A Randomized Phase II Study of Anti-PD1 Antibody [MK-3475 (Pembrolizumab)] Alone Versus Anti-PD1 Antibody Plus Stereotactic Body Radiation Therapy in Advanced Merkel Cell Carcinoma
Phase: PHASE2
Conditions: Advanced Merkel Cell Carcinoma, Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8, Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8, Metastatic Merkel Cell Carcinoma, Pathologic Stage III Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIA Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IIIB Cutaneous Merkel Cell Carcinoma AJCC v8, Pathologic Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8
Sponsor: National Cancer Institute (NCI)

 
 
 
1 
Update #09 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
__________________________________________________ 
UPDATE TO ALLIANCE A091605 
__________________________________________________ 
 
A RANDOMIZED PHASE II STUDY OF ANTI-PD1 ANTIBODY [MK-3475 (PEMBROLIZUMAB)] ALONE 
VERSUS ANTI-PD1 ANTIBODY PLUS STEREOTACTIC BODY RADIATION THERAPY IN ADVANCED 
MERKEL CELL CARCINOMA 
 
 
 
 
 
X Update: 
 
  
Status Change: 
 
 
 
 
 
 
Eligibility changes 
 
 
Pre-Activation 
 
 
 
 
 
 
Therapy / Dose Modifications / Study Calendar changes 
 
 
Activation 
 
 
 
 
 
X Informed Consent changes 
 
 
Closure 
 
 
 
 
 
 
Scientific / Statistical Considerations changes 
 
 
Suspension / temporary closure 
 
 
 
 
 
 
Data Submission / Forms changes 
 
 
Reactivation 
 
 
 
 
 
X Editorial / Administrative changes 
 
 
 
 
 
 
 
 
X Other:MK-3475 (Pembrolizumab) CAEPR update 
 
 
 
 
The changes included in this update to A091605 have been made in response to an action letter from 
Dr. Elad Sharon (sharone@mail.nih.gov). This Action Letter is posted on the A091605 Study Page on 
the Alliance and CTSU web sites. A revised CAEPR with the new risks has been added to the protocol. 
Therefore, the model consent form has been revised to incorporate these new risks consistent with the 
new NCI Model Template Instructions. There are no changes to the risk/benefit ratio. 
 
If your site utilizes the CIRB as your IRB of record: 
No recommended IRB level of review is provided by the Alliance since the CIRB is the IRB of record for 
this trial. The site has 30 days after the posting of this amendment to implement it at their site. Please 
refer to the amendment application and CIRB guidelines for further instructions. 
 
If your site utilizes a local IRB as your IRB of record: 
Expedited IRB is allowed. IRB approval (or disapproval) is required within 90 days. Please follow your 
local IRB guidelines. The proposed changes in this amendment are minor and do not affect the overall 
risk/benefit ratio. 
 
UPDATES TO THE PROTOCOL: 
 
Section 9.4.1 (CAEPR for MK-3475) 
The CAEPR for MK-3475 (pembrolizumab) has been updated with the most recent version, Version 2.6, 
July 15, 2021. Changes from version 2.5 to 2.6 include the following:  
• 
Added New Risk:  
• 
Rare but Serious: Hepatobiliary disorders - Other (sclerosing cholangitis) 
• 
Decrease in Risk Attribution: 

 
 
 
2 
• 
Changed to Rare but Serious from Less Likely: Blood and lymphatic system disorders - 
Other (immune thrombocytopenic purpura) 
• 
Provided Further Clarification: 
• 
Thrombotic thrombocytopenic purpura is now reported as Blood and lymphatic system 
disorders - Other (immune thrombocytopenic purpura). 
 
UPDATES TO THE MODEL CONSENT: 
 
What possible risks can I expect from taking part in this study? 
Based on the revisions to the MK-3475 (pembrolizumab) CAEPR that were previously described, the 
NCI had made the following changes to the NCI condensed risk profile for MK-3475 (pembrolizumab): 
• 
Added New Risk: 
• 
Rare: Swelling of the gallbladder 
 
A replacement protocol document and model consent form have been issued. 
 
This study remains permanently closed to new patient accrual. 
____________________________________________________________ 
ATTACH TO THE FRONT OF EVERY COPY OF THIS PROTOCOL 
____________________________________________________________ 

 
NCI Version Date: 10/15/2021 
 
Update #09 
1 
ALLIANCE FOR CLINICAL TRIALS IN ONCOLOGY 
 
ALLIANCE A091605 
 
A RANDOMIZED PHASE II STUDY OF ANTI-PD1 ANTIBODY [PEMBROLIZUMAB (MK-3475)] ALONE 
VERSUS ANTI-PD1 ANTIBODY PLUS STEREOTACTIC BODY RADIATION THERAPY IN ADVANCED 
MERKEL CELL CARCINOMA 
NCI-supplied agents: Pembrolizumab (MK-3475) (NSC # 776864) 
 
ClinicalTrials.gov Identifier: NCT#03304639 
Study Co-Chair 
Study Co-Chair 
Jason Luke, MD 
Steven Chmura, MD, PhD 
University of Pittsburgh 
University of Chicago 
5150 Centre Ave. Room 564 
5841 S. Maryland Ave. MC9006 
Tel: 412-647-2811  
Tel: 773-702-4056  Fax: 773-834-7168 
lukejj@upmc.edu 
SChmura@radonc.uchicago.edu 
 
Community Oncology Co-chair 
Mark F. Kozloff, MD 
71 W.156th Street Suite 401 
Tel: 708-339-4800 Fax: 708-339-4814 
mfkozloff@aol.com 
 
SWOG Study Champion 
NRG Study Champion 
ECOG Study Champion 
Charles Hsu, MD, PhD 
Sue Yom, MD, PhD 
Andrew Poklepovic, MD 
University of Arizona 
University of California San 
Francisco 
VCU Massey 
cchsu@email.arizona.edu 
Sue.Yom@ucsf.edu 
andrew.poklepovic@vcuhealth.org 
 
Radiation Oncology PI 
Medical Physics PI 
Joseph K. Salama, MD 
Hania Al-Hallaq, PhD  
Duke University 
University of Chicago 
Joseph.salama@duke.edu 
halhallaq@radonc.uchicago.edu 
 
Experimental Therapeutics Committee Co-Chair 
Experimental Therapeutics Committee Co-Chair 
Pamela Munster, MD 
Gary Schwartz, MD 
Tel: 415 502-3598 Fax: 111-111-1111 
Tel: 212-305-2055 Fax: 212- 305-3035 
Pmunster@medicine.ucsf.edu 
gks2123@cumc.columbia.edu 
 
Primary Statistician 
Jacob B. Allred 
Tel: 507-206-0868 Fax: 507-266-2477 
allred@mayo.edu 
 
Protocol Coordinator 
Data Manager 
Krista L. Garbacz 
Brandon Bright 
Tel: 773-702-9269 Fax: 312-345-0117 
Tel: 507-538-1484 Fax: 507-284-1902 
kgarbacz@uchicago.edu 
Bright.brandon@mayo.edu 
 
Participating NCTN Organizations:  
Alliance/Alliance for Clinical Trials in Oncology (lead), ECOG-ACRIN / ECOG-ACRIN Cancer Research Group, 
NRG / NRG Oncology, SWOG / SWOG

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Update #09 
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Study Resources: 
Expedited Adverse Event Reporting 
http://eapps-ctep.nci.nih.gov/ctepaers/ 
Medidata Rave iMedidata portal 
https://login.imedidata.com 
OPEN (Oncology Patient Enrollment 
Network) 
https://open.ctsu.org 
Biospecimen Management System 
http://bioms.allianceforclinicaltrialsinoncology.org 
 
Protocol Contacts: 
A091605 Nursing Contact 
Lisa Kottschade, APRN, MSN, CNP 
Mayo Clinic 
Tel: 507-538-7888 
Email: kottschade.lisa@mayo.edu 
 
A091605 Pharmacy Contact 
Heidi Finnes, PharmD, BCOP 
Mayo Clinic 
Tel: 507-538-7066  
Email: finnes.heidi@mayo.edu 
 
Drug Supply Questions 
Pharmaceutical Management Branch, 
CTEP/DCTD/NCI 
(240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov 
Alliance Biorepository at Ohio State 
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
path.calgb@osumc.edu 
IROC Rhode Island 
640 George Washington Highway 
Building B, Suite 201 
Lincoln, RI 02865 
Tel: 401-753-7600  Fax: 401-753-7601 
www.irocri.qarc.org 
 
Protocol-related questions may be directed as follows: 
Questions 
Contact (via email) 
Questions regarding patient eligibility, treatment, 
and dose modification: 
Study Chair, Nursing Contact, Protocol 
Coordinator, and (where applicable) Data 
Manager 
Questions related to data submission, RAVE or 
patient follow-up: 
Data Manager  
Questions regarding the protocol document and 
model informed consent: 
Protocol Coordinator 
Questions related to IRB review 
Alliance Regulatory Inbox 
regulatory@allianceNCTN.org 
Questions regarding CTEP-AERS reporting: 
Alliance Pharmacovigilance Inbox: 
pharmacovigilance@alliancenctn.org 
Questions regarding specimens/specimen 
submissions: 
appropriate Alliance Biorepository  
Questions regarding drug supply 
PMB 
Questions regarding drug administration 
Pharmacy Contact 
 
The specimen collection of this study is supported by the Ludwig Center for Metastasis Research at the 
University of Chicago.  

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NCI Version Date: 10/15/2021 
 
Update #09 
3 
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 CTSU via 
the Regulatory Submission 
Portal. 
 (Sign in at 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 at 1-866-651-
2878 to receive further 
instruction and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
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_SYS
TEM/ 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). Access to the CTSU members’ website is managed through the Cancer 
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration 
system and requires log in with a CTEP-IAM username and password. 
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.  
 

Alliance A091605 
NCI Version Date: 10/15/2021 
 
Update #09 
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A RANDOMIZED PHASE II STUDY OF ANTI-PD1 ANTIBODY [PEMBROLIZUMAB (MK-3475)] ALONE 
VERSUS ANTI-PD1 ANTIBODY PLUS STEREOTACTIC BODY RADIATION THERAPY IN ADVANCED 
MERKEL CELL CARCINOMA 
 
Registration Eligibility Criteria (See Section 3.2) 
Pathologically (histologically or cytologically) proven diagnosis  
of MCC by local pathology review. 
Have measurable disease based on RECIST 1.1 with at least two 
cancerous deposits. At least one deposit must be RECIST 
measurable while at least one deposit must meet criteria for SBRT 
(See Section 7.1)  
Advanced or metastatic MCC defined as evidence of distant 
metastasis(es) on imaging. 
No prior immunotherapy for advanced/metastatic MCC (prior 
palliative RT is allowed as long as there are two unirradiated 
measurable cancerous deposits 
No History of the following:  
- 
Autoimmunity requiring systemic immunosuppression 
within 2 years 
 
- 
Patients known to be HIV positive are eligible if they meet 
the following criteria within 30 days prior to registration: 
stable and adequate CD4 counts (≥ 350 mm3), and serum 
HIV viral load of < 25,000 IU/ml. Patients may be on or off antiviral therapy so long as they meet the 
CD4 count criteria. 
No other active malignancy that the investigator determines would interfere with treatment and safety analysis. 
Not pregnant and not nursing (See Section 3.2) 
Age ≥ 18 
ECOG performance status 0 - 2 
Schema 
1 Cycle = 21 Days 
 
R 
A 
D 
O 
M 
I 
Z
E* 
 
ARM 1 
Pembrolizumab (MK-3475) 200 mg IV q3 
weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM 2 
Pembrolizumab (MK-3475) 200 mg IV q3 
weeks  
 
SBRT** 
 
 
 
* All sites have identified the metastasis to be irradiated in the event their patient is 
randomized to arm 2. 
 
** Radiation therapy will be administered to 1 cancer deposit concurrent with the first dose or started 
within the first cycle of pembrolizumab (MK-3475) administration. This cancer deposit to be irradiated 
will be defined prior to randomization and treatment per the guidelines in Section 7.1. 
 
Treatment is to continue until disease progression or unacceptable adverse event for a maximum period of 
two years. Patients will be followed for 5 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. 
 
Required Initial Laboratory Values 
Absolute 
neutrophil count 
(ANC) 
≥ 1500/mm3 
Platelet Count 
≥ 100,000/mm3 
Hemoglobin 
≥ 9.0g/dl 
Total Bilirubin 
≤ 2.0 mg/dl 
AST / ALT  
 
≤ 3.0 x ULN 
WNL* 
Systolic BP 
≤150 mg HG 
Diastolic BP 
≤ 90 mg HG 
Albumin 
>3mg/dl 
BUN 
≤30 mg/dl 
Creatinine 
≤1.7 mg/dl 
* Supplementation acceptable 

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Update #09 
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Table of Contents 
1.0 
Background ...................................................................................................................................... 5 
1.1  
Merkel cell carcinoma background and role of PD1 blockade .................................................... 5 
1.2  
Rationale ...................................................................................................................................... 6 
2.0 
Objectives ........................................................................................................................................ 6 
2.1 
Primary objective ......................................................................................................................... 6 
2.2 
Secondary objective(s) ................................................................................................................ 6 
2.3 
Correlative science objective(s) ................................................................................................... 7 
3.0 
Patient Selection .............................................................................................................................. 7 
3.1 
On-Study Guidelines ................................................................................................................... 7 
3.2 
Eligibility Criteria ........................................................................................................................ 7 
4.0 
Patient Registration .......................................................................................................................... 9 
4.1 
CTEP Investigator Registration Procedures ................................................................................ 9 
4.2 
CTSU Site Registration Procedures .......................................................................................... 10 
4.3 
Patient Registration Requirements ............................................................................................ 12 
4.4 
Patient Registration/Randomization Procedures ....................................................................... 12 
4.5 
Stratification Factors and Treatment Assignments .................................................................... 12 
5.0 
Study Calendar ............................................................................................................................... 13 
6.0 
Data and Specimen Submission ..................................................................................................... 15 
6.1 
Data Collection and Submission ................................................................................................ 15 
6.2 
Data Quality Portal .................................................................................................................... 16 
6.3 
Specimen collection and submission ......................................................................................... 16 
6.4 
Digital RT Submission Using Triad .......................................................................................... 21 
7.0 
Treatment Plan/Intervention .......................................................................................................... 22 
7.1 
Radiotherapy .............................................................................................................................. 23 
8.0 
Dose and Treatment Modifications ................................................................................................ 37 
8.1 
Supportive Care ......................................................................................................................... 40 
8.2 
Dose Modifications ................................................................................................................... 44 
9.0 
Adverse Events .............................................................................................................................. 44 
9.1 
Routine Adverse Event Reporting ............................................................................................. 44 
9.2 
CTCAE Routine Reporting Requirements ................................................................................ 46 
9.3 
Expedited Adverse Event Reporting (CTEP-AERS) ................................................................ 46 
9.4 
CAEPRs ..................................................................................................................................... 49 
10.0 
Drug Information ........................................................................................................................... 53 
10.1 
General Considerations: ............................................................................................................ 53 
10.2 
Pembrolizumab (MK-3475) (NSC 776864, IND Holder: CTEP) ............................................. 54 
11.0 
Measurement of Effect ................................................................................................................... 57 

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Update #09 
4 
11.1 
Schedule of Evaluations ............................................................................................................ 57 
11.2 
Definitions of Measurable and Non-Measurable Disease ......................................................... 57 
11.3 
Guidelines for Evaluation of Measurable Disease ..................................................................... 57 
11.4 
Measurement of Treatment/Intervention Effect ........................................................................ 59 
11.5 
Immune-Related Response Assessment (iRECIST) .................................................................. 62 
11.6 
Definitions of Analysis Variables .............................................................................................. 64 
12.0 
End of Treatment/Intervention ....................................................................................................... 64 
12.1 
Duration of Treatment ............................................................................................................... 64 
12.2 
Follow-up for patients who stop protocol therapy ..................................................................... 65 
12.3 
Managing ineligible patients and registered patients who never receive protocol intervention 65 
12.4 
Extraordinary Medical Circumstances ...................................................................................... 65 
13.0 
Statistical Considerations ............................................................................................................... 66 
13.1 
Study Design ............................................................................................................................. 66 
13.2 
Statistical Design and Analysis for the Primary Endpoint ........................................................ 66 
13.3 Sample Size, Accrual time, and Study Duration ............................................................................. 67 
13.4 Supplementary Analysis Plans ........................................................................................................ 67 
13.5 Adverse Event Stopping Rule: ........................................................................................................ 68 
13.6 Study Reporting .............................................................................................................................. 68 
13.7 
Inclusion of Women and Minorities .......................................................................................... 69 
14.0 
Correlative And Companion Studies ............................................................................................. 70 
14.1 
Biobanking for future Correlative Science ................................................................................ 70 
15.0 
General Regulatory Considerations and Credentialing .................................................................. 72 
15.1 
Institutional Credentialing ......................................................................................................... 72 
15.2 
Individual Credentialing ............................................................................................................ 72 
16.0 
References ...................................................................................................................................... 73 
Appendix I 
Registration Fatigue/Uniscale Assessments ..................................................................... 76 
Appendix II 
CRADA ............................................................................................................................ 77 
Appendix III 
Examples of confirmed progression ................................................................................. 79 
 
