A Phase 2 Study of MK-3475 for the Treatment of Relapsed/Refractory Mycosis Fungoides/Sezary Syndrome
Phase: PHASE2
Conditions: Recurrent Mycosis Fungoides and Sezary Syndrome, Refractory Mycosis Fungoides and Sezary Syndrome, Stage IB Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage IIA Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage IIB Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage IIIA Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage IIIB Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage IVA Mycosis Fungoides and Sezary Syndrome AJCC v7, Stage IVB Mycosis Fungoides and Sezary Syndrome AJCC v7
Sponsor: National Cancer Institute (NCI)

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SUMMARY OF CHANGES 
 
For Protocol Amendment #4, Version 2.0 
 
NCI Protocol #: CITN-10 
Local Protocol #: CITN-10 
 
Protocol Date: March 8, 2018  
 
 
I. Comments Requiring a Response– Administrative & Editorial Issues: 
# 
Section 
Comments 
1. 
ICD 
Risks 
When updating risks outside of the CTEP process, they should be placed outside 
of the CTEP provided condensed risk list tables. 
That said, with an extensive set of changes, please contact CTEP in the future to 
discuss prior to making changes to the “Condensed Risk List.”  CTEP is 
undergoing a review of the latest (mid-October version) Investigator Brochure for 
MK-3475.  A Request for Rapid Amendment is forthcoming, which could 
complicate any changes that CITN is contemplating. 
PI Response: Agree. See ICD Summary of Changes 
 
 
II. Recommendations: 
# 
Section 
Comments 
2. 
8.1.1 
MK-3475 Storage: following “Store intact vials between 2°C - 8°C (36°F - 46°F). 
Do not freeze.” please add: 
If a storage temperature 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. 
PI Response: Agree. The recommended wording was added to section 8.1.1 
 
 
 
 
 

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III. Changes Recommended by CTEP 
# 
Section 
Page(s) 
Change 
3.  8.1.1 
63 
Information regarding MK-3475 storage was updated to include “If 
a storage temperature 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.” 
 
IV.  Administrative Changes 
# 
Section 
Page(s) 
Change 
4.  Throughout 
protocol 
All 
pages 
 
Updated version date in header 
5.  Title Page 
2 
Updated protocol type, version number and version date. Date matches 
revised consent form.   
 
 
V. Changes Requested by CTEP 
# 
Section 
Page(s) 
Change 
6.  Title page  
3 
CTSU Regulatory Office mailing address change implemented 
7.  4.2.2 
Submitting 
Regulatory 
Documents 
30 
CTSU Regulatory Office mailing address change implemented 
 
8.  Throughout 
42 
Updated CTCAE v4.0 to CTCAE v5.0 throughout document with the 
exception of the CAEPR (Section 7.1.1) 
9.  7.2 Adverse 
Event 
Characteristics 
57 
Added language pertaining to timing of implementation of CTCAE v 
5.0 reporting 
10.  7.3.3 
Expedited 
Reporting 
Guidelines 
58 
Revised language concerning expedited reporting of death due to 
progressive disease. 
11.  7.3.3 
Expedited 
Reporting 
Guidelines 
59 
Added language concerning reporting pregnancy loss. 
 
12.  7.3.3 
Expedited 
Reporting 
Guidelines 
59 
Added language concerning reporting neonatal death. 

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NCI Protocol #: 
CITN-10 
 
Local Protocol #: 
CITN-10 
 
TITLE: A Phase 2 Study of MK-3475 for the treatment of Relapsed/Refractory 
Mycosis Fungoides/Sézary Syndrome 
 
Coordinating Center: 
Cancer Immunotherapy Trials Network, Fred Hutchinson 
Cancer Research Center  
Principal Investigator (PI): 
Youn Kim, M.D. 
Department of Dermatology, Stanford Univ.  
School of Medicine 
900 Blake Wilbur Drive, Room W1005 
Stanford, CA 94305 
CTEP Institution Organization ID#:  CA141  
Tel: (650) 721-7186 
Email: younkim@stanford.edu 
 
 
 
 
Participating Organizations :  CITN – Cancer Immunotherapy Trials Network 
 
 
 

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Statistician: 
 
 
Study Coordinator: N/A 
Shufeng Li 
Department of Dermatology, Stanford Univ. School of Medicine  
900 Blake Wilbur Drive, Room 1080 
Stanford, CA 94305 
717-406-4371 
shufeng@stanford.edu 
 
 
Responsible Research Nurse: N/A  
Responsible Data Manager: N/A 
NCI-Supplied Agent: MK-3475, (SCH 900475) NSC# 776864/ Merck Sharp & Dohme Corp. a 
Subsidiary of Merck & Co. Inc.  
IND #: 123635 
IND Sponsor: DCTD, NCI  
Protocol Type/Version #/Version Date: 
  Amendment 4/Version 2/March 8, 2018   
   
 
 

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CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
To submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 
3000 
Philadelphia, PA 19103 
Phone – 1-866-651-CTSU 
Fax – 215-569-0206 
Email: 
CTSURegulatory@ctsu.cocc
g.org (for submitting 
regulatory documents only) 
Please refer to the patient enrollment 
section for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) at 
https://www.ctsu.org/OPEN_SYSTE
M/ 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 current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org. Access to the CTSU members’ website is managed through the Cancer 
Therapy and Evaluation Program - Identity and Access Management (CTEP-IAM) registration 
system and requires 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 206-667-1216 
For nonclinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
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. 
 
 

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SCHEMA 
 
Abbreviated Title 
MK-3475 For the Treatment Of Relapsed/Refractory 
Mycosis Fungoides/Sézary Syndrome (MF/SS) 
Trial Phase 
Phase II 
Clinical Indication 
Stage IB-IVB MF/SS, and who have relapsed, are refractory, 
or progressed after at least one standard systemic therapy 
Trial Type 
Nonrandomized, open-label, phase II, interventional study 
Type of control 
None 
Route of administration 
Intravenous (IV) 
Trial Blinding 
None 
Treatment Groups 
The dose level of MK-3475 proposed to be tested in this 
study will be 2 mg/kg administered by IV infusion q3w 
(21 [± 3] days). Treatment cycles will be 21 days with the 
first clinical response assessment at week 12 (after 4 doses 
of MK-3475 have been administered during week 1, 4, 7 and 
10). If progression is seen at week 12 a confirmatory 
assessment will be performed at week 16.  If progression is 
confirmed at week 16 or beyond, patients may continue to 
receive MK-3475 therapy if otherwise clinically stable.  If 
no progression is seen at week 12, the next assessment will 
be at week 18, then every 2 cycles (every 6 weeks) through 
week #30. (Assessments will be performed at weeks 24 and 
30). After week #30 study assessments will be reduced to 
every 4 cycles (every 12 weeks) and will be performed at 
weeks 42, 54, 66, 78, 90 and 104 (end of study). Not all 
MF/SS patients have disease that is measurable by computed 
tomography (CT) scan so the term “assessment” refers to the 
Olsen global assessments which include composite 
assessments of skin (assessed by mSWAT), lymph nodes 
(assessed by CT), viscera (by CT) and blood tumor burden 
of circulating Sézary cells (CSCs) via flow cytometry. At 
each assessment time point patients will receive CT scans (if 
they have measurable disease), mSWAT and flow cytometry 
for CSCs. Subjects with CR after receiving a minimum of 6 
months of treatment with at least 2 doses since CR may 
discontinue therapy. Subjects with a CR who progress may 
be retreated if (1) no cancer treatment was administered 
since the last dose of MK-3475, (2) subject continues to 
meet eligibility criteria, and (3) the trial is open. Subjects 
without confirmed progression of disease may receive up to 
a maximum of 2 years of therapy.  

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Number of trial subjects 
In this Phase II trial, 9 subjects will be enrolled in Stage 1 
and 15 subjects may be enrolled in Stage 2. In total a 
maximum of 24 subjects will be enrolled. 
Estimated duration of trial In this Phase II trial Stage 1 will enroll over 5-10 months, 
and Stage 2 will enroll over 10-20 months. In total the trial 
will be enrolled over 15-30 months. 
Duration of Participation 
First assessment of primary endpoint of clinical response at 
week 12. If progression, confirmatory assessment at week 
16. If no progression, next assessment at week 18 and then 
every 6 weeks (every 2 cycles) through week #30.  
Assessments after week 30 will be every 4 cycles (every 12 
weeks) including weeks 42, 54, 66, 78, 90 and 104 (end of 
study).  Subjects are followed for overall response, 
progression free survival, duration of response, and overall 
survival. Immune response assays will be performed pre-
study, following cycle 1 (on the first day of cycle #2) and 
then upon the first day of every 3rd cycle thereafter including 
cycles 5,8,11, etc.    
 
SCHEMA (Continued) 
CITN, multi-institution, non-randomized, open-label, phase II study of systemic intravenous 
infusion of MK-3475 in relapsed/refractory MF/SS. Simon’s Optimal Two-Stage Design: 
Stage 1 will enroll 9 patients.  Stage 2:  Will enroll an additional 15 patients (for a total of 
24).  If there are one or more responses (PR or CR) amongst the nine patients enrolled in Stage 1, 
Stage 2 enrollment will proceed.  If there are no responses (PR or CR) amongst the nine patients 
enrolled in Stage 1, enrollment into Stage 2 will not proceed.  The null hypothesis (H0) MK-
3475 will show less than 5% overall response rate.  The alternative hypothesis (H1) MK-3475 
will show greater than 25% overall response rate (PR and CR).   
 
 

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TRIAL DIAGRAM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relapsed/Refractory 
MF and SS 
Stage 1 
N=9 
• Tx - MK-3475 will be 2 mg/kg administered by IV infusion q3w (21 [± 
3] days). Treatment cycles will be 21 days with first clinical response 
assessment at week 12, then again at either week 16 or 18, then after every 
2 cycles (every 6 weeks) through week 30, then every 4 cycles (every 12 
weeks) with treatment continued until confirmed progression by repeat 
assessment at least 4 weeks later.  If progression is confirmed at week 16 
or beyond, patients may continue to receive MK-3475 therapy if otherwise 
clinically stable.  Subjects with CR after receiving a minimum of six 
months of treatment with at least two doses since CR may discontinue 
therapy. Subjects with a CR who progress may be retreated if (1) no cancer 
treatment was administered since the last dose of MK-3475, (2) subject 
continues to meet eligibility criteria, and (3) the trial is open. Subjects may 
receive up to a maximum of 2 years of therapy if clinically improving or 
stable (Section 5.4). 
• Assessment –  
o Clinical response – At week 12, then at either week 16 or 18, then every 
6 weeks to week #30, then every 12 weeks thereafter.  
o Immune response – following cycle 1 and upon completion of every 3rd 
cycle. and at time of confirmed CR, PR, PD or EOT visit 
With regard to efficacy/clinical 
response, in order to determine the 
sample size, we use an optimal 2-stage 
design since it minimizes the expected 
sample size given a poor response 
rate. The null hypothesis is set at 5% 
(p0 0.05), the alternative hypothesis is 
25% (p1 0.25) and the desired 
significance level (α) and desired 
power (β) are 0.1 and 0.9, 
respectively. The total number of 
subjects for the trial will be 24 
subjects, whereas 9 subjects will be 
accrued during stage 1 and 15 subjects 
accrued during stage 2. However, if 
no responses (CR or PR) are observed 
during the first stage, then further 
enrollment will be suspended.  
Patients currently on study who 
qualify will continue to be treated and 
followed.   
Stage 2 
N=15 
• Tx - MK-3475 will be 2 mg/kg administered by IV infusion q3w (21 [± 
3] days). Treatment cycles will be 21 days with first clinical response 
assessment at week 12, then again at either week 16 or week 18, then 
every 2 cycles to week #30, then every 4 cycles (every 12 weeks) with 
treatment continued until confirmed progression by repeat assessment at 
least 4 weeks later.  If progression is confirmed at week 16 or beyond, 
patients may continue to receive MK-3475 therapy if otherwise 
clinically stable. Subjects with CR after receiving a minimum of six 
months of treatment with at least two doses since CR may discontinue 
therapy. Subjects with a CR who progress may be retreated if (1) no 
cancer treatment was administered since the last dose of MK-3475, (2) 
subject continues to meet eligibility criteria, and (3) the trial is open. 
Subjects may receive up to a maximum of 2 years of therapy if clinically 
improving or stable. 
• Assessment –  
o Clinical response – At week 12, then at either week 16 or 18, then 
every 6 weeks to week #30, then every 12 weeks thereafter. 
o Immune response – following cycle 1 and upon completion of every 
3rd cycle. and at time of confirmed CR, PR, PD or EOT visit 
 
Final Assessment: 
With regard to efficacy/clinical 
response, in order to determine the 
sample size, we used an optimal 2-
stage design since it minimizes the 
expected sample size given a poor 
response rate. The null hypothesis is 
set at 5% (p0 0.05), the alternative 
hypothesis is 25% (p1 0.25) and the 
desired significance level (α) and 
desired power (β) are 0.1 and 0.9, 
respectively. The total number of 
subjects for the trial will be 24 
subjects, 15 subjects will be accrued 
during stage 2. However, if 3 or more 
responses (CR or PR) are observed 
during the first and second stage 
combined, the trial will be considered 
a success 

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TABLE OF CONTENTS 
SCHEMA .........................................................................................................................................4
1.
OBJECTIVES ....................................................................................................................10
Primary Objectives .................................................................................................10
Secondary Objectives .............................................................................................10
2.
BACKGROUND ...............................................................................................................10
Relapsed/Refractory Mycosis Fungoides/Sézary Syndrome .................................10
CTEP IND Agent: MK-3475 .................................................................................12
Rationale ................................................................................................................15
Correlative Studies Background ............................................................................19
3.
PATIENT SELECTION ....................................................................................................23
Eligibility criteria ...................................................................................................23
Exclusion Criteria ..................................................................................................25
Inclusion of Women and Minorities ......................................................................28
4.
REGISTRATION PROCEDURES ...................................................................................29
Investigator and Research Associate Registration with CTEP ..............................29
Site Registration .....................................................................................................30
Patient Registration ................................................................................................31
General Guidelines .................................................................................................32
5.
TREATMENT PLAN ........................................................................................................32
Agent Administration .............................................................................................32
Definition of Dose-Limiting Toxicity: N/A ...........................................................33
General Concomitant Medication and Supportive Care Guidelines ......................33
Duration of Therapy ...............................................................................................34
Duration of Follow Up ...........................................................................................36
Criteria for Removal from Study ...........................................................................36
Criteria to Resume Treatment ................................................................................36
Treatment Beyond Progression ..............................................................................37
Discontinuation of Treatment Following Complete Response ..............................39
Treatment Up to 2 Years ........................................................................................39
6.
DOSING DELAYS/DOSE MODIFICATIONS................................................................39
6.1
MK-3475 Dose Modifications ...............................................................................39
7.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................53
Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................53
Adverse Event Characteristics ...............................................................................57
Expedited Adverse Event Reporting ......................................................................58
Routine Adverse Event Reporting .........................................................................61
Secondary Malignancy ...........................................................................................61
Second Malignancy ................................................................................................61
7.7
Reporting of Pregnancy and Lactation to the Sponsor ..........................................62

