Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) With a GNRH Agonist vs. Dose Escalated Radiation Therapy and Enhanced ADT With a GNRH Agonist and TAK-700 For Men With High Risk Prostate Cancer
Phase: PHASE3
Conditions: Prostate Cancer
Sponsor: Radiation Therapy Oncology Group

NRG ONCOLOGY 
Radiation Therapy Oncology Group 
 
RTOG 1115 
 
(ClinicalTrials.gov NCT #: 01546987) 
 
 
Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen 
Deprivation Therapy (ADT) with a GnRH Agonist vs. Dose Escalated 
Radiation Therapy and Enhanced ADT with a GnRH Agonist and TAK-700 
for Men with High Risk Prostate Cancer 
 
 
 
Amendment 3:  June 12, 2018 

1 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
NRG ONCOLOGY 
RTOG 1115 
 
PHASE III TRIAL OF DOSE ESCALATED RADIATION THERAPY AND STANDARD 
ANDROGEN DEPRIVATION THERAPY (ADT) WITH A GNRH AGONIST VS. DOSE 
ESCALATED RADIATION THERAPY AND ENHANCED ADT WITH A GNRH 
AGONIST AND TAK-700 FOR MEN WITH HIGH RISK PROSTATE CANCER 
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by the 
National Cancer Institute (NCI). The trial will be led by NRG Oncology with the participation of the network 
of NCTN organizations: the Alliance, ECOG-ACRIN, and SWOG. 
 
Study Chairs (12Jun2018) 
Principal Investigator/Medical Oncology 
M. Dror Michaelson, MD, PhD 
Massachusetts General Hospital 
32 Fruit Street, Yaw 7E 
Boston, MA 02114 
Phone: 617-726-1594/Fax: 617-726-3440 
E-mail: dmichaelson1@partners.org 
Radiation Oncology Co-Chair 
Daniel Hamstra, MD, PhD 
William Beaumont Hospital 
18101 Oakwood Blvd. 
Dearborn, MI 48124 
Phone: 313-593-3773/Fax: 313-593-8844 
E-mail:  Daniel.Hamstra@Beaumont.org 
Brachytherapy Co-Chair 
François Bachand, MD, FRCPC 
Radiation Oncology 
BC Cancer Agency 
Center for Southern Interior 
399 Royal Avenue 
Kelowna, BC 
V1Y 5L3 
Phone: 250-979-6645/Fax: 250-712-3911 
E-mail: FBachand@bccancer.bc.ca 
Urology Co-Chair 
Viraj Master, MD PhD 
Emory University 
Emory Clinic Building B-1400  
1365 Clifton Road, NE  
Atlanta, GA 30322 
Phone: 404-778-4898 
E-mail: virajmaster@gmail.com 
 
 
Outcomes Co-Chair 
Deborah Watkins Bruner, RN, PhD, FAAN 
Nell Hodgson Woodruff School of Nursing 
Emory University 
1520 Clifton Road, Room 232 
Atlanta, GA 30322 
Phone: 404-712-9695/Fax: 404-727-8514 
E-mail: deborah.w.bruner@emory.edu 
Fatigue Co-Chair 
Mylin A. Torres, MD 
Department of Radiation Oncology 
Emory University School of Medicine 
1365-C Clifton Road Northeast 
Clinic C Suite 3012 
Atlanta, GA 30322 
Phone: 404-778-3473/Fax: 404-778-4139 
E-mail: matorre@emory.edu 
Translational Research Co-Chair 
Philip J. Saylor, MD 
Massachusetts General Hospital Cancer Center 
55 Fruit Street, Yaw 7E 
Boston, MA 02114 
Phone: 617-724-4000/Fax: 617-726-8685  
E-mail: psaylor@partners.org 
 
 
Medical Physics Co-Chair 
Robert E. Wallace, PhD 
Cedars-Sinai Medical Center 
Department of Radiation Oncology 
8700 Beverly Boulevard 
Los Angeles, CA 90048 
Phone: 310-423-1113 
E-mail: robert.wallace@cshs.org 
 

2 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
NRG ONCOLOGY 
 
RTOG 1115 
 
Study Chairs (continued) 
Senior Statistician 
James J. Dignam, PhD 
NRG Oncology Statistical and Data Management 
Center & The University of Chicago Biological 
Sciences 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
Phone: 215-574-3174/Fax: 215-928-0153 
E-mail: dignamj@nrgoncology.org 
 
Radiation Oncology Co-Chair/ECOG 
Neha Vapiwala, MD 
Perelman Center for Advanced Medicine 
Radiation Oncology 
3400 Civic Center Boulevard 
Fourth Floor West Pavilion 
Philadelphia, PA 19104 
Phone: 215-662-2337 
E-mail: vapiwala@uphs.upenn.edu 
 
 
 
Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
TAK-700 
Millennium 
N/A 
115368 
Leuprolide 
Goserelin 
Buserelin 
Triptorelin 
Flutamide 
Bicalutamide 
Commercial 
 
N/A 
 
Exempt 
 
 
Participating Sites: 
 U.S. and Canada 
Document History 
 
Version/Update Date 
Broadcast Date 
Amendment 3 
June 12, 2018 
N/A  
Closure 
-- 
September 30, 2014 
Amendment 2 
April 16, 2014 
June 17, 2014 
Update 
February 4, 2014 
February 4, 2014 
Amendment 1 
December 17, 2013 
February 4, 2014 
Update 
February 5, 2013 
February 5, 2013 
Update  
August 9, 2012 
August 9, 2012 
Update 
May 2, 2012 
May 2, 2012 
Update 
May 1, 2012 
May 1, 2012 
Activation 
February 10, 2012 
May 1, 2012 
 
  
NRG Oncology 
1-800-227-5463, ext. 4189 
 
  
 
 
 
 
 
 
This protocol was designed and developed by NRG Oncology.  It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry.  
No other use or reproduction is authorized by NRG Oncology nor does NRG 
Oncology assume any responsibility for unauthorized use of this protocol. 

3 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
NRG ONCOLOGY 
RTOG 1115 
 
PHASE III TRIAL OF DOSE ESCALATED RADIATION THERAPY AND STANDARD ANDROGEN 
DEPRIVATION THERAPY (ADT) WITH A GNRH AGONIST VS. DOSE ESCALATED RADIATION 
THERAPY AND ENHANCED ADT WITH A GNRH AGONIST AND TAK-700 FOR MEN WITH HIGH 
RISK PROSTATE CANCER 
 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION (12Jun2018) 
To submit site registration 
documents: 
For patient enrollments:  
Submit study data  directly 
to the Lead Cooperative 
Group unless otherwise 
specified in the protocol:  
Regulatory documentation can 
be submitted to the CTSU via: 
ONLINE: Regulatory 
Submission Portal (Sign in at 
www.ctsu.org, and select the 
Regulatory Submission sub-tab 
under the Regulatory tab.)  
 
 
Please refer to the patient 
enrollment section for instructions 
on using the OPEN system. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol for 
further instructions.  
 
Do not submit study data 
or forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ web site is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
 
For patient eligibility or treatment-related questions Contact the Study PI of the Lead 
Protocol Organization  
 
For questions unrelated to patient eligibility, treatment, or data submission contact 
the CTSU Help Desk by phone or e-mail:  
 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls 
and correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 
 
The CTSU Web site is located at   https://www.ctsu.org 
 
The following Cooperative Groups have endorsed this trial: ECOG: Co-Chair: Neha Vapiwala, MD. 
ECOG members will enroll patients to this study via the Cancer Trials Support unit (CTSU). 
 

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RTOG 1115, Version Date June 12, 2018 
 
 
Table of Contents 
RTOG 1115 ................................................................................................................................................... 1 
SCHEMA ....................................................................................................................................................... 6 
ELIGIBILITY CHECKLIST ............................................................................................................................. 7 
1.0 
INTRODUCTION ............................................................................................................................. 12 
1.1 
Background ................................................................................................................................. 12 
1.2 
Adjuvant/concurrent/neoadjuvant ADT with Radiation Therapy ................................................. 12 
1.3 
Safety of Proposed Therapy ....................................................................................................... 12 
1.4 
Prostate Cancer Survivorship ..................................................................................................... 13 
1.5 
Fatigue ........................................................................................................................................ 14 
2.0 
OBJECTIVES .................................................................................................................................. 17 
2.1 
Primary Objective ........................................................................................................................ 17 
2.2 
Secondary Objectives ................................................................................................................. 17 
3.0 
PATIENT SELECTION .................................................................................................................... 17 
3.1 
Conditions for Patient Eligibility ................................................................................................... 17 
3.2 
Conditions for Patient Ineligibility) ............................................................................................... 18 
4.0 
PRETREATMENT EVALUATIONS/MANAGEMENT...................................................................... 19 
4.1 
Required Evaluations/Management ............................................................................................ 19 
5.0 
REGISTRATION PROCEDURES ................................................................................................... 20 
Access Requirements for OPEN, Medidata Rave®, and TRIAD ............................................................ 20 
5.1 
Pre-Registration Requirements for IMRT Treatment Approach .................................................. 21 
5.2 
Pre-Registration Requirements for 3DCRT Treatment Approach .............................................. 21 
5.3 
Pre-Registration Requirements for Brachytherapy Treatment Approach ................................... 21 
5.4 
Digital RT Data Submission to RTOG Using TRIAD................................................................... 22 
5.5  
Regulatory Pre-Registration Requirements) ............................................................................... 22 
5.6 
OPEN Registration ...................................................................................................................... 24 
6.0 
RADIATION THERAPY ................................................................................................................... 25 
6.1  
Two Stage Radiation Plan ........................................................................................................... 25 
6.2 
Technical Factors ........................................................................................................................ 26 
6.3 
EBRT Localization, Simulation, and Immobilization.................................................................... 26 
6.4 
Treatment Planning/Target Volumes .......................................................................................... 27 
6.5 
Critical Structures ........................................................................................................................ 29 
6.6 
Treatment Verification ................................................................................................................. 30 
6.7 
Quality Assurance ....................................................................................................................... 30 
6.8  
Dose Specifications/Technical Considerations: LDR Brachytherapy Boost ............................... 31 
6.9  
Dose Specifications/Technical Considerations: HDR Brachytherapy Boost .............................. 32 
6.10 
R.T. Quality Assurance Reviews................................................................................................. 35 
6.11 
Radiation Therapy Adverse Events ............................................................................................ 35 
6.12 
Radiation Therapy Adverse Event Reporting .............................................................................. 36 
7.0 
DRUG THERAPY ............................................................................................................................ 36 
7.1 
Treatment .................................................................................................................................... 36 
7.2 
LHRH agonists (such as leuprolide, goserelin, buserelin, triptorelin) ......................................... 36 
7.3 
Eulexin (flutamide) ...................................................................................................................... 37 
7.4 
Casodex (bicalutamide) .............................................................................................................. 37 
7.5  
Study Drug (TAK-700) Administration (TAK-700, IND # 115368) ............................................... 38 
7.6  
TAK-700 Dose Modification and Supportive Care Guidelines .................................................... 38 
7.7  
Excluded Concomitant Medications and Procedures ................................................................. 41 
7.8  
Precautions and Restrictions ...................................................................................................... 41 
7.9  
Blinding and Unblinding .............................................................................................................. 42 
7.10  
Description of Investigational Agent ............................................................................................ 42 
7.11  
Preparation, Reconstitution, and Dispensation ........................................................................... 42 
7.12  
Packaging and Labeling .............................................................................................................. 42 
7.13  
Storage, Handling, and Accountability ........................................................................................ 42 

5 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
7.14 
Supply ......................................................................................................................................... 43 
7.15 
Modality Reviews ........................................................................................................................ 44 
7.16 
Adverse Events ........................................................................................................................... 45 
7.17 
CTEP-AERS Adverse Event Reporting Requirements ............................................................... 46 
8.0 
SURGERY ....................................................................................................................................... 47 
9.0 
OTHER THERAPY .......................................................................................................................... 48 
9.1 
Permitted Supportive Therapy .................................................................................................... 48 
9.2 
Non-permitted Supportive Therapy ............................................................................................. 48 
10.0 
TISSUE/SPECIMEN SUBMISSION ................................................................................................ 48 
10.1 
Tissue/Specimen Submission ..................................................................................................... 48 
10.2 
Specimen Collection for Translational Research (Mandatory) ................................................... 48 
10.3 
Specimen Collection for Tissue Banking and Translational Research (Strongly Recommended) 
(12/17/13) ................................................................................................................................................ 49 
10.4 
Storage Conditions ...................................................................................................................... 51 
10.5 
Submit materials for Tissue Banking and Translational Research ............................................. 51 
10.6 
Reimbursement ........................................................................................................................... 51 
10.7 
Confidentiality/Storage ................................................................................................................ 52 
11.0 
PATIENT ASSESSMENTS ............................................................................................................. 52 
11.1 
Study Parameters ....................................................................................................................... 52 
11.2  
PROMIS-Fatigue Short Form ...................................................................................................... 52 
11.3  
Health Related Quality of Life (HRQOL) Assessments .............................................................. 53 
11.4 
Criteria for Discontinuation of Protocol Treatment ...................................................................... 54 
12.0 
DATA COLLECTION ....................................................................................................................... 54 
12.1 
Summary of Data Submission..................................................................................................... 55 
12.2  
Summary of Dosimetry Digital Data Submission ........................................................................ 58 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 59 
13.1 
Primary Endpoint ......................................................................................................................... 59 
13.2 
Secondary Endpoints .................................................................................................................. 59 
13.3 
Sample Size Determination ......................................................................................................... 60 
13.4   Randomization ............................................................................................................................... 60 
13.5   Analysis Plan ................................................................................................................................. 61 
13.6 
Gender and Minorities ................................................................................................................. 66 
REFERENCES ............................................................................................................................................ 67 
APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (12/17/13) ............... 73 
APPENDIX II ............................................................................................................................................... 78 
APPENDIX III .............................................................................................................................................. 79 
APPENDIX IV .............................................................................................................................................. 81 
APPENDIX V ............................................................................................................................................... 82 
APPENDIX VI .............................................................................................................................................. 86 
APPENDIX VII ............................................................................................................................................. 89 
 
 
 
 
 
 
  

6 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
NRG ONCOLOGY 
 
RTOG 1115 
 
Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy 
(ADT) with a GnRH Agonist vs. Dose Escalated Radiation Therapy and Enhanced ADT with a 
GnRH Agonist and TAK-700 for Men with High Risk Prostate Cancer 
SCHEMA 
(12/17/13) 
 
 
 
 
 
S 
T 
R 
A 
T 
I 
F 
Y 
 
 
Risk Groups 
 
1. Gleason ≥ 9, PSA ≤ 150, any T-stage 
 
2. Gleason 8, PSA < 20, and ≥ T2 
 
3. Gleason 8, PSA ≥ 20-150, any T-
stage 
 
4. Gleason 7, PSA ≥ 20-150, any T-
stage 
 
 
 
 
 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
(1:1) 
 
Arm 1: 
Androgen Deprivation Therapy: 
GnRH agonist for 24 months with concurrent 
oral antiandrogen until completion of radiation 
+ 
Dose Escalated Radiation: 
To start 8-10 weeks after initiation of ADT. 
Initially, 45 Gy to prostate and pelvic lymph 
nodes delivered with 3DCRT/IMRT with a boost 
to be provided with IMRT, LDR implant, or HDR 
implant. 
 
 
Type of RT Boost 
 
1. IMRT 
 
2. Brachytherapy  
(LDR using PPI or HDR) 
 
 
Arm 2: 
Androgen Deprivation Therapy: 
GnRH agonist for 24 months with concurrent 
oral antiandrogen until completion of radiation 
+ 
TAK-700 twice daily for 24 months 
+ 
Dose Escalated Radiation: 
To start 8-10 weeks after initiation of ADT. 
Initially, 45 Gy to prostate and pelvic lymph 
nodes delivered with 3DCRT/IMRT with a boost 
to be provided with IMRT, LDR implant, or HDR 
implant. 
 
 
ADT Started Prior to Registration 
 
1. No 
 
2. Yes 
 
 
See pre-registration requirements in Section 5.0. See Section 7.0 for details/doses of study drug. 
 
Patient Population:  (See Section 3.0 for Eligibility)  
Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration 
at high risk for recurrence as determined by one of the following combinations:  
 
Gleason score 
 
PSA 
 
T-Stage 
> 9 
and 
< 150 
and 
Any 
8 
and 
< 20 
and 
> T2 
8 
and 
> 20-150 
and 
Any 
7 
and 
> 20-150 
and 
Any 
 
 
Required Sample Size: 900 

7 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
ELIGIBILITY CHECKLIST (4/16/14) 
(page 1 of 5) 
NRG Oncology Institution #   
 
RTOG 1115 
 
 
 
 
Case #  
1. 
____(Y)  Does the patient have a histologically confirmed diagnosis of adenocarcinoma of the 
prostate within 180 days prior to registration? 
 
2. 
____(Y)  Was a history/physical examination done within 60 days prior to registration? 
 
3. 
____(Y)  Did the patient have clinically negative lymph nodes within 90 days prior to registration 
demonstrated by imaging (abdominal and/or pelvic CT or MRI) which if deemed equivocal or questionable 
the nodes are less than 2.0 cm or negative nodes per nodal sampling or dissection? 
 
4. 
____(Y)  Did a bone scan demonstrate no distant metastases (M0) within 90 days prior to 
registration (18F-Na PET is an acceptable substitute)—and if the bone scan was equivocal were plain 
films negative? 
 
5. 
____(Y)  Was the study entry (baseline) PSA performed with an FDA approved assay within 180 
days prior to registration and prior to the start of any hormone ablation therapy?  
 
6. 
____N/Y  Was ADT started prior to registration (must be 50 days or less from registration)? 
 
 
If yes: 
 
 
 
Date started___________ 
 
 
 
Drug(s) started__________ 
Please note: If patient has started ADT prior to registration, he is not eligible to participate in the 
quality of life component of this study. 
 
7. 
____(N)  Did the patient have testosterone administered within 90 days prior to registration? 
 
8. 
____(Y)  Is the patient’s performance status 0 or 1 documented within 21 days prior to 
registration? 
 
9. 
____(Y)  Is the patient’s age 18 years or greater? 
 
10. 
____(Y)  Has a CBC with differential been obtained within 14 days prior to registration 
demonstrating adequate bone marrow function as follows? 
 Absolute neutrophil count (ANC) ≥ 1800 cells/mm3 
 Platelets ≥ 100,000 cells/mm3 
 Hemoglobin ≥ 8.0 g/dl  
 
11.  
Y) Has a serum creatinine with a value of <2.0 ng/dL and a creatinine clearance (calculated can 
be used) showing 40 mL/min been obtained within 21 days prior to registration?  
 
12. 
(Y) Has a total bilirubin with a value of < 1.5x the institutional ULN and an ALT or AST < 2.5x the 
institutional ULN been obtained within 21 days prior to registration? 
 
13. 
(Y) Has serum testosterone been obtained within 21 days prior to registration?  
 
14. 
(Y) Has a chemistry panel (including sodium, potassium, chloride, bicarbonate (carbon dioxide), 
BUN, glucose, calcium, magnesium and phosphorus) and liver studies (including albumin and alkaline 
phosphatase) been obtained within 21 days prior to registration? 
 
15. 
(Y) Has a fasting glucose, fasting insulin, lipid panel (cholesterol, triglyceride, HDL, LDL), and 
Hemoglobin A1C been obtained within 21 days prior to registration? 
 

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RTOG 1115, Version Date June 12, 2018 
 
 
NRG Oncology Institution #   
 
RTOG 1115 
 
 
 
ELIGIBILITY CHECKLIST (12/17/13) 
Case #  
 
 
 
     (page 2 of 5) 
 
16. 
____(Y)  Has a screening calculated ejection fraction been obtained by multiple gated acquisition 
(MUGA) scan or by echocardiogram (ECHO) demonstrating a result of ≥ to institutional lower limit of 
normal? 
 
17. 
____(Y)  Has a baseline ECG been obtained within 180 days prior to registration? 
 
18. 
____(Y/N/A)  If the patient is a man of child-producing potential has he agreed to use effective 
contraception while on treatment and for at least 120 days after treatment has been completed? 
 
19. 
____(Y)  Is the patient able to provide study specific informed consent prior to study registration? 
 
20. 
____(Y)  Does the patient demonstrate a high risk for prostate cancer recurrence as determined 
by one of the following combinations? 
 
 Gleason score ≥ 9 and PSA ≤ 150 and Any T-stage 
 
 Gleason score 8 and PSA < 20 and T-stage ≥ T2 
 
 Gleason score 8 and PSA ≥ 20-150 and Any T-stage 
 
 Gleason score 7 and PSA ≥ 20-150 and Any T-stage 
 
______  What is the Gleason score? 
 
______  What is the PSA value? 
 
______  What is the T-stage? 
 
21. 
____(N)  Is the PSA value > 150? 
 
22. 
____(N)  Is there evidence of metastatic disease? 
 
23. 
____(N)  Are there pathologically positive pelvic lymph nodes or pelvic lymph nodes > 2.0 cm 
demonstrated by imaging (CT or MR)? 
 
24. 
____(N)  Has the patient had a radical prostatectomy, cryosurgery for prostate cancer or a 
bilateral orchiectomy for any reason? 
 
25. 
____(N)  Has the patient had a prior invasive malignancy (except non-melanoma skin cancer) 
unless disease free or not requiring systemic therapy for a minimum of 3 years? 
 
26. 
____(N)  Has the patient had prior systemic chemotherapy for prostate cancer? 
 
27. 
____(N)  Has the patient had prior radiotherapy, including brachytherapy, to the region of the 
prostate that would result in overlap of radiation therapy fields?  
 
28. 
____(N)  Has the patient had previous hormonal therapy for > 50 days prior to registration? 
 
29. 
____(N)  Does the patient have a known hypersensitivity to TAK-700 or related compounds or 
any other drugs being used in this study? 
 

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RTOG 1115, Version Date June 12, 2018 
 
 
NRG Oncology Institution #  
 
 
RTOG 1115 
 
 
 
ELIGIBILITY CHECKLIST (12/17/13) 
Case #  
 
 
 
 
     (page 3 of 5) 
 
30. 
____(N)  Has the study entry PSA been obtained during either of the following time frames:  
10 day period following a prostate biopsy or following the initiation of hormonal therapy? 
 
31. 
____ (N)  Does the patient have a history of adrenal insufficiency? 
 
32. ____ (N) Does this patient have any severe or active co-morbidities as defined by the following? 
 A major surgical procedure within 14 days prior to registration 
 Ongoing arrhythmias (greater than grade 2); thromboembolic events or any other cardiac 
condition (such as pericardial effusion, etc.) within 6 months prior to registration 
 Class III or IV heart failure per New York Heart Association classification 
 ECG abnormalities: 
-Q-wave infarction unless identified more than 6 months prior to registration 
-QTc interval greater than 460 msec 
 
Chronic liver disease (bilirubin > 1.5 x ULN; ALT or AST > 2.5x ULN) 
 
Serious infection within 14 days prior to registration 
 
Unstable symptomatic ischemic heart disease 
 
History of myocardial infarction 
 
33.____(N)  Does the patient have a history of Cushing’s syndrome? 
 
34. ____(N)  Does the patient have a history of severe chronic renal disease demonstrated by a serum 
Creatinine > 2.0 mg/dl and a Creatinine clearance of < 40 mL/min? 
 
35. ____(N)  Has the patient had chronic treatment with glucocorticoids within the last year? 
 
36. ____(N)  Does the patient have uncontrolled hypertension despite appropriate medical therapy 
characterized by a blood pressure of greater than 150 mm Hg systolic and 90 mm Hg diastolic at two 
separate measurements no more than 60 minutes apart within 21 days prior to registration? 
 
37. ____(N)  Does the patient have uncontrolled nausea, vomiting or diarrhea (grade 3 or greater) despite 
appropriate medical therapy at the time of registration? 
 
38. ____(N)  Does the patient have a known gastrointestinal disease or procedure that might interfere 
with the oral absorption or tolerance of TAK-700, including difficulty swallowing tablets at the time of 
registration? 
  
39 ____(Y) Even if surgically sterilized (vasectomy), does the patient agree to practice effective barrier 
contraception during the entire study treatment period and for (4) months after the last dose of study drug 
or abstain from intercourse completely? 
 
 

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RTOG 1115, Version Date June 12, 2018 
 
 
NRG Oncology Institution #   
 
RTOG 1115 
 
 
 
ELIGIBILITY CHECKLIST (12/17/13) (2/4/14) 
Case #  
 
 
 
     (page 4 of 5)  
 
The following questions will be asked at Study Registration:  
IMRT CREDENTIALING IS REQUIRED BEFORE REGISTRATION 
 
 
         
1. 
Institutional person randomizing case. 
 
                  (Y) 2. 
Has the Eligibility Checklist been completed? 
 
                  (Y) 3. 
In the opinion of the investigator, is the patient eligible? 
 
 
         
4. 
Date informed consent signed 
 
 
         
5. 
Patient’s Initials (First Middle Last) 
 
 
         
6. 
Verifying Physician 
 
 
         
7. 
Patient ID  
 
 
         
8. 
Date of Birth 
 
 
         
9. 
Race 
 
 
         
10. 
Ethnicity 
 
 
         
11. 
Gender 
 
 
         
12. 
Country of Residence 
 
 
         
13. 
Zip Code (U.S. Residents) 
 
 
         
14. 
Method of Payment 
 
 
         
15. 
Any care at a VA or Military Hospital? 
 
 
         
16. 
Calendar Base Date (date hormone ablation to start—if hormones started prior to       
registration use today’s date) 
 
 
         
17. 
Randomization date 
 
              (Y/N) 18. 
Have you obtained the patient's consent for his or her tissue to be kept for use in 
research to learn about, prevent, treat, or cure cancer?  
 
              (Y/N) 19.  
Have you obtained the patient's consent for his or her blood to be kept for use in  
research to learn about, prevent, treat, or cure cancer? (Note: Blood collection is 
mandatory for patients participating in QOL). 
 
              (Y/N) 20. 
Have you obtained the patient's consent for his or her tissue to be kept for use in  
research about other health problems (for example: causes of diabetes, 
Alzheimer's disease, and heart disease)?   
 
              (Y/N) 21. 
Have you obtained the patient's consent for his or her blood to be kept for use in  

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RTOG 1115, Version Date June 12, 2018 
 
 
NRG Oncology Institution #   
 
RTOG 1115 
 
 
 
ELIGIBILITY CHECKLIST (4/16/14) 
Case #  
 
 
 
     (page 5 of 5)  
 
 
research about other health problems (for example: diabetes, Alzheimer's 
disease, or heart disease). (Note: Blood collection is mandatory for patients 
participating in QOL). 
 
              (Y/N) 22. 
Have you obtained the patient's consent to allow someone from this institution to  
contact him or her in the future to take part in more research?  
  
              (N/Y) 23. 
Did the patient agree to participate in the quality of life component? 
 
 
         
 
If no, please specify the reason from the following: 
 
 
 
 
1. Patient refused due to illness 
 
 
 
 
2. Patient refused for other reason: specify _____________ 
 
 
 
 
3. Not approved by institutional IRB 
 
 
 
 
4. Tool not available in patient’s language 
 
 
 
 
5. Other reason: specify_________________ 
 
Note: If the patient started ADT prior to registration, then he cannot participate in the quality of life 
component. 
 
_____________24. 
Risk group (specify): 
1. Gleason ≥ 9, PSA ≤ 150, any T-stage 
2. Gleason 8, PSA < 20, and ≥ T2 
 
 
 
3. Gleason 8, PSA ≥ 20-150, any T-stage 
 
 
 
4. Gleason 7, PSA ≥ 20-150, any T-stage 
 
_________(N/Y)  25.     Androgen deprivation therapy (ADT) started prior to registration? 
 
 
         
 
If yes, treatment start date (Must be ≤50 days from registration):  
 
 
 
 
 
 
_____________26.  
RT Modality for boost (specify):  
1. IMRT  
2. LDR Permanent Prostate Implant (PPI) Boost  
3. HDR Boost 
 
_________( N/Y) 27.  
Use of IMRT 
 
 
 
 
The Eligibility Checklist must be completed in its entirety prior to web registration. The completed, signed, 
and dated checklist used at study entry must be retained in the patient’s study file and will be evaluated 
during an institutional NCI/NRG Oncology audit. 
 
Completed by  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 

12 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
1.0 INTRODUCTION 
1.1 
Background 
Prostate cancer is the most common cancer in men. Androgen deprivation therapy (ADT) with 
gonadotropin releasing hormone (GnRH) agonists is the foundation of advanced prostate cancer 
treatment and is given as neoadjuvant/concomitant/adjuvant treatment with radiation for intermediate and 
high risk localized disease. GnRH agonist therapy causes cessation of gonadal androgen production, 
resulting in a reduction in serum testosterone levels by more than 95% and estrogen levels by 
approximately 80%. Adrenal androgen synthesis accounts for most of the small persistent level of serum 
androgens. 
 
