Phase I Trial of High Dose Rate Brachytherapy Combined With Stereotactic Body Radiation Therapy for Intermediate Risk Prostate Cancer Patients
Phase: PHASE1
Conditions: Prostate Cancer, Adenocarcinoma of the Prostate, Recurrent Prostate Cancer, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University

 
 
 
 
THOMAS JEFFERSON UNIVERSITY 
 
 
PHASE I TRIAL OF HIGH DOSE RATE BRACHYTHERAPY 
COMBINED WITH STEREOTACTIC BODY RADIATION 
THERAPY FOR INTERMEDIATE RISK PROSTATE CANCER 
PATIENTS 
 
 
Regulatory Sponsor: 
Robert B Den, MD 
Department of Radiation Oncology 
111. South 11th St. Bodine Cancer Center 
215-955-0284 
Co-Investigator(s): 
Adam Dicker, MD PhD 
Department of Radiation Oncology 
 
Leonard Gomella, MD 
Department of Urology 
 
Edouard Trabulsi, MD 
Department of Urology 
 
Costas Lallas, MD 
Department of Urology 
 
Rani P. Anne, MD 
Department of Radiation Oncology 
 
Maria Werner-Wasik, MD 
Department of Radiation Oncology 
 
Voichita BarAd, MD 
Department of Radiation Oncology 
 
Wenyin Shi, MD 
Department of Radiation Oncology 
 
Mark Hurwitz, MD 
Department of Radiation Oncology 
 
 
Amy Harrison, MS 
Department of Radiation Oncology 
 
Laura Doyle, MS 
Department of Radiation Oncology 
 
Yan Yu, PhD 
Department of Radiation Oncology 
 
Kevin Kelly, DO 

 
 
 
 
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Department of Medical Oncology 
 
Jean Hoffman-Censits, MD 
Department of Medical Oncology 
 
Jianqing Lin, MD 
Department of Medical Oncology 
 
Terry Hyslop, PhD 
Department of Biostatistics 
Funding Sponsor: 
N/A 
Study Product: 
N/A 
Protocol Number: 
CCRRC# 2012-10 IRB # 12D.210 
IND Number: 
Not  applicable 
 
Date:  5.2.12 
 
10.10.12 
 
03.08.13 
Version: 1.0 
 
Version: 1.1 
 
Version: 1.2 
07.25.2019 
Version 1.3 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of THOMAS JEFFERSON 
UNIVERSITY.  No part of it may be transmitted, reproduced, published, or used by 
other persons without prior written authorization from the study sponsor. 

 
 
 
 
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Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................................. 7 
1.1 
SPECIFIC AIMS ............................................................................................................................................. 7 
1.2 
BACKGROUND ............................................................................................................................................. 7 
1.3 
INVESTIGATIONAL AGENT ........................................................................................................................... 7 
2 
STUDY OBJECTIVES ...................................................................................................................................... 9 
3 
STUDY DESIGN .............................................................................................................................................. 10 
3.1 
GENERAL DESIGN...................................................................................................................................... 10 
3.2 
PRIMARY STUDY ENDPOINTS .................................................................................................................... 10 
3.3 
SECONDARY STUDY ENDPOINTS ............................................................................................................... 11 
4 
SUBJECT SELECTION AND WITHDRAWAL.......................................................................................... 12 
4.1 
INCLUSION CRITERIA ................................................................................................................................. 12 
4.2 
EXCLUSION CRITERIA ............................................................................................................................... 12 
4.3 
GENDER/MINORITY/PEDIATRIC INCLUSION FOR RESEARCH ...................................................................... 13 
4.4 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................. 13 
4.5 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 13 
5 
RADIATION .................................................................................................................................................... 14 
6 
STUDY PROCEDURES .................................................................................................................................. 16 
7 
STATISTICAL PLAN ..................................................................................................................................... 17 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 18 
8.1 
DEFINITIONS .............................................................................................................................................. 18 
8.2 
RECORDING OF ADVERSE EVENTS............................................................................................................. 20 
8.5 
DATA AND SAFETY MONITORING PLAN .................................................................................................... 20 
8.5.1 
Medical Monitoring and AE/SAE Reporting ....................................................................................... 22 
9 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 23 
9.1 
CONFIDENTIALITY ..................................................................................................................................... 23 
9.2 
SOURCE DOCUMENTS ................................................................................................................................ 23 
9.3 
CASE REPORT FORMS ................................................................................................................................ 24 
9.4 
RECORDS RETENTION ................................................................................................................................ 24 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 24 
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 24 
10.2 
AUDITING AND INSPECTING ....................................................................................................................... 25 
 
11 
ETHICAL CONSIDERATIONS .................................................................................................................... 26 
12 
STUDY FINANCES ......................................................................................................................................... 27 
12.1 
FUNDING SOURCE ..................................................................................................................................... 27 
12.2 
CONFLICT OF INTEREST ............................................................................................................................. 27 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................................................................................ 27 
13 
PUBLICATION PLAN .................................................................................................................................... 27 
14 
REFERENCES ................................................................................................................................................. 27 
15 
ATTACHMENTS ........................................................................................................................................... 31 

 
 
 
 
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List of Abbreviations 
 
SBRT Stereotactic Body Radiation Therapy 
HDR High dose rate 
LDR low dose rate 
IMRT Intensity Modulated Radiation Therapy 
VMAT Volumetric Modulated Arc Therapy 
NCCN National Comprehensive Cancer Network 
GI gastrointestinal 
GU genitourinary 
PSA prostate specific antigen 
EBRT externa beam radiation therapy 
CREST(calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) 
EPIC Expanded Prostate Cancer Index Composite 
MTD maximum tolerated dose 
AUA American Urologic Association 
DLT dose limiting toxicity 
CTV clinical target volume 
PTV planning target volume 
Vx volume of tissue receiving X Gy of radiation therapy 
Dx dose that X volume of tissue is receiving 
ICRU International Commission on Radiation Units 
Gy Gray 
CT computed tomography 
QOL quality of life 
CRMO Clinical Research Management Office 
FDA Food and Drug Administration 
KCC Kimmel Cancer Center 
DSMC Data and Safety Monitoring Committee 
IRB Institutional Review Board 
SAE Severe adverse event 
AE Adverse event 
TJUH Thomas Jefferson University Hospital 
CRF Case report forms 
 
 
 
 
 
 

 
 
 
 
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Study Summary 
Title 
PHASE I TRIAL OF HIGH DOSE RATE 
BRACHYTHERAPY COMBINED WITH STEREOTACTIC 
BODY RADIATION THERAPY FOR INTERMEDIATE 
RISK PROSTATE CANCER PATIENTS 
Short Title 
Using a temporary radioactive implant and short course 
of radiation to treat prostate cancer 
Protocol Number 
CCRRC # 2012-10 
IRB # 12D.210)   
Phase 
Phase I 
Methodology/Study 
Design 
Single Arm Dose Escalation Trial  
Study Duration 
28  years (to reach MTD, 5 years including expansion 
cohort)  
Study Center(s) 
Single-center 
Objectives 
To determine the safety of hypofractionation in 
combination with a high dose rate implant for men with 
prostate cancer 
Number of 
Subjects 
42 (maximum)  
Diagnosis and 
Main Inclusion 
Criteria 
Adenocarcinoma of the prostate, T2b-T2c or Gleason 
score 7 or PSA 10-20 ng/ml, no prior pelvic radiation, 
KPS>70 
Study Product, 
Dose, Route, 
Regimen 
N/A 
Duration of 
administration 
N/A 
Reference therapy 
IMRT alone or LDR implant with IMRT 
Statistical 
Methodology 
‘3+3’ Phase I Design. Data analysis of phase I studies is 
descriptive.  All estimates of dose specific rates (e.g., 
toxicity) will be presented with corresponding confidence 
intervals using the exact method. 
 