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8.
PHARMACEUTICAL INFORMATION ..........................................................................62
CTEP IND Agent(s) (MK-3475) ...........................................................................62
9.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................64
Biomarker Studies ..................................................................................................65
Laboratory Correlative Studies ..............................................................................68
Special Studies (Kyn/Trp Ratio) ............................................................................73
10.
STUDY CALENDAR .......................................................................................................74
11.
MEASUREMENT OF EFFECT........................................................................................79
Antitumor Effect – Solid Tumors ..........................................................................79
Antitumor Effect – Hematologic Tumors: N/A .....................................................85
Other Response Parameters: N/A ..........................................................................85
12.
DATA REPORTING/REGULATORY REQUIREMENTS .............................................85
Data Reporting .......................................................................................................85
CTEP Multicenter Guidelines ................................................................................87
Collaborative Agreements Language .....................................................................87
13.
STATISTICAL CONSIDERATIONS...............................................................................89
13.1
Responsibility for Analyses ...................................................................................89
13.2
Study Design/Endpoints.........................................................................................90
13.3
Analysis Endpoints ................................................................................................90
13.4
Analysis Populations ..............................................................................................91
13.5
Statistical Methods .................................................................................................91
13.6
Multiplicity ............................................................................................................93
13.7
Sample Size/Accrual Rate and Power Calculations ...............................................93
13.8
Stratification Factors- N/A .....................................................................................93
13.9
Interim Analyses ....................................................................................................94
13.10 Compliance (Medication Adherence) ....................................................................94
13.11 Extent of Exposure .................................................................................................94
13.12 Analysis of Secondary Endpoints ..........................................................................94
13.13 Reporting and Exclusions ......................................................................................94
14.
Study Status Updates and Study Closure ...........................................................................95
Definitions of Study Status Changes .....................................................................95
Responsibility for Filing Protocol Status Update Forms .......................................96
REFERENCES ..............................................................................................................................98
APPENDIX A 
PERFORMANCE STATUS CRITERIA ................................................104
APPENDIX B 
CTEP MULTICENTER GUIDELINES ..................................................105
APPENDIX C  
STANDARDIZED MEDICAL PHOTOGRAPHY .................................107
APPENDIX D 
BIOASSAY TEMPLATES .....................................................................108

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APPENDIX E 
MODIFIED SEVERITY-WEIGHTED ASSESSMENT TOOL  ............110 
APPENDIX F 
TNMB CLASSIFICATION AND STAGING OF  MF/SS .....................112 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. OBJECTIVES 
Primary Objectives 
To assess the response rate of MK-3475 in subjects with relapsed/refractory mycosis 
fungoides/Sézary syndrome (MF/SS). 
Hypothesis: Administration of MK-3475 to subjects with relapsed/refractory MF and SS will 
result in a clinically meaningful objective response rate. 
Secondary Objectives
To explore the clinical activity of MK-3475 in subjects with relapsed/refractory MF and SS with 
respect to the following endpoints: 
• Duration of response (DOR) 
• Progression-free survival (PFS) 
• Overall survival (OS) 
Hypothesis: Induction of a meaningful objective response rate with MK-3475 will be reflected 
in other clinical outcome parameters including DOR, PFS, and OS. 
2. BACKGROUND 
 
Relapsed/Refractory Mycosis Fungoides/Sézary Syndrome
Mycosis fungoides/Sézary syndrome is the most common type of cutaneous T-cell lymphoma 
(CTCL), a subset of mature non-Hodgkin lymphoma. MF exhibits an epidermotropic clonal 
expansion of cluster of differentiation 4–positive (CD4+) T helper cells that induces pleomorphic 
skin lesions. MF may present gradually over many years as an indolent, chronic skin disease or 
present with more rapidly advancing skin disease, especially in those with worse prognostic 
factors such as folliculotropism or large cell transformation. SS is a leukemic variant of CTCL in 
which subjects have generalized erythroderma and are at risk for lymph node and visceral 
disease. MF/SS comprise the most common CTCLs, with continued increase in overall 
annual incidence (currently approximately 0.9 per 100,000 persons in the United States) [Hoppe 
1995]. There is a 2:1 male to female prevalence and peak age of presentation is 55 to 60 years. It 
is rarely seen in the pediatric age group (i.e., diagnosis at age <18 years of age). The cutaneous 
manifestations of MF are heterogeneous [Horwitz 2008]. 
Therapeutic options for MF and SS are primarily determined by the patient’s clinical stage. The 
National Comprehensive Cancer Network (NCCN) has recently published consensus guidelines 
for stage-based treatment of MF/SS [NCCN]. The first-line treatment of early stage MF (IA, IB, 
and IIA) are skin-directed therapies including phototherapy, topical medications (corticosteroids, 
chemotherapeutic agents, and retinoids), and radiation therapy. 
At more advanced stages (i.e., IIB and higher), systemic therapies are often utilized. These 
include bexarotene, approved by the U.S. Food and Drug Administration (FDA) based on 
improved response rates, vorinostat, interferons, extracorporeal photopheresis (ECP), denileukin 

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diftitox, radiation therapy, traditional chemotherapeutic agents (methotrexate, doxorubicin, 
gemcitabine, and chlorambucil), and investigational agents. Despite a wide array of available 
therapeutic options, subjects with MF and SS remain largely incurable. Response rates for most 
of these systemic agents are 30-40% with infrequent complete responses (CR); these 
clinical responses are often short-lived with most approved agents yielding median DORs in 
the range of 6-12 months [Duvic 2001]; [Olsen 2001]; [Olsen 2007]; [Whittaker 2010].  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis 2010]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable 
prognosis in various malignancies [Dong 2002]; [Sharpe 2002]; [Brown 2003]; [Thompson 
2007]; [Francisco 2010]. In particular, the presence of CD8+ T cells and the ratio of CD8+ 
effector T cells/FoxP3+ regulatory T cells (Tregs) seems to correlate with improved prognosis 
and long-term survival in many solid tumors. 
There is mounting evidence that T cell immunity may be responsible for clinical antitumor 
activity in MF/SS: 
2.1.1 Tumor-infiltrating T cells are prognostic of survival. 
a. Hoppe et al. identified improved survival in MF subjects whose biopsies 
demonstrated CD8+ TILs, even when controlling for stage [Hoppe 1995]. 
2.1.2 Therapies which augment T cell function are effective in MF/SS. 
a. Interferon alpha has been shown in a number of studies to be a highly active agent in 
CTCL with overall response rates (ORRs) ranging from 40% to 80% with concurrent 
improvement in T cell cytotoxicity [Bunn 1986]; [Olsen 1995]. 
b. Interferon gamma has been used as a monotherapy in 16 patients with refractory 
disease, with an ORR of 30% and DOR of 10 months and concurrent augmented T-
cell activity [Kaplan 1990]. 
c. Early studies with high-dose interleukin 2 (IL-2) demonstrated activity in relapsed 
CTCL but with significant toxicity [Heald 1992]; [Heald 1990]. 
d. IL-12 has also demonstrated activity in relapsed CTCL. In phase I and II studies, 
nearly half of the 32 evaluable patients achieved a response, and toxicities included 
myalgias, fatigue, and chills [Rook 2002]; [Rook 2001]. 
e. ECP is an immunomodulatory apheresis-based therapy that works directly on both 
subsets of T cells and on the precursors of maturing dendritic cells [Heald 1992]; 
[Heald 1990]; [Zic 1992]; [Prinz 1995]; [Owsianowski 1996]; [Di Renzo 1997] 
[Miracco 1997]; [Jiang 1999]. 
f. Other immunotherapy agents have been combined with photophoresis including 
retinoids, interferons, and cytokine growth factors. 

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i.
Richardson and colleagues have reported high response rates in patients with the 
SS when ECP therapy was administration with immune adjuvant therapies, 
including interferon alpha (INF-α) and bexarotene [Rook 2002]. 
g. A modification of ECP known as transimmunization may improve tumor-targeted 
response. 
i. 
Transimmunization involves co-incubating the apoptotic malignant T cells and 
the newly formed dendritic cells prior to reinfusion in order to optimize antigen 
processing and stimulate a more efficient induction of tumor-targeted immunity. 
The goal of treatment is to transfer the disease-associated antigens to antigen-
presenting dendritic cells, thus initiating immunization against these antigens 
[Girardi 2002], [Girardi 2002], [Berger 2002], [Edelson 2001]. 
h. In a phase I study of 28 patients with recurrent or advanced CTCL who received 
CPG7909, the Toll-like receptor 9 (TLR9) agonist, in weekly subcutaneous doses of 
0.08, 0.16, 0.24, or 0.28 mg/kg for 24 weeks, the ORR was 25% [Kim 2004]. Five 
patients (18%) achieved partial response (PR) and 2 (7%) achieved CR. Kim reported 
clinical responses in 5/15 subjects in an in-situ vaccination trial in which CPG (a 
TLR9 agonist) was combined with local radiation therapy [Kim 2012] validating the 
potential of T-cell responses and the likelihood of existent nascent T-cell responses. 
i. Allogeneic stem cell transplantation (SCT) is superior to autologous. Allogeneic SCT 
in MF/SS demonstrates improved overall and event-free survival than autologous 
SCT recipients, possibly due to a graft versus lymphoma effect [Wu 2009], validating 
that T-cell responses can potentially eradicate the disease. 
j. Alemtuzumab removes circulating T central memory cells, without effect on T 
effector memory cells, and Sézary cells from the circulation. 
CTEP IND Agent: MK-3475 
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 

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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 
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-

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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 
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 

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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.
Rationale 
Recent evidence of expression of PD-1 and PD-L1 in MF/SS has uncovered an additional 
mechanism of potential immune escape and a new therapeutic target. Current data suggest that 
the PD-1/PD-L1 may play a significant role in preventing immune-driven eradication of MF/SS 
tumor population. A 2012 study evaluated the expression of PD-1 and PD-L1 in various 
morphological subsets of MF ranging from patch/plaque to tumor stage with or without large cell 
transformation [Kantekure 2012] (Figure 2.3.1).  
Figure 2.3.1 PD-1/PD-L1 Expression in CTCL/MF
PD-1 and PD-L1 expression at various stages of CTCL/MF: patch/plague (upper row), tumor 

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(middle row), and large cell transformation (lower row). The formalin-fixed paraffin-embedded 
(FFPE) skin biopsy tissue sections were stained with H&E (left column) or antibodies against 
PD-1 (middle column) or PD-L1 (right column). The depicted images are representative of the 
26 CTCL cases examined and were captured at the 4003 magnification. The blue arrows in the 
PD-1 stain of the large cell transformation case highlight the negative large lymphocytes). 
A 2012 study evaluated the expression of PD-1 and PD-L1 in various morphological subsets of 
MF ranging from patch/plaque to tumor stage with or without large cell transformation 
[Kantekure 2012]. In this study, 9/9 patch/plaque and 5/6 tumor lesions showed >2% PD-1 
expression of atypical lymphocytes via immunohistochemistry. In comparison, large transformed 
lymphocytes showed reduced expression of PD-1, with only 2/11 demonstrating >2% 
expression. On the other hand, PD-L1 expression was quite strong across all subsets, with 
7/9 patch/plaque, 6/6 tumor stage, and 11/11 large transformed lymphocytes demonstrating 
>50% expression. In the 2/9 patch/plaque lesions with less than 50% PD-L1 expression, the 
staining was still greater than 2%. 
Figure 2.3.2 PD-1 Expression 
Figure 2.3.3 Blocking PD-1 Increases INF-γ 
 
 
[Samimi 2010]; and [Rook 2002] also demonstrated higher expression of PD-1 and PD-L1 via 
flow cytometry on peripheral blood T cells in SS subjects [Samimi 2010] (See Figure 2.3.2. 
Increased expression of PD-1 on CD4+ T cells from patients with SS. The peripheral blood 
mononuclear cells (PBMCs) from patients with SS (n=7), patients with MF (n=4), and healthy 
donors (n=4) were stained with anti-CD4, anti-PD-1, and anti-CD26, and were analyzed by flow 
cytometry. The percentage of CD4+PD-1+ is demonstrated according to patient population and 
CD26 status. Error bars indicate the standard deviation of uncertainty.) 
When blocking PD-1 and PD-L1 in vitro, interferon-γ (IFN-γ) production increased, perhaps 
indicating recovery of T-cell function after withdrawing the suppressive PD-1/PD-L1 signal 
(Figure 2.3.3.) Blocking the pathway of PD-1 and its ligand PD-L1 results in increased IFN-γ 
production by patients’ PBMCs stimulated with anti-CD3/CD28. The PBMCs of patients with 
SS were cultured for 72 hours with either medium or anti-CD3/CD28 alone, and with the 
following: murine IgG (mIgG), anti-PD-1, or anti-PD-L1. Subsequently, culture supernatants 
were collected and tested for the presence of IFN-γ. Furthermore, PD-1 expression levels, along 
with the overall proportion of the malignant T-cell population, decreased as a SS patient 
improved clinically during treatment. Preliminary data supports the induction of PD-L1 by 
standard therapies in MF/SS including radiation, epigenetic therapies, and interferon. 

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Collectively, these data suggest that PD-1 and PD-L1 are expressed aberrantly on the malignant 
tumor cells of MF/SS, further augmented by current therapies, and that blockage of these signals 
may lead to reduced antitumor T-cell inhibition and thus tumor eradication. 
Recent data of BMS-936558 have validated PD-1 as an attractive target for clinical intervention 
and have provided proof of concept for anti-PD-1 mAbs in melanoma and renal cell carcinoma 
(RCC) [Sznol 2010]. BMS-936558 has shown an ORR of approximately 30% in patients with 
advanced melanoma and RCC who had failed prior therapy [Sznol 2010]. In addition, ORR of 
near 20% was observed in patients with NSCLC [Brahmer 2012]; [Sznol 2010]. Importantly, 
responses were of long duration, and BMS-936558 was generally well tolerated. The repeat dose 
study tested multiple dose levels (0.1, 0.3, 1, 3, and 10 mg/kg every 2 weeks) [Sznol 2010]; 
[Robert 2011]. Importantly, as MF/SS appears to express a high level of PD-L1, the ability of 
PD-L1 to predict response to PD-1 targeted therapy is of relevance. In mixed tumor types 
including melanoma and NSCLC, among others, this observation has been reported and 
validated. In 3 recent reports, response rates among PD-L1–positive patients are 42%, 41%, and 
34%, compared to 0%, 14%, and 16% among PD-L1–negative patients [Topalian 2012]. 
Additional biomarker analysis to predict response to PD-1 targeted therapies, demonstrated that 
patients with a history of or present tobacco use and thus a higher rate and number of mutations 
in NSCLC respond more frequently, 26%, than those without a tobacco history (10%). As 
MF/SS is considered a highly immunogenic and PD-L1–expressing tumor, it is likely to be 
responsive to PD-1 targeted therapy. 
Figure 2.3.4 MF response to 8 cycles 
Figure 2.3.5 MF response to 3 cycles 
 
Finally, 2 recent cases of MF/SS enrolled on the MPDL3280A clinical trial of an IgG1 
engineered mAb against PD-L1 both of whom obtained PRs support further testing of PD-1 
targeted agents in this disease [Kohrt ASCO 2013]. The first patient was a 65-year-old man with 
Stage IB multiply relapsed MF (history of phototherapy: PUVA, bexarotene, anti-CD4 mAb, 

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forodesine, CpG and radiation, lenalidomide, sapacitabine, enzastaurin, and total skin electron 
beam therapy) who obtained a PR at first assessment (following 2 cycles) and has maintained a 
deep PR following 16 cycles (1 year) of treatment. (See Figure 2.3.4. Lesion on right forearm 
pretreatment [top left] and following 8 cycles of therapy [top right]. Lesion on right upper thigh 
pretreatment [bottom left] and following 8 cycles of therapy [bottom right]). The second case 
was a 58-year-old woman with Stage IIIB multiply relapsed MF (history of photochemotherapy: 
PUVA + bexarotene, CpG and radiation, vorinostat, forodesine, bexarotene, sapacitabine, 
lenalidomide, enzastaurin, low-dose total skin electron beam therapy) who obtained a PR after 2 
cycles of therapy with a reduction in Modified Severity-Weighted Assessment Tool (mSWAT) 
score (which scores extent and burden of disease in MF) from 90 at baseline to 42. Following 7 
cycles of therapy, anti-PD-L1 was discontinued due to patient-reported profound fatigue and her 
disease progressed thereafter (See Figure 2.3.5. Lesion on right foot consistent with 
erythroderma prior to therapy [top left] and on day 1 of cycle 3 [top right]. mSWAT score over 
the course of treatment on clinical trial MPDL3280A [bottom]). 
The primary endpoint of this current study (CITN-10) is clinical response. This endpoint will 
first be evaluated by clinical response (global) assessment per [Olsen] at week 12 (after 4 doses 
of MK-3475 during week 1, 4,7 and 10). If progressive disease (PD) is seen at week 12, a 
confirmatory assessment will be performed at week 16. If no progression is seen at week 12, 
subjects will be assessed again at week 18. After this, subjects will be assessed every 2 cycles 
(every 6 weeks) through week #30, then every 4 cycles (every 12 weeks) thereafter with the best 
response being assessed based on specific criteria relevant to the histologies of MF/SS: 
1) Consensus response criteria in MF/SS [Olsen 2011] 
2) Compartmental assessments of skin, blood, lymph nodes, and viscera, as appropriate 
(Olsen response criteria, see Protocol Section 11)) 
3) Global response will be determined from compartmental response, to determine ORR 
(Protocol Section 11) 
 
If progression is determined at week 16 or beyond, patients will be eligible to receive continued 
MK-3475 if they are clinically stable as defined by the following criteria.  (The maximum 
duration of therapy in this setting is the same as for other patients, 2 years).    
• Absence of signs and symptoms indicating disease progression 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
The following assessment and stopping criteria apply to patients who continue MK-3475 beyond 
progression: 
• Patients who continue therapy after progression will have mSWAT performed with every 
cycle (every 3 weeks) and a full Olsen Criteria assessment including mSWAT, CT scans, 
for those with measurable disease, and CSC, if positive for Sézary cells, every 4 cycles 
(every 12 weeks).  At the discretion of the investigator these assessments may be 
repeated more frequently. 