TAK-700 is an oral, selective nonsteroidal inhibitor of (Keating 2006, Eri 1995) lyase that blocks synthesis 
of both gonadal and adrenal dehydroepiandrosterone sulfate (DHEA) and androstenedione. TAK-700 has 
been shown to further reduce serum testosterone levels in men already maintained on a GnRH agonist.  
In Phase I and II clinical trials in men with advanced prostate cancer, TAK-700 has demonstrated notable 
efficacy with excellent tolerability (Dreicer 2010a, Dreicer 2010b). The most common adverse effects 
have included fatigue, nausea and constipation, and are generally mild in nature.  TAK-700 has been 
administered alone to a maximum recommended dose of 300 mg BID, and together with low-dose 
prednisone to a maximum dose of 600 mg BID.  In two ongoing, pivotal phase III trials, TAK-700 is being 
administered at either 400 mg BID along with 5 mg daily of prednisone (metastatic prostate cancer) or 
300 mg BID without prednisone (nonmetastatic prostate cancer).   
 
1.2 
Adjuvant/concurrent/neoadjuvant ADT with Radiation Therapy 
Risk stratification of patients prior to primary therapy for prostate cancer yields important prognostic 
information and can be used to guide therapeutic choices. Three factors that are independently 
associated with relapse risk are clinical tumor stage, Gleason score, and pretreatment PSA level (Chism, 
2004, D’Amico 2002, Levegrun 2002, Pisansky 1997, Symon 2003). Prostate cancer is categorized as 
high risk if it features extraprostatic extension (T3), Gleason > 8, or PSA > 20. Standard-of-care for men 
with high risk disease treated with external beam radiation is 2 – 3 years of ADT with a GnRH agonist 
based on phase III trials demonstrating an overall survival benefit (Bolla 1997, Pilepich 2005, Mohler 
2010). Recently reported data from an EORTC trial comparing 6 months of ADT to 3 years of ADT for 
men with locally advanced disease showed a significant 5 year overall survival advantage for the longer 
term ADT group (15.2% vs. 19.0% mortality) (Bolla 2009). Efforts to achieve further benefit through 
intensified systemic therapy for this patient population led to RTOG 05-21, a randomized phase III trial in 
which adjuvant docetaxel chemotherapy was added to standard radiation and neoadjuvant/ 
concomitant/adjuvant ADT. RTOG 05-21 has completed accrual, but analysis is still several years away. 
 
Though standard ADT with a GnRH agonist has clearly been shown to improve the efficacy of radiation 
therapy, no trial has yet built upon this foundation with the use of more profound androgen deprivation in 
this clinical setting. We propose to examine the combination of radiation with enhanced ADT using a 
GnRH agonist and TAK-700. This combination of hormonal agents has been shown to suppress serum 
testosterone to undetectable levels.  Given the survival benefit conferred by lowering serum androgens 
with 2 – 3 years of GnRH agonist treatment in combination with radiation for high risk prostate cancer, we 
hypothesize that further lowering of serum androgens will produce additional clinical benefit. 
 
1.3 
Safety of Proposed Therapy 
Based upon experience from phase I and ongoing II and III trials, TAK-700 is generally well tolerated 
when given in combination with a GnRH agonist. Adverse events that have been observed to occur 
frequently include fatigue, nausea, constipation, anorexia and vomiting (Dreicer 2010a, Dreicer 2010b) 
The most prominent safety concerns are primarily related to the risk of hypertension and electrolyte 
abnormalities secondary to mineralocorticoid excess, an effect that has been observed with other lyase 
inhibitors (Attard 2005, Attard 2008).  However, this has generally not been a concern in early trials with 
TAK-700.  In this study, electrolytes including serum potassium will be monitored regularly. 
 
No completed study has examined the combination of TAK-700 with a GnRH agonist and concurrent 
radiation. Though the tolerability of this combination is anticipated to be similar to that of radiation with 
concurrent GnRH agonist therapy, the absence of unexpected adverse events must be verified and is a 
co-primary endpoint of the study. Formal toxicity assessment will be carried out after follow-up of 200 
patients (100 per treatment arm) through six months of therapy. Adverse events will be measured by NCI 

13 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
CTCAE criteria and compared between arms. The trial will be halted if unacceptable levels of toxicity are 
found among patients randomized to TAK-700 relative to standard ADT, with threshold criteria for excess 
incidence derived from observed adverse event data from similar patients who underwent radiation and 
ADT per the control arm of this trial. If the toxicity profile is acceptable as defined in Section 13.5.7, the 
trial will continue to full accrual. Quality of life measured by the EPIC (32 item) and EQ-5D (5 item) 
questionnaires and fatigue measured by the Patient-Reported Outcome Measurement Information 
System (PROMIS) Fatigue Scale also will be examined as supporting information regarding tolerability of 
TAK-700. In addition to this early safety assessment and continuous CTCAE adverse event monitoring 
throughout the trial, detailed studies with respect to both short and long term potential adverse 
consequences of TAK-700 will be conducted, as described in Sections 1.4 and 1.5. 
 
1.4 
Prostate Cancer Survivorship 
A major consideration in the treatment of prostate cancer is achievement of a satisfactory risk-benefit ratio 
with respect to treatment. While men with disease meeting disease stage criteria here are deemed high-
risk and thus candidates for multimodality therapy including 2-year androgen deprivation, their likelihood 
to non-cancer morbidity and mortality may still exceed their prostate cancer mortality risk, and thus it is 
necessary to carefully assess the totality of impacts treatment may exert, including adverse 
consequences. These are considered in a series of studies as follows. 
1.4.1  
Metabolic Consequences of Androgen Deprivation 
Androgen deprivation therapy (ADT) can be accomplished with medical or surgical castration. 
This hypogonadism produces several well-described treatment-related adverse effects 
including insulin resistance, elevated lipoproteins, and weight gain.(Smith, Finkelstein et al. 
2002; Smith, Lee et al. 2006; Saylor and Smith 2009) Consistent with these adverse effects, 
GnRH agonist treatment has been associated with increased risk for diabetes and 
cardiovascular disease.(Keating, O'Malley et al. 2006; Saigal, Gore et al. 2007; Allibhai 2008; 
Keating, O'Malley et al. 2010; Saylor, Keating et al. 2011) The metabolic impact of the more 
profound hypogonadism produced by an androgen biosynthesis inhibitor in combination with 
GnRH agonist therapy has not yet been evaluated. 
  
Castrate testosterone is defined as serum testosterone < 50 ng/dL. TAK-700 is an androgen 
biosynthesis inhibitor that further reduces serum testosterone in men with castrate testosterone 
levels due to GnRH agonist therapy.(Dreicer, Agus et al. 2010) Testosterone measurement 
using widely-available radioimmunoassays and chemiluminescent testing is notably imprecise 
when measuring testosterone levels at the low end of the spectrum.(Fitzgerald and Herold 
1996; Taieb, Mathian et al. 2003; Wang, Catlin et al. 2004) We therefore plan to measure on-
treatment testosterone using liquid chromatography tandem mass spectrometry (LC/MS/MS), a 
technique that maintains precision when testosterone levels are below 50 ng/dL.(Taieb, 
Mathian et al. 2003; Wang, Catlin et al. 2004) It is expected that nadir testosterone will be lower 
among men who receive TAK-700 in addition to a GnRH agonist. Serum testosterone levels 
drawn at intervals throughout the 24 months of ADT will be analyzed to investigate whether 
there is lower cumulative androgen exposure during those 24 months, a putative mechanism of 
the proposed therapy. 
  
The metabolic impact of this lower androgen exposure will be evaluated in several ways. 
Glycemic parameters, lipid profiles, and body mass index (BMI) will be serially evaluated during 
systemic treatment and during follow-up. Insulin resistance is an independent risk factor for 
cardiovascular disease and is present in about one fourth of adults in the general 
population.(Despres, Lamarche et al. 1996; Pyorala, Miettinen et al. 1998) Existing data 
demonstrate that standard ADT with a GnRH agonist decreases insulin sensitivity(Smith, Lee et 
al. 2006) and is associated with an increased incidence of type 2 diabetes.(Allibhai 2008; 
Keating, O'Malley et al. 2010) We will investigate whether long-term treatment with TAK-700 
increases the incidence of insulin resistance, prediabetes, or diabetes. Standard ADT with a 
GnRH agonist causes increases in total cholesterol, triglycerides, and high density lipoprotein 
(HDL).(Eri, Urdal et al. 1995; Dockery, Bulpitt et al. 2003; Smith, Lee et al. 2008) We will 
investigate whether long-term treatment with TAK-700 results in higher lipid levels. Finally, 
prospective studies have demonstrated that one year of GnRH agonist therapy increases total 
body weight by approximately 2%.(Smith, Finkelstein et al. 2002; Smith 2004) We will 

14 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
investigate whether long-term treatment with TAK-700 results in higher body mass index when 
compared to GnRH agonist monotherapy. 
 
1.4.2  
Androgen Recovery after Treatment 
Withdrawal of GnRH agonist therapy usually leads to recovery of androgen production to non-
castrate levels, though the timing of this recovery is quite variable. Among studies that have 
described the recovery of androgen production after ADT, median time to normalization of 
serum testosterone varied greatly.(Hall, Fritzsch et al. 1999; Nejat, Rashid et al. 2000; Pickles, 
Agranovich et al. 2002; Gulley, Figg et al. 2005; Kaku, Saika et al. 2006; Gulley, Aragon-Ching 
et al. 2008) One study reported normalization within a median of 15.4 weeks in men who had 
received six months of ADT(Gulley, Aragon-Ching et al. 2008) while another reported a median 
of 24 months to testosterone normalization in men who had received a median of 30 months of 
ADT.(Kaku, Saika et al. 2006) Androgen recovery after blockade of both gonadal and adrenal 
androgen synthesis using a GnRH agonist with TAK-700 has not yet been described. In this 
phase III trial, the timing of androgen recovery after cessation of ADT will be important to the 
interpretation of the primary results. If the experimental arm is found to have superior overall 
survival when compared to the control arm, it will be essential to also know the kinetics of 
androgen recovery. We hypothesize that recovery of testosterone to above the accepted 
threshold for supplementation in the general population will be similar in the two treatment 
arms. We will measure serum testosterone during the first 5 years of follow-up after cessation 
of systemic therapy. 
1.4.3  
Evaluation of Clinical and Chronic Disease Outcomes 
Clinical outcomes that have been shown to be associated with GnRH agonist therapy include 
new diagnosis of diabetes, osteoporotic fracture, coronary artery disease, myocardial infarction, 
stroke, pulmonary embolism, and deep vein thrombosis. Post-hoc analyses of clinical outcomes 
among men who participated in RTOG clinical trials (trials 85-31(Efstathiou, Bae et al. 2008), 
86-10(Roach, Bae et al. 2008), and 92-02(Efstathiou, Bae et al. 2008)) have been important in 
clarifying these risks as they found no association between GnRH agonist treatment and 
cardiovascular mortality. Unfortunately, those trials were not designed to assess non-fatal 
cardiovascular events or other clinical endpoints relevant to prostate cancer survivorship. The 
proposed study presents an important opportunity to formally collect data on these clinical 
outcomes in a large prospective trial. 
 
It is not known whether more intensive androgen deprivation with a GnRH agonist and an 
androgen biosynthesis inhibitor is associated with additional risk for these outcomes. The 
proposed study provides an ideal setting in which to examine this possibility as it is a 
randomized controlled trial with long term follow-up. Long term safety of such novel hormonal 
agents cannot optimally be evaluated in clinical trials in patients with more advanced disease 
because such patients suffer from more substantial cancer disease burden and more 
commonly move on promptly to subsequent therapies.  
 
Abiraterone acetate is another androgen biosynthesis inhibitor that recently has been shown to 
improve survival in men with metastatic CRPC after failure of first line chemotherapy.(de Bono, 
Logothetis et al. 2011) With the current and planned development of TAK-700 and other agents 
in this class, it is likely that increasing numbers of men will be exposed to such enhanced 
hypogonadism, and for increasing durations. The risks for adverse clinical outcomes as a 
consequence of systemic therapy among prostate cancer survivors is a particularly important 
issue among men treated with curative intent. This study will rigorously measure the incidence 
of important adverse clinical outcomes and chronic diseases among men treated with standard 
ADT with those treated with the combination of a GnRH agonist with TAK-700.  
 
1.5 
Fatigue (12Jun2018) 
A second key facet of risk-benefit evaluation for prostate cancer evaluation is patient reported outcomes 
relating to well-being, with fatigue being principal among these in prostate cancer. A comprehensive 
evaluation of fatigue is thus an integral component of this clinical trial. 
 
Fatigue has been described as the most frequent and distressing symptom related to cancer and its 
treatment (Bower 2005). Radiotherapy-induced fatigue is a common early side effect reported by 80% of 

15 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
patients during treatment (Jereczek-Fossa 2001). There is evidence that cancer-related fatigue (CRF) has 
profound effects on ability to function in usual roles and activities and can linger for months or years after 
treatment completion (Lilleby 1999; Monga 1999; Monga 2005; Truong 2006).   Following RT and/or ADT, 
approximately one third of prostate cancer survivors report clinically relevant fatigue one year post 
treatment (Storey et al. 2011, Kyrdalen et al., 2010).  The high prevalence of this symptom in persons 
treated for prostate cancer, as well as its association with poor quality of life, mark it as a significant 
problem that requires further scientific study. 
 
The etiology of fatigue, its correlates, and prevalence in the context of prostate cancer treatment are 
poorly understood.  RT field size (whole pelvis vs. prostate only RT), ADT, and TAK-700 have been 
associated with the development of fatigue. (Danjoux 2007, Beard et al. 1997, Fransson 2010, Saad et al. 
2011, Agust et al. 2011).  During prostate RT, fatigue has been found to increase significantly with the 
most severe fatigue being reported the last week of RT.  (Jereczek-Fossa 2001; Truong 2006; Beard 
1997; Danjoux 2007; Prue 2006, Fransson 2010). However, a significant increase in fatigue between 
baseline and all follow-up time points, including end of RT, 3 months, 1 year, 3 years, and 5 years 
following RT has been noted in prostate cancer patients (Fransson et al. 2010).  For example, five years 
after RT, 66% of living patients had fatigue, while only 41% reported fatigue at baseline (Fransson et al. 
2010).  Patients who continued to undergo ADT for bone metastasis had the highest levels of fatigue.  
Other studies of prostate cancer patients support the notion that ADT has been independently associated 
with higher fatigue levels.  When measured at baseline and 3 months post neoadjuvant ADT alone, 
fatigue increased in as many as two thirds of patients all before the first day of RT.  (Stephens 2007; 
Stone 2000). In men receiving both ADT and RT, fatigue appears to be considerably worse than in men 
receiving RT alone. (Voermen et al. 2006)  Kyrdalen et al (2010) found that 40% of >1 year prostate 
cancer survivors on ADT reported chronic fatigue, while only 20% of men who discontinued ADT reported 
fatigue at the same time point.   Men who discontinued ADT had a fatigue rate comparable to men treated 
with RT alone and to age-matched controls from the general population.  Like ADT, TAK-700 is 
associated with higher fatigue levels. In Phase I and II clinical trials in men with metastatic prostate 
cancer treated with TAK-700 [Saad et al. 2011, Agust et al. 2011] (both are abstracts), the most common 
adverse effect was fatigue (16 of 26 patients) but only one patient developed grade 3 or higher fatigue. 
The effect of TAK-700 on fatigue levels in non-metastatic prostate cancer patients treated with ADT and 
RT is expected to be moderate, although there is no data at this time, only the clinical experience of the 
investigators.  
 
In order to minimize the potential impact of various confounding factors on fatigue, a secondary endpoint 
of this study, the following key information regarding potential confounds will also be collected at the time 
of the PROMIS-fatigue short form (using limited questions to minimize patient burden): The 
Anxiety/Depression Item in the EQ-5D;  Overall Sleep Quality: Item from Pittsburgh Sleep Quality Index 
(Buysse 1989); 1 item (Q3) of the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire which 
measures sleep quality and disturbances over a 1-week or 1-month time period; and Participants’ level of 
physical activity will be assessed using 3-items from the Godin Leisure-Time Exercise Questionnaire 
(GLTEQ) [Godin 1986; Gionet 1989]. Please see Section 11.0 for further details. 
1.5.1 
Correlation of Circulating Proinflammatory Cytokines to Fatigue 
The etiology of fatigue, its correlates, and prevalence in the context of prostate cancer 
treatment are poorly understood.  There is growing evidence that pro-inflammatory cytokines 
play a role in cancer-related fatigue (CRF) and fatigue from other chronic illnesses (Schubert 
2007).  Most of the research has been generated in breast cancer patients, and the most 
commonly implicated cytokines are IL-1, IL-6, TNF alpha, sTNFR2, and IFN alpha (Ryan 2007).  
These cytokines will be measured in the proposed study of prostate cancer patients in addition 
to NF-Kappa B DNA binding which has been found by our group to be elevated in fatigued 
women undergoing breast RT (Torres 2011).  Additionally, SNPs in the promoters of cytokine 
genes, IL6, IL1, and TNF alpha have been associated with fatigue in breast cancer survivors 
(Collado-Hidalgo 2008) and prostate cancer patients (Aouizerat 2009, Miaskowski 2010).  
These SNPs found in genes integral to the inflammatory response will be assessed in the 
proposed study, as they may identify patients at risk for fatigue development.  RT and ADT may 
initiate a constellation of molecular events that include activation of the inflammatory signaling 
molecule, nuclear factor kappa B (NF-kB) as well as the local and peripheral release of 
inflammatory cytokines (Anscher 2005). Work by Raison et al. (2009) and others have 
demonstrated that peripherally elaborated inflammatory cytokines can enter the brain and 

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RTOG 1115, Version Date June 12, 2018 
 
 
activate a central inflammatory response that is associated with fatigue.(Capuron 2007)  
Studies have shown that the development of fatigue during radiation therapy for prostate 
cancer is significantly correlated with increases in peripheral inflammatory markers including 
interleukin (IL)-1 receptor antagonist (IL-1ra), IL-6 and c-reactive protein (CRP).(Bower 2009) In 
contrast, the effect of hormonal therapy on inflammatory markers is less well known.  Small 
studies have shown altered cytokine expression by prostate tumors after hormonal therapy 
(Sugihara 1998), but levels of systemic cytokines after hormonal therapy for prostate cancer 
are not well described.  Fatigue, however, is a well-known complication of hormonal therapy for 
prostate cancer and has been independently associated with increased inflammation (Peters 
2008). Activation of the inflammatory response may be a fundamental consequence of ADT 
and RT leading to fatigue.  Indeed, the combination of these two treatments may result in a 
more persistent and prolonged fatigue compared to the series evaluating fatigue after radiation 
alone, with as many as 32% of patients experiencing fatigue at the completion of radiation and 
a substantial number experiencing fatigue as late as 6.5 weeks after completion of radiation 
(Stone 2000).  Given its primary importance in regulating the inflammatory response, NF-kB 
may play a prominent role in the link between cancer treatment and subsequent fatigue.(Bower 
In press, Torres preliminary data 2011) 
 
It will be strongly recommended that patients consent to having a blood sample sent for storage 
to the RTOG Biospecimen Resource. Blood will be collected from patients enrolled on this 
protocol at baseline, 1 year, and 2.5 years after therapy begins to follow trends in inflammatory 
biomarkers that may correlate with fatigue levels. The specimens will be collected and 
processed according to the RTOG specimen processing guidelines and must be clearly labeled 
with the patient identification number.   Specimens from participating institutions will be banked 
in the RTOG Biospecimen Resource for future translational analyses. The buffy coat will be 
isolated from each sample and the DNA extracted. Anticipated analyses for collected 
specimens include circulating markers that may correlate to patient reported outcomes. An 
example of one anticipated analysis is the evaluation of plasma cytokines for correlation to 
fatigue as measured by the PROMIS instrument in patients enrolled on this trial. Examples of 
inflammatory markers that will be tested include CRP, NF- kappa B, TNF alpha, IL-1, IL-1ra, 
sTNFR2, and IL-6. 
1.5.2 
Genetic Predictors of Fatigue  
Evidence that specific genetic variants are associated with the development of such adverse 
effects arises from several studies. In one case/control study, 141 prostate cancer patients 
treated with radiotherapy were screened for SNPs in TGFB1 (Burri in press). Those subjects 
who possessed either the T/T genotype at position -509, the C/C genotype at position 869 or 
the G/C genotype at position 915 were significantly associated with the development of a 
decline in erectile function compared with those who did not have these genotypes. In addition, 
patients with the -509 T/T genotype had a significantly increased risk of developing late rectal 
bleeding compared with those who had either the C/T or C/C genotype at this position. These 
subjects were also genotyped for SNPs in SOD2, XRCC1, and XRCC3 (Damaraju 2006). 
Patients possessing the XRCC1 rs25489 G/A genotype were more likely to develop erectile 
dysfunction following irradiation compared to patients who had the G/G genotype. The 
estimated CAG haplotype frequency for XRCC1 was significantly higher in men with late rectal 
bleeding than in men without late rectal bleeding. In addition, patients who possessed the 
SOD2 rs4880 C/T genotype exhibited a significant increase in grade 2 late rectal bleeding 
compared to patients who had either the C/C or T/T genotype for this SNP. Furthermore, 
patients possessing the combination of the SOD2 rs4880 C/T genotype and XRCC3 rs861539 
C/T genotype experienced a significant increase in grade 2 late rectal bleeding compared to 
patients without this particular genotypic arrangement. Another important study reported that 
possession of SNPs in the LIG4, ERCC2, and CYP2D6 was significantly associated with the 
development of clinical toxicity, including urinary morbidity, in patients treated with radiotherapy 
for prostate cancer (Dudbridge 2006). Taken together, the results of these studies provide a 
strong basis for the role of genetic factors in the ability to predict which prostate cancer patients 
will exhibit adverse radiotherapy responses. Thus, the hypothesis that forms the basis for this 
study is that SNPs and/or CNVs in certain genes are associated with the development of 
fatigue after radiotherapy for prostate cancer. This effect may be further exacerbated by 
profound androgen deprivation via agents such as TAK-700. 

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RTOG 1115, Version Date June 12, 2018 
 
 
 
It will be strongly recommended that patients consent to having a blood sample sent for storage 
to the RTOG Biospecimen Resource. The buffy coat will be isolated from each sample and the 
DNA extracted. The specimens will be collected and processed according to the RTOG 
specimen processing guidelines. Anticipated analyses include evaluation of single nucleotide 
polymorphisms (SNPs) and copy number variants (CNVs) through screening DNA samples 
derived from case and matched control subjects using Affymetrix 6.0 microarrays. Genes to be 
investigated for SNPs and CNVs include TNFAIP1, IL6, IL6R, CRP, IL1R1, IL1A, IL1B. Case 
subjects will be patients that represent the 20% of patients in this study exhibiting the highest 
levels of  fatigue as defined and measured by the PROMIS instrument used in this study while 
controls will be the 20% of patients who reported the lowest levels  of fatigue as quantified 
using PROMIS. The goal of this study will be to identify SNPs and CNVs associated with the 
development of fatigue in prostate cancer patients following radiotherapy.  
 
2.0 OBJECTIVES 
2.1 
Primary Objective 
To evaluate the difference in overall survival in men with clinically localized prostate cancer with 
unfavorable prognostic features between a) standard treatment (ADT + radiotherapy) and b) standard 
treatment with the addition of 24 months of TAK-700. 
 
2.2 
Secondary Objectives (12Jun2018) 
2.2.1 
To characterize differences between the treatment groups with respect to incidence of unexpected grade 
≥ 3 adverse events and/or clinically significant decrement in patient reported quality of life among subjects 
treated with TAK-700. 
 
Additional secondary objectives are to compare the treatment groups with respect to: 
2.2.2  
Rates and cumulative incidence of biochemical control (freedom from PSA failure), local/regional 
progression, and distant metastases 
2.2.3  
Rate and cumulative incidence of clinical failure, defined as: PSA > 25 ng/ml, documented local disease 
progression, regional or distant metastasis, or initiation of androgen deprivation therapy 
2.2.4  
Prostate-cancer specific survival and other-cause mortality 
2.2.5  
Change in severity of fatigue as measured by the Patient-Reported Outcome Measurement Information 
System (PROMIS) fatigue short form 
2.2.6 
Changes in patient reported quality of life as measured by Expanded Prostate Cancer Index Composite 
(EPIC) 
2.2.7 
Assess quality adjusted survival using the EQ-5D (Will not be completed and is not part of the revised 
quality of life substudy per Amendment 3.) 
2.2.8 
Nadir and average serum testosterone at 12 and 24 months during treatment 
2.2.9  
Changes in hemoglobin A1C, fasting glucose, and fasting insulin during 24 months of systemic treatment 
and during the first three years of follow-up  
2.2.10  Changes in fasting lipid levels during 24 months of treatment and during the first three years of follow-up  
2.2.11  Changes in body mass index (BMI) during 24 months of treatment and during the first three years of 
follow-up 
2.2.12  Incidence of adverse events ascertained via CTCAE version 4. 
2.2.13 Rate of recovery of testosterone to >230 ng/dL (accepted threshold for supplementation) after 12 and 24 
months of follow-up 
2.2.14 Median time to recovery of testosterone to >230 ng/dL during the first five years of follow-up 
2.2.15 Cumulative incidence of relevant clinical survivorship endpoints including new diagnosis of type 2 
diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, deep vein 
thrombosis, or osteoporotic fracture 
 
3.0 PATIENT SELECTION 
 
 
NOTE: PER NCI GUIDELINES, EXCEPTIONS TO ELIGIBILITY ARE NOT PERMITTED  
 
3.1 
Conditions for Patient Eligibility (4/16/14)  
For questions concerning eligibility, please contact the study data manager. 
 

18 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
3.1.1 
Histologically confirmed diagnosis of adenocarcinoma of the prostate within 180 days prior to registration 
at high risk for recurrence as determined by one of the following combinations:  
 
Gleason score 
 
PSA 
 
T-Stage 
> 9 
and 
< 150 
and 
Any 
8 
and 
< 20 
and 
> T2 
8 
and 
> 20-150 
and 
Any 
7 
and 
> 20 – 150 
and 
Any 
 
3.1.2 
History/physical examination within 60 days prior to registration. 
3.1.3 
Clinically negative lymph nodes as established by imaging (abdominal and/or pelvic CT or abdominal 
and/or pelvic MRI), nodal sampling, or dissection within 90 days prior to registration. 
 
Patients with lymph nodes equivocal or questionable by imaging are eligible if the nodes are < 2.0 
cm.  
3.1.4 
No distant metastases (M0) on bone scan within 90 days prior to registration (18F-Na bone scan is an 
acceptable substitute).  
 
Equivocal bone scan findings are allowed if plain films are negative for metastasis.  
3.1.5 
Baseline serum PSA value performed with an FDA-approved assay (e.g., Abbott, Hybritech), obtained 
prior to any LHRH or anti-androgen therapy, within 180 days of randomization. 
3.1.6   Androgen deprivation therapy (ADT), such as LHRH agonists (e.g., goserelin, leuprolide), anti-androgens 
(e.g., flutamide, bicalutamide), estrogens (e.g., DES), or surgical castration (orchiectomy), may have been 
started prior to registration, provided that registration is within 50 days of beginning ADT. Please note: If 
the patient has started ADT he will not be eligible to participate in the quality of life component of 
this study. 
3.1.7 
Prior testosterone administration is allowed if last administered at least 90 days prior to registration. 
3.1.8 
Zubrod Performance Status 0-1 within 21 days prior to registration 
3.1.9 
Age ≥ 18 
3.1.10 CBC/differential obtained within 14 days prior to registration on study, with adequate bone marrow 
function defined as follows: 
 
Absolute neutrophil count (ANC) ≥ 1,800 cells/mm3  
 
Platelets ≥ 100,000 cells/mm3  
 
Hemoglobin ≥ 8.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 8.0 g/dl is 
acceptable.) 
3.1.11 Serum creatinine < 2.0 mg/dl and creatinine clearance (can be calculated) > 40 mL/minute within 21 days 
prior to registration 
3.1.12 Bilirubin < 1.5x ULN and ALT or AST < 2.5x ULN within 21 days prior to registration 
3.1.13 Serum testosterone within 21 days prior to registration 
3.1.14 Chemistry (including sodium, potassium, chloride, bicarbonate (carbon dioxide), BUN, glucose, calcium, 
magnesium and phosphorous) and liver panels (including albumin and alkaline phosphatase) obtained 
within 21 days prior to registration 
3.1.15 Fasting glucose, fasting insulin, lipid panel (cholesterol, triglyceride, HDL, LDL), and Hemoglobin A1C 
within 21 days prior to registration  
3.1.16 Screening calculated ejection fraction of ≥ to institutional lower limit of normal by multiple gated 
acquisition (MUGA) scan or by echocardiogram ECHO. 
3.1.17 Baseline ECG within 180 days prior to registration 
3.1.18 Patients, even if surgically sterilized (ie, status post vasectomy), who: 
(a) Agree to practice effective barrier contraception during the entire study treatment period and 
for 4 months (120 days) after the last dose of study drug, or 
(b) Agree to completely abstain from intercourse. 
3.1.19 Patient must be able to provide study-specific informed consent prior to study entry. 
 