 
 
 
 
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1.0 INTRODUCTION 
 
This document is a protocol for a human research study. This study is to be 
conducted according to US and international standards of Good Clinical Practice 
(FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and 
procedures. The primary objective of this study is to determine the safety and 
toxicity profiles of HDR combined with SBRT. This is a Phase I trial that uses a 
standard “3+3” design for dose escalation through escalation of radiation dose 
fraction size with 3 planned dose levels. 
1.2 Background and Rationale 
Prostate cancer is the most common non cutaneous malignancy diagnosed in the 
United States [Jemal et al., 2011].  Men with newly diagnosed disease are currently 
stratified based on their PSA, Gleason score, and DRE into one of three groups: 
low risk, intermediate risk, or high risk [D'amico et al., 1998].  Low risk is defined 
as either Gleason score 6 or below, PSA <10, and T1-T2a.  Intermediate risk is 
defined as T2b-T2c or Gleason score 7 or PSA 10-20 ng/ml.  High-risk disease is 
defined as PSA >20 or Gleason >7 or T2c or greater.  The current standard non-
surgical treatment for men with intermediate risk prostate cancer is radiation 
therapy [Mohler et al., 2010]. 
 
Benefit of Dose Escalation 
 
Recently, there have been multiple phase III trials demonstrating the benefit of 
radiation dose escalation in the treatment of both low risk, intermediate risk, and 
high risk prostate cancer [Dearnaley et al., 2007, Al-Mamgani et al., 2008, Kuban 
et al., 2008, Zietman et al., 2010].  These trials have all used external beam 
radiation therapy and have set a new standard dose for radiation treatment for men 
with prostate cancer that has been endorsed by the NCCN.  
 
Dose Escalation with HDR 
 
In addition to increasing the total dose delivered by EBRT, dose escalation can be 
achieved using brachytherapy.  The radiation can be delivered either with low 
activity radioactive seed sources (termed low dose rate or LDR brachytherapy) or 
using a temporary implant with a higher activity source (high dose rate or HDR 
brachytherapy).  HDR brachytherapy is a standard of care in the United States and 
Europe to deliver a radiation boost to the prostate when combined with external 
beam radiation.  Three large studies [Galalae et al., 2002, Demanes et al., 2005, 
Vargas et al., 2006] including over 500 men received a combination of EBRT and 
HDR.  All reported excellent outcome with PSA progression free survival between 
70-90% for men with both intermediate and high-risk disease.  Further, the rate of 
late GI/GU toxicity was quite low as well with late grade 3 GU toxicity ranging from 

 
 
 
 
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2.1-6.7%, late grade 4 GU toxicity of 0-1%, late grade 3 GI toxicity of 0-1% and 
late grade 4 GI toxicity of 0-0.5%.   
 
In addition, a phase III randomized trial compared EBRT alone or EBRT combined 
with an HDR boost [Hoskin et al., 2007].  This trial demonstrated a significant 
improvement in actuarial biochemical relapse-free survival is seen in favor of the 
combined brachytherapy schedule.  However, this trial was criticized that the 
EBRT alone arm had a lower biologic radiation dose than the combined arm.  A 
retrospective study from Memorial Sloan Kettering Cancer Center compared 
patients who received EBRT alone to 86.4 Gy with those who underwent HDR 
brachytherapy combined with EBRT [Deutsch et al., 2010]. Dose escalation by 
adding HDR brachytherapy provided improved PSA relapse-free survival in the 
treatment of prostate cancer compared with ultra-high-dose EBRT, independent of 
risk group on multivariate analysis, with the most significant benefit for 
intermediate-risk patients.  Finally, a systemic review of the literature [Pieters et 
al., 2009] compared results from EBRT alone, EBRT combined with LDR, and 
EBRT combined with HDR.  This study concluded that combination of external 
beam radiotherapy and HDR brachytherapy results in a superior biochemical 
control and overall survival.  
  
Biologic Benefit of Hypofractionated Radiation for Prostate Cancer 
 
Radiation effects in prostate cancer cells have been typically studied using 
clonogenic cell survival curves, which allow cell death to be modeled using a linear 
quadratic equation.  The dose response of tumors and normal tissues to 
fractionated radiation therapy can be predicted according to a formula: S= e^(-αD-
βD2), where α and β are the linear and quadratic components of the model. Based 
upon this model, an alpha/beta ratio can be calculated which allows various dose 
and fractionation schemes to be compared.  The alpha-beta ratio is generally >10 
Gy for early-responding tissue such as skin, mucosa, and most tumors and <5 Gy 
for late responding tissue such as connective tissues and muscles.  Recent 
evidence reveals that prostate cancer has a low alpha/beta ratio, implying that 
those cells are more sensitive to doses delivered in larger fraction size [Fowler et 
al., 2001].  Further, given the lower alpha-beta ratio for prostate cancer than 
bladder and rectal mucosa (where the most significant late toxicity occurs) creates 
the potential for therapeutic gain with larger fraction sizes [Brenner et al., 2002, 
Fowler et al., 2003].  Based upon this, there is an increasing trend to reduce the 
total treatment time by administering higher dose/fraction [Ritter et al., 2009]. 
 
Clinical Experience Using Hypofractionation or SBRT in Prostate 
 
There have been a number of phase I trials reporting the use of hypofractionated 
regimens for the treatment of low and intermediate risk prostate cancer in the 
(primary) definitive setting [Adkison et al., 2010, Jabbari et al., 2010, Oermann et 
al., 2010, Boike et al., 2011, King, 2011].  These trials show excellent biochemical 

 
 
 
 
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control and toxicity profiles.  A five institutional cooperative phase I/II trial that 
explored the tolerance and efficacy of 3 increasingly hypofractionated radiation 
regimens with equivalent predicted late toxicity was recently reported in abstract 
form [Ritter et al., 2009].  A total of 307 men were enrolled and biochemical 
progression free survival was 95% at 5 years.  At 2 years, actuarial rectal bleeding 
was 8% with all cases resolving either spontaneously or after minor intervention. 
 
