Phase II Randomized Trial of Immunotherapy Versus Immunotherapy and Radiation Therapy for Platinum Ineligible/Refractory Metastatic Urothelial Cancer (IMMORTAL)
Phase: PHASE2
Conditions: Metastatic Urothelial Carcinoma, Platinum-Resistant Urothelial Carcinoma, Stage IV Bladder Cancer AJCC v8
Sponsor: National Cancer Institute (NCI)



2 
 
This section has been revised in its entirety to align with current CTEP boilerplate language. 
Section 4.2.2 Protocol specific requirements for A032002 site registration 
This section has been revised in its entirety to align with current CTEP boilerplate language. 
 
Section 4.4 Patient Registration Procedures 
This section has been revised in its entirety to align with current CTEP boilerplate language. 
 
Section 6.1.2 (Medidata Rave) 
This section has been revised in its entirety to align with current CTEP boilerplate language. 
 
Section 6.1.4 (Rave-CTEP-AERS integration) 
This section has been completely removed as this study will no longer be using the Rave-CTEP-
AERS system for reporting serious adverse events. Subsequent sections have been renumbered 
accordingly.  
 
Section 6.3.1 TRIAD Access Requirements 
The second bullet has been revised its entirety to align with current CTEP boilerplate language. 
 
Section 8.2.1 General AE Management and Dose Modification Guidelines for Pembrolizumab 
(MK-3475) 
In the “Table for Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
and Infusion Reactions Associated with Pembrolizumab”, item #3 under ‘General Instructions’ has 
been revised to the following: “Generally, when corticosteroids (prednisone) are used, investigators 
should begin a taper when the irAE is Grade 1 and continue at least 4 weeks.”   
 
Section 9.1.1 CTEP-AERS integration 
The section entitled “Rave-CTEP-AERS integration” has been completely removed as the trial is now 
IND exempt due to the change in drug from “atezolizumab” to “pembrolizumab.” Subsequent sections 
have been renumbered accordingly.  
 
Section 9.3 Expedited Adverse Event Reporting (Rave-CTEP-AERS) 
The section heading has been updated to the following as this study will no longer be using the Rave-
CTEP-AERS system for reporting serious adverse events: “Expedited Adverse Event Reporting 
(Rave CTEP-AERS).”  
-This section has been completely updated as this study will no longer be using the Rave-CTEP-
AERS system for reporting serious adverse events.  
 
UPDATES TO THE MODEL CONSENT: 
There have been no changes made to the model consent. 
 
A replacement protocol document and model consent form have been issued 
 
 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments:  
For data submission:  
Regulatory documentation must 
be submitted to the Cancer 
Trials Support Unit (CTSU) via 
the Regulatory Submission 
Portal. 
(Sign in at 
https://www.ctsu.org, and select 
the Regulatory > Regulatory 
Submission.)  
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or email: 
1-866-651-CTSU (2878) or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org for 
regulatory assistance. 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_S
YSTEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions by phone or email: 
1-888-823-5923, or 
ctsucontact@westat.com 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the protocol 
for further instructions.  
 
 
 
The most current version of the study protocol and all supporting documents must be downloaded from 
the protocol-specific page located on the CTSU members’ website (https://www.ctsu.org). 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the Roster Maintenance application and in most cases 
viewable and manageable via the Roster Update Management System (RUMS) on the CTSU members’ 
website. 
For clinical questions (i.e., patient eligibility or treatment-related) see the Protocol Contacts, Page 2. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or email:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
 
 
 

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PHASE II RANDOMIZED TRIAL OF IMMUNOTHERAPY VERSUS IMMUNOTHERAPY AND RADIATION THERAPY 
FOR PLATINUM INELIGIBLE/REFRACTORY METASTATIC UROTHELIAL CANCER (IMMORTAL) 
 
Key Eligibility Criteria 
 
Eligibility Criteria (see Section 3.2) 
x 
Men and women, ages 18 years of age. 
x 
ECOG performance status 2 
x 
No prior treatment per Section 3.2.7 
x 
No comorbid conditions per Section 3.2.8 
x 
No active infections requiring systemic antibiotics  
within 2 weeks prior to registration. See Section 3.2.8 
x 
No live vaccine within 30 days. See Section 3.2.8 
 
 
 
 
 
 
 
 
 
Schema 
 
1 Cycle = 21 Days 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment is to continue until disease progression and no longer benefiting clinically or unacceptable adverse 
event. Patients will be followed for 3 years or until death, whichever comes first. 
 
Please refer to the full protocol text for a complete description of the eligibility criteria and treatment 
plan. 
 
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the credited Group 
may apply. 
 
Required Initial Laboratory Values 
ANC  1500/mm3 
Platelet count:  100,000/mm3 
Leukocytes 
2,500/mm3 
Hemoglobin 
8 g/dL 
Total bilirubin: 
 1.5 x ULN* 
AST/ALT: 
 3.0 x ULN** 
Alk Phos 
2.5 î ULN*** 
INR, PTT 
1.5 x ULN† 
* pts w/Gilbert disease  3 are eligible 
**  5 ULN for pts w/liver involvement 
***  5 ULN for pts w/liver involvement or if 
due to bone metastases primarily in absence of 
liver disease, no limitation 
Arm B: 
Pembrolizumab + 
RT (8 Gy x 3 fractions) 
Arm A: 
Pembrolizumab 
200mg q3 weeks 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
Randomize/Stratification 
1. Platinum 
Ineligibility/Refractory 
Criteria 
2. Visceral Metastasis 
Platinum 
Ineligible/Refractory 
Metastatic Urothelial 
Cancer with >1 
measurable site of 
disease and 1 target 
to radiate 

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Table of Contents 
1.0 
BACKGROUND .............................................................................................................................. 7 
1.1 
Rationale for selected approach and trial design ........................................................................... 7 
1.2 
Registration Patient Reported Outcomes (PROs) and Quality of Life (QOL) Measurements ...... 9 
2.0 
OBJECTIVES .................................................................................................................................. 9 
2.1 
Primary objective .......................................................................................................................... 9 
2.2 
Secondary objectives ..................................................................................................................... 9 
2.3 
Quality of Life Correlative Study Objectives .............................................................................. 10 
3.0 
PATIENT SELECTION ............................................................................................................... 10 
3.1 
On-Study Guidelines ................................................................................................................... 10 
3.2 
Eligibility Criteria ....................................................................................................................... 11 
4.0 
PATIENT REGISTRATION ....................................................................................................... 14 
4.1 
Investigator and Research Associate registration with CTEP ..................................................... 14 
4.2 
Cancer Trials Support Unit registration procedures .................................................................... 15 
4.3 
Patient Registration Requirements .............................................................................................. 18 
4.4 
Patient Registration Procedures ................................................................................................... 18 
4.5 
Registration to substudies and companion studies ...................................................................... 19 
4.6 
Stratification Factors and Treatment Assignments ...................................................................... 19 
5.0 
STUDY CALENDAR .................................................................................................................... 19 
6.0 
DATA AND SPECIMEN SUBMISSION .................................................................................... 21 
6.1 
Data Collection and Submission ................................................................................................. 21 
6.2 
Specimen collection and submission ........................................................................................... 23 
6.3 
Digital radiation therapy data submission using Transfer of Images and Data (TRIAD) ........... 24 
6.4 
Imaging Data Submission Methods ............................................................................................ 25 
6.5 
Submission of Patient Completed Measures ............................................................................... 27 
7.0 
TREATMENT PLAN/INTERVENTION ................................................................................... 27 
7.1 
Immunotherapy with Pembrolizumab ......................................................................................... 28 
7.2 
Radiotherapy ............................................................................................................................... 28 
8.0 
DOSE AND TREATMENT MODIFICATIONS ....................................................................... 55 
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care ......................................... 55 
8.2 
Dose Modification and Treatment Modifications ....................................................................... 56 
9.0 
ADVERSE EVENTS ..................................................................................................................... 68 
9.1 
Routine Adverse Event Reporting ............................................................................................... 68 
9.2 
CTCAE Routine Reporting Requirements .................................................................................. 69 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) .................................................................. 69 
9.4 
CAEPRs ...................................................................................................................................... 73 
10.0 
DRUG INFORMATION .............................................................................................................. 77 
10.1 
Pembrolizumab (MK-3475, NSC 776864).................................................................................. 77 
11.0 
MEASUREMENT OF EFFECT .................................................................................................. 79 
11.1 
Target Lesions ............................................................................................................................. 79 
11.2 
Non-target Lesions ...................................................................................................................... 80 
11.3 
Cytology and Histology............................................................................................................... 80 
11.4 
Evaluation of Best Overall Response .......................................................................................... 80 
11.5 
Guidelines for Evaluation of Measurable Disease ...................................................................... 81 
11.6 
Confirmation Measurement/Duration of Response ..................................................................... 82 
11.7 
iRECIST guidelines ..................................................................................................................... 82 
12.0 
END OF TREATMENT/INTERVENTION ............................................................................... 85 
12.1 
Duration of Protocol Treatment .................................................................................................. 85 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention ................................................ 85 
12.3 
Follow-up .................................................................................................................................... 85 

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12.4 
Extraordinary Medical Circumstances ........................................................................................ 85 
12.5 
Managing ineligible patients and registered patients who never receive protocol intervention .. 86 
13.0 
STATISTICAL CONSIDERATIONS ......................................................................................... 86 
13.1 
Study Design ............................................................................................................................... 86 
13.2  Study Endpoints .......................................................................................................................... 86 
13.3 
Subgroup Analysis ...................................................................................................................... 87 
13.4 
Sample Size Calculation .............................................................................................................. 87 
13.5 
Accrual time and study duration ................................................................................................. 87 
13.6 
Primary Analysis Plan ................................................................................................................. 87 
13.7 
Secondary Analysis Plans ........................................................................................................... 87 
13.8 
Study Monitoring ........................................................................................................................ 88 
13.9 
Inclusion of Women and Minorities ............................................................................................ 88 
14.0 
CORRELATIVE AND COMPANION STUDIES ..................................................................... 89 
14.1 
Quality of Life Studies (Alliance A032002-HO1) ...................................................................... 89 
14.2 
Correlative Science...................................................................................................................... 93 
15.0 
GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING ..................... 93 
15.1 
Institutional Credentialing ........................................................................................................... 93 
16.0 
REFERENCES .............................................................................................................................. 94 
APPENDIX I REGISTRATION FATIGUE/UNISCALE ASSESSMENT ......................................... 96 
APPENDIX II SUMMARY OF SUGGESTED DOSE CONSTRAINTS ............................................ 97 
APPENDIX III NCI/DCTD COLLABORATIVE AGREEMENT LANGUAGE .............................. 98 
 
 
 

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1.0 
BACKGROUND 
1.1 
Rationale for selected approach and trial design 
Treatment for metastatic urothelial carcinoma has remained mostly unchanged over the past 3 decades. 
The estimated 5ဨyear survival for metastatic disease has been approximately 5 2. Platinumဨbased 
chemotherapy regimens was the current standard of care for firstဨline treatment. Responses for patients 
that received platinum-based chemotherapy tend to be shortဨlived (median survival with cisplatin-
based therapy is ~14 months) and nearly all patients experience disease progression after treatment 3. 
Until recently, the standardဨofဨcare secondဨline therapies of docetaxel and paclitaxel (in the USA) and 
vinflunine (in Europe) resulted in only short survival, often resulting in only single digit response 
rates4. There have been few exciting advances with regards to systemic therapy for urothelial cancer 
until the approval of atezolizumab in 2016, quickly followed by four more immunotherapy options in 
2017 (pembrolizumab, nivolumab, durvalumab, avelumab).  
The KEYNOTE-045 phase III trial that compared pembrolizumab and investigator’s choice of 
chemotherapy (paclitaxel, docetaxel, or vinflunine) reported a median overall survival (OS) of 10.3 
months (95CI 8.0-11.8) in the pembrolizumab group, compared with 7.4 months (95CI 6.1-8.3) in 
the chemotherapy group (HR 0.73, 95CI 0.59-0.91) 6. 
As such, immunotherapy has clear activity in urothelial cancer, but the clinical benefit can be improved 
upon. The pre-existing immune infiltrate of tumors likely dictate response to immunotherapy and 
prognosis 7. Combining therapies with methods to create an immunogenic tumor microenvironment 
may potentially increase the durable clinical benefit with immunotherapy 8. 
 
Tumor-targeted radiotherapy can generate immune-stimulating effects and not immune suppression as 
was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects 
on tumor cells and on the tumor microenvironment that can enhance or trigger an anticancer immune 
response. Radiotherapy triggers antigen release from tumor cells, and the release of cytokines and 
chemokines from the tumor and its microenvironment. Immature antigen-presenting cells (APCs) are 
recruited to the tumor microenvironment, where they uptake tumor antigens and mature. These mature 
APCs then traffic to tumor-draining lymph nodes, where they prime CD8+ T lymphocytes that 
recognize the presented tumor antigens. Activated CD8+ T cells expand into effector cytotoxic T 
lymphocytes (CTLs), which home to the tumor site where they recognize and kill the tumor cells 9. 
The current immune checkpoint blocking agents utilized in the clinical setting focus on the blockade 
of cytotoxic T lymphocyte antigen-4 (CTLA-4) at the CD8+ T-cell priming phase, and blockade of the 
programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction at the 
CTL effector phase. 

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8 
As radiotherapy is under investigation for its ability to enhance responses to immunotherapy, the 
mechanisms by which radiation induces anti-tumor T cells is being elucidated. The DNA exonuclease 
Trex1 is induced by radiation doses above 12–18 Gy in different cancer cells, and attenuates their 
immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA 
stimulates secretion of interferon-beta by cancer cells following activation of the DNA sensor cGAS 
and its downstream effector STING. Repeated irradiation at doses that do not induce Trex1 amplifies 
interferon-beta production, resulting in recruitment and activation of Batf3-dependent dendritic cells. 
This effect is essential for priming of CD8 T cells that mediate systemic tumor rejection in the context 
of immune checkpoint blockade. Thus, Trex1 is an upstream regulator of radiation-driven anti-tumor 
immunity and can guide the selection of radiation dose and fractionation in patients treated with 
immunotherapy 10. 
Based on promising preclinical data and enticing clinical case reports, there are more than 100 accruing 
clinical trials combining radiation therapy with various forms of immune checkpoint inhibitors. This 
randomized phase II trial is unique and crucial for the following reasons:
1)
Testing the hypothesis of immune rejection and the abscopal effect needs to move beyond 
single institution, academic center efforts into a cooperative group setting involving patients 
treated in academic and community-based settings. As immune checkpoint blockade has 
activity, although limited, in urothelial cancer, this is an ideal setting to further test this 
phenomenon to improve upon its efficacy given that many patients will lack additional 
therapies. Until this phenomenon is tested in a cooperative group setting on a national level 
with homogeneity in radiotherapy and immunotherapy and without industry bias of single or 
combinatorial untested agents, thousands of patients will continue to be accrued to early stage 
studies hinting at an effect but providing no clinical guidance.
2)
Unlike many other trials testing this phenomenon, this trial strictly adheres to one specific 
radiation dose (8 Gy x 3) in one disease site with specific criteria (platinum ineligible or 
refractory metastatic urothelial cancer). 

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9 
The data from this randomized phase II trial (clinical and correlative) is a necessary step to 
guide other phase II trials in this and other disease settings and potentially the first step to a 
larger phase III design. There are 3 envisioned outcomes for this trial: 1) positive - evaluate in 
a phase 3 trial, 2) positive utilizing iRECIST in aforementioned point 1, 3) evaluate to propose 
a phase 3 design with iRECIST as primary endpoint and  
3) negative - ending further investigation as this question would be answered in this disease site 
with this therapy. 
Recently, Sundahl and colleagues reported on a randomized phase 1 trial of pembrolizumab with 
sequential versus concomitant stereotactic body radiotherapy (8 Gy x 3) in metastatic urothelial 
carcinoma 28. Safety was the primary outcome, with dose limiting toxicity defined as any grade 3–5 
metabolic or hematological toxicity or any grade 3–5 non-hematological toxicity that was (probably 
or possibly) related to SBRT, and that occurred between the start of SBRT and 12 weeks after the end 
of SBRT. No DLTs occurred in any of the 18 patients. Secondary endpoints included best overall 
objective response as per Response Evaluation Criteria in Solid Tumors v1.1, progression-free 
survival, OS, and local response in the irradiated lesion as per RECIST 1.1. A response rate of 0 
(RECIST 1.1) was observed in the sequential arm, with all patients experiencing progressive disease 
as the best overall objective response in non-irradiated lesions. Two patients had an initial partial 
response (PR) at first evaluation, which progressed shortly afterward and therefore does not qualify as 
a PR according to RECIST 1.1. In the concomitant arm, a response rate of 44 was noted in non-
irradiated lesions, with three patients experiencing a PR and one patient experiencing a complete 
response. Although not powered to detect a difference in OS, median OS was 4.5 and 12.1 months in 
sequential and concomitant arms, respectively. 
1.2 
Registration Patient Reported Outcomes (PROs) and Quality of Life (QOL) Measurements 
PROs, particularly involving symptomatic toxicities, provide discrepant yet complementary 
information compared with clinician interpreted data12-16. In particular, greater sensitivity for adverse 
event reporting, auxiliary characterization of performance status and earlier detection of 
symptoms12,14,17-20. Implementation of PRO systems has shown feasibility in the clinical trial setting 
demonstrating 78 to 96 adherence21,22 and several studies report that baseline PRO and QOL data 
may prognosticate survival better than performance status in clinical trials23-25. A landmark prospective 
study also now suggests that serial monitoring of patient reported symptoms may improve median 
overall survival by up to 5 months for patients undergoing treatment of solid malignancies22.  
QOL measurements of fatigue and overall perception of QOL are routinely included in Alliance studies 
and will be assessed upon registration in this study. Baseline single-item assessments of fatigue and 
overall QOL are strong prognostic indicators for survival in cancer patients, independent of 
performance status26-28. Routine inclusion of these measures should be considered similar to that of 
including performance status, either as stratification or prognostic covariates. 
2.0 
OBJECTIVES 
2.1 
Primary objective  
The primary objective is to compare the overall response rates by 6 months in patients with advanced 
urothelial carcinoma when treated with immunotherapy alone and immunotherapy plus radiotherapy 
to a single site. 
2.2 
Secondary objectives 
2.2.1 
To compare the response rates using iRECIST as assessed by central review 
2.2.2 
To compare progression-free survival (PFS) and overall survival (OS) for patients treated with 
immunotherapy and immunotherapy plus radiotherapy 
2.2.3 
To compare the rates of treatment discontinuation at 1 year 
2.2.4 
To assess adverse events experienced by patients treated with immunotherapy and 
immunotherapy plus radiotherapy via the CTCAE and PRO-CTCAE. 

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10 
2.2.5 
To determine whether treatment effects are similar for key subgroups including those defined 
by the stratification variables. 
2.3 
Quality of Life Correlative Study Objectives 
2.3.1 
To compare patient-reported fatigue as assessed by the PROMIS-Fatigue 8a from baseline 
through 24 months between patients treated with immunotherapy alone and immunotherapy 
plus radiotherapy to a single site. 
2.3.2 
To compare health-related quality of life (HRQOL) as assessed by the EORTC QLQ-C30 from 
baseline through 24 months between patients treated with immunotherapy alone and 
immunotherapy plus radiotherapy to a single site. 
2.3.3 
To compare urinary symptoms as assessed by the EORTC QLQ-BLM30 from baseline through 
24 months between patients treated with immunotherapy alone and immunotherapy plus 
radiotherapy to a single site. 
2.3.4 
To compare patient-reported diarrhea, shortness of breath and pain as assessed by the EORTC 
QLQ-C30 from baseline through 24 months between patients treated with immunotherapy alone 
and immunotherapy plus radiotherapy to a single site. 
2.3.5 
To compare health utilities and quality-adjusted survival between patients treated with 
immunotherapy alone and immunotherapy plus radiotherapy to a single site. 
2.3.6 
To compare other scale scores of the EORTC QLQ-C30 (global health status and quality of life; 
physical, role, emotional, cognitive, and social function; symptoms) and EORTC QLQ-BLM30 
(urostomy problems, catheter problems, future perspectives, abdominal bloating and flatulence, 
body image, sexual function) at 45 days, and at 6, 12, and 24 months between patients treated 
with immunotherapy alone and immunotherapy plus radiotherapy to a single site. 
3.0 
PATIENT SELECTION 
For questions regarding eligibility criteria, see the Study Resources page. Please note that the Study Chair 
cannot grant waivers to eligibility requirements.  
3.1 
On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for this trial are enrolled. All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient. Physicians should consider the risks and benefits of any 
therapy, and therefore only enroll patients for whom this treatment is appropriate.  
Physicians should consider whether any of the following may render the patient inappropriate for this 
protocol: 
x 
Patients with life expectancy of less than 6 months 
x 
Psychiatric illness which would prevent the patient from giving informed consent. 
x 
Medical conditions such as uncontrolled infection, uncontrolled diabetes mellitus or cardiac 
disease which, in the opinion of the treating physician, would make this protocol unreasonably 
hazardous for the patient. 
o HIV-infected patients on effective anti-retroviral therapy with undetectable viral load 
within 6 months are eligible for this trial. 
o For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral 
load must be undetectable on suppressive therapy, if indicated. 
o Patients with a history of hepatitis C virus (HCV) infection must have been treated 
and cured. For patients with HCV infection who are currently on treatment, they are 
eligible if they have an undetectable HCV viral load. 
x 
Patients with a “currently active” second malignancy other than non-melanoma skin cancers 
or cervical carcinoma in situ. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy and are free of disease for  3 years. 

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11 
In addition: 
Women and men of reproductive potential should agree to use an appropriate method of birth control 
throughout their participation in this study and for 4 months (120 days) after the last dose of study 
agent due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth 
control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier 
method (diaphragm plus condom). Should a woman become pregnant or suspect she is pregnant while 
she or her partner is participating in this study, she should inform her treating physician immediately. 
A female of childbearing potential is a sexually mature female who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 
consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 
3.2 
Eligibility Criteria 
Use the spaces provided to confirm a patient’s eligibility by indicating Yes or No as appropriate. It is 
not required to complete or submit the following page(s). 
When calculating days of tests and measurements, the day a test or measurement is done is considered 
Day 0. Therefore, if a test were done on a Monday, the Monday one week later would be considered 
Day 7. 
___ 
3.2.1 
Documentation of disease 
• 
Histologically confirmed metastatic urothelial carcinoma 
___ 
3.2.2 
Patients must be either ineligible for platinum treatment or platinum refractory as 
defined below: 
Platinum-ineligible: If patients meet any one of the following criteria: 
1. Impaired renal function [creatinine clearance (CrCl) of <30 mL/min] 
2. Grade >2 peripheral neuropathy 
3. NYHA Heart Failure of >3 
Platinum-refractory: If patients meet any one of the following criteria: 
1. Prior platinum-based perioperative chemotherapy within 12 months of relapse 
2. Prior platinum-based chemotherapy for metastatic disease 
___ 
3.2.3 
Measurable disease as defined in Section 11.0. 
Patients must have at least one measurable site 1 cm in diameter per RECIST 1.1 and a 
site targetable for radiotherapy. Measurable site must not overlap with radiated site such 
that measurable site cannot receive >2 Gy per fraction. 
 
Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for non-
nodal lesions and short axis for nodal lesions). See Section 11.0 for the evaluation of 
measurable disease. 
___ 
3.2.4 
Men and women, ages  18 years of age 
___ 
3.2.5 
ECOG performance status  2  
___ 
3.2.6 
Required Initial Lab Values 
• 
Leukocytes 
2,500/mm3 
• 
Absolute neutrophil count 
1,500/mm3 
• 
Platelets 
100,000/mm3 

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• 
Hemoglobin 
8 g/dL 
• 
Total bilirubin 1.5 î institutional upper limit of normal (ULN) (however, patients with 
known Gilbert disease who have serum bilirubin level d3 u ULN may be enrolled) 
• 
AST(SGOT)/ALT(SGPT) 
3 î ULN* 
• 
Alkaline phosphatase 
 
2.5 î ULN** 
* 
AST and/or ALT d5 u ULN for patients with liver involvement 
** 
d5 u ULN for patients with documented liver involvement or if due to bone 
metastases primarily in absence of liver disease, no limitation. 
___ 
3.2.7 
Prior Treatment 
• 
No prior allogeneic bone marrow transplantation or prior solid organ transplantation. 
• 
No Prior radiotherapy to targetable site or measurable site. 
• 
No chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who 
have not recovered from adverse events (other than alopecia) due to agents administered more 
than 4 weeks earlier. However, the following therapies are allowed: 
o Hormone-replacement therapy or oral contraceptives 
o Palliative radiotherapy for bone metastases !2 weeks prior to registration 
• 
No prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies. 
• 
No treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is 
longer) prior to initiation of study treatment 
• 
No prior treatment with any other investigational agent within 4 weeks prior to registration. 
• 
No prior treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon [IFN]-D or interleukin [IL]-2) within 6 weeks prior to registration. 
• 
Any prior systemic therapy is permitted except therapy with PD1/PDL1 inhibitor. 
• 
Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., 
a one-time dose of dexamethasone for nausea) may be enrolled. 
• 
The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients 
with orthostatic hypotension or adrenocortical insufficiency is allowed. 
___ 
3.2.8 
Comorbid conditions 
• 
No active tuberculosis (TB) 
• 
No known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin 
that has undergone potentially curative therapy or in situ cervical cancer. 
• 
Patients with known primary central nervous system (CNS) malignancy or symptomatic 
CNS metastases are excluded, with the following exceptions: 
Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the 
following criteria are met: 
x 
Evaluable or measurable disease outside the CNS 
x 
No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm 
of the optic apparatus (optic nerves and chiasm) 
x 
No history of intracranial hemorrhage or spinal cord hemorrhage 
x 
No ongoing requirement for dexamethasone for CNS disease; patients on a stable 

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dose of anticonvulsants are permitted. 
x 
No neurosurgical resection or brain biopsy within 28 days prior to registration 
 
• 
Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria 
listed above are met as well as the following: 
x 
Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic study 
x 
No stereotactic radiation or whole-brain radiation within 28 days prior to 
registration 
x 
Screening CNS radiographic study t4 weeks from completion of radiotherapy and 
t2 weeks from discontinuation of corticosteroids 
 
• 
No active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 
• 
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone are eligible. 
• 
No known history of, or any evidence of active, non-infectious pneumonitis or colitis. 
• 
No known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies. 
• 
No history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
• 
No known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; or inherited liver disease causing decompensated cirrhosis. 
• 
No history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.  
History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
• 
No significant cardiovascular disease (such as New York Heart Association Class II or greater 
cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to 
initiation of study treatment, unstable arrhythmia, or unstable angina. 
• 
No other disease, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding that contraindicates the use of an investigational drug, may affect the interpretation 
of the results, or may render the patient at high risk from treatment complications. 
• 
No history of leptomenigeal disease. 
• 
No uncontrolled tumor-related pain. 
• 
Patients requiring pain medication must be on a stable regimen at study entry. 
• 
Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) 
amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be 
recovered from the effects of radiation. There is no required minimum recovery period. 
• 
Asymptomatic metastatic lesions that would likely cause functional deficits or intractable 
pain with further growth (e.g., epidural metastasis that is not currently associated with spinal 
cord compression) should be considered for loco-regional therapy if appropriate prior to 
enrollment. 

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• 
No uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage 
procedures (once monthly or more frequently). 
Patients with indwelling catheters (e.g., PleurX£) are allowed. 
• 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible. 
• 
Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted 
provided that they meet the following conditions: 
x 
Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular 
manifestations 
x 
Rash must cover less than 10 of body surface area (BSA) 
x 
Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5, hydrocortisone butyrate 0.1, flucinolone 
0.01, desonide 0.05, aclometasone dipropionate 0.05). 
 
• 
No acute exacerbations of underlying condition within the last 12 months (not requiring 
psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral 
calcineurin inhibitors; high potency or oral steroids). 
• 
No uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
or psychiatric illness/social situations that would limit compliance with study requirements. 
• 
No active infections requiring systemic antibiotics within 2 weeks prior to registration. 
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or 
chronic obstructive pulmonary disease) are eligible. 
• 
No Major surgical procedure within 28 days prior to registration or anticipation of need for 
a major surgical procedure during the course of the study. 
• 
No administration of a live, attenuated vaccine within 30 days before registration or 
anticipation that such a live, attenuated vaccine will be required during the study and up to 5 
months after the last dose of immunotherapy. 
• 
Patients who have received live attenuated vaccines within 30 days of the first dose of trial 
treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and 
vaccines intended to prevent SARS-CoV-2 and coronavirus disease 2019 (COVID-19) are 
allowed. 
4.0 
PATIENT REGISTRATION 
4.1 
Investigator and Research Associate registration with CTEP 
Food and Drug Administration (FDA) regulations require sponsors to select qualified investigators. 
National Cancer Institute (NCI) policy requires all individuals contributing to NCI-sponsored trials to 
register with their qualifications and credentials and to renew their registration annually. To register, 
all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) credentials necessary to 
access secure NCI Clinical Oncology Research Enterprise (CORE) systems. Investigators and clinical 
site staff who are significant contributors to research must register in the Registration and Credential 
Repository (RCR). The RCR is a self-service online person registration application with electronic 
signature and document submission capability. 
RCR utilizes six person registration types. 
x 
Investigator (IVR) — MD, DO, or international equivalent; 
x 
Non Physician Investigator (NPIVR) — advanced practice providers (e.g., NP or PA) or 
graduate level researchers (e.g., PhD); 

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previously open at the site under the local IRB. International sites should continue to submit Research 
Ethics Board (REB) approval to the CTSU Regulatory Office following country-specific regulations.  
Sites participating through the NCI CIRB must submit the Study Specific Worksheet (SSW) for Local 
Context to the CIRB using IRBManager to indicate their intent to open the study locally. The NCI 
CIRB’s approval of the SSW is automatically communicated to the CTSU Regulatory Office, but sites 
are required to contact the CTSU Regulatory Office at CTSURegPref@ctsu.coccg.org to establish site 
preferences for applying NCI CIRB approvals across their Signatory Network. Site preferences can be 
set at the network or protocol level. Questions about establishing site preferences can be addressed to 
the CTSU Regulatory Office by email (CTSURegPref@ctsu.coccg.org) or by calling 1-888-651-
CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory Office using 
the Regulatory Submission Portal located in the Regulatory section of the CTSU website. Acceptable 
documentation of local IRB/REB approval includes: 
x 
Local IRB documentation; 
x 
IRB-signed CTSU IRB Certification Form; and/or 
x 
Protocol of Human Subjects Assurance Identification/IRB Certification/Declaration of 
Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e., the investigator on the IRB/REB 
approval) must meet the following criteria for the site to be able to have an Approved status following 
processing of the IRB/REB approval record: 
x 
Have an active CTEP status; 
x 
Have an active status at the site(s) on the IRB/REB approval (applies to US and Canadian sites 
only) on at least one participating organization’s roster; 
x 
If using NCI CIRB, be active on the NCI CIRB roster under the applicable CIRB Signatory 
Institution(s) record; 
x 
Include the IRB number of the IRB providing approval in the Form FDA 1572 in the RCR 
profile;  
x 
List all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the RCR 
profile; and 
x 
Have the appropriate CTEP registration type for the protocol.  
4.2.1 
Additional site registration requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO);  
• 
An active roster affiliation with the NCI CIRB roster under at least on CIRB Signatory 
Institution (US sites only); and 
Compliance with all protocol-specific requirements (PSRs). 
4.2.2 
Protocol specific requirements for A032002 site registration 
IROC credentialing: 
This is a study with a radiation and/or imaging (RTI) component and the enrolling site must be 
aligned to an RTI provider. To manage provider associations, access the Provider Association 
page 
from 
the 
Regulatory 
section 
on 
the 
CTSU 
members’ 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at least one Imaging 
and Radiation Oncology Core (IROC) provider to participate on trials with an RTI component. 
Enrolling sites are responsible for ensuring that the appropriate agreements and IRB approvals 
are in place with their RTI provider. Only an individual with a primary role on a treating site 

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roster can update the provider associations, though all individuals at a site may view provider 
associations. To find who holds primary roles at your site, view the Person Roster Browser under 
the RUMS section on the CTSU members’ website. 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC Houston to 
verify credentialing status or to begin a new modality credentialing process.  
To complete protocol-specific credentialing the RTI provider or enrolling site should follow 
instructions in the protocol to submit documentation or other materials to the designated IROC 
Quality Assurance (QA) center. Upon the IROC QA center approving the RTI provider for the 
study modality, IROC will automatically send the approval to the Regulatory and Roster 
Maintenance applications to comply with the protocol-specific requirement, unless otherwise 
noted at the bottom of the IROC Credentialing Approval notification. IROC will continue to copy 
the provider and/or enrolling site on modality approvals. 
Upon site registration approval in the Regulatory application, the enrolling site may access 
Oncology Patient Enrollment Network (OPEN) to complete enrollments. If the study is using the 
IROC integration suite, the enrolling site will select their credentialed provider treating the subject 
in the OPEN credentialing screen and may need to answer additional questions related to 
treatment in the eligibility checklist.   
4.2.3 
Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the CTSU 
members’ website. Permission to view and download this protocol and its supporting documents 
is restricted to institutions and its associated investigators and staff or on a participating roster. 
To view/download site registration forms: 
• 
Log in to the CTSU members’ website (https://www.ctsu.org); 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the protocol tree; or 
o Click on the By Lead Organization folder to expand, then select Alliance, and 
protocol number A032002. 
Click on Documents, Protocol Related Documents, and use the Document Type filter and select 
Site Registration to download and complete the forms provided. (Note: For sites under the CIRB, 
IRB data will load automatically to the CTSU.) 
4.2.4 
Submitting regulatory documents 
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to the 
Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal should 
alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-CTSU (2878), or 
CTSURegHelp@coccg.org in order to receive further instruction and support. 
4.2.5 
Checking site registration status 
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the site’s 5-character CTEP Institution Code and click on Go. 
- 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 

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Note: The status shown only reflects institutional compliance with site registration requirements 
as outlined within the protocol. It does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling investigator’s status with NCI or their 
affiliated networks. 
4.3 
Patient Registration Requirements 
4.3.1 
Informed consent 
The patient must be aware of the neoplastic nature of his/her disease and willingly consent after 
being informed of the procedure to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, side-effects, risks, and discomforts. Current human protection 
committee approval of this protocol and a consent form is required prior to patient consent and 
registration. 
4.3.2 
Patient questionnaire booklets 
Patient-completed booklets should be downloaded prior to the pre-registration of any patients. 
These booklets can be downloaded from the CIRB Approved Documents tab on the CTSU 
website. Patient-completed booklets will only be available in English. 
4.4 
Patient Registration Procedures  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system available on a 
24/7 basis. OPEN is integrated with CTSU regulatory and roster data and with the LPOs 
registration/randomization systems or the Theradex Interactive Web Response System (IWRS) for 
retrieval of patient registration/randomization assignment. OPEN will populate the patient enrollment 
data in NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
x 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 
x 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
Corresponding roster, or participating organization roster with the role of Registrar. Registrars 
must hold a minimum of an Associate Plus (AP) registration type; 
x 
Have an approved site registration for the protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, crediting, 
consenting, drug shipment (IVR only), or receiving investigator for a patient transfer in OPEN, the 
IVR or NPIVR must list the Institutional Review Board (IRB) number used on the site’s IRB approval 
on their Form Food and Drug Administration (FDA) 1572 in the Registration and Credential 
Repository (RCR.). If a DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
x 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
x 
All patients have signed an appropriate consent form and Health Insurance Portability and 
Accountability Act (HIPAA) authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration and 
treatment information. You may print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ website. Further 
instructional information is in the OPEN section of the CTSU website at https://www.ctsu.org or 
https://open.ctsu.org. For any additional questions, contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 

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4.5 
Registration to substudies and companion studies 
4.5.1 
Registration to Substudies described in Section 14.0 
There is 1 substudy within Alliance A032002. This correlative science study must be offered to 
all English-speaking patients enrolled on Alliance A032002 (although patients may opt to not 
participate). This substudy does not require separate IRB approval. The substudies included 
within Alliance A032002 are: 
• 
Quality of Life, Alliance A032002-HO1 (Section 14.1) 
If a patient answers “yes” to “I choose to take part in the Quality of Life study and will fill out 
these forms,” Question #1 in the model consent, they have consented to participate in the substudy 
described in Section 14.1. The patient should be registered to Alliance A032002-HO1 at the same 
time they are registered to the treatment trial (A032002). Questionnaires should be submitted per 
Section 14.1. 
4.6 
Stratification Factors and Treatment Assignments 
4.6.1 
Stratification Factors 
1) Platinum Status: Ineligible vs. Refractory 
o Platinum ineligible is defined as meeting any one of the following criteria: Impaired 
renal function [creatinine clearance (CrCl) of <30 mL/min], >2 peripheral 
neuropathy, or NYHA Heart Failure of >3. 
o Platinum-refractory is defined as prior platinum-based perioperative chemotherapy 
within 12 months of relapse or prior platinum-based chemotherapy for metastatic 
disease. 
2) Visceral Metastasis: Yes vs. No 
4.6.2 
Treatment Assignments 
Patients will be randomized 1:1 to the two treatment arms. The factors defined in Section 4.8.1 
will be used as stratification factors. 
After the patient has been registered into the study, the values of the stratification factors will be 
recorded, and the patient will be randomized to one of the following treatment groups using the 
Pocock and Simon dynamic allocation procedure which balances the marginal distributions of the 
stratification factors between the treatment groups. 
1) Immunotherapy 
2) Immunotherapy + Single Site Radiotherapy 
5.0 
STUDY CALENDAR 
Pre-study Testing Intervals 
The pre-study testing intervals are guidelines only. Laboratory and clinical parameters during treatment are 
to be followed using individual institutional guidelines and the best clinical judgment of the responsible 
physician. It is expected that patients on this study will be cared for by physicians experienced in the 
treatment and supportive care of patients on this trial. 
When calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0. Therefore, if a test were done on a Monday, the Monday one week later would be considered Day 7. 
To be completed  28 DAYS before registration: All laboratory studies, history and physical. 
To be completed  42 DAYS before registration: Any X-ray, scan of any type or ultrasound which is 
utilized for tumor measurement per protocol. 
To be completed  60 DAYS before registration: Any baseline exams used for screening, or any X-ray, 
scan of any type or ultrasound of uninvolved organs which is not utilized for tumor measurement. 
 

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Prior to 
Registration* 
Day 1 of each 
cycle* 
Post-treatment 
follow up** 
At PD, 
withdrawal, or 
removal**  
Tests & Observations 
 
 
 
 
History and physical, weight, 
PS*** 
X 
X 
X 
X 
Pulse, Blood Pressure 
X 
X 
 
 
ECG 
X(6) 
 
 
 
Adverse Event Assessment- 
CTCAE 
 
X 
X 
 
Adverse Event Assessment- 
PRO-CTCAE 
X(1) 
X(1) 
X 
 
Registration Fatigue/Uniscale 
Assessment 
X(2) 
 
 
 
Laboratory Studies 
 
 
 
 
Complete Blood Count, 
Differential, Platelets 
X 
X 
 
 
Serum Creatinine 
X 
X 
 
 
Albumin, glucose 
X 
X 
 
 
AST, ALT, Alk. Phos., Bili 
X 
X 
 
 
TSH with reflex T4 
 
X 
 
 
Serum or Urine hCG 
X(3) 
 
 
 
UPC ratio/urine protein 
X 
A 
 
 
Staging 
 
 
 
 
Tumor Measurement 
X 
C 
X 
 
CT chest/abd/pelvis 
X(5) 
D 
D 
 
Correlative studies 
QOL assessment 
From baseline through 24 months, see  Section 6.5. 
Tissue, blood, and urine 
samples 
See Section 6.2. 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained  14 days prior to 
treatment. For subsequent cycles, labs, scans, tests and observations may be obtained  72 hours prior to 
day of treatment. 
** 
Physical examination and staging scans are required  12 weeks after the end of treatment, then every 12 
weeks until disease progression; thereafter, survival information is required every 3 months until 3 years 
following registration. See also Section 12.0. 
*** 
Patients receiving immunotherapy will be assessed for pulmonary signs and symptoms throughout the 
study. 
1 
The PRO-CTCAE assessment is required for all patients. If the PRO-CTCAE assessment completed prior 
to registration is obtained  14 days prior to treatment, then the PRO-CTCAE assessment on day 1 of 
cycle 1 may be skipped. The PRO-CTCAE patient-completed booklet for this protocol can be found on 
the ‘CIRB Approved Documents’ tab on the CTSU website. 
2 
To be completed after registration and  21 days prior to treatment. 
3 
For women of childbearing potential. Must be done  14 days prior to initiation of study treatment. 
4 
See Section 6.2. 

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5 
Baseline scans can include either: 1) a CT, spiral CT, or MRI and bone scan, or 2) an FDG-PET scan and 
diagnostic CT performed with both IV and oral contrast, and the CT acquired with 5 mm or less slice 
thickness. Supporting documentation is to be submitted, per Section 6.1.1. 
6 
ECG prior to registration should be performed if clinically indicated. 
A. All patients receiving immunotherapy will have a urinalysis or urine protein performed  72 hours prior 
to every dose. If urine protein is  2+, 24-hour urine collection or UPC ratio will be required. 
B. Required only if signs or symptoms suggestive of metastases develop. 
C.  2 days prior to each treatment if accessible to physical examination. 
D. Every 3 months until evidence of progression or relapse. If the baseline scans were a CT or MRI and bone 
scan, follow-up bone scans are required only for patients with bone metastases as the only site of evaluable 
disease, and are optional for other patients. Response assessment should include assessment of all sites of 
disease and use the same imaging method as was used at baseline. Bone imaging (after baseline) is 
required only if indicative of metastases at baseline or if signs or symptoms suggestive of metastases 
develop. 
6.0 
DATA AND SPECIMEN SUBMISSION 
6.1 
Data Collection and Submission 
6.1.1 
Data submission schedule 
A Data Submission Schedule (DSS) is available on the Alliance study webpage, within the Case 
Report Forms section. The Data Submission Schedule is also available on the CTSU site within 
the study-specific Case Report Forms folder. 
6.1.2 
Medidata Rave 
Medidata Rave is the clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments. 
Requirements to access Rave via iMedidata: 
• 
Active CTEP registration with the credentials necessary to access secure NCI/CTSU IT 
systems; 
and 
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician Investigator (NPIVR), or 
Investigator (IVR); and 
• 
Rave Read Only or Rave SLA role must have at a minimum an Associate (A) registration 
type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required.  
Upon initial site registration approval for the study in the Regulatory application, all persons with 
Rave roles assigned on the appropriate roster will be sent a study invitation email from iMedidata. 
No action will be required; each study invitation will be automatically accepted and study access 
in Rave will be automatically granted. Site staff will not be able to access the study in Rave until 
all required Medidata and study-specific trainings are completed. Trainings will be in the form of 
electronic learnings (eLearnings) and can be accessed by clicking on the eLearning link in the 
Tasks pane located in the upper right corner of the iMedidata screen. If an eLearning is required 
for a study and has not yet been taken, the link to the eLearning will appear under the study name 
in the Studies pane located in the center of the iMedidata screen; once the successful completion 

