A Phase II Study of MK-3475 in Patients With Advanced Merkel Cell Carcinoma (MCC)
Phase: PHASE2
Conditions: Recurrent Merkel Cell Carcinoma, Stage III Merkel Cell Carcinoma AJCC v7, Stage IIIA Merkel Cell Carcinoma AJCC v7, Stage IIIB Merkel Cell Carcinoma AJCC v7, Stage IV Merkel Cell Carcinoma AJCC v7
Sponsor: National Cancer Institute (NCI)

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
i 
SUMMARY OF CHANGES 
 
For Protocol Amendment 9, Version 2.0 
 
NCI Protocol #:  CITN-09  
Local Protocol #:  CITN-09 
 
Protocol Date:  May 22, 2018 
 
I. 
Changes Requested by CTEP  
 
# 
Section 
Pages 
Revision 
1.  
7.1.1 
71-76 Updated CAEPR content to version 2.4 per CTEP Request for Rapid 
Amendment dated 4/26/18. Updated risks following CAEPR table. The 
following changes are incorporated: 
• 
Added New Risk:  
• 
Less Likely: Immune system disorders - Other (sarcoidosis) 
• 
Rare but Serious: Immune system disorders - Other (acute 
graft-versus-host-disease); Metabolism and nutrition 
disorders - Other (diabetic ketoacidosis); Metabolism and 
nutrition disorders - Other (type 1 diabetes mellitus); Nervous 
system disorders - Other (non-infectious encephalitis); 
Nervous system disorders - Other (non-infectious 
meningitis); Palmar-plantar erythrodysesthesia syndrome 
 
• 
Increase in Risk Attribution:  
• 
Changed to Less Likely from Also Reported on MK-3475 
Trials But With Insufficient Evidence for Attribution: 
Abdominal pain; Back pain; Cough; Hyponatremia 
 
• 
Provided Further Clarification:  
• 
Footnotes have been reordered.  
• 
Footnote #2 has been updated and now reads: “Immune-
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.” 
• 
Footnote #3 has been added and reads: “Acute graft-versus-
host disease has been observed in patients treated with MK-
3475 (pembrolizumab) who received hematopoeitic stem cell 
transplants.” 
• 
Thrombotic thrombocytopenic purpura, previously listed 
under the IMMUNE SYSTEM DISORDERS SOC (CTCAE 
4.0 language), is now listed under the BLOOD AND 
LYMPHATIC SYSTEM DISORDERS SOC. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
ii 
# 
Section 
Pages 
Revision 
• 
Endocrine disorders - Other (hypophysitis, hypopituitarism) 
(CTCAE 4.0 language) is now reported as Hypophysitis and 
Hypopituitarism. 
• 
Infusion related reaction, previously listed under the 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS SOC (CTCAE 4.0 language), is now listed 
under the INJURY, POISONING AND PROCEDURAL 
COMPLICATIONS SOC. 
• 
Nervous system disorders - Other (Guillain-Barre syndrome) 
(CTCAE 4.0 language) is now reported as Guillain-Barre 
syndrome. 
• 
General disorders and administration site conditions - Other 
(generalized edema) (CTCAE 4.0 language) is now reported 
as Generalized edema 
• 
Renal and urinary disorders - Other (nephrotic syndrome) 
(CTCAE 4.0 language) is now reported as Nephrotic 
syndrome 
 
 
 
II. 
Comments Requiring a Response– Administrative & Editorial Issues: 
# 
Section 
Comments 
2. 
7.1.1 
In the CAEPR table, “Erythroderma” should not have the footnote 2 attached. 
PI Response:  Agree. Corrected. 
3. 
7.1.1 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS is 
missing the G. 
PI Response:  Agree.  Corrected. 
 
III. 
Changes Initiated by P.I. 
 
2.  
Title 
page 
Revised Amendment number, version number and date. 
3.  Through
out 
Revised date in header. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
1 
NCI Protocol #: 
CITN-09: Merkel Cell Carcinoma – MK-3475  
 
Local Protocol #: 
CITN-09: Merkel Cell Carcinoma – MK-3475  
 
TITLE: A Phase II Study of MK-3475 in Patients with Advanced Merkel Cell Carcinoma 
(MCC) 
 
Coordinating Center: 
 
 
Cancer Immunotherapy Trials Network (CITN), 
Fred Hutchinson Cancer Research Center 
 
Principal Investigator: 
Paul T. Nghiem, MD, PhD 
 
 
 
Seattle Cancer Care Alliance (WA102) 
MS: G3-303    
825 Eastlake Ave E 
Seattle, WA 98109-1023 
 
Phone: 206-221-2632 
 
Fax: 206-221-4364 
 
pnghiem@uw.edu 
 
Participating organizations: CITN – Cancer Immunotherapy Trials Network 
 
 
 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
2 
Statistician:  
 
 
 
 
 
 
Study Coordinator: N/A  
Lynn Shemanski, Ph.D. 
Cancer Research and Biostatistics (CRAB) 
1730 Minor Ave, Suite 1900 
Seattle, WA  98101  
206-652-9711 
lynns@crab.org 
 
Responsible Research Nurse: N/A 
Responsible Data Manager: N/A 
 
 
NCI-Supplied Agent(s): MK-3475 (pembrolizumab, SCH 900475) (NSC # 776864).  
 
Other Agent(s): N/A 
 
Non-NCI Supplied Agent(s)/Supplier(s): N/A 
 
IND Sponsor: CTEP 
 
Protocol Type / Version # / Version Date: Amendment 9/Version 2.0/May 22, 2018 
 
IND #: 123618 
 
IND Sponsor: DCTD, NCI 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
3 
 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
To submit study data 
 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal: 
 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
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. 
Please refer to the patient enrollment 
section for instructions on using the 
Oncology Patient Enrollment Network 
(OPEN) at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done via 
Medidata Rave 
(FHCRC/AXIO 
Research, Inc.). Please 
refer to the data 
submission section of the 
protocol for Medidata 
Rave instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member website located at https://www.ctsu.org. 
Access to the CTSU members’ Web site is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the CTSU 
RSS. 
For clinical questions (i.e. patient eligibility or treatment-related): 
Contact the CITN Central Operations and Statistical Center at citn@fhcrc.org or 206-667-7607 
For nonclinical 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.  
The CTSU Web site is located at https://www.ctsu.org. 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
4 
STUDY SUMMARY 
 
Abbreviated Title 
Merkel Cell Carcinoma (MCC) Therapy with MK-3475 
Trial Phase 
Phase II 
Clinical Indication 
Advanced stage MCC: Locally advanced or metastatic 
Trial Type 
Single Arm, Simon Two-Stage, Therapeutic 
Type of control 
Nonrandomized trial with primary end point of overall 
response rate (ORR). Secondary endpoint of progression-
free survival (PFS) will be compared to recent historical 
controls receiving standard chemotherapy.  
Route of administration 
Intravenous (IV)  
Trial Blinding 
None 
Treatment Group  
MK-3475, 2 mg/kg every 3 weeks (q3wks)  
Number of trial patients 
Initial enrollment included 26 patients. 
Twenty-four (24) additional patients -were enrolled to 
provide an expanded safety and efficacy profile. 
Estimated duration of trial  The first 26 patients were enrolled over 11 months. The 
additional 24 patients were enrolled over the following 18 
months. Study to continue for up to 2 years beyond 
enrollment plus follow-up of last subject. 
Duration of Participation 
Each patient will participate in the trial from the time the 
Informed Consent Form (ICF) is signed through final 
protocol-specified contact. After a screening phase for 
eligibility, patients will receive MK-3475 every 3 weeks.  
Treatment for patients that achieve a stable disease (SD) or a 
partial response (PR) can continue for a maximum of 2 
years.  If progression is confirmed at week 17 or beyond, 
patients will be eligible to continue treatment with MK-3475 
if otherwise clinically stable. Patients that achieve a 
complete response (CR) can discontinue treatment after 6 
months of therapy provided the patient has had at least 2 
cycles past validation of CR. At the discretion of the 
investigator, these patients will be eligible for retreatment if 
they experience disease progression, as long as they meet the 
criteria for retreatment and the trial is ongoing. Patients who 
have received 2 years of treatment on study and have a PR or 
SD and then progress, may be eligible for retreatment. 
Administration of MK-3475 will be stopped with: 
documented disease progression warranting alternative 
systemic therapy, ≥25% increase in tumor burden following 
initial confirmation of PD, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
5 
treatment, investigator’s decision to withdraw the patient, 
patient withdraws consent, pregnancy of the patient, 
noncompliance with trial treatment or procedure 
requirements, or administrative reasons.  
After the end of treatment, each patient will be followed for 
30 days for adverse event monitoring (serious adverse events 
will be collected for 90 days after the end of treatment with 
investigator attribution as to whether the SAE is associated 
with MK-3475 or subsequent therapies). After the Post-
Treatment Safety Follow-Up Visit, patients will be followed 
for survival via phone contact every 12 weeks. 
Patients who discontinue study therapy without documented 
disease progression should continue to be monitored for 
disease status by radiologic imaging according to the 
guidelines described in the Study Schema for post-treatment 
follow-up. 
 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
6 
Overall Trial Schema (PD1 Trial Timeline_v10Jun16) 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
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NCI Protocol # CITN-09 
Version Date: May 22, 2018 
8 
TABLE OF CONTENTS 
1. 
OBJECTIVES ....................................................................................................................10 
 
Primary Objectives.................................................................................................10 
 
Secondary Objectives.............................................................................................10 
 
Exploratory Objectives ..........................................................................................10 
2. 
BACKGROUND ...............................................................................................................11 
 
Study Disease .........................................................................................................11 
 
CTEP IND Agent: MK-3475 .................................................................................19 
 
Other Agent(s): N/A ..............................................................................................23 
 
Rationale for Trial of MK-3475 in Merkel Cell Carcinoma Patients ....................23 
 
Correlative Studies Background ............................................................................26 
3. 
PATIENT SELECTION ....................................................................................................31 
 
Eligibility Criteria ..................................................................................................31 
 
Exclusion Criteria ..................................................................................................33 
 
Inclusion of Women and Minorities ......................................................................36 
4. 
REGISTRATION PROCEDURES ...................................................................................36 
 
Investigator (IVR), Non-Physician Investigator (NPIVR), and Associate 
Plus (AP) Registration with CTEP ........................................................................36 
 
Site Registration .....................................................................................................38 
 
Patient Registration ................................................................................................39 
 
General Guidelines.................................................................................................40 
5. 
TREATMENT PLAN ........................................................................................................41 
 
Agent Administration.............................................................................................42 
 
Definition of Dose-Limiting Toxicity: N/A ...........................................................50 
 
General Concomitant Medication and Supportive Care Guidelines ......................50 
 
Duration of Therapy ...............................................................................................51 
 
Duration of Follow Up ...........................................................................................52 
 
Criteria for Removal from Study ...........................................................................53 
 
Criteria to Resume Treatment ................................................................................53 
 
Treatment Beyond Progression ..............................................................................54 
 
Discontinuation of Treatment Following Complete Response ..............................55 
 
Retreatment with MK-3475 of patients with recurrence .......................................55 
 
Beginning and End of the Trial ..............................................................................56 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................56 
 
MK-3475 Dose Modifications ...............................................................................56 
 
Delayed Visits for Reasons Other Than Toxicity ..................................................70 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................70 
 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............70 
 
Adverse Event Characteristics ...............................................................................76 
 
Expedited Adverse Event Reporting ......................................................................77 

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9 
 
Routine Adverse Event Reporting .........................................................................80 
 
Secondary Malignancy...........................................................................................80 
 
Second Malignancy ................................................................................................80 
7.7 
Reporting of Pregnancy and Lactation to the Sponsor ..........................................80 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................81 
 
CTEP IND Agent ...................................................................................................81 
 
Agent Ordering and Agent Accountability ............................................................82 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................83 
 
Biomarker Studies ..................................................................................................84 
 
Laboratory Correlative Studies ..............................................................................84 
 
Special Studies-N/A ...............................................................................................90 
10. 
STUDY CALENDAR .......................................................................................................91 
11. 
MEASUREMENT OF EFFECT........................................................................................96 
 
Antitumor Effect—Solid Tumors ..........................................................................96 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS .........................................101 
 
Data Reporting .....................................................................................................101 
 
CTEP Multicenter Guidelines ..............................................................................103 
 
Collaborative Agreements Language ...................................................................103 
13. 
STATISTICAL CONSIDERATIONS.............................................................................105 
 
Responsibility for Analyses .................................................................................105 
 
Study Design/Endpoints.......................................................................................105 
 
Analysis Endpoints ..............................................................................................106 
 
Analysis Populations ............................................................................................106 
 
Statistical Methods ...............................................................................................107 
 
Multiplicity ..........................................................................................................109 
 
Sample Size/Accrual Rate and Power Calculations .............................................109 
 
Stratification Factors- N/A ...................................................................................110 
 
Interim Analyses ..................................................................................................110 
 
Compliance (Medication Adherence) ..................................................................110 
 
Extent of Exposure ...............................................................................................110 
 
Analysis of Secondary Endpoints ........................................................................110 
 
Reporting and Exclusions ....................................................................................110 
REFERENCES ............................................................................................................................112 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................118 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ..................................................119 
APPENDIX C 
BIOASSAY TEMPLATES .....................................................................121 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
10 
1. OBJECTIVES 
 
The goal of this trial is to determine the antitumor efficacy of MK-3475 in patients with 
advanced Merkel cell carcinoma (MCC). The trial is an open-labeled, non-randomized trial with 
a Simon two-stage design. Patients who have not received any previous systemic therapy for 
their disease will be treated with MK-3475 2 mg/kg administered every 3 weeks. Objective 
responses and disease progression will be monitored by computed tomography (CT) scans and 
assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).  
 
Primary Objectives 
To determine the clinical efficacy of MK-3475 as the first systemic intervention for patients with 
advanced MCC.  
The primary endpoint will be objective response rate (ORR) as measured by RECIST 1.1.  
Hypothesis: Cellular immunity plays a major role in the outcome of MCC. Thus, therapy with 
MK-3475 will induce substantial objective responses and a portion of the responses will be 
durable.  
 
Secondary Objectives 
To determine the clinical activity of MK-3475 as the first systemic intervention for patients with 
advanced MCC. 
The secondary endpoints will be progression-free survival (PFS), duration of response (DOR) 
and overall survival (OS), as measured by RECIST 1.1. The PFS will be determined at 
16 months and compared to the historical PFS for patients treated with chemotherapy, which is 
5% at 16 months.  
• Progression-free survival (PFS) 
• Duration of response (DOR) 
• Overall survival (OS) 
Hypothesis: Because of the strong links between cellular immunity and MCC survival, 
responses to MK-3475 are likely to be more durable, as assessed at 16 months, than responses to 
the selected comparator, recent historical controls treated with systemic chemotherapy, which 
tends to be immunosuppressive. 
 
Exploratory Objectives 
To determine the immune correlates of the clinical activity of MK-3475 
The endpoints will include immunohistochemical (IHC) and gene expression analysis, whole 
exome sequencing, and neoantigen identification focusing on delineating the immune 
components and immunologic milieu within the tumor before therapy. The IHC analytes will 
include, but are not limited to Merkel cell polyomavirus (MCPyV) tumor antigen (T-Ag), 
programmed cell death 1 (PD-1), and its ligand 1 (PD-L1), CD8, CD3, CD68, CD45, and CD56. 
In addition, MCPyV viral DNA will be quantified in the tumor and T cell receptor sequencing in 
tumor infiltrating lymphocytes (TIL) will be performed where pre- and post-treatment biopsies 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
11 
are available. Cellular and humoral MCPyV-specific immune responses will be assessed with 
Enzyme-Linked ImmunoSpot (ELISpot) serology assays in blood samples at baseline, after 
initiating MK-3475 therapy, and correlated with clinical responses over time. Among patients 
with corresponding major histocompatibility complex (MHC)-peptide tetramers, pre-and post-
treatment samples of circulating MCPyV-specific CD8 T cells will be isolated by flow cytometry 
and subjected to deep immunophenotyping by messenger RNA (mRNA) expression analysis.   
Hypothesis: MK-3475 will enhance functional activity of MCC-specific lymphocytes and 
facilitate tumor regression. Thus, the clinical endpoints associated with tumor regression and 
durability of response will be correlated with the pretreatment levels and type of immune cell 
infiltration in the tumor, PD-1 and PD-L1 expression and association in the tumor, or systemic 
measures of immune response to tumor-specific viral MCPyV antigens.  
2. BACKGROUND  
 
 
Study Disease 
MCC is an aggressive skin cancer with a 5-year disease-associated mortality of 46% [Lemos 
2010]. Nearly 50% of patients with MCC develop distant disease typically within 2 to 3 years of 
diagnosis. Systemic chemotherapy is commonly used, but is fairly toxic with limited, transient 
efficacy. The reported incidence of MCC has quadrupled in the past 20 years to an estimated 
~1600 cases/year in the United States [Hodgson 2005; Albores-Saavedra 2010]. This increasing 
incidence is partly due to improved detection using a specific IHC marker, cytokeratin-20,[Moll 
1992] but may also be due to the higher prevalence of known risk factors for MCC: chronic T-
cell immune suppression[Penn 1999; Engels 2002; Heath 2008] and the number of Caucasians 
over 50 years of age with extensive prior sun exposure[Heath 2008]. Despite its growing health 
impact and aggressive behavior, very few clinical trials have focused on this disease. There is an 
unmet need for biology-driven therapy in MCC. 
MCC is causally associated with the MCPyV [Feng 2008, Houben 2010, Rodig 2012]. The viral 
T-Ag oncoproteins, present in approximately 80% of MCC tumors, are required for ongoing 
tumor growth [Houben 2010]. The cellular immune response is strongly linked to outcome in 
MCC. Specifically, intratumoral CD8+ lymphocyte infiltration is associated with improved 
survival independent of stage at presentation [Paulson 2011]. MCPyV-specific T cells have been 
isolated from the blood and tumors of patients with MCC and track with disease burden.  
PD-1 is likely playing a key role in MCC immune evasion in many patients [Afanasiev 2013]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells is to 
downmodulate unwanted or excessive immune responses, including autoimmune reactions. Over 
90% of MCPyV-specific T cells express PD-1. The fact that PD-1 expression is high on these 
T cells, in combination with frequent expression of related T-cell immunoglobulin mucin-3 
(TIM-3), suggests T-cell exhaustion/dysfunction is prevalent. Although these virus-specific 
T cells are present in many patients with MCC, they often fail to control progression of MCC, 
potentially due to immune evasion and exhaustion. 
2.1.1 Merkel cell polyomavirus (MCPyV) and MCC 
The discovery of the MCPyV in 2008, and its causal association with ~80–95% of 

NCI Protocol # CITN-09 
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12 
MCCs, [Feng 2008; Houben 2010; Rodig 2012] has provided new insight into MCC 
pathogenesis and underscores the importance of characterizing MCPyV-specific immune 
responses. MCC typically requires persistent expression of immunogenic polyomavirus 
T-Ag oncoproteins for ongoing growth and survival [Houben 2012]. The necessary and 
persistent [Houben 2010] expression of MCPyV T-Ag oncoproteins in MCC tumors 
provides a unique opportunity, not available for most cancers, to study antitumor 
immunity and immune evasion by assessing responses against virus-derived, tumor-
specific antigens. 
2.1.2 Cellular Immunity and MCC 
There is substantial evidence that cellular immune function is important for survival from 
MCC. Intratumoral CD8+ lymphocyte infiltration is associated with improved survival as 
first reported by the Nghiem group [Paulson 2011]. This association has been validated in 
a second, large, independent cohort[Sihto 2012]. In a similar vein, patients with profound 
T-cell dysfunction,[Penn 1999; Engels 2002; Heath 2008] such as hematologic 
malignancies, HIV/AIDS, and immunosuppressive medications for autoimmune disease 
or transplant, have 10- to 30-fold increased MCC risk, and MCC sometimes 
spontaneously regresses after improvement in immune function in those patients. 
Moreover, patients with systemic immune suppression have decreased median survival in 
MCC independently of stage [Paulson 2013]. 
2.1.3 Cellular Immune Response against MCPyV in MCC 
The persistent expression of MCPyV oncoproteins in MCC provides a unique 
opportunity to characterize immune evasion mechanisms in this cancer. Patients with 
MCPyV-positive MCC tumors frequently have T cells specific for these persistently 
expressed oncoproteins [Iyer 2011]. We hypothesized that these MCPyV-specific T cells, 
although present in the blood of patients with MCC, were unable to eliminate MCC 
tumors, either because they were dysfunctional and/or due to the other immune evasion 
mechanisms. We determined the presence and functional status of tumor-infiltrating 
lymphocytes (TIL, n=7) and virus-specific peripheral blood T cells from 18 patients with 
MCC and 10 control patients. MCPyV-specific CD8 T cells were detected directly ex 
vivo from the blood of 7 of 11 (64%) patients with MCPyV-positive tumors. In contrast, 
0 of 10 control patients had detectable levels of these cells in their blood (P<0.01) 
[Afanasiev 2013]. MCPyV-specific T cells in serial blood specimens increased with 
MCC disease progression and decreased with effective disease therapy. Because T-cell 
number increases with disease burden, there is a need for careful interpretation of 
immunotherapy efficacy data aimed at increasing tumor-specific T-cell frequency. The 
presence and expansion of MCC-specific T cells with increasing tumor burden is highly 
suggestive that tumor immune escape mechanisms are active in MCC. 
2.1.4 Active Immune Evasion Mechanism in MCC 
In MCC tumors, PD-L1 expression within the tumor microenvironment has been 
observed and is positively correlated with the number of infiltrating CD8 lymphocytes 
using both histologic and mRNA-based analyses in independent cohorts [Afanasiev 2013; 
Lipson 2013]. Over 90% of MCPyV-specific T cells express PD-1 (as compared with 
approximately 30% of all CD8+ T cells, approximately 50% of cytomegalovirus [CMV]-
specific T cells, and approximately 80% of Epstein-Barr virus [EBV]-specific T cells). 

NCI Protocol # CITN-09 
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Furthermore, PD-1 surface expression on MCPyV-specific T cells is >2-fold higher 
compared to EBV- or CMV-specific T cells and it ligand, PD-L1, was present in 9 of 13 
(69%) of MCC tumors [Afanasiev 2013]. PD-1 and TIM-3 are simultaneously co-
expressed on the majority MCC-specific T cells, a combination that is often associated 
with dysfunction [Fourcade 2010; Sakuishi 2010]. T-cell dysfunction mediated by 
surface expression of these inhibitory molecules on T cells may, at least in part, explain 
why MCC tumors grow despite the presence of an immune response. These findings are 
consistent with prior reports indicating that chronic antigen exposure to tumor and viral 
antigens leads to the upregulation of inhibitory receptors such as PD-1 and TIM-3, which 
results in reversible T-cell dysfunction [Barber 2006; Jones 2008; Fourcade 2010; 
Greenough 2010; Wherry 2011]. In contrast to prior studies of virus- or tumor-specific 
CD8-T cells that show upregulation of PD-1 with acute infection[Greenough 2010] or 
with increasing tumor stage,[Kronig 2012] PD-1 expression on MCPyV-specific T cells 
was maintained at high levels throughout the MCC disease course even during declining 
T-cell absolute numbers during remission [Afanasiev 2013]. 
In melanoma, most circulating melanoma-specific CD8 T cells have been reported to be 
functionally active, whereas those derived from tumor lesions are functionally tolerant 
[Zippelius 2004]. In contrast, in MCC, T cells derived from the blood and tumor 
compartments have similar phenotypic profiles, both indicative of T-cell dysfunction 
[Afanasiev 2013]. Activation and inhibitory receptors tend to be induced simultaneously 
on MCC-specific T cells, consistent with chronic antigen exposure likely triggering 
immune tolerance, in agreement with prior studies of HIV-specific CD8 T 
cells[Trautmann 2006; Sauce 2007].  
PD-1 upregulation on tumor-targeting CD8 T cells is particularly relevant if its ligand is 
expressed within the tumor microenvironment, which can lead to inhibitory pathway 
activation. PD-L1 is selectively expressed on many tumors[Hamanishi 2007; Zou 2008; 
Hino 2010] and on cells within the tumor microenvironment [Curiel 2003] and blockade 
of the PD-1/PD-L1 pathway has been recently shown to effectively induce durable tumor 
regression and stabilization of disease in a subset of several diverse types of 
cancer[Sakuishi 2010; Fisher 2012]. 
In summary, MCPyV-specific T cells: (1) dynamically correlate in frequency with 
clinical disease burden and with antibodies against the viral oncoprotein (T-Ag), (2) co-
express markers of exhaustion, PD-1 and TIM-3, at far higher levels than T cells specific 
for other common human viruses such as EBV, (3) display minimal interferon gamma 
(IFN-γ) production in response to cognate peptide, which can be augmented after culture 
with inhibitory receptor blocking agents, and (4) are likely to encounter the relevant 
inhibitory receptor ligand, PD-L1, within the MCC tumor microenvironment. 
2.1.5 MCC as a Candidate for Testing MK-3475 
MK-3475 is a potent and highly selective humanized monoclonal antibody (mAb) of the 
immunoglobin G4 (IgG4)/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional 
activity of the target T cells to facilitate tumor regression and ultimately immune 
rejection.  

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14 
The expression of PD-1 and PD-L1 support the testing of the antibody to PD-1 (anti-PD-
1) as a targeted approach to overcome tumor immune evasion mechanisms in MCC. The 
direct relationship of T-cell and antibody responses to the burden of MCC provide 
clinical biomarkers of disease status and may also serve as a potential indicator of 
response to anti-PD-1. 
2.1.6 Orphan Disease with Important Unmet Medical Needs 
Despite the strong rationale for investigation of immunotherapy in this virus-associated 
cancer, there are no systemic immune therapies approved or currently being investigated 
[Miller 2013]. The chances of successful immunotherapy for MCC are fairly high, in part 
due to its obligate viral protein expression [Houben 2010]. 
2.1.7 Treatment with Cytotoxic Chemotherapy 
There are no FDA-approved therapies for MCC. However, systemic chemotherapy has 
been commonly used to manage metastatic MCC, despite toxicity and limited, transient 
efficacy. The National Comprehensive Cancer Network (NCCN) Merkel Cell Carcinoma 
Guidelines Version 1.2012 [Page MS-4] states “Data are insufficient to assess whether 
chemotherapy regimens improve either relapse-free or overall survival in MCC patients 
with distant metastatic disease.” Data from patients treated by the Nghiem group at the 
Fred Hutchinson/University of Washington Cancer Consortium (FH/UW Consortium) 
shows that responders have a prolonged PFS compared to nonresponders, but without 
randomized data for the disease there is no firm evidence that chemotherapy improves 
OS.  
If chemotherapy is used, the NCCN recommends cisplatin or carboplatin with or without 
etoposide [NCCN 2012]. Most patients with metastatic MCC will respond to 
chemotherapy, but will progress between 3 and 5 months and have a median time to 
death of 9 months after initial metastasis. Accordingly, the NCCN concludes “Clinicians 
should exercise independent medical judgment in choosing the chemotherapeutic 
regimen. Although the NCCN panel recognized that MCC is a rare disease that precludes 
robust randomized studies, enrollment in clinical trials is encouraged whenever available 
and appropriate.”  
The MCC team at the FH/UW Consortium has analyzed data from 58 patients in the 
Seattle cohort who developed distant metastatic disease, received first-line chemotherapy, 
and had evaluable metastatic lesion(s) that were not also treated with radiation or surgery 
(allowing the effects of chemo-mono-therapy to be evaluated). The median time to 
progression following chemotherapy in the Seattle cohort with “-platin”–based regimens 
was 98 days for the whole treated population and 145 days for the responding patients 
(details below).  