Patient Logistical Benefit of Hypofractionation 
 
One caveat with dose escalation to doses between 74-80 Gy is that current 
radiation therapy treatment is given in daily fractions of sizes of 2 Gy/day and 
treatments last for approximately 2 months.  The prolonged nature of the radiation 
treatment course has been cited by prostate cancer patients as a primary reason 
for not choosing RT [Holmboe et al., 2000].  
  
Combination of HDR and hypofractionated radiation therapy 
 
The combination of high dose rate brachytherapy and external beam radiation 
therapy has been recently published [Morton et al., 2011].  The protocol used a 
single HDR treatment of 15 Gy followed by EBRT to a dose of 37.5 Gy in 15 
fractions.  One hundred and twenty three patients were followed for a median of 
45 months.  Biochemical disease-free survival was 95% and the two year prostate 
biopsy was positive in only 4% of men.  Further, acute grade 3 or higher GU toxicity 
was experienced by only 2 patients and 1 patient developed a grade 3 late GU 
toxicity. The grade 3 toxicity was hemorrhagic cystitis that required cysto-
prostatectomy; however the patient was also diagnosed with scleroderma and 
telangiectasia (CREST) syndrome, which is generally a contraindication to 
radiation therapy and may have been a contributing factor to his toxicity.  There 
was 4% grade 2 GI toxicity consisting of proctitis.  Patient reported toxicity using 
the EPIC tool was notable for decrease in urinary, bowel and sexual domain scores 
in the first 2 years following treatment, but median urinary and bowel domain 
scores were not significantly different from baseline at 3 and 4 years. 
2.0 STUDY OBJECTIVES 
 
Primary Objective: 
The primary objective of this study is to determine the safety and feasibility of 
delivering HDR brachytherapy with SBRT for the treatment of men with 
intermediate risk prostate cancer. The maximally tolerated dose (MTD) will thus be 
determined. 
 
Secondary Objective: 
 
To determine the acute and late hematologic and late nonhematologic toxicity 
profile of HDR and SBRT combination. 

 
 
 
 
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To evaluate dosimetric parameters, including dose-volume factors for bladder 
and rectum that are associated with HDR and SBRT related toxicity. 
 
To describe patient-reported outcomes including EPIC and AUA Symptom Index 
for patients treated HDR and SBRT. 
3.0 STUDY DESIGN 
This is a single-center, open-label, non-randomized Phase I study in patients with 
Intermediate risk prostate cancer. We will use standard “3+3” dose escalation 
design. 
3.1 General Design 
SCHEMA 
 
 
 
 
 
*Note: Patients will start radiation therapy 2 weeks after the implant procedure, 
with the possibility of starting up to 3 weeks afterward (Day 22). 
 
Patients will be accrued in a standard “3+3” dose-escalation design during ongoing 
dose exploration. Dose escalation will continue until the maximum tolerated dose 
(MTD), the appropriate dose for Phase II study.  During dose exploration, cohorts 
of 3-6 patients will be treated as a cohort. The initial cohort will be treated at Dose 
Level 1. The enrollment scheme is a conventional 3 + 3 design. If 0/3 or 1/6 patients 
initially treated at Dose Level 1 have DLT at the first treatment cycle, the SBRT 
dose per fraction will be escalated, and the next cohort of 3-6 patients will be 
treated at Dose Level 2. In like manner, depending on cohort toxicity, the SBRT 
dose/fraction will be escalated as needed to determine the highest level for which 
2 of 6 patients has DLT. The dose level below this level will be declared the MTD. 
Dose level 3 will be the highest dose for this study and no further dose escalation 
will be performed.  If Dose level 1 has 2 or greater patients with DLT, then dose 
level -1 will be used.  We will allow for an expansion cohort of an additional 30 
patients at the MTD dose level. 
Planned Dose Levels During Exploration 
Dose 
Level 
Pts Number 
of 
Fractions 
SBRT 
Dose/Fraction 
HDR 
Dose 
BED 
tumor+ 
BED 
Acute 
BED 
Normal 
Tissue* 

 
 
 
 
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Normal 
Tissue% 
-1 
3-6 15 
2.5 Gy 
15 Gy 113.5 
Gy2 
70.3 Gy2 95 Gy2 
1 
3-6 10 
3.2 Gy 
15 Gy 113.5 
Gy2 
66.5 Gy2 94 Gy2 
2 
3-6 7 
3.94 Gy 
15 Gy 113.5 
Gy2 
63.2 Gy2 92 Gy2 
3 
3-6 5 
4.78 Gy 
15 Gy 113.5 
Gy2 
60.7 Gy2 91 Gy2 
+ For tumor alpha beta ratio is 1.5 for prostate 
% For normal tissue alpha beta ratio for acute toxicity is 10. 
* For normal Tissue alpha beta ratio for late toxicity is 3. 
 
While the number of fractions is being reduced, the overall treatment length will 
remain unchanged.  The dose level -1 (15 fractions) is given daily over 15 
treatment days.  For dose level 1 (10 fractions), this will also be given over 15 
treatment days (3-4 treatments per week).  For dose level 2, 2-3 treatments will be 
given per week over 15 treatment days.  For dose level 3, 2 fractions will be given 
per week for a total length of 15 treatment days.  In this trial design, weeks are not 
specified, as a patient may begin treatment midweek (i.e. Wednesday or Thursday 
and then treatment would last into a fourth week).   
 
There will be an expansion cohort at the maximum tolerated dose.  This will consist 
of 30 total patients (including the original 3 or 6).  This patient number is calculated 
statistically.  Based on the published dose level -1 toxicity, the total toxicity rate is 
6.5%.  Thus, using a binomial distribution, the probability of seeing a toxicity rate 
above 10% would be 13% using a 30 patient cohort.  This will provide valuable 
information for a phase II trial. 
3.2 Primary Study Endpoints 
The primary study endpoint is safety.  Toxicities will be Graded according to the 
National Cancer Institute, Common Toxicity Criteria (NCI, CTC), version 4.0. If 

 
 
 
 
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multiple toxicities are seen, the presence of DLT will be based on the most severe 
toxicity experienced.  
For this protocol, DLT will be defined as any of the following events occurring 
during or within 3 months of radiation treatment attributable to treatment toxicity:  
Non- Hematologic: Any Grade 4 toxicity or any grade 3 GU toxicity or Grade 3 
diarrhea/nausea/vomiting/stomatitis lasting for more than 7 days despite optimal 
treatments.  
Dose escalation will not occur until three patients at the current dose level have 
completed the combination of HDR and SBRT and have follow up for 3 months. 
Late toxicities after the treatment period will not be used to consider dose 
escalation but will be recorded and reported. 
3.3 Secondary Study Endpoints 
 
The secondary endpoint is to assess the late nonhematologic toxicity profile and 
the acute and late hematologic toxicity profile of HDR and SBRT combination. 
 
