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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
rtog 1115
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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                                 |
rtog 1115
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| 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 |  
| 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        |
rtog 1115
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.
rtog 1115
nrg oncology 1-800-227-5463 ext. 4189

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  For patient enrollments: Submit study data directly  documents: 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. Data collection for this  study will be done  exclusively through  Medidata Rave. Please  see the data submission  section of the protocol for  further instructions.  Contact the CTSU Help Desk with  any OPEN-related questions at  ctsucontact@westat.com. 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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| Table of Contents                                                                                                                    |                                                                                                                                                                    |
|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| RTOG 1115                                                                                                                            |                                                                                                                                                                    |
| SCHEMA                                                                                                                               |                                                                                                                                                                    |
| ELIGIBILITY CHECKLIST                                                                                                                |                                                                                                                                                                    |
| INTRODUCTION                                                                                                                         |                                                                                                                                                                    |
| 1.0                                                                                                                                  |                                                                                                                                                                    |
| 1.1                                                                                                                                  | Background .                                                                                                                                                       |
| 1.2                                                                                                                                  | Adjuvant/concurrent/neoadjuvant ADT with Radiation Therapy ........................................................... 12                                          |
| 1.3                                                                                                                                  | Safety of Proposed Therapy .                                                                                                                                       |
| 1.4                                                                                                                                  | Prostate Cancer Survivorship .                                                                                                                                     |
| 1.5                                                                                                                                  | Fatigue                                                                                                                                                            |
| 2.0                                                                                                                                  | OBJECTIVES                                                                                                                                                         |
| 2.1                                                                                                                                  | Primary Objective                                                                                                                                                  |
| 2.2                                                                                                                                  | Secondary Objectives .                                                                                                                                             |
| 3.0                                                                                                                                  | PATIENT SELECTION                                                                                                                                                  |
| 3.1                                                                                                                                  | Conditions for Patient Eligibility                                                                                                                                 |
| 3.2                                                                                                                                  | Conditions for Patient Ineligibility)                                                                                                                              |
| 4.0                                                                                                                                  | PRETREATMENT EVALUATIONS/MANAGEMENT                                                                                                                                |
| 4.1                                                                                                                                  | Required Evaluations/Management                                                                                                                                    |
| 5.0                                                                                                                                  | REGISTRATION PROCEDURES                                                                                                                                            |
| Access Requirements for OPEN, Medidata Rave®, and TRIAD ..........................................................................20 |                                                                                                                                                                    |
| 5.1                                                                                                                                  | Pre-Registration Requirements for IMRT Treatment Approach                                                                                                          |
| Pre-Registration Requirements for 3DCRT Treatment Approach .......................................................21                 |                                                                                                                                                                    |
| 5.2                                                                                                                                  |                                                                                                                                                                    |
| 5.3                                                                                                                                  | Pre-Registration Requirements for Brachytherapy Treatment Approach ............................................21                                                  |
| Digital RT Data Submission to RTOG Using TRIAD                                                                                       |                                                                                                                                                                    |
| 5.4                                                                                                                                  |                                                                                                                                                                    |
| 5.5                                                                                                                                  | Regulatory Pre-Registration Reguirements)                                                                                                                          |
| 5.6                                                                                                                                  | OEN Registration .                                                                                                                                                 |
| 6.0                                                                                                                                  | RADIATION THERAPY                                                                                                                                                  |
| 6.1                                                                                                                                  | T Two Stage Radiation Plan                                                                                                                                         |
| 6.2                                                                                                                                  | Technical Factors                                                                                                                                                  |
| 6.3                                                                                                                                  | EBRT Localization, Simulation, and Immobilization                                                                                                                  |
| 6.4                                                                                                                                  | T Treatment Planning/Target Volumes                                                                                                                                |
| 6.5                                                                                                                                  | Critical Structures                                                                                                                                                |
| 6.6                                                                                                                                  | T Treatment Verification .                                                                                                                                         |
| 6.7                                                                                                                                  | Quality Assurance                                                                                                                                                  |
| 6.8                                                                                                                                  | Dose Specifications/Technical Considerations: LDR Brachytherapy Boost ..................................31                                                         |
| 6.9                                                                                                                                  | Dose Specifications/Technical Considerations: HDR Brachytherapy Boost ..................................32                                                         |
| R.T. Quality Assurance Reviews                                                                                                       |                                                                                                                                                                    |
| 6.10                                                                                                                                 |                                                                                                                                                                    |
| 6.11                                                                                                                                 | Radiation Therapy Adverse Events .                                                                                                                                 |
| 6.12                                                                                                                                 | Radiation Therapy Adverse Event Reporting                                                                                                                          |
| 7.0                                                                                                                                  | DRUG THERAPY .                                                                                                                                                     |
| 7.1                                                                                                                                  | T Treatment .                                                                                                                                                      |
| 7.2                                                                                                                                  | LHRH agonists (such as leuprolide, goserelin, buserelin, triptorelin) ....................................................36                                       |
| 7.3                                                                                                                                  | Eulexin (flutamide)                                                                                                                                                |
| 7.4                                                                                                                                  | Casodex (bicalutamide) .                                                                                                                                           |