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• Study drug will be discontinued if any compartment increases in value by 25% or more 
over the new baseline including mSWAT score, measurable disease by CT scan, or 
Circulating Sezary Cell Counts.  The new baseline being defined as the assessments 
obtained at the confirmation of progression.       
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” 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].  
Subjects will be assessed using the modified SWAT (mSWAT or modified skin weighted 
assessment tool) [see Appendix E] to capture percent body surface involvement with patches, 
plaques, or tumors. Patches will be multiplied × 1, plaques × 2, and tumors or nodules × 4. Full-
body and half-body photographs will be taken at baseline, at each on-study evaluation visit, 
and at the end of treatment visit.  Refer to Appendix C for full instructions. Radiographic 
imaging will be required with a full-body positron emission tomography(PET)/computed 
tomography (CT) with contrast performed prior to study entry and scored by Olsen criteria. 
Subjects without extracutaneous disease at screening (those with nonmeasureable disease by CT) 
will have repeat imaging at the discretion of the investigator for PD. Repeat imaging is not 
necessary for CR, PR, or stable disease (SD) in those patients with nonmeasurable disease. For 
subjects with known extracutaneous disease (those with measurable disease by CT), imaging will 
be performed at week 12 (after 4 doses of MK-3475). If progression is seen at week 12, a 
confirmatory scan will be repeated at week 16. If no progression is seen at week 12, imaging will 
be repeated at week 18 then every 6 weeks (every 2 cycles) through week #30, then every 4 
cycles (every 12 weeks). At time of CR/PR confirmation or PD and end of therapy (EOT), an 
imaging study will be performed. 
Immunotherapeutic agents such as MK-3475 may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses, which 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 criteria may not provide a 
complete response assessment of immunotherapeutic agents such as MK-3475. 
Correlative Studies Background 
Cancer treatment has evolved significantly since the original introduction of nitrogen mustard 
during World War II for subjects with lymphoma [Alexander 2011]. Today mAbs are the 
standard of care for multiple tumor histologies [Dalle 2008], a dendritic cell vaccine is approved 
by the FDA for the treatment of hormone-resistant prostate cancer [Kantoff 2010], and an 
immunomodulating mAb is approved for melanoma [Hodi 2010], [Mellman 2011], [Topalian 
2011]. This evolving field of immunotherapy provides the potential to eliminate cytotoxic, 
conventional chemotherapy, which results in significant toxicity to normal tissue in an effort to 
increase its antitumor efficacy. Uniquely, immunotherapy to date is well-tolerated or 

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demonstrates predictable toxicity as a result of immunostimulation, such as the autoimmune AEs 
due to anti-CTLA4 or anti-PD-1 therapy [Attia 2005]; [Hodi 2010]. The drug development 
pipeline of both academic and pharmaceutical efforts appears rich in novel immunotherapeutics, 
suggesting that the field of immunotherapy is likely to be a mainstay of future cancer treatment. 
In contrast to the evolution of alkylating agents, topoisomerase inhibitors, and other conventional 
chemotherapies, the development of immunotherapy necessitates multiple shifts in the paradigm 
of cancer drug development. Development of new criteria to assess response to 
immunomodulating therapies is exemplary of the immunotherapy-specific shift [Alexander 
2011]. This transition in response evaluation, though led by a single institution, is now 
implemented near-universally across U.S. and European institutions evaluating activity of 
immunotherapies. Similarly at the larger cooperative group and societal levels, efforts are 
ongoing to harmonize immune monitoring and immunologic biomarkers [Britten 2008]; [van der 
Burg 2011]. Despite immune-specific clinical trial monitoring, biomarkers, and response 
assessment, immunotherapy trials, to date, have yet to properly define immune-specific inclusion 
criteria. Defining which patient cohorts are responsive to immunotherapy or, more easily, 
excluding enrollment of subjects who have no likelihood of response based on an incompetent 
immune system will be of substantial significance to the field by (a) increasing the efficiency of 
immunotherapy trials, (b) reducing the needed sample size of early phase proof-of-concept 
studies, and (c) reducing the cost of clinical development by approximately 35%. The impact of 
this in-depth analysis of immune competency in cancer will provide mechanistic insight into the 
tumor-immune interactions, uncover biomarkers of response to therapy and patient prognosis, 
and ultimately aid in discovery of novel immunotherapeutics that improve patient survival while 
maintaining quality of life. 
Anti-PD-1 therapy, as an immunotherapy, unlike conventional modalities of cancer treatment, 
targets and modulate the patient’s immune system. Tumor-immune interactions occur at the level 
of the tumor microenvironment, including TILs and systemic macroenvironment, including 
circulating lymphocytes that may be recruited to the tumor. The state of a patient’s immune 
system and its responsiveness to therapy influence the efficacy of immunotherapy. It is now 
well-established that tumor-induced immune suppression prevents the naturally protective 
antitumor immune response in subjects with cancer. The magnitude of immune suppression is 
heterogeneous dependent on disease histology, extent, duration, and prior therapies. Taken 
together, the efficacy of an immunotherapy is a balance that is dependent on the therapeutic and 
its ability to enhance an antitumor immune response and the patient’s immune system, which 
may be variably suppressed by cancer. 
Current efforts to improve immunotherapy are focused on identifying and developing novel 
therapeutics. Due to the complexity, lack of in-depth methods, and limited incentive from a 
pharmaceutical perspective, little attention has been placed on thoroughly evaluating the immune 
competency of subjects with cancer. Unfortunately, therapeutics that appear highly promising, 
based on preclinical or early phase data, have failed in larger clinical application due, in part, to 
poor immune competency of the larger patient population [Houot 2009]; [Alexander 2011]; 
[Sznol 2012]. This leads to early abandoning of otherwise promising therapies. 
MF skin lesions are often readily accessible with minimally invasive skin biopsies. Thus, from 
an exploratory biomarker perspective, this disease offers an almost unique opportunity to 
investigate the determinants of response and resistance to anti-PD-1 therapy as well as to 

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discover additional molecular targets governing immune dysregulation in cancer. We anticipate 
that these studies will yield candidate biomarkers that will correlate with prognosis, have 
predictive value in the selection of which subjects benefit from anti-PD-1 mAb immunotherapy, 
and offer insight into new therapeutic approaches based on the mechanisms of immune 
suppression observed. 
Our exploratory biomarker approach will focus on blood (98 mL total volume) and tissue 
sampling performed at screening, following cycle 1, and upon completion of every 3rd cycle as 
well as at time of confirmed CR, PR, PD, or EOT visit. In order to reduce the number of patient 
visits, the biomarkers “following cycle 1” will be drawn on the first day of cycle 2, prior to study 
drug administration. Biomarkers will then be drawn on the first day of every 3rd cycle thereafter 
including cycle 5, 8, 11, 14, 17, etc. 
Biomarker and correlative studies for the CITN-10 trial will include the following: 
2.4.1 Chromogenic (Single-Color) Immunohistochemistry (IHC) for PD-L1 
PD-L1 expression has been identified as a potential biomarker for response to anti-PD-1 
therapy. It is anticipated that FFPE samples will be sent to a clinical research 
organization (CRO) for staining with our 22C3 anti-PD-L1 assay. We will test whether 
PD-L1 expression correlates with MK-3475 response in the MF/SS population. 
2.4.2 Multiparametric (Two-Color) IHC 
Spatial association of PD-1+ TILs and PD-L1+ cells (tumor and myeloid cells) suggests 
“induction” of PD-L1. INF-γ production by antigen-specific PD-1+ CD8+ T cells is 
hypothesized to drive local intratumoral upregulation of PD-L1 on adjacent tumor and 
myeloid cells, leading to a “stalled cytotoxic T lymphocyte (CTL)” response, which may 
be predictive of response to MK-3475 therapy. By assessing both of the required 
elements (i.e., PD-L1 positive cells and PD-1+ T cells), a two-color IHC assay may be a 
better predictor of response than PD-L1 positivity alone. Merck will perform this testing. 
Additional analytes may be assessed based upon funding. If so, an amendment to the 
protocol will be made.  
2.4.3 Transcriptional Analyses 
The Nanostring platform will be used to profile messenger RNA (mRNA) expression in 
archival biopsy material (and potentially PBMC material as well) to assess expression of 
over 650 genes and attempt to define a gene set critical for clinical response to MK-3475. 
The hypothesis to be tested is that MK-3475 responders will exhibit a “stalled CTL” 
response within the tumor reflected in the physical proximity between PD-1 and PD-L1 
expression and the presence of an aborted (e.g., weak but discernible) INF-γ 
transcriptional program. Global profiling by next-generation sequencing (RNAseq) will 
also be pursued. The nanostring testing will be performed by Merck.  
2.4.4 Immunophenotyping and T cell function assays 
CyTOF and multiparametric flow cytomety will be employed to extensively 
immunophenotype circulating peripheral leukocytes both prior to and during MK-3475 
treatment. We anticipate that these studies will provide a more granular view of the 
tolerized PD-1+ target cell and its response to anti-PD-1 blockade, which will guide the 
future choice of rational immunomodulatory combination therapies. In addition, other 

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cell types (e.g., Tregs and myeloid-derived cells with T cell suppressor function) and 
immunomodulatory molecules (e.g., IL-10) may be identified as additional components 
of the immunosuppressive milieu in MF/SS.  
Table 2.4: Immunophenotype Studies 
Immunophenotyping will be augmented by assays of T cell function. Activation of 
discrete T cell subsets and/or combinations of T cells with putative “suppressor cells” 
will be assayed by intracellular cytokines, cell surface activation markers of proliferation 
when challenged with autologous tumor cells or autologous dendritic cells pulsed with 
tumor lysate. 
2.4.5 Cytokine/Chemokine Analysis (serum enzyme-linked immunosorbent assay [ELISA]) 
Using a highly multiplexed ELISA-based platform, we will perform a longitudinal 
analysis of cytokines, chemokines, and other serum tumor-/oncogene-associated proteins 
at baseline (prior to treatment), on treatment, and at time of response assessment. 
2.4.6 Whole Exome Sequencing and Neoantigen Identification 
Genomic studies of CTCL have revealed frequent alterations in T cell receptor signaling 
and CD28 co-stimulatory pathways as well as a translocation event involving PD-L1.  
We propose to perform whole exome sequencing of paired germline/tumor DNA to 
determine whether these or other genomic alterations are associated with response to PD-
1 blockade.  Mutational burden and neoantigen burden have been found to correlate with 
response to immune checkpoint blockade in other malignancies.  Somatic mutations 
identified by whole exome sequencing will be analyzed for predicted formation of 
neoantigens. Subsequent individualized testing of immune responses directed against 
candidate neoantigens may be performed.  Depending on availability of resources, this 
may be limited to a subset of patients.  

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3. PATIENT SELECTION 
Eligibility criteria 
3.1.1
This trial will include subjects with Stage IB-IVB MF/SS (maximal stage since diagnosis 
will determine eligibility), and who have relapsed, are refractory, or progressed after at 
least one standard systemic therapy.  Current disease stage at time of entry will also be 
documented but will not be used for eligibility.    
3.1.2 Subjects must have the following minimum washout and AE recovery period from 
previous treatments without treatment between documentation of relapse/progression and 
enrollment of specifically: 
a. ≥2 weeks for local radiation therapy.  
b. ≥4 weeks for systemic cytotoxic anticancer agents, anticancer investigational agents 
that are not defined as immunotherapy, or for tumor-targeting monoclonal antibodies 
(mAbs) with the exception of alemutuzumab for which the washout is at least 8 
weeks. 
c. ≥15 weeks for anti-CD137 or anti-CTLA-4 (including ipilimumab or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
d. ≥2 weeks from resolution (i.e., < Grade 1 or at baseline) from AEs due to procedures 
performed or therapeutic agents administered. 
e. ≥2 weeks for retinoids, interferons, vorinostat, romidepsin, denileukin diftitox, and 
therapeutic doses of oral corticosteroids (physiologic replacement doses of oral 
corticosteroids are allowed, topical corticosteroids are allowed). 
f. ≥2 weeks for phototherapy. 
g. ≥1 week for topical therapy (including retinoid, nitrogen mustard, or imiquimod). 
3.1.3
Be ≥18 years of age on day of signing informed consent.  Because no dosing or adverse 
event data are currently available on the use of MK-3475 in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
3.1.4
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale. 
3.1.5 Life expectancy of at least 6 months. 
3.1.6 Patients must have normal organ and marrow function (all screening labs should be 
performed within 10 days of treatment initiation) as defined below: 
 
System 
Laboratory value 
− 
leukocytes 
≥2,000/mcL 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL 

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− 
hemoglobin 
≥9 g/dL OR ≥5.6 mmol/L 
− 
serum total bilirubin 
≤1.5 X upper limit of normal (ULN) 
OR direct bilirubin ≤ ULN for patients 
with total bilirubin levels >1.5 ULN 
− 
AST(SGOT)/ALT(SGPT) 
≤2.5 × institutional ULN OR ≤5 X 
ULN for patients with liver metastases 
− 
serum creatinine 
≤1.5 X ULN 
OR 
− 
Measured or calculateda creatinine 
clearance (CrCl) (Glomerular filtration 
rate [GFR] can also be used in place of 
creatinine or CrCl) 
≥60 mL/min for subject with 
creatinine levels >1.5 X institutional 
ULN 
− 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
≤1.5 X ULN unless subject is 
receiving anticoagulant therapy in 
which case the INR or PT must be 
within the therapeutic range of 
intended use for the anticoagulant. 
 
− 
Activated Partial Thromboplastin 
Time (aPTT) 
 
 
 
-    Thyroid Stimulating Hormone (TSH) 
≤1.5 X ULN unless subject is 
receiving anticoagulant therapy in 
which case the aPTT must be within 
the therapeutic range of intended use 
for the anticoagulant. 
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 a punch biopsy of the skin at baseline, at the time of a 
clinical event (at the time of response, progression or appearance of a new lesion) and at 
the end of treatment.  Additional punch biopsies every 3 cycles are optional.  An archival 
tissue sample is optional. 
 
3.1.8 Have measurable disease based on mSWAT (definition provided in Appendix E). Tumor 
lesions situated in a previously irradiated area are considered measurable if progression 
has been demonstrated in such lesions. 
3.1.9 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 and 
men must agree to use adequate contraception (hormonal or barrier method of birth 
control; abstinence) from the time of the pre-study visit, through the course of the study 
and for 120 days after the last dose of study medication.     

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Female patients of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to 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. 
Female patients of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity from the time of the 
pre-study visit, through the course of the study and for 120 days after the last dose of 
study medication.  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 is participating in 
this study, she should inform her treating physician immediately.  Men treated or enrolled 
on this protocol must also agree to use adequate contraception prior to the study, for the 
duration of study participation, and 4 months after completion of MK-3475   
administration. 
3.1.10 Ability to understand and the willingness to sign a written informed consent document. 
 