The dosimetric parameters, including dose-volume factors for bladder and rectum, 
will be correlated with acute toxicity. 
 
Multiple patient reported outcome instruments will be used including EPIC, AUA 
symptom score. 
 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
4.1 Inclusion Criteria 
Adenocarcinoma of the prostate with intermediate risk disease T2b-T2c or 
Gleason score 7 or PSA 10-20 ng/ml, without metastatic disease 
 
•To rule out metastatic disease, patients must have the following tests: 
• Bone scan within 60 days prior to registration 
 
• CT of abdomen/pelvis within 60 days prior to registration 
• Karnofsky Performance Status >70 
• Age > 18 
 
• PSA blood test within 60 days prior to registration 
 

 
 
 
 
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• Prostate biopsy within 180 days prior to registration 
• Within 60 days prior to registration, hematologic minimal values: 
 
• Absolute neutrophil count > 1,500/mm3 
 
• Hemoglobin > 8.0 g/dl 
 
• Platelet count > 100,000/mm3 
• Men of childbearing potential must be willing to consent to using effective 
contraception while on treatment and for at least 3 months thereafter. 
• No history of previous pelvic irradiation 
4.2 Exclusion Criteria 
• History of urological surgery or procedures predisposing to GU 
complications after radiation, i.e., anastomoses, stricture repair, etc. (will be 
determined by radiation oncologist) 
• History of prior pelvic irradiation 
• Documented distant metastatic disease. 
• Prior radical prostatectomy or cryosurgery for prostate cancer  
 
4.3 Gender/Minority/Pediatric Inclusion for Research 
Women and children will not be entered into this protocol as they do not suffer from 
prostate adenocarcinoma.  There is no exclusion of minorities in this protocol. 
4.4 Subject Recruitment and Screening 
Subjects will be recruited for the study from investigator or sub-investigator’s 
clinical practices and referring physicians. Patients will be screened based on 
pathology, PSA values, image studies etc. 
4.5 Early Withdrawal of Subjects 
Subject may be withdrawn from the study prior the expected completion of that 
subject if : 
Disease progression, 
Study closure, 
Unacceptable adverse event(s), 
Patient decision to withdraw from the study, or 
In the judgment of the investigator, further treatment would not be in the best 

 
 
 
 
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interest of the patient. 
4.5.2 Data Collection and Follow-up for Withdrawn Subjects 
Even though subjects may be withdrawn prematurely from the study, it is 
imperative to collect data on such subjects throughout the protocol defined 
followup period outlined in the Study Calendar (Appendix IV) for that subject 
(though careful thought should be given to the full data set that should be collected 
on such subjects to fully support the analysis).  Such data is important to the 
integrity of the final study analysis since early withdrawal could be related to the 
safety profile of the study drug. If a subject withdraws consent to participate in the 
study, attempts should be made to obtain permission to record at least survival 
data up to the protocol-described end of subject follow-up period. IT MUST BE A 
HIGH PRIORITY TO TRY TO OBTAIN AT LEAST SURVIVAL DATA ON ALL 
SUBJECTS LOST TO FOLLOW-UP AND TO NOTE WHAT METHODS SHOULD 
BE USED BEFORE ONE CAN STATE THE SUBJECT IS TRULY LOST TO 
FOLLOW-UP (e.g. number of phone calls to subject, phone calls to next-of-kin if 
possible, certified letters, etc.).  A subject who withdraws from the study for any 
reason prior to completing radiation therapy will not be counted as evaluable for 
the purposes of the study. 
5.0 Radiation Therapy  
 
5.1 HDR 
 
HDR will be performed using intra-operative real time 3D ultrasound planning with 
Oncentra Prostate under general anaesthesia. Patients will need routine pre-
operative work-up and anesthesia pre-assessment as indicated.  Standardized 
template-based catheter configuration will be used, and dwell time optimization 
performed using ultrasound. 
 
CTV = Prostate + any gross extension 
PTV = CTV 
Dose Prescription = 15 Gy in single fraction to CTV 
 
Planning Goals: 
V100: 95-99% 
V90: 99-100% 
V150 < 35% 
V200: < 11% 
Urethra D10: < 118% 
Rectal V80 < 0.5 cc 
 
5.2 SBRT 

 
 
 
 
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CT Simulation will be performed either same day or day after HDR. Patients will 
be positioned supine on a flat tabletop with customized thermoplastic mold or 
footbox.  A full bladder and empty rectum will be encouraged. CT images will be 
obtained with slice thickness of 3 mm from the top of the iliac crests to the 
perineum. 
 
Target volumes and normal tissue organs will be contoured for IMRT planning. 
Daily imaging will be performed for target localization. The definition of volumes 
will be in accordance with ICRU Report #50: Prescribing, Recording and Reporting 
Photon Beam Therapy.  
 
Radiation Therapy staff will contour the entire bladder, the rectum from the bottom 
of the ischium to the sigmoid flexure (usually 11-13 cm), and both femoral heads. 
 
CTV = Prostate + Inferior 2 cm of Seminal Vesicles 
PTV = CTV + 0.7 cm all around except 0.5cm posteriorly. 
 
Treatment Technique: IMRT or VMAT with appropriate CBCT image guidance to 
prostate prior to delivery of each fraction of radiation. 
 
Beam Energy: 10-18 MV 
 
 
Dose Cohort 
Fractions 
Fraction Size 
Total Dose 
-1 
15 
2.5 Gy 
37.5 Gy 
1 
10 
3.2 Gy 
32 Gy 
2 
7 
3.94 Gy 
27.6 Gy 
3 
5 
4.78 Gy 
23.9 Gy 
 
 
 
 
 
 
 
Planning Volumes Constraints 
 
 
Dose 
Level 
CTV 
PTV 
Rectum 
Bladder Femoral 
Heads 
 
≥ 
99% 
≥ 99% 
<1% 
<20% <35% 
<50% 
<35% 
<5% 
-1 
V37.5 
V35.6 
V39.4 
V33 
V29 
V24 
V29 
V24 
1 
V32 
V31 
V32.9 V30.2 V27.7 
V24.3 
V27.7 
V24.3 

 
 
 
 
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2 
V27.6 
V26.7 
V28.4 V26.7 V24.5 
V21.7 
V24.5 
V21.7 
3 
V23.9 
V23.2 
V24.5 V23.6 V21.7 
V19.25 
V21.7 
V19.25 
 
 
5.3 Radiation Toxicity 
Adverse events include: skin reactions; loss of pelvic hair; transitory fatigue; 
infertility; impotence that could be permanent; urethral stricuture; small bowel or 
rectal irritation manifesting as abdominal cramping, diarrhea, rectal urgency, rectal 
bleeding, hematochezia, and bowel incontinence; bladder complications including 
urinary frequency, dysuria, hematuria, urinary tract infections, and urinary 
incontinence; injuries to the rectum, bowel, or urinary system that could result in 
colostomy or other major surgical procedures. 
 
