nrg oncology institution # rtog
shipment schedule

Initial shipment - 18 Bottles of study drug to be taken continuously 6 months at 300mg (3 tabs/100mg each) PO BID  
Biologics places follow-up call during month 5 for subsequent shipment of study drug Subsequent shipment 2 - 18 Bottles of study drug to be taken continuously 6 months at 300mg (3 tabs/100mg each) PO BID  
Biologics places follow-up call during month 11 for subsequent shipment of study drug Subsequent shipment 3 - 18 Bottles of study drug to be taken continuously 6 months at 300mg (3 tabs/100mg each) PO BID
Biologics places follow-up call during month 17 for subsequent shipment of study drug Subsequent shipment 4 - 18 Bottles of study drug to be taken continuously 6 months at 300mg (3 tabs/100mg each) PO BID  
For all drug shipments from Biologics, Inc.:
Study Drug will be shipped in original manufacturers packaging. Bottles are placed in a Ziploc bag with a patient specific label adhered to the outside of the bag.  
Each shipment includes a patient label on the Ziploc bags with the following information:
The Study Number (i.e. RTOG 1115);
IND caution statement and/or local regulatory statements; Drug identification (TAK-700)
Expiration Storage conditions Dosing instructions (Take as Directed per Protocol)
Subject ID number (e.g. 1115-YYY, where the study number and sequence number represents the unique patient identifier assigned by NRG Oncology at registration);
The patient's initials (i.e. first, middle, last)
A blank line for the site pharmacist to enter the patient's name; Administration instructions (i.e. "Take xx tablets every day for xx days");
Storage instructions (i.e. "Store at controlled room temperature, xx degrees"); Emergency contact instructions; Enclose a packing slip that includes the quantity of drug provided with a section to be completed once received by the site coordinator. This section includes confirmation of drug receipt, verification of package contents, and instruction to fax the completed packing slip to Biologics.  
Packages are tracked until confirmed delivered and delivery exceptions are managed with the highest level of urgency to ensure therapy start date adherence. Packing slips with the shipment tracking number included will be faxed to the designated site coordinator for all shipments.  
Please contact the drug distributor, as listed below, directly for shipment tracking information and anticipated delivery dates or if a shipment has not been received by the expected date.  
Unused supplies at the sites will be destroyed on site per local guidelines/standard operating procedures. Additional questions about supply and delivery should be directed to:
Clinical Trial Services Biologics, Inc.  
120 Weston Oaks Court Cary, NC 27513
(800) 693-4906 clinicaltrials@biologicstoday.com 7.14.2 Study Agent Accountability Drug accountability records must be maintained at all sites according to good clinical practices and NCI guidelines using the Investigational Agent Accountability Record (IAAR) form.  
7.15 Modality Reviews (2/4/14)
This study will undergo hormone therapy review for TAK-700. The Principal Investigator, M. Dror Michaelson, MD, PhD, will perform a Hormone Therapy Assurance Review of all patients who receive or are to receive TAK-700 in this trial. The goal of the review is to evaluate protocol compliance. The review process is contingent on timely submission of hormone treatment data as specified in Section 12.1. The scoring mechanism is: per protocol; unacceptable deviation; not evaluable. A report is sent to each institution once per year to notify the institution about compliance for each case reviewed in that year.
nrg oncology institution # rtog
7.16 adverse events (12jun2018)

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

All serious adverse events that meet expedited reporting criteria defined in the reporting table below will be reported via CTEP-AERS, the CTEP Adverse Event Reporting System, accessed via the CTEP web site, https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613.  
Submitting a report via CTEP-AERS serves as notification to NRG Oncology and satisfies NRG Oncology requirements for expedited adverse event reporting.  
CTEP-AERS provides a radiation therapy-only pathway for events experienced that involve radiation therapy only. These events must be reported via the CTEP-AERS radiation therapy-only pathway. In the rare event when Internet connectivity is disrupted, a 24-hour notification must be made to the NRG Oncology Office at 1-800-227-5463, ext. 4189, for instances when Internet fails. Once internet connectivity is restored, an AE report submitted by phone must be entered electronically into CTEPAERS.  
CTEP-AERS 24-Hour Notification requires that a CTEP-AERS 24-hour notification is electronically submitted within 24 hours of learning of the adverse event. Each CTEP-AERS
24-hour notification must be followed by a CTEP-AERS 5 Calendar Day Report. Serious adverse events that require 24 hour CTEP-AERS notification are defined in the expedited reporting table below.  
Supporting source document is not mandatory. However, if the CTEP-AERS report indicates in the *Additional Information* section that source documentation will be provided, then it is expected. If supporting source documentation accompanies an CTEP-AERS report, include the protocol number, patient ID number, and CTEP-AERS ticket number on each page, and fax supporting documentation **to the NRG Oncology dedicated SAE FAX, 215-717-0990.**
A serious adverse event that meets expedited reporting criteria outlined in the following table but is assessed by the CTEP-AERS System as "expedited reporting NOT required" must still be reported to fulfill NRG Oncology safety reporting obligations. Sites must bypass the "NOT
Required" assessment; the CTEP-AERS System allows submission of all reports regardless of the results of the assessment.
CTEP defines expedited AE reporting requirements for phase 3 trials as described in the table below.  
Important: All AEs reported via CTEP-AERS also must be reported on the AE section of the appropriate case report form (see Section 12.1).  
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the Investigational Agent/Intervention**1, 2**
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
ALL **SERIOUS** adverse events that meet the above criteria **MUST** be immediately reported to the NCI via CTEPAERS within the timeframes detailed in the table below.  
| Hospitalization               | Grade 1          | Timeframes       | Grade 3 Timeframes   | Grade 4 & 5   |
|-------------------------------|------------------|------------------|----------------------|---------------|
| Grade 2                       |                  |                  |                      |               |
| Timeframes                    | Timeframes       |                  |                      |               |
| Resulting in  Hospitalization | 10 Calendar Days |                  |                      |               |
| ≥ 24 hrs                      | 24-Hour 5        |                  |                      |               |
| Not resulting in              | Calendar Days    |                  |                      |               |
| Hospitalization               | Not required     | 10 Calendar Days |                      |               |
| ≥ 24 hrs                      |                  |                  |                      |               |  
NOTE:Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR
Expedited AE reporting timelines are defined as:
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24hour report.  
o "10 Calendar Days" - A complete expedited report on the AE must be submitted within 10 calendar days of learning of the AE.  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/
intervention and have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for:
All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization Grade 3 adverse events 2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote "1" above applies after this reporting period.  
Effective Date: May 5, 2011
nrg oncology institution # rtog
9.0 other therapy 9.1 permitted

All supportive therapy for optimal medical care will be given during the study period at the discretion of the attending physician(s) within the parameters of the protocol and documented on each site's source documents as concomitant medication.  
9.1.1 Anticonvulsants 9.1.2 Antiemetics 9.1.3 Anticoagulants 9.1.4 Antidiarrheals 9.1.5 Analgesics 9.1.6 Hematopoietic Growth Factors 9.1.7 Herbal products 9.1.8 Nutritional supplementation 9.2 Non-permitted Supportive Therapy Patients must be instructed not to take any medications, including over-the-counter products and vitamins, minerals and other dietary supplements, without first consulting with the investigator, as noted in Section 7.7 above.
nrg oncology institution # rtog
10.0 tissue/specimen submission note patients

component of the protocol. If the patient consents to participate in this component of the study, the site is required to submit the patient's specimens as specified below.  
Sites are not permitted to delete the tissue/specimen submission component from the protocol or from the sample consent.  
10.1 Tissue/Specimen Submission The NRG Oncology Biospecimen Bank at the University of California San Francisco acquires and maintains high quality specimens from NRG Oncology trials. Tissue from each block is preserved through careful block storage and processing. NRG Oncology encourages participants in protocol studies to consent to the banking of their tissue. The Biospecimen Bank provides tissue specimens to investigators for translational research studies. Translational research studies integrate the newest research findings into current protocols to investigate important biologic questions.  
10.2 Specimen Collection for Translational Research (Mandatory) (12/17/13)
For patients who have consented to participate in the tissue/blood component of the study (See sample consent).  
10.2.1 Specimen Submission See Section 10.5 for the address information for sending specimens.  
10.2.2 Specimen Collection Summary for Translational Research (mandatory for all patients)  
| Serum Specimens for Translational Research (mandatory for all patients)                                                                         |                                                                  |                                       |                |
|-------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------|---------------------------------------|----------------|
| Specimens taken                                                                                                                                 | Collected when:                                                  | Submitted as:                         | Shipped:       |
| from patient:                                                                                                                                   |                                                                  |                                       |                |
| SERUM for baseline and  follow up Testosterone,  processed as per local  laboratory requirements                                                | (1) Baseline/ pre-treatment:  Within 21 days prior to  treatment | Testing performed on                  | Not applicable |
| site at local laboratory                                                                                                                        |                                                                  |                                       |                |
| Note: Collect  testosterone in the a.m.  at same time of day as  collection of Fasting  Insulin/Fasting Glucose/ Fasting Lipids/ Hemoglobin A1C | (2) At 30 months (3) Follow Up: Every 12 months for 3  years 48  | RTOG 1115, Version Date June 12, 2018 |                |  
| SERUM for Testosterone (LC/MS/MS):  5 mL (no-additive redtop), processed as  detailed in Appendix V                                                                                                             | (1) During ADT:   (a) At 12 months  (b) At 24 months                                     | Frozen serum  samples containing  0.5 mL per aliquot in  1 mL cryovials (five to ten)   | Serum sent frozen on  dry ice via overnight  carrier to the NRG  Oncology Biospecimen Bank   |
|-------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|
| Note: Collect  testosterone in the a.m.  at same time of day as  collection of Fasting  Insulin/Fasting Glucose/ Fasting  Lipids/Hemoglobin A1C SERUM for Fasting  Insulin: 5 mL (no-additive redtop), processed as  detailed in Appendix V                                                                                                             | (1) Baseline/ pre-treatment: Within  21 days prior to  registration                      | Frozen serum  samples containing  0.5 mL per aliquot in  1 mL cryovials (five to ten)   | Serum sent frozen on  dry ice via overnight  carrier to the NRG  Oncology Biospecimen Bank   |
| (2) During ADT:   (a) At 12 months  (b) At 24 months                                                        |                                                                                          |                                                                                         |                                                                                              |
| Note: Collect in the a.m.  at same time of day as  testosterone                                             | (3) Follow Up: Every 12 months for 3  years                                              |                                                                                         |                                                                                              |
| SERUM for Fasting  Glucose/Fasting  Lipids/Hemoglobin A1C,  processed as per local  laboratory requirements | (1) Baseline/ pre-treatment: Within 21 days prior to  registration                       | Testing performed on                                                                    | Not applicable                                                                               |
| site at local laboratory                                                                                    |                                                                                          |                                                                                         |                                                                                              |
| 2) During ADT:   (a) At 12 months  (b) At 24 months                                                         |                                                                                          |                                                                                         |                                                                                              |
| Note: Collect in the a.m.  at same time of day as  testosterone                                             | (3) Follow Up: Every 12 months for 3  years                                              |                                                                                         |                                                                                              |
| 10.3                                                                                                        | Specimen Collection for Tissue Banking and Translational Research (Strongly Recommended) |                                                                                         |                                                                                              |  
10.3 Specimen Collection for Tissue Banking and Translational Research (Strongly Recommended)
nrg oncology institution # rtog
(12jun2018)