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of the eLearning has been recorded, access to the study in Rave will be granted, and a Rave EDC 
link will replace the eLearning link under the study name.  
No action will be required by site staff (to activate their account) who have not previously 
activated their iMedidata/Rave account at the time of initial site registration approval for the study 
in the Regulatory application. Pending study invitations (previously sent but not accepted or 
declined by a site user) will be automatically accepted and study access in Rave will be 
automatically granted for the site user. Account activation instructions are located on the CTSU 
website in the Data Management section under the Data Management Help Topics > Rave 
resource materials (Medidata Account Activation and Study Invitation). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management > Rave 
section or by contacting the CTSU Help Desk at 1-888-823-5923 or by email at 
ctsucontact@westat.com.   
6.1.3 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff to manage unanswered 
queries and form delinquencies, monitor data quality and timeliness, generate reports, and review 
metrics.  
The DQP is located on the CTSU members’ website under Data Management. The Rave Home 
section displays a table providing summary counts of Total Delinquencies and Total Queries. 
DQP Queries, DQP Delinquent Forms, DQP Form Status and the DQP Reports modules are 
available to access details and reports of unanswered queries, delinquent forms, forms with 
current status, and timeliness reports. Site staff should review the DQP modules on a regular basis 
to manage specified queries and delinquent forms. 
The DQP is accessible by site staff who are rostered to a site and have access to the CTSU 
website. Staff who have Rave study access can access the Rave study data via direct links 
available in the DQP modules. 
CTSU Delinquency Notification emails are sent to primary contacts at sites twice a month. These 
notifications serve as alerts that queries and/or delinquent forms require site review, providing a 
summary count of queries and delinquent forms for each Rave study that a site is participating in. 
Additional site staff can subscribe and unsubscribe to these notifications using the CTSU Report 
and Information Subscription Portal on the CTSU members’ website. 
To learn more about DQP use and access, click on the Help Topics button displayed on the Rave 
Home, DQP Queries, DQP Delinquent Forms, DQP Form Status, and DQP Reports modules. 
6.1.4 
ICAREdata® Project 
Selected sites will be participating in the ICAREdata® project. - The Integrating Clinical Trials 
and Real-world Endpoints data (ICAREdata) initiative is a program led by the Alliance Data 
Innovation Lab which is a component of the Alliance for Clinical Trials in Oncology.  
The ICAREdata® project aims to expand the ability to achieve clinical research goals by 
providing new ways to collect data required for clinical trials.  Today, virtually all clinical trials 
data are collected using special forms and computer applications, such as a software known as 
Medidata Rave.  Instead of using these “add on” data collection systems, the ICAREdata project 
will gather study data directly from the Electronic Health Record (EHR).  As with all research 
data collections, data collected by the ICAREdata project are stored in a secured repository.  
Select institutions will be invited to participate and will receive training on the specific 
ICAREdata® requirements. As with all clinical trials data management, the nature of data 
collected using the ICAREdata methods will be specific to a particular research protocol, and 
might include demographic information, diagnosis, laboratory values, physician assessments, 
and other results, such as adverse event reports.  The Data Innovation Lab will manage data 
collection, working with the IT department at these sites to configure the EHR to deliver 
mCODE (minimal common oncology data elements) data and other required outcome data in 
the form of structured ICAREdata questions. Clinicians will provide the study required data by 

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answering standardized questions or data fields as part of their encounter visit with the subjects.  
The IT departments will also work to implement the data transfer capability from the site EHR 
to the Alliance Data Innovation Lab via a secure/tested extraction method.  
Investigators and research staff at limited select sites that utilize the EHR research adverse 
events data collection tool will be asked to complete a brief voluntary survey. The research staff 
and investigator’s email addresses at these predetermined sites will be submitted at the time of 
Adverse Events data collection tool training.  The survey will take approximately 5 minutes to 
complete.  It will solicit feedback on the investigators and study staff experiences including 
overall staff acceptance, usability, preferences for using the tool to document any adverse 
events.  The plan survey administration timeline is at baseline and then a select period 
thereafter. Ultimately, the survey will be used to gather general feedback of the usability of the 
tool across multiple site level stakeholders. 
Data will be encrypted at-rest and in-transit using a secure interface with an established 
authorization protocol handled by the ICAREdata infrastructure. Alliance Data Lab staff will 
issue a client ID and credentials to participating ICAREdata sites that will be used to 
authenticate those sites for access to the ICAREdata infrastructure service/extraction method to 
submit data. The clinical site will be responsible for securely storing these credentials (e.g., 
installed on a server that an IT administrator manages) such that those staff responsible for 
submitting data will have the proper access. Data will be stored and maintained in HIPAA 
compliant data repositories (such as AWS) and access controlled by an identity server with 
strict management to ensure confidentiality, integrity, and availability of PHI. Strict access 
controls will be maintained.  Only authorized Alliance Data Lab personnel will have access to 
the data and scope of access will be further controlled based on role and level of need to know. 
Participating 
institutions 
may 
email 
the 
Alliance 
Data 
Innovation 
Lab 
at 
ICAREdata@alliancefoundationtrials.org with any questions. 
6.1.5 
IRB Termination 
Until institutions receive a formal notice from the Alliance regarding termination to patient 
follow-up, institutions must not close this trial with the IRB of record for the study.  Please contact 
the Alliance Regulatory team at regulatory@alliancenctn.org with any questions. 
6.2 
Specimen collection and submission 
6.2.1  Correlative Science Manual (CSM) 
The Alliance A032002 Correlative Science Manual (CSM) contains instructions for specimen 
collection, processing and shipping. The manual can be found on the BioMS and CTSU websites. 
Questions regarding the CSM should be addressed to the contacts specified in the manual. 
6.2.2 
Central Pathology Review 
Retrospective central pathology review using patient diagnostic material is required for all 
patients registered to this study. 
6.2.3 
A032002 Biobanking 
All participating institutions must ask patients for their consent to participate in the biobanking 
planned for Alliance A032002, although patient participation is optional. For patients who 
consent to participate (model consent question, “I agree that my samples and related health 
information may be kept in a biobank for use in future health research”). Biomarker studies will 
be performed. Rationale and methods for the scientific components of these studies are described 
in Section 14.2. 

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6.2.4 
Overview of Specimen Requirements 
 
After 
registration & 
prior to C1D1* 
 
6 weeks 
after 
registration  
 
3 months 
after 
registration 
Disease 
progression** 
Mandatory for all patients: 
Diagnostic H & E 
slides for 
histopathology 
review 
X 
 
 
 
For patients consented to A032002 biobanking: 
FFPE tumor tissue  
X 
 
 
 
Peripheral Whole 
blood (EDTA 
tubes) 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
2 x 10 mL 
Urine (EDTA 
tubes) 
X 
X 
X 
X 
* 
Blood and urine samples should be collected before patient receives first dose of study drug, 
recommend on the same day of registration 
** Progression samples may be collected and submitted up to 1 month after progression. Continue 
peripheral Whole Blood (EDTA tubes) for ct-DNA specimen submission if there is early 
discontinuation of protocol therapy until disease progression 
6.3 
Digital radiation therapy data submission using Transfer of Images and Data (TRIAD) 
Transfer of Images and Data (TRIAD) is the American College of Radiology’s (ACR) image exchange 
application. TRIAD provides sites participating in clinical trials a secure method to transmit images. 
TRIAD anonymizes and validates the images as they are transferred. 
6.3.1 
TRIAD Access Requirements 
• 
A valid Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) (CTEP-IAM) account. 
• 
Registration type of: Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR), or Investigator (IVR). Refer to the CTEP Registration Procedures section for 
instructions on how to request a CTEP-IAM account and complete registration in RCR; 
and 
• 
TRIAD Site User role on an NCTN or ETCTN roster. 
All individuals on the Imaging and Radiation Oncology Core provider roster have access to 
TRIAD and may submit images for credentialing purposes, or for enrollments to which the 
provider is linked in OPEN. 
6.3.2 
TRIAD Installations 
To submit images, the individual holding the TRIAD Site User role will need to install the TRIAD 
application on their workstation. TRIAD installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM account and RCR registration. 

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For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org or 1-
703-390-9858. 
6.3.3 
Procedures for Data Submission via TRIAD 
See Section 7.2.1 for details regarding data to be submitted via TRIAD for patients receiving 
radiation therapy. 
6.4 
Imaging Data Submission Methods 
Data must be submitted according to the protocol requirements for ALL patients registered, whether 
or not assigned treatment is administered, including patients deemed to be ineligible. 
DICOM images uploading is preferred to be submitted using TRIAD, however these methodologies 
are supported: 
a. 
TRIAD-based (a PC with internet access and TRIAD software installation will be needed) 
b. 
Web transfer-based (a PC with internet access and a web browser will be needed) 
c. 
FTP transfer-based (a PC with internet access and any FTP software will be needed) 
d. 
Mail/CD Shipment-based (only if electronic transfer approaches cannot be achieved) 
Questions regarding image submissions can be sent to ALLIANCE032002@irocohio.org. 
6.4.1 
Detailed Steps of Data Submission 
Collection of images is required. Alliance A032002 prescribes limited image acquisition 
requirements, so any imaging acquired is expected to be done per protocol rather than the site’s 
own standard of care. Specifically, PET/CT, CT, MRI and bone scans must be acquired at the 
following times and subsequently submitted. Supporting documentation must accompany all 
submissions for this trial. Images will be collected digitally for central archiving and curation. 
Imaging studies will be collected digitally at the following time points: 
1. Baseline – within 42 days before registration 
a. CT of the chest/abdomen/pelvis 
i. 
Intravenous and oral contrast unless contraindicated 
ii. 5mm of less slice thickness 
b. Substitutions allowed: 
i. 
CT of the chest and MRI of the abdomen/pelvis 
1. 
Must be diagnostic quality 
2. 
Intravenous and oral contrast unless contraindicated 
3. 
5mm or less slice thickness 
ii. FDG-PET/CT of the whole body or limited whole body 
1. 
CT must be of diagnostic quality 
2. 
Intravenous and oral contrast unless contraindicated 
3. 
5mm or less slice thickness 
c. Bone scan of the whole body 
2. Restaging – every 3 months +/- 14 days 
a. Same imaging as acquired at baseline 
b. Bone imaging only required if indicative of metastases at baseline or if signs 
or symptoms develop 
3. Progression 

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4. Confirmatory Follow-up – 12 weeks after evidence of objective response 
The complete imaging data set in digital DICOM format will be submitted electronically to the 
Imaging and Radiation Oncology Core at Ohio (IROC Ohio) within no more than 3 business days 
upon the image acquisition completeness. BMP files, JPG files, or hard copies (films) are not 
acceptable. The raw data of the entire study should be saved until the imaging data is accepted by 
IROC Ohio. 
If not using TRIAD, sites need to de-identify the patient data using institutional procedures to 
remove patient name and medical record number while preserving the Alliance patient ID number 
(e.g., 112136) and protocol number (e.g., ALLIANCE032002), respectively. 
DICOM tag dates and times cannot be altered prior to submission as they are used to put 
submissions into context regarding patient treatment.  Additional changes to DICOM tags prior 
to submission impede further technical analysis and should be avoided whenever possible. 
Imaging data should be submitted electronically to IROC Ohio via TRIAD, Web Transfer or FTP 
Transfer: 
1. TRIAD based data transfer 
The standard TRIAD based data transfer approach will be provided separately through 
IROC efforts via the specific trial e-mail ALLIANCE032002@irocohio.org per the 
request by participating sites before their first data submission. 
2. Web Transfer 
(http://upload.IROCOhio.org or https://moveit.imres.med.ohio-state.edu) 
Any PCs with internet access and web browser (e.g., Chrome, Edge, Internet Explorer, 
Mozilla Firefox) can be used to web transfer DICOM images and other required files to 
IROC Ohio. The standard Web Transfer information will be provided separately through 
the specific trial e-mail ALLIANCE032002@irocohio.org per the request by 
participating sites before their first data submission. 
3. FTP Transfer 
Any FTP software can be used to initiate access to the secure FTP Server of IROC Ohio. 
The standard FTP access information will be provided separately through the specific 
trial e-mail ALLIANCE032002@irocohio.org per the request by participating sites 
before their first data submission. 
4. Mail/CD Shipment 
Only if electronic data transfer approaches cannot be achieved, the de-identified images 
in digital DICOM format can be burned to a CD and mailed to IROC Ohio. Submit only 
one patient’s images per CD, with the patient’s Alliance ID number, study type, date of 
scans, and name of submitting institution. 
Submit these data to: 
IROC Ohio 
Attn: ALLIANCE A032002 
The Ohio State University 
395 W. 12th Avenue, Suite 
 
Columbus, Ohio, 43210 
Phone: (614) 293-2929 
Fax: (614) 293-9275 
Once the imaging data submission is done, send an e-mail to IROC Ohio at the specific trial email 
ALLIANCE032002@irocohio.org to inform that the study has been submitted from the 
institution. IROC Ohio will notify site and ALLIANCE A032002 imaging committee within 2 
business days of the data receipt, and then, within 3 business days following the data receipt, of 
the quality check report. 

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Send any questions or problems about the data submission to IROC Ohio email 
ALLIANCE032002@irocohio.org or call (614) 293-2929 for help. 
6.5 
Submission of Patient Completed Measures 
All participating institutions must ask English-speaking patients for their consent to participate in the 
correlative study planned for Alliance A032002, although patient participation is optional. For patients 
registered to correlative study A032002-HO1 (model consent question, “I choose to take part in the 
Quality of Life study and will fill out these forms”) the quality of life evaluations will be performed. 
For patients who consent to participate the questionnaires will be completed at the time points listed 
in the table below (quality of life evaluations should continue in patients who have experienced disease 
progression, it may be mailed or e-mailed to patients who do not have a planned clinic visit at the 
specified QOL time point). 
Please note that PRO-CTCAE is contained in a separate booklet and is required for all patients per the 
study calendar. The schedule below only pertains to patients who consent to participate in the Quality 
of Life study. 
Patient-completed booklets for this study are to be ordered prior to the pre-registration of any patients 
(see Section 4.3.2). These booklets can be downloaded from the CIRB Approved Documents tab on 
the CTSU website. Booklets must be given to patients to complete and patients should be instructed to 
return the booklets/responses to site staff (either in person, by mail, by email, or by phone), and site 
staff will enter patient responses into Rave. At visits in which booklets are to be completed, the booklet 
should be given to the patient before any discussion of the patient’s health status or test results. Booklet 
administration schedule is provided below. 
 
 
Treatment Arm 
 21 days 
prior to 
treatment 
45 days 
after 
registration 
(+/- 14 
days) 
6 months 
after 
registration 
(+/- 14 
days) 
12 months 
after 
registration 
(+/- 14 
days) 
24 months 
after 
registration 
(+/- 14 
days) 
For patients registered to A032002-HO1, submit patient-completed questionnaires* at the following time 
points: 
EORTC QLQ-C30  
X 
X 
X 
X 
X 
EORTC QLQ-BLM30  
X 
X 
X 
X 
X 
PROMIS-Fatigue 8a 
X 
X 
X 
X 
X 
EQ-5D-5L 
X 
X 
X 
X 
X 
* 
 Download EORTC QLQ-C30, QLQ-BLM30, PROMIS-Fatigue 8a and EQ-5D-5L 
questionnaires for IRB submission and review from the ‘CIRB Approved Documents’ tab on the 
CTSU website. Verbal administration of the measures for visually impaired patients is permitted if 
the measure and verbal administration of the measure is conducted in a language understandable to 
the patients. 
6.5.1 
Patient Language Considerations 
The PROMIS-Fatigue 8a, EORTC QLQ-BLM30, EORTC QLQ-C30, and EQ-5D-5L are 
available in English only. 
7.0 
TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin  14 days of registration. 
For questions regarding treatment, please see the study contacts page. 
Patients must have completed last systemic cancer therapy within 4 weeks prior to the start of protocol 
treatment. 

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It is acceptable for individual chemotherapy doses to be delivered  a 24-hour (business day) window before 
and after the protocol-defined date for Day 1 of a new cycle. For example, if the treatment due date is a 
Friday, the window for treatment includes the preceding Thursday through the following Monday. In 
addition, patients are permitted to have a new cycle of chemotherapy delayed up to 7 days for major life 
events (e.g., serious illness in a family member, major holiday, vacation that cannot be rescheduled) without 
this being considered a protocol violation. Documentation to justify this delay should be provided. 
7.1 
Immunotherapy with Pembrolizumab 
Protocol therapy will consist of 1 cycle administered every 21 days. Treatment will continue until 
disease progression and no longer benefiting clinically, or unacceptable adverse event. Treatment may 
continue beyond disease progression per iRECIST guidelines. That is, treatment may continue beyond 
assessment of progressive disease (PD) provided the patient is clinically stable and felt to be continuing 
to benefit from therapy. A patient may be deemed clinically stable provided that no worsening of 
performance status has occurred, there have been no clinically relevant increases in disease-related 
symptoms such as pain or dyspnea that are thought to be associated with disease progression, and there 
has been no requirement for intensified management of disease-related symptoms, including increased 
analgesia, radiotherapy, or other palliative care. Repeat imaging should be obtained within 4-8 weeks 
if feasible, and no later than 3 months. If the subsequent scan shows additional new lesions or increase 
in new lesion size (sum of measurements  5 mm), treatment should be discontinued. 
Arm 
Agent 
Dose 
Route 
Day 
Rx 
A 
Pembrolizumab 
200 mg 
IV* 
Day 1 
Every 3 weeks 
B 
Pembrolizumab + 
RT 
200 mg + RT** 
IV*  
Day 1 
Every 3 weeks*** 
* Infused over approximately 30 minutes (range: 25-40 minutes). 
** Patients will receive 3 fractions of radiation to a total dose of 24 Gy (8 Gy x 3 fractions). 
Administration of radiotherapy will occur to a single site for subjects randomized to the 
pembrolizumab and radiotherapy group. 
***Radiotherapy can be initiated after the first dose of immunotherapy and must be completed before 
12 weeks after first dose of immunotherapy administered. 
7.2 
Radiotherapy 
Administration of radiotherapy will occur to a single site for subjects randomized to the 
pembrolizumab and radiotherapy group. 
Radiotherapy can be initiated after the first dose of immunotherapy and must be completed before 12 
weeks after first dose of immunotherapy administered. 
There is no size criterion for irradiated site and should follow this priority list: 
1. Growing area that may cause symptoms. 
2. Area that can tolerate the highest dose prescription (8 Gy x 3) based on normal tissue 
constraints. 
3. If all above equal, then order would be Pelvis, Abdomen, Liver, Lung, Bone. 
The goal of RT treatment is to deliver appropriate radiotherapy while minimizing exposure of 
surrounding normal tissues. Many different ways of delivering RT exist, and all are acceptable as long 
as the treating institution has completed the necessary credentialing. Most commercially available 
electron and photon-producing treatment units are allowed. As such, conventional linear accelerators 
and specialized linear accelerators with image guidance (e.g., Novalis, Trilogy, Synergy, Artiste, 
TrueBeam, Unity, ViewRay) are allowed. These units can be used with conformal dose delivery or 
IMRT. Specialized dose painting accelerators (e.g., Cyberknife, or Tomotherapy) are allowed provided 
they meet the technical specifications of the protocol and are used in a fashion that passes the 

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credentialing required by the protocol. Conventional linear accelerators without add-on IGRT must 
have some other IGRT capability like CT-on-rails in the treatment room. 
IGRT is required for this study. Either 3DCRT or IMRT (including VMAT) are acceptable planning 
techniques. IMRT (including VMAT) can result in dosimetric inaccuracies in circumstances where 
tumor motion is not properly considered. Planning techniques may differ for each lesion to be treated 
provided that the tumor motion is properly accounted for with each technique when the target or targets 
are in or near the thorax region. 
i. 
Dose Fractionation 
Patients will receive 3 fractions of radiation to a total dose of 24 Gy. 
For each metastatic location, Variation Acceptable range is described for plan 
scoring. Doses falling outside the range of Per Protocol and Variation Acceptable 
will be scored as Deviation Unacceptable. 
There should be a minimum of 40 hours between treatments to any single 
metastasis. 
ii. 
Technical Factors 
Physical Factors 
Only photon (x-ray) beams with photon energies  6MV or electron beam with 
electron energies 4 MeV – 20 MeV will be allowed. For metastases located 
within 3 cm of the lungs, photon energies of 6-10MV are required. Cobalt-60 and 
charged particle beams (including proton and heavier ions) are not allowed. 
For lung central and lung peripheral metastases, photon beam energies > 10 MV 
are allowed only for a limited number ( 50 of all beams or all beam angles) of 
beams that must travel more than a cumulative distance of 10 cm through soft 
tissue (not lung) to reach the isocenter OR a shorter distance if the tumor abuts 
the chest or abdominal wall (i.e., to spare skin dose). 
FFF photon beams are allowed if the institution has performed SBRT 
credentialing with FFF beams. 
Treatment Technology 
This protocol requires photon or electron treatment. Techniques including 
3DCRT, IMRT, VMAT are allowed. Delivery on LINACs, Tomotherapy, or 
CyberKnife are acceptable. 
Minimum Field Aperture (Field Size) Dimension 
Because of uncertainties in beam commissioning resulting from electronic 
disequilibrium within small beam apertures, an equivalent square field dimension 
of 3 cm is required for any field used for treatment delivery for sites using 
standard 3-D conformal technique where nearly all of the PTV is encompassed for 
each beam. It is understood that this may exceed the technical requirements for 
small lesions. In such cases, the prescription dose is still prescribed to the edge of 
the defined planning treatment volume (PTV). For sites using dose painting 
including IMRT techniques, whereby design the entire PTV is not encompassed 
for each beam, smaller beam apertures are allowed. In addition, if the site has 
specifically commissioned the beams for smaller field sizes, and if these same 
beams have been employed in IROC Houston QA Center credentialing, they may 
reduce the minimum field aperture requirement to the size that has been 
commissioned and credentialed. 
All institutions must use heterogeneity correction dose calculation algorithms 
approved by the IROC Houston QA Center independent of the treatment 
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Stereotactic Targeting 
For the purposes of this protocol, the term ‘stereotactic’ implies the targeting, 
planning, and directing of radiation beams along any trajectory in 3-D space 
toward a target of known 3-D coordinates. The coordinate system is defined by 
reliable ‘fiducials.’ A fiducial may be external or internal to the patient’s body. 
External fiducials may relate to a frame or treatment device. Internal fiducials 
may be implanted markers OR reliably identifiable anatomy that is clearly visible 
on orthogonal kV imaging, including the tumor itself. In all cases, the 
relationship between the fiducial and the actual tumor position in real-time 
should be reliably understood for both planning and treatment. 
Isocenter Placement 
When using a gantry mounted linear accelerator for this protocol, the isocenter is defined as the 
common intersection point of gantry, collimator, and couch rotation for the treatment unit. For 
other types of treatment units (e.g., Tomotherapy or CyberKnife), a reference point in space that 
is typically positioned at the center of the target is used instead of a mechanical isocenter. 
iii. 
Localization, Simulation, and Immobilization 
Patient Positioning (Immobilization) 
Patients will be positioned in a stable pose conducive to allowing accurate 
reproducibility of the target position throughout treatment. Positions 
uncomfortable for the patient should be avoided so as to prevent uncontrolled 
movement during treatments. Patient immobilization must be reliable enough to 
ensure that the gross tumor volume (GTV) does not deviate beyond the confines 
of the planning treatment volume (PTV). 
Positioning patients directly on the couch and relying solely on image-
guidance for reproducible set-up is strongly discouraged. 
Simulation 
All patients will undergo CT-based treatment planning in custom made 
immobilization devices. CT scan range must allow simultaneous view of the 
patient anatomy and fiducial system for stereotactic targeting (if used), and be 
adequate to ensure contouring of all targeted metastases, as well as necessary 
organs at risk (OAR), defined below. High- resolution CT scans should be 
obtained with uniform slice thickness of  3mm throughout. If a single CT scan 
cannot be obtained due to a large spatial separation between metastases (i.e., 
cervical and femoral metastases), or planning system slice number limitation, 
multiple CT scans are allowed provided that OAR are entirely encompassed in a 
single CT scan. 
Use of Contrast Agents 
The use of IV contrast will be required for liver metastases unless using an 
MRLinac. For other metastases (central & peripheral lung, cervical/mediastinal, 
abdominal-pelvic, and spinal/paraspinal), the use of IV contrast is encouraged but 
will be left to the discretion of the treating physician. 
The use of other contrast agents is left to the discretion of the treating 
oncologist. Vascular contrast from the planning dataset is recommended to 
be converted to water equivalent density if used for planning. Duplicate 
planning datasets obtained prior to injection of intravenous contrast may be 
used for dose calculation. 
Respiratory Motion Assessment and Management 