3.2 
Conditions for Patient Ineligibility (12/17/13) 
3.2.1 
PSA > 150 
3.2.2 
Definite evidence of metastatic disease. 
3.2.3 
Pathologically positive lymph nodes or nodes > 2.0 cm on imaging. 
3.2.4 
Prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason. 
3.2.5 
Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free or not requiring 
systemic therapy for a minimum of 3 years. 

19 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
3.2.6 
Prior systemic chemotherapy for prostate cancer (Note that prior chemotherapy for a different cancer is 
allowed, per Section 3.2.5). 
3.2.7 
Prior radiotherapy, including brachytherapy, to the region of the prostate that would result in overlap of 
radiation therapy fields. 
 
Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostate 
volume <60 cc, AUA score ≤15 within 60 days of registration, and no history of prior transurethral 
resection of the prostate (TURP); prior TURP is permitted for patients who receive EBRT only). 
3.2.8 
Previous hormonal therapy for > 50 days (see Section 3.1.6). 
3.2.9 
Known hypersensitivity to TAK-700 or related compounds 
3.2.10 A history of adrenal insufficiency 
3.2.11 History of myocardial infarction, unstable symptomatic ischemic heart disease, ongoing arrhythmias of 
Grade > 2 [NCI CTCAE, version 4.02] (U.S. Department of Health and Human Services, National 
Institutes of Health National Cancer Institute, 2009), thromboembolic events (eg, deep vein thrombosis, 
pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, 
pericardial effusion restrictive cardiomyopathy) within 6 months prior to registration. Chronic stable atrial 
fibrillation on stable anticoagulant therapy is allowed. 
3.2.12 New York Heart Association Class III or IV heart failure (see Appendix IV). 
3.2.13 ECG abnormalities of: 
 
(a) Q-wave infarction, unless identified 6 or more months prior to screening 
 
(b) QTc interval > 460 msec 
3.2.14 Patients who are sexually active and not willing/able to use medically acceptable forms of contraception; 
this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.  
3.2.15 Prior allergic reaction to the drugs involved in this protocol. 
3.2.16 Study entry PSA obtained during the following time frames:  
 
(a) 10-day period following prostate biopsy; 
 
(b) following initiation of hormonal therapy. 
3.2.17 Cushing’s syndrome 
3.2.18 Severe chronic renal disease (serum creatinine > 2.0 mg/dl and confirmed by creatinine clearance < 40 
mL/minute) 
3.2.19 Chronic liver disease (bilirubin > 1.5x ULN, ALT or AST > 2.5x ULN) 
3.2.20 Chronic treatment with glucocorticoids within one year 
3.2.21 Uncontrolled hypertension despite appropriate medical therapy within 21 days prior to registration (blood 
pressure of greater than 150 mm Hg systolic and 90 mm Hg diastolic at 2 separate measurements no 
more than 60 minutes apart during Screening visit) 
3.2.22 Unwilling or unable to comply with the protocol or cooperate fully with the investigator and site personnel. 
3.2.23 Major surgery within 14 days prior to registration 
3.2.24 Serious infection within 14 days prior to registration 
3.2.25 Uncontrolled nausea, vomiting, or diarrhea (CTCAE grade ≥ 3) despite appropriate medical therapy at the 
time of registration 
3.2.26 Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or 
tolerance of TAK-700, including difficulty swallowing tablets 
 
4.0 PRETREATMENT EVALUATIONS/MANAGEMENT 
 
NOTE: This section lists baseline evaluations needed before the initiation of protocol treatment that do 
not affect eligibility. 
 
4.1 
Required Evaluations/Management (12/17/13) (2/4/14) 
4.1.1 
Review of medications at time of registration [drug names and dosages, frequency, route, start dates (at 
least the year that the drug was started), etc.] 
4.1.2 
Completion of the Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue Short 
Form, Expanded Prostate Cancer Index Composite (EPIC), and EuroQol (EQ-5D) is required for the 
patients who have consented to participate in the optional quality of life assessment (up to a maximum of 
458 patients). However, patients participating in the QOL assessment may not have started LHRH 
or other anti-androgen therapy prior to enrollment and completing the QOL forms. 
4.1.3 
Any patient undergoing brachytherapy must have transrectal ultrasound confirmation of prostatic volume 
< 60 cc and American Urologic Association (AUA) symptom index composite score ≤ 15 within 60 days of 
registration. If a patient is thought to be a poor brachytherapy candidate based on anatomy at the time of 

20 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
ultrasound, he may still participate in the study but must receive EBRT only per protocol guidelines. If a 
patient is deemed an inadequate brachytherapy candidate after he has already been enrolled on the 
protocol, he may be switched to EBRT administered per protocol guidelines, but this will result in a 
protocol deviation. 
4.1.4 
Height and weight 
 
5.0 REGISTRATION PROCEDURES (12JUN2018) 
 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored trials to register and to renew their registration annually.  To 
register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a registration type 
of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per registration type are outlined in the 
table below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
 
Added to a site roster 
 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
 
Act as the site-protocol PI on the IRB approval 
 
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please contact the RCR Help 
Desk by email at < RCRHelpDesk@nih.gov >. 
 
TRIAD, the American College of Radiology’s (ACR) image exchange application, will be used for 
dosimetry digital treatment data submission on this trial. See below for information on installing 
TRIAD for submission of digital RT data prior to enrolling patients. 

21 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
5.1 
Pre-Registration Requirements for IMRT Treatment Approach (4/16/14) 
5.1.1 
In order to utilize IMRT on this study, the institution must have met specific technology requirements and 
have provided baseline physics information. Instructions for completing these requirements or 
determining if they already have been met are available on the Imaging and Radiation Oncology Core 
(IROC) Houston QA Center [formerly the Radiological Physics Center (RPC)] web site. Visit 
http://irochouston.mdanderson.org and select “Credentialing” and “Credentialing Status Inquiry”. The 
institution or investigator must update or complete a new IMRT Facility Questionnaire (available on the 
IROC Houston web site at http://irochouston.mdanderson.org) and send it to NRG Oncology for review 
prior to entering any cases. 
 
An IMRT phantom study with IROC Houston must be successfully completed (if the institution has not 
previously met this IMRT credentialing requirement). Instructions for requesting and irradiating the 
phantom are available on the IROC Houston web site at http://irochouston.mdanderson.org; select 
“Credentialing” and “NRG”. Upon review and successful completion of the phantom irradiation, IROC 
Houston will notify both the registering institution and NRG Oncology that the institution has completed 
this requirement. Subsequently, NRG Oncology will notify the institution that the IMRT credentialing 
requirement has been met. 
 
5.2 
Pre-Registration Requirements for 3DCRT Treatment Approach (4/16/14) 
5.2.1 
Only institutions that have met the technology requirements and that have provided the baseline physics 
information that are described in 3D-CRT Quality Assurance Guidelines may enter patients onto this 
study. 
5.2.2 
A new or updated Facility Questionnaire (one per institution, available on the IROC Houston web site at 
http://irochouston.mdanderson.org) is to be sent to NRG Oncology for review prior to entering any cases. 
NRG Oncology will notify the institution when all requirements have been met and the institution is RT 
credentialed to enter patients onto this study.  Institutions that have previously enrolled patients on 3D-
CRT trials of this same disease site may enroll patients on this study without further credentialing. 
 
5.3 
Pre-Registration Requirements for Brachytherapy Treatment Approach (4/16/14) 
5.3.1  
Brachytherapy 
Institutions must be credentialed by IROC Houston prior to registering any cases to this study. The 
credentialing materials may be found on the IROC Houston web site at http://irochouston.mdanderson.org 
under the “credentialing” tab. Upon review and successful completion, IROC Houston will notify both the 
registering institution and NRG Oncology that the institution has successfully completed this requirement. 
NRG Oncology will notify the institution when all requirements have been met and the institution is RT 
credentialed to enter subsequent patients onto this study. 
5.3.2 
Brachytherapy Credentialing 
Radiation Oncologists and Physicists are credentialed as a team for LDR brachytherapy (seed 
dependent), CT planned HDR brachytherapy, and TRUS planned HDR brachytherapy. The following can 
be found on the IROC Houston web site at http://irochouston.mdanderson.org and must be completed for 
each technique and/or seed: 
 
 
Knowledge Assessment Questionnaire to be submitted to IROC Houston. 
 
Facility Questionnaire to be submitted to IROC Houston. 
 
2 Benchmark Cases to be submitted to IROC Houston. 
 
A recent clinical case treated per protocol and a completed Implant Dosimetry Data Form to 
be submitted to IROC Houston and electronically sent to NRG Oncology (see Section 12.2) 
   
If an institution has been credentialed for a previous NRG Oncology/RTOG LDR prostate brachytherapy 
trial (RTOG 0526, RTOG 0815), RTOG HDR prostate brachytherapy trial for CT planned HDR, and/or 
RTOG HDR prostate brachytherapy trial for TRUS planned HDR, and the radiation oncologist and 
physicist team are the same as on the approved credentialing request, and the institution is using the 
same seed model and planning system as on the approved credentialing request, then they do not have 
to be re-credentialed for that modality for this trial with the exception of completing the Knowledge 
Assessment Form specific to this protocol. 
 

22 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
A change of physician will require submission of the Knowledge Assessment Form and 
Clinical Test Case.  
 
A change in physicist will require submission of the Knowledge Assessment Form and the 
Benchmark Cases.   
 
A change in either the treatment planning computer or brachytherapy source model will 
require resubmission of only the Benchmark Cases.  
 
Brachytherapy sources to be used on this protocol must be listed on the joint RPC/AAPM source registry 
at http://irochouston.mdanderson.org; select “brachy sources”. 
 
5.4 
Digital RT Data Submission to NRG Oncology Using TRIAD 
TRIAD is the American College of Radiology’s (ACR) image exchange application. TRIAD provides sites 
participating in NRG Oncology clinical trials a secure method to transmit DICOM RT and other objects. 
TRIAD anonymizes and validates the images as they are transferred. 
 
TRIAD Access Requirements: 
 
Site physics staff who will submit images through TRIAD will need to be registered with 
The Cancer Therapy Evaluation Program (CTEP) and have a valid and active CTEP 
Identity and Access Management (IAM) account. Please refer to Section 5.0 above for 
instructions on how to request a CTEP-IAM account. 
 
To submit images, the site physics user must have been assigned the 'TRIAD site user' 
role on the relevant Group or CTSU roster.  
 
RAs are able to submit standard of care imaging through the same method. 
 
TRIAD Installations: 
When a user applies for a CTEP-IAM account with proper user role, he/she will need to 
have the TRIAD application installed on his/her workstation to be able to submit images. 
TRIAD installation documentation can be found on the NRG Oncology/RTOG website Core 
Lab tab.    
 
This process can be done in parallel to obtaining your CTEP-IAM account username and 
password. 
 
If you have any questions regarding this information, please send an e-mail to the TRIAD Support 
mailbox at TRIAD-Support@acr.org.  
 
5.5  
Regulatory Pre-Registration Requirements (12Jun2018)  
5.5.1 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this protocol and 
submit IRB approval and supporting documentation to the CTSU Regulatory Office before they can enroll 
patients.  
Assignment of site registration status in the CTSU Regulatory Support System (RSS) uses extensive data 
to make a determination of whether a site has fulfilled all regulatory criteria including but not limited to the 
following: 
 
An active Federal Wide Assurance (FWA) number 
 
An active roster affiliation with the Lead Network or a participating organization 
 
A valid IRB approval 
 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
 
Active registration status 
 
The IRB number of the site IRB of record listed on their Form FDA 1572 
 
An active status on a participating roster at the registering site. 
 

23 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are not required 
to submit IRB approval documentation to the CTSU Regulatory Office. For sites using the CIRB, IRB 
approval information is received from the CIRB and applied to the RSS in an automated process. 
Signatory Institutions must submit a Study Specific Worksheet for Local Context (SSW) to the CIRB via 
IRB Manager to indicate their intent to open the study locally.  The CIRB’s approval of the SSW is then 
communicated to the CTSU Regulatory Office.  In order for the SSW approval to be processed, the 
Signatory Institution must inform the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the RTOG 1115 protocol page located on the CTSU 
members’ web site.  Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the NRG Oncology link to expand, then select trial protocol #RTOG-1115. 
 
Click on LPO Documents, select the Site Registration Documents link and download and complete 
the forms provided 
 
Requirements for RTOG 1115 site registration: 
 IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted) 
 CTSU RT Facilities Inventory Form (if applicable) 
 IRB/REB approved consent (English and native language versions*) 
*Note: Institutions must provide certification/verification of IRB/REB consent translation to 
NRG Oncology (described below). 
 
Non-English Speaking Canadian and Non-North American Institutions 
Translation of documents is critical. The institution is responsible for all translation costs. All regulatory 
documents, including the IRB/REB approved consent, must be provided in English and in the native 
language. Certification of the translation is optimal but due to the prohibitive costs involved NRG 
Oncology will accept, at a minimum, a verified translation. A verified translation consists of the actual REB 
approved consent document in English and in the native language, along with a cover letter on 
organizational/letterhead stationery that includes the professional title, credentials, and signature of the 
translator as well as signed documentation of the review and verification of the translation by a neutral 
third party. The professional title and credentials of the neutral third party translator must be specified as 
well. 
 
Submit completed forms along with a copy of your IRB Approval and Informed Consent to the 
CTSU Regulatory Office, where they will be entered and tracked in the CTSU RSS:  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab Regulatory 
Submission 
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Check the status of your site’s registration packets by querying the RSS site registration status page of 
the members’ section of the CTSU web site.  (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.) 
 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username and 
password; 

24 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
Click on the Regulatory tab at the top of your screen; 
 
Click on the Site Registration tab; 
 
Enter your 5-character CTEP Institution Code and click on Go. 
 
5.5.2 
Pre-Registration Requirements FOR CANADIAN INSTITUTIONS 
In addition to the requirements above, Canadian institutions also must complete and submit to the  
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab Regulatory 
Submission 
 
Health Canada’s Therapeutic Products Directorates’ Clinical Trial Site Information Form, 
 
Qualified Investigator Undertaking Form, and  
 
Research Ethics Board Attestation Form. 
5.5.3 
Pre-Registration Requirements for the Initial Shipment of TAK-700:  
 
U.S. and Canadian Institutions: 
All pre-registration requirements must be met before registering the first case. Institutions must 
electronically complete (versus hand write) a Study Agent Shipment Form (SASF) available on the NRG 
Oncology/RTOG web site, www.rtog.org, under protocol-specific materials/regulatory resources. U.S. and 
Canadian institutions must fax the SASF to the CTSU Regulatory Office (Fax 215-569-0206) as soon as 
the individual responsible for the study agent has been identified. The completed SASF document also 
may be e-mailed to the CTSU at CTSURegulatory@ctsu.coccg.org. 
 
5.6 
OPEN Registration (12/17/13)  
5.6.1  
OPEN Registration Instructions 
Patient registration can occur only after evaluation for eligibility is complete, eligibility criteria have been 
met, and the study site is listed as ‘approved’ in the CTSU RSS.  Patients must have signed and dated all 
applicable consents and authorization forms.   
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN). OPEN is a 
web-based registration system available on a 24/7 basis. All site staff will use OPEN to enroll patients to 
this study. OPEN can be accessed at https://open.ctsu.org or from the OPEN tab on the CTSU members’ 
web site https://www.ctsu.org. 
 
Prior to accessing OPEN site staff should verify the following: 
 
All eligibility criteria have been met within the protocol stated timeframes. Site staff should 
use the registration forms provided on the group or CTSU web site as a tool to verify 
eligibility. 
 
All patients have signed an appropriate consent form and HIPPA authorization form (if 
applicable).  
 
Access requirements for OPEN: 
 
See Section 5.0 for obtaining a CTEP-IAM account.  
 
To perform registrations, the site user must have been assigned the 'Registrar' role on the 
relevant Group or CTSU roster.  
 
To perform registrations on protocols for which you are a member of NRG Oncology, you 
must have an equivalent 'Registrar' role on the NRG Oncology roster.  Role assignments 
are handled through the Groups in which you are a member.  
 
To perform registrations to trials accessed via the CTSU mechanism (i.e., non-Lead Group 
registrations) you must have the role of Registrar on the CTSU roster. Site and/or Data 
Administrators can manage CTSU roster roles via the new Site Roles maintenance feature 
under RSS on the CTSU members' web site. This will allow them to assign staff the 
"Registrar" role. 
 
The OPEN system will provide the site with a printable confirmation of registration and treatment 
information. Please print this confirmation for your records.  
 
Further instructional information is provided on the CTSU members' web site OPEN tab or within the 
OPEN URL. For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com.  

25 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
5.6.2 
In the event that the OPEN system is not accessible, participating sites can contact web support for 
assistance with web registration: websupport@acr.org or call the Registration Desk at (215) 574-3191, 
Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. The registrar will ask the site to fax in the eligibility 
checklist and will need the registering individual’s e-mail address and/or return fax number. This 
information is required to assure that mechanisms usually triggered by the OPEN web registration system 
(e.g. drug shipment and confirmation of registration) will occur.  
 
6.0 RADIATION THERAPY (12/17/13) (2/4/14) 
TRIAD, the American College of Radiology’s (ACR) image exchange application, will be used for 
dosimetry digital treatment data submission. See Section 5.0 for information on installing TRIAD 
for submission of digital RT data PRIOR TO ENROLLING PATIENTS. 
 
In both arms, radiotherapy should begin within 8-10 weeks after the date of the first LHRH agonist 
injection. 
 
Note: There is no difference in radiation requirements between arms as the randomized question is in 
regard to hormonal therapy. However, as this protocol allows for treatment with EBRT exclusively or EBRT 
+ a brachytherapy boost (at the discretion of the treating physician) this must be specified at the time of 
study enrollment. Because patients are stratified by type of boost treatment delivered (IMRT vs. 
brachytherapy), if a patient who was originally intended to receive brachytherapy be found, post-enrollment, 
to be a poor brachytherapy candidate based on transrectal ultrasound examination, he may be switched to 
external beam radiotherapy administered per protocol guidelines, but this will result in a protocol deviation. 
Therefore, it is strongly recommended to obtain ultrasound assessment of prospective brachytherapy 
patients before enrollment on this study. 
 
When an IMRT (rather than brachytherapy) boost is used to meet the dose constraints, the composite 
EBRT plan (see Sections 6.4 – 6.5) that includes Phases 1 and 2 must be generated and summed at the 
beginning of the patient’s treatment to verify adherence to the required dose constraints. In the case of an 
inability to meet normal tissue dose-constraints on the summed plan a decrease in PTV dose to achieve 
normal tissue sparing is recommended (see Section 6.5). 
 
6.1  
Two Stage Radiation Plan (12/17/13)  
6.1.1 
Phase 1: Whole pelvis including prostate and seminal vesicles 
Acceptable Treatment Modalities: 
3D-CRT or IMRT 
 
Prescription Dose (See Table 1): 
45 Gy to cover 98% of PTV 
 
Minimum dose within PTV – 95% of prescribed dose and for a volume that is 0.03 cc 
 
Maximum dose within the PTV – 110% of prescribed dose and for a volume that is 0.03 cc 
 
Table 1: 3D-CRT and IMRT Dose Objectives for Phase 1 – Pelvic and Prostate Radiation 
  
Phase 1 
  PTV_4500 
Dose, 
Gy 
Volume, 
cc or 
%PTV 
Per 
Protocol 
Variation 
Acceptable 
included in 
range of  
Coverage 
DI
Rx(V%) 
98%  
equals  45  44 to 46 
Minimum 
Dose 
DI
Min(Vcc) 
0.03cc 
not less 
than 42.8 
40.5  to 
42.8 
Maximum 
Dose 
DI
Max(Vcc) 
0.03cc 
not more 
than 49.5  
49.5  to 54 
Homogeneity 
DI
PTV_4500 
V(49.5Gy) 
not more 
than 10%  
 
DMax in 
Patient 
 
 
In 
PTV_4500 
 
Note:  Dosimetric and/or volumetric parameters falling outside the Per Protocol and Variation Acceptable 
specifications are classified as Deviation Unacceptable. 

26 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
6.1.2 
Phase 2: Reduce volume to boost prostate and proximal seminal vesicles 
Acceptable Treatment Modalities: 
IMRT or permanent prostate implant (PPI) brachytherapy or HDR brachytherapy 
 
Prescribed Dose for IMRT boost (See Table 2): 
34.2 Gy for IMRT to cover 98% of the PTV 
 
Minimum dose within PTV – 95% of prescribed dose and for a volume that is 0.03 cc 
 
Maximum dose within the PTV – 107% of prescribed dose and for a volume that is 0.03 cc 
 
 
 
 
Prescription Dose for brachytherapy: 
110 Gy for low dose rate PPI with I–125 
100 Gy for low dose rate PPI with Pd-103 
15 Gy in one fraction for HDR or two fractions of 10.5 Gy  
 
Table 2: IMRT Dose Objectives for Prostate and Proximal Seminal Vesicle Boost 
Phase 2 
  PTV_7920 
Dose, 
Gy 
Volume, 
cc or 
%PTV 
Per 
Protocol 
Variation 
Acceptable 
included in 
range of 
Coverage 
DII
Rx(V%) 
98% 
  equals  
34.2 
       33.4  
to  35 
Minimum 
Dose 
DII
Min(Vcc) 
0.03cc 
  not less 
than  32.5 
       30.8  
to  32.5 
Maximum 
Dose 
DII
Max(Vcc) 
0.03cc 
  not more 
than  36.6 
       36.6  
to  37.6 
Homogeneity 
DII
PTV_7920 
V(36.6Gy) 
  not more 
than  10% 
 
DMax in 
Patient 
 
 
  In 
PTV_7920 
 
Note:  Dosimetric and/or volumetric parameters falling outside the Per Protocol and Variation Acceptable 
specifications are classified as Deviation Unacceptable. 
 
6.2 
Technical Factors  
6.2.1 
Either 3DCRT or IMRT may be used for phase 1 of either Arm 1 or 2. For 3DCRT treating the whole 
pelvis (WPRT), a minimum of 4-fields should be used and a 4 field plan is recommended.   For IMRT, no 
specific field arrangement is required.  
6.2.2 
RT will be delivered with megavoltage equipment at energies ≥ 6 MV. Typically, except for tomotherapy 
and VMAT techniques, 5 to 9 gantry angles are employed for the boost IMRT treatment. 
6.2.3 
Patients who receive brachytherapy as a boost component of their RT will undergo EBRT for Phase 1 
implementing either 3DCRT or IMRT as described. The prostate and seminal vesicles will be treated to a 
dose of 45 Gy in 1.8 Gy fractions prescribed to a PTV dose as above. 
 
6.3 
EBRT Localization, Simulation, and Immobilization (12/17/13) 
Simulation will be CT-based in all cases. The use of urethral contrast at the time of simulation is not 
required to help identify the apex of the prostate. Rectal contrast is discouraged because it may distend 
the rectum and artificially displace the prostate in the anterior direction. Intravenous contrast is permitted 
but not required to assist in identifying the pelvic vessels. Patients will be positioned supine or prone on a 
flat tabletop and a customized thermoplastic immobilization cast or a molded foam cradle or similar 
immobilization for stabilization and setup reproducibility is suggested. The degree of bladder fullness 
should be made to duplicate the degree of fullness anticipated for daily treatment, i.e., if the patient is 
instructed to maintain a full bladder for treatment, he should be simulated as such (especially for cases in 
which image guidance is not implemented). The rectum should be kept as empty as possible; consider an 
enema 1-2 hours prior to simulation. CT images should be acquired at a slice thickness of ≤3 mm from 
the top of the iliac crests superiorly to the perineum inferiorly. Target volumes (Section 6.4) and normal 
critical structures (Section 6.4.4) will be defined in the slices in which they are visualized. The 3DCRT 
cases (Phase 1) must utilize “beam’s eye view” representations to define final beam aperture. 
6.3.1  
CT Slice Thickness, Dose Matrix Spatial Resolution, and DVH Fidelity 

27 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
A CT slice thickness of 3mm with a linear dose matrix spatial resolution of 3mm, provides a dose voxel of 
0.027cc, just sufficient to determine doses in Vcc = 0.03cc for compliance assessment via DVH analyses. 
Higher spatial resolution in imaging and in dose matrices improve the DVH analyses in the point-dose 
surrogate volume, Vcc = 0.03cc. 
 
 
Imaging slice thickness 
≤ 3mm 
 
Dose matrix resolution 
≤ 3mm 
 
For planning systems that calculate DVH by super-sampling of the dose matrix data, planners may find it 
useful to set the secondary DVH resolution in number of points sampling an object volume (i.e., PTV, 
OAR,…) to obtain a planning_DVH_Vcc smaller than 0.03cc. The lower bound on the number of sampling 
points is given by Object_Volume(cc)/0.03cc. A factor of two to three increasing this number improves the 
fidelity of the DVH derived from the calculated dose matrix. 
 
6.4 
Treatment Planning/Target Volumes (4/16/14) 
6.4.1 
Patients treated with an IMRT boost (Phase 2) must have a composite treatment plan generated at 
the beginning of Phase 1 so that the final EBRT dose to critical structures is evaluated before any 
dose delivery has begun. 
 
Dose for Phase 1 (CTV_4500/PTV_4500) will be 45.0 Gy at 1.8 Gy per fraction in both arms. Once Phase 
1 is completed, a cone down boost to the prostate and proximal vesicles will be delivered in Phase 2 by 
any one of the three acceptable methods: IMRT, HDR or LDR permanent prostate implant. If an EBRT 
boost is planned, the prostate will receive 34.2 Gy at 1.8 Gy per fraction, for a total prostate dose of 79.2 
Gy. For pelvic 3D-CRT, a 4-field technique, using opposed anterior-posterior and opposed lateral fields, is 
recommended.  All fields should conform to the beam’s-eye-view of the target. No specific field 
arrangement is required for IMRT, although typically 5-9 fields are used for fixed gantry treatment.  
Tomotherapy and VMAT also are allowed for IMRT treatment on this protocol. However, both of these 
techniques must be credentialed separately from general IMRT credentialing. 
6.4.2 
The definition of GTV, CTV and PTV will be in accordance with the ICRU Report #50: Prescribing, 
Recording, and Reporting Photon Beam Therapy. 
Phase 1 Pelvis, including prostate and seminal vesicles (Arms 1 and 2) 
Gross Target Volume (GTV) 
The GTV is defined by the physician as all known disease as defined by the planning CT, urethrogram, 
and clinical information. If a urethrogram is used, the GTV will encompass a volume inferiorly 5 mm 
superior to the tip of the dye and no less than the entire prostate. Prostate dimensions should be defined 
as visualized on CT scan. 
Clinical Target Volume (CTV_4500) 
The CTV_4500 will include the prostate and entire seminal vesicles (SeminalVesicle), the obturator, 
external iliac, proximal internal iliac and common iliac nodes (CTVn), using the vascular structures, up to 
a level corresponding to the top of L4-L5. Please refer to the pelvic nodal atlas at the RTOG Web site 
(Pelvic 
Lymph 
Node 
Volumes 
for 
Prostate 
Cancer 
Atlas; 
http://www.rtog.org/CoreLab/ContouringAtlases/ProstatePelvicLymphNodes.aspx). The presacral 
nodes from L5-S1 to S3 may be included if desired depending on whether the dose constraints to the 
rectum are achievable (see Table 1). The CTV_4500 will extend superiorly from L4-L5 to 0.5 cm below 
the tip of the urethral contrast dye (if used) and no less than the entire prostate gland. Lateral borders will 
be at least 1 cm from the pelvic brim. In the lateral fields, the external and internal iliac lymph nodes 
below the SI joints, and the posterior extension of the seminal vesicles should be covered. The usual 
posterior border is approximately S2-3, but CT anatomy should take precedence. The inferior extent of 
the external iliac lymph nodes is at the top of the femoral heads. The inferior extent of the obturator lymph 
nodes is at the top of the symphysis pubis. The CTV_4500 will include a 7 mm margin in 3-dimensions to 
the contoured iliac vessels, but not extend outside of the true pelvis, into the pelvic musculature nor into 
adjacent identifiable organs, such as the bladder, rectum or other bowel. Extension of the CTV into 
adjacent bone may be carved out. 
Planning Target Volume 
The PTV_4500 margins should be a minimum of 0.5 cm and a maximum of 1.5 cm in all dimensions. 
 