 
 

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Update #09 
5 
1.0 
BACKGROUND 
1.1  
Merkel cell carcinoma background and role of PD1 blockade 
Merkel cell carcinoma (MCC) is a rare but extremely aggressive cutaneous malignancy. Risk 
factors for the development of MCC include chronic ultraviolet light exposure as well as 
immunosuppression. [1, 2]Approximately 80-90% of MCC are associated with infection by the 
Merkel cell polyomomavirus which leads to oncogenic expression of viral proteins including 
the large and small T antigens [3-5]. Approximately 40% of MCC patients develop metastatic 
disease with a median overall survival of approximately 9.5 months [6]. Similar to other 
neuroendocrine cancers, standard treatment for metastatic MCC has historically included 
platinum based chemotherapy with radiation therapy reserved for palliation in appropriate 
symptomatic patients.[7] 
However, given poor survival in metastatic MCC, novel treatment strategies are needed. One 
such strategy is using immune based therapies to treat metastatic MCC. These approaches are 
based on the viral etiology for a large fraction of MCC. Blockade of the PD1/L1 axis particularly 
has been an attractive target given the known association of PD-L1 expression in virally infected 
cells. Given that MCPyV-specific T cells are detected in up to 67% of MCC tumors [8], and 
approximately 55% of MCC tumor cells express PD-L1[9] there is a strong rationale for anti-
PD-L1 therapy in MCC. Furthermore, MCPyV-negative tumors have higher mutation and 
neoantigen burden[3], which may be associated with higher response to PD-L1. 
The activity of anti-PD1/L1 antibodies has been recently described in MCC suggesting that this 
approach is likely to become firstline standard of care therapy for metastatic MCC. In a phase 
II study of the anti-PD1 antibody pembrolizumab (MK-3475) in previously untreated metastatic 
MCC patients a response rate of 56% was observed[10]. Similar to what has been observed in 
other tumors, the median duration of response was not reached with 86% of responses on-going 
at the time of datalock. Furthermore, in the second line setting, the anti-PD-L1 antibody 
avelumab has been associated with substantial clinical benefit. Presented at ASCO 2016 an 
objective response rate of 32% was seen with a 6-mo durable response rate of 29.1% (95% CI: 
19.5, 38.8). These responses lead to this agent being awarded Breakthrough Designation for 
MCC treatment by the FDA[11][11][11]. Despite the ability to get good responses with anti-
PD1/L1 therapy the median progression free survival is only nine months indicating that while 
an important step forward, this treatment paradigm needs to be augmented to improve response 
rates and survival of metastatic MCC patients. 
Rationale for radiation with immunotherapy and in Merkel Cell Carcinoma 
Radiation therapy has long been used to treat MCC either definitively, adjuvantly or 
palliatively. In the palliative setting for MCC, a single 8 Gy dose of radiation therapy for 
metastatic MCC has been associated with high response rates, and prolonged treated 
metastasis control, and minimal toxicity [12]. This approach is associated with a robust initial 
response rate however modest progression-free survival (~3 months) and no known overall 
survival benefit[13]. More recently, data has emerged indicating that 24 Gy delivered in three, 
8 Gy doses is associated with improved treated tumor control, compared to a single 8 Gy 
fraction.[14]. 
Newer radiation techniques, commonly termed stereotactic body radiotherapy (SBRT) or 
stereotactic ablative radiotherapy (SABR), but perhaps most accurately described as 
hypofractionated image-guided radiotherapy (HIGRT), precisely deliver single or few 
radiation treatments at doses 2-10 times that of conventional radiation treatments[15]. Derived 
from intracranial stereotactic radiosurgery, these treatments deliver radiation doses wrapped 
tightly around targeted metastases, while sparing surrounding normal tissues. Stereotactic 

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Update #09 
6 
Body Radiotherapy (SBRT) reduces the overall time of radiation treatment and offers a greater 
potential for cell kill compared to standard fractionation schemas of 1.8-3.0 Gy/day. SBRT 
Treatments have been shown to have high rates of treated tumor control and is standard of care 
for inoperable early stage NSCLC, prostate cancer, pancreatic cancer, and hepatocellular 
cancer. Furthermore, SBRT has been shown to have high rates of treated tumor control for 
patients with limited metastases in the lung, liver, adrenal gland, spine, and other locations 
[15] with limited toxicity. 
Implanted tumor models show that concomitant administration of radiation and anti-PD-L1 
antibody results in significantly greater tumor reduction, as compared with radiation or anti-PD-
L1 antibody treatment alone, in a murine system.[16] This effect was observed in both tumors 
within the radiation field as well as distant tumors, suggesting the beneficial effects of radiation 
on the immune response have systemic impact. Case reports of patients having responses in 
distant sites from radiation, while undergoing immunotherapy, also support this [17]. SBRT to 
metastatic sites may improve the efficacy of immune modulating agents. Described mechanisms 
for this improvement include but are not limited to increased tumor antigen exposure, improved 
antigen presentation and T cell function as well as modulation of immunosuppressive cell 
populations such as T regulatory cells and myeloid derived suppressor cells.[18-20] Preclinical 
modeling also supports a benefit when combining radiation with anti-PD1 axis blockade. 
Beyond synergistic mechanisms of modulating the immune response, direct tumor debulking by 
radiation may also be particularly well suited as an adjunct to immunotherapy. Additionally, 
higher dose per fraction of radiation has been associated with more robust adaptive immune 
responses in multiple tumors. Radiation to sites of bulk tumor would be presumed to improve 
the overall response rate of combination therapy. Additionally, reports of SBRT combinations 
with systemic therapies have suggested that time to progression is improved.[21, 22] Therefore, 
the combination of SBRT and anti-PD-1/PD-L1 treatment may not only have improved treated 
tumor control, but may also have improved overall progression free survival if SBRT enhances 
the effect of systemic therapy 
1.2  
Rationale 
Here we propose a clinical trial testing the hypothesis that the addition of SBRT radiation to 
pembrolizumab will improve progression-free survival and clinical benefit compared to 
pembrolizumab alone in MCC. 
2.0 
OBJECTIVES 
2.1 
Primary objective 
To describe the PFS of SBRT + pembrolizumab (MK-3475) compared to pembrolizumab (MK-
3475) alone in advanced/metastatic MCC patients. 
2.2 
Secondary objective(s) 
2.2.1 
To describe the PFS of SBRT + pembrolizumab (MK-3475) compared to pembrolizumab 
(MK-3475) alone across RECIST measurable (including both radiated and non-radiated) 
cancer deposits. 
2.2.2 
To describe the overall response rate of SBRT + pembrolizumab (MK-3475) compared to 
pembrolizumab (MK-3475) alone in both radiated and in non-radiated deposit(s). 
2.2.3 
To determine the PFS at 6 months of SBRT + pembrolizumab (MK-3475) compared to 
pembrolizumab (MK-3475) alone across all cancerous deposits by RECIST. 
2.2.4 
To determine the rate of grade >3-4 adverse events, by organ system, by CTCAEv5.0. 

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2.2.5 
To determine the local control of SBRT treated tumors. 
2.2.6 
To calculate delivered radiation dose using cone-beam CT images collected on the 
radiation treatment table in the final treatment position. 
2.3 
Correlative science objective(s) 
2.3.1 
To test the utility of CT-based radiomics to predict radiation-induced pneumonitis and 
true delivered dose of SBRT based on cone beam collected imaging and diagnostic scans. 
2.3.2 
Biobanking for future correlative science projects 
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: 
• 
Psychiatric illness which would prevent the patient from giving informed consent. 
• 
Medical condition such as uncontrolled infection (including HIV), uncontrolled 
diabetes mellitus or cardiac disease which, in the opinion of the treating physician, 
would make this protocol unreasonably hazardous for the patient. 
• 
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. 
In addition: 
• 
Women and men of reproductive potential should agree to use an appropriate method 
of birth control throughout their participation in this study due to the teratogenic 
potential of the therapy utilized in this trial. Include as applicable: Appropriate methods 
of birth control include abstinence, oral contraceptives, implantable hormonal 
contraceptives or double barrier method (diaphragm plus condom). 
3.2 
Eligibility Criteria  
___ 
3.2.1 
Documentation of Disease: 
Patients must have pathologically (histologically or cytologically) proven diagnosis of 
MCC by local pathology review.  
___ 
3.2.2 
Measurable disease and/or non-measurable disease as defined in Section 11.0. 
Have measurable disease based on RECIST 1.1 including at least two cancerous deposits. 
At least one deposit must be RECIST measurable while at least one deposit must meet criteria 
for SBRT (See Section 7.1). Non-radiated tumor will be identified prior to randomization on 
the protocol. 

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___ 
3.2.3  Patients must have advanced or metastatic MCC defined as evidence of 
distant metastasis(es) on imaging. 
• 
Patients with locoregionally confined disease are not eligible. 
___ 
3.2.4 
Prior Treatment  
• 
No prior immunotherapy for advanced/metastatic MCC  
• 
Patients with known or suspected CNS metastases, untreated CNS metastases, or with 
the CNS as the only site of disease are excluded. However, subjects with controlled 
brain metastases will be allowed to enroll. Controlled brain metastases are defined as 
no radiographic progression for at least 4 weeks following radiation and/or surgical 
treatment (or 4 weeks of observation if no intervention is clinically indicated), and off 
of steroids for at least 2 weeks, and no new or progressive neurological signs and 
symptoms 
• 
Patients having received palliative radiotherapy for extracranial metastasis(es) are 
eligible as long as there are 2 cancerous deposits that have not received prior RT and 
they meet the following criteria.  
o 
No prior radiation therapy (>5 Gy) to the metastasis intended to be treated with 
SBRT 
___ 
3.2.5 
No History of the following:  
• 
Autoimmunity requiring systemic immunosuppression within 2 years 
• 
Patients known to be HIV positive are eligible if they meet the following:  
• 
CD4 counts ≥ 350 mm3 
• 
Serum HIV viral load of <25,000 IU/ml. 
___ 
3.2.6 
No other active malignancy that the investigator determines would interfere 
with the treatment and safety analysis.  
___ 
3.2.7 
Not pregnant and not nursing, because this study involves an investigational 
agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown. 
Therefore, for women of childbearing potential only, a negative (if your test schedule 
specifically indicates a urine or serum pregnancy test, add that information at this point) 
pregnancy test done ≤ 28 days prior to registration is required. 
___ 
3.2.8 
Age ≥ 18 years  
___ 
3.2.9 
ECOG Performance Status 0-2 
___ 
3.2.10 Required Initial Laboratory Values:  
Absolute Neutrophil Count (ANC) 
≥ 1,500/mm3 
Platelet Count 
≥ 100,000/mm3 
Hemoglobin 
≥ 9.0g/dl 
Total Bilirubin 
≤ 2.0 mg/dl 
AST / ALT  
≤ 3.0 x ULN 
Systolic BP 
≤150 mg HG 
Diastolic BP 
≤ 90 mg HG 
Albumin 
>3mg/dl 
BUN 
≤30 mg/dl 
Creatinine 
≤1.7 mg/dl 

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___ 
3.2.11 Required pre-treatment diagnostic imaging: 
The following imaging workup to document metastases within 45 days prior to study 
registration are required: CT scans of the chest, abdomen and pelvis with radionuclide bone 
scan OR whole body (at least skullbase to midthigh) PET/CT. 
4.0 
PATIENT REGISTRATION 
4.1 
CTEP Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and renew their 
registration annually. To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository (RCR) at 
https://ctepcore.nci.nih.gov/rcr. 
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers (e.g., 
PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System [RUMS], OPEN, Rave, acting as a primary 
site contact, or with consenting privileges; 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
 
 
 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, and 
certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering 
their practice sites on the FDA Form 1572 in RCR to allow the following: 

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Update #09 
10 
• Addition to a site roster; 
• Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the 
RCR Help Desk by email at RCRHelpDesk@nih.gov. 
4.2 
CTSU Site Registration Procedures 
This study is supported by the NCI CTSU. 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical Trials 
Network (NCTN) and NCI Community Oncology Research Program (NCORP) Research Bases 
after March 1, 2019, all U.S.-based sites must be members of the NCI Central Institutional 
Review Board (NCI CIRB). In addition, U.S.-based sites must accept the NCI CIRB review to 
activate new studies at the site after March 1, 2019. Local IRB review will continue to be 
accepted for studies that are not reviewed by the CIRB, or if the study was 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 with the NCI CIRB must submit the Study Specific Worksheet for Local 
Context (SSW) 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 or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the IRB/REB 
approval) must meet the following criteria in order for the processing of the IRB/REB approval 
record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites only) 
and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 

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Update #09 
11 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a Participating 
Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
4.2.1 
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 based on person and site roster assignment. To participate, the 
institution and its associated investigators and staff must be associated with the LPO or a 
Protocol Organization (PO) on the protocol. One way to search for a protocol is listed 
below. 
• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
• 
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 A091605. 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
4.2.2 
Checking Site’s 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 sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
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. 
4.2.3 
Submitting Regulatory Documents  
Submit required forms and documents to the CTSU Regulatory Office using the Regulatory 
Submission Portal on the CTSU 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 at 1-866-651-2878 in order to 
receive further instruction and support. 
4.2.4 
Credentialing 
See Section 15.0 for credentialing requirements.  

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12 
4.3 
Patient Registration Requirements 
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. 
Patients with impaired decision making capacity may be enrolled on this study, where 
institutional policy and IRB of record allow. 
4.4 
Patient Registration/Randomization 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: 
• 
A valid CTEP-IAM account; 
• 
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; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
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 IRB number used on the site's IRB approval on their 
Form FDA 1572 in 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: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and 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. 
4.5 
Stratification Factors and Treatment Assignments 
Number of metastases (2-4 vs. >4) 
Age <70 vs. ≥ 70 years old 
ECOG 0-1 vs 2 

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5.0 
STUDY CALENDAR 
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.  
• 
To be completed ≤ 28 DAYS before registration: All laboratory studies, history and physical. 
• 
To be completed ≤ 28 DAYS before registration: Any X-ray, scan of any type or ultrasound which 
is utilized for tumor measurement per protocol. 
• 
To be completed ≤ 28 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. 
 
Prior to 
Registration* 
Arm 2 only: 
Radiation***  
Arms 1&2 
(MK3475): Day 
1 of each cycle 
Post 
treatment 
follow-up**  
Tests & Observations 
 
 
 
 
History and physical, 
weight, PS 
X 
X 
X 
X 
Height 
X 
 
 
 
Adverse Event Assessment 
 
X 
X 
X 
Registration 
Fatigue/Uniscale 
Assessment 
X(1) 
 
 
 
Laboratory Studies 
 
 
 
 
Complete Blood Count, 
Differential, Platelets 
X 
 
X 
X 
Serum Creatinine,  
X 
 
X 
X 
Albumin, glucose 
X 
 
X 
X 
AST, ALT, Alk. Phos., Bili 
X 
 
X 
X 
TSH (with reflexive TFTs 
if abnormal) 
X 
 
X 
X 
Serum or Urine HCG 
X(2) 
 
 
 
Staging 
 
 
 
 
Brain Imaging (MRI or CT 
with contrast)† 
X 
 
 
 
Tumor Measurement 
X 
 
A 
X 
CT/MRI chest/abd/pelvis # 
X(3) 
 
A 
X 
Correlative studies: For patients who consent to participate 
Blood samples 
Collected at baseline, after RT (prior to pembrolizumab (MK-
3475)(Arm 2 patients only), day 1 of cycle 3, and at the time of 
first restaging imaging (i.e. 3 months after cycle 1), see Section 
6.2. 
Tissue 
Collected at baseline prior to any treatment 
* 
Labs completed prior to registration may be used for day 1 of cycle 1 tests if obtained ≤ 7 days 
prior to treatment. For subsequent cycles, labs, scans, tests and observations may be obtained ≤ 72 
hours prior to day of treatment.  