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TOTAL PATIENTS RECEIVING FIRST-LINE CHEMOTHERAPY (n = 58)  
 
Complete response (CR): 8 of 58 (14%) 
Partial response (PR): 24 of 58 (41%) 
Stable disease (SD): 4 of 58 (7%) 
TOTAL CR/PR/SD: 36 of 58 (64%)  
 
Total Progressed at time of analysis (November 2013): 56 of 58 (97%) 
Total not progressed 2 of 58 (1 CR and 1 PR) (3%)  
 
Time to progression among all 58 evaluable chemo-treated cases: 
50% progressed (Median time from start of chemotherapy) = 98.5 days  
80% progressed = 222 days 
90% progressed = 290 days 
95% progressed = 428 days  
 
Note: the progression from 0% to 95% looks like a straight line on a semi-log plot with no 
evidence of a plateau.  
 
TOTAL PATIENTS THAT RESPONDED TO FIRST-LINE CHEMOTHERAPY 
(CR/PR/SD) (n = 36)  
 
Progressed: 34 of 36 (94.4%) 
Not progressed: 2 of 36 (5.5%) (1 CR and 1 PR) 
 
Time to progression among “chemo responders”: 
50% (median) progressed 145 days  
50% (median) of CR patients = 303 days  
50% (median) of PR patients = 145 days  
50% (median) of SD patients = 132 days  
80% progressed = 288 days 
90% progressed = 316 days 
94.4% progressed = 466 days  
 

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Figure 1: First-line chemotherapy and progression-free survival (PFS) in MCC patients with metastatic disease.  
These data are derived from 58 patients in the Seattle cohort who developed distant metastatic disease, received first-line 
chemotherapy, and had evaluable metastatic lesion(s) that were not also treated with radiation or surgery (allowing the effects of 
chemo-mono-therapy to be evaluated). The vertical axis represents the number of DAYS between the start of first-line chemotherapy 
and progression (or death). Etoposide was combined with a “platin” in the 40 cases shown as blue bars. Among these 40 cases, the 
“platin” was carboplatin in 29 cases and cisplatin in 11. Patients 57 and 58 (asterisks) are the only ones who did not progress on 
chemotherapy or die, as of most recent data. Median PFS was 98.5 days from start of chemotherapy to progression or death. These 58 
patients are a subset of the 179 patients we recently reported in which median OS was 289 days (9.5 months) from the date when 
distant disease was identified (Figure 3).  

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Figure 2: Progression-free survival (PFS) in MCC patients with metastatic disease, treated with first-line chemotherapy and 
responded with CR, PR, or SD.  
These data represent the 36 “chemo responders” among the full cohort of 58 chemotherapy-treated patients in the Seattle cohort 
shown in Figure 1. Specifically, these 36 patients developed distant metastatic disease, received first-line chemotherapy, and achieved 
a complete or partial response. The vertical axis represents the number of DAYS between the start of first-line chemotherapy and 
progression (or death). Median PFS was 145 days from start of chemotherapy to progression or death. These 36 patients are a subset 
of the 179 patients with distant disease shown in Figure 3.  

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Figure 3: Disease-specific survival in patients who developed metastatic MCC. 
Survival data are shown from 179 patients with metastatic MCC who were followed at the 
FH/UW Consortium [Miller 2013]. Median survival was 289 days from initial diagnosis of 
metastatic disease. When measured starting at the time of developing metastatic disease, there 
were no significant differences in survival based on the initial stage at presentation (data not 
shown). However, stage greatly influenced the likelihood of and median time to developing 
metastatic disease. 
Given that cytotoxic chemotherapy-induced responses are typically very short in duration and 
there is no proven beneficial effect of cytotoxic chemotherapy on OS, the proposed trial will be 
conducted in chemotherapy-naïve patients and patients who received prior adjuvant 
chemotherapy more than 6 months before study participation. The likelihood of success with 
MK-3475 should be greater if given to patients who are immunocompetent (more likely in 
chemotherapy-naïve patients). In general, response rates and DOR are expected to be diminished 
with each subsequent line of therapy. This was indeed the case for MCC, with median PFS of 98 
days in first line that decreased to 61 days in second-line chemotherapy, and overall response 
rate that fell from 54% to 23% in second line (Iyer, Nghiem, et al, unpublished). Finally, the 
antitumor activity of PD-1 in several malignancies, melanoma, renal cell carcinoma (RCC), and 
non–small cell lung cancer (NSCLC), is greater than the efficacy of chemotherapy in MCC, 
further supporting the study of anti-PD-1 as first-line therapy. Subjects who are treated with anti-
PD-1 therapy are therefore unlikely to give up a substantially meaningful benefit from front-line 
chemotherapy. This will be explained to patients in detail in the consent form.  
Radiation therapy is commonly used to treat MCC, but is not considered to be a systemic therapy 
in this protocol. Radiation therapy is considered useful as a treatment option for all stages of 
MCC [NCCN 2015]. For radiation as adjuvant to surgery, a meta-analysis comparing surgery 
alone with surgery plus adjuvant radiation revealed that the use of adjuvant radiation after 
complete excision lowered the risk of local and regional recurrences [Lewis 2006]. For radiation 
to the primary tumor or regional lymph nodes, a review of 83 cases diagnosed between 1992 and 
2004 showed that administration prolonged time to recurrence and survival [Jabbour 2007]. For 
primary therapy, radiation is considered acceptable in select cases when complete excision is not 
feasible or refused by the patient. An Australian retrospective review of 43 patients reported an 
in-field tumor control rate of 75% using radiation alone [Veness 2010]. Radiation may also be 

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useful in the palliative setting. 
 
CTEP IND Agent: MK-3475 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized mAb 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  
PD-1 is an immune-checkpoint receptor expressed on T cells that can suppress antitumor 
immunity when bound to either of its ligands, PD-L1 or PD-L2. Some tumor cells upregulate the 
PD-1 ligands to evade active T-cell immune surveillance. MK-3475 is a potent and highly 
selective humanized mAb designed to directly block the interaction between PD-1 and its 
ligands, thereby enhancing tumor regression and ultimately immune rejection. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD-1, expressed on the cell surface of activated T cells under 
healthy conditions, is to downmodulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4), which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-
L2) [Usubutun 1998; Talmadge 2007]. 
The structure of murine PD-1 has been resolved [Al-Shibli 2008]. PD-1 and family members are 
type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail, which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM). After T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 
and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 T-cell 
signaling cascade [Diez 1998; Galon 2006; Talmadge 2007; Deschoolmeester 2010].  
The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from, 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins [Nobili 2008; 
Hiraoka 2010]. PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T cells, B cells, T regulatory cells (T regs), and natural killer (NK) cells [Kloor 
2009; Hodi 2010]. Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T cells as well as subsets of macrophages and dendritic cells [Hillen 2008]. 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including nonhematopoietic tissues as well as in various tumor [Nishimura 
2000; Lee 2008; Leffers 2009; Hiraoka 2010]. Both ligands are type I transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 
inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels 
on various nonhematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 
protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or 
chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 

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tissues [Hiraoka 2010]. Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumor-specific T-cell expansion in patients with melanoma. This suggests 
that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention.  
In mouse models, blockade of the PD-1 pathway effectively promoted CD8+ T-cell infiltration 
into the tumor and the presence of IFN-γ, granzyme B, and perforin, indicating that the 
mechanism of action involved local infiltration and activation of effector T-cell function in vivo 
[Korman 2007]. In addition, the combination of gemcitabine and anti-PD-L1 mAb demonstrated 
synergy in the rejection of pancreatic mouse tumors [Nomi 2007]. Merck in-house experiments 
have confirmed the in vivo efficacy of PD-1 blockade as a monotherapy. Therapeutic studies in 
mouse models show that administration of antibodies blocking PD-1/PD-L1 interaction enhances 
infiltration of tumor-specific CD8+ T cells and leads ultimately to tumor rejection, either as a 
monotherapy or in combination with other treatment modalities. Anti-mouse PD-1 or anti-mouse 
PD-L1 have demonstrated antitumor responses as a monotherapy in models of squamous cell 
carcinoma, pancreatic carcinoma, melanoma, and colorectal carcinoma. Blockade of the PD-1 
pathway effectively unleashes a T-cell response when used alone as well as in combination with 
chemotherapy in syngeneic mouse tumor models.  
MK-3475 is a humanized IgG4 anti-PD-1 mAb with similar preclinical characteristics as BMS-
936558. Both MK-3475 and BMS-936558 contain the S228P stabilizing mutation. MK-3475 is a 
pure PD-1 antagonist. MK-3475 potency in PD-1 binding, inhibition of ligand binding, and 
inhibition of PD-1 function has been similar or up to several-fold higher than that of an analogue 
of BMS-936558. Modeling of MK-3475 pharmacokinetics (PK) in monkeys vs BMS-936558 PK 
reported in humans suggested comparable concentration-time curves at various dose levels. A 1 
month, repeat-dose, Good Laboratory Practice toxicity study with 4-month observation after 
dosing of MK-3475 revealed no major safety findings. The “No observed adverse effect level” 
(NOAEL) was ≥200 mg/kg.  
Recent data of MK-3475 have validated PD-1 as an attractive target for clinical intervention and 
have provided proof of concept for anti-PD-1 mAbs in melanoma [Hamid 2013]. Patients with 
advanced melanoma were treated with MK-3575 with 10 mg/kg every 2 or 3 weeks. The 
response rate by RECIST was 38%. Responses were durable in the majority of patients (median 
follow-up, 11 months among patients who had a response); 81% of the patients who had a 
response (42 of 52) were still receiving treatment at the time of last published analysis in March 
2013. The overall median PFS among the 135 patients was longer than 7 months. Common 
adverse events (AEs) attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of 
the AEs were low grade (Trial detailed below in Section 2.2.1.1).  
These data are similar to data in melanoma and renal carcinoma published for a similar agent, 
BMS-936558 [Sznol 2010]. BMS-936558 has shown an overall response rate of approximately 
30% in patients with advanced melanoma and RCC who had failed prior therapy. Responses 
were of long duration, and the agent was generally well tolerated. 

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2.2.1 MK-3475  
 
MK-3475 (SCH 900475) is a humanized immunoglobulin (Ig) G4 monoclonal antibody 
(mAb) which binds the programmed death 1 (PD-1) receptor, thus inhibiting the 
interaction with its ligands, PD-L1 or PD-L2 (Investigator’s Brochure, 2014).  PD-1 is an 
immune-checkpoint receptor expressed by T cells.  When bound to either PD-L1 or PD-
L2, the PD-1 pathway negatively regulates T-cell effector functions.  The PD-1 pathway 
functions to limit unwanted or excessive immune responses, including autoimmune 
reactions.  PD-L1 is typically expressed at low levels on various non-hematopoietic 
tissues, and PD-L2 is only detectably expressed on antigen-presenting cells in the 
lymphoid tissue or chronic inflammatory environments.   
 
PD-L1 is also expressed in the tumor microenvironment of various cancers (Zou and 
Chen, 2008).  Activation of the PD-1 pathway may be a critical mechanism to evade T-
cell mediated tumor rejection (Dong et al., 2002; Pardoll, 2012).  High levels of PD-L1 
expression are correlated with poor prognosis and survival in renal cell carcinoma (RCC) 
(Thompson et al., 2007), pancreatic carcinoma (Nomi et al., 2007), hepatocellular 
carcinoma (HCC) (Gao et al., 2009), and ovarian carcinoma (Hamanishi et al., 2007).   
 
Immune-checkpoint inhibition of another inhibitory T-cell receptor, cytotoxic T-
lymphocyte-associated antigen 4 (CTLA-4), with the mAb ipilimumab demonstrated 
significant prolongation of overall survival (OS) in patients with melanoma in two phase 
3 trials (Hodi et al., 2010; Robert et al., 2011; Ribas, 2012).  As an immunotherapy 
target, PD-1 is distinct from CTLA-4 because it can be activated directly by the cancer 
and it regulates the effector phase of T-cell response, whereas CTLA-4 regulates the 
initial stage of T-cell activation (Pardoll, 2012; Ribas, 2012).  Antibodies targeting the 
PD-1 pathway have demonstrated durable objective responses in phase 1 and 2 trials.  
Nivolumab showed an overall response rate (ORR) of approximately 28% in subjects 
with advanced melanoma, 27% in subjects with RCC, and 18% in subjects with non-
small cell lung cancer (NSCLC) who had failed prior therapy (Topalian et al., 2012).  
MK-3475 has shown an ORR of approximately 38% in patients with melanoma (Hamid 
et al., 2013) and ~20% in patients with NSCLC (Investigator’s Brochure, 2014). 
 
2.2.1.1 
Clinical Development of MK-3475 
 
Clinical data are derived from an ongoing, first-in human phase 1 study (PN001, 
NCT01295827) to evaluate the safety and clinical activity of MK-3475 as a 
monotherapy, sponsored by Merck Sharp & Dohme.  There are five parts to this study 
(Parts A-D and F) (Investigator’s Brochure, 2014).   
 
Part A was a 3+3 dose-escalation study in subjects with solid tumors to evaluate safety, 
tolerability, pharmacokinetics (PK), and pharmacodynamics, and to determine a 
maximum tolerated dose (MTD) or preliminary recommended phase 2 doses (RP2Ds).  
Doses were 1, 3, and 10 mg/kg every 2 weeks (Q2W); doses of either 2 mg/kg or 10 
mg/kg were also administered every 3 weeks (Q3W).  All 3 dose levels were well 
tolerated and no dose-limiting toxicities (DLTs) were observed; therefore, the MTD was 

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not determined.  The RP2D was determined by the sponsor based on safety, PK, and 
pharmacodynamic measurements, along with the strength of antitumor activity signals 
observed. 
 
The remaining four parts aim to characterize the safety profile and tolerability of MK-
3475 and to evaluate the clinical activity of MK-3475 in the following patient 
populations:  
 
Part B: Advanced melanoma patients who have either received prior ipilimumab (IPI-
treated) or were naïve to prior ipilimumab (IPI-naïve).  Patients in Part B receive MK-
3475 at three dose levels: 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W.   
 
Part C: NSCLC patients.  Patients in Part C receive MK-3475 at 10 mg/kg Q3W.   
 
Part D: Advanced melanoma patients that are IPI-naïve.  Patients in Part D receive MK-
3475 at 2 mg/kg Q3W and 10 mg/kg Q3W.  
 
Part F: NSCLC patients with and without prior systemic therapy whose tumors express 
PD-L1 when exposed to MK-3475.  Patients in Part F receive MK-3475 at 2 mg/kg or 10 
mg/kg Q3W, or 10 mg/kg Q2W.  
 
 
Pharmacokinetics  
The half-life (t1/2) of MK-3475 is approximately 4 weeks and there is no indication of 
dose dependency of half-life in the three dose groups (1, 3, and 10 mg/kg) (Investigator’s 
Brochure, 2014).  The long t1/2 supports a dosing interval of every 2 or 3 weeks. 
 
There was a dose-related increase in exposure from 1 to 10 mg/kg (Investigator’s 
Brochure, 2014).  Serum concentrations of MK-3475 were lower by a factor of 
approximately 5 in patients receiving 2 mg/kg Q3W than in those receiving 10 mg/kg 
Q3W (Hamid et al., 2013, Investigator’s Brochure, 2014).  Steady-state trough 
concentrations were 20% greater in the patients receiving 10 mg/kg Q2W than in those 
receiving the same dose Q3W. 
 
Anti-Drug Antibodies (ADA) Data 
The occurrence of ADA has been observed in less than 1% of the patients screened, 
indicating a low potential of MK-3475 to elicit the formation of ADA (Investigator’s 
Brochure, 2014).  No impact of ADA on MK-3475 exposure has been observed. 
 
 
Efficacy 
When treated with MK-3475 monotherapy, the ORR for IPI-treated patients with 
melanoma (Part B) was 25%/27% according to the Response Evaluation Criteria in Solid 
Tumors (RECIST)/investigator-assessed immune-related response criteria (irRC), 
respectively (Investigator’s Brochure, 2014).  The ORR for IPI-naïve patients with 
melanoma (Parts B and D) was 39%/43% by RECIST/investigator-assessed irRC, 
respectively.  The majority of responses were seen in patients with melanoma by 16 
weeks of therapy with MK-3475; however, some responses have been reported after 24 

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23 
weeks or more of therapy with MK-3475.  Responses can be delayed, and in some 
patients, a RECIST-defined progression followed by a response has been observed. 
 
The preliminary objective response rate for 38 patients with NSCLC (Part C) was 
21%/24% by RECIST/investigator-assessed irRC, respectively (Investigator’s Brochure, 
2014).   
 
Pharmacodynamics/Biomarkers  
PD-L1 is being investigated as a predictive biomarker for MK-3475 treatment.  At the 
15th World Conference on Lung Cancer, Garon et al. presented preliminary data on a 
subset of patients suggesting that higher levels of tumor PD-L1 expression are associated 
with increased clinical activity (Garon et al., 2013).  Objective responses by RECIST 1.1 
occurred in 4 out of 7 patients with higher levels of PD-L1 expression (57%, 95% 
confidence interval [CI] 18-90%) vs. 2 out of 22 patients with lower levels of PD-L1 
expression (9%, 95% CI 1-29%).  These data are extremely preliminary, and PD-L1 is 
not being used for patient selection.   
 
Biomarkers to evaluate immune modulation and markers in the tumor microenvironment, 
such as T-cell infiltration, the baseline expression of markers of T-cell suppression FoxP3 
or the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor biopsies, 
were associated with a high response rate (Berman et al., 2009; Hamid et al., 2009). 
 
2.2.1.2 
Safety data   
 
The most frequent treatment-related adverse events (AEs) were fatigue, nausea, cough, 
pruritus, diarrhea, and rash (Investigator’s Brochure, 2014).  Most AEs were not 
considered serious.  The most commonly reported immune-related AEs were rash, 
pruritus, vitiligo, hypothyroidism, arthralgia, diarrhea, and pneumonitis. 
 
Important identified risks include: pneumonitis, thyroid disorders (hypothyroidism and 
hyperthyroidism), colitis, diarrhea, hepatitis, nephritis, uveitis, rash/pruritus and 
neuropathy. 
 
 
Other Agent(s): N/A 
 
Rationale for Trial of MK-3475 in Merkel Cell Carcinoma Patients 
Patients with advanced and progressing MCC will receive MK-3475 as first systemic therapy. 
MK-3475 is a potent and highly selective humanized mAb of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade 
enhances functional activity of the target lymphocytes to facilitate tumor regression and 
ultimately immune rejection.  
Cellular immune response is strongly linked to outcome with intratumoral CD8+ lymphocyte 
infiltration associated with improved survival. PD-1 expression is likely playing a key role in 
MCC immune evasion: The PD-1 receptor-ligand interaction is a major pathway hijacked by 
tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface 

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of activated T cells under healthy conditions, is to downmodulate unwanted or excessive immune 
responses, including autoimmune reactions.  
The necessary and persistent [Houben 2010] expression of MCPyV T-Ag oncoproteins in MCC 
tumors provides a unique opportunity. The viral T-Ag oncoproteins are present in 80% of MCC 
tumors and are required for ongoing tumor growth. There is often a T cell response specifically 
against virus positive cells. Over 90% of MCPyV-specific T cells express PD-1, the level of PD-
1 expression is relatively high on a given cell, and it is frequently co-expressed with TIM-3, a 
combination that is strongly associated with immune dysfunction [Afanasiev 2013].  
MCC-specific T cells co-express markers of exhaustion, PD-1 and TIM-3 at far higher levels 
than T cells specific for other common human viruses, and are likely to encounter the relevant 
inhibitory receptor ligand, PD-L1, within the MCC tumor microenvironment. Specifically, in 
MCC tumors, using both histologic and mRNA-based analyses in independent cohorts, PD-L1 
expression within the tumor microenvironment has been observed and is positively correlated 
with the number of infiltrating CD8 lymphocytes [Afanasiev 2013; Lipson 2013]. The data 
suggest that the PD-1/PD-L1 inhibitory axis is a likely immune evasion strategy in MCC tumors. 
Importantly, the blockade of the PD-1/PD-L1 pathway has been recently shown to effectively 
induce durable tumor regression and stabilization of disease in a subset of several diverse types 
of cancer [Brahmer 2012; Topalian 2012, Hamid 2013].  
The expression of PD-1 and PD-L1 support the testing of anti-PD-1 as a targeted approach to 
overcome tumor immune evasion mechanisms in MCC. MK-3475 offers the possibility of 
“unleashing” T cell responses to viral antigens expressed by MCC cells as well as cancer 
antigens. The trial also offers the opportunity to study antitumor immunity and immune evasion 
by assessing responses against a virus-derived, tumor-specific antigen. These studies could lead 
to the elucidation of other potentially effective immunotherapy regimens. 
ORR will be the primary endpoint; PFS will be determined and reported and compared at 
16 months to the historical control of first-line chemotherapy (5% PFS at 16 months). The 
expectation is that MK-3475 will induce durable responses in a substantial proportion of patients 
and that MK-3475 will demonstrate a real and substantial patient benefit compared to recent 
historical controls.  
Cellular immunity is known to play a major role in the outcome of MCC. Although the majority 
of patients respond to standard chemotherapy, virtually all relapse, most often within a few 
months as shown in Figures 1-3 above. There is thus a good possibility that responses to MK-
3475 may be more substantial and durable than responses to chemotherapy. Because systemic 
cytotoxic chemotherapy is associated with immune suppression and is not well tolerated in this 
older population, MK-3475 may have many advantages over this traditional approach. 
Finally, the antitumor activity of PD-1 in several malignancies, melanoma, RCC, and NSCLC, is 
greater than the efficacy of chemotherapy in MCC, further supporting the use of anti-PD-1 as 
first-line therapy. The subjects thusly treated are unlikely to give up any substantially meaningful 
benefit from front-line chemotherapy. This is explained to patients in detail in the consent form. 
 

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2.4.1 Rationale for expansion of enrollment 
Rationale for expanding enrollment from 26 to 50 patients in order to provide an expanded safety 
and efficacy profile: 
Data to date on this trial (CITN-09 trial of MK-3475 as first systemic intervention in advanced 
MCC) has been positive enough to consider applying to the FDA for indication approval.  The 
data has been assessed from the Simon two-stage trial design used in its initial enrollment phase.  
Stage 1 was to enroll 9 patients and stage 2 was to enroll an additional 15 patients.  The trial was 
to be suspended and any further enrollment stopped if no responses were seen in stage 1. Since 
responses were observed among the first 9 patients enrolled, the study was allowed to proceed to 
stage 2 and enroll 15 additional patients.  Treatment was discontinued in 2 patients due to drug-
related adverse events after receiving 1 dose of MK-3475, and enrollment of an additional 2 
patients was allowed per protocol, bringing the total enrollment to 26 patients.  
Preliminary results of this trial were presented at the European Cancer Congress 2015 on 
September 27, 2015 [Nghiem 2015], and at the American Association for Cancer Research 
Annual Meeting on April 19, 2016 [Nghiem 2016], and summarized in the New England Journal 
of Medicine [Nghiem 2016].  Of the 26 pts who had received at least 1 dose of pembrolizumab, 
25 had undergone at least one radiologic and clinical response assessment. Of these 25pts, 4 had 
a complete response (CR), , 10 had a partial response (PR), 1 had an unconfirmed PR, and 9 
progressed and are off trial.  The objective response rate (calculated on confirmed responses) cut 
was 14/25 (56%). 
One patient had grade 4 myocarditis after 1 dose of MK-3475, and one had grade 4 transaminase 
elevation after 2 doses, with improvement in both patients after discontinuation of MK-3475 
followed by steroid administration. Strikingly, both of these patients had favorable tumor 
responses (skin metastases regressed in one; the other has an ongoing PR of extensive visceral 
metastases).In summary, among 25 radiographically evaluable MCC pts treated with MK-3475 
alone as first systemic intervention, 15 showed evidence (14 confirmed and 1 unconfirmed by 
subsequent scans) of response to PD-1 pathway blockade. The authors speculated that the high 
response rate may in part be due to the immune response to antigens from the polyomavirus that 
often drives MCC.  
Since the rate of response thus far in this trial is greater than anticipated and more favorable than 
historical data on response to cytotoxic chemotherapy regimens, this protocol is being amended 
to include up to 50 patients for whom MK-3475 will be the first systemic treatment for MCC. 
The additional data will provide for a more robust safety and efficacy profile. 
2.4.2 Rationale for continuing MK-3475 in patients with tumors that progress 
It is expected that many Merkel cell tumors will fail to respond to MK-3475. Patients with 
documented progressing MCC will have the option of continuing MK-3475, because a small 
subset of patients with melanoma respond to continued therapy.  Patients being treated with MK-
3475 for melanoma have experienced late responses with continued therapy.  In the KEYNOTE-
001 melanoma trial using MK-3475 there was an additional 3.6% response rate with continued 
therapy.  This category of response in that trial was defined as an “unconventional response” 

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with “delayed pseudoprogression: ≥25% increase in tumor burden at any assessment after week 
12 that was not confirmed as progressive disease per irRC at the next assessment”. [Hodi 2014].  
 