Phase 2 Prostate and Proximal Seminal Vesicles Boost with IMRT (Arms 1 and 2) 
Gross Target Volume (GTV) 

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RTOG 1115, Version Date June 12, 2018 
 
 
The expansion will be based on GTV in phase 1 above (see Section 6.4.2). 
Clinical Target Volume (CTV_7920) 
The CTV_7920 is the GTV plus areas considered to contain microscopic disease, delineated by the 
treating physician. The CTV_7920 includes the GTV (prostate) plus areas at risk for microscopic disease 
extension plus the proximal bilateral seminal vesicles. Only the proximal 1.0 cm of seminal vesicle tissue 
adjacent to the prostate shall be included in the clinical target volume. This 1.0 cm of seminal vesicles 
refers to both radial (in plane) and superior (out of plane) extent. If both prostate and seminal vesicle are 
visualized in the same CT slice, this seminal vesicle tissue will contribute to the 1.0 cm of tissue as seen 
on the CT simulation scan. For patients with clinical biopsy proven involvement of the seminal vesicles 
treatment of the entire seminal vesicles is acceptable as long as it does interfere with the ability to 
achieve dose constraints to the critical normal structures (see Section 6.5). 
Planning Target Volume (PTV_7920) 
The PTV_7920 will provide a margin around the CTV_7920 to compensate for the variability of treatment 
set up and internal organ motion. A range of 5-10 mm around the CTV is required to define each 
respective PTV. Individual selection of a PTV margin should be based on the institution’s level of 
confidence in patient set-up and the availability of image guidance. Superior and inferior margins 
(capping) should be 5-10 mm depending on the thickness and spacing of the planning CT scan. Careful 
consideration should be made when defining the 5-10 mm margin in 3 dimensions. 
6.4.3 
Normal Critical Structures 
Normal critical structures to be defined on the treatment planning CT scan will include the following: 
bladder, rectum (from its origin at the rectosigmoid flexure superiorly or the bottom of the SI joints, 
whichever is more inferior to the inferior-most extent of the ischial tuberosities), bilateral femora (to the 
level of ischial tuberosity), penile bulb, and skin. Any small bowel within the primary beam aperture should 
be defined as well. The normal tissues will be contoured and considered as solid organs. The bladder 
should be contoured from its base to the dome, and the rectum from the anus (at the level of the ischial 
tuberosities) for a length of 15 cm or to the rectosigmoid flexure. This generally is below the bottom of the 
sacroiliac joints. If IMRT is being used to treat the pelvic nodes, the potential bowel space (not just 
individual loops of bowel) where the small and large bowel may fall should be outlined. The borders are 
the abdominal wall anteriorly, pelvic sidewalls laterally (excluding the pelvic lymph node regions), 
superiorly to one cut above the last axial CT image on which the lymph nodes are outlined and inferiorly 
from the level of the top of CTV_4500 (outlining around the sides of the bladder near the top of the 
bladder to encompass the bowel that may fall into these regions). See the NRG Oncology/RTOG web site 
(http://www.rtog.org/CoreLab/ContouringAtlases/MaleRTOGNormalPelvisAtlas.aspx) to view the normal 
pelvis atlas for examples of target and normal tissue contours. 

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RTOG 1115, Version Date June 12, 2018 
 
 
 
The following table summarizes the naming of targets and critical structures for submission of data to 
NRG Oncology via TRIAD. 
 
Note: All required structures must be labeled as listed in the table below for digital RT data submission. 
Resubmission of data may be required if labeling of structures does not conform to the standard DICOM 
name listed. 
 
EBRT 1115 
Standard DICOM Name 
GTV 
CTV_4500  
CTV_7920  
PTV_4500  
PTV_7920  
NonPTV 
Femur_L  
Femur_R  
Bladder  
PenileBulb  
Rectum  
External  
BowelSpace 
SeminalVesicle 
CTVn 
LDR 
ETV 
Rectum 
Bladder 
External 
HDR 
CTV 
PTV 
Prostate 
SeminalVesicle 
Urethra 
Bladder 
Rectum 
External 
 
6.4.4 
The PTV forms the entire target as described. 3D conformal beams will be shaped to include the entire 
PTV and minimize dose to surrounding critical structures as described. IMRT using inverse planning is 
permitted with constraints placed to adhere to critical structure dose limitations as defined below. 
 
6.5 
Critical Structures 
Critical structure dose constraints shall remain consistent with those represented in prior RTOG 
3DCRT/IMRT prostate protocols (see Table 3 below). 

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RTOG 1115, Version Date June 12, 2018 
 
 
 
 
Table 3:  Critical Structure Dose Constraints 
Normal organ 
limit† 
No more than 15% 
volume receives 
dose that exceeds 
No more than 
25% volume 
receives dose 
that exceeds 
No more than 
35% volume 
receives dose 
that exceeds 
No more than 
50% volume 
receives dose 
that exceeds 
Bladder 
Constraint 
80 Gy 
75 Gy 
70 Gy 
65 Gy 
Rectum 
Constraint 
75 Gy 
70 Gy 
65 Gy 
60 Gy 
Penile Bulb 
Mean dose less than or equal to 52.5 Gy 
†Normal organ limit refers to the volume of that organ that should not exceed the dose limit.   
 
While every effort should be made to deliver prescription doses to the PTV as specified while adhering to 
these constraints, it is recognized that certain anatomical factors may prevent this. As mentioned in 
Section 6.1, a prescription dose reduction to a level of 77.4 Gy or 75.6 Gy is permitted if constraints 
cannot be met at a prescription dose of 79.2 Gy. For purposes of compliance, up to a 5% absolute 
increase in the volume of critical structure receiving greater than the specified dose will be considered 
”variation acceptable,” e.g. up to 20% of the rectum may receive a dose of > 75.6 Gy without a protocol 
deviation. Any increase in critical structure volume greater than 5% receiving more than the specified 
dose will be considered a “deviation unacceptable.” It is at this point that a dose reduction to 77.4 Gy or 
75.6 Gy should be implemented. The prescription dose should be the maximum deliverable up to 79.2 Gy 
while respecting the critical normal structure constraints. Of note, the penile bulb constraint is to be 
regarded as a guideline, and adherence to this should not, in any way, result in a reduction of the 
prescription dose or compromised dose coverage of the target volume. 
 
6.6 
Treatment Verification (12/17/13) 
6.6.1 
First day portal images of each field along with orthogonal isocenter verification images must be obtained. 
If modifications are made in field shaping or design, a portal image of each modified field along with 
orthogonal isocenter verification images are required on the first day’s treatment of that field. Thereafter, 
weekly verification images of orthogonal isocenter views (anterior to posterior and lateral projection) are 
required.  
 
 
 
For IMRT the intensity profiles of each beam must be independently verified and compared to the 
planned field intensity. Portal images are not required for IMRT but orthogonal verification images are 
required, just as for 3DCRT. Real-time ultrasound localization and on-line cone beam CT image guidance 
are important complements to conventional port films or portal imaging and should be used when 
available. When CBCT is not available for daily use, weekly port filming/imaging will be required on this 
study. 
6.6.2 
Daily on-line target localization (kV or MV imaging with fiducials, trans-abdominal ultrasound, or other) or 
off-line adaptive approaches to account for interfraction organ motion and setup variability are permitted 
on this study but not required.  
 
6.7 
Quality Assurance (4/16/14) 
6.7.1 
Compliance Criteria for Cases Treated with EBRT 
Cases that are treated entirely with external beam radiation therapy must meet the criteria as 
stated in Sections 6.1.1 and 6.1.2 (see also Tables 1 and 2) to be scored as per protocol. That is, 
each case will have to meet the requirements in these sections depending on the particular arm of the 
study selected during randomization.  Both the Phase 1 and 2 requirements for a particular arm must be 
met in order to be scored as per protocol.  If only one phase of treatment meets the requirement, the case 
will be scored with the lower score of either variation acceptable or deviation unacceptable.  In addition, 
the critical structure dose constraints of Section 6.5 and Table 3 must be met.  In this case also, the 
patient’s treatment will be scored lower when the critical structure score is lower. 
 
The compliance criteria for the situation where the Phase 2 boost is accomplished with brachytherapy is 
given in Sections 6.8 and 6.9 below. 

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 
Acceptable dose heterogeneity for external beam treatment is summarized in Tables 1 and 2. 
The treating physician must carefully consider the tolerance dose/volume to each critical normal 
structure and unspecified tissue. 
 
Dose Distribution 
IROC Philadelphia will display, and compare with isodose distributions for the axial and coronal 
planes through the planning target volume to verify correct digital submission and conversion. 
The submitted DVHs for the PTV will then be compared with those generated by NRG Oncology. 
Per protocol scoring will be considered for those cases in which 98% of the PTV receives the 
prescription dose. 
 
Elapsed Days During Radiotherapy   
Per Protocol: 1 to 7 break days 
Variation Acceptable: 8 to 14 days 
Deviation Unacceptable: > 14 days 
 
6.8  
Dose Specifications/Technical Considerations: LDR Brachytherapy Boost (12/17/13) (2/4/14) 
Note: As this protocol allows for treatment with exclusively EBRT or EBRT + a brachytherapy 
boost (at the discretion of the treating physician) this must be specified at the time of study 
enrollment. If a patient who was originally intended to receive brachytherapy be found, post-
enrollment, to be a poor brachytherapy candidate based on transrectal ultrasound examination, 
he may be switched to EBRT administered per protocol guidelines, but this will result in a 
protocol deviation. Therefore, it is strongly recommended to obtain ultrasound assessment of 
prospective brachytherapy patients before enrollment on this study. 
6.8.1 
LDR, permanent seed, brachytherapy boost is permitted at the discretion of the treating radiation 
oncologist in conjunction with EBRT as described in Section 6.2.3. Implants will only be offered to 
patients with a prostate volume documented to be <60 cc by transrectal ultrasound examination, an AUA 
score ≤15, and no prior history of TURP (Section 3.2.7). The implant may be performed under either 
general or spinal anesthesia and will be performed following the EBRT portion of treatment no more than 
4 weeks after its completion. 
6.8.2 
Preplanning  
This will be carried out prior to the procedure or intra-operatively via transrectal ultrasound examination. 
The prostate will be defined from base to apex in the axial plane at 5 mm slice intervals. The treatment 
length and prostate volume will be recorded. The CTV is the prostate gland and the proximal seminal 
vesicles (CTV_7920). The PTV may be the same as the CTV or a 2-3 mm margin may be added 
anteriorly and up to 5 mm craniocaudally and laterally at the discretion of the treating physician. 
6.8.3 
Isotope Selection 
Iodine-125 or Palladium-103 seeds may be used. The sources will be received and inventoried in 
accordance with state and federal regulations. If nonsterile loose sources or cartridges are used, at least 
10% of the sources will be assayed in such a manner that direct traceability to either the National Institute 
of Standards and Technology (NIST), an Accredited Dosimetry Calibration Lab (ADCL) or for international 
participants, the national standards laboratory in their respective country, is maintained. NIST 1999 
standards will be used. If sterile source assemblies or strands are used, alternatively non-stranded loose 
seeds equal to 5% of the total, or five seeds, whichever is fewer, may be ordered and assayed. 
Agreement of the average measured source strength shall agree with that indicated in the vendor’s 
calibration certificate to within 5%. No measured source strengths should fall outside 10% of that 
indicated in the vendor’s calibration certificate. 
 
For I-125, the allowable source strength for each seed is 0.277 U to .650 U (NIST 99 or later). For 
Pd-103 sources, this range is 1.29 U to 2.61 U (NIST 99 or later). 
 
The vendor’s stated source strength shall be used in all dosimetry calculations. Calculations will 
be performed in accordance with NIST 1999 calibration standards, the point source formalism 
described in the report generated by AAPM Task Group 43 and subsequent published AAPM 
Subcommittee Reports. The AAPM’s recommendations for Pd-103 dose specifications and 
prescription are being followed. 
6.8.4  
Prescription Doses 
The prescription dose for permanent seed interstitial boost will be 110 Gy for I-125 and 100 Gy for Pd-
103. Doses will be prescribed as minimal peripheral dose to the PTV. 
6.8.5 
Postimplant Imaging 
A pelvic x-ray with seed count verification will be obtained immediately postimplant. If the seed count 
does not match the number of seeds implanted, PA and lateral chest x-rays will be obtained to rule out 

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RTOG 1115, Version Date June 12, 2018 
 
 
pulmonary seed migration. CT scan for postimplant dosimetric analysis will be obtained following implant 
completion. Use of a Foley catheter for this test is encouraged for accurate urethral dosimetry but not 
required. This may be obtained immediately postoperative on the day of the implant if desired but no later 
than 5 weeks postimplant. The use of intravesical contrast is encouraged. CT slices should be acquired at 
≤3 mm thickness and should encompass the pelvis from, at minimum, the bottom of the sacroiliac joints 
superiorly to 2 cm caudal to the prostatic apex.  
 
Structures defined will include the prostate, bladder, and rectum. The rectum will be defined from 
the bottom of the sacroiliac joints to the ischial tuberosity and will extend to the outer surface of 
the visualized rectal wall. The postimplant, CT-defined prostate will be defined as the “evaluated 
target volume” (ETV) and will form the basis for dosimetric analysis. 
6.8.6 
Dosimetry 
Postimplant evaluation will be performed on equipment capable of providing structural and volume-based 
dosimetric assessment on both the target and critical structures. Volume acquisition will be based on 
contiguous axial CT slices as described above. Both target volume and critical structures will be 
contoured on each applicable axial slice. Isodose line displays and dose-volume histograms for all 
structures will be generated. 
 
The calculation grid should be set no larger than (2 mm x 2 mm x axial slice width). 
 
The planning system shall be capable of transmitting data via DICOM RT to TRIAD electronically. 
 
Guidelines established by the American Brachytherapy Society (Nag 2000) are to be followed. 
DVH-based analysis must be used in the postplan evaluation. The following values shall be 
reported. Vn is the percentage of the ETV that received at least n% of the prescription dose. Dm 
is the minimum dose received by m% of the ETV. 
 
Target coverage will be documented in terms of V100, V90, V80, D90. 
 
Dose uniformity will be expressed in terms of V150. 
 
The rectum will be defined from the bottom of the SI joints to the ischial tuberosity. The maximum 
rectal dose as well as the volume and percentage of rectum receiving > 100% of the prescription 
dose will be recorded. 
Note: All required LDR Brachytherapy Boost structures must be labeled as listed in the table in Section 
6.4.3 for digital RT data submission. Resubmission of data may be required if labeling of structures does 
not conform to the standard DICOM name listed. 
6.8.7 
Compliance Criteria 
 
Per protocol: D90 for the ETV is greater than 90% of the prescription dose but less than 130% of 
the prescription dose. 
 
Variation acceptable: D90 for the ETV is greater than 80% of the prescription dose, but less than 
90% of the prescription dose, or greater than 130% of the prescription dose. 
 
Deviation unacceptable: D90 for the ETV is less than 80% of the prescription dose. 
6.8.8 
Dosimetric Data to be Submitted to RTOG  
 
Copies of preimplant TRUS images with CTV and PTV annotated 
 
A copy of the implant record generated during the procedure 
 
A copy of the image taken after the procedure and a copy of the image or scout taken during the 
post implant CT 
 
A copy of the postimplant CT scan, ETV and bladder and rectum delineation and dosimetry 
calculations (must be submitted electronically) 
 
A copy of the postimplant dosimetry report that contains the information required in Section 6.8.6 
above. 
 
6.9  
Dose Specifications/Technical Considerations: HDR Brachytherapy Boost (4/16/14) 
Note: As this protocol allows for treatment with exclusively EBRT or EBRT + a brachytherapy 
boost (at the discretion of the treating physician) this must be specified at the time of study 
enrollment. If a patient who was originally intended to receive brachytherapy be found, post-
enrollment, to be a poor brachytherapy candidate based on transrectal ultrasound examination, 
he may be switched to EBRT administered per protocol guidelines, but this will result in a 
protocol deviation. Therefore, it is strongly recommended to obtain ultrasound assessment of 
prospective brachytherapy patients before enrollment on this study. 
 

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RTOG 1115, Version Date June 12, 2018 
 
 
Type of HDR planning (CT or TRUS) must be specified at the time of enrollment.  Any change of HDR 
planning technique must be reported to the HDR study co-chair Dr. Bachand in writing prior to the 
implant, otherwise the patient will no longer be eligible. 
 
6.9.1 
HDR brachytherapy boost is permitted at the discretion of the treating radiation oncologist in conjunction 
with EBRT as described in Section 6.2.3. Implants will only be offered to patients with a prostate volume 
documented to be <60 cc by transrectal ultrasound examination, AUA symptom index ≤15, and no prior 
history of TURP (Section 3.2.7). The implant may be performed during the EBRT portion of the treatment 
or within 2 weeks prior to its initiation or following its completion. The RT should start within 8-10 weeks 
following the first LHRH administration. The date of HDR brachytherapy implant will constitute the start of 
RT for those patients receiving implants prior to EBRT. 
6.9.2 
CT Based HDR Brachytherapy 
 
All implants will be performed under transrectal ultrasound guidance. Epidural, spinal, or general 
anesthesia may be used. A 12-16 French Foley catheter should be inserted to allow visualization 
of the urethra. Posterior rows of catheters may be advanced into the seminal vesicles under 
TRUS guidance.   
 
At least 14 treatment catheters should be used to ensure adequate CTV coverage with   
acceptable dose heterogeneity. 
 
Fiducial markers identifying the prostatic base and apex could be placed at the time of the implant 
procedure unless previously placed for guidance of EBRT.  
 
The use of intraoperative cystoscopy can be used to ensure the absence of treatment catheters 
within the urethra or bladder. The cystoscope should be retroflexed within the bladder for 
visualization of the bladder neck. Light pressure on the treatment catheters should result in 
mucosal tenting confirming adequate coverage at the prostatic base. 
 
Patients will be treated with either a single implant-single HDR fraction, a single implant-2 HDR 
fractions delivered over 24 hours with a minimum of 6 hours in between or 2 implants-2 HDR 
fractions. For patients receiving 2 fractions over 2 implants, the insertions should be done 7 to 14 
days apart.  No EBRT treatment will be delivered on the day of HDR treatment. 
 
The treatment planning CT scan must be performed with the patients in the supine position with  
the Foley catheter in place. Metallic obturators, dummy ribbons and rectal tube or marker must be 
removed prior to the CT scan. If contrast material is used in the bladder, rectum or urethra, it 
should be diluted to 10% or less to minimize CT artifact. The scan must include all of the CTV 
with at least 9 mm superior and inferior margin, and the scan must include the tips of all the 
implanted catheters. The scan thickness must be ≤0.3 cm and the slices must be contiguous. The 
field of view (FOV) of axial CT slice should include all the critical structures and target volume on 
that slice while minimized the overall FOV size to approximately 20 x 20 cm.  FOV does not need 
to include the contour of pelvis. The brachytherapy target volume and normal critical structures 
must be outlined on all CT slices including the prostate, seminal vesicles, urethra, bladder, and 
rectum. 
 
The evaluation of the quality of the implant will be based on the CT using criteria defined below 
(Section 6.9.10) 
 
Dwell times in positions located outside of the PTV should be turned down or off to minimize 
normal tissue irradiated. A dwell time optimization program based on implant geometry or an 
inverse planning algorithm may be used. Manual optimization is also accepted. An activation 
volume can be created around the CTV (not posteriorly), allowing optimization of the dwell 
times immediately outside the CTV/PTV.   
 
The Clinical Target Volume (CTV) is defined by the physician on the treatment planning CT scan. 
The CTV is the prostate gland plus any visualized extracapsular extension of tumor. The 
brachytherapy Planning Target Volume (PTV) is identical to the CTV. 
 
Critical structures to be defined include the bladder, rectum, and urethra, within the volume of 
interest defined in. The outermost extent of the bladder/rectal wall will define those structures with 
particular attention to bladder base. The urethra is defined by the outer surface of the Foley 
catheter.  
 
The volume of bladder and rectum receiving 75% of the prescription dose must be kept to less 
than 1 cc (V75 <1 cc) and the volume of urethra receiving 125% of the prescription dose must be 
kept to less than 1 cc (V125 <1 cc) and urethral V150 should be 0 cc (V150 = 0 cc). Attempts 
should be made to limit the volume of urethra receiving ≥115% of the prescription dose to 

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RTOG 1115, Version Date June 12, 2018 
 
 
≤5%. Up to 10% will be considered variation acceptable. If the dose to normal critical structures 
cannot be kept below the specified level, we recommend readjusting the implant or repeating the 
implant procedure until a more optimal implant is obtained. 
Note: All required HDR Brachytherapy Boost structures must be labeled as listed in the table in Section 
6.4.3 for digital RT data submission. Resubmission of data may be required if labeling of structures does 
not conform to the standard DICOM name listed. 
6.9.3 
Compliance Criteria 
The prescription dose and fractionation is at the discretion of the prescribing physician.   
 
Single implant-single fraction: 
 
A prescription dose of 15 Gy will be delivered to the PTV.   
 
Single implant-2 fractions: 
A prescription dose of 21 Gy will be delivered to the PTV in two equal fractions of 10.5 Gy. The 
first fraction of 10.5 Gy will be delivered as soon as possible following completion of the implant 
procedure and treatment planning. Both fractions must be delivered within a single 24-hour period 
and separated by a minimum of 6 hours. Overnight hospital stay is permitted between fractions if 
necessary. 
 
2 implants-2 fractions: 
A prescription dose of 21 Gy will be delivered to the PTV in two equal fractions of 10.5 Gy, using 
one implant for each fraction. Both fractions of 10.5 Gy will be delivered as soon as possible 
following completion of the implant procedure and treatment planning.  All catheters will be 
removed following completion of the treatment after each fraction. Both fractions must be 
separated by 7 to 14 days. 
 
Ninety percent coverage of the PTV with the prescription dose is considered per protocol, 85% 
but <90% is considered variation acceptable, and <85% coverage is considered deviation 
unacceptable.  Urethral dose above limits (V125 ≥ 1cc and V150 > 0 cc) is considered deviation 
unacceptable.  
6.9.4 
Catheter Position Verification 
Visual inspection of the catheters prior to delivery of each treatment is required. If readjustment is 
needed, the CT planning should be repeated. The physician may adjust the catheters if catheter 
displacement is identified prior to the treatment. 
6.9.5 
Catheter Removal  
After completion of the treatment all implant catheters will be removed. 
6.9.6 
Data Submission 
All data will be digitally submitted to the IROC Philadelphia and include CT data, normal critical structures, 
all PTV contours, and digital DVH data for all normal critical structures, the PTV for dose plan, a copy of 
the daily treatment chart for EBRT and Brachytherapy. 
6.9.7 
Quality Assurance 
Individual case review will be overseen by Dr. Bachand, the HDR brachytherapy study co-chair 
overseeing this subgroup of patients enrolled on this protocol, as specified in Section 6.10. 
6.9.8  
TRUS Based HDR Brachytherapy 
 
All implants will be performed under transrectal ultrasound guidance. Epidural, spinal, or general 
anesthesia may be used.  
 
At least 14 treatment catheters should be used to ensure adequate CTV coverage with 
acceptable dose heterogeneity.  
 
The treatment planning TRUS must be performed with the patient in the supine position with the 
12-16 French Foley catheter in place. Two sets of TRUS images are taken.  The first set will be 
done prior to the insertion of implant catheters when the target volume and the urethra are visible. 
The second set of images is done after the insertion of the implant catheters and is used for 
treatment planning.  The scan must include all of the CTV with at least 1 cm superior and inferior 
margin, and the scan must include the tips of all the implanted catheters. The scan thickness 
must be ≤0.3 cm and the slices must be contiguous. The brachytherapy target volume and 
normal critical structures must be outlined on all slices including the CTV, urethra and rectum.  
 
Both transrectal ultrasound scans, one prior to implant catheter insertion and one with catheters 
in place, must be submitted for each patient. 
 
Dwell times in positions located outside of the PTV should be turned down or off to minimize 
normal tissue irradiated. A dwell time optimization program based on implant geometry or 
an inverse planning algorithm may be used. Manual optimization is also accepted.  An 
activation volume can be created around the CTV (not posteriorly), allowing optimization of the 

35 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
dwell times immediately outside the CTV/PTV.  A dwell time optimization program based on 
implant geometry or an inverse planning algorithm may be used. Manual optimization is also 
accepted. 
 
The Clinical Target Volume (CTV) is defined by the physician on the treatment planning CT scan. 
The CTV is the prostate gland plus any visualized extracapsular extension of tumor.  The 
brachytherapy Planning Target Volume (PTV) is identical to the CTV. 
 
Critical structures to be defined using TRUS planning include the rectum and the urethra within 
the volume of interest defined above. The rectum is defined as the outermost extent of the rectal 
wall from the TRUS probe, the lateral boarders extends to the edge of the TRUS image. The 
urethra is defined by the outer surface of the Foley catheter and it is contoured as a solid 
structure.  
 
The volume of rectum receiving 80% of the prescription dose must be kept to less than 0.5 cc 
(V80 <0.5 cc) and the volume of urethra receiving 130% of the prescription dose should be 0 cc 
and the urethra D10 should be < 115%. Attempts should be made to limit the volume of 
urethra receiving ≥115% of the prescription dose to ≤5%. 
 
All TRUS based HDR treatment should be delivered with TRUS probe in the patient so the 
dosimetry may be accurately reproduced. 
Note: All required HDR Brachytherapy Boost structures must be labeled as listed in the table in Section 
6.4.3 for digital RT data submission. Resubmission of data may be required if labeling of structures does 
not conform to the standard DICOM name listed. 
6.9.9 
Compliance Criteria 
The prescription dose and fractionation is at the discretion of the prescribing physician. 
 
Single implant-single fraction: 
A prescription dose of 15 Gy will be delivered to the PTV.   
 
Single implant-2 fractions: 
A prescription dose of 21 Gy will be delivered to the PTV in two equal fractions of 10.5 Gy. The 
first fraction of 10.5 Gy will be delivered as soon as possible following completion of the implant 
procedure and treatment planning. Both fractions must be delivered within a single 24-hour period 
and separated by a minimum of 6 hours. Overnight hospital stay  is permitted between fractions if 
necessary. 
 
2 implants-2 fractions: 
A prescription dose of 21 Gy will be delivered to the PTV in two equal fractions of 10.5 Gy, using 
one implant for each fraction. Both fractions of 10.5 Gy will be delivered as soon as possible 
following completion of the implant procedure and treatment planning. All catheters will be 
removed following completion of the treatment after each fraction. Both fractions must be 
separated by 7 to 14 days. 
 
Ninety percent coverage of the PTV with the prescription dose is considered per protocol, 85% 
but <90% is considered variation acceptable, and <85% coverage is considered  deviation 
unacceptable.  Urethral dose above limits (V130 > 0 cc and D10 < 118%) is considered deviation 
unacceptable. 
6.9.10  Catheter Removal 
After completion of the treatment all implant catheters will be removed.  
6.9.11  Data Submission 
All data will be digitally submitted to TRIAD and include both TRUS scans (with/without implant catheter), 
normal critical structures, all PTV contours, and digital DVH data for all normal critical structures, and the 
PTV for dose plan.  
6.9.12  Quality Assurance 
Individual case review will be overseen by Dr. Bachand, the HDR brachytherapy study co-chair 
overseeing this subgroup of patients enrolled on this protocol, as specified in Section 6.10. 
 
6.10 
R.T. Quality Assurance Reviews (4/16/14) 
The study co-chairs for the respective RT modalities offered in this trial will oversee quality assurance 
reviews for patients treated in those respective fashions. These reviews will be ongoing and performed 
remotely. RT quality assurance reviews will be facilitated by IROC Philadelphia.  
 
6.11 
Radiation Therapy Adverse Events 
6.11.1 All patients will be seen weekly by their treating radiation oncologist while undergoing EBRT. Any 
observations with respect to the following symptoms/side effects will be recorded: 

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 
Bowel/rectal irritation manifesting as cramping, diarrhea, urgency, proctitis, or hematochezia 
 
Urinary frequency, urgency, dysuria, hematuria, urinary tract infection, or incontinence 
 
Radiation dermatitis 
 
6.11.2  Clinical discretion may be used in managing radiotherapy-related side effects. Diarrhea/rectal 
frequency/urgency may be managed with diphenoxylate or loperamide. Bladder irritation may be 
mitigated with phenazopyridine. Urinary frequency/urgency can be managed with anticholinergic agents 
or alpha-blockers such as tamsulosin. Erectile dysfunction can be managed with phosphodiesterase 
(PDE) inhibitors such as sildenafil. 
 
 
6.12 
Radiation Therapy Adverse Event Reporting 
 
See Section 7.17. 
 
7.0 DRUG THERAPY 
7.1 
Treatment (12/17/13) 
Androgen suppression (AS) must begin within 6 weeks after registration (if not started prior to 
registration) and will be administered in both Arms 1 and Arm 2. TAK-700 will begin at the same 
time as AS. Radiation therapy will begin 8-10 weeks after the initiation of AS and will be given as 
specified in Section 6.0. 
 
For those who started LHRH therapy prior to enrollment, they must have started this <50 days 
prior to enrollment. In addition, the same goal of starting RT 8-10 weeks from the start of LHRH 
therapy will be maintained. 
 