Exclusion Criteria 
3.2.1
Patients who have had chemotherapy or targeted small molecule therapy within 4 weeks 
(6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have 
not recovered from adverse events due to agents administered more than 4 weeks earlier.  
-Note:  Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
 
-Note:  If patients received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy. 
3.2.2
Patients who are currently participating in or have participated in a study of an 
investigational agent or using an investigational device within 4 weeks of the first dose of 
treatment. 
3.2.3
Has a diagnosis of immunodeficiency or is receiving therapeutic systemic steroid therapy 
or any other form of immunosuppressive therapy within 7 days prior to the first dose of 
trial treatment.  See section 5.3.1.1 for additional information on acceptable and 
prohibited concomitant medications.   
3.2.4
Has had a prior monoclonal antibody 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. 

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3.2.5 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.   
 
3.2.6 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events.  
 
Patients with carcinomatous meningitis should also be excluded.   
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 
of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to 
trial treatment.   
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MK-3475.   
 
3.2.8 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 Sjogren’s syndrome will not be excluded from the study. 
 
3.2.9 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. 
 
3.2.10 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
3.2.11 Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2.  
 
3.2.12 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
interstitial lung disease or active, non-infectious pneumonitis, symptomatic congestive 
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
3.2.13 History of other pulmonary disease such as emphysema or chronic obstructive pulmonary 
disease, (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.  

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3.2.14 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-study visit through 120 days after the 
last dose of trial treatment.  Pregnant women are excluded from this study because MK-
3475 is an agent with the potential for teratogenic or abortifacient effects.  Because there 
is an unknown but potential risk for adverse events 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.  Patients are 
excluded from this study if pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial, starting with the pre-screening or 
screening visit through 120 days after the last dose of trial treatment.   
Men and non-pregnant, 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 two birth control methods can be barrier method or a barrier method plus a hormonal 
method to prevent pregnancy.  Patients should start using birth control from the time of 
the pre-study visit, through the course of the study and for 120 days after the last dose of 
study medication. 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 defined in section 
7.7-Reporting of Pregnancy and Lactation.  If there is any question that a patient will not 
reliably comply with the requirements for contraception, that patient 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.  
 

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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, patients who are breast-feeding are not eligible for enrollment. 
 
3.2.15 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. 
 
3.2.16 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
3.2.17 Has received a live vaccine within 30 days prior to the first dose of trial treatment.  
3.2.18 Has a known Human T-lymphotropic virus Type 1 (HTLV) infection. 
3.2.19 Patient has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
Table 3.3 Accrual Targets Table 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
1 
= 
2 
Not Hispanic or Latino 
9 
+ 
13 
= 
22 
Ethnic Category: Total of all subjects 
 
10 
+ 
 
14 
= 
 
(24) 
Racial Category 
 
American Indian or Alaskan Native 
 
+ 
 
= 
 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
1 
= 
2 
Native Hawaiian or other Pacific 
Islander 
 
+ 
 
= 
 
White 
8 
+ 
12 
= 
20 
Racial Category: Total of all subjects 
 
10 
+ 
 
14 
= 
 
(24) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 

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4. REGISTRATION PROCEDURES 
Investigator and Research Associate 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. 
Registration requires the submission of: 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. For questions, 
please contact the CTEP Investigator Registration Help Desk by email at 
pmbregpend@ctep.nci.nih.gov. 
4.1.2
CTEP Associate Registration Procedures / CTEP-IAM Account 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
An active CTEP-IAM user account is needed to access all CTEP and CTSU (Cancer 
Trials Support Unit) websites and applications, and is critical to the conduct of this study, 
including document access, patient enrollment, and clinical data submission. 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm.  For questions, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov.

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4.1.3
For Questions and Support
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk: pmbregpend@ctep.nci.nih.gov.
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Registration Help Desk: ctepreghelp@ctep.nci.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. 
 
The CTSU Regulatory Office tracks receipt of these documents in the CTSU Regulatory Support 
System (RSS), reviews for compliance, and transmits site approval data to CTEP. 
4.2.1
Downloading Regulatory Documents 
Site registration forms may be downloaded from the CITN-10 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, 
Investigators and Associates 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  
• Click on the CITN link to expand, followed by protocol #CITN-10.   
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.   
 
4.2.2
Submitting Regulatory Documents 
Submit completed forms along with a copy of your IRB Approval and Model Informed 
Consent to the CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.   
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
Phone:  1-866-651-2878 
Fax:  215-569-0206 
E-mail:  CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 

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4.2.3
Checking Site Registration Status 
Sites can check the status of their registration packets by querying the Site Registration 
subtab of the members’ section of the CTSU Web site.  (Note: Sites will not receive 
formal notification of regulatory approval from the CTSU Regulatory Office.) 
• Go to https://www.ctsu.org and log in using your CTEP IAM username and 
password. 
• Click on the Regulatory tab at the top of your screen. 
• Click on the Site Registration subtab. 
• Enter your 5-character CTEP Institution Code and click on Go. 
Note: If possible, please allow three working days for site registration approval before 
attempting to enroll your first patient. 
Patient Registration 
4.3.1
OPEN  
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.  
All CITN member site staff will use OPEN to enroll patients to this study. 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. 
Through both the first and second stages of this trial patient enrollment will be facilitated using 
the Slot-Reservation System in conjunction with the Patient 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 is obtained site staff will have 14 days to 
complete screening and to enroll the patient on study.    
Prior to accessing OPEN CITN member site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes. Site staff 
should use the registration forms provided on the CTSU web site as a tool to verify 
eligibility. 
• 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.  

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• 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. 
5. TREATMENT PLAN 
Agent Administration 
Treatment will be administered on an outpatient basis. Reported AEs 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. 
The treatment to be used in this trial is outlined below. 
Trial Treatment 
Drug 
Dose/ 
Potency
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
MK-3475 2mg/kg 
q 3 weeks 
IV infusion 
Day 1 of each cycle 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 6. 
 
Note: 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 measurement. 
 
Trial treatment should begin on day 1 of treatment or as close as possible to the date on which 
treatment is enrolled. 
5.1.1
MK-3475 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed.  Trial treatment may be administered up to 

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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).  Infusion timing should be as 
close to 30 minutes as possible; however, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Definition of Dose-Limiting Toxicity: N/A 
General Concomitant Medication and Supportive Care Guidelines 
5.3.1
MK-3475  
 
5.3.1.1 
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  

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o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after consultation with the Protocol PI and CITN.   
− 
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.  Both rabies and typhoid are also available as 
killed vaccines. The killed versions of rabies and typhoid vaccines are acceptable. 
− 
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 
approved after consultation with the  Protocol PI and CITN.  
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. 
 
5.3.2 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
• Nausea/vomiting: Nausea and 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. Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
• Antiinfectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other antiinfective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 
 
Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue for up to two 
years, or until one of the following criteria applies: 
• 
Disease progression warranting alternative systemic therapy and without evidence of 
clinical benefit from continued MK-3475,  
• 
Patients who continue MK-3475 after initial disease progression will be discontinued 
from study for any additional disease progression of 25% or more.  
 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Patient decides to withdraw from the study. 

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• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
• 
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 
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 therapeutic 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 

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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 
All patients, regardless of reason for discontinuation from study, will be followed for AE/SAE 
resolution for 30 days after removal from study.  Patients removed from study for unacceptable 
adverse event(s) will be followed every 12 weeks until progression is documented.  All patients 
will be followed for survival either by in-person visit or by telephone assessment every 12 weeks 
until death.  
In subjects who discontinue study therapy without documented disease progression, every effort 
should be made to continue monitoring their disease status by Olsen assessment every 12 weeks 
(± 7 days) until (1) the start of new anticancer treatment, (2) documented disease progression, (3) 
death, or (4) the end of the study, whichever occurs first. If a previous assessment was obtained 
within 4 weeks prior to the date of discontinuation, then an additional assessment at treatment 
discontinuation isn’t mandatory. 
 
Criteria for Removal from Study 
Patients will be removed from study when any of the applicable criteria, including progressive 
disease warranting alternative systemic therapy and without evidence of clinical benefit on study 
therapy, 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. 
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. 
 

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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). 
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 Olsen Global Disease Assessment (including CT scans if applicable, mSWAT and Circulating 
Sézary Cells) shows progressive disease (PD), tumor assessment may be repeated by the site 
approximately 4 weeks later in order to confirm PD with the option of continuing treatment per 
the instructions below while awaiting for confirmation of progression.  If repeat disease 
assessment shows a reduction in the tumor burden compared to the initial assessment 
demonstrating PD, treatment may be continued as per treatment calendar.  In determining 
whether or not the tumor burden has increased or decreased, investigators should follow Olsen 
Disease Assessment Criteria (Protocol, Section 11).  The decision to continue study treatment 
after the 1st evidence of disease progression determined by disease assessment is at the 
Investigator’s discretion based on the clinical status of the patient as described in the table below.   
A subject with unconfirmed progression of disease may continue trial treatment if clinically 
stable other than disease progression.  A biopsy is recommended in cases of suspected 
pseudoprogression to determine if the patient has true progression of disease or 
pseudoprogression. Patients in whom the biopsy confirms pseudoprogression based on a 
predominance of immune infiltrate are recommended to remain on study. Biopsy findings 
consistent with pseudoprogression, evidence of a lymphoid infiltrate, necrotic tumor, without 
significant increase in viable tumor at site of suspected pseudoprogression, may justify continued 
treatment at the discretion of the PI. 
Patients may receive study treatment while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
 
If progression is determined at week 16 or beyond, patients will be eligible to receive continued 
MK-3475 if they are otherwise clinically stable as defined by the following criteria.  (The 
maximum duration of therapy in this setting is the same as for other patients, 2 years).   

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• Absence of signs and symptoms indicating disease progression 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention   
 
The following assessment and stopping criteria apply to patients who continue MK-3475 beyond 
progression: 
• Patients who continue therapy after progression will have mSWAT performed with every 
cycle (every 3 weeks) and a full Olsen Criteria assessment including mSWAT, CT scans, 
for those with measurable disease, and CSC, if positive for Sézary cells, every 4 cycles 
(every 12 weeks).  At the discretion of the investigator these assessments may be 
repeated more frequently.  
• Study drug will be discontinued if any compartment increases in value by 25% or more 
over the new baseline including mSWAT score, measurable disease by CT scan, or 
Circulating Sezary Cell Counts.  The new baseline being defined as the assessments 
obtained at the confirmation of progression.       
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” 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].  
 
  
Clinically Stable 
Clinically Unstable 
 
Imaging 
Treatment 
Imaging 
Treatment 
1st  evidence of 
PD** (Based 
upon Olsen 
Criteria 
including scans 
(if applicable), 
mSWAT and 
Circulating 
Sézary Cells) 
Repeat 
assessment at 
approximately 4 
weeks to 
confirm PD 
May continue 
study treatment 
at the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
assessment 
Repeat 
assessment at 
approximately 4 
weeks to 
confirm PD if 
possible 
Discontinue 
treatment 
Repeat 
assessment 
confirms PD** 
If patient 
continues with 
MK-3475 
therapy, repeat 
mSWAT every 
cycle.  mSWAT, 
CT scans, for 
measurable 
disease, and 
Patient may 
continue therapy 
with MK-3475. 
No additional 
assessments 
required 
N/A 

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CSC, for patients 
who are positive, 
will be repeated 
every 4 cycles 
(every 12 weeks) 
Repeat 
assessment 
shows SD, PR, 
or CR** 
Continue 
regularly 
scheduled  
assessments per 
the study 
calendar 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled  
assessments per 
the study 
calendar 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
Investigator’s 
discretion 
Tumors will be assessed first at week 12, then every 6 weeks (42 ±3 days) until week 30.  
Subsequently, tumor imaging will be performed every 12 weeks (84 ±7 days). 
** Note:  Mycosis Fungoides and Sézary Syndrome may not be measurable by CT scan.  Disease 
assessments will include CT Scans (only for those patients with measurable disease), mSWAT 
and Circulating Sézary Cell (CSC) measurement by flow cytometry.  All of these will be taken 
into account to assess disease progression or regression through the use of the Olsen global 
assessment criteria for MF/SS.  In the table above PD, SD, PR and CR will be determined by 
Global Response Assessment as described in section 11.  
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.   
Treatment Up to 2 Years 
Treatment with MK-3475 monotherapy will continue for up to two years.  Treatment will be 
discontinued for documented disease progression in patients warranting other systemic therapy 
as described above, unacceptable adverse event(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. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
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.   

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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 
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 

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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). 
 
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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AE-Specific Dose Modification Guidelines for Drug-Related Adverse Events 
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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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. 
Vomiting 
≤Grade 1 
No change in dose 
• Vomiting should be treated aggressively, and consideration 
 
 

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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 
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.  
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 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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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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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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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 v4.0 (CTCAE) at 
http://ctep.cancer.gov 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (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 (CAEPR) 
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 
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. 

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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 
 
7.1.1.1 
CAEPR for MK-3475 
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
MK-3475 (pembrolizumab, NSC 776864) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
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 2.3, March 9, 20171 
 
 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 4.0 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 
 
 
 
CARDIAC DISORDERS 
 
 
 
 
Myocarditis2 
 
 
 
 
Pericarditis2 
 
 
ENDOCRINE DISORDERS 
  
 
Adrenal insufficiency2 
 
  
 
Endocrine disorders - Other 
(hypophysitis, hypopituitarism)2 
 
  
 
Endocrine disorders - Other 
(thyroiditis)2 
 
  
 
Hyperthyroidism2 
 
  
 
Hypothyroidism2 
 
  
EYE DISORDERS 
  
 
 
Uveitis2 
  
GASTROINTESTINAL DISORDERS 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 4.0 Term) 
[n= 3793] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
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 
 
  
 
Infusion related reaction 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(autoimmune hepatitis)2 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis2 
  
 
 
Cytokine release syndrome2 
  
 
 
Immune system disorders - Other 
(hemophagocytic 
lymphohistiocytosis)2 
  
 
Immune system disorders - Other 
(immune thrombocytopenic purpura)2 
 
  
 
Immune system disorders - Other 
(pseudoprogression/tumor 
inflammation)2 
 
  
 
 
Serum sickness2 
  
INFECTIONS AND INFESTATIONS 
  
 
Infection3 
 
  
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 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia2 
 
 Arthralgia2 (Gr 2) 
 
Arthritis2 
 
  
 
Avascular necrosis2 
 
  
 
Joint effusion2 
 
  
 
Joint range of motion decreased 
 
  
 
Musculoskeletal and connective 
tissue disorder - Other 
(tenosynovitis)2 
 
  
 
Myalgia2 
 
  

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 Adverse Events with Possible  
 Relationship to MK-3475 (pembrolizumab) 
 (CTCAE 4.0 Term) 
[n= 3793] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Myositis2 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
 
Nervous system disorders - Other 
(Guillain-Barre syndrome)2 
  
 
 
Nervous system disorders - Other 
(myasthenic syndrome)2 
  
 
 
Nervous system disorders - Other 
(neuromyopathy)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 
  
 
 Pleuritic pain2 
 
  
 
 Pneumonitis2 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Bullous dermatitis2 
 
  
 
 
 Erythema multiforme2 
  
 
Erythroderma 
 
  
 
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 necrolysis2 
  
 
Urticaria2 
 
  
VASCULAR DISORDERS 
  
 
 
Vasculitis2 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Immune-mediated adverse reactions have been reported in patients receiving MK-3475.  Adverse events 
potentially related to MK-3475 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, administration of corticosteroids and supportive care. 
 
3Infection 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 

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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; Abdominal pain; 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); General disorders and administration site conditions - Other (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; Hyponatremia; 
Hypophosphatemia; Metabolism and nutrition disorders - Other (failure to thrive); Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain; Generalized 
muscle weakness; Musculoskeletal and connective tissue disorder - Other (groin pain); Pain in extremity 
NERVOUS SYSTEM DISORDERS - Aphonia; Depressed level of consciousness; Dysarthria; Edema 
cerebral; Encephalopathy; Headache; Hydrocephalus; Lethargy; Meningismus; Nervous system disorders 
- Other (brainstem herniation); Seizure; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Confusion 
RENAL AND URINARY DISORDERS - Acute kidney injury; Proteinuria; Renal and urinary disorders - 
Other (hydronephrosis); Renal and urinary disorders - Other (nephrotic syndrome); Urinary incontinence; 
Urinary tract pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; 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 
4.0 will be utilized until March 31, 2018 for AE reporting. 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. 