Correlative Studies Background  
The links between the immune system and MCC are particularly strong due to the frequent 
presence of the MCPyV and the documented improved survival of MCC patients based on T-cell 
immune function. It is therefore plausible that MK-3475 responses will correlate with the nature 
of the immune response in the tumor microenvironment including PD-L1 expression. In addition, 
there are several unique aspects of the correlative studies proposed for this trial. These include 
the ability to study MCPyV-specific T cells (in a subset of patients with corresponding MHC-
peptide tetramers) in terms of their number, functional status, and surface receptor phenotype 
and gene expression profile. These correlative studies will attempt to address the following 
questions: 
1) Are MCPyV-positive tumors more likely to respond to PD-1? 
2) Does the MCPyV DNA copy number or extent of viral protein expression by IHC predict 
responsiveness? 
3) Is intratumoral CD8 T-cell infiltration a marker for patients that will respond to MK-
3475?  
4) Are patients with antibodies to the MCPyV oncoprotein more likely to respond to MK-
3475? 
5) Do antibody titers to the viral oncoprotein provide greater or different insights into 
responses than gold-standard imaging studies? 
6) Do responsive patients (as compared to non-responders) demonstrate changes in cell 
surface exhaustion parameters (PD-1/TIM-3) for virus-specific T cells? 
7) Are virus-specific or neoantigen-specific T cells more active following PD-1 therapy? (as 
assessed by interferon and other cytokine production after peptide stimulation and assay 
by ELISpot and/or intracellular cytokine analysis) 
8) What immune evasion mechanisms are active in tumors that fail to respond to MK-3475? 
(Biopsies will be carried out when feasible, on accessible tumor sites.) 
9) How does the mutanome landscape of MCPyV-positive patients compare to that of 
MCPyV-negative patients?  How does mutational load rank within the NIH Cancer 
Genome Atlas (TCGA)? 
10) How does predicted immunogenicity of neoantigens differ between MCPyVpos and 
MCPyVneg tumors? Does this difference correlate with response to pembrolizumab? 
11) How does the T cell response to either viral antigens or neoantigens change over the 
course of treatment with pembrolizumab? 
12) What is the phenotype of neoantigen-reactive or virus-reactive T cells and how does this 
phenotype change over the course of pembrolizumab therapy? Does a particular 
phenotype correlate with response? 

NCI Protocol # CITN-09 
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27 
2.5.1 Evaluation of Tumor Biopsies for Immune Cell Infiltrate—Laboratory Correlative 
Study #1  
All patients recruited in the study must have an available archival tumor biopsy for 
biomarker analyses. If sufficient archival tumor tissue (at least 0.5 × 0.5 × 0.5 cm) 
collected before MK-3475 therapy is not available, a baseline biopsy will be obtained 
before enrolling in the study, assuming this can be carried out safely. Because tumor-
infiltrating immune cells are associated with clinical outcome in MCC tumors, infiltrates 
derived from pre-therapy tumor tissue and from optional biopsies of responding, stable or 
progressing lesions in patients who have not achieved CR will be assessed by IHC to 
determine extent and the nature of the T-cell infiltration and the immune milieu of the 
tumor microenvironment. PD-L1 is a critical ligand for PD-1 and may be associated with 
response to MK-3475, hence, PD-L1 expression will be quantitated in the baseline 
formalin-fixed paraffin-embedded tumor specimens from all cases at a Merck-designated 
contract research organization (CRO). The following cellular markers will also be 
analyzed by IHC analyses in this study: CD3, CD8, PD-1, MHC Class 1, and anti-
MCPyV T-Ag.  
Additionally, with a view to further characterize the immune cell infiltrate (pending 
discussions between investigators and Merck in light of study results and current 
literature), tumors may also be assayed by IHC for a variety of other markers including 
CD4 (T cells), CD56 and CD16 (NK and NK T cells—because many MCC tumors are 
CD56-positive themselves, CD16 is an important additional marker), CD45 (leukocytes), 
CD19 (B cells), CD68, glucocorticoid-induced tumor necrosis factor receptor family–
related gene (GITR), TIM-3, forkhead box P3 (FOXP3), and lymphocyte-activation 
gene 3 (LAG3). Tumor tissue may also be tested for gene expression (NanoString 
Technologies). 
In patients  who have not achieved CR (either responding, stable or progressing lesions) a 
biopsy sample of a tumor may be obtained if feasible and safe (core, punch or excisional 
biopsy).  This biopsy is highly preferred, but optional. The biopsy will be analyzed as 
outlined above. All studies indicated above maybe carried out for the biopsy. 
2.5.2 Merkel Cell Polyomavirus DNA and Protein Expression in Tumor Biopsies—
Laboratory Correlative Study #2 
To determine whether MCPyV-positive MCCs are more likely to respond to anti-PD-1 
and if the DNA copy number or extent of viral protein expression by IHC predict 
responsiveness, tumor biopsies will be analyzed for presence of the MCPyV in 2 ways: 
(1) determine MCPyV oncoprotein expression in tumor cells using an optimized IHC 
protocol and (2) determine DNA status (and copy number) via polymerase chain reaction 
(PCR) of tumor DNA. Optimized protocols were described by Rodig and colleagues 
[Rodig 2012]. The IHC studies have been optimized and validated at University of 
Washington (UW) pathology laboratories. The DNA-PCR assay has been established by 
Dr. Meei-Li Huang in a clinical grade virology laboratory (Vaccine and Infectious 
Disease Division at Fred Hutchinson Cancer Research Center [FHCRC]) with oversight 
by Dr. Nghiem’s laboratory. 
These studies will be conducted on pretreatment biopsy samples and on biopsy samples 

NCI Protocol # CITN-09 
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28 
collected from patients who have not achieved CR (either responding, stable or 
progressing lesions), when available, as described for Laboratory Correlative Study #1. 
2.5.3 Merkel Cell Polyomavirus–Specific Cellular Immune Responses—Laboratory 
Correlative Studies #3–#5 
Dr. Nghiem’s lab has developed several MHC-peptide tetramer reagents, which will 
enable the identification and isolation of circulating MCPyV-specific CD8 T cells [Iyer 
2011; Afanasiev 2013]. To determine whether and which of these tetramer reagents 
would be applicable for a given patient, a low-resolution human leukocyte antigen (HLA) 
Class I typing assay will be performed after enrollment on study. Although MCPyV-
positive MCC patients often have circulating MCPyV-specific CD8+ T cells, these cells 
are often functionally “exhausted” and display a PD-1hiTIM-3hi phenotype, which likely 
comprise a representative subset of the target cell population in MCC. The phenotype of 
MCPyV-positive T cells or neoantigen-reactive T cells will be followed over the course 
of treatment.  To comprehensively evaluate cellular immune responses in these patients, 
the following correlative studies will be conducted: 
2.5.3.1 
Laboratory Correlative Study #3: Immunophenotyping of Merkel Cell 
Polyomavirus–specific CD8+ T cells 
In this study, peripheral blood tumor-specific CD8 T cells will be evaluated 
by multiparametric flow cytometry at baseline and at multiple time points 
after initiation of MK-3475 therapy. These studies will be performed by the 
Nghiem Laboratory and CITN Immune Monitoring Laboratory at the UW. 
2.5.3.2 
Laboratory Correlative Study #4: mRNA Expression Analysis of Merkel Cell 
Polyomavirus–specific CD8+ T cells 
In this study, (to be performed if mutually agreed to be feasible and indicated 
by Merck & Investigators) peripheral blood Merkel cell polyomavirus–
specific CD8 T cells will be isolated using fluorescence-activated cell sorting 
(FACS) from frozen cells that were harvested at baseline and at multiple time 
points after initiation of MK-3475 therapy. FACS purification and mRNA 
expression analysis by Nanostring would be performed in collaboration with 
Merck Research Laboratories–Palo Alto.  
We estimate that ~25% patients enrolled in the study will have a tetramer-
matching HLA type and produce MCPyV-oncoprotein–specific T cells 
detectable by tetramer. In these cases, this will be a powerful direct way to 
assess number and function of virus- and tumor-specific T-cells (through 
Laboratory Correlative Studies #3 and #4).  
2.5.3.3 
Laboratory Correlative Study #5: Analysis of Merkel Cell Polyomavirus–specific T 
cell specificities by interferon-gamma ELISpot or by intracellular cytokine staining 
(ICS) 
In this study, all patients, regardless of HLA type, will have cryopreserved 
peripheral blood mononuclear cells (PBMC) tested for responses to MCPyV 
peptides using standard ELISpot and/or ICS assays. These experiments will 
determine whether epitope spreading has occurred and whether it correlates 

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29 
with viral status and clinical response. 
Key questions that these correlative studies will address include: (1) Will the surface 
marker phenotype and/or transcriptional state of a patient’s “exhausted” tumor-specific 
PD-1+ CD8 T cell predict response to MK-3475?; (2) Does the surface marker phenotype 
and/or transcriptional state of a patient’s “exhausted” tumor-specific PD-1+ CD8 T cells 
correlate with features such as CD8 infiltration in the pretreatment tumor? And, are these 
features modulated with MK-3475 treatment?; and (3)Will PD-1+ T cells from 
nonresponding patients be characterized by a specific pattern of gene regulation, 
mutanome landscape or neoantigen array compared to those of responders? Specifically, 
are additional counter-regulatory immune modulators expressed to compensate for PD-1 
blockade? If so, these secondary counter-regulatory immune modulators may represent 
relevant targets to overcome resistance to PD-1 therapy. 
ELISpot analysis will be performed by the CITN Immune Monitoring Laboratory under 
the direction of Dr. Steven Fling.  ICS analyses will be performed by the laboratory of 
Dr. Julie McElrath at FHCRC.  
2.5.4 Merkel Cell Polyomavirus–Specific Antibody Responses—Laboratory Correlative 
Studies #6 
Because antibody titers for the T-Ag oncoprotein are a marker of disease burden and 
immune responsiveness to the virus, we will also test for these antibodies at baseline 
[Paulson 2010]. If positive, this assay will be carried out on serum collected at the time of 
scans. We anticipate that 50% of patients will make antibody to the MCPyV oncoprotein. 
Key questions include (1) Are seropositive patients more likely to respond to anti-PD-1? 
and (2) Do antibody titers provide greater or different insights into responses than gold-
standard imaging studies? In several cases, rises in oncoprotein antibody have occurred 
before detection of disease by CT and may herald early immune recognition of recurrent 
disease. This serologic assay will be performed by Luminex and carried out by the CLIA-
certified Clinical Immunology Laboratory, Department of Laboratory Medicine, at the 
UW in conjunction with Dr. Paul Nghiem’s lab. 
2.5.5 Quantification of PBMC and T-cell Subsets—Laboratory Correlative Study #7 
The effect of MK-3475 on lymphocyte number and phenotype will be assessed at 
baseline and at defined time points during the trial. The frequency and percentage of 
PBMC and T-cell subsets (CD4 and CD8 effector memory, central memory and Treg 
subsets, NK cells and myeloid-derived suppressor cells) will be determined using 
multiparameter flow cytometric analysis on whole blood and/or cryopreserved PBMC. 
Assays will be performed under the direction of Dr. Steven Fling in the CITN Central 
Laboratory in collaboration Dr. Nghiem’s laboratory. 
2.5.6 Whole Exome Sequencing and RNA Sequencing--Laboratory Correlative Study #8 
In order to investigate the role of T cell mediated immunity directed towards tumor-
specific mutant antigens, whole exome sequencing (WES) and RNA sequencing will be 
performed on MCC tumor samples collected at baseline and on PBMC DNA (to establish 
non-mutated sequence.)    

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30 
The mutanome landscape in MCPyV-positive patients and MCPyV-negative patients will 
be compared.  Correlation of these results to patients’ responses to MK-3475 will be 
investigated. Results will also be compared to data on mutational load in other cancers 
currently documented in the NIH Cancer Genome Atlas (TCGA).  
Studies using tumor tissue will be conducted on pretreatment biopsy samples, obtained as 
described for Laboratory Correlative Study #1. 
2.5.7 Neoantigen Identification—Laboratory Correlative Study #9 
Using results of exome sequencing and RNA sequencing performed on baseline tumor 
samples and matched PBMC, neoantigen identification will be performed using Neon 
Therapeutics’ neoantigen prediction MIKEY algorithm or similar technology and 
algorithms to predict and rank-order immunogenic epitopes from MCPyV-positive and 
MCPyV-negative tumors.  Neon Therapeutics or another designated vendor will 
synthesize candidate peptides.  The following will be identified, as indicated:  number of 
predicted neo-antigens, characteristics of the predicted peptides (including affinity 
values, RNA expression values of the mutated genes, and variant allele frequency). 
We will compare predicted immunogenicity of neoantigens between MCPyV-positive 
and MCPyV-negative tumors and assess correlation of immunogenicity with responses to 
pembrolizumab. 
2.5.8  T cell Receptor Sequencing and Functional Phenotyping—Lab Correlative Study #10 
In parallel to neoantigen identification and to help address questions 10-12 raised in 
Section 2.5, we will perform T cell receptor (TCR) sequencing of tumor-infiltrating 
lymphocytes (TIL) where pre-treatment and post-treatment biopsies are available. We 
hypothesize that expansion of specific T cell clones in TIL (exhibited by higher TCR 
clonality) will be associated with improved response to PD1 therapy.  Two methods of 
sequencing will be employed, depending on the availability of tissue type for a given 
subject.  In the first, TCR beta chain (TCRB) high throughput sequencing will be done on 
genomic DNA extracted and PCR amplified from fixed tumor samples (pre- and post- 
treatment) using the ImmunoSeq hsTCRB kit (Adaptive Biotechnologies), and sequenced 
on the Illumina MiSeq platform in collaboration with Dr. Edus Warren (FHCRC) and 
analyzed using ‘LymphoSeq’ software, or using similar technologies. 
In a second approach, where fresh biopsies are available, we will sequence TCRα and 
TCRβ genes in single T cells (sorted by flow cytometry) using the approach pioneered by 
Han et al [Han 2014] and now established in the Edus Warren Lab at FHCRC.  Using this 
technology, we will be amplifying functional genes characteristic of different T cell 
subsets, which can then be associated with specific T cell clones.  This information will 
be used to determine the T cell phenotype associated with clinically beneficial responses.  
PBMC samples will also be sequenced as a surrogate of TCR usage in the non-TIL T cell 
population, in order to help delineate tumor specific TCRs.  In subjects where vital 
correlations are observed, we will use the same single cell sorting and phenotyping 
technology to investigate the development of these responses in serial PBMC samples 
collected pre-treatment and at several time points post treatment. 

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31 
2.5.9 Kynurenine/Tryptophan (Kyn/Trp) Ratio 
Over expression of indoleamine 2,3-dioxygenase (IDO) results in increases in the 
Kyn/Trp ratio in blood and in the subsequent suppression of T-cell responses [Liu 2009]. 
IDO is expressed by some tumors, but probably more importantly, it is expressed by 
lymphocytes as a normal mechanism to dampen immune responses. Expression of IDO is 
one likely mechanism of anti-PD-1 failure. Kyn/Trp ratios will be analyzed at baseline, 
during treatment, and at end of treatment. 
2.5.10 Samples for CITN Repository 
Any samples (serum, plasma, PBMC, tissue) collected for correlative assays will be 
stored in the CITN Repository at the CITN Central Laboratory before use, as will 
residual samples after use. Ancillary studies may be proposed, approved by the relevant 
CITN Committee, and conducted by proposing investigators according to the CITN 
Manual of Operations Guidelines for Ancillary Studies. 
3. PATIENT SELECTION 
 
 
Eligibility Criteria 
In order to be eligible for participation in this trial, the patient must: 
3.1.1 Patients must have biopsy-proven metastatic MCC or locoregional MCC that has 
recurred following standard locoregional therapy with surgery and/or radiation therapy. 
3.1.2 Patients must have measurable disease per RECIST 1.1 assessed by  CT scan, or for skin 
lesions not measurable by CT scan, measurements may be performed with caliper or 
flexible ruler.   
Note: Stage IV no evidence of disease (NED) is excluded by this criterion. 
3.1.3 Be ≥18 years of age on day of signing informed consent 
Note: Because no dosing or AE data are currently available on the use of MK-3475 in 
patients <18 years of age, children are excluded from this study. 
3.1.4 Have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale (see Appendix A) 
3.1.5 Life expectancy of greater than 6 months 
3.1.6 Patients must have normal organ and marrow function (all screening labs should be 
performed within 14 days of treatment initiation) as defined below: 
System 
Laboratory value 
− 
leukocytes 
≥2,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 
− 
hemoglobin 
≥9 g/dL OR ≥5.6 mmol/L 

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32 
− 
serum total bilirubin 
≤1.5 X upper limit of normal (ULN) OR 
direct bilirubin ≤ ULN for patients with 
total bilirubin levels >1.5 X ULN 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN OR ≤5 X ULN 
for patients with liver metastases 
− 
serum creatinine 
≤2.5X ULN 
OR 
− 
Measured or calculateda creatinine 
clearance (CrCl) (Glomerular filtration 
rate [GFR] can also be used in place of 
creatinine or CrCl) 
≥30 mL/min for subject with creatinine 
levels >2.5 X institutional ULN 
 
 
 
 
− 
Thyroid Stimulating Hormone (TSH) 
 
 
Within Institutional Limits (ie:  Normal).  
If TSH is greater or less than institutional 
limits patients may participate if their T4 
is WNL.  Patients may be on a stable 
dose of replacement thyroid medication.  
Dose adjustments are allowed if needed.     
aCreatinine clearance should be calculated per institutional standard. 
 
3.1.7 Patients must provide tissue from an archival tumor sample or newly obtained core, 
punch or excisional biopsy of a tumor lesion if deemed relatively safe and technically 
feasible. 
Note: Newly obtained biopsy is preferable. 
3.1.8 Female patients of childbearing potential must have a negative urine or serum pregnancy 
within 72 hours before receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
Note:  The effects of MK-3475 on the developing human fetus are unknown.  For this 
reason and because anti-PD-1agents may be teratogenic, women of child-bearing 
potential must agree to use 2 methods of birth control, or be surgically sterile, or abstain 
from heterosexual activity beginning with the screening visit and for the duration of study 
participation, through 120 days beyond last dose of MK-3475 administration. Patients of 
childbearing potential are those who have not been surgically sterilized or have not been 
free from menses for >1 year. 
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study, she should inform her treating physician immediately.   
3.1.9 Men treated or enrolled on this protocol must agree to use 2 adequate methods of 
contraception starting with the screening visit, for the duration of study participation, and 
through 120 days after the last dose of MK-3475 administration.  
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 

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33 
 
Exclusion Criteria 
The patient must be excluded from participating in the trial if the patient: 
3.2.1 Has had prior systemic therapy for MCC 
Note: Prior systemic cytotoxic chemotherapy will be allowed if it was administered in the 
adjuvant setting (no clinically detectable MCC at the time) and treatment concluded more 
than 6 months prior to beginning study treatment. 
3.2.2 Is currently participating in or has participated in a study of an investigational systemic 
agent to treat MCC; or is using an investigational device within 4 weeks of the first dose 
of treatment 
Note: If patient received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention before starting therapy.  
Toxicity from surgery or associated interventions that has not recovered to ≤Grade 1 is 
allowed if it meets the inclusion requirements for laboratory parameters. 
3.2.3 Patients with locoregional disease that have not received appropriate standard 
locoregional therapy with surgery and/or radiation therapy 
3.2.4 Has had radiation therapy within 2 weeks of beginning study treatment 
3.2.5 Toxicity from prior radiation therapy has NOT resolved to grade 1 or less. 
3.2.6 Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
3.2.7 Has had a prior monoclonal antibody for treatment of MCC.  
3.2.8 Has had a prior monoclonal antibody for a non–cancer therapy indication within 4 weeks 
prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs 
due to agents administered more than 4 weeks earlier. 
3.2.9 Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy.  
3.2.10 Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. These patients should be excluded because of their poor prognosis and 
because they often develop progressive neurologic dysfunction that would confound the 
evaluation of neurologic and other AEs.  
Patients with previously treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging for at least 4 weeks prior to the first dose of 
trial treatment and any neurologic symptoms have returned to baseline), have no evidence 

NCI Protocol # CITN-09 
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34 
of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to 
trial treatment.   
 
3.2.11 Has a history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to MK-3475. 
3.2.12 Has an active autoimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. Patients with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule. Patients that require 
intermittent use of bronchodilators or local steroid injections would not be excluded from 
the study. The use of physiologic doses of corticosteroids may be approved after 
consultation with the Protocol PI and CITN.  Patients with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
3.2.13 Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the patient’s participation for 
the full duration of the trial, or is not in the best interest of the patient to participate, in the 
opinion of the treating investigator 
3.2.14 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
3.2.15 Has uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, interstitial lung disease, non-infectious pneumonitis, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements  
3.2.16 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of MK-3475 administration. 
Note: Pregnant women are excluded from this study because MK-3475 is an agent with 
the potential for teratogenic or abortifacient effects. Because of unknown but potential 
risks for AEs in nursing infants secondary to treatment of the mother with MK-3475, 
breastfeeding should be discontinued if the mother is treated with MK-3475.  
MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.   
Men and nonpregnant, non–breast-feeding women may be enrolled if they are willing to 
use 2 methods of birth control or are considered highly unlikely to conceive. Highly 
unlikely to conceive is defined as (1) surgically sterilized, or (2) postmenopausal (a 
woman who is ≥45 years of age and has not had menses for greater than 1 year will be 
considered postmenopausal), or (3) not heterosexually active for the duration of the 
study. The 2 birth control methods can be barrier method or a barrier method plus a 
hormonal method to prevent pregnancy. Subjects should start using birth control from the 

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35 
screening visit throughout the study period up to 120 days after the last dose of study 
therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, 
condom (by the partner), copper intrauterine device, sponge, or spermicide. Appropriate 
hormonal contraceptives will include any registered and marketed contraceptive agent 
that contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). 
Patients should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study, they must adhere to the contraception requirement (described 
above) for the duration of the study and during the follow-up period described above. If 
there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
Pregnancy: If a patient inadvertently becomes pregnant while on treatment with MK-
3475, the patient will immediately be removed from the study. The site will contact the 
patient at least monthly and document the patient’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported without delay 
and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow 
the outcome of the pregnancy and report the condition of the fetus or newborn. If a male 
patient impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported and followed as described in Section 7.7. 
It is unknown whether MK-3475 is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
3.2.17 Patient is Human Immunodeficiency Virus (HIV) positive. 
Note: Patients who are Human Immunodeficiency Virus (HIV) positive may participate 
IF they meet the following eligibility requirements: 
1. They must be stable on their anti-retroviral regimen, and they must be healthy 
from an HIV perspective.  
2. They must have a CD4 count of greater than 250 cells/mcL.  
3. They must not be receiving prophylactic therapy for an opportunistic 
infection. 
 
3.2.18 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
Note: A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb-
positive and HBcAb-negative) or a fully resolved acute hepatitis B infection is not an 
exclusion criterion.  

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36 
3.2.19 Has active non-infectious pneumonitis ≥ grade 2; or history of grade 3 non-infectious 
pneumonitis within the past 12 months; or any history of grade 4 non-infectious 
pneumonitis. 
3.2.20 History of other pulmonary disease such as emphysema or chronic obstructive pulmonary 
disease (COPD), (FEV1<60% of predicted for height and age). Pulmonary function tests 
(PFTs) are required in patients with prolonged smoking history or symptoms of 
respiratory dysfunction.  
3.2.21 Cardiovascular disease that meets one of the following: congestive heart failure (New 
York Heart Association Class III or IV), active angina pectoris, or recent myocardial 
infarction (within the last 6 months) 
3.2.22 Prior organ allograft or allogeneic transplantation, if the transplanted tissue is still in 
place 
3.2.23 Has had live vaccines within 30 days before the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, 
rabies, BCG, and typhoid vaccine. 
 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. REGISTRATION PROCEDURES 
 
 
Investigator (IVR), Non-Physician Investigator (NPIVR), and Associate Plus (AP) 
Registration with CTEP 
 
4.1.1 CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. 
 
To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity 
and Access Management (IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons 
with a registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate 
Plus (AP) (i.e., clinical site staff requiring write access to OPEN or RAVE, or acting as a primary 
site contact) must complete their annual registration using CTEP’s web-based Registration and 
Credential Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  Documentation requirements per 
registration type are outlined in the table below. 

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37 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, employment, 
license, and certification) 
 
 
 
HSP/GCP training (GCP training certificate must 
be dated within 3 years) 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and 
NPIVRs must list all clinical practice sites and IRBs covering their practice sites on the FDA 
Form 1572 in RCR to allow the following: 
• Added to a site roster 
• Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• Act as the site-protocol PI on the IRB approval 
 
NCI Person Registration must be completed using the CTEP’s Registration and 
Credential Repository (RCR) system. IVR, NPIVR, and AP will use their CTEP-IAM 
credentials to access RCR (https://ctepcore.nci.nih.gov/rcr) and to electronically sign 
and submit required registration documents.  
Additional information can be found on the CTEP website at < 
https://ctep.cancer.gov/investigatorResources/default.htm >.  For questions, please 
contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
4.1.2 CTEP IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application  required to be used by all registration types 
(IVR, NPIVR, AP, Associate (A) and Associate Basic (AB)). IAM provides a solution 
for CTEP Enterprise and CTSU applications with the primary goal of streamlining user 
provisioning. 
 
 

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38 
 Additional information can be found on the CTEP website at 
https://ctepcore.nci.nih.gov/iam/index.jsp 
For questions, please contact the CTEP Registration Help Desk by email at 
CTEPRegHelp@nih.gov. 
 
 
 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain Institutional Review 
Board (IRB) approval for this protocol and submit all required regulatory documents (including 
any protocol specific documents) to the CTSU Regulatory Office before they can be approved to 
enroll patients. Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled all regulatory 
criteria including but not limited to: an active Federal Wide Assurance (FWA) number, an active 
roster affiliation with the Lead Network or a participating organization, a valid IRB approval, 
and compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following criteria: 
• Active registration status 
• The IRB number of the site IRB of record listed on their Form FDA 1572 
• An active status on a participating roster at the registering site. 
 
 
4.2.1 Downloading Lead Protocol Organization Documents 
Site registration forms may be downloaded from the CITN-09 protocol page located on 
the CTSU Web site.  Permission to view and download this protocol is restricted and is 
based on person and site roster data housed in the CTSU RSS. To participate, the users 
must be associated with the Corresponding or Participating protocol organization in the 
RSS. 
 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password 
• Click on the Protocols tab in the upper left of your screen 
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand 
• Click on the CITN link to expand, followed by protocol #CITN-09 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided. 
   
4.2.2 Requirements for CITN-09 Site Registration: 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an 
IRB-signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance 

NCI Protocol # CITN-09 
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39 
Identification/IRB Certification/Declaration of Exemption Form, or combination is 
accepted ) 
 
4.2.3 Submitting Regulatory Documents 
 
Submit your IRB approval, model Informed Consent Form and other protocol-specific regulatory 
documentation to the CTSU Regulatory Office via the Regulatory Submission Portal, where they 
will be entered and tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area)  Regulatory Tab  
Regulatory Submission 
 
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU 
Regulatory Office immediately at 1-866-651-2878 in order to receive further instruction and 
support. 
 
 
4.2.4 Checking Site Registration Status 
Sites can verify their registration status on the members’ section of the CTSU Web site.   
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Regulatory tab.  
• Click on the Site Registration subtab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements outlined by the Lead Network (LPO). It 
does not reflect compliance with protocol requirements for individuals participating on 
the protocol or the enrolling investigator’s status with the NCI or their affiliated 
networks.  
 