5.4 Radiation Adverse Event Reporting 
See Section 8.0 for adverse event reporting instructions. 
6.0 STUDY PROCEDURES 
All patients will be evaluated by a radiation oncologist.  Initial visit will include overall 
assessment of health as well as determination of eligibility.  Pretreatment PSA and 
staging will be obtained. Prostate volume will be determined based on trans rectal 
ultrasound performed at biopsy.  If ultrasound volume unable to be obtained, then 
prostate will be measured on CT imaging. 
 
Prior to HDR procedure, the patient will be assessed through pre admission testing 
to ascertain safety of anesthesia.  On the night prior to the procedure, the patient 
will undergo a bowel preparation consisting of a Fleets enema. 
 
On day of HDR procedure, patient will be intubated and sedated.  The patient will 
be placed in the dorsal lithotomy position and an ultrasound will inserted into the 
rectum and images will be acquired.  The treating radiation oncologist will define 
the prostate, urethra, and anterior rectal wall.  Catheters will be inserted into the 
prostate and a 3 dimensional treatment plan will be generated.  Dwell positions and 
times will be calculated.  The catheters will be connected to the HDR afterloader 
and the treartment plan will be reviewed and approved by the treating radiation 
oncologist.  After completion of the treatment, the catheters will be removed and 3 
fiducial markers will be inserted into the prostate. 
 
The patient will be taken to a post operative recovery area and medically cleared 
to leave the hospital.  The patient will then undergo a CT scan either on the same 
day or a week after the HDR procedure.   The treating radiation oncologist will 
define the CTV, PTV, bladder, and the rectum. An IMRT/VMAT plan will be 
generated and reviewed and approved by the treating radiation oncologist. 
 
The patient will return to the department for external beam treatment two weeks 
(and up to 3 weeks) after the implant procedure.  The patient will be seen once per 

 
 
 
 
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week by the treating radiation oncologist during external beam therapy.  After 
completion of external beam treatment, the patient will be seen again at first follow 
up at 1 month or sooner if medically necessary to assess toxicity and then at 3 
months after the procedure with a PSA test.  The patient will have routine follow up 
of every 3 months for the first 2 years, 6 months from years 3-4, and then annually 
with PSA evaluation prior to each of these follow-up visits as is standard of care.  
See Study Calendar (Appendix IV). 
 
Patients will also be asked to complete two (2) quality of life (QOL) questionnaires, 
so that patient-reported outcomes can be captured.  The questionnaires are the 
Expanded Prostate Cancer Index Composite (EPIC) and the American  Urological 
Association BPH Symptom Score Questionnaire (AUA Index).  Questionnaires 
should be completed at the follow time points: pre-treatment, 3 months post-RT, 6 
months post-RT, 9 months post-RT, 1 year post-RT, then every 3 months for 1 
year, then every 6 months for 2 years, and then annually. 
7.0 STATISTICAL PLAN 
 
We will use a two-stage accrual design at each radiation fraction size considered. 
We will initially enter 3 subjects at each radiation fraction size. If none of the three 
experiences a dose-limiting toxicity we will proceed to the next radiation fraction 
size. If one of the three experiences that level of toxicity, we will accrue 3 more 
subjects at that fraction size. If at any time there are two or more dose-limiting 
toxicities (in the 3-6 subjects) on a given fraction size, we will terminate accrual to 
the trial. No patient will be treated at a higher fraction size until the 3 or 6 patients 
have completed their toxicity evaluation period at the current dose. With this plan, 
a dose with a 50% or greater probability of causing a dose-limiting toxicity has at 
most a 12.5% chance of satisfying the conditions for dose escalation after the first 
3 subjects and at least a 50% chance of stopping at 3. With the two-stages (3-6) 
together, there is at most a 17.2% chance of escalation. 
 
The maximally tolerated dose (MTD) will then be the last dose studied or the 
previous dose, based on clinical judgment of the degree of toxicity seen at the last 
dose. While waiting for the 3 or 6 subjects accrued according to plan to complete 
their toxicity evaluation period, additional subjects may be accrued at the current 
dose. These additional subjects will not count towards the formal plan of stopping 
at two or more toxicity occurrences, but will contribute to the judgment as to the 
MTD. 
 
Data analysis of phase I studies is descriptive. All estimates of dose-specific rates 
(e.g.,response and toxicity) will be presented with corresponding confidence 
intervals using the exact method. 

 
 
 
 
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7.1 Sample Size Determination 
The total sample size would vary depending upon the DLTs observed and the 
resulting influence on cohort size and number of dose levels tested. We plan to 
have 3 dose levels for testing, depending on toxicity, with 3 to 6 patients enrolled 
at a particular dose level during dose exploration. Once the MTD has been 
determined, additional patients maybe added.  The total sample size will be 3-42 
patients. 
7.2 Subject Population(s) for Analysis 
All-treated population: Any subject in the study that received HDR implant will be 
followed and analyzed. 
8.0 SAFETY AND ADVERSE EVENTS 
8.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that 
develops or worsens in severity during the course of the study.  Intercurrent 
illnesses or injuries should be regarded as adverse events.  Abnormal results 
of diagnostic procedures are considered to be adverse events if the 
abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse 
event is any AE that is:  
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 
 
Important medical events are those that may not be immediately life 
threatening, but are clearly of major clinical significance. They may jeopardize 
the subject, and may require intervention to prevent one of the other serious 
outcomes noted above.  For example, drug overdose or abuse, a seizure that 
did not result in in-patient hospitalization, or intensive treatment of 
bronchospasm in an emergency department would typically be considered 
serious.  

 
 
 
 
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All adverse events that do not meet any of the criteria for serious should be 
regarded as non-serious adverse events.  
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally 
defined as the period from the initiation of any study procedures to the end of 
the study treatment follow-up.  For this study, the study treatment follow-up is 
defined as 90 days following the last administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A 
preexisting condition should be recorded as an adverse event if the 
frequency, intensity, or the character of the condition worsens during the 
study period. 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a 
preexisting condition.  At the end of the study, any new clinically significant 
findings/abnormalities that meet the definition of an adverse event must also 
be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the 
events are resolved, the subject is lost to follow-up, or the adverse event is 
otherwise explained.  At the last scheduled visit, the investigator should 
instruct each subject to report any subsequent event(s) that the subject, or 
the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the principal 
investigator at TJUH of any death or adverse event occurring at any time after 
a subject has discontinued or terminated study participation that may 
reasonably be related to this study.  The principal investigator at TJUH should 
also be notified if the investigator should become aware of the development 
of cancer or of a congenital anomaly in a subsequently conceived offspring 
of a subject that has participated in this study.  
Abnormal Laboratory Values 
A clinical laboratory abnormality as evidenced on CBC should be 
documented as an adverse event if any one of the following conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to 
confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. 
change of dose, discontinuation of the drug, more frequent follow-up 
assessments, further diagnostic investigation, etc. 
Hospitalization, Prolonged Hospitalization or Surgery 