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All metastases with potential for respiratory motion should be evaluated by 
appropriate means including 4D CT scan, implanted fiducial marker, or 
fluoroscopy at the time of simulation. 
Respiratory motion management (RMM) including abdominal compression, 
active breathing control, breath hold, end expiratory gating, or fiducial marker 
tracking, is recommended for any metastasis to be treated with motion > 5mm. 
A recommended approach would be to use an ITV technique for motion < 1cm, 
but for motion > 1cm (typically too large for a free breathing ITV) motion 
management including but not limited to abdominal compression, active-
breathing control (ABC), gating, breath hold, etc. should be used. 
Localization Using Daily IGRT 
As an RT protocol, this study requires the use of IGRT. IGRT is a computer 
assisted process that uses imaging devices that generate a series of coordinates for 
shifting the patient support system in three orthogonal directions (sometimes also 
including rotational changes) to position the treatment beams relative to target 
regions. The allowed technologies are as follows: cone-beam CT (CBCT) using 
either a specially mounted kV imaging head or the MV treatment beam with an 
opposed electronic imaging panel, dual fixed-position in-room kV imaging 
systems that are orthogonal or near orthogonal, an in-room standard diagnostic 
CT scanner that is geometrically linked to the treatment unit, and the 
Tomotherapy or MRLinac approach. Although all of these units are allowed, 
some might not be appropriate for some disease sites. For example, orthogonal 
imaging techniques result in overlapping structures that are not as easily 
visualized compared to 3D cone-beam approaches. Simple portal imaging 
approaches that do not use computer assistance are not considered suitable for 
this study. 
When the treatment equipment does not include any device that allows direct 
visualization of anatomical structures using the treatment beam, the 
recommendations of AAPM Task Group Report 142 for testing the coincidence of 
the imaging and treatment reference points must be implemented. When 
specialized units such as Tomotherapy or Cyberknife are employed, the relevant 
AAPM guidance documents should be followed for testing the coincidence of 
imaging and treatment systems. 
IGRT Requirements 
The minimum IGRT requirement for each metastatic location is listed in Table 5-3. Volumetric 
imaging refers to 3D modalities (e.g., kV cone-beam, MV cone-beam, CT onrails, MRLinac), 
while orthogonal imaging refers to 2D modalities (e.g., kV OBI, ExacTrac). For volumetric 
imaging, appropriate CT window/level thresholds must be employed for registration at each 
metastatic location as outlined in Table 5-4. Additional IGRT may be employed at the 
discretion of the treating physician (i.e., orthogonal kV imaging prior to required volumetric 
imaging or volumetric imaging even if only orthogonal kV imaging is required). Note that when 
orthogonal kV imaging is employed for sites where respiratory motion is expected and not 
controlled via motion management techniques, care must be taken to ensure accurate targeting 
of the ITV within the treatment. For example, static kV imaging at an undetermined breath hold 
position would not be adequate IGRT for treating a free-breathing lung tumor. 
 

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Metastatic Location 
Minimum IGRT Requirement 
 
No Fiducials 
With Fiducials** 
Lung--Peripheral+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Lung—Central+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Mediastinal/Cervical LN 
Volumetric (3D) 
N/A 
Liver+ 
Volumetric (3D) 
Orthogonal kV (2D) 
Spinal 
Orthogonal kV (2D) 
Orthogonal kV (2D) 
Osseous* 
Orthogonal kV (2D) 
N/A 
Abdominal-pelvic+ 
Volumetric (3D) 
Orthogonal kV (2D) 
*NOTE: When osseous/rib metastases are classified into another metastatic location, follow 
the IGRT guidelines for that site. 
**NOTE: When a metastasis contains an implanted fiducial that is clearly visible on kV 
orthogonal or volumetric imaging, either method can be used. 
+NOTE: Registration to a soft tissue surrogate for the tumor is recommended for lung, liver, 
and abdominal-pelvic metastases for both 3D and 2D IGRT datasets. 
Use of a shortened CT planning scan for registration may be important for IGRT 
systems that cannot handle a large number of CT slices. A subset of the planning 
CT scan can be uploaded to the IGRT system for localization of each metastasis. 
The CT data should include the metastasis of interest plus at least 5 cm superiorly 
and inferiorly. 
iv. 
Target Volumes 
Site Location Definition: 
Site to be treated will be assigned to one of the seven “Metastasis Locations” as 
described below. 
Site Locations: 
Lung Central: GTV within 2 cm of proximal bronchial tree as described 
in RTOG 0813/0915: 
Tumor within or touching the zone of the proximal bronchial tree, defined as a 
volume 2 cm in all directions around the proximal bronchial tree (carina, right 
and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, 
right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi) 
[See Figure 5-1]. Tumors that are immediately adjacent to mediastinal or 
pericardial pleura (PTV touching the pleura) also are considered central tumors 
and are eligible for this protocol. A visual representation is shown below in 
Figure 5-1. 

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Figure 5-1 
Lung Peripheral: Metastases within the lung parenchyma with GTV outside of 
the proximal bronchial tree as described above. 
Mediastinal/Cervical LN: Mediastinal: GTV arising within the anatomic space 
between the lungs, above the diaphragm, and below the thoracic inlet at the level 
of the top of the sternal notch. Cervical Lymph nodes: GTV occurring within 
cervical lymph node Levels I-VI and/or retropharyngeal spaces. 
x 
Sternal metastases will be assigned to the mediastinal/cervical lymph 
node location based on potential for normal tissue toxicity. 
 
Liver: GTV arising within the liver. 
x 
Rib metastases immediately adjacent to the liver will be assigned to 
the liver metastasis location based on potential for normal tissue 
toxicity. 
Spinal: Metastases will be assigned to the spinal/paraspinal site if the GTV arises 
within the vertebral bodies expanded by 1 cm. Spinal metastases, shown in Figure 
5-2 in black, can involve: 
(a) The vertebral body only OR 
(b) The vertebral body and pedicle OR 
(c) Posterior elements only 
 

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Figure 5-2 
 
For each of these metastases, the PTV delineation will include: 
(a) the involved vertebral body and both pedicles (solid red line in Figure 5-2a) OR 
(b) a more generous delineation of the involved vertebral body and both 
pedicles (dashed red line in Figure 5-2b) OR 
(c) the involved vertebral body, both pedicles, and the anterior and posterior elements of 
the spine (solid red line in Figure 5-2b) OR 
(d) the spinous process and laminae (solid red line in Figure 5-2c) 
 
The target volume may be chosen at the discretion of 
the treating Radiation Oncologist based on the extent of 
tumor involvement. 
 
Spinal metastases with epidural extension will only be 
included if there is > 3 mm gap between the edge of the 
epidural metastasis and edge of the spinal cord. 
 
Metastases arising in the ribs within 1 cm of the edge of the 
vertebral body should be included in the spinal metastasis 
location, but osseous metastases planning guidelines are to 
be used. 
Osseous: GTV arising within an osseous structure, part of the axial 
skeleton, not included in the spinal definition. 
x 
Rib metastases that are within 1 cm of the vertebral bodies will be 
classified into the spinal metastasis location given the similar 
normal tissues at risk. 
x 
Rib/scapular metastases within the thorax adjacent to lung parenchyma 
will be classified into the lung metastasis location given the similar 
normal tissues at risk. 
x 
Rib/osseous metastases adjacent (< 1cm) to mediastinal or cervical 
structures will be classified into the mediastinal/cervical lymph node 
location given the similar normal tissues at risk. 
x 
Rib metastases adjacent (< 1cm) to the liver will be classified into 
the liver location given the similar normal tissues at risk. 
x 
Rib metastases adjacent to the stomach/abdominal wall will be 
classified into the intra-abdominal location given the similar normal 
tissues at risk. 
x 
Sternal metastases will be considered part of the 

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mediastinal/cervical lymph nodes location given the similar normal 
tissues at risk. 
Abdominal-pelvic: GTV arising within the anatomic space defined by the 
diaphragm superiorly, the genitourinary diaphragm inferiorly including the 
peritoneal and retroperitoneal spaces, not including liver, osseous, or spinal 
metastases. 
Target Volume Definition Based on Metastatic Location: 
Specific RT planning parameters depend on the location of the treated metastasis as well as mechanism 
used for motion management/evaluation. The table below defines appropriate planning CT 
window/leveling, recommended additional modality scans to be fused, as well as how to define the 
GTC, ITV, CTV, and PTV for each metastatic location. Only rigid registration will be permitted for 
multi-modality fusion. In general, the GTV is defined as the entirety of the metastasis as seen on 
planning CT scan aided by additional diagnostic imaging studies (i.e., PET/CT or MRI). Use of 
additional diagnostic studies is left to the discretion of the treating physician. The CTV=GTV; there is 
no margin added for microscopic extension. In general, either a helical CT or 4DCT will be used for 
defining the GTV/ITV depending upon the tumor motion encountered, although both scans may be 
acquired at the time of simulation. Typically, the ITV is generated using either expiratory/inspiratory 
phase scans or from reconstructed maximum intensity projection (MIP) scans. Maximum/minimum 
intensity projections (MIP/MinIP) should be used with caution because the MIP reconstruction for 
lung or MinIP reconstruction for liver may erroneously define an ITV in cases of significant irregular 
breathing or when tumors abut soft tissue structures (e.g., the diaphragm for MIP) or fat (for the 
MinIP). 
 
Metastatic Location 
Planning 
Parameter 
Lung 
Central 
Lung 
Peripheral 
Liver 
Abdominal
-pelvic 
Mediastinal 
/Cervical 
Lymph 
Nodes 
Osseos 
Spinal 
CT 
window/level 
Pulmonary/ 
Mediastinal 
Pulmonary/ 
Mediastinal 
Hepatic 
Soft 
tissue 
Pulmonary
/ Mediastin 
al 
Bone/ 
soft tissue 
Bone/ 
soft tissue 
Additional 
Studies 
PET/CT 
PET/CT 
PET/CT 
MRI 
PET/CT 
MRI 
PET/CT 
PET/CT 
MRI 
PET/CT 
MRI 
Multiphase 
CT 
N/A 
N/A 
N/A 
Yes 
N/A 
N/A 
N/A 
 
 
 
 
 
 
 
 
Anatomy of 
focus for 
multi- 
modality 
fusion 
Bony 
Anatomy 
Bony 
Anatomy 
Liver 
Bony 
Anatomy 
Bony 
Anatomy 
Bony 
Anatomy 
Bony 
Anatomy 
GTV 
definition 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
Metastasis 
CTV 
definition 
= GTV/ITV* = GTV/ITV* 
= GTV/ 
ITV* 
=GTV/ 
ITV* 
=GTV/ 
ITV*+ 
= GTV 
= GTV 
PTV axial 
expansion 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= CTV + 
5mm** 
= PTV in 
RTOG 
0631** 
(see Figure 
5-2) 

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PTV 
craniocaudal 
expansion 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= CTV + 
7mm** 
= PTV in 
RTOG 
0631** 
(see Figure 
5-2) 
*NOTE: A GTV to ITV expansion of greater than 1cm in any one direction is 
strongly discouraged and alternative respiratory management technique is 
suggested. 
**NOTE: When osseous/rib metastases are classified into other specific metastatic locations, the 
planning guidelines for that metastatic location should be used. If rib metastases are grouped into 
the spinal metastasis location, then the metastasis should be contoured as defined for osseous 
metastases, but the prescription doses for the spinal region should be used. 
+NOTE: Mediastinal lymph nodes should undergo motion assessment and an ITV 
should be generated to account for motion. 
v. 
Treatment Planning 
Planning Techniques 
General Considerations: A variety of planning techniques can be used to deliver RT. General 
guidelines include the following: 
x 
Multiple coplanar or non-coplanar beam arrangements are acceptable. 
x 
Typically 7-13 static radiation beams with equal weighting are 
used. It is recommended that at least 10 beams be used when 
possible. 
x 
A minimum field dimension of 3 cm should be observed while 
treating small metastases with 3D-CRT. 
x 
Dynamic conformal arcs are acceptable. It is recommended that arcs 
span a total for all beams of 340 degrees. 
x 
For non-IMRT or dose painting techniques, the conformal field aperture 
size and shape should correspond nearly identically to the projection of 
the PTV along a beam’s eye view (i.e., no additional “margin” for dose 
buildup at the edges of the blocks or MLC jaws beyond the PTV). The 
only exception will be when observing the minimum field dimension of 3 
cm when treating small lesions. 
x 
The prescription isodose line covering 95 the PTV will generally be 80-
90, but may range from 60-90 where the maximum dose is 100. As 
a result, a “hotspot” will exist within the PTV that is equal to the 
prescription dose divided by the prescription isodose line (i.e., 45 Gy/0.6 
= 75 Gy when 45 Gy is prescribed to the 60 isodose). 
x 
Doses higher than the prescription isodose (i.e., hotspots) should be 
manipulated to occur within the target. 
Dose calculations: All dose distributions shall include corrections for tissue 
heterogeneities. The approved algorithms to be used are found on the IROC 
Houston website (http://irochouston.mdanderson.org). 
Successful treatment planning will require accomplishment of all of the following 
criteria: 
1. 
Normalization: The treatment plan should be initially normalized 
such that 100 corresponds to the maximum dose within the PTV 
(MAXPTV). While this point will typically correspond to the PTV 
center of mass, it can be located elsewhere within the PTV. 
2. 
Prescription Isodose Surface Coverage: The prescription isodose 
surface will be chosen such that 95 of the target volume (PTV) is 

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conformally covered by the prescription isodose surface. Doses less 
than 95 of the prescription dose are restricted to the outside edges 
of the PTV as shown in Figure 5-3. The prescription isodose 
surface selected MUST be  60 and  90 of the dose maximum 
within the PTV (MAXPTV). The MAXPTV corresponds to the 
normalization point (100) of the plan as noted in number 1 
above. 
3. 
Target Dose Heterogeneity: Rather than prioritizing target dose 
homogeneity, RT treatment planning prioritizes adequate minimum 
target coverage and rapid dose fall-off gradients outside of the 
target. Hot spots within targets are generally accepted without 
consequence since targets are mostly tumor. The only exception is 
when the hotspot within the PTV also intersects an OAR (see 
Figure 5-3). 
4. 
Critical Organ Doses: Respect all critical organ dose-volume limits.  
5. 
High-Dose Spillage: 
a. Location: Any dose > 105 of the prescription dose should occur 
within the PTV and not within the normal tissues outside the PTV. 
See Figure 5-3. 
b. Volume: Acceptable isodose distributions should be as conformal 
as possible. To this end, the ratio of prescription isodose volume to 
PTV should be as small as possible. 
i. The ratio of the prescription isodose volume to the PTV 
volume should be < 1.2. Acceptable variations include a ratio 
of 1.2-1.5. Ratios above 1.5 will be considered unacceptable 
deviations. The prescription line for each lesion will be 
contoured for calculation of this ratio. The prescription line 
will be labelled as V_5000 with the 5000 changing to reflect 
the prescription dose in cGy. Contours with identical doses 
should be distinguished. 
ii. Guidelines for the ratio of the 50 prescription isodose 
volume to the PTV volume (R50) and for the maximum 
dose at 2cm (D2cm) from the PTV are given in Table 5-5. 
Additionally, the 50 isodose volume may be elongated 
deliberately in order to avoid OAR, thereby making it difficult 
to meet the guidelines in Table 5-5. This is acceptable as long 
as normal tissue constraints are met. 
iii. Given that conformal tumor coverage is often more difficult to 
achieve in lung than in more homogeneous organs, these ratios 
should serve as a guide for liver, abdominal-pelvic, 
mediastinal/cervical metastases as well. 
iv. Elliptically shaped metastases as well as extremity metastases 
may not meet these guidelines. This is acceptable as long as 
normal tissue constraints are respected. These criteria will not 
be required in treating very small tumors (< 2.5 cm axial GTV 
dimension or < 1.5 cm craniocaudal GTV dimension) in which 
the required minimum field size of 3 cm results in the inability 
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Table 5-5 
PTV Volume (cc) 
Ratio of 50% Prescription 
Isodose Volume to PTV 
Volume, R50% 
Maximum Dose at 2cm 
(D2cm) from PTV in any 
direction as % of 
Prescribed Dose 
1.8 
< 7.5 
<57.0 
3.8 
< 6.5 
<57.0 
7.4 
< 6.0 
<58.0 
13.2 
< 5.8 
<58.0 
22.0 
< 5.5 
<63.0 
34.0 
< 5.3 
<68.0 
50.0 
< 5.0 
<77.0 
70.0 
< 4.8 
<86.0 
95.0 
< 4.4 
<89.0 
126.0 
< 4.0 
<91.0 
163.0 
< 3.7 
<94.0 
 
NOTE: For values of PTV dimension or volume not specified, linear 
interpolation between table entries is required. 
NOTE: For tumors within 2 cm of the skin, it may be difficult to meet the 
values for D2cm and R50. In these cases, these criteria will not be used. 
Figure 5-3 
 
Planning Priorities 
Every attempt should be made to successfully satisfy all of the planning goals 
and OAR criteria without receiving a plan score of Deviation Unacceptable. In 
some circumstances, it may not be possible to meet all the ideal criteria, leading 

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to plans in the Variation Acceptable range. Thus, suggested priority of planning 
goals in order of importance is: 
1. Respect spinal cord, cauda equina, sacral plexus and brachial 
plexus dose constraints. 
2. Meet dose “compactness” constraints including the prescription 
isodose surface coverage, high-dose spillage (location and volume), 
and intermediate dose spillage (D2cm, and R50) as these define the 
aim in using RT. Dose compactness should be assessed for plans based 
on treatment dose for a single lesion.  
Meet critical structure constraints other than those listed in 1. The 
OAR constraints are last in priority (except for nervous system 
tolerance) because they are the least validated. The aim of a RT plan is 
captured mostly in the dose compactness criteria, thereby justifying 
their higher priority. As an example, in a case where not all goals can 
be met, it would be suggested to meet dose compactness goals without 
deviation, even at the expense of a non- spinal cord normal tissue 
having an acceptable variation. Unacceptable deviations should be 
avoided in all cases. 
3. In cases where PTV coverage cannot be achieved while avoiding 
unacceptable deviations to OARs coverage of a section of PTV 
including or immediately adjacent to the OAR may be as low as 70 
of the prescription dose ONLY in this situation.  
vi. 
Critical Structures 
Note: All required structures must be labeled as listed below in Table 5-6 for 
digital RT data submission.  
The following table outlines the required naming of the various normal and 
critical structures. 
Table 5-6 
Standard Name 
Description 
Group 1 : Lung - Peripheral 
 
PTV_2400_1 
For peripheral lung tumors. 
GTV_2400_1 
For peripheral lung tumors 
PTV_20_1 
PTV with 2cm expansion 
NonPTV_1 
External minus PTV 
NonPTV_20_1 
External minus PTV_20 (PTV 
with a 2 cm expansion) 
SpinalCord 
Spinal cord 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, 
lingular bronchus right and left 
lower lobe bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
proximal bronchial tree expanded by 
2cm 

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Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured 
Heart 
Heart 
External 
Body surface 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Liver 
Liver 
BileDuct 
Bile duct 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Group 2 : Lung - Central 
Description 
PTV_2400_2 
For central lung tumors 
GTV_2400_2 
For central lung tumors 
PTV_20_2 
PTV with 2cm expansion 
NonPTV_2 
External minus PTV 
NonPTV_20_2 
External minus PTV_20 (PTV with a 2 
cm expansion) 
SpinalCord 
Spinal cord 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, 
lingular bronchus right and left lower 
lobe bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
proximal bronchial tree expanded by 
2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured 
Heart 
Heart 
External 
Body surface 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 

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Kidneys 
Total kidneys 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 3 : Mediastinal/ Cervical Lymph Node 
Description 
PTV_2400_3 
For mediastinal and cervical lymph 
node tumors. 
GTV_2400_3 
For mediastinal and cervical lymph 
node tumors. 
PTV_20_3 
PTV with 2cm expansion 
NonPTV_3 
External minus PTV 
NonPTV_20_3 
External minus PTV_20 (PTV with a 2 
cm expansion) 
SpinalCord 
Spinal cord 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
BronchialTree 
carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, lingular bronchus right 
and left 
lower lobe bronchi 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchTree_20 
proximal bronchial tree expanded by 
2cm 
Larynx 
Larynx 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured by outlining the bone and 
marrow 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 
Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 4 : Liver 
Description 
PTV_2400_4 
For liver tumors. 
GTV_2400_4 
For liver tumors. 
PTV_20_4 
PTV with 2cm expansion 
NonPTV_4 
External minus PTV 
NonPTV_20_4 
External minus PTV_20 (PTV with a 2 
cm expansion) 

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SpinalCord 
Spinal cord 
ChestWall 
Chest wall 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Femurs 
Both Femurs 
Duodenum 
Duodenum 
Bladder 
Bladder 
Liver 
Liver 
BileDuct 
Bile duct 
Ureter 
Ureter 
Bowel 
Large and Small Bowel 
Group 5 : Spinal/ Paraspinal 
Description 
PTV_2400_5 
For spinal/paraspinal tumors. 
GTV_2400_5 
For spinal/paraspinal tumors. 
NonPTV_5 
External minus PTV 
NonPTV_10_5 
External minus PTV_10 (PTV with a 1 
cm expansion) 
NonPTV_20_5 
External minus PTV_20 (PTV with a 
2.0 cm expansion) 
SpinalCord 
Spinal cord 
SpinalCord_Prt 
A portion of the spinal cord contoured 
near a target 
BrachialPlexus 
Brachial plexus 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
CaudaEquina 
Cauda equine 
SacralPlexus 
Sacral plexus 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchialTree 
Carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, 
lingular bronchus right and left lower 
lobe bronchi 
BronchTree_20 
Proximal bronchial tree expanded by 
2cm 
 
 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured by outlining 
the bone and marrow 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 

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Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Liver 
Liver 
BileDuct 
Bile duct 
Duodenum 
Duodenum 
Bowel 
Large and Small Bowel 
Rectum 
Rectum 
Bladder 
Bladder 
Femurs 
 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 6 : Osseous 
Description 
PTV_2400 _6 
 
For non-spinal osseous tumors. 
GTV_2400_6 
For non-spinal osseous tumors. 
 