 
Patient Registration 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network (OPEN).  
OPEN is a web-based registration system available to users on a 24/7 basis.   
All site staff will use OPEN to enroll patients to this study. It is integrated with the CTSU 
Enterprise System for regulatory and roster data and, upon enrollment, initializes the patient 
position in the Rave database. OPEN can be accessed at https://open.ctsu.org or from the OPEN 
tab on the CTSU members’ side of the website at https://www.ctsu.org.  

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40 
To access OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating organization 
roster. Registrars must hold a minimum of an AP registration type. Patient enrollment data entered by 
Registrars in OPEN will automatically transfer to the NCI’s clinical data management system, Medidata 
Rave. 
To assign an IVR or NPIVR as the treating, crediting, consenting, drug shipment (IVR only), or 
investigator receiving a transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval.   
Enrollment will be facilitated using the Slot-Reservation System in conjunction with the Registration 
system in the Oncology Patient Enrollment Network (OPEN). Prior to discussing protocol entry with the 
patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that a slot on the 
protocol is available to the patient. Once a slot-reservation confirmation is obtained, site staff may then 
proceed to enroll patients to this study. 
Enrollment will be facilitated using the Slot-Reservation System in conjunction with the 
Registration system in the Oncology Patient Enrollment Network (OPEN). Prior to discussing 
protocol entry with the patient, all site staff must use the CTSU OPEN Slot Reservation System 
to ensure that a slot on the protocol is available to the patient. Once a slot-reservation 
confirmation is obtained, site staff may then proceed to enroll patients to this study.  
Prior to accessing OPEN CITN member site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.  
• All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable).  
Access requirements for OPEN: 
• CITN member site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account. This is the same account (user id and password) used for the CTSU 
members’ web site.  
• To perform registrations, the site user must have been assigned the ‘Registrar’ role on the 
CITN roster.  
Note: The OPEN system will provide the site with a printable confirmation of registration 
information and treatment information. Please print this confirmation for your records. 
Further instructional information is provided on the OPEN tab of the CTSU members’ side of the 
CTSU website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
 
General Guidelines 
 
Following registration, patients should begin protocol treatment as soon as possible.*  Issues that 
would cause treatment delays should be discussed with the Principal Investigator.  If a patient 
does not receive protocol therapy following registration, the patient’s registration on the study 
may be canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 

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5. TREATMENT PLAN 
 
This is a multi-institution, CITN Cooperative trial of MK-3475 in patients with advanced MCC, 
who have not received prior systemic therapy for their disease. The trial is open-labeled and 
nonrandomized. Patients who have not received any previous systemic therapy for their disease 
will be treated with MK-3475, given every 3 weeks. 
ORR, PFS, and DOR will be monitored by CT scans at week 13 and then at 9-week intervals. At 
1 year, the scan frequency will be decreased to every 12 weeks. Responses and progression will 
be assessed by RECIST 1.1 criteria. OS will be chronicled and reported.  
Patients who appear to progress on the initial scan, occurring at week 13 of therapy, will be 
allowed to continue on therapy if otherwise stable, until a confirmatory scan is obtained at 
17 weeks. If the 17-week scan confirms progression, the study treatment will be discontinued 
and the patient will be followed for survival. Alternatively, MK-3475 treatment may be 
continued in the setting of progressive disease if the patient is otherwise clinically stable as 
defined by the following criteria: 
• Absence of clinical symptoms or signs indicating clinically significant disease 
progression 
• ECOG performance status ≤1 
• Absence of rapid disease progression or threat to vital organs or critical anatomical sites 
(e.g., spinal cord compression) requiring urgent alternative medical intervention  
Patients who appear to progress on any subsequent scan will be allowed to continue on therapy if 
otherwise stable, until a confirmatory scan is obtained 4 weeks later. If the scan repeated 4 weeks 
later confirms progression, the study treatment will be discontinued and the patient will be 
followed for survival, or alternatively, continue MK-3475 treatment, if patient is otherwise 
clinically stable as described above.  
Therapy after progression is at the discretion of the patient and primary physician. 
Patients with stable disease (SD) or partial response (PR) can be treated up to 2 years at patient 
and investigator discretion. Patients that achieve a complete response (CR) can discontinue 
treatment after 6 months of therapy provided that patient has had at least 2 cycles past validation 
of CR. Patients that recur off of therapy will be eligible for retreatment at patient and investigator 
discretion, provided they meet the criteria for retreatment and the trial is ongoing.  
Administration of MK-3475 will be stopped with documented disease progression warranting 
alternative systemic therapy, unacceptable AE(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the patient, patient withdraws 
consent, pregnancy of the patient, noncompliance with trial treatment or procedure requirements, 
or administrative reasons.  In patients with documented disease progression, treatment can 
continue until there is an increase in tumor burden of 25% or more following initial confirmation 
of progression. 

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42 
The primary objective is to determine the clinical efficacy of MK-3475 as the first systemic 
intervention for patients with advanced MCC. The primary endpoint will be ORR as measured 
by RECIST 1.1.  
The secondary objectives are to determine the clinical activity of MK-3475 as the first systemic 
intervention by determining PFS, DOR, and OS. The secondary endpoints will be PFS and DOR 
as measured by RECIST 1.1. PFS will be compared at 16 months to the historical PFS for 
patients treated with standard chemotherapy (5% PFS at 16 months). OS will be chronicled and 
reported.  
The exploratory objectives are to determine the immune correlates of the clinical activity of MK-
3475 (Section 1.3). 
The protocol will follow the standard Simon two-stage design. Stage 1 will enroll 9 patients and 
stage 2 will enroll 15 additional patients. The trial will be suspended and any further enrollment 
stopped if no responses are seen in the first stage. The protocol initially enrolled 9 patients in 
Stage 1, and enrolled an additional 15 patients in Stage 2, achieving enrollment of 24. Treatment 
was discontinued in 2 patients due to drug-related adverse events after receiving 1 dose of MK-
3475, and enrollment of an additional 2 patients was allowed per protocol, bringing the total 
enrollment to 26 patients.    
Protocol Amendment 4 increased the total number of patients from 26 to 50 to provide an 
expanded safety and efficacy profile.   
Patients who have confirmed progression of disease on MK-3475 therapy will stop study therapy 
but will continue to be followed for survival. Alternatively, MK-3475 treatment may continue in 
patients with confirmed progression, if they are otherwise clinically stable, as described above. 
Additional therapies will be chronicled and reported, but will not be considered part of this 
protocol. 
 
Agent Administration 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
5.1.1 CTEP IND Agent: MK-3475 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Study Calendar (Section 
10). Trial treatment may be administered up to 3 days before or after the scheduled Day 1 
of each cycle due to administrative reasons. 
 
MK-3475 treatment will be administered on an outpatient basis. 
 
MK-3475 will be administered as a 30-minute IV infusion (treatment cycle intervals may 
be increased due to toxicity as described in Section 6.1). Sites should make every effort 
to target infusion timing to be as close to 30 minutes as possible. A window of −5 

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43 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: −5 min/+10 min). 
Study Treatment 
Drug 
Dose Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
MK-3475 
2 mg/kg 
every 3 weeks 
IV infusion 
Day 1 of each cycle 
 
Note: Calculate the required dose amount (2 mg/kg) based on subject’s baseline  weight.  The dose 
amount should be recalculated if the subject's weight changes by more than 10% from the baseline 
weight measurement.  If the patient’s weight changes again by 10% or more (either increase or 
decrease) from the most recent weight used for dose calculation, recalculation of the dose is 
required. 
 
Protocol Section 8.1 provides specific instructions for MK-3475 dose preparation, and 
drug administration.  
Treatment with MK-3475 study drug may continue until one of the following events 
occurs: 
• Documented disease progression warranting alternative systemic therapy 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse experiences (see Section 6.1). 
• Need for >2 dose delays due to toxicity as per the dose modification guidelines 
described in Section 6 
• Patient withdraws consent 
• If in the opinion of the investigator and CITN Coordinating Center, a change or 
temporary or permanent discontinuation of therapy would be in the best interest of the 
patient.  
• Pregnancy in patient  
• Patient completes 24 months of treatment with MK-3475 
• In patients with documented disease progression, treatment with MK-3475 can 
continue until one of the above occurs or until there is an increase in tumor burden of 
25% or more following initial confirmation of progression.    
 
Note: Patients will receive up to 24 months of trial treatment calculated from the date of 
first dose. Subjects who stop MK-3475 after 24 months may be eligible for up to 1 year 
of additional trial treatment if they progress after stopping trial treatment provided they 
meet the requirements detailed in Section 5.10. 
The first radiologic assessment of tumor response status will be performed at Week 13 
(as consistent with standard of care). This assessment shall occur before drug 
administration scheduled for Week 13. However, if a patient is found to be progressing 
on MK-3475 at this initial scan, the patient can continue on MK-3475 if otherwise stable 
(see criteria below). A confirmatory scan will be performed at week 17, as 
immunomodulatory therapies may result in an early increase in lesion size due to influx 

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44 
of immune cells. This immune activation and infiltration reflects the therapeutic 
mechanism and, therefore, an early increase in tumor size in this context may herald a 
therapeutic response rather than progression.  
Thus, it is recommended that a patient with an unconfirmed early (<17 weeks) 
progression should continue therapy with MK-3475 waiting for confirmation of disease 
progression, but ONLY if the following criteria are met: 
• Absence of clinical signs and symptoms (including worsening of laboratory values) 
indicating clinically significant disease progression  
• ECOG performance status ≤ 1 
• Absence of rapid disease progression or threat to vital organs or 
critical anatomical sites (e.g., spinal cord compression) requiring urgent alternative 
medical intervention  
As depicted in the Overall Trial Schema, an MK-3475-treated patient whose progression 
is confirmed at the 17-week scan will discontinue therapy. Alternatively, if patient is 
otherwise clinically stable per criteria above, they may be continued on MK-3475 
treatment.  The next scan will be performed at Week 22 and then every 9 or 12 weeks per 
the Patient Visit Timeline.  MK-3475 will be discontinued if the tumor burden increases 
by 25% or more following initial confirmation of progression.  
In patients without progression and in patients with progression who continue treatment 
with MK-3475, disease radiologic monitoring should continue to be assessed at 9-week 
intervals through the first year of treatment and then at 12-week intervals throughout the 
duration of the study.  Section 5.4 describes criteria for discontinuing treatment.   
After a patient is discontinued from study therapy, an end of therapy visit should be 
performed as soon as possible following the decision to stop study drug treatment or in 
conjunction with last treatment visit if discontinuation of therapy is anticipated. A 
mandatory safety follow-up visit should be performed approximately 30 days after the 
last infusion of study medication. All AEs occurring within 30 days after the last dose of 
trial treatment will be recorded. 
All patients who discontinue treatment due to progression will be followed for at least 30 
days after their last dose of study drug or until initiation of a new anticancer treatment, 
whichever occurs first. After the safety follow-up visit, patients will be followed for 
survival via phone contact every 12 weeks.  
Patients who discontinue study therapy without documented disease progression will 
have a mandatory safety follow-up visit approximately 30 days after the last infusion of 
study drug, and should continue to be monitored for disease status by radiologic imaging  
according to the guidelines described in the Visit Requirements and Study Calendar for 
post-treatment follow-up. Imaging may be performed at the investigative site or locally; 
scans will be collected and RECIST 1.1 assessments performed. Collection of disease 
assessments will continue until progression, start of a new anticancer therapy, death or 
end of study, whichever occurs first. Thereafter, patients who progressed or started new 
treatment will be followed for survival via phone contact every 12 weeks ± 1 week. 

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AE reporting with begin with administration of first dose of study medication.  All AEs 
occurring within 30 days after the last dose of study treatment will be reported. Serious 
adverse events (SAE) related and unrelated to trial treatment will be collected for 90 days 
after the last dose of trial treatment or the start of new anticancer treatment, whichever 
comes first. Afterwards, only SAEs that are related to trial treatment will be reported. All 
SAE should be reported to the Sponsor via CTEP Adverse Event Reporting System 
(CTEP AERS). 
Patients who are discontinued from the study due to an unacceptable drug-related AE will 
be followed for resolution of the AE to Grade 0–1 or stabilization, and monitored for 
disease status by radiologic imaging until progression or initiation of a new therapy for 
their cancer, whichever occurs first.  
Patients in whom MK-3475 is stopped due to AE, can have the agent restarted 
(rechallenged) after resolution of the AE to Grade 1. If the same AE occurs at the same 
grade, MK-3475 will be discontinued.  
VISIT REQUIREMENTS (also refer to Study Calendars):  
 
Screening phase (pre-study; Day -28 to day 0): 
• Obtain informed consent 
• Record demographics 
• Obtain medical history 
• Tumor imaging  
• Tumor biopsies/archival tissue collection* 
 
*If sufficient archival tumor tissue (at least 0.5 × 0.5 × 0.5 cm) collected before MK-3475 
therapy is not available, a baseline biopsy (core biopsy, punch biopsy or excisional biopsy) will 
be obtained before enrolling in the study assuming this can be carried out safely. 
Screening phase (pre-study, Day -14 to day 0) 
• Record concomitant medications 
• Physical exam 
• Vital signs 
• Performance status 
• 12-lead electrocardiogram (EKG) 
• Pulmonary function testing (for patients with a history of pulmonary disease, prolonged 
smoking history, or symptoms of respiratory dysfunction). 
 
• Laboratory tests: 
o Urine or serum B-HCG in women* 
o Complete blood count (CBC) with differential 
o Comprehensive serum chemistry panel 
o Urinalysis 
o T3, FT4, and TSH 
 

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*For women of reproductive potential, a urine pregnancy test should be performed within 72 
hours before first dose of trial treatment. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test performed by the local study site laboratory will be required. 
Treatment Cycles (to be repeated every 3 weeks) 
 
Cycle 1 
Day 1 ± 3, prior to MK-3475 administration  
• AE evaluation 
• Physical examination 
• Vital signs, height and weight (height required only for first treatment visit) 
• Performance status 
• Laboratory tests: 
o Kyn/Trp ratio 
o IFN-γ ELISpot 
o Immunophenotyping 
o T cell gene expression and phenotyping 
o MCPyV antibody levels 
o Serum, plasma, and PBMC storage 
 
On Day 1 ± 3, MK-3475 is administered after above procedures completed. 
 
After MK-3475 infusion, a 12-lead EKG is performed within 30 minutes of end of infusion. 
Subsequent Cycles without Scheduled Tumor Imaging (every 3 weeks)* 
*See study Patient Visit Timeline and Study Calendar 
Day 1 ± 3, prior to MK-3475 administration: 
• Concomitant medications 
• Review of AEs 
• Physical examination (limited) 
• Vital signs and weight 
• Performance status 
• Laboratory tests: 
o CBC with differential 
o Comprehensive serum chemistry panel 
o Urinalysis* 
o T3, FT4, and TSH* 
• Optional tumor biopsy/tissue collection if safe and feasible (core biopsy, punch biopsy or 
excisional biopsy) in patients who have not achieved CR (either responding, stable or 
progressing lesions). 
 
*Urinalysis and thyroid function testing to be performed at Baseline, Cycle 6, and then every 6 
cycles after baseline. After baseline, this will correlate with visits when scans and correlative 
blood draws are not scheduled. 
On Day 1 ± 3, MK-3475 is administered after above procedures completed. 

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47 
Subsequent Cycles with Tumor Imaging Scheduled* 
*See Patient Visit Timeline and Study Calendar 
Day 1, within 7 days, before MK-3475 administration.  
• Tumor imaging [Frequency of imaging is every 9 weeks ± 3 days  (every 3rd cycle) for 
first year of treatment, and then every 12 weeks ± 7 days (every 4th cycle) during second 
year of treatment].  
 
Day 1 ± 3, prior to MK-3475 administration*: 
*Blood will be drawn for correlative studies during Year 1 of treatment; during Year 2, 
correlative blood draws are required only around time of confirmation of progressive disease or 
at time of discontinuation of study drug.  Safety labs (CBC and comprehensive serum chemistry) 
will occur with every cycle. 
• Concomitant medications 
• Review of AEs 
• Physical examination 
• Vital signs and weight 
• Performance status 
• 12-lead EKG* 
• Laboratory tests: 
o CBC with differential 
o Comprehensive serum chemistry panel 
o Kyn/Trp ratio 
o IFN-γ ELISpot 
o Immunophenotyping 
o T cell gene expression and phenotyping 
o MCPyV antibody levels 
o Serum, plasma, and PBMC storage 
• Optional tumor biopsy/tissue collection if safe and feasible (core biopsy, punch biopsy or 
excisional biopsy) in patients who have not achieved CR (either  responding, stable or 
progressing lesions). 
 
On Day 1 ± 3, MK-3475 is administered after above procedures completed. 
*In Cycle 8 (and Cycle 1), 12-lead EKG is performed within 30 minutes after end of MK-3475 
infusion. 
Confirmatory Tumor Imaging 
When tumor imaging is performed to confirm progressive disease (PD; refer to Patient Visit 
Timeline), the following laboratory tests should be performed. If not possible to schedule a blood 
draw around the time of confirmatory scan, blood for these laboratory tests will be collected at 
the end-of-therapy visit.  
o CBC with differential 
o Comprehensive serum chemistry panel 
o Kyn/Trp ratio 
o IFN-γ ELISpot 
o Immunophenotyping 

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48 
o T cell gene expression and phenotyping 
o MCPyV antibody levels 
o Serum, plasma, and PBMC storage 
o Optional tumor biopsy/tissue collection (core biopsy, punch biopsy or excisional 
biopsy) if PD is confirmed. 
 
End of Therapy  
• (The End of Therapy Visit is performed as soon as possible following the decision to stop 
study drug treatment or in conjunction with last treatment visit if discontinuation of 
therapy is anticipated). 
• Concomitant medications 
• Review of AEs 
• Physical exam 
• Vital signs and weight 
• 12-lead EKG 
• Performance status 
• Laboratory tests: 
o Urine or serum HCG in women 
o CBC with differential 
o Comprehensive serum chemistry panel 
• Laboratory tests (if not collected at time of determination of CR, PR, or disease 
progression): 
o Kyn/Trp ratio 
o INF-γ ELISpot 
o Immunophenotyping 
o T cell gene expression and phenotyping 
o MCPyV antibody levels 
o Serum, plasma, and PBMC storage 
• Tumor imaging (not required if scan was performed within prior 4 weeks). 
• Optional tumor biopsy/tissue collection if safe and feasible (core biopsy, punch biopsy or 
excisional biopsy), in patients who have not achieved CR (either responding, stable or 
progressing lesions) (Section 2.5.1). 
 

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Post-Treatment Follow-Up 
 
Post-Treatment Safety Follow-Up (30 Days Post Treatment ± 3 days). (This visit may be 
combined with End of Treatment Visit if decision to discontinue treatment is delayed). 
• Concomitant medications 
• Review of AEs  
o All AEs occurring within 30 days after the last dose of study treatment will be 
reported. Serious adverse events (SAE) related and unrelated to trial treatment will be 
collected for 90 days after the last dose of trial treatment or the start of new anticancer 
treatment, whichever comes first. Afterwards, only SAEs that are related to trial 
treatment will be reported. 
• Physical exam 
• Vital signs and weight 
• Performance status 
• Laboratory tests: 
o Complete blood count (CBC) with differential 
o Comprehensive serum chemistry panel 
o Urinalysis 
o T3, FT4, and TSH 
 
Post-Treatment Disease Assessments 
 
• Upon discontinuation of treatment in patients without documented progression, 
radiologic imaging for disease assessment will continue either at the investigative site or 
locally.  Imaging will be collected and evaluated per RECIST 1.1. 
 
• Year 1 Post-Treatment: Imaging will be performed Q 3 months (+/-14 days) or as 
clinically indicated for the first year post-completion of treatment. 
 
• Years 2 and 3 Post-Treatment: Imaging will be performed Q 6 months (± 1 month) or as 
clinically indicated during years 2 and 3 post-treatment. 
 
• If the study remains open, imaging will be performed annually or as clinically indicated 
once patient has completed 3 years of follow up for disease assessment. 
 
• Collection of standard of care disease assessments will continue until progression, start of 
a new anticancer therapy, death or end of study, whichever occurs first. 
 
Survival Follow-Up Phone Contacts (every 12 weeks ± 1 week) 
Begin survival follow-up phone contacts after discontinuing MK-3475 due to disease 
progression or start of a new anticancer therapy (initiate 12 weeks ± 1 week following the Post-
Treatment Safety Follow-Up Visit).  Survival follow-up will continue until death or the end of 
the study, whichever occurs first. 
5.1.2 Other Agent(s): N/A 
 

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Definition of Dose-Limiting Toxicity: N/A 
 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1 MK-3475 Concomitant Medication 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
CTEP.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician; however, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the Investigator, CTEP, and 
the patient. 
 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs. 
 
Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
− 
Anti-cancer systemic chemotherapy or biological therapy.  
− 
Immunotherapy not specified in this protocol. 
− 
Chemotherapy not specified in this protocol. 
− 
Investigational agents other than MK-3475. 
− 
Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with Protocol P.I and CITN. Any lesion treated with 
radiation can no longer be considered as a target lesion for evaluating MK-3475 
efficacy. 
− 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid 
(oral) vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
− 
Glucocorticoids for any purpose other than to modulate symptoms from an event of 
suspected immunologic etiology.  The use of physiologic doses of corticosteroids may be 

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51 
approved after consultation with the Protocol P.I.  
 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Patients may receive other 
medications that the investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
 
 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to 2 
years or until one of the following criteria applies: 
 
• 
Disease progression warranting alternative systemic therapy, 
 
• 
Intercurrent illness that prevents further administration of treatment, 
 
• 
Patient decides to withdraw from the study. 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
• 
In patients with documented disease progression, treatment with MK-3475 can 
continue until one of the above occurs or until there is an increase in tumor burden of 
25% or more following initial confirmation of progression.    
 
• 
Unacceptable adverse event(s), including: 
 
• 
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not 
respond to topical therapy and does not improve to Grade 1 severity within the re-
treatment period OR requires systemic treatment.  
 
• 
Grade 3 drug-related autoimmune or inflammatory event including uveitis, 
pneumonitis, diarrhea, colitis, neurologic adverse events, hypersensitivity 
reaction, or infusion reaction of any duration requires discontinuation. 
 
• 
Any Grade 3 or 4 drug-related laboratory imbalance or electrolyte abnormality,  
not associated with underlying organ pathology and that do not require treatment 
except for electrolyte replacements do not require treatment discontinuation, with 
the following exceptions with approval of the Principal Investigator: 
 
• 
Hypophysitis or pan-hypopituitarism any grade should discontinue treatment. 
 
• 
Grade 4 amylase or lipase abnormalities that are not associated with DM, 
associated liver or gall bladder inflammation clinical manifestations of 
pancreatitis and which decrease to <Grade 4 within 1 week of onset may stay 

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52 
on study.  
 
• 
Any drug-related liver function test (LFT) abnormality that meets the 
following criteria requires discontinuation: Grade 3 AST or ALT (>5 x ULN) 
and total bilirubin >3 x ULN. 
 
• 
Grade 3 drug-related thrombocytopenia >7 days or associated with bleeding 
requires discontinuation. 
 
• 
Any patient requiring systemic steroid or other immunosuppressive treatment.  
 
• 
For patients with skin-only toxicity, when symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks.  Discontinue 
MK-3475 if unable to reduce corticosteroid dose for irAEs to ≤10 mg. MK-3475 
treatment may be restarted and the dose modified as specified in the protocol. 
 
• 
Patients with peripheral thyroiditis and no other autoimmune/inflammatory event may 
be restarted after a short course of steroids on a stable replacement regimen. 
 
• 
Any dosing interruption lasting >12 weeks with the following exceptions: 
• 
Dosing interruptions >12 weeks that occur for non-drug-related reasons may 
be allowed if approved by the Principal Investigator.  Prior to re-initiating 
treatment in a subject with a dosing interruption lasting >12 weeks, the 
Principal Investigator must be consulted.  
• 
Tumor assessments should continue as per protocol even if dosing is 
interrupted. 
 
 
Duration of Follow Up 
 
Upon discontinuation of therapy in patients without documented disease progression, every 
effort should be made to continue monitoring patients’ disease status by radiologic imaging 
either at the investigative site or locally. Imaging will be collected and evaluated per RECIST 
1.1. 
• Year 1 Post-Treatment: Imaging will be performed Q 3 months (+/-14 days) or as 
clinically indicated for the first year post-completion of treatment. 
 
• Years 2 and 3 Post-Treatment: Imaging will be performed Q 6 months (± 1 month) or as 
clinically indicated during years 2 and 3 post-treatment. 
 
• If the study remains open, imaging will be performed annually once patient has 
completed 3 years of follow up for disease assessment. 
 
• Collection of standard of care disease assessments will continue until progression, start of 
a new anticancer therapy, death or end of study, whichever occurs first. 
 

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53 
Patients removed from protocol therapy for unacceptable AE(s) will be followed for resolution 
or stabilization of the AE or 1 year, whichever is longer, in addition to following for disease 
assessments. 
Disease assessments will be collected until (1) the start of new anticancer treatment, (2) 
documented disease progression, (3) death, or (4) the end of the study, whichever occurs first.    
After progression or start of a new anticancer treatment, patients will be followed for survival 
(Section 5.1.1). Time to death will be chronicled for all patients. 
 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the applicable criteria, including progressive 
disease, withdrawal, or inability to follow study protocol as listed in Section 5.4.  The reason for 
study removal and the date the patient was removed must be documented in the Case Report 
Form. 
 
5.6.1 Patient Replacement Strategy 
Patients that have received only 1 dose of MK-3475 will not be replaced unless therapy was 
stopped due to toxicity.  
 
Criteria to Resume Treatment 
 
For non-autoimmune or inflammatory events, patients may resume treatment with study drug 
when the drug-related AE(s) resolve to Grade ≤1 or baseline value, with the following 
exceptions: 
• Patients may resume treatment in the presence of Grade 2 fatigue.  
• Patients with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in 
the presence of Grade 2 AST/ALT OR total bilirubin. 
• Patients with combined Grade 2 AST/ALT AND total bilirubin values meeting study 
parameters outlined in Section 5.4 should have treatment permanently discontinued. 
• Non-drug-related toxicity including hepatic, pulmonary toxicity, diarrhea, or colitis, must 
have resolved to baseline before treatment is resumed. 
• Drug-related endocrinopathies (not including drug-related adrenal insufficiency or 
hypophysitis) adequately controlled with only physiologic hormone replacement may 
resume treatment after replacement correction and clinically stable regimen. 
If the criteria to resume treatment are met, the patient should restart treatment no sooner than the 
next scheduled time point per protocol.  However, if the treatment is delayed past the next 
scheduled time point per protocol, the treatment should resume at the earliest convenient point 
that is within the 12 week delay period.  
 