Alliance A091605 
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** 
Physical examination, adverse event assessments, labs and scans are required ≤ 12 weeks after the 
end of treatment; thereafter, every 6 months until disease progression for a maximum of 5 years 
following registration or more frequently as clinically indicated. See also Section 12.0. At time of 
progression, withdrawal or removal, only survival information should be collected every 6 months 
for 5 years after registration. 
*** Radiation therapy will be administered to 1 cancer deposit concurrent with the first dose or started 
within the first cycle of pembrolizumab (MK-3475) administration. Eligibility must have been 
documented prior to administration of radiation. 
† 
Only required if there is evidence or suspected brain mets 
# 
All sites of known disease as clinically indicated.  
1 
To be completed after registration and prior to treatment (See Appendix I). This questionnaire is 
included on all Alliance trials in order to further study the relationship between these assessments 
and overall survival in a meta-analysis setting. 
2 
For women of childbearing potential (see Section 3.2). Must be done ≤7 days prior to registration. 
3 
Baseline scans can include either: 1) a CT, spiral CT, or MRI 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. Response assessment 
should include assessment of all sites of disease and use the same imaging method as was used at 
baseline. 
A 
After Cycle 3 (prior to cycle 4) then every 9 weeks, (prior to the start of cycles 4, 7,10, 13, 15, etc.). 
 
 

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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 a 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: 
• 
A valid CTEP-IAM account; 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 an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types 
and documentation required. 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access 
to Rave must also be assigned the appropriate Rave tasks on the DTL. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study invitation 
e-mail from iMedidata. To accept the invitation, site staff must log in to the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM username and password 
and click on the accept link in the upper right-corner of the iMedidata page. 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 link in the upper right pane of the iMedidata screen. 
If an eLearning is required and has not yet been taken, the link to the eLearning will appear 
under the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will be granted, 
and a Rave EDC link will display under the study name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the 
CTSU website in the Data Management section under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional information 
on iMedidata/Rave is available on the CTSU members’ website in the Data Management 

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16 
> Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com. 
ePRO: 
The data from the patients’ responses are submitted directly from the device into the Rave 
database. There are no documents to audit. The electronic responses are the source 
documentation. 
6.1.3 Supporting documentation 
This study requires supporting documentation for diagnosis and progression. Supporting 
documentation will include a pathology report and radiology report. These must be de-
identified and uploaded into iMedidata Rave at registration and progression. 
6.2 
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 and the DQP Reports modules are available to access 
details and reports of unanswered queries, delinquent forms, and timeliness reports. Review the 
DQP modules on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to the CTSU 
website. Staff that have Rave study access can access the Rave study data using a direct link on 
the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the Rave Home, 
DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on the 
DQP. A protocol must have the Calendar functionality implemented in Rave by the Lead 
Protocol Organization for delinquent form details and reports to be available on the DQP. Site 
staff should contact the LPO Data Manager for their protocol regarding questions about Rave 
Calendaring functionality. 
6.3 
Specimen collection and submission  
6.3.1 
Overview of specimen collection and submission 
For patients who consent to participate, tissue, blood, and fecal samples will be collected 
at the following time points for these studies: 
 
Before first dose 
of 
pembrolizumab 
(MK-3475) 
(Arm 1 & 2) 
After RT 
(Arm 2 
Only) 
Day 1 of 
Cycle 3 
(Arm 1 & 
2) 
First 
Restaging 
(i.e 3 Months 
after Cycle 1) 
(Arm 1 & 2) 
Storage/ 
Shipping 
conditions 
Submit to: 
For patients consented to A091605 biobanking, submit the following: 
Paraffin block 
OR unstained 
X(1) 
 
 
 
Ambient/ 
shipping 
overnight 
ABOSU 

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Update #09 
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slides of tumor 
tissue 
Peripheral whole  
blood (EDTA)(2) 
1 x 10 mL 
 
 
 
Cool 
pack/ship 
overnight 
ABOSU 
Peripheral whole  
Blood (green top  
heparin) (3) 
5 x 10 mL 
5 x 10 mL 
 
 
Ambient/ 
shipping 
overnight 
ABOSU 
Peripheral whole 
blood for serum 
(red top) (3) 
1 x 10 mL 
 
1 x 10 mL 
1 x 10 mL 
Cool 
pack/ship 
overnight 
ABOSU 
Stool for 
microbiome 
(kit provided) (4) 
X 
 
 
 
Dry ice/ship 
overnight 
ABOSU 
1 
Blocks are preferred. Paraffin blocks of primary and, when available, metastatic 
tissue obtained from archival tumor specimens should be sent. If not please submit 20 
unstained slides (5 micron thickness) charged (or as many as possible) but up to 20. 
For patient who consented to model consent question “I agree to have my blood and 
tissue collected and I agree that my tissue and blood and related information may be 
kept in a Biobank for use in future health research.” Tissue will be used as described 
in Section 14.1 
2 
For patient who consented to model consent question “I agree to have my blood and 
tissue collected and I agree that my tissue and blood and related information may be 
kept in a Biobank for use in future health research.” Whole blood in EDTA tubes will 
be used as described in Section 14.1. This whole blood can be collected at any time 
while patient is on study, but the preferred time is before the first dose of 
pembrolizumab (MK-3475). 
3 
For patient who consented to model consent question “I agree to have my blood and 
tissue collected and I agree that my tissue and blood and related information may be 
kept in a Biobank for use in future health research.” Blood samples will be used as 
described in Section 14.1. 
4 
For patient who consented to model consent question “I agree to have my stool 
collected and I agree that my stool and related information may be kept in a Biobank 
for use in future health research.” Stool samples will be used as described in Section 
14.1. 
6.3.2 
Specimen Submission Using the Alliance Biospecimen Management System  
USE OF THE ALLIANCE BIOSPECIMEN MANAGEMENT SYSTEM (BioMS) IS 
MANDATORY AND ALL SPECIMENS MUST BE LOGGED AND SHIPPED VIA 
THIS SYSTEM.  
BioMS is a web-based system for logging and tracking all biospecimens collected on 
Alliance trials. Authorized individuals may access BioMS at the following URL: 
http://bioms.allianceforclinicaltrialsinoncology.org using most standard web browsers 
(Safari, Firefox, Internet Explorer). For information on using the BioMS system, please 
refer to the ‘Help’ links on the BioMS webpage to access the on-line user manual, FAQs, 
and training videos. To report technical problems, such as login issues or application errors, 
please contact: 1-855-55-BIOMS or Bioms@alliancenctn.org. For assistance in using the 

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application or questions or problems related to specific specimen logging, please contact: 
1-855-55-BIOMS or Bioms@alliancenctn.org. 
After logging collected specimens in BioMS, the system will create a shipping manifest. 
This shipping manifest must be printed and placed in the shipment container with the 
specimens. 
All submitted specimens must be labeled with the protocol number (A091605), Alliance 
patient number, patient’s initials, date and type of specimen collected (e.g., serum, whole 
blood). 
Note to study authors: When specimens are time-sensitive, and/or are required for 
communication of test results back to institutions and patients, they should be labeled with 
patient initials and date of procurement, in addition to protocol number, Alliance patient 
number and specimen type. Specimens that are not time-sensitive, and/or are not submitted 
for the purpose of performing an integral test that will be reported back to patients, should 
not include patient initials or date of procurement.  
A copy of the Shipment Packing Slip produced by BioMS must be printed and placed in 
the shipment with the specimens. 
Instructions for the collection of samples are included below. Please be sure to use a method 
of shipping that is secure and traceable. Extreme heat precautions should be taken when 
necessary.  
Ship specimens on Monday through Thursday only. Shipping by overnight service to 
assure receipt is encouraged. Do not ship specimens on Fridays or Saturdays, or the day 
before a holiday. 
All specimens should be sent to the following address: 
Alliance Biorepository at Ohio State  
The Ohio State University 
Innovation Centre 
2001 Polaris Parkway 
Columbus, OH 43240 
Tel: 614-293-7073  Fax: 614-293-7967 
6.3.3 
Collection of paraffin tumor tissue 
For patients who consent to participate in A091605 biobanking (model consent question, 
“I agree to have my blood and tissue collected and I agree that my tissue and blood and 
related information may be kept in a Biobank for use in future health research”), tumor 
blocks/slides will be used as described in Section 14.1. 
Paraffin blocks of primary and, when available, metastatic tissue obtained from archival 
tumor specimens should be sent to the Alliance biorepository at Ohio State University 
(ABOSU). Please specify the source of the tumor block (primary or metastatic site).  
Label the blocks with the following information: 
1) Alliance Patient ID Number 
2) Patient Initials 
3) Alliance Study Number (i.e. A091605) 

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4) Institutional Surgical Pathology Number/Block ID 
Please DO NOT use sticky labels, and DO NOT put labels/tape on top of the actual 
tissue. 
The goal of the Alliance Biorepository is to provide investigators with quality histology 
sections for their research while maintaining the integrity of the tissue. For these reasons it 
is preferred that the Alliance Biorepository bank the block until the study investigator 
requests thin sections. Please contact the Alliance Biorepository if additional assurances 
with your hospital pathology department are required. 
The Alliance has instituted special considerations for the small percentage of hospitals 
whose policy prohibits long-term storage of blocks, and the smaller percentage of hospitals 
whose policies prohibit release of any block. If, due to institutional policy, a block cannot 
be sent, please submit 20 unstained slides at 4-6 micron thickness on plus charged slides. 
However, blocks are strongly preferred over slides. 
Label the slides with the following information: 
1) Thickness (e.g. 5 microns) 
2) Institutional Surgical Pathology Number/Block ID (either via your institution’s 
standard method for labeling clinical slides or using a permanent marker).  
Please DO NOT use sticky labels, and DO NOT put labels/tape on top of the actual 
tissue. 
The slide container should have a label affixed that includes the following information: 
1) Date of Collection 
2) Alliance Patient ID Number 
3) Patient Initials 
4) Alliance Study Number (i.e. A091605) 
When shipping FFPE tissues (blocks or unstained slides) it is important to avoid extreme 
heat. If environmental conditions indicate, FFPE tissues should be shipped in containers 
containing cold packs. It is also important that tissues are shipped in appropriately padded 
and secure containers to avoid physical damage. 
Ship specimens to the Alliance Biorepository at OSU with Priority Overnight on 
Monday through Thursday for next day delivery. Do not send specimens the day 
before a holiday. 
The goal of the Alliance Biorepository is to provide investigators with quality histology 
sections for their research while maintaining the integrity of the tissue. For these reasons, 
it is preferred that the Alliance Biorepository bank the block until the study investigator 
requests thin sections. Please contact the Alliance Biorepository if additional assurances 
with your hospital pathology department are required. 
A copy of de-identified surgical pathology report should be sent with all tissue submission. 
Usually, this is generated by obscuring all PHI (names and dates) with white-out or a black 
magic marker, labeling each page of the report with the Alliance patient ID, and 
photocopying the report. The surgical pathology case number and block identifier (if 
applicable) should be maintained on the report so that it can be matched with the physical 
labeling on the sample. 

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Specimens may be shipped Priority Overnight to the Alliance biorepository on Monday 
through Thursday for next day delivery. The biorepository cannot receive specimens on 
Sundays or holidays. Do not send specimens on Saturday or the day before a holiday. 
Please refer to the holiday shipping schedule posted in BioMS. 
6.3.4 
Blood sample submission 
For patients who consent to participate in A091605 biobanking (model consent question, 
“I agree to have my blood and tissue collected and I agree that my tissue and blood and 
related information may be kept in a Biobank for use in future health research”), blood 
samples will be used as described in Section 14.1. This sample should be collected prior to 
1st dose of pembrolizumab (MK-3475).  
Whole Blood in EDTA Lavender Top Tube: 
Collect 10 mL of peripheral venous blood in one lavender top tube (K2 or K3 EDTA anti-
coagulant) before the 1st dose of pembrolizumab (MK-3475) (baseline). The tubes should 
be inverted approximately 8-10 times to mix the EDTA. Refrigerate sample until shipping. 
The blood sample should be placed in a biohazard bag and shipped the same day as the 
blood is drawn on a cold pack by overnight courier service to the Alliance Biorepository 
at Ohio State University, where it will then be processed. 
Whole Blood in Heparin Green Top Tubes: 
Collect 5 x 10 mL of peripheral venous blood into green top (sodium heparin) vacutainer 
tubes at the following time points: before the 1st dose of pembrolizumab (MK-3475), after 
radiation (for Arm 2 patients only) and after 4 doses of pembrolizumab (MK-3475) 
Specimens should be kept at room temperature until shipping. Invert tubes approximately 
8-10 times to mix the additive. Samples should be then placed in a biohazard bag and 
shipped according to IATA guidelines the same day as the blood is drawn and shipped at 
ambient temperature by overnight courier service to the Alliance Biorepository at OSU 
for PBMC isolation. Please do NOT use cold pack during shipping for the whole blood 
sodium heparin (green top) samples. 
Whole Blood in Red Top Tubes 
Collect ~10 mL peripheral venous blood plain red top vacutainer tube(s). Gently invert 
approximately 5 times to mix clot activator with blood. Let blood clot for 30 minutes. 
Observe a dense clot. Centrifuge at approximately 1300g (or in accordance with centrifuge 
manufacturer’s instructions) for 10 minutes. The sample should be refrigerated until 
shipped. Samples should be placed in a biohazard bag and shipped according to IATA 
guidelines on cool pack by overnight mail to the appropriate Alliance biorepository. The 
sample should be shipped the same day that the blood is drawn. 
All blood samples should be labeled with the following identification: 
1) Alliance study number (A091605) 
2) Alliance patient ID number 
3) Patient’s initials 
4) Date and time of collection  
5) Sample type (eg whole blood). 

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Specimens may be shipped Priority Overnight to the Alliance biorepository on Monday 
through Thursday for next day delivery. The biorepository cannot receive specimens on 
Sundays or holidays. Do not send specimens on Saturday or the day before a holiday. 
6.3.5 
Stool Specimen Submission 
Stool kits should be ordered through BioMS. 
For patients who consent to participate in A091605 (model consent question, “I agree to 
have my stool collected and I agree that my stool and related information may be kept in a 
Biobank for use in future health research.”), fecal samples will be used as described in 
Section 14.1. This sample should be collected prior to 1st dose of pembrolizumab (MK-
3475).  
Study subjects will receive a fecal collection kit. that includes a 9x9x9” cardboard box with 
a Styrofoam container, 2 nitrile gloves, a Ziploc bag with absorbent material containing 
three 25 ml fecal collection vials with spoons for the stool sample, a disposable “specimen 
collection toilet adapter with white container” to be placed over the toilet bowl to collect 
the bowel movement, Wypall absorbent material, parafilm and a sheet of patient 
instructions. Kits should be ordered through the BioMS website. Study subjects will return 
the fecal collection kit to the site within 48 hours of collection. Patient does not need to 
refrigerate the sample.  
Once the laboratory at the site receives the stool collection kit, they should perform the 
following: 
• 
Aliquot the sample into four cryovials* (~100mg per vial). Any extra stool sample 
should be kept in the original large leak-proof receptacle. 
• 
Label the cryovials with Alliance study number (A091605), Alliance Patient ID, 
Patient’s initials, Date of collection, Sample type (stool). 
• 
Freeze aliquots and the original container at -80°C. Once frozen, samples should not 
be allowed to thaw. 
• 
Ship samples within 30 days on dry ice by overnight express courier to the Alliance 
Biorepository at Ohio State University. The biorepository cannot receive specimens on 
Saturdays, Sundays or holidays. Please keep the stool refrigerated until shipping. 
Please keep the stool samples frozen until shipping. Sufficient dry ice should be used 
in the shipping container to ensure that samples remain frozen for at least 72 hours. 
Keep at least one vial or large receptacle at shipping site. 
* Cryovial Choices: Some examples of acceptable 1.8-2.0 mL cryovials are Nalgene (Cat 
#5012-0020), Fisher (Cat #10-500-26), Corning (Cat #430488), and Nunc (Cat #347627). 
6.4 
Digital RT Submission Using 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. 
6.4.1 
TRIAD Access Requirements 
Site staff that will be submitting images via TRIAD will need to register with CTEP and 
have a valid and active CTEP-IAM account.  
• 
Must be registered as an Associate, Associate Plus, Non-Physician Investigator, or 
Investigator registration type. Refer to the CTEP Registration Procedures section 

