nrg oncology institution # rtog
h0 l1 <= l2vs. ha

where λ1 and λ2 are the hazard rate for Arm 1 and Arm 2, respectively. If the H0 is rejected, then we conclude that the OS rate of Arm 2 will be better than Arm 1 and stop accrual if applicable.  
| Time                                                                                                                                             | Time*      | Deaths in the   | Level for      |
|--------------------------------------------------------------------------------------------------------------------------------------------------|------------|-----------------|----------------|
| Two Arms                                                                                                                                         | Efficacy   |                 |                |
| (Z-value)                                                                                                                                        |            |                 |                |
| 0.25                                                                                                                                             | 4.7 years  | 55              | 0.0001 (4.049) |
| 0.50                                                                                                                                             | 6.8 years  | 109             | 0.0018 (2.863) |
| 0.75                                                                                                                                             | 8.9 years  | 163             | 0.015 (2.338)  |
| 1.00                                                                                                                                             | 11.1 years | 218             | 0.025 (2.024)  |
| *Time to the interim analysis from the first patient entry without considering ineligibility or lack-of-data rate and  under the null hypothesis |            |                 |                |  
For futility testing, the alternative hypotheses, HA (λ1 = λ 2 + 0.0072) will be tested at 0.005 level (the futility nominal significance level). If the computed p-value is less than 0.005 then we will consider stopping the trial in favor of the H0 and conclude that the overall survival rate of Arm 1 will be better than Arm 2. Otherwise, we will continue the trial. Based on the results of each interim analysis, the following action will be taken and the responsible statistician will recommend to the NRG Oncology Data Monitoring Committee (DMC) that the randomization be discontinued, if applicable, and the study be considered for early publication. Before making such a recommendation, the accrual rate, treatment compliance, safety of the treatments, and the importance of the study are taken into consideration along with the p-value. The DMC will then make a recommendation about the trial to the appropriate NRG Oncology Leadership as needed.  
13.4.10 Interim Report to Monitor the Study Progress Interim reports with descriptive statistics will be prepared twice per year until the initial paper reporting the treatment results has been submitted. In general, the interim reports will contain information about the patient accrual rate with a projected completion date for the accrual phase, compliance rate of treatment delivery with the distributions of important prognostic baseline variables, and the frequencies and severity of the adverse event by treatment arm. The interim reports will not contain the results of the treatment comparisons with respect to the primary endpoint and secondary endpoints.  
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. Cumulative CDUS
data will be submitted quarterly by electronic means. Reports are due January 31, April 30, July 31, and October 31.  
13.4.11 Reporting the Initial Treatment Analysis The analysis reporting the treatment results will be carried out after the criteria for early stopping/reporting are met. Five interim analyses and one final analysis will be performed for efficacy and futility of the addition of ADT and will be carried out as described in Section 13.4.9. It will include tabulation of all cases entered and those excluded from the analyses; the distribution of the important prognostic baseline variables; safety treatments; treatment compliance; and observed results with respect to the primary and secondary endpoints will be shown. All eligible patients randomized will be included in the comparison and will be grouped by assigned treatment in the analysis (intent-to-treat analysis). In addition, exploratory analyses of treatment comparisons of the primary and secondary survival endpoints will be tested using the Cox or Fine and Gray's proportional hazard model that includes treatment arms, the stratification factors (the number of risk factors and RT modality), age, and race (as appropriate).  
13.5 Gender and Minorities In conformance with the National Institute of Health (NIH) Revitalization Act of 1993 with regard to inclusion of women and minorities in clinical research, participation rates of men will be examined in the interim analyses. Based on the accrual statistics from RTOG 94-08, we project that 81% of the men in the study will be White, 15% will be Black or African American, 3% will be Hispanic, 0.5% will be Asian, 0.3%
will be Pacific Islander and 0.2% will be American Indian or Alaskan Native. The following table lists the projected accrual by race/ethnicity.
nrg oncology institution # rtog
projected distribution of gender and