If treatment is delayed >12 weeks, the patient must be permanently discontinued from study 
therapy, except as specified in Section 5.4 (Duration of Therapy). 
 

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54 
 
Treatment Beyond Progression 
 
Immunotherapeutic agents such as MK-3475 may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
 
If radiologic imaging shows progressive disease (PD), tumor assessment will be repeated by the 
site approximately 4 weeks later in order to confirm PD with the option of continuing treatment 
per below while awaiting radiologic confirmation of progression.  If repeat imaging shows a 
reduction in the tumor burden compared to the initial scan demonstrating PD, treatment may be 
continued as per treatment calendar.  If repeat imaging confirms PD, patients will be 
discontinued from study therapy, if alternate therapy is needed.  Alternatively, patients who are 
otherwise clinically stable may be continued on MK-3475, per investigator discretion.   Even if 
the patient remains otherwise stable, MK-3475 treatment will be discontinued if tumor burden 
increases by 25% or more following initial confirmation of progression. 
 
In determining whether or not the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as non-target lesions.  The decision to continue study treatment 
after the first evidence of disease progression, and upon confirmation of PD, determined by 
radiologic imaging, is at the Investigator’s discretion based on the clinical status of the patient as 
described in the table below.   
 
Patients may receive study treatment while waiting for confirmation of PD and if continuing 
MK-3475 after confirmation of PD, if they are otherwise clinically stable as defined by the 
following criteria: 
 
• Absence of clinical symptoms or signs indicating disease clinically significant disease 
progression 
• ECOG performance status ≤ 1 
Absence of rapid disease progression or threat to vital organs or critical anatomical sites 
(e.g., spinal cord compression) requiring urgent alternative medical intervention 
 
 
 
Clinically Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st radiologic 
evidence of PD 
Repeat imaging 
at approximately 
4 weeks to 
confirm PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging 
at approximately 
4 weeks to 
confirm PD if 
possible 
Discontinue  
treatment 
Repeat scan 
No additional 
Discontinue 
No additional 
N/A 

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55 
confirms PD 
imaging required 
if treatment 
discontinued. If 
treatment 
continues, 
regularly 
scheduled 
imaging 
assessments 
continue every 9 
or 12 weeks 
treatment or 
continue 
treatment at the 
Investigator’s 
discretion 
imaging required 
Repeat scan 
shows SD, PR, 
or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 or 12 
weeks 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 9 or 
12weeks 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion 
Tumor imaging will be assessed first at week 13, then every 9 weeks (63±3 days) during the 
first year of treatment.  Subsequently, tumor imaging will be performed every 12 weeks (84 ±7 
days). 
 
 
Discontinuation of Treatment Following Complete Response   
 
Discontinuation of treatment may be considered for patients who have attained a confirmed 
complete response (CR) that have been treated for at least 24 weeks with MK-3475 and had at 
least two treatments with MK-3475 beyond the date when the initial CR was declared.   
 
 
Retreatment with MK-3475 of patients with recurrence 
Some patients may be eligible to receive MK-3475 in the Retreatment Period of this 
study if the study remains open and the patient meets the following conditions: 
 
• Patient stopped initial treatment with MK-3475 after attaining an investigator-
determined confirmed CR on MK-3475 therapy 
o Was treated for at least 24 weeks with MK-3475 before discontinuing therapy;   
o Received at least 2 treatments with MK-3475 beyond the date when the initial CR 
was declared; or 
• Patient with confirmed SD or PR completed 2 years of MK-3475 study treatment. 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with MK-3475 
• Did not receive any anticancer treatment since the last dose of MK-3475  

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56 
• Meets safety parameters in Eligibility/Exclusion Criteria outlined in Section 3.1 and 
3.2 
Note: Patients that relapse on MK-3475 and are eligible for retreatment are 
encouraged to be retreated, however, the final decision is up to the treating physician 
and the patient.  
Patients who restart treatment will be retreated at the same dose and frequency as when they last 
received MK-3475. 
 
 
Beginning and End of the Trial 
The study begins when the first patient signs the informed consent. The end of the study may be 
designated as the time point when all patients have discontinued the study or are a minimum of 
6 months post-completion of study medication administration. At this point, a database lock of 
the trial may occur to allow the analysis of the study data. (Prior to the final database lock at the 
end of the study, interim database locks may occur to allow interim analysis of study data). Any 
remaining patients may continue to receive study medication and be seen by the investigator per 
usual standard of care for this patient population. In addition, the investigator will be expected to 
monitor for and report any SAEs, or pregnancies, as detailed in Section 7. The patient is 
considered on study until such time that he/she meets any of the discontinuation criteria and 
written notification is given to the Protocol P.I./CITN. 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
 
MK-3475 Dose Modifications 
6.1.1 General MK-3475 Dose Modifications 
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities, non-hematological 
toxicity ≥Grade 3 including laboratory abnormalities, and severe or life-threatening AEs. 
The table below includes general guidelines for toxicities that are not listed in the AE-specific 
table (see section 6.1.2). 
 
 General Dose Modification Guidelines for Drug-Related Adverse Events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Hematological Toxicity 
 
1, 2, 3 
No 
N/A 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval by 
1 week  
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 

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57 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
• Grade 2 alopecia 
• Grade 2 fatigue 
 
For 
additional 
information 
regarding Adverse Events with 
a potential Immune-Etiology 
reference Section 6.1.2. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and schedule  
Clinical AE does 
not resolve within 
4 weeks:  May 
increase the 
dosing interval by 
1 week for each 
occurrence 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
3 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval by 
1 week for each 
occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
 
4 
Yes 
N/A 
N/A 
Subject must be 
discontinued 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued.  With Principal Investigator agreement, subjects with a laboratory 
adverse event still at Grade 2 after 12 weeks may continue treatment in the trial only if 
asymptomatic and controlled.  Patients who experience a recurrence of the same severe or life-
threatening event at the same grade or greater with re-challenge of MK-3475 should be 
discontinued from trial treatment. 
 
Additionally, immune-related adverse events (irAEs), defined as adverse events of unknown 
etiology, associated with drug exposure and consistent with an immune phenomenon, may be 
predicted based on the nature of the MK-3475 compound, its mechanism of action, and reported 
experience with immunotherapies that have a similar mechanism of action.  Special attention 
should be paid to AEs that may be suggestive of potential irAEs.  An irAE can occur shortly 
after the first dose or several months after the last dose of treatment.  All AEs of unknown 
etiology associated with drug exposure should be evaluated to determine if they are possibly 
immune-related.  If an irAE is suspected, efforts should be made to rule out neoplastic, 
infectious, metabolic, toxin or other etiologic causes prior to labeling an adverse event as an 
irAE. 
 
The table below includes guidelines for managing irAEs that are not listed in the AE-specific 
table (see section 6.1.2). 

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General Dose Modification Guidelines for Drug-Related Immune-Related Adverse Events 
irAE 
Withhold/Discontinue MK-
3475? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold MK-3475 
Discontinue if unable to reduce 
corticosteroid dose to < 10 mg 
per day prednisone equivalent 
within 12 weeks of toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 2 
mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 4 
weeks. 
 
6.1.2 AE-specific MK-3475 Dose Modifications and Supportive Care Guidelines  
 
The table below includes recommendations on the management of specific AEs and when to 
hold and/or discontinue MK-3475.  These guidelines are intended to be applied when the 
investigator determines the events to be treatment-related.  Note: if after the evaluation the event 
is determined not to be related, the investigator does not need to follow the treatment guidance. 
Therefore, these recommendations should be seen as guidelines and the treating physician should 
exercise individual clinical judgment based on the patient. 

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59 
 
Event(s) 
 
CTCAE 
v5.0 
Grade 
Management /  
Next Dose for MK-
3475 
Action / Supportive Care Guidelines  
Symptomsa 
Differential 
Diagnosis 
Colitis events 
• Bowel 
obstruction  
• Colitis  
• Colitis 
microscopic 
• Enterocolitis 
• Enterocolitis 
hemorrhagic  
• Gastrointestinal 
(GI) perforation 
• Necrotizing 
colitis 
 
 
Diarrhea 
 
All patients who 
experience diarrhea 
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. 
 
≤Grade 1 No change in dose 
• 
For diarrhea, treat symptomatically (loperamide, oral 
hydration, electrolyte substitution and ADA colitis diet).  
Endoscopy is recommended if symptoms persist. 
• 
Grade 1 diarrhea that persist for >1 week should be 
treated with the addition of oral diphenoxylate 
hydrochloride and atropine sulfate four times daily and 
budesonide 9 mg daily. 
Symptoms may include 
(but not limited to): 
• Abdominal pain, 
cramping and/or 
bloating 
• Blood and/or mucus 
in stool with or 
without fever 
• Constipation 
• Diarrhea 
• Ileus 
• Nausea and/or 
vomiting 
• Peritoneal signs 
consistent with 
bowel perforation 
• Rectal bleeding  
• With or without 
fever 
 
Patients with diarrhea 
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 
All attempts 
should be made to 
rule out other 
causes such as 
metastatic 
disease, bacterial 
or parasitic 
infection, viral 
gastroenteritis, or 
the first 
manifestation of 
an inflammatory 
bowel disease by 
examination for 
stool leukocytes, 
stool cultures, and 
a Clostridium 
difficile titer. 
Grade 2 
Hold until ≤Grade 
1.   
 
Resume at same 
dose level.  May 
increase dosing 
interval by 1 week 
if it takes more than 
4 weeks for 
toxicities to resolve. 
• 
GI consultation and endoscopy is recommended to 
confirm or rule out colitis for grade 2 diarrhea that 
persists >1 week or grade 1-2 diarrhea with rectal 
bleeding (additional guidelines for the treatment of 
persistent colitis are provided below).   
• 
Grade 2 diarrhea should be treated with the addition of 
oral diphenoxylate hydrochloride and atropine sulfate 
four times daily and budesonide 9 mg daily.  
• 
Grade 2 diarrhea with diffuse ulceration and bleeding 
seen on endoscopy may require oral steroids with 
prolonged taper and represent an increased risk for the 
development of bowel perforation. 
• 
When symptoms improve to grade 1 or less, steroid taper 
should be started and continued over no less than 4 
weeks. 
• 
In patients with Grade 2 enterocolitis, MK-3475 should 
be withheld and anti-diarrheal treatment should be 
started.  If symptoms are persistent for more than one 
week, systemic corticosteroids should be initiated (e.g., 
0.5 mg/kg/day of prednisone or equivalent).  When 
symptoms improve to Grade 1 or less, corticosteroid 
taper should be started and continued over at least 1 
month.   

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Event(s) 
 
CTCAE 
v5.0 
Grade 
Management /  
Next Dose for MK-
3475 
Action / Supportive Care Guidelines  
Symptomsa 
Differential 
Diagnosis 
Grade 3-4 Withhold MK-3475 
 
Discontinue if 
unable to reduce 
corticosteroid dose 
to <10 mg per day 
prednisone 
equivalent within 
12 weeks of toxicity 
• In patients with Grade 3 enterocolitis, MK-3475 will be 
permanently discontinued and treatment with systemic 
corticosteroids should be initiated at a dose of 1 to 2 
mg/kg/day of prednisone or equivalent.  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be 
started and continued over at least 1 month. 
 
For Grade 3-4 diarrhea (or Grade 2 diarrhea that persists after 
initial steroid treatment),  
• Rule out bowel perforation.  Imaging with plain films or 
computed tomography (CT) can be useful. 
• Consider consultation with gastroenterologist and 
confirmation biopsy with endoscopy. 
• Treat with intravenous (IV) steroids (methylprednisolone 
125 mg) followed by high-dose oral steroids (prednisone 1-
2 mg/kg once per day or dexamethasone 4 mg every 4 
hours).  When symptoms improve to grade 1 or less, steroid 
taper should be started and continued over no less than 4 
weeks.  Taper over 6-8 weeks in patients with diffuse and 
severe ulceration and/or bleeding. 
• If IV steroids followed by high-dose oral steroids does not 
reduce initial symptoms within 48-72 hours, consider 
treatment with infliximab at 5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom relief and initiate a 
prolonged steroid taper over 45-60 days. If symptoms 
worsen during steroid reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg followed 
by a more prolonged taper and administer infliximab.  
CAUTION: infliximab is contraindicated in patients with 
bowel perforation or sepsisb. 
• If symptoms persist despite the above treatment a surgical 
consult should be obtained. 
peritoneal signs and 
ileus).  In symptomatic 
patients, infectious 
etiologies should be 
ruled out, and if 
symptoms are persistent 
and/or severe, 
endoscopic evaluation 
should be considered. 

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Event(s) 
 
CTCAE 
v5.0 
Grade 
Management /  
Next Dose for MK-
3475 
Action / Supportive Care Guidelines  
Symptomsa 
Differential 
Diagnosis 
Endocrine events 
• Hyperthyroidism 
• Hypophysitis 
• Hypopituitarism  
• Hypothyroidism 
• Thyroid disorder  
• Thyroiditis 
 
Grade 1-2 No change in dose 
• Monitor thyroid function or other hormonal level tests and 
serum chemistries more frequently until returned to 
baseline values. 
 
Symptoms may include 
(but not limited to): 
• Abdominal pain 
• Abnormal thyroid 
function tests and/or 
serum chemistries 
(Thyroid-stimulating 
hormone increased 
[decreased], Free 
thyroxine increased, 
Tri-iodothyronine 
increased.)   
• Arrhythmiasc 
• Cold or heat 
intolerance 
• Fatigue  
• Fever 
• Headache 
• Hypotensionc 
• Loss of appetite 
• Mental status and/or 
behavior changes 
• Nausea and/or 
vomiting  
• Unusual bowel 
habits 
• Vision disturbances 
• Weakness 
All attempts 
should be made to 
rule out other 
causes such as 
brain metastases, 
sepsis, and/or 
infection.  An 
endocrinology 
consultation is 
recommended. 
Grade 3-4  
 
 
Hold/discontinue 
MK-3475. 
 
• Consider endocrine consultation. 
• Rule out infection and sepsis with appropriate cultures and 
imaging. 
• Treat with an initial dose of methylprednisolone 1-2 mg/kg 
IV followed by oral prednisone 1-2 mg/kg per day.  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.  
 
Endocrine events 
• Adrenal 
insufficiency 
• Hypophysitis 
• Pan-
hypopituitarism 
 
Grade 1-4  
 
Discontinue MK-
3475. 
• 
Thyroid hormone and/or steroid replacement therapy to 
manage adrenal insufficiency. 
• 
If Grade 1-2 hypophysitis is considered, pituitary gland 
imaging should be considered (magnetic resonance 
imaging [MRIs] with gadolinium and selective cuts of the 
pituitary can show enlargement or heterogeneity and 
confirm the diagnosis). 
• 
Grade 3-4 hypophysitis with clinically significant adrenal 
insufficiency and hypotension, dehydration, and 
electrolyte abnormalities (such as hyponatremia and 
hyperkalemia) constitutes adrenal crisis. Hospitalization 
and IV methylprednisolone should be initiated. 
Eye event 
• Uveitis 
Grade 1 
Discontinue MK-
3475 if symptoms 
persist despite 
treatment with 
topical 
immunosuppressive 
therapy  
• Evaluation by an ophthalmologist is strongly 
recommended. 
• Treat with topical steroids such as 1% prednisolone acetate 
suspension and iridocyclitics. 
 
 
Symptoms may include 
(but not limited to): 
• Blurred vision 
• Diffuse erythema 
and a prominent 
blush on the sclerae 
• Dryness of the eyes 
All attempts 
should be made to 
rule out other 
causes such as 
metastatic 
disease, infection, 
or other ocular 

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Event(s) 
 
CTCAE 
v5.0 
Grade 
Management /  
Next Dose for MK-
3475 
Action / Supportive Care Guidelines  
Symptomsa 
Differential 
Diagnosis 
Grade 2 
Discontinue MK-
3475 if symptoms 
persist despite 
treatment with 
topical 
immunosuppressive 
therapy and does 
not improve to 
Grade 1 within the 
re-treatment period 
OR requires 
systemic treatment. 
• Evaluation by an ophthalmologist is strongly 
recommended. 
• Treat with topical steroids such as 1% prednisolone acetate 
suspension and iridocyclitics. 
 
• Pain 
• Photophobia 
disease (e.g., 
glaucoma or 
cataracts). 
Grade 3-4 Discontinue MK-
3475. 
• Treat with systemic corticosteroids such as prednisone at a 
dose of 1-2 mg/kg per day.  When symptoms improve to 
≤Grade 1, steroid taper should be started and continued 
over no less than 4 weeks. 
Hepatic events 
• 
Hepatitis  
• 
Hepatitis, 
Autoimmune 
Grade 1-2 No change in dose 
• Monitor liver function tests more frequently until returned 
to baseline values. 
Symptoms may include 
(but not limited to): 
• 
Elevations in: 
o AST >2.5 
times ULN 
o ALT >2.5 
times ULN 
o Total bilirubin 
>1.5 X ULN 
• 
Fever 
• 
Malaise 
• 
Upper quadrant 
abdominal pain 
All attempts 
should be made to 
rule out other 
causes such as 
metastatic 
disease, 
progressive liver 
disease, viral 
hepatitis, 
alternative drug 
toxicity, 
infectious causes 
and/or myositis.   
 
 
 
 
 
 
 
Grade 3-4 Discontinue MK-
3475 when AST or 
ALT >5.0 times 
ULN and/or total 
bilirubin >3.0 times 
ULN. 
 
• Consider appropriate consultation and liver biopsy to 
establish etiology of hepatic injury, if necessary. 
• Treat with high-dose IV glucocorticosteroids for 24-48 
hours.  When symptoms improve to grade 1 or less, a 
steroid taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1-2 mg/kg should be started and continued 
over no less than 4 weeks.  
• If serum transaminase levels do not decrease 48 hours after 
initiation of systemic steroids, oral mycophenolate mofetil 
500 mg every 12 hours may be given.  Infliximab is not 
recommended due to its potential for hepatotoxicityb. 
• Several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is decreased 
 
 
 
 
 
. 

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63 
Event(s) 
 
CTCAE 
v5.0 
Grade 
Management /  
Next Dose for MK-
3475 
Action / Supportive Care Guidelines  
Symptomsa 
Differential 
Diagnosis 
Nausea 
 
≤Grade 1 No change in dose 
• Nausea should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration 
of prophylactic antiemetic therapy according to standard 
institutional practice.  Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 
 
 
Grade 2 
Hold until ≤Grade 
1.   
 
Resume at same 
dose level.  May 
increase dosing 
interval by 1 week 
if it takes more than 
4 weeks for 
toxicities to resolve. 
Grade 3 
Hold until <Grade 
2.  May increase 
dosing interval by 1 
week for each 
occurrence.  
 
Discontinue if 
toxicities do not 
resolve within 12 
weeks.  
Grade 4 
Off protocol 
therapy 
Neutropenia 
≤Grade 1 
No change in dose 
 
 
 
Grade 2 
No change in dose 
Grade 3 
No change in dose 
Grade 4 
Hold until resolves 
to ≤Grade 1.  May 
increase the dosing 
interval by 1 week. 
 
Discontinue if 
toxicities do not 
resolve within 12 
weeks. 
 
 
 

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Event(s) 
 
CTCAE 
v5.0 
Grade 
Management / 
Next Dose for MK-
3475 
Action / Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Pneumonitis events 
• Pneumonitis 
• Interstitial lung 
disease 
• Acute 
interstitial 
pneumonitis 
Grade 1 
 
MK-3475 may be 
continued with 
close monitoring. 
• Radiologic findings should be followed on serial imaging 
studies.  
• Consider pulmonary consultation and/or bronchoscopy if 
clinically indicated. 
Symptoms may include 
(but not limited to): 
• Abnormal breath 
sounds 
• Chest pain and/or 
tightnessc 
• Dyspneac 
• Dry cough 
• Fatigue 
• Fever 
• Hemoptysis 
All attempts 
should be made to 
rule out other 
causes such as 
metastatic 
disease, bacterial 
or viral infection. 
Grade 2 
Hold MK-3475  
To rule out other causes such as infection: 
• Consider pulmonary consultation with bronchoscopy and 
biopsy/bronchoalveolar lavage (BAL). 
• Consider pulmonary function tests. 
If the patient is determined to have study drug associated 
pneumonitis: 
• Treat with systemic corticosteroids at a dose of 1-2 
mg/kg/day prednisone or equivalent.  When symptoms 
improve to grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.   
• Treatment with MK-3475 may be resumed if the event 
improves to ≤Grade 1 within 12 weeks and corticosteroids 
have been reduced to the equivalent of methylprednisolone 
10 mg by mouth daily or less.  Repeat chest imaging 
monthly as clinically indicated. 
For Grade 2 pneumonitis that improves to ≤Grade 1 
within 12 weeks, the following rules should apply: 
• First episode of pneumonitis: May increase dosing interval 
by one week in subsequent cycles. 
• Second episode of pneumonitis: Discontinue MK-3475 if 
upon rechallenge the patient develops a second episode of 
≥Grade 2 pneumonitis. 

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Event(s) 
 
CTCAE 
v5.0 
Grade 
Management / 
Next Dose for MK-
3475 
Action / Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Grade 3-4 Discontinue MK-
3475. 
• Consider pulmonary function tests with pulmonary consult. 
• Bronchoscopy with biopsy and/or BAL is recommended. 
• Treat with IV steroids (methylprednisolone 125 mg). When 
symptoms improve to grade 1 or less, a high-dose oral 
steroid (prednisone 1-2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper should be started 
and continued over no less than 4 weeks. 
• If IV steroids followed by high-dose oral steroids does not 
reduce initial symptoms within 48-72 hours, treat with 
infliximab at 5 mg/kg once every 2 weeks.  Discontinue 
infliximab upon symptom relief and initiate a prolonged 
steroid taper over 45-60 days.  If symptoms worsen during 
steroid reduction, initiate a retapering of steroids starting at 
a higher dose of 80 or 100 mg followed by a more 
prolonged taper and administer infliximab. 
Renal events 
• Nephritis 
• Nephritis 
autoimmune 
• Renal failure 
• Renal failure, 
Acute 
Grade 1  
Consider 
withholding MK-
3475 if Grade 1 
does not improve 
with symptomatic 
treatment 
• Provide symptomatic treatment. 
Symptoms may include 
(but not limited to): 
• Fatigue  
• High blood pressure  
• Increased serum 
creatinine 
• Swelling 
All attempts 
should be made to 
rule out other 
causes such as 
obstructive 
uropathy, 
progression of 
disease, or injury 
to other 
chemotherapy 
agents.  A renal 
consultation is 
recommended. 
Grade 2  
Consider 
withholding MK-
3475.   
• Systemic corticosteroids may be indicated. 
Grade 3-4  Discontinue MK-
3475. 
 
• Renal consultation with consideration of ultrasound and/or 
biopsy as appropriate. 
• Treat with systemic corticosteroids at a dose of 1-2 mg/kg 
prednisone or equivalent once per day.   
• When symptoms improve to grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.   
• Discontinue MK-3475 if unable to reduce corticosteroid 
dose for irAEs to ≤10 mg.    
• MK-3475 treatment may be restarted and the dose 
modified as specified in the protocol. 

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Event(s) 
 
CTCAE 
v5.0 
Grade 
Management / 
Next Dose for MK-
3475 
Action / Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Skin events 
• Dermatitis 
exfoliative 
• Erythema 
multiforme 
• Stevens-Johnson 
syndrome 
• Toxic epidermal 
necrolysis 
 
If they are 
considered to be 
immune related, 
≥Grade 3 or result in 
dose modification or 
discontinuation:   
• 
Pruritus 
• 
Rash 
• 
Rash 
generalized 
• 
Rash maculo-
papular 
• 
Vitiligo 
Grade 1-2 No change in dose 
• Symptomatic treatment should be given such as topical 
glucocorticosteroids (e.g., betamethasone 0.1% cream or 
hydrocortisone 1%) or urea-containing creams in 
combination with oral antipruritics (e.g., diphenhydramine 
HCl or hydroxyzine HCl).  
• Treatment with oral steroids is at investigator discretion for 
grade 2 events. 
 
All attempts 
should be made to 
rule out other 
causes such as 
metastatic 
disease, infection, 
or allergic 
dermatitis. 
Grade 3 
Hold MK-3475. 
 
• Consider dermatology consultation and biopsy for 
confirmation of diagnosis. 
• Treatment with oral steroids is recommended, starting with 
1 mg/kg prednisone or equivalent once per day or 
dexamethasone 4 mg four times orally daily.  When 
symptoms improve to grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks. 
Grade 4 
Permanently 
discontinue MK-
3475. 
 
• Dermatology consultation and consideration of biopsy and 
clinical dermatology photograph. 
• Initiate steroids at 1-2 mg/kg prednisone or equivalent.  
When symptoms improve to grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
Thrombocytopenia 
≤Grade 1 
No change in dose 
 
 
 
Grade 2 
No change in dose 
 
Grade 3 
No change in dose 
• Grade 3 drug-related thrombocytopenia >7 days or 
associated with bleeding requires discontinuation. 
Grade 4 
Hold MK-3475 
until resolves to 
≤Grade 1.  May 
increase the dosing 
interval by 1 week. 
 
• 
Grade 4 drug-related thrombocytopenia >7 days or 
associated with bleeding requires discontinuation. 

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67 
Event(s) 
 
CTCAE 
v5.0 
Grade 
Management / 
Next Dose for MK-
3475 
Action / Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Vomiting 
≤Grade 1 
No change in dose 
• Vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration 
of prophylactic antiemetic therapy according to standard 
institutional practice.  Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 
 
 
Grade 2 
Hold until ≤Grade 
1.  Resume at same 
dose level.  May 
increase dosing 
interval by 1 week 
if it takes more than 
4 weeks for 
toxicities to resolve.  
Grade 3 
Hold until <Grade 
2.  May increase 
dosing interval by 1 
week for each 
occurrence. 
 
Discontinue if 
toxicities do not 
resolve within 12 
weeks. 
Grade 4 
Off protocol therapy 
 
 
 

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68 
Event(s) 
 
CTCAE 
v5.0 
Grade 
Management / 
Next Dose for MK-
3475 
Action / Supportive Care Guidelines 
Symptomsa 
Differential 
Diagnosis 
Other events 
• Autoimmune 
neuropathy 
• Demyelinating 
polyneuropathy 
• Guillain-Barre 
• Myasthenia 
gravis-like 
syndrome 
• Non-infectious 
myocarditis 
• Non-infectious 
pericarditis 
• Pancreatitis 
• Rapid onset of 
grade 3 fatigue in 
the absence of 
disease 
progression 
Grade 1  
Consider 
withholding MK-
3475 for Grade 1 
that does not 
improve with 
symptomatic 
treatment. 
• Provide symptomatic treatment. 
 