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• 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. 
 
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. 

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Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”   
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
 
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. 
• A pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently 
CTEPAERS recognizes this event as a patient death.  
 
 
A neonatal death should be reported expeditiously as Grade 4, “Death neonatal” under 
the General disorders and administration SOC. 
 

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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 
AdEERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥24 hrs 
Not required 
10 Calendar Days 
NOTE: Protocol-specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via AdEERS 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 
For this protocol only, the AEs/grades listed below do not require expedited reporting via 
CTEP-AERS. However, they still must be reported through the routine reporting 
mechanism (Section 7.4): 

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CTCAE 
SOC 
Adverse 
Event 
Grade 
Hospitalization/ 
Prolongation of 
Hospitalization 
Attribution 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.   
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. 

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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 
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(s) (MK-3475) 
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 

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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 
 
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 measurement. 
 
Storage: Store intact vials between 2°C - 8°C (36°F - 46°F).  Do not freeze. If a storage 
temperature 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. 
 
Availability 
 
MK-3475 is an investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 

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MK-3475 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 N/A 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designee) at each participating institution.  Pharmaceutical Management 
Branch (PMB) policy requires that agent be shipped directly to the institution where 
the patient is to be treated.  PMB does not permit the transfer of agents between 
institutions (unless prior approval from PMB is obtained).  The CTEP-assigned 
protocol number must be used for ordering all CTEP-supplied investigational agents.  
The responsible investigator at each participating institution must be registered with 
CTEP, DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), and 
Financial Disclosure Form (FDF).  If there are several participating investigators at 
one institution, CTEP-supplied investigational agents for the study should be ordered 
under the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent 
Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” account 
status and a “current” password.  For questions about drug orders, transfers, returns, 
or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 
4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
 
8.1.3.2 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all 
agents received from DCTD using the NCI Drug Accountability Record Form 
(DARF).  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
This study will require approximately 500 mL of blood to be drawn during the first 3 cycles 
(9 weeks) of therapy. After this, approximately 250 mL of blood will be drawn every 9 weeks. 
These quantities include blood drawn for safety labs, research labs, and for the 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. The results of the CBC will be reviewed and the 

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following blood volumes will be drawn based upon the patient hemoglobin level: 
• For a hemoglobin over 10.0, draw the full volume of blood for safety labs, research labs, 
and for the biorepository. The biorepository volume of 100 mL will include 10 mL for 
plasma, and 90 mL of whole blood to be used for cells. 
• For a hemoglobin between 9.0 and 10.0, draw the full volume of blood for safety labs and 
research labs, however draw only 30 mL for the biorepository as opposed to drawing the 
full 100 mL. The 30 mL will include 10 mL for plasma and 20 mL of whole blood to be 
used for cells.  
• For a hemoglobin less than 9.0, only draw the safety labs which will include a CBC and a 
Comprehensive Metabolic Panel.
Biomarker Studies 
To assess the immune response and pre-determined correlative studies a skin biopsy will be 
collected and peripheral blood (98mL total) collected at baseline.  Blood samples will also be 
collected after cycle 1 (on the first day of cycle 2, prior to dosing) then on the first day of every 
3rd cycle thereafter, prior to dosing (i.e., day 1 cycle 5, day 1 cycle 8, day 1 cycle 11, etc.), and at 
time of confirmed CR or PR, & at PD or EOT visit.  After the skin punch biopsy at baseline 
patients must also provide a biopsy at the time of a clinical event (at the time of response, 
progression or appearance of a new lesion) and at the end of treatment.  Additional punch 
biopsies every 3 cycles are optional.  An archival tissue sample is optional.    
All patients will have an additional 10ml of blood drawn at each of the above specified intervals 
for Kyn/Trp ratio testing. We have listed this test as a “Special Correlative Study” as opposed to 
a Biomarker Study because we will be testing Kyn/Trp ratio as a potential mechanism of 
resistance. 
 
Table 9.1 Tumor Tissue and Blood Collection 
 
Screening/Post cycle 1 (day 
1 of cycle 2, prior to 
dosing)/Post every 3rd cycle 
(day 1 of every 3rd cycle, 
prior to dosing, day 1 cycle 
5,8,11, etc.) 
Response/PD 
EOT 
5 mm punch biopsy (#1)* 
Required at baseline – 
(Sent to CITN Central Lab 
in formalin)  Biopsies at 
other “every 3rd cycle” time 
points are optional. 
 
Required at response, 
progression or 
appearance of a new 
lesion –(Sent to CITN 
Central Lab in formalin)  
Required – (Sent to CITN 
Central Lab in formalin) 
5 mm punch biopsy – 
immediately adjacent 
(#2)*
Optional – (To CITN 
Central Lab in formalin) 
Optional -(To CITN 
Central Lab in formalin) 
Optional –(To CITN 
Central Lab in formalin) 
FNA + Core Biopsy 
(subjects with known LN 
disease only) 
Optional – (FNA to Stanford 
in RPMI, Core biopsy to 
CITN Central Laboratory in 
Formalin) 
Optional – (FNA to 
Stanford in RPMI, Core 
biopsy to CITN Central 
Laboratory in Formalin) 
Optional – (FNA to 
Stanford in RPMI, Core 
biopsy to CITN Central 
Laboratory in Formalin)    
Biomarkers (blood) 
Required (Sent to CITN 
Required (Sent to CITN 
Central Lab)
Required (Sent to CITN 
Central Lab)

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Central Lab) 
Kyn/Trp Ratio, 1GTT 
(10 mL) 
Required (Frozen plasma 
sent to CITN Central Lab) 
Required (Frozen plasma 
sent to CITN Central Lab) 
Required (Frozen Plasma 
sent to CITN Central Lab) 
Biorepository: 110ml 
total volume with 100ml 
used for cells (PBMC’s) 
and 10ml used for serum 
with reduced volumes in 
anemic patients.  Hgb > 
10,  draw the full 110ml.  
Hgb 9-10, draw only 30ml 
(10ml Serum, 20ml cells).  
Hgb < 9.0, no 
Biorepository volumes 
drawn.   
Optional (Sent to CITN 
Central Lab) 
Optional (Sent to CITN 
Central Lab) 
Optional (Sent to CITN 
Central Lab) 
*Any tissue remaining after testing has been completed will be stored in the CITN Central 
Laboratory Biorepository for storage and future testing if the patient has given permission in the 
consent form.  
**All blood that is drawn for storage in the Biorepository will be shipped to the CITN Central 
Laboratory Biorepository for storage and future testing. 
9.1.1 Archival Tissue 
Archival tissue is not mandatory, however if it is available and if the patient has given 
permission in the consent form an FFPE block will be sent to the CITN Central 
Laboratory where slides will be made and shipped to Qualtek for Chromogenic (Single-
Color) IHC for PD-L1 and to Merck, Palo Alto, for Multiparametric (Two-Color) IHC 
and Transcriptional Analyses using the Nanostring platform. If archival tissue is not 
available it is important to review the pathology report and confirm the diagnosis.  
Skin specimens may be obtained at other study visits depending on principal investigator 
decision. At the response/PD visit and the end of treatment visit, 2 side-by-side 5-mm 
punch biopsies may be optionally obtained from each [anatomical] site biopsied at 
screening. Biopsies will be obtained at the respective Cancer Center clinics according to 
their clinical SOPs. 
If a patient has known lymph node disease an optional Fine Needle Aspiration (FNA) of 
the lymph node and an optional core biopsy of the lymph node will be obtained at 
screening, after cycle 1, after every 3rd cycle, at response/PD visit, and end of treatment 
visit.  Patients may refuse the lymph node biopsies and still participate in the trial.  Patients 
may agree to only one type of lymph node biopsy (FNA or Core) if they are uncomfortable 
providing both and still participate in the trial.  Lymph node biopsies and core biopsies will 
be obtained at the respective Cancer Center according to their clinical SOP’s.    
9.1.2 Laboratory Procedures/Assessments 
9.1.2.1 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified below:  
 

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Table 9.2: Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin (β-hCG)* 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) 
Platelet count 
Alanine aminotransferase (ALT) Protein 
aPTT 
WBC (total and 
differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity 
Total thriiodothyronine (T3) 
Red Blood Cell 
Count 
Lactate dehydrogenase (LDH) 
Microscopic exam, if 
abnormal results are noted 
Free thyroxin (T4) 
 
Blood Urea Nitrogen (BUN) 
 
 
Absolute 
Neutrophil Count 
Carbon Dioxide (CO2 or 
bicarbonate) 
Urine pregnancy test* 
Thyroid stimulating 
hormone (TSH) 
Absolute 
Lymphocyte Count 
Creatinine 
 
 
 
Uric Acid 
 
 
 
Calcium 
 
Blood for correlative studies 
 
Chloride 
 
 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
* Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required. 
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment. 
9.1.2.2 
Circulating Tumor Cells (will be referred to as circulating Sézary cells or 
CSCs in this protocol). 
In this protocol Sézary cells are defined as T cells which are either CD4+CD7- OR 
CD4+CD26-. For an individual patient only one of the phenotypes will be used, not both. 
The protocol allows the use of either CD4+CD7- or CD4+CD26- T cells since there is 
variation in which phenotype best represents an individual patient’s Sézary phenotype. 
The Olsen Criteria for response assessment include the use of either phenotype. [Olsen 

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2011] 
One of the Global Measurements for response will be Response in Blood which will 
involve a quantitative measurement of blood tumor burden using flow cytometry (testing 
for the percentage of Circulating Sézary Cells).  This test is considered Standard-of-Care 
for patients with MF/SS  so the flow cytometry for CSC testing will take place at the 
individual research sites.  Since this test will be used as part of the disease assessment it 
will be performed at the same time points as the CT scans (for those with measurable 
disease) and mSWAT testing.  Circulating Sézary Cell (CSC) burden will be determined 
at baseline then again at week 12 (after 4 doses of MK-3475).  If progression is seen at 
week 12 CSC will be repeated at week 16.  If no progression is seen at week 12 CSC will 
be repeated at week 18.  CSC will be repeated every 2 cycles (every 6 weeks) out to week 
#30 (including week 24 and week 30).  Repeat CSC after week 30 will take place every 4 
cycles (every 12 weeks) including week 42, 54, 66, 78, 90 and 104 (end of study). 
All patients who are positive for CSC’s in blood at baseline should receive continued 
CSC testing at the intervals described above.  Those patients who have measurable 
disease by CT scan (either LN or viscera) should receive continued CSC testing per the 
above schedule EVEN if they are negative at baseline.  Those patients who do NOT have 
measurable disease by CT scan should NOT have regular, ongoing, CSC testing if they 
are negative at baseline however these patients will have repeat CSC testing for CR, PR, 
PD or EOT.  As a quality assurance tool for this trial we will obtain data from all CSC 
results and send the data to Stanford University for central review by their pathologists.   
Laboratory Correlative Studies 
The biomarker and correlative studies that will be performed at the time points described above 
are as follows: 
9.2.1 Chromogenic (Single-Color) IHC for PD-L1 - Laboratory Correlative Study #1.  
PD-L1 expression has been identified as a potential biomarker for response to anti-PD-1 
therapy. We will test whether PD-L1 expression correlates with MK-3475 response in the 
MF/SS population. 
9.2.1.1 
Collection of Specimen(s):  Specimens will include archived and 
prospectively obtained tumor biopsies including skin and/or lymph nodes 
including possible punch and/or core biopsies 
9.2.1.1.1. 
Timing of specimen collection will include a biopsy at 
baseline, at the time of a clinical event (at the time of response, 
progression or appearance of a new lesion) and at the end of treatment.  
Additional punch biopsies every 3 cycles are optional.   
 
 
9.2.1.2 
Handling of Specimen(s). Biopsy samples will be placed in formalin and 
shipped to the CITN Central Laboratory.  

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9.2.1.3 
Shipping of Specimen(s). Participating sites will send biopsy tissue in 
formalin for overnight delivery to the CITN Central Laboratory. The CITN 
Central Laboratory or designate will prepare FFPE blocks then prepare slides. 
Slides will be sent to Qualtek for staining with anti-22C3 anti-PD-L1 IHC 
Assay. 
9.2.1.4 
Site(s) Performing Correlative Study. Merck CRO, Qualtek, will perform the 
testing using the slides sent by the CITN Central Laboratory.  
9.2.2 Multiparametric (Two-Color) IHC – Laboratory Correlative Study #2. 
Spatial association of PD-1+ TILs and PD-L1+ cells (tumor and myeloid cells) suggests 
“induction” of PD-L1. Interferon-gamma production by antigenspecific PD-1+ CD8+ T 
cells is hypothesized to drive local intratumoral upregulation of PD-L1 on adjacent tumor 
and myeloid cells, leading to a “stalled CTL” response which may be predictive of 
response to MK-3475 therapy. By assessing both of the required elements, i.e., PD-L1 
positive cells and PD-1+ T cells, a two-color IHC assay may be a better predictor of 
response than PD-L1 positivity alone.  Immunohistochemical staining for CD3 and CD8 
may also be performed if funds become available. 
9.2.2.1 
Collection of Specimen(s) 
9.2.2.1.1. Specimens will include archived and prospectively obtained tumor 
biopsies from skin and/or lymph nodes including possible punch and/or 
core biopsies 
9.2.2.1.2. Timing of specimen collection will include a biopsy at baseline, at the 
time of a clinical event (at the time of response, progression or 
appearance of a new lesion) and at the end of treatment.  Additional 
punch biopsies every 3 cycles are optional.    
9.2.2.2 
Handling of Specimen(s). Biopsy samples will be placed in formalin and 
shipped to the CITN Central Laboratory. 
9.2.2.3 
Shipping of Specimen(s). Participating sites will send biopsy tissue in 
formalin to the CITN Central Laboratory. The CITN Central Laboratory or 
designate will prepare FFPE blocks then prepare slides. Slides will be sent to 
Merck, Palo Alto, where multiparametric immunohistochemical assays will be 
performed to identify and enumerate key cellular components and 
immunoregulatory molecules to include PD-1, PD-L1, among other analytes. 
9.2.2.4 
Site(s) Performing Correlative Study. Merck, Palo Alto, will perform the 
testing using the slides sent by the CITN Central Laboratory.  
9.2.3 Transcriptional Analyses – Laboratory Correlative Study #3. 
The Nanostring platform will be used to profile mRNA expression in archival material, to 
assess expression of approximately 650 genes and attempt to define a gene set critical for 
clinical response to MK-3475. The hypothesis to be tested is that MK-3475 responders 
will exhibit a “stalled Cytotoxic T Lymphocyte (CTL)” response within the tumor 
reflected in the physical proximity between PD-1 and PD-L1 expression and the presence 

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of an aborted (e.g., weak but discernible) INF-γ transcriptional program.  
9.2.3.1 
Collection of Specimen(s) 
9.2.3.1.1. Specimens will include archived and prospectively obtained tumor 
biopsies including skin and/or lymph nodes including possible punch 
and/or core biopsies 
9.2.3.1.2. Timing of specimen collection will include a biopsy at baseline, at the 
time of a clinical event (at the time of response, progression or 
appearance of a new lesion) and at the end of treatment.  Additional 
punch biopsies every 3 cycles are optional.    
9.2.3.2 
Handling of Specimen(s). Biopsy samples will be placed in formalin and 
shipped to the CITN Central Laboratory.  
9.2.3.3 
Shipping of Specimen(s). Participating sites will send biopsy tissue in 
formalin to the CITN Central Laboratory. The CITN Central Laboratory or 
designate will prepare FFPE blocks then prepare slides. Slides will be sent to 
Merck, Palo Alto for Nanostring analysis and global profiling by next-
generation sequencing (RNAseq). 
9.2.3.4 
Site(s) Performing Correlative Study. Merck, Palo Alto, will perform the 
testing using the slides sent by the CITN Central Laboratory. 
9.2.4 Immunophenotyping & T cell function assays-Laboratory Correlative Study #4. 
CyTOF and multiparametric flow cytomety will be employed to extensively 
immunophenotype the tumor and associated immune infiltrates both prior to and during 
MK-3475 treatment. We anticipate that these studies will provide a more granular view 
of the tolerized PD-1+ target cell and its response to anti-PD-1 blockade, which will guide 
the future choice of rational immunomodulatory combination therapies. In addition, other 
cell types (e.g., Tregs and myeloid-derived cells with T cell suppressor function) and 
immunomodulatory molecules (e.g., IL-10) may be identified as additional components 
of the immunosuppressive milieu in MF/SS.  
Immunophenotyping will be augmented by assays of T cell function. Activation of 
discrete T cell subsets and/or combinations of T cells with putative “suppressor cells” 
will be assayed by intracellular cytokines, cell surface activation markers of proliferation 
when challenged with autologous tumor cells or autologous dendritic cells pulsed with 
tumor lysate.  