 
 
 
 
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Any adverse event that results in hospitalization or prolonged hospitalization 
should be documented and reported as a serious adverse event unless 
specifically instructed otherwise in this protocol.  Any condition responsible 
for surgery should be documented as an adverse event if the condition meets 
the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery 
are reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective 
surgical procedures for a preexisting condition.  Surgery should not be 
reported as an outcome of an adverse event if the purpose of the 
surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target 
disease of the study, unless it is a worsening or increase in frequency 
of hospital admissions as judged by the clinical investigator. 
8.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse 
events by specific questioning and, as appropriate, by examination.  Information 
on all adverse events should be recorded immediately in the source document, 
and also in the appropriate adverse event module of the case report form (CRF).  
All clearly related signs, symptoms, and abnormal diagnostic procedures results 
should recorded in the source document, though should be grouped under one 
diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The 
clinical course of each event should be followed until resolution, stabilization, or 
until it has been determined that the study treatment or participation is not the 
cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event 
that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported 
immediately. 
8.4 Stopping Rules 
Patients will be taken off study for persistent grade 3 or 4 GI/GU toxicity, or grade 
3 or 4 hematological toxicity(ies) that lasts for more than 2 weeks. A patient who 
withdraws prematurely from the study for any reason either prior to completing 

 
 
 
 
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radiation therapy or after completing radiation therapy should be followed per the 
Study Calendar (Appendix IV) schedule.  
8.5 Data and Safety Monitoring Plan 
It is the responsibility of the Principal Investigator to oversee the safety of the study 
at his/her site.  This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above, as well as the compliance 
and implementation of the KCC data and safety-monitoring plan.  Medical 
monitoring will include a regular assessment of the number and type of serious 
adverse events by both the assigned Medical Monitor and the KCC DSMC. 
 
8.5.1 Medical Monitoring and AE/SAE Reporting 
Every KCC investigator initiated protocol includes requirements for reporting of 
adverse events based on CTC 4.0. All events are reported to the IRB and Medical 
Monitor using a password protected web-site. In addition all unexpected and serious 
adverse events (SAEs) are reported to the TJU IRB and to the Food and Drug 
Administration (FDA) if applicable. The investigator is required to submit all 
unexpected and serious adverse events to the TJU IRB and the Medical Monitor within 
the timeframes outlined in the below table. All AE/SAEs will be reported to the DSMC 
at the quarterly DSMC review meetings; however, if the Medical Monitor determines 
corrective action is necessary, and “ad hoc” DSMC meeting will be called. Fatal 
adverse events related to treatment which are unexpected must be reported 
within 24 hours to the TJU IRB and the DSMC. Fatalities not related to the study 
drug/device must be reported within 5 days. A summary of the reporting 
requirements for KCC investigator initiated Phase I and Phase II studies are presented 
below. Reporting requirements for Phase III investigator initiated studies are described 
in the protocol reviewed by the CCRRC and TJU IRB. 
 
 
Grade 1 
Grade 2 
Grade 2 
Grade 3 
Grade 3 
Grades 
4 
and 5 
 
Unexpected 
and 
Expected 
Unexpected 
Expected 
Unexpected 
with 
Hospitalization 
Unexpected 
without 
Hospitalization 
Expected with 
Hospitalization 
Expected 
without 
Hospitalization 
Unexpected 
and 
Expected 
Unrelated 
Unlikely 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and 
IRB 
Annual 
Review 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and 
IRB 
Annual 
Review 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
5 
Working 
Days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and 
IRB 
Annual 
Review 
5 
Working 
Days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and 
IRB 
Annual 
Review 
Phase 1 -   
48 
Hours   
(Death: 24 
Hours) 
 
Phase 2 -   
5 Working 
Days          

 
 
 
 
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Possible 
Probable 
Definite 
Reviewed 
at Quarterly 
DSMC 
Meeting 
and 
IRB 
Annual 
Review 
5 working 
days 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and IRB 
Annual 
Review 
48 
Hours   
(Death: 
24 
Hours) 
Phase 
1 
-   
48 Hours   
 
Phase 
2 
-   
5 
Working 
Days 
48 
Hours   
(Death: 
24 
Hours) 
Reviewed 
at 
Quarterly 
DSMC 
Meeting 
and 
IRB 
Annual 
Review 
Phase 1 and 
Phase 2 -   
48 
Hours   
(Death: 24 
Hours) 
 
 
**NOTE: This table is based on the NCI AE/SAE reporting Guidelines and the TJU IRB Policy and 
Procedures. Please follow the individual protocol AE/SAE reporting guidelines if more stringent 
reporting procedures are specified. 
 
 
8.5.2 Data and Safety Monitoring Committee 
Data and Safety Monitoring Committee (DSMC) is the Data and Safety Monitoring 
Board (DSMB) for the KCC. The DSMC is a multidisciplinary committee charged 
with overseeing the monitoring of safety of participants in clinical trials, and the 
conduct, progress, validity, and integrity of the data for all clinical trials at the 
Thomas Jefferson University KCC. The committee meets quarterly to review the 
progress and safety of all active research protocols that are not monitored by 
another safety and data monitoring committee or board. 
• The DSMC shall consist of a minimum 14 (including one non-voting 
member) members (see below) from the Department of Pharmacy 
(Thomas Jefferson University Hospital), the Clinical Cancer Research 
Review Committee (CCRRC), Thomas Jefferson University Division of 
Human Subjects Protection (responsible for the administration of the 
TJU IRBs), Thomas Jefferson University faculty, external members of 
the scientific community, and the KCC Clinical Trials Support Office 
(CRMO).  
• The DSMC meets quarterly. Additional DSMC meetings are scheduled 
based on the nature and number of trials being monitored over a 
specified time period. The DSMC meets (by conference call) within 24 
hours following the notification of an unexpected adverse event felt to be 
related to the study drug.  
• Prior to each DSMC meeting, each board member, is provided a printout 
of all reported AEs and SAEs occurring during the reporting period for 
this clinical trial. The principal investigator provides a detailed and 
comprehensive narrative assessment of current adverse events to date, 
indicating their possible significance and whether these toxicities have 
affected the conduct of the trial. DSMC members are provided with the 
principal investigator’s assessment, a written report summarizing 
adverse events, safety data, and activity data observed during the 
specified time period described in each protocol, as well as 

 
 
 
 
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recommendations from the Medical Monitor. A review of outcome results 
(response, toxicity and adverse events) and factors external to the study 
(such as scientific or therapeutic developments) is discussed, and the 
Committee votes on the status of each study.  
• A summary of the board’s action is sent to each investigator, the CCRRC 
and 
TJU 
IRBs. 
The 
DSMC 
actions 
may 
include 
recommendations/requirements that will lead to improved patient safety 
and/or efficacy, significant benefits or risks that have developed, or other 
changes determined to be necessary. The DSMC may also take note of 
slow accrual or lack of scientific progress, and refer such issues to the 
CCRRC. The DSMC provides the investigator with the rationale for any 
decision made. If for any reason the PI of the trial disagrees with the 
conclusions of the DSMC, the issue will be referred to the Associate 
Director of Clinical Investigations, who will be responsible for dispute 
resolution. The DSMC board action is also described in the progress 
report submitted by the principal investigator as part of the annual review 
of the protocol by the TJU IRBs. Any action resulting in temporary or 
permanent suspension of an NCI-funded clinical trial is reported to the 
NCI program director responsible for that grant by the CRMO with a copy 
of the communication to the principal investigator. 
 