All attempts 
should be made to 
rule out other 
causes.  
Therapeutic 
specialists should 
be consulted as 
appropriate. 
Grade 2  
Consider 
withholding MK-
3475. 
• Systemic corticosteroids may be indicated. 
• Consider biopsy for confirmation of diagnosis. 
Grade 3-4 Discontinue MK-
3475. 
• Treat with systemic corticosteroids at a dose of 1-2 mg/kg 
prednisone or equivalent once per day.  
• When symptoms improve to grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks.   
• Discontinue MK-3475 if unable to reduce corticosteroid 
dose for irAEs to ≤10 mg.    
• MK-3475 treatment may be restarted and the dose 
modified as specified in the protocol. 
 
a The signs and symptoms may be associated with any of the diagnoses in the associated “Event(s)” column.   
b Janssen Biotech, Inc.: REMICADE (Infliximab) prescribing information revised September 2011.  
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo 
c If symptoms indicate possible new or worsening cardiac abnormalities, additional testing and/or a cardiology consultation should be considered

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69 
6.1.3 Treatment Guidelines for Infusion Reactions  
 
Acute infusion reactions (which can include cytokine release syndrome, angioedema, or 
anaphylaxis) are different from allergic/hypersensitive reactions, although some of the 
manifestations are common to both AEs.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of infusion.  
 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug fever); 
Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue 
(asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); 
Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; 
Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria (hives, welts, 
wheals); Vomiting. 
 
The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475. 
 
Treatment Guidelines for Infusion Reactions 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated 
for ≤24 hours 
 
Stop Infusion and Monitor Symptoms. 
Additional supportive care, as per institutional 
guidelines.  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).  Please 
note: prior to restarting the infusion, confirm 
that the 4 hour room temperature stability from 
the time of the IV bag preparation will not be 
exceeded.  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 upon 
rechallenge despite adequate premedication 
should be permanently discontinued from 
further trial treatment administration. 
 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
MK-3475 with: 
 
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg PO 
(or equivalent dose of antipyretic). 

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70 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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 and Monitor Symptoms. 
Subject is permanently discontinued from 
further trial treatment administration. 
Dexamethasone should be administered at a 
dose of at least 24 mg per day (8 mg every 8 
hours PO or IV) for up to three days. 
The dexamethasone dose will then be reduced 
step-wise over up to four days. 
 
Additional supportive care, as per institutional 
guidelines.  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 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 
Delayed Visits for Reasons Other Than Toxicity 
A schedule for return visits should be established at the first visit. If a participant misses a 
treatment, the missed treatment will be administered as soon as possible, so that the subsequent 
treatments are given in the appropriate intervals. Treatment may be continued for an additional 
time period, if needed. Participants who are treated outside of the established schedule should 
return to the original schedule as soon as possible. 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
AE monitoring and reporting is a routine part of every clinical trial. The following list of AEs 
(Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the 
event requires expedited reporting via the CTEP Adverse Event Reporting System (CTEP-
AERS) in addition to routine reporting. 
 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential AE associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset of AEs, the Specific Protocol 
Exceptions to Expedited Reporting (SPEER), appears in a separate column and is identified with 

NCI Protocol # CITN-09 
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71 
bold and italicized text. The SPEER is a list of events that are protocol-specific exceptions to 
expedited reporting to NCI via CTEP-AERS (except as noted below). Refer to the CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm for further clarification.  
Note: The highest grade currently reported is noted in parentheses next to the AE in the SPEER. 
Report ONLY AEs higher than this grade expeditiously via CTEP-AERS. 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. 
7.1.1 CAEPRs for CTEP IND Agent(s): 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, NSC 776864). 
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. 
Version 2.4, March 16, 20181 
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 
 
  
 
Lymph node pain2 
 
  
 
Thrombotic thrombocytopenic 
purpura2 
 
  
CARDIAC DISORDERS 
  
 
 
Myocarditis2 
  

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72 
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%) 
 
 
 
 
Pericarditis2 
  
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypophysitis2 
 
  
 
Hypopituitarism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
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 
 
  
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 
  
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation)2 
 
  
 
Immune system disorders – Other 
(sarcoidosis)2 
 
  
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  

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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%) 
 
 
 
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 
 
  
 
 
Metabolic 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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74 
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 (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 email. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
75 
2 Immune-mediate 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. 
3 Acute graft-versus-host disease has been observed in patients treated with MK-3475 
(pembrolizumab) who received hematopoietic stem cell transplants. 
4 Infection 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 

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RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and 
urinary disorders - Other (hydronephrosis); Nephrotic syndrome; 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. 
 
Adverse Event Characteristics 
• CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting beginning April 1, 2018. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
• For expedited reporting purposes only:  
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in 
the SPEER column, Section 7.1.1) should be reported through CTEP-AERS only 
if the grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
• Attribution of the AE: 
- Definite – The AE is clearly related to the study treatment. 
- Probable – The AE is likely related to the study treatment. 
- Possible – The AE may be related to the study treatment. 
- Unlikely – The AE is doubtfully related to the study treatment. 
- Unrelated – The AE is clearly NOT related to the study treatment. 

NCI Protocol # CITN-09 
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77 
 
Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
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. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization, the local treating physician, and the 
Reporter and Submitter.  CTEP-AERS provides a copy feature for other e-mail recipients.  
 
The Coordinating Center of the Corresponding Organization is responsible for submitting 
to the CTSU documentation of AEs that they deem reportable for posting on the CTSU 
protocol web page and inclusion on the CTSU bi-monthly broadcast. 
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease Progression” 
under 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.  
 
 
Pregnancy loss 
 
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. 

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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. 
 

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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 CTEP-
AERSwithin 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 reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For 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 
 
7.3.4 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions: N/A 
mechanism (Section 7.4): 
 

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Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
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.  AEs are reported in a routine manner at scheduled times 
during the trial using Medidata Rave.  For this trial the [form name] is used for routine AE 
reporting in Rave. 
 
 
Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 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 AE 
reporting unless otherwise specified. 
 
7.7 
Reporting of Pregnancy and Lactation to the Sponsor 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them) that occurs during the trial or within 120 days of completing the trial, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier.  All subjects who become pregnant must be followed to the completion/termination of 
the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must 

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be reported as serious events (Important Medical Events).  If the pregnancy continues to term, 
the outcome (health of infant) must also be reported. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the AEs and potential risks associated with the investigational agent administered in this 
study can be found in Section 7.1. 
 
CTEP IND Agent 
8.1.1 MK-3475 (SCH 900475) (NSC 776864) 
Other Names: SCH 900475 
 
Classification: Anti-PD-1 MAb 
 
Molecular Weight: 148.9-149.5 KDa 
 
CAS Number: 1374853-91-4 
 
Mode of Action: The programmed cell death 1 (PD-1) receptor is an inhibitory receptor expressed 
by T cells.  When bound to either of its ligands, PD-L1 or PD-L2, activated PD-1 negatively 
regulates T-cell activation and effector function.  The pathway may be engaged by tumor cells to 
suppress immune control.  MK-3475 blocks the negative immune regulatory signaling by binding 
to the PD-1 receptor, inhibiting the interaction between PD-1 and its ligands. 
 
Description: MK-3475 is a humanized MAb of the IgG4/kappa isotype. 
 
How Supplied: MK-3475 is supplied by Merck & Co., Inc. and distributed by the Pharmaceutical 
Management Branch, CTEP/DCTD/NCI as single-use 50 mg vials containing a sterile, non-
pyrogenic white to off-white lyophilized powder formulated in 10mM histidine buffer, pH 5.2-5.8, 
containing 7% sucrose and 0.02% polysorbate 80. 
 
Preparation: Allow the required number of MK-3475 vials to equilibrate to room temperature.  
Reconstitute the lyophilized powder by adding 2.3 mL of Sterile Water for Injection (SWFI) to the 
vial to yield 2.4 mL of solution containing 25 mg/mL of MK-3475.  The vial contains an excess 
fill of 10 mg (0.4 mL) to ensure recovery of 50 mg (2 mL) per vial.  Add SWFI along the walls of 
the vial to avoid foaming.  Swirl the vial, do not shake.  Discard vial if extraneous particulate matter 
other than translucent to white proteinaceous particles is observed.  Do not use if discolored.  To 
prepare the final solution for IV administration add the dose volume of MK-3475 to an infusion bag 
containing 0.9% Sodium Chloride Injection, USP and gently invert the bag 10-15 times to mix the 
solution.  The final concentration must be between 1 mg/mL to 10 mg/mL. 
 
Compatible IV bag materials: PVC plasticized with DEHP, non-PVC (polyolefin), EVA, 
or PE lined polyolefin 
 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze. If a storage temperature 

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excursion is identified, promptly return 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: Stability testing of the intact vials is on-going. 
 
Administer prepared solutions immediately after preparation.  If not administered immediately, 
prepared solutions may be stored refrigerated for up to 20 hours.  MK-3475 solutions may be stored 
at room temperature for a cumulative time of up to 4 hours.  This includes room temperature storage 
of reconstituted solution in vials, room temperature storage of admixture solutions in the IV bags, and 
the duration of infusion. 
 
Route of Administration: IV infusion only.  Do not administer as an IV push or bolus injection. 
 
Method of Administration: 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. 
 
Compatible infusion set materials: PVC plasticized with DEHP or DEHT, PVC and tri-(2-
ethylhexyl) trimellitate, polyethylene lined PVC, polyurethane, or polybutadiene 
 
Patient Care Implications: Refer to the protocol for information on evaluation and management 
of potential immune-related adverse events. 
 
Dose Calculation:  Calculate the required dose amount based on dose level and subject weight.  
The dose amount should be recalculated if the subject's weight changes by more than 10% from 
the baseline weight measurement. If the patient’s weight changes again by 10% or more (either 
increase or decrease) from the most recent weight used for dose calculation, recalculation of the 
dose is required.  
 
Availability: MK-3475 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
MK-3475 is provided to the NCI under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI (see Section 12.3). 
 
 
Agent Ordering and Agent Accountability 
 
8.2.1 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 

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are several participating investigators at one institution, CTEP-supplied investigational 
agents for the study should be ordered under the name of one lead participating 
investigator at that institution. 
   
8.2.2 Agent Inventory Records –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. 
8.2.3 Investigator Brochure Availability - The current version of the 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,  a 
“current” password and active person registration status.  Questions about IB access may 
be directed to the PMB IB coordinator via email.  
8.2.4 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/ 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov 
PMB email:  PMBAfterHours@mail.nih.gov 
IB Coordinator: 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) 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
The study calendars and lab manual describe blood draws for safety labs, research labs, and the 
CITN Central Laboratory Biorepository. In the interest of patient safety, we are including a 
provision to draw less blood if patients are anemic. A CBC will be performed as part of the 
safety labs each time research labs and biorepository blood needs to be drawn (safety labs drawn 

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for screening will used for this purpose prior to the first blood draws for research and the 
biorepository). The results of the CBC will be reviewed and the following blood volumes will be 
drawn based upon the patient’s hemoglobin level: 
• For a hemoglobin over 10.0 g/dL, draw the full volume of blood for safety labs, research 
labs, and biorepository. The biorepository volume of 10 mL will be used for cells. 
• For a hemoglobin between 9.0 and 10.0 g/dL, draw the full volume of blood for safety 
labs, decrease blood volume drawn for yellow top tubes (from 130  mL to 110 mL(this 
decrease eliminates blood draws for the biorepository). Draw remaining research labs. 
• For a hemoglobin less than 9.0 g/dL, draw the full volume of blood for safety labs, 
MCPyV antibody levels (10 ml or 5 ml red top), immunophenotyping (10 ml green top),   
and T cell functioning/phenotyping (10 ml yellow top).Eliminate other research labs 
including blood draw for biorepository. 
 
Biomarker Studies  
See Laboratory Correlative Studies, Section 9.2 
 
Laboratory Correlative Studies 
Hypotheses, rationale and literature citations are provided in Section 2.5 for the 
ancillary/exploratory immune correlative studies in this protocol. 
9.2.1 Evaluation of Tumor Biopsies for Immune Cell Infiltrate, Merkel Cell Polyomavirus, 
and mRNA expression—Laboratory Correlative Studies#1 and #2  
9.2.1.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor 
obtained before MK-3475 will be identified by the clinical site at the relevant 
pathology laboratories where they were processed and stored. Alternatively, 
patients will undergo a baseline biopsy (core, punch or excisional) as part of 
this protocol. In patients who have not achieved CR (either responding, stable 
or progressing lesions) a biopsy sample of a tumor may be obtained if feasible 
and safe (core, punch or excisional biopsy).  This biopsy is highly preferred, 
but optional. The biopsies will be analyzed as outlined above. All studies 
indicated in Section 2.5.1 may be carried out on the archival tissue or baseline 
biopsies as well as biopsies collected from responding, stable or progressing 
lesions. 
9.2.1.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by 
fax and phone by the clinical site from the relevant pathology laboratory by 
providing the patient’s name, consent form, and date of collection. If patients 
undergo biopsy as part of this protocol, tissue will be placed in formalin for 
overnight shipping to the CITN Central Laboratory. 
9.2.1.3 
Shipping of Specimen(s) 
The clinical site will arrange for the formalin-fixed, paraffin-embedded 
archival tumor blocks to be shipped at ambient temperature to the CITN 
Central Laboratory. For biopsies done as part of this protocol, tissue in 

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formalin will be shipped overnight at ambient temperature to the CITN 
Central Laboratory. Clinical sites will utilize a web-based specimen system 
(BSI-Web) to communicate with the CITN Central Laboratory. All samples 
will then be delivered to FHCRC Core/Habecker Laboratory. 
Following sectioning at the CITN Central Lab, unstained slides will be 
shipped by CITN Central Laboratory to Merck Research Laboratories in Palo 
Alto, CA, to Merck-designated CRO, or to PhenoPath, Seattle, WA. DNA 
extracted from the archival material will be provided to Dr. Meei-Li Huang 
clinical virology laboratory at FHCRC for DNA PCR analysis. 
9.2.1.4 
Site(s) Performing Correlative Study 
The majority of the IHC studies will be performed at the FHCRC 
Core/Habecker Laboratory with oversight by Dr. Paul Nghiem’s laboratory or 
at PhenoPath in Seattle, WA. Pre- and post-treatment levels of CD8+ T-cell 
tumor infiltrates will be assessed using criteria defined in Paulson, et al 
[Paulson 2011]. MCPyV protein expression in tumor tissue will also be 
assessed by IHC. 
The DNA-PCR assay will be performed by Dr. Meei-Li Huang in a clinical 
grade virology laboratory (Vaccine and Infectious Disease Division at 
FHCRC). 
PD-1 and PD-L1 expression will be tested by multiparametric IHC at Merck 
Research Laboratories in Palo Alto, CA, and PD-1 expression will also be 
tested with chromogenic IHC at a Merck-designated CRO. The 
multiparametric studies performed by Merck Research Laboratories will allow 
simultaneous determination of subcellular localization and identity of 
tumor/inflammatory cell types expressing PD-L1. When feasible, samples will 
also be assessed by Dr. Janis Taube at Johns Hopkins using multi-spectral 
immunofluorescence as detailed in the NEJM manuscript [Nghiem 2016]. The 
option will be left open to subsequently assess further analytes by IHC at 
PhenoPath or other collaborators based on mutual agreement with the 
investigators/CITN and Merck.  
mRNA expression (Nanostring) will be performed at Merck Research 
Laboratories in Palo Alto using unstained tissue slide material or may be 
performed at NanoString Technologies in Seattle, WA, pending mutual 
agreement on feasibility and logistics between NanoString Technologies & 
Investigators/CITN. 
9.2.2 Merkel Cell Polyomavirus–Specific Cellular Immune Responses—Laboratory 
Correlative Studies #3–#5 
9.2.2.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects just before, 
during, and at end of treatment. These blood draws will typically be carried 
out on the same visit as imaging scans. 

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9.2.2.2 
Handling of Specimens(s) 
Yellow-top tubes (for subsequent PBMC isolation) will be shipped on day of 
blood draw for overnight delivery to the CITN Central Laboratory. 
9.2.2.3 
Shipping of Specimen(s) 
Yellow-top tubes will be shipped overnight at ambient temperature to the 
CITN Central Laboratory. Clinical sites will utilize a web-based specimen 
system (BSI-Web) to communicate with the CITN Central Laboratory. The 
CITN Central Laboratory will coordinate the shipment of study samples for 
FACS-based sorting and T cell activation to the Nghiem and McElrath Labs, 
and samples for mRNA expression to Merck Research Laboratories in Palo 
Alto, pending mutual agreement on feasibility and logistics between Merck & 
Investigators/CITN.  
9.2.2.4 
Site(s) Performing Correlative Study 
Merkel cell polyomavirus–specific cellular immune responses will be assessed 
at the UW at the laboratory of Dr. Paul Nghiem and the CITN Central 
Laboratory. ICS analyses will be performed by the McElrath Lab at FHCRC. 
mRNA expression (Nanostring) will be performed at Merck Research 
Laboratories in Palo Alto, pending mutual agreement on feasibility and 
logistics between Merck & Investigators/CITN. 
9.2.3 Merkel Cell Polyomavirus–Specific Antibody Responses—Laboratory Correlative 
Study #6 
9.2.3.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects just before, 
during, and at end of treatment. These blood draws will typically be carried 
out on the same visit as imaging scans. 
9.2.3.2 
Handling of Specimens(s) 
Serum specimens will be processed and frozen at the clinical collection site 
for batch shipment to the CITN Central Laboratory. 
9.2.3.3 
Shipping of Specimen(s) 
Serum samples will be batch shipped overnight on dry ice to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-
Web) to communicate with the CITN Central Laboratory. The CITN Central 
Laboratory will coordinate the shipment of serum samples to the UW 
Department of Laboratory Medicine. 
9.2.3.4 
Site(s) Performing Correlative Study 
Merkel cell polyomavirus–specific antibody responses will be assessed by 
Luminex by the UW Laboratory Medicine under the supervision of Dr. Mark 
Wener. 

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9.2.4 Quantification of PBMC and T-cell Subsets—Laboratory Correlative Study #7 
9.2.4.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects just before, 
during, and at end of treatment. These blood draws will typically be carried 
out on the same visit as imaging scans. 
9.2.4.2 
Handling of Specimens(s) 
Blood Samples will be collected at room temperature and shipped ambient to 
the CITN Central Laboratory the same day as the blood draw, so that the 
sample is received at the central laboratory within 24 hours of blood draw. 
9.2.4.3 
Shipping of Specimen(s) 
Green-top tubes will be shipped at ambient temperature to the CITN Central 
Laboratory. Clinical sites will utilize a web-based specimen system (BSI-
Web) to communicate with the CITN Central Laboratory.  
9.2.4.4 
Site(s) Performing Correlative Study 
 Quantification of PBMC and T-cell subsets will be performed under the 
direction of Dr. Morishima at the CITN Central Laboratory. 
9.2.5 Whole-Exome Sequencing and RNA Sequencing—Laboratory Correlative Study #8 
9.2.5.1 
Collection of Specimen(s) 
Testing will be performed on matched tumor collected at baseline and 
peripheral blood samples. 
9.2.5.2 
Handling of Specimen(s) 
Blood samples will be collected at room temperature and shipped ambient to 
the CITN Central Laboratory the same day as the blood draw, so that the 
sample is received at the CITN Central Laboratory within 24 hours of blood 
draw.  
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor 
obtained before MK-3475 treatment will be obtained as described in 9.2.1. If 
sufficient archival material for performance of WES and RNA sequencing is 
not available, additional archival material may be requested from the site. 
9.2.5.3 
Shipping of Specimen(s) 
Blood tubes will be shipped at ambient temperature to the CITN Central 
Laboratory.  
The clinical site will arrange for the formalin-fixed, paraffin-embedded 
archival tumor blocks to be shipped at ambient temperature to the CITN 
Central Laboratory. For biopsies done as part of this protocol, tissue in 
formalin will be shipped overnight at ambient temperature to the CITN 
Central Laboratory. Clinical sites will utilize a web-based specimen system 
(BSI-Web) to communicate with the CITN Central Laboratory.  

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Following sectioning at the CITN Central Laboratory, unstained slides will be 
shipped by CITN Central Lab to Neon Therapeutics or equivalent designated 
collaborator.  
9.2.5.4 
Site(s) Performing Correlative Study 
Whole exome sequencing and RNA sequencing will be performed by Neon 
Therapeutics, Cambridge, MA, or equivalent designated vendor. 
 
9.2.6 Neoantigen Identification—Laboratory Correlative Study #9 
9.2.6.1 
Collection of Specimen(s): NA 
No additional specimens are required for this correlative study once WES and 
RNA sequencing are performed.  Neoantigen prediction will be based on 
WES and RNA sequencing (Correlative Study #8, Section 9.2.5).  
9.2.6.2 
Handling of Specimen(s): NA 
9.2.6.3 
Shipping of Specimen(s): NA 
 
9.2.6.4 
Site(s) Performing Correlative Study 
Neoantigen identification will be performed by Neon Therapeutics, 
Cambridge, MA, or equivalent designated vendor. 
9.2.7  T cell Receptor (TCR) Sequencing and Functional Phenotyping—Lab Correlative 
Study #10  
9.2.7.1 
Collection of Specimen(s) 
Testing will be performed on tumor biopsies and peripheral blood samples 
collected at baseline and post-treatment. 
9.2.7.2 
Handling of Specimen(s) 
Blood samples will be collected at room temperature and shipped ambient to 
the CITN Central Laboratory the same day as the blood draw, so that the 
sample is received at the CITN Central Laboratory within 24 hours of blood 
draw.  
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor 
obtained before MK-3475 treatment will be obtained as described in 9.2.1. If 
sufficient archival material for performance of TCR sequencing is not 
available, additional archival material may be requested from the site. 
Fresh tumor biopsies at a minimum of 100 milligram will be collected, 
transported in appropriate media, and dissociated using mechanical and 
enzymatic digestion with collagenase, DNAase, and hyaluronidase.  The 
resulting single cell suspension will be collected by centrifugation and 
cryopreserved viably in 10% dimethyl sulfoxide (DMSO) and either 12.5% 
HSA (or 12.5% FCS (Fetal calf serum) or CryoStor10.  Samples will be stored 
at -80°C and then transferred appropriately to liquid nitrogen for long term 

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storage until shipment. 
9.2.7.3 
 Shipping of Specimen(s) 
Blood sample tubes will be shipped at ambient temperature to the CITN 
Central Laboratory.  
The clinical site will arrange for the formalin-fixed, paraffin-embedded 
archival tumor blocks to be shipped at ambient temperature to the CITN 
Central Laboratory. For formalin-fixed biopsies done as part of this protocol, 
tissue in formalin will be shipped overnight at ambient temperature to the 
CITN Central Laboratory. Clinical sites will utilize a web-based specimen 
system (BSI-Web) to communicate with the CITN Central Laboratory.  
The clinical site will arrange for cryo-preserved tumor biopsy specimens to be 
shipped on dry ice to the CITN Central Laboratory. Clinical sites will utilize a 
web-based specimen system (BSI-Web) to communicate with the CITN 
Central Laboratory. 
Biopsies and PBMC will be shipped by CITN Central Lab to the Warren Lab 
or equivalent designated collaborator. 
9.2.7.4 
Site(s) Performing Correlative Study 
T cell receptor sequencing and functional phenotyping will be performed by 
the Warren Lab, or equivalent designated vendor. 
9.2.8 Kynurenine/Tryptophan (Kyn/Trp) Ratio--Laboratory Correlative Study  
9.2.8.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects at time 
points before, during, and after treatment. 
9.2.8.2 
Handling of Specimens(s) 
Plasma will be isolated by the local laboratory and frozen at -80°C 
9.2.8.3 
Shipping of Specimen(s) 
Plasma samples will be batch shipped overnight on dry ice to the CITN 
Central Laboratory. Sites will utilize a web-based specimen system (BSI-
Web) to communicate with the CITN Central Laboratory. The CITN Central 
Laboratory will coordinate the shipment of samples to Incyte Corporation. 
9.2.8.4 
Site(s) Performing Correlative Study 
Kynurenine and tryptophan levels will be assessed at Incyte Corporation. 
9.2.9 CITN Central Laboratory Biorepository 
On days of blood draws for correlative studies, there is also a planned blood draw of 
20 mL for the biorepository (PBMC storage). Blood that is drawn for the biorepository 
will be shipped to the CITN Central Laboratory for storage and future testing.  

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Any tissue remaining after testing has been completed will be kept in the CITN Central 
Laboratory Biorepository for storage and future testing. 
 
Special Studies-N/A 
9.3.1 HLA Class I and Class II typing 
DNA will be extracted from residual blood collected at baseline, and assayed either at 
Puget Sound Blood Center or the laboratory of Dr. Dan Geraghty (FHCRC). CITN 
Central Laboratory will coordinate sample shipping to Puget Sound Blood Center or 
Geraghty Lab.