For patients who have consented to participate in the tissue/blood component of the study (See sample consent). **Note: Plasma and whole blood collection is mandatory for patients participating in**
quality of life [QOL].  
The following must be provided in order for the case to be evaluable for the NRG Oncology Biospecimen Bank:
10.3.1 One H&E stained slide (slide can be a duplicate cut stained H&E of the diagnostic slide (block); it does not have to be the diagnostic slide itself)
10.3.2 A corresponding paraffin-embedded tissue block of the tumor (the block must match the H&E being submitted) or 10-15 unstained sections cut onto positive charged slides from the tumor tissue block (must be from same block as H&E). Block or slides must be clearly labeled with the pathology identification number and block \# that corresponds to the Pathology Report.  
10.3.3 A Pathology Report documenting that the submitted block or slides contains tumor. The report must include the RTOG (NRG) protocol number and patient's case number. The patient's name and/or other identifying information should be removed from the report. The surgical pathology numbers and information must NOT be removed from the report.
The submitted material must be from malignant tumor, not necrotic or fibrotic tissue. If the submitted material is reviewed and is not tumor, the site may be assessed a protocol violation.  
10.3.4 A Specimen Transmittal Form clearly stating that tissue is being submitted for the NRG Oncology Biospecimen Bank; if for translational research, this should be stated on the form. The form must include the RTOG (NRG) protocol number and patient's case number.  
| 10.3.5 Specimen Collection Summary for Tissue Banking and Translational Research (strongly recommended)  Specimens for Tissue Banking and Translational Research (strongly recommended) *Note: Plasma and whole blood is mandatory for patients participating in QOL. Specimens taken  Collected when: Submitted as: Shipped: from patient: Representative H&E  stained slides of the  primary tumor Pre-treatment H&E stained slide Slide shipped ambient Pre-treatment A paraffin-embedded  tissue block of the  primary tumor taken  before initiation of  treatment or 10-15  unstained slides Pre-treatment Paraffin-embedded  tissue block or 15  unstained slides (must match the H&E  slide being submitted) Block or slides shipped  ambient PLASMA*:  5-10 mL of  anticoagulated whole  blood in EDTA tube #1  (purple/ lavender top)  and centrifuge (1) Pre-treatment Frozen plasma  samples containing  0.5 mL per aliquot in 1  mL cryovials (five to  ten) Plasma sent frozen on  dry ice via overnight  carrier to the NRG  Oncology Biospecimen  Bank (2) 1 year (12 months)  after therapy starts (3) 2.5 years (30  months) after therapy  starts [For inflammatory  cytokines and markers  including CRP, NFkappa B, TNF alpha, IL1, IL-1ra, sTNFR2, and  IL-6] WHOLE BLOOD* for  DNA: 5-10 mL of  anticoagulated whole  blood in EDTA tube #2  (purple/ lavender top)  and mix Pre-treatment Frozen whole blood  samples containing 1 mL in 1mL cryovials  (three to five) Whole blood sent  frozen on dry ice via  overnight carrier to the  NRG Oncology  Biospecimen Bank Note: If site missed this  collection time point  they may collect this  specimen at any other  time point instead but  must note this on the  Specimen Transmittal  Form. [For SNPs and CNVs in  TNFAIP1, IL6, IL6R,  CRP, IL1R1, IL1A, IL1B] PBMCs: 5-10ml of whole  blood in EDTA purple/lavender top tube  (tube #3). See Appendix  VI for processing  instructions. (1) Pre-treatment Frozen PBMC samples (one to two).  See Appendix VI for  study-specific  processing  instructions. PBMC sent frozen on  dry ice via overnight  courier to the NRG  Oncology Biospecimen  Bank(2) 1 year (12 months)  after therapy starts (3) 2.5 years (30  months) after therapy  starts [For NF Kappa B] 50  RTOG 1115, Version Date June 12, 2018   |
|---|  
10.3.6 See Appendix V for the specimen collection kit and detailed collection instructions. See Appendix VI for detailed PBMC collection, processing, and shipping information. Note: Kits can be requested from the NRG Oncology Biospecimen Bank at **NRGBB@ucsf.edu**. Please include in the e-mail if you are requesting the complete kit or the kit without the PBMC processing component. PBMC processing components will not be shipped to sites that are unable to follow the PBMC processing instruction. The following materials must be provided to the NRG Oncology Biospecimen Bank: A Specimen Transmittal Form documenting the date of collection of the biospecimen; the RTOG protocol number, the patient's case number, time point of study, and method of storage, for example, stored at -80 C, must be included.  
10.4 Storage Conditions (5/1/12)
Store frozen specimens at -80C (-70C to -90C) until ready to ship. Frozen specimens can be stored - 80C (-70C to -90C) for up to six months before shipping. If a -80C freezer is not available:
Samples can be stored short term in a -20 C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
OR:
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out MondayWednesday only; Canada: Monday-Tuesday).  
OR: Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
Please indicate on the Specimen Transmittal Form the storage conditions used and time stored.
nrg oncology institution # rtog
for pbmc specimens only

Store frozen specimens immediately at -80°C. Samples must then be kept at -80°C during storage and shipping (please ship out Monday-Wednesday only; Canada: Monday-Tuesday)
OR:
If a -80°C freezer is not available: Samples can be stored in plenty of dry ice for up to one week, replenishing daily (ship out Monday-Wednesday only; Canada: Monday-Tuesday).  
Please indicate on the Specimen Transmittal Form the storage conditions used and time stored. **See**
Appendix VI for detailed PBMC collection, processing, and shipping information.  
10.5 Submit materials for Tissue Banking and Translational Research as follows: (12Jun2018)
U. S. Postal Service Mailing Address: For Non-frozen Specimens Only NRG Oncology Biospecimen Bank University of California San Francisco - Box 1800 Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143 Courier Address (FedEx, UPS, etc.): For Trackable FFPE and ALL Frozen Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Questions: 415-476-7864/FAX 415-476-5271; NRGBB@ucsf.edu 10.6 Reimbursement (4/16/14)
Please note that with the start of the new NCI National Clinical Trials Network (NCTN) Program, NCI funds for reimbursement for protocol-specified biospecimen materials will be distributed per the requirements/methods specified by the new NCTN Program. This information will be made available with the other registration materials in the Oncology Patient Enrollment Network (OPEN) portal system. OPEN
will serve as the registration system for all patient enrollments onto NCI-sponsored NCTN trials, including this study, which will be transitioned into the new Program from the NCI-sponsored Cooperative Group Clinical Trials Program.  
10.7 Confidentiality/Storage
(See the Patient Tissue Consent Frequently Asked Questions, http://www.rtog.org/Researchers/BiospecimenResource/BiospecimenResourceFAQs.aspx for further details.)
10.7.1 Upon receipt, the specimen is labeled with the RTOG (NRG) protocol number and the patient's case number only. The NRG Oncology Biospecimen Bank database only includes the following information: the number of specimens received, the date the specimens were received, documentation of material sent to a qualified investigator, type of material sent, and the date the specimens were sent to the investigator. No clinical information is kept in the database.  
10.7.2 Specimens for tissue banking will be stored for an indefinite period of time. Specimens for the translational research component of this protocol will be retained until the study is terminated, unless the patient has consented to storage for future studies. If at any time the patient withdraws consent to store and use specimens, the material will be returned to the institution that submitted it.
nrg oncology institution # rtog
11.0 patient assessments (12/17/13)

11.1 Study Parameters See Appendix I for assessments and timeframes. See Sections 11.1.1 and 11.1.2 below for details and/or exceptions to Appendix I.  
11.1.1 Chemistry and liver panels (sodium, potassium, chloride, bicarbonate (carbon dioxide), BUN, creatinine, glucose, calcium, magnesium, phosphorus, albumin, AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin) will be checked monthly during ADT until three consecutive normal potassium values have been obtained, then the chemistry and liver panels will be spaced to every 3 months.  
11.1.2 Collect blood for testosterone in the morning at the same time of day as collection of blood for Fasting Insulin/Fasting Glucose/ Fasting Lipids/Hemoglobin A1C.
nrg oncology institution # rtog
11.2 promis-fatigue short form (12/17/13)

study, such as quality of life (QOL) assessment. Participation in QOL is optional, with a goal of enrolling 458 patients in the QOL study. There is additional case credit and financial reimbursement to the institutions for participating in the QOL studies to take into account the additional time, effort, and cost involved. In addition, patients participating in the QOL studies may not have started anti-androgen therapy (either LHRH therapy or oral anti-androgens) prior to completing the QOL forms and getting baseline blood collection. Thus, patients who have started LHRH therapy prior to enrollment will be excluded from participating in the QOL studies.  
If the patient consents to participate in the QOL component of the study, sites are required to administer the PROMIS, EPIC-26, and the EQ-5D assessments at baseline and as specified in Appendix I of the protocol. Sites are not permitted to delete the QOL component from the protocol or from the sample consent. **Blood collection is mandatory for patients participating in the QOL.**
The PROMIS Fatigue Scale (7 items) was developed by the Patient-Reported Outcome Measurement Information System (PROMIS), part of the NIH Roadmap Initiative, focused on developing a publicly available resource of standardized, accurate, and efficient patient-reported outcome (PRO) measures of symptoms, distress, and functioning. Two content domains of fatigue, experience and impact, were identified by a panel of experts. An item pool of 58 fatigue experience and 54 fatigue impact items were developed. The psychometric properties of these items were evaluated in a sample of 450 individuals from the general US population using classical test theory indices, monotonicity, and scalability. The expert panel selected the 10 best items in each domain. These 20 items were presented to a panel of clinical experts. Only one item was dropped because of redundancy. A preliminary fatigue short-form measure of 7 items was created using items selected for consistency in the response scale, broad coverage across the fatigue continuum (i.e., high to low), and good precision of measurement
(discrimination function).  
The following items are being measured due to the fact that sleep quality and exercise are documented confounders of fatigue:
Muscle weakness question (scale of 1-5, from none to very much) Overall Sleep Quality: Item from Pittsburgh Sleep Quality Index (Buysse 1989):
Sleep quality will be measured by 1 item (Q3) of the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire which measures sleep quality and disturbances over a 1-week or 1-month time period.  
| Very               | Fairly                                              | Fairly   | Very   |
|--------------------|-----------------------------------------------------|----------|--------|
| bad                | bad                                                 | good     | good   |
| 1.                 | During the past week, how would you rate your sleep |          |        |
| quality overall? 0 | 1                                                   | 2        | 3      |  
Participants' level of physical activity will be assessed using the three item Godin Leisure-Time Exercise Questionnaire (GLTEQ) [Godin 1986; Gionet 1989], which measures time spent per week in each of light, moderate, and vigorous activities. A score can be computed for each level of exercise. A total score is computed by summing the three levels weighted by their respective MET equivalents of 3, 5, and 9. The GLTEQ has good test-retest reliability and has shown convergent validity with both objective and other self-report measures of physical activity (Godin 1986; Gionet 1989). The following questions are about your average weekly exercise. When answering the questions only count exercise that you do during free time (ignore exercise associated with your occupation and housework). Considering a typical week (7 days), how many times, on average, do you perform mild, moderate, or strenuous exercise? And when you engage in exercise, how long do you exercise, on average?  
Times Per Week
(a)  
| average?                                                                                                                                                                             | Times                |              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|--------------|
| Per Week (a)                                                                                                                                                                         | Average Duration (b) |              |
| 1. Mild exercise - that is, minimal effort exercise that did not make you  perspire, such as easy walking, yoga, bowling, lawn bowling,                                              | ______               | ______ mins. |
| shuffleboard, or golf 2. Moderate exercise - that is, exercise that is not exhausting and which  made you perspire lightly, such as fast walking, tennis, easy bicycling,            | ______               | ______ mins. |
| easy swimming, or popular and folk dancing 3. Strenuous exercise - that is, exercise that made your heart beat  rapidly and made you sweat, such as running, aerobics classes, cross | ______               | ______ mins. |
| country skiing, vigorous swimming, or vigorous bicycling                                                                                                                             |                      |              |
nrg oncology institution # rtog
11.3 health related quality of