| Gender          |         |       |       |
|-----------------|---------|-------|-------|
| Ethnic Category | Females | Males | Total |  
| Gender                                    |         |       |       |
|-------------------------------------------|---------|-------|-------|
| Ethnic Category                           | Females | Males | Total |
| Hispanic or Latino                        | N/A     | 46    | 46    |
| Not Hispanic or Latino                    | N/A     | 1474  | 1474  |
| Ethnic Category: Total of all subjects    | N/A     | 1520  | 1520  |
| Gender                                    |         |       |       |
| Racial Category                           | Females | Males | Total |
| American Indian or Alaskan Native         | N/A     | 49    | 49    |
| Asian                                     | N/A     | 7     | 7     |
| Black or African American                 | N/A     | 228   | 228   |
| Native Hawaiian or other Pacific Islander | N/A     | 5     | 5     |
| White                                     | N/A     | 1231  | 1231  |
| Racial Category: Total of all subjects    | N/A     | 1520  | 1520  |  
13.5.1 In the setting of prostate cancer, African American ethnicity has been associated with both increased incidence and inferior clinical outcomes. The etiology of this phenomenon remains unclear. As such, no specific differences in outcome are hypothesized based on race/ethnicity in this study. Data will be collected and available for retrospective outcomes analysis at the time of study conclusion.
nrg oncology institution # rtog
references

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| STUDY PARAMETER TABLE: PRE-TREATMENT ASSESSMENTS (may be required for eligibility) < 6 months prior to registration < 60 days prior to registration                                         |                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|
| Elig-related tissue collection                                                                                                                                                              | x                                                                 |
| History/physical                                                                                                                                                                            | x                                                                 |
| CT or MRI abd/pelvis & bone scan                                                                                                                                                            | x                                                                 |
| Transrectal ultrasound                                                                                                                                                                      | For brachy patients only                                          |
| Performance status                                                                                                                                                                          | x                                                                 |
| AUA                                                                                                                                                                                         | For brachy patients only (AUA) symptom index  composite score ≤15 |
| PSA                                                                                                                                                                                         | x                                                                 |
| CBC w/ diff & ANC                                                                                                                                                                           | For brachy patients only                                          |
| AST, ALT, alk phosphatase                                                                                                                                                                   | Pre-treatment                                                     |
| Serum testosterone                                                                                                                                                                          | x                                                                 |
| Statin                                                                                                                                                                                      | x                                                                 |
| QOL Assess. (if patient consents):  EPIC, PROMIS, EQ-5D,  PSQI/ GLTEQ                                                                                                                       | Pretreatment                                                      |
| Tissue for banking (if patient  consents) Blood for banking (if patient  consents)* *Blood collection is mandatory for patients who have provided consent for the QOL portion of the study. |                                                                   |
nrg oncology institution # rtog
appendix i (4/21/15)

| APPENDIX I (continued)                                                                                                                  |                 |
|-----------------------------------------------------------------------------------------------------------------------------------------|-----------------|
| STUDY PARAMETER TABLE: ASSESSMENTS DURING TREATMENT Weekly during  Weeks 1 and 5  Week 3 of RT;  RT of RT last week of  RT Monthly (Arm | 6-8 weeks       |
| 2 only)                                                                                                                                 | post RT         |
| Performance                                                                                                                             | x               |
| status PSA                                                                                                                              | x               |
| CBC w/ diff &                                                                                                                           | x               |
| ANC AST, ALT, alk                                                                                                                       | See 11.1.5      |
| phosphatase Serum                                                                                                                       | See 11.1.5      |
| testosterone Statin                                                                                                                     | x               |
| QOL Assess.  (if patient  consents):  EPIC, PROMIS,  EQ-5D, PSQI/  GLTEQ                                                                | Last week of RT |
| Blood for  banking (if  patient  consents)*                                                                                             | Last week of RT |
| AE evaluation                                                                                                                           | x               |
| *Blood collection is mandatory for patients who have provided consent for the QOL portion of the study.                                 |                 |  
| APPENDIX I (continued)                                                                                                                                                          |            |    |    |    |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------|----|----|----|
| STUDY PARAMETER TABLE: FOLLOW UP ASSESSMENTS ARM 1 3, 6, 9, and 12  months post RT ARM 2 6, 9, and 12  months post  RT 6 mos, 1 yr, 5  Every 6  yrs post RT months for 4  years | Annually   |    |    |    |
| Performance                                                                                                                                                                     | x          | x  | x  | x  |
| status Serum                                                                                                                                                                    | See 11.1.5 |    |    |    |
| testosterone Statin                                                                                                                                                             | x          |    |    |    |
| Tumor response  eval: physical,  DRE, PSA                                                                                                                                       | x          | x  | x  | x  |
| QOL Assess. (if  patient  consents): EPIC,  PROMIS,  EQ-5D, PSQI/  GLTEQ                                                                                                        | x          |    |    |    |
| AE evaluation                                                                                                                                                                   | x          | x  | x  | x  |
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 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited self-care, confined to bed or chair 50% or more of waking hours 4 Completely disabled. Cannot carry on self-care. Totally confined to bed 5 Death
appendix iii ajcc staging system
primary tumor clinical (t) tx