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10. STUDY CALENDAR 
All baseline evaluations with the exception of scans are to be conducted within 14 days before start of protocol therapy. Scans must be 
done ≤4 weeks before the start of therapy. In the event that the patient’s condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours before initiating the next cycle of therapy. Treatment Year 1 
Trial Period 
Screening 
Phase 
Treatment Cycles Year 1 a 
End of Tx 
Post-treatment follow-up 
 
 
To be repeated up to 2 years 
 
 
Tx Cycle/Title 
Pre-Therapy 
 
Cycle 
1 
Cycle 
2 
Cycles 
without 
scans 
(q 3 weeks) 
Cycles with scans (Cycle 
5 then q 9 
weeks(through Cycle 17) 
n 
D/C 
therapy 
Post-Tx 
Safety FU 
Post-Tx 
Disease 
Assessments  o 
,t 
Survival 
Follow-up r 
Scheduling Window (Days) 
Day -28 to 
Day 0 
Day 1 
±3 
Day 1 
±3 
Day 1±3 
Day 1 ±3 
At time of 
D/C 
30 days ± 3 
days post 
D/C 
Variable 
frequencyopost-
D/C 
Every 12 
weeks 
±1week 
phone 
contact 
MK-3475 administration b 
 
X 
X 
X 
 
X 
 
 
 
 
Administrative procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Concomitant Medications m 
X 
 
X 
X 
X 
X 
X 
 
X 
Medical History, 
demographics, etc. 
X 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments a 
Review of AEs d, e 
 
X 
X 
X 
X 
X 
X 
Xe 
 
Physical Exam u 
X 
X 
Xu 
Xu 
X 
X 
X 
 
 
Vital Signs, Height and 
Weight f 
Xf 
X 
X 
X 
X 
X 
X 
 
 
12-Lead EKG g 
X 
X 
 
 
 
X 
 
 
 
Pulmonary function v 
X 
 
 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Assessments (Safety Labs)a,h,j,s 
Pregnancy Test  
(Urine or Serum HCG) h, i 
X 
 
 
 
 
X 
 
 
 
CBC with Differential. 
X 
 
X 
X 
X 
X 
X l 
 
 
Comprehensive Serum 
Chemistry Panel j 
X 
 
X 
X 
X 
X 
X l 
 
 
Urinalysis j, k 
X 
 
 
X k 
 
X l 
 
 
T3, FT4, and TSH j, k 
X 
 
 
X k 
 
X l 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
92 
Trial Period 
Screening 
Phase 
Treatment Cycles Year 1 a 
End of Tx 
Post-treatment follow-up 
 
 
To be repeated up to 2 years 
 
 
Tx Cycle/Title 
Pre-Therapy 
 
Cycle 
1 
Cycle 
2 
Cycles 
without 
scans 
(q 3 weeks) 
Cycles with scans (Cycle 
5 then q 9 
weeks(through Cycle 17) 
n 
D/C 
therapy 
Post-Tx 
Safety FU 
Post-Tx 
Disease 
Assessments  o 
,t 
Survival 
Follow-up r 
Scheduling Window (Days) 
Day -28 to 
Day 0 
Day 1 
±3 
Day 1 
±3 
Day 1±3 
Day 1 ±3 
At time of 
D/C 
30 days ± 3 
days post 
D/C 
Variable 
frequencyopost-
D/C 
Every 12 
weeks 
±1week 
phone 
contact 
Correlative Studies Blood Draws c 
Kyn/Trp ratio 
 
X 
X 
 
X 
X 
 
 
 
IFN-γ ELISpot/ICS 
 
X 
X 
 
X 
X 
 
 
 
Immunophenotyping 
 
X 
X 
 
X 
X 
 
 
 
T cell Gene Expression and 
Phenotyping 
 
X 
X 
 
X 
X 
 
 
 
MCPyV Antibody Levels 
 
X 
X 
 
X 
X 
 
 
 
Serum, plasma and PBMC 
storage 
 
X 
X 
 
X 
X 
 
 
 
Efficacy Measurements 
Tumor Imaging n, o, p 
X 
 
 
 
X 
X 
 
X 
 
Tumor Biopsies/Archival Tissue Collection 
Tumor Biopsies q 
X 
 
 
 
 
X 
 
 
 
 
See calendar footnotes following Treatment Year 2 Calendar. 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
93 
Treatment Year 2 
Trial Period 
Treatment Cycles Year 2a 
End of Tx 
Post-treatment follow-up 
 
To be repeated up to 2 years 
 
 
Tx Cycle/Title 
Cycles without 
scans 
(q 3 weeks) 
Cycles with scans, 
(q 12 weeks year 2)n 
D/C therapy 
Post-Tx Safety FU 
Post-Tx Disease 
Assessments o ,t 
Survival Follow-up r 
Scheduling Window (Days) 
Day 1±3 
Day 1 ±3 
At time of D/C 
30 days ±3 days 
post- D/C 
Variable 
frequencyopost-D/C 
Every 12 weeks ±1 
week phone contact 
MK-3475 administration b 
X 
 
X 
 
 
 
 
Administrative Procedures 
Informed Consent 
 
 
 
 
 
 
Concomitant Medications m 
X 
X 
X 
X 
 
X 
Medical History, 
demographics, etc. 
 
 
 
 
 
 
Clinical Procedures 
Review of AEs d, e 
X 
X 
X 
X 
Xe 
 
Physical Exam u 
Xu 
X 
X 
X 
 
 
Vital Signs, Height and 
Weight f 
X 
X 
X 
X 
 
 
12-Lead EKG g 
 
 
X 
 
 
 
Pulmonary function v 
 
 
 
 
 
 
ECOG PS 
X 
X 
X 
X 
 
 
Laboratory Assessments 
Pregnancy Test  
(Urine or Serum HCG) h, i 
 
 
X 
 
 
 
CBC with Differential. 
X 
X 
X 
X l 
 
 
Comprehensive Serum 
Chemistry Panel j 
X 
X 
X 
X l 
 
 
Urinalysis j, k 
X k 
 
X l 
 
 
T3, FT4, and TSH j, k 
X k 
 
X l 
 
 
Correlative Blood Draws 
Kyn/Trp ratio 
 
 
X 
 
 
 
IFN-γ ELISpot/ICS 
 
 
X 
 
 
 
Immunophenotyping 
 
 
X 
 
 
 
T cell Gene Expression and 
Phenotyping 
 
 
X 
 
 
 
MCPyV Antibody Levels 
 
 
X 
 
 
 
Serum, plasma and PBMC 
storage 
 
 
X 
 
 
 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
94 
Trial Period 
Treatment Cycles Year 2a 
End of Tx 
Post-treatment follow-up 
 
To be repeated up to 2 years 
 
 
Tx Cycle/Title 
Cycles without 
scans 
(q 3 weeks) 
Cycles with scans, 
(q 12 weeks year 2)n 
D/C therapy 
Post-Tx Safety FU 
Post-Tx Disease 
Assessments o ,t 
Survival Follow-up r 
Scheduling Window (Days) 
Day 1±3 
Day 1 ±3 
At time of D/C 
30 days ±3 days 
post- D/C 
Variable 
frequencyopost-D/C 
Every 12 weeks ±1 
week phone contact 
Efficacy Measurements 
Tumor Imaging n, o, p 
 
X 
X 
 
X 
 
Tumor Biopsies/Archival Tissue Collection 
 Tumor Biopsies q 
 
 
X 
 
 
 
 
Abbreviations: AE, adverse event(s); CBC, complete blood count; D/C, discontinuation/discontinue; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; 
EOC, end of cycle; FU, follow-up; HCG, human chorionic gonadotropin; Kyn/Trp, kynurenine/tryptophan; PS, performance status; TSH, thyroid-stimulating hormone; tx, 
treatment 
a. In general, safety labs and assessments/procedures are to be performed on Day 1 and before the first dose of treatment for each cycle unless otherwise specified. In general, the 
window for each visit is ± 3 days unless otherwise noted. Treatment cycles are 3 weeks (21 days); however the treatment cycle interval may be increased due to toxicity 
according to the dose-modification guidelines provided in Section 6. If the interval is increased, all procedures except imaging should be performed based on the new dosing 
schedule.  
b. MK-3475 will be administered as an IV infusion over 30 minutes. The dose is 2mg/kg every 3 weeks (21 days ± 3 days). The infusion is given in an out-patient setting. 
Patients who restart treatment after relapse from CR should resume at the same dose and cycle interval which they were receiving before discontinuation. 
c. Blood for correlative studies will be drawn on Day 1 of Cycle 1, prior to drug administration, then prior to study drug infusion on day 1 of Cycle 2 and Cycle 5, then prior to 
drug administration every 3rd cycle (i.e., day 1, Cycle 8, 11, 14, etc.) during first year of treatment. After 1 year of therapy,blood for correlative studies is also drawn upon 
confirmed CR or PR and at the time of disease progression. If the correlative blood draw is not obtained at time of determination of CR, PR or disease progression, then this 
collection will be done at the end-of-therapy visit.  
d. AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0. All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
e. Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) occurring up until 90 days after the last 
dose of trial treatment or the start of new anticancer treatment, whichever comes first. Afterwards, report only SAEs that are related to trial treatment. 
f. 
Vital signs to include temperature, pulse, respiratory rate, weight, and blood pressure. Height will be measured at baseline only. 
g. EKG should be performed at baseline, and then within 30 minutes of the end of infusion after dosing for Cycle 1 and Cycle 8 and at discontinuation.  
h. Laboratory tests for screening are to be performed within 14 days before the first dose of trial treatment. See Section 5.1.1 for details regarding laboratory tests. 
i. 
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours before first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines. 
 
j. 
After Cycle 1, lab samples can be collected up to 72 hours before the scheduled time point. See Section 5.1.1 for details regarding laboratory tests. 
k. Urinalysis and thyroid function testing to be repeated every 6 cycles after baseline (cycles 6, 12, 18, etc.) and at the Post-Treatment Follow Up visit. 
l. 
Unresolved abnormal labs that are drug related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal 
range. 
m. Concomitant medications – Enter new medications started during the trial through the safety follow-up visit. Record all medications taken for SAE reporting as defined in 
Section 5.3.1. 
n. The initial tumor imaging will be performed within 28 days before the first dose of trial treatment. Scans performed as part of routine clinical management are acceptable for 
use as the screening scan if they are of diagnostic quality and performed within 28 days before the first dose of trial treatment. On-study imaging will be performed and 
reviewed at week 13 before drug administration. Patients who show progression at week 13 will continue on therapy and have a conformational scan at week 17. Patients with 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
95 
no evidence of disease progression will have scans every 3 cycles (every 9 weeks ± 3 days) during the first year of treatment. Scan frequency will be decreased to every 12 
weeks ± 7 days during second year of treatment. For cycles with scans scheduled, scans should occur within 7 days before scheduled drug administration so that the 
investigator may evaluate the patient for possible progression before administering the next dose of study medication.  The same imaging technique should be used in a patient 
throughout the trial with the exception that patients who have discontinued treatment without evidence of progression may have scans performed either at investigative site or 
locally. Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for patient management; Sponsor may collect radiological 
assessments for retrospective analysis by a central vendor. (See Overall Trial Schema and Patient Visit Timeline). 
o. In patients who discontinue study therapy without confirmed disease progression, a radiological evaluation should be performed at the time of treatment discontinuation (i.e., 
date of discontinuation ± 4 week window). If a previous scan was obtained within 4 weeks before the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. Every effort should be made to continue monitoring their disease status by radiologic imaging at the investigative site or locally as follows: Year 1 Post-Treatment: 
imaging will be performed Q 3 months (+/-14 days) or as clinically indicated. Years 2 and 3 Post-Treatment: imaging will be performed Q 6 months (± 1 month) or as 
clinically indicated. If the study remains open, imaging will be performed annually once patient has completed 3 years of follow-up for disease assessment. Collection of 
imaging for disease assessments will continue until (1) the start of new anticancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, 
whichever occurs first.    
p. A scan must be performed within 28 days before restarting treatment with MK-3475 after relapse from CR. Imaging should continue to be performed at frequencies described 
in footnote “n” above from the first dose of trial treatment or more frequently if clinically indicated. The Sponsor may collect radiological assessments for retrospective 
analysis by a central vendor. 
q. Tumor biopsy tissue (archival or fresh) is required per screening requirements. In patients who have not achieved CR (either responding, stable or progressing lesions), a 
biopsy sample of a tumor may be obtained if feasible and safe (core, punch or excisional biopsy).  This post-treatment biopsy is highly preferred, but optional.  
r. 
After the start of new anticancer treatment or documented disease progression, the patient should be contacted by telephone every 12 weeks ± 1 week to assess for survival 
status. Survival follow-up will continue until death or end of the study, whichever occurs first. 
s. Laboratory tests for determining eligibility for retreatment in patients who relapse from CR are to be performed within 7 days before the first retreatment dose of MK-3475. 
See Section 3.1.6 for details regarding laboratory tests. 
t. Patients who attain a CR and discontinue treatment or those who attain a PR or SD after completion of 2 years of treatment may restart trial treatment if they meet the criteria 
specified in Section 5.4.3.   
u. After cycle 1, limited physical exam performed on visits not correlated with scans. 
v. For patients with a history of pulmonary disease, prolonged smoking history, or symptoms of respiratory dysfunction.

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
96 
11. MEASUREMENT OF EFFECT 
 
Therapeutic response will be assessed by serial scans. Overall clinical response rate and tumor 
progression will be assessed by evaluating nonbiopsied lesions if present, using standard 
methods (RECIST), including physical exam and CT scans performed before therapy, at 
13 weeks (before drug administration), and every subsequent 9 weeks through 1 year and every 
12 weeks in year 2 according to standard practice. For cycles with scans scheduled, the scans 
shall occur before MK-3475 administration. Patients will be managed in accordance with 
RECIST guidelines as published by Eisenhauer [Eisenhauer 2009]. However, MK-3475-treated 
patients who appear to be progressing at the 13-week scan can continue therapy until progression 
is confirmed at the 17-week scan, provided the patient is otherwise stable.  
 
Antitumor Effect—Solid Tumors 
For the purposes of this study, patients with advanced MCC should be evaluated for response by 
spiral CT scan in accordance with standard practice at 9-week intervals, with the initial scan at 
week 13 of the trial, before drug administration. Throughout the trial, for cycles with scans 
scheduled, scans shall occur before scheduled drug administration so that the investigator may 
evaluate the patient for possible progression before administering the next dose of study 
medication. Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised RECIST guideline (Version 1.1)[Eisenhauer 2009]. Changes in 
the largest diameter (unidimensional measurement) of the tumor lesions and the shortest 
diameter in the case of malignant lymph nodes are used in RECIST.  
Immunotherapeutic agents such as MK-3475 may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses that may be functionally anergic. The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard RECIST guidelines may not provide a 
CR assessment of immunotherapeutic agents such as MK-3475, especially at early therapeutic 
time points. Because of the possibility that the initial scan at 13 weeks may misclassify MK-3475 
responders as progressing on therapy, those MK-3475–treated patients who appear to be 
progressing at week 13 can continue therapy until progression is confirmed at the 17-week scan, 
providing they meet the guidelines stated above (Section 5.1.1). If the patient is found to be 
progressing on the 17-week scan, the investigator will determine whether to discontinue protocol 
therapy and begin other systemic therapy, such as cytotoxic chemotherapy, or alternatively to 
continue MK-3475 treatment.  If MK-3475 therapy is discontinued, the patient will attend the 
end-of-treatment and 30-day follow-up visits. The time of progression will be reported as the 
first time that progression was noted. If patients regress or have SD as determined by the 
confirmatory 17-week imaging study, the time of eventual progression will be separately 
reported. 
If progression is noted on subsequent routine disease monitoring scans (≥22 weeks), which will 
continue throughout the trial at 9- or 12-week intervals, a confirmatory scan will be obtained 
4 weeks later. If this confirmatory scan identifies an MK-3475-treated patient as progressing on 
therapy, the investigator will determine whether to discontinue protocol therapy and begin other 
systemic therapy, such as cytotoxic chemotherapy, and follow patient as indicated above, or 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
97 
alternatively to continue MK-3475 treatment.  (See Overall Trial Schema and Patient Visit 
Timeline). 
11.1.1 Definitions 
Evaluable for Objective Response. All patients that have received at least 1 injection of 
MK-3475 will be considered evaluable for response.  
A patient on MK-3475 who is identified as progressing on therapy at the initial 13-week 
scan may continue receiving MK-3475 until progression is confirmed by a subsequent 
scan at 17 weeks. Patients may only receive treatment while waiting for confirmation of 
PD if the following criteria are met:  
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease  
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
If these criteria are met, it is advisable to keep patients on MK-3475 until confirmation of 
progression but is subject to the discretion of the treating physician. Patients that are 
deemed clinically unstable are not required to have repeat imaging for confirmation.  
If progression is confirmed, then the patient will be discontinued from trial treatment. If 
progression is not confirmed, then the patient should resume/continue trial treatment and 
have their next scan according to the standard follow-up schedule on week 22 then every 
9 weeks thereafter during the first year of treatment and every 12 weeks during the 
second year of treatment.  
Alternatively, if progression is confirmed, patients who are clinically stable will be 
eligible to receive continued MK-3475.  Patients who have not achieved CR (either 
responding, stable or progressing lesions) may have an optional biopsy of tumor prior to 
continuing therapy to assess potential reasons for the lack of response to MK-3475.  
Patients will then continue MK-3475 treatment and scans per the study calendar.  
For patients who discontinue trial treatment for reasons other than disease progression,  
imaging during the post-treatment follow-up period is to continue as described in Section 
5.1.1  until confirmed disease progression,start of a new antineoplastic therapy, death or 
end of study, whichever occurs first.  
Local reading (investigator assessment with site radiology reading by RECIST 1.1 
criteria) will be used to determine patient eligibility and for patient management. 
Radiologic images will be collected and stored for a possible retrospective analysis of 
patient eligibility and treatment response to be performed by a central vendor, including 
RECIST 1.1. 
Evaluable Non–target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least 1 cycle of therapy, and have had their disease re-evaluated will be considered 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
98 
evaluable for non–target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
Patients who do not receive a post-baseline scan due to discontinuing treatment as a result 
of toxicity should be considered evaluable for response. 
11.1.2 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, magnetic resonance imaging (MRI), or calipers by 
clinical exam. All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area or in an area 
subjected to other locoregional therapy are usually not considered measurable unless 
there has been demonstrated progression in the lesion.  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. 
Nonmeasurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered nonmeasurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as nonmeasurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor nonmeasurable) 
since they are, by definition, simple cysts. 
“Cystic lesions” thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement, in which circumstance the next largest lesion that can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 

NCI Protocol # CITN-09 
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99 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
11.1.3 Methods for Evaluation of Measurable Disease 
In this study, all tumors will be measured using spiral CT scan. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
11.1.4 Response Criteria 
11.1.4.1 
Evaluation of Target Lesions by RECIST 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction 
in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the 
diameters of target lesions, taking as reference the smallest sum on study (this 
includes the baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
11.1.4.2 
Evaluation of Non-Target Lesions by RECIST 
Complete Response (CR): Disappearance of all non-target lesions and 
normalization of tumor marker level. All lymph nodes must be non-
pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or 

NCI Protocol # CITN-09 
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100 
unequivocal progression of existing non-target lesions. Unequivocal 
progression should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase.  
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
PI). 
11.1.4.3 
Evaluation of Best Overall Response (RECIST) 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for PD the 
smallest measurements recorded since the treatment started). The patient’s 
best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target Lesions New Lesions Overall Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
≥4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD 
/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD 
/not evaluated 
No 
SD 
Documented at least once 
≥4 wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR, or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for nonrandomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Nonmeasurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ “Non-CR/non-PD” is preferred over ‘stable disease’ for non–target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no 
lesions can be measured is not advised 

NCI Protocol # CITN-09 
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101 
11.1.5 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
11.1.6 Duration of Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for PD the smallest measurements 
recorded since the treatment started).  
11.1.7 Overall Survival 
Status of patient survival will be reported to the CITN by the primary treating physicians 
on an every 6 months schedule.  
11.1.8 Response Review 
Imaging studies will be collected for a possible expert review of responses. Investigator 
determined responses will be chronicled and reported unless or until a central expert 
review takes place. 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
AE lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse 
Events: List and Reporting Requirements). 
 
Data Reporting 
Data collection for this study will be done exclusively through Medidata Rave. Access to the trial 
in Rave is granted through the iMedidata application to all persons with the appropriate Rave 
roles in the CTSU Regulatory Support System (RSS). To access iMedidata/Rave the site user 
must have an active CTEP IAM account (check at < https://ctepcore.nci.nih.gov/iam >). In 
addition, site users that are members of the CITN must have the appropriate Rave roles (Rave 
CRA, site PI, or Read-Only) in RSS at the enrolling site. To hold the Rave CRA role or CRA 
Lab Admin role, the user must hold a minimum of an AP registration type.  To hold the Rave 
Site Investigator role, the individual must be registered as an NPIVR or IVR.  Associates can 
hold read-only roles in Rave.   
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the CITN roster will be sent a study invitation email from iMedidata. To accept the invitation, 
site users must log into the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM user name and password, and click on the “accept” link in the upper right corner of 
the iMedidata page. Please note, site users 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 will be listed 
in the upper right pane of the iMedidata screen. 
Users who have not previously activated their iMedidata/Rave accounts at the time of initial site 
registration approval for the study in RSS will also receive a separate invitation from iMedidata 
to activate their account. Account activation instructions are located on the CTSU website, Rave 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
102 
tab under the Rave resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 
or by email at ctsucontact@westat.com. 
12.1.1 Method 
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, either by FTP burst of data or via the CDS web application. 
Reports are due January 31, April 30, July 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). 
All AEs (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.  
12.1.2 Responsibility for Data Submission  
 
For CITN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the CITN Sites understand the procedures for data submission for each 
CITN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CITN data management organization via the electronic data capture 
system, Medidata Rave. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CITN data management 
organization on an ongoing basis as data is received.  Queries will be issued by CITN 
data management organization directly within Rave.  The queries will appear on the Task 
Summary Tab within Rave for the CRA at the CITN to resolve.  Monthly web-based 
reports are posted for review by the Drug Monitors in the IDB, CTEP.  Onsite audits will 
be conducted to ensure compliance with regulatory requirements, GCP, and NCI policies 
and procedures with the overarching goal of ensuring the integrity of data generated from 
NCI-sponsored clinical trials, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
) and CTSU websites. 
The CITN data management organization will utilize a core set of eCRFs that are Cancer 
Data Standards Registry and Repository (caDSR) compliant 
(http://cbiit.nci.nih.gov/ncip/biomedical-informatics-resources/interoperability-and-
semantics/metadata-and-models).  Customized eCRFs will be included when appropriate 
to meet unique study requirements.  The PI is encouraged to review the eCRFs, working 
closely with the CITN data management organization to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  The 
CITN data management organization will prepare the eCRFs with built-in edit checks to 
the extent possible to promote data integrity. 
 

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CDUS data submissions will be carried out by the CITN data management organization 
contractor, Axio.  CDUS submissions are performed by Axio on a quarterly basis.  The 
trial’s lead institution is responsible for timely submission to the CITN data management 
organization via Rave, as above. 
 
See Section 12.1.1 for details on CDUS reporting.  As the data management center for 
this trial, Axio is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review.   
 
 
CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. 
The specific responsibilities of the PI and the Coordinating Center and the procedures for 
auditing are presented in Appendix B. 
• The PI/Coordinating Center is responsible for distributing all IND Action Letters or 
Safety Reports received from CTEP to all participating institutions for submission to their 
individual IRBs for action as required. Submit documentation of reportable adverse 
events to CTSUprotocol@westat.com and state in the subject line “Safety Report for NCI 
protocol #” or “Action Letter for NCI protocol #”, as appropriate.  A brief summary 
cover page on Coordinating Center letterhead is encouraged.  These documents will be 
posted to the CTSU protocol web page and included in the next CTSU bi-monthly 
broadcast. 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP. Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Clinical Research 
Site to the CTSU Regulatory Office for entry in the Regulatory Support System (RSS) 
and transmission to CTEP.  
 
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 

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(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. 
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, 

NCI Protocol # CITN-09 
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105 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential/ proprietary information. 
13. STATISTICAL CONSIDERATIONS 
 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but before the conduct of any analysis, changes are made to primary and/or key 
secondary hypotheses or the statistical methods related to those hypotheses, then the protocol 
will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. 
Post hoc exploratory analyses will be clearly identified in the CSR. No separate Statistical 
Analysis Plan (SAP) will be issued for this study. 
 
Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
FHCRC as part of the CITN. 
This trial is being conducted as an open-label study, i.e., patients, investigators, and trial 
personnel will be aware of patient treatment.  
A single interim analysis will be conducted at the end of Stage 1 (Section 13.10). If at least 
1 response is observed among the 9 enrolled patients, the trial will proceed to enroll an additional 
15 patients in Stage 2.  
 
Study Design/Endpoints 
13.2.1 Primary Objective 
• To determine the clinical efficacy of MK-3475 as the first systemic intervention for 
patients with advanced MCC 
The primary endpoint will be ORR as measured by RECIST 1.1.  
13.2.2 Secondary Objectives 
• To determine the clinical activity of MK-3475 as the first systemic intervention for 
patients with advanced MCC 
The secondary endpoints will be PFS, DOR, and OS, as measured by RECIST 1.1. The 
PFS will be determined at 16 months and compared to the historical PFS for patients 
treated with chemotherapy, which is 5% at 16 months.  
13.2.3 Exploratory Objectives 
• To determine the immune correlates of the clinical activity of MK-3475  
The endpoints will include IHC and gene expression analysis focusing on delineating the 
immune components and immunologic milieu within the tumor before therapy. The IHC 
analyses performed will include, but is not limited to, MCPyV T-Ag, PD-1, CD8, and CD3. In 
addition, MCPyV viral DNA will be quantified in the tumor (Section 2.5.2). 

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Cellular and humoral MCPyV–specific immune responses will be assessed with ELISpot and 
serology assays in blood samples at baseline, after initiating MK-3475 therapy, and correlated 
with clinical responses over time. Among patients with corresponding MHC-peptide tetramers, 
pre- and post-treatment samples of circulating MCPyV-specific CD8 T cells will be isolated and 
subjected to deep immunophenotyping by mRNA expression analysis (Section 2.5.3).  
 
Analysis Endpoints 
13.3.1 Efficacy Endpoints 
The primary and secondary efficacy endpoints are described below. 
Objective response rate (ORR) is defined as the proportion of patients who have achieved 
CR or PR according to RECIST 1.1. 
Progression-Free Survival (PFS) is defined as the time from randomization to PD or 
death, whichever occurs earlier, based upon investigator assessment using RECIST 1.1. 
Patients without documented PD/death will be censored at the last disease assessment 
date. 
Duration of response (DOR) is defined as the time interval between the date of first 
response (CR/PR) and the date of progression. 
Overall survival (OS) is defined as the time from randomization to death due to any 
cause. Patients without documented death at the time of analysis will be censored at the 
date last known to be alive. 
13.3.2 Safety Endpoints 
The primary safety endpoints are AEs graded using CTCAE (Version 5.0) criteria. Safety 
will be assessed by quantifying the toxicities and grades experienced by subjects who 
have received MK-3475 including AEs and SAEs. Safety will be monitored by 
cumulative data reviews throughout the trial. 
Other safety endpoints include laboratory safety assessments, ECOG performance status, 
vital signs, and physical examinations.  
Note: Patients discontinuing MK-3475 due to toxicity will still be considered evaluable 
for response.  
 
Analysis Populations 
13.4.1 Efficacy Analysis Population 
The population of eligible subjects who receive at least 1 dose of treatment will serve as 
the primary population for the analysis of efficacy data in this study.  
13.4.2 Safety Analysis Population 
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data 
in this study. The ASaT population consists of all patients who received at least 1 dose of 
study treatment. . Patients who do not receive the study treatment will be excluded from 
analysis. 

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At least one laboratory or vital sign measurement obtained subsequent to at least 1 dose 
of study treatment is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required. 
 