7.1.1  
Arm 1 
Patients on Arm 1 will receive standard AS with LHRH agonist and oral anti-androgen. LHRH agonist will 
continue for 24 months (cumulative 24 month total dose) from initiation. Oral anti-androgen will be 
discontinued at the end of radiation therapy. 
7.1.2  
Arm 2  
Patients on Arm 2 will receive the same standard AS with LHRH agonist and oral antiandrogen as 
administered in Arm 1, but also will receive the study drug TAK-700 (for 2 years) as detailed in Section 
7.5 below. 
7.1.3 
For patients on either Arm 1 or Arm 2 who began ADT prior to enrollment, if prior treatment was 
with LHRH agonist alone, an oral anti-androgen (plus or minus TAK-700) should be added at the 
time of enrollment. 
 
7.2 
LHRH agonists (such as leuprolide, goserelin, buserelin, triptorelin) (12/17/13) 
Refer to the package insert for detailed pharmacologic and safety information. 
,7.2.1 
Description: LHRH agonists are long-acting analogs of the native LHRH peptide and are effective at 
reducing serum testosterone. Analogs approved by the FDA (or by Health Canada for Canadian 
institutions) can be used in this study. 
7.2.2 
Supply: Commercially available. (NOTE: Buserelin is not commercially available in the United States. It is 
commercially available for use in Canada and other countries outside of the United States.) 
7.2.3 
Storage: LHRH analogs should be stored as directed by the commercial supplier. 
7.2.4 
Administration: LHRH analogs are administered with a variety of techniques, including subcutaneous 
insertion of a solid plug in the abdominal wall (Zoladex), intramuscular injection (Lupron), subcutaneous 
injection (Eligard), or insertion of a long-acting cylinder that slowly releases the agent (Viadur). The 
manufacturer’s instructions should be followed. 
7.2.5 
Toxicity: Consult the package insert for comprehensive toxicity information. Class-related toxicity is 
generally a manifestation of the mechanism of action and due to low testosterone levels. In the majority of 
patients testosterone levels increased above baseline during the first week, declining thereafter to 
baseline levels or below by the end of the second week of treatment. The most common side effect of 
LHRH analogs is vasomotor hot flashes; edema, gynecomastia, bone pain, thrombosis, and 
gastrointestinal disturbances have occurred. Potential exacerbations of signs and symptoms during the 
first few weeks of treatment is a concern in patients with vertebral metastases and/or urinary obstruction 
or hematuria which, if aggravated, may lead to neurological problems such as temporary weakness 
and/or paresthesia of the lower limbs or worsening of urinary symptoms. Other side effects include 
impotence and loss of libido, weight gain, depression, dizziness, loss of bone density, anemia, increased 
thirst and urination, unusual taste in the mouth, skin redness or hives, pain at injection site, and muscle 

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mass and strength loss, hair changes, penile length and testicular volume loss, increased cholesterol, 
hypertension, diabetes exacerbation, emotional lability, nausea, vomiting, and rarely allergic generalized 
rash and difficulty breathing.  
 
7.3 
Eulexin (flutamide) (12/17/13)  
Refer to the package insert for detailed pharmacologic and safety information.  
7.3.1 
Description: Flutamide is a substituted anilide. It is a fine, light, yellow powder, insoluble in water but 
soluble in common organic solvents such as aromatic or halogenated hydrocarbons. Its concentration in 
plasma can be determined by gas chromatography. Flutamide is a nonsteroidal antiandrogen that is 
metabolized into a hydroxylated derivative, which effectively competes with the hydrotestosterone for 
androgen receptor sites. 
7.3.2 
Supply: Commercially available. 
7.3.3 
Storage: Flutamide should be stored at temperatures ranging from 20-30 °C (36 °-86 °F) and protected 
from excessive moisture. 
7.3.4 
Administration: The drug is administered orally at a dose of 250 mg (two 125-mg capsules) three times a 
day for a total daily dose of 750 mg. Flutamide will begin 8-10 weeks prior to radiotherapy and continue 
throughout radiotherapy. Administration will be suspended only if there is an apparent or suspected 
reaction to the drug. See Section 7.3.6. Flutamide will be terminated on the last day of radiotherapy. 
During radiotherapy interruptions, flutamide will be continued. 
7.3.5 
Toxicity: Consult the package insert for comprehensive toxicity information. The reported side effects of 
treatment include diarrhea and anemia. A high percentage of patients treated with flutamide alone 
developed gynecomastia within 2 to 8 months. There have been post-marketing reports of hospitalization, 
and, rarely, death due to liver failure in patients taking flutamide. Evidence of hepatic injury included 
elevated serum transaminase levels, jaundice, hepatic encephalopathy, and death related to acute 
hepatic failure. The hepatic injury was reversible after prompt discontinuation of therapy in some patients. 
Approximately half of the reported cases occurred within the initial 3 months of treatment with flutamide. 
Other side effects include impotence and loss of libido, fatigue, and rarely photosensitivity. 
7.3.6 
Dose Modifications: If gastrointestinal disturbances (cramps, diarrhea) occur prior to initiation of 
radiotherapy, flutamide will be withheld until the side effects subside; the drug will then be reintroduced at 
a dose of 250 mg/day and increased (at 3-day intervals) to 500 mg/day and then to 750 mg/day as 
tolerated. If gastrointestinal disturbances occur after administration of radiotherapy, it might be difficult to 
identify their cause. However, if severity of diarrhea exceeds the level commonly observed during pelvic 
irradiation, the toxicity will be ascribed to flutamide and the drug will be permanently discontinued. ALT 
will be measured pretreatment, then monthly during oral antiandrogen therapy. If ALT increases ≥ 2 x 
upper institutional limit of normal, flutamide must be discontinued. Elevated ALT values to < 2x the 
institutional upper limit of normal are subject to dose modifications or discontinuation of anti-androgen at 
the discretion of the treating physician. 
 
7.4 
Casodex (bicalutamide) (12/17/13)  
Refer to the package insert for detailed pharmacologic and safety information.  
7.4.1 
Description: Bicalutamide is a nonsteroidal antiandrogen, which has no androgenic or progestational 
properties. The chemical name is propanamide, N-[4-cyano-3(trifluoromethyl)phenyl]- 3- [(4-
fluorophenyl)sulphonyl]- 2- hydroxy- 2- methyl, (+,-). Bicalutamide is a racemic mixture with the 
antiandrogen activity residing exclusively in the (-) or R-enantiomer. Bicalutamide has a long half-life 
compatible with once-daily dosing. Bicalutamide is well tolerated and has good response rates in phase II 
trials (Kennealey and Furr, 1991, Tyrrell 1994). 
7.4.2 
Supply: Commercially available. 
7.4.3 
Storage: Bicalutamide should be stored in a dry place at room temperature between 68°-77°F. 
7.4.4 
Administration: Bicalutamide is administered orally at a dose of one 50 mg tablet per day. Bicalutamide 
will begin 8-10 weeks prior to radiotherapy and continue throughout radiotherapy. Administration will be 
suspended only if there is an apparent or suspected reaction to the drug. Bicalutamide will be 
terminated on the last day of radiotherapy. During radiotherapy interruptions, bicalutamide will be 
continued. 
7.4.5 
Toxicity: Consult the package insert for comprehensive toxicity information. In animal experiments, birth 
defects (abnormal genitalia, hypospadias) were found in male offspring from female animals dosed with 
bicalutamide during pregnancy. Although offspring from male animals dosed with bicalutamide did not 
show any birth defects, patients enrolled in this trial are advised not to cause pregnancy nor donate 
sperm while receiving protocol therapy or during the first 3 months after cessation of therapy. The use of 

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barrier contraceptives is advised. The most frequent adverse events reported among subjects receiving 
bicalutamide therapy are breast tenderness, breast swelling, and hot flashes. When bicalutamide 50 mg 
was given in combination with an LHRH analog, the LHRH analog adverse event profile predominated 
with a high incidence of hot flashes (53%) and relatively low incidences of gynecomastia (4.7%) and 
breast pain (3.2%). Other side effects include impotence and loss of libido, fatigue, and rarely 
photosensitivity and diarrhea. 
7.4.6 
Dose Modifications: Bicalutamide should be discontinued in instances of chemical liver toxicity. ALT will 
be measured pretreatment and then monthly during antiandrogen therapy. If the ALT rises ≥ 2 x the 
institutional upper limit of normal, bicalutamide must discontinued. Elevated ALT values to < 2x the 
institutional upper limit of normal are subject to dose modifications or discontinuation of anti-androgen at 
the discretion of the treating physician. 
 
7.5  
Study Drug (TAK-700) Administration (TAK-700, IND # 115368) (12/17/13)  
To supplement the toxicity information contained in this document, investigators must obtain the current 
version of the Investigator Brochure for comprehensive pharmacologic and safety information. The 
Investigator’s Brochure is available on the NRG Oncology/RTOG web site under protocol-specific 
materials/regulatory resources. 
7.5.1  
Dose and Regimen 
TAK-700 will initially be given at 300 mg BID (600 mg per day) orally, continuously for 2 years, beginning 
at the same time as androgen suppression (AS). See Section 7.6 for dose modification and supportive 
care guidelines. TAK-700 should be taken twice daily at the same time each day, but not less than 6 
hours apart, and may be taken with or without food. Missed doses of study drug will not be made up. 
Patients will be given a diary to record study drug dosing. If a dose is missed, the missed dose will be 
recorded as “not taken.” The next dose will be taken at the next scheduled time. 
 
7.6  
TAK-700 Dose Modification and Supportive Care Guidelines (12/17/13)  
The investigator should determine if an AE is related to TAK-700. Adverse events considered at least 
possibly related to TAK-700 may require a dose reduction (Table 7-1), a temporary hold, or permanent 
discontinuation. 
 
Depending on the AE, following partial or complete resolution of symptoms, the dose of TAK-700 may be 
increased at 2-week intervals to the next higher dose level until the original dose level has been reached. 
Guidelines for modification of the dose based on the severity of the AE are provided in this section. 
7.6.1  
Dose Levels for TAK-700 
The TAK-700 dose levels to be applied for all dose modifications are defined in Table 7-1. 
 
Table 7-1 Dose Modifications for TAK-700 
Dose Level 
TAK-700 Dose  
(Tablets and Timing of Administration) 
0 
300 mg BID (100 mg x 3 BID) 
-1 
200 mg BID (100 mg x 2 BID) 
-2 
None (dosing hold or temporary 
discontinuation) 
 
7.6.2  
Dose Modifications 
Dose modifications should be based on CTCAE version 4.0. Dose reduction for Grade 1 AEs is not 
required. Dose reduction for Grade 2 events should only be considered when the AE is judged by the 
investigator to be clinically intolerable. For TAK-700 Grade >2 AEs, the dose modification of TAK-700 
should follow the Dose Reduction and Re-escalation guidelines (Sections 7.6.3 and 7.6.4, respectively). 
For events of fatigue, nausea, vomiting, diarrhea, and hypertension, refer to Section 7.6.6, Specific 
Guidelines for Possible TAK-700 Related Toxicities. 
7.6.3  
Criteria for TAK-700 Initial Dose Reduction 
Asymptomatic Grade 3 or 4 laboratory findings may not require dose modification (i.e. dose hold or 
reduction) especially if these are not considered to be clinically significant or related to study drug. The 
decision to modify the dose should be based on the investigator’s clinical judgment. 
 
Grade 3 or 4 AEs that are considered at least possibly related to study drug require a dosing hold, i.e. 
hold for a minimum of 2 weeks. The investigator should identify other potential causes of AEs. For a 

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clinically intolerable Grade 2 AE that is considered at least possibly related to study drug, the dose should 
be decreased by 1 dose level for 2 weeks. 
 
Once the dose is reduced, reassessment is required at least every 2 weeks until the event is resolved or 
stabilized. However, the frequency of reassessment should be increased as clinically indicated. If the 
grade worsens at any time, the dose should be decreased in accordance with the guidelines for the worst 
grade. 
7.6.4  
Criteria for TAK-700 Dose Re-escalation 
Re-escalation for Grade 2 Intolerable Adverse Events 
Re-escalation of TAK-700 after resolution or improvement of a Grade 2 intolerable AE will follow the 
criteria below: 
(1)  If the AE grade improves to Grade 0, 1, or Grade 2 tolerable AE, re-escalate the dose by 1 level. 
(2) If the AE remains at intolerable Grade 2 or worsens to Grade > 3, hold TAK-700 for 2 weeks followed 
by a reassessment. Follow the re-escalation guidelines for Grade 3 or 4 AEs as defined below. 
 
Reassess the AE after 2 weeks, or sooner if the AE worsens. Continue to reassess at least every 2 
weeks until the event is resolved or stabilized. Continue to adjust the TAK-700 dose until the dose is 
optimally titrated. If the dose has been held for 6 weeks, TAK-700 should be discontinued permanently. 
 
 
Re-escalation of TAK-700 Following a Grade 3 or 4 Adverse Event 
Re-escalation following a Grade 3 or 4 AE will follow the criteria below: 
(1)  If the AE grade improves to Grade 0, 1, or Grade 2 tolerable AE, re-escalate the TAK-700 dose by 1 
level. 
(2)  If the AE improves to Grade 2 but is still intolerable, hold dosing for another 2 weeks.  Follow the re-
escalation guidelines for Grade 2 intolerable AEs as defined in Section 7.6.4. 
(3) If the AE is Grade 3 or 4 after 2 weeks, hold dosing for another 2 weeks and reassess again after 2 
weeks.  
 
Reassess the AE after 2 weeks, or sooner if the AE worsens. Continue to reassess at least every 2 
weeks until the event is resolved or stabilized. Continue TAK-700 dose adjustment until the dose is 
optimally titrated. 
7.6.5  
Criteria for Discontinuation of TAK-700 
If the adverse event persists at > Grade 3 for more than 6 weeks, permanently discontinue treatment with 
TAK-700. The TAK-700 dose may also be discontinued permanently if judged by the 
investigator to be clinically intolerable despite dose reduction, and the dose cannot be optimally 
titrated. 
7.6.6  
Specific Guidelines for Possible TAK-700-Related Toxicities 
This section provides the required dose modifications for study drugs and recommended clinical 
management of patients who experience AEs that are considered by the investigator to be related to 
TAK-700.   
Fatigue 
Grade 2 to Grade 3 fatigue has occurred in some patients receiving TAK-700 without concomitant 
prednisone. Less severe Grade 1 or Grade 2 fatigue has been reported in some men receiving 
concomitant prednisone; other factors such as acute androgen deprivation may also contribute to 
symptoms.   
 
Dose modification for Grade 2 fatigue is optional but may be helpful by slowing the induction to full 
androgen deprivation. Grade 3 fatigue should be treated according to the general outlines in Section 
7.6.2, including initial hold and re-introduction of TAK-700 with subsequent titration at 2 week intervals to 
the patient’s tolerated dose level. 
 
Gastrointestinal Adverse Events 
In previous and ongoing clinical studies, episodic and not necessarily dose-related gastrointestinal 
toxicities have occurred. 
Nausea and/or Vomiting 
Grade 1 – No action required 

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Grade 2 – Concomitant antiemetics may initially be administered without dose reduction.  If Grade 2 
nausea or vomiting persists and is intolerable, dose reduction and re-escalation should follow Grade 2 
Dose Reduction and Dose Re-escalation guidelines. 
Grade 3 or 4 – Supportive care regimen should follow local standard of care. Follow Dose Reduction and 
Dose Re-escalation guidelines. 
 
Note: It is possible that nausea and vomiting could be secondary to acute adrenal insufficiency. If nausea 
and vomiting occur in the setting of severe fatigue, prostration, or hypotension, blood should be obtained 
to check the electrolytes. Institutional standard of care should be followed in the presence of electrolytes 
imbalance. Even if the vomiting occurs shortly following the TAK-700 dose, no re-dosing of TAK-700 will 
be done. 
Diarrhea 
Prophylactic antidiarrheals will not be used in this protocol; however, patients will be treated according to 
institutional standard of care. Fluid intake should be maintained to avoid dehydration. 
 
Hypertension 
If new onset or worsening of established hypertension occurs and the potassium level is < 3.5 mEq/L, in 
the absence of other causes such as new diuretic therapy, it suggests a TAK-700-related 
mineralocorticoid syndrome.  A plasma renin activity that is undetectable or low also suggests such a 
syndrome rather than a secondary cause. While addressing underlying factors or compliance with current 
antihypertensives, dose modification should be initiated according to the general guidelines outlined in 
Section 7.6.3. 
 
If other causes are identified as the reason for new or worsening hypertension, the investigator should 
follow the institution’s local standard of care treatment and the dose of TAK-700 can be adjusted upwards 
in accordance with the general guidelines in Section 7.6.3. 
 
Suspected or Possible Adrenal Insufficiency 
If patients experience adrenal insufficiency, the adrenal insufficiency may have the more nonspecific 
manifestations of glucocorticoid insufficiency, rather than the more specific electrolyte abnormalities of 
mineralocorticoid insufficiency. Patients experiencing severe physiological stress (eg, surgery, severe 
infection) should be carefully monitored for adrenal insufficiency.  Concomitant medications may 
complicate the picture of adrenal insufficiency, in particular in patients who are on beta-blockers or 
diuretics. Concomitant illness such as infection might similarly trigger or worsen symptoms of otherwise 
mild adrenal insufficiency.  Grading of adrenal insufficiency should follow CTCAE criteria (version 4.0).  In 
all cases, actions should include a thorough review for other possible causes or contributors to the 
presenting symptoms (eg, infection, anemia, or newly introduced concomitant medications). 
 
Abnormal Liver Enzymes 
 
Table 7-2 Management of Abnormal AST or ALT Bearing a Possible Relationship  
to TAK-700 Treatment 
AST and/or ALT 
Elevation Grade 
(Per NCI CTCAE) 
Concurrent Bilirubin Level 
TAK-700 Dose Modification 
Grade 1 
≥ 1.5 x ULN 
Hold until bilirubin resolves to 
< 1.5 ULN 
 
Dose at the next lower dose 
level 
Grade 2 
< 1.5 x ULN 
Hold until ALT/AST resolve to 
Grade 1 
 
Dose at the next lower dose 
level 
Grade 2 
≥ 1.5 x ULN 
Discontinue TAK-700 
Grade ≥ 3 
Any 
Discontinue TAK-700 
Note: Following TAK-700 dose de-escalation due to AST/ALT and/or bilirubin abnormalities, no  

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re-escalation is permitted. 
 
7.6.7  Overdose 
The maximum tolerated or efficacious dose for TAK-700 has not been determined. An overdose is 
defined as deliberate or accidental administration of study medication at a dose above that which is 
assigned to that individual subject. In the event of drug overdose, the principal investigator should be 
notified immediately and the patient observed closely for adverse effects. The patient should be treated 
symptomatically as appropriate, and the incident of overdose and related AEs and/or treatment-
documented in the patient’s medical record. Patients who may have overdosed and who have possible 
manifestations of adrenal insufficiency may be treated acutely with oral steroids as tolerated. 
 
7.7  
Excluded Concomitant Medications and Procedures 
The following medications and procedures are prohibited during the study: 
 
Any investigational agent other than TAK-700 
 
Other anticancer therapy, except for GnRH analogs, antiandrogens, and radiation therapy 
 
Hormonal therapies including estrogens or herbal products 
 
Ketoconazole or aminoglutethimide 
 
Chronic use of systemic corticosteroids, such as oral prednisone 
 
Patients must be instructed not to take any medications, including over-the-counter products 
and vitamins, minerals and other dietary supplements, without first consulting with the 
investigator. 
 
7.8  
Precautions and Restrictions 
It is not known what effects TAK-700 has on human pregnancy or development of the embryo or fetus. 
Therefore, male patients should avoid impregnating a female partner. Patients should use effective 
methods of contraception through defined periods during and after study treatment as specified below. If 
a female partner of a male patient becomes pregnant during the male patient’s participation in this study, 
this must be reported to Millennium Pharmacovigilance (or designee) immediately (see below). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome (i.e. delivery, still birth, 
miscarriage). 
 
 
Millennium Pharmacovigilance 
SAE and Pregnancy Reporting Contact Information: 
North America 
PPD, Inc. 
Safety and Medical Management, US 
Fax:  +1 888-488-9697 
Hotline number (available 24/7):  1-800-201-8725 
 
 
Male patients, even if surgically sterilized (eg, status postvasectomy) must agree to either practice 
effective barrier contraception during the entire study treatment period and through 4 months after the last 
dose of study drug, or completely abstain from intercourse. 
 
Nonclinical studies of TAK-700 biotransformation by human hepatic and intestinal microsomes indicate 
that CYP enzymes have only a minor role in the metabolism of TAK-700. Based on these findings, there 
is very low risk that the metabolism of TAK-700 will be affected by CYP-mediated interactions due to 
other drugs. 
 
In vitro studies indicate that TAK-700 is a weak to moderate inhibitor of CYP1A2, 2C9, and 2C19 (Kis of 
8.9, 15.4, and 19.4 μmol/L, respectively). These findings indicate that TAK-700 has the potential to inhibit 
the metabolism of drugs that are substrates of CYP1A2 and may possibly inhibit the metabolism of drugs 
that are substrates of 2C9 and 2C19. 
 
Drugs that are primarily metabolized by these CYP isoforms should be used with caution when 
administered concomitantly with TAK-700. 
 

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In vitro studies demonstrate that TAK-700 is a substrate for P-gp but the affinity of TAK-700 for P-gp is 
low. Studies show that TAK-700 was not an inhibitor of P-gp. Based on these findings, there is very low 
risk of a P-gp-based interaction of TAK-700 with other drugs. 
 
No single-dose effect of TAK-700 on QTc interval has been observed in healthy male subjects, and no 
trend in QTc interval has been observed to date in patients with mCRPC in the open-label phase 1/2 
TAK-700_201 study. Until more data are available, patients with underlying cardiac rhythm abnormalities 
or in patients on other drugs that may affect the QTc interval should be monitored closely.  
 
7.9  
Blinding and Unblinding 
This is an open-label study. 
 
7.10  
Description of Investigational Agent (5/2/12) 
TAK-700 is manufactured by Takeda Pharmaceutical Company, Ltd., Osaka, Japan. TAK-700 will be 
supplied as pale red film-coated tablets. Each tablet will contain 100 mg of TAK-700. Further details are 
provided in the TAK-700 Investigator’s Brochure which is available on the RTOG web site under protocol-
specific materials/regulatory resources. 
 
7.11  
Preparation, Reconstitution, and Dispensation 
TAK-700 is an antineoplastic agent, and as with other potentially toxic compounds, caution should be 
exercised when handling TAK-700. 
  
7.12  
Packaging and Labeling 
TAK-700 supplied as 100 mg tablets packaged in high density polyethylene bottles with child-resistant 
cap and with a 3 gram desiccant. Each bottle will be labeled in accordance with all regulatory 
requirements appropriate for the country(ies) in which the study will be conducted. 
 
7.13  
Storage, Handling, and Accountability (12/17/13)  
TAK-700 supplied as 100-mg film-coated tablets should be stored in the original dispensing bottle at the 
conditions described in the product label.  The drug supply must be kept in an appropriate, limited-
access, secure place until it is dispensed to study enrollees, returned to the sponsor, or forwarded to the 
sponsor’s designee for destruction. Drug supplies will be counted and reconciled at the site before being 
returned. 
 
At the completion of the study, unused supplies will be destroyed at the site according to the institution's 
policy for drug destruction. Sites should complete the drug destruction form located on the NRG 
Oncology/RTOG website (www.rtog.org) under protocol-specific materials/regulatory resources and send 
it to Biologics (see Section 7.14.1 below for contact information). 
 
The investigator must maintain 100% accountability for all study medication received and dispensed 
during his or her entire participation in the study. Proper drug accountability includes, but is not limited to: 
 
Continuously monitoring expiration dates if retest date is provided to the investigator. 
 
Frequently verifying that actual inventory matches documented inventory. Verifying that the drug 
accountability log is completed for the drug lot used to prepare each dose. 
 
Verifying that all containers used are documented accurately on the log. 
 
Verifying that required fields are completed accurately and legibly. 
 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.  The 
investigator must maintain a current inventory (drug accountability log) of all study medication delivered to 
the site, inventory at the site, and patients’ use records. This log must accurately reflect the drug 
accountability of the study medication at all times. The following information will be recorded at a 
minimum: protocol number and title, name of the investigator, site identifier and number, description of 
the study medication, expiry and/or retest date, date and amount dispensed, and the date and amount 
returned to the site by the patient, including the initials of the person dispensing and receiving the study 
medication. The log should include all required information as a separate entry for each patient to whom 
study medication is dispensed.  At appropriate intervals, a representative from the sponsor will perform 
clinical study material accountability and reconciliation. The investigator will retain the original 
documentation regarding clinical study material accountability, return, and/or destruction. The investigator 

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will be notified of any expiry date or retest date extension of clinical study material during the study 
conduct. On expiry date notification from the sponsor or designee, the site must complete all instructions 
outlined in the notification, including segregation of expired clinical study material for return to the sponsor 
or its designee for destruction. In the event of expiry date extension of supplies already at the study site, 
supplies will be relabeled with the new expiry date at that site.  
 
 
7.14 
Supply (5/1/12) 
This study will be conducted under an IND to be held by RTOG (NRG Oncology) and will require FDA 
submission and approval as part of the IND. TAK-700 will be supplied to patients in the study free of 
charge. 
 
The Study Agent Shipment Form [SASF; available on the NRG Oncology/RTOG web site, www.rtog.org, 
under protocol-specific materials/regulatory resources] for U.S. and Canadian sites must be submitted to 
the CTSU Regulatory Office (Fax 215-569-0206) as soon as the individual responsible for the study agent 
has been identified.  This must be done prior to registration of the institution’s first case.  The drug supply 
will not be shipped by Biologics, Inc. until the patient has been registered. Canadian shipments may 
require additional time. NRG Oncology will notify Biologics, Inc. to initiate each of these shipments after 
registration of the patient. Drug shipments may not be immediate if the protocol includes a delay in the 
initial dosing. Drug will be delivered in time for the patient’s first dose. 
7.14.1   Biologics, Inc. TAK-700 Distribution 
Upon receipt of patient registration/randomization, NRG Oncology will notify Biologics via e-mail. 
Biologics will then perform the following process: 
 
Confirm SASF and Registration/Randomization; 
 
Place call directly to the study site contact listed on the SASF confirming that the 
registration/randomization was received and to: 
o 
Collect any additional patient or shipping information required per protocol; 
o 
Arrange the date and time of arrival for the study drug;  
o 
Ship the initial shipment of study drug supply per protocol directly to SASF 
address; any discrepancies will be addressed with the CTSU. 
 
Biologics, Inc. ships study drug the same day of receipt of patient registration/randomization if received 
before 2:00pm ET on Monday through Friday. Ambient drug like TAK-700 allows for Friday shipment with 
Monday delivery. Authorized and complete orders received after 2:00pm ET Monday through Friday will 
be processed and shipped the next business morning.   
 
TAK-700 Shipment Schedule 
Patient 
registered with 
NRG Oncology 
E-order 
transmitted by 
NRG Oncology 
E-order 
Received by 
Biologics 
(before 2PM ET) 
Order shipped  
Order received 
at site 
Monday 
Monday 
Monday 
Monday 
Tuesday 
Tuesday 
Tuesday 
Tuesday 
Tuesday 
Wednesday 
Wednesday 
Wednesday 
Wednesday 
Wednesday 
Thursday 
Thursday 
Thursday 
Thursday 
Thursday 
Friday 
Friday 
Friday 
Friday 
Friday 
Monday 
 
All shipments are sent via FedEx for Priority Overnight delivery. Study Drug (TAK-700) is shipped in a 
Biologics, Inc. branded container appropriate to maintain temperature stability. 
 
Shipment Schedule 
 
Initial shipment – 18 Bottles of study drug to be taken continuously   
 
6 months at 300mg (3 tabs/100mg each) PO BID 
        
Biologics places follow-up call during month 5 for subsequent shipment of study drug 
Subsequent shipment 2 – 18 Bottles of study drug to be taken continuously   
 
6 months at 300mg (3 tabs/100mg each) PO BID 

44 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
       
Biologics places follow-up call during month 11 for subsequent shipment of study drug 
Subsequent shipment 3 – 18 Bottles of study drug to be taken continuously   
 
6 months at 300mg (3 tabs/100mg each) PO BID 
 
Biologics places follow-up call during month 17 for subsequent shipment of study drug 
Subsequent shipment 4 – 18 Bottles of study drug to be taken continuously   
 
6 months at 300mg (3 tabs/100mg each) PO BID 
              
For all drug shipments from Biologics, Inc.: 
 
Study Drug will be shipped in original manufacturers packaging.  Bottles are placed in a Ziploc 
bag with a patient specific label adhered to the outside of the bag. 
 