T0 No evidence of primary tumor T1 Clinically inapparent tumor neither palpable or 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 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: bladder neck, external sphincter, rectum, 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 ajcc staging system
regional lymph nodes (n)

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s)
(continued on next page)
appendix iii (continued) ajcc staging
primary tumor pathologic (pt)

pT2* Organ confined pT2a Unilateral, involving one-half of one lobe or less pT2b Unilateral, involving more than one-half of one lobe but not both lobes pT2c Bilateral disease pT3 Extraprostatic extension pT3a Extraprostatic extension**
pT3b Seminal vesicle invasion pT4 Invasion of bladder, rectum *Note: There is no pathologic T1 classification
**Note: Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).
appendix iii (continued) ajcc staging
distant metastasis (m)

MX Presence of distant metastasis cannot be assessed (not evaluated by any modality) 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.  
Histopathologic Grade (G) GX Grade cannot be assessed G1 Well-differentiated (slight anaplasia [Gleason 2-4])
G2 Moderately differentiated (moderate anaplasia [Gleason 5-6]) G3-4 Poorly undifferentiated or undifferentiated (marked anaplasia [Gleason 7-10])
(continued on next page)
APPENDIX III (continued)
AJCC STAGING SYSTEM
PROSTATE, 6th **Edition**  
Stage Grouping  
Stage I T1a N0 M0 G1  
Stage II T1a N0 M0 G2, G3-4  
T1b N0 M0 Any G T1c N0 M0 Any G T1 N0 M0 Any G  
T2 N0 M0 Any G  
Stage III T3 N0 M0 Any G Stage IV T4 N0 M0 Any G  
Any T N1 M0 Any G  
Any T Any N M1 Any G  
APPENDIX IV (4/21/15)
appendix for nrg oncology biospecimen
shipping instructions

US 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 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 (STF) has the consent boxes checked off. Check that all samples are labeled with the NRG Oncology study and case number, and include date of collection as well as collection time point (e.g., pretreatment, post-treatment).  
**FFPE Specimens:**
o Slides should be shipped in a plastic slide holder/slide box. Place a small wad of padding in top of the container. If you can hear the slides shaking it is likely that they will break during shipping.  
o FFPE Blocks can be wrapped with paper towel, or placed in a cardboard box with padding. Do not wrap blocks with bubble wrap. Place padding in top of container so that if you shake the container the blocks are not shaking. If you can hear the slides shaking it is likely that they will break during shipping.  
o Slides, Blocks, or Plugs can be shipped ambient or with a cold pack either by United States Postal Service (USPS) to the USPS address (94143) or by Courier to the Street Address (94115). **Do NOT** ship on Dry Ice.  
**Frozen Specimens:**
o Multiple cases may be shipped in the same cooler, but make sure each one is in a separate bag and clearly identified.  
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 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.**
(continued on next page)
appendix iv
shipping instructions

NRG ONCOLOGY BLOOD COLLECTION KIT INSTRUCTIONS (continued)
This Kit is for collection, processing, storage, and shipping of plasma or whole blood *(as specified by the* protocol):
appendix iv
kit contents

One Purple Top EDTA tube for plasma pre-tx (A)
One Purple Top EDTA tube for Whole Blood (B)
Twenty-one (21) 1 ml cryovials Biohazard bags (3) and Absorbent shipping material (3)
Styrofoam container (inner) and Cardboard shipping (outer) box UN1845 DRY Ice Sticker and UN3373 Biological Substance Category B Stickers Specimen Transmittal Form (STF) and Kit Instructions
appendix iv
preparation and processing of plasma

Label as many 1ml cryovials (5 to 8) as necessary for the plasma collected. Label them with the NRG
Oncology 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 8) labeled with NRG Oncology 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 STF.
appendix iv
(c) whole blood for dna

Label as many 1ml cryovials (up to 5) as necessary for the whole blood collected..Label them with the NRG Oncology 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 (up to 5) labeled with NRG Oncology 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 iv
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 iv
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. 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.edu or call (415)476-7864.
appendix iv
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