Statistical Methods 
The protocol has a standard Simon two stage design. The null hypothesis that the true response 
rate is 5% will be tested against a one-sided alternative. In the first stage, 9 patients will be 
accrued. If there are no responses in these 9 patients, the study will be stopped. Otherwise, 15 
additional patients will be accrued for a total of 24. The null hypothesis will be rejected if 3 or 
more responses are observed in 24 patients. This design yields a type I error rate of 0.10 and 
power of 0.90 when the true response rate is 25%. PFS at 16 months will be estimated by 
Kaplan-Meier method. 
The current protocol will increase the total number of patients from 26 to 50.  The initial protocol 
enrolled nine subjects in Stage 1, and planned to enroll an additional 15 subjects in Stage 2 for a 
total enrollment of 24. Treatment was discontinued in 2 patients due to drug-related adverse 
events after receiving 1 dose of MK-3475, and enrollment of an additional 2 patients was 
allowed per protocol, bringing the total enrollment to 26 patients. The current protocol 
amendment will increase the total number to 50 to provide an expanded safety and efficacy 
profile. 
Unless otherwise stated, all statistical tests will be conducted at the α=0.05(1-sided) level. 
13.5.1 Statistical Methods for Efficacy Analyses 
13.5.1.1 
ORR 
ORR will be estimated as the number of responders as a percent of the number of 
eligible participants who received at least 1 dose of treatment. If a substantial amount 
of primary endpoint data are missing (at least 1 value missing from more than 20% of 
participants), using nonparametric estimation to estimate the ORR requires the 
missing completely at random assumption may give misleading results. In this 
situation, analyses of the primary endpoint at the primary time point will be 
performed using parametric generalized linear models fit by maximum likelihood. 
These methods provide unbiased estimation and inferences under the parametric 
modeling assumptions and the assumption that the missing data are missing at 
random (MAR). MAR assumes that the probability of an observation being missing 
may depend upon the observed responses and upon observed covariates, but not upon 
any unobserved factors. A generalized linear model for the ORR will use a binomial 
error distribution. The model will include as covariates all available baseline 
predictors of the missing outcomes. 
Note: Patients with confirmed progression will be declared as having progressive 
disease for statistical purposes even if they remain on study and respond continued 
MK-3575. Responses to continued MK-3575 will be chronicled and reported.  
13.5.1.2 
PFS, DOR, and OS 
Survival curves for PFS, DOR, and OS will be estimated using the Kaplan-Meier 

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method.  
For PFS, subjects without documented PD/death will be censored at the last disease 
assessment date. Any subject who is lost to follow-up will be included in the analysis 
and their PFS time will be censored on the last date that the subject was known to be 
progression-free, defined as the date of the last tumor assessment not indicating 
progression. As a sensitivity analysis, the primary analysis of PFS will be performed 
reconsidering subjects without documented PD or death who discontinued treatment 
or received new anticancer therapy to have been progressed at the date of treatment 
discontinuation or initiation of new anticancer therapy, whichever occurs later. 
For OS, subjects without documented death at the time of analysis will be censored at 
the date last known to be alive. 
For DOR, subjects who have not yet progressed by the last disease assessment will be 
censored at the last disease assessment—this is intended to describe censoring rules 
for the analysis where only responders are used. 
Table 13.1 Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable 
(Description, Time point) 
Statistical Method 
Analysis Population 
Missing Data 
Approach 
Primary Hypothesis 
ORR 
Simon Two Stage 
design analysis 
Eligible subjects who 
receive at least 1 dose of 
treatment 
See 13.5.1. 
Secondary Objectives 
PFS  
Estimation: Kaplan-
Meier method for PFS 
curve estimation 
Eligible subjects who 
receive at least 1 dose of 
treatment 
Model based 
(censored at last 
assessment) 
DOR 
Summary statistics 
using Kaplan-Meier 
method 
All responders 
Nonresponders are 
excluded in 
analysis 
OS 
Summary statistics 
using Kaplan-Meier 
method  
Eligible subjects who 
receive at least 1 dose of 
treatment 
Model based 
(censored at last 
date) 
Exploratory Objectives 
PFS and OS by the following 
biomarker categories: 
• 
pre-therapy CD8+  
• 
pre-therapy CD3+ T-cell 
infiltration in tumor 
• 
pre-therapy PD-1 and 
PD-L1 expression in 
tumor, 
• * pre-therapy immune 
response to MCPyV 
Descriptive statistics 
Eligible subjects who 
receive at least 1 dose of 
treatment 
censored at last 
assessment 

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Note: PD after 1 or more missed visits will be counted as PD as of the date of documented disease progression. An 
additional sensitivity analysis will be performed where subjects with 2 or more missed visits before progression will 
be censored at the last disease assessment before the ≥2 missed disease assessments. 
13.5.2 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters 
including adverse experiences, laboratory tests, vital signs, and ECG measurements.  
Adverse experiences will be summarized as counts and frequencies by toxicity grade. 
Summary statistics (median and range) for time to onset of first drug-related toxicity will 
be provided. 
Laboratory assessments, vital signs, and other safety endpoints will be summarized using 
descriptive statistics as appropriate. 
13.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses 
The number and percentage of subjects enrolled, and the primary reason for 
discontinuation will be displayed. Demographic variables (such as age) and baseline 
characteristics will be summarized either by descriptive statistics or categorical tables. No 
statistical hypothesis tests will be performed on these characteristics. 
 
Multiplicity 
The treatment comparison will be tested at one sided 5% alpha level and no multiplicity 
adjustment will be applied.  
 
Sample Size/Accrual Rate and Power Calculations  
To date, the trial has enrolled 26 patients. The initial plan was to “enroll between 9 and 24 
subjects to receive MK-3475 in a two-stage Simon design with 90% power to reject the null 
hypothesis of a 5% true response rate against a 1-sided alternative when the true response rate is 
25%. The study will enroll the first 9 patients over a 6-month period, followed by enrollment of 
15 more subjects over 10 months”. 
“In the first stage, 9 patients will be accrued. If there are no responses in these 9 patients, the 
study will be stopped. Otherwise, 15 additional patients will be accrued for a total of 24. The null 
hypothesis will be rejected if 3 or more responses are observed in 24 patients. This design yields 
a type I error rate of 0.10 and power of 0.90 when the true response rate is 25%”. 
ORR by the following 
biomarker categories: 
• 
pre-therapy CD8+  
• 
pre-therapy CD3+ T-cell 
infiltration in tumor 
• 
pre-therapy PD-1 and 
PD-L1 expression in 
tumor, 
* pre-therapy immune 
response to MCPyV 
Descriptive statistics 
Eligible subjects who 
receive at least 1 dose of 
treatment 
Missing value 
considered 
nonresponder 

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The current protocol amendment will increase the total number of patients to 50 to provide an 
expanded safety and efficacy profile. The analysis will utilize the same statistical test.  
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
 
+ 
 
= 
 
Not Hispanic or Latino 
21 
+ 
29 
= 
50 
Ethnic Category: Total of all subjects 
21 
+ 
29 
= 
(50) 
Racial Category 
 
American Indian or Alaskan Native 
 
+ 
 
= 
 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
 
+ 
1 
= 
1 
Native Hawaiian or other Pacific 
Islander 
 
+ 
 
= 
 
White 
20 
+ 
27 
= 
47 
Racial Category: Total of all subjects 
21 
+ 
29 
= 
(50) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
 
Stratification Factors- N/A 
 
Interim Analyses  
There will be one interim analysis at the end of Stage 1, on the first 9 patients (Section 13.8). If 
there are no responses in these 9 patients, the study will be stopped. Otherwise, 15 additional 
patients will be accrued for a total of 24.  
 Compliance (Medication Adherence) 
Drug accountability data for trial treatment will be collected during the study. Compliance with 
trial treatment administration will be measured by subjects: (1) receiving unscheduled study 
agent infusions/injections; (2) missing an infusion/injection. Numbers and percentages of 
subjects and infusion/injection visits with any deviation in these measures will be reported for 
the eligible subjects 
 Extent of Exposure 
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity will 
also be summarized as appropriate. 
 Analysis of Secondary Endpoints 
Analysis of secondary endpoints is addressed in Section 13.6.1. 
 Reporting and Exclusions 
13.13.1Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with MK-

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111 
3475. 
13.13.2Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: (1) CR, (2) PR, (3) SD, (4) PD, (5) early death 
from malignant disease, (6) early death from toxicity, (7) early death because of other 
cause, or (9) unknown (not assessable, insufficient data).  
Note: By arbitrary convention, category 9 usually designates the “unknown” status of any 
type of data in a clinical database. 
All of the patients who met the eligibility criteria (with the exception of those who 
received no study medication) should be included in the main analysis of the response 
rate. Patients in response categories 4–9 should be considered to have a treatment failure 
(disease progression). Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate. Precise definitions for 
categories 4–9 will be protocol specific.  
All conclusions should be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.). However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 
reasons for excluding patients from the analysis should be clearly reported. The 95% 
confidence intervals should also be provided.  
 
 

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REFERENCES 
 
Afanasiev OK, Yelistratova L, Miller N, Nagase K, Paulson K, Iyer JG, et al. (2013). Merkel 
polyomavirus-specific T cells fluctuate with merkel cell carcinoma burden and express 
therapeutically targetable PD-1 and Tim-3 exhaustion markers. Clin Cancer Res 19(19):5351-60. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT (2008). Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin 
Cancer Res 14(16): 5220-5227. 
Albores-Saavedra J, Batich K, Chable-Montero F, Sagy N, Schwartz AM, Henson DE (2010). 
Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a 
population based study. J Cutan Pathol 37(1): 20-27. 
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. (2006). Restoring 
function in exhausted CD8 T cells during chronic viral infection. Nature 439(7077): 682-687. 
Berman, D.M., J. Wolchok, J. Weber, et al. (2009).  Association of peripheral blood absolute 
lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated 
with ipilimumab. J Clin Oncol.  27:A3020. 
Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. (2010). Phase I 
study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, 
clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19): 3167-
3175. 
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. (2012). Safety and 
activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26): 2455-
2465. 
Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, et al. (2003). Blockade of B7-H1 
improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9(5): 562-567. 
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et al. (2010). 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. 
BMC Immunol 11: 19. 
Diez M, Pollan M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. (1998). 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 18(1B): 689-
694. 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. (2002). Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat 
Med 8(8): 793-800. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. (2009). New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 45(2): 228-247. 
Engels EA, Frisch M, Goedert JJ, Biggar RJ, Miller RW (2002). Merkel cell carcinoma and HIV 
infection. Lancet 359(9305): 497-498. 
Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, et al. (2012). 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
113 
Immunotype and immunohistologic characteristics of tumor-infiltrating immune cells are 
associated with clinical outcome in metastatic melanoma. Cancer Res 72(5): 1070-1080. 
Feng H, Shuda M, Chang Y, Moore PS (2008). Clonal integration of a polyomavirus in human 
Merkel cell carcinoma. Science 319(5866): 1096-1100. 
Fisher TS, Kamperschroer C, Oliphant T, Love VA, Lira PD, Doyonnas R, et al. (2012). 
Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and 
promotes anti-tumor activity. Cancer Immunol Immunother 61(10): 1721-1733. 
Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. (2010). 
Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T 
cell dysfunction in melanoma patients. J Exp Med 207(10): 2175-2186. 
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. (2006). 
Type, density, and location of immune cells within human colorectal tumors predict clinical 
outcome. Science 313(5795): 1960-1964. 
Gao, Q., X.Y. Wang, S.J. Qiu, et al.  (2009).  Overexpression of PD-L1 significantly associates 
with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma.  
Clin Cancer Res.  15:971-979. 
Garon E.  Preliminary Clinical Sefety and activity of MK-3475 monotherapy for the treatment of 
previously treated patients with non-small cell lung cancer (NSCLC).  World Conference on 
Lung Cancer 2013. 
Greenough TC, Campellone SC, Brody R, Jain S, Sanchez-Merino V, Somasundaran M, et al. 
(2010). Programmed Death-1 expression on Epstein Barr virus specific CD8+ T cells varies by 
stage of infection, epitope specificity, and T-cell receptor usage. PLoS One 5(9): e12926. 
Hamid, O., S.D. Chasalow, Z. Tsuchihashi, et al. (2009).  Association of baseline and on-study 
tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated 
with ipilimumab. J Clin Oncol.  27:A9008. 
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. (2013). Safety and tumor 
responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2): 134-144. 
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. (2007). 
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic 
factors of human ovarian cancer. Proc Natl Acad Sci U S A 104(9): 3360-3365. 
Han A, Glanville J, Hansmann L, et al. (2014). Linking T-cell receptor sequence to functional 
phenotype at the single-cell level. Nature Biotechnol 32(7):684-92. 
Heath M, Jaimes N, Lemos B, Mostaghimi A, Wang LC, Penas PF, et al. (2008). Clinical 
characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am 
Acad Dermatol 58(3): 375-381. 
Hillen F, Baeten CI, van de Winkel A, Creytens D, van der Schaft DW, Winnepenninckx V, et 
al. (2008). Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in 
primary cutaneous melanoma. Cancer Immunol Immunother 57(1): 97-106. 
Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. (2010). Tumor cell 
expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
114 
Cancer 116(7): 1757-1766. 
Hiraoka N (2010). Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 15(6): 544-551. 
Hodgson NC (2005). Merkel cell carcinoma: changing incidence trends. J Surg Oncol 89(1): 1-4. 
Hodi FS, Dranoff G (2010). The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 37 Suppl 1: 48-53. 
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. (2010). Improved 
survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8): 711-723. 
Hodi FS, Ribas A, Daud A, Hamid O, Robert C, Kefford R, et al. (2014) Evaluation of immune-
related response criteria (irRC) in patients with advanced melanoma treated with the anti-PD-1 
monoclonal antibody MK-3475. J Clin Oncol 32:5s (suppl; abstr 3006). 
Houben R, Shuda M, Weinkam R, Schrama D, Feng H, Chang Y, et al. (2010). Merkel cell 
polyomavirus-infected Merkel cell carcinoma cells require expression of viral T antigens. J Virol 
84(14): 7064-7072. 
Houben R, Adam C, Baeurle A, Hesbacher S, Grimm J, Angermeyer S, et al. (2012). An intact 
retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for 
promoting growth of Merkel cell carcinoma cells. Int J Cancer 130(4): 847-856. 
Investigator’s Brochure.  (2014).   MK-3475.  Merck Sharp & Dohme Corp., a Subsidiary of 
Merck & Co.,Inc.   
Iyer JG, Afanasiev OK, McClurkan C, Paulson K, Nagase K, Jing L, et al. (2011). Merkel cell 
polyomavirus-specific CD8(+) and CD4(+) T-cell responses identified in Merkel cell carcinomas 
and blood. Clin Cancer Res 17(21): 6671-6680. 
Jabbour J, Cumming R, Scolyer RA, Hruby G, Thompson JF, Lee S (2007). Merkel cell 
carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy 
on recurrence and survival in early-stage disease--results from a review of 82 consecutive cases 
diagnosed between 1992 and 2004. Ann Surg Oncol 14(6): 1943-1952. 
Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. (2008). Tim-3 
expression defines a novel population of dysfunctional T cells with highly elevated frequencies 
in progressive HIV-1 infection. J Exp Med 205(12): 2763-2779. 
Kloor M (2009). Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol 10(9): 
840-841. 
Korman A, Chen B, Wang C, Wu L, Cardarelli J, Selby M (2007). Activity of anti-PD-1 in 
murine tumor models: role of "host" PD-L1 and synergistic effect of anti-PD-1 and anti-CTLA-
4. . J Immunol 178: abstr 48.37. 
Kronig H, Julia Falchner K, Odendahl M, Brackertz B, Conrad H, Muck D, et al. (2012). PD-1 
expression on Melan-A-reactive T cells increases during progression to metastatic disease. Int J 
Cancer 130(10): 2327-2336. 
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. (2008). Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 99(10): 1704-
1711. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
115 
Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, et al. (2009). 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of 
advanced stage ovarian cancer. Cancer Immunol Immunother 58(3): 449-459. 
Lemos BD, Storer BE, Iyer JG, Phillips JL, Bichakjian CK, Fang LC, et al. (2010). Pathologic 
nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases 
as the basis of the first consensus staging system. J Am Acad Dermatol 63(5): 751-761. 
Lewis KG, Weinstock MA, Weaver AL, Otley CC (2006). Adjuvant local irradiation for Merkel 
cell carcinoma. Arch Dermatol 142(6): 693-700. 
Lipson EJ, Vincent JG, Loyo M, Kagohara LT, Luber BS, Wang H, et al. (2013). PD-L1 
expression in the Merkel cell carcinoma microenvironment: Association with inflammation, 
Merkel cell polyomavirus and overall survival. Cancer Immunol Res 1(1): 54-63.. 
Liu, X., R. C. Newton, et al. (2009). Indoleamine 2,3-dioxygenase, an emerging target for anti-
cancer therapy. Curr Cancer Drug Targets 9(8): 938-952. 
Miller NJ, Bhatia S, Parvathaneni U, Iyer JG, Nghiem P (2013). Emerging and Mechanism-
Based Therapies for Recurrent or Metastatic Merkel Cell Carcinoma. Curr Treat Options Oncol 
14(2):249-63. 
Moll R, Lowe A, Laufer J, Franke WW (1992). Cytokeratin 20 in human carcinomas. A new 
histodiagnostic marker detected by monoclonal antibodies. Am J Pathol 140(2): 427-447. 
National Comprehensive Cancer Network (NCCN). (2015). Clinical practice guidelines in 
oncology: Merkel cell carcinoma v. 1.2015. Accessed January 14, 2015, from www.nccn.org. 
Nghiem P, Bhatia S, Daud A, et al. Activity of PD-1 blockade with pembrolizumab as first 
systemic therapy in patients with advanced Merkel cell carcinoma. European Journal of Cancer 
2015;51:S720-S721. 
Nghiem P, Bhatia S, Lipson E, et al. (2016) Clinical activity, immune and viral correlates of PD-
1 blockade with pembrolizumab as first systemic therapy in patients with advanced Merkel cell 
carcinoma. American Association for Cancer Research 2016 Annual Meeting.  New Orleans, 
LA, April 16-20, 2016.  Abstract CT096. 
Nghiem P, Bhatia S, Lipson E, et al. (2016). PD-1 blockade with pembrolizumab in advanced 
Merkel-cell carcinoma. N Engl J Med 10.1056/NEJMoa1603702 Epub Apr 20, 2016. 
Nishimura H, Honjo T, Minato N (2000). Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 191(5): 891-898. 
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. (2008). Prolonged 
survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and 
dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 94(3): 
426-430. 
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. (2007). Clinical significance 
and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res 13(7): 2151-2157. 
Pardoll, D.M.  (2012).  The blockade of immune checkpoints in cancer immunotherapy.  Nat Rev 
Cancer.  12:252-264. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
116 
Paulson KG, Carter JJ, Johnson LG, Cahill KW, Iyer JG, Schrama D, et al. (2010). Antibodies to 
merkel cell polyomavirus T antigen oncoproteins reflect tumor burden in merkel cell carcinoma 
patients. Cancer Res 70(21): 8388-8397. 
Paulson KG, Iyer JG, Tegeder AR, Thibodeau R, Schelter J, Koba S, et al. (2011). 
Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ 
lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29(12): 1539-1546. 
Paulson KG, Iyer JG, Blom A, Warton EM, Sokil M, Yelistratova L, et al. (2013). Systemic 
immune suppression predicts diminished Merkel cell carcinoma-specific survival independent of 
stage. J Invest Dermatol 133(3): 642-646. 
Penn I, First MR (1999). Merkel's cell carcinoma in organ recipients: report of 41 cases. 
Transplantation 68(11): 1717-1721. 
Ribas, A.  (2012).  Tumor immunotherapy directed at PD-1.  N Engl J Med.  366:2517-2519. 
Robert C, Thomas L, Bondarenko I, O’Day S, M DJ, Garbe C, et al. (2011). Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26): 2517-2526. 
Rodig SJ, Cheng J, Wardzala J, DoRosario A, Scanlon JJ, Laga AC, et al. (2012). Improved 
detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. J Clin Invest 
122(12): 4645-4653. 
Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (2010). Targeting 
Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp 
Med 207(10): 2187-2194. 
Sauce D, Almeida JR, Larsen M, Haro L, Autran B, Freeman GJ, et al. (2007). PD-1 expression 
on human CD8 T cells depends on both state of differentiation and activation status. AIDS 
21(15): 2005-2013. 
Sihto H, Bohling T, Kavola H, Koljonen V, Salmi M, Jalkanen S, et al. (2012). Tumor 
infiltrating immune cells and outcome of Merkel cell carcinoma: a population-based study. Clin 
Cancer Res 18(10): 2872-2881. 
Sznol M, Powderly JD, Smith DC, Brahmer JR, Drake CG, McDermott DF (2010). Safety and 
antitumor activity of biweekly MDX-1106 (anti-PD-1, BMS936558/ONO-4538) in patients with 
advanced refractory malignancies. Proc Am Soc Clin Oncol 28: abstr 2506. 
Talmadge JE, Donkor M, Scholar E (2007). Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 26(3-4): 373-400. 
Thompson RH, Dong H, Lohse CM, Liebovich BC, Blute ML, Cheville JC, et al.  PD-1 is 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients 
with renal cell carcinoma.  Clin Cancer Res 2007;13:1757-61. 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. (2012). 
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26): 
2443-2454. 
Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. (2006). 
Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune 
dysfunction. Nat Med 12(10): 1198-1202. 

NCI Protocol # CITN-09 
Version Date: May 22, 2018 
117 
Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S (1998). Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 17(1): 77-81. 
Veness M, Foote M, Gebski V, Poulsen M (2010). The role of radiotherapy alone in patients 
with merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat 
Oncol Biol Phys 78(3): 703-709. 
Wherry EJ (2011). T cell exhaustion. Nat Immunol 12(6): 492-499. 
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. (2009). Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin 
Cancer Res 15(23): 7412-7420. 
Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D, Lejeune F, et al. (2004). Effector 
function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional 
tolerance. Cancer Res 64(8): 2865-2873. 
Zou W, Chen L (2008). Inhibitory B7-family molecules in the tumour microenvironment. Nat 
Rev Immunol 8(6): 467-477. 
 

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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 

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119 
APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP-sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO). The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments. The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair. 
There will be only one version of the protocol, and each participating institution will use 
that document. The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress. All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH. The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Before the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration. The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site before the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports. There are 2 options 
for AE reporting: (1) participating institutions may report directly to CTEP with a copy to 
the Coordinating Center, or (2) participating institutions report to the Coordinating Center 
who in turn report to CTEP. The Coordinating Center will submit AE reports to the 
Protocol Chair for timely review. 
• Audits may be accomplished in one of 2 ways: (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites. If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
 

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120 
Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and 
the name, telephone number and email address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required. The procedures for registration must be 
stated in the protocol. 
 Data collection forms should be of a common format. Sample forms should be 
submitted with the protocol. The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP. Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 

NCI Protocol # CITN-09 
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121 
APPENDIX C 
BIOASSAY TEMPLATES  
 
Correlative objective 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
M/O  
mRNA expression profiling (Nanostring 
focused on immune genes) 
Jennifer Yearly, MD (Merck Research Labs) 
Nanostring mRNA 
expression on approximately 
400 immune genes 
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible) 
M 
Gene expression profiling (Nanostring) 
(NanoString Technologies) 
Nanostring gene expression 
of up to 800 genes 
Tumor: Prior to treatment , and at 
time of confirmed progression (if 
feasible) 
M 
Tumor PD-L1 Expression 
Mary Savage, PhD (Merck Research Labs) 
Chromogenic IHC 
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible) 
M 
Tumor PD-1 & PD-L1 Expression 
Jennifer Yearly, DVM PhD (Merck Research 
Labs) 
Multicolor IHC  
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible)  
M 
Tumor PD-1 & PD-L1 Expression 
Janis Taube MD (Johns Hopkins) 
Multispectral 
immunofluorescence 
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible) 
M 
Immune cell infiltrate markers: CD3, CD8, 
and MHC Class I. Optional markers: CD4, 
CD56, CD16, CD45, CD19, CD68, GITR, 
TIM-3, FOXP3 and LAG3 
Julie Habecker MD 
(FHCRC Core Lab or PhenoPath) 
IHC  
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible) 
M 
Merkel cell polyomavirus (MCPyV) DNA 
Meei-Li Huang PhD (FHCRC) 
PCR 
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible) 
M 
Merkel cell polyomavirus (MCPyV) 
Protein Expression 
Julie Habecker MD (FHCRC Core Lab) 
IHC 
Tumor: Prior to treatment biopsy 
tissue and at time of confirmed 
progression (if feasible) 
M 
MCPyV specific T cell 
Immunophenotyping 
Paul Nghiem MD PhD  
(University of Washington) 
MCPyV peptide specific 
tetramer isolation 
 
PBMC: Prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy.  
M 
MCPyV specific T cell gene expression 
analysis 
Jennifer Yearly, MD (Merck Research Labs) 
mRNA expression 
(Nanostring) 
PBMC: Prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy 
M 
MCPyV specific T cell IFN-γ responses 
Steve Fling PhD (University of Washington) 
IFN-γ ELISpot 
PBMC: Prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy 
M 
MCPyV specific antibody specific for T-
Ag oncoprotein & VP1  
Mark Wener MD  
(University of Washington, Lab Medicine) 
Luminex 
Serum: Prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy. 
M 
PBMC and T cell subset quantification 
(frequency and percent) of CD4 T cells, 
CD8 effector memory and central 
memory, Treg, NK and MDSC. 
Steve Fling PhD (University of Washington) 
Multiparameter flow 
cytometric analysis  
PBMC: Prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy 
M 
T cell functional status/phenotype 
Julie McElrath MD PhD (FHCRC) 
Intracellular cytokine 
staining 
PBMC: Prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy 
M 

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122 
Correlative objective 
Assay 
Tissue/Body Fluid Tested 
and Timing of Assay 
M/O  
Exome sequencing and RNA sequencing 
Neon Therapeutics or equivalent vendor 
Gene sequencing 
Tumor: Prior to treatment 
M 
Neoantigen identification 
Neon Therapeutics or equivalent vendor 
Bioinformatics 
Tumor: Prior to treatment 
M 
T cell receptor sequencing 
Edus Warren Lab (FHCRC)  
PCR 
Tumor: Prior to treatment 
M 
PBMC functional phenotyping 
Edus Warren Lab (FHCRC) 
Flow cytometry 
PBMC: Prior to treatment 
M 
Kyn/Trp ratio 
Incyte Corporation 
mass spectrometry 
Plasma: prior to treatment & every 
9 to 12 weeks (prior to cycles 
correlated with tumor imaging) 
and end of therapy  
M 
 
 
This 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. PMCID: PMCID 
 
This 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. PMCID: PMCID 
 
Bianchini M, De Pietri L, Villa E. Coagulopathy in liver diseases: complication or therapy? Dig 
Dis 2014;32(5):609-614. PMCID,  
 
Blasi A. Coagulopathy in liver disease: Lack of an assessment tool. World J Gastroenterol 
2015;21(35):10062-10071. PMCID: PMC4572787 
 
Haq I, Tripathi D. Recent advances in the management of variceal bleeding. Gastroenterol Rep 
(Oxf) 2017;5(2):113-126. PMCID: PMC5421505