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9.2.4.1 
Collection of Specimens 
9.2.4.1.1. Whole blood will be collected into heparinized tubes.  For patients with 
lymph node disease who agree to the optional Fine Needle Aspiration 
(FNA), the sample will be obtained locally using routine clinic SOP’s.    
9.2.4.1.2. Timing of specimen collection will include mandatory collection prior to 
treatment, post cycle 1 (on the 1st day of cycle 2 just prior to dosing), on 
the first day of every 3rd cycle thereafter, prior to dosing (i.e., day 1 of 
cycle 5, 8, 11, etc), response/PD visit and end of treatment visit.  
9.2.4.2 
Handling of Specimen(s)  
Blood samples will be shipped to the CITN Central Laboratory for processing. 
The CITN Central Laboratory will subsequently ship frozen PBMC samples 
to Stanford for testing.  FNA samples will be placed in RPMI and will be 
shipped to the Stanford Laboratory overnight for flow cytometry.   
9.2.4.3 
Shipping of Specimens 
Frozen PBMCs and FNA samples in RPMI will be shipped to Stanford 
University.  
9.2.4.4 
Site(s) Performing Correlative Study. 
All sites will provide samples for analysis to be performed at Stanford 
University.  
9.2.5 Cytokine/Chemokine Analysis (serum ELISA)-Laboratory Correlative Study #5. 
Using a highly multiplexed ELISA-based platform, we will perform a longitudinal 
analysis of cytokines, chemokines, and other serum tumor/oncogene-associated proteins 
at baseline (prior to treatment), on treatment, and at time of response assessment.  
 

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9.2.5.1 
Collection of Specimens 
9.2.5.1.1. Whole blood will be collected into red-top tubes.   
9.2.5.1.2. Timing of specimen collection will include mandatory collection prior to 
treatment, post cycle 1 (on the 1st day of cycle 2 just prior to dosing), on 
the first day of every 3rd cycle thereafter, prior to dosing (i.e., day 1 of 
cycle 5, 8, 11, etc), response/PD visit and end of treatment visit.  
9.2.5.2 
Handling of Specimen(s)  
Blood samples will be processed to frozen serum at the local labs. Frozen 
serum vials will be shipped from clinical sites to the CITN Central 
Laboratory. The Central Laboratory will subsequently ship aliquots of serum 
to Stanford University, Kohrt Laboratory. Aliquots will be thawed and 
analyzed by Luminex.  
9.2.5.3 
Shipping of Specimens 
Frozen serum will be shipped by the CITN Central Laboratory to Stanford 
University. 
9.2.5.4 
Site(s) Performing Correlative Study. All sites will provide samples for 
analysis to be performed at Stanford University.  
9.2.6 Whole Exome Sequencing and Neoantigen Identification (Laboratory Correlative 
Study #6):   We propose performing whole exome sequencing of pre-treatment samples 
using paired germline/tumor DNA.  Depending on availability of resources, this may be 
limited to a subset of patients.  Subsequent bioinformatic prediction of neoantigens and 
individualized testing of immune responses directed against candidate neoantigens may 
be performed.   
9.2.6.1      Collection of Specimen(s) 
Germline DNA will be collected from FACS sorting of cryopreserved PBMCs 
for all patients.  Tumor DNA will either be collected from sorting PBMCs (in 
patients with sufficient numbers of circulating tumor cells) or else from skin 
and/or lymph node biopsy specimens.   
9.2.6.2   
Handling of Specimen(s)   
Biopsy samples will be placed in formalin and shipped to the CITN Central 
Laboratory.  In situations where PBMC’s will be tested, the sites will ship 
tubes to the Central Lab for processing.  PBMCs will then be processed and 
cryopreserved at the Central Lab. 
9.2.6.3   
Shipping of Specimens 
The CITN Central Lab will send frozen PBMC’s for all patients to provide 
germline DNA and/or tumor DNA when circulating tumor cells are present.  
For patients with insufficient numbers of circulating tumor cells, the CITN 
Central Lab will section and ship material from FFPE preserved tissue blocks.   
9.2.6.4    Site(s) performing correlative study   
The Stanford Laboratory of Dr. Michael Khodadoust (or an equivalent 

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laboratory) will perform the Exome Sequencing and neoantigen identification.   
Special Studies (Kyn/Trp Ratio) 
9.3.1
Special Correlative Study #1: Whole Blood Kyn/Trp Ratios 
Kyn/Trp ratios will be assayed in patients receiving a regimen of MK-3475 as measured 
in peripheral blood at baseline and at specified intervals throughout the trial. We have 
defined the Kyn/Trp Ratio as a special study because the results may help to elucidate a 
likely mechanism for anti-PD-1 failure. It is postulated that enhanced IDO expression 
may occur in patients who fail anti-PD-1 therapy. IDO catabolizes the conversion of 
Tryptophan to Kynurenine, which has potent immunosuppressant properties. An increase 
in Kynurenine levels over time, relative to Tryptophan levels, in patients who are failing 
anti-PD-1 therapy would indicate that IDO expression may be leading to treatment 
failure. This mechanism of resistance could potentially be overcome with an IDO 
inhibitor.  
9.3.1.1 
Collection of Specimens 
9.3.1.1.1. Whole blood will be collected into heparinized tubes and processed to 
frozen plasma at the local lab.   
9.3.1.1.2. Timing of specimen collection will include mandatory collection prior to 
treatment, post cycle 1 (on the 1st day of cycle 2 just prior to dosing), on 
the first day of every 3rd cycle thereafter, prior to dosing (i.e., day 1 of 
cycle 5, 8, 11, etc), response/PD visit and end of treatment visit. 
9.3.1.2
Handling of Specimen(s)  
Frozen vials of plasma will be batch shipped to the CITN Central Laboratory.  
9.3.1.3
Shipping of Specimens 
Frozen vials of plasma will be shipped from the CITN Central Laboratory to 
the Incyte Corporation for testing. 
9.3.1.4
Site(s) Performing Correlative Study  
The Kyn/Trp analysis will be conducted at Incyte Corporation.

 
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10. STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of therapy. Scans and x-rays must be done <4 weeks prior to the start of therapy.  
Treatment Cyclea 
(Cycle Number) 
Pre- 
Study 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Response/ 
PD Assess 
or at discon. 
Off 
Studyb,c 
EOT 
Weeks (Week Numbers) 
 
1-3 
4-6 
7-9 
10-12 13-15 16-18 19-21 22-24 25-27 28-30 31-33 34-36 37-39 40-42 43-45 46-48 49-51 52-54 
 
 
Scheduling Window (days) 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
MK-3475 AdministrationA 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Procedures/Assessments 
Concurrent Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessmentd,e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Limited Physical exam 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
Comprehensive Physical Exam 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
X 
Vital Signs & Weightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 Lead Electrocardiogramg 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
ECOG Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulmonary Function Testing ͫ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Assessments (Safety Labs) 
CBC w/diff, pltsk  
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryi,k 
Xh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisk 
Xh 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
T3, FT4 and TSHk 
Xh 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
Pregnancy Testj,k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR, aPTTk,l 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

 
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Treatment Cyclea 
(Cycle Number) 
Pre- 
Study 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Response/ 
PD Assess 
or at discon. 
Off 
Studyb,c 
EOT 
Weeks (Week Numbers) 
 
1-3 
4-6 
7-9 
10-12 13-15 16-18 19-21 22-24 25-27 28-30 31-33 34-36 37-39 40-42 43-45 46-48 49-51 52-54 
 
 
Efficacy Measurements 
Tumor Imaging (CT/PET) for 
pts with measurable diseasen 
X 
 
 
 
X*±
3 
 
X*±
3 
 
X*±
3 
 
X*±
3 
 
 
 
X*±
7 
 
 
 
X*±
7 
X 
X 
Tumor Imaging for pts with 
nonmeasurable disease 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Circulating Sézary cells** 
X 
 
 
 
X*±
3 
 
X*±
3 
 
X*±
3 
 
X*±
3 
 
 
 
X*±
7 
 
 
 
X*±
7 
X 
X 
mSWAT Scoring/Photography 
X 
 
 
  
X*±
3 
 
X*±
3 
 
X*±
3 
 
X*±
3 
 
 
 
X*±
7 
 
 
 
X*±
7 
X 
X 
Tumor Biopsy/Correlative Blood Samples 
Skin Biopsyo  (See Section 9.1)     
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Lymph Node Biopsyo(Optional) 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Blood Samples (Biomarkers)o 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Kyn/Trp Ratioo 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Biorepository (Section 9) 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 

 
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Treatment Cyclea 
(Cycle Number) 
Pre- 
Study 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Response/ 
PD Assess 
or at discon. 
Off 
Studyb,c 
EOT 
Weeks (Week Numbers) 
 
1-3 
4-6 
7-9 
10-12 13-15 16-18 19-21 22-24 25-27 28-30 31-33 34-36 37-39 40-42 43-45 46-48 49-51 52-54 
 
 
A: The dose of MK-3475 is 2mg/kg q 21 days.  
a. 
In general, safety labs, assessments/procedures are to be performed on Day 1 and prior to the dose of MK3475 for each cycle unless otherwise specified.   
b. 
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by Olsen assessment every 12 weeks 
(± 7 days) until (1) the start of new anticancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs first. If a previous assessment was obtained 
within 4 weeks prior to the date of discontinuation, then an additional assessment at treatment discontinuation isn’t mandatory. 
c. 
After the start of new anticancer treatment or documented disease progression, the subject should be contacted by telephone every 12 weeks to assess for survival status. 
d. 
AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0. All AEs will also be evaluated for seriousness. 
e. 
Follow and document resolution of all AEs and SAEs for 30 days after the last dose of trial treatment.  
f. 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 2 only. 
g. 
ECG should be performed at baseline, 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 10 days prior to the first dose of trial treatment. See table 9.2 for details regarding laboratory tests. After Cycle 1, lab samples can be 
collected up to 72 hours prior to the scheduled time point.  
i. 
Tests to be included in the chemistries are found in table 9.2.  
j. 
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  
k. 
Safety labs. These labs will be drawn, processed and resulted locally. 
l. 
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. 
m. PFT required at baseline for patients with a history of pulmonary disease, prolonged smoking history, or symptoms of respiratory dysfunction.  
n. 
For scan schedules see section 11.1. For mSWAT and CSC see section 11.1.3. Note: mSWAT and CSCs will be measured during the same weeks as CT scans. 
o. Blood for biomarkers will be drawn during screening (within 28 days), again after the first cycle (day 1 of cycle 2, prior to study drug infusion), then prior to study drug infusion on day 1 of every 
3rd cycle (i.e., day 1, cycle 5, 8, 11, 14, etc.) then again for a confirmed CR or PR and at the time of PD and at EOT. Mandatory and optional biopsies will be performed at these same time points.   
* The first clinical assessment including mSWAT, CSCs, and CT or PET/CT (for those with measurable or extracutaneous disease) will occur at week 12. For those with PD at week 12 the same 
assessments will be repeated in a confirmatory fashion at week 16. Those who do not have PD at week 12 will have the same assessments repeated at week 18, then every 2 cycles (every 6 
weeks) through week #30, then every 4 cycles (12 weeks) for the duration of the study.  Assessments will occur at week 12, (16 for PD), 18, 24, 30, 42, 54, 66, 78, 90 and 104 (EOS).  If patients 
continue with MK-3475 therapy after confirmed progression, mSWAT frequency will increase to every cycle.  CT or PET/CT and CSC (both, if indicated) will continue every 4 cycles,. 
**CSC Testing will be performed at the individual research sites with central review of results at Stanford University.  Refer to section 9.1.2.2 for additional CSC testing information.   
 

 
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Study Calendar (Continued) 
Treatment Cyclea 
(Cycle Number) 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
Response/ 
PD Assess 
or at discon. 
Off Studyb,c 
EOT 
Weeks (Week Numbers) 
55-57 58-60 61-63 64-66 67-69 70-72 73-75 76-78 79-81 82-84 85-87 88-90 91-93 94-96 97-99 
100-102 
 
 
Scheduling Window (days) 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
Study Drug Administration 
MK-3475 AdministrationA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical Procedures/Assessments 
Concurrent Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Assessmentd,e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Limited Physical exam 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
Comprehensive Physical Exam 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Vital Signs & Weightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead Electrocardiogramg 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
ECOG Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Assessments (Safety Labs) 
CBC w/diff, pltsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryi,k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysisk 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
T3, FT4 and TSHk 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
PT/INR, aPTTk,l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Efficacy Measurements 
Tumor Imaging (CT/PET) for 
pts with measurable diseasen 
 
 
 
X±7 
 
 
 
X±7 
 
 
 
X±7 
 
 
 
 
X 
X (wk 104) 
Tumor Imaging for pts with 
nonmeasurable disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Circulating Sézary cells** 
 
 
 
X±7 
 
 
 
X±7 
 
 
 
X±7 
 
 
 
 
X 
X (wk 104) 
mSWAT Scoring/Photography 
 
 
 
X±7 
 
 
 
X±7 
 
 
 
X±7 
 
 
 
 
X 
X (wk 104) 

 
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Treatment Cyclea 
(Cycle Number) 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
Response/ 
PD Assess 
or at discon. 
Off Studyb,c 
EOT 
Weeks (Week Numbers) 
55-57 58-60 61-63 64-66 67-69 70-72 73-75 76-78 79-81 82-84 85-87 88-90 91-93 94-96 97-99 
100-102 
 
 
Tumor Biopsy/Correlative Blood Samples 
Skin Biopsyo  (See Sectin 9.1) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Lymph Node Biopsyo(Optional) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Blood Samples (Biomarkers)o 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Kyn/Trp Ratioo 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Biorepository (Section 9) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
A: The dose of MK-3475 is 2mg/kg q 21 days.  
a. In general, safety labs, assessments/procedures are to be performed on Day 1 and prior to the dose of MK3475 for each cycle unless otherwise specified. Subjects with CR after 
receiving a minimum of 6 months of treatment with at least 2 doses since CR may discontinue therapy. Subjects without symptomatic progression may receive up to a maximum of 
2 years.  
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by Olsen assessment 
every 12 weeks (± 7 days) until (1) the start of new anticancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever occurs first. If a 
previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory. 
c. After the start of new anticancer treatment or documented disease progression, the subject should be contacted by telephone every 12 weeks to assess for survival status. 
d. AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0. All AEs will also be evaluated for seriousness. 
e. Record all AEs and SAEs occurring within 30 days after the last dose of trial treatment.  
f. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 2 only. 
g. ECG should be performed 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 10 days prior to the first dose of trial treatment. See table 9.2 for details regarding laboratory tests. After Cycle 1, lab 
samples can be collected up to 72 hours prior to the scheduled time point.  
i. Tests to be included in the chemistries are found in table 9.2.  
j. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  
k. Safety labs. These labs will be drawn, processed and resulted locally. 
l. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. 
m.  
n. For scan schedules see section 11.1. For mSWAT and CSC see section 11.1.3. Note: mSWAT and CSCs will be measured during the same weeks as CT scans so that all 
assessments are done at the same time. mSWAT and CSC may be done on the same day as the CT scans or they may be done another day that week if needed for patient 
convenience.  If patients continue therapy after progression, mSWAT will increase to every cycle.  CT or PET/CT and CSC (both, if indicated) will continue every 4 cycles.    
o. Blood for biomarkers will be drawn during screening (within 28 days), again after the first cycle (day 1 of cycle 2, prior to study drug infusion), then prior to study drug infusion on 
day 1 of every 3rd cycle (i.e., day 1, cycle 5, 8, 11, 14, etc.) then again for a confirmed CR or PR and at the time of PD and at EOT. Mandatory and optional biopsies will be 
performed at these same time points 
**CSC Testing will be performed at the individual research sites with central review of results at Stanford University.  Refer to section 9.1.2.2 for additional CSC testing information.   