Note: Patients must be offered the opportunity to participate in the correlative components of the study, such as quality of life (QOL) assessment. Participation in QOL is optional, with a goal of enrolling 458 patients in the QOL study. There is additional case credit and financial reimbursement to the institutions for participating in the QOL studies to take into account the additional time, effort, and cost involved. In addition, patients participating in the QOL studies may not have started anti-androgen therapy (either LHRH therapy or oral anti-androgens) prior to completing the QOL forms and getting baseline blood collection. Thus, patients who have started LHRH therapy prior to enrollment will be excluded from participating in the QOL studies. If the patient consents to participate in the QOL component of the study, sites are required to administer the PROMIS, EPIC-26, and the EQ-5D assessments at baseline and as specified in Appendix I of the protocol. Sites are not permitted to delete the QOL component from the protocol or from the sample consent. **Blood collection is mandatory for patients participating in QOL.**
The following instruments will be used to assess health related quality of life (HRQOL), including quality adjusted survival: the Expanded Prostate Cancer Index (EPIC)-26, and the EuroQol (EQ-5D) instrument.  
These outcomes measurements will be administered to 458 patients (229 in each arm). Of note, these are essentially the same instruments (and similar time points) that are being studied in two related trials, RTOG 0815 and 0924, which are currently accruing patients. In RTOG 0815, patients with "lower" intermediate risk prostate cancer all receive high dose RT and are randomized to +/- short term hormones. In RTOG 0924, patients with intermediate to high risk prostate cancer are randomized to +/- whole pelvic RT and are stratified by short (6 months) or long term (32 months) ADT. Ultimately, use of essentially the same instruments and time points in all three studies (RTOG 0815, RTOG 0924, and RTOG 1115) will create a large database of relevant information related to QOL, QAS, and fatigue issues in prostate cancer patients that will facilitate a large combined analysis in the future. The outcomes instruments in this study are as follows:
11.3.1 Prostate Cancer-Specific Health-Related Quality of Life: EPIC-26 The Expanded Prostate Cancer Index Composite (EPIC) is a prostate cancer health-related quality of life
(HRQOL) patient self-administered instrument that measures a broad spectrum of urinary, bowel, sexual, and hormonal symptoms related to radiotherapy and hormonal therapy (van Andel 2003;Wei 2000). To minimize patient burden, the abbreviated, validated EPIC-26 will be used (Szymanski 2010).  
11.3.2 Quality-Adjusted Survival Analysis: EuroQol (EQ-5D)
The EQ-5D is a patient self-administrated questionnaire that takes approximately 5 minutes to complete
(Schulz 2002). The first part consists of 5 items covering 5 dimensions including: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Each dimension can be graded on 3 levels: 1-no problems, 2-moderate problems, and 3-extreme problems. Health states are defined by the combination of the leveled responses to the 5 dimensions, generating 243 (35) health states to which unconsciousness and death are added (Badia 1998).  
The 5-item index score is transformed into a utility score between 0, "Worst health state," and 1, "Best health state." The index score or the cost-utility equation can be used in the quality adjusted survival analysis depending on the health state(s) of interest (Wu 2002). For this study we plan to report the multidimensional utilities for comparative purposes. The EQ-5D has been used across numerous disease sites (Milne 2006; Wildi 2004) and has been used to assess quality adjusted survival of prostate cancer screening and treatment (Essink-Bok 1998; Sandblom 2004; Sennfalt 2004).
nrg oncology institution # rtog
11.4 criteria for discontinuation of

If radiation therapy begins more than 240 days after initiation of ADT.  
If protocol treatment is discontinued, follow up and data collection will continue as specified in the protocol.  
12.0 DATA COLLECTION (12/17/13)
This study will utilize Medidata Rave® for remote data capture (RDC) of all data. Access to the trial in Rave is granted through the iMedidata application (https://login.imedidata.com) to all persons with the appropriate roles in RSS. To access iMedidata/Rave see Section 5.0.  
Each person responsible for data entry must be on the NRG Oncology roster in order to receive access to Medidata Rave®.  
Upon initial site registration approval for the study in RSS (Regulatory Support System), all CRAs at participating sites will receive e-mail invitations from iMedidata (iMedidata-Notification@mdsol.com) to activate their account. Once an account is activated, eLearning modules will be available for Rave RDC instructions. Site users must complete all modules before access to data entry in Rave is granted. Further training opportunities will be communicated through the web site. Users that have not previously activated their iMedidata/Rave accounts will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com.  
12.1 Summary of Data Submission (12/17/13)
Adverse event data collection and reporting, which are required as part of every clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those who will enroll in future studies using similar agents. Adverse events are reported in a routine manner at scheduled times during the trial using Medidata Rave. Additionally, certain adverse events must be reported in an expedited manner for timely monitoring of patient safety and care. The following sections provide information about expedited reporting. For this trial the *Adverse Event* forms are used for routine AE reporting in Rave.  
| reporting. For this trial the Adverse Event forms are used for routine AE reporting in Rave.  Folder Form/Item Due                                                                                                                       |                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                |                         |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|
| Registration via the OPEN                                                                                                                                                                                                                |                                                                                                                                                                                                                   | Subject Enrollment Form (1)                                                                                                                                                                                                                                                                                                                    | At time of registration |
| System Enrollment When pushed into RAVE  there will be 5 forms  representing registration                                                                                                                                                |                                                                                                                                                                                                                   | Demography Form (2)                                                                                                                                                                                                                                                                                                                            |                         |
|                                                                                                                                                                                                                                         | Step Information Form (3)                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                |                         |
|                                                                                                                                                                                                                                         | Treatment Assignment Form (4)                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                |                         |
|                                                                                                                                                                                                                                         | Eligibility Checklist Form (5)                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                |                         |
| Concomitant Medications                                                                                                                                                                                                                  | Review at baseline and  then every 3 months  during treatment (24  months) for changes (in  frequency, dose,  additional drugs or  discontinuation of drugs)                                                       |                                                                                                                                                                                                                                                                                                                                                |                         |
| PSA Measurements                                                                                                                                                                                                                         | All required  measurements will be  collected in this folder— every 3 months during  treatment; then every 6  months for 3 years; then  annually--the follow up  form will prompt reporting  of these measurements |                                                                                                                                                                                                                                                                                                                                                |                         |
| Quality of Life (Optional for patients not  previously on LHRH or oral  anti-androgens. A total of 458 patients may participate in the  QOL studies; when QOL  accrual achieved this folder  will not be available for future  patients) |                                                                                                                                                                                                                   | EQ-5D (QF)                                                                                                                                                                                                                                                                                                                                     |                         |
|                                                                                                                                                                                                                                         | EPIC-26 (FA)                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                                |                         |
|                                                                                                                                                                                                                                         | PROMIS (HP)                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                |                         |
|                                                                                                                                                                                                                                         | PSQI/GLTEQ (QL)                                                                                                                                                                                                    | Collected at 5 time  points (only if answer to  quality of life participation  = yes at registration): 1) Prior to the start of  protocol hormone  treatment (baseline); 2) Prior to RT; 3) During the last week of  RT;  4) At one year (12  months) after the start of  protocol treatment;  5) At 2.5 years (30  months) after the start of |                         |
| 55                                                                                                                                                                                                                                       | RTOG 1115, Version Date June 12, 2018                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                |                         |  
| Folder                                                               | Form/Item                                                                                           | Due                                                                                                                                |                                                                                                                  |
|----------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------|
| protocol treatment                                                   |                                                                                                     |                                                                                                                                    |                                                                                                                  |
| Baseline Folder                                                      |                                                                                                    | Patient History Form (formerly  known as the A5; voluntary form  completed by the patient or with  help from site staff or family) |                                                                                                                  |
|                                                                     | Work Up Form                                                                                        |                                                                                                                                    |                                                                                                                  |
|                                                                     | Diagnostic Staging Form                                                                             |                                                                                                                                    |                                                                                                                  |
|                                                                     | Prior Treatment Form                                                                                |                                                                                                                                    |                                                                                                                  |
|                                                                     | Pathology Report Form (a copy of  this report will be scanned and  uploaded into RAVE)              |                                                                                                                                    |                                                                                                                  |
|                                                                     | Chemistry Panel Form                                                                                |                                                                                                                                    |                                                                                                                  |
|                                                                     | Liver Panel Form                                                                                    |                                                                                                                                    |                                                                                                                  |
|                                                                     | Fasting Lipid Panel Form                                                                            |                                                                                                                                    |                                                                                                                  |
|                                                                     | CBC w/Differential Form                                                                             |                                                                                                                                    |                                                                                                                  |
|                                                                     | Hemoglobin A1C Form                                                                                 |                                                                                                                                    |                                                                                                                  |
|                                                                     | Serum Testosterone Form                                                                             | Within 2 weeks after  registration                                                                                                 |                                                                                                                  |
| Month 1 visit                                                        |                                                                                                    | Chemistry Panel Form                                                                                                               | After 30 days of                                                                                                 |
|                                                                     | Liver Panel Form                                                                                    | hormonal treatment/ registration to the trial For relevant labs  necessary during  hormonal treatment +/- TAK700                   |                                                                                                                  |
| Month 2 visit                                                        |                                                                                                    | Chemistry Panel Form                                                                                                               | After 60 days of                                                                                                 |
|                                                                      |                                                                                                    | Liver Panel Form                                                                                                                   | hormonal treatment/ registration to the trial For relevant labs  necessary during  hormonal treatment +/- TAK700 |
| Follow-Up Folders                                                    |                                                                                                    | Follow up Form - if Patient  Contacted = "yes"                                                                                     |                                                                                                                  |
|                                                                     | Primary Cause of Death Form - if Patient's Vital Status = 'dead'                                    |                                                                                                                                    |                                                                                                                  |
|                                                                     | Disease Assessment Form - if  Documented clinical assessment =  'yes'                               |                                                                                                                                    |                                                                                                                  |
|                                                                     | New Primary Cancer Form - if New  Primary Cancer = 'yes'                                            |                                                                                                                                    |                                                                                                                  |
|                                                                     | Non-protocol Treatment Form - if patient started on non-protocol  cancer therapy = 'yes'            |                                                                                                                                    |                                                                                                                  |
|                                                                     | Complete Appropriate Lab Form - if labs performed = 'yes' (chemistry  and liver panel forms every 3 | Every 3 months from the  start of treatment/ registration to the trial during years 1 and 2 (to  capture hormone +/- TAK700 administration);                                                                                                                                    |                                                                                                                  |
| Month 3 Month 6 Month 9 Month 12 Month 15 Month 18 Month 21 Month 24 | 56                                                                                                  |                                                                                                                                    |                                                                                                                  |  
56  
| Folder                                                                                                                                                                | Form/Item                                                                                                                                                                                                  | Due                                                                                          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------|
| months and at 12 and 24 month  visits fasting lipid panel form and  hemoglobin A1C form will be  added)                                                               |                                                                                                                                                                                                            |                                                                                              |
|                                                                                                                                                                      | PSA Measurement Form - if PSA  assessed = 'yes'                                                                                                                                                            |                                                                                              |
|                                                                                                                                                                      | Adverse Event Form - if new or  continuing adverse events = 'yes'                                                                                                                                          |                                                                                              |
|                                                                                                                                                                      | Concomitant Medication Form if  Changes in Medication = 'yes'                                                                                                                                              |                                                                                              |
| Hormonal Treatment                                                                                                                                                    |                                                                                                                                                                                                           | Oral Antiandrogen Form                                                                       |
| with or without TAK-700                                                                                                                                               |                                                                                                                                                                                                           | LHRH Agonist Form                                                                            |
|                                                                                                                                                                      | Agent TAK700 Form                                                                                                                                                                                          | Every 3 months (from  the start of hormonal  therapy/registration to  the trial) for 2 years |
| Month 30 Visit  Marks the start of follow  up without treatment  Questions answered as  'yes' generate additional  forms—similar to 'filter  questions' being asked |                                                                                                                                                                                                           | Follow up Form - if Patient  Contacted = "yes"                                               |
|                                                                                                                                                                      | Primary cause of death form - if Patient's Vital Status = 'dead'                                                                                                                                           |                                                                                              |
|                                                                                                                                                                      | Disease Assessment Form - if Documented clinical assessment =  'yes'                                                                                                                                       |                                                                                              |
|                                                                                                                                                                      | New Primary Cancer Form - if New  Primary Cancer = 'yes'                                                                                                                                                   |                                                                                              |
|                                                                                                                                                                      | Non-protocol Treatment Form - if patient started on non-protocol  cancer therapy = 'yes'                                                                                                                   |                                                                                              |
|                                                                                                                                                                      | Complete Appropriate Lab Form - if labs performed = 'yes' (at 36, 48  and 60 month visits a chemistry  panel form-- for fasting glucose;  fasting lipids form; testosterone  form and hemoglobin A1C form) |                                                                                              |
|                                                                                                                                                                      | PSA Measurement Form - if PSA  assessed = 'yes'                                                                                                                                                            |                                                                                              |
|                                                                                                                                                                      | Adverse Event Form - if new or  continuing adverse events = 'yes'                                                                                                                                          | Every 6 months for 3  years                                                                  |
| Month 36 Month 42 Month 48 Month 54 Month 60 Month 72  Start of annual visits                                                                                        | Annual visits                                                                                                                                                                                              |                                                                                              |  
12.2 Summary of Dosimetry Digital Data Submission (4/16/14)
Note: Submit digital RT data to TRIAD; see Section 5.0 for account access and installation instructions.  
| instructions. Folder                                                                                                                                                                                                                                                                                                            | Form/Item                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Due                                                                                         |     |        |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------|-----|--------|
| N/A                                                                                                                                                                                                                                                                                                                             | Preliminary Dosimetry Information Digital Data Submission - Treatment  Plan submitted to IROC Houston via  TRIAD account exported from  treatment planning machine by Physics  staff Digital data submission includes the  following:  CT data, critical normal  structures, all GTV, CTV, and  PTV contours  Digital beam geometry for  initial, boost and composite beam sets  Doses for initial, boost and  composite sets of concurrently  treated beams  Digital DVH data for all  required critical normal structures, GTV, CTV, and  PTVs for total dose plan Digital Data Submission Information  (DDSI) Upload confirmation email  that digital data was submitted | Within 1 week of start of  RT Within 1 week of RT end  (external beam RT +/- brachytherapy) |     |        |
| RT Administration If  answered as 'yes' then RT Treatment form will be  added                                                                                                                                                                                                                                                  | Final Dosimetry Information RT Treatment form [for EBRT +/- brachytherapy]    Daily Treatment Record Please note: Daily Treatment Record  will be uploaded via Rave to IROC  Philadelphia                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | If applicable: 3-5 weeks  post implant—submit  listed items to TRIAD                        |     |        |
| NOTE:                                                                                                                                                                                                                                                                                                                           | All                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Simulation                                                                                  | and | Portal |
| Images will be kept by the Institution  and only submitted if requested. LDR Brachytherapy Post-implant evaluation CT scan Post-implant structure set Post-implant plan  Post-implant dose distribution RTOG Prostate Brachytherapy  Protocol Compliance Form-Available  on the RPC website,  http://irochouston.mdanderson.org | If applicable: 3-5 weeks  post implant—submit  listed items to TRIAD                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                             |     |        |
| 58                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                             |     |        |  
| Folder                                                                                                                                                                                                                                                                                                                                             | Form/Item   | Due   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|-------|
| HDR Brachytherapy Implant CT scan Implant structure set Implant plan  Implant dose distribution RTOG Prostate Brachytherapy Protocol  Compliance Form-Available on the  RPC website,  http://irochouston.mdanderson.org NOTE: Copies of simulation and port  films/images will be submitted to IROC  Philadelphia ONLY if specifically  requested. |             |       |
nrg oncology institution # rtog
13.0 statistical considerations 13.1 primary