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for instructions on how to request a CTEP-IAM account and complete registration 
in Registration and Credential Repository (RCR). 
To submit images, site staff must hold the TRIAD Site User role on an NCTN or ETCTN 
roster. Individuals requiring a TRIAD Site User role should contact the person holding a 
primary role at the site for their affiliated 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. 
6.4.2 
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 username and 
password and RCR registration. 
For questions, contact TRIAD Technical Support staff via email TRIAD-Support@acr.org 
or 1-703-390-9858. 
6.4.3 
Procedures for Data Submission via TRIAD 
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 as described above. Additional 
information is available at: 
http://triadhelp.acr.org/ClinicalTrials/NCISponsoredTrials.aspx 
In the event that a site has not completed all steps required for TRIAD data submission in time 
to meet the timeline for pre-treatment review, data submitted via SFTP will also be accepted. 
See the instructions for submission of data via SFTP on the IROC Rhode Island website under 
Digital Data. 
See Section 7.3.7 for items to be submitted for RT QA pre-treatment review 
 7.0 TREATMENT PLAN/INTERVENTION 
Protocol treatment is to begin ≤ 21 days of registration.  
For questions regarding treatment, please see the study contacts page.  
It is acceptable for individual pembrolizumab (MK-3475) to be delivered ≤ a 72-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 Tuesday through the 
following Monday. In addition, patients are permitted to have a new cycle of pembrolizumab (MK-
3475) 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. 
Pembrolizumab (MK-3475)) is administered on an outpatient basis. Infusion timing should be as 
close to 30 minutes as possible; however, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 25-40 minutes). Please refer to Section 10.2 for pembrolizumab (MK-3475) 
compatible infusion set materials, including in-line filter. 
Protocol therapy will include pembrolizumab (MK-3475) in both arms (Arms 1 & 2) and radiation 
(SBRT) in one arm (Arm 2). Radiation will be administered concurrent with the first dose or started 

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within the first cycle of pembrolizumab (MK-3475). The radiated lesion will be identified prior to 
randomization and that this lesion will be excluded from the primary endpoint (PFS) calculation. 
pembrolizumab (MK-3475) treatment will be administered once every 21 days (1 cycle). Treatment 
will continue until disease progression or unacceptable adverse event for a maximum period of two 
years. 
Agent 
Dose 
Route 
Day 
ReRx 
pembrolizumab 
(MK-3475) 
200 mg 
IV 
Day 1 
every 3 weeks 
7.1 
Radiotherapy 
Patients in Arm 2 will receive three 8 Gy doses of radiation for a total dose of 24 Gy to a single 
metastasis (cancer deposit). The radiated lesion will be identified prior to randomization and 
that this lesion will be excluded from the primary endpoint (PFS) calculation. Each treatment 
will be separated by a minimum of 40 hours. The expectation is that SBRT will be used for 
treatment. In cases where the treated tumor is superficial, the use of an electron 3D conformal 
plan is permitted provided that it provides superior sparing of the organs-at-risk.  
Selection of Metastasis to be Irradiated: 
In general, the following guidelines in order should be followed when selecting the metastasis 
to be irradiated. 
1. Do not reirradiate a previously irradiated metastasis that has received > 5Gy. 
2. Do not reirradiate previously irradiated OAR that have reached the following 
tolerances in conventional fractionation (please contact study chairs if patient has 
previously received other fractionation for guidance on prior radiation delivery): 
• 
Spinal cord previously irradiated to > 40 Gy 
• 
Brachial plexus previously irradiated to > 50 Gy 
• 
Small intestine, large intestine, or stomach previously irradiated to > 45 
Gy 
• 
Brainstem previously irradiated to > 50 Gy 
• 
Lung previously irradiated with prior V20Gy > 30% 
3. Prioritize irradiating a visceral metastasis over an osseous metastasis 
4. Of visceral metastases, prioritize treating a hepatic metastasis 
5. Prioritize treating a larger metastasis 
6. Limit the treated metastasis diameter to 10 cm 
7.1.1. Technical radiotherapy requirements: 
To successfully treat using SBRT, centers must satisfy technology requirements for 
immobilization, simulation, planning, and image-guidance (IGRT) for radiotherapy. These 
are summarized in the following tables. Questions regarding appropriate technology for 
this protocol can be directed to the Radiation Oncology PI or medical physics PI. 
Table 1.1 Technology Requirements for SBRT 
Technology  
Requirement  
Comments  
Beam Modality  
MV Photons  
ViewRay & Linac are allowed. 
For superficial tumors, electrons 

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are allowed**. Other charged 
particles including protons, and 
heavier ions are not permitted. 
Beam Energy  
1 to 10 MV  
For targets in the lung, >50 % of target 
dose should be delivered by beams with 
energy ≤10 MV 
10-18 MV may be used in selected cases 
with >10 cm from skin to target  
Minimize use of high energy in 
lung. 6 MV or lower energies 
should be predominately used in 
low-density tissue.  
Treatment 
Technique  
3DCRT (static, arc) 
Intensity modulation (IMRT, VMAT)  
Tomographic and robotic^ 
techniques allowed.  
Image Guidance  
Treatment machine must be equipped to 
provide daily volumetric 3D image 
guidance* (kV cone-beam, MV-cone beam, 
CT on rails, MRI)  
Non-ionizing guidance (RF 
transponders, optical surface 
imaging) is permitted but does 
not preclude the volumetric 
imaging requirement. Use of 2D 
orthogonal image guidance (kV 
OBI, ExacTrac) is permitted for 
targets with implanted fiducials 
or spinal targets but does not 
preclude the volumetric imaging 
requirement.  
*Note: Each treatment fraction must be documented with volumetric imaging to enable delivered dose 
assessment per Section 2.2.6 with the exception of a) robotic systems that do not possess this capability 
and b) treatments delivered with electrons.  
**Exception: Select metastases located within 2cm of the skin may be targeted with a 3D conformal plan 
developed with electron beams. In these cases, the institution must be capable of generating a 3D 
conformal plan calculated on a CT scan. All calculation algorithms for electrons are permitted (e.g., pencil 
beam, Monte Carlo). If the skin normal tissue constraints cannot be met with an electron plan, 3D 
conformal SBRT approach with photons should be used instead.  
^Note: Robotic techniques without the ability to acquire volumetric image guidance (e.g., CyberKnife) 
are excluded from the volumetric imaging requirement. 
Table 1.2 Simulation Guidelines  
Topic/Parameter 
Guideline* 
Immobilization 
Proper immobilization (e.g., stereotactic body frame, custom-fabricated 
immobilization) with appropriate clinical devices to ensure 
reproducibility is required. Patient comfort should be prioritized. 
Positioning the patient on the treatment couch without any support is 
discouraged. 
Motion Assessment 
Ascertain the characteristics of target (and normal tissue) motion with 
regard to magnitude (amplitude), timing (period), and regularity to 
determine the need or success of motion control. This is carried out 
both in simulation and treatment using real time monitoring (e.g., 
fluoroscopy, 4D CT, beacon tracking, etc.). 

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Motion Control 
Motion control is strongly encouraged when the GTV excursion > 1 cm 
in any direction. Typical motion control maneuvers include inhibition 
strategies (e.g., abdominal compression and active breath hold), 
tracking based on a motion model, and gating to part of the breathing 
cycle, but others may be applicable. Internal organ management 
maneuvers must be reliable enough to insure that the GTV does not 
deviate beyond the confines of the PTV with any significant probability 
(i.e., < 5%). 
CT Slice Thickness 
Within 10cm of the PTV, ≤3 mm is recommended. Do not exceed 3 
mm. Slices of 1-2 mm are recommended for tumors that are 1 cm or 
less in the largest dimension. 
Use of Contrast 
IV contrast is required for treatment of a metastasis in the liver. For 
targets in other sites, IV contrast is encouraged for better delineation 
between tumor, pathologic lymph nodes, atelectasis, and vascular 
structures as well as better definition of normal tissue contours. Oral 
contrast can be used for OAR delineation at the clinical discretion of 
the treating physician. Generally, contrast scans are acceptable for dose 
calculations, although density overrides may be applied in areas of 
strong contrast (e.g., oral contrast in esophagus). No overrides should 
be used in the GTV.  
CT Scan Range 
The CT scan range should include the entirety of the organ that the 
metastasis to be treated resides in. Additionally, at minimum it should 
be 10 cm superior and inferior to the treated tumor. 
*Note: A target amenable to treatment with electron beams should adhere to these guidelines. If motion 
for such a target > 1cm, please consider instead the use of a 3DCRT technique with photon beams.  
 
Table 1.3. IGRT Motion Assessment/Management Recommendations for Simulation and 
Treatment 
Treatment 
Technique 
Recommended 
Method for Motion 
Assessment During 
Simulation 
Minimum Method 
for Motion 
Assessment During 
Simulation 
Scan(s) 
Recommended for 
Treatment Planning 
Imaging 
Recommended 
for Treatment*  
Free-breathing 
using an internal 
gross target 
volume (IGTV) 
approach including 
abdominal 
compression 
4D CT or 
fluoroscopy as long 
as tumor can be 
directly visualized 
Repeated slow 
acquisition CT 
scanning through 
the target (to 
sample motion) 
fused to the 
planning CT 
dataset  
Average intensity 
projection (AIP) 
scan from a full 
field-of-view 4D CT 
for dose 
calculations; 
Maximum intensity 
projection (MIP) 
scan to aid IGTV 
definition; Free-
breathing scans are 
not recommended. 
Free-breathing 
3D IGRT to 
ensure visible 
tumor aligns to 
IGTV** 
 
Gating with a 
gating window 
4D CT 
Exhale CT plus 
fluoroscopy (free-
breathing + 
Reconstructed 
average of gating 
window scans from 
Gated 3D 
IGRT or 
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fluoroscopy 
strongly 
discouraged due to 
baseline shift) 
4D CT. Maximum 
intensity projection 
(MIP) scan limited 
to gating window to 
aid IGTV definition. 
not available, 
then free-
breathing CT to 
ensure visible 
tumor aligns to 
MIP contour 
from 4D CT 
limited to the 
gating window 
Breath hold (i.e. 
ABC) 
Reproducibility of 
breath hold 
confirmed 
(examples: multiple 
low dose scans over 
tumor, repeat 
fluoroscopy or scout 
images) 
N/A 
Scan in breath hold 
position (inhale 
recommended since 
it maximizes lung 
volume) 
Gated 3D 
IGRT; if not 
available use 
manual beam-
hold during 
CBCT 
acquisition 
over multiple 
breath-holds to 
ensure tumor 
aligns to 
IGTV** 
Tracking^ 
4D CT or breath 
hold CT 
N/A 
4D CT or breath 
hold CT 
Volumetric 
imaging or 
real-time 
imaging of 
tumor 
surrogate 
required based 
on treatment 
machine 
capabilities. 
*Note: Volumetric IGRT for each site must be acquired and submitted for post-treatment 
assessment of dose per Section 2.2.6 and Table 1.1, except for treatments delivered with 
electrons or robotic systems without the capability of volumetric IGRT. 
**Note: IGTV is defined in section 7.1.2. In the case when tumor is not visible, please use an 
appropriate organ surrogate for alignment (i.e., liver as surrogate for a non-visible liver 
metastasis). 
^Note: Tracking methods refer to use of robotic or similar systems that provide real-time 
imaging (i.e., CyberKnife, ViewRay). 
7.1.2 Target Volumes and Margins 
Definitions of GTV, CTV, IGTV, PTV: 
• 
GTV: The GTV will consist of all known radiographic, metabolic, and clinical 
extent of the metastasis to be treated as contoured on the planning CT scan. 
• 
For tumors with respiratory motion, the motion encompassing GTV will be 
defined at the internal gross tumor volume (IGTV). Note that the term “ITV” is 

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explicitly avoided to prevent confusion between a motion encompassing CTV 
and GTV: 
 
• 
The GTV (or IGTV) = CTV 
• 
The PTV = IGTV (or GTV when strict motion control is applied/unnecessary) 
+ 5mm 
All PTV structures must be named for digital RT data submission as listed in the table 
below. 
Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name listed. Capital letters, spacing and use of underscores must be 
applied exactly as indicated.  
Standard Name  Description  
PTV_2400  
PTV to be treated to 2400cGy.  
GTV_2400 
GTV to be treated to 2400cGy.  
IGTV_2400 
IGTV to be treated to 2400cGy.  
PTV20  
PTV with 2cm expansion  
E-PTV_2400  
External minus PTV  
E-PTV20  
External minus PTV_20 (PTV with a 2 cm expansion)  
7.1.3. Organs-At-Risk (OAR) Naming/Delineation,  
Note: All structures must be named for digital RT data submission as listed in the table 
below.  
Resubmission of data may be required if labeling of structures does not conform to the 
standard DICOM name listed. Capital letters, spacing and use of underscores must be 
applied exactly as indicated.  
Standard Name 
Description  
BileDuct_Common  Common Bile duct  
Bladder  
Bladder  
BrachialPlex_L  
Left Brachial Plexus  
BrachialPlex_R  
Right Brachial Plexus  
BrachialPlexs  
Left plus Right Brachial Plexus  
Bronchus  
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 
Bronchus_NAdj 
Non Adjacent Bronchus 

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Critical structure contours will be drawn in axial planes of the primary planning dataset. In general, 
critical structures should be contoured if they are found within an axial slice within 10 cm in the 
craniocaudal direction of the PTV to be treated on protocol. Parallel organs must be contoured in their 
entirety.  
 
Detailed 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. 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 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.  
 
Bowel_Large 
Large Bowel 
CaudaEquina  
Cauda equina  
Duodenum  
Duodenum  
Esophagus  
Esophagus  
Esophagus_NAdj 
Non Adjacent Esophagus 
External  
Body surface  
Femur_L  
Left whole Femur  
Femur_R  
Right whole Femur  
Femurs  
Combined Left and Right Femurs  
GreatVes 
Great Vessels of the heart (aorta, vena cava S&I, pulmonary A&V) 
GreatVes_NAdj 
Non Adjacent Great Vessels 
Heart 
Heart 
Jejunum_Ileum  
Both ileum and jejunum  
Larynx 
Larynx 
Liver 
Liver 
Liver-GTV 
Liver minus GTV 
Lung_L 
Left Lung 
Lung_R 
Right Lung 
Lungs 
Left plus Right Lungs 
Lungs-GTV 
Lungs minus GTV 
Kidney_Cortex  
Renal cortex for both Kidneys  
PenileBulb 
Penile Bulb 
Rectum 
Rectum 
Rib 
Ribs within 10cm of the PTV  
SacralPlex 
Sacral Plexus 
Skin 
Outer 0.5cm of the body surface (rind) 
SpinalCord 
Spinal cord 
Stomach 
Stomach 
Trachea  
Trachea  
Trachea_NAdj  
Trachea non-adjacent wall  
Ureter  
Ureter  

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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, 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.  
 
Trachea and Proximal Bronchial Tree  
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 proximal bronchial tree.  
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. 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.  
 
Lungs 
Both the right and left lungs should be contoured individually (Lung_L, Lung_R) and also combined as 
one structure (Lungs). 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 for the structure created and labeled as Lungs - GTV.  

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Skin  
The skin 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).  
 
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.  
 
Jejunum/Ileum(Small bowel) 
As a conglomerate of bowel loops within the abdomen distinguished from stomach, duodenum, and 
colorectum. 
 
Bowel (Large)  
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.  
 
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.  
 

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Bile ducts  
May use the portal vein from its juncture with the splenic vein to its right and left birfurcation in the liver 
as a surrogate to identify the bile ducts.  
 
Femoral Heads  
The ball of the head and socket joint.  
 
Rib  
Ribs within 10 cm of the PTV should be contoured by outlining the bone and marrow. 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).  
 
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. If possible this structure should be constructed as a 
single contour that is 2 cm larger than the PTV.  
 
Other Structures  
The constraints tables below contain other structures. These are required if the structure is within 10 cm 
of the PTV. 
7.1.4 Treatment Planning Guidelines 
Table 1.4 Summary of General Treatment Planning Guidelines 
Number of Beams 
Typically 7-13 static radiation beams with equal weighting are generally 
suitable. It is recommended that at least 10 beams be used when possible. 
Note that dose should be properly distributed between beams due to skin 
toxicity considerations. Similarly, arcs should cover an appropriate range (≥ 
340o) so as to deliver a safe dose to the skin. Single arc plans may be 
suitable for simple geometries while additional arcs are preferred for more 
complex geometries. 
Beam Arrangement 
Coplanar or non-coplanar (non-coplanar are encouraged), non-overlapping, 
non-opposing beams or arc therapy (non-coplanar arcs encouraged to 
improve conformity and OAR sparing in complex geometries). Combination 
of static and arc beams allowed. Gantry clearance verification prior to 
treatment is recommended. 
Minimum Field Size 
As planning dictates although only the smallest field size accurately 
commissioned (e.g. small field output factors are within 5% of published 
standards or values) at the institution should be used. Because of concerns 
with small field dosimetry, field sizes above 2 cm x 2 cm are preferable. 
Dose Calculation Algorithm* 
Modern algorithms that accurately handle tissue heterogeneity and scatter 
should be used. IROC maintains an updated list of approved algorithms. 
Density corrections must be applied. Density overrides of the GTV are not 
recommended for photon treatment.  
Dose Grid Resolution 
3 mm x 3 mm dose grid resolution or smaller is required. Use of 2 mm x 2 
mm is recommended, especially for targets less than 2 cm in diameter. 
*Note: For treatment of a superficial metastasis with electrons, the institution must be capable of 
generating a 3D conformal plan calculated on a CT scan. All calculation algorithms for electrons are 
permitted (e.g., pencil beam, Monte Carlo). 