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11. MEASUREMENT OF EFFECT 
 
Antitumor Effect – Solid Tumors 
MF and SS are unique in that some patients will not have disease that is measurable by CT or 
PET/CT. Patients who have cutaneous disease only will not have measurable disease by CT or 
PET/CT. Patients who have extracutaneous disease will have disease that is measurable by CT or 
PET/CT. Patients with measurable (extracutaneous) disease will have scans at the intervals 
specified in the paragraph below. Patients who have nonmeasurable disease by CT and/or PET 
CT will have a scan at baseline (before study drug is initiated). This scan will be done as 
standard of care before study entry and will be used to determine the presence or absence or 
measurable disease. Subsequent scans in patients with nonmeasurable disease will only occur at 
the discretion of the investigator. Patients with nonmeasurable disease will not be required to 
have repeat scans for CR, PR or SD.  
There will be other criteria in addition to standard radiographic evaluation used in this study to 
determine progression or regression of disease including mSWAT (modified severity-weighted 
assessment tool) to determine response in skin. Flow cytometry will be used to determine the 
number of circulating sézary cells (CSC’s) in the blood in order to evaluate response. Lastly, all 
of the measures including Skin (mSWAT), Lymph Nodes (CT), Visceral Disease (CT) and 
Blood (Flow Cytometry) will be combined to determine a Global Response Score. All of these 
evaluations, including the Global Response Score will be described in further detail in this 
section of the protocol. 
The tests other than radiographic scans will include mSWAT and flow cytometry for CSCs. 
These tests will be performed on all patients (those with and without measurable disease) at the 
same intervals as CT scans described in the next paragraph for patients with measurable disease. 
All assessments including CT scans (for patients with measurable disease), mSWAT, and CSC 
will be performed at the same intervals and time points.  Assessments for patients with 
measurable disease will include radiologic scans, mSWAT and CSC.  Assessments for patients 
with nonmeasurable disease will consist of mSWAT and CSC (if indicated). 
For the purposes of this study, patients will first be assessed for response at week 12 (after 4 
cycles of MK-3475).  If progression is seen at week 12, confirmatory assessments will be 
repeated at week 16.  If no progression is seen at week 12, assessments will be repeated at week 
18. Assessments will then be repeated every 2 cycles (every 6 weeks) until week #30.  
(Assessments will be repeated at week 24 and week 30).  Repeat assessments after week 30 will 
take place every 4 cycles (every 12 weeks) including week #42, 54, 66, 78, 90 and 104 (end of 
study). Assessments will also be performed at the time of CR/PR confirmation, or PD. Note: 
Only patients with extracutaneous disease (measurable by CT scan) will have scans done at these 
specified intervals. Those with nonmeasurable disease are only scanned at baseline, then at the 
discretion of the investigator.  Patients with nonmeasurable disease will not be required to have 
repeat scans for CR, PR, or SD.  
If a CR is achieved patients may stop study drug therapy after 2 additional cycles have been 
given after 6 months of therapy have been completed. (i.e., 6 months + 2 cycles). If patients who 
have stopped after a CR have disease recurrence, they may re-start therapy if they have not 

 
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received additional therapy in the interim, if they are still eligible for the trial and the trial is still 
open to enrollment. Patients who are treated again after a CR will have scans, tests, procedures, 
biopsies and study drug administration at intervals just like a new patient beginning protocol 
therapy.  
11.1.1 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with MK-3475.  
Evaluable for objective response. As described above patients enrolled in this trial may 
not have disease that is measurable by CT and/or PET/CT however they can still be 
objectively evaluated for disease response using parameters unique to MF/SS.  
11.1.2 Disease Parameters N/A 
11.1.3 Tumor Imaging and Assessment of Disease 
The primary outcome is antitumor effect. Definitions for global response, CR, PR, PD, 
and SD (in skin/LN/viscera/blood) are detailed here. 
11.1.3.1 
Measurement Methods 
• Skin: mSWAT. 
• Lymph nodes: CT or PET/CT (Olsen criteria). 
• Viscera: CT or PET/CT (Olsen criteria). 
o If using a PET/CT the CT should be of diagnostic quality 
• Blood: Flow cytometry. 
The skin compartment is the target of primary efficacy assessment, however in those 
subjects with extracutaneous disease, all involved compartments will be assessed 
separately and a global response will be determined. 
Subjects will have a skin evaluation (mSWAT) at screening, then again at week 12 (after 
4 cycles of MK-3475). mSWAT will be repeated at week 16 if patients have progressive 
disease (PD) at week 12. If no PD is seen at week 12, the mSWAT will be repeated at 
week 18.  mSWAT will then be repeated every 2 cycles (every 6 weeks) to week #30 
including assessments at week 24 and week 30.  After week 30 mSWAT will be repeated 
every 4 cycles (every 12 weeks) including week 42, 54, 66, 78, 90 and 104 (end of 
study).   Clinical response in the skin compartment will be assessed according to changes 
in the modified Severity-Weighted Assessment Tool (mSWAT) [Appendix E] and 
documented as SD, PR, complete clinical response, or PD as defined below. The 
response in the lymph node compartment will be assessed by IWG criteria, in blood by 
flow cytometry, and global response will be assigned adhering to the consensus criteria 
below. All objective response (PR or CR) and progression (PD) must be confirmed after 
4 weeks.  
Regardless of treatment delays, response assessment including mSWAT and imaging 
should always be performed on the aforementioned schedules. (i.e., the imaging and 
mSWAT schedules do not change if there are treatment delays). Subjects with CR after 

 
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81 
 
receiving a minimum of 6 months of treatment with at least 2 doses since CR may 
discontinue therapy. Subjects with a CR who progress may be retreated if (1) no cancer 
treatment was administered since the last dose of MK-3475, (2) subject continues to meet 
eligibility criteria, and (3) the trial is open. Subjects without symptomatic progression 
may receive up to a maximum of 2 years if radiologically and clinically improving or 
stable after 12 cycles. 
11.1.4 Initial Tumor Imaging 
Initial tumor imaging with a CT or PET/CT must be performed within 28 days prior to 
the first dose of trial treatment. For subjects with documented extracutaneous disease 
imaging will be repeated at the intervals specified in section 11.1. For consistency in 
interpretation, perform the same type of radiologic evaluation that was performed at 
screening. All subjects on the trial will have an EOT scan. 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 prior to the first dose of trial treatment. 
Imaging timing should follow calendar days and should not be adjusted for delays in 
cycle starts or extension of MK-3475 cycle frequencies. The same imaging technique 
should be used in a subject throughout the trial. The site study team must review pre-trial 
images to confirm the subject has measurable disease per Olsen criteria if the patient is 
going to be entered on trial with radiographically measurable disease. Patients with 
only cutaneous disease (nonmeasurable by CT) are also eligible for the study.  
11.1.5 Tumor Imaging During Trial 
Tumor imaging may be performed by full-body CT or full-body PET/CT and the same 
imaging technique should be used in a subject throughout the trial as response will be 
assessed by Olsen criteria. Imaging should be performed as described in section 11.1.3 
Imaging should be performed if possible progression is considered or to confirm 
response. Imaging should not be delayed for delays in cycle starts or extension of MK-
3475 cycle intervals. 
11.1.5.1 
Measurement Methods 
- Lymph nodes: CT or PET-CT (Olsen criteria). 
- Viscera: CT or PET-CT (Olsen criteria). 
If using a PET/CT the CT should be of diagnostic quality. Imaging should continue to be 
performed until documented disease progression, the start of new anticancer treatment, 
withdrawal of consent, death, or the end of the study, whichever occurs first. Disease 
progression should be confirmed at least 4 weeks after the first scan indicating PD in 
clinically stable subjects. Subjects who have unconfirmed disease progression may 
continue on treatment until progression is confirmed provided they have met the 
conditions detailed in Section 5.8.  
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. MRI is also acceptable in certain situations (e.g., for body 

 
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82 
 
scans).  
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for accurate measurement. 
However, if the site can document that the CT performed as part of a PET-CT is of 
identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for tumor measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time. 
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed.  
11.1.6 Response Criteria 
Primary outcome measure is clinical response rate as assessed by the standard response 
criteria used in MF and SS (skin, LN, viscera, blood, global) 23. 
Response in Skin* 
Complete 
response (CR) 
100% clearance of skin lesions# 
Partial 
response (PR) 
50-99% clearance of skin disease from baseline without new tumors (T3) in subjects 
with T1, T2 or T4 only skin disease 
Stable disease 
(SD) 
<25% increase to <50% clearance in skin disease from baseline without new tumors 
(T3) in subjects with T1, T2 or T4 only skin disease 
Progressive 
disease (PD)♦ 
(1) >25% increase in skin disease from baseline or 
(2) New tumors (T3) in subjects with T1, T2 or T4 only skin disease or 
(3) Loss of response: in those with CR or PR, increase of skin score of greater than 
the sum of nadir plus 50% baseline score 
Relapse 
Any disease recurrence in those with CR 
*Based on mSWAT score. 
# A biopsy of normal appearing skin is unnecessary to assign a CR. However, a skin biopsy should be 
performed of a representative area of the skin if there is any question of residual disease where otherwise a CR 
would exist. If histologic features are suspicious or suggestive of MF/SS (see histologic criteria for early MF7), 
the response should be considered a PR only. 
♦ Whichever criterion occurs first. 
Response in Lymph Nodes* 
CR 
All lymph nodes are now <1.5 cm in greatest transverse (long axis) diameter by method 
used to assess lymph nodes at baseline or biopsy negative for lymphoma. In addition, 
lymph nodes that were N3 classification and <1.5 cm in long axis diameter at baseline, 
must now be <1 cm in diameter of the short axis or biopsy negative for lymphoma 
PR 
(1) Cumulative reduction >50% of the SPD [sum of the maximum linear dimension 
(major axis) x longest perpendicular dimension (minor axis) of each abnormal lymph 
node at baseline and no new lymph node >1.5 cm or >1.0 cm in the short axis if long 
axis 1-1.5cm diameter. 
SD 
Fails to attain the criteria for CR, PR and PD 
PD ♦ 
(1) >50% increase in SPD from baseline of lymph nodes or 
(2) Any new node >1.5 cm in greatest transverse diameter or >1 cm in short axis 
diameter if 1-1.5 cm in long axis that is proven to be N3 histologically or 
(3) Loss of response: in those with PR or CR, >50% increase from nadir in SPD of 
lymph nodes 

 
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Relapse 
Any new lymph node >1.5cm in long axis diameter in those with CR 
* Peripheral and central lymph nodes. 
♦Whichever criterion occurs first. 
Response in Blood* 
CR** 
B0 
PR# 
>50% decrease in quantitative measurements of blood tumor burden from baseline 
in those with high tumor burden at baseline (B2) 
SD 
Fails to attain criteria for CR, PR or PD 
PD♦ 
(1) B0 to B2 or 
(2) >50% increase from baseline and at least 5,000 neoplastic cells/μL42 or 
(3) Loss of response: 
in those with CR who were B1 or B2 at baseline, increase in neoplastic >1000 
neoplastic cells/ μL or 
in those with PR who were originally B2 at baseline, >50% increase from nadir and 
at least 5,000 neoplastic cells/μL 
Relapse 
Increase of neoplastic blood lymphocytes to ≥B1 in those with CR 
* As determined by absolute numbers of neoplastic cells/uL. 
** If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of 
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for B0, a 
repeat bone marrow biopsy must show no residual disease or the response should be considered a PR only. 
# There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells that 
define B1 is not considered significant and should not affect determination of global objective response. 
♦ Whichever occurs first. 
Response in Viscera 
CR 
Liver or spleen or any organ considered involved at baseline should not be enlarged on 
physical exam and should be considered normal by imaging. No nodules should be 
present on imaging of liver or spleen. Any post treatment mass must be determined to be 
biopsy to be negative for lymphoma 
PR 
>50% regression in any splenic or liver nodules, or in measureable disease (SPD) in any 
organs abnormal at baseline. No increase in size of liver or spleen and no new sites of 
involvement. 
SD 
Fails to attain the criteria for CR, PR or PD 
PD♦ 
(1) >50% increase in size (SPD) of any organs involved at baseline or 
(2) New organ involvement or 
(3) Loss of response: in those with PR or CR, >50% increase from nadir in the size 
(SPD) of any previous organ involvement 
Relapse 
New organ involvement in those with CR 
♦Whichever criterion occurs first. 
Global Response Score 
Global 
Score* 
Definition 
Skin 
Nodes 
Blood 
Viscera 
CR 
Complete 
disappearance of all 
clinical evidence of 
disease 
CR 
All categories have CR/NI 
 
PR 
Regression of 
measurable disease 
CR 
All categories do not have a CR/NI and no category has a PD 
PR 
No category has a PD and if any other category involved at 

 
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Global 
Score* 
Definition 
Skin 
Nodes 
Blood 
Viscera 
baseline, at least one has a CR or PR 
SD 
Failure to attain CR, 
PR or PD 
representative of all 
disease 
PR 
No category has a PD and if any other category involved at 
baseline, no CR or PR in any 
SD 
CR/NI, PR, SD in any category and no category has a PD 
PD 
Progressive disease 
PD in any category 
 
Relapse 
Recurrence disease 
in prior CR 
Relapse in any category 
NI= noninvolved 
*It is recommended that not only the proportion of subjects who achieve a response or an unfavorable outcome be 
calculated but a life table account for the length of the interval. 
After the first documentation of progression, it is at the discretion of the investigator to 
keep a clinically stable subject on trial treatment or to stop trial treatment until repeat 
imaging performed at least 28 days later confirms progression. A subject with 
unconfirmed progression of disease may continue trial treatment until progression of 
disease is confirmed as long as section 5.8 criteria are met. Subjects with suspected 
pseudoprogression should have biopsy proven confirmation of progression of disease 
during the 4 week interval between initial demonstration of progression and confirmation 
of progression of disease. Biopsy findings consistent with pseudoprogression, evidence of 
a lymphoid infiltrate, necrotic tumor, without significant increase in viable tumor at site 
of suspected pseudoprogression, may justify continued treatment at the discretion of the 
PI. 
Subjects may only receive study treatment while waiting for confirmation of PD versus 
pseudoprogression if the following criteria are met:  “Section 5.8 Criteria” 
• Absence of signs and symptoms indicating disease progression 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
If at the subsequent response assessment a patient is noted to have confirmed, continued, 
progression of disease by global response criteria, the patient may not continue on MK-
3475. 
Disease assessments during the follow-up period is to be repeated every 12 weeks (± 7 
days) for subjects who discontinue trial treatment for reasons other than disease 
progression until the subject experiences confirmed disease progression or starts a new 
antineoplastic therapy. 
Local reading (investigator assessment with site radiology reading) will be used to 
determine subject eligibility and for subject management. Radiologic scans may be sent 
to a central vendor for evaluation.   