 
NonPTV _6 
External minus PTV 
NonPTV_10 _6 
External minus PTV_10 (PTV with a 1 
cm expansion) 
NonPTV_20 _6 
External minus PTV_20 (PTV with a 
2.0 cm expansion) 
SpinalCord 
Spinal cord 
SpinalCord_Prt 
A portion of the spinal cord contoured 
near a target 
BrachialPlexus 
Brachial plexus 
CaudaEquina 
Cauda equine 
BrachialPlex_L 
Left Brachial Plexus 
BrachialPlex_R 
Right Brachial Plexus 
SacralPlexus 
Sacral plexus 
Esophagus 
Esophagus 
GreatVessels 
Great Vessels 
BronchialTree 
Carina, right and left main bronchi, 
right and left upper lobe bronchi, 
intermedius bronchus, right middle 
lobe bronchus, 
lingular bronchus right and left lower 
lobe bronchi 
BronchTree_20 
Proximal bronchial tree expanded by 
2cm 
ChestWall 
Chest wall 
Rib 
Ribs within 5 cm of the PTV should be 
contoured by outlining 
the bone and marrow 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Lungs 
Combined Left and Right Lungs 
Lung_R 
Right Lung 

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Lung_L 
Left Lung 
Trachea 
Trachea 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Liver 
Liver 
BileDuct 
Bile duct 
Duodenum 
Duodenum 
Bowel 
Large and Small Bowel 
Rectum 
Rectum 
Bladder 
Bladder 
Femurs 
 
Esoph_NonAdj 
Esophagus (Non-adjacent wall) 
Trachea_NonAdj 
Trachea (Non-adjacent wall) 
GrVess_NonAdj 
Great vessels (Non-adjacent wall) 
Group 7 : 
Abdominal-pelvic 
metastases (lymph node/ adrenal gland) 
Description 
PTV_2400 _7 
For abdominal-pelvic tumors. 
GTV_2400 _7 
For abdominal-pelvic tumors. 
PTV_20 _7 
PTV with 2cm expansion 
NonPTV _7 
External minus PTV 
NonPTV_20 _7 
External minus PTV_20 (PTV with a 2 
cm expansion) 
SpinalCord 
Spinal cord 
CaudaEquina 
Cauda equina 
SacralPlexus 
Sacral plexus 
ChestWall 
Chest wall 
Heart 
Heart 
External 
Skin 
SkinOAR 
skin will be defined as the outer 
0.5 cm of the body surface 
Stomach 
Stomach 
Kidney_R 
Right Kidney 
Kidney_L 
Left Kidney 
Kidneys 
Total kidneys 
Femurs 
Both Femurs 
Duodenum 
Duodenum 
Bladder 
Bladder 
Liver 
Liver 
BileDuct 
Bile duct 
Bowel 
Large and Small Bowel 
 
Planning RT Near Prior Radiotherapy Volumes 
The toxicity of delivering RT to an area in close proximity to prior 
conventionally fractionated external beam radiotherapy (EBRT) volumes is not 
known. Therefore, overlap of protocol treatment SBRT isodoses with prior 
fractionated external beam volumes must be minimized. 
Organs at Risk 
For all metastases, specific organs at risk (OAR) must be contoured. The specific OAR to be 
contoured will depend on the location of the metastasis to be treated. The contour of structures 
that have a lumen (bronchus, trachea, esophagus, etc.) will include both the “wall” and the 

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“lumen” to result in a cylindrical structure. In general, OAR within 3 cm of any single 
metastasis should be contoured. To identify these OARs, all PTVs will be expanded by 3cm and 
any OAR that overlaps with PTV + 3cm must be contoured. 
Lung Central/Lung Peripheral/Mediastinal/Cervical Lymph Node metastases: 
x 
Proximal tracheobronchial tree (as defined by Timmerman et al. 2006) 
x 
Lungs, left/right/combined 
x 
Heart 
x 
Great vessels 
x 
Trachea 
x 
Esophagus 
x 
Spinal cord 
x 
Chest wall 
x 
Brachial plexus 
x 
Skin 
x 
Liver 
x 
Bile duct 
x 
Kidney, left/right 
x 
Larynx 
x 
Stomach 
x 
Rib 
Liver/Abdominal-pelvic metastases: 
x 
Heart 
x 
Stomach 
x 
Duodenum 
x 
Spinal cord 
x 
Kidney, left/right 
x 
Bowel 
x 
Rectum 
x 
Bladder 
x 
Skin 
x 
Lungs, left/right/combined 
x 
Liver 
x 
Bile duct 
x 
Chestwall 
x 
Sacral plexus 
x 
Cauda equine 
x 
Femurs 
 
Spinal Metastases: 
x 
For all spinal metastases, the partial spinal cord volume as per 
RTOG 0631 should be defined as follows: the partial spinal cord 
should be contoured starting from 5-6 mm above the superior extent 
of the target volume to 5-6 mm below the inferior extent of the 
target volume. 
x 
For thoracic and cervical spinal metastases, follow guidelines for 
pulmonary/ mediastinal/cervical metastases depending upon nearby 
organs at risk. 
x 
For lumbar metastases, follow guidelines for abdominal-pelvic 

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metastases. 
Osseous Metastases: 
x 
OAR for osseous metastases will depend on the location of the 
osseous metastasis. 
NOTE: OARs listed above should be contoured in their entirety if a portion of 
that organ is located within 3 cm of the osseous metastases. 
Contouring of Normal Tissue Structures 
In order to verify each of these limits, the organs must be contoured such that 
appropriate volume histograms can be generated. Instructions for the contouring of 
these organs are as follows: 
Spinal Cord 
The spinal cord will be contoured based on the bony limits of the spinal canal 
ending at L2. The spinal cord should be contoured starting at least 10 cm above the 
superior extent of the PTV and continuing on every CT slice to at least 10 cm 
below the inferior extent of the PTV. 
Cauda Equina 
Starting at the conus (end of spinal cord, typically around L1 or L2), include 
the entire spinal canal into the sacrum to the filum. 
Sacral Plexus 
Include the nerve roots from L5 to S3 on each side from the 
neuroforamina to the coalescing of the nerves at the obturator internus 
muscle. 
Esophagus 
The esophagus will be contoured using mediastinal windowing on CT to 
correspond to the mucosal, submucosa, lumen, and all muscular layers out to the 
fatty adventitia. The esophagus should be contoured starting at least 10 cm 
above the superior extent of the PTV and continuing on every CT slice to at 
least 10 cm below the inferior extent of the PTV. 
Brachial Plexus 
The defined ipsilateral brachial plexus originates from the spinal nerves exiting 
the neuroforamine on the involved side from around C5 to T2. However, for the 
purposes of this protocol, only the major trunks of the brachial plexus will be 
contoured using the subclavian and axillary vessels as a surrogate for identifying 
the location of the brachial plexus. This neurovascular complex will be contoured 
starting proximally at the bifurcation of the brachiocephalic trunk into the 
jugular/subclavian veins (or carotid/subclavian arteries) and following along the 
route of the subclavian vein to the axillary vein ending after the neurovascular 
structures cross the second rib. If PTV of all metastases are more than 10 cm away 
from the brachial plexus, this structure need not be contoured. 
Heart 
The heart will be contoured along with the pericardial sac. The superior aspect (or 
base), for purposes of contouring, will begin at the level of the inferior aspect of 
the aortic arch (aortopulmonary window) and extend inferiorly to the apex of the 
heart. 
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The trachea and proximal bronchial tree will be contoured as two separate 
structures using mediastinal windows on CT to correspond to the mucosal, 
submucosa, and cartilage rings and airway channels associated with these 
structures. For this purpose, the trachea will be divided into two sections: the 
proximal trachea and the distal 2 cm of trachea. The proximal trachea will be 
contoured as one structure, and the distal 2 cm of trachea will be included in the 
structure identified as the proximal bronchial tree. 
x 
Proximal Trachea 
Contouring of the proximal trachea should begin at least 10 cm 
superior to the extent of the PTV for lung metastases or 5 cm superior 
to the carina (whichever is more superior) and continue inferiorly to 
the superior aspect of the proximal bronchial tree. 
 
Proximal Bronchial Tree 
The proximal bronchial tree will include the most inferior 2 cm of 
distal trachea and the proximal airways on both sides, as indicated in 
Figure 5-1. The following airways will be included according to 
standard anatomic relationships: the distal 2 cm of trachea, the carina, 
the right and left mainstem bronchi, the right and left upper lobe 
bronchi, the intermedius bronchus, the right middle lobe bronchus, the 
lingular bronchus, and the right and left lower lobe bronchi. 
Contouring of the lobar bronchi will end immediately at the site of a 
segmental bifurcation. If there are parts of the proximal bronchial tree 
that are within GTV, they should be contoured separately, as 
“proximal bronchial tree GTV,” not as part of the “proximal bronchial 
tree.” 
Whole Lung 
Both the right and left lungs should be contoured as one structure. Contouring 
should be carried out using pulmonary windows. All inflated and collapsed lung 
should be contoured; however, gross tumor (GTV) and trachea/ipsilateral 
bronchus as defined above should not be included in this structure. 
Proximal Bronchial Tree Plus 2 cm 
As part of determining if lung metastases are central or peripheral, adhering to the 
eligibility of the zone of the proximal bronchial tree, the RTOG SBRT protocols 
defined an artificial structure 2 cm larger in all directions from the proximal 
bronchial tree. If the GTV falls within this structure, the patient is eligible for this 
protocol. Most treatment planning systems have automatic contouring features 
that will generate this structure without prohibitive effort at the time of treatment 
planning. This structure is not required by the protocol, but its construction is 
suggested to facilitate appropriateness of patient selection. Alternately, 
participating sites may use ruler tools in the treatment planning software to ensure 
protocol compliance. 
Skin 
The external contour of the patient will be contoured. The skin OAR will be 
defined as the outer 0.5 cm of the body surface. As such it is a rind of 
uniform thickness (0.5 cm) which envelopes the entire body in the axial planes. 
The cranial and caudal surface of the superior and inferior limits of the planning 
CT should not be contoured as skin unless skin is actually present in these 
locations (e.g., the scalp on the top of the head). 

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Great Vessels 
The great vessels (aorta and vena cava, not the pulmonary artery or vein) will be 
contoured using mediastinal windowing on CT to correspond to the vascular wall 
and all muscular layers out to the fatty adventitia. The great vessel should be 
contoured starting at least 10 cm above the superior extent of the PTV and 
continuing on every CT slice to at least 10 cm below the inferior extent of the 
PTV. For right-sided tumors, the vena cava will be contoured, and for left-sided 
tumors, the aorta will be contoured. 
Non-adjacent Wall of a Structure 
For the esophagus, trachea and proximal bronchial tree, and great vessels, the 
nonadjacent wall corresponds to the half circumference of the tubular structure 
not immediately touching the GTV or PTV. These contours would start and stop 
superiorly and inferiorly just as with the named structure. The half lumen of the 
structure should be included in this contour. 
Stomach 
The entire stomach and its contents should be contoured as a single structure as a 
continuation of the esophagus and ending at the first part of the duodenum. 
Duodenum 
The wall and contents of the 1st, 2nd, and 3rd parts of the duodenum will be 
contoured as one structure beginning where the stomach ends and finishing as the 
superior mesenteric artery crosses over the third part of the duodenum. 
Bowel (Large/Small) 
The bowel should be contoured from the ileocecal area to include the ascending, 
transverse, descending, and sigmoid colon as one structure. 
Rectum 
The entire rectum with contents from the peritoneal reflection of the sigmoid to 
the anus should be contoured. 
Bladder 
This organ will be contoured as bladder wall exclusive of urinary contents. 
Kidney (renal cortex) 
Both the right and left kidney, excluding renal pelvis/collecting system, should be contoured in 
their entirety (the renal cortex). 
Liver 
The entire liver minus the GTV targets should be contoured. 
Bile ducts 
To contour the bile ducts, use the portal vein from its juncture with the splenic 
vein to its right and left bifurcation in the liver (as a surrogate to identify the bile 
ducts). 
Femoral Heads 
The ball of the head and socket joint should be contoured. 
Rib 
Ribs within 5 cm of the PTV should be contoured by outlining the cortical bone 
including the intramedullary space. Typically, several portions of adjacent ribs will 
be contoured as one structure. Adjacent ribs, however, should not be contoured in a 
contiguous fashion (i.e., do not include the inter-costal space as part of the ribs). 

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PTV + 2 cm 
As part of the QA requirements for “low-dose spillage” listed above, a maximum 
dose to any point 2 cm away in any direction is to be determined (D2cm). To 
facilitate this QA requirement, an artificial structure 2 cm larger in all directions 
from the PTV is required. Most treatment planning systems have automatic 
contouring features that will generate this structure without prohibitive effort at 
the time of treatment planning. If possible, this structure should be constructed as 
a single contour that is 2 cm larger than the PTV. 
Other Structures 
The constraints tables above contain other structures. These are required if the 
structure is within 3 cm of the PTV. 
Planning priorities for Organs at Risk: 
The spinal cord doses are absolute limits, and treatment delivery that exceeds these 
limits will constitute an unacceptable deviation. However, some OAR (i.e., the 
esophagus, trachea, bronchi and heart within the lung) may be situated adjacent to 
the treated GTV/PTV. As such, there is no specified limit as tumors that are 
immediately adjacent to that organ will not be able to be treated to the prescription 
doses without irradiating a small volume of that organ to the prescribed dose. In 
such a case, the planning must be accomplished so that there is no hot spot within 
that organ, even if that organ is part of the GTV/PTV, i.e., that no part of any 
serial OAR receives more than 105 of the prescribed dose (deviation 
unacceptable). In addition, the volume of the OAR in question needs to be 
minimized, both in length and in the width (i.e., circumference), with efforts made 
to reduce the dose to the contralateral wall of the organ. For parallel OAR, 
exceeding the doses in Table 5-7 by more than 110 of the prescribed dose will 
be considered an unacceptable deviation. 
For non-spinal cord OAR with known sensitivity to high doses of radiation 
(including the bowel, esophagus, and stomach) included within a PTV or 
immediately adjacent to PTVs, a prescription dose at the lower end of acceptable 
variation should be used. 
Additionally, every effort should be made to cover the GTV with the prescription 
dose while ensuring rapid falloff to the organ at risk. Coverage of a section of 
PTV including or immediately adjacent to the OAR may be as low as 70 of the 
prescription dose ONLY in this situation. Every effort should be made to cover 
100 of the GTV by the prescription dose at the lower end of acceptable 
variation. Since the tumor and normal tissue may not allow strict avoidance, the 
larger volume limits will not be scored as unacceptable deviations if exceeded. 
For tumors that are not immediately adjacent to any OAR, centers are encouraged to 
observe prudent treatment planning principles in avoiding unnecessary radiation exposure 
to critical normal structures; we expect that the OAR doses will be as low as achievable 
(ideally, < 6 Gy/fraction). 
Table 5-7 
Serial Organ 
DVH Metric 
Per Protocol 
Dose (Gy) 
Variation 
Acceptable 
Dose (Gy) 
Avoidance 
Endpoint 
Spinal Cord 
D1.2cc[Gy] 
<13 
----- 
Myelitis (Timmerman) 
 
D0.03cc[Gy] 
<22.5 
----- 
Myelitis (Timmerman) 
Ipsilateral 
Brachial Plexus 
D3cc[Gy] 
<22 
<25.2 
Brachial Plexopathy 
(Timmerman) 
 
D0.03cc[Gy] 
<26 
----- 
Brachial Plexopathy 
(Timmerman) 

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Cauda Equina 
D0.03cc[Gy] 
<25.5 
----- 
Neuritis (Timmerman) 
 
D5cc[Gy] 
<21.9 
----- 
Neuritis (AAPM TG-101) 
Sacral Plexus 
D0.03cc[Gy] 
<24 
----- 
Neuropathy (AAPM TG-
101) 
 
D5cc[Gy] 
<22.5 
----- 
Neuropathy (AAPM TG-
101) 
Trachea and 
Ipsilateral 
Bronchus * 
D5cc[Gy] 
<25.8 
----- 
Stenosis/Fistula 
(Timmerman) 
 
D0.03cc[Gy] 
<30 
----- 
Stenosis/Fistula (Z4099) 
Esophagus * 
D5cc[Gy] 
<17.7 
<25.2 
Stenosis/Fistula (Z4099) 
 
D0.03cc[Gy] 
<27 
----- 
Stenosis/Fistula 
(Timmerman 
2006/RTOG0618) 
Heart 
D15cc[Gy] 
<24 
<25.2 
Pericarditis (Z4099) 
 
D0.03cc[Gy] 
<30 
----- 
Pericarditis (Z4099) 
Great Vessels 
D10cc[Gy] 
<39 
----- 
Aneurysm (Z4099) 
 
D0.03cc[Gy] 
<45 
----- 
Aneurysm(Z4099) 
Skin 
D10cc[Gy] 
<31 
----- 
Ulceration (Timmerman) 
 
D0.03cc[Gy] 
<33 
----- 
Ulceration (Z4099) 
Stomach 
D10cc[Gy] 
<22.5 
<25.2 
Ulceration/Fistula 
(Timmerman) 
 
D0.03cc[Gy] 
<30 
----- 
Ulceration/Fistula 
(Timmerman) 
Duodenum * 
D10cc[Gy] 
<15 
<25.2 
Ulceration (Timmerman 
2006) 
 
D0.03cc[Gy] 
<24 
<25.2 
Ulceration(Timmerman 
2006) 
Bowel * 
D20cc[Gy] 
<24 
<25.2 
Colitis/Fistula (Z4099) 
 
D0.03cc[Gy] 
<34.5 
----- 
Ulceration (Timmerman) 
Rectum* 
D0.03cc[Gy] 
<49.5 
----- 
Ulceration (Timmerman) 
 
D3.5cc[Gy] 
<45 
----- 
Proctitis/Fistula 
(Timmerman) 
 
D20cc[Gy] 
<27.5 
----- 
Proctitis/Fistula 
(Timmerman) 
Bladder 
D0.03cc[Gy] 
<33 
----- 
Cystitis/Fistula 
(Timmerman) 
 
D15cc[Gy] 
<16.8 
<25.2 
Cystitis/Fistula (AAPM 
TG-101) 
Ureter 
D0.03cc[Gy] 
<40 
----- 
Stenosis (Timmerman) 
Penile bulb 
D3cc[Gy] 
<25 
<25.2 
Impotence (Timmerman) 
Femoral heads 
D10cc[Gy] 
<24 
<25.2 
Necrosis (Timmerman) 
Bile duct 
D0.03cc[Gy] 
<36 
----- 
Stenosis (Timmerman) 
Renal 
hilum/vascular 
trunk 
D15cc[Gy] 
<19.5 
<25.2 
Malignant Hypertension 
(Timmerman) 
Rib 
D5cc[Gy] 
<40 
----- 
Pain/Fracture 
(Timmerman) 
 
D0.03cc[Gy] 
<50 
----- 
Pain/Fracture 
(Timmerman) 
Parallel Organ 
 
 
 
 
Lung Total 
D15[Gy] 
<20 
<22 
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D37[Gy] 
<11 
<12.1 
Pneumonitis (Timmerman) 
 
CV10.5Gy[cc]** 
>1500 cc 
------- 
Basic Lung Function 
(Z4099) 
 
CV11.4Gy[cc]** 
>1000 cc 
------- 
Pneumonitis (Z4099) 
Total Kidney 
CV15Gy[cc]** 
>200 cc 
------- 
Basic Kidney 
Function (Timmerman) 
Liver 
CV17.1Gy[cc]** 
>700 cc 
------- 
Liver Function 
(Timmerman 2006, Z4099) 
*  NOTE: 1) Every effort should be made to avoid circumferential irradiation. 
    NOTE: 2) Doses to serial OARs up to and including 105 of the dose 
prescribed to the PTV will be scored as Variation Acceptable. Doses 
to parallel OARs up to 110 of the values listed in the table will be 
scored as Variation Acceptable. Doses above these values will be 
scored as Deviation Unacceptable. 
** NOTE: 3) A complementary volume (CV) or “cold volume” is the volume of 
tissue receiving the indicated dose or less. CVxGy[cc] are 
complementary or cold volume objectives for parallel tissues, where 
"xGy" is the threshold dose and the critical volumes are displayed in 
the table. 
Rib/Chest Wall Dose Constraints 
Recent reports have highlighted that the rib and chest wall in proximity to the 
treated lesion may represent an organ at risk for complication. Tumor location, 
particularly when located peripherally, will enhance the potential risk for chest 
wall toxicity. While target coverage should not be compromised to limit dose to 
the rib/chest wall, every effort should be made to minimize dose to this OAR. 
vii. 
Documentation Requirements 
Treatment Interruptions 
In general, treatment interruptions should be avoided by preventative medical 
measures and supportive therapies. Treatment breaks, including indications, must 
be clearly documented on the treatment record. 
Quality Assurance Documentation 
See Section 7.2.1 for the list of items to be submitted for review. 
viii. 
Compliance Criteria 
Treatment Duration 
Treatment Duration will be defined per metastasis 
Per Protocol: 
x 
3 fraction treatment: All 3 fractions of SBRT should be completed 
within 2 weeks of first SBRT dose 
Acceptable Variation: Treatment completing > 2 but < 3 weeks 
Unacceptable Deviation: Treatment completed > 3 weeks 
PTV Dosimetry Compliance 
Per Protocol: The entire PTV receives >95 of the prescription dose. 
Variation Acceptable: The entire PTV receives 70-95 of the prescription dose. 
Deviation Unacceptable: The entire PTV receives <70 of the prescription dose. 
Conformity Compliance 