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Table 1.5 Dosimetric Guidelines for SBRT Target Coverage 
Metric 
Guideline 
Dose Heterogeneity within PTV  
Rather than prioritizing target dose homogeneity, 
SBRT treatment planning prioritizes adequate 
minimum target coverage and rapid dose fall-off 
gradients outside of the target. This is achieved 
using typical normalization of 60-90% with the 
hotspot located within GTV*.  
R100% (Rx Isodose volume/PTV)  
See Table 1.6 below. 
Every attempt should be made to achieve R100% 
<1.2, unless the block/MLC margin is larger than 
PTV to satisfy small field dosimetry criteria. 
Avoid dose > 105% of the prescription dose 
outside of the PTV.  
R50% (50% Rx Isodose volume/PTV) 
D2cm[%] (Max dose at 2cm from PTV) 
See Table 1.6 below. 
Effort should be made to reduce the 50% isodose 
volume and the maximum dose at 2cm.  
*Note: If target overlaps with OAR please use planning priorities in section 7.1.6 to determine dose 
coverage. 
Table 1.6 Recommendations for Allowable Dose Spillage 
PTV Volume 
(cc) 
R50% 
Ratio of 50% Isodose Volume 
to the PTV Volume 
D2cm[%] 
Maximum Dose at 2 cm from PTV 
in any direction as % of Prescription Dose 
Per Protocol  
Acceptable 
Variation  
Per Protocol  
Acceptable 
Variation  
1.8  
<5.9  
<7.5  
<50.0  
<57.0  
3.8  
<5.5  
<6.5  
<50.0  
<57.0  
7.4  
<5.1  
<6.0  
<50.0  
<58.0  
13.2  
<4.7  
<5.8  
<50.0  
<58.0  
22.0  
<4.5  
<5.5  
<54.0  
<63.0  
34.0  
<4.3  
<5.3  
<58.0  
<68.0  
50.0  
<4.0  
<5.0  
<62.0  
<77.0  
70.0  
<3.5  
<4.8  
<66.0  
<86.0  
95.0  
<3.3  
<4.4  
<70.0  
<89.0  
126.0  
<3.1  
<4.0  
<73.0  
<91.0  
163.0  
<2.9  
<3.7  
<77.0  
<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 applied. 
7.1.6 Treatment Planning Priorities 
In general, attempts should be made to successfully satisfy all of the treatment planning 
criteria without deviation. In some circumstances, improvements can be made to the 
dosimetry plan beyond simply meeting the specified goals. In other circumstances, it may 
not be possible to meet the per protocol or variation acceptable criteria for all metrics. In 

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cases where tradeoffs are required, the priorities listed in Table 1.7 should be followed. 
Figure 1 demonstrates these priorities graphically.  
Table 1.7 Treatment Planning Priorities 
Planning 
Priority 
Instructions 
1 
Respect constraints for all priority 1 OAR in Table 1.9 regardless of the dose delivered to 
the PTV*. 
2 
Meet dose “compactness” constraints by: 
a) Covering 95% of the PTV with the prescription isodose (or at a minimum the 
variation acceptable dose in Table 1.8). 
b) Limiting the hotspot (>100% of the prescribed dose) volumes and limiting their 
location to within the PTV volume. In cases where the PTV overlaps with OARs, 
it is recommended to allow variation acceptable levels of target coverage and to 
minimize hotspots in OAR overlap areas. Intensity modulated planning techniques 
may be beneficial in this scenario. 
c) Limiting intermediate dose spillage (D2cm and R50) according to Table 1.6.  
3 
Meet critical structure constraints other than those listed in 1 (i.e., priority 3 in Table 1.9).  
*Note: PTV coverage that falls below the variation acceptable range in Table 1.8 in order to meet priority 
1 OAR constraints will not be scored an unacceptable deviation. 
 
Figure 1 Graphical representation of preferred planning tradeoffs in areas of overlap. See Table 1.7 
for more detail. 
 
Section 7.1.7 Dose Constraints  
Table 1.8 Dosimetry Compliance for Target 
Structure 
Dosimetric Parameter 
Per Protocol 
Variation Acceptable 
PTV_2400 
D95%[Gy] 
24 
22.5-25.6 
(excluding 24) 
 
Table 1.9 Normal Structure Constraints and Compliance Criteria  
Serial Organ 
Dosimetric 
Priority 
Volume 
Volume Dose 
(Gy) 
Spinal Cord 
1 
<0.03 cc 
22.5 

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<1.2 cc 
13 
Ipsilateral Brachial 
Plexus 
1 
< 0.03 cc 
26 
 
 
<3 cc 
22 
Cauda Equina 
1 
<0.03 cc 
22.5 
 
 
<5 cc 
21.9 
Sacral Plexus 
1 
<0.03 cc 
24 
 
 
<5 cc 
22.5 
Trachea and 
Ipsilateral Bronchus  
(Non-adjacent wall) 
3 
<0.03 cc 
30 
 
 
<5cc 
25.8 
Esophagus 
(Non-adjacent wall) 
1 
<0.03 cc 
27 
 
 
<5cc 
17.7 
Heart/Pericardium 
1 
<0.03cc 
30 
 
 
<15 cc 
24 
Great vessels 
(Non-adjacent wall) 
3 
<0.03cc 
45 
 
 
<10 cc 
39 
Skin (non-tumor 
involved) 
1 
<0.03cc 
33 
 
 
<10cc 
31 
Stomach 
1 
<0.03cc 
30 
 
 
<10cc 
22.5 
Duodenum* 
1 
<0.03cc 
24 
 
 
<10cc 
15 
Jejunum/ileum* 
1 
<0.03cc 
27 
 
 
<30cc 
17.4 

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Bowel* 
1 
<0.03 cc 
34.5 
 
 
<20cc 
24 
Rectum* 
3 
<0.03 cc 
49.5 
 
 
<3.5 cc 
45 
 
 
< 20 cc 
27.5 
Bladder 
3 
0.03cc 
33 
 
 
<15 cc 
16.8 
Ureter 
3 
<0.03 cc 
40 
Penile bulb 
3 
< 3cc 
25 
Femoral heads 
3 
<10 cc 
24 
Bile duct 
3 
< 0.3 cc 
36 
Renal hilum/vascular 
trunk 
3 
<15 cc 
19.5 
Rib 
3 
< 0.03 cc 
50 
 
 
<5 cc 
40 
Parallel Organ 
 
Volume 
Volume Dose 
(Gy) 
Lung (total) 
3 
<15% lung volume 
20 
 
 
< 37% lung volume 
11 
 
 
1500 cc 
10.5 
 
 
1000 cc 
11.4 
Total Kidney 
3 
<200cc 
15 
Liver 
3 
<700 cc 
17.1 
*NOTE: Avoid circumferential irradiation. 
 
NOTE: For all priority-1 OAR, these are absolute limits, and treatment delivery that exceeds 
these limits will constitute a major protocol violation.  
Table 1.10 OAR Compliance Criteria 
Structure 
Dosimetric Parameter 
Per Protocol 
Variation Acceptable 

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OAR priority 1 
Maximum point dose* 
& 
 Dose volume constraint 
See Table 1.9 
Must meet constraints in Table 
1.9 
Serial OAR priority 3 
Maximum point dose*  
& Dose volume 
constraint 
See Table 1.9 
< 25.2 Gy**  
(105% of prescription dose) 
Parallel OAR priority 3 
Dose volume constraint 
See Table 1.9 
< 105% of dose in Table 1.9  
*Note: Maximum point dose is assessed using dose to a volume of 0.03cc.  
**Note: This dose is considered acceptable only when OAR are adjacent to or overlapping with PTV (see 
Figure 1). Otherwise, every effort should be to meet constraints in Table 1.9. 
7.1.8 
Submission of Digital Radiation Therapy Data 
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 for details. 
Additional information is available at:  
http://triadhelp.acr.org/ClinicalTrials/NCISponsoredTrials.aspx 
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. 
One week prior to the start of radiotherapy, the following data shall be submitted for pre-
treatment review for all cases: 
Treatment Planning System Output 
RT treatment plans including CT, structures, dose and plan files. These items are included 
in the digital plan. 
Digitally reconstructed radiographs (DRR) for each treatment field, showing the collimator 
and beam aperture. Submission of DRR's is not required for IMRT/VMT plans. 
Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics. 
Supportive Data 
Copies and reports of all imaging studies used to define the target volume. 
Prescription sheet for entire treatment. 
Forms 
RT-1 Dosimetry Summary Form 
Motion Management Reporting Form  
Within 21 days of the completion of radiotherapy, the following data shall be 
submitted for all patients: 
IGRT Data -- Volumetric IGRT data in DICOM format from each of the 3 treatment 
fractions, including the DICOM spatial registration file (REG file) for each fraction if 
available from your image guidance system. 
The RT-2 Radiotherapy Total Dose Record Form 

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A copy of the patient's radiotherapy record including the prescription, and the daily and 
cumulative doses to all required areas. 
Documentation listed above showing any modifications from the original submission. 
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 
7.1.9 
Compliance Criteria 
Definitions of Deviations in Dose to Target Volumes 
Per Protocol: The dose to the target volume meets the "Per Protocol" requirements 
specified in Tables 1.6 and 1.8. 
Variation Acceptable: The dose to the target volume falls within the "Variable Acceptable" 
range specified in Tables 1.6 and 1.8. 
Deviation Unacceptable: The dose to the target volume falls outside the "Variable 
Acceptable" range specified in Tables 1.6 and 1.8. 
Definitions of Deviations in Dose to Normal Structures 
Per Protocol: The dose to normal structures meets the constraints in Table 1.9. 
Variation Acceptable: The dose to normal structures falls within the "Variable Acceptable" 
range specified in Table 1.9 & 1.10. 
Deviation Unacceptable: The dose to normal structures falls outside the "Variable 
Acceptable" range specified in Table 1.9 & 1.10. 
Definitions of Deviations in Volumes Drawn 
Per protocol: All specified contouring volumes are drawn as specified in the protocol. 
Variation Acceptable: Delineation of specified contouring volumes deviates from protocol 
guidelines but the protocol intended volumes are adequately covered by the prescribed 
doses. 
Deviation Unacceptable: Delineation of specified contouring volumes deviates 
significantly from protocol guidelines and the protocol intended volumes are not 
adequately covered by the prescribed doses 
8.0 
DOSE AND TREATMENT MODIFICATIONS  
Adverse events (both non-serious and serious) associated with pembrolizumab (MK-3475) exposure 
after radiation may represent an immunologic etiology. These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. pembrolizumab (MK-3475) must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per below. See Section 5.6.1 
and Events of Clinical Interest Guidance Document for supportive care guidelines, including use of 
corticosteroids. 
 

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Table 2 Dose Modification Guidelines for Drug-Related Adverse Event 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 
after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
•  Administer 
corticosteroids 
(initial dose of 1 - 2 
mg/kg prednisone 
or equivalent) 
followed by taper 
•  Add prophylactic 
antibiotics for 
opportunistic 
infections 
•  Monitor participants for 
signs and symptoms of 
pneumonitis 
•  Evaluate participants 
with suspected 
pneumonitis with 
radiographic imaging 
and initiate 
corticosteroid treatment 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
•  Administer 
corticosteroids 
(initial dose of 1 - 2 
mg/kg prednisone 
or equivalent) 
followed by taper 
•  Monitor participants for 
signs and symptoms of 
enterocolitis (ie, 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (ie, 
peritoneal signs and 
ileus) 
•  Participants with 
≥Grade 2 diarrhea 
suspecting colitis should 
consider GI consultation 
and performing 
endoscopy to rule out 
colitis 
•  Participants with 
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 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 

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substituted via IV 
infusion 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
•  Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer 
corticosteroids 
(initial dose of 1 - 2 
mg/kg prednisone 
or equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
•  Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
•  Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
•  Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated 
•  Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism  
Grade 2 
Continue 
•  Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
•  Monitor for signs and 
symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3, 4 
Continue 
•  Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
•  Monitor for signs and 
symptoms of thyroid 
disorders 

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liothyronine) per 
standard of care 
Nephritis: 
grading according 
to increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
•  Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) 
followed by taper 
•  Monitor changes of 
renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
•  Based on severity 
of AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Persistent Grade 2 
Withhold 
•  Based on severity 
of AE administer 
corticosteroids 
•  Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
event e  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; 
bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or 
treating physician. If control achieved or ≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, 
Stevens-Johnson Syndrome and toxic epidermal necrolysis. 
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). 
Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Principal Investigator. The reason for interruption should be documented in 
the patient's study record. 
8.1 
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include the 
use of oral or intravenous 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. 

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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 
(MK-3475) and/or Bifidobacterium dietary supplement.  
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. 
8.1.1 
Pneumonitis: 
• 
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. 
• 
For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
• 
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
8.1.2 
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). 
• 
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. 
• 
For Grade 2 diarrhea/colitis, that persists greater than 3 days, administer oral 
corticosteroids. 
• 
For Grade 3 or 4 diarrhea/colitis, that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
• 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
8.1.3 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
• 
For T1DM or Grade 3-4 Hyperglycemia 
• 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
• 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
8.1.4 
Hypophysitis: 
• 
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. 
• 
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 

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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. 
8.1.5 
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. 
• 
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
• 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
• 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
• 
Grade 3-4 hyperthyroidism  
• 
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. 
8.1.6 
Hepatic: 
• 
For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
• 
Treat with IV or oral corticosteroids 
• 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
• 
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
8.1.7 
Renal Failure or Nephritis: 
• 
For Grade 2 events, treat with corticosteroids. 
• 
For Grade 3-4 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.  
8.1.8 
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.  
Table 3 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 3 Infusion Reaction Treatment Guidelines 
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 
Stop Infusion and monitor 
symptoms. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
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 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. 
of pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic). 
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. 
No subsequent dosing 

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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Subject is permanently 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration. 
 
 
8.1.9 
Management of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis: 
To date, approximately 11,000 patients in clinical trials and 27,000 patients in the post-
marketing setting have been treated with pembrolizumab (MK-3475). One fatal case of 
SJS in a clinical trial and one fatal case of TEN in the post-marketing setting have been 
reported in patients treated with pembrolizumab (MK-3475). Including these cases, there 
have been 8 cases of SJS (6 in clinical trials, and 2 post-marketing) and 2 cases of TEN 
(both post-marketing) all of which were serious. 
• 
For signs or symptoms of SJS or TEN, withhold pembrolizumab (MK-3475) 
and refer the patient for specialized care for assessment and treatment.  
• 
If SJS or TEN is confirmed, permanently discontinue pembrolizumab (MK-
3475).  
8.1.10 Management of Immune-mediated myocarditis: 
A total of 6 cases of myocarditis have been reported in patients treated with pembrolizumab 
(MK-3475) in clinical trials or in an expanded access program. There was 1 fatal case 
reported in a clinical trial. 
• 
For suspected immune-mediated myocarditis, ensure adequate evaluation to 
exclude other etiologies, and administer corticosteroids as appropriate. 
8.2 
Dose Modifications 
The dose of pembrolizumab (MK-3475) is not modified. Doses may be delayed or held as above. 
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.  
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 using similar agents. Adverse events are reported in a routine manner at scheduled 
times according to the study calendar in Section 5.0. For this trial, the form “Adverse Events” 
is used for routine AE reporting in Rave. 