9.0 DATA HANDLING AND RECORD KEEPING 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of 
the trial.  Source data are contained in source documents   Examples of these 
original documents, and data records include: hospital records, clinical and office 
charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies 
or transcriptions certified after verification as being accurate and complete, 

 
 
 
 
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microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-
technical departments involved in the clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done 
or the question was not asked, write “N/D”.  If the item is not applicable to the 
individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line 
through the incorrect entry and enter the correct data above it.  All such changes 
must be initialed and dated.  DO NOT ERASE OR WHITE OUT ERRORS.  For 
clarification of illegible or uncertain entries, print the clarification above the item, 
then initial and date it. 
9.4 Records Retention 
For non-FDA regulated studies, summarize the record retention plan applicable to 
the study (taking into account any applicable Department, Division or Research 
Center requirements) 
 
For FDA-regulated studies the following sample language is appropriate: 
 
It is the investigator’s responsibility to retain study essential documents for at least 
2 years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at 
least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the 
responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.  
 
10.0 STUDY MONITORING, AUDITING, AND INSPECTING 
10.1 Study Monitoring Plan 
The investigator will allocate adequate time for monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality 
assurance reviewer is given access to all the above noted study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), 
and has adequate space to conduct the monitoring visit. 
 
KCC Investigator Initiated Phase I Studies  

 
 
 
 
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Phase I studies require continuous monitoring by the PI of the study with quarterly 
safety and monitoring reports submitted to the CRMO and the DSMC. The investigator 
is required to submit all unexpected on-site adverse events and serious adverse 
events (SAEs) to the TJU IRB and the DSMC within 48 hours. Fatal adverse events 
which are unexpected must be reported within 24 hours to the TJU IRB and the DSMC. 
Fatalities not related to the study drug/device must be reported within 5 days.  
 
Each protocol is assigned to a medical monitor (a physician or other member of the 
DSMC who has expertise in the therapeutic area of the protocol and is not directly 
involved in this trial). The medical monitor reviews all adverse events (in addition to 
unexpected adverse events), safety data and activity data observed in the ongoing 
clinical trial at each new dose level, prior to dose escalation.  
 
The PI provides a report to the DSMC of all AE/SAEs, safety and toxicity data, and 
any corrective action that occurred on a quarterly basis. The medical monitor also 
provides a summary of their review. The summary of all discussions of adverse events 
are submitted to the DSMC, and these reports are reviewed during the DSMC 
meetings that take place quarterly. Patients are only identified by initials, and no other 
personal health information (PHI) is included in the reports.  
The medical monitor may recommend reporting adverse events and relevant safety 
data not previously reported, and may recommend suspension or termination of the 
trial based on their review of AE/SAE data observed throughout the life of a clinical 
trial. In such circumstances, and “ad hoc” DSMC meeting will be called to discuss 
corrective action with the PI. If for any reason the PI of the trial disagrees with the 
conclusions of the Medical Monitor or DSMC, the issue will be referred to the Associate 
Director of Clinical Investigations, who will be responsible for dispute resolution.  
 
The summary of all discussions of adverse events are included in the KCC 
investigator’s reports to the TJU IRBs as part of its annual progress report. The DSMC 
and the TJU IRBs may, based on the monitor’s recommendation suspend or terminate 
the trial. The quarterly safety and monitoring reports include a statement as to whether 
this data has invoked any stopping criteria in the clinical protocol.  
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the sponsor, government regulatory bodies, and University compliance and 
quality assurance groups of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The 
investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable University 
compliance and quality assurance offices. 
 

 
 
 
 
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10.2.1 Independent External and Internal Audits  
In addition to review by the DSMC, all studies initiated by KCC investigators are 
audited by an independent auditor once they have achieved 10% of target accrual. 
However, a study can be audited at any time based on recommendations by the IRB, 
DSMC, CCRRC and/or the Director of Clinical Investigations, KCC. Studies are re-
audited once they have achieved 50% of target accrual. Special audits may be 
recommended by the IRB, DSMC or CCRRC based on prior findings, allegations of 
scientific misconduct and where significant irregularities are found through quality 
control procedures. Any irregularities identified as part of this process would result in 
a full audit of that study.  
 
In addition to the audits at 10 and 50%, the CRMO randomly audits at least 10 percent 
of all patients entered into therapeutic KCC trials and other trials as necessary, on at 
least a bi-annual basis, to verify that there is a signed and dated patient consent form, 
the patient has met the eligibility criteria, and that SAEs are documented and reported 
to the TJU IRB.  
 
All audit reports are submitted to the DSMC for review and action (when appropriate). 
A copy of this report and recommended DSMC action is sent to the CCRRC and TJU 
IRB. The committee regards the scientific review process as dynamic and constructive 
rather than punitive. The review process is designed to assist Principal Investigators 
in ensuring the safety of study subjects and the adequacy and accuracy of any data 
generated. The TJU IRB may, based on the DSMC and auditor’s recommendation, 
suspend or terminate the trial.  
11.0 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good 
Clinical Practice (FDA Title 21 part 312 and International Conference on 
Harmonization guidelines), applicable government regulations and Institutional 
research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted 
independent Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator 
before commencement of this study.   
 
All subjects for this study will be provided a consent form that is compliant with 
local and federal regulations, describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in 
this study.  See Attachment for a copy of the Subject Informed Consent Form.  This 
consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent 
form, must be obtained before that subject is submitted to any study procedure.  
This consent form must be signed by the subject or legally acceptable surrogate, 
and the investigator-designated research professional obtaining the consent.  