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Per Protocol: The ratio of the prescription isodose volume to the PTV volume is 
<1.2. 
Variation Acceptable: The ratio of the prescription isodose volume to the PTV 
volume is <1.5. 
Deviation Unacceptable: The ratio of the prescription isodose volume to the PTV 
volume is >1.5. 
Organ at Risk Dosimetry Compliance 
Respect spinal cord, cauda equina, sacral plexus and brachial plexus dose 
constraints. Any dose to spinal cord, cauda equina, sacral plexus above that listed 
in Table 5-7 will be considered an unacceptable deviation. For all other serial 
OARs, when OAR dose criteria provided in Table 5-7 cannot be accomplished by 
following planning priorities listed above, doses to the OARs of more than 105 
of the dose prescribed to the PTV will be scored as Deviations Unacceptable. For 
serial OARs with per protocol limits greater than 105 of the prescribed dose, 
there are no variation acceptable criteria, and exceeding the per protocol limit will 
be considered an unacceptable deviation. Doses to parallel OARs exceeding 
110 of the doses listed in Table 5-7 will be scored as unacceptable deviations. 
Radiation Therapy Adverse Events 
All Radiation Therapy AEs will be scored according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4. 
Adverse events related to SBRT for the treatment of metastases are dependent on the location of the 
metastases treated, as well as from exposure of surrounding normal tissues. 
For all treated metastases, fatigue is likely to occur and should be transient, lasting < 8 weeks. Other 
adverse events are likely to be related to the specific metastatic location receiving SBRT. 
Lung (Central and Peripheral), Mediastinal/Cervical Lymph Node Metastases: 
Cardiac and Pericardial Injury 
Although cardiac and pericardial injury is uncommon in the conventionally fractionated course of RT, 
with large doses per fraction of RT a number of possible side-effects can be seen. 
Gastrointestinal/Esophageal Injury 
The radiation effects on the esophagus can be acute: esophagitis (i.e., dysphagia, causing pain on 
swallowing, typically relatively soon after RT course is completed, and typically resolves on its own 
within days to a week or longer), or chronic, typically manifesting with dysphagia due to stenosis, or 
esophageal ulceration, with perforation in the extreme cases. 
Central Airway/Bronchial Injury 
This bronchial injury with subsequent focal collapse of lung may impair overall pulmonary status. It 
also makes further assessment of tumor response more difficult as the collapsed lung approximates the 
treated tumor. Because atelectatic lung and tumor have similar imaging characteristics, radiology 
reports will often describe the overall process as progressive disease, while the actual tumor may be 
stable or shrinking. 
The consequences of bronchial toxicity, e.g., cough, dyspnea, hypoxia, impairment of pulmonary 
function test parameters, pleural effusion or pleuritic pain (associated with collapse), should all be 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE), v. 4; MedDRA, 
v. 12.0. 
Lung Injury 
Radiation pneumonitis is a subacute (weeks to months from treatment) inflammation of the end 
bronchioles and alveoli. Radiation fibrosis is a late manifestation of radiation injury to the irradiated 
lung. Given the small amount of lung that is typically included in the SBRT portals, lung toxicity has 

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not been as dose-limiting as in conventionally fractionated, large-field RT, but it is nevertheless seen, 
can be symptomatic, and may be confused with other causes of respiratory deterioration, including 
infections, and tumor recurrence. 
Given that larger volumes of lung may be irradiated in this protocol compared to SBRT for primary 
tumors, it is very important that a Radiation Oncologist participate in the care of the patient, as the 
clinical picture may be very similar to acute bacterial pneumonia, with fatigue, fever, shortness of 
breath, nonproductive cough, and a pulmonary infiltrate on chest x-ray. The infiltrate on chest x-ray 
should include the area treated to high dose, but may extend outside of these regions. The infiltrates 
may be characteristically “geometric” corresponding to the radiation portal, but may also be ill defined. 
Patients reporting symptoms as above will be promptly evaluated and treated. Mild radiation 
pneumonitis may be treated with nonsteroidal anti-inflammatory agents or steroid inhalers. More 
significant pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary 
hygiene. Supra- and concurrent infections should be treated with antibiotics. Consideration of 
prophylaxis of opportunistic infections should be considered in immunocompromised patients. 
Liver/abdominal-pelvic metastases 
Very likely (80-90): Patients may experience fatigue (which generally goes away after the radiation 
therapy is completed), skin irritation, redness, itchiness, discomfort, temporary changes in blood work 
(decrease in blood counts, increase in liver enzymes), without symptoms. 
Less likely (30%): Patients may experience nausea, vomiting (during therapy) – more common if 
stomach or gastrointestinal tract irradiated, gastric, esophagus, small bowel or large bowel 
irritation/ulceration, bleeding, fistula, obstruction or changes in motility following therapy (may 
require medications or surgery) (<10 permanent changes), chest wall pain, and rib fracture (< 10). 
Less likely, but serious (<20%): Patients may experience radiation-induced liver disease (RILD) 
(<5). Classic RILD is a clinical diagnosis of anicteric ascites, hepatomegaly and elevation of alkaline 
phosphatase relative to other transaminases that may occur 2 weeks to 3 months following radiation to 
the Liver; non-classic RILD includes elevation of liver enzymes and/or any decline in liver function 
within 12 weeks from start of therapy (~20). RILD can lead to liver failure that could lead to death. 
There is an increased risk of liver toxicity in patients with large tumors and in patients with pre- 
existing liver disease. In addition, permanent thrombocytopenia (<1) may lead to bleeding, and 
kidney injury (<1) may lead to changes on imaging and more rarely the need for medication. 
Spinal metastases 
Radiation Myelitis 
Given the proximity and position of the spinal cord in relation to the radiosurgery target, every effort 
should be made to minimize the radiation dose to the spinal cord. Radiation myelitis is a subacute or 
chronic clinical syndrome after radiation. The symptoms may include paresthesia, sensory changes, 
and motor weakness including paralysis. There is no active treatment for radiation myelitis; therefore, 
it is important to prevent any injury to the spinal cord. Corticosteroids are used when clinical symptoms 
develop. 
Radiation Esophagitis 
Patients with thoracic spine treatment will likely develop esophageal mucositis within the first 2 weeks. 
These symptoms subside with time; however, adequate symptomatic treatment including hydration is 
advised. There are no long-term adverse events reported with spine radiosurgery. However, it is 
prudent to minimize the radiation spillage in the normal esophagus. The consequences of esophageal 
toxicity, e.g., swallowing difficulty, dysphagia, cough, dehydration, and fistula, should be documented. 
Radiation Laryngitis or Pharyngitis 
Patients with cervical spine treatment will likely develop laryngopharyngeal mucositis within the first 
2 weeks. These symptoms subside with time; however, adequate symptomatic treatment including 
hydration is advised. No long-term laryngopharyngeal toxicity has been reported with spine 
radiosurgery. However, it is prudent to minimize the radiation spillage in the normal larynx and 

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pharynx. The consequences of toxicity, e.g., swallowing difficulty, dysphagia, cough, dysphonia 
dehydration, and fistula, should be documented. 
Tracheal Injury 
Although no cases of tracheal injury have been reported with spine radiosurgery, it is prudent to 
minimize the radiation spillage in the normal trachea. The consequences of tracheobronchial toxicity, 
e.g., cough, dyspnea, hypoxia, impairment of pulmonary function test parameters, pleural effusion or 
pleuritic pain (associated with collapse), should be documented. 
Radiation Pneumonitis 
There have been no reported cases of symptomatic radiation pneumonitis with spine radiosurgery. 
However, it is prudent to minimize the radiation spillage in the lung tissue. It is strongly recommended 
to use radiation beams directed from the posterior to avoid passage of radiation through the lungs. 
Patients with symptoms of pneumonitis will be promptly evaluated and treated. Mild radiation 
pneumonitis may be treated with non- steroidal anti-inflammatory agents or steroid inhalers. More 
significant pneumonitis will be treated with systemic steroids, bronchodilators, and pulmonary 
hygiene. Supra- and concurrent infections should be treated with antibiotics. Consideration of 
prophylaxis of opportunistic infections should be considered in immunocompromised patients. 
Compression Fracture of Treated Vertebra 
Radiation doses in excess of 19 Gy for a single fraction are associated with higher rates of vertebral 
body compression (Saghal 2013). In this protocol, doses per fraction this high are not used, so that the 
estimated rate of vertebral body compression fracture following spinal metastases treatment should be 
approximately 10. 
Other Adverse Events 
Short-term or long-term injury to the kidney or upper airway has not been reported. If other severe 
adverse events occur, details should be documented. 
Osseous: 
Erythema, desquamation and alopecia are common side effects from radiation therapy for osseous 
metastases; other effects are determinate on location of metastasis, and may include pain, edema and 
neuralgia. 
7.2.1 
Radiation Therapy Quality Assurance 
Submission of treatment plans in digital format as DICOM RT is required. Digital data must 
include CT scans, structures, plan, and dose files. This study uses TRIAD for RT data submission. 
Use of TRIAD requires several preliminary steps (see Section 6.3). Additional information is 
available at: https://triadinstall.acr.org/triadclient/ 
Any items on the list below that are not part of the digital submission may be included with the 
transmission of the digital RT data. https://irocri.qarc.org/ 
Within one week following the completion of radiotherapy, the following data must be submitted 
for all patients: 
• 
RT treatment plans including treatment planning CT, structures, dose and plan files. 
These items are included in the digital plan. 
• 
Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics. 
• 
RT-1 Dosimetry Summary Form 
• 
Motion Management Reporting Form (if applicable) 
• 
The RT-2 Radiotherapy Total Dose Record Form 
• 
A copy of the patient's radiotherapy record including the prescription, and the daily and 
cumulative doses to all required areas. 

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Supportive data and forms may be included with the transmission of the digital RT data or 
submitted separately via e-mail to DataSubmission@qarc.org. 
Questions regarding the dose calculations or documentation should be directed to: 
Protocol Dosimetrist 
IROC Rhode Island QA Center 
Phone: (401) 753-7600 
Email: physics@qarc.org 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
8.1 
Ancillary Therapy, Concomitant Medications, and Supportive Care 
8.1.1 
Patients should not receive any other treatment which would be considered treatment for the 
neoplasm or impact the primary endpoint. 
 
This includes any surgical intervention, radiotherapy, cryotherapy, ablation, etc. 
8.1.2 
Patients should receive full supportive care while on this study. This includes blood product 
support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical 
conditions. All blood products and concomitant medications such as antidiarrheals, analgesics, 
and/or antiemetics received from the first day of study treatment administration until 30 days 
after the final dose will be recorded in the medical records. 
8.1.3 
Treatment with hormones or other chemotherapeutic agents may not be administered 
except for steroids given for adrenal failure; hormones administered for non-disease-related 
conditions (e.g., insulin for diabetes); and intermittent use of dexamethasone as an antiemetic in 
solid tumor protocols. Use of dexamethasone and other steroidal antiemetics is prohibited in 
leukemia and lymphoma protocols. 
8.1.4 
Antiemetics may be used at the discretion of the attending physician, with the exception of 
steroids above. 
8.1.5 
Diarrhea management is per the discretion of the treating physician. Diarrhea could be 
managed conservatively with medications such as loperamide. 
Patients with severe diarrhea should be assessed for intravenous hydration and correction of 
electrolyte imbalances. 
8.1.6 
Palliative radiation therapy may not be administered. 
Patients who require radiation therapy during protocol treatment will be removed from protocol 
therapy due to disease progression. 
8.1.7 
Alliance Policy Concerning the Use of Growth Factors 
Blood products and growth factors should be utilized as clinically warranted and following 
institutional policies and recommendations. The use of growth factors should follow published 
guidelines of the American Society of Clinical Oncology Clinical Practice Guideline Update. J 
Clin Oncol 33: 3199-3212, 2015 and American Society of Clinical Oncology – American Society 
of Hematology Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin in 
Adult Patients with Cancer. J Clin Oncol 28:4996-5010, 2010. 
Epoetin (EPO): Use of epoetin in this protocol is permitted at the discretion of the treating 
physician. 
Filgrastim (G-CSF) tbo-filgrastim, and sargramostim (GM-CSF) are prohibited OR permitted at 
the discretion of the treating physician. 
Use of white blood cell growth factors (which includes: filgrastim (G-CSF), pegfilgrastim) and 
other FDA approved white blood cell growth factor biologics) should adhere to the following 
guidelines: 

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1. White blood cell growth factor treatment for patients on protocols that do not specify 
their use is discouraged. 
2. White blood cell growth factor may not be used: 
a. To avoid dose reductions, delays or to allow for dose escalations specified in the 
protocol. 
b. For the treatment of febrile neutropenia the use of CSFs should not be routinely 
instituted as an adjunct to appropriate antibiotic therapy. However, the use of CSFs may 
be indicated in patients who have prognostic factors that are predictive of clinical 
deterioration such as pneumonia, hypotension, multi-organ dysfunction (sepsis 
syndrome) or fungal infection, as per the ASCO guidelines. Investigators should 
therefore use their own discretion in using the CSFs in this setting. The use of CSF 
(filgrastim/pegfilgrastim) must be documented and reported. (e.g. on CRFs per protocol 
requirements) 
c. If white blood cell growth factors are used, they must be obtained from commercial 
sources. Selection of white blood cell growth factor products should be per institutional 
guidelines. 
8.2 
Dose Modification and Treatment Modifications 
x 
Any patients with autoimmune toxicity who require additional immune suppressive treatment 
beyond steroids should go off treatment. 
x 
Dose delays may occur for toxicity with re-initiation of treatment as per protocol. 
x 
Any patient started on corticosteroids initially for a presumed autoimmune adverse event, and 
subsequently found to not have an autoimmune etiology of their adverse event, may resume 
therapy after a 2-week observation period without recurrence of symptoms.  
x 
No dose reductions will be made for MK-3475 (pembrolizumab) during this study, only dose 
delays. 
8.2.1 
General AE Management and Dose Modification Guidelines for Pembrolizumab (MK-
3475) 
Dose Modifications 
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or several 
months after the last dose of treatment.  Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as described below. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays).  Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the patient's study record. 
Dose Modification and Toxicity Management for Immune-related Adverse Events Associated 
with Pembrolizumab   
AEs associated with pembrolizumab exposure may represent an immunologic etiology.  These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than one body system simultaneously.  
Therefore, early recognition and initiation of treatment is critical to reduce complications.  Based 
on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive care.  
For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  
Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as 
part of the evaluation. Based on the severity of irAEs, withhold or permanently discontinue 
pembrolizumab and administer corticosteroids.  Pembrolizumab may cause severe or life-
threatening infusion-reactions including severe hypersensitivity or anaphylaxis.  Signs and 

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a Pembrolizumab may be withheld for a longer period of time (i.e., !12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of d10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefitrisk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over t1 month to the equivalent 
of d10 mg/day oral prednisone before pembrolizumab can be resumed. 
c Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate). 
 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
x 
Continue pembrolizumab unless symptoms worsen or do not 
improve. 
x 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
x 
Permanently discontinue pembrolizumab.  
x 
Investigate etiology and refer patient to a neurologist. 
x 
Rule out infection. 
x 
Initiate treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
x 
Permanently discontinue pembrolizumab. 
x 
Refer patient to a neurologist. 
x 
Initiate treatment as per institutional guidelines. 
 
Event 
Management 
Immune-mediated 
meningoencephalitis, all 
grades 
x 
Permanently discontinue pembrolizumab. a 
x 
Refer patient to neurologist. 
x 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
x 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
x 
If event resolves to Grade 1 or better, taper corticosteroids over 
t1 month. 
a Resumption of pembrolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-mediated event.  The decision to re-challenge patients 
with pembrolizumab should be based on investigator's assessment of benefitrisk and 
documented by the investigator (or an appropriate delegate). 
8.2.2 
Pembrolizumab (MK-3475) Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are also outlined in the table in Section 8.2.1.  Where appropriate, these 
guidelines include the use of oral or IV treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.  Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased.  For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care.  The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab. 

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Note:  If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
x 
Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
x 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
x 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis >DKA@) or  
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
x 
For T1DM or Grade 3-4 Hyperglycemia 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
x 
Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
x 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 

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x 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
x 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
x 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
x 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
o Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
x 
Renal Failure or Nephritis with relationship to study therapy: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
x 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
The table below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of MK-3475 (pembrolizumab). 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50 of the original 
infusion rate (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the subject 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 
(pembrolizumab) with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 
 
 
9.0 
ADVERSE EVENTS 
The prompt reporting of adverse events is the responsibility of each investigator engaged in clinical 
research, as required by Federal Regulations. Adverse events must be described and graded using the 
terminology and grading categories defined in the NCI’s Common Terminology Criteria for Adverse Events 
(CTCAE), 
Version 
5.0. 
The 
CTCAE 
is 
available 
at 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. Attribution to protocol treatment 
for each adverse event must be determined by the investigator and reported on the required forms. Please 
refer the NCI Guidelines: Adverse Event Reporting Requirements for further details on AE reporting 
procedures.  
Clinician graded CTCAE is the AE safety standard. PRO-CTCAE items are to complement CTCAE 
reporting. Patients will respond to PRO-CTCAE items, but no protocol directed action will be taken. The 
PRO-CTCAE patient-completed booklet for this protocol can be downloaded from the CIRB Approved 
Documents tab on the CTSU website. PRO-CTCAE is not intended for expedited reporting, real time 
review, or safety reporting. All dose interruptions and treatment modifications will be guided by clinician 
interpreted CTCAE. PRO-CTCAE should not be used for determining dose delays or dose modifications or 
any other protocol directed action. 
9.1 
Routine Adverse Event Reporting 
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 

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using similar agents. Adverse events are reported in a routine manner at scheduled times according to 
the study calendar in Section 5.0. 
9.1.1 
Solicited adverse events 
The following adverse events are considered "expected" and their presence/absence should be 
solicited, and severity graded, at baseline and for each cycle of treatment. Symptomatic adverse 
events reported by patients through PRO-CTCAE are not safety reporting and may be presented 
with other routine Adverse Event data. 
 
9.2 
CTCAE Routine Reporting Requirements 
In addition to the solicited adverse events listed in Section 9.1, the following table outlines the 
combinations of time points, grades and attributions of AEs that require routine reporting to the 
Alliance Statistics and Data Center. Questions about routine reporting should be directed to the Data 
Manager. 
Combinations of CTCAE Grade & Attribution Required for Routine AE Data Submission on Case 
Report Forms (CRFs) 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
 
 
a 
a 
a 
Unlikely 
 
 
a 
a 
a 
Possible 
 
 
a, b 
a, b 
a, b 
Probable 
 
 
a, b 
a, b 
a, b 
Definite 
 
 
a, b 
a, b 
a, b 
a) Adverse Events: Other CRF - Applies to AEs occurring between registration and within 30 
days of the patient’s last treatment date, or as part of the Clinical Follow-Up Phase. 
b) Adverse Events: Late CRF - Applies to AEs occurring greater than 30 days after the patient’s 
last treatment date. 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) 
Investigators are required by Federal Regulations to report serious adverse events as defined in the 
table below. The descriptions and grading scales found in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5 will be utilized for AE reporting. The CTCAE is identified and 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ 
Class (SOC) 
PRO-CTCAE Term 
Neutrophil count decreased 
Investigations 
N/A 
Platelet count decreased 
Investigations 
N/A 
Diarrhea 
Gastrointestinal Disorders 
Diarrhea 
Colitis 
Gastrointestinal Disorders 
Diarrhea, Abdominal Pain 
Rash maculo-papular 
Skin and subcutaneous tissue 
disorders 
Rash 
Hyperglycemia 
Metabolism 
and 
nutrition 
disorders 
N/A 
Electrocardiogram 
QT 
corrected 
interval prolonged 
Investigations 
N/A 

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9.3.2 
Expedited AE reporting timelines defined 
• 
“24 hours; 5 calendar days” – The investigator must initially report the AE via CTEP-
AERS  24 hours of learning of the event followed by a complete CTEP-AERS report  
5 calendar days of the initial 24-hour report. 
• 
“10 calendar days” - A complete CTEP-AERS report on the AE must be submitted  10 
calendar days of the investigator learning of the event.  
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or 
prolongation of existing hospitalization) must be reported regardless of attribution and 
designation as expected or unexpected with the exception of any events identified as protocol-
specific expedited adverse event reporting exclusions (see below). 
Any event that results in persistent or significant disabilities/incapacities, congenital anomalies, 
or birth defects must be reported via CTEP-AERS if the event occurs following treatment with 
an agent under an IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Adverse Events of Special Interest in Pembrolizumab Studies 
Adverse events of special interest for this study include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
o Treatment-emergent ALT or AST ! 3 u ULN in combination with total bilirubin 
! 2 u ULN 
o Treatment-emergent ALT or AST ! 3 u ULN in combination with clinical 
jaundice 
• 
Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent. A transmission of an infectious agent may be suspected from clinical symptoms or 
laboratory findings that indicate an infection in a patient exposed to a medicinal product.  This 
term applies only when a contamination of the study drug is suspected 
The Pembrolizumab Events of Special Interest Are: 
• 
Systemic lupus erythematosus 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, macrophage activating syndrome, hemophagocytic lymphohistiocytosis 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Grade  2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
9.3.4 
Additional Instructions or Exclusions to CTEP-AERS Expedited Reporting Requirements  
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also be 
forwarded to your local IRB. 

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Alliance A032002 uses a drug under a CTEP IND. The reporting requirements for investigational 
agents under a CTEP IND should be followed for all agents (any arm) in this trial. 
Treatment expected adverse events include those listed in Section 10.0 and in the package insert. 
CTEP-AERS reports should be submitted electronically. 
Exclusions 
 Grade 4 hematosuppression and hospitalization resulting from such do not require CTEP-
AERS, but should be submitted as part of study results.  
Grade 1-3 nausea or vomiting and hospitalization resulting from such do not require AERS 
reporting, but should be reported via routine AE reporting 
Grade 3 nausea or vomiting does not require AERS reporting, but should be reported via routine 
AE reporting.  
Death 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.” Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
Any death occurring within 30 days of the last dose, regardless of attribution to the investigational 
agent/intervention requires expedited reporting within 24 hours.  
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
Pregnancy loss and neonatal death 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any Pregnancy loss should be reported 
expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC. A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-AERS recognizes this 
event as a patient death. 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under the General 
disorders and administration SOC. 
New Malignancies 
All new malignancies must be reported via CTEP-AERS whether or not they are thought to be 
related to either previous or current treatment. All new malignancies should be reported, i.e. solid 
tumors 
(including 
non-melanoma 
skin 
malignancies), 
hematologic 
malignancies, 
myelodysplastic syndrome/acute myelogenous leukemia, and in situ tumors.  
Whenever possible, the CTEP-AERS reports for new malignancies should include tumor 
pathology, history or prior tumors, prior treatment/current treatment including duration, any 
associated risk factors or evidence regarding how long the new malignancy may have been 
present, when and how the new malignancy was detected, molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor, and new malignancy 
treatment and outcome, if available. 
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.  