 
Each shipment includes a patient label on the Ziploc bags with the following information: 
 
The Study Number (i.e. RTOG 1115); 
 
IND caution statement and/or local regulatory statements; 
 
Drug identification (TAK-700) 
 
Expiration 
 
Storage conditions 
 
Dosing instructions (Take as Directed per Protocol) 
 
Subject ID number (e.g. 1115-YYY, where the study number and sequence number 
represents the unique patient identifier assigned by NRG Oncology at registration); 
 
The patient’s initials (i.e. first, middle, last) 
 
A blank line for the site pharmacist to enter the patient’s name; 
 
Administration instructions (i.e. “Take xx tablets every day for xx days”); 
 
Storage instructions (i.e. “Store at controlled room temperature, xx degrees”); 
 
Emergency contact instructions; 
 
 
Enclose a packing slip that includes the quantity of drug provided with a section to be completed 
once received by the site coordinator. This section includes confirmation of drug receipt, 
verification of package contents, and instruction to fax the completed packing slip to Biologics.  
 
 
Packages are tracked until confirmed delivered and delivery exceptions are managed with the 
highest level of urgency to ensure therapy start date adherence. Packing slips with the shipment 
tracking number included will be faxed to the designated site coordinator for all shipments. 
 
Please contact the drug distributor, as listed below, directly for shipment tracking information and 
anticipated delivery dates or if a shipment has not been received by the expected date.  
 
Unused supplies at the sites will be destroyed on site per local guidelines/standard operating 
procedures. Additional questions about supply and delivery should be directed to: 
Clinical Trial Services 
Biologics, Inc. 
120 Weston Oaks Court 
Cary, NC 27513 
(800) 693-4906 
clinicaltrials@biologicstoday.com 
 
7.14.2 Study Agent Accountability 
Drug accountability records must be maintained at all sites according to good clinical practices and NCI 
guidelines using the Investigational Agent Accountability Record (IAAR) form. 
 
7.15 
Modality Reviews (2/4/14) 
This study will undergo hormone therapy review for TAK-700. The Principal Investigator, M. Dror 
Michaelson, MD, PhD, will perform a Hormone Therapy Assurance Review of all patients who receive or 
are to receive TAK-700 in this trial. The goal of the review is to evaluate protocol compliance. The review 
process is contingent on timely submission of hormone treatment data as specified in Section 12.1. The 

45 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
scoring mechanism is: per protocol; unacceptable deviation; not evaluable. A report is sent to each 
institution once per year to notify the institution about compliance for each case reviewed in that year. 
 
7.16 
Adverse Events (12Jun2018) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0 will be utilized until March 31, 2018, for all AE reporting, CTEP-AERS, and 
case report forms. CTCAE version 5.0 will be utilized for CTEP-AERS reporting beginning April 1, 2018; 
all study case report forms will continue to use CTCAE version 4.0. All appropriate treatment areas should 
have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from the CTEP web 
site (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
 
Adverse events (AEs) that meet expedited reporting criteria defined in the table(s) below will be reported 
via the CTEP-AERS (CTEP Adverse Event Reporting System) application accessed via either the CTEP 
web site (https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613). 
 
7.16.1 Adverse Events (AEs)  
 
Definition of an AE: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related.  Therefore, an AE can be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal (investigational) 
product (attribution of unrelated, unlikely, possible, probable, or definite). (International Conference on 
Harmonisation [ICH], E2A, E6). [CTEP, NCI Guidelines: Adverse Event Reporting Requirements. 
February 29, 2012; 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm] 
 
  
7.16.2 Serious Adverse Events (SAEs) — Serious adverse events (SAEs) that meet expedited reporting criteria 
defined in the table in Section 7.17 will be reported via CTEP-AERS. SAEs that require 24 hour CTEP-
AERS notification are defined in the expedited reporting table in Section 7.17.  Contact the CTEP-AERS 
Help Desk if assistance is required. 
 
 
Definition of an SAE: Any adverse drug event (experience) occurring at any dose that results in any of 
the following outcomes: 
 
Death; 
 
A life-threatening adverse drug experience; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant disability/incapacity; 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE, when, based upon medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in the definition.  
 
Due to the risk of intrauterine exposure of a fetus to potentially teratogenic agents, the pregnancy of a 
study participant, including a male patient’s impregnation of his partner, must be reported via CTEP-
AERS in an expedited manner. 
 
7.16.3 Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
AML or MDS that is diagnosed as a secondary malignancy during or subsequent to treatment in patients 
on NCI/CTEP-sponsored clinical trials must be reported via the CTEP-AERS system within 30 days of 
AML/MDS diagnosis.  
 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm.  
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an NCI 
IND/IDE be reported via CTEP-AERS. Three options are available to describe the event: 

46 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML])  
 
Myelodysplastic syndrome (MDS) 
 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) also should be reported via 
the routine reporting mechanisms outlined in each protocol.  
 
Second Malignancy  
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a metastasis 
from the initial malignancy).  Second malignancies require ONLY routine reporting via CDUS unless 
otherwise specified. 
 
7.17 
CTEP-AERS Adverse Event Reporting Requirements (4/16/14) 
All serious adverse events that meet expedited reporting criteria defined in the reporting table below will 
be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed via the CTEP web 
site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613. 
 
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology 
requirements for expedited adverse event reporting. 
 
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation 
therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the NRG 
Oncology Office at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet 
connectivity is restored, an AE report submitted by phone must be entered electronically into CTEP-
AERS. 
 
 
CTEP-AERS 24-Hour Notification requires that a CTEP-AERS 24-hour notification is 
electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS 
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious 
adverse events that require 24 hour CTEP-AERS notification are defined in the expedited 
reporting table below. 
 
Supporting source document is not mandatory.  However, if the CTEP-AERS report indicates 
in the Additional Information section that source documentation will be provided, then it is 
expected.  If supporting source documentation accompanies an CTEP-AERS report, include 
the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and 
fax supporting documentation to the NRG Oncology dedicated SAE FAX, 215-717-0990. 
 
A serious adverse event that meets expedited reporting criteria outlined in the following table 
but is assessed by the CTEP-AERS System as “expedited reporting NOT required” must still 
be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the “NOT 
Required” assessment; the CTEP-AERS System allows submission of all reports regardless 
of the results of the assessment. 
 
 
 
 
 
 
 
 
 
 
 
 
 

47 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
CTEP defines expedited AE reporting requirements for phase 3 trials as described in the table below. 
Important: All AEs reported via CTEP-AERS also must be reported on the AE section of the appropriate 
case report form (see Section 12.1). 
  
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/ 
intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
 Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
 Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
8.0 SURGERY 
Not applicable to this study 
 

48 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
9.0 OTHER THERAPY 
9.1 
Permitted Supportive Therapy 
All supportive therapy for optimal medical care will be given during the study period at the discretion of 
the attending physician(s) within the parameters of the protocol and documented on each site’s source 
documents as concomitant medication. 
9.1.1 
Anticonvulsants 
9.1.2 
Antiemetics 
9.1.3 
Anticoagulants 
9.1.4 
Antidiarrheals 
9.1.5 
Analgesics 
9.1.6 
Hematopoietic Growth Factors 
9.1.7 
Herbal products 
9.1.8 
Nutritional supplementation 
 
9.2 
Non-permitted Supportive Therapy 
Patients must be instructed not to take any medications, including over-the-counter products and 
vitamins, minerals and other dietary supplements, without first consulting with the investigator, as noted in 
Section 7.7 above. 
 
10.0 
TISSUE/SPECIMEN SUBMISSION 
NOTE: Patients must be offered the opportunity to participate in the tissue/specimen submission 
component of the protocol. If the patient consents to participate in this component of the study, the site 
is required to submit the patient’s specimens as specified below.  
 
Sites are not permitted to delete the tissue/specimen submission component from the protocol or from the 
sample consent. 
 
10.1 
Tissue/Specimen Submission  
The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and 
maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through 
careful block storage and processing. NRG Oncology encourages participants in protocol studies to 
consent to the banking of their tissue. The Biospecimen Bank provides tissue specimens to investigators 
for translational research studies. Translational research studies integrate the newest research findings 
into current protocols to investigate important biologic questions. 
 
10.2 
Specimen Collection for Translational Research (Mandatory) (12/17/13) 
For patients who have consented to participate in the tissue/blood component of the study (See sample 
consent). 
10.2.1 Specimen Submission 
See Section 10.5 for the address information for sending specimens. 
10.2.2 Specimen Collection Summary for Translational Research (mandatory for all patients) 
 
Serum Specimens for Translational Research (mandatory for all patients) 
 
Specimens taken  
from patient: 
Collected when: 
 
Submitted as: 
Shipped: 
SERUM for baseline and 
follow up Testosterone, 
processed as per local 
laboratory requirements 
 
Note: Collect 
testosterone in the a.m. 
at same time of day as 
collection of Fasting 
Insulin/Fasting Glucose/ 
Fasting Lipids/ 
Hemoglobin A1C 
(1) Baseline/ 
pre-treatment:  
Within 21 days prior to 
treatment 
 
(2) At 30 months 
 
(3) Follow Up: 
Every 12 months for 3 
years 
 
Testing performed on 
site at local laboratory 
Not applicable 

49 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
SERUM for Testosterone 
(LC/MS/MS):  
5 mL (no-additive red-
top), processed as 
detailed in Appendix V 
 
Note: Collect 
testosterone in the a.m. 
at same time of day as 
collection of Fasting 
Insulin/Fasting Glucose/ 
Fasting 
Lipids/Hemoglobin A1C 
(1) During ADT:  
    (a) At 12 months 
    (b) At 24 months 
Frozen serum 
samples containing 
0.5 mL per aliquot in 
1 mL cryovials  
(five to ten) 
Serum sent frozen on 
dry ice via overnight 
carrier to the NRG 
Oncology 
Biospecimen Bank 
 
SERUM for Fasting 
Insulin: 
5 mL (no-additive red-
top), processed as 
detailed in Appendix V 
 
Note: Collect in the a.m. 
at same time of day as 
testosterone 
(1) Baseline/ 
pre-treatment: Within 
21 days prior to 
registration 
 
(2) During ADT:  
    (a) At 12 months 
    (b) At 24 months 
 
(3) Follow Up: 
Every 12 months for 3 
years 
 
Frozen serum 
samples containing 
0.5 mL per aliquot in 
1 mL cryovials 
(five to ten) 
Serum sent frozen on 
dry ice via overnight 
carrier to the NRG 
Oncology 
Biospecimen Bank 
SERUM for Fasting 
Glucose/Fasting 
Lipids/Hemoglobin A1C, 
processed as per local 
laboratory requirements 
 
Note: Collect in the a.m. 
at same time of day as 
testosterone 
(1) Baseline/ 
pre-treatment:  
Within 21 days prior to 
registration 
  
2) During ADT:  
    (a) At 12 months 
    (b) At 24 months 
 
(3) Follow Up: 
Every 12 months for 3 
years 
 
Testing performed on 
site at local laboratory 
Not applicable 
 
10.3 
Specimen Collection for Tissue Banking and Translational Research (Strongly Recommended) 
(12Jun2018)  
For patients who have consented to participate in the tissue/blood component of the study (See sample 
consent). Note: Plasma and whole blood collection is mandatory for patients participating in 
quality of life [QOL]. 
 
The following must be provided in order for the case to be evaluable for the NRG Oncology Biospecimen 
Bank:  
10.3.1 One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide (block); it does 
not have to be the diagnostic slide itself) 
10.3.2 A corresponding paraffin-embedded tissue block of the tumor (the block must match the H&E being 
submitted) or 10-15 unstained sections cut onto positive charged slides from the tumor tissue block (must 
be from same block as H&E). Block or slides must be clearly labeled with the pathology identification 
number and block # that corresponds to the Pathology Report. 
10.3.3 A Pathology Report documenting that the submitted block or slides contains tumor. The report must 
include the RTOG (NRG) protocol number and patient’s case number. The patient’s name and/or other 
identifying information should be removed from the report. The surgical pathology numbers and 
information must NOT be removed from the report. 

50 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the 
submitted material is reviewed and is not tumor, the site may be assessed a protocol 
violation. 
10.3.4 A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG Oncology 
Biospecimen Bank; if for translational research, this should be stated on the form. The form must include 
the RTOG (NRG) protocol number and patient’s case number. 
 
10.3.5 Specimen Collection Summary for Tissue Banking and Translational Research (strongly recommended)  
 
Specimens for Tissue Banking and Translational Research (strongly recommended) 
*Note: Plasma and whole blood is mandatory for patients participating in QOL. 
 
Specimens taken  
from patient: 
Collected when: 
 
Submitted as: 
Shipped: 
Representative H&E 
stained slides of the 
primary tumor 
Pre-treatment 
H&E stained slide 
Pre-treatment 
Slide shipped ambient 
A paraffin-embedded 
tissue block of the 
primary tumor taken 
before initiation of 
treatment or 10-15 
unstained slides  
Pre-treatment 
Paraffin-embedded 
tissue block or 15 
unstained slides  
(must match the H&E 
slide being submitted) 
 
Block or slides shipped 
ambient 
 
PLASMA*:  
5-10 mL of 
anticoagulated whole 
blood in EDTA tube #1 
(purple/ lavender top) 
and centrifuge 
 
[For inflammatory 
cytokines and markers 
including CRP, NF- 
kappa B, TNF alpha, IL-
1, IL-1ra, sTNFR2, and 
IL-6] 
 
(1) Pre-treatment 
 
(2) 1 year (12 months) 
after therapy starts 
 
(3) 2.5 years (30 
months) after therapy 
starts 
Frozen plasma 
samples containing 
0.5 mL per aliquot in 1 
mL cryovials (five to 
ten) 
Plasma sent frozen on 
dry ice via overnight 
carrier to the NRG 
Oncology Biospecimen 
Bank 
WHOLE BLOOD* for 
DNA:  
5-10 mL of 
anticoagulated whole 
blood in EDTA tube #2 
(purple/ lavender top) 
and mix 
 
[For SNPs and CNVs in 
TNFAIP1, IL6, IL6R, 
CRP, IL1R1, IL1A, IL1B] 
 
Pre-treatment 
 
Note: If site missed this 
collection time point 
they may collect this 
specimen at any other 
time point instead but 
must note this on the 
Specimen Transmittal 
Form. 
 
Frozen whole blood 
samples containing 
1 mL in 1mL cryovials 
(three to five) 
 
Whole blood sent 
frozen on dry ice via 
overnight carrier to the 
NRG Oncology 
Biospecimen Bank 
 
PBMCs: 5-10ml of whole 
blood in EDTA 
purple/lavender top tube 
(tube #3). See Appendix 
VI for processing 
instructions. 
 
[For NF Kappa B] 
(1) Pre-treatment 
 
(2) 1 year (12 months) 
after therapy starts 
 
(3) 2.5 years (30 
months) after therapy 
starts  
Frozen PBMC 
samples (one to two). 
See Appendix VI for 
study-specific 
processing 
instructions. 
PBMC sent frozen on 
dry ice via overnight 
courier to the NRG 
Oncology Biospecimen 
Bank 
 

51 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
 
 
 
10.3.6 See Appendix V for the specimen collection kit and detailed collection instructions. See Appendix 
VI for detailed PBMC collection, processing, and shipping information. Note: Kits can be requested 
from the NRG Oncology Biospecimen Bank at NRGBB@ucsf.edu. Please include in the e-mail if you are 
requesting the complete kit or the kit without the PBMC processing component. PBMC processing 
components will not be shipped to sites that are unable to follow the PBMC processing instruction. The 
following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen Transmittal 
Form documenting the date of collection of the biospecimen; the RTOG protocol number, the patient’s 
case number, time point of study, and method of storage, for example, stored at -80 C, must be included. 
 
10.4 
Storage Conditions (5/1/12) 
Store frozen specimens at -80C (-70C to -90C) until ready to ship. Frozen specimens can be stored -
80C (-70C to -90C) for up to six months before shipping. If a -80C freezer is not available:  
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please 
ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
OR: 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out Monday-
Wednesday only; Canada: Monday-Tuesday). 
OR: 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: 
Monday-Tuesday). 
 
Please indicate on the Specimen Transmittal Form the storage conditions used and time stored. 
 
For PBMC Specimens Only: 
Store frozen specimens immediately at -80°C. Samples must then be kept at -80°C during storage and 
shipping (please ship out Monday-Wednesday only; Canada: Monday-Tuesday) 
OR: 
If a -80°C freezer is not available: Samples can be stored in plenty of dry ice for up to one week, 
replenishing daily (ship out Monday-Wednesday only; Canada: Monday-Tuesday). 
 
Please indicate on the Specimen Transmittal Form the storage conditions used and time stored. See 
Appendix VI for detailed PBMC collection, processing, and shipping information. 
 
10.5 
Submit materials for Tissue Banking and Translational Research as follows: (12Jun2018) 
 
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank 
University of California San Francisco – Box 1800 
Campus Box 1800 
 
2340 Sutter Street, Room S341 
San Francisco, CA 94143 
 
Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
 
Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 
 
 
10.6 
Reimbursement (4/16/14) 
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) Program, NCI 
funds for reimbursement for protocol-specified biospecimen materials will be distributed per the 
requirements/methods specified by the new NCTN Program. This information will be made available with 
the other registration materials in the Oncology Patient Enrollment Network (OPEN) portal system. OPEN 

52 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
will serve as the registration system for all patient enrollments onto NCI-sponsored NCTN trials, including 
this study, which will be transitioned into the new Program from the NCI-sponsored Cooperative Group 
Clinical Trials Program.  
 
10.7 
Confidentiality/Storage  
 
(See 
the 
Patient 
Tissue 
Consent 
Frequently 
Asked 
Questions, 
http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx 
for 
further 
details.) 
10.7.1 Upon receipt, the specimen is labeled with the RTOG (NRG) protocol number and the patient’s case 
number only. The NRG Oncology Biospecimen Bank database only includes the following information: 
the number of specimens received, the date the specimens were received, documentation of material 
sent to a qualified investigator, type of material sent, and the date the specimens were sent to the 
investigator. No clinical information is kept in the database. 
10.7.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the 
translational research component of this protocol will be retained until the study is terminated, unless the 
patient has consented to storage for future studies. If at any time the patient withdraws consent to store 
and use specimens, the material will be returned to the institution that submitted it. 
 
11.0 
PATIENT ASSESSMENTS (12/17/13)  
11.1 
Study Parameters 
See Appendix I for assessments and timeframes. See Sections 11.1.1 and 11.1.2 below for details and/or 
exceptions to Appendix I. 
11.1.1 Chemistry and liver panels (sodium, potassium, chloride, bicarbonate (carbon dioxide), BUN, creatinine, 
glucose, calcium, magnesium, phosphorus, albumin, AST, ALT, alkaline phosphatase, total bilirubin, 
direct bilirubin) will be checked monthly during ADT until three consecutive normal potassium values have 
been obtained, then the chemistry and liver panels will be spaced to every 3 months. 
11.1.2  Collect blood for testosterone in the morning at the same time of day as collection of blood for Fasting 
Insulin/Fasting Glucose/ Fasting Lipids/Hemoglobin A1C. 
 
11.2  
PROMIS-Fatigue Short Form (12/17/13) 
Note: Patients must be offered the opportunity to participate in the correlative components of the 
study, such as quality of life (QOL) assessment. Participation in QOL is optional, with a goal of 
enrolling 458 patients in the QOL study. There is additional case credit and financial reimbursement to the 
institutions for participating in the QOL studies to take into account the additional time, effort, and cost 
involved. In addition, patients participating in the QOL studies may not have started anti-androgen 
therapy (either LHRH therapy or oral anti-androgens) prior to completing the QOL forms and 
getting baseline blood collection.  Thus, patients who have started LHRH therapy prior to enrollment 
will be excluded from participating in the QOL studies.  
 
If the patient consents to participate in the QOL component of the study, sites are required to administer 
the PROMIS, EPIC-26, and the EQ-5D assessments at baseline and as specified in Appendix I of the 
protocol. Sites are not permitted to delete the QOL component from the protocol or from the sample 
consent. Blood collection is mandatory for patients participating in the QOL. 
 
The PROMIS Fatigue Scale (7 items) was developed by the Patient-Reported Outcome Measurement 
Information System (PROMIS), part of the NIH Roadmap Initiative, focused on developing a publicly 
available resource of standardized, accurate, and efficient patient-reported outcome (PRO) measures of 
symptoms, distress, and functioning. Two content domains of fatigue, experience and impact, were 
identified by a panel of experts. An item pool of 58 fatigue experience and 54 fatigue impact items were 
developed. The psychometric properties of these items were evaluated in a sample of 450 individuals 
from the general US population using classical test theory indices, monotonicity, and scalability. The 
expert panel selected the 10 best items in each domain. These 20 items were presented to a panel of 
clinical experts. Only one item was dropped because of redundancy. A preliminary fatigue short-form 
measure of 7 items was created using items selected for consistency in the response scale, broad 
coverage across the fatigue continuum (i.e., high to low), and good precision of measurement 
(discrimination function). 
 

53 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
The following items are being measured due to the fact that sleep quality and exercise are documented 
confounders of fatigue: 
 
Muscle weakness question (scale of 1-5, from none to very much) 
Overall Sleep Quality: Item from Pittsburgh Sleep Quality Index (Buysse 1989): 
Sleep quality will be measured by 1 item (Q3) of the Pittsburgh Sleep Quality Index (PSQI), a self-rated 
questionnaire which measures sleep quality and disturbances over a 1-week or 1-month time period.  
 
 
Very 
Fairly 
Fairly 
Very 
 
bad 
bad 
good 
good 
 
 
 
1. During the past week, how would you rate your sleep  
quality overall? ............................................................................................ 0 
1 
2 
3 
 
 
 
Participants’ level of physical activity will be assessed using the three item Godin Leisure-Time Exercise 
Questionnaire (GLTEQ) [Godin 1986; Gionet 1989], which measures time spent per week in each of light, 
moderate, and vigorous activities. A score can be computed for each level of exercise. A total score is 
computed by summing the three levels weighted by their respective MET equivalents of 3, 5, and 9. The 
GLTEQ has good test-retest reliability and has shown convergent validity with both objective and other 
self-report measures of physical activity (Godin 1986; Gionet 1989).  
 
 
The following questions are about your average weekly exercise. When answering the questions only 
count exercise that you do during free time (ignore exercise associated with your occupation and 
housework). Considering a typical week (7 days), how many times, on average, do you perform mild, 
moderate, or strenuous exercise? And when you engage in exercise, how long do you exercise, on 
average? 
Times 
Per Week 
(a) 
Average Duration 
(b) 
1. Mild exercise – that is, minimal effort exercise that did not make you 
perspire, such as easy walking, yoga, bowling, lawn bowling, 
shuffleboard, or golf 
 
______ 
 
______ mins. 
2. Moderate exercise – that is, exercise that is not exhausting and which 
made you perspire lightly, such as fast walking, tennis, easy bicycling, 
easy swimming, or popular and folk dancing 
 
______ 
 
______ mins. 
3. Strenuous exercise – that is, exercise that made your heart beat 
rapidly and made you sweat, such as running, aerobics classes, cross 
country skiing, vigorous swimming, or vigorous bicycling 
 
______ 
 
______ mins. 
 
11.3  
Health Related Quality of Life (HRQOL) Assessments (12/17/13) 
Note: Patients must be offered the opportunity to participate in the correlative components of the 
study, such as quality of life (QOL) assessment. Participation in QOL is optional, with a goal of 
enrolling 458 patients in the QOL study. There is additional case credit and financial reimbursement to the 
institutions for participating in the QOL studies to take into account the additional time, effort, and cost 
involved. In addition, patients participating in the QOL studies may not have started anti-androgen 
therapy (either LHRH therapy or oral anti-androgens) prior to completing the QOL forms and 
getting baseline blood collection.  Thus, patients who have started LHRH therapy prior to enrollment 
will be excluded from participating in the QOL studies.  
 
If the patient consents to participate in the QOL component of the study, sites are required to administer 
the PROMIS, EPIC-26, and the EQ-5D assessments at baseline and as specified in Appendix I of the 

54 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
protocol. Sites are not permitted to delete the QOL component from the protocol or from the sample 
consent. Blood collection is mandatory for patients participating in QOL. 
 
The following instruments will be used to assess health related quality of life (HRQOL), including quality 
adjusted survival: the Expanded Prostate Cancer Index (EPIC)-26, and the EuroQol (EQ-5D) instrument. 
These outcomes measurements will be administered to 458 patients (229 in each arm). Of note, 
these are essentially the same instruments (and similar time points) that are being studied in two related 
trials, RTOG 0815 and 0924, which are currently accruing patients. In RTOG 0815, patients with “lower” 
intermediate risk prostate cancer all receive high dose RT and are randomized to +/- short term 
hormones. In RTOG 0924, patients with intermediate to high risk prostate cancer are randomized to +/- 
whole pelvic RT and are stratified by short (6 months) or long term (32 months) ADT. Ultimately, use of 
essentially the same instruments and time points in all three studies (RTOG 0815, RTOG 0924, and 
RTOG 1115) will create a large database of relevant information related to QOL, QAS, and fatigue issues 
in prostate cancer patients that will facilitate a large combined analysis in the future. The outcomes 
instruments in this study are as follows: 
11.3.1 Prostate Cancer-Specific Health-Related Quality of Life: EPIC-26 
The Expanded Prostate Cancer Index Composite (EPIC) is a prostate cancer health-related quality of life 
(HRQOL) patient self-administered instrument that measures a broad spectrum of urinary, bowel, sexual, 
and hormonal symptoms related to radiotherapy and hormonal therapy (van Andel 2003;Wei 2000). To 
minimize patient burden, the abbreviated, validated EPIC-26 will be used (Szymanski 2010).  
11.3.2 Quality-Adjusted Survival Analysis: EuroQol (EQ-5D) 
The EQ-5D is a patient self-administrated questionnaire that takes approximately 5 minutes to complete 
(Schulz 2002). The first part consists of 5 items covering 5 dimensions including: mobility, self care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension can be graded on 3 levels: 1-no 
problems, 2-moderate problems, and 3-extreme problems. Health states are defined by the combination 
of the leveled responses to the 5 dimensions, generating 243 (35) health states to which unconsciousness 
and death are added (Badia 1998).  
 
The 5-item index score is transformed into a utility score between 0, “Worst health state,” and 1, “Best 
health state.” The index score or the cost-utility equation can be used in the quality adjusted survival 
analysis depending on the health state(s) of interest (Wu 2002). For this study we plan to report the 
multidimensional utilities for comparative purposes. The EQ-5D has been used across numerous disease 
sites (Milne 2006; Wildi 2004) and has been used to assess quality adjusted survival of prostate cancer 
screening and treatment (Essink-Bok 1998; Sandblom 2004; Sennfalt 2004). 
 
 
11.4 
Criteria for Discontinuation of Protocol Treatment (12/17/13) 
 
Progression of disease; 
 
If radiation therapy begins more than 240 days after initiation of ADT. 
 
If protocol treatment is discontinued, follow up and data collection will continue as specified in the 
protocol. 
 
12.0 
DATA COLLECTION (12/17/13) 
This study will utilize Medidata Rave® for remote data capture (RDC) of all data. Access to the trial in 
Rave is granted through the iMedidata application (https://login.imedidata.com) to all persons with the 
appropriate roles in RSS. To access iMedidata/Rave see Section 5.0.  
 
Each person responsible for data entry must be on the NRG Oncology roster in order to receive access to 
Medidata Rave®.  
 
Upon initial site registration approval for the study in RSS (Regulatory Support System), all CRAs at 
participating sites will receive e-mail invitations from iMedidata (iMedidata-Notification@mdsol.com) to 
activate their account. Once an account is activated, eLearning modules will be available for Rave RDC 
instructions. Site users must complete all modules before access to data entry in Rave is granted. Further 
training opportunities will be communicated through the web site.     
 
Users that have not previously activated their iMedidata/Rave accounts will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions are located on the 
CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study 

55 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
Invitation Acceptance).  Additional information on iMedidata/Rave is available on the CTSU website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com.  
 
12.1 
Summary of Data Submission (12/17/13) 
 
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using 
similar agents. Adverse events are reported in a routine manner at scheduled times during the trial using 
Medidata Rave. Additionally, certain adverse events must be reported in an expedited manner for timely 
monitoring of patient safety and care. The following sections provide information about expedited 
reporting.  For this trial the Adverse Event forms are used for routine AE reporting in Rave. 
 