 
 
 
 
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12.0 STUDY FINANCES 
12.1 Funding Source 
This study is currently unfunded and will be supported by departmental funds. 
12.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, 
etc.) must have the conflict reviewed by a properly constituted Conflict of Interest 
Committee with a Committee-sanctioned conflict management plan that has been 
reviewed and approved by the study sponsor prior to participation in this study.  All 
Jefferson University Investigators will follow the TJU Conflicts of Interest Policy for 
Employees (107.03). 
12.3 Subject Stipends or Payments 
There is no subject stipend/payment.  
14.0 REFERENCES 
Adkison, J.B., Mchaffie, D.R., Bentzen, S.M., Patel, R.R., Khuntia, D., Petereit, 
D.G. et al. (2010) Phase I Trial of Pelvic Nodal Dose Escalation with 
Hypofractionated Imrt for High-Risk Prostate Cancer. Int J Radiat Oncol Biol 
Phys:  
 
Al-Mamgani, A., Van Putten, W.L., Heemsbergen, W.D., Van Leenders, G.J., 
Slot, A., Dielwart, M.F. et al. (2008) Update of Dutch Multicenter Dose-Escalation 
Trial of Radiotherapy for Localized Prostate Cancer. Int J Radiat Oncol Biol Phys 
72: 980-988. 
 
Boike, T.P., Lotan, Y., Cho, L.C., Brindle, J., Derose, P., Xie, X.J. et al. (2011) 
Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- 
and Intermediate-Risk Prostate Cancer. J Clin Oncol 29: 2020-2026. 
 
Brenner, D.J., Martinez, A.A., Edmundson, G.K., Mitchell, C., Thames, H.D., and 
Armour, E.P. (2002) Direct Evidence That Prostate Tumors Show High 
Sensitivity to Fractionation (Low Alpha/Beta Ratio), Similar to Late-Responding 
Normal Tissue. Int J Radiat Oncol Biol Phys 52: 6-13. 
 
D'amico, A.V., Whittington, R., Malkowicz, S.B., Schultz, D., Blank, K., Broderick, 
G.A. et al. (1998) Biochemical Outcome after Radical Prostatectomy, External 
Beam Radiation Therapy, or Interstitial Radiation Therapy for Clinically Localized 
Prostate Cancer. JAMA 280: 969-974. 
 

 
 
 
 
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Dearnaley, D.P., Sydes, M.R., Graham, J.D., Aird, E.G., Bottomley, D., Cowan, 
R.A. et al. (2007) Escalated-Dose Versus Standard-Dose Conformal 
Radiotherapy in Prostate Cancer: First Results from the Mrc Rt01 Randomised 
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Demanes, D.J., Rodriguez, R.R., Schour, L., Brandt, D., and Altieri, G. (2005) 
High-Dose-Rate Intensity-Modulated Brachytherapy with External Beam 
Radiotherapy for Prostate Cancer: California Endocurietherapy's 10-Year 
Results. Int J Radiat Oncol Biol Phys 61: 1306-1316. 
 
Deutsch, I., Zelefsky, M.J., Zhang, Z., Mo, Q., Zaider, M., Cohen, G. et al. (2010) 
Comparison of Psa Relapse-Free Survival in Patients Treated with Ultra-High-
Dose Imrt Versus Combination Hdr Brachytherapy and Imrt. Brachytherapy 9: 
313-318. 
 
Fowler, J., Chappell, R., and Ritter, M. (2001) Is Alpha/Beta for Prostate Tumors 
Really Low? Int J Radiat Oncol Biol Phys 50: 1021-1031. 
 
Fowler, J.F., Ritter, M.A., Chappell, R.J., and Brenner, D.J. (2003) What 
Hypofractionated Protocols Should Be Tested for Prostate Cancer? Int J Radiat 
Oncol Biol Phys 56: 1093-1104. 
 
Galalae, R.M., Kovacs, G., Schultze, J., Loch, T., Rzehak, P., Wilhelm, R. et al. 
(2002) Long-Term Outcome after Elective Irradiation of the Pelvic Lymphatics 
and Local Dose Escalation Using High-Dose-Rate Brachytherapy for Locally 
Advanced Prostate Cancer. Int J Radiat Oncol Biol Phys 52: 81-90. 
 
Holmboe, E.S. and Concato, J. (2000) Treatment Decisions for Localized 
Prostate Cancer: Asking Men What's Important. J Gen Intern Med 15: 694-701. 
 
Hoskin, P.J., Motohashi, K., Bownes, P., Bryant, L., and Ostler, P. (2007) High 
Dose Rate Brachytherapy in Combination with External Beam Radiotherapy in 
the Radical Treatment of Prostate Cancer: Initial Results of a Randomised Phase 
Three Trial. Radiother Oncol 84: 114-120. 
 
Jabbari, S., Weinberg, V.K., Kaprealian, T., Hsu, I.C., Ma, L., Chuang, C. et al. 
(2010) Stereotactic Body Radiotherapy as Monotherapy or Post-External Beam 
Radiotherapy Boost for Prostate Cancer: Technique, Early Toxicity, and Psa 
Response. Int J Radiat Oncol Biol Phys:  
 
Jemal, A., Bray, F., Center, M.M., Ferlay, J., Ward, E., and Forman, D. (2011) 
Global Cancer Statistics. CA Cancer J Clin 61: 69-90. 
 
King, C. (2011) Stereotactic Body Radiotherapy for Prostate Cancer: Current 
Results of a Phase Ii Trial. Front Radiat Ther Oncol 43: 428-437. 

 
 
 
 
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Kuban, D.A., Tucker, S.L., Dong, L., Starkschall, G., Huang, E.H., Cheung, M.R. 
et al. (2008) Long-Term Results of the M. D. Anderson Randomized Dose-
Escalation Trial for Prostate Cancer. Int J Radiat Oncol Biol Phys 70: 67-74. 
 
Mohler, J., Bahnson, R.R., Boston, B., Busby, J.E., D'amico, A., Eastham, J.A. et 
al. (2010) Nccn Clinical Practice Guidelines in Oncology: Prostate Cancer. J Natl 
Compr Canc Netw 8: 162-200. 
 
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15.0 APPENDICES 
 
Appendix I 
EPIC questionnaire 
Appendix II AUA Index 
Appendix III Karnofsky Performance Status scale 
Appendix IV Study Calendar 

 
 
 
 
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Appendix II  
 
AUA Index
 
Appendix III 
 
Karnofsky Performance Status scale 

 
 
 
 
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100 
Normal; no complaints; no evidence of disease 
 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
 
80 
Normal activity with effort; some sign or symptoms of disease 
 
70 
Cares for self; unable to carry on normal activity or do active work 
 
60 
Requires occasional assistance, but is able to care for most personal 
needs 
 
50 
Requires considerable assistance and frequent medical care 
 
40 
Disabled; requires special care and assistance 
 
30 
Severely disabled; hospitalization is indicated, although death not 
imminent 
 
20 
Very sick; hospitalization necessary; active support treatment is necessary 
 
10 
Moribund; fatal processes progressing rapidly 
 
0 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix IV 
 
Study Calendar 

 
 
 
 
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See Sections 4.1 and 6.0 for additional details.