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This trial will be utilizing the Rave-CTEP-AERS integration. All routine, post-baseline adverse 
events reported in Rave will be evaluated for expedited reporting using protocol-specific rules. 
If an expedited report is recommended, a deep-link within Rave can be used to automatically 
launch and log-in to CTEP-AERS to complete the expedited report. Adverse event data in Rave 
that is required for expedited reporting will be pushed to CTEP-AERS. 
Note: Modifications to AE data must begin in Rave since it is the data source. Any adverse event 
data modified in Rave must be re-submitted for rule evaluation and will then be pushed to CTEP-
AERS. 
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 by CTCAE. 
CTCAE v5.0 Term 
CTCAE v5.0 System Organ Class (SOC) 
Hyperthyroidism 
Endocrine disorders 
Hypothyroidism 
Endocrine disorders 
Headache 
Nervous system disorders 
Blurred Vision 
Eye disorders 
Agitation 
Psychiatric disorders 
Libido decreased 
Psychiatric disorders 
Personality change 
Psychiatric disorders 
Diarrhea 
Gastrointestinal disorders 
Colitis 
Gastrointestinal disorders 
Abdominal Pain 
Gastrointestinal disorders 
Pruritus 
Skin and subcutaneous tissue disorders 
Rash maculo-papular 
Skin and subcutaneous tissue disorders 
Bullous dermatitis 
Skin and subcutaneous tissue disorders 
Mucositis oral 
Gastrointestinal disorders 
Bruising 
Injury, poisoning and procedural 
complications 
Generalized muscle weakness 
Musculoskeletal and connective tissue 
disorders 
Peripheral sensory neuropathy 
Nervous system disorders 
Dyspnea 
Respiratory, thoracic and mediastinal 
disorders 

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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 
a 
a, b 
a, b 
a, b 
Probable 
a 
a 
a, b 
a, b 
a, b 
Definite 
a 
a 
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. Alliance investigators are required to notify the Alliance Central Protocol 
Operations Program, the Study Chair, and their Institutional Review Board if a patient has a 
reportable serious adverse event. 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 
located 
on 
the 
CTEP 
website 
at: 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All 
appropriate 
treatment areas should have access to a copy of the CTCAE. All appropriate treatment areas 
should have access to a copy of the CTCAE. All reactions must first be reported in Rave on the 
“Adverse Events” Form and sent for rule evaluation at the time the event is known. Adverse 
event data should not be entered in CTEP-AERS prior to entry in Rave for rules evaluation. 
Additional information about Rave-CTEP-AERS is available on the CTSU website 
(https://www.ctsu.org) under the “Resources” tab. 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
For further information on the NCI requirements for SAE reporting, please refer to the ‘NCI 
Guidelines for Investigators: Adverse Event Reporting Requirements’ document published by 
the NCI.  
Note: All deaths on study require both routine and expedited reporting regardless of causality. 
Attribution to treatment or other cause should be provided. 

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9.3.1 
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes: 
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
electronic submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 

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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 a CTEP IND. 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
9.3.3 
Additional Instructions or Exclusion to CTEP-AERS Expedited Reporting 
Requirements for Phase 2 and 3 Trials Utilizing an Agent Under a CTEP IND or 
non-CTEP IND 
• 
All adverse events reported via CTEP-AERS (i.e., serious adverse events) should also 
be forwarded to your local IRB. 
• 
Alliance A091605 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. 
• 
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. 
• 
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. In CTCAE version 5.0, the events may be reported as either: (1) 
Leukemia secondary to oncology chemotherapy, (2) Myelodysplastic syndrome, or (3) 
Treatment-related secondary malignancy. 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 

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the original tumor (if available) and of any new tumor, and new malignancy treatment 
and outcome, if available. 
• 
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol. 
Second Malignancy: 
• 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy). Second malignancies require ONLY 
routine reporting unless otherwise specified. 
• 
Treatment expected adverse events include those listed in Section 10.0 and in the 
package insert. 
• 
CTEP-AERS reports should be submitted electronically. 
• 
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. 
9.4 CAEPRs 
9.4.1 
CAEPR for MK-3475 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for MK-3475 
(pembrolizumab, NSC 776864) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) 
is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 3793 patients. Below is the 
CAEPR for MK-3475 (pembrolizumab). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 

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Version 2.6, July 15, 20211 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
 
Anemia2 
 
 
 
 
 
Blood and lymphatic system 
disorders - Other (immune 
thrombocytopenic purpura)2 
 
 
 
Lymph node pain2 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
 
 
Eye disorders - Other (Vogt-
Koyanagi-Harada syndrome) 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
Colitis2 
 
  
 
Diarrhea2 
 
 Diarrhea2 (Gr 2) 
 
Mucositis oral2 
 
  
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
  
 
Small intestinal mucositis2 
 
  
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills2 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever2 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
 
 
Hepatobiliary disorders - Other 
(sclerosing cholangitis) 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - 
Other (acute graft-versus-host-
disease)2,3 
  
 
 
Immune system disorders - 
Other (hemophagocytic 
lymphohistiocytosis)2 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation)2 
 
  
 
Immune system disorders - Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection4 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
 Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased2 
 
  
 
Alkaline phosphatase increased 
 
  
 
Aspartate aminotransferase 
increased2 
 
  
 
Blood bilirubin increased 
 
  
 
CPK increased 
 
  
 
 
GGT increased 
  
 
 
Serum amylase increased 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
  
 
Hyponatremia 
 
  
 
 
Metabolism and nutrition 
disorders - Other (diabetic 
ketoacidosis)2 
  
 
 
Metabolism and nutrition 
disorders - Other (type 1 
diabetes mellitus)2 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Avascular necrosis2 
 
  
 
Back pain 
 
  
 
Joint effusion2 
 
  
 
Joint range of motion decreased 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(tenosynovitis)2 
 
  
 
Myalgia2 
 
  
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Guillain-Barre syndrome2 
  
 
 
Nervous system disorders - 
Other (myasthenic syndrome)2 
  
 
 
Nervous system disorders - 
Other (neuromyopathy)2 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 5.0 Term) 
[n= 3793] 
 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
 
Nervous system disorders - 
Other (non-infectious 
encephalitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious 
meningitis)2 
  
 
 
Nervous system disorders - 
Other (non-infectious myelitis) 
  
 
 
Nervous system disorders - 
Other (polyneuropathy)2 
  
 
 
Paresthesia 
  
 
 
Peripheral motor neuropathy2 
  
RENAL AND URINARY DISORDERS 
  
 
 
Renal and urinary disorders - 
Other (autoimmune nephritis)2 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
 Cough 
 
  
 
 Pleuritic pain2 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus2 
 
 Pruritus2 (Gr 2) 
 
Rash acneiform2 
 
  
 
Rash maculo-papular2 
 
 Rash maculo-papular2 (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (dermatitis)2 
 
  
 
Skin hypopigmentation2 
 
  
 
 
Stevens-Johnson syndrome2 
  
 
 
Toxic epidermal necrolysis 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
2Immune-mediated adverse reactions have been reported in patients receiving MK-3475 
(pembrolizumab).  Adverse events potentially related to MK-3475 (pembrolizumab) may be 
manifestations of immune-mediated adverse events. In clinical trials, most immune-mediated adverse 
reactions were reversible and managed with interruptions of MK-3475 (pembrolizumab), administration 
of corticosteroids and supportive care. 
3Acute graft-versus-host disease has been observed in patients treated with MK-3475 (pembrolizumab) 
who received hematopoeitic stem cell transplants. 

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4Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
Adverse events reported on MK-3475 (pembrolizumab) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that MK-3475 (pembrolizumab) 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 - 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; 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; 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: MK-3475 (pembrolizumab) 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 
General Considerations: 
The total administered dose of pembrolizumab (MK-3475) is 200mg in all infusions.  
Pembrolizumab (MK-3475) may be administered at a non-registering institution.  
If the Group credited for enrollment is a non-Alliance Group, then other requirements from the 
credited Group may apply. 

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10.2 
Pembrolizumab (MK-3475) (NSC 776864, IND Holder: CTEP) 
Investigator Brochure Availability  
The current version of the Investigator Brochure (IB) will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application. Access to 
OAOP requires the establishment of a CTEP Identity and Access Management (IAM) account 
and the maintenance of an “active” account status and a “current” password and active person 
registration status. Questions about IB access may be directed to the PMB IB coordinator via 
email.  
Procurement and Availability  
Pembrolizumab (MK-3475) is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. Pembrolizumab (MK-3475) is provided to 
the NCI under a Collaborative Agreement between the Pharmaceutical Collaborator and the 
DCTD, NCI. 
NCI-supplied agents may be requested by eligible participating Investigators (or their authorized 
designee) at each participating institution. The CTEP-assigned protocol number must be used 
for ordering all CTEP-supplied investigational agents. The eligible participating investigators at 
each participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF). If there are several participating investigators at 
one institution, CTEP supplied investigational agents for the study should be ordered under the 
name of one lead investigator at that institution.  
In general, sites may order initial agent supplies when a subject is being screened for enrollment 
onto the study. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account and the maintenance of an “active” account status and a “current” 
password. For questions about drug orders, transfers, returns, or accountability, call or email 
PMB any time. Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
Supply 
Pembrolizumab (MK-3475) is supplied by Merck & Co., Inc. and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI. Pembrolizumab (MK-3475) injection 
is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution 
for intravenous use. 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 
Pembrolizumab (MK-3475) solution for infusion must be diluted prior to administration. Allow 
the required number of vials to equilibrate to room temperature. 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 pembrolizumab (MK-3475) to an infusion bag containing 0.9% Sodium Chloride 
Injection, USP or 5% Dextrose Injection, USP. Gently invert the bag 10-15 times to mix the 
solution. The final concentration must be between 1 mg/mL to 10 mg/mL. 

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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. 
If a storage temperature excursion is identified, promptly return pembrolizumab (MK-3475) to 
between 2-8°C and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation 
of 
temperature 
monitoring 
and 
duration 
of 
the 
excursion) 
to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability 
Refer to the package label for expiration. 
Administer prepared solutions immediately after preparation. If not administered immediately, 
prepared solutions may be stored refrigerated for up to 24 hours. Pembrolizumab (MK-3475) 
solutions may be stored at room temperature for a cumulative time of up to 6 hours. This 
includes room temperature storage of liquid drug product solution in vials, room temperature 
storage of infusion solution in the IV bag, and the duration of infusion. 
Route/Method of Administration 
IV infusion only. Do not administer as an IV push or bolus injection. 
Infuse over approximately 30 minutes (range: 25 - 40 minutes) using an infusion set containing 
a low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone or polysulfone. 
Infusion rate should not exceed 6.7 mL/min. 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. 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-(2-
ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
Drug Accountability  
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the receipt, dispensing and final disposition of all agents received from the PMB using 
the appropriate NCI Investigational Agent (Drug) Accountability Record (DARF) available on 
the CTEP forms page. 
Store and maintain separate NCI Investigational Agent Accountability Records for each agent, 
strength, formulation and ordering investigator on this protocol.  
Useful Links and Contacts  
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/  
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
PMB policies and guidelines: http://ctep.cancer.gov/branches/pmb/agent_management.htm 
PMB Online Agent Order Processing (OAOP) application: https://ctepcore.nci.nih.gov/OAOP/ 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account: 
https://ctepcore.nci.nih.gov/iam/index.jsp  
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 

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PMB email: PMBAfterHours@mail.nih.gov  
IB Coordinator email: IBCoordinator@mail.nih.gov  
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) 
Adverse Events 
See CAEPR in Section 9.4.1 
Nursing Guidelines 
• 
Pembrolizumab (MK-3475) 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. 
• 
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.  
• 
Rash/pruirits/dermatitis is seen. Patients should report any rash to the study team. Treat 
per section 9.0 and monitor for effectiveness.  
• 
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. 
• 
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. 
• 
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.  
• 
Patients who are started on steroid therapy for any side effects of pembrolizimab 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.  
• 
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. 
• 
Patients should avoid receiving live vaccines within 30 days of study drug administration 
or per other study guidelines.  
• 
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 pembrolizumab (MK-3475) 
• 
Myocarditis has been reported and associated with pembrolizumab (MK-3475). Instruct 
patients to report chest pain, SOB, or dyspnea to study team immediately and/or seek 
emergency medical attention. 

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11.0 MEASUREMENT OF EFFECT 
Response and progression will be evaluated in this study using the new international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). [23] 
Changes in the largest diameter (unidimensional measurement) of the tumors and the short axis 
measurements in the case of lymph nodes are used in the RECIST guideline. 
11.1 
Schedule of Evaluations 
For the purposes of this study, patients should be reevaluated every 9 weeks. 
11.2 
Definitions of Measurable and Non-Measurable Disease 
11.2.1 Measurable Disease 
• 
A non-nodal lesion is considered measurable if its longest diameter can be 
accurately measured as ≥ 2.0 cm with chest x-ray, or as ≥1.0 cm with CT scan, CT 
component of a PET/CT, or MRI.  
• 
A superficial non-nodal lesion is measurable if its longest diameter is ≥ 1.0 cm in 
diameter as assessed using calipers (e.g. skin nodules) or imaging. In the case of 
skin lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended. 
• 
A malignant lymph node is considered measurable if its short axis is >1.5 cm when 
assessed by CT scan (CT scan slice thickness recommended to be no greater than 
5 mm). 
• 
Tumor lesions in a previously irradiated area are considered measurable disease 
under the following conditions:  
- 
If there is a soft tissue component that has grown since completion of radiation. 
- 
Bone metastases with a soft tissue component are considered measureable.  
11.2.2 Non-Measurable Disease 
• 
All other lesions (or sites of disease) are considered non-measurable disease, 
including pathological nodes (those with a short axis ≥ 1.0 to < 1.5 cm). Bone 
lesions, 
leptomeningeal 
disease, 
ascites, 
pleural/pericardial 
effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable as well. 
• 
Note: ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. In addition, lymph nodes that have a short axis < 1.0 
cm are considered non-pathological (i.e., normal) and should not be recorded or 
followed. 
11.3 
Guidelines for Evaluation of Measurable Disease 
11.3.1 Measurement Methods 
• 
All measurements should be recorded in metric notation (i.e., decimal fractions of 
centimeters) using a ruler or calipers. 
• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during follow-up. 

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For patients having only lesions measuring at least 1 cm to less than 2 cm must use 
CT imaging for both pre- and post-treatment tumor assessments. 
• 
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used at the same evaluation to assess the antitumor effect 
of a treatment.  
11.3.2 Acceptable Modalities for Measurable Disease 
• 
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. 
o 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. The lesions should be measured on the same pulse 
sequence. 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. 
• 
PET-CT: 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. 
• 
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 scans are 
preferable. 
• 
Physical Examination: For superficial non-nodal lesions, physical examination is 
acceptable, but imaging is preferable, if both can be done. In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is recommended. 
• 
FDG-PET: FDG-PET scanning is allowed to complement CT scanning in 
assessment of progressive disease [PD] and particularly possible 'new' disease. A 
‘positive’ FDG-PET scanned lesion is defined as one which is FDG avid with an 
update greater than twice that of the surrounding tissue on the attenuation corrected 
image; otherwise, an FDG-PET scanned lesion is considered ‘negative.’ New 
lesions on the basis of FDG-PET imaging can be identified according to the 
following algorithm: 
o Negative FDG-PET at baseline with a positive FDG-PET at follow-up is 
a sign of PD based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up: 
▪ 
If the positive FDG-PET at follow-up corresponds to a new site of 
disease confirmed by CT, this is PD. 
▪ 
If the positive FDG-PET at follow-up is not confirmed as a new 
site of disease on CT at the same evaluation, additional follow-up 
CT scans (i.e., additional follow-up scans at least 4 weeks later) 
are needed to determine if there is truly progression occurring at 

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that site. In this situation, the date of PD will be the date of the 
initial abnormal PDG-PET scan. 
▪ 
If the positive FDG-PET at follow-up corresponds to a pre-
existing site of disease on CT that is not progressing on the basis 
of the anatomic images, it is not classified as PD. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
The use of FDG-PET in this circumstance has been described in the protocol and supported 
by disease-specific medical literature for the indication  
However, it must be acknowledged that both approaches may lead to false positive CR due 
to limitations of FDG-PET and biopsy resolution/sensitivity. 
11.3.3 Measurement at Follow-up Evaluation: 
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. 
Cytologic and histologic techniques can be used to differentiate between PR and CR in rare 
cases (e.g., residual lesions in tumor types such as germ cell tumors, where known residual 
benign tumors can remain.) 
11.4 
Measurement of Treatment/Intervention Effect 
11.4.1 Target Lesions & Target Lymph Nodes 
• 
The protocol defined irradiated tumor will not be considered for response in the 
primary endpoint. 
• 
The protocol defined irradiated tumor will be considered for secondary endpoint 
response. 
• 
Measurable lesions (as defined in Section 11.2.1) up to a maximum of 5 lesions, 
representative of all involved organs, should be identified as “Target Lesions” and 
recorded and measured at baseline. These lesions can be non-nodal or nodal (as 
defined in Section 11.2.1), where no more than 2 lesions are from the same organ 
and no more than 2 malignant nodal lesions are selected. 
• 
Note: If fewer than 5 (for phase III trials replace with “3”) target lesions and target 
lymph nodes are identified (as there often will be), there is no reason to perform 
additional studies beyond those specified in the protocol to discover new lesions. 
• 
Target lesions and target lymph nodes should be selected on the basis of their size, 
be representative of all involved sites of disease, but in addition should be those 
that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion (or malignant lymph node) does not lend itself 
to reproducible measurements in which circumstance the next largest lesion (or 
malignant lymph node) which can be measured reproducibly should be selected.  
• 
Baseline Sum of Dimensions (BSD): A sum of the longest diameter for all target 
lesions plus the sum of the short axis of all the target lymph nodes will be 
calculated and reported as the baseline sum of dimensions (BSD). The BSD will 
be used as reference to further characterize any objective tumor response in the 
measurable dimension of the disease. 