Folder 
Form/Item 
Due 
Registration via the OPEN 
System 
 
 
Subject Enrollment Form (1) 
 
At time of registration 
Enrollment 
When pushed into RAVE 
there will be 5 forms 
representing registration 
 
Demography Form (2) 
 
Step Information Form (3) 
 
Treatment Assignment Form (4) 
 
Eligibility Checklist Form (5) 
 
 
 
 
 
Concomitant Medications 
 
 
Review at baseline and 
then every 3 months 
during treatment (24 
months) for changes (in 
frequency, dose, 
additional drugs or 
discontinuation of drugs) 
 
 
 
PSA Measurements 
 
 
All required 
measurements will be 
collected in this folder— 
every 3 months during 
treatment; then every 6 
months for 3 years; then 
annually--the follow up 
form will prompt reporting 
of these measurements 
 
 
 
Quality of Life 
(Optional for patients not 
previously on LHRH or oral 
anti-androgens.  A total of 458 
patients may participate in the 
QOL studies; when QOL 
accrual achieved this folder 
will not be available for future 
patients) 
 
 
EQ-5D (QF) 
 
EPIC-26 (FA) 
 
PROMIS (HP) 
 
PSQI/GLTEQ (QL) 
Collected at 5 time 
points (only if answer to 
quality of life participation 
= yes at registration): 
1) Prior to the start of 
protocol hormone 
treatment (baseline); 
2) Prior to RT; 
3) During the last week of 
RT;  
4) At one year (12 
months) after the start of 
protocol treatment;  
5) At 2.5 years (30 
months) after the start of 

56 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
Folder 
Form/Item 
Due 
protocol treatment 
 
 
 
 
Baseline Folder  
 
 
Patient History Form (formerly 
known as the A5; voluntary form 
completed by the patient or with 
help from site staff or family) 
 
Work Up Form 
 
Diagnostic Staging Form 
 
Prior Treatment Form 
 
Pathology Report Form (a copy of 
this report will be scanned and 
uploaded into RAVE) 
 
Chemistry Panel Form 
 
Liver Panel Form 
 
Fasting Lipid Panel Form 
 
CBC w/Differential Form 
 
Hemoglobin A1C Form 
 
Serum Testosterone Form 
 
Within 2 weeks after 
registration 
 
 
 
 
Month 1 visit 
 
 
Chemistry Panel Form 
 
Liver Panel Form 
After 30 days of 
hormonal treatment/ 
registration to the trial 
For relevant labs 
necessary during 
hormonal treatment +/- 
TAK700 
 
Month 2 visit 
   
 
Chemistry Panel Form 
 
Liver Panel Form 
 
After 60 days of 
hormonal treatment/ 
registration to the trial 
For relevant labs 
necessary during 
hormonal treatment +/- 
TAK700 
 
 
 
 
Follow-Up Folders 
 
Month 3 
Month 6 
Month 9 
Month 12 
Month 15 
Month 18 
Month 21 
Month 24 
 
 
 
Follow up Form – if Patient 
Contacted = “yes” 
 
Primary Cause of Death Form – if 
Patient’s Vital Status = ‘dead’ 
 
Disease Assessment Form – if  
Documented clinical assessment = 
‘yes’ 
 
New Primary Cancer Form – if New 
Primary Cancer = ‘yes’ 
 
Non-protocol Treatment Form – if 
patient started on non-protocol 
cancer therapy = ‘yes’ 
 
Complete Appropriate Lab Form  - 
if labs performed = ‘yes’ (chemistry 
and liver panel forms every 3 
Every 3 months from the 
start of treatment/ 
registration to the trial 
during years 1 and 2 (to 
capture hormone +/- TAK-
700 administration);  
    
 

57 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
Folder 
Form/Item 
Due 
months and at 12 and 24 month 
visits fasting lipid panel form and 
hemoglobin A1C form will be 
added) 
 
PSA Measurement Form – if PSA 
assessed = ‘yes’ 
 
Adverse Event Form – if new or 
continuing adverse events = ‘yes’  
 
Concomitant Medication Form if 
Changes in Medication = ‘yes’ 
 
Hormonal Treatment 
with or without TAK-700 
 
 
Oral Antiandrogen Form 
 
LHRH Agonist Form 
 
Agent TAK700 Form 
 
Every 3 months (from 
the start of hormonal 
therapy/registration to 
the trial) for 2 years 
Month 30 Visit  
 
Marks the start of follow 
up without treatment 
 
Questions answered as 
‘yes’ generate additional 
forms—similar to ‘filter 
questions’ being asked 
 
Month 36 
Month 42 
Month 48 
Month 54 
Month 60 
 
Month 72 
 
Start of annual visits 
 
Follow up Form – if Patient 
Contacted = “yes” 
 
Primary cause of death form – if 
Patient’s Vital Status = ‘dead’ 
 
Disease Assessment Form – if 
Documented clinical assessment = 
‘yes’ 
 
New Primary Cancer Form – if New 
Primary Cancer = ‘yes’ 
 
Non-protocol Treatment Form – if 
patient started on non-protocol 
cancer therapy = ‘yes’ 
 
Complete Appropriate Lab Form  - 
if labs performed = ‘yes’ (at 36, 48 
and 60 month visits a chemistry 
panel form-- for fasting glucose; 
fasting lipids form; testosterone 
form and hemoglobin A1C form) 
 
PSA Measurement Form – if PSA 
assessed = ‘yes’ 
 
Adverse Event Form – if new or 
continuing adverse events = ‘yes’  
 
 
Every 6 months for 3 
years 
 
 
 
 
 
 
 
 
 
 
 
 
Annual visits 
 
 
 
 
 

58 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
12.2  
Summary of Dosimetry Digital Data Submission (4/16/14) 
Note: Submit digital RT data to TRIAD; see Section 5.0 for account access and installation 
instructions. 
 
Folder 
Form/Item 
Due 
N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RT Administration If 
answered as ‘yes’ then 
RT Treatment form will be 
added 
 
 
Preliminary Dosimetry Information 
Digital Data Submission – Treatment 
Plan submitted to IROC Houston via 
TRIAD 
account 
exported 
from 
treatment planning machine by Physics 
staff 
Digital data submission includes the 
following: 
 
CT 
data, 
critical 
normal 
structures, all GTV, CTV, and 
PTV contours  
 
Digital 
beam 
geometry 
for 
initial, boost and composite 
beam sets 
 
Doses for initial, boost and 
composite sets of concurrently 
treated beams 
 
Digital 
DVH 
data 
for 
all 
required 
critical 
normal 
structures, GTV, CTV, and 
PTVs for total dose plan 
Digital Data Submission Information 
(DDSI) Upload confirmation email 
that digital data was submitted  
 
 
Final Dosimetry Information 
 RT Treatment form [for EBRT +/- 
brachytherapy]  
        
Daily Treatment Record 
Please note: Daily Treatment Record 
will be uploaded via Rave to IROC 
Philadelphia 
 
NOTE:  All Simulation and Portal 
Images will be kept by the Institution 
and only submitted if requested. 
 
 
LDR Brachytherapy 
Post-implant evaluation CT scan 
Post-implant structure set 
Post-implant plan  
Post-implant dose distribution 
RTOG Prostate Brachytherapy 
Protocol Compliance Form-Available 
on the RPC website, 
http://irochouston.mdanderson.org 
 
 
Within 1 week of start of 
RT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Within 1 week of RT end  
(external beam RT +/- 
brachytherapy)  
 
 
 
 
 
 
 
 
If applicable: 3-5 weeks 
post implant—submit 
listed items to TRIAD 
 
 
 
 
 
If applicable: 3-5 weeks 
post implant—submit 
listed items to TRIAD 

59 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
Folder 
Form/Item 
Due 
HDR Brachytherapy 
Implant CT scan 
Implant structure set 
Implant plan  
Implant dose distribution 
RTOG Prostate Brachytherapy Protocol 
Compliance Form-Available on the 
RPC website, 
http://irochouston.mdanderson.org 
 
NOTE: Copies of simulation and port 
films/images will be submitted to IROC 
Philadelphia ONLY if specifically 
requested. 
 
 
 
  
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Primary Endpoint 
13.1.1  Overall Survival (failure: death due to any cause)  
 
13.2 
Secondary Endpoints (12Jun2018) 
13.2.1  Incidence of unexpected grade ≥ 3 adverse events and/or clinically significant decrement in patient 
reported quality of life among subjects treated with TAK-700 
13.2.2  Rates and cumulative incidence of biochemical control (freedom from PSA failure), local/regional 
progression, and distant metastases 
 
 Biochemical failure will be defined by the Phoenix definition (PSA ≥ 2 ng/ml over the 
nadir PSA, the presence of local, regional, or distant recurrence, or the initiation of 
salvage androgen deprivation therapy) [Roach 2006]. 
 
 Local failure will be defined as biopsy proven recurrence within the prostate gland. 
 
 Regional or distant metastasis will be defined as imaging or biopsy demonstrated 
evidence for recurrence in the pelvic lymph nodes (regional) or systemically. Biopsy is 
not required to define regional or distant metastasis; however, in absence of a rising 
PSA biopsy is encouraged. 
13.2.3  General clinical treatment failure free interval (general clinical treatment failure [GCTF] is defined as: PSA 
> 25 ng/ml, documented local disease progression, regional or distant metastasis, or initiation of 
androgen deprivation therapy). Deaths prior to any of these events are treated as censoring for this 
endpoint. 
13.2.4  Prostate cancer specific survival (failure: death due to prostate cancer) and other-cause survival (failure: 
death due to other causes) 
13.2.5  Change in fatigue from baseline to 1 year, as measured by PROMIS 
13.2.6 Changes in patient reported quality of life as measured by Expanded Prostate Cancer Index Composite 
(EPIC) 
13.2.7 Assessment of quality adjusted survival using the EQ-5D (Will not be completed and is not part of the 
revised quality of life substudy per Amendment 3.) 
13.2.8  Nadir and average serum testosterone at 12 and 24 months during treatment 
13.2.9  Lipid profiles at 12 and 24 months 
13.2.10 Fasting plasma glucose, fasting plasma insulin, and hemoglobin A1c at 12 and 24 months 
13.2.11 Changes in body mass index (BMI) during 24 months of treatment and during the first three years of 
follow-up 
13.2.12 Incidence of adverse events ascertained via CTCAE version 4 
13.2.13 Rate of recovery of testosterone to >230 ng/dL (accepted threshold for supplementation) after 12 and 24 
months of follow-up 
13.2.14 Median time to recovery of testosterone to >230 ng/dL during the first five years of follow-up 

60 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
13.2.15 Cumulative incidence of relevant clinical survivorship endpoints including new diagnosis of type 2 
diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, deep vein 
thrombosis, or osteoporotic fracture 
 
13.3 
Sample Size Determination (12/17/13) (12Jun2018) 
13.3.1  Sample Size for Primary Endpoint 
Patients with disease characteristics meeting the eligibility criteria for this study (Section 3.0) historically 
have 5-year survival of 78% and 8-year survival of 61.5%. We assume an annual hazard rate of 0.055, 
and aim to detect a 33% reduction in failure rate for the experimental arm. Assuming a two-sided alpha 
level of 0.05 (adjusted for interim analysis, see below), observation of 239 events is required for 85% 
statistical power to detect this effect. This relative hazard reduction implies an absolute survival difference 
of 7% at five years. 
 
It is anticipated that patients can be accrued to this study at a rate of 30 per month. If 870 patients are 
accrued over 29 months, then the requisite events for definitive analysis would be accumulated after an 
additional 67 months, or 96 months from commencement of accrual. To account for a potential ineligibility 
and follow-up loss rate of 3%, 900 patients will be enrolled. 
13.3.2   Statistical Power for Other Time to Event Endpoints 
Patients in this risk class have biochemical failure rates of approximately 8% per year between years 5 
and 8. The trial will provide for detection of a 30% relative reduction in biochemical failure rate with 
statistical power approaching 90% at eight years. The distant failure rate for these patients is 2.0% per 
year. A 50% relative reduction in hazard of distant metastases for the experimental treatment group can 
be detected with statistical power of 88% at eight years. 
13.3.3 Statistical Power for Primary Survivorship Endpoints 
 
Hemoglobin A1c will be measured at baseline, 12 months and 24 months, with scores reflecting change 
from baseline compared at the follow-up time-points. A 0.1% difference in A1c between treatments would 
be considered of clinical interest. Given the precision of measurement in HB A1c in prior studies involving 
men receiving GnRH therapy (mean to standard error ratio greater than 10), power for detection of such 
differences would easily exceed 90%, even after controlling for multiple comparisons.  
 
 
 
For diabetes/pre-diabetes incidence, the standard treatment frequency is expected to be in the range of 
12-15%. Odds ratios of 1.5 or greater for the TAK-700 group will be detectable with power exceeding 
80%. 
13.3.4 Statistical Power for Primary Quality of Life Endpoint 
It is not anticipated that the entire trial participant cohort will be enrolled in the QOL correlative study. 
However, it is of interest to establish whether the addition of TAK-700 contributes to diminished quality of 
life scores and increased fatigue, and thus is desirable to have a sufficient sample to rule out smaller 
differences that would be considered clinically material. Fatigue, as measured by the PROMIS, will be the 
primary QOL analysis and therefore will be used in the sample size calculation. If we consider a 0.33 
standard deviation effect size and a two-sided type I error = 0.05, we obtain a required sample size of 390 
patients (195 patients per arm) for 90% power. To account for losses, such as ineligibility and non-
compliance, 15% inflation in sample size is applied, resulting in 458 patients. A total of 458 patients 
enrolled in the study will participate in the QOL portion of the trial. 
 
The study closed to accrual with 239 patients enrolled.  Given this enrollment, it is assumed that there will 
be 130 patients evaluable at 1 year, with those not evaluable due to ineligibility, non-compliance and not 
consenting to this correlative study.  With this sample size, a moderate effect size of 0.5 can be detected 
with 81% power using a two-sample test of the difference in means with a two-sided type I error = 0.05. 
13.3.5 Software for Sample Size Calculations 
For the above calculations, the statistical software package EAST was used. Additional calculations 
verifying study duration and power for time to event endpoints were performed with user-written programs 
in the SAS statistical language. 
 
13.4   Randomization 
Patients will be stratified before randomization by the composite risk score (based on Gleason score, PSA, 
and tumor stage) defined in Section 3.1.1, type of RT boost, and use of ADT prior to registration. Treatment 
arms will be balanced with respect to risk score via a permuted block procedure (Zelen 1974). 
 

61 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
13.5   Analysis Plan (12Jun2018) 
13.5.1 Primary Efficacy Endpoint 
Primary analysis will include all eligible randomized patients with follow-up information, with patients 
included in the group to which they were assigned, regardless of whether they started treatment. Overall 
survival will be compared between treatment arms using the log-rank test (Mantel 1966). The Kaplan-
Meier estimator will be used to estimate overall survival by treatment group (Kaplan 1958). Event times 
are measured from the date of study registration to the date of failure, or last follow up. 
13.5.2 Other Efficacy Endpoints 
 
Cumulative probability over time of PSA failure, local/regional recurrence, distant metastases and clinical 
failure will be estimated via the cumulative incidence function, which correctly accounts for competing 
risks (Korn 1992). Primary putative treatment effect comparisons for these endpoints will be based on 
cause-specific hazards using logrank tests (Friedlin 2005, Dignam 2008). To evaluate differences 
specifically in cumulative incidence of these events, we may also employ Gray’s test (Gray 1988). 
 
 
If there are imbalances in covariates by treatment arm, then hazard regression models will be used to 
produce adjusted treatment effect estimates and tests.  Appropriate models will be applied based on 
which metric is being examined (cause-specific hazard or cumulative incidence) [Prentice 1978, Fine 
1999]. If model-specific assumptions are not met (for example, proportionality), then alternative 
approaches will be sought. 
13.5.3 Longitudinal Quality of Life (QOL) and Patient Reported Outcome (PRO) Endpoints 
The primary hypothesis of the QOL endpoints are that QOL and fatigue scores will not differ significantly 
between the control group and the experimental group receiving both a GnRH agonist and TAK-700.  
Quality of life will be measured with the prostate cancer-focused 32-question EPIC (The Expanded 
Prostate Cancer Index Composite) questionnaire and by the 5-question EQ-5D global quality of life 
assessment. Fatigue will be measured by the 7-question PROMIS (Patient-Reported Outcome 
Measurement Information System) fatigue short form questionnaire. The EPIC-26, PROMIS-fatigue short 
form, and EQ-5D will be collected at pretreatment (baseline), the week prior to starting RT, the last week 
of RT, and 1 year and 2.5 years after initiation of therapy. 
 
The primary objective in the fatigue analysis is to determine the QOL differences at 1 year. The response 
will be the change of measurement from baseline for each measurement.  Using the sample size 
specified in section 13.3.3 of 130 evaluable patients, we will have 64% statistical power assuming a type I 
error = 0.05 (with appropriate type I error control for multiplicity using the Bonferroni correction) to detect 
a standard deviation effect size of 0.5 between the treatment arms for the 4 domains of the EPIC. 
 
For these investigations, a longitudinal analysis will be conducted that will focus on patterns of scores 
over time points (baseline, the week prior to starting RT, the last week of RT, and 1 year and 2.5 years 
after initiation of therapy) for the QOL and PRO instruments (EPIC, PROMIS and EQ-5D).  Following 
descriptive statistics on assessments and tests of the primary endpoint of change from baseline to 1 year, 
repeated measures analysis of covariance (ANCOVA) will be used on scores for the assessment 
measures, where time points are considered the within-patient factor and treatment groups is considered 
the between-patient factor (Diggle 1994).  While scales for the individual instrument questions are 
quantitative, they represent ordinal values on a bounded range rather than continuous quantities. 
Nonetheless, in aggregate these approximate continuous distributions, and appropriate transforms will be 
applied to improve consistency with model assumptions. The hierarchical analytic approach described 
below permits tests of omnibus hypotheses that control for multiple comparisons among time points and 
treatment groups. The analysis will be conducted as follows: 
 
(1) 
The ANCOVA model will be used to carry out an omnibus test of the hypothesis that there is a 
common mean score across time point within the treatment groups: H0: it = i., where i = 
treatment group 1 or 2, t = time point (baseline, the week prior to starting RT, the last week of 
RT, 1 year and 2.5 years) and it is the mean score in treatment group i at time t. 
 
(2) 
If the hypothesis in (1) is rejected, individual comparisons of the post-RT and subsequent 
scores will be conducted within treatment groups. Additional modeling and graphical methods 
to determine trends or patterns of change in scores over time points will be conducted. 
 

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RTOG 1115, Version Date June 12, 2018 
 
 
(3) 
The ANCOVA model will be used to carry out an omnibus test of the hypothesis that there is a 
common mean score at each time point among the treatments: H0: it = .t, where again it is 
the mean score in treatment group i at time t.  
 
(4) 
Assuming the result of the hypothesis test in (3) is significant (H0 rejected), individual tests will 
be carried out to determine differences between treatment groups at specific time points. If 
there are no significant treatment differences identified in (3), an overall test of trend in scores 
can be aggregated over treatment groups. Additional modeling to characterize patterns of 
change over time will be conducted. 
 
Information regarding potential confounds will be collected in a short form (QL) using limited questions to 
minimize patient burden. This information can be used to evaluate the potential impact of these 
confounding factors on fatigue. Patient responses to the following will be collected in the QL form: muscle 
weakness (one item), overall sleep quality as measured by one item from the Pittsburgh Sleep Quality 
Index (PSQI) [Buysse 1989] and level of physical activity as measured by the Godin Leisure-Time 
Exercise Questionnaire (GLTEQ) (Godin 1986; Gionet 1989). Anxiety/depression is also a potential 
confound with fatigue and patient responses to the anxiety/depression item in the EQ-5D can be used.  At 
the same time points, the QL form (i.e., one item from the PSQI, 3 items from the GLTEQ, and one 
question regarding general muscle weakness) will be collected. In addition, in order to correlate fatigue 
with the cytokine changes, the PROMIS-fatigue short form (and the associated questions) will be 
collected at the following time points: at baseline, the week prior to starting RT, the last week of RT, 1 
year and 2.5 years after therapy starts.  
 
These confounding factors may be incorporated into the above hypothesis tests via the ANCOVA model. 
The effects of these covariates on scores may also be evaluated separately in exploratory analyses. Also 
note that baseline scores will be analyzed in relation to subsequent impairment or decline for both 
treatment groups (hypothesis (1) above). The use of change scores (relative to baseline) for the main 
analysis also may be explored to account for the influence of per patient conditions prior to undergoing 
treatment. 
 
A certain degree of attrition from the study, due to both patient withdrawal and mortality, is expected. 
Characteristics of patients with missing data will be evaluated to identify imbalance in factors such as 
treatment, baseline scores, and other clinical and demographic features. In the absence of apparent 
systematic missing data patterns, data will be analyzed assuming that the observations are missing at 
random, employing appropriate methodology for this purpose (Little 1992). In the case of evidence for 
systematic patterns of missing data (‘informative’ missingness), alternative strategies for analyzing such 
data, depending on the pattern (e.g., intermittent versus complete dropout pattern) will be investigated 
(Wu 1988, Little 1992). 
 
In this study, the addition of TAK-700 is hypothesized to improve overall survival (OS), without having a 
significant a negative impact on health related quality of life (HRQOL). As there are competing pros and 
cons of this treatment, it is useful to combine these factors into one equation to determine whether the 
potential benefits of this treatment (dose-escalated RT combined with short-term androgen deprivation), 
in terms of OS, outweigh the potential risks, in terms of negatively impacting on global HRQOL, compared 
to RT and ADT alone. Such a quality adjusted survival analysis can be invaluable for assisting in the 
decisions of future patients as well as clinicians faced with these treatment options. 
  
Quality-adjusted survival can be defined by the weighted sum of different time episodes added up to a 
total quality-adjusted life-year [U= sum of quality (qi) of health states K times the duration (si) spent in 
each health state] (Glasziou 1990): 
 



K
1
i
i
is
q
 
 
U
 
 
We will use Glasziou’s multiple health-state (Q-TwiST) models to use the repeated measures of EQ-5D. 
Because Glasziou’s method incorporates longitudinal QOL data into an analysis of quality-adjusted 
survival, the health stated model must be constructed on the following assumptions: 
 

63 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
A1) QOL is independent from treatment. 
A2) A health state is independent from previous states. 
A3) Proportionality of quality-adjusted duration and duration of the actual state of health 
 
Assumption A1 can be checked by plotting QOL over time according to treatment, and the t-test can be 
used to compare the mean QOL scores of each treatment arm. Assumption A2 can be checked by 
comparing the QOL for patient groups in a given health state where the groups are defined by duration of 
previous health state experience using a regression model. Suitable checks for assumption A3 at 
minimum would be a simple plot. If data does not support these assumptions, we will use a method which 
uses the longitudinal QOL data directly. We will use the 5-item utility score in EQ-5D for the cost-utility 
analysis. We will use the Z-test to test the hypothesis that the cost-utility in the 2 treatment arms is the 
same at 1 year after initiation of treatment with a significance level of 0.05 and a 2-sided test.  The 
remaining timepoints in which the EQ-5D is collected will also be assessed using similar longitudinal 
analysis techniques as described for the primary endpoint. 
13.5.4 Testosterone Kinetics 
Comparison of testosterone levels at designated time points will be conducted via t-tests on baseline-
corrected and appropriately transformed measurement values. Nonparametric tests to compare medians 
may also be conducted.  
 
Time to recovery of testosterone to >230 ng/dL (accepted threshold for supplementation) after treatment 
will be estimated using time to event data methods. Specifically, the cumulative incidence of >230 ng/dL 
level achievement will be computed, accounting for competing events in the form of 1) interventions due 
to clinical failure that may suppress recovery and 2) deaths. 
13.5.5 Lipid Profiles, Glycemic Parameters, and Body Mass Index 
Comparison of baseline-adjusted values for fasting glucose, fasting insulin, lipid levels, and hemoglobin 
A1c will be carried out between treatment groups at designated time points. Additionally, longitudinal 
models as described above may be used to characterize changes in these parameters over time within 
and between treatment groups. Body mass index will similarly be contrasted at specific time points and 
modeled as a function of time from treatment initiation. 
13.5.6 Clinical Survivorship Endpoints 
Incidence rates (events/person years of exposure) and cumulative incidence over time of specific clinical 
events (type 2 diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, 
deep vein thrombosis, osteoporotic fracture) will be estimated by treatment arm. Poisson regression or 
other appropriate methods will be used to investigate the role of other explanatory risk factors in 
conjunction with treatment exposure. 
13.5.7  Trial Monitoring 
Data Monitoring Committee 
Phase III trials are required by NCI Cooperative Group Program Guidelines to be reviewed by a Data and 
Safety Monitoring Committee (DSMC). This study will be reviewed by the NRG Oncology Data Monitoring 
Committee (DMC) on a semi-annual basis.    
 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0 (CDUS 
Abbreviated). Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
 
 
Interim Efficacy and Futility Analysis Plan 
There will be three interim analyses of the primary hypotheses, at equally spaced increments of 25%, 
50%, and 75% of the requisite events for definitive analysis. A conservative upper superiority bound, 
based on a Lan-DeMets approximation to the O’Brien and Fleming boundary (DeMets 1994) provides test 
criteria of Z > 4.33 at the first interim analysis, Z > 2.96 at the second interim analysis, and Z > 2.36 at the 
third interim analysis. At the final analysis, a test statistic of Z > 2.01 will be required to reject H0. 
 
Interim futility analysis will be based on the rule of Freidlin, Korn, and Gray (Freidlin 2010). This rule 
provides the opportunity to terminate early for evidence that the experimental arm will not prove superior, 
but protects against aggressive early termination for treatment effect sizes smaller than planned. 
 
The following table summarizes the interim efficacy/futility monitoring schedule with respect to the primary 
endpoint: 

64 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
Analysis 
Time 
(month) 
Prop.  
Total 
events 
Cumulative 
Total Events 
(Both Arms) 
Efficacy 
boundary 
Futility boundary 
Z> 
P< 
Z< 
P> 
Interim 1 
33 
0.25 
60 
4.33 
0.00001 
-1.64* 
0.05* 
Interim 2 
54 
0.50 
120 
2.96 
0.0015 
0.06 
0.476 
Interim 3 
75 
0.75 
180 
2.36 
0.009 
0.31 
0.378 
final 
96 
1.00 
239 
2.01 
0.022 
- 
- 
 
 
* Early look for detriment in experimental arm, left-tail p < 0.05 will prompt stopping 
 
In addition to the futility boundary for the primary endpoint, we will also implement a futility rule based on 
an intermediate endpoint for which evidence of efficacy is expected if there is eventual efficacy on the 
primary endpoint. Specifically, hormone deprivation agents that have shown favorable survival benefit 
typically demonstrate reductions in clinical outcomes such as time free from PSA progression or clinical 
failure (local, regional, or distant disease progression). Thus, early evidence of activity will be assessed 
by comparing the rate of general clinical treatment failure (GCTF, defined as time to any of the following 
events: PSA failure, local/regional recurrence, distant recurrence, hormone initiation) between treatment 
groups. The approach will involve testing for a difference in GCTF with adequately high power but a 
rather less stringent alpha level, following the strategy in multi-arm multi-stage clinical trials, where 
regimens are evaluated early based on intermediate endpoints to assure some level of activity before 
continuing to definitive endpoints (Sydes 2009).  
 
Assuming an annual GCTF hazard rate of 0.125, a one-sided alpha of 0.10 and statistical power of 0.90, 
detection of a 40% reduction in GCTF hazard for patients receiving TAK-700 requires observation of 100 
events. Because the most frequent GCTF event is PSA failure, and this event is delayed during active 
treatment, analysis will take place only on the cohort of patients consisting of those entering through the 
first 1.5 years (450 patients). This cohort will be observed for an additional 1.75 years, or to approximately 
3.25 years from commencement of accrual, when the requisite number events for the above comparison 
will have been observed. At this time, GCTF will be compared between treatments, and if the null 
hypothesis of no difference in GCTF rate cannot be rejected in favor of a lower GCTF rate for patients 
receiving TAK-700 (one-sided 0.10 test), then discontinuation of the trial for futility will be considered. 
Within the time frame described above, there will be at least 80% power for any treatment difference 
equal to or greater than a 33% relative reduction in GCTF events. Results of this analysis will be reported 
only to the RTOG Data Monitoring Committee and not in any scientific forum or publication. 
 
 
Interim Safety Analysis Plan 
After the accrual and follow-up of 100 patients per treatment arm through completion of six months of 
therapy, adverse event (CTCAE) frequencies will be formally compared between treatment arms. 
 
Analysis will focus on specific organ system class and specific adverse event types, in addition to 
frequency of grade 3 and higher adverse events overall (i.e., any type). Adverse events of interest are 
shown below, accompanied by expected frequencies for the control arm of this trial, based on observed 
rates in previous RTOG prostate cancer trials using prolonged androgen suppression. 
 
 
CTCAE (4.0) category 
CTCAE specific 
Expected % grade 3 or  greater on 
standard ADT 
Any 
Any 
22.0 
Renal and urinary disorders 
Any 
3.0 
Gastrointestinal  disorders 
Any 
3.6 
Reproductive 
system 
and 
breast disorders 
Any 
10.4 
General 
disorders 
and 
administration site conditions 
Fatigue 
1.9 
Vascular disorders 
 
Hypertension 
0.0 
Metabolism 
and 
nutrition 
disorders 
Hypokalemia 
0.0 

65 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
Frequencies will be compared between treatment arms via Fisher’s exact test. A one-sided criterion will 
be used to determine whether there is higher frequency of a given adverse event in the ADT+TAK700 
arm.  Including 200 patients with six months of follow-up (100 in each treatment group) and using a one-
sided 0.01 alpha level, a 15% absolute increase in event types with expected frequency < 4% under 
standard ADT (for example, GU, GI, fatigue) can be detected with statistical power of 85% or greater. For 
those events with expected frequency in the range of 10%-25% in the control arm, statistical power for 
detecting a 25% absolute increase exceeds 85%. If there are imbalances between treatments in patient 
demographic or radiation treatment parameters that may affect adverse event rates, then stratification or 
modeling methods will be used. 
 