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11.1.7 Duration of Response
Duration of overall 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 PD is objectively documented (taking as reference for PD the 
smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that PD is objectively documented. 
Duration of stable disease: SD is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
11.1.8 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
11.1.9 Response Review 
No review of response rate is contemplated. Investigator determined responses will be 
chronicled.  
Antitumor Effect – Hematologic Tumors: N/A  
Other Response Parameters: N/A  
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 (https://eapps-ctep.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 
Site co-PI) in RSS at the enrolling site. 
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 e-mail 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 

 
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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 
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 e-mail 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).  
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 are to be submitted via Medidata Rave to the CITN data management organization 
on a real-time basis, but no less than 72 hours after data has been collected.  (ie: 72 hours 
after a visit). The timeliness of data submissions and timeliness in resolving data queries 
will be tracked by the CITN data management organization.  Metrics for timeliness will 
be followed and assessed on a quarterly basis.  For the purpose of Institutional 
Performance Monitoring, data will be considered delinquent if it is greater than 4 weeks 
past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CITN coordinating center 
and by the CITN data management organization on an ongoing basis as data is received.  
Queries will be issued by the CITN data management organization directly within Rave.  
The queries will appear on the Task Summary Tab within Rave for the CRA at the 
clinical site to resolve.  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. 
 

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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 CITN data management organization will 
prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
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 Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/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 to the CTSU Regulatory 
Office as detailed in the Site Registration section of this protocol.  The CTSU Regulatory 
Office will enter and track IRB approval information in the CTSU Regulatory Support 
System (RSS) where it will be transmitted to CTEP for fulfillment of agent requests. 
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” 

 
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(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall 
be maintained as such by the investigators. The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without the 
permission of the NCI. If a copy of this protocol is requested by a patient or patient’s family 
member participating on the study, the individual should sign a confidentiality agreement. A 
suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as “Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI’s participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator (http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection of 
human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator’s wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 

 
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6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date 
of receipt for review. Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least 3 days prior to submission, but in any case, 
prior to presentation at the meeting or publication in the proceedings. Press releases and other 
media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to 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 
nonconfirmatory 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. 
13.1 
Responsibility for Analyses 
 
The statistical analysis of the data obtained from this study will be the responsibility of the Fred 
Hutchinson Cancer Research Center as part of the Cancer Immunotherapy Trials Network 
(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:  Stage 1 will enroll 9 
patients.  Stage 2:  Will enroll an additional 15 patients (for a total of 24).  If there are one or 
more responses (PR or CR) amongst the nine patients enrolled in Stage 1, Stage 2 enrollment 
will proceed.  If there are no responses (PR or CR) amongst the nine patients enrolled in Stage 1, 
enrollment into Stage 2 will not proceed.  The null hypothesis (H0) MK-3475 will show less than 
5% overall response rate.  The alternative hypothesis (H1) MK-3475 will show greater than 25% 

 
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overall response rate (PR and CR).   
 
13.2 
Study Design/Endpoints 
 
13.2.1 Primary Objective 
To determine the clinical efficacy of MK-3475 for the treatment of relapsed or refractory 
MF or SS. 
The primary endpoint will be Objective Response Rate (ORR) as measured by the global 
assessment standard response criteria for MF and SS [Olsen 2011]. Response is defined 
as a confirmed PR or a confirmed CR with the confirmation assessment no less than 4 
weeks after criteria for response is first met.  
13.2.2 Secondary Objectives 
To determine the clinical activity of MK-3475 for the treatment of patients with relapsed 
or refractory MF or SS.  
The secondary endpoints will be PFS, DOR, and OS, as measured by the global 
assessment standard response criteria for MF and SS [Olsen 2011]. PFS is defined as the 
time from allocation to the first documented disease progression or death due to any 
cause, whichever comes first.  
13.3 
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 the global assessment standard response criteria for MF 
and SS [Olsen 2011].  
Progression-free Survival (PFS): is defined as the time from enrollment 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. 

 
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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.  
13.4 
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. 
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. 
13.5 
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.  Stage 1 will enroll 9 patients.  Stage 
2:  Will enroll an additional 15 patients (for a total of 24).  If there are one or more responses 
(PR or CR) amongst the nine patients enrolled in Stage 1, Stage 2 enrollment will proceed.  If 
there are no responses (PR or CR) amongst the nine patients enrolled in Stage 1, enrollment into 
Stage 2 will not proceed.  The null hypothesis (H0) MK-3475 will show less than 5% overall 
response rate.  The alternative hypothesis (H1) MK-3475 will show greater than 25% overall 
response rate (PR and CR). 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 0.1 and power of 0.9 when the 
true response rate is 25%. 
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 

 
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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 objective 
response rate will use a binomial error distribution. The model will include as 
covariates all available baseline predictors of the missing outcomes. 
Note:  Patients who progress on MK-3475 but remain on study with continued 
MK-3475 therapy will be considered to have progressive disease.  Any 
delayed responses with continued therapy in this group will be chronicled and 
reported.   
13.5.1.2 
PFS, DOR and OS  
Survival curves for PFS, DOS and OS will be estimated using the Kaplan-
Meier 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 13.5 Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable 
(Description, Timepoint) 
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) 

 
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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 prior to progression 
will be censored at the last disease assessment prior to 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 (AEs), 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. 
13.6 
Multiplicity 
 
No multiplicity adjustment will be applied.  
13.7 
Sample Size/Accrual Rate and Power Calculations 
 
This study will 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 one-
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, further 
enrollment will be suspended. If there are one or more responses amongst the first nine patients 
an additional 15 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 0.1 and 
power of 0.9 when the true response rate is 25%. 
13.8 
Stratification Factors- N/A 
 
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) 

 
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13.9 
Interim Analyses  
 
There will be one interim analysis at the end of Stage 1, on the first 9 patients.   If there are no 
responses in these 9 patients further enrollment will be suspended however patients who are 
actively being treated on study will continue therapy and will continue to be followed for 
response.  If there are one or more responses amongst the first nine patients we will proceed on 
to Stage 2 and enroll an additional 15 subjects for a total of 24.   
13.10 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 
13.11 Extent of Exposure 
 
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity will 
also be summarized as appropriate. 
13.12 Analysis of Secondary Endpoints 
 
Analysis of secondary endpoints is addressed in Section 13.2 
13.13 Reporting and Exclusions 
 
13.13.1 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with MK-
3475. 
13.13.2 Evaluation 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.  

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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.  
 
14. STUDY STATUS UPDATES AND STUDY CLOSURE 
 
Definitions of Study Status Changes 
14.1.1 Temporarily Closed to Accrual 
 
The study status is Temporarily Closed to Accrual when no patient slots are currently 
available, but there is the possibility that the trial will re-open for accrual (patient slots 
become available).  Sites are not permitted to accrue additional patients until CTEP is 
notified of Re-Activation. 
 
Study status will need to be changed to Temporarily Closed to Accrual when any of the 
following criteria are met: 
 
• Sites are notified by CTEP (via Request for Rapid Amendment [RRA]) of 
changes in the risk/benefit ratio that necessitate changes to the patient Informed 
Consent document.  Requested changes will be specified in the RRA and must be 
reviewed by the study’s IRB. 
• CTEP and the lead investigator agree that unacceptable toxicities necessitate a 
discussion to change the dosing/regimen. 
• A protocol-defined benchmark has been achieved (such as an interim analysis 
before proceeding to the next stage).  
 
14.1.2 Closed to Accrual 
 
The study status is (permanently) Closed to Accrual when no more patient enrollment 
slots are available, and at least one patient is still actively receiving the study treatment.  
Sites are no longer permitted to enroll additional patients. 
Patient slots are no longer available when the following criteria are met: 
• The pre-specified number of evaluable patients has been successfully enrolled, 
treated, and evaluated. 
• The study treatment has failed to meet the pre-specified efficacy goal at the stage 
1 interim analysis. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 

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enrollment. 
14.1.3 Closed to Accrual and Treatment 
The study status is Closed to Accrual and Treatment when no more patient enrollment 
slots are available and no patients are currently receiving the study treatment.  Patients 
may still be enrolled on the protocol only for the purposes of follow-up. 
Patient accrual and treatment will be permanently halted when any of the following 
criteria are met: 
• Enrollment was previously closed (study status of “Closed to Accrual”), and no 
patients are receiving the study treatment. 
• CTEP and the investigators agree that unacceptable toxicities preclude further 
enrollment.  In this case, CTEP and the investigators must collaborate to alter the 
regimen or to halt the study treatment altogether as soon as it can be safely done 
for patients currently receiving treatment.  
CTEP and Axio must be notified when patients are no longer receiving treatment [i.e., 
when the last patient(s) to be receiving treatment is/are no longer receiving the study 
regimen for any reason]. 
 
14.1.4 Closed to Follow-Up 
 
The study is considered Closed to Follow-Up when all protocol-defined follow-up 
procedures have been completed for all patients who have not been removed from the 
study for other reasons.  That is, there are no outstanding follow-up procedures to be 
performed as mandated by the protocol. 
CTEP does not need to be notified of a status change to “Closed to Follow Up.” 
14.1.5 Complete 
 
Study is considered Complete if it has been at least thirty (30) days since the last patient 
follow-up evaluation.   
A citation to a final study report (manuscript, meeting abstract, etc.) is required with the 
submission of the Protocol Status Update Form to CTEP PIO.   
Responsibility for Filing Protocol Status Update Forms
CTEP must be notified of all study status changes in Section 14.1 (except for Closed to Follow-
Up) by the Corresponding Organization via Protocol Status Update Form, available from the 
CTEP website at http://ctep.cancer.gov/protocolDevelopment/default.htm#amendments.    

 
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Axio must be notified as soon as all patients are off treatment (i.e., when study status changes to 
Closed to Accrual and Treatment).  Axio will produce a report within 90 days of this notification. 
 
 

 
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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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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol that does not use the CTSU/OPEN rostered model, 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 AEs to ensure 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.  
• Prior to 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 prior to 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 two 
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 two 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 

 
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IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
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 e-mail 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.  
 
 

 
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APPENDIX C  
STANDARDIZED MEDICAL PHOTOGRAPHY 
 
Using a standard medical blue background and with the patient in anatomical position (palms 
placed anteriorly), the following photos will be taken of the study participant: 
 
1. Global (full body). 
2. Half-global (half body – anterior and posterior aspect). 
3. Additional photographs will be taken at a short distance (1 foot) of biopsy sites. 
 
 
 
 
 
 

 
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APPENDIX D 
BIOASSAY TEMPLATES 
 
Biomarker name 
(Lead PI and Site) 
Assay & Method/Template/SOP 
& Hypothesis 
Tissue/Body Fluid Tested & 
Timing of Assay 
Prioritization 
& Funding 
Tissue PD-L1 
Expression 
Holbrook Kohrt, MD 
PhD 
(Stanford University) 
Testing to be 
performed by 
Qualtek, a Merck 
CRO. 
• Chromogenic (Single-Color) 
IHC for PD-L1 
• Hypothesis: A direct 
correlation exists between 
tissue PD-L1 expression and 
clinical efficacy endpoints. 
Tissue: 
• Tumor Biopsy including skin 
and/or lymph node 
Timing: 
• Prior to treatment, following the 
1st cycle, then following every 3rd 
cycle thereafter, at the time of 
response and EOT. 
1 
Merck 
TIL gene expression 
profile 
Holbrook Kohrt, MD 
PhD 
(Stanford University) 
Testing to be 
performed by Merck, 
Palo Alto. 
• Nanostring platform will be 
used to profile mRNA 
expression in archival material, 
to assess expression of 
approximately 650 genes 
• Merck SOP 
• Hypothesis: A Th1 
inflammatory T cell gene 
expression profile directly 
correlates with clinical efficacy 
endpoints. 
Tissue: 
• Tumor Biopsy including skin 
and/or lymph node 
Timing: 
• Prior to treatment, following the 
1st cycle, then following every 3rd 
cycle thereafter, at the time of 
response and EOT. 
2 
Merck 
Cytokine & 
chemokine analysis 
Holbrook Kohrt, MD 
PhD 
Testing to be 
performed at Stanford 
University 
• Luminex multiplexed ELISA-
based platform 
• Stanford Human Immune 
Monitoring Core SOP 
• Hypothesis: A Th1 cytokine 
profile directly correlates with 
clinical efficacy endpoints. 
Tissue: 
• Blood 
Timing: 
• Prior to treatment, following the 
1st cycle, then following every 3rd 
cycle thereafter, at the time of 
response and EOT. 
3 
Merck 
Spatial association 
of PD-1+ TILs and 
PD-L1+ cells 
Holbrook Kohrt, MD 
PhD 
(Stanford University) 
Testing performed by 
Merck, Palo Alto 
• Multiparametric 
immunohistochemical assays 
will be performed to include 
PD-1 and PD-L1. 
• Merck SOP 
 
Tissue: 
• Tumor Biopsy including skin 
and/or lymph node 
Timing: 
• Prior to treatment, following the 
1st cycle, then following every 3rd 
cycle thereafter, at the time of 
response and EOT. 
4 
Merck 

 
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Biomarker name 
(Lead PI and Site) 
Assay & Method/Template/SOP 
& Hypothesis 
Tissue/Body Fluid Tested & 
Timing of Assay 
Prioritization 
& Funding 
T cell 
immunophenotype 
Holbrook Kohrt, MD 
PhD 
Testing to be 
performed at 
Standord University 
• CyTOF and multiparametric 
flow cytometry 
• Stanford Human Immune 
Monitoring Core SOP 
  
Tissue: 
• PBMC 
Timing: 
• Prior to treatment, following the 
1st cycle, then following every 3rd 
cycle thereafter, at the time of 
response and EOT. 
5 
Merck 
T cell receptor 
sequencing 
Holbrook Kohrt, MD 
PhD 
(Stanford University) 
• Next-generation sequencing of 
T cell-specific CDR 
rearrangements will be 
performed to analyze the 
breadth of the CD4 and CD8 
repertoire 
• Stanford Human Immune 
Monitoring Core SOP 
 
Tissue: 
• PBMC 
Timing: 
• Prior to treatment, at the end of 
cycle 1, following every 3rd cycle, 
at end of treatment, at follow-up 
visits 
6 
Merck 
Note: This is 
an exploratory 
assay that will 
be performed 
should funding 
become 
available. 
TIL, tumor-infiltrating lymphocyte 
 
 

 
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APPENDIX E 
MODIFIED SEVERITY-WEIGHTED ASSESSMENT TOOL 
(MSWAT) 
 
The mSWAT is an objective, quantitative, severity- weighted method to assess the extent of MF 
lesions. A SWAT score is derived by measuring each lesion as a percentage of total body surface 
area (%TBSA) and multiplying it by a severity-weighting factor (1 = patch, 2 = plaque, 4 = 
tumor). All individual numbers are then added to produce a total score. 
The body is divided into 12 regions with pre-assigned %TBSA based on methodology used to 
assess burns. The extent of skin disease is assessed for each region and quantified by using the 
subject’s palm as a “ruler” to measure the %TBSA involvement within each region. 
Subject’s palm with 4 fingers, including the thumb and measured from wrist to fingertips, is 1% 
of TBSA. 
Subject’s palm without fingers is 0.5% of TBSA. 
Modified Severity Weighted Assessment Tool 
Modified Severity Weighted Assessment Tool 
MF lesion type 
Elevation description 
Erythema description 
Patch 
Abnormal skin not elevated 
from normal skin 
Flat erythema or erythema with mild infiltration 
Plaque 
Abnormal skin elevated from 
normal skin by <5 mm 
Elevated erythema or erythema with moderate 
infiltration 
Tumor 
Abnormal skin elevated from 
normal skin by ≥5 mm 
Erythema with fissuring, ulceration, or tumor 
SWAT Score Calculation 
 
 
Sum of %TBSA from all body regions affected by patches x severity weighted factor of 1 
+ Sum of %TBSA from all body regions affected by plaques x severity weighted factor of 2 
+ Sum of %TBSA from all body regions affected by tumors x severity weighted factor of 4 
= TOTAL SWAT: (maximum score = 400) 
 
 
 

 
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APPENDIX F 
TNMB CLASSIFICATION AND STAGING OF MYCOSIS 
FUNGOIDES AND SÉZARY SYNDROME 
 
 
 
NCCN practice guidelines for Non-Hodgkin’s Lymphomas Guidelines 2.2011. National 
Comprehensive Cancer Network. www.nccn.org. Accessed: March 24, 2011.