| 7.5                                                                                                                                  | Study Drug (TAK-700) Administration (TAK-700, IND # 115368)                                                                                                        |
| 7.6                                                                                                                                  | TAK-700 Dose Modification and Supportive Care Guidelines .                                                                                                         |
| 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                                                                                                                               |
| 7.11                                                                                                                                 | Preparation, Reconstitution, and Dispensation ...........................................................................................42                        |
| 7.12                                                                                                                                 | Packaging and Labeling .......................................................................................................................................42   |
| 7.13                                                                                                                                 | Storage, Handling, and Accountability .........................................................................................................42                  |
| 4                                                                                                                                    |                                                                                                                                                                    |  
| 7.14                                                                                                                                                 | Supply .............................................................................................................................................................43   |
|------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 7.15                                                                                                                                                 | Modality Reviews .                                                                                                                                                       |
| 7.16                                                                                                                                                 | Adverse Events .......................................................................................................................................45                 |
| 7.17                                                                                                                                                 | CTEP-AERS Adverse Event Reporting Requirements .........................................................................46                                               |
| SURGERY                                                                                                                                              |                                                                                                                                                                          |
| 8.0                                                                                                                                                  |                                                                                                                                                                          |
| 9.0                                                                                                                                                  | OTHER THERAPY.                                                                                                                                                           |
| Permitted Supportive Therapy .....................................................................................................................48 |                                                                                                                                                                          |
| 9.1                                                                                                                                                  |                                                                                                                                                                          |
| 9.2                                                                                                                                                  | Non-permitted Supportive Therapy ........................................................................................................48                              |
| 10.0                                                                                                                                                 | TISSUE/SPECIMEN SUBMISSION                                                                                                                                               |
| 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) .                                                                                                                                         |                                                                                                                                                                          |
| 10.4                                                                                                                                                 | Storage Conditions                                                                                                                                                       |
| 10.5                                                                                                                                                 | Submit materials for Tissue Banking and Translational Research ........................................................51                                                |
| 10.6                                                                                                                                                 | Reimbursement                                                                                                                                                            |
| 10.7                                                                                                                                                 | Confidentiality/Storage                                                                                                                                                  |
| 1.0                                                                                                                                                  | PATIENT ASSESSMENTS                                                                                                                                                      |
| Study Parameters .                                                                                                                                   |                                                                                                                                                                          |
| 11.1                                                                                                                                                 | PROMIS-Fatigue Short Form                                                                                                                                                |
| 11.2                                                                                                                                                 |                                                                                                                                                                          |
| 1.3                                                                                                                                                  | Health Related Quality of Life (HRQOL) Assessments .                                                                                                                     |
| 1.4                                                                                                                                                  | Criteria for Discontinuation of Protocol Treatment                                                                                                                       |
| DATA COLLECTION                                                                                                                                      |                                                                                                                                                                          |
| 12.0                                                                                                                                                 |                                                                                                                                                                          |
| 12.1                                                                                                                                                 | Summary of Data Submission                                                                                                                                               |
| Summary of Dosimetry Digital Data Submission .                                                                                                       |                                                                                                                                                                          |
| 12.2                                                                                                                                                 |                                                                                                                                                                          |
| 13.0                                                                                                                                                 | STATISTICAL CONSIDERATIONS                                                                                                                                               |
| 13.1                                                                                                                                                 | Primary Endpoint                                                                                                                                                         |
| 13.2                                                                                                                                                 | Secondary Endpoints                                                                                                                                                      |
| 13.3                                                                                                                                                 | Sample Size Determination                                                                                                                                                |
| 13.4                                                                                                                                                 | Randomization                                                                                                                                                            |
| 13.5                                                                                                                                                 | Analysis Plan                                                                                                                                                            |
| 13.6                                                                                                                                                 | Gender and Minorities                                                                                                                                                    |
| REFERENCES                                                                                                                                           |                                                                                                                                                                          |
| APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (12/17/13) ................73                                                           |                                                                                                                                                                          |
| APPENDIX II                                                                                                                                          |                                                                                                                                                                          |
| APPENDIX III .                                                                                                                                       |                                                                                                                                                                          |
| APPENDIX IV                                                                                                                                          |                                                                                                                                                                          |
| APPENDIX V                                                                                                                                           |                                                                                                                                                                          |
| APPENDIX VI                                                                                                                                          |                                                                                                                                                                          |
| APPENDIX VII                                                                                                                                         |                                                                                                                                                                          |
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  
Risk Groups  
  