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• 
Post-Baseline Sum of the Dimensions (PBSD): A sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target lymph nodes will 
be calculated and reported as the post-baseline sum of dimensions (PBSD). If the 
radiologist is able to provide an actual measure for the target lesion (or target 
lymph node), that should be recorded, even if it is below 0.5 cm. If the target lesion 
(or target lymph node) is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm should be assigned. If it is the opinion of the 
radiologist that the target lesion or target lymph node has likely disappeared, the 
measurement should be recorded as 0 cm. 
• 
The minimum sum of the dimensions (MSD) is the minimum of the BSD and the 
PBSD. 
• 
 
11.4.2 Non-Target Lesions & Non-Target Lymph Nodes 
Non-measurable sites of disease (Section 11.2.2) are classified as non- target lesions or 
non-target lymph nodes and should also be recorded at baseline. These lesions and lymph 
nodes should be followed in accord with 11.4.3.3. 
11.4.3 Response Criteria 
All target lesions and target lymph nodes followed by CT/MRI/PET-CT/Chest X-
ray/physical examination must be measured on re-evaluation at evaluation times specified 
in Section 11.1. Specifically, a change in objective status to either a PR or CR cannot be 
done without re-measuring target lesions and target lymph nodes.  
Note: Non-target lesions and non-target lymph nodes should be evaluated at each 
assessment, especially in the case of first response or confirmation of response. In selected 
circumstances, certain non-target organs may be evaluated less frequently. For example, 
bone scans may need to be repeated only when complete response is identified in target 
disease or when progression in bone is suspected. 
• 
Evaluation of Target Lesions 
o Complete Response (CR): All of the following must be true: 
▪ 
Disappearance of all target lesions. 
▪ 
Each target lymph node must have reduction in short axis to < 1.0 
cm. 
o Partial Response (PR): At least a 30% decrease in PBSD (sum of the 
longest diameter for all target lesions plus the sum of the short axis of all 
the target lymph nodes at current evaluation) taking as reference the BSD 
(see Section 11.4.1). 
o Progression (PD): At least one of the following must be true: 
▪ 
At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up.  
▪ 
At least a 20% increase in PBSD (sum of the longest diameter for 
all target lesions plus the sum of the short axis of all the target 
lymph nodes at current evaluation) taking as reference the MSD 
(Section 11.4.1). In addition, the PBSD must also demonstrate an 
absolute increase of at least 0.5 cm from the MSD.  

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▪ 
See Section 11.3.2 for details in regards to the requirements for 
PD via FDG-PET imaging. 
o Stable Disease (SD): Neither sufficient shrinkage to qualify for PR, nor 
sufficient increase to qualify for PD taking as reference the MSD. 
• 
Evaluation of Non-Target Lesions & Non-target Lymph Nodes 
o Complete Response (CR): All of the following must be true: 
▪ 
Disappearance of all non-target lesions.  
▪ 
Each non-target lymph node must have a reduction in short axis 
to <1.0 cm. 
o Non-CR/Non-PD: Persistence of one or more non-target lesions or non-
target lymph nodes. 
o Progression (PD): At least one of the following must be true: 
▪ 
At least one new malignant lesion, which also includes any lymph 
node that was normal at baseline (< 1.0 cm short axis) and 
increased to ≥ 1.0 cm short axis during follow-up. 
▪ 
Unequivocal progression of existing non-target lesions and non-
target lymph nodes. (NOTE: Unequivocal progression should not 
normally trump target lesion and target lymph node status. It must 
be representative of overall disease status change.)  
▪ 
See Section 11.3.2 for details in regards to the requirements for 
PD via FDG-PET imaging. 
• 
Evaluation of Elevated Hormone Levels (when present) 
o This evaluation will be done for each patient for descriptive purposes only 
and will not be used to evaluate the primary endpoint of objective 
response. Biochemical progression without the demonstration of objective 
progression of target or nontarget lesion will not be sufficient indication 
to remove the patient from the study (refer to Section 13.1). 
o Biochemical response (B-RESP): Reduction in elevated hormone level by 
at least 50% of normalization of an elevated value, confirmed with 2 
successive measures. 
o Biochemical progression (B-PROG): Increase in elevated hormone level 
by 50%, confirmed with 2 successive measures. If patient has had 
biochemical response as defined above, then subsequent biochemical 
progression is defined as >50% increase from the lowest recorded level 
while on study. 
o Biochemical stability (B-STAB): Elevated hormone level does not change 
enough to qualify as response or progression. 
11.4.4 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the patient’s 
status on target lesions, target lymph nodes, non-target lesions, non-target lymph nodes, 
and new disease as defined in the following tables:  
For Patients with Measurable Disease  

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Target Lesions & 
Target Lymph Nodes 
Non-Target Lesions & 
Non-Target Lymph 
Nodes 
New  
Sites of Disease 
Overall Objective 
Status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
PR 
CR 
Non-CR/Non-PD 
No 
PR 
CR/PR 
Not All Evaluated* 
No 
PR 
SD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
SD 
Not all Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
No 
Not Evaluated 
(NE) 
PD 
Unequivocal PD 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
Unequivocal PD 
Yes or No 
PD 
CR/PR/SD/PD/Not all 
Evaluated 
CR 
Non-CR/Non-PD 
Not All Evaluated* 
Yes 
PD 
* 
See Section 11.4.3.1 
11.4.5 Symptomatic Deterioration  
Patients with global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time, and not either related to 
study treatment or other medical conditions, should be reported as PD due to “symptomatic 
deterioration.” Every effort should be made to document the objective progression even 
after discontinuation of treatment due to symptomatic deterioration. 
11.5 
Immune-Related Response Assessment (iRECIST) 
All study endpoints requiring measurement data will be assessed per RECIST criteria 
(defined above). Patients will not be required to end study participation at the first 
evidence of progression since Immunotherapeutics may result in infiltration of 
immune cells leading to transient increase in the size of malignant lesions, or 
undetectable lesions becoming detectable. For this reason, iRECIST [24] will be 
utilized in order to help to make the decision to remove a patient from the study after 
first evidence of progression. The criteria are identical to those of RECIST 1.1 in 
many respects but have been adapted to account for instances where an increase in 
tumor burden, or the appearance of new lesions, does not reflect true tumor 
progression. Key differences are described below. All responses defined using 
iRECIST criteria are designated with a prefix. 
 
11.5.1 Confirming Progression  
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms 
iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans 
should be performed at least 4 weeks, but not longer than 9 weeks after iUPD. 

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For patients that had an iUPD in the previous assessment, iCPD is confirmed in two ways: 
1) Existing iUPD gets worse in any lesion type (target, non-target, or new lesions) 
which contributed to the current iUPD status (a patient can have more than one of 
the following sources of iUPD). 
If iUPD was at least 
partially based on… 
Then iCPD is confirmed if… 
Target lesions 
A cumulative increase (can occur over multiple 
assessments) of at least 5 mm in the absolute 
value of the sum from the first occurrence of the 
current iUPD 
Non-target lesions 
Any increase in the non-target lesion burden 
from the first occurrence of the current iUPD 
New lesions 
A cumulative increase (can occur over multiple 
assessments) of at least 5 mm in the absolute 
value of the sum of those considered to be target 
new lesions or any new lesions (from the first 
occurrence of the current iUPD) 
2) RECIST 1.1 criteria are met in lesion types (target, non-target, or new lesions) 
which did not contribute to current iUPD status, including the appearance of new 
lesions. 
If a patient meets either (or both) of these criteria, they are considered to have confirmed 
progression (iCPD). See Appendix III for examples of confirming progression. 
11.5.2 New Lesions  
New lesions should be assessed and measured as they appear using RECIST 1.1 
criteria, and recorded as New Lesion-Target (NLT) and New Lesion-Non-Target 
(NLNT) to allow clear differentiation from baseline target and non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of NLT should NOT be included in the sum of measures 
of original target lesions identified at baseline. 
 
Progression is confirmed in the New Lesion category if the next imaging assessment, 
conducted at least 4 weeks (but not more than 9 weeks) after iUPD confirms further 
progression from iUPD with either an increase of at least 5 mm in the absolute value 
of the sum of NLT OR and increase (but not necessarily unequivocal increase) in the 
size of NLNT lesions OR the appearance of new lesions. 
 
The following table summarizes how to use iRECIST in a number of different 
scenarios. 
 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 

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iPR 
Non-iCR/Non-
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non-
iUPD 
No 
iSD 
iSD 
iUPD with 
no change 
OR decrease 
from last TP 
iUPD with no 
change OR 
decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥5 mm in SOM for 
NLT or any increase for NLNT) or number. If no 
change in NLs (size or number) from last TP, 
remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in 
further increase in size of NT disease (need not 
meet RECIST 1.1 criteria for unequivocal PD) 
iUPD 
Non-iCR/Non-
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
- further increase in SOM of at least 5 mm, 
otherwise remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
- previously identified T lesion iUPD SOM ≥5 
mm and / or 
- NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
further increase in: 
- previously identified T lesion iUPD ≥5 mm and 
/ or 
- previously identified NT lesion iUPD (need not 
be unequivocal) and /or 
- size or number of new lesions previously 
identified 
Non-
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
- increase in size or number of new lesions 
previously identified 
*  
Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD 
would be the same. 
** In any lesion category. 
*** Previously identified in assessment immediately prior to this TP. 
11.6 
Definitions of Analysis Variables 
Formal definitions of variables used in analyses can be found in the Statistical Considerations 
section of the protocol. 
12.0 END OF TREATMENT/INTERVENTION 
12.1 
Duration of Treatment  
12.1.1 CR, PR, or SD 
Patients who are in CR, PR or SD will continue on therapy for a total of two years of 
treatment. After treatment is discontinued, patients will be followed per the study calendar 
in section 5.0. 
12.1.2 Disease Progression 
Remove from protocol therapy any patient with confirmed disease progression. Document 
details, including tumor measurements, on data forms. Patients who are clinically well may 

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continue on therapy following RECIST progression with new lesions or increase in target 
lesions if the increase in disease burden does not meet the definition of iCPD by immune 
response criteria [24] outlined in section 11.5. 
After removal for disease progression, patients should be followed for survival per the 
study calendar (Section 5.0). 
12.1.3 Discontinuation of Study Agent 
If the patient discontinues pembrolizumab (MK-3475), patients should be followed for 
survival per the study calendar (Section 5.0). 
12.2 
Follow-up for patients who stop protocol therapy 
12.2.1 Withdrawal of consent 
Patients who withdraw consent should not be followed anymore and should not be 
contacted for any study related inquiries. 
12.2.2 Stopping study treatment due to toxicity 
If the patient discontinues study treatment due to toxicity they will be followed for survival 
per the study calendar (Section 5.0). 
12.3 
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. All scans, tests, and data submission are to continue as 
if the patient were eligible. 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), the follow-up requirements are specified below.  
Randomized phase II and phase III: Baseline, off treatment, and post-treatment follow up (i.e., 
relapse, progression, and survival) data submission required. See the Data Submission Schedule 
accompanying the All Forms Packet. 
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: 

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Document the reason(s) for discontinuation of therapy on data forms. 
Follow the patient for protocol endpoints as required by the Study Calendar. 
13.0 STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
The study population in this randomized phase II trial are patients with advanced Merkel cell 
carcinoma. The trial is designed to compare Progression Free Survival (PFS) in patients that 
receive SBRT + pembrolizumab (MK-3475) compared to pembrolizumab (MK-3475) alone in 
non-radiated lesion(s). This trial implements a group sequential design with one interim analysis 
for futility. East v6 was utilized to create the statistical design described below. 
13.2 
Statistical Design and Analysis for the Primary Endpoint 
13.2.1 Primary Endpoint: 
We are comparing the Progression Free Survival (PFS) in non-radiated lesion(s) of patients 
receiving either (a) SBRT + pembrolizumab (MK-3475) compared to (b) pembrolizumab 
(MK-3475) alone in patients with advanced Merkel cell carcinoma. For each patient, 
during screening, one lesion will be identified as the one to be potentially radiated (if 
randomized to the arm with SBRT). Then up to 5 additional lesions will be identified that 
are followed for PFS. For patients in both arms, the lesion identified to be radiated (pre-
randomization) will be followed separately (i.e. it will not be a target lesion). If this lesion 
changes in a way that leads to a change in the patient’s treatment (e.g. adding a non-
protocol treatment or removal of the patient from the study), then the patient’s PFS data 
would be considered censored at the time of the change in their treatment. 
A patient is considered an event for this endpoint at the time of first evidence of disease 
progression or death (without evidence of progression) and their PFS time is defined as the 
time from randomization to either disease progression or death (without progression). For 
patients that are not considered an event for this endpoint, the PFS time will be censored 
at their last evaluation for progression. All randomized patients meeting the eligibility 
criteria who received any quantity of their randomized care and did not have a major 
treatment violation will be part of the analysis group for the primary endpoint. 
13.2.2 Statistical Design: 
Based on the patient population in this study it is believed that the median PFS time in 
patients with pembrolizumab (MK-3475) along will be approximately 9 months.[25] We 
seek to detect a 50% improvement on this (to 13.5 months) utilizing a design that has an 
attained type I error rate of 0.20. With 96 evaluable patients (48 randomized to each arm), 
a one-sided alpha=0.20 log rank test will have 80% power to detect a 33% decrease in the 
hazard of progression with SBRT + pembrolizumab (MK-3475) compared to 
pembrolizumab (MK-3475) alone, which corresponds to a 50% increase in the median PFS 
time. If after 75 events have been observed, the hazard ratio is greater than 0.837, the study 
will be declared unpromising. 
Interim Analysis Decision Rules: The chosen design has one interim look for futility that 
will occur after the 38th event is observed. If, at this time, the hazard ratio is greater than 
1.013 accrual will be suspended due to futility and the study will be declared unpromising. 

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13.2.3 Analysis Plan: 
The main analysis with regards to the primary endpoint is described above, in section 
13.2.2. In addition to this Kaplan- Meier curves will be constructed and median PFS times 
will be calculated for each arm. 
13.3 Sample Size, Accrual time, and Study Duration 
13.3.1 Sample Size 
The chosen design requires 75 events (progressions plus deaths without progressions) and 
will accrue 96 evaluable patients (48 to each arm) to attain these events. In order to account 
for patients that: (a) do not have any non-radiated lesions, (b) are deemed ineligible, (c) 
cancel study participation prior to receiving any randomized treatment, or (d) have a major 
protocol violation, we will plan to accrue an additional 4 patients making the maximum 
overall accrual N=100 patients. 
13.3.2 Accrual Rate and Study Duration: 
The disease sites applicable to this study have not yet been studied extensively within the 
Alliance. As such an accrual rate of 3 evaluable patients per month was estimated based on 
experience in the clinic. The study team believes that this rate will be on the low end of 
what is possible. 
At this rate, the accrual phase of the trial will require ~32 months. Under the alternative 
hypothesis (i.e. that there is a PFS benefit for SBRT + pembrolizumab (MK-3475) 
compared to pembrolizumab (MK-3475) alone) the 75th event will occur at ~41 months. 
To account for data entry and cleaning, this means the primary endpoint analysis can occur 
approximately 45 months after the beginning of the trial, depending on the actual rate of 
observed events. 
13.3.3 Primary Endpoint Completion Date for ClinicalTrials.gov Reporting: 
For purpose of ClinicalTrail.gov reporting, the Primary Endpoint Completion Date (PECD) 
for this study is the time that the 75th event is observed on an evaluable patient. This will 
be approximately 45 months after the study has begun enrollment under the alternative 
hypothesis. 
13.4 Supplementary Analysis Plans 
13.4.1 Secondary Endpoints 
Progression Free Survival among all RECIST lesions: This endpoint is the same as the 
primary endpoint, but includes both irradiated and non-radiated lesions. It is a time to event 
endpoint and will be evaluated using the Kaplan- Meier method. PFS time is defined as the 
number of days from randomization to either evidence of disease progression or death 
(without evidence of progression). Median PFS times will be calculated for each arm and 
a cox proportional hazards model will be constructed to determine if there is a PFS benefit 
for patients receiving SBRT + pembrolizumab (MK-3475) compared to pembrolizumab 
(MK-3475) alone. 
Overall Response Rate (OS): A patient will be declared to have responded to therapy if 
they have at least a PR on 2 consecutive evaluations (i.e. the response is confirmed). 
Response rates will be calculated and compared across treatment arms utilizing a chi-
square test. 