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Adverse events reported on Pembrolizumab (MK-3475) trials, but for which there is insufficient evidence 
to suggest that there was a reasonable possibility that Pembrolizumab (MK-3475) caused the adverse 
event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Chest pain - cardiac; Heart failure; Myocardial 
infarction; Pericardial effusion; Pericardial tamponade; Ventricular arrhythmia 
EYE DISORDERS - Eye pain 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Constipation; Duodenal hemorrhage; 
Dysphagia; Gastritis; Gastrointestinal disorders - Other (diverticulitis); Gastrointestinal disorders - Other 
(intestinal obstruction); Gastrointestinal disorders - Other (intussusception); Oral pain; Rectal hemorrhage; 
Small intestinal perforation; Upper gastrointestinal hemorrhage; Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema face; Edema limbs; 
Facial pain; Gait disturbance; General disorders and administration site conditions - Other (general physical 
health deterioration); Generalized edema; Malaise; Non-cardiac chest pain; Pain 
INVESTIGATIONS - CPK increased; Cholesterol high; Creatinine increased; Fibrinogen decreased; 
Lymphocyte count decreased; Neutrophil count decreased; Platelet count decreased; Weight loss; White blood 
cell decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperglycemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypokalemia; Hypophosphatemia; 
Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Joint effusion2; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders - 
Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Nephrotic syndrome; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Urinary incontinence; Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Dyspnea; Hypoxia; Laryngeal 
inflammation; Pleural effusion; Pleuritic pain2; Pneumothorax; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; Skin and subcutaneous tissue 
disorders - Other (drug eruption) 
VASCULAR DISORDERS - Hypertension; Peripheral ischemia; Thromboembolic event 
Note: Pembrolizumab (MK-3475) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never previously 
associated with either agent. 
10.0 DRUG INFORMATION 
10.1 
Pembrolizumab (MK-3475, NSC 776864) 
Availability 
Commercial supplies. Pharmacies or clinics shall obtain supplies from normal commercial supply 
chain or wholesaler. 
Pembrolizumab is commercially available. Pembrolizumab (MK-3475) injection is a sterile, 
preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous use. 

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Each vial contains 100 mg of pembrolizumab (MK-3475) in 4 mL of solution. Each 1 mL of solution 
contains 25 mg of pembrolizumab (MK-3475) and is formulated in: L-histidine (1.55 mg), polysorbate 
80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP.  
Preparation 
Follow institutional standards. 
MK-3475 (pembrolizumab) solution for infusion must be diluted prior to administration. Do not shake 
the vials. Do not use if opaque or extraneous particulate matter other than translucent to white 
proteinaceous particles is observed. Do not use if discolored. To prepare the infusion solution add the 
dose volume of MK-3475 (pembrolizumab) to an infusion bag containing 0.9 Sodium Chloride 
Injection, USP or 5 Dextrose Injection, USP. Mix diluted solution by gentle inversion. The final 
concentration must be between 1 mg/mL to 10 mg/mL. 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, or PE lined 
polyolefin. 
Storage  
Store intact vials between 2°C - 8°C (36°F - 46°F). Do not freeze. Protect from light by storing in the 
original box. 
Stability 
Store the diluted solution at room temperature for no more than 6 hours from the time of dilution, 
including room temperature storage of the diluted solution and the duration of infusion, or under 
refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 96 hours from the time of dilution. Do not 
shake. Discard after 6 hours at room temperature or after 96 hours under refrigeration. 
Administration 
IV infusion only. Do not administer as an IV push or bolus injection. If refrigerated, allow the diluted 
solution to come to room temperature prior to administration. 
Infuse over approximately 30 minutes (range: 25 - 40 minutes) using an infusion set containing a low-
protein binding 0.2 to 5 micron in-line filter made of polyethersulfone or polysulfone. A central line is 
not required; however, if a subject has a central venous catheter in place, it is recommended that it be 
used for the infusion. Do not co-administer other drugs through the same infusion line. Following the 
infusion, flush the IV line with normal saline. 
Adverse Events 
See Comprehensive Adverse Events and Potential Risks list (CAEPR) for MK-3475 (pembrolizumab, 
NSC 776864) CAEPRs in Section 9.4. 
Nursing Guidelines 
1) MK-3475 (pembrolizumab) side effects vary greatly from those of traditional chemotherapy 
and can vary in severity from mild to life threatening. Instruct patients to report any side effects 
to the study team immediately. Side effects may be immediate or delayed up to months after 
discontinuation of therapy. Most side effects are reversible with prompt intervention of 
corticosteroids. 
2) Diarrhea can be seen however is less common than that seen with anti-CTLA-4 agents. 
However it can be severe, leading to colonic perforation. Instruct patients to report ANY 
increase in the number of stools and/or change in baseline, blood in the stool, abdominal pain 
to the study team immediately. 
3) Rash/pruritus/dermatitis is seen. Patients should report any rash to the study team. Treat per 
section 8.0 and monitor for effectiveness. 
4) Monitor LFT’s closely as elevations in these levels could indicate early onset autoimmune 
hepatitis. Patients should also be instructed to report any jaundice, or right upper quadrant pain 
to the study team immediately. 

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5) Pneumonitis can be seen and may be mild (only seen on imaging) to severe. Patients should 
be instructed to report any SOB, dyspnea, cough, chest pain, etc. to the study team 
immediately. Patients reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
6) Endocrinopathies (including hypopituitarism, hypothyroidism, hypophysistis, and adrenal 
insufficiency) are seen with this agent. Patients may present only with the vague sense of 
fatigue and “not feeling well.” Additional symptoms may be that of nausea, sweating and 
decreased activity tolerance. Instruct patients to report these signs or symptoms immediately 
and obtain appropriate labs as ordered by MD. 
7) Patients who are started on steroid therapy for any side effects of MK-3475 (pembrolizumab) 
toxicity should be instructed to take the steroids as ordered, and not to discontinue abruptly as 
symptoms may return and be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any dosage decrease as patients 
may need a slower taper. 
8) Fatigue is common and may or may not be associated with immune related side effects. Assess 
patient’s fatigue level prior to each cycle of therapy and report any changes to the study team. 
9) Patients should avoid receiving live vaccines within 30 days of study drug administration or 
per other study guidelines. 
10) Patients who have undergone an allogenic bone marrow transplant, have an increased risk of 
severe complications including early GVHD, and venoocclusive disease, if they have 
previously been treated with MK-3475. 
11) Myocarditis has been reported and associated with MK-3475. Instruct patients to report chest 
pain, SOB, or dyspnea to study team immediately and/or seek emergency medical attention. 
11.0 MEASUREMENT OF EFFECT  
Disease should be re-evaluated every 12 weeks after C1D1. Disease response will be made by institutional 
investigator assessment, based on local radiology review and RECIST v1.1 criteria. Refer to the Study 
Calendar to determine the allowable scan windows (Section 5.0). This study uses iRECIST guidelines to 
guide treatment beyond progressive disease. Irradiated lesion will not be included in RECIST v1.1 or 
iRECIST evaluation. 
11.1 
Target Lesions  
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative 
of all involved organs, should be identified as target lesions and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, and should be chosen based on their suitability for accurate 
repetitive measurements. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible repeated measurements in which case the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If 
lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline 
sum LD will be used as reference to further characterize the objective tumor response of the measurable 
dimension of the disease. 
11.1.1 Complete Response: Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
11.1.2 Partial Response (PR): At least a 30 decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
11.1.3 Progressive Disease (PD): At least a 20 increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20, the sum must also demonstrate 

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an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
11.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum diameters while on study. 
11.2 
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal 
progression of each should be noted throughout follow-up. 
11.2.1 Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). Note: If 
tumor markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
11.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of one or more 
non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. 
11.2.3 Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of non-target lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed 
later on by the review panel (or Study Chair). 
11.3 
Cytology and Histology 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
These techniques can be used to differentiate between PR and CR in rare cases (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain).  
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease. 
11.4 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria (see Section 11.6.1) 

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11.5
Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more 
than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam.
11.5.1 Clinical Lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes) and  10 mm diameter as assessed using calipers (e.g., skin 
nodules). For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended.
11.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.
11.5.3 Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g., for body scans). Use of MRI 
remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, 
there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 

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scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
11.5.4 PET-CT: At present, the low dose or attenuation correction CT portion of a combined PETCT 
is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can 
be used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
11.5.5 Ultrasound (US): Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety 
for independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
11.5.6 Endoscopy and Laparoscopy: The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
11.5.7 Tumor markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalize for a patient to be considered in complete clinical 
response. 
11.6 
Confirmation Measurement/Duration of Response 
11.6.1 Confirmation: To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat studies that should be performed at least 4 weeks after the criteria for 
response are first met. In the case of SD, follow-up measurements must have met the SD criteria 
at least once after study entry at a minimum interval of 8 weeks. 
11.6.2 Duration of Overall Response: The duration of overall response is measured from the time 
measurement criteria are met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively documented. 
11.6.3 Duration of Stable Disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
11.7 
iRECIST guidelines 
Since A032002 includes the main treatment backbone with immunotherapy, this trial will adopt 
iRECIST guidelines for assessments of radiographic responses (31), one of the secondary endpoints 
of the trial. This section gives a summary of iRECIST guidelines and the application to A032002. 
The following table, adapted from the iRECIST guidelines, is a snapshot of changes between RECIST 
1.1 and iRECIST guidelines. 
 
 
 

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RECIST 1.1 
iRECIST 
Measurable and non-measurable 
disease, number and site of target 
disease 
Measurable: >10mm for visceral 
disease, >15mm for LN lesions,  
Maximum 5 lesions (2 per organ) 
All other disease non-target 
(>10mm for LN disease) 
Measurability as per RECIST 1.1 
New lesions assessed per RECIST 
1.1 but recorded separately for 
target vs non-target 
CR, PR, or SD 
Cannot have met criteria for PD 
before CR, PR, or SD 
Can have had iUPD (one or more) 
but not iCPD, before iCR, iPR, or 
iSD 
Confirmation of CR or PR 
Not required for randomized trials 
As per RECIST 1.1 
Confirmation of SD 
Not required 
As per RECIST 1.1 
After initial progression (iUPD) 
but then iCR, iPR, or iSD 
Any PD precludes later CR, PR, 
or SD 
iCR/iPR/iSD can be achieved after 
initial iUPD. Sum of target lesion 
diameters at time of iCR/iPR/iSD 
should be noted and status should 
be reset.  
Subsequent progression after 
iCR/iPR/iSD should be another 
iUPD, until confirmation iCPD 
New lesions 
Result in PD; recorded but not 
measured 
Results in iUPD at first occurrence 
iCPD only assigned on basis of 
new lesions if at next assessment 
additional new lesions appear or 
an increase in size of new lesions 
seen (>5mm of sum of new lesion 
target or any increase in new 
lesion non-target) 
If non-target or target lesions have 
unequivocal PD, iCPD can be 
assigned at time of first 
progression 
Independent blinded review and 
central scan collection 
Collection of scans required on 
A031704 
Collection of scans required on 
A031704 
Confirmation of progression 
Not required unless equivocal 
Required 
Consideration of clinical status 
Not included in assessment 
Clinical stability is considered 
when deciding whether treatment 
should continue after iUPD 
In general, iRECIST guidelines help define progression in the context of immune therapy. New lesions 
should be assessed and subcategorized as target lesions (new lesion, target) and measured for further 
follow up, or non-target lesions (new lesion, non-target). At the time of initial iUPD, patients must be 
clinically stable by investigator assessment (see definition below) in order to continue immunotherapy-
based treatments. iRECIST guidelines also recommend that confirmation of progression be obtained 
between 4 to 8 weeks of the initial iUPD scan date. For purposes of this trial, these scans can be 
obtained after 4 weeks, and no more than 13 weeks after initial iUPD scans (as standard of care, 
depending on insurance coverage, as scans will not be billable to this study). 
Investigators will need to assess clinical stability to continue treatments at time of iUPD. Clinical 
stability to continue treatment in light of iUPD is defined as follows. Absence of any of the following: 

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worsening of performance status, clinically relevant increase in disease-related symptoms such as pain 
or dyspnea that are associated with disease progression, and increased management/treatments of 
disease-related symptoms (including increased analgesic agents, radiation, or other palliative 
treatments). Imaging findings and recommendation to continue with treatment should be discussed 
with the patient before the decision to continue.
Patients with iUPD and who are clinically unstable should be designated as clinically unstable in the 
database. Patients with iUPD and clinically unstable will stop study treatments and continue with 
standard of care treatments. These patients will continue to be followed for other outcomes.
Please refer to full iRECIST guidelines for further guidance (31) on assessing response/progression. 
In particular, Table 2 of the guidelines give specific recommendations of timepoint response 
assignment and is replicated below. When needed, please contact medical monitor/study chairs to help 
adjudicate response/progression.
Abbreviations:
CR: complete response
iCR: immune complete response
iPR: immune partial response
iUPD: immune unconfirmed progressive disease
iCPD: immune confirmed progressive disease
iSD: immune stable disease
LN: lymph node
PD: progression of disease
PR: partial response
SD: stable disease

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12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Protocol Treatment  
Protocol treatment is to continue until disease progression and no longer benefitting clinically or 
unacceptable toxicity. Please see the study calendar (Section 5.0) and the treatment section (Section 
7.0) for treatment and follow-up time periods. 
12.2 
Criteria for Discontinuation of Protocol Treatment/Intervention 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
x 
Disease progression per iRECIST guidelines, e.g., discontinuation due to clinical instability or 
additional new lesions or increase in new lesion size (see Section 11.7) 
x 
Intercurrent illness that prevents further administration of treatment 
x 
Unacceptable adverse event(s) 
x 
Patient decides to withdraw from the study 
x 
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator 
x 
Clinical progression 
x 
Patient non-compliance 
x 
Pregnancy 
x 
All women of child bearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual period) at 
any time during study participation. 
x 
The investigator must immediately notify CTEP in the event of a confirmed pregnancy in a 
patient participating in the study. 
x 
Termination of the study by sponsor 
x 
The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the Case Report Form (CRF). 
12.3 
Follow-up  
12.3.1 Duration of Follow-up: Physical examination and staging scans are required within 12 weeks 
after the end of treatment, then every 12 weeks until disease progression; thereafter, survival 
information is required every 3 months until 3 years following registration. 
12.3.2 Follow-up for Patients who Stop Study Treatment/Intervention Early  
Follow up for patients who receive non-protocol therapy will be for event monitoring 
12.3.3 Follow-up for Specimen and QOL Submission 
QOL measures are to be completed at baseline, and at 45 days, and at 6, 12, and 24 months 
following registration. Measures should continue to be submitted following progression. 
12.4 
Extraordinary Medical Circumstances 
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the patient 
no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In this event: 
x 
Document the reason(s) for discontinuation of therapy on data forms. 
x 
Follow the patient for protocol endpoints as required by the Study Calendar. 

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12.5 
Managing ineligible patients and registered patients who never receive protocol intervention  
Definition of ineligible patient 
 A study participant who is registered to the trial but does not meet all of the eligibility criteria is 
deemed to be ineligible. 
Follow-up for ineligible patients who continue with protocol treatment 
Patients who are deemed ineligible after registering may continue protocol treatment, provided the 
treating physician, study chair, and executive officer agree there are no safety concerns if the patient 
continues protocol treatment. No further follow-up will be required for these patients. Notification of 
the local IRB may be necessary per local IRB policies. 
Follow-up for ineligible patients who discontinue protocol treatment 
For patients who are deemed ineligible after registering to the trial, who start treatment, but then 
discontinue study treatment, the same data submission requirements are to be followed as for those 
patients who are eligible and who discontinue study treatment. 
Follow-up for patients who are registered, but who never start study treatment 
For all study participants who are registered to the trial but who never receive study intervention 
(regardless of eligibility), no follow-up will be required. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
This is a prospective multicenter, randomized, open-label, phase 2 study evaluating whether the 
addition of radiation therapy to immunotherapy improves tumor response rate compared to treatment 
with immunotherapy alone in patients with platinum ineligible/refractory metastatic urothelial cancer. 
Allocation to the two study arms will be performed using stratified randomization as described in 
Section 4.6. Patients will be randomized 1:1 to immunotherapy (Arm A) or to immunotherapy plus 
radiation (Arm B). This trial is a superiority trial with the primary endpoint of tumor response. One 
formal interim analysis will be conducted for futility after 50 of the patients have been followed for 
6 months after randomization; accrual will not be suspended for the interim analysis. 
13.2  Study Endpoints 
13.2.1 Primary Endpoint 
The primary endpoint is tumor response within 6 months of randomization. Tumor response is 
defined as a complete response (CR) or partial response (PR) as assessed by the treating physician 
using RECIST v1.1 criteria. 
13.2.2 Secondary Endpoints 
Tumor response using iRECIST: A patient will be determined to have a tumor response if they 
have a CR or PR as assessed using iRECIST by central review. 
Progression-free survival (PFS): This will be the time from randomization until disease 
progression as assessed by the treating physician using RECIST 1.1 or death due to any cause. 
Patients who are alive and without documented progression will be censored at the time of last 
disease evaluation. 
Overall survival (OS): This will be the time from randomization until death due to any cause. 
Patients who are not known to be dead at time of analysis will be censored at the time of their last 
follow-up. 
Rate of treatment discontinuation at 1 year: The proportion of patients who discontinue their 
protocol directed treatment prior to one year from date of study registration will be determined. 
Patients who stop their protocol directed treatment for any reason prior to one year from study 
registration will be considered to have discontinued their treatment. 
Adverse events: These will be assessed using CTCAE v5.0. 

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13.3 
Subgroup Analysis 
Subgroup analysis may be conducted in the following groups for efficacy endpoints including tumor 
response, PFS, and OS. 
1) Platinum status: platinum ineligible versus platinum refractory 
2) Visceral metastasis: present versus absent 
13.4 
Sample Size Calculation 
The sample size was determined with nQuery (v8.6.1.0) under the following assumptions: 
1) one-sided alpha = 0.10 
2) power = 90 
3) arm A (control arm) tumor response rate = 20 
4) minimum detectable increase in response rate = 20 (absolute) 
5) one interim analysis for futility after 50 of patients followed for response 
This requires a total sample size = 136 evaluable patients (68 in each arm). The sample size will be 
inflated by 5 to account for ineligible or non-evaluable patients, so the target accrual is 144 patients. 
13.5 
Accrual time and study duration 
The anticipated accrual rate is approximately 5 patients per month. The maximum expected accrual 
period is approximately 30 months (if trial is not stopped early for futility). Patients will be followed 
for tumor response for 6 months following randomization; therefore the maximum total study duration 
for the primary endpoint (including OS follow-up) approximately 36 months. Patients will be followed 
for PFS and OS for 3 years. 
13.6 
Primary Analysis Plan 
Interim analysis for futility: There will be one interim analyses for futility. The interim analysis will 
occur after 50 of the patients (i.e. 68) have been followed for six months. If at this time the tumor 
response for Arm A (immunotherapy alone) is greater than the tumor response rate for Arm B 
(immunotherapy plus radiation), which would correspond to an OR > 1, the recommendation will be 
to stop the trial due to futility. 
Final Analysis: The final analysis will occur after 136 evaluable patients have completed 6 months of 
follow-up. The tumor response rate will be analyzed with a Mantel-Haenszel test (that accounts for the 
randomization stratification factors) comparing the response rates between the two treatment arms. 
The analysis will be a modified intent-to-treat analysis where patients are ineligible or not evaluable 
will be excluded. An additional analysis will be conducted using logistic regression analysis that 
includes treatment arm and any baseline variables that are imbalanced between the arms as explanatory 
variable. 
13.7 
Secondary Analysis Plans 
A key secondary analysis will be to repeat the primary analysis that defines a tumor response by central 
review using iRECIST criteria. 
For the secondary time-to-event endpoints, stratified Cox models will be used to compare the outcomes 
between the two treatment groups. This includes PFS and OS. The subgroup analyses will be done 
using a stratified Cox model that includes the treatment arm assignment as an explanatory variable and 
a separate model will be generated for each level for the subgroup of interest. The results will be 
summarized with a forest plot displaying the estimate of the hazard ratio and corresponding 95 
confidence interval. 
The rates of treatment discontinuation at one year will be summarized with a binomial point estimate 
and corresponding 95 confidence interval by arm. The denominator will be all patients randomized 
to the treatment arm and who are still alive and progression-free at one year and the numerator will be 
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treatment prior to one year. A comparison between the rates will be performed with a chi-square test 
or a Fisher’s exact test if the assumptions of the chi-square test are violated. 
Adverse events will be summarized with frequencies and relative frequencies. The maximum grade 
for an AE will be recorded for each patient by treatment arm. The number (percent) of patients that 
experience each observed adverse event will be summarized by treatment arm. In addition, the 
proportion of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be 
summarized as the number and percent of patients by treatment arm. The primary summary will be 
regardless of attribution. We will also do an analogous summary of the adverse events that were 
deemed at least possibly related to treatment. 
To evaluate between-arm differences in patient-reported adverse events as assessed by the PRO-
CTCAE from baseline through 24 months, the frequency and proportion of patients with a maximum 
post-baseline score greater than 0 will be compared across arms using a χ2 test or Fisher’s exact test 
with a nominal significance level of α = .10. Similarly, the frequency and proportion of patients with 
a maximum post-baseline score greater than or equal to 3 will be compared across arms using a χ2 test 
or Fisher’s exact test with a nominal significance level of α = .10. The same procedure will be applied 
to patients’ maximum baseline-adjusted scores. Patients’ maximum baseline-adjusted scores will be 
calculated using the method described by Dueck et al. If the patient’s maximum post-baseline score is 
greater than his/her baseline score, then the patient’s maximum baseline-adjusted score will equal 
his/her maximum post-baseline score; otherwise, if the patient’s maximum post-baseline score is less 
than or equal to his/her baseline score, then the patient’s maximum baseline-adjusted score will equal 
0. The aforementioned analyses will be based on all available PRO-CTCAE data. However, the 
proportion of, and reported reasons for, missing data will be presented by time point and arm. 
Correlation analysis and logistic regression analysis will be used to examine whether baseline patient 
characteristics and prognostic factors predict missingness. As a sensitivity analysis, multiple 
imputation may be performed to assess the robustness of results across different assumptions about the 
missing data. Since a preferred or optimal statistical methodology for PRO-CTCAE data is yet to be 
determined, additional analyses of PRO-CTCAE data beyond those specified above may be undertaken 
based on the current state of the science at time of data maturity for this study. 
13.8 
Study Monitoring 
Data for this study will be submitted via the Data Mapping Utility (DMU). Cumulative protocol- and 
patient-specific data will be submitted weekly to CTEP electronically via the DMU. DMU Light 
reporting consists of Patient Demographics, On/Off Treatment Status, Abbreviated Treatment and 
Course information, and Adverse Events as applicable. Instructions for setting up and submitting data 
via 
DMU 
are 
available 
on 
the 
CTEP 
Website:  
(https://ctep.cancer.gov/protocolDevelopment/dmu.htm). 
 