In addition, scores for EPIC, EQ-5D, and PROMIS in this cohort will be compared between treatment 
groups, using the scheduled post-RT assessment. Differences will be assessed via t-tests on suitably 
transformed score sums, corrected for baseline values. A formal stopping criterion for these scores will 
not be specified. 
13.5.8  Trial Reporting 
The primary trial endpoint will be reported when specific criteria described in Section 13.5.7 are met. In 
particular, when either the number of events for definitive analysis is reached or an interim analysis 
indicates that early stopping is warranted, then the primary endpoint will be considered eligible for 
reporting.  
 
13.5.9 Revised Sample Size, Statistical Power, and Analysis Plan  
In June 2014, Millennium Pharmaceuticals informed NRG Oncology of their intention to no longer pursue 
development of the experimental agent (TAK-700) in prostate cancer. Subsequent discussion established 
that patients having entered the trial as of the accrual closure date would be provided assigned therapy to 
complete the regimen as described in 7.1.2. At trial accrual closure (September 30, 2014), 239 patients 
had been enrolled. 
 
Statistical power for the primary and secondary endpoints will thus be compromised regardless of the 
length of follow-up time, and thus in order to frame completion of primary analysis that is practical with 
respect to time to reporting, a plan for seeking to obtain suitably reliable information on the effects of the 
intervention on PSA failure was developed, with a goal of reporting on the trial after 5 additional years of 
follow-up from accrual closure. 
 
The assumed rate of PSA failure for the control arm is .08/year. With 239 patients accrued over 28 
months (assuming 230 eligible and analyzed), additional follow-up (from September 2014) of 5 years will 
yield the following (based on projections computed as in Rubinstein, Gail, and Santner (1981)). 
 
TAK-700 Treatment Effect 
 
HR 0.60 
HR 0.55 
HR 0.50 
TAK-700 group failure rate 
0.048 
0.044 
0.040 
Number of events at 5 years 
70 
67 
65 
Power at 5 years* 
0.68 
0.78 
0.86 
* at one-sided alpha = 0.05 
 
The PSA failure endpoint will be analyzed when 70 events have been observed, which is expected to 
occur relatively close to 5 years under any of these scenarios. If the relative reduction exceeds 40%, then 
power will be greater than 70% (at one-sided alpha = 0.05). For this number of events, if the relative 
reduction is 45%, power will reach 80%, and will reach 90% for a 50% reduction in PSA failure rate. 
 
For the original primary endpoint (OS) and other secondary time to event endpoints, statistical power at 
the expected time of this first report is as follows. At the assumed failure rates, power for the originally 
planned detection of a 33% reduction in hazard of death would be approximately 28% (at two-sided alpha 
= 0.05). For distant metastasis, power to detect a 50% failure rate reduction would be approximately 32%. 
 
At the time when PSA failure results are reported based on reaching the above criterion, these other 
endpoints will be reported.  Confidence bounds will be provided for hazard ratio estimates and estimated 
percent event-free at specific time points, in order to illustrate the degree of uncertainty in these endpoints 
for which statistical power is less than desired. It will be determined at that time whether further (long-
term) follow-up would be sufficiently informative towards evaluating the effect of experimental treatment 

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RTOG 1115, Version Date June 12, 2018 
 
 
on these endpoints. At this time, it is not anticipated that a longer duration of follow-up would materially 
improve power or precision on estimates, given the low event rates for these endpoints. 
 
13.5.10 Revised Trial Monitoring Plan  
Given the curtailed sample size and plan to report results when PSA failure data is mature, the interim 
monitoring plan will be revised. The trial will be evaluated for futility after one-half of the target of 70 
events is observed. Efficacy will also be evaluated using an extreme boundary (consistent with an 
approximate 67% reduction in hazard), with the rationale being that early stopping for efficacy given the 
suboptimal sample size should only be considered in extraordinary circumstances.  
 
The following table summarizes the interim efficacy/futility monitoring schedule with respect to the PSA 
failure endpoint: 
 
Analysis 
Time (mo) 
from trial 
start 
Prop.  
Total 
events 
Cumulative 
Total Events 
(Both Arms) 
Efficacy boundary 
Futility 
boundary 
Z> 
P< 
Z< 
P> 
Interim  
42 
0.5 
35 
3.70 
0.0001 
0.00 
0.5 
final 
84 
1.00 
70 
1.65 
0.05 
- 
- 
 
 
13.6 
Gender and Minorities 
Men of all races and ethnic groups are eligible for this study. Clinically important race/ethnicity differences 
are not expected from the intervention effect. 
 
 
 
Projected Distribution of Gender and Minorities 
 
 
Gender 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
N/A 
27 
27 
Not Hispanic or Latino 
N/A 
873 
873 
Ethnic Category: Total of all subjects 
N/A 
900 
900 
 
Gender 
Racial Category 
Females 
Males 
Total 
American Indian or Alaskan Native 
N/A 
2 
2 
Asian 
N/A 
4 
4 
Black or African American 
N/A 
135 
135 
Native Hawaiian or other Pacific Islander 
N/A 
3 
3 
White 
N/A 
756 
756 
Racial Category: Total of all subjects 
N/A 
900 
900 
 
  

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RTOG 1115, Version Date June 12, 2018 
 
 
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Levegrun S, Jackson A, Zelefsky MJ, et al. Risk group dependence of dose-response for biopsy outcome after 
three-dimensional conformal radiation therapy of prostate cancer. Radiother Oncol 2002;63:11-26. 
 

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Lilleby, W., et al., Long-term morbidity and quality of life in patients with localized prostate cancer undergoing 
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Milne RJ, Heaton-Brown KH,Hansen P, Thomas D, Harvey V, Cubitt A. Quality-of-life valuations of advanced 
breast cancer by New Zealand women. Pharmacoeconomics. 2006;24(3):281-92. 
 
Mohler J, Bahnson RR, Boston B, et al. NCCN clinical practice guidelines in oncology: prostate cancer. J Natl 
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Monga, U., et al., Longitudinal study of quality of life in patients with localized prostate cancer undergoing 
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Monga, U., et al., Prospective study of fatigue in localized prostate cancer patients undergoing radiotherapy. 
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Peters, CA, Stock, RG, Cesaretti, JA, et al. TGFB1 single nucleotide polymorphisms are associated with adverse 
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carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285-90. 
 
Pisansky TM, Kahn MJ, Bostwick DG. An enhanced prognostic system for clinically localized carcinoma of the 
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APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (4/16/14)  
 
Note: See Sections 3.0 and 4.0 (pre-study entry) for details and/or exceptions to this table. 
Assessments (may be 
required for eligibility) 
w/in 180 
days prior to 
registration 
w/in 90 days 
prior to 
registration 
w/in 60 days 
prior to 
registration 
w/in 21 days 
(3 weeks) 
prior to 
registration 
w/in 14 days 
(2 weeks) 
prior to 
registration 
Biopsy 
X 
 
 
 
 
History/physical 
 
 
X 
 
 
Ht/Wt/PS 
 
 
 
X 
 
PSA 
X 
 
 
 
 
CBC/diff 
 
 
 
 
X 
Chemistry & liver panels 
 
 
 
X 
 
Testosterone (standard 
assay unless otherwise 
noted) 
  
Note: Collect blood for 
testosterone in the a.m. at 
same time of day as 
collection of fasting 
insulin/ fasting glucose/ 
fasting lipids/hemoglobin 
A1C 
 
 
 
X 
 
Fasting glucose/ fasting 
lipids/ hemoglobin A1C 
 
Note: Collect blood in the 
a.m. at same time of day 
as collection of 
testosterone 
 
 
 
X 
 
Fasting insulin (ship 
specimen to UCSF BSR) 
 
Note: Collect blood in the 
a.m. at same time of day 
as collection of 
testosterone 
 
 
 
X 
 
MUGA scan or 
echocardiogram 
Prior to registration 
Bone scan 
 
X 
 
 
 
CT or MRI 
 
X 
 
 
 
Transrectal ultrasound 
and AUA 
 
 
X (for 
brachy 
patients 
only) 
 
 
-Continued on next page- 
 

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APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS continued 
Note: See Sections 3.0 and 4.0 (pre-study entry) for details and/or exceptions to this table. 
Assessments (may 
be required for 
eligibility) 
w/in 180 
days prior to 
registration 
w/in 90 days 
prior to 
registration 
w/in 60 days 
prior to 
registration 
w/in 21 days 
(3 weeks) 
prior to 
registration 
w/in 14 days 
(2 weeks) 
prior to 
registration 
Review of 
medications 
At registration 
*Clinical 
survivorship 
 
X* 
 
 
 
†PROMIS-fatigue, 
EPIC, EQ-5D, 
PSQI/GLTEQ (if 
patient consents) 
 
Pre-treatment 
Tissue for banking 
(if patient consents) 
 
Pre-treatment 
†Blood for 
banking/QOL (if 
patient consents) 
 
Pre-treatment (see also Section 10.0 for specific collection requirements) 
*See Section 1.0 of protocol under Evaluation of Clinical and Chronic Disease Outcomes (1st 
sentence). 
 
†Blood (Plasma & whole blood) collection is mandatory for patients participating in QOL. 
 
-Continued on next page- 
 

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APPENDIX I, STUDY PARAMETER TABLE:  ASSESSMENTS DURING TREATMENT (12/17/13) 
Note: See Sections 10.0 (specimen collection), and 11.1 (during treatment) for details and/or 
exceptions to this table. 
Assessments 
During 24 months of ADT +/- TAK-700 
30 months 
 
q 1 
month 
q 3 
months 
12 months 
24 months 
History/physical 
 
X 
 
 
 
Ht/Wt/PS 
 
X 
 
 
 
PSA 
 
X 
 
 
X 
Chemistry & liver panels 
See 
11.1 
See 
11.1 
 
 
 
Testosterone (standard 
assay unless otherwise 
noted) 
 
Note: Collect blood for 
testosterone in the a.m. at 
same time of day as 
collection of fasting insulin/ 
fasting glucose/ fasting 
lipids/hemoglobin A1C 
 
 
X (by LC/MS/MS; 
ship specimen to 
NRG Oncology 
Biospecimen 
Bank) 
X (by LC/MS/MS; 
ship specimen to 
NRG Oncology 
Biospecimen 
Bank) 
X 
Fasting glucose/ fasting 
lipids/hemoglobin A1C 
 
Note: Collect blood in the 
a.m. at same time of day as 
collection of testosterone 
 
 
X 
X 
 
Fasting insulin (ship 
specimen to UCSF BSR) 
 
Note: Collect blood in the 
a.m. at same time of day as 
collection of testosterone 
 
 
X 
X 
 
Review of medications 
 
X 
 
 
 
AE evaluation 
X 
 
 
 
 
*Clinical survivorship 
 
X 
 
 
 
†PROMIS-fatigue, EPIC, 
EQ-5D, PSQI/GLTEQ (if 
patient consents) 
 
(1) In the week prior to RT start; (2) during the last week of RT;  
(3) at 1 year (12 months) after therapy starts 
 
 
†Blood for banking/QOL (if 
patient consents) 
 
At 1 year (12 months) after therapy starts 
(see also Section 10.0 for specific collection requirements) 
 
*See Section 1.0 of protocol under Evaluation of Clinical and Chronic Disease Outcomes (1st 
sentence). 
 
†Blood (Plasma & whole blood) collection is mandatory for patients participating in QOL. 
 
-Continued on next page- 
 

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APPENDIX I, STUDY PARAMETER TABLE:  FOLLOW UP ASSESSMENTS (12/17/13) 
Note: See Sections 10.0 (specimen collection), and 11.1 (during treatment) for details and/or 
exceptions to this table. 
Assessments 
Follow Up (beginning at 36 months) 
 
q 6 months for 3 years and then annually 
q 12 months for 3 years 
History/physical 
X 
 
Ht/Wt/PS 
X 
 
PSA 
X 
 
Testosterone 
(standard assay 
unless otherwise 
noted) 
 
Note: Collect blood 
for testosterone in 
the a.m. at same 
time of day as 
collection of fasting 
insulin/ fasting 
glucose/ fasting 
lipids/hemoglobin 
A1C 
 
X 
Fasting glucose/ 
fasting lipids/ 
hemoglobin A1C 
 
Note: Collect blood 
in the a.m. at same 
time of day as 
collection of 
testosterone 
 
X 
Fasting insulin (ship 
specimen to UCSF 
BSR) 
 
Note: Collect blood 
in the a.m. at same 
time of day as 
collection of 
testosterone 
 
X 
Bone scan 
As clinically indicated, q 6 months after PSA relapse 
AE evaluation 
X 
 
-Continued on next page- 
 

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APPENDIX I, STUDY PARAMETER TABLE:  FOLLOW UP ASSESSMENTS continued (12/17/13) 
Note: See Sections 10.0 (specimen collection), and 11.1 (during treatment) for details and/or 
exceptions to this table. 
Assessments 
Follow Up (beginning at 36 months) 
 
q 6 months for 3 years and then annually 
q 12 months for 3 years 
*Clinical 
survivorship 
X 
 
†PROMIS-
fatigue, EPIC, 
EQ-5D, 
PSQI/GLTEQ 
(if patient 
consents) 
At 2.5 years (30 months) after therapy starts 
†Blood for 
banking/QOL 
(if patient 
consents) 
At 2.5 years (30 months) after therapy starts 
(see also Section 10.0 for specific collection requirements) 
*See Section 1.0 of protocol under Evaluation of Clinical and Chronic Disease Outcomes (1st 
sentence). 
 
†Blood (Plasma and whole blood) collection is mandatory for patients participating in QOL. 
 
 
 

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APPENDIX II 
 
ZUBROD PERFORMANCE SCALE 
 
0 
Fully active, able to carry on all predisease activities without restriction  
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
work of a light or sedentary nature.  For example, light housework, office 
work  
 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours  
 
3 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
 
4 
Completely disabled. Cannot carry on self-care. Totally confined to bed  
 
5 
Death  
 
 
 
 
 
 

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APPENDIX III 
Staging System, Prostate, 7th Edition 
DEFINITIONS OF TNM 
 
Primary Tumor, Clinical (T) 
TX  
Primary tumor cannot be assessed 
 
T0  
No evidence of primary tumor 
 
T1  
Clinically inapparent tumor neither palpable nor visible by imaging 
T1a  
Tumor incidental histologic finding in 5% or less of tissue resected 
T1b  
Tumor incidental histologic finding in more than 5% of tissue resected 
T1c  
Tumor identified by needle biopsy (e.g., because of elevated PSA) 
 
T2  
Tumor confined with prostate* 
T2a  
Tumor involves one-half of one lobe or less 
T2b  
Tumor involves more than one-half of one lobe but not both lobes 
T2c  
Tumor involves both lobes 
 
T3  
Tumor extends through the prostate capsule** 
T3a  
Extracapsular extension (unilateral or bilateral) 
T3b  
Tumor involves the seminal vesicle(s) 
 
T4  
Tumor is fixed or invades adjacent structures other than seminal vesicles such as external 
sphincter, rectum, bladder, levator muscles and/or pelvic wall 
 
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is 
classified as T1c 
 
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but 
as T2. 
 
Primary Tumor, Pathologic (pT) * 
pT2 
Organ confined 
pT2a  Unilateral, one-half of one side or less 
pT2b  Unilateral, involving more than one-half of side but not both sides 
pT2c  
Bilateral disease 
 
pT3  
Extraprostatic extension 
pT3a  Extraprostatic extension or microscopic invasion of bladder neck** 
pT3b  Seminal vesicle invasion 
 
pT4  
Invasion of rectum, levator muscles, and/or pelvic wall 
 
*Note: There is no pathologic T1 classification 
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease). 
 
Regional Lymph Nodes (N) 
Clinical 
NX  
Regional lymph nodes were not assessed 
N0  
No regional lymph node metastasis 
N1  
Metastasis in regional lymph node(s) 
 
Pathologic 
pNX 
Regional nodes not sampled 
pN0 
No positive regional nodes 
pN1 
Metastases in regional node(s) 

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APPENDIX III 
Staging System, Prostate, 7th Edition 
DEFINITIONS OF TNM 
 
Distant Metastasis (M)* 
M0  
No distant metastasis 
M1  
Distant metastasis 
M1a  
Nonregional lymph node(s) 
M1b  
Bone(s) 
M1c  
Other site(s) with or without bone disease 
 
*Note: When more than one site of metastasis is present, the most advanced category is used; 
pM1c is most advanced. 
 
Histologic Grade (G) 
Gleason X  
Gleason score cannot be processed 
Gleason ≤6  
Well-differentiated (slight anaplasia]) 
Gleason 7  
Moderately differentiated (moderate anaplasia) 
Gleason 8-10  Poorly differentiated/undifferentiated (marked anaplasia) 
 
Anatomic Stage/Prognostic Groups* 
Stage I   
T1a-c  N0  
M0  
PSA <10 
Gleason ≤6 
 
 
T2a 
N0 
M0 
PSA <10 
Gleason ≤6 
 
 
T1-2a N0 
M0 
PSA X  
Gleason X 
 
Stage IIA  
T1a-c  N0  
M0 
PSA <20 
Gleason 7 
T1a-c N0 
M0 
PSA ≥10<20 
Gleason ≤6 
T2a 
N0 
M0 
PSA <20 
Gleason ≤7 
T2b 
N0 
M0 
PSA <20 
Gleason ≤7 
T2b 
N0 
M0 
PSA X  
Gleason X 
 
Stage IIB 
T2c 
N0 
M0 
Any PSA 
Any Gleason 
 
 
T1-2 
N0 
M0 
PSA ≥20 
Any Gleason 
 
 
T1-2 
N0 
M0 
Any PSA 
Gleason ≥8 
 
Stage III  
T3a-b  N0  
M0  
Any PSA 
Any Gleason 
 
Stage IV  
T4  
N0  
M0  
Any PSA 
Any Gleason 
Any T  N1  
M0  
Any PSA 
Any Gleason 
Any T  Any N  M1  
Any PSA 
Any Gleason 
 
*Note: When either PSA or Gleason is not available, grouping should be determined by T stage and/or either PSA 
or Gleason as available. 
 
 
 
 
 
Source: Edge, SB, ed. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. 

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APPENDIX IV 
New York Heart Association Classification of Cardiac Disease 
 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or the 
anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of Diseases of the Heart 
and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 

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APPENDIX V (12JUN2018) 
APPENDICES FOR NRG ONCOLOGY BIOSPECIMEN COLLECTION  
(as specified by the protocol) 
 
Shipping Instructions: 
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only 
NRG Oncology Biospecimen Bank  
University of California San Francisco 
Campus Box 1800 
2340 Sutter Street, Room S341 
San Francisco, CA 94143-1800 
Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341  
San Francisco, CA 94115 
 
 
Include all NRG Oncology paperwork in pocket of biohazard bag.  
 
Check that the Specimen Transmittal Form has the consent boxes checked off.  
 
Check that all samples are labeled with the RTOG (NRG) study and case number, and include date of 
collection as well as collection time point (e.g., pretreatment, post-treatment). 
 
 
FFPE Specimens: 
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the 
container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap 
blocks with bubble wrap or gauze. Place padding in top of container so that if you shake the container 
the blocks are not shaking. If you can hear the block shaking, it might break during shipping.   
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal 
Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). Do NOT 
ship on Dry Ice. 
 
 
Frozen Specimens:  
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and 
clearly identified. If possible keep Serum, Plasma, Whole Bloods in separate bags. 
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs). 
There should be plenty of dry ice under and above the specimens. If the volume of specimens is 
greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any 
Styrofoam box can be used, as long as it is big enough. 
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site 
will be notified.  
o Send frozen specimens on Dry Ice via overnight courier to the address above. Specimens should only 
be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to 
delivery delays. Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -
80 C until ready to ship. 
 
 
For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank 
by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271. 

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RTOG 1115, Version Date June 12, 2018 
 
 
APPENDIX V (continued) 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (12/17/13) 
 
Note: There is a separate appendix for PBMC preparation not included in this instruction (See Appendix 
VI). This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as 
specified by the protocol): 
 
Kit contents: 
 
Red Top tubes for mandatory serum – shipped separate (A) 
 
Three Purple Top EDTA tubes for plasma (B) 
 
One Purple Top EDTA tube for Whole Blood (C) 
 
Thirty-five (35) 1 ml cryovials 
 
Biohazard bags (2) and Absorbent shipping material (2) 
 
Styrofoam container (inner) and Cardboard shipping (outer) box 
 
UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers 
 
Specimen Transmittal Form and Kit Instructions 
 
PREPARATION AND PROCESSING OF SERUM, PLASMA AND WHOLE BLOOD: 
(A) Serum (if requested): Red Top Tube 
 
Label as many 1ml cryovials (5 to 10) as necessary for the serum collected. Label them with the 
RTOG (NRG) study and case number, collection date, time, and time point, and clearly mark 
cryovials “serum”. 
Process: 
1. Allow one red top tube to clot for 30 minutes at room temperature. 
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are 
unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 
hours of draw but must be noted on the Specimen Transmittal Form. 
3. Aliquot 0.5 ml serum into as many cryovials as are necessary for the serum collected (5 to 10) 
labeled with RTOG (NRG) study and case numbers, collection date/time, protocol time-point collected 
(e.g. pretreatment, post-treatment), and clearly mark specimen as “serum”. 
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen until 
ready to ship. See below for storage conditions. 
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the STF. 
 
(B) Plasma (If requested): Purple Top EDTA tube #1 
 
Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with the 
RTOG (NRG) study and case number, collection date, time, and time point, and clearly mark 
cryovials “plasma”. 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. 
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM 
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room 
temperature is acceptable if done within 2 hours of draw but must be noted on the STF..  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, 
keep specimen on ice until centrifuging is performed. 
4. Carefully pipette and aliquot 0.5 ml plasma into as many cryovials as are necessary for the plasma 
collected (5 to 10)  labeled with RTOG (NRG) study and case numbers, collection date/time, time point 
collected and clearly mark specimen as “plasma”.  Avoid pipetting up the buffy coat layer. 
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C. 
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the 
Specimen Transmittal Form. 
 
 
 
 
 
(continued on next page) 

84 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
APPENDIX V 
 
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
(C) Whole Blood for DNA (if requested): Purple Top EDTA tube #2 
 
Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with the 
RTOG (NRG) study and case number, collection date/time, and time point, and clearly mark cryovials 
“blood”. 
 
Process: 
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be 
mixed for 5 minutes on a mixer at room temperature. 
2. Carefully pipette and aliquot 1.0 ml blood into as many cryovials as are necessary for the blood 
collected (3 to 5) labeled with RTOG (NRG) study and case numbers, collection date/time, time point 
collected and clearly mark specimen as “blood”. 
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius. 
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions. 
 
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on 
Specimen Transmittal Form. 
 
Freezing and Storage: 
 Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen. 
 
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available,  
 
Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to 
one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please 
ship out on Monday-Wednesday only; Canada: Monday-Tuesday only). 
OR: 
 
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; 
Canada: Monday-Tuesday only). 
 
Please indicate on Specimen Transmittal Form the storage conditions used and time stored. 
 
Shipping/Mailing: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent 
thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam 
box. 
 
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods 
together) in absorbent shipping material and place each specimen type in a separate biohazard bag.   
(continued on next page) 

85 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
APPENDIX V (12Jun2018) 
 
RTOG BLOOD COLLECTION KIT INSTRUCTIONS (continued) 
 
 
Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box.   
 
Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that 
there is enough room for plenty of dry ice. Add padding to avoid the dry ice from breaking the tubes. 
 
For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail 
NRGBB@ucsf.eduor call (415) 476-7864. 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank 
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu  

86 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
APPENDIX VI (12JUN2018) 
 
PBMC PREPARATION INSTRUCTIONS 
Peripheral blood mononuclear cell (PBMC) isolation 
 
1. Collect whole blood into one lavender top tube (EDTA tube #3), invert to mix (total volume about 6 ml per tube). 
Keep blood at room temperature (RT).  
 
2. Within 10 mins if possible (no more than 2 hours), transfer the whole blood from collection tubes into a 50 ml 
conical tube. Note the volume of blood. 
 
3. Dilute whole blood. Adjust blood volume to 1:1 with 1X Dulbeccos-PBS (CMF Free) (e.g. 6 whole blood + 6 ml 
1X PBS), invert to mix. 
 
4. Add 5 ml lymphocyte separation medium (LSM) per 15 ml conical tube. 
 
5. Carefully add the diluted whole blood on the top of LSM using the disposable blunt tip transfer pipette, 
pipetting slowly alongside of the tube to get two layers.  Do not mix diluted whole blood with LSM. Note: If you 
have more diluted blood than will fit in a single tube, you can divide it into two tubes so as not to waste any 
sample. 
 
6. Carefully transfer the tube with diluted whole blood/LSM into a swing bucket centrifuge. Spin at 705 RCF for 10 
minutes, RT, with the brake off. The figure below shows what to expect. (Note: Ficoll is another type of LSM). 
 
 
7. Collect PBMCs with a disposable thin tip transfer pipet, and deposit to a new 15ml tube.  
 
8. Wash cells: bring volume in the tubes up to 14ml with 1X PBS (still RT). 
 
9. Centrifuge for 10 mins at 194 RCF, RT, brake on. 
 
 
 
(continued on next page) 

87 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
APPENDIX VI 
 
PBMC PREPARATION INSTRUCTIONS (continued) 
Peripheral blood mononuclear cell (PBMC) isolation 
 
10. Discard supernatant and wash again with 14ml of 1X PBS, RT. 
 
11. Centrifuge for 10 mins again at 194 RCF, RT, brake on. 
 
12. Discard the supernatant. Re-suspend the pellet by gently flicking the bottom of the tube. Transfer the pellet by 
re-suspending it using 0.5-1.0 mL of the freezering serum mix and add this back to the cryovial containing the 
remaining freezing serum mix (FBS + 10% DMSO). 
 
13. Store immediately at -80°C in 2 ml cryovial. Samples must then be kept at -80C during storage and  
shipping. 
 
14.  SHIPPING INSTRUCTIONS: 
 
Ship specimens on Dry Ice overnight Monday-Wednesday (Monday-Tuesday from Canada) to prevent 
thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted. 
 
 
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam 
box. 
 
 
Wrap frozen specimens in absorbent shipping material, and place inside zip-lock biohazard bags. Place 
specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  Add 
padding to avoid the dry ice from breaking the tubes.  
 
 
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 
stickers to outer cardboard box. 
 
 
For questions regarding collection or processing of PBMC’s please e-mail RTOG@emory.edu 
 
 or call (404) 778-5564. 
  
 
To order a kit please contact the NRG Oncology Biospecimen Bank at NRGBB@ucsf.edu 
 
 or call (415) 476-7864 
 
Shipping Address: 
Courier Address (FedEx, UPS, etc.): For all Frozen Specimens 
NRG Oncology Biospecimen Bank  
University of California San Francisco 
2340 Sutter Street, Room S341 
San Francisco, CA 94115 
Phone: +1 415-476-7864 
 
 
(continued on next page) 
 
 
 
 
 

88 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
 
APPENDIX VI 
 
PBMC PREPARATION INSTRUCTIONS (continued) 
Peripheral blood mononuclear cell (PBMC) isolation 
 
PBMC Collection Kit Contents 
Lavender top tubes: Becton Dickson 366450 
1X PBS: Store at room temperature or 4C until ready for use. Keep sterile. 
50 ml conical tube: Becton Dickson 352070 
lymphocyte separation medium: Mediatech 25-072-CL - Store at room temperature. 
disposable blunt tip transfer pipettes: Fisher 13-711-7M 
disposable thin tip transfer pipettes: Thermo Scientific Samco 232 
15 ml conical tubes: Becton Dickson 352097 
1.5 mls Freezing medium in 2ml Cryovials: (store frozen until ready to use) 
(90% Fetal Bovine Serum, Hyclone SH30071.03; 10% DMSO, Sigma D2650) 
  

89 
 
 
RTOG 1115, Version Date June 12, 2018 
 
 
 
APPENDIX VII 
 
MONTHLY PILL DIARY FOR RTOG 1115 TAK-700 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
AM DOSE 
300mg____ 
 
PM DOSE 
300mg____ 
 
 
 
 
 
____1115___/______________  
 
 
 
__________________  
Study number/case number 
 
 
 
 
 
 
Date 
 
Comments_________________________________________________________________________________
__________________________________________________________________________________________
____________________________________ 
**Please file this diary in the patient’s research chart.  Do not mail to NRG Oncology. 
 
Patient 
Instructions: 
 
Place a () next to 
each dose taken on 
a daily basis.  If you 
were instructed to 
take a different 
daily dose, write 
that dose in the 
box.  If you missed 
a dose or a day, 
indicate that by 
placing an ‘M’ after 
the dose rather 
than a (). 
 
Be sure to bring 
your pill bottles and 
diaries with you for 
your return 
appointment. 
 
Return 
appointment date: 
 
____/____/_____