13.2 Secondary Endpoints (12Jun2018)
13.2.1 Incidence of unexpected grade ≥ 3 adverse events and/or clinically significant decrement in patient reported quality of life among subjects treated with TAK-700 13.2.2 Rates and cumulative incidence of biochemical control (freedom from PSA failure), local/regional progression, and distant metastases Biochemical failure will be defined by the Phoenix definition (PSA ≥ 2 ng/ml over the nadir PSA, the presence of local, regional, or distant recurrence, or the initiation of salvage androgen deprivation therapy) [Roach 2006].  
Local failure will be defined as biopsy proven recurrence within the prostate gland. Regional or distant metastasis will be defined as imaging or biopsy demonstrated evidence for recurrence in the pelvic lymph nodes (regional) or systemically. Biopsy is not required to define regional or distant metastasis; however, in absence of a rising PSA biopsy is encouraged.  
13.2.3 General clinical treatment failure free interval (general clinical treatment failure [GCTF] is defined as: PSA
> 25 ng/ml, documented local disease progression, regional or distant metastasis, or initiation of androgen deprivation therapy). Deaths prior to any of these events are treated as censoring for this endpoint.  
13.2.4 Prostate cancer specific survival (failure: death due to prostate cancer) and other-cause survival (failure:
death due to other causes)
13.2.5 Change in fatigue from baseline to 1 year, as measured by PROMIS
13.2.6 Changes in patient reported quality of life as measured by Expanded Prostate Cancer Index Composite
(EPIC)
13.2.7 Assessment of quality adjusted survival using the EQ-5D **(Will not be completed and is not part of the**
revised quality of life substudy per Amendment 3.)
13.2.8 Nadir and average serum testosterone at 12 and 24 months during treatment 13.2.9 Lipid profiles at 12 and 24 months 13.2.10 Fasting plasma glucose, fasting plasma insulin, and hemoglobin A1c at 12 and 24 months 13.2.11 Changes in body mass index (BMI) during 24 months of treatment and during the first three years of follow-up 13.2.12 Incidence of adverse events ascertained via CTCAE version 4 13.2.13 Rate of recovery of testosterone to >230 ng/dL (accepted threshold for supplementation) after 12 and 24 months of follow-up 13.2.14 Median time to recovery of testosterone to >230 ng/dL during the first five years of follow-up  
13.2.15 Cumulative incidence of relevant clinical survivorship endpoints including new diagnosis of type 2 diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, or osteoporotic fracture
nrg oncology institution # rtog
13.3 sample size determination (12/17/13)

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

Patients will be stratified before randomization by the composite risk score (based on Gleason score, PSA,
and tumor stage) defined in Section 3.1.1, type of RT boost, and use of ADT prior to registration. Treatment arms will be balanced with respect to risk score via a permuted block procedure (Zelen 1974).
nrg oncology institution # rtog
13.5 analysis plan (12jun2018) 13.5.1