Note: All adverse events (both routine and serious) that meet the protocol mandatory reporting 
requirements must be reported via DMU in addition to expedited reporting of serious adverse events 
via CTEP-AERS. 
The study team and DSMB will monitor the study for safety and whether the trial is meeting its accrual 
goals in a satisfactory manner. Monthly reports summarizing the adverse events will be generated and 
reviewed by the study. If at any time after 20 patients are 30 or more of the patients experience a 
grade 3 or higher AE, accrual will be suspended and the study team will review the adverse event data. 
In collaboration with CTEP, a decision will be made whether to resume accrual with the original 
treatment, modify the treatment and resume accrual, or close the study to accrual due to an 
unacceptable adverse event rate. 
Note: Serious adverse events must be submitted via CTEP-AERS per protocol guidelines. 
13.9 
Inclusion of Women and Minorities 
Gender or race/ethnicity differences in the intervention effect are not expected. Based on previous data 
from advanced or metastatic urothelial carcinoma patients enrolled, the accrual targets in individual 
cells are not large enough to perform subgroup analysis by the two treatment groups. This table is 

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The European Organization for Research and Treatment of Cancer (EORTC) quality of life 
instruments consist of a common component (QLQ-C30) which includes questions broadly 
applicable to all cancer patients, which is meant to be combined with a disease-specific 
component, in this case QLQ-BLM30. QLQ-C30 assesses 5 functional domains (physical, role, 
cognitive, emotional, social) and 8 symptoms (fatigue, pain, nausea/vomiting, dyspnea, loss of 
appetite, insomnia, constipation, diarrhea), together with financial problems and global quality of 
life. The QLQ-BLM30 bladder-specific module further assesses symptoms in several domains, 
including urinary function, bowel symptoms, and sexual function (for men and women). 
Together, the EORTC instrument consists of a total of 60 questions, which takes approximately 
10 minutes to complete. The PROMIS-Fatigue 8a consists of eight items that require a response 
on a scale from “not at all” to “very much.” This questionnaire will take approximately 1 minute 
to complete34. 
Several questions of the EORTC instrument specifically measure potential side effects of 
immunotherapy, including fatigue, weakness, diarrhea, dyspnea and pain. The PROMIS-Fatigue 
8a will interrogate fatigue in greater detail, which is of particular interest for patients receiving 
both immunotherapy and radiation therapy. QOL data will allow an examination of whether 
combination immunotherapy-radiotherapy exacerbates urinary and other QOL components 
compared to immunotherapy alone – which has not been previously studied. 
The EQ-5D-5L is a short, 6-question, instrument which assesses a patient’s overall quality of life 
or health state35. The addition of the EQ-5D-5L will allow for computation and comparison 
between arms of health utilities and quality adjusted survival. 
The quality of life questionnaire is expected to take about 15 minutes total to complete, and will 
be assessed at baseline and 4 follow-up time points over 2 years. 
14.1.2 Objectives 
Primary Objective 
To compare patient-reported fatigue as assessed by the PROMIS-Fatigue 8a from baseline 
through 24 months between patients treated with immunotherapy alone and immunotherapy plus 
radiotherapy to a single site. Hypothesis: Fatigue from baseline through 24 months will be worse 
in patients randomized to immunotherapy plus radiotherapy to a single site compared to 
immunotherapy alone. 
Secondary Objectives 
To compare health-related quality of life (HRQOL) as assessed by the EORTC QLQ-C30 from 
baseline through 24 months between patients treated with immunotherapy alone and 
immunotherapy plus radiotherapy to a single site. Hypothesis: HRQOL from baseline through 24 
months will be worse in patients randomized to immunotherapy plus radiotherapy to a single site 
compared to immunotherapy alone.  
To compare urinary symptoms as assessed by the EORTC QLQ-BLM30 from baseline through 
24 months between patients treated with immunotherapy alone and immunotherapy plus 
radiotherapy to a single site. Hypothesis: Urinary symptoms from baseline through 24 months 
will be worse in patients randomized to immunotherapy plus radiotherapy to a single site 
compared to immunotherapy alone. 
To compare patient-reported diarrhea, shortness of breath and pain as assessed by the EORTC 
QLQ-C30 from baseline through 24 months between patients treated with immunotherapy alone 
and immunotherapy plus radiotherapy to a single site. Hypothesis: Diarrhea, shortness of breath 
and pain from baseline through 24 months will be worse in patients randomized to 
immunotherapy plus radiotherapy to a single site compared to immunotherapy alone. 
To compare health utilities and quality-adjusted survival between patients treated with 
immunotherapy alone and immunotherapy plus radiotherapy to a single site. Hypothesis: Health 
utilities (based on the EQ-5D-5L index score at 45 days, and at 6, 12, and 24 months) will be 
worse in patients randomized to immunotherapy plus radiotherapy to a single site compared to 

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immunotherapy alone; however, quality-adjusted survival (which combines health utilities at 
baseline, at 45 days, and at 6, 12, and 24 months with overall survival) will continue to favor 
immunotherapy plus radiotherapy to a single site over immunotherapy alone. 
Exploratory Objective 
To compare other scale scores of the EORTC QLQ-C30 (global health status and quality of life; 
physical, role, emotional, cognitive, and social function; symptoms) and EORTC QLQ-BLM30 
(urostomy problems, catheter problems, future perspectives, abdominal bloating and flatulence, 
body image, sexual function) at 45 days, and at 6, 12, and 24 months between patients treated 
with immunotherapy alone and immunotherapy plus radiotherapy to a single site. 
14.1.3 Methods 
For Schedule of Assessments for this quality of life study, see Section 6.5. All participating 
institutions must ask patients for their consent to participate in this quality of life study (A032002-
HO1), although patient participation is optional. Paper booklets will be used for this study. For 
information regarding ordering the booklets, see Section 4.5. For all patients who consent to 
participate in this quality of life study (A032002-HO1), a booklet will be given to the patient to 
complete at the specified planned clinic visits before any procedures/tests are initiated at the site 
visit and prior to any discussion of their status with healthcare personnel at the site. Booklets will 
be collected at the following time points: during screening and approximately at 45 days, and at 
6, 12, and 24 months post-randomization. The booklet contains 66 questions and it is anticipated 
that the booklet will take approximately 10-15 minutes for the patient to complete at each 
administration time point. We anticipate having booklets available in a range of languages. 
Patients who consent to participate in this quality of life study (A0320021-HO1) may decline to 
complete a booklet at any time. The primary reason for each missed booklet will be collected on 
a case report form. 
14.1.4 Statistical Considerations 
All questionnaires will be scored according to published scoring algorithms, including 
recommendations for addressing missing items within a scale. An intent-to-treat approach will be 
used for all analyses. To evaluate between-arm differences in patient-reported fatigue from 
baseline through 24 months, the area under the curve will be calculated as a summary statistic for 
each arm based on estimates from a mixed model for patient-reported fatigue as assessed by the 
PROMIS-Fatigue 8a at baseline, at 45 days, and at 6, 12, and 24 months. This approach of 
estimating each arm’s area under the curve as a summary statistic (rather than each patient’s area 
under the curve as a summary measure) is recommended for addressing missing data over time27. 
The mixed model will include a fixed intercept; fixed effect for time, arm, and arm by time 
interaction; and residual covariance matrix based on the observed covariances. An unstructured 
residual covariance matrix will initially be used, though alternative structures will be investigated 
with final selection based on convergence of the mixed model and minimization of the Akaike 
information criterion. Stratification factors used in the randomization as well as baseline patient 
characteristics and prognostic factors may be included in the mixed model as covariates. 
Estimates from the mixed model will be used to construct a 90 confidence interval for the 
difference in area under the curve between arms. The contrast estimated via the mixed model will 
involve a two-sided t-test with a nominal significance level of α = .10. 
To evaluate between-arm differences in HRQOL from baseline through 24 months, the area under 
the curve will be calculated as a summary statistic for each arm based on estimates from a mixed 
model for HRQOL as assessed by the EORTC QLQ-C30 at baseline, at 45 days, and at 6, 12, and 
24 months. Estimates from the mixed model will be used to construct a 90 confidence interval 
for the difference in area under the curve between arms. The contrast estimated via the mixed 
model will involve a two-sided t-test with a nominal significance level of α = .10. 
To evaluate between-arm differences in urinary symptoms from baseline through 24 months for 
patients with a urostomy, the area under the curve will be calculated as a summary statistic for 
each arm based on estimates from a mixed model for urinary symptoms as assessed by the 

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EORTC QLQ-BLM30 at baseline, at 45 days, and at 6, 12, and 24 months. Estimates from the 
mixed model will be used to construct a 90 confidence interval for the difference in area under 
the curve between arms. The contrast estimated via the mixed model will involve a two-sided t-
test with a nominal significance level of α = .10. If the sample size permits, the same procedure 
will be used to evaluate between-arm differences in urinary symptoms from baseline through 24 
months for patients with a urostomy. 
To evaluate between-arm differences in patient-reported diarrhea from baseline through 24 
months, the area under the curve will be calculated as a summary statistic for each arm based on 
estimates from a mixed model for patient-reported diarrhea as assessed by the EORTC QLQ-C30 
at baseline, at 45 days, and at 6, 12, and 24 months. Estimates from the mixed model will be used 
to construct a 90 confidence interval for the difference in area under the curve between arms. 
The contrast estimated via the mixed model will involve a two-sided t-test with a nominal 
significance level of α = .10. The same procedure will be used to evaluate between-arm 
differences in patient-reported shortness of breath and pain from baseline through 24 months. 
To evaluate between-arm differences in quality-adjusted survival, each patient’s quality-adjusted 
survival will be calculated using the area under the curve approach (with and without discounting) 
based on health utilities derived from the EQ-5D-5L. All data through the follow-up of the earliest 
censored patient will be used. A population-based approach will also be used such that the area 
under the curve of a quality-adjusted survival curve (i.e., mean health utility multiplied by the 
proportion of patients surviving based on Kaplan-Meier estimates) is the mean quality-adjusted 
survival for the population. Mean quality-adjusted survival will be compared between arms using 
a bootstrap approach. 
To evaluate between-arm differences in all other scale scores of the EORTC QLQ-C30(global 
health status and quality of life; physical, role, emotional, cognitive, and social function; 
symptoms) and, EORTC QLQ-BLM30, (urostomy problems, catheter problems, future 
perspectives, abdominal bloating and flatulence, body image, sexual function) at 45 days, and at 
6, 12, and 24 months, a mixed model will be estimated for each scale score. Estimates from the 
mixed model will be used to construct a 90 confidence interval for the mean difference in each 
scale score between arms at each time point. The contrast estimated via the mixed model will 
involve a two-sided t-test with a nominal significance level of α = .10. 
The proportion of, and reported reasons for, missing data will be presented by time point and arm. 
Correlation analysis and logistic regression analysis will be used to examine whether baseline 
patient characteristics and prognostic factors predict missingness. The mixed models will provide 
unbiased parameter estimates under a missing completely at random or missing at random 
mechanism. However, a sensitivity analysis will be conducted to assess the robustness of the 
results across various assumptions about the missing data. 
Power: To evaluate between-arm differences in patient-reported fatigue from baseline through 24 
months, 120 evaluable patients from among the 143 randomized patients on the parent protocol 
(i.e., allowing 15 of patients to decline consent or miss booklets for any reason) provide 80 
power to detect a mean difference in patient-reported fatigue between arms based on a two-sided 
t-test estimated via a mixed model with 5 assessments per patient, nominal significance level of 
α = .10, intraclass correlation of 0.50, and population standardized mean difference of 0.35 (i.e., 
between a small and moderate effect size based on Cohen’s conventions)36. The same power 
calculation applies when evaluating between-arm differences in HRQOL, urinary symptoms, 
diarrhea, shortness of breath, and pain from baseline through 24 months. 
Analyses will be coordinated by the Alliance SDC A032002 Statistician using the dataset used 
for the analysis of the clinical endpoints to ensure consistent data is reported for the primary and 
secondary endpoints (e.g., data associated with censoring, proper inclusion of crossover data, and 
data to be excluded in cases of consent withdrawals for follow-up and correlative studies).  

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14.2 
Correlative Science  
14.2.1  Central Pathology Review and Specimen Biobanking 
Tissue, urine and blood samples described in Section 6.2 for mandatory central pathology review 
and optional biobanking. Biospecimens will be submitted and stored at the Alliance 
Biorepository. Testing of banked samples will not occur until an amendment to this treatment 
protocol (or separate correlative science protocol) is reviewed and approved by NCI in accordance 
with National Clinical Trials Network (NCTN) policies. 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
15.1 
Institutional Credentialing 
15.1.1 IROC Institutional Requirements 
Institutions using IMRT or SBRT must be credentialed prior to delivery of radiation therapy on 
any protocol patient. Institutions previously credentialed for use of IMRT in clinical trials need 
not repeat IMRT credentialing for this trial. 
Web 
Link 
for 
Credentialing 
Procedures 
and 
Instructions: 
http://irochouston.mdanderson.org 
 
Treatment 
Modality 
 
RT 
Credentialing 
Requirements 
Photon 
Key Information 
Facility 
Questionnaire 
X 
The IROC Houston electronic facility questionnaire 
(FQ) should be completed or updated with the most 
recent information about your institution. To access this 
FQ, email irochouston@mdanderson.org to receive 
your FQ link. 
Credentialing 
Status Inquiry 
form 
 
X 
To determine if your institution has completed the 
credentialing 
requirements, 
please 
complete 
a 
“Credentialing Status Inquiry Form” found under 
Credentialing on the IROC Houston QA Center website 
(http://irochouston.mdanderson.org). 
Phantom 
Irradiation 
X 
An IMRT HN phantom and a lung phantom on 
appropriate motion platform must be successfully 
completed. Instructions for requesting and irradiating 
the phantom are found on the IROC Houston web site 
(http://irochouston.mdanderson.org). 
IGRT 
Verification 
Study 
X 
Institutions must be credentialed for soft tissue IGRT 
by IROC Houston. Find details on the IROC Houston 
QA 
Center 
website 
(http://irochouston.mdanderson.org) Institutions that 
have previously been approved for IGRT may not need 
to repeat credentialing. 
Institution 
X 
Institutions will be credentialed for the treatment 
modality that they intend to use on all patients. IROC 
Houston QA Center will notify the institution and 
Alliance Headquarters that all desired credentialing 
requirements have been met. 
 
 

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16.0 REFERENCES 
1. 
Basch E, Bennett A, Pietanza MC: Use of Patient-Reported Outcomes to Improve the Predictive Accuracy 
of Clinician-Reported Adverse Events. Journal of the National Cancer Institute 103:1808-1810, 2011 
2. 
Fromme EK, Eilers KM, Mori M, et al: How accurate is clinician reporting of chemotherapy adverse 
effects? A comparison with patient-reported symptoms from the Quality-of-Life Questionnaire C30. J Clin 
Oncol 22:3485-90, 2004 
3. 
Basch E, Jia X, Heller G, et al: Adverse symptom event reporting by patients vs clinicians: relationships 
with clinical outcomes. J Natl Cancer Inst 101:1624-32, 2009 
4. 
Atkinson TM, Li Y, Coffey CW, et al: Reliability of adverse symptom event reporting by clinicians. Qual 
Life Res 21:1159-64, 2012 
5. 
U.S. Department of Health and Human Services FaDA: Guidance for industry: Patient-reported outcomes 
measures: Use in medical product development to support labeling claims., December 2009 
6. 
Basch  E: The Missing Voice of Patients in Drug-Safety Reporting. New England Journal of Medicine 
362:865-869, 2010 
7. 
Basch E, Rogak LJ, Dueck AC: Methods for Implementing and Reporting Patient-reported Outcome 
(PRO) Measures of Symptomatic Adverse Events in Cancer Clinical Trials. Clin Ther 38:821-30, 2016 
8. 
Atherton PJ, Watkins-Bruner DW, Gotay C, et al: The Complementary Nature of Patient-Reported 
Outcomes and Adverse Event Reporting in Cooperative Group Oncology Clinical Trials: A Pooled 
Analysis (NCCTG N0591). J Pain Symptom Manage 50:470-9.e9, 2015 
9. 
Atkinson TM, Andreotti CF, Roberts KE, et al: The level of association between functional performance 
status measures and patient-reported outcomes in cancer patients: a systematic review. Supportive care in 
cancer : official journal of the Multinational Association of Supportive Care in Cancer 23:3645-3652, 2015 
10. Basch E, Iasonos A, Barz A, et al: Long-term toxicity monitoring via electronic patient-reported outcomes 
in patients receiving chemotherapy. J Clin Oncol 25, 2007 
11. Dueck AC, Mendoza TR, Mitchell SA, et al: Validity and Reliability of the U.S. National Cancer Institute's 
Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-
CTCAE). JAMA oncology 1:1051-1059, 2015 
12. Gotay CC, Kawamoto CT, Bottomley A, et al: The prognostic significance of patient-reported outcomes in 
cancer clinical trials. J Clin Oncol 26:1355-63, 2008 
13. Efficace F, Bottomley A, Smit EF, et al: Is a patient's self-reported health-related quality of life a 
prognostic factor for survival in non-small-cell lung cancer patients? A multivariate analysis of prognostic 
factors of EORTC study 08975. Ann Oncol 17:1698-704, 2006 
14. Ediebah DE, Coens C, Zikos E, et al: Does change in health-related quality of life score predict survival? 
Analysis of EORTC 08975 lung cancer trial. British Journal of Cancer 110:2427-2433, 2014 
15. Tan, A., et al. A patient-level meta-analytic investigation of the prognostic significance of baseline quality 
of life (QOL) for overall survival (OS) among 3,704 patients participating in 24 North Central Cancer 
Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MC) oncology clinical trials. in ASCO 
Annual Meeting Proceedings. 2008. 
16. Sloan, J., et al. A patient-level pooled analysis of the prognostic significance of baseline fatigue for overall 
survival (OS) among 3,915 patients participating in 43 North Central Cancer Treatment Group (NCCTG) 
and Mayo Clinic Cancer Center (MC) oncology clinical trials. in ASCO Annual Meeting Proceedings. 
2009. 
17. Galsky, M.D., et al., Treatment of patients with metastatic urothelial cancer "unfit" for Cisplatin-based 
chemotherapy. J Clin Oncol, 2011. 29(17): p. 2432-8. 
18. Galsky, M.D. et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer 
(IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. The Lancet. 2020. 
19. Powles, T et al. Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or 
metastatic urothelial carcinoma (IMvigor211): a multicentre, open-label, phase 3 randomised controlled 
trial. The Lancet. 2018. 
20. Groenvold, M. et al. Validation of the EORTC QLQ-C30 quality of life questionnaire through combined 
qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol. 1997 
Apr;50(4):441-50. 
21. Blazeby, J.M. et al. Validation and Reliability Testing of the EORTC QLQ-NMIBC24 Questionnaire 
Module to Assess Patient-reported Outcomes in Non–Muscle-invasive Bladder Cancer. European Urology. 
2014. 

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22. Botteman, M., et al., Quality of life aspects of bladder cancer: a review of the literature. Quality of Life 
Research, 2003. 12(6): p. 675-688. 
23. Cessna, J.M. et al. Evaluation of the psychometric properties of the PROMIS Cancer Fatigue Short Form 
with cancer patients. Journal of Psychosomatic Research. 2015. doi:10.1016/j.jpsychores.2015.12.002 
24. Janssen, M., et al., Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight 
patient groups: a multi-country study. Quality of Life Research, 2013. 22(7): p. 1717-1727. 
25. Cohen J. Statistical Power Analysis for the Behavorial Science. 2nd ed. Hillsdale, NJ: Lawerence Erlbaum 
Associates; 1988. 
26. Benedict et al.: Steriotactic body radiation therapy: The report of TG101. Medical Physics, Vol. 37, No. 8, 
p. 4086. August 2010. 
27. Bell ML, King MT, Fairclough DL. Bias in area under the curve for longitudinal clinical trials with 
missing patient reported outcome data: Summary measures versus summary statistics. SAGE Open 2014; 
4(2): 1-12. 
28. Sundahl, N., et al. Randomized Phase 1 Trial of Pembrolizumab with Sequential Versus Concomitant 
Stereotactic Body Radiotherapy in Metastatic Urothelial Carcinoma. Eur Urol 75, 707-711 (2019). 
29. Joshi, M., &amp; Hahn, N. M. (2020, December 09). Managing bladder cancer: Chemotherapy ineligibility 
compared with cisplatin ineligibility. Retrieved May 13, 2021, from 
https://dailynews.ascopubs.org/do/10.1200/ADN.20.200388/full/?utm_source=TrendMD&amp;utm_mediu
m=cpc&amp;utm_campaign=ASCO_Daily_News_TrendMD_0 
30. Dueck AC, Scher HI, Bennett AV, Mazza GL, Thanarajasingam G, Schwab G, Weitzman AL, Rogak LJ, 
Basch E. Assessment of Adverse Events From the Patient Perspective in a Phase 3 Metastatic Castration-
Resistant Prostate Cancer Clinical Trial. JAMA Oncol. 2020 Feb 1;6(2):e193332. doi: 
10.1001/jamaoncol.2019.3332. Epub 2020 Feb 13. PMID: 31556911; PMCID: PMC6764147. 
 

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APPENDIX I REGISTRATION FATIGUE/UNISCALE ASSESSMENT 
 
At patient registration, this form is to be administered by a nurse/CRP, completed by the patient, and entered 
into Medidata Rave at the time of registration. 
 
If needed, this appendix can be adapted to use as a source document. A booklet containing this assessment does 
not exist – please do not order this booklet. 
 
 
 
 
How would you describe: 
 
your level of fatigue, on the average in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No Fatigue 
 
 
 
 
 
 
 
Fatigue as bad as it can be 
 
your overall quality of life in the past week including today? 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
As bad as it can be 
 
 
 
 
 
 
 
As good as it can be 
 
 
 

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APPENDIX II SUMMARY OF SUGGESTED DOSE CONSTRAINTS

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APPENDIX III NCI/DCTD COLLABORATIVE AGREEMENT LANGUAGE 
 
NCI/DCTD Collaborative Agreement Language 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within 
the terms of award, apply to the use of the Agent(s) in this study: 
 
1.   Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
 
2.   For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as “Multi-Party Data”): 
 
a.   NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b.   Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
 
c.   Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of its 
own Agent. 
 
3.   Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
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subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
4.   When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5.   Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
 
6.   Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property 
rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
Use of this document is governed by the terms of use on the first page of this document