S
T R
A T I F
Y  
  
SCHEMA  
(12/17/13)  
| 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.   |                                                                                                                                                                                                                                                                                                                                                                                                     |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1. Gleason ≥ 9, PSA ≤ 150, any T-stage                                                                                                                                                                                                                                                                                                                            | R A N D O M I Z E                                                                                                                                                                                                                                                                                                                                                                                   |
| (1:1)                                                                                                                                                                                                                                                                                                                                                             | 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. |  
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
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eligibility checklist (4/16/14) (page 1

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?
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6. n/y was adt started

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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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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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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the following questions will be

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                                                                                                   |                                                                                                                                                                                                                        |
| 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)?                  |  
9. Race  
(Y/N) 21. Have you obtained the patient's consent for his or her blood to be kept for use in
nrg oncology institution # rtog
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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
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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).
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1.2 adjuvant/concurrent/neoadjuvant adt with radiation

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
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 highrisk 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 ontreatment 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 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 noncastrate 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 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 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.  
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.
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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
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3.0 patient selection note per

3.1 Conditions for Patient Eligibility (4/16/14)
For questions concerning eligibility, please contact the study data manager.  
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
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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.
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3.2 conditions for patient ineligibility

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.  
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
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4.0 pretreatment evaluations/management note this

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 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
nrg oncology institution # rtog
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.
nrg oncology institution # rtog
5.1 pre-registration requirements for imrt

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.
nrg oncology institution # rtog
5.2 pre-registration requirements for 3dcrt

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 3DCRT trials of this same disease site may enroll patients on this study without further credentialing.
nrg oncology institution # rtog
5.3 pre-registration requirements for brachytherapy

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.  
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".
nrg oncology institution # rtog
5.4 digital rt data submission

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.
nrg oncology institution # rtog
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.  
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.
nrg oncology institution # rtog
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.
nrg oncology institution # rtog
submit completed forms along with

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;  
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.
nrg oncology institution # rtog
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.  
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.
nrg oncology institution # rtog
6.0 radiation therapy (12/17/13) (2/4/14)