Primary analysis will include all eligible randomized patients with follow-up information, with patients included in the group to which they were assigned, regardless of whether they started treatment. Overall survival will be compared between treatment arms using the log-rank test (Mantel 1966). The KaplanMeier estimator will be used to estimate overall survival by treatment group (Kaplan 1958). Event times are measured from the date of study registration to the date of failure, or last follow up.  
13.5.2 Other Efficacy Endpoints Cumulative probability over time of PSA failure, local/regional recurrence, distant metastases and clinical failure will be estimated via the cumulative incidence function, which correctly accounts for competing risks (Korn 1992). Primary putative treatment effect comparisons for these endpoints will be based on cause-specific hazards using logrank tests (Friedlin 2005, Dignam 2008). To evaluate differences specifically in cumulative incidence of these events, we may also employ Gray's test (Gray 1988).  
If there are imbalances in covariates by treatment arm, then hazard regression models will be used to produce adjusted treatment effect estimates and tests. Appropriate models will be applied based on which metric is being examined (cause-specific hazard or cumulative incidence) [Prentice 1978, Fine 1999]. If model-specific assumptions are not met (for example, proportionality), then alternative approaches will be sought.  
13.5.3 Longitudinal Quality of Life (QOL) and Patient Reported Outcome (PRO) Endpoints The primary hypothesis of the QOL endpoints are that QOL and fatigue scores will not differ significantly between the control group and the experimental group receiving both a GnRH agonist and TAK-700.  
Quality of life will be measured with the prostate cancer-focused 32-question EPIC (The Expanded Prostate Cancer Index Composite) questionnaire and by the 5-question EQ-5D global quality of life assessment. Fatigue will be measured by the 7-question PROMIS (Patient-Reported Outcome Measurement Information System) fatigue short form questionnaire. The EPIC-26, PROMIS-fatigue short form, and EQ-5D will be collected at pretreatment (baseline), the week prior to starting RT, the last week of RT, and 1 year and 2.5 years after initiation of therapy.  
The primary objective in the fatigue analysis is to determine the QOL differences at 1 year. The response will be the change of measurement from baseline for each measurement. Using the sample size specified in section 13.3.3 of 130 evaluable patients, we will have 64% statistical power assuming a type I error = 0.05 (with appropriate type I error control for multiplicity using the Bonferroni correction) to detect a standard deviation effect size of 0.5 between the treatment arms for the 4 domains of the EPIC.  
For these investigations, a longitudinal analysis will be conducted that will focus on patterns of scores over time points (baseline, the week prior to starting RT, the last week of RT, and 1 year and 2.5 years after initiation of therapy) for the QOL and PRO instruments (EPIC, PROMIS and EQ-5D). Following descriptive statistics on assessments and tests of the primary endpoint of change from baseline to 1 year, repeated measures analysis of covariance (ANCOVA) will be used on scores for the assessment measures, where time points are considered the within-patient factor and treatment groups is considered the between-patient factor (Diggle 1994). While scales for the individual instrument questions are quantitative, they represent ordinal values on a bounded range rather than continuous quantities. Nonetheless, in aggregate these approximate continuous distributions, and appropriate transforms will be applied to improve consistency with model assumptions. The hierarchical analytic approach described below permits tests of omnibus hypotheses that control for multiple comparisons among time points and treatment groups. The analysis will be conducted as follows:
(1) The ANCOVA model will be used to carry out an omnibus test of the hypothesis that there is a common mean score across time point within the treatment groups: H0: it = i., where i =
treatment group 1 or 2, t = time point (baseline, the week prior to starting RT, the last week of RT, 1 year and 2.5 years) and it is the mean score in treatment group i at time t.  
(2) If the hypothesis in (1) is rejected, individual comparisons of the post-RT and subsequent scores will be conducted within treatment groups. Additional modeling and graphical methods to determine trends or patterns of change in scores over time points will be conducted.
(3) The ANCOVA model will be used to carry out an omnibus test of the hypothesis that there is a common mean score at each time point among the treatments: H0: it = .t, where again it is the mean score in treatment group i at time t.  
(4) Assuming the result of the hypothesis test in (3) is significant (H0 rejected), individual tests will be carried out to determine differences between treatment groups at specific time points. If there are no significant treatment differences identified in (3), an overall test of trend in scores can be aggregated over treatment groups. Additional modeling to characterize patterns of change over time will be conducted.
Information regarding potential confounds will be collected in a short form (QL) using limited questions to minimize patient burden. This information can be used to evaluate the potential impact of these confounding factors on fatigue. Patient responses to the following will be collected in the QL form: muscle weakness (one item), overall sleep quality as measured by one item from the Pittsburgh Sleep Quality Index (PSQI) [Buysse 1989] and level of physical activity as measured by the Godin Leisure-Time Exercise Questionnaire (GLTEQ) (Godin 1986; Gionet 1989). Anxiety/depression is also a potential confound with fatigue and patient responses to the anxiety/depression item in the EQ-5D can be used. At the same time points, the QL form (i.e., one item from the PSQI, 3 items from the GLTEQ, and one question regarding general muscle weakness) will be collected. In addition, in order to correlate fatigue with the cytokine changes, the PROMIS-fatigue short form (and the associated questions) will be collected at the following time points: at baseline, the week prior to starting RT, the last week of RT, 1 year and 2.5 years after therapy starts.  
These confounding factors may be incorporated into the above hypothesis tests via the ANCOVA model. The effects of these covariates on scores may also be evaluated separately in exploratory analyses. Also note that baseline scores will be analyzed in relation to subsequent impairment or decline for both treatment groups (hypothesis (1) above). The use of change scores (relative to baseline) for the main analysis also may be explored to account for the influence of per patient conditions prior to undergoing treatment.  
A certain degree of attrition from the study, due to both patient withdrawal and mortality, is expected. Characteristics of patients with missing data will be evaluated to identify imbalance in factors such as treatment, baseline scores, and other clinical and demographic features. In the absence of apparent systematic missing data patterns, data will be analyzed assuming that the observations are missing at random, employing appropriate methodology for this purpose (Little 1992). In the case of evidence for systematic patterns of missing data ('informative' missingness), alternative strategies for analyzing such data, depending on the pattern (e.g., intermittent versus complete dropout pattern) will be investigated
(Wu 1988, Little 1992). In this study, the addition of TAK-700 is hypothesized to improve overall survival (OS), without having a significant a negative impact on health related quality of life (HRQOL). As there are competing pros and cons of this treatment, it is useful to combine these factors into one equation to determine whether the potential benefits of this treatment (dose-escalated RT combined with short-term androgen deprivation),
in terms of OS, outweigh the potential risks, in terms of negatively impacting on global HRQOL, compared to RT and ADT alone. Such a quality adjusted survival analysis can be invaluable for assisting in the decisions of future patients as well as clinicians faced with these treatment options.  
Quality-adjusted survival can be defined by the weighted sum of different time episodes added up to a total quality-adjusted life-year [U= sum of quality (qi) of health states K times the duration (si) spent in each health state] (Glasziou 1990):  
  
We will use Glasziou's multiple health-state (Q-TwiST) models to use the repeated measures of EQ-5D. Because Glasziou's method incorporates longitudinal QOL data into an analysis of quality-adjusted survival, the health stated model must be constructed on the following assumptions:
nrg oncology institution # rtog
a1) qol is independent from

Assumption A1 can be checked by plotting QOL over time according to treatment, and the t-test can be used to compare the mean QOL scores of each treatment arm. Assumption A2 can be checked by comparing the QOL for patient groups in a given health state where the groups are defined by duration of previous health state experience using a regression model. Suitable checks for assumption A3 at minimum would be a simple plot. If data does not support these assumptions, we will use a method which uses the longitudinal QOL data directly. We will use the 5-item utility score in EQ-5D for the cost-utility analysis. We will use the Z-test to test the hypothesis that the cost-utility in the 2 treatment arms is the same at 1 year after initiation of treatment with a significance level of 0.05 and a 2-sided test. The remaining timepoints in which the EQ-5D is collected will also be assessed using similar longitudinal analysis techniques as described for the primary endpoint.  
13.5.4 Testosterone Kinetics Comparison of testosterone levels at designated time points will be conducted via t-tests on baselinecorrected and appropriately transformed measurement values. Nonparametric tests to compare medians may also be conducted.  
Time to recovery of testosterone to >230 ng/dL (accepted threshold for supplementation) after treatment will be estimated using time to event data methods. Specifically, the cumulative incidence of >230 ng/dL level achievement will be computed, accounting for competing events in the form of 1) interventions due to clinical failure that may suppress recovery and 2) deaths.  
13.5.5 Lipid Profiles, Glycemic Parameters, and Body Mass Index Comparison of baseline-adjusted values for fasting glucose, fasting insulin, lipid levels, and hemoglobin A1c will be carried out between treatment groups at designated time points. Additionally, longitudinal models as described above may be used to characterize changes in these parameters over time within and between treatment groups. Body mass index will similarly be contrasted at specific time points and modeled as a function of time from treatment initiation.  
13.5.6 Clinical Survivorship Endpoints Incidence rates (events/person years of exposure) and cumulative incidence over time of specific clinical events (type 2 diabetes, coronary artery disease, myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, osteoporotic fracture) will be estimated by treatment arm. Poisson regression or other appropriate methods will be used to investigate the role of other explanatory risk factors in conjunction with treatment exposure.  
13.5.7 Trial Monitoring Data Monitoring Committee Phase III trials are required by NCI Cooperative Group Program Guidelines to be reviewed by a Data and Safety Monitoring Committee (DSMC). This study will be reviewed by the NRG Oncology Data Monitoring Committee (DMC) on a semi-annual basis.
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0 (CDUS Abbreviated). Cumulative CDUS data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October 31.
nrg oncology institution # rtog
interim efficacy and futility analysis

There will be three interim analyses of the primary hypotheses, at equally spaced increments of 25%,
50%, and 75% of the requisite events for definitive analysis. A conservative upper superiority bound, based on a Lan-DeMets approximation to the O'Brien and Fleming boundary (DeMets 1994) provides test criteria of Z > 4.33 at the first interim analysis, Z > 2.96 at the second interim analysis, and Z > 2.36 at the third interim analysis. At the final analysis, a test statistic of Z > 2.01 will be required to reject H0.  
Interim futility analysis will be based on the rule of Freidlin, Korn, and Gray (Freidlin 2010). This rule provides the opportunity to terminate early for evidence that the experimental arm will not prove superior, but protects against aggressive early termination for treatment effect sizes smaller than planned.  
The following table summarizes the interim efficacy/futility monitoring schedule with respect to the primary endpoint:  
| Analysis   | Time                                                                                    | Prop.                                 |          |                   |         |        |       |
|------------|-----------------------------------------------------------------------------------------|---------------------------------------|----------|-------------------|---------|--------|-------|
| (month)    | Total  events                                                                           | Cumulative  Total Events  (Both Arms) | Efficacy | Futility boundary |         |        |       |
| boundary   |                                                                                         |                                       |          |                   |         |        |       |
| Z>         | P<                                                                                      | Z<                                    | P>       |                   |         |        |       |
| Interim 1  | 33                                                                                      | 0.25                                  | 60       | 4.33              | 0.00001 | -1.64* | 0.05* |
| Interim 2  | 54                                                                                      | 0.50                                  | 120      | 2.96              | 0.0015  | 0.06   | 0.476 |
| Interim 3  | 75                                                                                      | 0.75                                  | 180      | 2.36              | 0.009   | 0.31   | 0.378 |
| final      | 96                                                                                      | 1.00                                  | 239      | 2.01              | 0.022   | -      | -     |
|            | * Early look for detriment in experimental arm, left-tail p < 0.05 will prompt stopping |                                       |          |                   |         |        |       |  
In addition to the futility boundary for the primary endpoint, we will also implement a futility rule based on an intermediate endpoint for which evidence of efficacy is expected if there is eventual efficacy on the primary endpoint. Specifically, hormone deprivation agents that have shown favorable survival benefit typically demonstrate reductions in clinical outcomes such as time free from PSA progression or clinical failure (local, regional, or distant disease progression). Thus, early evidence of activity will be assessed by comparing the rate of general clinical treatment failure (GCTF, defined as time to any of the following events: PSA failure, local/regional recurrence, distant recurrence, hormone initiation) between treatment groups. The approach will involve testing for a difference in GCTF with adequately high power but a rather less stringent alpha level, following the strategy in multi-arm multi-stage clinical trials, where regimens are evaluated early based on intermediate endpoints to assure some level of activity before continuing to definitive endpoints (Sydes 2009).  
Assuming an annual GCTF hazard rate of 0.125, a one-sided alpha of 0.10 and statistical power of 0.90, detection of a 40% reduction in GCTF hazard for patients receiving TAK-700 requires observation of 100 events. Because the most frequent GCTF event is PSA failure, and this event is delayed during active treatment, analysis will take place only on the cohort of patients consisting of those entering through the first 1.5 years (450 patients). This cohort will be observed for an additional 1.75 years, or to approximately 3.25 years from commencement of accrual, when the requisite number events for the above comparison will have been observed. At this time, GCTF will be compared between treatments, and if the null hypothesis of no difference in GCTF rate cannot be rejected in favor of a lower GCTF rate for patients receiving TAK-700 (one-sided 0.10 test), then discontinuation of the trial for futility will be considered.  
Within the time frame described above, there will be at least 80% power for any treatment difference equal to or greater than a 33% relative reduction in GCTF events. Results of this analysis will be reported only to the RTOG Data Monitoring Committee and not in any scientific forum or publication.
nrg oncology institution # rtog
interim safety analysis plan