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Progression Free Survival at 6 months (PFS6): A patient will be declared a success for 
this endpoint if they remain on study and progression free at 6 months. The rates of success 
will be calculated and compared across treatment arms utilizing a chi-square test. 
Safety/Toxicity: Maximum grade adverse events will be summarized by treatment arm in 
a tabular setting. This will be done overall and for the 3 month time period from date of 
registration. 
Local control of SBRT treated lesion: The protocol irradiated tumors are considered to 
be controlled if they have no evidence of progression. No evidence of progression is 
defined as CR, PR, or SD. If the protocol irradiated tumor progresses the date of 
progression will be recorded. Local control of the protocol-irradiated tumor will be 
described using the Kaplan-Meier technique. 
Delivered radiation dose using cone-beam CT images: These radiation doses will be 
summarized descriptively and compared to the planned dose. 
 
13.4.2 Correlative Endpoints 
Test utility of CT-based radiomics: To test the utility of CT-based radiomics algorithms 
to predict radiation-induced and drug induced pneumonitis. Patient imaging will be 
analyzed based on known radiomic signatures and correlated to incidence of pneumonitis 
reported as adverse events. The incidence of pneumonitis in total as well as by radiomic 
signatures will be descriptively summarized. 
13.5 Adverse Event Stopping Rule: 
The Alliance Data Safety Monitoring Board (DSMB) is responsible for reviewing accrual and 
safety data for this trial at least twice a year, based on reports provided by the study statistician. 
Additionally, in order to ascertain if the study treatments are safe for patients, the following 
adverse event stopping rules will be employed. The following rules will be applied to each arm 
separately. If any rule is crossed then accrual will be suspended while the study team evaluates 
the data, develops a plan, and receives approval for re-opening from the DSMB. 
• 
If at any point during the first 10 patients at least 3 patients experience at least 1 grade 4+ 
non-hematologic adverse event that is deemed at least possibly related to study treatment, or… 
• 
If at any point after the first 10 patients at least 30% of all patients experience at least 1 
grade 4+ non-hematologic adverse event that is deemed at least possibly related to study 
treatment. 
13.6 Study Reporting 
13.6.1 Alliance DSMB 
This study will be monitored by the Alliance Data Safety Monitoring Board (DSMB), an 
NCI-approved functioning body. Reports containing efficacy, adverse event, and 
administrative information will be provided to the DSMB every six months as per NCI 
guidelines. 
13.6.2 Clinical data Update System (CDUS) 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0. 
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis by FTP burst of data. Reports are due January 31, April 30, July 

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31, and October 31. Instructions for submitting data using the CDUS can be found on the 
CTEP Web site  
(http://ctep.cancer.gov/reporting/cdus.html). 
Note: If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above. 
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS, but expedited adverse 
events are still required to be submitted via CTEP-AERS. 
13.6.3 Result Reporting on ClinicalTrials.Gov 
At study activation, this study will have been registered within the “ClincialTrails.gov” 
web site. The Primary and Secondary Endpoints (i.e., “Outcome Measures”) along with 
other required information for this study will be reported on ClinicalTrials.gov. 
13.7 
Inclusion of Women and Minorities 
This study will be available to all eligible patients, regardless of race, gender, or ethnic origin. 
There is no information currently available regarding differential effects of study treatment in 
subsets defined by race, gender, or ethnicity. Although there is insufficient power to detect small 
or moderate effects, we will, as always, report the results by gender and ethnicity in exploratory 
analyses. 
There is no reason to believe that there will be a gender difference in this disease and the study 
team expects there to be approximately 5% racial minorities. 
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American 
Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native 
Hawaiian or 
Other Pacific 
Islander 
0 
1 
0 
0 
1 
Black or 
African 
American 
1 
1 
1 
1 
4 
White 
48 
47 
0 
0 
95 
More Than One 
Race 
0 
0 
0 
0 
0 
Total 
49 
49 
1 
1 
100 

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Ethnic Categories: 
 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial Categories 
 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, Southeast 
Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, 
Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: 
Individuals from the Philippine Islands have been recorded as Pacific Islanders in 
previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial groups 
of Africa. Terms such as “Haitian” or “Negro” can be used in addition to “Black or 
African American.” 
Native Hawaiian or other Pacific Islander – a person having origins in any of the original 
peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
14.0 CORRELATIVE AND COMPANION STUDIES  
There is specimen biobanking for this study for future use and all patients are encouraged to 
participate.  
14.1 
Biobanking for future Correlative Science 
Blood, tissue, and stool specimens will be collected and stored for future translational research 
for patients who consent to participate. Testing of banked specimens will not occur until an 
amendment to this treatment protocol (or separate correlative science protocol) is reviewed and 
approved in accordance with National Clinical Trials Network (NCTN) policies. Future studies 
may include the following aims: 
Hypotheses/aims for correlative studies: 
1. Gene expression profiling based on T cell based immune signatures may better predict 
response or lack of response to monotherapy anti-PD1 and may suggest expression 
phenotypes where the addition of radiation can facilitate response.* 
a) Gene expression profiling assays have a robust capacity to capture the tumor-
immune microenvironment with prior analysis from metastatic melanoma clearly 
correlating with treatment outcomes to immunotherapy[26-28]. Further in prior 
studies of pembrolizumab (MK-3475) in head and neck, gastric, urothelial cancers 
and melanoma, large datasets have supported gene expression as harboring a greater 
ability to stratify treatment response relative to PD-L1 immunohistochemistry[29-
32]. Further, IHC for PD-L1 as well as Merkel-cell polyomavirus did not show 
statistically significant associations with treatment outcomes in the NEJM report of 
pembrolizumab (MK-3475), though sample sizes were small[10].  

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2. The intensity and/or location of staining for CD8 and PD-L1 by immunohistochemistry 
may differentiate responding vs. non-responding patients to monotherapy anti-PD1 or 
radiation with immunotherapy.* 
a) Though statistically significant associations have not been observed for PD-L1 and 
CD8 in MCC to date, the sample sizes investigated were small and such associations 
have been observed in other tumors[33].  
3. Tumor intrinsic mutations or mutational load may predict resistance or response to anti-
PD-1 and/or the combination of radiation and immunotherapy.* 
a) Multiple papers have demonstrated associations between mutational load and 
treatment outcome to anti-PD1 immunotherapy. Further, a hypothesis in the field of 
MCC has been that non- Merkel-cell polyomavirus associated tumors may have a 
high response rate due to the presence of increase mutational load (and by 
extrapolation neoantigen burden). 
b) Recent reports have suggested that de novo or acquired resistance to 
immunotherapy can be mediated via mutation in JAK/STAT signaling or the 
antigen processing machinery[34]. Exploratory DNA based genomic analysis will 
thus be particularly of interest in any patients who have no clinical benefit to this 
approach of radiation with PD1 Ab. 
4. Single nucleotide polymorphisms from the germline DNA may be identified that 
portend an improved response phenotype to immunotherapy. 
a) The identification of SNPs in immune regulatory genes is an area of increasing 
interest in the field of immunotherapy. At the University of Chicago, we have 
identified multiple such targets (data unpublished) and several commercial entities 
are also moving forward in this space (personal communication Foundation 
Medicine and Nanostring technologies). 
5. The composition of the fecal microbiota may predict the likelihood or response or 
toxicity to anti-PD1 or radiation with immunotherapy. 
a) We and other groups have previously identified an important role for the gut 
microbiome in modulating both immunotherapy treatment response outcome as 
well as toxicity[35-37]. 
6. Changes in MCPyV specific T lymphocytes and other circulating factors such as 
MCPyV small T-antigen oncoprotein antibody titers will associated with outcomes to 
immunotherapy*. 
Changes in circulating immune cell populations have been associated with treatment outcome 
with both CTLA4 and PD1/L1 blocking immunotherapy[38, 39]. 
* Available tumor tissue will be prioritized for 1 (gene expression) > 2 (IHC) > 3 (exome 
sequencing) 
*Tumor Merkel Cell Polyomavirus (MCPyV) Status 
Serology: Baseline serum samples from all patients will be used to measure MCPyV small T-
antigen oncoprotein antibody titers at Laboratory Medicine (University of Washington, Seattle, 
WA) as described[40]. Titers above 74 will be considered positive. 
Oncoprotein-specific T cells: All patients will be HLA genotyped to determine eligibility for 
CD8 T cell specific MCPyV peptide-MHC tetramer screening (Bloodworks Northwest, Seattle, 
WA). Pretreatment peripheral blood mononuclear cells (PBMCs) will be collected from patients 

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with HLA-I types that corresponded to available MCPyV-specific tetramers will be tetramer 
stained to identify MCPyVspecific T cells, and analyzed by flow cytometry. Samples with 
>0.01% of CD8+ T cells co-staining with tetramers will be considered positive. In addition, 
PBMCs from patients with available pretreatment and week 12 post-treatment blood collections 
will be stimulated with pools of MCPyV-specific peptides in a flow cytometry-based 
intracellular cytokine secretion assay (HIV Vaccine Trials Network, Seattle, WA). PBMCs that 
secrete interferon-γ and/or IL-2 robustly (≥0.1% of CD8 T cells after background subtraction) 
will be considered reactive to MCPyV. 
15.0 GENERAL REGULATORY CONSIDERATIONS AND CREDENTIALING 
15.1 
Institutional Credentialing 
15.1.1 IROC Ohio Institutional Requirements 
15.1.2 Radiation Therapy Requirements 
RT 
Credentialing 
Requirements 
 
Web Link for Procedures and Instructions: http//irochouston.mdanderson.org  
Treatment Modality 
Key Information 
SBRT 
IMRT 
3D 
 
Facility 
Questionnaire  
 
 
 
The IROC Houston electronic facility questionnaire (FQ) should be 
completed or updated with the most recent information about your 
institution. To access this FQ go to http://irochouston.mdanderson  
org/questionnaires.  
Credentialing 
Status Inquiry 
Form  
 
 
 
To determine whether your institution needs to complete any further 
credentialing requirements, please complete the “Credentialing Status 
Inquiry Form” found under credentialing on the IROC Houston QA 
Center website (http://irochouston.mdanderson.org)  
Phantom 
Irradiation  
 
 
 
 
Either the lung or liver phantom available from IROC Houston must 
be successfully irradiated (if the institution has not previously met this 
credentialing requirement). Credentialing for IMRT allows the 
institution to also use 3D-CRT SBRT, but credentialing for 3D-CRT 
SBRT does not allow the institution to use IMRT. Flattening-filter-
free (FFF) photon beam delivery, Tomotherapy and Cyberknife 
treatment delivery modalities must be credentialed individually. 
Instructions for requesting and irradiating the phantoms are available 
on the IROC Houston website under credentialing 
(http//irochouston.mdanderson.org). The phantom must be irradiated 
with the motion management technique (e.g., tracking, gating) to be 
used for SBRT protocol treatments.  
IGRT 
Verification 
Study  
 
 
 
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.  
Pre-Treatment 
Review  
 
 
 
Pre-treatment review of each case will be performed by IROC-Rhode 
Island  
 
 
 
 
 
Credentialing 
Notification 
 
 
 
IROC Houston QA Center will notify the a) institution and b) IROC 
Rhode Island once credentialing requirements have been met. 
15.2 
Individual Credentialing 
15.2.1  Radiological credentialing 
Contact IROC for appropriate language. 
 

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Seiwert, T.Y., et al., Inflamed-phenotype gene expression signatures to predict benefit 
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Shankaran, V., et al., Correlation of gene expression signatures and clinical outcomes in 
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32. 
Plimack, E.R., et al., Pembrolizumab (pembrolizumab (MK-3475)) for advanced 
urothelial cancer: Updated results and biomarker analysis from KEYNOTE-012. J Clin 
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33. 
Tumeh, P.C., et al., PD-1 blockade induces responses by inhibiting adaptive immune 
resistance. Nature, 2014. 515(7528): p. 568-71. 
34. 
Zaretsky, J.M., et al., Mutations Associated with Acquired Resistance to PD-1 Blockade 
in Melanoma. N Engl J Med, 2016. 375(9): p. 819-29. 
35. 
Sivan, A., et al., Commensal Bifidobacterium promotes antitumor immunity and 
facilitates anti-PD-L1 efficacy. Science, 2015. 350(6264): p. 1084-9. 
36. 
Vetizou, M., et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut 
microbiota. Science, 2015. 350(6264): p. 1079-84. 
37. 
Dubin, K., et al., Intestinal microbiome analyses identify melanoma patients at risk for 
checkpoint-blockade-induced colitis. Nat Commun, 2016. 7: p. 10391. 

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38. 
Wistuba-Hamprecht, K., et al., Proportions of blood-borne Vdelta1+ and Vdelta2+ T-
cells are associated with overall survival of melanoma patients treated with ipilimumab. 
Eur J Cancer, 2016. 64: p. 116-26. 
39. 
Herbst, R.S., et al., Predictive correlates of response to the anti-PD-L1 antibody 
MPDL3280A in cancer patients. Nature, 2014. 515(7528): p. 563-7. 
40. 
Paulson, K.G., et al., Antibodies to merkel cell polyomavirus T antigen oncoproteins 
reflect tumor burden in merkel cell carcinoma patients. Cancer Res, 2010. 70(21): p. 
8388-97. 

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APPENDIX I 
REGISTRATION FATIGUE/UNISCALE ASSESSMENTS 
 
 
Registration Fatigue/Uniscale Assessments 
 
At patient registration, this form is to be administered by a nurse/CRA, 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 
CRADA 
Collaborative Agreements 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 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. 
 

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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. 
 
 

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APPENDIX III EXAMPLES OF CONFIRMED PROGRESSION  
The following examples show how a patient that is currently an iUPD can become an iCPD (confirmed 
progression). These examples all use target lesion growth as the source of the first progression (iUPD) 
and show how additional information in future assessments can lead to iCPD. The examples are not 
exhaustive, but are meant to be illustrative of how iCPD can occur. Similar examples can be created 
where non-target lesions and/or new lesions led to the initial iUPD. 
1) iUPD due to target lesion growth from baseline followed by iCPD due to continued growth of 
target lesions (by at least 5 mm). 
 
Baseline 
TP1 
TP2 
T lesions (sum) 
100 
125 
132 
NT lesions 
Pres 
No change 
No change 
New lesions 
 
None 
None 
TP response (R) 
 
PD 
PD 
TP response (iR) 
 
iUPD 
iCPD 
2) iUPD due to target lesion growth from baseline followed by iCPD due to gradual continued 
growth (over 2 assessments) of target lesions (by at least 5 mm from time of first iUPD). 
 
Baseline 
TP1 
TP2 
TP3 
T lesions (sum) 
100 
125 
128 
132 
NT lesions 
Pres 
No change 
No change 
No change 
New lesions 
 
None 
None 
None 
TP response (R) 
 
PD 
PD 
PD 
TP response (iR) 
 
iUPD 
iUPD 
iCPD 
3) iUPD due to target lesion growth from baseline followed by iCPD due to new lesion appearing 
after start of iUPD. This iCPD is based on criteria #2 outlined in section 11.5.1. 
 
Baseline 
TP1 
TP2 
T lesions (sum) 
100 
125 
125 
NT lesions 
Pres 
No change 
No change 
New lesions 
 
None 
1 new lesion 
TP response (R) 
 
PD 
PD 
TP response (iR) 
 
iUPD 
iCPD 
4) iUPD due to target lesion growth from baseline followed by iCPD due to additional target lesion 
growth as well as a new lesion. 
 
Baseline 
TP1 
TP2 
T lesions (sum) 
100 
125 
132 
NT lesions 
Pres 
No change 
No change 
New lesions 
 
None 
1 new lesion 
TP response (R) 
 
PD 
PD