all, 
constant leakage 
Which best describes your urinary control? 
0 
1 
2 
3 
4 
 
 
 
 
 
 
 
 
Patient Signature ______________________________ 
 
 
 
 
 
 
 
 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
31 
APPENDIX B 
 
Sexual Health Inventory for Men 
 
Name   ______________________________ 
Date  _________________ 
 
Circle the number of the response that best describes your own situation. Please be sure that you select one and only one 
response for each question, describing your experience over the past 6 months.  
 
Check here if you use one of the following: Viagra, Cialis, Levitra (please answer questions according to your condition 
when taking the medication)___________ 
 
OVER THE PAST 6 MONTHS:    (CHECK HERE IF YOU HAVE NOT BEEN SEXUALLY ACTIVE ___________) 
1. How do you rate your confidence that you could get and keep an erection?   
Very low 
Low 
Moderate 
High 
Very high 
1 
2 
3 
4 
5 
 
2. When you had erections, how often were your erections hard enough for penetration  (entering your partner)?  
No sexual activity 
Almost never or 
never 
A few times 
(much less than 
half the time) 
Sometimes (about 
half the time) 
Most times (much 
more than, half 
the time) 
Almost always or 
always 
0 
1 
2 
3 
4 
5 
 
3. How often were you able to maintain your erection after you had penetrated (entered) your partner?   
Did not attempt 
intercourse 
Almost never or 
never 
A few times 
(much less than 
half the time) 
Sometimes (about 
half the time) 
Most times (much 
more than, half 
the time) 
Almost always or 
always 
0 
1 
2 
3 
4 
5 
 
4. During sexual intercourse, how difficult was it to maintain your erection to completion of intercourse?  
Did not attempt  
Extremely difficult 
Very difficult 
Difficult 
Slightly difficult 
Not difficult 
0 
1 
2 
3 
4 
5 
 
5. When you attempted sexual intercourse, how often was it satisfactory for you?  
Did not attempt 
intercourse 
Almost never or 
never 
A few times 
(much less than 
half the time) 
Sometimes (about 
half the time) 
Most times (much 
more than, half 
the time) 
Almost always or 
always 
0 
1 
2 
3 
4 
5 
 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
32 
Total Score 
________________ 
 
 
Patient Signature ______________________________ 
 
APPENDIX C 
BOWEL HABITS 
The next section is about your bowel habits and abdominal pain. 
Please consider ONLY THE LAST 4 WEEKS. 
 
 
Name   ______________________________ 
Date  _________________ 
 
Never 
Rarely 
About half 
the time 
Usually 
but not 
always 
Always 
1.  How often have you had rectal urgency (felt like 
you had to pass stool, but did not) during the last 4 
weeks? 
 
0 
 
1 
 
2 
 
 
3 
 
4 
2.  How often have you had uncontrollable leakage 
of stool of feces? 
 
1 
 
2 
 
3 
 
 
4 
 
5 
3.  How often have you had crampy pain in your 
abdomen, pelvis or rectum during the last 4 
weeks? 
 
1 
 
 
2 
 
3 
 
4 
 
5 
4.  How often have you had stools (bowel 
movements) that were loose or liquid (no form, 
watery, mushy) during the last 4 weeks? 
 
1 
 
2 
 
3 
 
4 
 
 
5 
5.  How often have you had bloody stools during 
the last 4 weeks? 
 
1 
 
 
2 
 
3 
 
4 
 
 
5 
6.  How often have your bowel movements been 
painful during the last 4 weeks? 
 
1 
 
 
2 
 
3 
 
4 
 
 
5 
7.  How often do you have to wear pads or diapers 
because of leakage of stools or mucus from your 
rectum? 
 
1 
 
2 
 
3 
 
 
4 
 
5 
8.  How often do you take anti-diarrheal medication 
(such as Imodium or Lomotil)? 
 
1 
 
 
2 
 
 
3 
 
4 
 
 
5 
9.  Overall, how often have your bowel habits been 
a problem for you during the last 4 weeks? 
 
1 
 
 
2 
 
3 
 
4 
 
 
5 

PI: Daniel Song, MD 
IRB00079078 
December 20, 2021 
 
33 
10. How many bowel movements have you had on 
a typical day during the last 4 weeks? 
 
 
 
2 or less 
 
 
3-4 
 
5 or more 
 
 
Total score _______________  
 
Patient Signature _____________________________