After the accrual and follow-up of 100 patients per treatment arm through completion of six months of therapy, adverse event (CTCAE) frequencies will be formally compared between treatment arms.  
Analysis will focus on specific organ system class and specific adverse event types, in addition to frequency of grade 3 and higher adverse events overall (i.e., any type). Adverse events of interest are shown below, accompanied by expected frequencies for the control arm of this trial, based on observed rates in previous RTOG prostate cancer trials using prolonged androgen suppression.  
| CTCAE (4.0) category                              | CTCAE specific   | Expected % grade 3 or   | greater on   |      |
|---------------------------------------------------|------------------|--------------------------|--------------|------|
| standard ADT                                      |                  |                          |              |      |
| Any                                               | Any              | 22.0                     |              |      |
| Renal and urinary disorders                       | Any              | 3.0                      |              |      |
| Gastrointestinal disorders                        | Any              | 3.6                      |              |      |
| Reproductive                                      | system           | and                      | Any          | 10.4 |
| breast disorders General disorders                | and              | Fatigue                  | 1.9          |      |
| administration site conditions Vascular disorders | Hypertension     | 0.0                      |              |      |
| Metabolism                                        | and              | nutrition                | Hypokalemia  | 0.0  |
| disorders                                         |                  |                          |              |      |  
Frequencies will be compared between treatment arms via Fisher's exact test. A one-sided criterion will be used to determine whether there is higher frequency of a given adverse event in the ADT+TAK700 arm. Including 200 patients with six months of follow-up (100 in each treatment group) and using a onesided 0.01 alpha level, a 15% absolute increase in event types with expected frequency < 4% under standard ADT (for example, GU, GI, fatigue) can be detected with statistical power of 85% or greater. For those events with expected frequency in the range of 10%-25% in the control arm, statistical power for detecting a 25% absolute increase exceeds 85%. If there are imbalances between treatments in patient demographic or radiation treatment parameters that may affect adverse event rates, then stratification or modeling methods will be used. In addition, scores for EPIC, EQ-5D, and PROMIS in this cohort will be compared between treatment groups, using the scheduled post-RT assessment. Differences will be assessed via t-tests on suitably transformed score sums, corrected for baseline values. A formal stopping criterion for these scores will not be specified.  
13.5.8 Trial Reporting The primary trial endpoint will be reported when specific criteria described in Section 13.5.7 are met. In particular, when either the number of events for definitive analysis is reached or an interim analysis indicates that early stopping is warranted, then the primary endpoint will be considered eligible for reporting.  
13.5.9 Revised Sample Size, Statistical Power, and Analysis Plan In June 2014, Millennium Pharmaceuticals informed NRG Oncology of their intention to no longer pursue development of the experimental agent (TAK-700) in prostate cancer. Subsequent discussion established that patients having entered the trial as of the accrual closure date would be provided assigned therapy to complete the regimen as described in 7.1.2. At trial accrual closure (September 30, 2014), 239 patients had been enrolled. Statistical power for the primary and secondary endpoints will thus be compromised regardless of the length of follow-up time, and thus in order to frame completion of primary analysis that is practical with respect to time to reporting, a plan for seeking to obtain suitably reliable information on the effects of the intervention on PSA failure was developed, with a goal of reporting on the trial after 5 additional years of follow-up from accrual closure.  
| yield the following (based on projections computed as in Rubinstein, Gail, and Santner (1981)). TAK-700 Treatment Effect HR 0.60 HR 0.55 HR 0.50 TAK-700 group failure rate 0.048 0.044 0.040 Number of events at 5 years 70 67 65 Power at 5 years* 0.68 0.78 0.86 * at one-sided alpha = 0.05   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
The PSA failure endpoint will be analyzed when 70 events have been observed, which is expected to occur relatively close to 5 years under any of these scenarios. If the relative reduction exceeds 40%, then power will be greater than 70% (at one-sided alpha = 0.05). For this number of events, if the relative reduction is 45%, power will reach 80%, and will reach 90% for a 50% reduction in PSA failure rate.  
For the original primary endpoint (OS) and other secondary time to event endpoints, statistical power at the expected time of this first report is as follows. At the assumed failure rates, power for the originally planned detection of a 33% reduction in hazard of death would be approximately 28% (at two-sided alpha
= 0.05). For distant metastasis, power to detect a 50% failure rate reduction would be approximately 32%. At the time when PSA failure results are reported based on reaching the above criterion, these other endpoints will be reported. Confidence bounds will be provided for hazard ratio estimates and estimated percent event-free at specific time points, in order to illustrate the degree of uncertainty in these endpoints for which statistical power is less than desired. It will be determined at that time whether further (longterm) follow-up would be sufficiently informative towards evaluating the effect of experimental treatment on these endpoints. At this time, it is not anticipated that a longer duration of follow-up would materially improve power or precision on estimates, given the low event rates for these endpoints.  
13.5.10 Revised Trial Monitoring Plan Given the curtailed sample size and plan to report results when PSA failure data is mature, the interim monitoring plan will be revised. The trial will be evaluated for futility after one-half of the target of 70 events is observed. Efficacy will also be evaluated using an extreme boundary (consistent with an approximate 67% reduction in hazard), with the rationale being that early stopping for efficacy given the suboptimal sample size should only be considered in extraordinary circumstances. The following table summarizes the interim efficacy/futility monitoring schedule with respect to the PSA
failure endpoint:  
Efficacy boundary Futility  
boundary  
Z> P< Z< P>  
Interim 42 0.5 35 3.70 0.0001 0.00 0.5  
final 84 1.00 70 1.65 0.05 - - 13.6 Gender and Minorities  
Men of all races and ethnic groups are eligible for this study. Clinically important race/ethnicity differences are not expected from the intervention effect.  
| Efficacy boundary   | Futility                     |                      |                                       |      |        |      |     |
|---------------------|------------------------------|----------------------|---------------------------------------|------|--------|------|-----|
| boundary            |                              |                      |                                       |      |        |      |     |
| Z>                  | P<                           | Z<                   | P>                                    |      |        |      |     |
| Interim             | 42                           | 0.5                  | 35                                    | 3.70 | 0.0001 | 0.00 | 0.5 |
| final               | 84                           | 1.00                 | 70                                    | 1.65 | 0.05   | -    | -   |
| Analysis            | Time (mo)  from trial  start | Prop.  Total  events | Cumulative  Total Events  (Both Arms) |      |        |      |     |  
| Gender                                    |         |       |       |
|-------------------------------------------|---------|-------|-------|
| Ethnic Category                           | Females | Males | Total |
| Hispanic or Latino                        | N/A     | 27    | 27    |
| Not Hispanic or Latino                    | N/A     | 873   | 873   |
| Ethnic Category: Total of all subjects    | N/A     | 900   | 900   |
| Gender                                    |         |       |       |
| Racial Category                           | Females | Males | Total |
| American Indian or Alaskan Native         | N/A     | 2     | 2     |
| Asian                                     | N/A     | 4     | 4     |
| Black or African American                 | N/A     | 135   | 135   |
| Native Hawaiian or other Pacific Islander | N/A     | 3     | 3     |
| White                                     | N/A     | 756   | 756   |
| Racial Category: Total of all subjects    | N/A     | 900   | 900   |
nrg oncology institution # rtog
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Sandblom G, Carlsson P, Sennfalt K, et al. A population-based study of pain and quality of life during the year before death in men with prostate cancer. Br J Cancer. 90:1163-1168, 2004. Saylor, P. J., N. L. Keating, et al. (2011). "Gonadotropin-releasing hormone agonists and the risks of type 2 diabetes and cardiovascular disease in men with prostate cancer." Drugs 71(3): 255-61. Saylor, P. J. and M. R. Smith (2009). "Metabolic complications of androgen deprivation therapy for prostate cancer." J Urol 181(5): 1998-2006; discussion 2007-8. Sennfalt K, Carlsson P, Sandblom G, et al. The estimated economic value of the welfare loss due to prostate cancer pain in a defined population. Acta Oncol. 43:290-296, 2004.  
Schubert, C., S. Hong, et al. (2007). "The association between fatigue and inflammatory marker levels in cancer patients: A quantitative review." Brain, Behavior, and Immunity 21(4): 413-427. Schulz MW, Chen J, Woo HH, et al. A comparison of techniques for eliciting patient preferences in patients with benign prostatic hyperplasia. *J Urol.* 168:155-159, 2002.  
Smith MR, Finkelstein JS, McGovern FJ, et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J Clin Endocrinol Metab 2002;87:599-603.  
Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. Urology 2008;71:318-22.  
Smith, MR, Lee, H, et al. (2006). Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 91(4): 1305-8.  
Smith MR. Changes in fat and lean body mass during androgen-deprivation therapy for prostate cancer. Urology 2004;63:742-5.  
Stone, P., Hardy, J., Huddart, R., A'Hern, R., & Richards, M. (2000). Fatigue in patients with prostate cancer receiving hormone therapy. European Journal of Cancer, 36(9), 1134-1141.  
Sugihara, A., O. Maeda, et al. (1998). "Expression of cytokines enhancing the osteoclast activity, and parathyroid hormone-related protein in prostatic cancers before and after endocrine therapy: an immunohistochemical study."
Oncol Rep 5(6): 1389-94.  
Stephens, R. J., Dearnaley, D. P., Cowan, R., Sydes, M., Naylor, S., Fallowfield, L., et al. (2007). The quality of life of men with locally advanced prostate cancer during neoadjuvant hormone therapy: data from the Medical Research Council RT01 trial (ISRCTN 47772397). BJU International, 99(2), 301-310. Storey DJ, McLaren DB, Atkinson MA, Butcher I, Liggatt S, O'Dea R, et al. Clinically relevant fatigue in recurrence-free prostate cancer survivors. Ann Oncol. 2011.  
Sydes MR, Parmar MK, James ND, Clarke NW, Dearnaley DP, Mason MD, Morgan RC, Sanders K, Royston P. Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE
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Symon Z, Griffith KA, McLaughlin PW, Sullivan M, Sandler HM. Dose escalation for localized prostate cancer: substantial benefit observed with 3D conformal therapy. Int J Radiat Oncol Biol Phys 2003;57:384-90.  
Szymanski KM, Wei JT, Dunn RL, Sanda MG. Development and validation of an abbreviated version of the Expanded Prostate Cancer Index Composite instrument for measuring health-related quality of life among prostate cancer survivors. Urology. 2010 Mar 27. [Epub ahead of print]).  
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Zelen M. The randomization and stratification of patients to clinical trials. J Chronic Dis. 1974;27:365-75.  
| APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (4/16/14)                                                                                                                                       |                                      |                                               |                                                  |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|-----------------------------------------------|--------------------------------------------------|
| Note: See Sections 3.0 and 4.0 (pre-study entry) for details and/or exceptions to this table.                                                                                                                |                                      |                                               |                                                  |
| Assessments (may be                                                                                                                                                                                          | w/in 180                             |                                               |                                                  |
| required for eligibility)                                                                                                                                                                                    | days prior to  registration          | w/in 14 days (2 weeks) prior to  registration |                                                  |
| Biopsy                                                                                                                                                                                                       | X                                    |                                               |                                                  |
| History/physical                                                                                                                                                                                             | X                                    |                                               |                                                  |
| Ht/Wt/PS                                                                                                                                                                                                     | X                                    |                                               |                                                  |
| PSA                                                                                                                                                                                                          | X                                    |                                               |                                                  |
| CBC/diff                                                                                                                                                                                                     | X                                    |                                               |                                                  |
| Chemistry & liver panels                                                                                                                                                                                     | X                                    |                                               |                                                  |
| Testosterone (standard  assay unless otherwise  noted)                                                                                                                                                       | w/in 90 days  prior to  registration | w/in 60 days  prior to  registration          | w/in 21 days (3 weeks)  prior to  registration X |
| Note: Collect blood for  testosterone in the a.m. at  same time of day as  collection of fasting  insulin/ fasting glucose/  fasting lipids/hemoglobin  A1C Fasting glucose/ fasting  lipids/ hemoglobin A1C | X                                    |                                               |                                                  |
| Note: Collect blood in the  a.m. at same time of day  as collection of  testosterone Fasting insulin (ship  specimen to UCSF BSR)                                                                            | X                                    |                                               |                                                  |
| Note: Collect blood in the  a.m. at same time of day  as collection of  testosterone MUGA scan or                                                                                                            | Prior to registration                |                                               |                                                  |
| echocardiogram Bone scan                                                                                                                                                                                     | X                                    |                                               |                                                  |
| CT or MRI                                                                                                                                                                                                    | X                                    | X (for brachy patients only)                  |                                                  |
| -Continued on next page-Transrectal ultrasound  and AUA                                                                                                                                                      |                                      |                                               |                                                  |  
| APPENDIX I, STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS continued Note: See Sections 3.0 and 4.0 (pre-study entry) for details and/or exceptions to this table.                                                                        |                                                                            |                                      |                                      |                                                |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------|--------------------------------------|--------------------------------------|------------------------------------------------|
| Assessments (may  be required for  eligibility)                                                                                                                                                                                             | w/in 14 days (2 weeks) prior to  registration                              |                                      |                                      |                                                |
| Review of                                                                                                                                                                                                                                   | At registration                                                            |                                      |                                      |                                                |
| medications                                                                                                                                                                                                                                 | w/in 180  days prior to  registration                                      | w/in 90 days  prior to  registration | w/in 60 days  prior to  registration | w/in 21 days (3 weeks)  prior to  registration |
| *Clinical                                                                                                                                                                                                                                   | X*                                                                         |                                      |                                      |                                                |
| survivorship †PROMIS-fatigue,  EPIC, EQ-5D,  PSQI/GLTEQ (if  patient consents)                                                                                                                                                              | Pre-treatment                                                              |                                      |                                      |                                                |
| Tissue for banking  (if patient consents)                                                                                                                                                                                                   | Pre-treatment                                                              |                                      |                                      |                                                |
| †Blood for  banking/QOL (if                                                                                                                                                                                                                 | Pre-treatment (see also Section 10.0 for specific collection requirements) |                                      |                                      |                                                |
| patient consents) *See Section 1.0 of protocol under Evaluation of Clinical and Chronic Disease Outcomes (1st  sentence). †Blood (Plasma & whole blood) collection is mandatory for patients participating in QOL. -Continued on next page- |                                                                            |                                      |                                      |                                                |  
| APPENDIX I, STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT (12/17/13) Note: See Sections 10.0 (specimen collection), and 11.1 (during treatment) for details and/or  exceptions to this table. Assessments During 24 months of ADT +/- TAK-700 30 months q 1  q 3  12 months 24 months month months   |                                                                     |                                                                     |    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|---------------------------------------------------------------------|----|
| History/physical                                                                                                                                                                                                                                                                                           | X                                                                   |                                                                     |    |
| Ht/Wt/PS                                                                                                                                                                                                                                                                                                   | X                                                                   |                                                                     |    |
| PSA                                                                                                                                                                                                                                                                                                        | X                                                                   | X                                                                   |    |
| Chemistry & liver panels                                                                                                                                                                                                                                                                                   | See                                                                 | See                                                                 |    |
| 11.1                                                                                                                                                                                                                                                                                                       | 11.1                                                                |                                                                     |    |
| Testosterone (standard  assay unless otherwise  noted)                                                                                                                                                                                                                                                     | X (by LC/MS/MS;  ship specimen to  NRG Oncology  Biospecimen  Bank) | X (by LC/MS/MS;  ship specimen to  NRG Oncology  Biospecimen  Bank) | X  |
| Note: Collect blood for  testosterone in the a.m. at  same time of day as  collection of fasting insulin/  fasting glucose/ fasting  lipids/hemoglobin A1C Fasting glucose/ fasting  lipids/hemoglobin A1C                                                                                                 | X                                                                   | X                                                                   |    |
| Note: Collect blood in the  a.m. at same time of day as  collection of testosterone Fasting insulin (ship  specimen to UCSF BSR)                                                                                                                                                                           | X                                                                   | X                                                                   |    |
| Note: Collect blood in the  a.m. at same time of day as  collection of testosterone Review of medications                                                                                                                                                                                                  | X                                                                   |                                                                     |    |
| AE evaluation                                                                                                                                                                                                                                                                                              | X                                                                   |                                                                     |    |
| *Clinical survivorship                                                                                                                                                                                                                                                                                     | X                                                                   |                                                                     |    |
| (1) In the week prior to RT start; (2) during the last week of RT;  (3) at 1 year (12 months) after therapy starts                                                                                                                                                                                         |                                                                     |                                                                     |    |
| †PROMIS-fatigue, EPIC,  EQ-5D, PSQI/GLTEQ (if  patient consents)                                                                                                                                                                                                                                           | At 1 year (12 months) after therapy starts                          |                                                                     |    |
| (see also Section 10.0 for specific collection requirements)                                                                                                                                                                                                                                               |                                                                     |                                                                     |    |
| †Blood for banking/QOL (if  patient consents) *See Section 1.0 of protocol under Evaluation of Clinical and Chronic Disease Outcomes (1st  sentence). †Blood (Plasma & whole blood) collection is mandatory for patients participating in QOL. -Continued on next page-                                    |                                                                     |                                                                     |    |  
| APPENDIX I, STUDY PARAMETER TABLE: FOLLOW UP ASSESSMENTS (12/17/13)                                                                                                                                            |                                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------|
| Note: See Sections 10.0 (specimen collection), and 11.1 (during treatment) for details and/or  exceptions to this table.                                                                                       |                                                       |
| Assessments                                                                                                                                                                                                    | Follow Up (beginning at 36 months)                    |
| q 6 months for 3 years and then annually                                                                                                                                                                       | q 12 months for 3 years                               |
| History/physical                                                                                                                                                                                               | X                                                     |
| Ht/Wt/PS                                                                                                                                                                                                       | X                                                     |
| PSA                                                                                                                                                                                                            | X                                                     |
| Testosterone  (standard assay  unless otherwise  noted)                                                                                                                                                        | X                                                     |
| Note: Collect blood  for testosterone in  the a.m. at same  time of day as  collection of fasting  insulin/ fasting  glucose/ fasting  lipids/hemoglobin  A1C Fasting glucose/  fasting lipids/ hemoglobin A1C | X                                                     |
| Note: Collect blood  in the a.m. at same  time of day as  collection of  testosterone Fasting insulin (ship  specimen to UCSF BSR)                                                                             | X                                                     |
| Note: Collect blood  in the a.m. at same  time of day as  collection of  testosterone Bone scan                                                                                                                | As clinically indicated, q 6 months after PSA relapse |
| AE evaluation                                                                                                                                                                                                  | X                                                     |
| -Continued on next page-                                                                                                                                                                                       |                                                       |  
| APPENDIX I, STUDY PARAMETER TABLE: FOLLOW UP ASSESSMENTS continued (12/17/13) Note: See Sections 10.0 (specimen collection), and 11.1 (during treatment) for details and/or  exceptions to this table.   |                                               |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------|
| Assessments                                                                                                                                                                                              | Follow Up (beginning at 36 months)            |
| q 6 months for 3 years and then annually                                                                                                                                                                 | q 12 months for 3 years                       |
| *Clinical                                                                                                                                                                                                | X                                             |
| survivorship †PROMISfatigue, EPIC,  EQ-5D,  PSQI/GLTEQ (if patient  consents)                                                                                                                                                                                                          | At 2.5 years (30 months) after therapy starts |
| †Blood for  banking/QOL (if patient  consents)                                                                                                                                                           | At 2.5 years (30 months) after therapy starts |
| (see also Section 10.0 for specific collection requirements)                                                                                                                                             |                                               |
| *See Section 1.0 of protocol under Evaluation of Clinical and Chronic Disease Outcomes (1st  sentence). †Blood (Plasma and whole blood) collection is mandatory for patients participating in QOL.       |                                               |
nrg oncology institution # rtog
appendix ii zubrod performance scale