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                                                                                                                                                           | Dose,                            | Volume,     |                    |            |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------|-------------|--------------------|------------|
| PTV_4500                                                                                                                                                          | Gy                               | cc or  %PTV | Per                | Variation  |
| Protocol                                                                                                                                                          | Acceptable included in  range of |             |                    |            |
| Coverage                                                                                                                                                          | D I Rx(V%)                       | 98%         | equals 45          | 44 to 46   |
| I                                                                                                                                                                 |                                  |             |                    |            |
| Minimum                                                                                                                                                           | D Min(Vcc)                       | 0.03cc      | not less           | 40.5 to    |
| Dose                                                                                                                                                              | than 42.8                        | 42.8        |                    |            |
| Maximum                                                                                                                                                           | D I Max(Vcc)                     | 0.03cc      | not more           | 49.5 to 54 |
| Dose                                                                                                                                                              | than 49.5                        |             |                    |            |
| Homogeneity                                                                                                                                                       | D I PTV_4500                     | V(49.5Gy)   | not more  than 10% |            |
| DMax in                                                                                                                                                           | In                               |             |                    |            |
| Patient                                                                                                                                                           | PTV_4500                         |             |                    |            |
| Note: Dosimetric and/or volumetric parameters falling outside the Per Protocol and Variation Acceptable  specifications are classified as Deviation Unacceptable. |                                  |             |                    |            |  
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                                                                         | Dose,                           | Volume,     |                    |           |      |
| PTV_7920                                                                        | Gy                              | cc or  %PTV | Per                | Variation |      |
| Protocol                                                                        | Acceptable included in range of |             |                    |           |      |
| Coverage                                                                        | D II Rx(V%)                     | 98%         | equals             |           | 33.4 |
| 34.2                                                                            | to 35                           |             |                    |           |      |
| II                                                                              |                                 |             |                    |           |      |
| Minimum                                                                         | D Min(Vcc)                      | 0.03cc      | not less           |           | 30.8 |
| Dose                                                                            | than 32.5                       | to 32.5     |                    |           |      |
| II                                                                              |                                 |             |                    |           |      |
| Maximum                                                                         | D Max(Vcc)                      | 0.03cc      | not more           |           | 36.6 |
| Dose                                                                            | than 36.6                       | to 37.6     |                    |           |      |
| Homogeneity                                                                     | D II PTV_7920                   | V(36.6Gy)   | not more  than 10% |           |      |
| DMax in                                                                         | In                              |             |                    |           |      |
| Patient                                                                         | PTV_7920                        |             |                    |           |      |  
Per  
Protocol  
Variation  
Acceptable  
included in  
range of  
Coverage D  
II  
Rx(V%) 98% equals  
34.2  
33.4  
to 35  
Minimum Dose  
D  
II  
Min(Vcc) 0.03cc not less  
than 32.5  
30.8 to 32.5  
Maximum  
Dose  
D  
II  
Max(Vcc) 0.03cc not more  
than 36.6  
36.6  
to 37.6  
Homogeneity D  
II  
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.  
6.3 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 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.  
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.
nrg oncology institution # rtog
6.4 treatment planning/target volumes (4/16/14)

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.
nrg oncology institution # rtog
phase 1 pelvis including prostate

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.
nrg oncology institution # rtog
phase 2 prostate and proximal

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.  
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).  
| Table 3: Critical Structure Dose Constraints                                                                                                                                                               |                                         |                                                       |       |       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|-------------------------------------------------------|-------|-------|
| Normal organ                                                                                                                                                                                               | No more than 15%                        |                                                       |       |       |
| limit†                                                                                                                                                                                                     | 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.  No more than  25% volume  receives dose  that exceeds No more than  35% volume  receives dose  that exceeds |                                         |                                                       |       |       |  
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.
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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.
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6.7 quality assurance (4/16/14) 6.7.1

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.  
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, postenrollment, 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 Pd103**. 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 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, postenrollment, 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.  
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
≤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 34 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.
nrg oncology institution # rtog
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:
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.
nrg oncology institution # rtog
7.0 drug therapy 7.1 treatment

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 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- [(4fluorophenyl)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 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.
nrg oncology institution # rtog
7.5 study drug (tak-700) administration

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.
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7.6 tak-700 dose modification and

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 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.
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7.6.4 criteria for tak-700 dose

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 reescalation 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.
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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 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.
nrg oncology institution # rtog
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).  
| 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 40     |                            |                                                                                |
nrg oncology institution # rtog
abnormal liver enzymes

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 treatmentdocumented 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.  
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.
nrg oncology institution # rtog
7.9 blinding and unblinding this

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 protocolspecific 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.
nrg oncology institution # rtog
7.13 storage handling and accountability

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, limitedaccess, 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 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.