0 **Fully active, able to carry on all predisease activities without restriction**  
1 Restricted in physically strenuous activity but ambulatory and able to carry work of a light or sedentary nature. For example, light housework, office work
5 Death  
| 2   | Ambulatory and capable of all self-care but unable to carry out any work  activities. Up and about more than 50% of waking hours   |
|-----|------------------------------------------------------------------------------------------------------------------------------------|  
| 3   | Capable of only limited self-care, confined to bed or chair 50% or more of  waking hours   |
|-----|--------------------------------------------------------------------------------------------|  
| 4   | Completely disabled. Cannot carry on self-care. Totally confined to bed   |
|-----|---------------------------------------------------------------------------|
appendix iii staging system prostate
primary tumor clinical (t) tx

T0 No evidence of primary tumor T1 Clinically inapparent tumor neither palpable nor visible by imaging T1a Tumor incidental histologic finding in 5% or less of tissue resected T1b Tumor incidental histologic finding in more than 5% of tissue resected T1c Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2 Tumor confined with prostate* T2a Tumor involves one-half of one lobe or less T2b Tumor involves more than one-half of one lobe but not both lobes T2c Tumor involves both lobes T3 Tumor extends through the prostate capsule**
T3a Extracapsular extension (unilateral or bilateral) T3b Tumor involves the seminal vesicle(s)  
T4 Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum, bladder, levator muscles and/or pelvic wall
*Note: Tumor found in one or both lobes by needle biopsy, but not palpable or reliably visible by imaging, is classified as T1c
**Note: Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2.
appendix iii staging system prostate
primary tumor pathologic (pt) pt2

pT2a Unilateral, one-half of one side or less pT2b Unilateral, involving more than one-half of side but not both sides pT2c Bilateral disease pT3 Extraprostatic extension pT3a Extraprostatic extension or microscopic invasion of bladder neck**
pT3b Seminal vesicle invasion pT4 Invasion of rectum, levator muscles, and/or pelvic wall *Note: There is no pathologic T1 classification
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).
appendix iii staging system prostate
regional lymph nodes (n)

Clinical NX Regional lymph nodes were not assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s)
Pathologic pNX Regional nodes not sampled pN0 No positive regional nodes pN1 Metastases in regional node(s)
appendix iii staging system prostate
distant metastasis (m)

M0 No distant metastasis M1 Distant metastasis M1a Nonregional lymph node(s) M1b Bone(s) M1c Other site(s) with or without bone disease
*Note: When more than one site of metastasis is present, the most advanced category is used; pM1c is most advanced.
appendix iii staging system prostate
histologic grade (g)

Gleason X Gleason score cannot be processed Gleason ≤6 Well-differentiated (slight anaplasia])
Gleason 7 Moderately differentiated (moderate anaplasia)
Gleason 8-10 Poorly differentiated/undifferentiated (marked anaplasia)  
Anatomic Stage/Prognostic Groups*  
Stage I T1a-c N0 M0 PSA <10 Gleason ≤6 T2a N0 M0 PSA <10 Gleason ≤6  
T1-2a N0 M0 PSA X Gleason X Stage IIA T1a-c N0 M0 PSA <20 Gleason 7  
T1a-c N0 M0 PSA ≥10<20 Gleason ≤6  
T2a N0 M0 PSA <20 Gleason ≤7  
T2b N0 M0 PSA <20 Gleason ≤7  
T2b N0 M0 PSA X Gleason X  
Stage IIB T2c N0 M0 Any PSA Any Gleason  
T1-2 N0 M0 PSA ≥20 Any Gleason  
T1-2 N0 M0 Any PSA Gleason ≥8  
Stage III T3a-b N0 M0 Any PSA Any Gleason Stage IV T4 N0 M0 Any PSA Any Gleason  
Any T N1 M0 Any PSA Any Gleason Any T Any N M1 Any PSA Any Gleason  
*Note: When either PSA or Gleason is not available, grouping should be determined by T stage and/or either PSA or Gleason as available.  
Source: Edge, SB, ed. *AJCC Cancer Staging Manual*. 7th ed. New York, NY: Springer; 2010.
appendix iii staging system prostate
appendix iv new york heart

| The following table presents the NYHA classification of cardiac disease.  Class Functional Capacity                                                                                                      | Objective  Assessment                                                                                                                                                                                                                                         |                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| I                                                                                                                                                                                                        | Patients with cardiac disease but without resulting limitations of  physical activity. Ordinary physical activity does not cause undue  fatigue, palpitation, dyspnea, or anginal pain.                                                                       | No objective evidence  of cardiovascular  disease.                 |
| II                                                                                                                                                                                                       | Patients with cardiac disease resulting in slight limitation of physical  activity. They are comfortable at rest. Ordinary physical activity  results in fatigue, palpitation, dyspnea, or anginal pain.                                                      | Objective evidence of  minimal cardiovascular  disease.            |
| III                                                                                                                                                                                                      | Patients with cardiac disease resulting in marked limitation of physical  activity. They are comfortable at rest. Less than ordinary activity  causes fatigue, palpitation, dyspnea, or anginal pain.                                                         | Objective evidence of  moderately severe  cardiovascular  disease. |
| IV                                                                                                                                                                                                       | Patients with cardiac disease resulting in inability to carry on any  physical activity without discomfort. Symptoms of heart failure or the  anginal syndrome may be present even at rest. If any physical  activity is undertaken, discomfort is increased. | Objective evidence of  severe cardiovascular  disease.             |
| Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart  and Great Vessels. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256. |                                                                                                                                                                                                                                                               |                                                                    |
appendix v (12jun2018) appendices for
appendix iv new york heart

Shipping Instructions:
U.S. Postal Service Mailing Address: For FFPE or Non-frozen Specimens Only NRG Oncology Biospecimen Bank University of California San Francisco Campus Box 1800 2340 Sutter Street, Room S341 San Francisco, CA 94143-1800 Courier Address (FedEx, UPS, etc.): For ALL Frozen or Trackable Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Include all NRG Oncology paperwork in pocket of biohazard bag.  
Check that the Specimen Transmittal Form has the consent boxes checked off. Check that all samples are labeled with the RTOG (NRG) study and case number, and include date of collection as well as collection time point (e.g., pretreatment, post-treatment).
appendix v (12jun2018) appendices for
ffpe specimens

o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap or gauze. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear the block shaking, it might break during shipping.  
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). **Do NOT** ship on Dry Ice.
appendix v (12jun2018) appendices for
frozen specimens

o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and clearly identified. If possible keep Serum, Plasma, Whole Bloods in separate bags.  
o Place specimens and absorbent shipping material in Styrofoam cooler filled with dry ice (at least 7 lbs).  
There should be plenty of dry ice under and above the specimens. If the volume of specimens is greater than the volume of dry ice then ship in a larger Styrofoam box, or two separate boxes. Any Styrofoam box can be used, as long as it is big enough.  
o Specimens received thawed due to insufficient dry ice or shipping delays will be discarded and the site will be notified.  
o Send frozen specimens on Dry Ice via overnight courier to the address above. Specimens should only be shipped Monday through Wednesday (Monday-Tuesday for Canada) to prevent thawing due to delivery delays. Saturday or holiday deliveries cannot be accepted. Samples can be stored frozen at -
80 C until ready to ship.  
For Questions regarding collection/shipping please contact the NRG Oncology Biospecimen Bank by e-mail: NRGBB@ucsf.edu or phone: 415-476-7864 or Fax: 415-476-5271.  
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (12/17/13)
Note: There is a separate appendix for PBMC preparation not included in this instruction (See Appendix VI). This Kit is for collection, processing, storage, and shipping of serum, plasma, or whole blood (as specified by the protocol):
appendix v (12jun2018) appendices for
kit contents

Red Top tubes for mandatory serum - shipped separate (A)
Three Purple Top EDTA tubes for plasma (B) One Purple Top EDTA tube for Whole Blood (C) Thirty-five (35) 1 ml cryovials Biohazard bags (2) and Absorbent shipping material (2) Styrofoam container (inner) and Cardboard shipping (outer) box UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers Specimen Transmittal Form and Kit Instructions
appendix v (12jun2018) appendices for
preparation and processing of serum

Label as many 1ml cryovials (5 to 10) as necessary for the serum collected. Label them with the RTOG (NRG) study and case number, collection date, time, and time point, and clearly mark cryovials "serum".  
Process:
1. Allow one red top tube to clot for 30 minutes at room temperature.  
2. Spin in a standard clinical centrifuge at ~2500 RPM for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the Specimen Transmittal Form.  
3. Aliquot **0.5 ml serum** into as many cryovials as are necessary for the serum collected (5 to 10)
labeled with RTOG (NRG) study and case numbers, collection date/time, protocol time-point collected (e.g. pretreatment, post-treatment), and clearly mark specimen as "serum".  
4. Place cryovials into biohazard bag and immediately freeze at -70 to -90 C, and store frozen until ready to ship. See below for storage conditions.  
5. Store serum at -70 to -90 C until ready to ship on dry ice. See below for storage conditions.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the STF.
appendix v (12jun2018) appendices for
(b) plasma (if requested) purple

Label as many 1ml cryovials (5 to 10) as necessary for the plasma collected. Label them with the RTOG (NRG) study and case number, collection date, time, and time point, and clearly mark cryovials "plasma".  
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA.  
2. Centrifuge specimen(s) within one hour of collection in a standard clinical centrifuge at ~2500 RPM
for 10 minutes at 4C (preferred). If sites are unable to process samples at 4C then spinning at room temperature is acceptable if done within 2 hours of draw but must be noted on the STF..  
3. If the interval between specimen collection and processing is anticipated to be more than one hour, keep specimen on ice until centrifuging is performed.  
4. Carefully pipette and aliquot **0.5 ml plasma** into as many cryovials as are necessary for the plasma collected (5 to 10) labeled with RTOG (NRG) study and case numbers, collection date/time, time point collected and clearly mark specimen as "plasma". Avoid pipetting up the buffy coat layer.  
5. Place cryovials into biohazard bag and immediately freeze at -70 to -90C.  
6. Store frozen plasma until ready to ship on dry ice.  
7. See below for storage conditions.  
PLEASE MAKE SURE THAT EVERY SPECIMEN IS LABELED and include collection time point on the Specimen Transmittal Form. (continued on next page)  
  
NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued)
appendix v (12jun2018) appendices for
(c) whole blood for dna

Label as many 1ml cryovials (3 to 5) as necessary for the whole blood collected. Label them with the RTOG (NRG) study and case number, collection date/time, and time point, and clearly mark cryovials "blood".  
Process:
1. After collection, invert tube(s) multiple times to ensure adequate mixing of EDTA. Blood can also be mixed for 5 minutes on a mixer at room temperature.  
2. Carefully pipette and aliquot **1.0 ml blood** into as many cryovials as are necessary for the blood collected (3 to 5) labeled with RTOG (NRG) study and case numbers, collection date/time, time point collected and clearly mark specimen as "blood".  
3. Place cryovials into biohazard bag and freeze immediately at -70 to -80 Celsius.  
4. Store blood samples frozen until ready to ship on dry ice.  
5. See below for storage conditions.
appendix v (12jun2018) appendices for
please make sure that every

Freeze Blood samples in a -80C Freezer or on Dry Ice or snap freeze in liquid nitrogen.  
Store at –80C (-70C to -90C) until ready to ship.  
If a -80C Freezer is not available, Samples can be stored short term in a -20C freezer (non-frost free preferred) for up to one week (please ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
Samples can be stored in plenty of dry ice for up to one week, replenishing daily (please ship out on Monday-Wednesday only; Canada: Monday-Tuesday only).  
OR:
Samples can be stored in liquid nitrogen vapor phase (ship out Monday-Wednesday only; Canada: Monday-Tuesday only).  
Please indicate on Specimen Transmittal Form the storage conditions used and time stored.
appendix v (12jun2018) appendices for
shipping/mailing

Ship specimens on Dry Ice overnight Monday-Wednesday **(Monday-Tuesday from Canada)** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Wrap frozen specimens of same type (i.e., all serum together, plasma together and whole bloods together) in absorbent shipping material and place each specimen type in a separate biohazard bag.  
(continued on next page)
appendix v (12jun2018)
rtog blood collection kit instructions

Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum).  
Add padding to avoid the dry ice from breaking the tubes.  
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
*Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and that* there is enough room for plenty of dry ice. *Add padding to avoid the dry ice from breaking the tubes.*
**For questions regarding collection, shipping or to order a Blood Collection Kit, please e-mail**
NRGBB@ucsf.eduor call (415) 476-7864.
appendix v (12jun2018)
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 For questions, call 415-476-7864 or e-mail: NRGBB@ucsf.edu
appendix vi (12jun2018) pbmc preparation
shipping address

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

10. Discard supernatant and wash again with 14ml of 1X PBS, RT.  
11. Centrifuge for 10 mins again at 194 RCF, RT, **brake on**.  
12. Discard the supernatant. Re-suspend the pellet by gently flicking the bottom of the tube. Transfer the pellet by re-suspending it using 0.5-1.0 mL of the freezering serum mix and add this back to the cryovial containing the remaining freezing serum mix (FBS + 10% DMSO).  
13. **Store immediately at -80°C** in 2 ml cryovial. Samples must then be kept at -80C during storage and shipping.
appendix vi pbmc preparation instructions
14. shipping instructions

Ship specimens on Dry Ice overnight Monday-Wednesday **(Monday-Tuesday from Canada)** to prevent thawing due to delivery delays. Saturday and holiday deliveries cannot be accepted.  
Include all NRG Oncology paperwork in a sealed plastic bag and tape to the outside top of the Styrofoam box.  
Wrap frozen specimens in absorbent shipping material, and place inside zip-lock biohazard bags. Place specimen bags into the Styrofoam cooler and fill with plenty of dry ice (7-10 lbs/3.5kg minimum). Add padding to avoid the dry ice from breaking the tubes.  
Place Styrofoam coolers into outer cardboard box, and attach shipping label and UN3373 and UN1895 stickers to outer cardboard box.  
For questions regarding *collection or processing of PBMC's* **please e-mail RTOG@emory.edu**
**or call (404) 778-5564.**  
*To order a kit* please contact the NRG Oncology Biospecimen Bank at NRGBB@ucsf.edu **or call (415) 476-7864**
appendix vi pbmc preparation instructions
shipping address

Courier Address (FedEx, UPS, etc.): For all Frozen Specimens NRG Oncology Biospecimen Bank University of California San Francisco 2340 Sutter Street, Room S341 San Francisco, CA 94115 Phone: +1 415-476-7864
(continued on next page)
appendix vi
pbmc collection kit contents

Lavender top tubes: Becton Dickson 366450 1X PBS: Store at room temperature or 4C until ready for use. Keep sterile.  
50 ml conical tube: Becton Dickson 352070 lymphocyte separation medium: Mediatech 25-072-CL - Store at room temperature.  
disposable blunt tip transfer pipettes: Fisher 13-711-7M
disposable thin tip transfer pipettes: Thermo Scientific Samco 232 15 ml conical tubes: Becton Dickson 352097 1.5 mls Freezing medium in 2ml Cryovials: (store frozen until ready to use)
(90% Fetal Bovine Serum, Hyclone SH30071.03; 10% DMSO, Sigma D2650)
appendix vii
pbmc collection kit contents

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